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Radiological pathology of epileptic disorders

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Radiological pathology of epileptic disorders
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  • 1. WWW.YASSERMETWALLY.COM CORPORATION 2014 Radiological pathology of seizure disorders Professor Yasser Metwally www.yassermetwally.com P R O F E S S O R O F N E U R O L O G Y , A I N S H A M S U N I V E R S I T Y , C A I R O , E G Y P T WWW.YASSERMETWALLY.COM CORPORATION 2014 Radiological pathology of seizure disorders Professor Yasser Metwally www.yassermetwally.com P R O F E S S O R O F N E U R O L O G Y , A I N S H A M S U N I V E R S I T Y , C A I R O , E G Y P T WWW.YASSERMETWALLY.COM CORPORATION 2014 Radiological pathology of seizure disorders Professor Yasser Metwally www.yassermetwally.com P R O F E S S O R O F N E U R O L O G Y , A I N S H A M S U N I V E R S I T Y , C A I R O , E G Y P T
  • 2. Preface Neuroimaging is nothing but how "neuropathology and neuroanatomy" are approached clinically by neurologists and neurosurgeons through radiological films. Neuroimaging from the neuropathological and neuroanatomical perspectives is how gross pathology and anatomy are demonstrated radiologically. Without having a good idea of neuropathology and neuroanatomy it is not possible at all to understand neuroimaging. Neuroimaging and neuropathology share common perspectives in medicine. In no field is this more evident than in the diagnosis and study of nervous system pathology: radiology and pathology are anatomically oriented specialties that depend primarily on structural changes to diagnose disease. Both specialties are broadening their perspectives of morphology to demonstrate metabolism, as with functional imaging in radiology and with immunocytochemical markers in anatomical pathology. Pathologists thus regard their radiologic counterparts as colleagues with similar morphologic approaches to diagnosis, despite the different tools used. In no discipline is this companionship more strongly felt than in the respective subspecialties that focus on disorders of the nervous system. Neuropathologists understand, acknowledge, and admire the numerous contributions by neuroimaging in defining many neurological disorders. Neuroimaging enable us to diagnose gross pathology during life. Neuropathologists usually must wait until autopsy to demonstrate tissue changes, but surgical specimens are becoming increasingly more frequent, for example, with the advent of epilepsy surgery. Neuroradiologists and neuropathologists have a mutual need for collaboration. Radiologists need tissue confirmation to fully understand the significance of images seen, and pathologists’ findings need to be relevant to diagnoses that often rest initially with the neurologist/neuroradiologist, and provide insight into pathogenesis through unique tissue examinations. The current publication is a compilation of all topics published under the category of seizure disorders in www.yassermetwally.net. The publication is composed of 227 pages that can be viewed online, downloaded and printed. Its main theme is how the MRI signal and the CT scan density are affected by the gross and the histopathology of the various CNS lesions in epileptic disorders and the impact of this on the radiological diagnosis of patients. Professor Yasser Metwally www.yassermetwally.com © Copyright yassermetwally.com corporation, all rights reserved
  • 3. IBDEX Pathology of seizure disorders MR imaging of seizure disorders Radiological pathology of seizure disorders Radiological pathology of status epilepticus Radiological pathology of cortical dysplasia Radiological pathology of focal cortical dysplasia Radiological pathology of Tuberous sclerosis Neuroimaging of Tuberous sclerosis Radiological pathology of Sturge-Weber syndrome Radiological pathology of Rasmussen encephalitis © Copyright yassermetwally.com corporation, all rights reserved
  • 4. INDEX |  INTRODUCTION  DEVELOPMENTAL ANOMALIES  NEOPLASMS  BACTERIAL, FUNGAL, VIRAL, AND PARASITIC DISEASES  IMMUNE-MEDIATED DISORDERS  CEREBROVASCULAR DISEASES  TRAUMA  SEIZURE-ASSOCIATED BRAIN PATHOLOGY PATHOLOGY OF SEIZURE DISORDERS Modern imaging techniques, particularly magnetic resonance (MR) imaging, have been crucial in detecting formerly cryptic seizure- related lesions, and new entities have been added to the ever-expanding list of seizure-associated pathologic conditions. Major pathologic lesions associated with seizures include: www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 1
  • 5.  Developmental disorders  Neuronal migration disorders, Cortical dysplasia of Taylor, Hemimegalencephaly, Neuronal heterotopia, Lissencephaly and pachygyria, Generalized cortical dysplasia, Polymicrogyria, Neurocutaneous syndromes  Tuberous sclerosis, Sturge-Weber syndrome  Hamartomas  Vascular malformations, Arteriovenous malformation, Cavernous hemangiomas  Neoplasms, Gliomas, Astrocytomas, Oligodendrogliomas, Mixed oligoastrocytomas, Mixed neuronoglial tumors, Gangliogliomas, Dysembryoplastic neuroepithelial  tumors, Others PATHOLOGY OF SEIZURE DISORDERS  Bacterial, viral, fungal, and parasitic diseases  Cerebrovascular diseases  Trauma  immune-mediated disorder  Rasmussen's syndrome  Seizure-associated brain pathology  Hippocampus  Amygdala  White matter  Others Seizure is one of many symptoms of a wide range of metabolic-toxic diseases and generalized central nervous system (CNS) disorders not listed here. These diseases are, in general, neuroradiologically or neurosurgically irrelevant. DEVELOPMENTAL ANOMALIES  Neuronal Migration Disorders Neuronal migration from the periventricular proliferative zone to the outer cortical plate is an elaborate and complex process, initially following the radial arrays of glial processes. During this complicated migratory phase, any disturbance in their journey may result in structural anomalies, often leading to mental retardation and seizures. o Cortical Dysplasia of Taylor Cortical dysplasia of Taylor, also called focal cortical dysplasia, is a migrational disorder often encountered in complex partial seizures. 86 Although the age of most patients at the time of surgery falls within the first three decades of life, the initial seizure is usually experienced in the first or second decade. 64, 86 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 2
  • 6. Grossly, the involved portion of the cerebral cortex is usually thickened, and the junction between the cerebral cortex and white matter is blurred. The most salient histologic feature of focal cortical dysplasia is the presence of large anomalous neurons in the cortex. Cortical lamination is sometimes indistinct, especially when anomalous neurons are abundant. The neurons are large with coarsely granular Nissl substance, and the polarity of anomalous neurons is often haphazard. Another interesting finding is the presence of large cells having large, round nuclei with prominent nucleoli and abundant pale eosinophilic cytoplasm ("balloon cells"). These cells are more abundant in the subcortical white matter, although similar cells are also encountered in the cortex. Morphologic similarities exist between balloon cells and neurons, but balloon cells lack Nissl substance and their cytoplasm is frequently glial fibrillary acidic protein (GFAP)-immunopositive. Tuberous sclerosis shares a similar histology, and it is difficult to histologically differentiate cortical dysplasia of Taylor from the forme furste of tuberous sclerosis. Although this form of tuberous sclerosis may have a tendency to show calcification or significant subpial gliosis, the histologic distinction between the two conditions is not always obvious. Furthermore, clinical and imaging studies are not helpful in distinguishing these two conditions from each other. 64 Separation of these conditions will remain debatable until a definite biochemical or molecular marker is found. o Hemimegalencephaly Hemimegalencephaly is unilateral hemispheric hypertrophy of the cerebrum. The involved cerebral hemisphere shows diffuse cortical thickening and firm consistency, although the gyral formation may be well preserved. There is considerable proliferation of large, anomalous neurons containing seemingly excessive Nissl substance. Normal cortical lamination becomes indistinct. Anomalous neurons may also be seen in the subcortical white matter. In addition, large cells with abundant cytoplasm and large, round nuclei with prominent nucleoli may also be observed. These cells are frequently immunopositive with anti- GFAP antibody, suggesting that some may represent abnormal astrocytic cells. In addition, fibrous astrocytes are generally increased in number. Hemimegalencephaly, therefore, shares a similar histology with cortical dysplasia of Taylor and, to some degree, with tuberous sclerosis. Because of its characteristic gross features, however, differentiating this condition from the aforementioned should be easy. Nevertheless, hemimegalencephalic cases may rarely possess other associated malformations suggestive of neurocutaneous syndrome. 52 In some cases, neuronal or glial cells (or both) are abundant enough to raise the possibility of a neoplastic process rather than a malformative phenomenon as the basic underlying mechanism of hemimegalencephaly. 88 An increased amount of DNA is found in neuronal and astrocytic cells of the involved hemisphere. 88 o Neuronal Heterotopia Neuronal heterotopia may encompass several patterns. Scattered heterotopic neurons are regularly present in the cerebral subcortical white matter and occasionally present in the cortical molecular layer of the nonepileptic population. These neurons may have no clinical significance. Nodular and laminar heterotopic gray structures in the white matter are www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 3
  • 7. definitely anomalous, however, and epilepsy is a common clinical presentation. They are usually found bilaterally and may be seen anywhere in the white matter between the cortex and ependymal lining. o Nodular Heterotopia Nodular heterotopia represents multiple small, round, or slightly elongated islands of gray matter and is almost exclusively seen in the periventricular (subependymal) region. This entity is occasionally observed in other cerebral malformations, including polymicrogyria. Laminar heterotopia is a large, elongated island of gray matter or small islands of gray structure arranged in a band-like fashion in the white matter, and separated from the overlying cortex and ventricular wall with intervening white matter. Laminar heterotopia is sometimes associated with pachygyria. The exact pathogenesis of neuronal heterotopia is unknown. Depending on its location, however, a complete migratory arrest is possible before departure from the germinal matrix, or disturbance of its migration during the journey toward the final destination. Rare cases of neuronal heterotopia are believed to occur because of prenatal ischemic conditions. 71 Recently, a hereditary form of periventricular heterotopia associated with epilepsy has been described, showing a transmission mode suggestive of X-linked dominance inheritance with nonviability in affected males. 27 Figure 1. Subependymal nodular heterotopia www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 4
  • 8. Figure 2. A, Coronal slice from the occipital lobe of a 13-month-old child. Several nodular gray matter heterotopias protrude into the ventricular cavity. No other malformations were present. B, Multiple nodules of gray matter deep within the occipital white matter (arrows). The brain of this 13-year-old weighed 1,645 g and also showed polymicrogyria (arrowheads) and a complex hindbrain malformation. o Lissencephaly (Agyria) and Pachygyria Both these conditions denote the absence of or reduced number of cerebral gyri, and they may result in severe mental retardation and seizures. The brain is small with enlarged lateral ventricles. The cerebral cortex is thick, and the white matter is reduced in volume. The cortex is frequently composed of four layers, although in some cases, it may consist of a single broad neuronal layer. The basic underlying mechanism for the malformations seems to be the migratory disturbance of neurons, and both sporadic and hereditary forms have been observed. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 5
  • 9. Figure 3. Gross specimen showing lissencephaly with pachygyria Figure 4. Lissencephaly with abnormally smooth agyric cortex www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 6
  • 10. Figure 5. Lissencephaly with abnormally smooth agyric cortex Figure 6. Lissencephaly with abnormally smooth agyric cortex o Generalized Cortical Dysplasia This condition is characterized by a diffusely thickened cortex and clusters of large, heterotopic neurons in the subcortical white matter, and is observed in children with intractable epilepsy and mental retardation. It is thought to represent a mild form of lissencephaly. 53 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 7
  • 11. Figure 7. Pachygyric brain o Polymicrogyria Polymicrogyria is characterized by the presence of numerous small, shallow gyri on the surface of the brain, rendering a cobblestone-like appearance. The cerebral cortex is composed of four layers, with the second layer usually showing excessive undulation. This malformation represents a neuronal migration defect, although postmigratory laminar necrosis sometimes may be the mechanism. Figure 8. Polymicrogyria www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 8
  • 12. Figure 9. Polymicrogyria o Microdysgenesis This is the term originally used by Meencke and Janz, 59 to describe certain histologic features in epilepsy cases that they believed were the morphologic substrate for epilepsy. Features include the presence of neurons in the molecular layer, protrusion of nervous tissue into the pia, columnar arrangement of neurons in the cortex, an increased number of neurons in the white matter, and presence of Purkinje cells in the granular and molecular layers and white matter; however, Lyon and Gastaut, 50 criticized this belief and correctly indicated that the changes are nonspecific and are observed-in patients with no history of seizures. Indeed, most histologic features identified by Meencke and Janz that they believed to be epilepsy-related can be encountered in routine neuropathologic specimens from nonepilepsy cases in daily neuropathologic practice. Although severe neuronal ectopia in the white matter and neuronal clusterings were apparently observed in intractable temporal epilepsy, 24 this needs to be confirmed by other investigators. Figure 10. Cortical dysplasia of Taylor, large anomalous neuron and balloons cells are scattered in the white matter www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 9
  • 13.  Neurocutaneous Syndromes Among neurocutaneous syndromes, tuberous sclerosis and Sturge-Weber syndrome are the two most commonly associated with epilepsy. o Tuberous Sclerosis In tuberous sclerosis, the most common clinical presentation is seizure, occurring in more than 80% of cases. 39 The brain characteristically reveals multiple nodules ("tuber") in the crest of cerebral gyri. The nodules are generally most abundant in the frontal lobe. The involved cortex is firm in consistency and shows some blurring of the junction between the cortex and white matter. Histologically, the subpial area is thickened by proliferating astrocytes that may be large and bizarre with abundant processes. Laminar organization of the cortex is obscured by numerous large, irregularly oriented neurons with coarsely granular Nissl substance. In addition, there are, large cells with abundant, pale cytoplasm and large, round nuclei with prominent nucleoli. These cells are free of Nissl substance and some seem to be of astrocytic lineage because of their GFAP immunopositivity. They are more frequently found in the white matter, occasionally arranged in clusters. Overall, these features are not dissimilar to those of cortical dysplasia of Taylor. In tuberous sclerosis, however, severe gliosis may be noted in the subpial area. Figure 11. Postmortem specimens showing cortical tubers, the affected gyri are abnormally broad and flat. Other significant alterations are also present in tuberous sclerosis of the brain, including focal nodular protrusions of the ventricular wall, which sometimes present as candle guttering-like linear nodular elevations. The nodules are composed of proliferating astrocytes, similar to cortical tubers. Calcification is often found in the subependymal nodules and in the subpial region. Subependymal giant cell astrocytoma is another lesion that may protrude into the ventricle. The tumor is extremely slow-growing, and focal calcification is sometimes observed. Heterogeneous gray structures in the white matter without calcification may also be present. Cerebellar folia may also show tubers. In a premature infant with tuberous sclerosis, immunohistochemistry disclosed astrocytic, www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 10
  • 14. oligodendroglial, and neuronal phenotypic expressions in scattered large cells, which suggests that hamartomatous differentiation of pluripotential germinal neuroglia in the subependymal layer in early gestational stage may cause aberrant or arrested migration, or both, toward the cortical surface. 16 Other organs are also commonly involved in tuberous sclerosis, including the skin (angiofibroma), retina (hamartoma), heart (rhabdomyoma), kidney (angiomyolipoma), and lung (lymphangiomyomatosis). Figure 12. Postmortem specimens showing cortical tubers in A and subependymal tubers in B o Sturge- Weber Syndrome This syndrome is also called encephalotrigeminal or encephalofacial angiomatosis, and typically consists of capillary hemangioma in the upper portion of the face, Leptomeningeal angiomatosis, and cerebral calcification. The brain has an anomalous proliferation of leptomeningeal veins, showing clustering of veins with a somewhat irregular thickened wall. The underlying cerebral cortex shows numerous calcospherites, particularly along its superficial layers. Two abutting calcified cortices around a sulcus may exhibit a tram track-like radiologic appearance. The involved cortex is frequently atrophic, showing neuronal loss and gliosis. As in tuberous sclerosis, seizures are the most common manifestation in Sturge-Weber syndrome, occurring in 71 % to 89% of patients. 39 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 11
  • 15. Figure 13. Sturge- Weber Syndrome he brain has an anomalous proliferation of leptomeningeal veins, showing clustering of veins with a somewhat irregular thickened wall. The underlying cerebral cortex shows numerous calcospherites, particularly along its superficial layers.  Hamartomas This represents a congenital tumorous condition of indigenous cells of the brain. The lesion lacks histologic evidence of active proliferation, including cellular atypia or vascular proliferation. The definition of hamartoma is highly subjective, as reflected by a wide variation in frequency. Most reports show rare or no hamartomas in epilepsy cases, with one exception where 15.7% of intractable temporal lobe epilepsy cases were reported to have this condition. 10  Vascular Malformations Seizure is the principal clinical presentation in arteriovenous malformations and cavernous hemangiomas, experienced in 24% to 69 %21, 61 and in 34% to 51%, 21,63 of cases, respectively. The majority of venous angiomas and capillary telangiectasias are, however, clinically silent. Approximately 5% of vascular malformations are of a mixed variety. Cavernous hemangioma is the most common component in mixed vascular malformations. 70,74 Postulated mechanisms of epileptogenesis in vascular malformations include neuronal loss and gliosis with abnormal glial physiology, altered neurotransmitter levels, free radical formations, and abnormal second messenger physiology. 41 o Arteriovenous Malformations Arteriovenous malformations consist of tangles of anomalous vessels with histologic features suggestive of arteries and veins without intervening capillaries; thick-walled vessels without internal elastic lamina ("arterialized veins") are also observed. Vessels have a great disparity in size and shape, showing marked irregularity in wall thickness. Multiplication of the internal elastic lamina is also common. Trapped or surrounding CNS tissue generally demonstrates reactive glial cells and hemosiderin granules. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 12
  • 16. Figure 14. Arteriovenous malformations consist of tangles of anomalous vessels with histologic features suggestive of arteries and veins without intervening capillaries; thick-walled vessels without internal elastic lamina ("arterialized veins") are also observed. Vessels have a great disparity in size and shape, showing marked irregularity in wall thickness. o Cavernous Hemangiomas (cavernomas, cavernous malformation) Cavernous hemangiomas are composed of tightly arranged, abnormal vessels with faintly laminar, somewhat amorphous, hypocellular wall. The vessels are considerably irregular in size and shape. Unlike arteriovenous malformations, there is no obvious trapped CNS tissue among the vessels and they share common walls among themselves. Hemosiderin granules are almost invariably present in the surrounding tissue. Figure 15. Cavernous hemangiomas are composed of tightly arranged, abnormal vessels with faintly laminar, somewhat amorphous, hypocellular wall. The vessels are considerably irregular in size and shape. NEOPLASMS Seizure is a common clinical manifestation of intracranial tumors, occurring as the initial event in approximately 33% to 38% of cases 32, 45, 58 and in approximately 54% of cases by the time of assessment. 85 Conversely, tumors are detected in 10% to 35% of surgical epilepsy cases. 9,11,17,69,72,83, 92 Thus, tumors are a major cause of seizures. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 13
  • 17.  Gliomas Gliomas account for approximately 72% to 88% of tumors associated with epilepsy. 17, 69,72,83 Gliomas associated with epilepsy behave more favorably than those without a history of epilepsy, thus revealing a longer survival in the former group. 10,11,22,34,69, 82,83 Outstanding seizure control is also expected after surgery in glioma-associated epilepsy. Most epilepsy-associated gliomas are low grade. This, however, does not necessarily explain the more favorable biologic behavior, because in patients with predominantly high grade gliomas, their tumors also behaved less aggressively in those patients with epilepsy than in those without. 82 Figure 16. Astrocytoma grade II Astrocytomas are the predominant tumor, ranging in frequency from 50% to 70% of gliomas. 22,69,72,83 The majority of astrocytomas are low grade. Oligodendrogliomas and mixed gliomas (oligoastrocytomas) comprise the remainder of gliomas associated with intractable epilepsy. Although the proportion between the two tumors is variable in different studies, the frequency is similar. 22,91,92 Glioblastomas are generally one of the most common primary brain tumors but are rarely encountered in most series of intractable epilepsy cases, which may be because of the young age of the majority of epileptic patients. In the elderly patient population, high-grade gliomas are more frequent. 49 Among gliomas, oligodendrogliomas show the highest potential to develop seizures; epileptogenicity is observed in 71% of oligodendrogliomas, followed by astrocytomas (59%) and glioblastomas (29%). 32 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 14
  • 18. Figure 17. Left hemispherical astrocytoma grade II. The tumour has markedly expanded the left hemisphere and distorted the normal anatomy with absence of the normal gray/ white matter junction, notice absence of a definite mass o Mixed Neuronoglial Tumors Although by broad definition of gliomas mixed neuronoglial tumors are a part of gliomas, they are treated separately here. Gangliogliomas and dysembryoplastic neuroepithelial tumors are the two mixed neuronoglial tumors that are primarily associated with seizures. Both share a favorable biologic behavior.  Gangliogliomas Gangliogliomas are uncommon, observed in 1.3% of brain tumors in the general population. 30,31 Seizures are experienced in 42% to 100% of gangliogliomas. 30,31 The tumors are predominantly observed in the pediatric patient group, accounting for up to 4.3% of childhood brain tumors. 7, 38,85 However, the incidence of gangliogliomas is higher in the epilepsy group, ranging from 3.2% to 18.3% (average, 10.5%) of intracranial tumors and tumorous conditions in the majority of series. 10, 11, 22, 66, 72, 83 There are, however, two reports revealing even higher incidences of gangliogliomas in epilepsy: 38.46% and 45.3%, respectively. 61,92 These high incidences may be related to unique patient populations studied. It could also, however, be because of differences in histologic interpretation of tissue slides. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 15
  • 19. Figure 18. Gangliogliomas is composed of neoplastic glial cells and malformed neurons. The latter are primarily binucleated, although large bizarre, abnormally oriented ganglion cells may also be noted. Perivascular mononuclear inflammatory cells are sometimes observed. Figure 19. Gangliogliomas is composed of neoplastic glial cells and malformed neurons. The latter are primarily binucleated, although large bizarre, abnormally oriented ganglion cells may also be noted. Perivascular mononuclear inflammatory cells are sometimes observed. Gangliogliomas are most commonly encountered in the temporal lobe. The tumors are frequently cystic with mural nodules. Calcification may be observed. Microscopically, the tumor is composed of neoplastic glial cells and malformed neurons. The latter are primarily binucleated, although large bizarre, abnormally oriented ganglion cells may also be noted. Perivascular mononuclear inflammatory cells are sometimes observed. The main histologic difference between astrocytomas and gangliogliomas is the presence of malformed neurons in the latter, as both of them share gliomatous components. The gray matter infiltrated by astrocytomas shows pre-existing neurons. Therefore, one caveat in www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 16
  • 20. establishing the diagnosis of astrocytomas is not to misinterpret entrapped pre-existing neurons as part of the tumor to avoid an overdiagnosis of ganglioglioma. 12 Entrapped neurons can survive in the glioma-infiltrated region for an extended time.  Dysembryoplastic Neuroepithelial Tumor Dysembryoplastic neuroepithelial tumor (DNT) is a recently introduced entity, occurring almost exclusively in the first two decades of life, 18 although it has also been identified in some elderly patients. The main clinical feature is a long history of seizures, although one case of DNT without a history of epilepsy has been reported. 42 The incidence of this tumor is not well known but, according to a few reports, it ranges from 1.7% to 7.6% of surgically treated intractable epilepsy cases. 18,90,92 The most salient feature of DNT is its remarkable biologic behavior, which borders on the nature of a hamartoma. Even with incomplete resection of the tumor, recurrences have not been found for a long period of follow-up. 18 Figure 20. Dysembryoplastic neuroepithelial tumor is histologically characterized by a multinodular, intracortical arrangement of the mixed neuronoglial population. In the majority of cases, oligodendroglial-like cells are seen in the background of a microcystic mucinous matrix, where isolated neurons also are demonstrated. In some cases, the predominant component may be astrocytic rather than oligodendroglial. The tumor is almost exclusively confined to the supratentorial region, particularly in the temporal lobe, although cases with multifocal or infratentorial DNTs (or both) have also been reported. 42,62 Neuroimaging studies may show a hypodense lesion on computed tomographic (CT) scan with superficial similarity to a cyst, and low signal intensity on Tl- weighted images and high signal intensity on T2-weighted images by MR imaging. 18,37 Calcification also may be demonstrated. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 17
  • 21. Figure 21. A, Dysembryoplastic neuroepithelial tumour (frontobasal surgical specimen). Irregular thickening of the cerebral cortex with multiple cortical and subcortical nodules. This complex tumour consists of a mixture of glial cells and nerve cells and is often associated with dysplastic cortical foci. It can occur in any part of the brain and generally causes long-standing focal seizures. B, Dysembryoplastic neuroepithelial tumour (MT x40). Oligodendroglial-like cells arranged in groups or columns within a loose, microcystic matrix containing several solitary "floating" neurons and numerous congestive capillaries. Calcifications are possible. The tumor is histologically characterized by a multinodular, intracortical arrangement of the mixed neuronoglial population. In the majority of cases, oligodendroglial-like cells are seen in the background of a microcystic mucinous matrix, where isolated neurons also are demonstrated. In some cases, the predominant component may be astrocytic rather than oligodendroglial. A recent immunohistochemical and ultrastructural study indicates that oligodendrocyte-like cells in DNT are indeed oligodendrocytes with focal astrocytic and neuronal differentiation. 26 The neuronal nature of the oligodendrocyte-like cells has also been found by immunohistochemical, 42 and ultrastructural studies. 46 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 18
  • 22.  Meningiomas and Metastatic Tumors These tumors are rare in the typically young epileptic population subjected to surgical intervention; however, they are commonly encountered in late onset epilepsy cases. 48,61 In patients who develop seizures after age 60 years, the most frequent brain neoplasms are metastatic tumors. 49 Figure 22. Parasagittal meningioma BACTERIAL, FUNGAL, VIRAL, AND PARASITIC DISEASES Approximately 5% of epilepsy cases are secondary to previous CNS infections. 75 Seizures are common in acute CNS infections (viral encephalitis and bacterial or aseptic meningitis), and 19% of patients experience early seizures during the acute phase of CNS infection. 3 The 20-year risk of developing unprovoked seizures is 6.8% in CNS infections, 3 and early seizures are an important predisposing factor for late unprovoked seizures. 3,77 Among CNS infections, patients developing encephalitis before 4 years of age or meningitis show a higher propensity to develop hippocampal sclerosis. 55 In bacterial brain abscesses, seizures are seen as an initial presenting symptom in 25% of cases, and are also a common neurologic sequela observed in 29% of cases. 1 Seizures are also frequent in mycotic CNS infections, shown in 41 % of CNS aspergillosis, 87 and in 15% of CNS cryptococcal infections. 78 Among parasitic infections that are frequently seizure-associated, seizures are extremely common in cysticercosis, experienced in 56% to 70% of cerebral cysticercosis cases. 2, 81 Cysticercosis is distributed world-wide, but is particularly common in Central and South America, Africa and some parts of Asia. Almost all single, small enhancing cerebral lesions in seizure patients in India are suspected or proven to be caused by neurocysticercosis. 15 Even in the United States, a drastic increase has occurred in the incidence of neurocysticercosis because of an increased number of Latin American immigrants and www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 19
  • 23. improved neuroimaging techniques. 81 Neurocysticercosis should be ruled out in seizure patients having isolated cerebral lesions with appropriate histories, imaging, and other laboratory studies. IMMUNE-MEDIATED DISORDERS  Rasmussen's Syndrome Rasmussen's syndrome is a rare enigmatic disorder observed in approximately 1 % to 2 % of general epilepsy cases, 65 and in 7.4% of pediatric patients who undergo cortical excision for intractable seizures. 67 This syndrome is seen primarily in children and, in the majority of cases, seizures occur in the first decade of life. 65, 67 The main clinical features are intractable epilepsy, hemiparesis, and mental deterioration. 67,68 An imaging study shows predominantly unilateral hemispheric atrophy of the brain. Histologic features of the biopsied brain tissue consist of glial nodules and perivascular cuffing of mononuclear inflammatory cells. In addition, neuronal loss and gliosis are seen in the later stage of disease. Glial nodules and perivascular mononuclear cell cuffing are typically observed in viral encephalomyelitis, raising the possibility of a viral etiology in Rasmussen's syndrome. Figure 23. Rasmussen's syndrome. The brain shows a striking pattern of cerebral atrophy confined to the right hemisphere with right ventricular enlargement, the right temporal pole had been previously surgically removed. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 20
  • 24. Figure 24. Rasmussen's syndrome. The brain shows a striking pattern of cerebral atrophy confined to the right hemisphere with contralateral (left) cerebellar atrophy; the right temporal pole had been previously surgically removed. A, shows the basal surface of the brain after removal of the brainstem and cerebellum; B, shows the right lateral aspect with atrophic right cerebral hemisphere and normal right cerebellar hemisphere; C, shows the left lateral aspect with normal left cerebral hemisphere and atrophic left cerebellar hemisphere. Figure 25. Rasmussen's syndrome. A, shows atrophy of the cerebral cortex and white matter, and atrophy of the right thalamus, subthalamic nucleus, lenticular nucleus, tail of the caudate and hippocampus with secondary enlargement of the right ventricular system. B, shows atrophy of the left cerebellar hemisphere and left dentate nucleus. Unlike typical viral encephalomyelitis, the inflammatory changes observed in an early stage of Rasmussen's syndrome may be present to a similar degree years after the initial biopsy. Efforts to isolate a virus also have been unsuccessful. A recent study has shown that an autoimmune mechanism is the underlying mechanism for this disease. Seizures developed in experimental animals with high titers of glutamate receptor 3 antibody, induced by immunization with glutamate receptor 3 fusion protein. The affected animals had histologic changes in the brain similar to those seen in Rasmussen's syndrome. 76 The presence of www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 21
  • 25. antibodies to glutamate receptor 3 was also demonstrated in humans with Rasmussen's syndrome, and considerable improvement of clinical symptoms was noted after repeated plasma exchanges. 76 It seems that we are finally beginning to understand the basic mechanism of this enigmatic disease and may have effective measures to modify its course. Figure 26. Histologic features of the biopsied brain tissue in Rasmussen's syndrome consist of glial nodules and perivascular cuffing of mononuclear inflammatory cells. In addition, neuronal loss and gliosis are seen in the later stage of disease. Glial nodules and perivascular mononuclear cell cuffing are typically observed in viral encephalomyelitis, raising the possibility of a viral etiology in Rasmussen's syndrome. CEREBROVASCULAR DISEASES  Stroke Stroke is a major cause of seizures in late- onset epilepsy. 48, 49,66 After age 50 years, stroke is the most common cause of seizures. 47, 49 Seizures are experienced in 4.4% to 17.0% of stroke cases. 23,25,33,40,44 Among cerebrovascular diseases, cerebral infarction is the most common cause of stroke-related seizures. 23,33,44 This is most likely due to the much higher incidence of cerebral infarcts, although epileptogenicity is higher in hemorrhagic conditions including subarachnoid hemorrhages, intracerebral hemorrhages, and hematomas. 23, 33,44 Prenatal and perinatal cerebrovascular disturbances may result in brain lesions that include porencephaly, migration disorders, and ulegyria. Seizures are frequently associated with these conditions. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 22
  • 26.  Porencephaly Porencephaly describes a brain with an often bilateral hemispheric cystic defect between the surface of the cerebrum and the ventricle. The cystic structure is not lined by ependyma, and its outer surface is covered by the arachnoid membrane. The affected area is usually within the area of the middle cerebral artery, and ischemic necrosis is the suspected cause of this condition. The adjacent areas reveal polymicrogyria or an anomalous gyral formation, and the term porencephaly is usually restricted to a parenchymal defect that may have occurred during an early fetal stage. Some migration disorders are also suspected to be caused by a cerebrovascular accident occurring at an early fetal stage. 71 Figure 27. A, Coronal section of the cerebral hemispheres at the level of the optic chiasm showing porencephaly involving both medial frontal lobes with communication with the lateral ventricles in a 16-year-old with a history of profound mental retardation and quadriplegia.  Ulegyria Ulegyria describes gyral atrophy and sclerosis, which are generally more pronounced near the depth of sulci. The lesions are usually bilateral, and are most commonly observed in the border zone between anterior and middle cerebral arterial territories. Ulegyria is believed to be caused by a perinatal anoxic or ischemic insult. Figure 28. Ulegyria TRAUMA  Head Trauma Head trauma is common between the third and fourth decades of life, with a strong male preponderance. 89 Among patients hospitalized for head trauma, the incidence of brain lesions is approximately 8% to 33%. 89 Trauma is the cause of seizures in 13% to 17% of the epilepsy population. 51,79 Five percent of unselected patients with head injuries www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 23
  • 27. develop at least one seizure during the first week post-trauma, and 5% of patients with head injury may develop late epilepsy. 29 In addition, the presence of acute hematoma, history of early epilepsy, or depressed skull fracture dramatically increases the risk of late epilepsy to 31%. 29 Posttraumatic temporal lobe epilepsy seems to be different from other post-traumatic seizures, as head injury usually occurs at a younger age (median, 2.5 years). No male preponderance is noted, and seizures occur much later (average, 12 years after injury). 57 Regardless of impact site, the frontotemporal area of the brain is the most commonly injured site, particularly the orbital surface of the frontal lobes, the ventral surface of the temporal lobes, and frontal and temporal poles. This is because of the irregularity of the skull base. Contusions are typically seen in the crest of gyri, although injury may extend into the white matter. The degree of brain injury is sometimes only microscopic, but areas of hemorrhagic destruction may be frankly visible. Later, the injured site shrinks, showing brown-yellow discoloration because of hemosiderin deposits. Gliosis is noted in and around the lesion. Diffuse axonal damage is also observed in some cases, particularly in comatose patients. Axonal injury occurs because of shearing of brain tissue at the time of impact, and is most commonly seen in the corpus callosum and midbrain. In such cases,hemorrhages may be seen in the involved areas, and scattered axonal bulbs are observed microscopically. Associated lesions in head trauma include hematomas or ischemic parenchymal changes. SEIZURE-ASSOCIATED BRAIN PATHOLOGY Hippocampus  Hippocampal Sclerosis Hippocampal sclerosis is a common finding in seizure disorders, representing neuronal loss and gliosis with secondary hippocampal atrophy and sclerosis. Mesial temporal sclerosis is another popular clinical term describing similar structural alterations. In addition to hippocampal changes, this cumbersome terminology depicts alterations in other medial temporal structures, such as the amygdaloid nuclear complex and hippocampal gyrus (including the entorhinal cortex). Because these extrahippocampal medial temporal structures are not always involved in cases of hippocampal sclerosis, 8,54,80 the term mesial temporal sclerosis may not be appropriate to use unless other medial temporal structures, in addition to the hippocampus, are found to be structurally altered by imaging or pathologic examinations. Ammon's horn sclerosis may have limited use, because the Ammon's horn generally represents the hippocampus proper only, excluding the dentate fascia. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 24
  • 28. Figure 29. A, Normal hippocampus, B, hippocampal sclerosis Hippocampal sclerosis has been reported in 49% to 72% of surgically resected hippocampi from medically intractable epilepsy cases, 10, 11, 14, 20, 36, 92 in 42% to 58% by imaging studies, 13, 43 and in 58% to 65% by postmortem studies. 54,80 Further, hippocampal sclerosis is more frequently found in temporal lobe epilepsy (84.6%) than in nontemporal lobe epilepsy (38.5 %). 54 Hippocampal sclerosis is mostly unilateral, although bilateral hippocampal sclerosis has been reported in 24% to 31 % of epilepsy cases by postmortem examination, 54,80 and MR imaging volumetric study. 28 Surgical materials do not allow a complete examination of the entire hippocampus; on MR imaging of pathologically proven hippocampal sclerosis, however, the hippocampal body was atrophic in 88% (50/57) of cases, the tail in 61% (35/55), and the head in 51% (29/55). 8 Hippocampal sclerosis is generally a reliable prognostic indicator for favorable clinical outcome following hippocampectomy. 8,11,17,6,84 This raises the possibility of a hippocampal origin of epileptogenesis, or the hippocampus could be part of an epileptogenic circuit. It is interesting to note that the abnormal discharge focus found by stereoencephalography in temporal lobe epilepsy was correlated with the site of reduced neuronal density in the hippocampus. 5 Also, seizure-like discharges were evoked from hippocampal slices from intractable epilepsy cases with a short train of pulses at a low frequency. 56 Several quantitative studies have evaluated neuronal loss in the hippocampus. 6, 34, 62, 79 Defining hippocampal sclerosis by either imaging study or quantitative and qualitative histologic evaluation is highly subjective and problematic. Using the formula ([control mean neuronal density - 2SDI/control mean neuronal density) X 100 for each subfield (CAl-4 and dentate fascia] in the control group, neuronal densities at or less than 59.96% of the control mean fall below the lower two standard deviation limit, which is used to define hippocampal sclerosis. 8,36 Using this definition, 102 of 150 temporal lobe epilepsy cases (68%) had hippocampal sclerosis. Hippocampal sclerosis was more frequent in the C- TLE group, and was noted in 99 of 116 C-TLE cases (85.3%) as opposed to three of 34 P- TLE cases (8.8%). www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 25
  • 29. A history of febrile seizures has been associated with lower neuronal density in the hippocampus. 36 In the current series of 150 epilepsy cases, hippocampal sclerosis was seen in 66 of 73 cases with a febrile seizure history (90.4%), compared with 36 of 77 cases with no history of febrile seizures (46.8%). Glial cell proliferation in the hippocampus in epilepsy seems to be a nonspecific reactive change to neuronal loss, resulting in hippocampal atrophy and sclerosis. Glial density in each hippocampal subfield appears to maintain an inverse relationship with neuronal density of the corresponding subfield. It remains unknown whether glial cells play a significant role in the epileptogenesis of the involved hippocampus or surrounding tissue.  Amygdala Amygdala sclerosis was seen in 22% to 27% of postmortem epilepsy cases. 54,80 Amygdala sclerosis was noted only in cases with hippocampal sclerosis; in 9% of epilepsy cases, the amygdala was bilaterally involved. 54 On review of MR imaging studies, only 12% revealed atrophy of the amygdala among 57 cases with pathology-proven hippocampal sclerosis. 8  Cerebral White Matter Diffuse glial cell proliferation is a prominent histologic feature in the white matter of the anterior lateral portion of the temporal lobe resected from intractable temporal lobe epilepsy cases. An almost 1.5-fold increase in glial density was noted in 25 intractable epilepsy cases, compared with the control group density. 35 The glial cells also possess large swollen nuclei. This hyperplasia and hypertrophy of glial cells may represent a nonspecific reactive change in response to altered physicochemical factor(s) created by seizure activity.  Others The cerebellum is another structure frequently involved with neuronal loss and gliosis: 45% to 67% of epilepsy cases. 54,80 Other cerebral structures showing similar changes are the thalamus (25%) and part of the neocortex, particularly the frontal or occipital cortex (22%). 54 The entorhinal cortex is also reported to have neuronal loss in layer III in temporal lobe epilepsy. 19 CONCLUSION A variety of pathologic lesions associated with seizures have been described in this article. Because of the concerted efforts of neurosurgeons neurroradiologists, neurologists, and neuopathologists, we have observed remark able progress in early detection, resection, and characterization of formerly poorly defined pathologic processes. This has resulted in newly defined lesions. In some reports, the term foreign or alien tissue is used for certain conditions, but is vague, retrogressive, and inadequate for meaningful use. We should eschew these expressions because specific terminologies are available for particular pathologic conditions. Most of the disorders discussed earlier may play a role in www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 26
  • 30. epileptogenic processes. Even in lesions clearly associated with seizures, little is known about their exact pathophysiologic mechanism of epileptogenesis. A larger segment of the epilepsy population is still contained in the cryptogenic group, which is not yet clearly understood, pathologically or otherwise. It is hoped that with further advancement of the neurosciences, most of the cryptogenic cases may be categorized so that we have a better understanding of the epileptogenic mechanism in individual lesions for the eventual benefit of epilepsy victims. References I Aebi C, Kaufmann F, Schaad UB: Brain abscess in childhood. Long-term experiences. Eur j Pediatr 150:282-286, 1991 2. Ahuja GK, Roy S, Kan-da G et al: Cerebral cysticercosis. j Neurol Sci 36:365-374, 1978 3. Annegers JF, Hauser WA, Beghi E, et al: The risk of unprovoked seizures after encephalitis and meningitis. Neurology 38:1407-1410, 1988 4. Awad IA, Robinson JR, Mohanty S, et al: Mixed vascular malformations of the brain: Clinical and pathological considerations. Neurosurgery 33:179-188, 1993 5. Babb TL, Lieb JP, Brown Wj, et al: Distribution of pyramidal cell density and hyperexcitability in the epileptic human hippocampal formation. Epilepsia 25:721-728, 1984 6. Babb TL, Brown Wj, Pretorius J, et al: Temporal lobe volumetric cell densities in temporal lobe epilepsy. Epilepsia 25:729-740, 1984 7. Becker LE, Yates AJ: Astrocytic tumors in children. Major problems in pathology. AJNR Am j Neuroradiol 18:373-396, 1986 8. Bronen RA, Fulbright RK, Kim JH, et al: Regional distribution of MR findings in hippocampal sclerosis. AJNR Am j Neuroradiol, 16:1193-1200,1995 9. Brown Wj: Structural substrates of seizure foci in the human temporal lobe. In Brazier MAB (ed): Epilepsy: Its Phenomena in Man. New York, Raven Press, 1973, p 339 10. Brown Wj, Babb TL: Neuropathological changes in the temporal lobe associated with complex partial seizures. In Hopkins A (ed): Epilepsy. London, Chapman & Hall, 1987, p 300 11. Bruton Cj: The Neuropathology of Temporal Lobe Epilepsy. London, Oxford University Press, 1988 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 27
  • 31. 12. Burger PC, Scheithauer BW: Tumors of the Central Nervous System. Washington, E)C, Armed Forces Institute of Pathology, 1994 13. Cascino GD, Jack CR, Parisi JE, et al: Magnetic resonance imaging based volume studies in temporal lobe epilepsy: Pathological correlations. Ann Neurol 30:31-36, 1991 14. Cavanagh JB, Meyer A: Aetiological aspects of Ammon's horn sclerosis associated with temporal lobe epilepsy. Br Med j 2:1403-1407, 1956 15. Chandy Mj, Rajshekhar V, Ghosh S, et al: Single small enhancing CT lesions in Indian patients with epilepsy: Clinical, radiological and pathological considerations. j Neurol Neurosurg Psychiatry 54:702-705, 1991 16. Chou TM, Chou SM: Tuberous sclerosis in the premature infant: A report of a case with immunohistochemistry on the CNS. Clin Neuropathol 8:45-52, 1989 17. Currie S, Heatherfield KWG, Henson RA et al: Clinical course and prognosis of temporal lobe epilepsy. A survey of 666 patients. Brain 94:173-190, 1971 18. Daumas-Duport C, Scheithuer BW, Chodkiewicz J, et al: Dysembryoplastic neuroepithelial tumor: A surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases. Neurosurgery 23:545-556, 1988 19. Du F, Whetsell WO Jr, Abou-Khalil B, et al: Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy. Epilepsy Res 16:223-233, 1993 20. Earle KM, Baldwin M, Penfield W: Incisural sclerosis and temporal lobe seizures produced by hippocampal herniation at birth. Arch Neurol Psychiatry 69:27- 42,1953 21. Forster DMC, Steiner L, Hakanson S: Arteriovenous malformations of the brain. A long-term clinical study. J Neurosurg 37:562-570, 1972 22. Fried 1, Kim JH, Spencer DD: Limbic and neocortical gliomas associated with intractable seizures: A distinct clinicopathological group. Neurosurgery 34:815-824, 1994 23. Giroud M, Gras P, Fayolle H, et al: Early seizures after acute stroke: A study of 1,650 cases. Epilepsia 35:956-964, 1994 24. Hardiman 0, Burke T, Murphy S, et al: Microdysgenesis in resected temporal neocortex: Incidence and clinical significance in focal epilepsy. Neurology 38:1041-1047, 1988 25. Hauser WA, Ramirez-Lassepas M, Rosenstein R: Risk for seizures and epilepsy following cerebrovascular insults. Epilepsia 25:666, 1984 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 28
  • 32. 26. Hirose T, Scheithauer BW, Lopes MBS, et al: Dysembryoplastic neuroepithelial tumor (DNT): An immunohistochemical and ultrastructural study. J Neuropathol Exp Neurol 53:184-195, 1984 27. Huttenlocher PR, Taravath S, Mojtahedi S: Periventricular heterotopia and epilepsy. Neurology 44:51-55, 1994 28. Jack CR, Sharbrough FW, Cascino GD, et al: Magnetic resonance image-based hippocampal volumetry: Correlation with outcome after temporal lobectomy. Ann Neurol 31:138-146, 1992 29. jennett B: Epilepsy After Non-missile Head Injuries. Chicago, W. Heinemann Medical, 1975 30. johannsson JH, Rekate HL, Roessmann U: Gangliogliomas: Pathological and clinical correlation. j Neurosurg 54:58-63, 1981 31. Kalyan-Raman UK, Olivero WC: Ganglioglioma: A correlative clinicopathological and radiological study of ten surgically treated cases with follow-up. Neurosurgery 20:428-433, 1987 32. Ketz E: Brain tumors and epilepsy. In Vinken Pj, Bruyn GW (eds): Handbook of Clinical Neurology, vol 16. Amsterdam North-Holland, 1974, pp 254-269 33. Kilpatrick Cj, Davis SM, Tress BM, et al: Epileptic seizures in acute stroke. Arch Neurol 47:157-160, 1990 34. Kim JH, Guimaraes PO, Shen MY, et al: Hippocampal neuronal density in temporal lobe epilepsy with and without gliomas. Acta Neuropathol 80:41-45, 1990 35. Kim JH, Murdoch GH, Hufnagel Tj, et al: White matter changes in intractable temporal lobe epilepsy [abstract]. Epilepsia 31:630-631, 1990 36. Kim JH, Kraemer DL, Spencer DD: The neuropathology of epilepsy. In Hopkins A, Shorvon S, Cascino G (eds): Epilepsy, ed 2. London, Chapman & Hall, 1995, pp 243-267 37. Koeller KK, Dillon WP: Dysembryoplastic neuroepithelial tumors: MR appearance. AJNR Am j Neuroradiol 13:1319-1325, 1992 38. Koos WT, Miller MH: Intracranial tumors of infants and children. Stuttgart, Georg Thieme-Verlag, 1971, p 15 39. Kotagal P, Rothner AD: Epilepsy in the setting of neurocutaneous syndromes. Epilepsia 34 (suppl 3):S71- S78, 1993 40. Kotila M, Waltimo 0: Epilepsy after stroke. Epilepsia 33:495-498, 1992 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 29
  • 33. 41. Kraemer DL, Awad IA: Vascular malformations and epilepsy: Clinical considerations and basic mechanisms. Epilepsia 35(suppl 6):S30-S43,1994 42. Kuchelmeister K, Den-drel T, Schlbrer E, et al: Dysembryoplastic neuroepithehal tumour of the cerebellum. Acta Neuropathol 89:385-390, 1995 43. Kuks JBM, Cook Mj, Fish DR, et al: Hippocampal sclerosis in epilepsy and childhood febrile seizures. Lancet 342:1391-1394, 1993 44. Lancman ME, Gohmstok A, Norscini J, et al: Risk factors for developing seizures after a stroke. Epilepsia 34:141-143, 1993 45. LeBlanc F, Rasmussen F: Cerebral seizures and brain tumors. In Vinken Pj, Bruyn GW (eds): Handbook of Clinical Neurology, vol 15. Amsterdam, North-Holland, 1974, p 295 46. Leung SY, Gwi E, Ng HK, et al: Dysembryoplastic neuroepithelial tumor. Am J Surg Pathol 18:606- 614, 1994 47. Loiseau J, Loiseau P, Duch B, et al: A survey of epileptic disorders in southwest France: Seizures in elderly patients. Ann Neurol 27:232-237, 1990 48. Lopez JLP, Longo J, Quintana F, et al: Late onset epileptic seizures. A retrospective study of 250 patients. Acta Neurol Scand 72:380-384, 1985 49. Liihdorf K, Jensen LK, Plesner AM: Etiology of seizures in the elderly. Epilepsia 27:458-463, 1986 50. Lyon G, Gastaut H: Considerations on the significance of attributed to unusual cerebral histological findings recently described in eight patients with primary generalized epilepsy. Epilepsia 26:365- 367, 1985 51. Majkowski J: Postraumatic epilepsy. In Dam M, Gram L (eds): Comprehensive Epileptology. New York, Raven Press, 1990, p 281 52. Manz H, Phillips TM, Rowden G, et al: Unilateral megalencephaly, cerebral cortical dysplasia, neuronal hypertrophy and heterotopia: cytomorphometric, fluorometric, Cytochemical and biochemical analysis. Acta Neuropathol 45:97-103, 1979 53. Marchal G, Andermann F, Tampieri D, et al: Generalized cortical dysplasia manifested by diffusely thick cerebral cortex. Arch Neurol 46:430-434, 1989 . 54. Margerison JH, Corsellis JAN: Epilepsy and the temporal lobes. Brain 89:499-529, 1966 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 30
  • 34. 55. Marks DA, Kim J, Spencer DD, et al: Characteristics of intractable seizures following meningitis and encephalitis. Neurology 42:1513-1518, 1992 56. Masukawa LM, Higashima M, Kim JH et al: Epileptiform discharges evoked in hippocampal brain slices from epileptic patients. Brain Res 493:168-174, 1989 57. Mathern GW, Babb TL, Vickrey BG, et al: Traumatic compared to non-traumatic clinical-pathologic associations in temporal lobe epilepsy. Epilepsy Res 19:129-139, 1994 58. McKeran RO, Thomas DGT: The clinical study of gliomas. In Thomas DGT, Graham DI (eds): Brain Tumors. Scientific Basis, Clinical Investigation and Current Therapy. London, Butterworths, 1984, p 194 59. Meencke H-J, janz D: Neuropathological findings in primary generalized epilepsy: A study of eight cases. Epilepsia 25:8-21, 1984 60. Morris HH, Eses ML, Gilmore R, et al: Chronic intractable epilepsy as the only symptom of primary brain tumor. Epilepsia 34:1038-1043, 1993 61. Mouritzen Dam A, Fuglang-Frederiksen A, Svarre- Olsen U, et al: Late-onset epilepsy: Etiologies, types of seizures, and value of clinical investigation, EEG, and computerized tomography scan. Epilepsia 26:227-231, 1985 62. Mouritzen Dam A: Hippocampal neuron loss in epilepsy and after experimental seizures. Acat Neurol Scand 66:601-642, 1982 63. Ondra SL, Troupp H, George ED, et al: The natural history of symptomatic arteriovenous malformations of the brain: A 24-year follow-up assessment. j Neurosurg 73:387-391, 1990 64. Palmini A, Andermann F, Oliver A, et al: Focal neuronal migration disorders and intractable partial epilepsy: A study of 30 patients. Ann Neurol 30:741-749, 1991 65. Piatt JH, Hwang PA, Amstrong DC, et al: Chronic focal encephalitis (Rasmussen syndrome): Six cases. Epilepsia 29:268-279, 1988 66. Plate KH, Wieser HG, Yasargil MG, et al: Neuropathological findings in 224 patients with temporal lobe epilepsy. Acta Neuropathol 86:433-438, 1993 67. Rasmussen T, Andermann F: Rasmussen!s syndrome: Symptomatology of the syndrome of chronic encephalitis and seizures: 35-vear experience with 51 cases. In Ltiders H (ed): Epilepsy Surgery. New York, Raven Press, 1991, p 173 68. Rasmussen T, Olszewski J, Lloyd-Smith D: Focal seizures due to chronic localized encephalitis. Neurology 8:435-445, 1958 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 31
  • 35. 69, Rasmussen TB: Surgical treatment of complex partial seizures: Results, lessons, and problems. Epilepsia 24(suppl 1):S65-S76, 1971 70. Requena 1, Lopz-fbor L, Pereiro 1, et al: Cavernomas of the central nervous system: Clinical and neuroimaging manifestations in 47 patients. J Neurol Neurosurg Psychiatry 54:590-594, 1991 71. Reutens DC, Berkovic SF, Kalnins RM, et al: Localized neuronal migration disorder and intractable epilepsy: A prenatal vascular etiology. J Neurol Neurosurg Psychiatry 56:314-316, 1993 72. Rich KM, Goldring S, Gado M: Computed tomography in chronic seizure disorder caused by glioma. Arch Neurol 42:26-27, 1985 73. Robain 0, Floquet CH, Heldt N, et al: Hemimegalencephaly: A clinicopathological study of four cases. Neuropathol Appl Neurol 14:125-135, 1988 74. Robinson JR, Awad IA, Little JR: Natural history of the cavernous angioma. J Neurosurg 75:709-714, 1991 75. Rocca WA, Sharbrough FW, Hauser A, et al: Risk factors for complex partial seizures: A population-based case-control study. Ann Neurol 21:22-31, 1987 76. Robers SW, Andrews PI, Gahring LC, et al: Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 265:648-651, 1994 77. Rosman NP, Peterson DB, Kaye EM, et al: Seizures in bacterial meningitis: Prevalence, patterns, pathogenesis, and prognosis. Pediatr Neurol 1:278-85, 1985 78. Sabetta JR, Andriole VT: Cryptococcal infection of the central nervous system. Med Clin North Am 69:333-342,1985 79. Sagar M, Oxbury JM: Hippocampal neuron loss in temporal lobe epilepsy: Correlation with early childhood convulsions. Ann Neurol 2:334-340, 1987 80. Sano K, Malamud N: Clinical significance of sclerosis of the cornu ammonis. Arch Neurol Psychiatry 70:40-53, 1953 81. Scharf D: Neurocysticercosis. Arch Neurol 45:777- 789, 1988 82. Scott GM, Gibberd FB: Epilepsy and other factors in the prognosis of gliomas. Acta Neurol Scand 61:227-239, 1980 83. Spencer DD, Spencer SS, Mattson RH, et al: Intracerebral masses in patients with intractable partial epilepsy. Neurology 34:432-436, 1984 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 32
  • 36. 84. Spencer D: Anteromedial Temporal Lobectomy: Directing the Surgical Approach to the Pathological Substrate. Oxford, Blackwell Scientific Publishers, 1991, p 129 85. Sutton LN, Packer Rj, Rorke LB, et al: Cerebral gangliogliomas during childhood. Neurosurgery 13:124- 128, 1983 86. Taylor DC, Falconer MA, Bruton Cj, et al: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 34:369-387, 1971 87. Torre-Cisneros J, Lopez OL, Kusne S, et al: CNS aspergillosis in organ transplantation: A clinicopathological study. J Neurol Neurosurg Psychiatry 56:188-193, 1993 88. Townsend jj, Nielsen SL, Malamud N: Unilateral megalencephaly: Hamartoma or neoplasm? Neurolog 25:448-453,1975 89. Vigouroux RP, Guillermain P: Posttraumatic hemispheric contusion and laceration. Prog Neurol Sur 10:49-163,1981 90. Vital A, Marchal C, Loiseau H, et al: Glial and neuronoglial malformative lesions associated with medically intractable epilepsy. Acta Neuropathol 87:196-201, 1994 91. Wilden JN, Kelly Pj: CT computerized stereotactic biopsy for low density CT lesions presenting with epilepsy. J Neurol Neurosurg Psychiatry 50:1302-1305, 1989 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 33
  • 37. INDEX  INTRODUCTION  THE ROLE OF MR IMAGING IN EPILEPSY  SUBSTRATES OF EPILEPSY o TUMOR o NEURONAL MIGRATION DISORDERS o VASCULAR MALFORMATION o MESIAL TEMPORAL SCLEROSIS o NEOCORTICAL SCLEROSIS DUE TO BRAIN INJURY o PRINCIPLES AND PROTOCOL OF MR IMAGING IN EPILEPSY MAGNETIC RESONANCE IMAGING A cause-and-effect relationship between pathologic alterations in brain structure and seizures has been recognized for more than 100 years. 49,50 Although the precise mechanism by which structural alterations of the brain produce seizures may not be known, the association between structural pathology and focal onset seizures originating in or near the lesion is well accepted. The pathologic basis of seizures in primary generalized epilepsy, however, is uncertain. In patients with primary generalized onset seizures and a focal structural brain abnormality, a cause-and-effect relationship between seizures and the lesion is difficult to postulate. This article focuses predominantly on the magnetic resonance imaging appearance of the known histologic substrates of recurrent seizures in patients with symptomatic focal onset epileptic syndromes. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 34
  • 38. Throughout this article, the term epileptogenic substrate is used to indicate a pathologic abnormality associated with production of spontaneous partial onset seizures. The substrate may be identified either by direct histologic examination of tissue or MR imaging; both methods are conceptually interchangeable. This article is written from the perspective that almost all pathologic abnormalities -associated with spontaneous partial onset seizures are detectable by MR imaging. The role of computed tomography (CT) in epilepsy is not reviewed. The properties of MR imaging-superior soft tissue contrast, multiplanar imaging capability, and lack of beam hardening artifacts-mean that virtually all substrates of epilepsy are visualized with greater sensitivity and accuracy by MR imaging than by CT. 38, 59, 60, 69, 77 Although many of the substrates of epilepsy are visible by CT some, such as mesial temporal sclerosis and subtle areas of focal cortical dysplasia, are readily visible with MR imaging and virtually undetectable by CT. THE ROLE OF MR IMAGING IN EPILEPSY  Neuroimaging and Anatomy MR imaging plays several important and distinct roles in the clinical management of patients with epilepsy, the most important being to identify and localize the structural substrate of partial onset seizures. In clinical practice, however, MR imaging has other important roles, some of which are discussed in other articles in this textbook and are mentioned here briefly for completeness. 17,41  Classification of Seizure Type Individual patients' seizures are usually classified on the basis of clinical findings and the results of interictal and ictal electrocardiographic (EEG) studies. Precise classification, however, may be uncertain. For example, partial onset seizures that secondarily generalize rapidly can be misinterpreted as primary generalized. The demonstration of an epileptogenic lesion on a MR scan may aid in classification of seizure type-in this example, by indicating the likelihood that the seizures were focal in onset.  Identification of Surgical Candidates The nature and location of an epileptogenic abnormality by MR imaging often determines if surgical resection is feasible.  Surgical Planning Prior to surgical resection of an epileptogenic lesion, MR imaging is essential to define the relationship between the surgical target and adjacent functionally important brain areas. MR imaging is also used preoperatively to identify the surgical approach and volume of tissue targeted for resection. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 35
  • 39.  Prognosis Resection of certain pathologies readily identifiable by MR imaging carries a favorable surgical prognosis (e.g., mesial temporal sclerosis or cavernous angioma), whereas patients with seizures due to certain neuronal migration abnormalities or with no MR image- defined abnormality carry a poor prognosis for postoperative seizure control. 24,25,32,45,87 The presence of MR image-identified mesial temporal sclerosis preoperatively also provides useful prognostic information with respect to memory outcome following temporal lobectomy. This information helps clarify the risk- to-benefit ratio of surgery for patients contemplating epilepsy surgery.  Classification of the Epilepsies Traditionally, seizures and epilepsy syndromes have been classified based on clinical and EEG information. 87,28,87 Experience with MR imaging over the last decade, however, has resulted in a shift from the rigid conceptualization of epilepsy in terms of electroclinical phenomena alone toward an emphasis on the morphologic substrates that produce the observed electroclinical abnormalities. Classification based on the substrate principle places MR imaging in a central role in conceptually defining the epilepsies. SUBSTRATES OF EPILEPSY  Classification of the Substrates of Symptomatic Epilepsy and Sensitivity of Their Detection by MR Imaging The precise sensitivity of MR imaging in the identification of the major substrates of epilepsy varies in the literature. 15, 18, 19, 38, 46, 51, 52, 57, 59, 60, 69, 77, 86,92 Some of this variation is because of technical evolution: for example, reports from 1985 naturally cite a lower sensitivity in the detection of epileptogenic substrates than 1995 reports, due to technical improvement in the modality. Other variation is because of interinstitutional differences in the interpretation of surgical pathology specimens. Epidemiologic studies reveal a striking age dependence in the known or presumed pathologic substrates of epilepsy. 37 The most common known cause in children is congenital or developmental anomalies, in young adults it is post-traumatic brain injury and, in the elderly it is cerebral infarction. These data, derived from epidemiologic studies on the proportional incidence of epilepsy by age and etiology, do not match the perception obtained from clinical experience held by many clinicians-that epilepsy is a disease of children and young adults primarily due to brain tumors and mesial temporal sclerosis. The reason for this discordance is that most data correlating epilepsy with its pathologic substrate are derived from surgical epilepsy series. Reliance on epilepsy surgery series for correlation between structural substrate and clinical manifestations of epilepsy produces a narrower viewpoint than from an epidemiologic perspective. For example, parasitic brain abscesses from cysticercosis, which are a common cause of partial onset seizures in some parts of the world, are rare in most epilepsy surgery series that generally originate from North American and European centers. As indicated earlier, because definite knowledge of www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 36
  • 40. the exact substrate of epilepsy requires MR imaging, surgical pathology, or autopsy documentation, reliable data regarding the substrate-specific prevalence of epilepsy are significantly biased toward those patients in whom surgical resection is being considered. Substrates known to be associated with a favorable surgical prognosis such as tumor, vascular malformation, and mesial temporal sclerosis are undoubtedly overrepresented, whereas substrates with a less favorable surgical prognosis such as neuronal migration disorders, sclerosis from trauma, infection, infarction, and patients with negative or nonspecific histology (i.e., negative preoperative MR imaging studies) are underrepresented with respect to the true etiology-specific prevalence rates in the general epilepsy population. Despite the biases introduced by using surgical epilepsy series as the primary source of information regarding the substrates of symptomatic epilepsy, surgical cases still provide the most certain correlation between seizures and their underlying pathologic basis.  Epileptogenic Substrate and Seizure Production The concept that brain lesions produce seizures is regarded to be true. A cause-and-effect relationship is implicit in the use of the term substrate to define pathologic alterations in brain structure that are associated with seizures. 85 On closer examination, however, the precise mechanistic relationship between a lesion and a seizure is less clear. It is presumed that seizures arise from neurons that lie adjacent to a lesion that are rendered by several possible mechanisms susceptible to spontaneous, coherent discharge. Mechanisms that have been implicated include dysfunction of the sodium/potassium ion pump, changes in N- methyl-D-aspartic acid receptor channels, abnormal regulation of gamma amino butyric acid (GABA), and abnormal glial calcium ion transports An exception to the general lack of understanding of seizure mechanisms is mesial temporal sclerosis. Studies on animals as well human surgical specimens have revealed that synaptic reorganization in the dentate hilus of the hippocampus is a basic feature of mesial temporal sclerosis; it is this abnormality that is at least partially responsible for recurrent seizure production. 16,26,62, 65, 79, 81, 82, 88, 90 TUMOR Tumors in Epilepsy Versus Neuro-oncology  Neuro-oncology o Clinical Manifestations and Management. Patients typically have a neurologic deficit as the most serious manifestation of their disease. Seizures, although common, are of secondary importance. Symptoms tend to be of recent onset and short duration. Tumors may be primary or metastatic and are often high grade. Although all ages are represented, the older patient is generally affected. Patients are managed clinically by neuro-oncologists at large centers. Prolonged EEG monitoring to identify seizure type is not performed. The surgical strategy varies depending on tumor type and location. At the some institutions, complete resection of many high grade primary tumors is not attempted; rather, the tumors are biopsied and then treated with radiation or www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 37
  • 41. chemotherapy protocols. Functional mapping is only occasionally performed if the proposed resection is close to the primary sensory motor cortex. Amytal testing is not performed. o Histology. All possible histologic types of brain tumors are represented in neurooncologic series, in contrast to the limited number represented in most epilepsy series. Also in contrast to the latter, the glial neoplasms are often high grade. Intraventricular and infratentorial tumors are found in neurooncologic series and not in epilepsy surgery series. Tumors that are common in epilepsy series, for example, DNET or ganglioglioma, are rare in neuro- oncologic series. o MR Imaging Features. The histology and clinical behavior predicts the different imaging appearance of the high grade intra-axial supratentorial tumors in neuro-oncologic series and low grade tumors observed in epilepsy series. Tumors tend to be more poorly demarcated from surrounding normal brain, and tend to enhance and may be large. Peritumoral edema is a consistent feature. Central necrosis is common; and calvarial remodeling is unusual.  Epilepsy o Clinical Manifestations and Management. The history of seizures typically extends over several years in an epilepsy patient with a tumor and an associated neurologic deficit is usually not present. Surgery is usually performed in children or young adults, and, occasionally, in middle-aged patients. Medical management is by epileptologists at large centers. Surgery is preceded by prolonged invasive or noninvasive EEG recording and tests of function such as neurophysiological testing, positron emission tomography (PET), single photon emission tomography (SPECT), and amytal testing. Operative or extraoperative cortical functional mapping is often performed, particularly for extratemporal surgeries. The surgical strategy is aimed at complete lesion removal. o Histology. Only primary tumors are found (not metastatic). Tumors are supratentorial and of glial, or of both glial and neuronal cell origin. 20, 33, 43 Typical tumor histologies include: www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 38
  • 42.  Astrocytoma: low grade diffuse fibrillary,  Pilocytic, or pleomorphic xanthoastrocytoma  Oligodendroglioma: low grade  Mixed oligodendroglial-astrocytic tumors: low grade  Dysembryopathic neuroepithelial tumors (DNET)  Ganglioglioma  Hamartoma o MR Imaging Features. Imaging features of the tumor match the prolonged clinical history and indolent histologic nature of the tumor. Tumors are (1) well-circumscribed; (2) have little or no peritumoral edema; (3) commonly remodel the inner table of the calvarium when in a cortical location; (4) have variable enhancement; (5) are usually located in the cortex (versus white matter); (6) tend to be small; (7) typically lack central necrosis; and (8) are supratentorial and extraventricular in location with a predilection for frontal and temporal lobes. 35  Histology and MR Imaging Appearance of Tumors in Epilepsy It is generally difficult to predict the precise histology of individual tumors on the basis of MR imaging. In addition, distinguishing focal cortical ctysplasia from some of these cortically based tumors, particularly oligodendroglioma, ganglioglioma, and DNET, can sometimes present a diagnostic challenge for MR imaging. The MR imaging characteristics of tumors in epilepsy described above can be generically applied to the following tumor types; several of these tumor types, however, have certain distinctive features. o Astrocytoma Several histologic grading schemes have been devised for diffuse astrocytomas. Histologic grading of malignancy is a function of features such as nuclear atypia, mitotic activity, cell arrangement and number, vessel proliferation, and necrosis. 68 Generally accepted grading terminology is as follows in order of increasing malignancy and dedifferentiation:astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme. Astrocytomas found in epilepsy series are those at the low end of the malignancy spectrum (i.e., "astrocytoma" in the above three-tiered grading scheme). Diffuse astrocytomas occur in a variety of morphologic subtypes (fibrillary, gemistocytic, giant cell, and protoplasmic) with fibrillary being the most common. On MR imaging, low grade diffuse astrocytomas are well-demarcated, produce little or no mass effect or edema, and do not enhance with contrast. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 39
  • 43. Figure 1. Astrocytoma: typical for neuro-oncologic series. A previously healthy 65-year-old man presented with a single generalized topic seizure. MR imaging revealed this left temporal lobe tumor, demonstrated to be a grade 4 fibrillary astrocytoma on biopsy. A is a spin density image and B is a post-contrast Tl -weighted image. Note the typical features of a high grade intra-axial neoplasm: mass effect, peritumoral edema, and an intensely enhancing ring with central necrosis malignancy spectrum (i.e., "Astrocytoma") Pilocytic astrocytomas (sometimes referred to as "juvenile pilocytic astrocytomas") are a special variant that is nearly as common as low grade diffuse astrocytomas in epilepsy surgery series. Pilocytic astrocytomas are, by definition, benign and usually do not infiltrate adjacent normal parenchyma. They may calcify, form cysts, and are characterized microscopically by abundant Rosenthal fiber formation. 68 Interestingly, intense enhancement is a common feature of these tumors. They commonly occur in the diencephalon, optic nerve or chiasm, and cerebellar hemisphere. Seizures are a common presenting symptom when they occur in the cerebral hemisphere. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 40
  • 44. Figure 2. Pilocytic astrocytoma. The tumor in the lateral aspect of the right anterior temporal lobe is sharply demarcated from adjacent, uninfiltrated normal brain tissue. The tumor is of increased signal on a T2-weighted image (A), decreased signal on a Tl -weighted image (B) and enhances intensely (C). Remodeling of the inner table of the calvarium indicates its longstanding clinical course. Figure 3. Mixed tumor. Subject is a 32-year-old woman with complex partial seizures since age 17 years MR imaging reveals an expanded right hippocampal formation with increased T2 (A) and decreased Tl signal (B). No evidence of mass effect, peritumoral edema, or enhancement is noted (B). This was a grade 1 to 2 mixed oligoastrocytoma at pathology. Pleomorphic xanthoastrocytoma is another special variant. It is rare but warrants mention because of a predilection for location in the temporal lobe. It is most commonly found in young adults or children with a long seizure history. It is histologically low grade and commonly forms a cyst. o Oligodendroglioma Overall, oligodendrogliomas comprise about 5% of all brain tumors; in epilepsy surgery series, however, oligodendrogliomas are only slightly less common than astrocytomas. They tend to preferentially infiltrate cortex. 68 This tendency, along with a generally more indolent histologic nature than astrocytomas, may account for the relatively high frequency of low to moderate grade oligodendrogliomas in epilepsy surgery series. Enhancement is variable, and dense tumoral calcification and formation of multiple cysts are common. o Mixed Low grade tumors composed of both diffuse astrocytic and oligodendroglial elements are common in epilepsy series. The MR imaging features are indistinguishable from low grade diffuse astrocytomas. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 41
  • 45. Figure 4. Astrocytoma: typical for epilepsy series. A 36-year-old woman presented with a 32-year history of complex partial seizures. Tl - (A) and T2- weighted (B) images demonstrate a tumor that expands the right amygdala and ambient gyrus. There is no mass effect, peritumoral edema, and the tumor did not enhance. Pathology was a grade 1 to 2 diffuse fibrillary astrocytoma. o Ganglioglioma These tumors occur most frequently in the temporal lobe. They contain differentiated glial and ganglion cells and, therefore, differ from most primary central nervous system neoplasms that contain only glial elements. 68 The astrocytic component may either be diffuse or pilocytic in nature. These tumors exist along a spectrum and are termed ganglioglioma if the glial component predominates and gangliocytoma if the neural elements predominates. Gangliogliomas most commonly have a cyst or multiple cysts, calcification, and enhancement. Figure 5. Ganglioglioma. Subject is a 37-year-old man with a 30-year history of complex partial seizures. MR imaging demonstrates a tumor involving the left hippocampal formation, parahippocampal gyrus, and fusiform gyrus. Although the involved gyri are expanded, the tumor is well demarcated from adjacent parenchyma with minimal peritumoral edema. Several cystic areas are demonstrated within the tumor. A, T2- weighted image; B, FLAIR image; C, Tl -weighted image. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 42
  • 46. o Dysembryoplastic neuroepithelial tumors (DNET) Dysembryoplastic neuroepithelial tumors have been described within the last decade. 30 They have unique histologic features consisting of all three cell lines (neuronal, oligodendroglia, and astrocytic elements) with little cellular atypia. They are located in and expand cortex and have a multinodular architecture and show a predilection for a temporal lobe location. Longstanding epilepsy with onset in early childhood is the most common clinical presentation. Because of the benign nature of the tumor, a complete cure is expected if completely resected. The MR image appearance is that of a multinodular, thickened irregular cortex with a variable degree of increased signal intensity on T2- weighted images. They often have a multicystic appearance and may have areas of enhancement or calcification. Erosion of the inner table is a common feature because these tumors, by definition, are cortically based and usually have a longstanding clinical history. Some authors classify DNET malformations not as tumors, but rather, a disorder of neuronal migration and proliferation. They are sometimes found in conjunction with an area of focal cortical dysplasia. This abnormality may thus be most appropriately classified somewhere between the categories of tumor and neuronal migration disorder. NEURONAL MIGRATION DISORDERS  Normal Development A complete description of the development of the cerebral cortex is beyond the scope of this article. A brief outline, however, should help understand the various anomalies that are subsequently described. Neurons and glial cells are generated in the germinal matrix that is located at the ventricular surface. Development of the cerebral cortex can be divided into stages of cell proliferation, differentiation, migration, and cortical organization. 3,5, 13, 54, 64, 78, 80 After their last cell division in the germinal matrix, most neurons reach the cortex through a process of radial migration. Most neurons migrate along radial glial fibers that span the entire thickness of the hemisphere from the ventricle to the pial surfaces. About 10% of neurons follow nonradial migratory routes. The six-layered cortex forms chronologically in an inside out fashion. Cells of layer six migrate first, and cells of layer two migrate last. The elapsed time between final cell division and arrival at the cortex is shorter for early migrating neurons than for those migrating later in development. The migratory rate is also variable in different parts of the telencephalon. Most cell migration extends from approximately the seventh to the 16th week of gestation. Differentiation of neurons into classes characteristic of each cortical layer follows migration, and this process is termed cortical organization. Major disorders of neuronal migration and organization, whether due to hypoxia, metabolic abnormalities, environmental toxin exposure, or a genetically determined defect in chemotaxis, exert their effect during this period. The type of insult is less important in determining the morphologic expression of a developmental disturbance than the timing. 13 Congenital disorders of brain development characterized by disturbances of neuron migration and organization (NMD) are commonly associated with epilepsy. 10, 13, 72, 83 (Many congenital brain malformations are not associated with epilepsy per se and are not www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 43
  • 47. discussed here.) NMDs without any apparent inheritance pattern (focal cortical dysplasia, schizencephaly, microdysgenesis) are likely due to randomly occurring insults during development. Conversely, a genetic basis is either known or highly likely for NMDs with familial association (lissencephaly/pachygyria, nodular heterotopia, laminar heterotopia, tuberous sclerosis). Several different schemes for classifying cerebral NMDs associated with epilepsy have been proposed. These have been based both on abnormalities in gross brain morphology and associated cellular abnormalities. The precise sequence of events during development that ultimately leads to the various NMDs observed in nature is only partly understood. Unfortunately, therefore, the descriptive terminology in this area is inadequate and does not always describe discrete universally recognized developmental or pathologic entities. Nevertheless, the terms employed below have been commonly used for several years and are familiar to most readers. The classification outlined below is one in which the major anomalies are classified by gross morphologic appearance (either at autopsy or on MR images). Figure 6. DNET. A 14-year-old girl a 5-year history of complex partial seizures. MR imaging reveals a lesion in the postero-inferior left temporal lobe that expands the cortex. It has a multicystic appearance, is well demarcated, produces no peritumoral edema, and does not enhance. At pathology, this was found to be a DNET tumor. A, T2-weighted image; B, spin density image; C, Tl -post contrast image.  Tuberous Sclerosis Cortical tubers are not the most common developmental anomaly associated with epilepsy. Their discussion first, however, is intended to emphasize that, like DNETS, cortical tubers have been classified both as tumors and NMDs by various authors and would seem to be most appropriately placed into an intermediate category. 36 The defect in tuberous sclerosis appears to be an abnormality in the radial neuron-glial unit in certain portions of the germinal matrix. 2 The result is radially oriented columns of dysplastic cells spanning focal subependymal and subcortical cell deposits. It is the cortical tuber component of this complex that is most likely responsible for seizures, as resection of a cortical tuber www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 44
  • 48. sometimes eliminates chronic seizures. Cortical tubers are composed of giant astrocytic and neuronal cells with abnormal organization. The appearance of cortical tubers on MR images is characteristic: it consists of a well-circumscribed area of increased T2 and decreased TI signal intensity; located immediately beneath the cortical gray mantel. Typically, the involved gyrus is expanded. A ray-like projection of increased signal intensity from the base of the tuber toward the ventricular surface is frequently observed; they are usually multiple. Very low signal intensity is present in densely calcified tubers, whereas minimally calcified tubers may have increased Tl signal. Because calcification of tubers increases with age, the MR image may change over time. 2  Focal Cortical Dysplasia Focal cortical dysplasia, along with anodular heterotopias, are the most common developmental causes of epilepsy. The term cortical dysplasia has been used to describe a family of abnormalities with a similar appearances. 8,13,22,54-56,58,71,91 NMDs that have been distinctly labeled by some authors-focal cortical dysplasia of Taylor, forme fruste of tuberous sclerosis, and polymicrogyria-have been grouped into the single category of focal cortical dysplasia by others. The term focal cortical dysplasia was first used by Taylor and colleagues 91 to describe dysplastic cortical abnormalities in pathologic specimens from epilepsy surgery patients. The dysplastic areas of brain fail to develop normal laminar cortical organization and contain giant balloon cells of glial, neuronal, and indeterminate lineage. Histologically, however, this dysplastic abnormality is similar in appearance to the cortical abnormality described in the form fruste of tuberous sclerosis (patients with a cortical lesions indicative of tuberous sclerosis but without the other classic stigmata-family history, adenoma sebaceum, periventricular lesions). The term focal cortical dysplasia has also been used when describing a circumscribed area of polymicrogyria. Polymicrogyria refers to an area of brain with several small abnormal gyri. Macroscopically, the microgyric nature of the abnormality may be evident, or the outer molecular layers of adjacent microgyri may be fused, creating an erroneous impression of a single large gyrus (i.e., macrogyria or pachygyria). Polymicrogyria is usually associated with focal cortical laminar necrosis. A late migratory vascular insult is the most likely etiology- most radially migrating neurons have arrived at the cortex, but organize abnormally because of the vascular event. The dysplastic cortex is often, but not always, centered on an abnormal cleft or sulcus of varying depth. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 45
  • 49. Figure 7. Severe focal cortical dysplasia. Subject is a 28-year- old man with poorly controlled seizures since age 10 months. MR imaging reveals an abnormal cleft in the medial left parietal cortex lined by polymicrogyric cortex. A, Sagittal image; B, axial Tl - weighted image. The appearance of focal cortical dysplasias on MR imaging mirrors their gross pathologic description. Focal cortical dysplasias exists along a spectrum. At the mild end the only evidence on MR images may be a subtle area of abnormal cortical thickening. At the other end, a large abnormal cortical cleft lined by polymicrogyric cortex is obvious on MR imaging. The MR image hallmark is a focal area of macroscopically thickened cortex. The normal thickness of the cortex is 4 mm. Although the cortex is actually thin in polymicrogyri, because the many shallow gyri are lumped together, the gross macroscopic appearance is that of a thickened cortex. These are often associated with laminar areas of increased T2 signal in the immediate subjacent white matter. Because of the manner in which orthogonal imaging planes intersect the curving surface of the cerebral cortex, however, apparent cortical thickness in excess of 4 mm strictly due to volume averaging effects is common in the normal brain. Identification of subtle areas of focal cortical dysplasia and distinguishing this from volume averaging of normal cortical sulcation is a challenging task in interpreting MR imaging studies in epilepsy patients. Three- dimensional volumetric MR acquisitions with slice thickness about 1.5 mm are extremely helpful in identifying these abnormalities and in differentiating them from normal cortical sulcation. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 46
  • 50. Figure 8. Mild focal cortical dysplasia. Coronal three- dimensional Tl -weighted image demonstrates a focal area of cortical thickening in the medial left parietal cortex (arrowhead) in this 26-year-old man with poorly controlled seizures since age 3 years. This was resected stereotactically and demonstrated to be an area of focal cortical dyspiasia at the mild end of the spectrum. The only abnormality is a focal area of thickened cortex with no evidence of a cleft.  Schizencephaly Schizencephaly denotes an abnormal cleft that extends from the pial cerebral surface to the ependymal surface. The cleft is typically lined by dysplastic gray matter-that is, polymicrogyric cortex. Schizencephalic clefts are most commonly found in the perisylvial regions. The clefts may be unilateral or, less commonly, bilateral. Schizencephaly has been divided into (1) Type I in which the lips of the cleft are in contact with each other and (2) Type 11 in which the cleft is open. The ventricular opening of a closed lip schizencephaly may be demarcated by a dimple on the ventricular surface on MR imaging. 7,9 Mental retardation, developmental delay, and motor or language disorders commonly accompany seizures as a primary clinical manifestations of schizencephaly. The severity of the clinical expression, however, ranges from severe impairment to essentially normal development and intellectual ability. Patients with bilateral clefts tend to be clustered at the more severe end of the spectrum. The motivation for grouping schizencephaly next to focal cortical dysplasia is a common dysplastic cortical architecture and, possibly, a common pathologic mechanism differing only in timing and severity of the vascular insult. 13 Although the etiology is actually unknown, it may be due to an intrauterine vascular injury to radial glial fibers, thus preventing normal radial migration of neurons. A vascular insult that occurs during, but prior to completion of, radial neuronal migration and that eliminates the radial glial fiber network in the brain from ventricular to pial surface may result in a schizencephalic cleft lined by polymicrogyria. A vascular insult that occurs prior to complete radial migration and that affects only the more distal ends of the radial glial fibers may result in focal cortical dysplasia without a schizencephalic cleft. The observation that focal cortical dysplasia is often associated with an abnormal cortical cleft of varying size supports this common pathologic mechanism, and the abnormal cleft may represent a rudimentary schizencephalic. 13,54 A common expression of this continuum between focal cortical dysplasia and schizencephaly is a syndrome of bilateral perisylvian polymicrogryia, originally described by Kuzniecky and colleagues, 56 in which an abnormal cleft of varying size continuous with the sylvian fissure is lined by polymicrogyric cortex. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 47
  • 51. Figure 9. Schizencephaly. A21- year-old woman with normal development and normal IQ presented with seizures that were well controlled with medication. MR imaging demonstrates a right medial frontal schizencephalic cleft, lined by polymicrogyric cortex. A, Sagittal Tl-weighted image; B, axial spin density image.  Nodular Heterotopia Along with focal cortical dysplasia, nodular heterotopia is the most common developmental disorder found in epilepsy. The term heterotopia refers to gray matter located in an abnormal position. Nodular heterotopias can be divided into those that are subependymal and subcortical 3,6,40, 84 ; the two types often coexist. Subependymal heterotopias appear as nodular rests of gray matter located subependymally. They project into the ventricle and may present as one or a few isolated nodules, or a conglomerate mass of gray matter lining the ventricular surface. They may be unilateral or bilateral, more commonly the latter, and may occur along any of the lateral ventricular ependymal surfaces. In unilateral nodular heterotopias, the relationship of subependymal heterotopias to seizure production is questionable, and patients are often developmentally and intellectually normal. Figure 10. A Subependymal nodular heterotopia. Corona] T2-weighted MR image demonstrates multiple heterotopic subependymal gray matter nodules projecting into the right ventricular atria. B Subcortical, nodular heterotopia. Coronal TI- weighted MR www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 48
  • 52. image demonstrates a nodular heterotopia involving much of the left temporal lobe. Heterotopic gray matter extends from the ependymal surface of the left temporal horn outward through the full thickness of the temporal lobe white matter. The overlying cortex is abnormal. C Lamina heterotopia. Subject is a 30-year-old woman with lifelong seizures, normal IQ, and normal development. Coronal Tl-weighted MR image demonstrate a band of heterotopic neurons clearly separated from the overlying cortex throughout both hemispheres by white matter. Nodular subcortical heterotopias are conglomerate masses of gray matter that may be purely subcortical in location or fan outward from the ependymal surface into the white matter. The overlying cortex is abnormal with polymicrogyria, pachygyria, or both. A ray- like finger of increased T2 signal may be identified projecting from the underlying ependymal surface to the base of the subcortical heterotopia. In addition to seizures, many patients have neurologic deficits, developmental delay, and intellectual impairment. It is sometimes difficult to distinguish nodular subcortical heterotopias from tumors. Four helpful distinguishing MR imaging features are that heterotopias (1) are always isointense to gray matter; (2) do not enhance; (3) do not exert mass effect on adjacent brain; and (4) are 3 not associated with white matter edema. 3 Figure 11. Pachygyria with lissencephaly  Laminar Heterotopia This is a relatively uncommon developmental anomaly characterized by a discreet laminar zone of heterotopic gray matter throughout both hemispheres that is bound on the inner and outer border by white matter. Thus, the term band heterotopia or double cortex syndrome has been used. 11,54,70 The overlying cortical mantle is abnormal, and it is commonly thicker than normal and usually associated with some areas of pachygyria. This abnormality is usually fatal in the developing male and, therefore, the anomaly is nearly exclusively found in women. Clinical symptomatology ranges from normal development and IQ to severe developmental delay with low IQ. Although laminar heterotopia is usually considered in the same category as nodular heterotopia it may be more appropriately www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 49
  • 53. considered within the family of lissencephalies on the basis of appearance and possibly etiology.  Lissencephaly The term lissencephaly refers to a brain with abnormal, deficient formation of sulci and gyri and encompasses a spectrum of morphologic abnormalities. 3,12,21,31,54 At the severe end of the spectrum are smooth brains completely devoid of sulci and gyri, also known as "agyria" or "complete lissencephaly." The term pachygyria refers to broad flat gyri. Patients with lissencephalic deformity may lie anywhere along this spectrum. Patients with agyria often also have areas of pachygyria. Infants and children with lissencephaly typically have severe intellectual impairment, developmental delay, hypotonia, and seizures of multiple types. The severity of the clinical impairment generally tracks with severity of the associated brain malformation. Lissencephaly is actually a family of disorders of cortical migration that may have differing genetic bases. Barkovich, 3 defines five distinct subcategories of lissencephaly: types I and 11 are the most well-recognized. Type I lissencephaly is also referred to as classic lissencephaly. Many patients with classic lissencephaly have abnormalities of chromosome 17pl3. 31 The category of type I lissencephaly itself contains subsets of patients with distinct clinical syndromes, the most well known being the Miller-Dieker syndrome. The abnormal cortex contains the following four layers from outside in: (1) molecular layer, (2) outer cellular layer (the true cortex); (3) a cell sparse zone; and (4) a thick inner layer of neurons whose outward migration was arrested prematurely. The appearance of type I lissencephaly on MR imaging is characteristic. A high-quality MR study will resolve the three layers described above. An MR study with limited resolution will fail to depict the thin outer layer of neurons and cell sparse layer, and the appearance is that of a markedly thickened cortex-10 to 20 mm in thickness. White matter volume is diminished. The sylvian fissures are oriented vertically, and the failure to form well-defined sylvian fissures results in a figure-of-eight appearance on axial images. The ventricular atria are often dilated, and the corpus callosum hypoplastic. Patients with type 11 lissencephaly consist of a spectrum of similar brain anomalies. The most common syndrome in type 11 lissencephaly is the Walker-Warburg syndrome. Similar to patients with type I lissencephaly, type 11 patients are severely impaired with developmental delay, severe retardation, hypotonia, and seizures. As with type 1, the malformation is due to a global arrest of radial neuronal migration. The inner margin of the thicken cortex in lissencephaly type 11 has a distinctive appearance, however, consisting of finger-like projections of cortex into the underlying white matter. It may be that lissencephaly, pachygyria, and band heterotopia share a common pathologic mechanism in that a global arrest in radial neuronal migration occurs in the brain. A spectrum of severity, therefore, exists with lissencephaly at the severe end of the spectrum and laminar heterotopia at the mild end. The earlier the arrest of neuronal migration during development, the more severe is the anomaly. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 50
  • 54.  Unilateral Hemimegaloencephaly This term refers to enlargement of all or part of one hemisphere, usually associated with dilatation of the ipsilateral ventricular system. 3,4,54 In addition to an enlarged ventricular system, ipsilateral white matter volume is increased. The cortex is grossly abnormal with areas of pachygyria, polymicrogyria, nodular heterotopic gray, and gliosis in the white matter. The affected portion of the brain is not functional. Extent of involvement is variable ranging from a single lobe to the entire hemisphere. Patients present with seizures, developmental delay, and functional impairments that match the portion of brain involved. lpsilateral somatic hypertrophy may also be present.  Microdysgenesis The term microdysgenesis was coined by Meencke and Janz 66,67 to describe subtle, microscopic alterations in cortical architecture. These have been described in patients with primary generalized epilepsy, particularly Lennox-Gastaut syndrome and West's syndrome, and in patients with focal onset seizures. The characteristic findings include (1) dystopic (misplaced) neurons in the subcortical white matter; (2) dystopic neurons in the molecular layer; (3) persistence of Cajal cells; and (4) columnar arrangement of neurons. The cause-and-effect relationship between microdysgenesis and epilepsy is controversial, because the same histologic features are encountered in pathologic specimens from nonepileptic brains. Microdysgenesis has not yet been described by MR imaging. VASCULAR MALFORMATION The spectrum of cerebral vascular malformations includes cavernous hemangioma, capillary telangiectasia, venous angioma, and arteriovenous malformation (AVM). The hallmark of an AVM is the presence of direct arteriovenous shunts without an intervening capillary network. The vessels that constitute the nidus of the AVM are abnormal, thick-walled, and of larger diameter than the normal capillary network, thus producing arteriovenous shunting and, by definition, decreased arteriovenous circulation time. Feeding arteries and draining veins are dilated from the increased flow. The most common presenting symptom, and that which poses the greatest risk to the patient with an AVM, is hemorrhage. Seizures are also common with AVM. At the author's institution, however, surgical decision-making in a patient with an AVM is primarily based upon the desire to minimize the risk of hemorrhage, with seizure control a secondary consideration. The term occult describes those vascular malformations that are not visualized on conventional arteriography; this encompasses cavernous hemangioma, capillary telangiectasia, and thrombosed AVM. These three malformations have a similar appearance and, therefore, cannot be distinguished from each other by MR imaging or CT. MR imaging is extremely sensitive in detecting these occult vascular malformations. 35 Cavernous hemangiomas (cavernomas) are composed of large abnormal vascular spaces. A gliotic hemosiderin-laden rim surrounds this abnormal vascular nidus accounting for the characteristic MR appearance of these lesions. The hemosiderin-stained rim appears dark www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 51
  • 55. on T2-weighted spin echo images or gradient echo images. The central nidus has a nonuniform reticulated signal intensity and is bright on both Tl and T2 images; this has been attributed to blood products that continuously "leak" through the walls of the hemangioma's nidus into surrounding tissue and gliosis. Normal neuronal tissue is not present. in the nidus of a cavernous hemangioma; although it is interspersed between the abnormal vascular channels in a capillary telangiectasia-this is the chief pathologic distinction between the two entities. Features of both conditions, however, commonly occur in single lesions, and it may be that these two entities actually represent different points along the spectrum of a common abnormality. When symptomatic, the most common clinical presentation of a cavernous hemangioma is a chronic seizure disorder. The cavernous hemangioma is the vascular malformation that is typically considered for surgical resection for relief of chronic intractable seizures. Figure 12. Cavernous hemangioma. Left temporal lobe cavernous hemangioma with classic MR features. Nonuniform mixed bright and isointense signal in the AVM nidus on both Tl (A) and T2-weighted (B) images. The dark hemosiderin staining rim around the periphery of the cavernous hemangiomas is evident in B. Venous angiomas consist of a "caput" of dilated draining veins that converge on a central large draining vein. Typically, the nidus is located along an ependymal surface. Venous angiomas are usually considered to represent normal variants. These are typically not associated with seizures; resection for control of seizures is not performed at the author's institution. Sturge-Weber disease is a phakomatosis syndrome characterized by facial, leptomeningeal and ocular angiomatosis, mental retardation, epilepsy, and neurologic deficits that depend on the location of the leptomeningeal angioma. It is mentioned here because of the central role seizures have in the clinical manifestation of the disease. 2, 35 The intracranial hallmark is a pial angioma that is believed to represent persistent embryonic vasculature; seizures are believed to occur because of the effects of this vascular malformation on the underlying brain. The MR imaging features of the syndrome include enhancement of the pial angioma and atrophy of the underlying cortex. A characteristic calcification pattern in opposing banks of the underlying cortex described as "tram track" in appearance produces a low signal intensity cortical ribbon on MR imaging. The dystrophic calcification in underlying white matter and cortical layers two and three, and the cortical atrophy are felt to be ischemic in nature resulting from the lack of normal cortical draining veins. The www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 52
  • 56. malformation is usually unilateral and located in the parietal-occipital region, but may be bilateral and be located in any neocortical area. The ipsilateral choroid plexus is enlarged and enhances prominently. Figure 13. Sturge Weber syndrome. right parietal occipital pial angioma that enhances with contrast administration (A). The underlying cortex is atrophic and MR imaging demonstrates decreased signal intensity throughout the atrophic cortical mantle, which may be due to hemosiderin deposition. calcification, or both (B). MESIAL TEMPORAL SCLEROSIS Mesial temporal sclerosis consists of cell loss and astrogliosis in the mesial temporal cortex, the hippocampal formation, amygdala, parahippocampal gyrus, and entorhinal cortex. These changes have been best described in the hippocampus, partly due to its severe involvement and the lamellar pattern of hippocampal organization that lends itself to histopathologic study. Two forms of hippocampal cell loss have been identified in mesial temporal sclerosis. Classic sclerosis, also known as Ammon's horn sclerosis, is the more frequent form. This consists of marked loss of the pyramidal cells in CA1, CA3, and the dentate hilus, with sparing of pyramidal cells in the CA2 sector. The second form is denoted as end folium sclerosis, which consists primarily of cell loss and astroglial proliferation in the end folium with relative sparing of the other sectors. 1, 29,63 Autopsy studies have demonstrated that mesial temporal sclerosis is present bilaterally, in up to 80% of cases. However, it is usually asymmetric in that one side is more severely involved than the other; the more severely involved of the two hippocampi typically denotes the site of origin of a patient's seizures. 63 The MR image counterparts to these two pathologic abnormalities are atrophy and signal change. 15, 18,46,51, 52, 57 Hippocampal atrophy is best identified on Tl-weighted images obtained coronally or, ideally, perpendicular to the principal axis of the hippocampal formation, which is variably canted downward from posterior to anterior. The identification of atrophy by MR imaging corresponds to cell loss identified in histologic specimens. The other principal finding is a signal intensity change consistent with increased tissue-free water- decreased signal intensity on Tl -weighted images and an increased signal intensity on Tl- weighted images. It is logical to assume that the abnormality in signal intensity is a function of astroglial proliferation. Several other findings on MR images have been helpful in identifying the temporal lobe predominantly involved in mesial temporal www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 53
  • 57. sclerosis; these include (1) loss of normal internal architecture of the involved hippocampus; (2) unilateral atrophy of the mammillary body; (3) unilateral atrophy of the columns of the fornix; (4) unilateral atrophy of the amygdala; and (5) unilateral atrophy of white matter bundle in the parahippocampal gyrus. Although all of these findings may occur in cases of mesial temporal sclerosis, the author believes that the small, bright hippocampus is the most reliable. Both of these findings are usually present in an individual patient. In some patients with mesial temporal sclerosis, however, the hippocampus may appear to be normal-sized but of increased signal, or atrophic without an obvious signal abnormality. Studies of the accuracy of visual perception have demonstrated that predominantly unilateral mesial temporal sclerosis can be identified with an accuracy of about 90% by knowledgeable readers. Although the unilateral dilatation of the temporal horn has been suggested as a useful marker of mesial temporal sclerosis, the author regards this finding as unreliable. Whereas this exists in cases of severe hippocampal atrophy because of mesial temporal sclerosis, it is not a reliable indicator of mesial temporal sclerosis because it also occurs as a common normal variant. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 54
  • 58. Figure 14. Mesial temporal sclerosis. Left-sided mesial temporal sclerosis. The four collage panels demonstrate the classic features of mesial temporal sclerosis. The Tl -weighted collage (A) demonstrates atrophy of the left hippocampus and a normal appearing right hippocampus. The other three collages demonstrate the second classic finding of mesial temporal sclerosis that is increased hippocampal signal. By visual inspection, increased signal is most striking on the FLAIR image (B), nearly equally as obvious on the T2- weighted image (C), and evident, but less obvious on the spin density-weighted image (D). The two main findings of mesial temporal sclerosis, hippocampal atrophy and signal change, have been successfully quantified. A technique for measuring the volume of the hippocampus has been developed and is widely used at major epilepsy surgery centers. , 42,43 The degree of volume loss correlates well with the degree of cell loss measured in subsequent histologic specimens. 23,61 Identification of predominantly unilateral atrophy has been shown to correlate with the side of seizure onset in patients with nonlesional www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 55
  • 59. complex partial seizures of temporal lobe origin; hippocampal volumetry was helpful in initially establishing the relationship between hippocampal atrophy and the presence of a distinct medial temporal lobe seizure onset syndrome. 46 Hippocampal volumetry has also been used to study outcome following temporal lobectomy and has demonstrated that when EEG evidence of unilateral temporal lobe seizure onset is concordant with predominantly unilateral hippocampal atrophy, the probability of an excellent surgical outcome exceeds 90%. 45 Conversely, in a patient with nonlesional temporal lobe epilepsy and EEG evidence of unilateral temporal lobe seizure onset but without volumetric evidence of predominantly unilateral hippocampal atrophy, the probability of an excellent surgical outcome is below 50%. Hippocampal volumes have also been correlated both with pre- and postoperative memory performance, which is the topic of another article in this volume. 93 Volumetric studies have also shown that the presence of hippocampal atrophy is correlated with the age of onset rather than the duration or severity of the seizure disorder. 94 It has been our experience that quantification of mesial temporal sclerosis by volumetry is beneficial, even essential, in performing correlative clinical research. Conversely, the identification of predominantly unilateral mesial temporal sclerosis for clinical purposes is accomplished as effectively simply by a visual inspection of images alone. T2 relaxometry has also been employed to quantify the signal change found in mesial temporal sclerosis. 53 Figure 15. Up mesial temporal sclerosis and below normal hippocampi As mentioned, mesial temporal sclerosis is found bilaterally in approximately 80% of autopsy cases. However, the goal of imaging and the assumption underlying treatment by temporal lobectomy would indicate that in most cases of mesial temporal sclerosis, only one of the temporal lobes actually produces seizures. This apparent discrepancy is best explained by regarding the entire spectrum of mesial temporal sclerosis in four categories 47 : (1) category 1, one hippocampus is entirely normal and the other is abnormal; (2) category 11, one hippocampus is slightly abnormal and the other severely abnormal; (3) category III, both hippocampi are abnormal to an equal degree; and (4) category IV, both hippocampi are normal. Clinical experience to date indicates that in category II patients, the more severely involved hippocampus typically represents the site of seizure onset. It is the distinction between categories 1/11 and III/IV that appears to be the most critical, both in terms of surgical outcome and imaging identification of the substrate of epilepsy. Patients in categories I and II both respond well following removal of the abnormal temporal lobe. Furthermore, visual identification of the more abnormal hippocampus is fairly straightforward when there is a significant side-to-side discrepancy in volume and www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 56
  • 60. signal intensity. On the basis of imaging criteria, however, it is impossible to identify the "more involved" hippocampus in categories III and IV because, by definition, the two hippocampi are either symmetrically abnormal or symmetrically normal. These two categories appear to have a similarly mediocre response to temporal lobectomy: fewer than 50% of patients are seizure free postoperatively.  Cause versus Effect? Sclerosis is defined as "cell loss and astro-glial proliferation." Regional sclerosis is commonly associated with epilepsy. An enduring controversy surrounds the cause-and- effect relationship between seizures and tissue sclerosis. Autopsy studies of individuals with a life-long history of seizures reveal astroglial proliferation and cell loss (in excess of that expected for the patients' age) in several different brain areas, particularly medial temporal lobe, cerebellum, and thalamus. 63 Experimental seizures in animals result in histologic changes of sclerosis in various brain areas, particularly the hippocampus. 11,62,65,81,82,88,90 Lobectomy specimens resected for surgical relief of seizures invariably reveal white matter and cortical astrogliosis in areas of the brain that are distant from the actual site of onset of the patient's typical seizures; these findings have led to the suggestion that sclerosis is the result of repetitive seizures. Conversely, sclerotic areas of the brain have been well-documented in humans to be the source of seizures or be closely related to the site of habitual seizure onset by (1) direct correlation between electric localization of seizure onset and sclerotic lesions by depth electrode and subdural grid implantation and (2) observation of seizure elimination when sclerotic lesions are resected. It is accepted that mesial temporal sclerosis is responsible for producing seizures. Whether the seizures originate within the hippocampus or surrounding medial temporal lobe cortical regions, or require synergy between various medial temporal lobe areas, however, is controversial. What is clear is that cell loss and astroglial proliferation do not produce seizures by themselves. Synaptic reorganization, particularly involving the dentate hilus, has been demonstrated with sophisticated staining techniques, and this is believed to be the actual "cause" of recurrent seizures in mesial temporal sclerosis. 26, 65, 81, 82, 88-90 The origin of mesial temporal sclerosis remains obscure. It is felt by many to be due to complicated febrile convulsions that occur during a specific window in early childhood (about 3 months to 5 years of age). Calcium- mediated excitotoxic cell injury is believed to be the primary noxious event that leads to this condition. 16, 62, 65, 81, 82, 90 Studies of newborn and developing animals indicate that there may, indeed, be a window of vulnerability during which the balance of glutamate receptors and intracellular calcium binding proteins may render pathways in the hippocampal formation, particularly the dentate hilus, vulnerable to excitotoxic injury. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 57
  • 61. NEOCORTICAL SCLEROSIS DUE TO BRAIN INJURY Sclerosis is the final common pathway of many brain insults, which can be grouped conveniently into four major categories: (1) trauma, (2) infection, (3) inflammation, and (4) infarction. Any of these four mechanisms may produce an area of brain necrosis, in which death of all cell lines has occurred. Necrosis is typically surrounded, however, by an area of sclerosis. Sclerosis, regardless of the causal mechanism, has a common MR appearance- atrophy and signal change consistent with increased tissue-free water. In cases of trauma, hemosiderin deposition in atrophic cortical tissue often occurs. The precise cause of seizures in patients with post-brain injury sclerosis is unknown. Detailed studies of synaptic reorganization have been performed for mesial temporal sclerosis but not for neocortical, post-brain injury sclerosis. Response to resective surgery is not as uniformly favorable for neocortical sclerosis as for mesial temporal sclerosis. Figure 16. Neocortical sclerosis Head trauma is recognized as a cause of focal onset epilepsy. The first cortical resection for intractable epilepsy was performed by Victor Horsely in 1886 who resected a posttraumatic cortical scar in a patient with a penetrating skull injury. 39 Seizures following head injury are more likely if the injury results in a depressed skull fracture and especially if the dura is penetrated. Head trauma accounts for a large portion of incident seizure disorders in young adults. Cerebral infarction is the most common etiology of new onset epilepsy in the elderly. At the other end of the age spectrum, perinatal or neonatal vascular insults may produce areas of cerebral infarction associated with seizures. Seizures are presumed to arise from gliotic tissue at the periphery of the infarcted zone. Mechanisms of infarction in this age group are diverse-embolic, secondary to infection, trauma, hypoxia, and hemorrhage. Although perinatal hypoxia may be associated with cerebral infarction, it is not a cause of neuronal migration disorders, which result from events between gestational weeks 7 and 16. On a worldwide scale, infection is a much more common substrate of epilepsy than in North America and Europe. In areas where cysticercosis is endemic, a significant percentage of the population may be infected and seizures are the most common clinical www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 58
  • 62. manifestation of neurocysticercosis. Tuberculomas are another common cause of seizures in populations where the disease is prevalent. Rasmussen's encephalitis, first described by Rasmussen in 1958. 74 also deserves special mention. On imaging, the condition is characterized by slowly spreading cortical atrophy and signal change that begins focally and spreads gradually. Although nonfatal, if untreated it may spread to involve an entire hemisphere and invariably leads to severe neurologic and intellectual impairment. Surgery is the only treatment known to be effective. Because of the relentlessly progressive nature of this condition, radical surgical procedures such as partial or complete hemispherectomies are often performed to halt the anatomic spread and to control seizures. Seizures are a hallmark of the condition, and patients often present with epilepsia partialis continua. This condition was previously believed to represent slow, indolent viral encephalitis because of some microscopic changes that were similar to viral infections; these changes include perivascular cuffing, glial nodules, and microglial proliferation. A more recent theory suggests that Rasmussen's encephalitis is actually an autoimmune phenomenon. More specifically, it has been linked to an autoimmune response to the three subunit of the glutamate neurotransmitter." Glutamate is the primary excitatory cerebral neurotransmitter and the relevant circulating antibodies in affected persons (usually children) may hypersensitive, or primarily interact with, the glutamate receptor. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 59
  • 63. Figure 17. Rasmussen's encephalitis with hemiatrophy and ventricular dilatation Figure 18. Rasmussen's encephalitis www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 60
  • 64. PRINCIPLES AND PROTOCOL OF MR IMAGING IN EPILEPSY Several principles should be observed when devising an appropriate examination for a patient referred for MR imaging with a chief complaint of seizures. 1. A standard protocol specifically tailored for epilepsy screening is advised. The examination should, however, always be monitored by an attending radiologist. Modification of the baseline, screening imaging sequences may be dictated by the clinical presentation of individual patients or the findings observed on the baseline screening pulse sequences. 2. The screening protocol examination should contain a pulse sequence with sufficient spatial resolution to detect the most subtle alterations in cortical architecture found in patients with epilepsy. The most subtle anatomic alterations in the author's experience that must be detected are mild hippocampal atrophy and cortical thickening. For this reason, a three-dimensional volumetric pulse sequence is highly recommended as an integral part of an epilepsy screening MR imaging examination. A three-dimensional sequence typically with 124 sections at 1.5 mm or 1.6 mm slice thickness will provide adequate spatial resolution to detect the above abnormalities. Because of the near isotropic small voxel size, these images can also be reformatted into any desired plane. This is particularly useful in attempting to distinguish volume averaging of normal cortical gyration from a subtle cortical dysplasia. The ability to reformat the images to correct for head rotation is also crucial in accurately identifying unilateral hippocampal atrophy by visual inspection of the images. If the patient's head is rotated in the coronal plane, a coronal cross-sectional image will intersect the two hippocampi at different points along their anteroposterior axes, thus making side-to-side comparison of hippocampal area extremely difficult. 3. The screening examination should also contain a pulse sequence with a sufficient T2 contrast-to-noise ratio to identify subtle areas of increased signal intensity. This is particularly necessary in attempting to identify the subtle increased signal intensity which is a typical finding in both Mesial temporal sclerosis and neocortical sclerosis. A study comparing fast spin echo to conventional spin echo imaging found that the conventional spin echo images were slightly more sensitive in detecting the signal alteration of mesial temporal sclerosis; therefore, we do not employ fast spin echo imaging in our epilepsy screening protocol. 44 A more recent development is fast fluid attenuated inversion recovery imaging (FLAIR). 76 The contrast properties of this pulse sequence are ideal for the detection of subtle areas of cortical tissue signal abnormality because the inversion time is set to null the cerebrospinal fluid signal, whereas the echo time is long enough to provide T2- weighting of parenchymal brain abnormalities. The lesion to background contrast and dynamic range properties for detection of small cortically based epileptogenic lesions are, therefore, superior with FLAIR compared with standard double echo pulse sequences. 14 4. A final principle that should be observed in designing a screening protocol is that the majority of. epileptogenic lesions are located in the temporal lobe, with mesial temporal sclerosis as the most common histologic substrate. The principal orientation axis of the temporal lobe and hippocampus is in a variably oblique coronal plane. This means that www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 61
  • 65. both a three-dimensional volumetric and T2-weighted or FLAIR sequence should be obtained either coronally, or better yet, obliquely perpendicular to the principal axis of the hippocampal formation. Our current protocol consists of a sagittal Tl-weighted set of spin echo images. This is used to examine midline structures for standard diagnostic imaging purposes and for subsequent landmarking. The second pulse sequence consists of an oblique coronal three dimensional volumetric acquisition with 124 partitions and 1.6 mm slice thickness. Although this oblique three-dimensional pulse sequence is not yet commercially available, a standard orthogonal coronal three-dimensional volumetric sequence will suffice for diagnostic purposes. The direct oblique acquisition provides more precise delineation of the hippocampal boundaries. The third sequence is a coronal double spin echo sequence, and the fourth is a coronal fast FLAIR sequence. Additional sequences may be necessary for individual patients. Although an axial sequence is not part of our baseline protocol, axial images may be helpful in evaluating extratemporal lesions. They are particularly useful in patients with a perirolandic epileptogenic lesion, as the relationship between the lesion and central sulcus may be identified directly. References 1. Babb TL, Brown Wj, Pratorius J, et al: Temporal lobe volumetric cell density in temporal lobe epilepsy. Epilepsia 25:729-7.40, 1984 2. Barkovich Ai: The phakomatosis. In Pediatric Neuro imaging. Raven Press, New York, 1995, p 277 3. Barkovich AJ: Congenital malformations of the brain and skull. In Pediatric Neuroimaging. Raven Press, New York, 1995, p 177 4. Barkovich Aj, Chuang SH: Unilateral megalencephaly: Correlation of MR imaging and pathologic characteristics. AJNR Am j Neuroradiol 1990,11:523 5. Barkovich Ai, Gressens P: Formation, maturation and disorders of brain neocortex. AJNR Am J Neuroradiol 1992, 13:423-426 6. Barkovich Ai, Kjos BO: Gray matter heterotopias: MR characteristics and correlation with developmental and neurologic manifestations. Radiology 182:493, 1992 7. Barkovich Aj, Kjos BO: Schizencephaly: Correlation of clinical findings with MR characteristics. AJNR Am j Neuroradiol 13:85-94, 1992 8. Barkovich Aj, Kjos BO: Nonlissencephalic cortical dysplasias: Correlation of imaging findings with clinical deficits. AJNR Am j Neuroradiol 13:95, 1992 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 62
  • 66. 9. Barkovich Aj, Norman D: MR of schizencephaly. AJNR Am j Neuroradiol 9:297-302, 1988 10. Barkovich Aj, Chuang SH, Norman D: MR of neuronal migration anomalies. AJNR Am j Neuroradiol 9: 1009-1017,1987 11. Barkovich Aj, Jackson DE Jr, Boyer RS: Band heterotopias: A newly recognized neuronal migration anomaly. Radiology 182:493, 1989 12. Barkovich Aj, Koch TK, Carrol CL: The spectrum of lissencephaly: Report of ten cases analyzed by magnetic resonance imaging. Ann Neurol 30:139-146,1991 13. Barth PG: Disorders of neuronal degeneration. Can j Neurol Sci 14:1-16, 1987 14. Bergin PS, Fish DR, Shorvon DS, et al: Magnetic resonance imaging in partial epilepsy: Additional abnormalities shown with the fluid attenuated inversion recovery (FLAIR) pulse sequence. J Neurol Neurosurg, Psychiatry 58:439-443, 1995 15. Berkovic SF, Andermann F, Olivier A, et al: Hippocampal sclerosis in temporal lobe epilepsy demonstrated by magnetic resonance imaging. Ann Neurol 29: 175-182,1991 16. Bertram EH, Lothman EW, Lenn NJ: The hippocampus in experimental chronic epilepsy: A morphometric analysis. Ann Neurol 27:43-48, 1990 17. Bronen RA. Epilepsy: the role of MR imaging. AJR Am J Roentgenol 159:1165-1174, 1992 18. Bronen RA, Cheung G, Charles JT, et al: Imaging findings in hippocampal sclerosis: Correlation with pathology. AJNR Am j Neuroradiol 12:933-940, 1991 19. Brooks BS, King SW, Gammal TE, et al: MR imaging in patients with intractable complex partial epileptic seizures. AJNR Am j Neuroradiol 11:93-99, 1990 20. Bruton Cj: The Neuropathology of Temporal Lobe Epilepsy. Oxford, UK, Oxford University Press, 1988 21. Byrd SE, Osborn RE, Bohan TP, et al: The CT and MR evaluation of migrational disorders of the brain. Part 1. Lissencephaly and pachygyria. Pediatr Radiol 19: 151- 156,1989 22. Byrd SE, Osborn RE, Bohan TP, et al: The CT and MR evaluation of migrational disorders of the brain. Part 11. Schizencephaly, heterotopia and polymicrogyria. Pediatr Radiol 19:219-222, 1989 23. Cascino GD, Jack CR Jr, Parisi JE, et al: MRI-based volume studies in temporal lobe epilepsy: Pathological correlations. Ann Neurol 30:31-36, 1991 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 63
  • 67. 24. Cascino GD, Jack CRJ, Parisi JE, et al: MRI in the presurgical evaluation of patients with frontal lobe epilepsy and children with temporal lobe epilepsy: Pathologic correlation and prognostic importance. Epilepsy Res 11:51-59, 1992 25. Cascino GD, Kelly Pj, Sharbrough FW, et al: Longterm follow up of stereotactic lesionectomy in partial epilepsy: Predictive factors and electroencephalographic results. Epilepsia 33:639-644, 1992 26. Cavazos JE, Golarai G, Sutula TP: Mossy fiber synaptic reorganization induced by kindling: Time course of development, progression, and permanence. J Neuroscience 11:2795-2803, 1991 27. Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 22:489-501, 1981 28. Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30:389-399, 1989 29. Dam AM: Epilepsy and neuron loss in the hippocampus. Epilepsia 21:617-629, 1980 30. Daumas-Duport C, Scheithauer B, Chadkiewicz, JP, et al: Dysembryoplastic neuroepithelial tumor: A surgically curable tumor of young patients with intractable partial seizures. Neurosurgery 23:545-556, 1988 31. Dobyns WB, Reiner 0, Carrozzo R, et al: Lissencephaly. A human brain malformation associated with deletion of the LISI gene located at chromosome 17pl3. JAMA 270:2838- 2842, 1993 32. Engel J Jr: Outcome with respect to epileptic seizures. In Engel J Jr (ed): Surgical Treatment of the Epilepsies. New York, Raven Press 1987, p 553 33. Falconer MA: Treatment of temporal lobe epilepsy and anterior lobectomy, a survey of findings and results. Lancet 1:827-835, 1955 34. Falconer MA: Genetic and related etiological factors in temporal lobe epilepsy: A review. Epilepsia 12:13-31, 1971 35. Friedland Rj, Bronen R: Tumors and vascular malformations. In Jack CR Jr, Cascino GD (eds): Neuroimaging in Epilepsy. Principles and Practice. Butterworth Heinmann, 1995 36. Gomez MR: Tuberous Sclerosis, ed. 2. New York, Raven Press, 1988 37. Hauser WA: Seizure disorders: The changes with age. Epilepsia 33:6-14, 1992 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 64
  • 68. 38. Heinz ER, Heinz TR, Radtke R: Efficacy of MR vs CT in epilepsy. AJNR Am j Neuroradiol 9:1123-1128,1988 39. Horsley V: Brain surgery. Br Med j 2:670-674, 1886 40. Huttenlocher PR, Taravath S, Mojtahedi S: Periventricular heterotopia and epilepsy. Neurology 44:51-55, 1994 41. Jack CR Jr: Epilepsy: surgery and imaging (state-of the-art). Radiology 189:635-646, 1993 42. Jack CR Jr, Bentley M, Twomey CK, et al: MR-based volume measurements of the hippocampal formation and anterior temporal lobe: Validation studies. Radiology 176:205- 209, 1990 43. Jack CR Jr, Gehring DC, Sharbrough FW: Temporal lobe volume measurement from MR images: Accuracy and left-right asymmetry in normal individuals. J Comput Axial Tomogr 12:21-29, 1988 44. Jack CR Jr, Krecke KN, Luetmer PH, et al: Conventional versus fast spin echo MRI in diagnosis of mesial temporal sclerosis. Radiology 192:123-127, 1994 45. Jack CR, Jr, Sharbrough FW, Cascino GD: Magnetic resonance image-based hippocampal volumetry: Correlation with outcome after temporal lobectomy. Ann Neurol 31:138-146, 1992 46. Jack CR, Sharbrough FW, Twomey CK, et al: Temporal lobe seizure: Lateralization with MR volume measurements of hippocampal formation. Radiology 175:423-429, 1990 47. Jack CR Jr, Trenerry MR, Cascino GD, et al: Bilaterally symmetric hippocampi and surgical outcome. Neurology 45:1353-1358, 1995 48. Jack CR Jr, Twomey CK, Zinsmeister AR: Anterior temporal lobes and hippocampal formations: Normative volumetric measurements for MR images in young adults. Radiology 172:549-554, 1989 49. Jackson JH: A study of convulsions. Trans St. Andrews Med Grad Assoc 3:1-45,1870 50. Jackson JH: On the anatomical, physiological, and pathological investigation of the epilepsies. West Riding Lunatic Asylum Medical Reports 3:1873 51. Jackson GD, Berkovic SF, Duncan JS, et al. Optimizing the diagnosis of hippocampal sclerosis using MR imaging. AJNR Am j Neuroradiol 14:753-762,1993 52. Jackson GD, Berkovic SD, Tress BM: Hippocampal sclerosis can be reliably detected by magnetic resonance imaging. Neurology 40:1869-1875, 1990 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 65
  • 69. 53. Jackson GD, Connell A, Duncan JS, et al. Detection of hippocampal pathology in intractable partial epilepsy: Increased sensitivity with quantitative magnetic resonance T2 relaxometry. Neurology 43:1793-1799, 1993 54. Kuzniecky R: Migration anomalies. In Jack CR Jr, Cascino GD (eds): Neuroimaging in Epilepsy: Principles and Practice. Newton, MA, Butterworth-Heinemann 55. Kuzniecky R, Anderman F, Tampieri D, et al: Bilateral central macrogyria: Epilepsy, pseudobulbar palsy, and mental retardation: A recognizable neuronal degeneration disorder. Ann Neurol 25:547-554, 1989 56. Kuzniecky R, Berkovic S, Andermann F, et al: Focal cortical myoclonus and rolandic cortical dysplasia: Clarification by magnetic resonance imaging. Ann Neurol 23:317-325, 1988 57. Kuzniecky R, de la Sayette V, Ethier R: Magnetic resonance imaging in temporal lobe epilepsy: Pathologic correlations. Ann Neurol 99:341-347,1987 58. Kuzniecky R, Garcia JH, Faught E, et al: Cortical dysplasia in temporal lobe epilepsy: Magnetic resonance imaging correlations. Ann Neurol 29:293-298, 1991 59. Laster WW, Penry JK, Moody DM, et al: Chronic seizure disorders: Contribution of MR imaging when CT is normal. AJNR Am j Neuroradiol 6:177-180, 1985 60. Latach JT, Abou-Khalil BW, Siegel Gj, et al: Patients with partial seizures: Evaluation by MR, CT, and PET imaging. Radiology 159:159-163, 1986 61. Lencz T, McCarthy G, Bronen RA, et al: Quantitative magnetic resonance imaging in temporal lobe epilepsy: Relationship to neuropathology and neuropsychological function. Ann Neurol 31:629-637, 1992 62. Lothman EW: Basic mechanisms of the epilepsies. Curr Opin Neurol Neurosurg 5:216- 223, 1992 63. Margerison JH, Coresllis JAN: Epilepsy and the temporal lobes. Brain 89:499-530, 1966 64. McConnell SK: Development and decision-making in the mammalian cerebral cortex. Brain Res Rev 13:1-23,1988 65. McDonald JW, Garofalo EA, Hood T, et al: Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy. Ann Neurol 29:529-541, 1991 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 66
  • 70. 66. Meencke Hj: Minimal development disturbances in epilepsy and MRI. In Shorvon SD, Fish DR, Andermann F, (eds): Magnetic Resonance Scanning and Epilepsy. Plenum Press, New York, 1994 67. Meencke Hj, janz D: Neuropathological findings in primary generalized epilepsy: A study of eight cases. Epilepsia 25:8-21, 1984 68. Okazaki H, Scheithauer BW: Atlas of Neuropathology Philadelphia, JB Lippincott, 1988, p 59 69. Ormson Mj, Vispert DB, Sharbrough FW, et al: Cryptic structural lesions in refractory partial epilepsy: MR imaging and CT studies. Radiology 160:215-219,1986 70. Palmini A, Andermann F, Aicardi J: Diffuse cortical dysplasia, or the "double cortex" syndrome: The clinical and epileptic spectrum in 10 patients. Neurology 41:1656-1662, 1991 71. Palmini A, Andermann F, Olivier A: Focal neuronal migration disorders and intractable partial epilepsy: A study of 30 patients. Ann Neurol 30:741-749, 1991 72. Rakic P: Neuronal migration and contact guidance in the primate telencephalon. Postgrad Med j 54:25-40, 1978 73. Rakic P: Defects of neuronal migration and the pathogenesis of cortical malformations. Prog Brain Res 73:435-455, 1988 74. Rasmussen T, Olszweski J, Lloyd-Smith DL: Focal seizures due to chronic localized encephalitis. Neurology 8:435-455, 1958 75. Rogers SW, Andrews PI, Gahring LC, et al: Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 265:648-651, 1994 -, 76. Rydberg JN, Hammond CA, Grimm RC, et al: Initial clinical experience in MR imaging of the brain using a fast FLAIR pulse sequence. Radiology 193:173- 180, 1994 77. Schoner W, Meencke Hj, Felix R: Temporal lobe epilepsy: Comparison of CT and MR imaging. AJNR Am j Neuroradiol 8:733-781, 1987 78. Shatz Cj: Dividing up the neocortex. Science 258:237-238 1992 79. Shin C, McKamara JO: Mechanism of epilepsy. Annu Rev Med 45:379-389, 1994 80. Sidman RL, Rakic P: Neuronal migration, with special reference to developing human brain: A review. Brain Res 62:1-35, 1973 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 67
  • 71. 81. Sloviter RS: Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: The "dormant basket cell" hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus 1:41-66,1991 82. Sloviter RS: The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy. Ann Neurol 35:640-654, 1994 83. Smith AS, Blaser SI, Ross JS, et al: Magnetic resonance imaging of disturbances in neuronal migration: Illustration of an embryologic process. Radio Graphics 9:509-522, 1989 84. Smith AS, Weinstein L, Quencer RM, et al: Association of heterotopic gray matter with seizures: MR imaging. Radiology 168:195-198, 1988 85. Spencer DD: Surgical planning in adults. In Jack CR Jr, Cascino GD (eds). Neuroimaging in Epilepsy: Principles and Practice. Newton, MA, Butterworth-Heinemann 86. Sperling MR, Wilson G, Engel Jj, et al: Magnetic resonance imaging in intractable partial epilepsy: Correlative studies. Ann Neurol 20:57-62, 1986 87. Surgery for epilepsy: National Institutes of Health Consensus Conference. JAMA 264:729-733, 1990 88. Sutula T, Cascino G, Cavazos F, et al: Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol 26:321-330, 1989 89. Sutula T, He XX, Cavazos J, et al: Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science 26:321-330, 1988 90. Tauck DL, Nadler JV: Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. j Neuroscience 5:1016-1102, 1985 91. Taylor DC, Falconer MA, Bruton Cj, et al: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiat 34:369-387, 1971 92. Theodore WH, Katz D, Kufta C, et al: Pathology of temporal lobe foci: Correlation with CT, MRI, and PET. Neurology 40:797-803, 1990 93. Trenerry MR, Jack CR, lvnik Rj,etal:MRI hippocampal volumes and memory function before and after temporal lobectomy. Neurology 43:1800-1805, 1993 94. Trenerry MR, Jack CR Jr, Sharbrough FW, et al: Quantitative MRI hippocampal volumes: Association with onset and duration of epilepsy, and febrile convulsions in temporal lobectomy patients. Epilepsy Res 15:247-252, 1993 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 68
  • 72. INDEX |  INTRODUCTION INTRODUCTION The epilepsies are common serious diseases of the brain, with an age adjusted prevalence of 4–8/1000 and an annual incidence of 20–50/100 000 in developed countries. Modern neuroimaging is central to the assessment of patients with epilepsy and has dramatically modified their management. Magnetic resonance imaging (MRI) can identify substrates underlying epilepsy, and guide clinicians in the determination of treatment and prognosis. The use of x ray computed tomography (CT) has been diminished by the superior www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 69
  • 73. sensitivity and specificity of MRI. The results of all imaging studies should be correlated with clinical and neurophysiological data. Epilepsies and epileptic syndromes are classified into focal and generalised. Seizures of focal origin begin in a specific cerebral area or network, most commonly in the temporal lobes. Focal epilepsies comprise 40–60% of all newly diagnosed cases. Up to 30% of these patients develop intractable epilepsy despite antiepileptic drug treatment. In patients with chronic intractable temporal lobe epilepsy (TLE) surgical treatment with removal of the epileptogenic lesion is vastly superior to medical treatment. Results in extratemporal epilepsy have been less favourable, particularly if there is not a discrete underlying structural abnormality. Therefore, visualisation of lesions that give rise to focal epilepsy and identification of patients who are suitable for surgical treatment are important goals in the imaging of epilepsy. CT SCAN IMAGING In the modern imaging of epilepsy CT is supplementary. CT is useful in acute situations when the suspected underlying cause of seizures is a neurological insult such as intracerebral haemorrhage, or abscess, and MRI is not readily available or cannot be acquired. Focal cortical calcifications can be identified with CT, and scanning may provide complementary information for the diagnosis of tuberous sclerosis and Sturge-Weber syndrome. CT is not as sensitive or specific as MRI in identifying common epileptogenic abnormalities, such as small tumours, vascular malformations, malformations of cortical development (MCD), and lesions in the medial temporal lobe. Thus, CT should not be a first line investigation for epilepsy, when MRI is the modality of choice, unless there are contraindications to MRI, such as a cardiac pacemaker or cochlear implants. MAGNETIC RESONANCE IMAGING  Indications In general, all patients who develop epilepsy or whose chronic epilepsy has not been fully assessed should be investigated with MRI. In patients with newly diagnosed epilepsy, MRI may identify an epileptogenic lesion in 12–14%, but up to 80% of the patients with recurrent seizures have structural abnormalities evident on MRI. MRI is not required in patients with a definite electroclinical diagnosis of idiopathic generalised epilepsy, or benign childhood epilepsy with centrotemporal spikes, who go into early remission. Table 1 summarises the situations in which obtaining MRI is particularly important. If access to MRI is limited, essential indications for scanning are evidence of progressive neurological deficit and intractable focal seizures. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 70
  • 74. Table 1 Indications for magnetic resonance imaging (MRI) in patients with epilepsy. Source: International League Against Epilepsy, 1997 1 Focal onset of seizures 2 Onset of generalised or unclassified seizures in the first year of life, or in adulthood 3 Focal deficit on neurological or neuropsychological examination 4 Difficulty in obtaining seizure control with first line antiepileptic drugs 5 Loss of seizure control or change in the seizure pattern  Patients with intractable epilepsy evaluated for surgery All patients with intractable epilepsy considered for surgery should undergo high resolution structural MRI as success of the operative treatment is directly related to the ability to localise precisely the region of seizure onset and underlying structural abnormalities. Since a structural abnormality does not necessarily indicate the site of seizure origin, clinical, electroencephalogram (EEG), and other data need to be correlated with imaging. MR based functional imaging methods, positron emission tomography (PET) and single photon emission computed tomography (SPECT) can provide additional information and assist in generating hypotheses for invasive EEG if structural imaging is normal or equivocal, shows diffuse abnormalities, or if there is discordance between different modalities. Postoperative MRI is useful to identify the extent of a cortical resection or the presence of residual pathology, particularly if seizures continue after surgery.  Techniques The sensitivity of MRI for detecting abnormalities depends on the pathological substrate, the MRI techniques applied, and the experience of the interpreting physician. A routine optimal MRI protocol should include T1 and T2 weighted, proton density and fluid attenuated inversion recovery (FLAIR) sequences. These contrasts need to be acquired in at least two orthogonal planes covering the whole brain, using the minimum slice thickness possible. An oblique coronal plane, orientated perpendicular to the long axis of the hippocampus, gives the best definition of medial temporal lobe structures. In general, T1 weighted images give the best definition of the anatomy and differentiate grey and white matter, while T2 weighted images provide high sensitivity for detecting pathology in the brain. A three dimensional T1 weighted volume sequence with a partition size of 1.5 mm or less should be included as these images may be reformatted in any orientation and used for post-acquisition processing such as measuring hippocampal volumes. FLAIR imaging produces heavy T2 weighting and suppresses signal from cerebrospinal fluid (CSF). This provides high lesion contrast in areas close to CSF and enables anatomical detail to be seen with greater conspicuity than with conventional T2 weighted sequences. Gadolinium does not improve the sensitivity of MRI in patients with epilepsy, but may be useful to characterise intracerebral lesions associated with breakdown of the blood–brain barrier. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 71
  • 75. Visual assessment of all images should be carried out in the knowledge of the clinical situation by a neuroimaging specialist who has expertise in the imaging of epilepsy. A systematic approach to image reporting is essential, in addition to identification of obvious lesions, as dual pathology is not uncommon. It is important to search for subtle cortical abnormalities, including focal atrophic abnormalities and dysplastic lesions without mass effect, and to evaluate the hippocampi regardless of other MR findings. Thick image slices, rotated orientation, and the presence of normal anatomical variation make visual assessment more difficult and increase the risk of misdiagnosis.  Epileptogenic substrates In developed countries hippocampal sclerosis (HS) and malformation of cortical development (MCD) are the most common identified structural causes of intractable seizures, followed by vascular malformations, tumours and post-traumatic, inflammatory or ischaemic lesions. o Hippocampal sclerosis Hippocampal sclerosis is characterised by neuronal cell loss and gliosis in CA1, CA3, and dentate hilus subfields of the hippocampus, and can be reliably identified with MRI. The hippocampus is best visualised by acquiring thin slices (1–3 mm) orthogonal to its long axis. The primary MRI features of HS are hippocampal atrophy, demonstrated with coronal T1 weighted images, and increased signal intensity within the hippocampus on T2 weighted images (fig 1). Additionally, decreased T1 weighted signal intensity and disruption of the internal structure of the hippocampus may be present. Other MRI abnormalities associated with hippocampal damage include atrophy of temporal lobe white matter and cortex, dilatation of the temporal horn, and a blurring of the grey-white border in the temporal neocortex. Atrophy of the amygdala and entorhinal cortex variably accompany hippocampal damage but may also occur in patients with TLE and normal hippocampi. FLAIR images provide an increased contrast between grey and white matter, and facilitate differentiation of the amygdala from the hippocampus. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 72
  • 76. Figure 1 Left hippocampal sclerosis (3.0 T MRI). (A) Inversion recovery prepared (IRprep) T1 weighted acquisition showing an atrophic hippocampus (on right of image: arrow). (B) T2 weighted fluid attenuated inversion recovery (FLAIR) image demonstrating increased T2 weighted signal within the sclerotic hippocampus. (C) Early echo image from dual echo data (TE 30 ms). (D) Later echo image from the same dual echo data (TE 120 ms). Hippocampal T2 relaxation times may be obtained using the data from the dual echo sequence.  Quantitative analysis of HS Visual assessment may reliably detect hippocampal volume asymmetry of more than 20%; however, lesser degrees of asymmetry require quantitative volumetric analysis. The use of contiguous thin slices increases the reliability of measurements and permits localisation of atrophy along the length of the hippocampus. It is necessary to correct hippocampal volumes for intracranial volume to identify symmetrical bilateral atrophy. Hippocampal volume reduction correlates with the severity of neuronal cell loss. Patients with unilateral hippocampal volume loss, no other imaging abnormality, and concordant clinical and EEG data have more than 70% chance of an excellent surgical outcome. Quantification of T2 relaxation time is another objective way to assess hippocampal damage. The advantage of this technique is that hippocampal T2 (HT2) times are absolute values, which can be compared against control values. Increased HT2 reflects underlying gliosis and neuronal loss. HT2 prolongation also correlates with hippocampal volume loss. Both volumetry and T2 relaxometry techniques can be applied for identifying subtle amygdala pathology. Volumetric studies of the entorhinal cortex may identify occult damage ipsilateral to the seizure focus that is not evident on visual inspection. o Malformations of cortical development www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 73
  • 77. There are a wide range of focal and generalised malformations. In focal cortical dysplasia (FCD) the key MRI findings are focal cortical thickening, simplified gyration, blurring of the cortical–white matter junction, and T2 prolongation in the underlying white matter, that often forms a cone tapering towards the lateral ventricle. Focal cortical dysplasia commonly involves the frontal lobe and, on occasion, co-exists with hippocampal sclerosis, giving rise to dual pathology. Complete surgical removal of FCD is accompanied by a high remission rate, but may be technically difficult and the epileptogenic zone may be more extensive than the abnormal area visible on MRI. Several gene mutations have been identified underlying lissencephalies resulting in characteristic MRI patterns of agyria/pachygyria. In heterotopias, collections of normal neurons are situated in abnormal locations: subependymally (fig 2), subcortically, or diffusively (band heterotopia). Band heterotopia is an example of a generalised MCD that may be present in patients with mild epilepsy and normal intellect. The abnormalities may be subtle and only be apparent if optimal MRI techniques are used. Figure 2 Subependymal heterotopia on the right (arrow) in coronal IRprep T1 weighted image (3.0 T MRI). Nodules isointense to grey matter are shown in the wall of the lateral ventricle. Polymicrogyria with excessive number of small and prominent convolutions is a frequently identified MCD that develops secondary to abnormal late migration. Several syndromes of region specific symmetric polymicrogyria have been reported, and some have been linked to specific genetic loci. Schizencephaly (cleft brain) is often found in MRI in conjunction with polymicrogyria. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 74
  • 78. o Primary brain tumours Patients with low grade primary brain tumours frequently have focal seizures as a presenting symptom. Underlying histopathologies include dysembryoplastic neuroepithelial tumours, ganglioglioma, gangliocytoma, and pilocytic and fibrillary astrocytoma. Most lesions have low signal on T1 and high signal on T2 weighted images, and are not usually associated with vasogenic oedema. Complete resection of the neoplasm and overlying cortex results in successful control of seizures in most cases. Dysembryoplastic neuroepithelial tumours are benign developmental tumours with features of a focal, circumscribed cortical mass that may indent the overlying skull (fig 3). Cyst formation and enhancement with gadolinium may occur. Calcification is present in some cases and may be more readily demonstrated with CT. Confident differentiation from low grade astrocytomas and gangliogliomas is not possible by MRI. Figure 3 Dysembryoplastic neuroepithelial tumour on the left (coronal 3.0 T MRI). (A) T2 weighted FLAIR image. (B) Dual echo late echo image (TE 120). The images show a circumscribed multicystic mass with hyperintense signal in the region of the left amygdala. o Vascular malformations Cavernous haemangiomas (cavernomas) carry a good surgical prognosis, with 70% of the patients being seizure-free after removal of the lesion. Cavernous haemangiomas are circumscribed and have the characteristic appearance of a range of blood products on MRI (fig 4). The central part contains areas of high signal on T1 and T2 weighted images, reflecting oxidised haemoglobin, with darker areas on T1 weighted images caused by www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 75
  • 79. deoxyhaemoglobin. The ring of surrounding haemosiderin appears dark on a T2 weighted image. Up to 50% of cavernous malformations are multiple, and may occur on a familial basis. Arteriovenous malformations with high blood flow have a different and distinctive appearance with a nidus, feeding arteries, and draining veins. Figure 4 Cavernoma on the left (coronal 3.0 T MRI). (A) IRprep T1 weighted image. (B) T2 weighted FLAIR image. Both acquisitions demonstrate heterogeneous hyperintense signal caused by blood products in different stages of evolution, surrounded by a rim of low signal intensity from haemosiderin. o Acquired damage Focal or diffuse cortical damage can develop as a consequence of trauma, infarction, or infection of the central nervous system. Cerebrovascular disease associated with epilepsy is particularly common in older age groups. Worldwide, neurocysticercosis (fig 5) and tuberculomas are the most common causes of intractable focal epilepsy. These lesions have typical appearances on MRI that evolve with time and which, unless calcified, may resolve. MRI has a prognostic value in identifying and characterising the lesions. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 76
  • 80. Figure 5 Cysticercosis. (A) Multiple ring enhancing lesions with surrounding oedema represent the inflammatory reactive stage of cysticercosis on this contrast enhanced T1 weighted axial image. (B) Corresponding CT scan shows calcification of these lesions. (C) In a different patient, the only MR abnormality was the punctuate signal void (arrow) in the right frontal lobe on this proton density weighted image. This was surgically proven to represent a calcified granuloma due to cysticercosis that caused chronic epilepsy.  Serial MRI studies of structural brain changes in epilepsy Longitudinal quantitative MRI studies provide a tool for the study of structural changes over time to determine the effects of epilepsy on the brain. A longstanding unanswered question in epilepsy research is whether focal or secondarily generalised seizures cause irreversible neuronal injury. Previous cross sectional MRI studies have inferred that more severe hippocampal damage is associated with a longer duration of epilepsy and a greater number of seizures. Longitudinal studies, however, are necessary to ascribe cause and effect. Changes in both hippocampal volume and T2 relaxation time have been found in serial MRI studies following prolonged early childhood convulsions. Neocortical, hippocampal, and cerebellar volume loss have been reported in follow up studies of adult patients with chronic epilepsy, implying that secondary brain damage may occur. The aims of future longitudinal studies are to identify those patients at risk of progressive damage and to develop surrogate markers of outcome for assessing the efficacy of disease modifying drugs.  Novel MRI techniques The sensitivity of MRI can be enhanced by new data acquisition and processing techniques. Image processing such as analysis of the texture, curvilinear reformatting, and three dimensional reconstruction of the neocortex may help to identify abnormal gyral patterns or subtle FCDs. Voxel based morphometry provides an automated quantitative analysis of the distribution of grey and white matter and may be applied to individuals, and to groups of patients. The technique has demonstrated neocortical grey matter abnormalities in TLE patients with hippocampal atrophy and in patients with juvenile myoclonic epilepsy. Newly developed MRI contrasts magnetisation transfer imaging, fast FLAIR T2, double inversion recovery and diffusion tensor imaging analysed with the voxel based approach are sensitive for detecting both developmental and acquired lesions in epilepsy, and identify focal abnormalities in some patients with refractory focal epilepsy and unremarkable www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 77
  • 81. conventional MRI scans. When used in combination these techniques may enable successful presurgical assessment for a greater number of patients with intractable epilepsy. Diffusion weighted imaging (DWI) can detect areas of reduced diffusivity co-localising with the electroclinical seizure focus in patients with focal status epilepticus. Postictal imaging has also demonstrated decreases in diffusion after single short seizures. The observed changes are thought to reflect cellular swelling in the areas of seizure onset and spread. Diffusion tensor imaging (DTI) is a development of DWI, which allows better delineation of the magnitude of diffusion as well as identifying the principal direction of diffusion in any voxel. DTI maps can be used to identify nerve fibre tracts through the brain and to demonstrate the structural basis of connectivity between brain regions. In patients being considered for surgery, tractography can be used to map the optic radiation and the connections of eloquent areas in vivo, in order to minimise the risk of causing a deficit. Continuous arterial spin labelling perfusion MRI assesses cerebral blood flow and can detect asymmetries in interictal mesial temporal lobe perfusion in patients with TLE. The technique is potentially a further useful non-invasive tool for investigation of both interictal and ictal states. If a patient is restless and can only tolerate short studies the new ultra fast, low angle rapid acquisition and relaxation enhancement may be a useful sequence. Improved gradient performance is anticipated to improve speed and spatial resolution. Phased array surface coils improve signal-to-noise ratio in superficial cortex and hippocampal regions and this also leads to improved spatial resolution. Imaging at high field strengths may also improve spatial resolution and 3T MRI scanners are now available as clinical instruments.  Functional magnetic resonance imaging Functional MRI (fMRI) offers a tool for visualising regional brain activity. The areas detected with changes in blood oxygenation level dependent (BOLD) contrast reflect local changes in the ratio of deoxy- and oxyhemoglobin that occur during cognitive, sensory, and other tasks and allow the mapping of neural networks involved in the performance of these tasks. The most important clinical application of fMRI is in the localisation and lateralisation of cognitive functions of epilepsy patients evaluated for surgery in order to minimise the risk of causing a fixed deficit. Non-invasive fMRI has excellent spatial resolution and can be repeated as often as indicated. However, the studies require patient cooperation, both in performing tasks and limiting motion. For preoperative fMRI, it is important to choose activation procedures that are appropriate tests of function in the area of brain to be resected. o Language Functional MRI provides a reliable way to lateralise language dominance. There may be considerable plasticity of language representation in the brains of epilepsy patients. Functional MRI has indicated that a high proportion (33%) of intractable left TLE patients have bilateral or right hemispheric language related lateralisation. When used for www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 78
  • 82. the purpose of lateralisation of language, fMRI eliminates the need for invasive intracarotid amobarbital test (IAT) in 80% or more of patients. Overt disagreement between the IAT and fMRI is uncommon, although some discrepancy should be expected because of fundamental differences in the nature of the methods. A series of related tests, such as verbal fluency and language comprehension, should be performed for functional language mapping. Functional MRI reading tasks can identify language dominance in frontal and temporal areas. While current paradigms may indicate cerebral areas involved in receptive and expressive language functions, these data cannot at present be used to reliably guide surgical excision to minimise risk to language function. It cannot be assumed that all activated areas are crucial for language functions, or that areas that do not activate are not functionally important. o Memory In addition to language, the assessment of memory functions dependent on the hippocampus is critical for planning anterior temporal resection. Functional MRI imaging of memory encoding and retrieval paradigms demonstrate that a wide range of stimuli can cause activation in mesial temporal structures. In normal individuals a verbal memory encoding task involves activation of the left hippocampus, whereas in patients with left hippocampal sclerosis the task is associated with reorganisation of activation to right hippocampus and parahippocampal gyrus. It is likely that fMRI with memory paradigms will be incorporated into the presurgical assessment in the coming years to minimise the adverse cognitive sequelae of anterior temporal lobe resection, and will result in less use of the IAT. o Sensory and motor Sensory and motor tasks are the most reliable and reproducible of fMRI paradigms. They may be used to identify sensorimotor cortex when planning frontal or parietal neocortical resections. o Seizure foci Ictal fMRI recordings are very difficult to obtain and are usually confounded by movement, but fMRI can be used to localise interictal epileptic activity. Technical developments enable simultaneous acquisition of EEG and fMRI data, and recent EEG- fMRI studies have shown reproducible BOLD activations concordant with EEG focus. Interictally spike related activation has been demonstrated in the perisylvian central region in benign childhood epilepsy with centro-temporal spikes. Further, bilateral activation of thalami and widespread cortical deactivation with a frontal maximum can be found in patients with idiopathic generalised epilepsy. Reflex epilepsies with induced seizure activity provide opportunities to image generators of interictal activity and the propagation of ictal activity. EEG-fMRI may aid EEG interpretation and understanding of the pathophysiological basis of epileptic activity. However, the approach must be evaluated and validated before being used clinically. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 79
  • 83.  Magnetic resonance spectroscopy Magnetic resonance spectroscopy (MRS) provides measurements of specific brain metabolites. Spectra are most commonly acquired from nuclei 1H and 31P using either single voxels or chemical shift imaging. Metabolites that are detectable with 1H MRS include N-acetylaspartate (NAA), choline, creatine, lactate, -aminobutyric acid (GABA), and glutamate. Compared to 31P MRS measuring phosphorus containing compounds, 1H MRS has greater signal-to-noise ratio and better spatial resolution, and it is also more easily carried out with MRI in a single examination. There is evidence that NAA is located primarily within neurons and precursor cells. Creatine and choline are found in both neurons and glia. Accurate definition of brain anatomy and the identification of structural abnormalities with MRI are necessary for the interpretation of MRS. o Temporal lobe epilepsy 1H MRS lateralises the seizure focus in up to 80–90% of the TLE patients. Patients with hippocampal sclerosis show a decrease in NAA and increases in choline, creatine, and myo- inositol signals ipsilaterally. Low hippocampal NAA together with elevated glutamate + glutamine values have also been reported in patients with normal MRI. Twenty to fifty five per cent of patients with unilateral TLE have bilateral temporal abnormalities in 1H MRS. Low NAA values have also been found in extratemporal neocortex in TLE. These widespread changes suggest that MRS abnormalities reflect cellular dysfunction—not merely neuronal loss or gliosis. The role of 1H MRS in predicting outcome of temporal lobe epilepsy surgery is not clear. Bilateral metabolic changes have been associated with poor outcome in TLE, especially if the preoperative contralateral abnormality is greater than the ipsilateral one. Metabolic abnormalities detected in 1H MRS may be transient and normalisation of the contralateral NAA can occur postoperatively in seizure-free patients. o Extratemporal epilepsy Frontal lobe epilepsy is associated with altered metabolic spectra with reduced NAA/creatine or NAA/choline ratios ipsilateral to the seizure focus. Thus 1H MRS may help to lateralise a frontal focus in MRI negative patients. Bilateral abnormalities may be detected in FLE patients with unilateral focal EEG findings, and the clinical significance of this is less clear. It has been demonstrated that different types of MCDs show different degrees of decrease of NAA. 1H MRS may also reveal metabolic abnormalities in the areas extending at a distance from the lesion and not evident on MRI. It is not certain whether this reflects more widespread pathology that is not evident on MRI, or is a functional consequence to an epileptic focus. Decreasing NAA has been correlated with increasing seizure frequency in FLE, suggesting that seizures are associated with neuronal dysfunction or loss. o Generalised epilepsies www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 80
  • 84. 1H MRS studies in patients with idiopathic generalised epilepsy have provided evidence of thalamic dysfunction. A negative correlation has been found between NAA/creatine and the duration of epilepsy, and a relation between frequent generalised tonic-clonic seizures and low thalamic NAA concentrations. 1H MRS also shows reduced frontal lobe concentrations of NAA in patients with juvenile myoclonic epilepsy. o Postictal MRS Increased lactate and inorganic phosphate and decreased intracellular pH and phosphomonoesters have been detected peri- and postictally at the side of seizure focus. Elevation of lactate may last for a few hours after complex partial seizures and could therefore constitute a marker for the ictal zone. Lactate and choline increase and NAA decreases focally during prolonged non-convulsive seizures. o MRS studies of neurotransmitters Low concentrations of GABA, the principal inhibitory neurotransmitter of brain, and homocarnosine have been detected using 1H MRS in the occipital lobes of patients with frequent complex partial seizures. Higher concentrations of homocarnosine are associated with better seizure control in both patients with complex partial seizures and with juvenile myoclonic epilepsy. Numerous studies have reported an elevation of brain GABA concentrations after administration of vigabatrin, gabapentin, and topiramate. Changes in glutamate, the main excitatory neurotransmitter of the cortex, play an important role in the control of cortical excitability. Hippocampal specimens obtained at temporal lobectomy show increased intracellular glutamate content using 1H MRS. Increases in glutamate and glutamine concentrations have also been measured after focal motor status epilepticus. In summary, 1H MRS may assist for lateralisation of the epileptic focus in TLE. The zone of altered metabolism extends beyond the structural and electrographic abnormalities, and may allow detection of pathologies in patients with normal MRI. Measurements of cerebral neurotransmitters, particularly GABA, glutamate, and glutamine, provide important information on the mechanisms related to epilepsy, as well as modes of action of antiepileptic drugs. Rapid developments in MR technology will improve spectral resolution and facilitate the investigation of metabolic dysfunction in epilepsy.  Single photon emission computed tomography Single photon emission computed tomography (SPECT) is a nuclear medicine imaging method that allows measurements of regional cerebral blood flow changes in the areas affected by epileptic activity. Radioligands principally used in SPECT studies are 99mTc- hexamethyl-propylenamine oxime (99mTc-HMPAO) and technetium-99mTc-cysteinate dimer (ECD, bicisate). Currently available stabilised forms of 99mTc-HMPAO and ECD are stable in vitro for several hours, whereas unstabilised 99mTc-HMPAO needs to be reconstructed immediately before intravenous injection. Seventy five per cent of 99mTc- www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 81
  • 85. HMPAO is extracted across the blood–brain barrier, reaching peak concentrations within one minute after injection. The images can then be acquired up to six hours after tracer injection. Both ictal and postictal SPECT studies should be performed during simultaneous video-EEG monitoring to determine the relation between seizure onset and tracer injection. Interictal SPECT images serve as a reference baseline study for the interpretation of ictal images. o Temporal lobe epilepsy  Ictal Ictal 99mTc-HMPAO SPECT is highly sensitive and specific in localising seizure onset in intractable TLE. Correct localisation of complex partial seizures may be achieved in over 90% of TLE patients. The use of subtraction ictal SPECT co-registered to MRI (SISCOM) improves the rate of localisation, and is particularly useful in patients with MCDs, or if there is no apparent lesion in the MRI. A characteristic pattern observed in temporal lobe seizures is an initial hyperperfusion of the temporal lobe, followed by medial temporal hyperperfusion and lateral temporal hypoperfusion. Analysis of ictal SPECT data with statistical parametric mapping (SPM) has shown more widespread activations in the cortico–thalamo–hippocampal–insular network of TLE. Hypoperfusion observed in the anterior frontal cortex may reflect ictal inhibition or deactivation. Postictal SPECT injections are easier to perform than ictal injections, but the images are more difficult to interpret and have lower sensitivity and specificity. Temporal lobe seizures are correctly localised in 70% of the patients with postictal SPECT. The problem of seizure propagation and non-localisation caused by an early switch from ictal hyperperfusion to postictal hypoperfusion may be helped by setting up self injection or automated injection systems to facilitate early ictal injections. o Interictal TLE patients show circumscribed hypoperfusion in interictal SPECT performed with 99mTc-HMPAO or with other cerebral blood flow ligands. The method is only moderately sensitive in localising a temporal lobe seizure focus (40–50% correct localisation), has a relatively high false positive rate, and in consequence is not clinically useful as a stand alone test. o Extratemporal epilepsy o Ictal Extratemporal seizures are often brief and it is therefore difficult to obtain an ictal recording. If true ictal 99mTc-HMPAO SPECT is obtained, accurate localisation of an extratemporal seizure focus may be possible in 90% of the cases using the SISCOM technique. Ictal SPECT demonstrates ipsilateral frontal hyperperfusion in FLE. Activations may also be detected in the ipsilateral basal ganglia and contralateral cerebellum. The method provides additional information in patients with unrevealing EEG www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 82
  • 86. and MRI results, and can also be used to study the blood flow changes underlying specific clinical features observed in extratemporal seizures. Postictal injections in extratemporal epilepsy are of limited localising value. Compared to the ictal studies the yield of postictal SPECT studies is much lower (correct localisation in 46%), and usually only very early postictal studies are diagnostic. Interictal SPECT is an insensitive method for localising extratemporal foci. In conclusion, ictal SPECT provides a complementary method for localisation of the seizure focus in patients with intractable focal epilepsy evaluated for surgical treatment. The investigation may be particularly valuable in patients with normal MRI and presumed extratemporal seizures in order to generate a hypothesis that may then be tested with intracranial EEG recordings.  Positron emission tomography o 18F-deoxyglucose (FDG) and 15O-water (H215O) Positron emission tomography (PET) maps cerebral glucose metabolism using 18F- deoxyglucose (18FDG) and cerebral blood flow using 15O-labelled water. Interictally PET shows areas of reduced glucose metabolism and blood flow that usually include the seizure focus but are more extensive. Regional hypometabolism is best analysed with co- registration of PET scans to MR images. Voxel based SPM has been shown to be useful in clinical evaluation of the data, and quantitative analysis with correction for partial volume effects further improves the accuracy of the method. The spatial resolution of quantitative 18FDG-PET is superior to SPECT or MRS. Ictal 18FDG-PET scans are difficult to obtain because cerebral uptake of 18FDG occurs over 40 minutes after injection. Ictal 15O-H2O is problematic, because of the short half life of 15O and unpredictable timing of seizure onsets.  Temporal lobe epilepsy 18FDG-PET detects interictal glucose hypometabolism ipsilateral to the seizure focus in 60–90% of TLE patients. Unilateral or asymmetric bilateral diffuse regional hypometabolism usually extends mesiolaterally in the temporal lobe. Some patients also have changes in extratemporal cortical areas or in the basal ganglia or thalamus. 18FDG- PET has some additional sensitivity over optimal, volumetric MRI but does not provide clinically useful information if hippocampal atrophy is present. 15O-H2O studies generally show hypoperfusion in the same areas as glucose hypometabolism, but are less sensitive and associated with more frequent false lateralisation. 18FDG-PET is more useful for lateralising than localising the epileptic focus. The sensitivity of the method differs according to the nature of underlying lesion, if any. Patients with hippocampal sclerosis have low glucose metabolism in the whole temporal lobe, while patients with mesiobasal temporal tumours show only a slight decrease in metabolism. Similar or elevated metabolic activity, compared to normal grey matter, has been detected in MCDs such as heterotopia. The metabolic pattern may be different in www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 83
  • 87. patients with mesial or lateral temporal seizure onset, but no clear correlation has been found between the degree of hypometabolism and the location of the epileptic focus. Hippocampal sclerosis with neuronal cell loss and gliosis is the primary underlying cause of glucose hypometabolism in mesial TLE. Reduced glucose consumption has also been described in patients with mild or no hippocampal damage, suggesting that neurons are functioning with decreased synaptic activity. There have been few studies of newly diagnosed patients with TLE. In children with new onset temporal lobe seizures, hypometabolism is found in only 24% of the cases, whereas 80–85% of adults with intractable TLE have low glucose utilisation in the temporal lobe. Unilateral focal temporal hypometabolism in 18FDG-PET predicts a good outcome of surgery for TLE. However, absence of reduced metabolism unilaterally does not preclude a favourable outcome. Symmetric, bilateral temporal hypometabolism is associated with higher incidence of postoperative seizures as are areas of severe extratemporal cortical, or thalamic hypometabolism. Postoperative increases have been found in inferior frontal and thalamic metabolism indicating that seizures may have a reversible effect on brain areas connected with the epileptic focus.  Extratemporal epilepsy 18FDG-PET has lower sensitivity for lateralisation of epileptic foci in extratemporal epilepsies than in TLE. The areas of decreased glucose metabolism are also less frequently well localised. Sixty per cent of patients with FLE show regional hypometabolism with 18FDG-PET, and a relevant underlying structural pathology is found on MRI in 90% of them. The area of hypometabolism may be either diffuse or widespread, or restricted to the co-localising MRI lesion. Statistical parametric mapping improves the diagnostic yield of 18FDG-PET, and assists the planning of implantation of intracranial electrodes in some intractable FLE patients with non-localising MRI or scalp EEG. In the majority of patients with FLE, however, 18FDG-PET does not appear to provide additional clinically useful information. In summary, the place of interictal 18FDG-PET is in determining the lateralisation of epileptic focus, especially in the presurgical assessment of patients where there is not good concordance between MRI, EEG, and other data, in order to generate a hypothesis to be tested with intracranial EEG recordings. Developments in MRI have reduced the need of 18FDG-PET for localisation of an epileptic focus.  PET studies of specific ligands PET may be used to demonstrate the binding of specific ligands—for example, 11C- flumazenil (FMZ) to the central benzodiazepine-GABAA receptor complex (cBZR), 11C- diprenorphine and 11C-carfentanil to opiate receptors, and 11C-deprenyl to MAO-B. The technique is costly and scarce, but gives quantitative data with superior spatial resolution to SPECT. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 84
  • 88. o GABAA–benzodiazepine receptors: flumazenil 11C-flumazenil (FMZ) is a useful marker of the GABAA–central benzodiazepine receptor (cBZR) complex.  Temporal lobe epilepsy 11C-FMZ-PET detects abnormalities in 11C-FMZ binding in over 90% of intractable TLE patients evaluated for surgery. The area of decreased 11C-FMZ binding is often smaller than that of glucose hypometabolism. In clinical terms, 11C-FMZ PET may be superior to 18FDG PET for the localisation of epileptic focus but does not provide additional useful information in the presurgical evaluation of patients with clear cut MRI findings of hippocampal sclerosis. 11C-FMZ PET also detects abnormalities in the medial temporal lobe of TLE patients with normal MRI. Potentially surgically useful reductions in hippocampal or extrahippocampal 11C-FMZ binding have been found in 47% of MRI negative TLE patients. o Extratemporal epilepsy Studies of extratemporal epilepsy patients including those with normal MRI have indicated that surgically useful abnormalities of 11C-FMZ binding can be found in half of the cases. In addition to decreased 11C-FMZ binding, focal increases have been reported in MRI negative patients possibly indicating an occult developmental lesion. In patients with MCD 11C-FMZ abnormalities frequently extend beyond the visible MRI lesion which could explain why surgical treatment of MCD is less successful than treatment of discrete lesions. o Other PET tracers The opioid system can be investigated with 11C-carfentanil, 11C-methylnaltrindole, and 11C-diprenorphine and the serotonin system with -[11C]methyl-L-tryptophan ([11C]AMT). These PET tracers provide interesting research data, but are not currently applied in clinical practice. In summary, PET offers a tool for investigating neurochemical abnormalities associated with epilepsies. The method is an important research tool and can be useful in selected clinical situations, especially when there is not good concordance between MRI, EEG, and other data. Further ligands, particularly tracers for excitatory amino acid receptors, subtypes of the opioid receptors and the GABAB receptor, will improve the characterisation of different epileptic syndromes. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 85
  • 89. REFERENCES 1. International League Against Epilepsy. Recommendations for neuroimaging of patients with epilepsy. Commission on neuroimaging of the International League Against Epilepsy. Epilepsia 1997;38:1255–6. 2. Systematic general guidelines for the structural imaging of patients with newly diagnosed epilepsy and those with chronic epilepsy who have not been fully evaluated 3. International League Against Epilepsy. Guidelines for neuroimaging evaluation of patients with uncontrolled epilepsy considered for surgery. Commission on neuroimaging of the International League Against Epilepsy. Epilepsia 1998;39:1375–6. 4. Structural imaging guidelines for patients with intractable epilepsy who are being evaluated for surgery. A useful supplement to the "Recommendations for neuroimaging of patients with epilepsy" 5. International League Against Epilepsy. Commission on diagnostic strategies. Recommendations for functional neuroimaging of persons with epilepsy. Neuroimaging subcommission of the International League Against Epilepsy. Epilepsia 2000;41:1350–6. 6. Evaluation of the roles of traditional functional imaging techniques and the emerging MR based functional imaging methods both in clinical practice and research 7. Detre JA. fMRI: applications in epilepsy. Epilepsia 2004;45:26–31. 8. A review of the physiological basis for functional MRI and its applications to epilepsy. 9. Duncan JS. Imaging and epilepsy. Brain 1997;120:339–77. 10. A comprehensive review of the structural and functional imaging methods in the investigation and management of epilepsy. 11. Hammen T, Stefan H, Eberhardt KE, et al. Clinical applications of 1H-MR spectroscopy in the evaluation of epilepsies—what do pathological spectra stand for with regard to current results and what answers do they give to common clinical questions concerning the treatment of epilepsies? Acta Neurol Scand 2003;108:223– 38. 12. An overview of the principles and clinical applications of 1H-MRS with special regard to the temporal lobe epilepsies. 13. Hammers A. Flumazenil positron emission tomography and other ligands for functional imaging. Neuroimag Clin N Am 2004;14:537–51. 14. This review focuses on the use of flumazenil PET and other ligands in focal and idiopathic generalised epilepsies. 15. Henry TR, Van Heertum RL. Positron emission tomography and single photon emission computed tomography in epilepsy care. Semin Nucl Med 2003;33:88–104. 16. Emission tomographic imaging methodology, findings in clinical epilepsy studies and in the presurgical evaluation are discussed in detail in this overview. 17. Koepp MJ, Duncan JS. Epilepsy. Curr Opin Neurol 2003;17:467–74. 18. An interesting review of the recent findings and potential role of neuroimaging from an epilepsy perspective. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 86
  • 90. 19. Rugg-Gunn FJ, Symms MR. Novel MR contrasts to reveal more about the brain. Neuroimag Clin N Am 2004;14:449–70. 20. This article describes novel MR contrasts which have the potential to identify some of the discrete focal abnormalities not detected on current conventional optimal MR imaging. 21. Vattipally VR, Bronen RA. MR imaging of epilepsy: strategies for successful interpretation. Neuroimag Clin N Am 2004;14:373–400. 22. A useful introduction and overview for MR imaging of epilepsy. This review also discusses strategies for successful interpretation of MR images from the seizure patient and differential diagnosis to avoid potential pitfalls. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 87
  • 91. INDEX |  INTRODUCTION INTRODUCTION Peri- and postictal changes on both anatomic and functional imaging examinations have been recognized for many years. With the wide availability of magnetic resonance imaging and positron emission tomography, a growing range of recognized acute imaging findings have been described. peri-ictal and postictal findings can be classified as either local or remote, with respect to the site of maximal ictal EEG abnormality. Although many of the findings described are reversible, the factors that determine whether findings will resolve www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 88
  • 92. are incompletely understood. This article considers the range of findings that have been described, places them into the context of known or hypothesized pathophysiologic mechanisms, and considers their clinical significance. A framework is proposed for considering the relation between ictal duration and severity, the characteristics of imaging abnormalities, and the mechanism of their underlying pathophysiology. Peri-ictal changes on anatomic and functional imaging studies have been recognized by clinicians since the early days of the computed tomography (CT) scan era (1). Patients with focal seizures were occasionally found to have effacement of gyral markings and diffuse patchy contrast enhancement on CT, usually colocalized with the presumed source of the ictal activity, and sometimes associated with apparent Todd's paralysis. These findings, which were sometimes mistakenly interpreted as evidence of an underlying brain tumor, typically resolved over hours or days, often to the embarrassment of the admitting physician. With the advent of [18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) scanning, occasional studies demonstrated hypermetabolism of glucose in patients who had fortuitous focal seizures during the period of tracer uptake (Figure 1A). In some patients, repeated studies obtained during interictal periods demonstrated local hypometabolism reflecting the disordered function of neuronal networks in the region of the epileptic focus. With the widespread availability of magnetic resonance imaging (MRI), sometimes in emergency department settings, a growing range of peri-ictal imaging findings have been described. In this article, I outline an approach to classifying these findings, and I consider their clinical significance and potential pathophysiologic basis. For this discussion, we consider findings on imaging studies that arise during or immediately after seizures, and we refer to this period as "peri-ictal." CLASSIFICATION OF PERI-ICTAL IMAGING FINDINGS Peri-ictal imaging changes may occur in the region of the epileptic discharge (local) or in distant structures (remote). Some of the findings that have been described are listed in Table 1. Each of these findings may be reversible or irreversible. Table 1. Classification of Peri-ictal imaging abnormalities www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 89
  • 93.  Remote peri-ictal findings The pathophysiologic basis of lesions that occur remote from the site of ictal activity is not understood. Presumably ipsilateral diencephalic and contralateral cerebellar lesions arise as a consequence of abnormal activity in those structures, driven by the epileptic activity. Crossed cerebellar diaschisis, observed in ischemia, may be a striking finding in status epilepticus (Figure 2). Transient lesions of the splenium (Figure 3) also may reflect abnormal activity in white matter tracts driven by the epileptic focus, but neither the mechanism nor the precise nature of the white matter change responsible for the increased T2 signal and restricted diffusion in the splenium is understood. One study suggested that corpus callosum lesions were due to anticonvulsant drug (AED) toxicity (3), but this seems unlikely, given the large number of patients taking AEDs who undergo MRI. Moreover, several cases have been reported in patients off AEDs who had flurries of seizures (4,5). Polster et al. (6) suggested that drug withdrawal might underlie this phenomenon, but their argument rested on the notion that the splenium lesion was vasogenic edema. Our finding that the lesion demonstrates a decreased apparent diffusion coefficient (ADC) is not consistent with their hypothesis, and rather supports the idea that in most cases, the lesion is likely to be related to the ictal activity per se (4). Figure 1. Ictal [18 F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) and [99 Tc]hexamethyl-propyleneamine-oxime (HMPAO)-single- photon emission computed tomography (SPECT) images. A: 18 FDG-PET image obtained from a 4-month-old infant subsequently found to have a focal cortical dysplasia in the region defined by glucose hypermetabolism. B: 99 Tc- HMPAO-SPECT image from a 24-year-old woman with partial epilepsy of previously uncertain origin. Tracer was injected 10 s after initial behavioral www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 90
  • 94. change. Scalp EEG recordings were completely obscured by muscle and movement artifact. Microvacuolization of the myelin is one pathologic substrate that could account for both the increased T2 signal, the decreased ADC, and the reversibility of the lesion that has been suggested. Interestingly, several patients with splenial lesions, all of which have been reversible, have had bitemporal independent epileptic foci and associated psychiatric disease. It is tempting to speculate that acute dysfunction of interhemispheric connections may contribute to the pathophysiology of postictal psychiatric disturbances. Careful examination of patients with postictal psychosis may clarify this point. The syndrome of posterior reversible leukoencephalopathy (RPLE), described in patients with hypertension, eclampsia, and sometimes in association with certain immunosupresssive drugs, is frequently associated with repeated seizures (7,8). Some patients with seizures, but without another obvious cause for posterior reversible leukoencephalopathy (RPLE), have been described, suggesting that seizures per se may contribute to the occurrence of this finding. This syndrome points out the difficulty of determining cause and effect with respect to seizures and imaging abnormalities, an exercise that should be undertaken with great caution. Figure 2. Crossed cerebellar diaschisis. Images obtained from a 38-year-old patient with recurrent right hemispheric seizures. Upper panels: Abnormal signal on fluid-attenuated inversion recovery images in the ipsilateral cortical ribbon and in the contralateral cerebellar hemisphere. Lower panels: Reduced diffusion on diffusion-weighted images in corresponding regions. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 91
  • 95. Figure 3. Transient diffusion-weighted imaging changes in the splenium after seizures. Representative images from two patients (upper and lower panels) demonstrate restricted diffusion (left) with associated decreased apparent diffusion coefficients (center) that resolved in 4-6 weeks (right).  Local peri-ictal findings It is, perhaps, conceptually easier to consider the pathophysiologic basis of local Peri-ictal imaging findings. These, which include T2 , ADC, and vascular changes are seemingly related to increased neuronal activity and its associated metabolic and vascular responses. Local swelling of hippocampus has been described in children with prolonged febrile convulsions (9), and effacement of gyri in the region of epileptic discharge may be seen in all age groups (10). Increased T2 signal intensity, indicating an increase in brain water, occurs in areas of cortex and subcortical white matter in association with some prolonged or intense seizures (11). Many of these lesions show restricted diffusion [bright on diffusion-weighted imaging (DWI), dark on ADC maps], supporting the idea that they represent cytotoxic rather than vasogenic edema; however, these lesions are reversible, at least initially, indicating that cell death is not an inevitable sequela (Figure 4). A particularly interesting finding is the occasional occurrence of migratory T2 and DWI lesions. In some case, evanescent lesions arising in widely separated areas of cortex, persisting for days to weeks, and then resolving are witnessed (Figure 5). By using coregistration of 18 FDGPET and MRI, lesions inevitably colocalized with regions of focal hypermetabolism are demonstrated (Figure 6), and these in turn corresponded to areas of maximal EEG abnormality. In this situation, it seems most likely that the lesions are the consequence of the epileptic activity, and not its cause. Magnetic resonance angiography www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 92
  • 96. studies in patients in status epilepticus may demonstrate increased flow-related enhancement, and this finding corresponds well to the observation of arterialization of venous blood reported by surgeons examining the cortex during provoked or spontaneous epileptic seizures (Figure 7). Simultaneous SPECT studies in this circumstance may not demonstrate evidence of increased perfusion at the microvascular level, suggesting that some portion of the local increased bloodflow represents arteriovenous shunting. Figure 4. Resolution of increased T2 signal associated with focal status epilepticus after 7 days of pentobarbital (PTB) anesthesia. Patient was a 12-year-old girl seen 14 days before left scan, with epilepsia patialis continua arising from the right hemisphere. After 7 days of PTB anesthesia titrated to produce burst-suppression on continuous EEG monitoring, T2 signal changes largely resolved (right). Images were obtained by using a fluid-attenuated inversion recovery protocol. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 93
  • 97. Figure 5. Migratory Peri-ictal imaging changes. Fluid-attenuated inversion recovery images obtained at multiple levels at time of presentation (A), on day 14 (B), on day 28 (C), and on day 35 (D) from a 28- year-old woman with recurrent partial seizures associated with a mtochondrial disease.  Relation between T2 and ADC findings Diffusivity is an intrinsic property of tissue, and the ADC is independent of both T1 and T2 relaxation times. T2 relaxation time is largely reflective of local brain water content. Whereas increased T2 signal suggests edema or gliosis, restricted diffusion is usually associated with metabolic dysfunction or energy deficiency. Some of the hypothesized causes of restricted diffusion are listed in Table 2. Restricted diffusion has commonly been www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 94
  • 98. identified as a marker of irreversible ischemic injury, but recent studies suggest that in some situations, decreased diffusion associated with seizures is reversible without the subsequent appearance of tissue injury (12). The temporal relation between the appearance of restricted diffusion and T2 signal change in association with seizures may be variable. Whereas in acute ischemia, DWI images reveal restricted diffusion before any abnormality of T2 signal becomes apparent, in ongoing status epilepticus, DWI and T2 signal changes appear to occur roughly synchronously. These differences in the timing of DWI and T2 signal change suggests a difference in the underlying pathophysiology. Whereas in ischemia, early energy failure occurs, in ongoing status, activity-induced injury with cytotoxic edema may precede overt energy deficiency. Table 2. Causes of restricted diffusion Figure 6. Multimodal imaging with magnetic resonance imaging and positron emission tomography (PET). Top: [18 F]fluorodeoxyglu- cose-PET images from patient described in Figure 5, obtained on day 25, showing multiple focal areas of hypermetabolism. Middle: Fluid-attenuated inversion recovery (FLAIR) images obtained on day 28. Bottom: Coregistration showing colocalization of areas of hypermetabolism and areas with FLAIR abnormalities. EEG recording (not shown) demonstrated a similar localization of ictal activity involving right frontal pole and left central region. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 95
  • 99. Figure 7. Cortical hyperemia associated with increased flow-related enhancement in a patient in focal status epilepticus. Magnetic resonance angiogram showing dilatation of the right middle cerebral artery (MCA) branches presumably reflecting increased blood flow to the active cortex (A). Intraoperative photograph showing right motor strip exposed beneath the dura (B). Variability in occurrence of Peri-ictal imaging changes An important and unresolved issue is why local acute Peri-ictal changes on MRI occur in some but not all patients after focal seizures. The fact that such changes are sometimes first apparent days or weeks after the start of focal status (13, for example) suggests that a threshold of seizure duration and/or severity exists, below which changes will not occur. Current knowledge does not allow us to predict with any degree of certainty where that threshold might lie, but in Figure 8, I have drawn a conceptual diagram that attempts to relate imaging changes to perfusion and energy demand. An important concept illustrated in the figure by the divergence between the dotted and solid lines is that at some point, imaging changes become irreversible. It is important that, as with most threshold phenomena in biology, it is likely that differences between individuals exist in both when imaging findings will become apparent and when they will become irreversible. Some critical variables that might determine whether seizures in a specific individual are sufficient to trigger acute imaging changes are listed in Table 3. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 96
  • 100. Table 3. Critical variables that may determine occurrence or severity of local Peri-ictal imaging changes CONCLUSIONS Although there is increased recognition of acute Peri-ictal imaging changes in the clinical community, most reports are anecdotal, and few if any series exist. Interpretation of these findings therefore remains highly speculative. Nonetheless, the variety of findings that have been described and the occurrence of changes both locally and remotely with respect to the ictal zone suggest a number of intriguing hypotheses and raise a variety of clinically relevant questions. Figure 8. Conceptual cartoon illustrating a possible relation between energy supply, energy demand, and observed Peri-ictal imaging changes. Red hatch marks, potential irreversibility due to energy deficit.Dotted blue lines, potential reversibility of diffusion- weighted imaging abnormalities before onset of unrecoverable energy deficit. A-C: Early, middle, and later stages of seizure severity/duration at which snapshot imaging findings might be predicted from the diagram. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 97
  • 101. Figure 9. At the admission, serial MRI scans were performed in a patient with status epilepticus. After repeated episodes of status epilepticus, diffusion-weighted images and T2- weighted images FLAIR exhibited abnormal hyperintense signals in bilateral temporal and insular cortices. These abnormalities appeared more extensive on diffusion-weighted images than on T2-weighted images FLAIR. The hippocampi appeared abnormal and also presented bilateral abnormal hyperintense signals, without atrophy, more extensive on the left hippocampus. There was no disruption of blood-brain barrier (BBB) on T1-weighted images after intravenous administration of Gd-DTPA. Two weeks, there were no signal abnormalities on diffusion-weighted images and T2-weighted images FLAIR. However, enlargement of the subarachnoid space just near the left temporal lobe and enlargement of the temporal horn of the right lateral ventricle were evident, indicating localized brain atrophy (hippocampal atrophy) www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 98
  • 102. Figure 10. Axial FLAIR image demonstrating focal hyperintensity involving the right mesial occipital cortex and underlying white matter associated with status epilepticus (arrow). (B) Axial FLAIR image taken 3 months later, demonstrating complete resolution of the previously seen abnormality. One hypothesis that can be tested in a prospective fashion is that the evolution of imaging changes, including the appearance of ADC decrease, T2 increase, changes in flow-related enhancement, and occurrence of irreversibility correlate with the evolution of electrophysiologic findings in status epilepticus and with the occurrence of irreversible neurologic deficits. Another important hypothesis is that the occurrence of specific imaging changes, particularly increased T2 and decreased ADC in the splenium of the corpus callosum, is associated with the development of postictal psychiatric or behavioral changes. This hypothesis could be addressed prospectively by systematically imaging patients who manifest postictal psychosis by using appropriate pulse sequences, and by examining them serially as psychiatric symptoms resolve either spontaneously or with treatment. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 99
  • 103. Many exciting questions emerge from this review. For example:  Which imaging findings are cause, which are consequence?  Are there critical characteristics of seizures or thresholds that determine appearance of Peri-ictal changes?  What is the relation between T2 and ADC changes?  What is the significance of distant imaging changes?  Can we use Peri-ictal imaging to detect localizing anatomic changes more reliably? It is not possible to address these questions effectively by using studies that are typically obtained fortuitously. Rather, it will require a more systematic approach to gathering postictal data prospectively in series of patients with specific epilepsy syndromes. Given the likely insights that imaging data can provide into pathophysiology and prognosis, it seems worthwhile to invest significant resources in such an undertaking. References 1. Goulatia RK, Verma A, Mishra NK, et al. Disappearing CT lesions in epilepsy. Epilepsia 1987;28:523-7. 2. Rowe CC, Berkovic SF, Austin MC, et al. Visual and quantitative analysis of interictal SPECT with technetium-99m-HMPAO in temporal lobe epilepsy. J Nucl Med 1991;32:1688-94. 3. Kim SS, Chang KH, Kim ST, et al. Focal lesion in the splenium of the corpus callosum in epileptic patients: antiepileptic drug toxicity? AJNR Am J Neuroradiol 1999;20:125-9. 4. Oster J, Doherty C, Grant PE, et al. Diffusion-weighted imaging abnormalities in the splenium after seizures. Epilepsia 2003;44:852- 4. 5. Mirsattari SM, Lee DH, Jones MW, et al. Transient lesion in the splenium of the corpus callosum in an epileptic patient. Neurology 2003;60:1838-41. 6. Polster T, Hoppe M, Ebner A. Transient lesion in the splenium of the corpus callosum: three further cases in epileptic patients and a pathophysiological hypothesis. J Neurol Neurosurg Psychiatry 2001;70:459-63. 7. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494- 500. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 100
  • 104. 8. Covarrubias DJ, Luetmer PH, Campeau NG. Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion- weighted MR images. AJNR Am J Neuroradiol 2002;23:1038-48. 9. VanLandingham KE, Heinz ER, Cavazos JE, et al. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions. Ann Neurol 1998;43:413-26. 10. Silverstein AM, Alexander JA. Acute postictal cerebral imaging. AJNR Am J Neuroradiol 1998;19:1485-8. 11. Lansberg MG, O'Brien MW, Norbash AM, et al. MRI abnormalities associated with partial status epilepticus. Neurology 1999;52: 1021-7. 12. Grant PE, He J, Halpern EF, et al. Frequency and clinical context of decreased apparent diffusion coefficient reversal in the human brain. Radiology 2001;221:43-50. 13. Doherty CP, Cole AJ, Grant PE, et al. Multi-modal longitudinal imaging in focal status epilepticus. Can J Neurol Sci 2004;31:27681. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 101
  • 105. INDEX  INTRODUCTION  BRAIN DEVELOPMENT  DISORDERS OF SEGMENTATION  DISORDERS OF PROSENCEPHALIC CLEAVAGE  DISORDERS OF CELL PROLIFERATION  DISORDERS OF NEURONAL DIFFERENTIATION  DISORDERS OF MIGRATION RADIOLOGICAL PATHOLOGY OF BRAIN DEVELOPMENTAL DISORDERS The brain is a seemingly nonsegmented organ that is, however, formed in a segmented fashion by the overlap of genes that define anatomic and probably functional components of the brain. Other genes and their encoded proteins regulate the processes of cell proliferation and migration; many of these genes have been identified based upon discoveries of human and mouse disease-causing genes. Human brain developmental disorders represent clinical challenges for the diagnosing clinician as well as for the treating physician. Some disorders represent well-defined www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 102
  • 106. clinical and genetic entities for which there are specific tests; others have ill-defined genetic causes, while others can have both genetic and destructive causes. In most cases the recognition of a disorder of brain development portends certain developmental disabilities and often seizure disorders that can be very difficult to treat. In addition, it now bears upon the treating physician to recognize the genetic causes, and to properly advise patients and their families of the risks of recurrence or refer them to the proper specialist who can do so. The genetics of some of these disorders are not all well defined at present, and the recognition of some disorders is variable; what is known is presented herein. The genetics and signaling utilized in brain development is briefly reviewed to provide the framework for the understanding of human brain developmental disorders. The well- defined genetic disorders of brain development are discussed, and a brief suggested algorithm for evaluation and for counseling of patients is provided. BRAIN DEVELOPMENT  Overview General mechanisms tend to recur in all phases of brain development, and these include induction, cell proliferation, cell fate determination (differentiation), cell process formation and targeting (synapse formation), and cell movement (migration). Induction is the process by which one group of cells or tissue determines the fate of another by the release of soluble factors or inducers. Cell fate or differentiation is dependent upon this process of induction, and probably can best be understood as the initiation of a genetic program by the recognition of an inducing molecule and/or expression of a transcriptional regulator. In general, it is rare that a cell in the nervous system is born and differentiates in the same location that it finally resides. Rather, cells migrate over long distances to reach their final locations. Similarly, cells in the nervous system must extend processes over long distances to reach their synaptic targets.  Neural tube formation The human brain is formed from the neuroectoderm, a placode of cells that are induced to differentiate from the surrounding ectoderm by the presence of the notochord at about 18 days gestation. Candidate inducing factors include the retinoids, follistatin, and Noggin [1- 4]. The neuroectoderm develops folds in the lateral aspects that begin to approximate in the region of the future medulla and fuse at 22 days gestation. This closure is known as neurulation, and results in the formation of a tube termed the neural tube [5]. The anterior neural tube closes by about 24 days gestation and serves as the foundation for further brain development; the posterior neural tube closes by about 26 days gestation and serves as the foundation for further spinal cord development. Defects in the closure of the neural tube lead to encephaloceles or myelomeningoceles. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 103
  • 107.  Nervous system segmentation At the rostral end of the newly closed neural tube flexures delineate the primary vesicles, which are designated as the hindbrain (rhombencephalon), mesencephalon, and forebrain (prosencephalon). The primary vesicles can be further subdivided into secondary vesicles that will form adult brain structures. The hindbrain can be divided into the metencephalon and myelencephalon, which will become the pons, cerebellum, and medulla oblongata of the adult. The mesencephalon will be the midbrain, and the prosencephalon divides into the telencephalon (two telencephalic vesicles) and diencephalon. The telencephalic vesicles will become the cerebral hemispheres; the diencephalon will become the thalamus and hypothalamus. Regional specification of the developing telencephalon is an important step in brain development, and is likely under control of a number of genes that encode transcription - regulators. In the fruit fly, Drosophila, these genes are involved in segmentation of this animal and define structures such as hair-like spiracles. Not surprisingly, the role of these genes in human brain development differs, yet it appears that the general role of these proteins is that of regional specification of clones of cells destined to form specific brain structures. Homeobox and other transcription genes encode some of these transcriptional regulators and these "turn on" genes by binding to specific DNA sequences, and in so doing initiate genetic programs that lead to cell and tissue differentiation. EMX2, a transcriptional regulator, has a homolog in Drosophila that defines the hair spiracles and has been implicated in human brain malformations. DISORDERS OF SEGMENTATION  Schizencephaly Schizencephaly (cleft in brain) has been regarded by many as a migration abnormality; however, it is best understood as a disorder of segmentation because one of the genes that is abnormal in the more severe and familial forms is EMX2 [6,7]. Thus, this developmental disorder, at least in the more severe cases, appears to be the result of failure of regional specification of a clone of cells that are destined to be part of the cortex. Clinically, these patients vary depending upon the size of the defect and upon whether bilateral disease is present [8]. The clefts extend from the pia to the ventricle and are lined with a polymicrogyric gray matter [9]. The pia and ependyma are usually in apposition, especially in severe cases. The defect is termed open-lipped if the cleft walls are separated by cerebrospinal fluid, and closed-lipped if the walls are in contact with one another. Bilateral schizencephaly is associated with mental retardation and spastic cerebral palsy; affected patients often are microcephalic. Seizures almost always accompany severe lesions, especially the open-lipped and bilateral schizencephalies. The exact frequency of seizures in patients with the less severe lesions is uncertain. Most patients in whom schizencephaly is diagnosed undergo neuroimaging because of seizures. Therefore, a bias in favor of a universal occurrence of seizures in this disorder is noted. Hence, patients with www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 104
  • 108. schizencephaly who do not have epilepsy might exist, but the malformation remains undetected because no imaging is performed. Figure 1. Closed-lip schizencephaly. Sagittal T1- weighted MRI shows gray matter (arrows) extending from cortex to a dimple in the surface of the left lateral ventricle. The lips of the schizencephaly are in apposition, making this a "closed-lip" schizencephaly. Figure 2. Bilateral open-lip schizencephaly. A,B: Axial T2- weighted images show open-lip schizencephalies in both hemispheres. Both images show vessels in the gray matter-lined clefts and large vessels (arrows) run at the outer surface of the right hemispheric cleft. This does not represent a vascular malformation. Seizure type and onset may also vary in this disorder. Patients may experience focal or generalized seizures, and some will present with infantile spasms. The onset varies from infancy to the early adult years. Seizures may be easily controlled or may be recalcitrant to standard anticonvulsant therapy. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 105
  • 109. Figure 3a. MRI T1 (A,B) and CT scan (D) showing open-lip schizencephaly with pachygyria. Notice the associated encephalocele that is sometimes associated with cortical dysplasias Figure 3b. Open-lip schizencephaly with cortical dysplasia Improvements in neuroimaging have enhanced the recognition of schizencephalic lesions [9-13]. The lesions may occur in isolation or may be associated with other anomalies of brain development such as septo-optic dysplasia [14]. Disorders of segmentation likely represent a heterogeneous set of abnormalities of varying etiologies. One theory holds that an early (first-trimester) destructive event disturbs www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 106
  • 110. subsequent formation of the cortex. Another theory is that segmental failure occurs in the formation of a portion of the germinal matrix or in the migration of primitive neuroblasts. Certainly, the finding of mutations of the EMX2 gene in some patients with the open-lipped form of schizencephaly supports the latter hypothesis.  Prosencephalon cleavage At about 42 days of gestation, the prosencephalon undergoes a division into two telencephalic vesicles that are destined to become the cerebral hemispheres. The anterior portion of this cleavage is induced by midline facial structures and the presence of the notochord. Abnormalities of this process are thought to result in holoprosencephaly, septo- optic dysplasia, and agenesis of the corpus callosum [I 5]. One of the important molecules responsible for the induction of this cleavage is Sonic hedgehog [16]. This protein is produced by the notochord, ventral forebrain, and the floor plate of the neural tube [17]. It interacts through at least one receptor, PTCH-A human homolog of patched, and alters the expression of transcription factors [18,19]. Furthermore, in an interesting link between these ventral inductive events and segmentation, Sonic hedgehog can alter the expression of the transcriptional regulating genes when applied to proliferating cells at critical times in development [21]. This ties the inductive proteins to the expression of transcriptional regulating genes and gives a hint as to the mechanisms involved in inductive processes. Figure 4a. Agenesis of the corpus callosum Other molecules of interest in this inductive process are the retinoids, which are lipids capable of crossing membranes and that have been shown to exist in posterior to anterior www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 107
  • 111. gradients across embryos [3,20]. Retinoic acid can alter the pattern of transcriptional factors in neuroepithelial cells [3] and can downregulate Sonic hedgehog, perhaps explaining some of the head defects seen in retinoid embryopathy [17,22]. Agenesis of the corpus callosum Etiology •Both genetic and sporadic Pathogenesis •Unknown, Epidemiology •Agenesis of the corpus callosum may be part of an extensive malformation complex or the callosum may be partially or completely absent or hypoplastic in an otherwise normal brain. •The malformation is relatively rare. General Gross Description •The brain in agenesis of the corpus callosum shows batwing shaped ventricles as well as loss of the corpus callosum and there is no cingulate gyrus. •The remainder of the abnormalities depend on what syndrome or other malformations are associated with the defect. In most cases there is a bundle of white matter processes on both cerebral hemispheres in the area where the corpus callosum should be, called the bundle of Probst. In some patients there is a lipoma or other tumor in the area where the corpus callosum should be. General Microscopic Description •None Clinical Correlation •Patients with agenesis of the corpus callosum may be normal or may have neurological abnormalities dependent on the other accompanying malformations. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 108
  • 112. Figure 4b. Agenesis of the corpus callosum DISORDERS OF PROSENCEPHALIC CLEAVAGE  Holoprosencephaly Holoprosencephaly is a heterogeneous disorder of prosencephalon cleavage that results from a failure of the prosencephalic vesicle to cleave normally. Three forms of this disorder have been described: alobar, semilobar, and lobar [23,24]. In the alobar form, the telencephalic vesicle completely fails to divide, producing a single horseshoe-shaped ventricle, sometimes with a dorsal cyst, fused thalami, and a malformed cortex. In the semilobar form, the interhemispheric fissure is present posteriorly, but the frontal and, sometimes, parietal lobes, continue across the midline [25]; in some cases just ventral fusion is noted. In the lobar form, only minor changes may be seen: the anterior falx and the septum pellucidum usually are absent, the frontal lobes and horns are hypoplastic, and the genu of the corpus callosum may be abnormal. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 109
  • 113. Figure 5. This is holoprosencephaly in which there is a single large ventricle with fusion of midline structures, including thalami. The affected fetuses and neonates typically have severe facial defects, such as cyclopia, as well. Underlying chromosomal abnormalities, such as trisomy 13, or maternal diabetes mellitus are possible causes, but some cases are sporadic. Holoprosencephaly is associated with a spectrum of midline facial defects. These include cyclopia, a supraorbital proboscis, ethmocephali, in which the nose is replaced by a proboscis located above hypoteloric eyes; cebocephaly, in which hypotelorism and a nose with a single nostril are seen; and premaxillary agenesis, with hypotelorism, a flat nose, and a midline cleft lip [26]. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 110
  • 114. Figure 6. (left three images) A,B semilobar holoprosencephaly from the same patient, C a patient with lobar holoprosencephaly. Arrowhead in A points to lack of ventral interhemispheric cleavage. Arrowhead in B points to fused thalami. The septum pellucidum is absent in B. In C notice the horseshoe or mushroom shaped single ventricle designated by * , arrowhead in C points to lack of interhemispheric fissure. (right image) MRI - Holoprosencephaly: This 6-day-old girl presented with laryngeal malacia and a diminished level of arousal. This proton density axial MR image shows an absence of the anterior horns of the lateral ventricles, fused thalami and absence of the corpus callosum anteriorly. Only children who have the lobar and semilobar forms are known to survive for more than a few months. An infant affected with the severe form is microcephalic, hypotonic, and visually inattentive [25]. In infants with the less severe forms of holoprosencephaly, myoclonic seizures frequently develop and, if the infant survives, autonomic dysfunction, failure to thrive, psychomotor retardation, and atonic or spastic cerebral palsy often are present. Some infants with the lobar form may be only mildly affected and, for example, present as a relatively mild spastic diplegia. Pituitary defects may be associated with these malformations, and may result in neuroendocrine dysfunction [27]. One, therefore, has to wonder how much genetic overlap exists between this condition and septo-optic dysplasia to be described below. Holoprosencephaly has been associated with maternal diabetes [28], retinoic acid exposure, cytomegalovirus, and rubella [29]. Chromosome abnormalities associated with this disorder include trisomies 13 and 18; duplications of 3p, 13q, and 18q; and deletions in 2p, 7q, 13q, and 18q [30]. Of particular concern to the clinician is the existence of an autosomal www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 111
  • 115. dominant form in which mutations in Sonic Hedgehog lead to variable expression of holoprosencephaly. In the mildest form of this genetic disorder, patients may have a single central incisor, a choroid fissure coloboma, or simply attention deficit disorder; a parent of a child with holoprosencephaly manifesting these features should be considered to be at high risk for recurrence of holoprosencephaly in their children (up to 50% risk) [31,32]. A number of other genes (HPE] (21 q22.3), HPE2 (2p2 1), HPE3 (7q36), HPE4 (18p), ZIC2, SIX3 (2p2l), and PATCHED) have been associated with holoprosencephaly, and although potentially inherited in an autosomal recessive fashion, most occurrence seems to be random [33,34].  Septo-optic dysplasia Septo-optic dysplasia (de Morsier syndrome) is a disorder characterized by the absence of the septum pellucidum, optic nerve hypoplasia, and hypothalamic dysfunction. It may be associated with agenesis of the corpus callosum. This disorder should be considered in any patient who exhibits at least two of the above abnormalities and perhaps even solely hypothalamic dysfunction [35]. Septo-optic dysplasia also appears to involve prosencephalic cleavage and development of anterior telencephalic structures [36]. About 50% of patients with septo-optic dysplasia have schizencephaly [14]. Figure 7. Septo-optic dysplasia associated with schizencephaly. Arrows in A,B point to absent septum pellucidum, arrow in C, and black arrowhead in D point to open lip schizencephaly, white arrow head point to polymicrogyria in D Patients may present with visual disturbance, seizures, mental retardation, hemiparesis (especially if associated with schizencephaly), quadriparesis, or hypothalamic dysfunction. Endocrine abnormalities may include growth hormone, thyroid hormone, or antidiuretic hormone function or levels. The consideration of septo-optic dysplasia necessitates an evaluation of the hypothalamic-pituitary axis because as many as 60% of the children with this disorder might exhibit evidence of a disturbance of endocrine function [37]. This www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 112
  • 116. evaluation can include thyroid function studies and electrolytes; these patients are at high risk for growth retardation. The recent identification of patients with this condition that harbor mutations in the transcriptional regulator gene HESX1, suggest that the mechanism of this disorder is likely genetic and a patterning or segmental abnormality [38]. Even though the genetic abnormality has been identified for a minority of patients, there exists the possibility that this may not represent an entirely genetic disorder because associations have been made with young maternal age, diabetes, the use of anticonvulsants, phencyclidine, cocaine, and alcohol [39], DISORDERS OF CELL PROLIFERATION  Normal cell proliferation Following telencephalic cleavage, a layer of proliferative pseudostratified neuroepithelium lines the ventricles of the telencephalic vesicles. These cells will give rise to the neurons and glia of the mature brain. The generation of the proper complement of cells is a highly ordered process that results in the generation of billions of neurons and glia. Neuroepithelial processes extend from the ventricular surface to the pial surface, and the nuclei of the primitive neuroepithelial cells move from the cortical surface in a premitotic phase to a mitotic phase near the ventricle. Cells divide at the most ventricular aspects of the developing telencephalon, and after division move back toward the pial surface. The pial processes of neuroepithelial cells near the ventricle often will detach from the cortical surface before a new cycle begins. Neuroepithelial cells divide in so-called proliferative units such that each unit will undergo a specific number of divisions resulting in the appropriate number of cells for the future cortex. Abnormalities in the number of proliferative units or in the total number of divisions can lead to disorders of the brain manifested by abnormal brain size and, therefore, an unusually small or large head circumference. Two such disorders resulting in small head size -radial microbrain and microcephaly vera- are believed to result from abnormalities of this phase of neurodevelopment [40]. Disorders in which too many cells are generated in the proliferative phase result in megalencephaly (large brain) or, if proliferative events go awry on only one side of the developing cortex, hemimegalencephaly. The genes and molecules involved in regulating the proliferative cycles in human brain formation are likely similar to those involved in other species. This cell cycle in the brain can be divided into a number of distinct phases: mitosis (M), first gap (GI), deoxyribonucleic acid synthesis (S), and second gap (G2) [41]. These phases appear to be regulated by key molecules to check the advancement of proliferation. Some cells enter a resting state (GO) that they maintain throughout life. Others temporarily enter this phase to await a specific signal to proliferate later. Probably the GI-S transition regulation determines the number of cell cycles and, therefore, the complement of cells that will make brain [40]. Cyclins are proteins that appear to be involved in cell cycle control. These www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 113
  • 117. proteins are activating subunits of cyclin-dependent kinases. Cyclins DI, D2, D3, C, and E seem to control the key transition of a cell to the GI S interface; this transition is regarded as important because it commits a cell to division [42-44]. Cyclin E seems to be the gatekeeper for this transition, and is essential for movement from the GI to the S phase [42,45]. The number of cells that finally make up the mature nervous system is less than that generated during proliferation. Cells appear not only to be programmed to proliferate during development but to contain programs that lead to cell death [46,47]. The term apoptosis (from the Greek, meaning "a falling off ") has been applied to this programmed loss of cells [48].  Non-neoplastic proliferative disorders o Microcephaly Although primary microcephaly may be a normal variant, in the classic symptomatic form, clinical and radiologic examinations reveal a receding forehead, flat occiput, early closure of fontanelles, and hair anomalies such as multiple hair whirls and an anterior cowlick. Neuroimaging may show small frontal and occipital lobes, open opercula, and a small cerebellum [24]. The cortex may appear thickened and the white matter reduced. Histologic examination may show a reduction of cell layers in some areas and an increase in others [49]. Neurologic findings also vary. Only mild psychomotor retardation may be noted, sometimes associated with pyramidal signs, or more severe retardation, seizures, and an atonic cerebral palsy might be evidenced. Primary microcephaly is seen in many genetic syndromes and, in its isolated form, may be autosomal recessive, autosomal dominant, or X-linked [50-52]. Microcephaly vera is the term most often alyplied to this genetic form of microcephaly. Affected children present with a head circumference that is usually more than 4 standard deviations below the mean, hypotonia, and psychomotor retardation. They later show mental retardation, dyspraxias, motor incoordination and, sometimes, seizures. On histologic examination, neurons in layers 11 and III are depleted [53]. Destructive lesions of the forming brain, such as those caused by teratogens and by infectious agents, also may result in microcephaly. Teratogens of note are alcohol, cocaine, and hyperphenylalaninemia (maternal phenylketonuria) [54]. Intense radiation exposure (such as that from a nuclear explosion) in the first trimester, can cause microcephaly [55]. Microcephaly and intracranial calcifications are likely due to well-recognized in utero infections caused by cytomegalovirus, toxoplasmosis, or the human immunodeficiency virus. o Megalencephaly and hemimegalencephaly The terms megalencephaly and hemimegalencephaly refer to disorders in which the brain volume is greater than normal (not owing to the abnormal storage of material); usually, the enlarged brain is accompanied by macrocephaly, or a large head. Although considered by www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 114
  • 118. some to be a migration disorder, the increase in brain size in these disorders appears to be attributable to errors in neuroepithelial proliferation, as the microscopic appearance of the brain is that of an increase in number of cells (both neurons and glia) and in cell size [56- 59]. Typically, patients are noted to have large heads at birth, and may manifest an accelerated head growth in the first few months of life [60,61]. Children with megalencephaly or hemimegalencephaly may come to medical attention when presenting with seizures, a developmental disorder (mental retardation), hemihypertrophy, or a hemiparesis (opposite the affected hemisphere). Seizures vary both in onset and in type, and usually are the most problematic symptom. sometimes necessitating hemispherectomy or callosotomy [58]. Approximately 50% of patients with linear sebaceous nevus syndrome have hemimegalencephaly [62,63]. Many patients with hypomelanosis of Ito also have hemimegalencephaly [64]. The neuropathologic and clinical pictures of these associations appear to be identical to the isolated hemimegalencephalies.  Neoplastic proliferative disorders Lesions of proliferation after an abnormal induction event during brain development may be malformative, hamartomatous, neoplastic, or a combination. Malformative disorders consisting of neoplasias on a background of disordered cortex or in association with focal cortical dysplasia include dysembryoplastic neuroepithelial tumor and ganglioglioma. [103,104] o Dysembryoplastic neuroepithelial tumours Dysembryoplastic neuroepithelial tumors are supratentorial, predominantly temporal lobe tumors that are typically multinodular with a heterogeneous cell composition, including oligodendrocytes, neurons, astrocytes, and other cells. These lesions are typically fairly well-demarcated, wedge-shaped lesions extending from the cortex to the ventricle. Calcification, enhancement, and peritumoral edema are lacking on neuroimaging studies. These low- attenuation lesions may suggest an infarct on computed tomography (CT), although there is no volume loss over time, and scalloping of the inner table or calvarial bulging suggests slow growth. Lesions are low in signal on Tl- weighted images and high in signal on T2- weighted images and often have a multinodular or pseudocystic appearance. There is a spectrum of pathology in dysembryoplastic neuroepithelial tumors. On one end of the spectrum are multinodular lesions with intervening malformed cortex, in which there is some hesitation to use the designation tumor. On the other end are lesions, which are clearly neoplastic and have clinically demonstrated some growth potential. Because the term dysembryoplastic neuroepithelial tumor has only recently been introduced, such malformative and neoplastic lesions were previously labeled as hamartomas, gangliogliomas, or mixed gliomas. [100,101,102] www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 115
  • 119. o Gangliogliomas Gangliogliomas are typically demonstrated within the temporal lobe. In one large series of 51 gangliogliomas, 84% were found in the temporal lobe, 10% were found in the frontal lobe, 2% were found in the occipital lobe, and 4% were found in the posterior fossa. These lesions are typically hypodense (60% to 70%) on CT, with focal calcifications seen in 35% to 40%, contrast enhancement in 45% to 50%, and cysts in nearly 60%. The reported incidence of calcifications demonstrated on imaging in pediatric gangliogliomas is higher, seen in 61% of one series of 42 children. Features on MR imaging are less specific, with solid components isointense on TI-weighted images, bright on proton density images, and slightly less bright on T2-weighted images. Although imaging features are not specific, an enhancing, cystic temporal lobe lesion with focal calcification should suggest the diagnosis of ganglioglioma. The pathologic features that suggest the diagnosis of ganglioglioma include a neoplastic glial and neoronal component and calcification. Because calcifications are often poorly demonstrated on MR imaging and because they increase specificity of imaging findings, documentation of calcium should be sought on CT after MR imaging demonstration of a temporal lobe tumor. [97,98,99] DISORDERS OF NEURONAL DIFFERENTIATION  Normal differentiation At the time of neuronal differentiation the neural tube consists of four consecutive layers: (1) the ventricular zone, the innermost layer, which gives rise to neurons and all of the glia of the central nervous system; (2) the subventricular zone, which is the adjacent, more superficial layer and is the staging area from which postmitotic neurons begin to differentiate and to migrate; (3) the intermediate zone, which is the contiguous, more superficial zone, and which is destined to become the cortical plate and the future cerebral cortex; and (4) the marginal zone, which is the outermost zone and is composed of the cytoplasmic extensions of ventricular neuroblasts, corticopetal fibers, and the terminal processes of radial glia (which, at this time, are completely spanning the neural tube). Differentiation of neuroepithelial cells begins in the subventricular layer at approximately gestational day 26. The older, larger pyramidal cells are the first cells to be born and probably differentiate early to act as targets in the migration of the nervous system.  Tuberous sclerosis Disorders such as tuberous sclerosis, in which both tumor development and areas of cortical dysplasia are seen, might be a differentiation disorder. The brain manifestations of this disorder include hamartomas of the subependymal layer, areas of cortical migration abnormalities (tubers, cortical dysgenesis), and the development of giant-cell astrocytomas in upwards of 5% of affected patients. Two genes for tuberous sclerosis have been identified: TSCI (encodes for Hamartin) has been localized to 9q34 [65], and TSC2 (encodes for Tuberin) has been localized to 16pl3.3 [65]. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 116
  • 120. Figure 8. Postmortem specimens showing cortical tubers in (A) and subependymal tubers in (B) Figure 9. Postmortem specimen showing cortical tubers, the affected gyri are abnormally broad and flat. DISORDERS OF MIGRATION  Normal migration At the most rostral end of the neural tube in the 40- to 41 -day-old fetus, the first mature neurons, Cajal-Retzius cells, begin the complex trip to the cortical surface. Cajal-Retzius cells, subplate neurons, and corticopetal nerve fibers form a preplate [66]. The,neurons generated in the proliferative phase of neurodevelopment represent billions of cells poised to begin the trip to the cortical surface and to form the cortical plate. These neurons accomplish this task by attaching to and migrating along radial glial in a process known as radial migration or by somal translocation in a neuronal process [67]. The radial glia www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 117
  • 121. extend from the ventricle to the cortical surface. In the process of migration, the deepest layer of the cortical plate migrates and deposits before the other layers. Therefore, the first neurons to arrive at the future cortex are layer VI neurons. More superficial layers of cortex then are formed-the neurons of layer V migrate and pass the neurons of layer VI; the same process occurs for layers IV, 111, and 11. The cortex therefore is formed in an inside-out fashion [67-69]. A possible mode of movement in neuronal migration on glia would be the attachment of the neuroblast to a matrix secreted by either the glia or the neurons. The attachment of the neuron would be through integrin receptors, cytoskeletal-linking membrane-bound recognition sites for adhesion molecules. That attachment serves as a stronghold for the leading process and soma of the migrating neuron. Neuron movement on radial glia involves an extension of a leading process, neural outgrowth having an orderly arrangement of microtubules. Shortening of the leading process owing to depolymerization or shifts of microtubules may result in movement of the soma relative to the attachment points. This theory of movement of neurons also must include a phase of detachment from the matrix at certain sites, so that the neuron can navigate successfully along as much as 6 cm of developing cortex (the maximum estimated distance of radial migration of a neuron in the human). Finally, the movement of cells must stop at the appropriate location, the boundary between layer I and the forming cortical plate. Therefore, some stop signal must be given for the migrating neuron to detach from the radial glia and begin to differentiate into a cortical neuron. Perhaps that signal is REELIN, a protein that is disrupted in the mouse mutant Reeler and is expressed solely in the Caial Retizius cells at this phase of development [66,70-73].  Migration disorders Advanced neuroimaging techniques, particularly magnetic resonance imaging, have allowed the recognition of major migration disorders and of the frequency of more subtle disorders of migration. Some of these disorders are associated with typical clinical features that might alert the clinician to the presence of such malformations even before imaging is obtained. In other disorders, the clinical features are so varied that a strong correlation between imaging and the clinical presentation points to a specific genetic syndrome.  Lissencephaly Lissencephaly (smooth brain) refers to the external appearance of the cerebral cortex in those disorders in which a neuronal migration aberration leads to a relatively smooth cortical surface. One should not consider only agyria in making this diagnosis, rather, the full spectrum includes agyria and pachygyria. Gyri and sulci do not form in this disorder because the lack of cortical-cortical attractive forces owing to improper axon pathways. At least two types have been identified: classic lissencephaly, and cobblestone lissencephaly. The distinction is based upon the external appearance and upon the underlying histology, and can be made with neuroimaging. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 118
  • 122. Figure 10. Pachygyric (A), and agyric (B) lissencephalic brain o Classic lissencephaly Classic lissencephaly may occur in isolation, owing to LIS1 or Doublecortin aberrations or in combination with somatic features and LIS1 deletions in the Miller-Dieker syndrome. The hallmarks on imaging are a lack of opercularization (covering of the sylvian fissure), large ventricles or colpocephaly (dilated posterior horns), and agyria or pachygyria. The corpus callosum is almost always present, and the posterior fossa is usually normal, although a form of lissencephaly does exist that includes cerebellar hypoplasia. The LIS1 protein forms complexes with other cellular proteins that are crucial for cell division, migration, and intracellular transport. Complete loss of LIS1 is fatal. Deletion of one copy of the gene is causes lissencephaly. The LIS1 gene is found in 17q13.3 location. Doublecortin (DCX), a gene on Xq22.3-q23 that codes for a microtubule associated protein, is responsible for migration of neurons. Mutation of this gene results in band heterotopia www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 119
  • 123. Figure 11. Classical lissencephaly with patchy agyria/agyria, thick Cortex and band heterotopia o LIS1 genetic syndromes The Miller-Dieker phenotype consists of distinct facial features that include bitemporal hallowing, upturned nares, and a peculiar burying of the upper lip by the lower lip at the corners of the mouth. The lissencephaly is usually more severe than isolated lissencephaly, and the prognosis is worse. Most affected patients die in the first few years of life. By both molecular and cytogenetic techniques, deletions in the terminal portion of one arm of chromosome 17 can be found in approximately 90% of Miller-Dicker lissencephaly cases [74]. The deletions of the terminal part of chromosome 17 in these cases have included microdeletions [74], ring 17 chromosome [75], pericentric inversions [76], and a partial monosomy of 17pl3.3 [77]. The most appropriate genetic test is a fluorescent in situ hybridization (FISH) for LIS1; this test involves marking chromosome 17 at the centromere and LIS1 with fluorescent probes. The greatest risk to future offspring exists when a parent harbors a balanced translocation involving this region of chromosome 17. In families that are affected in this manner, screening by amniocentesis can be performed in subsequent pregnancies. Therefore, it is recommended that both parents have screening for chromosome 17 rearrangements by FISH for LIS1. Should a translocation be present in a parent, then the LIS1 fluorescence will be on another chromosome. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 120
  • 124. Figure 12. A, Type I lissencephaly, agyria type. Axial T2-weighted image shows a brain with a "figure-8" configuration secondary to the immature Sylvian fissures. A band of neurons (arrows) that was arrested during migration lies between the thin cortex and the lateral ventricles. B, Type 1 lissencephaly, pachygyria type. Axial T2-weighted image is similar to that shown in (A), with the exception that a few broad gyri with shallow sulci are present. C, Type 1 lissencephaly, pachygyria type. Axial T2-weighted image shows broad, flat gyri with shallow sulci throughout the cerebrum. o Isolated lissencephaly Classic lissencephaly without somatic or facial features represents a distinct genetic syndrome from Miller-Dieker, but it involves the same gene LIS1. Approximately 40% of patients with isolated lissencephaly have FISH detectable deletions of LIS1, and about 20% of additional patients harbor mutations of this gene [78-80]. The remaining patients may have mutations involving promoter regions of LIS1 or abnormalities of other genes such as Doublecortin or the involvement of other genes that have not been recognized. The genetic risk of recurrence is highest when rearrangements of chromosome 17 exist in one parent. This is rare in isolated lissencephaly, but could occur. Therefore, it would be prudent to perform FISH for LIS1 in the parents of children with isolated lissencephaly who have FISH proven deletions for the LIS1 region. The prognosis for this disorder is better than that for Miller-Dieker syndrome, but it is not consistent with long-term survival. These patients typically present in the first few months of life with hypotonia, lack of visual fixation, and often seizures. Patients with lissencephaly will uniformly have seizures and profound mental retardation. Often, seizures are very difficult to control and require multiple anticonvulsant drugs. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 121
  • 125. o X-linked lissencephaly The imaging of X-linked lissencephaly looks nearly identical to the images of lissencephaly involving LIS1. Patients have classic lissencephaly, and the neurologic presentation described above. However, the skeletal and other anomalies seen in the Miller-Dieker are not noted in this form of lissencephaly. When viewing the images from patients with lissencephaly owing to abnormalities of LIS1 and of Doublecortin it is apparent that differences in an anterior to posterior gradient of severity exists [81-83]. Doublecortin mutations result in anterior greater than posterior severity, whereas LIS1 mutations result in posterior greater than anterior severity [84]. In addition, X-linked lissencephaly occurs mostly in boys; girls who are heterozygous for Doublecortin mutations have band heterotopia [80,81,85]. Women with band heterotopia have been known to give birth to boys with lissencephaly. In female patients, the less severe phenotype probably is attributed to random lyonization of the X chromosome, such that in a variable number of cells, normal gene expression is seen and, in the remaining cells, the Doublecortin mutation-containing X chromosome is expressed. It is presumed that those cells expressing the abnormal X chromosome will be arrested in the migration to the surface of the brain and reside in a subcortical band. Figure 13. Gross specimen showing lissencephaly with pachygyria and agyria www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 122
  • 126. Figure 14. Lissencephaly with abnormally smooth agyric, pachygyric cortex Figure 15. Lissencephaly with abnormally smooth agyric cortex When viewing images from patients with this disorder, a thick band of tissue that is isointense with cerebral gray matter is seen within what should be the white matter of the hemispheres. The overlying gyral appearance may vary from normal cortex to a pachygyria. A brain biopsy performed in a patient demonstrated well-preserved lamination in cortical layers I-IV [86]. Layers V-VI were not clearly separated and merged with underlying white matter. Beneath the white matter was a coalescent cluster of large, well-differentiated neurons. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 123
  • 127. Figure 16. A, Band heterotopia with pachygyria. B, band heterotopia with mild periventricular nodular heterotopia o Lissencephaly with cerebellar hypoplasia The association of lissencephaly with cerebellar hypoplasia represents a distinct malformation from both a genetic and clinical standpoint to those described above. The cerebellar hypoplasia is usually extreme, and the brainstem may be small. Patients may or may not have an associated microcephaly. This disorder is often inherited in an autosomal recessive fashion and may be due to mutations in REELIN in some families [87]. Figure 17. Lissencephalic brain with hydrocephalus and cerebellar hypoplasia www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 124
  • 128. Figure 18. MRI showing a mild form of lissencephaly (pachygyria), the brain have a few broad, flat gyri with thick cortex and separated by shallow sulci (pachygyria). The cerebellum and the brain stem are hypoplastic, the brain volume is also reduced especially the temporal lobes. o Cobblestone lissencephaly Cobblestone lissencephalies are disorders in which a smooth configuration of cortex is noted, but the distinction from classic lissencephaly is made based upon the clinical association of eye abnormalities, muscle disease, and progressive hydrocephalus. The term "cobblestone" refers to the appearance of the cortical surface upon pathologic examination. In these disorders, cells pass their stopping point and erupt over the surface of the cortex into the subarachnoid spaces. This results in a cobblestone street appearance to the surface, and therefore, the name. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 125
  • 129. Figure 19. A, Type II lissencephaly, Cobblestone lissencephaly (Walker-Warburg syndrome). The cortex is lissencephalic and thickened, with an irregular gray matter-white matter junction that probably represents the bundles of disorganized cortex surrounded by fibroglial tissue. The patient has been shunted for hydrocephalus. The brain is hypomyelinated. B, Presumed microcephalia vera. The brain is completely smooth (lissencephaly) with a very thin cortex. No layer of arrested neurons is present in the white matter. C, Presumed radial microbrain. Axial T2- weighted image shows an immature gyral pattern and hypomyelination. Cortical thickness is normal. This patient was profoundly microcephalic (head circumference 19 cm). The Walker-Warburg, muscle-eye-brain, and HARD +/- syndromes are likely all varying degrees of the same entity. Abnormalities that may or may not be seen in these disorders include muscular dystrophy, ocular anterior chamber abnormalities, retinal dysplasias (evidenced by abnormal electroretinogram and visual evoked responses), hydrocephalus (usually of an obstructive type), and encephaloceles. The Walker-Warburg syndrome might be diagnosed even if the ocular examination and muscle biopsies are normal if on MRI, an abnormal white matter signal and a thickened falx suggest the diagnosis. Neuroimaging of the muscle-eye-brain disorders often reveals focal white matter abnormalities. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 126
  • 130. Figure 20. Cobblestone lissencephaly Fukuyama muscular dystrophy is distinguished from the Walker Warburg-like syndromes by the severity of the muscular dystrophy [88-91]. This disorder is seen more often in Japan than in the Western hemisphere, probably because it is the result of a founder mutation. Patients typically present with evidence of a neuronal migration defect, hypotonia, and depressed reflexes. Recent identification of Fukutin as the causative gene in this disorder should provide insight into the pathogenesis of the cobblestone lissencephalies [92]. This disorder is inherited as an autosomal recessive disorder. The cobblestone lissencephalies often have an associated cerebellar and brainstem hypoplasia, and therefore may be difficult to distinguish from lissencephaly with cerebellar hypoplasia described above. The presence of eye abnormalities, elevated CPK, or other evidence for the presence of muscle disease and progressive hydrocephalus distinguish this disorder. These disorders may be inherited in an autosomal recessive manner. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 127
  • 131. Table 1. The lissencephalies syndromes TYPE DESCRIPTION GENE LIS1 genetic syndromes The Miller-Dieker phenotype consists of distinct facial features that include bitemporal hallowing, upturned nares, and a peculiar burying of the upper lip by the lower lip at the corners of the mouth. The lissencephaly is usually more severe than isolated lissencephaly, and the prognosis is worse. Most affected patients die in the first few years of life. By both molecular and cytogenetic techniques, deletions in the terminal portion of one arm of chromosome 17 can be found in approximately 90% of Miller-Dicker lissencephaly cases [74]. The deletions of the terminal part of chromosome 17 in these cases have included microdeletions [74], ring 17 chromosome [75], pericentric inversions [76], and a partial monosomy of 17pl3.3 [77]. The most appropriate genetic test is a fluorescent in situ hybridization (FISH) for LIS1; this test involves marking chromosome 17 at the centromere and LIS1 with fluorescent probes. Isolated lissencephaly Classic lissencephaly without somatic or facial features represents a distinct genetic syndrome from Miller-Dieker, It involves the same gene LIS1. Approximately 40% of patients with isolated lissencephaly have FISH detectable deletions of LIS1, and about 20% of additional patients harbor mutations of this gene [78- 80]. The remaining patients may have mutations involving promoter regions of LIS1 or abnormalities of other genes such as Doublecortin or the involvement of other genes that have not been recognized. X-linked lissencephaly- subcortical band heterotopia (XLIS-SBH)  The imaging of X-linked lissencephaly looks nearly identical to the images of lissencephaly involving LIS1. Patients have classic lissencephaly, and the neurologic presentation described above. However, the skeletal and other anomalies seen in the Miller- Dieker are not noted in this form of lissencephaly.  LIS1 gene mutation results in lissencephaly  Doublecortin gene mutation results in band heterotopia (Doublecortin (DCX), a gene on Xq22.3-q23 that codes for a microtubule associated protein, is responsible for migration neurons. Mutation of this gene results in band heterotopia) www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 128
  • 132.  In addition, X-linked lissencephaly occurs mostly in boys; girls who are heterozygous for Doublecortin mutations have band heterotopia [80,81,85] Lissencephaly with cerebellar hypoplasia The association of lissencephaly with cerebellar hypoplasia represents a distinct malformation from both a genetic and clinical standpoint to those described above. The cerebellar hypoplasia is usually extreme, and the brainstem may be small. Patients may or may not have an associated microcephaly. This disorder is often inherited in an autosomal recessive fashion and may be due to mutations in REELIN in some families [87]. Cobblestone lissencephalies are disorders in which a smooth configuration of cortex is noted, but the distinction from classic lissencephaly is made based upon the clinical association of eye abnormalities, muscle disease, and progressive hydrocephalus. The term "cobblestone" refers to the appearance of the cortical surface upon pathologic examination. In these disorders, cells pass their stopping point and erupt over the surface of the cortex into the subarachnoid spaces. This results in a cobblestone street appearance to the surface, and therefore, the name. ?  Polymicrogyria Polymicrogyria (many small gyri) is a disorder often considered to be a neuronal migration disorder, but alternate theories exist regarding its pathogenesis, The microscopic appearance of the lesion is that of too many small abnormal gyri. The gyri may be shallow and separated by shallow sulci, which may be associated with an apparent increased cortical thickness on neuroimaging. The multiple small convolutions may not have intervening sulci, or the sulci may be bridged by fusion of overlying molecular layer, which may give a smooth appearance to the brain's surface. The interface of white matter with gray matter is not distinct and often this observation serves as the confirmation of the presence of polymicrogyria. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 129
  • 133. Figure 21. Polymicrogyria Figure 22. A, Polymicrogyria. B, pachygyria with polymicrogyria, notice the subependymal nodular heterotopia Polymicrogyria has also been associated with genetic and chromosomal disorders. It is found in disorders of peroxisomal metabolism such as Zellweger syndrome and neonatal adrenal leukodystrophy . Familial bilateral frontal polymicrogyria and bilateral perisylvian polymicrogyria have been reported. Therefore, if no identifiable cause of the polymicrogyric malformation is found, the recurrence risk may be that of an autosomal recessive disorder. A bilateral parasagittal parieto-occipital polymicrogyria has also been described. The clinical picture varies depending on the location, extent, and cause of the abnormality. Microcephaly with severe developmental delay and hypertonia may result when www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 130
  • 134. polymicrogyria is diffuse. When polymicrogyria is unilateral, focal deficits might be seen. Epilepsy often is present, characterized by partial complex seizures or partial seizures that secondarily generalize. The age at presentation and severity of seizures depends on the extent of the associated pathology. Figure 23. A, pachygyria with polymicrogyria. B, pachygyria with polymicrogyria, notice the subependymal nodular heterotopia Bilateral perisylvian dysplasia is a disorder of perisylvian polymicrogyria resulting in an uncovered sylvian fissure on neuroimaging and on sagittal imaging an extension of the sylvian fissure to the top of the convexity. Patients with bilateral perisylvian dysplasia have a pseudobulbar palsy, and often dysphagia can impair proper nutrition. The majority of patients have epilepsy with early onset; infantile spasms are common. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 131
  • 135. Figure 24. Polymicrogyria with pachygyria Figure 25. Polymicrogyri. In B the patient also had meningomyelocele, obstructive hydrocephalic and Arnold -Chiari type II malformation The cause of this syndrome remains unknown, although hints of a genetic mechanism exist. Detailed chromosomal analyses have revealed deletions of chromosomes 1, 2, 6, 21, and 22 [93], and an X-linked form has been also described [94,95]. Monozygotic twins and siblings with this disorder have been described, suggesting a possible autosomal recessive www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 132
  • 136. mechanism. Some speculate that this is a disorder of regional specification, given the bilateral, symmetric nature of the lesions.  Heterotopias Heterotopias are collections of normal-appearing neurons in an abnormal location, presumably secondary to a disturbance in migration. The exact mechanism of the migration aberration has not been established, although various hypotheses have been proposed. These include damage to the radial glial fibers, premature transformation of radial glial cells into astrocytes, or a deficiency of specific molecules on the surface of neuroblasts or of the radial glial cells (or the receptors for those molecules) that results in disruption of the normal migration process [96]. Heterotopias often occur as isolated defects that may result in only epilepsy. However, when they are multiple, heterotopias might also be associated with a developmental disorder and cerebral palsy (usually spastic). In addition, if other migration defects such as gyral abnormalities are present, the clinical syndrome may be more profound. Usually, no cause is apparent. Occasionally, heterotopias may be found in a variety of syndromes, including neonatal adrenal leukodystrophy, glutaric aciduria type 2, GMI gangliosidosis, neurocutaneous syndromes, multiple congenital anomaly syndromes, chromosomal abnormalities, and fetal toxic exposures. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 133
  • 137. Figure 26. Subependymal nodular heterotopia Figure 27. CT scan showing Subependymal nodular heterotopia with cerebellar hypoplasia Heterotopias may be classified by their location: subpial, within the cerebral white matter, and in the subependymal region. When subependymal, one must consider the X-linked dominant disorder associated with Filamin mutations (Xq28). Leptomeningeal heterotopias www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 134
  • 138. often contain astrocytes mixed with ectopic neurons and may resemble a gliotic scar. They may be related to discontinuities in the external limiting membrane and often are associated with cobblestone lissencephaly. These subarachnoid heterotopias are responsible for the pebbled appearance of the surface of the brain. White matter heterotopias may be focal, subcortical, or diffuse. They may cause distortion of the ventricles and may be associated with diminished white matter in the surrounding area. Figure 28. MRI showing Subependymal nodular heterotopia SUMMARY The progress made in the understanding of the genetics of human brain malformations has lead to insight into the formation of brain and into mechanisms of disease affecting brain. It bears upon neurologists and geneticists to recognize the patterns of diseases of brain formation, to properly diagnose such disorders, to assess the recurrence risk of these malformations, and to guide families with appropriate expectations for outcomes. This article may serve as a guide to neurologists in their approach to these disorders. Because this area is one of rapid progress, the clinician is advised to seek more current information that may be available through on-line databases and other sources. Table 2. Definition of developmental disorders. Type Comment schizencephaly (disorder of segmentation) Schizencephaly (cleft in brain) has been regarded by many as a migration abnormality; however, it is best understood as a disorder of segmentation because one of the genes that is abnormal in the more severe and familial forms is EMX2 [6,7]. Thus, this developmental disorder, at least in the more severe cases, appears to be the result of failure of regional specification of a clone of cells that are destined to be part of the cortex. Megalencephaly (Non-neoplastic The terms megalencephaly and hemimegalencephaly refer to disorders in which the brain volume is greater than normal (not owing to the abnormal storage of material); usually, the enlarged brain is www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 135
  • 139. disorder of neuronal proliferation) accompanied by macrocephaly, or a large head. Microcephaly (Non-neoplastic disorder of neuronal proliferation) The term microcephaly refers to disorders in which the brain volume is smaller than normal Dysembryoplastic neuroepithelial tumor and ganglioglioma Neoplastic proliferative disorders Lissencephaly (disorder of neuronal migration) Lissencephaly (smooth brain) refers to the external appearance of the cerebral cortex in those disorders in which a neuronal migration aberration leads to a relatively smooth cortical surface. One should not consider only agyria in making this diagnosis, rather, the full spectrum includes agyria and pachygyria. Agyria (disorder of neuronal migration) Extreme end of lissencephaly (sever lissencephaly) spectrum in which gyri are completely absent and the brain surface is completely smooth. Pachygyria (disorder of neuronal migration) The other end of lissencephaly spectrum (mild lissencephaly), the brain have a few broad, flat gyri separated by shallow sulci (pachygyria). The cortex is thick in pachygyria. Polymicrogyria (disorder of neuronal migration) Polymicrogyria (many small gyri) is a disorder often considered to be a neuronal migration disorder, but alternate theories exist regarding its pathogenesis, The microscopic appearance of the lesion is that of too many small abnormal gyri. The gyri may be shallow and separated by shallow sulci, which may be associated with an apparent increased cortical thickness on neuroimaging. The multiple small convolutions may not have intervening sulci, or the sulci may be bridged by fusion of overlying molecular layer, which may give a smooth appearance to the brain's surface. Heterotopias (disorder of neuronal migration) Heterotopias are collections of normal-appearing neurons in an abnormal location, presumably secondary to a disturbance in migration. Heterotopias may be classified by their location: subpial, within the cerebral white matter, and in the subependymal region. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 136
  • 140. Tuberous sclerosis (differentiation disorder) Disorders such as tuberous sclerosis, in which both tumor development and areas of cortical dysplasia are seen, might be a differentiation disorder. The brain manifestations of this disorder include hamartomas of the subependymal layer, areas of cortical migration abnormalities (tubers, cortical dysgenesis), and the development of giant-cell astrocytomas in upwards of 5% of affected patients. References [1] Brockes J. Reading the retinoid signals. Nature 1990;145(6278):766-8. [2] Lemire R, Loeser J, Leech R, et al. Normal and abnormal development of the human nervous system. New York: Harper & Row; 1975. [3] Scotting PJ, Rex M. Transcription factors in early development of the central nervous system. Neuropathol Appl Neurobiol 1996;22:469 81. [4] Thaller C, Eichele G. Isolation of 3,4-didehrdroretinic acid, a novel morphogenetic signal in the chick wing bud. Nature 1990;345(6278):815-22. [5] Geelan JA, Langman J. Closure of the neural tube in the cephalic region of the mouse embryo. Anat Rec 1977;189:625-40. [6] Brunelli S, Faiella A, Capra V, et al. Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet 1996;12:94-6. [7] Hillburger AC, Willis JK, Bouldin E, et al. Familial schizencephaly. Brain Dev 1993;15: 234-6. [8] Barkovich AJ, Kjos BO. Schizencephaly: correlation of clinical findings with MR characteristics. Am J Neuroradiol 1992;13:85-94. [9] Barth P. Disorders of neuronal migration. Can J Neurol Sci 1987;14:1-16. [10] Barkovich A, Chuang S, Norman D. MR of neuronal migration anomalies. Am J Neuroradiol 1987;8:1009-17. [11] Barkovich A, Kjos B. Schizencephaly: correlation of clinical findings with MR characteristics. Am J Neuroradiol 1992;13:85-94. [12] Brodtkorb E, Nilsen G, Smevik 0, et al. Epilepsy and anomalies of neuronal migration: MRI and clinical aspects. Acta Neurol Scand 1992;86:24-32. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 137
  • 141. [13] Kuzniecky R. Magnetic resonance imaging in developmental disorders of the cerebral cortex. Epilepsia 1994;35(Suppl 6):S44-56. [14] Aicardi J, Goutieres F. The syndrome of absence of the septum pellucidum with porencephalies and other developmental defects. Neuropediatrics 1981;12:319-29. [15] Leech R, Shuman R. Midline telencephalic dysgenesis: report of three cases. J Child Neurol 1986;1:224-32. [16] Smith J. Hedgehog, the floor plate, and the zone of polarizing activity. Cell 1994;76:193-6. [17] Helms JA, Kim CH, Hu D, et al. Sonic hedgehog participates in craniofacial morphogenesis and is down-regulated by teratogenic doses of retinoic acid. Dev Biol 1997;187:25-35. [18] Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996;272:1668-71. [19] Stone DM, Hynes M, Armanini M, et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 1996;384:129-34. [20] Conlon RA. Retinoic acid and pattern formation in vertebrates. Trends Genet 1995; 1 1:314-9. [21] Nakagawa Y, Kaneko T, Ogura T, et al. Roles of cell-autonomous mechanisms for differential expression of region-specific transcription factors in neuroepithelial cells. Development 1996; 122:2449-(A. [22] Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313:837-41. [23] Barkovich AJ. Imaging aspects of static encephalopathies. In Miller G, Ramer JC, editors Static encephalopathies of infancy and childhood. New York: Raven Press; 1992. p. 45-94 [24] Dobyns WB. Cerebral dysgenesis: causes and consequences. In Miller G, Ramer JC, editors. Static encephalopathies of infancy and childhood. New York: Raven Press; 1992. p. 235-48. [25] Nyberg DA, Mack LA, Bronstein A, et al. Holoprosencephaly: prenatal monographic diagnosis. Am J Radiol 1987;149:1051-8. [26] Souza JP, Siebert JR, Beckwith JB. An anatomic comparison of cebocephaly and ethmocephaly. Teratology 1990;42:347-57. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 138
  • 142. [27] Romshe CA, Sotos JF. Hypothalamic-pituitary dysfunction in siblings of patients with holoprosencephaly. J Pediatr 1973;83:1088-90. [28] Barr M, Hansen JW, Currey K, et al. Holoprosencephaly in infants of diabetic mothers J Pediatr 1983;102:565-8. [29] Cohen MMJ, Lemire RJ. Syndromes with cephaloceles. Teratology 1983;25:161-72. [30] Muenke M. Clinical, cytogenetic, and molecular approaches to the genetic heterogeneity of holoprosencephaly. Am J Med Genet 1989;34:237-45. [31] Heussler HS, Suri M, Young ID, et al. Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly. Arch Dis Child 2002;86:293-6. [32] Roessler E, Belloni E, Gaudenz K, et al. Mutations in the human Sonic hedgehog gene cause holoprosencephaly. Nat Genet 1996;14:357-60. [33] Ming JE, Kaupas ME, Roessler E, et al. Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet 2002;110: 297- 301. [34] Wallis D, Muenke M. Mutations in holoprosencephaly. Hum Mutat 2000;16:99 108. [35] Brickman JM, Clements M, Tyrell R, et al. Molecular effects of novel mutations in Hesxl/HESXI associated with human pituitary disorders. Development 2001;128:5189-99. [36] Ouvier R, Billson F. Optic nerve hypoplasia: a review. J Child Neurol 1986;1:181-8. [37] Costin G, Murphree AL. Hypothalamic-pituitary function in children with optic nerve hypoplasia. Am J Dis Child 1985;139:249-54. [38] Dattani MT, Martinez-Barbera JP, Thomas PQ, et al. Mutations in the homeobox gene HESXI/Hesxl associated with septo-optic dysplasia in human and mouse. Nat Genet 1998; 19:125-33. [39] Patel H, Tze WJ, Crichton JU, et al. Optic nerve hypoplasia with hypopituitarism: septo- optic dysplasia with hypopituitarism. Am J Dis Child 1975;129:175-80. [40] Caviness VS, Takahashi T. Proliferative events in the cerebral ventricular zone. Brain Dev 1995;17:159-63. [41] Ross ME. Cell division and the nervous system: regulating the cycle from neural differentiation to death. Trends Neurosci 1996;19:62 8. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 139
  • 143. [42] Matsushime H, Quelle DE, Shurtleff SA, et al. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol 1994;14:2066-76. [43] Meyerson M, Harlow M. Identification of GI kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol 1994;14:2077-86. [44] Pardee AB. GI events and regulation of cell proliferation. Science 1989;246:603-8. [45] Sherr CJ. GI phase progression: cycling on cue. Cell 1994;79:551 5. [46] Clarke PG. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl) 1990;181:195-213. [47] Schwartz LM, Smith SW, Jones MEE, et al. Do all programmed cell deaths occur via apoptosis? Proc Natl Acad Sci USA 1993;90:980-4. [48] Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239-57. [49] Warkany J, Lemire RJ, Cohen MM. Mental retardation and congenital malformations of the central nervous system. Chicago: Year Book Medical; 1981. p. 13-40. [50] Haslam R, Smith DW. Autosomal dominant microcephaly. J Pediatr 1979;95:701-5. [51] Optiz JM, Holt MC. Microcephaly: general considerations and aids to nosology. Craniofac Genet Dev Biol 1990;10:175-204. [52] Renier WO, Gabreels FJM, Jasper TWJ, et al. An x-linked syndrome with microcephaly, severe mental retardation, spasticity, epilepsy and deafness. J Ment Defic Res 1982;26: 27-40. [53] Evrard P, De Saint-Georges P, Kadhim H, et al. Pathology of prenatal encephalopathies. In French JH, Harel S, Casaer P, editors. Child neurology and development disabilities. Baltimore: PH Books; 1989. p. 153-76. [54] Lenke RR, Levy HL. Matemal phenylketonuria and hyperphenylaianinemia. N Engl J Med 1980;303:1202-8. [55] Yamazaki JN, Schull WJ. Perinatal loss and neurological abnormalities among children of the atomic bomb. Nagasaki and Hiroshima revisited, 1949 to 1989. JAMA 1990;264: 605-9. [56] Barkovich AJ, Chuang SH. Unilateral megalencephaly: correlation of MR imaging and pathologic characteristics. Am J Neuroradiol 1990; 1 1:523-3 1. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 140
  • 144. [57] DeRosa MJ, Secor DL, Barsom M, et al. Neuropathologic findings in surgically treated hemimegalencephaly: immunohistochemical, morphometric and ultrastructural study. Acta Neuropathol (Berl) 1992;84:250-60. [58] Renowden S, Squier M. Unusual magnetic resonance and neuropathological findings in hemi-megalencephaly: report of a case following hemispherectomy. Dev Med Child Neurol 1994;36:357-69. [59] Rintahaka P, Chugani H, Messa C, et al. Hemimegalencephaly: evaluation with positron emission tomography. Pediatr Neurol 1993;9:21-8. [60] DeMyer W. Megalencephaly in children. Clinical syndromes, genetic patterns and differential diagnosis from other cases of megalencephaly. Neurology 1972;22:634-A3. [61] DeMyer W. Megalencephaly: types, clinical syndromes and management. Pediatr Neurol 1986;2:321-8. [62] Hager BC, Dyme IZ, Guertin SR, et al. Linear nevus sebaccous syndrome: megalencephaly and heterotopic gray matter. Pediatr Neurol 1991;7:45-9. [63] Pavone L, Curatolo P, Rizzo R, et al. Epidermal nevus syndrome: a neurologic variant with hemimegalencephaly, gyral malformation, mental retardation, seizures, and facial hemihypertrophy. Neurology 1991;41:266-71. [64] Jelinek JE, Bart RS, Schiff GM. Hypomelanosis of Ito ("incontinentia pigmenti achromians"): report of three cases and review of the literature. Arch Dermatol 1973;107: 596-601. [65] Haines JL, Short MP, Kwiatkowski DJ, et al. Localization of one gene for tuberous sclerosis within 9q32-9q34, and further evidence for heterogeneity. Am J Hum Genet 1991; 49:764--72. [66] Ogawa M, Miyata T, Nakajima K, et al. The reeler gene-associated antigen on Cajal- Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neurons 1995;14:899-912. [67] Sidman R, Rakic P. Neuronal migration with special reference to developing human brain, a review. Brain Res 1973;62:1-35. [68] Aicardi J. The place of neuronal migration abnormalities in child neurology. Can J Neurol Sci 1994;21:185-93. [69] Angevine J, Sidman R. Autoradiographic study of cell migration during histogenesis of cerebral cortex of the mouse. Nature 1961;192:766-8. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 141
  • 145. [70] D'Arcangelo G, Miao GG, Chen S-C, et al. A protein related to extracellular matrix proteins deleted in the mouse reeler. Nature 1995;374:719 23. [71] D'Arcangelo G, Miao GG, Curran T. Detection of the reelin breakpoint in reeler mice. Brain Res Mol Brain Res 1996;39:234-6. [72] Hirotsune S, Takahara T, Sasaki N, et al. The reeler gene encodes a protein with an EGF- like motif expressed by pioneer neurons. Nat Genet 1995;10:77-83. [73] Rommsdorff M, Gotthardt M, Hiesberger T, et al. Reeler/disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 1999;97:689-701. [74] Ledbetter SA, Kuwano A, Dobyns WB, et al. Microdeletions of chromosome 17pl3 as a cause of isolated lissencephaly. Am J Hum Genet 1992;50:182-9. [75] Sharief N, Craze J, Summers D, et al. Miller-Dieker syndrome with ring chromosome 17. Arch Dis Child 1991;66:710-2. [76] Greenberg F, Stratton R, Lockhart L, et al. Familial Miller-Dieker syndrome associated with pericentric inversion of chromosome 17. Am J Med Genet 1986;23:853-9. [77] Dobyns WB, Stratton RF, Parke JT, et al. Miller-Dieker syndrome: lissencephaly and monosomy 17p. J Pediatr 1983;102:552-8. [78] Chong SS, Pack SD, Roschke AV, et al. A revision of the lissencephaly and Miller- Dieker syndrome critical regions in chromosome 17pl3.3. Hum Mol Genet 1997;6:147 55. [79] Lo Nigro C, Chong SS, Smith ACM, et al. Pbint mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller- Dieker syndrome. Hum Mol Genet 1997;6:157-64. [80] Pilz DT, Matsumoto N, Minnerath S, et al. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Mol Genet 1998;7: 2029-37. [81] Gleeson JG, Luo RF, Grant PE, et al. Genetic and neuroradiological heterogeneity of double cortex syndrome. Ann Neurol 2000;47:265-9. [82] Leventer RJ, Pilz DT, Matsumoto N, et al. Lissencephaly and subcortical band heterotopia: molecular basis and diagnosis. Mol Med Today 2000;6:277-84. [83] Matsumoto N, Leventer RJ, Kuc J, et al. Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia. Eur J Hum Genet 2000;9(t):5-12. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 142
  • 146. [84] Dobyns WB, Truwit CL, Ross ME, et al. Differences in the gyral pattern distinguish chromosome 17-linked and X-linked lissencephaly. Neurology 1999;53:270-7. [85] Gleeson JG, Allen KM, Fox JW, et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998;92:63-72. [86] Palmini A, Andermann F, Aicardi J, et al. Diffuse cortical dysplasia, or the "double cortex syndrome": the clinical and epileptic spectrum in 10 patients. Neurology 1991;41: 1656-62. [87] Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 2000;26:93-6. [88] Fukuyama Y, Ohsawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type-clinical, genetic and pathologic considerations. Brain Dev 1981;3:1-29. [89] Takashirna S, Becker L, Chan F, et al. A Golgi study of the cerebral cortex in Fukuyama- type congenital muscular dystrophy, Walker-type "lissencephaly," and classical lissencephaly. Brain Dev 1987;9:621-6. [90] Toda T, Miyake M, Kobayashi K, et al. Linkage-disequilibrium mapping narrows the Fukuyama-type congenital muscular dystrophy (FCMD) candidate region to less than 100 kb. Am J Hum Genet 1996;59:1313-20. [91] Toda T, Yoshioka M, Nakahori Y, et al. Genetic identity of Fukuyama-type congenital muscular dystrophy and Walker-Warburg syndrome. Ann Neurol 1995;37:99-101. [92] Kobayashi K, Nakahori Y, Miyake M, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394:388-92. [93] Worthington S, Turner A, Elber J, et al. 22q II deletion and polymicrogyria-cause or coincidence? [In Process Citation]. Clin Dysmorphol 2000;9:193-7. [94] Leventer RJ, Lese CM, Cardoso C, et al. A study of 220 patients with polymicrogyria delineates distinct phenotypes and reveals genetic loci on chromosome I p, 2p, 6q, 21 q and 22q. Am J Hum Gen 2001;70(Suppi):Abstract. [95] Villard L, Nguyen K, Winter RM, et al. X-linked bilateral perisylvian polymicrogyria maps to Xq28. In Am J Hum Gen 2001;70(Suppl):Abstract. [96] Raymond AA, Fish D, Sisodiya S, et al. Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy: clinical, EEG and neuroimaging features in I 00 adult patients. Brain 1995; 1 18:629-60. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 143
  • 147. [97] Dome HL, O'Gorman AM, Melanson D: Computed tomography of intracranial gangliogliomas. AJNR Am j Neuroradiol 7:281-285, 1986 [98] Otsubo H, Hoffman Hj, Humphreys RP, et al: Detection and management of gangliogliomas in children. Surg Neurol 38:371-378,1992 [99] Zentner J, Wolf HK, Ostertun B, et al: Gangliogliomas: Clinical, radiological, and histopathological findings in 51 patients. I Neurol Neurosurg Psychiatry 57:1497- 1502,1994 [100] Daumas-Duport C, Scheithauer BW, Chodkiewicz JP: Dysembryoplastic neuroepithelial tumor: A surgically curable tumor of young patients with intractable partial seizures. Neurosurgery 23:545-556, 1988 [101] Jay V, Becker LE, Otsubo H, et al: Pathology of temporal lobectomy for refractory seizures in children: Re- [102] Kuroiwa T, Bergey GK, Rothman MI, et al: Radiologic appearance of the dysembroplastic neuroepithelial tumor. Radiology 197:233-238,1995 [103] Barkovich Aj, Kuzniecky RI, Dobyns WB, et al: A classification scheme for malformations of cortical development. Neuropediatrics 27:59-63, 1996 [104] Becker LE: Central neuronal tumors in childhood: Relationship to dysplasia. J Neurooncol 24:13-19, 1995 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 144
  • 148. INDEX |  INTRODUCTION INTRODUCTION Focal cortical dysplasia (FCD) is found in approximately one-half of patients with medically refractory epilepsy. These lesions may involve only mild disorganization of the cortex, but they may also contain abnormal neuronal elements such as balloon cells. Advances in neuroimaging have allowed better identification of these lesions, and thus more patients have become surgical candidates. Molecular biology techniques have been used to explore the genetics and pathophysiological characteristics of FCD. Data from surgical series have shown that surgery often results in significant reduction or cessation of seizures, especially if the entire lesion is resected. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 145
  • 149. Focal cortical dysplasia is a significant cause of medically refractory epilepsy. Although aberrant cortical lamination had been described in epilepsy patients in the past, FCD was not extensively studied until Taylor, et al.,[50] in 1971 described a series of 10 epileptic patients with various degrees of cortical dysplasia. The characteristic balloon cells in these lesions were first described in this report. During the last 35 years, developments in imaging, electroencephalography, and electrocorticography have allowed more patients with medically refractory epilepsy to undergo resective surgery. Advances in molecular biology and physiology have led to a better understanding of the genetics and pathophysiological characteristics of FCD. We review the pathological features, pathophysiological characteristics, and genetics of FCD, as well as report on surgical outcomes in patients with FCD.  Pathological and Pathophysiological Features Focal cortical dysplasias are part of an array of disorders described variously as disorders of cortical development, cortical dysplasias, cortical dysgenesis, or neuronal migration disorders.[42] Classification of these disorders depends on either their pathological characteristics or the proposed origin of the pathological elements (for example, neuronal migration). Histological findings in cortical dysplasia include architectural abnormalities such as cortical laminar disorganization and columnar disorganization. More severe forms of FCD are characterized by the presence of abnormal neuronal elements, such as immature neurons, dysmorphic neurons, giant cells, and balloon cells. Immature neurons are round homogeneous cells with large nuclei.[42] Dysmorphic neurons have distorted cell body, axon, and dendrite morphology caused by the accumulation of neurofilaments within the cytoplasm.[44,45] Giant cells are increased in size but are normal in shape and do not show an accumulation of neurofilaments.[42,47] Balloon cells are considered a hallmark of FCD, although they are not present in all patients with FCD. First described by Taylor, et al.,[50] these cells have an eosinophilic cytoplasm and an eccentric nucleus. Immunohistochemical studies have shown that balloon cells have both neuronal and glial characteristics. Many of these cells are immunopositive for vimentin, and others are immunopositive for glial fibrillary acidic protein, neuron-specific enolase, microtubule- associated protein, or neuronal-specific nuclear protein.[42,44,45,48]  Classification of FCD To further classify the pathological features associated with FCD, a panel of epileptologists and neuropathologists devised a classification scheme[42] in 2004 that has been widely adopted. They distinguished two types of dysplasia based on the presence or absence of dysmorphic neurons or balloon cells. In Type I FCD, there are no dysmorphic neurons or balloon cells. In Type IA, isolated architectural abnormalities, usually laminar or columnar disorganization, are found. Type IB is also characterized by architectural abnormalities, but giant cells or immature neurons are also seen. It is important to note that no abnormal cells are present in Type I FCD. On the other hand, abnormal neurons are found in type II FCD. In Type IIA, there are dysmorphic cells but no balloon cells. In Type IIB, both dysmorphic cells and balloon cells are found. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 146
  • 150. Some correlation exists between the neuropathological findings, clinical presentation, and radiographic findings for these types. Type I FCD can be clinically silent and found in healthy patients. Indeed, autopsy studies have revealed that FCD is found in about 1.7% of healthy brains.[6] Some patients with Type I FCD may have cognitive impairment instead of epilepsy.[42] Magnetic resonance imaging findings associated with Type I FCD may include focal cortical thickening, reduced demarcation of the gray-white matter junction, hyperdensity of gray and subcortical white matter on T2-weighted images, hypodensity of subcortical white matter on T1-weighted images, lobar hypoplasia, and atrophy of the white matter core.[1,2,11] On the other hand, Type II FCD is more likely to be associated with medically refractory epilepsy. On MR images, these lesions may be seen as focal areas of increased cortical thickness, blurring of the gray-white junction, increased signal intensity on T2 weighted images, or extension of cortical tissue with increased signal intensity from the surface to the ventricle.[1-3,8,11,26,32] Although different MR findings are associated with Types I and II FCD, there is significant overlap. Thus, a specific categorization of FCD cannot be made solely on the basis of MR imaging findings and must ultimately be based on histological findings.[11] Figure 1. Focal cortical dysplasia  Investigation of Mechanisms Leading to Epilesy Investigation of the mechanisms by which focal cortical dysplastic lesions cause epilepsy is an active area of research. There is evidence for both an increased excitatory state and decreased inhibition. Molecular characterization of these lesions has suggested several potential mechanisms that can lead to hyperactivity of these lesions. One such mechanism is altered expression of NMDA receptors, which are excitatory glutamate receptors that conduct calcium. They are composed of heterodimers of two families, NR1 and NR2.[51] Numerous studies have demonstrated that FCD lesions have an elevated expression of NR2A/B subunit proteins and their associated clustering protein PSD95 in the dysplastic neurons and that these substances have a low expression level in normal neuronal tissues.[15,34,37,53-55] There is some evidence to suggest a correlation between the elevation of NR2A/B subunit expression and the degree of in vivo epileptogenicity.[37] In one animal model of FCD, an NR2B receptor antagonist has raised the threshold of bicuculline-induced epileptic discharge, suggesting that NR2B subunits may have a functional role in the hyperexcitability of the dysplastic lesions.[16] Nevertheless, the exact mechanism by which elevation of NR2A/B subunit expression leads to epileptogenicity is still unclear. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 147
  • 151. Another class of glutamate receptors, AMPA receptors, has also been implicated in the pathogenesis of FCD. AMPA receptors are composed of four subunits (Glu R1-4) and conduct sodium. AMPA receptors interact with NMDA receptors by removing the magnesium blockade on the NMDA receptors. Elevated expression of GluR2/3 subunits has been found in FCD lesions.[23] Increased GluR4 messenger RNA expression has also shown in FCD neurons.[15] Whether the AMPA receptors contribute to the hyper- excitability through interaction with the NMDA receptors is unclear at this point. In addition to hyperexcitability, decreased inhibition is also implicated in the pathogenesis of FCD. Early studies have shown that parvalbumin and calbindin D28K immunoreactive neurons, which are inhibitory GABAergic neurons, are absent in dysplastic lesions.[19] The reduction of GABAergic neurons has been confirmed by Spreafico, et al.,[46] who have shown that the level of glutamic acid decarboxylase, the rate-limiting enzyme for GABA synthesis, is greatly reduced in dysplastic regions resected from human patients. These authors have also reported differences in organization of GABAergic neurons in Types I and II cortical dysplasia. In lesions of Type I cortical dysplasia, which have no giant neurons or balloon cells, a reduction in parvalbumin and glutamic acid decarboxylase immunoreactivity has been found. In contrast, lesions of Type II cortical dysplasia have shown an overall reduction of parvalbumin, but the giant cells are surrounded by terminals that are positive for parvalbumin and glutamic acid decarboxylase.[46] This reduction of GABAergic neurons has also been seen in experimental models of cortical dysplasia.[43] In contrast, Calcagnotto, et al.,[7] have not found an overall reduction of glutamic acid decarboxylase expression in Type II dysplastic lesions. Instead, they have described a reorganization of GABAergic neurons, including parvalbumin-positive and calbindin-positive interneurons. In contrast to normal tissue, where these interneurons are found in layer II/III, the interneurons in dysplastic lesions were found to be evenly distributed in all cortical layers. In addition, they have found effects on GABA transport in dysplastic lesions, including reduced expression of GABA transporter. The overall effect of these alterations is reduced inhibitory postsynaptic current frequency in type II cortical dysplasia tissue. Thus, there is evidence for both increased excitation and reduced inhibition in various experimental models, as well as in human cortical dysplasia. The exact role of balloon cells in the production of an epilepsy phenotype is unknown.  Genetics Of FCD Focal cortical dysplasia is thought to be a neuronal migration disorder. It lies at the milder end of the spectrum of neuronal migration disorders that exhibit only focal abnormalities. The other end of spectrum includes diseases such as lissencephaly, in which there is a significant reduction of gyri and thickening of gray matter over a large area of the brain. Although all of these diseases involve neuronal migration as part of their pathogenesis, the underlying causes of neuronal migration dysfunction in the various disorders may be different. Lissencephaly, periventricular nodular heterotopia, and subcortical band heterotopia (double cortex) are single-gene disorders involving proteins that interact with the cytoskeleton.[14] Lissencephaly, the most severe neuronal migration disorder, is characterized by a smooth brain surface, marked reduction of gyri, and increased cortical www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 148
  • 152. thickness.[27] Mutations in five different genes (LIS1, DCX, 14-3-3e, RELN, and ARX) have been shown to cause lissencephaly.[27] Although mutations in each of these genes have been associated with lissencephaly, a different phenotype exists depending on the gene in which the mutation occurs. For example, mutations in DCX and RELN are more likely to lead to anterior cortex involvement, and mutations in LIS1, 14-3-3?, and ARX are more likely to lead to posterior cortex involvement.[27] Mutations in DCX lead to a characteristic subcortical band of heterotopic neuronal elements, and hence the name doublecortin has been given to the protein encoded by DCX.[27] Each of the proteins encoded by these genes has some interaction with the cytoskeleton. The LIS1 protein, for example, interacts with tubulin and suppresses microtubule dynamics.[27] The DCX protein also has a motif that binds to tubulin and may interact with the LIS1 protein. The protein encoded by RELN, on the other hand, is an extracellular protein that interacts with integrin and lipoprotein receptors, which in turn act on downstream protein kinases that regulate cytoskeletal formation.[27] Mutations in filamin1 have been identified in another class of disease, periventricular nodular heterotopia, which is characterized by differentiated neurons inside misplaced nodules.[14] Filamin1 protein has been thought to be involved in the formation of filopodia, the cell processes that lead and guidea cell's migration, and disruption of filopodia formation may lead to dysfunction in neuronal migration.[14] A common theme in all of these disorders is involvement of proteins that interact with or regulate cytoskeleton formation. Lissencephaly and periventricular nodular heterotopia are the best studied neuronal migration disorders. The mechanisms of other diseases are less well understood. Recent evidence has suggested that mutations in other classes of genes may also cause neuronal migration disorders. For example, mutations in Emx2, which encodes a transcription factor involved in forebrain formation, have been found in patients with schizencephaly, although not in all cases.[20] Schizencephaly is characterized by clefts extending from the pial surface to the lateral ventricle that are lined with abnormally laminated polymicrogyric cortex. It is unclear how Emx2 mutations lead to neuronal migration problems in these patients. Both congenital and genetic causes have been proposed for FCD. Some evidence supports a genetic basis for FCD or at least a genetic contribution to its pathogenesis. In two studies, patients with FCD were noted to have a family history of epilepsy.[35,36] In addition, a positive family history of epilepsy was found to predict an earlier age at onset of seizures in patients with FCD.[35] Studies that include larger numbers of patients are needed to determine whether FCD has a genetic basis or genetic modifiers. Overlapping clinical and pathological findings have been noted in brains of patients with tuberous sclerosis and in those of patients with other types of cortical dysplasia. Authors of several interesting papers have suggested that TSC1 is involved in the pathogenesis of FCD.[5,17] Mutations in TSC1 are known to cause tuberous sclerosis, which, like FCD, is characterized by balloon cells, but also has a number of other clinical features.[20] Amino acid polymorphisms involving exons 5 and 17 in TSC1 and silent base substitutions in exons 14 and 22 were found in a significantly higher proportion of patients with focal dysplasia, compared with controls.[5] In addition, loss of TSC1 heterozygosity has been www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 149
  • 153. noted in focal cortical dysplastic lesions themselves.[5] This loss of heterozygosity is specific to TSC1, as no genomewide genetic instability has been observed.[17] It is still unclear how mutation or dysfunction of TSC1 leads to neuronal migration disorder. In a recent study, however, the protein encoded by TSC1 was found to be part of the mTOR signaling pathway, a protein kinase pathway involved in cell growth, apoptosis, and cell cycle regulation.[31] Loss of function of TSC1 affects soma size and dendritic spine formation.[49] If the formation of some of these neuronal processes is involved in neuronal migration, this relationship would explain the role of TSC1 in regulation of neuronal migration; however, the exact mechanism is still unclear. Other proteins that have been shown to be altered in FCD neurons are the Notch and Wnt pathway proteins. These two signaling pathways are known to be involved in neuronal migration.[12] It is unlikely that patients with FCD have a mutation in the genes that encode these proteins, as mutations in the genes for the key proteins in these pathways usually have widespread phenotypes; however, mutations in genes for the regulators of these genetic pathways may be one cause of FCD. Indeed, it is thought that one mechanism by which Emx2 mutations cause schizencephaly is through alteration of the Wnt1 expression level.[33] Indirect evidence from experimental models has suggested that interruption of genetic material can lead to FCD. For example, application of radiation or methylazoxymethanol, which both act to disrupt DNA structure, has been used to create models of FCD.[7] There are several reasons why no single genetic mutation has been shown to cause cortical dysplasia. First, FCD represents a rather diverse group of neuron structural abnormalities. As described earlier, FCD can be classified into several types (Types IA, IB, IIA, and IIB) on the basis of histopathological criteria. A second reason is that most surgical series have involved only 20 to 60 patients (see later), and these numbers are too low for detection of most rare events. Third and most important, FCD is unlikely to be associated with a single gene mutation, as is lissencephaly or periventricular nodular heterotopia. Rather, it is likely to be associated with subtle polymorphism mutations in the regulatory elements, or to involve multiple genes, as observed in the case of TSC1. Candidate genes that could cause FCD are those involved in neuronal migration pathways, such as the Notch or Wnt signaling pathways.[13] Mutations in these genes that lead to a loss of function, however, are usually lethal in the embryo. Thus, it is more likely that hypomorphic mutations, or mutations in the regulatory elements, are associated with FCD. Detecting such mutations is much more difficult and requires studies involving large numbers of patients. New mutation analysis methods and new genome investigations such as the International HapMap Project should shed light on the pathogenesis of FCD.  Surgery for FCD Since the report by Taylor, et al., in 1971,[50] FCD has become increasingly recognized as a cause of medically refractory epilepsy. With advances in neuroimaging and electrophysiological monitoring, lesions in FCD can be more accurately identified and are thus more amenable to resection. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 150
  • 154. Epilepsy remains the most common presentation of FCD. Approximately one half of patients with epilepsy have some form of FCD;[6] however, some patients with Type I FCD may not show symptoms or may show only mild cognitive impairment. Medically refractory epilepsy is the main reason for surgical intervention in patients with FCD. Preoperative neuroimaging usually includes high-resolution MR imaging, which can reveal approximately 60 to 90% of cortical abnormalities in these patients.[4,6,10] Characteristic findings include an abnormal gyral pattern, increased cortical thickness, poor gray-white matter differentiation, and increased subcortical signal intensity on T2- weighted and fluid-attenuated inversion-recovery MR images.[4,6,11] Many patients, especially those with normal MR imaging findings, undergo additional diagnostic procedures. Scalp EEG is frequently used and was one of the more important modalities during early surgical series. Approximately one half to two thirds of patients with abnormal EEG findings have a regional ictal abnormality.[4,6] In some cases, intracranial subdural recordings, most commonly with grid arrays, are used. Chronic subdural recording allows identification of eloquent cortex, in addition to definition of the epileptogenic region.[6] The first published description of a surgical series of patients with FCD was by Taylor, et al.,[50] in 1971. This seminal study included a total of 10 patients, eight of whom had FCD that was confirmed by histological findings. Six of these patients became seizure free after surgery. The first large series was described by Palmini, et al.,[40] in 1991. This series included 26 patients with focal neuronal migration disorders, 12 of whom had definitive FCD. Five of the 12 patients had lesions confined to one lobe or one area of the brain, and seven had multilobar involvement. Seven of the 12 patients had complete cessation or excellent control of seizures after surgery.[39] Seizure control was highly correlated with successful resection of the entire lesion or at least the majority of the abnormal tissue. Complete resection did not necessarily predict cessation of seizures, however, as poor control of seizures remained in some patients despite removal of all of the tissue associated with epileptiform discharges in EEG or electrocorticography findings. In 1995, Palmini, et al.,[41] further characterized these patients, as well as additional patients from two other institutions. In this series of 34 patients, outcome data were available for 27 patients. An important aspect of this study was the careful documentation of the EEG findings in patients with cortical dysplasia. Approximately two thirds of the patients demonstrated characteristic epileptic discharges, including repetitive electrographic seizure activity, repetitive bursting discharges, and continuous or quasicontinuous rhythmic spiking. In this expanded series with longer follow up, 75% of the patients who underwent complete resection of regions associated with abnormal electrical activities had a good outcome, and the patients in whom some of these areas remained had relatively poor seizure control. Thus, the concept of combined resection of areas showing radiological and electrophysiological abnormalities was emphasized. Several reports on surgical series were published in the 1990s. Hirabayshi, et al.,[24] compared seizure control after surgery in patients with FCD and patients with mesial www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 151
  • 155. temporal sclerosis. Only six of 17 patients with FCD became seizure free or almost seizure free after the surgery, a significantly worse rate of seizure control, compared with the rate for patients who underwent surgery for mesial temporal sclerosis. Outcome was correlated with the extent of the pathological lesions. Involvement of tissue outside of the temporal or frontal lobes was an independent predictor of poor outcome, whereas frontal lesions and temporal locations were factors favoring a good surgical outcome. Otsubo, et al.,[38] reported on nine children with FCD who underwent resection between 1987 and 1991. Three patients became seizure free after the surgery. There was no conclusion about a relationship between the extent of resection and outcome.Wyllie, et al.,[52] reported results for 30 patients after surgery for migration disorders. Sixteen patients with extratemporal epilepsy were available for follow up, 13 of whom either became seizure free or had greater than 90% reduction of seizure frequency. In this study, 13 patients had Type I FCD involving the temporal lobe. None of them showed abnormalities on MR images. It is important to note that 10 of these patients became seizure free after surgery and the other three reported significant reductions in seizures. Kuzniecky, et al.,[30] described 11 patients who underwent resection for frontocentral malformations. In 10 of the 11 patients, MR images showed abnormalities. In a group of four patients with frontal involvement, one patient became seizure free and the other three had significant reductions in seizures. Three of the five patients with central lesions demonstrated improvement in seizures after surgery, and the remaining two did not have significant improvement. The authors emphasized that regions of dysplasia could contain normally functioning tissue, which would preclude aggressive resection without production of significant neurological deficits. In the past few years, descriptions of several additional series of patients who underwent surgery for FCD have been published. It is important to note that many of these studies have had longer follow-up times and have included the use of more advanced imaging techniques, compared with earlier studies. Kloss, et al.,[28] have reported on a series of 68 pediatric patients with FCD. Long-term complete seizure control was achieved in approximately 50% of the patients, and another 20% of the patients had excellent seizure control. No significant difference in seizure control after surgery was found between the patients who had Type I FCD and those who had Type II FCD. Again, complete resection of the lesion was the most important factor for complete seizure control. Hong, et al.,[25] have described a series of patients with cortical dysplasia who underwent surgery; nine of these patients had FCD. Complete cessation of seizures was observed in seven of the nine patients after surgery. Tassi, et al.,[47] have reported on a series of 52 patients with focal dysplasia who underwent surgery. In addition to MR imaging and scalp EEG, stereo-EEG was used in some patients to localize the lesions. Overall, 70% of the patients who underwent resection experienced excellent outcomes, with cessation of seizures or more than a 90% reduction in seizure frequency. One interesting observation in this series was that patients with Type II FCD fared better than patients with Type I FCD. Seventy-five percent of the patients with Type II FCD had complete cessation of seizures, compared with 62% of patients with Type IA FCD and 50% of patients with Type IB FCD. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 152
  • 156. Kral, et al.,[29] have described 53 patients in whom a diagnosis of FCD was made, 72% of whom had complete cessation of seizures after surgery and an additional 4% of whom had no more than two seizures per year after surgery. Identification of structural abnormalities on MR images was key to predicting seizure outcome. Multilobar involvement was identified as a predictor of poor outcome in this study. It is important to note that there was no difference in outcome between the patients with temporal as compared to extratemporal involvement in this series. This finding is probably partly due to the fact that most of the extratemporal involvement was in the frontal lobe. Bautista, et al.,[4] have reviewed their experience with surgical treatment of FCD in adults. In this large series of 55 patients, 36 patients had temporal lesions, 19 had extratemporal lesions, and four had multilobar involvement. Most of the patients (87%) showed focal lesions on MR images, and approximately 60% showed additional pathological features such as central nervous system infection, hippocampal sclerosis, or low-grade tumor. Overall, 65% of these patients became seizure free, and 19% had significant improvement. In contrast, in a series of 39 pediatric patients that has been described by Hader, et al.,[21] 72% of the patients had good seizure control, although there was no significant correlation between seizure control and imaging characteristics, histopathological findings, or location of the lesions. It is important to note that 16 patients had incomplete resection of the lesion and underwent multiple subpial resections. One half of these demonstrated good seizure control after the procedure. Thus, multiple subpial resections may offer additional benefit, especially for patients in whom the abnormal tissue cannot be resected due to functional considerations. Cohen-Gadol, et al.,[10] have reported their experience with 22 patients with FCD. As in other series, complete resection with histopathological confirmation of a clean margin predicted good outcome. Ninety-two percent of patients who underwent complete resection became seizure free after the procedure, compared with only 43% of the patients who had margins still positive for FCD. Of the 22 patients, 20 patients harbored abnormalities identified on MR images. As in other series, the lesion areas with abnormal discharge often extended beyond the abnormal area identified on MR images. Fauser, et al.,[18] have correlated the control of seizures after resection with histopathological findings and have found that patients with Type I FCD fared better than those with Type II FCD. Sixty-three percent of patients with Type IA and 55% of those with Type IB were seizure free after surgery, compared with 43% of patients with Type IIA and 50% of those with Type IIB. Chapman, et al.,[9] have described outcomes for 24 patients who had intractable seizures and normal MR imaging findings. In 42% of these patients, FCD was found. Overall, 80% of the patients had a significant reduction in the number of seizures after resection. This finding suggests that many patients with intractable seizures and normal MR imaging findings may have FCD and that resection should still be attempted in these patients, as good outcomes are frequently observed. Hamiwka, et al.,[22] have reported results of a 10-year follow up of patients who had cortical malformations and underwent resection. Thirty-one of these patients had FCD. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 153
  • 157. Only 32% of the patients remained seizure free over 10 years. Once again, the extent of resection was the most important factor in determining seizure control outcome. SUMMARY Surgery for FCD can benefit many patients, especially if complete resection of abnormal regions is possible. The preoperative workup should include high-resolution MR imaging, videotelemetry, and EEG. It is important to recognize that MR imaging findings may be normal in some cases and that regions of histological FCD may extend beyond the abnormal areas identified on MR images. Intraoperative monitoring frequently includes electrocorticography, cortical stimulation for motor mapping, and, sometimes, somatosensory evoked potentials if the lesion is near the central sulcus. In recent years, frameless navigation systems have been useful in resection. The best outcomes result when resection of areas with radiological and electrophysiological abnormalities can be achieved. When the results from published descriptions of surgical series were combined, approximately 60% of patients with FCD experienced good seizure control after resection of the lesion ( Table 1 ). As normal radiological studies do not preclude a diagnosis of cortical dysplasia, only careful and complete histopathological examination of tissue removed from patients with pharmacoresistant epilepsy will help to determine the percentage of cases where FCD exists. Neuroimaging techniques will continue to improve over time and will likely be more useful for identifying the extent of lesions in the future. Co-registration of data from high-resolution MR imaging, EEG, magnetoencephalography, positron emission tomography, and functional MR imaging will allow maximal resection of the abnormal regions with less morbidity. Table 1. Summary of Outcomes in Surgical Series of Patients With FCD Authors & Year No. of Patients % w/ Favorable Outcome* Taylor, et al.,1971 8 75 Palmini, et al.,1991 12 58 Hirabayshi, et al.,1993 17 35 Otsubo, et al.,1993 9 33 Wyllie, et al.,1994 28 89 Kuzniecky, et al.,1995 11 64 Palmini, et 27 41 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 154
  • 158. al.,1995† Hong, et al.,2000 9 89 Kloss, et al.,2002 68 70 Tassi, et al.,2002 52 70 Bautista, et al.,2003 55 84 Kral, et al.,2003 53 72 Cohen-Gadol, et al.,2004 22 73 Hader, et al.,2004 39 72 Chapman, et al.,2005 10 80 Hamiwka, et al.,2005 31 32 overall 58 * Favorable outcome includes cessation of seizures and significant reduction(at least 70%) of seizure frequency. † This series included some patients References 1. Barkovich AJ, Kjos BO: Nonlissencephalic cortical dysplasias: correlation of imaging findings with clinical deficits. AJNR Am J Neuroradiol 13:95-103, 1992 2. Barkovich AJ, Kuzniecky RI: Neuroimaging of focal malformations of cortical development. J Clin Neurophysiol 13: 481-494, 1996 3. Bastos AC, Comeau RM, Andermann F, et al: Diagnosis of subtle focal dysplastic lesions: curvilinear reformatting from three-dimensional magnetic resonance imaging. Ann Neurol 46: 88-94, 1999 4. Bautista JF, Foldvary-Schaefer N, Bingaman WE, et al: Focal cortical dysplasia and intractable epilepsy in adults: clinical, EEG, imaging, and surgical features. Epilepsy Res 55: 131-136, 2003 5. Becker AJ, Urbach H, Scheffler B, et al: Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis. Ann Neurol 52:29-37, 2002 6. Bingaman WE: Surgery for focal cortical dysplasia. Neurology 62:S30-S34, 2004 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 155
  • 159. 7. Calcagnotto ME, Paredes MF, Tihan T, et al: Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia. J Neurosci 25:9649-9657, 2005 8. Chan S, Chin SS, Nordli DR, et al: Prospective magnetic resonance imaging identification of focal cortical dysplasia, including the non-balloon cell subtype. Ann Neurol 44:749-757, 1998 9. Chapman K, Wyllie E, Najm I, et al: Seizure outcome after epilepsy surgery in patients with normal preoperative MRI. J Neurol Neurosurg Psychiatry 76:710-713, 2005 10. Cohen-Gadol AA, Ozduman K, Bronen RA, et al: Long-term outcome after epilepsy surgery for focal cortical dysplasia. J Neurosurg 101:55-65, 2004 11. Colombo N, Citterio A, Galli C, et al: Neuroimaging of focal cortical dysplasia: neuropathological correlations. Epileptic Disord 5 Suppl 2:S67-72, 2003 12. Cotter D, Honavar M, Lovestone S, et al: Disturbance of Notch-1 and Wnt signalling proteins in neuroglial balloon cells and abnormal large neurons in focal cortical dysplasia in human cortex. Acta Neuropathol 98:465-472, 1999 13. Cotter DR, Honavar M, Everall I: Focal cortical dysplasia: a neuropathological and developmental perspective. Epilepsy Res 36:155-164, 1999 14. Couillard-Despres S, Winkler J, Uyanik G, et al: Molecular mechanisms of neuronal migration disorders, quo vadis? Curr Mol Med 1:677-688, 2001 15. Crino PB, Duhaime AC, Baltuch G, et al: Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia. Neurology 56:906-913, 2001 16. DeFazio RA, Hablitz JJ: Alterations in NMDA receptors in a rat model of cortical dysplasia. J Neurophysiol 83:315-321, 2000 17. Fassunke J, Blumcke I, Lahl R, et al: Analysis of chromosomal instability in focal cortical dysplasia of Taylor's balloon cell type. Acta Neuropathol 108:129-134, 2004 18. Fauser S, Schulze-Bonhage A, Honegger J, et al: Focal cortical dysplasias: surgical outcome in 67 patients in relation to histological subtypes and dual pathology. Brain 127:2406-2418, 2004 19. Ferrer I, Oliver B, Russi A, et al: Parvalbumin and calbindin-D28k immunocytochemistry in human neocortical epileptic foci. J Neurol Sci 123:18-25, 1994 20. Foldvary-Schaefer N, Bautista J, Andermann F, et al: Focal malformations of cortical development. Neurology 62:S14-S19, 2004 21. Hader WJ, Mackay M, Otsubo H, et al: Cortical dysplastic lesions in children with intractable epilepsy: role of complete resection. J Neurosurg 100:110-117, 2004 22. Hamiwka L, Jayakar P, Resnick T, et al: Surgery for epilepsy due to cortical malformations: ten-year follow-up. Epilepsia 46: 556-560, 2005 23. Hilbig A, Babb TL, Najm I, et al: Focal cortical dysplasia in children. Dev Neurosci 21:271-280, 1999 24. Hirabayashi S, Binnie CD, Janota I, et al: Surgical treatment of epilepsy due to cortical dysplasia: clinical and EEG findings. J Neurol Neurosurg Psychiatry 56:765-770, 1993 25. Hong SC, Kang KS, Seo DW, et al: Surgical treatment of intractable epilepsy accompanying cortical dysplasia. J Neurosurg 93:766-773, 2000 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 156
  • 160. 26. Hudson TW, Zawko S, Deister C, et al: Optimized acellular nerve graft is immunologically tolerated and supports regeneration. Tissue Eng 10:1641-1651, 2004 27. Kato M, Dobyns WB: Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet 12:R89-R96, 2003 28. Kloss S, Pieper T, Pannek H, et al: Epilepsy surgery in children with focal cortical dysplasia (FCD): results of long-term seizure outcome. Neuropediatrics 33:21-26, 2002 29. Kral T, Clusmann H, Blumcke I, et al: Outcome of epilepsy surgery in focal cortical dysplasia. J Neurol Neurosurg Psychiatry 74:183-188, 2003 30. Kuzniecky R, Morawetz R, Faught E, et al: Frontal and central lobe focal dysplasia: clinical, EEG and imaging features. Dev Med Child Neurol 37:159-166, 1995 31. Kwiatkowski DJ, Manning BD: Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet 14 Spec No. 2:R251-258, 2005 32. Lee BC, Schmidt RE, Hatfield GA, et al: MRI of focal cortical dysplasia. Neuroradiology 40:675-683, 1998 33. Ligon KL, Echelard Y, Assimacopoulos S, et al: Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia. Development 130: 2275-2287, 2003 34. Mikuni N, Babb TL, Ying Z, et al: NMDA-receptors 1 and 2A/B coassembly increased in human epileptic focal cortical dysplasia. Epilepsia 40:1683-1687, 1999 35. Montenegro MA, Guerreiro MM, Lopes-Cendes I, et al: Association of family history of epilepsy with earlier age at seizure onset in patients with focal cortical dysplasia. Mayo Clin Proc 77:1291-1294, 2002 36. Montenegro MA, Guerreiro MM, Lopes-Cendes I, et al: Interrelationship of genetics and prenatal injury in the genesis of malformations of cortical development. Arch Neurol 59: 1147-1153, 2002 37. Najm IM, Ying Z, Babb T, et al: Epileptogenicity correlated with increased N- methyl-D-aspartate receptor subunit NR2A/B in human focal cortical dysplasia. Epilepsia 41:971-976, 2000 38. Otsubo H, Hwang PA, Jay V, et al: Focal cortical dysplasia in children with localization-related epilepsy: EEG, MRI, and SPECT findings. Pediatr Neurol 9:101-107, 1993 39. Palmini A, Andermann F, Olivier A, et al: Focal neuronal migration disorders and intractable partial epilepsy: results of surgical treatment. Ann Neurol 30:750-757, 1991 40. Palmini A, Andermann F, Olivier A, et al: Focal neuronal migration disorders and intractable partial epilepsy: a study of 30 patients. Ann Neurol 30:741-749, 1991 41. Palmini A, Gambardella A, Andermann F, et al: Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 37:476-487, 1995 42. Palmini A, Najm I, Avanzini G, et al: Terminology and classification of the cortical dysplasias. Neurology 62:S2-S8, 2004 43. Roper SN, Eisenschenk S, King MA: Reduced density of parvalbumin-and calbindin D28-immunoreactive neurons in experimental cortical dysplasia. Epilepsy Res 37:63-71, 1999 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 157
  • 161. 44. Spreafico R, Battaglia G, Arcelli P, et al: Cortical dysplasia: an immunocytochemical study of three patients. Neurology 50: 27-36, 1998 45. Spreafico R, Pasquier B, Minotti L, et al: Immunocytochemical investigation on dysplastic human tissue from epileptic patients. Epilepsy Res 32:34-48, 1998 46. Spreafico R, Tassi L, Colombo N, et al: Inhibitory circuits in human dysplastic tissue. Epilepsia 41 Suppl 6:S168-S173, 2000 47. Tassi L, Colombo N, Garbelli R, et al: Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 125:1719-1732, 2002 48. Tassi L, Pasquier B, Minotti L, et al: Cortical dysplasia: electroclinical, imaging, and neuropathologic study of 13 patients. Epilepsia 42:1112-1123, 2001 49. Tavazoie SF, Alvarez VA, Ridenour DA, et al: Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci 8:1727-1734, 2005 50. Taylor DC, Falconer MA, Bruton CJ, et al: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 34:369-387, 1971 51. Waxman EA, Lynch DR: N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease. Neuroscientist 11:37-49, 2005 52. Wyllie E, Baumgartner, C, Prayson, R, et al: The clinical spectrum of focal cortical dysplasia and epilepsy. J Epilepsy 7:303-312, 1994 53. Ying Z, Babb TL, Mikuni N, et al: Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in dysplastic neurons of human epileptic cortex. Exp Neurol 159:409-418, 1999 54. Ying Z, Bingaman W, Najm IM: Increased numbers of co-assembled PSD-95 to NMDA-receptor subunits NR2B and NR1 in human epileptic cortical dysplasia. Epilepsia 45: 314-321, 2004 55. Ying Z, Najm IM: Mechanisms of epileptogenicity in focal malformations caused by abnormal cortical development. Neurosurg Clin N Am 13:27-33, vii, 2002 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 158
  • 162. INDEX  INTRODUCTION TUBEROUS SCLEROSIS Tuberous sclerosis is a hereditable disorder characterized by the development of early in childhood of hamartomas, malformations and congenital tumours of the CNS, skin and viscera. The pathological changes of tuberous sclerosis are widespread and include lesions in the brain, skin, bone, retina, skin and others. Clinically it is characterized by the occurrence of epilepsy, mental retardation and adenoma sebaceous in various combination. Tuberous sclerosis (TS) is one of the most common phakomatoses. Its occurrence is around 1-20:500,000 births 1 , and Donegani et al. 2 , based on autopsy records, estimate its www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 159
  • 163. prevalence at 1:10,000. Ahlsen et al. 3 in a study carried out in Sweden on a population up to 20 years old, observed a prevalence of 1: 12,900 with a peak of 1:6,800 in the 11-15-year age group. TS is inherited as an autosomal dominant disorder with high penetrance and variable expressivity, with no racial or sexual predilection. As many as 60% of cases have been described as sporadic, resulting from spontaneous genetic mutations in the offspring of healthy parents.4 The number of true sporadic cases is now decreasing as the parents of affected children undergo ocular fundoscopy and renal and cardiac echography.5 TS, like every phakomatosis, can be defined as a primary cytologic dysgenesis.6 The genetic disorder has been identified, with the TSCI and TSC2 genes localized respectively on chromosome 9 band q 34.3 and chromosome 16 band p 13.3.7,8 Nevertheless, a specific molecular marker that would allow recognition of the asymptomatic and quasi- asymptomatic cases has not yet been found.9 TS is a multiorgan disease (skin, retina, lungs, heart, skeleton, and kidneys) involving the embryonic ectoderm, mesoderm, and endoderm. The central nervous system (CNS) is always affected, and CNS disease is often the first indicator of the disorder.10 The primary anomaly of TS is an abnormal differentiation and growth of the neuronal and glial cells, associated with migration anomalies and disorganization of the cortical architecture, formation of tumor-like cell clusters [hamartias or hamartomas according to Gomez 11 ], and rarely neoplasia. The presence of cell dysplasia, however, differentiates phakomatoses from CNS malformations.6  Genetic causes TSC is inherited in an autosomal dominant pattern. An affected parent has a 50% chance of transmitting the disease to offspring. There are a significant number of sporadic mutations, estimated to occur in approximately two thirds of cases. 9 Two genes, TSC1 and TSC2, have been identified. TSC1 is located on chromosome 9 and was identified in 1997. This gene encodes for the protein hamartin. The protein tuberin is encoded by the gene TSC2. TSC2, located on chromosome 16, was the first TSC gene discovered in 1993. Approximately 50% of cases are due to TSC1, and the remaining 50% are due to TSC2. Of sporadic cases, 75% are due to a mutation in the TSC2 gene.9 Table 1. Genetics of tuberous sclerosis Gene Gene Location Gene product Comment TSC1 Chromosome 9 Hamartin Recent findings support the hypothesis that the TSC2 gene and perhaps the TSC I gene act as tumor suppressors. When the TSC mutation occurs, the defective gene product of the TSC mutation is unable to suppress the tumor growth caused by a random somatic cell mutation that produces an oncogene stimulating the formation and growth of hamartomas.9 TSC2 Chromosome 16 Tuberin www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 160
  • 164. At the present time, TSC is a clinical diagnosis, because genetic testing currently is not routinely available. Genetic mutation analysis is available on a research basis. Family members may also be tested on a clinical basis if a mutation is detected. Information regarding this topic is available at the following website: www.geneclinics.org Criteria for germline mosaicism have recently been outlined. Parents who have no evidence of either major or minor criteria of TSC and also have 2 or more children affected with TSC are said to meet the criteria for germline mosaicism. For this reason, parents who have none of the manifestations of TSC but do have 1 child affected with TSC should be counseled about a 1-2% chance of having another child affected with TSC. The incidence of germline mosaicism is estimated to be approximately 10-25%. 9 RADIOLOGICAL PATHOLOGY OF TUBEROUS SCLEROSIS Pathologically tuberous sclerosis is characterized by the presence of Cortical tubers. Subependymal nodule, Giant cell astrocytoma, White matter lesions and Deep white matter lesions. Table 2. Pathology of tuberous sclerosis Pathology Comment Cortical tubers They involve gray matter and contiguous white matter. Sometimes two or more adjacent gyri are affected. They may cause gyral broadening and thickening. At histologic examination the laminar architecture of affected cortex is completely disorganized. Normal neurons and normal glial cells are scanty and abundant undifferentiated neuroepithelial cells and atypical neuron-like cells are observed, with rare clusters of abnormal bizarre glial cells. The subcortical white matter adjacent to a cortical tubers is abnormal, and is usually with defective myelination of neural fibers and gliosis.13 The cortical tubers surface is smooth but becomes depressed due to degenerative phenomena with cellular loss in the affected cortex. Dystrophic calcifications are infrequently present in cortical tubers Subependymal nodule Typically located in the subependymal walls of the lateral ventricles, usually bilateral and mainly at the foramina of Monro. subependymal nodules have never been observed in the third ventricle.9,11 Their number and size are quite variable. Subependymal nodules contain the same kind of cell abnormalities as cortical tubers, but with very many large, bizarre glial cells, fusiform cells, and undifferentiated neuroectodermal cells. However, neuron-like cells are scant. Much vascular and fibroglial stroma with accumulations of calcium deposits is often found. Focal hemorrhages and necrosis have also been reported.9,11,16 Giant cell astrocytoma Subependymal Giant-Cell Astrocytomas are clinically and histopathologically benign.20 They grow slowly, have no surrounding edema, are noninvasive, and rarely show malignant degeneration.21 There are no qualitative histopathologic differences between subependymal www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 161
  • 165. nodules and Subependymal Giant-Cell Astrocytomas. Like subependymal nodules, Subependymal Giant-Cell Astrocytomas contain large amounts of undifferentiated giant cells or abnormally differentiated cells resembling astrocytes or spongioblasts, together with a few abnormal neurons. The fibrovascular stroma contains dystrophic calcifications and cystic or necrotic areas of degeneration.22 Subependymal Giant-Cell Astrocytomas may originate from subependymal nodules located near the foramen of Monro. Recent findings support the hypothesis that the TSC2 gene and perhaps the TSC I gene act as tumor suppressors. When the TSC mutation occurs, the defective gene product of the TSC mutation is unable to suppress the tumor growth caused by a random somatic cell mutation that produces an oncogene stimulating the formation and growth of hamartomas.9 White matter lesions Radial curvilinear bands, straight or wedge-shaped bands, and nodular foci were found. Radial white matter lesions run from the ventricle through the cerebral mantle to the normal cortex or cortical tuber, wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber, and nodular foci are located in the deep white matter. White matter lesions are composed of clusters of dysplastic giant and heterotopic cells, with gliosis and abnormal nerve fiber myelination.1 These anomalies are almost identical to those of the inner core of the cortical tubers. The site, shape, and histopathologic findings of white matter lesions confirm that TSC is a disorder of both histogenesis and cell migration. Deep white matter lesions These are focal, single or multiple lesions, always in the deep or periventricular white matter.9  Cortical tubers In tuberous sclerosis, the most common clinical presentation is seizure, occurring in more than 80% of cases. 9 The brain characteristically reveals multiple nodules ("tuber") in the crest of cerebral gyri. The nodules are generally most abundant in the frontal lobe. The involved cortex is firm in consistency and shows some blurring of the junction between the cortex and white matter. Histologically, the subpial area is thickened by proliferating astrocytes that may be large and bizarre with abundant processes. Laminar organization of the cortex is obscured by numerous large, irregularly oriented neurons with coarsely granular Nissl substance. In addition, there are, large cells with abundant, pale cytoplasm and large, round nuclei with prominent nucleoli. These cells are free of Nissl substance and some seem to be of astrocytic lineage because of their GFAP immunopositivity. They are more frequently found in the white matter, occasionally arranged in clusters. Overall, these features are not dissimilar to those of cortical dysplasia of Taylor. In tuberous sclerosis, however, severe gliosis may be noted in the subpial area. 9 Tuberous sclerosis histopathological features are not dissimilar to those of cortical dysplasia. In tuberous sclerosis, however, severe gliosis may be noted in the subpial area. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 162
  • 166. Figure 1. Postmortem specimens showing cortical tubers, the affected gyri are abnormally broad and flat. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 163
  • 167. Figure 2. A,B CT scan precontrast and C, CT scan postcontrast study, D,E,F precontrast MRI T1 images, G,H,I MRI T2 images. Notice the calcified cortical tuber in the left frontal region. The tuber is hyperdense in CT scan studies and hypointense on the MRI T2 studies (due to calcification). The precontrast T1 hyperintensity observed in the subcortical white matter in (E,F,G) could be due to defective myelination. The cerebral cortex appears lissencephalic and pachygyric especially over he frontal lobes. The cortical tubers surface is smooth but depressed due to degenerative phenomena with cellular loss in the affected cortex. The subcortical white matter adjacent to the cortical tubers shows the characteristic radial white matter lesions, they are wedge-shaped white matter lesions with their apex near the ventricle and their base at the cortex or at the cortical tuber. These white matter lesion are hyperintense on the T2 MRI images and hypointense on the MRI T1 images. They can also be seen as hypodense regions in CT scan studies. Radial white www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 164
  • 168. matter lesions are dysplastic heterotopic neurons seen as migration lines running though the cerebral mantle to a normal cortex or a cortical tuber. Subependymal nodules are also seen in (F) forming what is called candle guttering. Cortical tubers involve gray matter and contiguous white matter. Sometimes two or more adjacent gyri are affected. They may cause gyral broadening and thickening. On MRI, the affected cortex is frequently pseudopachygyric, but the gray matter does not show signal abnormalities on both short and long TR SE images. At histologic examination the laminar architecture of affected cortex is completely disorganized. Normal neurons and normal glial cells are scanty and abundant undifferentiated neuroepithelial cells and atypical neuron-like cells are observed, with rare clusters of abnormal bizarre glial cells.6 The high cortical cellularity implies a free water loss in gray matter, and this explains the normality of the MR signal.12 Figure 3. MRI T1 images (A,B,C,D) and MRI T2 images (E,F). A case of tuberous sclerosis, notice that cortical tubers have broad, irregular, and slightly depressed surface and most marked in the frontoparietal regions. The brain is lissencephalic and pachygyric. Also notice the characteristic radial white matter lesions, they are wedge-shaped white matter lesions with their apex near the ventricle and their base at the cortex or at the cortical tuber. These white matter lesion are hyperintense on the T2 MRI images and hypointense on the MRI T1 images. Radial white matter lesions are dysplastic heterotopic neurons seen as migration lines running though the cerebral mantle to a normal cortex or a cortical www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 165
  • 169. tuber. The precontrast T1 hyperintensity observed in the subcortical white matter in (E) could be due to defective myelination or hypercellularity (Normal neurons and normal glial cells are scanty and abundant undifferentiated neuroepithelial cells and atypical neuron- like cells are seen as migration lines running though the cerebral mantle to a normal cortex or a cortical tuber, these neurons might have a high nuclear to cytoplasmic ratio, with little extracellular water resulting in precontrast T1 hyperintensity and T2 hypointensity) However, the subcortical white matter MR signal is abnormal adjacent to a cortical tuber, and is usually hyperintense on long TR SE images. This is due to defective myelination of neural fibers and gliosis.13 The subcortical white matter in newborns and very young infants appears hyperintense on TIWI and hypointense on T2WI. This can be explained by a greater amount of free water in the unmyelinated white matter compared to the inner core of the cortical tubers.14 The cortical tubers surface is smooth but becomes depressed due to degenerative phenomena with cellular loss in the affected cortex. Dystrophic calcifications cause marked focal hypointensity on T2WI. 11 This is not common in cortical tubers. Signal enhancement on TIWI after GD-DTPA administration is reported in less than 5% of cases.15 Follow-up MRI might show an increase in the number and/or size, or increase of signal enhancement after GD-DTPA of cortical tubers. Figure 4. Postmortem specimens showing cortical tubers with flat surface  Subependymal nodule Typically located in the subependymal walls of the lateral ventricles, usually bilateral and mainly at the foramina of Monro. subependymal nodules have never been observed in the third ventricle.9,11 eir number is quite variable in each patient, and their size from a few millimeters to over I cm. subependymal nodules contain the same kind of cell abnormalities as cortical tubers, but with very many large, bizarre glial cells, fusiform cells, and undifferentiated neuroectodermal cells. However, neuron-like cells are scant. Much vascular and fibroglial stroma with accumulations of calcium deposits is often found. Focal hemorrhages and necrosis have also been reported.9,11,16 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 166
  • 170. Figure 5. Postmortem specimens showing cortical tubers in A and subependymal tubers in B Figure 6. CT scan precontrast showing subependymal calcified nodules projecting into the ventricular cavity (candle guttering) www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 167
  • 171. Figure 7. MRI T1 images showing cortical tuber, radial white matter lesions and subependymal nodules forming candle guttering. The cerebral cortex appears lissencephalic and pachygyric especially over he frontal lobes. The brain is usually normal in size, but several or many hard nodules occur on the surface of the cortex or along the subependymal covering of the ventricular system. These nodules are smooth, rounded or polygonal and project slightly above the surface of the neighboring cortex. They are whitish in colour and firm. Figure 8. CT scan precontrast in two cases of tuberous sclerosis showing subependymal noncalcified nodules projecting into the ventricular cavity (A,B) and a calcified nodule at the foramen of monro (C) On MRI, the subependymal nodules appear to impinge on the ventricular cavity from the subependymal walls. Their signal depends mainly on the presence and amount of mineral deposits. If calcifications are widespread, subependymal nodules are very hypointense in all pulse sequences, occasionally surrounded by a hyperintense rim on long TRI; otherwise, they are usually isointense to white matter on short TR and slightly hyperintense on long TRI.9,12 Calcifications are rare in newborns and infants, making diagnosis difficult both by CT and MRI.14 However, in children over I year and in Histopathologically, the nodules are characterized by the presence of a cluster of atypical glial cells in the center and giant cells in the periphery. The nodules are frequently, but not necessarily, calcified. These nodules occasionally give rise to giant cell astrocytoma when they are large in size. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 168
  • 172. adults, calcification of the stroma is usual, and CT, owing to its greater ability to detect calcium, has been considered best for assessment of subependymal nodules.17 Nevertheless, MR gradient echo pulse sequences with short flip angle are equally useful because of the magnetic susceptibility of calcified lesions, which appear profoundly hypointense.18 After contrast medium, subependymal nodules do not enhance on CT, whereas on MRI they show nodular or annular hyperintensity.16 This may be due to higher MRI sensitivity and also to enhancement of uncalcified gliovascular stroma after GD-DTPA administration, while the calcified component remains markedly hypointense.15 The tuberous sclerosis nodules are variable in size and might attain a huge size. On sectioning the brain, sclerotic nodules may be found in the subcortical gray matter, the white matter and the basal ganglia. The lining of the lateral ventricles is frequently the site of numerous small nodules that project into the ventricular cavity (candle gutterings). Sclerotic nodules are characteristically found in or near the foramen of monro and commonly induce hydrocephalus. The cerebellum, brain stem, and spinal cord are less frequently involved. Figure 9. (A,B) In tuberous sclerosis the lining of the lateral ventricles is frequently the site of numerous small nodules that project into the ventricular cavity (candle gutterings) (blue arrows in A). Also notice cortical tubers (black arrow in A)  Giant cell astrocytoma The subependymal giant cell astrocytoma (SGCA) is another low-grade (WHO grade 1) astrocytic neoplasm. 13 This neoplasm is most commonly seen (>90%) in association with clinical or radiologic evidence for tuberous sclerosis. 13 Tuberous sclerosis is an autosomal dominant phakomatosis, characterized by disseminated hamartomas of the CNS, kidneys, skin, and bone. True neoplasms also occur, with approximately 15% of patients developing www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 169
  • 173. SGCA. The tumor is sometimes called the intraventricular tumor of tuberous sclerosis. The lesion usually presents in the teens or 20s. Subependymal Giant-Cell Astrocytomas are clinically and histopathologically benign 20 . They grow slowly, have no surrounding edema, are noninvasive, and rarely show malignant degeneration.21 There are no qualitative histopathologic differences between subependymal nodules and Subependymal Giant-Cell Astrocytomas. Like subependymal nodules, Subependymal Giant-Cell Astrocytomas contain large amounts of undifferentiated giant cells or abnormally differentiated cells resembling astrocytes or spongioblasts, together with a few abnormal neurons. The fibrovascular stroma contains dystrophic calcifications and cystic or necrotic areas of degeneration.22 Subependymal Giant-Cell Astrocytomas may originate from subependymal nodules located near the foramen of Monro. Figure 10. Close-up view of the frontal horn of the left lateral ventricle, showing a giant cell astrocytoma filling the anterior horn in a 15- year-old boy with tuberous sclerosis. On MRI, uncalcified Subependymal giant-cell astrocytomas are isointense to white matter on short TR images: calcified components are hypointense. On long TR images the signal increases in the parenchymal component of the lesion, whereas calcifications become profoundly hypointense on T2WI. Serpentine, linear, or punctate signal voids believed to be due to dilated tumor vessels. 9 Subependymal Giant-Cell Astrocytomas enhance on CT after iodinated contrast medium administration, whereas subependymal nodules do not increase in density. This was believed to be due to a breakdown of the blood-brain barrier in the Subependymal Giant-Cell Astrocytomas 14 , and therefore CT was considered best for differential diagnosis. Both Subependymal Giant-Cell Astrocytomas and subependymal nodules located at the foramen of Monro show nodular enhancement on MRI after GD- DTPA.15 Recent findings support the hypothesis that the TSC2 gene and perhaps the TSC I gene act as tumor suppressors. When the TSC mutation occurs, the defective gene product of the TSC mutation is unable to suppress the tumor growth caused by a random somatic cell mutation that produces an oncogene stimulating the formation and growth of hamartomas. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 170
  • 174. Figure 11. Giant cell astrocytoma. Figure 12. Subependymal giant cell astrocytoma. Axial T1- weighted gadolinium-enhanced MR image (A) and postcontrast CT scan (B) show a well- demarcated intraventricular mass in the left frontal horn at the foramen of Monro. The lesion is growing into the ventricle as a polypoid lesion, attached to the head of the caudate nucleus. Grossly the lesion is a well-demarcated mass. It is almost always in the lateral ventricle, near the foramen of Monro. The lesion is fixed to the head of the caudate nucleus but does not spread through it. As the name implies, an intact layer of ependyma covers the tumor. Thus cerebrospinal fluid dissemination and spread through the brain are not typical. Histologically the lesion contains giant cells that have been variously described as astrocytes, neuronal derivatives, or something in between. The histology is distinctive and may suggest not only this particular tumor, but also the association with tuberous sclerosis that is so common. Calcification is frequent. 9 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 171
  • 175. Figure 13. Subependymal giant cell astrocytoma. The appearance of SGCA on imaging studies is usually typical, characteristic, and almost pathognomonic. First, most patients show other features of tuberous sclerosis, including cortical tubers and subependymal modules. Second, the tumor location is almost unique- intraventricular, near the foramen of Monro, and attached to the head of the caudate nucleus. Enhancement is often present on both CT and MR. Calcification is common and may be in the form of irregular chunks and nodules. The lesion has a polypoid shape as it protrudes into the lumen of the lateral ventricle. Secondary changes of hydrocephalus, from obstruction of the foramen of Monro, are frequent. Ventricular enlargement may be unilateral (on the side of the tumor) or bilateral.  White matter lesions Radial curvilinear bands, straight or wedge- shaped bands, and nodular foci are found. Radial white matter lesions run from the ventricle through the cerebral mantle to the normal cortex or cortical tuber, wedge- shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber, and nodular foci are located in the deep white matter. White matter lesions are composed of clusters of dysplastic giant and heterotopic cells, with gliosis and abnormal nerve fiber myelination.1 These anomalies are almost identical to those of the inner core of the cortical tubers. Therefore, on MRI, the white matter lesions are similarly hyperintense on long TR and isointense or hypointense on short TR images. No signal enhancement with GD-DTPA contrast WAS found. The site, shape, and histopathologic findings of white matter lesions confirm that TSC is a disorder of both histogenesis and cell migration. Heterogeneous gray structures in the white matter without calcification may also be present. 9 White matter lesions are dysplastic heterotopic neurons seen as migration lines running from though the cerebral mantle to a normal cortex or a cortical tuber. They are wedge-shaped with their apex near the ventricle and their base at the cortex or at the cortical tuber. Gliosis is commonly present in white matter lesion of tuberous sclerosis. 9 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 172
  • 176.  Deep white matter lesions These are focal, single or multiple lesions, always in the deep or periventricular white matter. On MRI they are isointense to the cerebrospinal fluid in all pulse sequences, sometimes surrounded by a hyperintense rim on T2WI, without mass effect. Table 3. Summary of radiological signs in tuberous sclerosis MRI or CT scan of the brain  An MRI of the brain is recommended for the detection and follow-up of cortical tubers, Subependymal nodule, and giant cell astrocytoma. Perform MRI during the initial diagnostic work-up and also every 1-3 years in children with TSC. The MRI may be performed less frequently in adults without lesions and as clinically indicated in adults with lesions. Also, perform an MRI in family members if their physical examinations are negative or not definitive for a diagnosis. MRI is preferred over CT scan due to improved visualization and no risk of radiation with repeat examinations.  Cortical tubers, best detected on T2-weighted images, often occur in the gray-white junction. On T2-weighted images, they have increased signal and often are in wedged (tuber) or linear shapes (radial migration lines). Conversely, they have decreased signal uptake on T1-weighted imaging. Previously thought to be pathognomonic, they no longer are considered specific for TSC since isolated cortical dysplasia may have a similar radiographic appearance. There appears to be a correlation between the number of tubers on MRI and severity of mental retardation or seizures.  Subependymal nodules (SEN) are located in the ventricles and often become calcified. The lesions are detected best by CT scan, although they sometimes are noted on MRI or plain film if calcified. They give a candle-dripping appearance.  Subependymal nodule may grow and give rise to a giant cell astrocytoma. A giant cell astrocytoma may cause obstruction with evidence of hydrocephalus or mass effect in some patients. These lesions usually appear in the region of the foramen of Monro, are partially calcified, and often are larger than 2 cm. Detection of a giant cell astrocytoma is slightly more sensitive with MRI than CT scan.  Tuberous sclerosis as a disorder of neuronal cell proliferation, differentiation and migration Tuberous sclerosis is a primary cell dysplasia resulting from embryonic ectoderm, mesoderm, and endoderm anomalies. In the CNS they involve neuroepithelial cells, which also show disordered cell migration and organization. All the lesions are hamartias or hamartomas, and histologic differences among them are slight and quantitative; therefore, all of these lesions may change with time. The arrest of cell migration at different stages explains the different sites of the various anomalies. Subependymal nodules and www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 173
  • 177. periventricular white matter anomalies reflect a failure of migration, white matter lesions an interruption, and cortical tubers an abnormal completion of migration with disordered cortical architecture. Subependymal giant-cell astrocytomas are the only neoplastic growth, and they derive from subependymal nodules that have some proliferative potential. 9 Disorders such as tuberous sclerosis, in which both tumor development and areas of cortical dysplasia are seen, might be a differentiation disorder. The brain manifestations of this disorder include hamartomas of the subependymal layer, areas of cortical migration abnormalities (tubers, cortical dysgenesis), and the development of giant-cell astrocytomas in upwards of 5% of affected patients. Two genes for tuberous sclerosis have been identified: TSCI (encodes for Hamartin) has been localized to 9q34 61 , and TSC2 (encodes for Tuberin) has been localized to 16pl3.3 .61 Table 4. Tuberous sclerosis as a disorder of neuronal cell proliferation, differentiation and migration Pathology Comment Subependymal nodules and periventricular white matter anomalies. Failure of migration. White matter lesion An interruption of migration. Cortical tubers. An abnormal completion of migration with disordered cortical architecture. Subependymal giant-cell astrocytomas ( the only neoplastic growth) They derive from subependymal nodules that have some proliferative potential.  Overview of normal neuronal migration At the most rostral end of the neural tube in the 40- to 41 -day-old fetus, the first mature neurons, Cajal-Retzius cells, begin the complex trip to the cortical surface. Cajal-Retzius cells, subplate neurons, and corticopetal nerve fibers form a preplate.62 The,neurons generated in the proliferative phase of neurodevelopment represent billions of cells poised to begin the trip to the cortical surface and to form the cortical plate. These neurons accomplish this task by attaching to and migrating along radial glial in a process known as radial migration or by somal translocation in a neuronal process.63 The radial glia extend from the ventricle to the cortical surface. In the process of migration, the deepest layer of the cortical plate migrates and deposits before the other layers. Therefore, the first neurons to arrive at the future cortex are layer VI neurons. More superficial layers of cortex then are formed-the neurons of layer V migrate and pass the neurons of layer VI; the same process occurs for layers IV, III, and II. The cortex therefore is formed in an inside-out fashion.63,64,65 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 174
  • 178. A possible mode of movement in neuronal migration on glia would be the attachment of the neuroblast to a matrix secreted by either the glia or the neurons. The attachment of the neuron would be through integrin receptors, cytoskeletal-linking membrane-bound recognition sites for adhesion molecules. That attachment serves as a stronghold for the leading process and soma of the migrating neuron. Neuron movement on radial glia involves an extension of a leading process, neural outgrowth having an orderly arrangement of microtubules. Shortening of the leading process owing to depolymerization or shifts of microtubules may result in movement of the soma relative to the attachment points. This theory of movement of neurons also must include a phase of detachment from the matrix at certain sites, so that the neuron can navigate successfully along as much as 6 cm of developing cortex (the maximum estimated distance of radial migration of a neuron in the human). Finally, the movement of cells must stop at the appropriate location, the boundary between layer I and the forming cortical plate. Therefore, some stop signal must be given for the migrating neuron to detach from the radial glia and begin to differentiate into a cortical neuron. Perhaps that signal is reelin, a protein that is disrupted in the mouse mutant Reeler and is expressed solely in the Cajal Retizius cells at this phase of development. 62,67 -69 REFERENCES 1. Braffman BH, Bilaniuk LT, Zimmermann RA. The central nervous system manifestation of the phakomatoses. Radiol Clin North Am 1988;26: 773-800. 2. Donegani G, Grattarola FR, Wildi E. Tuberous sclerosis. In: Vinken PJ, Bruyn GB, eds. The phakomatoses. Vol. 14. Handbook of clinical neurology. Amsterdam: Elsevier, 1972. 3. Ahlsen G, Gilberg IC, Lindblom R, Gilberg G. Tuberous sclerosis in western Sweden. Arch Neurol 1994;51:76-81. 4. Sampson JR, Schahill SJ, Stephenson JBP, Mann L, Connor JM. Genetic aspects of tuberous sclerosis in the west of Scotland. J Med Genet 1989; 26:28-31. 5. Perelman R. Pgdiatrie pratique: pathologie du systeme nerveux et des muscles. Paris: Maloine, 1990. 6. Sarnat HB. Cerebral dysgenesis. Embryology and clinical expression. New York, Oxford: Oxford University Press, 1992. 7. Fryer AE, Chalmers AH, Connor JM, et al. Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1987;1:659-61. 8. Kandt RS, Haines L, Smith S, et al. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nature Genet 1992;2:37-41. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 175
  • 179. 9. Braffman BH, Bilaniuk LT, Naidich TP, et al. MR imaging of tuberous sclerosis: pathogenesis of this phakomatosis, use of gadopentetate dimeglumine, and literature review. Radiology 1992;183:227-38. 10. Roach ES, Smith M, Huttenlocher P, Bhat M, Alcorn D, Hawley L. Diagnostic criteria of tuberous sclerosis complex. J Child Neural 1992;7:221-4. 11. Gomez MR. Tuberous sclerosis. New York: Raven Press, 1989. 12. Nixon JR, Houser OW, Gomez MR, Okazaki H. Cerebral tuberous sclerosis: MR imaging. Radiology 1989; 170:869-73. 13. Nixon JR, Okazaki H, Miller GM, Gomez MR. Cerebral tuberous sclerosis: postmortem magnetic resonance imaging and pathologic anatomy. Mayo Clin Proc 1989;64:305-1 1. 14. Altmann NR, Purser RK, Donovan Post MJ. Tuberous sclerosis: characteristics at CT and MR imaging. Radiology 1988;167:527-32. 15. Martin N, Debussche C, De Broucker T, Mompoint D, Marsault C, Nahum H. Gadolinium- DTPA enhanced MR imaging in tuberous sclerosis. Neuroradiology 1990;31:492-7. 16. Wippold FJ 11, Baber WW, Gado M, Tobben PJ, Bartnicke BJ. Pre- and postcontrast MR studies in tuberous sclerosis. J Comput Assist Tomogr 1992; 161:69-72. 17. Inoue Y, Nakajima S, Fukuda T, et al. Magnetic resonance images of tuberous sclerosis. Further observations and clinical correlations. Neuroradiology 1988;30:379-84. 18. Berns DH, Masaryk TJ, Weisman B, Modic MT, Blaser SI. Tuberous sclerosis: increased MR detection using gradient echo techniques. J Comput Assist Tomogr 1989;13:896-8. 19. Abbruzzese A, Bianchi MC, Puglioli M, et al. Astrocitomi gigantocellulari nella scierosi tuberosa. Rivista Neuroradiol 1992;5(suppi 1):11-116. 20. Morimoto K, Mogami H. Sequential CT study of subependymal giant-cell astrocytoma associated with tuberous sclerosis. J Neurosurg 1986;65: 874-7. 21. Fitz CR, Harwood-Nash DC, Thompson JR. Neuroradiology of tuberous sclerosis in children. Radiology 1974;110:635. 22. Russell DS, Rubinstein LJ. Pathology of tumors of the nervous system, 5th ed. Baltimore: Williams & Wilkins, 1989. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 176
  • 180. 23. The European Chromosome 16 Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993;75: 1305-15. 24. Pont MS, Elster AD. Lesion of skin and brain: modern imaging of the neurocutaneous syndromes. AJR 1992;158:1193-7. 25. Abbruzzese A, Montanaro D, Calabrese R, Valleriani AM, Bianchi MC, Canapicchi R. La RM nella sclerosi tuberosa. Atti X congresso nazionale Associazione Italiana di Neuroradiologia. Udine: Centauro Ed., 1992:457-64. 26. Martin N, De Broucker T, Cambier J, Marsault C, Nahum H. MRI evaluation of tuberous sclerosis. Neuroradiology 1987;29:437-43. 27. Kim EE, Wong FCL, Wong WH, et al. Positron- emission tomography in clinical neurooncology. Neuroim Clin North Am 1993;3:771-8. 28. Szelies B, Herholz K, Heiss WD, et al. Hypometabolic cortical lesions in tuberous sclerosis with epilepsy: demonstration by positron emission tomography. J Comput Assist Tomogr 1983;7:946. 29. Ariel IM: Tumors of the peripheral nervous system. CA Cancer J Clin 1983 Sep-Oct; 33(5): 282-99. 30. Crowe FW, Schull WJ, Neel JV: A Clinical, Pathological, and Genetic Study of Multiple Neurofibromatosis. 1956. 31. Fountain JW, Wallace MR, Bruce MA, et al: Physical mapping of a translocation breakpoint in neurofibromatosis. Science 1989 Jun 2; 244(4908): 1085-7. 32. Glaser JS, Hoyt WF, Corbett J: Visual morbidity with chiasmal glioma. Long-term studies of visual fields in untreated and irradiated cases. Arch Ophthalmol 1971 Jan; 85(1): 3-12. 33. Holman RE, Grimson BS, Drayer BP, et al: Magnetic resonance imaging of optic gliomas. Am J Ophthalmol 1985 Oct 15; 100(4): 596-601. 34. Lewis RA, Gerson LP, Axelson KA, et al: von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology 1984 Aug; 91(8): 929-35. 35. Listernick R, Charrow J, Greenwald MJ, Esterly NB: Optic gliomas in children with neurofibromatosis type 1. J Pediatr 1989 May; 114(5): 788-92. 36. Manger WM, Gifford RW Jr: Pheochromocytoma. 1977. 37. Miller NR, Iliff WJ, Green WR: Evaluation and management of gliomas of the anterior visual pathways. Brain 1974 Dec; 97(4): 743-54. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 177
  • 181. 38. Montgomery AB, Griffin T, Parker RG, Gerdes AJ: Optic nerve glioma: the role of radiation therapy. Cancer 1977 Nov; 40(5): 2079-80. 39. Parker JC Jr, Smith JL, Reyes P, Vuksanovic MM: Chiasmal optic glioma after radiation therapy. Neuro- ophthalmologic/pathologic correlation. J Clin Neuroophthalmol 1981 Mar; 1(1): 31-43. 40. Ricardi VM: Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. 2nd ed. John Hopkins Univ Pr; 1992. 41. Rubenstein AE, Korf BR: Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals. Thieme Medical Publishers; 1990. 42. Sorensen SA, Mulvihill JJ, Nielsen A: Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med 1986 Apr 17; 314(16): 1010-5. 43. Aguiar PH, Tatagiba M, Samii M: The comparison between the growth fraction of bilateral vestibular schwannomas in neurofibromatosis 2 (NF2) and unilateral vestibular schwannomas using the monoclonal antibody MIB 1. Acta Neurochir (Wien) 1995; 134(1- 2): 40-5. 44. Baser M, MacCollin M, Sujansky E, et al: Malignant nervous system tumors in patients with neurofibromatosis 2. FASEB Summer Research Conference on Neurofibromatosis 1996. 45. Briggs RJ, Brackmann DE, Baser ME: Comprehensive management of bilateral acoustic neuromas. Current perspectives. Arch Otolaryngol Head Neck Surg 1994 Dec; 120(12): 1307-14. 46. Epstein FJ, Farmer JP, Freed D: Adult intramedullary spinal cord ependymomas: the result of surgery in 38 patients . J Neurosurg 1993 Aug; 79(2): 204-9. 47. Evans DG, Huson SM, Donnai D: A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet 1992 Dec; 29(12): 841-6. 48. Evans DG, Huson SM, Donnai D: A clinical study of type 2 neurofibromatosis. Q J Med 1992 Aug; 84(304): 603-18. 49. Hoffman RA, Kohan D, Cohen NL: Cochlear implants in the management of bilateral acoustic neuromas. Am J Otol 1992 Nov; 13(6): 525-8. 50. Kanter WR, Eldridge R, Fabricant R: Central neurofibromatosis with bilateral acoustic neuroma: genetic, clinical and biochemical distinctions from peripheral neurofibromatosis. Neurology 1980 Aug; 30(8): 851-9. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 178
  • 182. 51. Laszig R, Sollmann WP, Marangos N: The restoration of hearing in neurofibromatosis type 2. J Laryngol Otol 1995 May; 109(5): 385-9. 52. Mautner VF, Tatagiba M, Guthoff R: Neurofibromatosis 2 in the pediatric age group. Neurosurgery 1993 Jul; 33(1): 92-6. 53. Mautner VF, Lindenau M, Baser ME: Skin abnormalities in neurofibromatosis 2. Arch Dermatol 1997 Dec; 133(12): 1539-43. 54. McCormick PC, Torres R, Post KD: Intramedullary ependymoma of the spinal cord. J Neurosurg 1990 Apr; 72(4): 523-32. 55. Ojemann RG: Management of acoustic neuromas (vestibular schwannomas) (honored guest presentation). Clin Neurosurg 1993; 40: 498-535. 56. Parry DM, Eldridge R, Kaiser-Kupfer MI: Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet 1994 Oct 1; 52(4): 450-61. 57. Samii M, Matthies C: Management of 1000 vestibular schwannomas (acoustic neuromas): hearing function in 1000 tumor resections . Neurosurgery 1997 Feb; 40(2): 248- 60. 58. Sobel RA: Vestibular (acoustic) schwannomas: histologic features in neurofibromatosis 2 and in unilateral cases. J Neuropathol Exp Neurol 1993 Mar; 52(2): 106-13. 59. Thomassin JM, Epron JP, Regis J: Preservation of hearing in acoustic neuromas treated by gamma knife surgery. Stereotact Funct Neurosurg 1998 Oct; 70 Suppl 1: 74-9. 60. Kotagal P, Rothner AD: Epilepsy in the setting of neurocutaneous syndromes. Epilepsia 34 (suppl 3):S71- S78, 1993 61. Haines JL, Short MP, Kwiatkowski DJ, et al. Localization of one gene for tuberous sclerosis within 9q32-9q34, and further evidence for heterogeneity. Am J Hum Genet 1991; 49:764--72. 62. Ogawa M, Miyata T, Nakajima K, et al. The reeler gene-associated antigen on Cajal- Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neurons 1995;14:899-912. 63. Sidman R, Rakic P. Neuronal migration with special reference to developing human brain, a review. Brain Res 1973;62:1-35. 64. Aicardi J. The place of neuronal migration abnormalities in child neurology. Can J Neurol Sci 1994;21:185-93. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 179
  • 183. 65. Angevine J, Sidman R. Autoradiographic study of cell migration during histogenesis of cerebral cortex of the mouse. Nature 1961;192:766-8. 66. D'Arcangelo G, Miao GG, Chen S-C, et al. A protein related to extracellular matrix proteins deleted in the mouse reeler. Nature 1995;374:719 23. 67. D'Arcangelo G, Miao GG, Curran T. Detection of the reelin breakpoint in reeler mice. Brain Res Mol Brain Res 1996;39:234-6. 68. Hirotsune S, Takahara T, Sasaki N, et al. The reeler gene encodes a protein with an EGF- like motif expressed by pioneer neurons. Nat Genet 1995;10:77-83. 69. Rommsdorff M, Gotthardt M, Hiesberger T, et al. Reeler/disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 1999;97:689-701. Professor Yasser Metwally www.yassermetwally.com www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 180
  • 184. INDEX |  INTRODUCTION  RADIOLOGICAL PATHOLOGY OF TUBEROUS SCLEROSIS INTRODUCTION Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by the formation of hamartomatous lesions in multiple organ systems. It is the second most common neurocutaneous syndrome after neurofibromatosis type 1 and has been recognized since the late 1800s. Although the disease has complete penetrance, there is also high phenotypic variability: some patients have obvious signs at birth, while others remain www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 181
  • 185. undiagnosed for many years. In addition to skin lesions, TSC patients develop numerous brain lesions, angiomyolipoma (AMLs), lymphangiomyomatosis (LAM) in the lungs, cardiac rhabdomyomas, skeletal lesions, and vascular anomalies, all of which are well seen with medical imaging. Our knowledge of TSC genetics and pathophysiology has expanded dramatically in recent years: two genetic loci were discovered in the 1990s and recent elucidation of TSC's interaction with the mTOR pathway has changed how we manage the disease. Meanwhile, medical imaging is playing an increasingly important role in the diagnosis, management, and treatment of TSC. We provide an update on the genetics and pathophysiology of TSC, review its clinical manifestations, and explore the breadth of imaging features in each organ system, from prenatal detection of cardiac rhabdomyomas to monitoring rapamycin therapy to treatment of AMLs by interventional radiology. Tuberous sclerosis complex (TSC) is the second most common phakomatosis after neurofibromatosis type 1 [1] and is characterized by the formation of histologically benign hamartomas and low-grade neoplasms in multiple organ systems. It has a prevalence of about 1 in 6,000 newborns and affects approximately 1.5 million people worldwide, occurring in all races and both genders equally. TSC is an autosomal-dominant disorder with high penetrance and variance [2]; obvious signs might be present at birth, while in other patients it eludes diagnosis for decades. Almost all patients with TSC have numerous cutaneous stigmata [3, 4], some of which can be subtle. The vast majority of patients have brain lesions [3] and, although these can cause seizures, learning difficulties, behavioral problems, and autism, only 50% of TSC patients have below average intelligence [5]. Most patients have renal lesions [6], which cause complications in about 10%. Cardiac tumors are usually clinically silent, although they occasionally cause obstruction and arrhythmias [7]. Fewer TSC patients have clinically evident lung disease, and still fewer have vascular complications. Skeletal lesions go largely unnoticed. All of these lesions are very well visualized by medical imaging. The broad spectrum of pathology seen in TSC is reflected in the expansive history of its elucidation. The disease was first reported in 1862 by Friedrich von Recklinghausen. He described an infant with cardiac rhabdomyomas and sclerotic brain lesions who died shortly after birth, but he did not appreciate how the lesions were related [8]. In 1880, Désiré Bourneville documented the neurologic symptoms of an infant with hard mass lesions in the cortex of the brain that he likened to hard potatoes, coining the term "tuberous sclerosis." The association of these neurologic abnormalities with skin lesions was made a decade later by John Pringle who described adenoma sebaceum in a patient with mental retardation [9]. During the next century, it became better understood that TSC encompassed abnormalities of the skin, central nervous system (CNS), heart, lungs, kidneys, bones, and blood vessels [10], and the full spectrum of the disease was summarized by Gomez et al. [8, 11] 25 years ago. In the last decade there have been many advances in the molecular genetics and understanding of the pathophysiology of TSC, including the mechanism of action of the TSC1 and TSC2 gene products and benign metastasis of smooth muscle cells causing lymphangiomyomatosis (LAM) [7]. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 182
  • 186.  Genetics TSC is an autosomal-dominant disorder caused by a mutation in either the TSC1 or TSC2 gene [12, 13]. These genes act as tumor suppressors, and a mutation to each allele at one of these loci is required for tumorigenesis, analogous to Knudson's hypothesis of retinoblastoma oncogenesis [14]. For a patient to express TSC, two mutational events occur: the first is a germ line mutation (spontaneous or familial), resulting in a loss of heterozygosity (LOH) at the TSC1 or TSC2 allele [15-18]; subsequent somatic mutations of the remaining allele result in the phenotype of TSC. Somatic mosaicism [19] can result in a less severe phenotype or a so-called forme fruste variation of the disease [20]. Similarly, it has been discovered that some cases of supposed sporadic TSC1 and TSC2 mutations actually represent inherited defects in nonaffected parents with gonadal mosaicism [20, 21]. TSC1 and TSC2 are found on chromosome 9p and 16q, respectively [12, 13]. TSC1 encodes for a protein called hamartin, which is smaller and thought to help stabilize the gene product of TSC2, tuberin. Hamartin and tuberin form a heterodimer that functions as a tumor suppressor by inhibiting the mTOR kinase cascade. Modulating mTOR activity is important in regulating cell growth and proliferation. Dysfunctional gene products from altered TSC1 or TSC2 gene loci lead to increased activation of mTOR kinase, which then results in disorganized cellular overgrowth and abnormal differentiation [15, 22]. Perhaps because it has a more important role in mTOR regulation, mutations of TSC2 lead to a more severe phenotype [23-25]. TSC1 mutates spontaneously less often than TSC2 and is thus more common in familial cases, but, overall, 70% of TSC mutations are spontaneous, with TSC2 mutations more than three times as common as TSC1 mutations [25]. Although LOH at the TSC loci leads to upregulation of mTOR and subsequent disorganized cell growth, other proposed mechanisms of tumorigenesis do not involve LOH at TSC1 or TSC2, but instead are predicated on the dissociation of the TSC heterodimer, leading to its inactivation. Dissociation of the TSC heterodimer occurs after phosphorylation by various kinases [26]. One important kinase that inactivates the TSC complex is extracellular signal-regulated kinase (ERK) [27], which has been shown to be integral in the formation of subependymal giant cell astrocytomas (SEGAs) and some cardiac rhabdomyomas [28, 29].  Clinical manifestations The clinical picture traditionally associated with TSC is Vogt's triad: epilepsy, mental retardation, and facial angiofibromas. This triad is actually seen in only 30-40% of TSC patients; about half of patients have normal intelligence [7]. The presentation of TSC is so variable that some patients are only diagnosed by genetic testing or careful screening after a child or sibling presents with more severe symptoms. For the purposes of this review, the clinical manifestations of TSC are discussed as they relate to imaging findings in the sections that follow, organized by organ system, but a brief discussion of the cutaneous manifestations and diagnostic criteria of TSC is merited.  Cutaneous manifestations www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 183
  • 187. There are many cutaneous stigmata of TSC and they are seen in almost all patients with the disorder [30-32]. The most common and earliest skin finding in TSC is multiple hypopigmented macules (also called ashleaf spots) [31, 32], which are seen in more than 90% of patients before 2 years of age [31]. Hypopigmented macules are not specific for TSC, but a patient with large numbers of such lesions is more likely to have TSC; a Wood's lamp might be needed to see hypopigmented macules. Several other stigmata are said to be near pathognomonic for TSC, including adenoma sebaceum. This name was first coined by Pringle and is actually a misnomer because the lesion has no sebaceous glands. The lesion is a hamartoma composed of connective and vascular elements and is properly termed an angiofibroma [33]. Angiofibromas form discrete pink papules on the malar region of the face in 70% of TSC patients. Closely related lesions are also found on the forehead of most TSC patients and are termed "forehead plaques." Shagreen patches are thick, rubbery plaques with a pebbly texture composed of raised connective tissue nevi [32, 34], and are found on the nape of the neck and lumbosacral trunk of 50% of TSC patients. Many older children and adults with TSC have fleshy, raised fibromas around or under the nail bed termed periungual fibromas [34]. Although not cutaneous lesions, dental pits, gingival fibromas, and retinal white patches are also commonly seen in TSC [7]. Less common and less specific lesions also include café-au-lait spots, molluscum fibrosum pendulum, and skin tags.  Diagnosis The diagnosis of TSC can be difficult because the manifestations are so varied and few signs are specific. For that reason, a set of criteria has been proposed to help clinicians reach a diagnosis. The criteria were revised in 1998 and distinguish between major and minor features. Patients are evaluated and said to have definite, probable, or suspected TSC based on the presence of these criteria (Table 1). Medical imaging is heavily relied upon for most of the major and several of the minor criteria. Genetic testing is also available.  Neurologic manifestations and imaging findings Neurologic manifestations of TSC are the most common cause of morbidity and mortality in TSC patients. They include seizures, developmental delay, behavioral problems, and autism [35, 36]. Seizures are the most common symptom and occur in 90% of TSC patients. About 50% have mental retardation and these children are more likely to have a TSC2 mutation [5, 7]. Mild to moderate autism is also very common in TSC and present in 25- 50% of patients [36]. TSC-associated autism is seen with equal predominance in males and females, as opposed to the male predisposition of autism observed in the general population. It is unclear whether autism is a direct or indirect result of TSC; it might be secondary to temporal lobe tubers or epileptiform foci [36]. Brain imaging findings of TSC include cortical and subcortical tubers, white matter abnormalities, subependymal nodules, and SEGAs. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 184
  • 188. Table 1. Major and minor features of TSC. The diagnosis is considered definite in the presence of two major features or one major and two minor features. A probable diagnosis of TSC is given if there is one major and one minor feature, and TSC is suspected if a patient has one major feature or two or more minor features.  Cortical and subcortical tubers Tubers are variably epileptogenic hamartomas that exhibit disorganized cortical lamination. They are formed during embryogenesis and are seen in 90% of TSC patients. The masses can be cortical or subcortical and expand the overlying gyri (Fig. 1). Their gross appearance resembles potatoes, which, with their hard texture, lends the name tuberous sclerosis to this disorder. Pathologically, the hamartomas contain glial and neuronal elements such as atypical giant astrocytes, maloriented neurons, and bizarre giant cells [15]. On CT imaging, tubers are low in attenuation and usually do not enhance [37, 38]. About half calcify [37], which is well seen on CT images and sometimes even on skull radiographs. On MRI, the lesions have low T1 signal and high T2 or FLAIR signal, unless they are calcified, in which case there can be significant signal loss and blooming artefact [37, 38]. The MRI pattern is reversed in young infants, in whom the surrounding unmyelinated brain has increased water content [39]. The imaging characteristics of tubers are also altered when they develop cyst-like changes. Cystic tubers have low T1 and high T2 signal centrally. FLAIR sequences typically show central signal loss with a high signal peripheral rim. The cause of these cystic changes is unknown but might reflect cellular degeneration. It is more commonly seen in children younger than 7 [40]. Proton spectroscopy of tubers generally demonstrates decreased Nacetyl aspartate (NAA) and increased myo-inositol. The former is thought to reflect a reduction of neurons, and increased myo-inositol might be caused by gliosis or immature neurons [41, 42]. Recently, advanced imaging techniques such as diffusion tensor imaging (DTI) and positron emission tomography (PET) have shown promise in localizing more epileptic tubers. DTI is an MRI technique that provides information regarding both the magnitude www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 185
  • 189. and the direction of water diffusion within a voxel. This is helpful in TSC patients because cortical and subcortical tubers have abnormal cortical architecture and altered axonal integrity, properties that can result in higher apparent diffusion coefficients (ADC) and lower fractional anisotropy (FA) in the lesions compared to normal white matter [43]. Tubers with significantly higher ADCs and lower FA have increased epileptogenic potential compared to other lesions [44, 45]. Thus DTI provides incremental information beyond morphologic MRI findings alone. Similarly, large areas of FDG-PET hypometabolism within tubers correlate with increased epileptogenicity more so than tumor size alone [46]. PET using alpha-[11C]methyl-L-tryptophan (AMT) is also helpful in identifying epileptogenic foci in TSC [45]. Tubers that have increased AMT uptake are more epileptogenic than tubers without increased AMT uptake; selective resection of such lesions improves the success of epilepsy surgery [47]. Magnetoencephalography also shows promise in improving precise localization of epileptic foci for surgical resection in TSC patients [48, 49]. Figure 1 Child with cortical and subcortical tubers. Unenhanced CT image (a) and axial FLAIR MR image (b) demonstrate a large subcortical tuber in the left frontal lobe (large arrow) merging with underlying white matter abnormality. Multiple smaller tubers (small black arrows) have a similar CT appearance. These smaller hamartomas, as well as www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 186
  • 190. another in the left posterior whiter matter (b white arrow) have a cystic appearance with low-signal intensity centrally and a rim of increased FLAIR signal peripherally. Another child has diffuse mineralization of a left frontal hamartoma that appears as poorly defined, hazy increased attenuation on the CT image (c) and shows corresponding signal loss on the T2-W image (d)  White matter abnormalities White matter abnormalities of TSC consist of radial glial bands and periventricular cyst- like lesions (Fig. 2). Radial glial bands extend from the ependymal surface of the ventricle to the cortex, sometimes terminating in a subcortical tuber [50]. Although the lesions are classically linear and referred to as bands, they can also be wedge-shaped and even tumefactive [51]. The bands are present in more than 80% of TSC patients and represent heterotopic neuronal and glial elements that arrested during cortical migration [51]. CT usually fails to demonstrate these lesions, but they are very well seen by MRI. They have similar signal characteristics to cortical tubers, with low signal on T1-W images and high signal on T2-W images. The lesions are best seen with FLAIR and rarely enhance [51, 52]. Small white matter cysts are seen in almost half of TSC patients, and their etiology is unknown [53]. They are low attenuation on CT images and isointense to CSF on all MRI pulse sequences; these lesions do not enhance [53].  Subependymal nodules Subependymal nodules (SENs) are hamartomatous lesions that dot the ependymal surface of the lateral ventricles (Fig. 2). The lesions are isointense to gray matter on MR images. SENs calcify in 90% of cases and therefore bloom secondary to dephasing artefact on MR images and are easily seen on CT images. It has been suggested that CT is useful in identifying SENs in undiagnosed family members with subtle symptoms of TSC [37]. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 187
  • 191. Figure 2. White matter abnormalities and SENs in TSC. a Coronal T2-W image shows abnormal increased signal extending from the ependymal surface of the ventricle through the white matter of the right frontal lobe (white arrow). This is a radial glial band and is in continuity with a subcortical tuber in the frontal lobe (upper black arrow). Another tuber is present in the ipsilateral temporal lobe (lower black arrow). White matter cysts in the left periventricular white matter (black arrows) follow CSF signal intensity on all sequences, where they are bright on T2-W images (b) and suppressed on FLAIR images (c). SENs (white arrows) are also present, dotting the ependymal surface of the ventricles. These are partially calcified, causing some signal loss on the MR images. d Calcification within SENs is better seen on CT images as high-attenuation nodules along the ventricular surface in another patient  Subependymal giant cell astrocytomas SEGAs are low-grade neoplasms that arise near the foramen of Monro in 10-15% of patients with TSC [37] (Fig. 3). They have a mixed glioneuronal lineage [54] and some investigators have reported subtle genetic changes that might account for their growth. These findings suggest that classifying SEGAs as astrocytomas is not completely correct [55]. Nevertheless, on imaging these lesions appear similar to SENs; consideration that one www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 188
  • 192. is dealing with a SEGA should be made if the lesion is greater than 5 mm, incompletely calcified, or enhances [56]. Because almost all of these lesions enhance, for practical purposes, SEGAs are diagnosed by size greater than 10 mm, demonstrable growth, or the production of symptoms of hydrocephalus. A lesion is termed a "probable SEGA" if it could cause obstruction based on its size or location [55]. Suspected SEGAs should be followed by MRI at least every year [56, 57] because hydrocephalus has been reported in 40% of TSC patients with SEGAs [56]. Figure 3. Enlarging SEGA in a child with headache. a Axial enhanced T1-W image shows two small enhancing masses at the bilateral foramina of Monro, left (white arrow) larger than right (black arrow). b Enhanced T1-W image obtained 10 months later shows interval growth of the left SEGA (white arrow) causing mild ventricular enlargement. Difference in slice angle causes the right SEGA to appear smaller and reveals another enhancing lesion more posterior on the right (black arrows)  Conclusion The understanding of TSC pathogenesis and genetics continues to grow, and despite available genetic testing, medical imaging continues to play an important role in its diagnosis. This role will probably expand as more and more subtle cases of TSC are discovered, and certainly, as more patients undergo treatment, imaging will play an even more important role. TSC characteristically involves multiple disparate organ systems, and therefore patients are often followed by several subspecialists, often leaving the radiologist as the only common consultant. This underscores the need for medical imagers to appreciate the depth and breadth of imaging abnormalities in this fascinating disease as well as to understand the clinical management of TSC patients. Table 3 provides a brief guide to the clinical and imaging findings discussed in this review. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 189
  • 193. References 1. Hurst JS, Wilcoski S (2000) Recognizing an index case of tuberous sclerosis. Am Fam Physician 61:703-708, 710 2. Sybert VP, Hall JG (1979) Inheritance of tuberous sclerosis. Lancet 1:783 3. Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med 355:1345-1356 4. Webb DW, Clarke A, Fryer A et al (1996) The cutaneous features of tuberous sclerosis: a population study. Br J Dermatol 135:1-5 5. Prather P, de Vries PJ (2004) Behavioral and cognitive aspects of tuberous sclerosis complex. J Child Neurol 19:666-674 6. van Baal JG, Fleury P, Brummelkamp WH (1989) Tuberous sclerosis and the relation with renal angiomyolipoma. A genetic study on the clinical aspects. Clin Genet 35:167-173 7. Maria BL, Deidrick KM, Roach ES et al (2004) Tuberous sclerosis complex: pathogenesis, diagnosis, strategies, therapies, and future research directions. J Child Neurol 19:632-642 8. Jansen FE, van Nieuwenhuizen O, van Huffelen AC (2004) Tuberous sclerosis complex and its founders. J Neurol Neurosurg Psychiatry 75:770 9. Pringle JJ (1890) A case of congenital adenoma sebaceum. Br J Dermatol 2:1-14 10. National Institute of Neurological Disorders and Stroke (2007) Tuberous sclerosis fact sheet. NIH publication no. 02-1846. National Institutes of Health, Bethesda, MD 11. Gomez MR, Sampson JR, Whittemore VH (1999) Tuberous sclerosis complex. Oxford University Press, New York 12. European Chromosome 16 Tuberous Sclerosis Consortium (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305-1315 13. van Slegtenhorst M, de Hoogt R, Hermans C et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805-808 14. Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820-823 15. Ess KC (2006) The neurobiology of tuberous sclerosis complex. Semin Pediatr Neurol 13:37-42 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 190
  • 194. 16. Green AJ, Smith M, Yates JRW (1994) Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat Genet 6:193-196 17. Henske EP, Scheithauer BW, Short MP et al (1996) Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet 59:400-406 18. Sepp T, Yates JR, Green AJ (1996) Loss of heterozygosity in tuberous sclerosis hamartomas. J Med Genet 33:962-964 19. Verhoef S, Vrtel R, van Essen T et al (1995) Somatic mosaicism and clinical variation in tuberous sclerosis complex. Lancet 345:202 20. Verhoef S, Bakker L, Tempelaars AM et al (1999) High rate of mosaicism in tuberous sclerosis complex. Am J Hum Genet 64:1632-1637 21. Rose VM, Au KS, Pollom G et al (1999) Germ-line mosaicism in tuberous sclerosis: how common? Am J Hum Genet 64:986- 992 22. Chan JA, Zhang H, Roberts PS et al (2004) Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 63:1236-1242 23. Dabora SL, Jozwiak S, Franz DN et al (2001) Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 68:64-80 24. Jones AC, Shyamsundar MM, Thomas MW et al (1999) Comprehensive mutation analysis of TSC1 and TSC2 and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet 64:1305-1315 25. Sancak O, Nellist M, Goedbloed M et al (2005) Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex. Eur J Hum Genet 13:731-741 26. Jozwiak J, Jozwiak S, Wlodarski P (2008) Possible mechanisms of disease development in tuberous sclerosis. Lancet Oncol 9:73-79 27. Ma L, Chen Z, Erdjument-Bromage H et al (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121:179- 193 28. Jozwiak J, Grajkowska W, Kotulska K et al (2007) Brain tumor formation in tuberous sclerosis depends on Erk activation. Neuromolecular Med 9:117-127 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 191
  • 195. 29. Ma L, Teruya-Feldstein J, Bonner P et al (2007) Identification of S664 TSC2 phosphorylation as a marker for extracellular signal- regulated kinase mediated mTOR activation in tuberous sclerosis and human cancer. Cancer Res 67:7106-7112 30. Online Mendelian Inheritance in Man (OMIM) (2008) #191100. Tuberous sclerosis. Johns Hopkins University, Baltimore, MD. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191100. Cited 3-Mar-2008 31. Jozwiak S, Schwartz RA, Janniger CK et al (1998) Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance. Int J Dermatol 37:911-917 32. Sun XF, Yan CL, Fang L et al (2005) Cutaneous lesions and visceral involvement of tuberous sclerosis. Chin Med J (Engl) 118:215-219 33. Sanchez NP, Wick MR, Perry HO (1981) Adenoma sebaceum of Pringle: a clinicopathologic review, with a discussion of related pathologic entities. J Cutan Pathol 8:395-403 34. Roach ES, Sparagana SP (2004) Diagnosis of tuberous sclerosis complex. J Child Neurol 19:643-649 35. Rosser T, Panigrahy A, McClintock W (2006) The diverse clinical manifestations of tuberous sclerosis complex: a review. Semin Pediatr Neurol 13:27-36 36. Wiznitzer M (2004) Autism and tuberous sclerosis. J Child Neurol 19:675-679 37. Altman NR, Purser RK, Post MJ (1988) Tuberous sclerosis: characteristics at CT and MR imaging. Radiology 167:527-532 38. Nixon JR, Houser OW, Gomez MR et al (1989) Cerebral tuberous sclerosis: MR imaging. Radiology 170:869-873 39. Baron Y, Barkovich AJ (1999) MR imaging of tuberous sclerosis in neonates and young infants. AJNR 20:907-916 40. Jurkiewicz E, Jozwiak S, Bekiesinska-Figatowska M et al (2006) Cyst-like cortical tubers in patients with tuberous sclerosis complex: MR imaging with the FLAIR sequence. Pediatr Radiol 36:498-501 41. Mizuno S, Takahashi Y, Kato Z et al (2000) Magnetic resonance spectroscopy of tubers in patients with tuberous sclerosis. Acta Neurol Scand 102:175-178 42. Mukonoweshuro W, Wilkinson ID, Griffiths PD (2001) Proton MR spectroscopy of cortical tubers in adults with tuberous sclerosis complex. AJNR 22:1920-1925 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 192
  • 196. 43. Karadag D, Mentzel HJ, Gullmar D et al (2005) Diffusion tensor imaging in children and adolescents with tuberous sclerosis. Pediatr Radiol 35:980-983 44. Jansen FE, Braun KP, van Nieuwenhuizen O et al (2003) Diffusion-weighted magnetic resonance imaging and identification of the epileptogenic tuber in patients with tuberous sclerosis. Arch Neurol 60:1580-1584 45. Luat AF, Makki M, Chugani HT (2007) Neuroimaging in tuberous sclerosis complex. Curr Opin Neurol 20:142-150 46. Chandra PS, Salamon N, Huang J et al (2006) FDG-PET/MRI coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex: a preliminary report. Epilepsia 47:1543-1549 47. Kagawa K, Chugani DC, Asano E et al (2005) Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET). J Child Neurol 20:429-438 48. Kamimura T, Tohyama J, Oishi M et al (2006) Magnetoencephalography in patients with tuberous sclerosis and localization-related epilepsy. Epilepsia 47:991-997 49. Iida K, Otsubo H, Mohamed IS et al (2005) Characterizing magnetoencephalographic spike sources in children with tuberous sclerosis complex. Epilepsia 46:1510-1517 50. Iwasaki S, Nakagawa H, Kichikawa K et al (1990) MR and CT of tuberous sclerosis: linear abnormalities in the cerebral white matter. AJNR 11:1029-1034 51. Braffman BH, Bilaniuk LT, Naidich TP et al (1992) MR imaging of tuberous sclerosis: pathogenesis of this phakomatosis, use of gadopentetate dimeglumine, and literature review. Radiology 183:227-238 52. Bernauer TA (1999) The radial bands sign. Radiology 212:761- 762 53. Van Tassel P, Cure JK, Holden KR (1997) Cystlike white matter lesions in tuberous sclerosis. AJNR 18:1367-1373 54. Kim SK, Wang KC, Cho BK et al (2001) Biological behavior and tumorigenesis of subependymal giant cell astrocytomas. J Neurooncol 52:217-225 55. Goh S, Butler W, Thiele EA (2004) Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 63:1457-1461 56. Clarke MJ, Foy AB, Wetjen N et al (2006) Imaging characteristics and growth of subependymal giant cell astrocytomas. Neurosurg Focus 20:E5 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 193
  • 197. 57. Nabbout R, Santos M, Rolland Y et al (1999) Early diagnosis of subependymal giant cell astrocytoma in children with tuberous sclerosis. J Neurol Neurosurg Psychiatry 66:370-375 58. Kleymenova E, Ibraghimov-Beskrovnaya O, Kugoh H et al (2001) Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Mol Cell 7:823-832 59. Culty T, Molinie V, Lebret T et al (2006) TSC2/PKD1 contiguous gene syndrome in an adult. Minerva Urol Nefrol 58:351-354 60. Henske EP (2005) Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond. Pediatr Nephrol 20: 854-857 61. Reeders ST, Breuning MH, Davies KE et al (1985) A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature 317:542-544 62. Casper KA, Donnelly LF, Chen B et al (2002) Tuberous sclerosis complex: renal imaging findings. Radiology 225:451-456 63. Ewalt DH, Diamond N, Rees C et al (2005) Long-term outcome of transcatheter embolization of renal angiomyolipomas due to tuberous sclerosis complex. J Urol 174:1764- 1766 64. Wagner BJ, Wong-You-Cheong JJ, Davis CJ Jr (1997) Adult renal hamartomas. Radiographics 17:155-169 65. Cook JD, Davis BJ, Cai SL et al (2005) Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance. Proc Natl Acad Sci USA 102:8644-8649 66. Yamakado K, Tanaka N, Nakagawa T et al (2002) Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology 225:78-82 67. Dickinson M, Ruckle H, Beaghler M et al (1998) Renal angiomyolipoma: optimal treatment based on size and symptoms. Clin Nephrol 49:281-286 68. Harabayashi T, Shinohara N, Katano H et al (2004) Management of renal angiomyolipomas associated with tuberous sclerosis complex. J Urol 171:102-105 69. Kang M, Khandelwal N, Lal A et al (2007) CT angiography in renal angiomyolipomas. Abdom Imaging 32:772-774 70. Logue LG, Acker RE, Sienko AE (2003) Best cases from the AFIP: angiomyolipomas in tuberous sclerosis. Radiographics 23:241-246 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 194
  • 198. 71. Kim JK, Park SY, Shon JH et al (2004) Angiomyolipoma with minimal fat: differentiation from renal cell carcinoma at biphasic helical CT. Radiology 230:677-684 72. Ren N, Qin LX, Tang ZY et al (2003) Diagnosis and treatment of hepatic angiomyolipoma in 26 cases. World J Gastroenterol 9:1856-1858 73. Tseng CA, Pan YS, Su YC et al (2004) Extrarenal retroperitoneal angiomyolipoma: case report and review of the literature. Abdom Imaging 29:721-723 74. Kandt RS, Haines JL, Smith M et al (1992) Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat Genet 2:37-41 75. Al-Saleem T, Wessner LL, Scheithauer BW et al (1998) Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 83:2208-2216 76. Bjornsson J, Short MP, Kwiatkowski DJ et al (1996) Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features. Am J Pathol 149:1201- 1208 77. Henske EP (2004) The genetic basis of kidney cancer: why is tuberous sclerosis complex often overlooked? Curr Mol Med 4:825-831 78. Fletcher CDM, Unni KK, Mertens F et al (2002) Pathology and genetics of tumours of soft tissue and bone. World Health Organization classification of tumours. IARC Press, Lyon, p 427 79. Hornick JL, Fletcher CD (2006) PEComa: what do we know so far? Histopathology 48:75-82 80. Flieder DB, Travis WD (1997) Clear cell "sugar" tumor of the lung: association with lymphangioleiomyomatosis and multifocal micronodular pneumocyte hyperplasia in a patient with tuberous sclerosis. Am J Surg Pathol 21:1242-1247 81. Pan CC, Chung MY, Ng KF et al (2007) Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma. J Pathol 214:387-393 82. Bonetti F, Martignoni G, Colato C et al (2001) Abdominopelvic sarcoma of perivascular epithelioid cells. Report of four cases in young women, one with tuberous sclerosis. Mod Pathol 14:563- 568 83. Folpe AL, Mentzel T, Lehr HA et al (2005) Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol 29:1558-1575 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 195
  • 199. 84. Armah HB, Parwani AV (2007) Malignant perivascular epithelioid cell tumor (PEComa) of the uterus with late renal and pulmonary metastases: a case report with review of the literature. Diagn Pathol 2:45 85. Folpe AL, Goodman ZD, Ishak KG et al (2000) Clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres: a novel member of the perivascular epithelioid clear cell family of tumors with a predilection for children and young adults. Am J Surg Pathol 24:1239-1246 86. Hancock E, Osborne J (2002) Lymphangioleiomyomatosis: a review of the literature. Respir Med 96:1-6 87. Hancock E, Tomkins S, Sampson J et al (2002) Lymphangioleiomyomatosis and tuberous sclerosis. Respir Med 96:7-13 88. Avila NA, Kelly JA, Chu SC et al (2000) Lymphangioleiomyomatosis: abdominopelvic CT and US findings. Radiology 216:147-153 89. Sherrier RH, Chiles C, Roggli V (1989) Pulmonary lymphangioleiomyomatosis: CT findings. AJR 153:937-940 90. Boehler A, Speich R, Russi EW et al (1996) Lung transplantation for lymphangioleiomyomatosis. N Engl J Med 335:1275-1280 91. Carsillo T, Astrinidis A, Henske EP (2000) Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 97:6085-6090 92. Sato T, Seyama K, Fujii H et al (2002) Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis. J Hum Genet 47:20-28 93. Avila NA, Dwyer AJ, Rabel A et al (2007) Sporadic lymphangioleiomyomatosis and tuberous sclerosis complex with lymphangioleiomyomatosis: comparison of CT features. Radiology 242:277-285 94. Henske EP (2003) Metastasis of benign tumor cells in tuberous sclerosis complex. Genes Chromosomes Cancer 38:376-381 95. Karbowniczek M, Astrinidis A, Balsara BR et al (2003) Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism. Am J Respir Crit Care Med 167:976-982 96. Yu J, Astrinidis A, Henske EP (2001) Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis. Am J Respir Crit Care Med 164:1537-1540 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 196
  • 200. 97. Strizheva GD, Carsillo T, Kruger WD et al (2001) The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis. Am J Respir Crit Care Med 163:253-258 98. Logginidou H, Ao X, Russo I et al (2000) Frequent estrogen and progesterone receptor immunoreactivity in renal angiomyolipomas from women with pulmonary lymphangioleiomyomatosis. Chest 117:25-30 99. Abbott GF, Rosado-de-Christenson ML, Frazier AA et al (2005) From the archives of the AFIP: lymphangioleiomyomatosis: radiologic-pathologic correlation. Radiographics 25:803-828 100. Torres VE, Bjornsson J, King BF et al (1995) Extrapulmonary lymphangioleiomyomatosis and lymphangiomatous cysts in tuberous sclerosis complex. Mayo Clin Proc 70:641-648 101. Beghetti M, Gow RM, Haney I et al (1997) Pediatric primary benign cardiac tumors: a 15-year review. Am Heart J 134:1107- 1114 102. Grebenc ML, Rosado de Christenson ML, Burke AP et al (2000) Primary cardiac and pericardial neoplasms: radiologic-pathologic correlation. Radiographics 20:1073-1103; quiz 1110-1111, 1112 103. Bosi G, Lintermans JP, Pellegrino PA et al (1996) The natural history of cardiac rhabdomyoma with and without tuberous sclerosis. Acta Paediatr 85:928-931 104. Carrico A, Moura C, Baptista MJ et al (2001) Cardiac rhabdomyomas presenting in neonates. Rev Port Cardiol 20:1095-1101 105. Jozwiak S, Kotulska K, Kasprzyk-Obara J et al (2006) Clinical and genotype studies of cardiac tumors in 154 patients with tuberous sclerosis complex. Pediatrics 118:e1146- e1151 106. Yu K, Liu Y, Wang H et al (2007) Epidemiological and pathological characteristics of cardiac tumors: a clinical study of 242 cases. Interact Cardiovasc Thorac Surg 6:636-639 107. Piazza N, Chughtai T, Toledano K et al (2004) Primary cardiac tumours: eighteen years of surgical experience on 21 patients. Can J Cardiol 20:1443-1448 108. Thomas-de-Montpreville V, Nottin R, Dulmet E et al (2007) Heart tumors in children and adults: clinicopathological study of 59 patients from a surgical center. Cardiovasc Pathol 16:22-28 109. Isaacs H Jr (2004) Fetal and neonatal cardiac tumors. Pediatr Cardiol 25:252-273 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 197
  • 201. 110. Shimizu M, Manabe T, Tazelaar HD et al (1994) Intramyocardial angiomyolipoma. Am J Surg Pathol 18:1164-1169 111. Tsai CC, Chou CY, Han SJ et al (1997) Cardiac angiomyoli- poma: radiologic and pathologic correlation. J Formos Med Assoc 96:653-656 112. Winterkorn EB, Dodd JD, Inglessis I et al (2007) Tuberous sclerosis complex and myocardial fat-containing lesions: a report of four cases. Clin Genet 71:371-373 113. Green GJ (1968) The radiology of tuberose sclerosis. Clin Radiol 19:135-147 114. Holt JF, Dickerson WW (1952) The osseous lesions of tuberous sclerosis. Radiology 58:1-8 115. Jost CJ, Gloviczki P, Edwards WD et al (2001) Aortic aneurysms in children and young adults with tuberous sclerosis: report of two cases and review of the literature. J Vasc Surg 33:639-642 116. Restrepo R, Ranson M, Chait PG et al (2003) Extracranial aneurysms in children: practical classification and correlative imaging. AJR 181:867-878 117. Rolfes DB, Towbin R, Bove KE (1985) Vascular dysplasia in a child with tuberous sclerosis. Pediatr Pathol 3:359-373 118. Burrows NJ, Johnson SR (2004) Pulmonary artery aneurysm and tuberous sclerosis. Thorax 59:86 119. Hagood CO Jr, Garvin DD, Lachina FM et al (1976) Abdominal aortic aneurysm and renal hamartoma in an infant with tuberous sclerosis. Surgery 79:713-715 120. Tamisier D, Goutiere F, Sidi D et al (1997) Abdominal aortic aneurysm in a child with tuberous sclerosis. Ann Vasc Surg 11:637-639 121. Beall S, Delaney P (1983) Tuberous sclerosis with intracranial aneurysm. Arch Neurol 40:826-827 122. Brill CB, Peyster RG, Hoover ED et al (1985) Giant intracranial aneurysm in a child with tuberous sclerosis: CT demonstration. J Comput Assist Tomogr 9:377-380 123. Jurkiewicz E, Jozwiak S (2006) Giant intracranial aneurysm in a 9-year-old boy with tuberous sclerosis. Pediatr Radiol 36:463 124. Chatrath R, Noronha PA (2000) Intracranial aneurysm in tuberous sclerosis. Int Pediatr 15:152-154 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 198
  • 202. 125. Beltramello A, Puppini G, Bricolo A et al (1999) Does the tuberous sclerosis complex include intracranial aneurysms? A case report with a review of the literature. Pediatr Radiol 29:206- 211 126. Huang S, Bjornsti MA, Houghton PJ (2003) Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther 2:222-232 127. Franz DN, Leonard J, Tudor C et al (2006) Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59:490-498 128. Herry I, Neukirch C, Debray MP et al (2007) Dramatic effect of sirolimus on renal angiomyolipomas in a patient with tuberous sclerosis complex. Eur J Intern Med 18:76-77 129. Lee L, Sudentas P, Donohue B et al (2005) Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer 42:213- 227 130. Bissler JJ, McCormack FX, Young LR et al (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358:140-151 131. Roach ES, Gomez MR, Northrup H (1998) Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 13:624-628 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 199
  • 203. INDEX |  INTRODUCTION INTRODUCTION Encephalotrigeminal angiomatosis classically includes the presence of cutaneous vascular portwine nevus of the face, contralateral hemiparesis or hemiatrophy, glaucoma, seizures and mental retardation. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 200
  • 204. The syndrome is a neurocutaneous syndrome (phakomatosis) characterized by a facial port-wine nevus (a capillary malformation), seizures, and mental retardation (1). Central nervous system manifestations include a leptomeningeal venous malformation (“angioma”) and cerebral hemiatrophy, which are typically, though not always, ipsilateral to the facial nevus. Calcifications are seen in the atrophic cortex deep to the venous malformation. Absence of cortical veins with centripetal venous drainage into enlarged medullary veins or anomalous deep veins in Sturge-Weber syndrome has been described in the angiographic, computed tomographic, and MR literature (2–10). These enlarged deep veins typically drain into the galenic venous system and likely represent collateral veins rather than primary vascular abnormalities. Dural venous sinus and galenic venous occlusions have also been documented with conventional and MR angiography in patients with Sturge- Weber syndrome (3, 6–10), and they may modify the pattern of centripetal venous drainage.  Pathology This syndrome is also called encephalotrigeminal or encephalofacial angiomatosis, and typically consists of capillary hemangioma in the upper portion of the face, Leptomeningeal angiomatosis, and cerebral calcification. The brain has an anomalous proliferation of leptomeningeal veins, showing clustering of veins with a somewhat irregular thickened wall. The underlying cerebral cortex shows numerous calcospherites, particularly along its superficial layers. Two abutting calcified cortices around a sulcus may exhibit a tram track-like radiologic appearance. The involved cortex is frequently atrophic, showing neuronal loss and gliosis. As in tuberous sclerosis, seizures are the most common manifestation in Sturge-Weber syndrome, occurring in 71 % to 89% of patients. It has been suggested that stepwise clinical deterioration in patients with Sturge-Weber syndrome might be caused by cerebral venous hypertension resulting from sluggish venous drainage through the leptomeningeal angioma (9). Probst (9) hypothesized that the latter might be further exacerbated by progressive occlusion of deep veins with resultant centrifugal rerouting of deep cerebral venous drainage into the already overburdened angioma. Slowing and diminution of regional cerebral blood low has been demonstrated by using radionuclide and xenon inhalation techniques in these patients (9, 11). On the basis of the postulate that these findings might be caused by progressive venous thrombosis, antiplatelet therapy was administered in one series of patients and resulted in stabilization of neurologic function (12). Isolated nonvisualization of cortical veins, deep veins, and dural venous sinuses on conventional or MR angiography in patients with Sturge-Weber syndrome does not establish whether these veins are aplastic, hypoplastic, thrombosed, or occluded by processes such as intimal hyperplasia or other nonthrombotic diseases. Without follow-up, these findings also do not prove a progressive venoocclusive process in Sturge-Weber syndrome. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 201
  • 205. Figure 1. Sturge-Weber Syndrome (or disease) is a congenital vascular malformation affecting the head, face, and brain. The primary process appears to be faulty development of the venous drainage for the cerebral capillary bed. A similar process affects the skin, eye, and the soft-tissues of the head. Development of the brain usually proceeds to a normal size, but after birth, there is progressive atrophy of the affected hemisphere(s). The disease is usually unilateral, but bilateral cases can occur. Typically the patient presents at birth with a "Port Wine Nevus" - a reddish-brown or pink discoloration of the face, often following the distribution of the trigeminal nerve. Intracranially, ipsilateral to the facial nevus, there is abnormal circulation that leads to 1) cerebral dysfunction; 2) electrical instability (seizures); and 3) cerebral cortical atrophy. Seizures usually present within the first two years of life. Typically the occipital lobes are affected first, and most severely, but the disease may also involve the parietal and temporal lobes, and (rarely) the frontal lobe. The observation of venous abnormalities in this neonate suggests that the venous pathology in Sturge-Weber syndrome might commence in utero and progress postnatally. A thrombotic Aetiology as the cause of progressive nonvisualization of veins in patients with Sturge Weber syndrome could not be proved, suggesting that nonthrombotic venoocclusive processes might play a role in the pathophysiology of Sturge-Weber syndrome. Indeed, abnormal veins with walls thickened by a layer of hyalinized connective tissue or fibrosis have been noted at pathologic examination within the leptomeninges and subcortical white matter of patients with Sturge-Weber syndrome. (9) The occipital lobes are affected most often, but lesions may affect the temporal or parietal lobes. Atrophy is characteristically unilateral and ipsilateral to the facial nevus. Leptomeningeal angiomatosis with small venules filling the subarachnoid spaces is a common finding. Calcifications of the arteries on the surface of the brain is very common and frequently extend to involve the intracerebral microvascular system. The trolley-track www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 202
  • 206. or curvilinear calcifications seen on skull x ray is due to calcification of the outer cortex or vascular calcification.60 Figure 2. Sturge- Weber Syndrome: The brain has an anomalous proliferation of leptomeningeal veins, showing clustering of veins with a somewhat irregular thickened wall. The underlying cerebral cortex shows numerous calcospherites, particularly along its superficial layers. Figure 3. Plain x ray skull in two patients with sturge weber syndrome, notice the trolley- track sign with curvilinear calcification which is due to cortical or vascular calcification www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 203
  • 207. Figure 4. Sturge Weber syndrome: Right parietal occipital pial angioma that enhances with contrast administration (A). The underlying cortex is atrophic and MR imaging demonstrates decreased signal intensity throughout the atrophic cortical mantle, which may be due to hemosiderin deposition. calcification, or both (B). Given the noninvasive nature of conventional MR and MR venography, it should be feasible to study a larger group of patients with Sturge-Weber syndrome to determine if there is a relationship between clinical deterioration and progressive venous occlusion, and to what extent venous thrombosis contributes to venous occlusion in these patients. If thrombosis is established as a significant contributor to the disease process, clinical trials that use antiplatelet medications could be guided by periodic MR venographic evaluation. References 1. Braffman B, Naidich TP. The phakomatoses: part II. Neuroimaging Clin North Am 1994;4:330–332 2. Elster AD, Chen MYM. MR imaging of Sturge-Weber syndrome: role of gadopentetate dimeglumine and gradient echo sequences. AJNR Am J Neuroradiol 1990;11:685–689 3. Terdjman P, Aicardi J, SainteRose C, Brunelle F. Neuroradiological findings in Sturge- Weber syndrome and isolated pial angiomatosis. Neuropediatrics 1990;22:115–120 4. Marti´-Bonmati´ L, Menor F, Poyatos C, Cortina H. Diagnosis of Sturge-Weber syndrome: comparison of the efficacy of CT and MR imaging in 14 cases. AJR Am J Roentgenol 1992;158:867– 871 5. Benedikt RA, Brown DC, Walker R, Ghaed VN, Mitchell M, Geyer CA. Sturge-Weber syndrome: cranial MR imaging with Gd-DTPA. AJNR Am J Neuroradiol 1993;14:409–415 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 204
  • 208. 6. Vogl TJ, Stemmler J, Bergman C, Pfluger T, Egger E, Lissner J. MR and MR angiography in Sturge- Weber syndrome. AJNR Am J Neuroradiol 1993;14:417–425 7. Bentson JR, Wilson GH, Newton TH. Cerebral venous drainage pattern of the Sturge- Weber syndrome. Radiology 1971;101:111– 118 8. Poser CM, Taveras JM. Cerebral angiography in encephalotrigeminal angiomatosis. Radiology 1957;68:327–336 9. Probst FP. Vascular morphology and angiographic flow patterns in Sturge-Weber angiomatosis: facts, thoughts, and suggestions. Neuroradiology 1980;20:73–78 10. Segall HD, Ahmadi J, McComb JG, Zee C, Becker TS, Han HS. Computed tomographic observations pertinent to intracranial occlusive disease in childhood. Radiology 1982;143:441–449 11. Garcia JC, Roach ES, McLean WT. Recurrent thrombotic deterioration in the Sturge- Weber syndrome. Childs Nerv Syst 1981;8: 427–433 12. Roach ES, Riela AR, McLean WT, Stump DA. Aspirin therapy for Sturge-Weber syndrome. Ann Neurol 1985;18:387 13. Wohlwill FJ, Yakovlev PL. Histopathology of meningofacial angiomatosis (Sturge-Weber disease): report of four cases. J Neuropathol Exp Neurol 1957;16:341–364 www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 205
  • 209. INDEX  INTRODUCTION INTRODUCTION The original proband was a boy referred to Dr. Wilder Penfield by Dr. Ed Fincher of Emory University in Atlanta because of intractable focal motor seizures. The boy eventually developed a hemiparesis, and serial pneumoencephalograms showed progressive enlargement of the contralateral ventricle. At the time, there was much discussion about whether the progressive nature of the neurologic disorder could be explained by the effect of the seizures alone or whether he had a progressive underlying neurologic disease. The finding of inflammatory changes in resected brain tissue suggested a viral encephalitis and www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 206
  • 210. militated towards the diagnosis of a progressive disorder, then termed chronic encephalitis and epilepsy. CLINICAL MANIFESTATIONS In the majority of instances, Rasmussen's syndrome develops in childhood, most commonly between the ages of 1 and 10 years; in one series of 48 patients, the median age at onset was 5 years (Oguni et al 1992). There is no major difference in incidence between the sexes. In about 50% of patients, the onset is preceded by an inflammatory episode (eg, an upper respiratory tract infection, otitis media, or tonsillitis) occurring in the previous 6 months. In the majority of children, the first sign of the condition is often the development of generalized tonic-clonic seizures, although simple partial or complex partial seizures occur as the initial seizure type in a significant proportion of the children. Status epilepticus is common and is the presenting feature in about 20% of patients. Seizures are usually refractory, with little response to standard antiepileptic drugs (Dubeau and Sherwin 1991). It is common for a variety of seizure types to develop over a period of time, with the seizures becoming increasingly severe and frequent. Focal motor seizures occur in about three quarters of patients at some time. Epilepsia partialis continua eventually occurs in about 50% of children, usually within 3 years of onset (Oguni et al 1992). When partial seizures occur, they almost invariably involve the same side of the body. Todd's paresis is relatively common, and in the early stages of illness, hemiparesis is postictal and transient. Exceptionally, hemiparesis occurring at this stage may be permanent. With progression of the disease, fixed neurologic deficits, including visual field deficits and hemiparesis (usually to the extent of the child losing fine finger movements and developing a hemiparetic gait), gradually ensue after a period varying from 3 months to 10 years from the onset of the epilepsy (Oguni et al 1991). Progressive intellectual impairment is also a feature of the condition, sometimes occurring or worsening in association with a deterioration in seizure control and sometimes apparently independent of seizure activity. As in the case of focal neurologic deficits, intellectual deterioration commonly occurs over a number of years, though sometimes over months. Speech deficits (including dysphasia and dysarthria) and cortical sensory loss are also features of the disease, depending on which hemisphere is involved. Despite the fact that the initial course of the illness is generally one of relentless progression, it is relatively unusual for it to cause death. Instead, the disease process eventually appears to burn itself out, usually at a stage at which there is moderate to severe neurologic deficit and intellectual impairment. As further progression of these deficits stops, the seizures often become less frequent and less severe. Rasmussen's original description of chronic localized encephalitis reported an inflammatory process, with marked perivascular cuffing by round cells in both the cortex and white matter. Diffuse patchy inflammatory changes were seen in the cortex and white www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 207
  • 211. matter, with prominent microglia in addition to small round cells and occasional polymorphonuclear cells. There was loss of nerve cells, some spongy degeneration, and hypertrophy of the astrocytes, which were also increased in number. Figure 1. Histologic features of the biopsied brain tissue in Rasmussen's syndrome consist of glial nodules and perivascular cuffing of mononuclear inflammatory cells. In addition, neuronal loss and gliosis are seen in the later stage of disease. Glial nodules and perivascular mononuclear cell cuffing are typically observed in viral encephalomyelitis, raising the possibility of a viral etiology in Rasmussen's syndrome. Figure 2. Rasmussen's syndrome. The brain shows a striking pattern of cerebral atrophy confined to the right hemisphere with right ventricular enlargement, the right temporal pole had been previously surgically removed. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 208
  • 212. Figure 3. Rasmussen's syndrome. The brain shows a striking pattern of cerebral atrophy confined to the right hemisphere with contralateral (left) cerebellar atrophy; the right temporal pole had been previously surgically removed. A, shows the basal surface of the brain after removal of the brainstem and cerebellum; B, shows the right lateral aspect with atrophic right cerebral hemisphere and normal right cerebellar hemisphere; C, shows the left lateral aspect with normal left cerebral hemisphere and atrophic left cerebellar hemisphere. Figure 4. Rasmussen's syndrome. A, shows atrophy of the cerebral cortex and white matter, and atrophy of the right thalamus, subthalamic nucleus, lenticular nucleus, tail of the caudate and hippocampus with secondary enlargement of the right ventricular system. B, shows atrophy of the left cerebellar hemisphere and left dentate nucleus. This description has been expanded by Robitaille, who reviewed the pathological specimens of 48 patients in the Montreal series (Robitaille 1991). He describes the features of the disease as the presence of microglial nodules, often displaying neuronophagia (mainly in the medium-sized pyramidal cells of the external pyramidal layer), and perivascular cuffs of small lymphocytes and monocytes. In the more active cases, he notes that the round cells fill the Virchow-Robin spaces and extend into the neuropil, forming microscopic clusters or larger aggregates. Spongiosis is particularly seen in association with inflammatory changes. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 209
  • 213. He notes the frequent presence of multifocal neuronal loss in the inflamed cortex, especially in the superficial and intermediate cortex. The smaller foci tend to coalesce into large areas of structural collapse surrounded by inflammatory changes and sprouting capillaries, which causes the area to resemble granulation tissue. Subarachnoid adhesions are not infrequently seen. Robitaille classifies the pathological specimens into four groups, according to the features of disease activity. Group 1 includes those with the most pathologically active disease. The features seen in these specimens are those of an ongoing inflammatory process, with numerous microglial nodules, with or without neuronophagia, perivascular round cells, and glial scarring. Included in Group 2 are those with "active and remote disease", indicated by the presence of several microglial nodules, cuffs of perivascular round cells, and at least one gyral segment of complete necrosis and cavitation including full-thickness cortex. Group 3 has less active "remote" disease, with pathological appearances of neuronal loss and gliosis, moderately abundant perivascular round cells, and only a few microglial nodules. Finally, Group 4 consists of those specimens showing non-specific changes, with few or no microglial nodules and only mild perivascular inflammation but with various degrees of neuronal loss and glial scarring. ETIOLOGY Since the original description of Rasmussen's encephalitis was published, the underlying cause has been the source of much speculation (Antel and Rasmussen 1996). The most likely mechanisms have been postulated as a chronic viral infection, an acute viral infection leading to a local immune response, or an independent autoimmune process, not linked to infection. Both the clinical aspects and the pathological features of the disease are strongly in favour of an underlying infective cause, as evidenced by the close resemblance of the clinical picture to that seen in Russian spring-summer tick-borne encephalitis, described by Kozhevnikov (Kozhevnikov 1991). Numerous attempts have been made to demonstrate viral particles or genetic evidence of viral material in specimens from patients with Rasmussen's encephalitis. Although there have been a number of positive results, it usually has not been possible to reproduce these, and the situation remains unresolved. Friedman and colleagues describe a 3-year-old child with hemiplegia, hemiconvulsions, and epilepsy in whom biopsy showed an encephalitic picture of perivascular cuffing with mononuclear cells, and electron microscopy of brain cells showed viral crystals resembling those of enteroviruses (Friedman et al 1977). Walter and Renella report two patients with chronic encephalitis and epilepsy in whom biopsy showed histological features of encephalitis, and in situ hybridization showed the Epstein- Barr virus genome in intranuclear central cores within the encephalitic infiltrations (Walter and Renella 1989). This raised the possibility of a role for the Epstein-Barr virus in the pathogenesis of Rasmussen's encephalitis. Power and colleagues carried out in situ hybridization for CMV on brain biopsy specimens from 10 patients with Rasmussen's encephalitis and 46 age-matched control patients with other neurologic diseases (Power et www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 210
  • 214. al 1990). They found CMV genomic material in seven of the ten patients with Rasmussen's encephalitis and in only two of the control patients. Probes of herpes simplex virus and hepatitis B were negative in all patients, although this work has been criticized (Gilden and Lipton 1991; Root-Bernstein 1991). From the same group, McLachlan and colleagues also demonstrated the CMV genome in neurons, glia, and endothelial cells of blood vessels by in situ hybridization in brain specimens from three patients who developed chronic encephalitis and epilepsy in adulthood (McLachlan et al 1993). Similar assessments for hepatitis B, herpes simplex, and Epstein-Barr virus genome were negative in these patients. Viral antibody titres in the serum and CSF samples were normal, and no viral inclusions or antigens were found in resected brain tissue. Jay and colleagues studied pathological specimens from ten patients with chronic encephalitis and intractable seizures by immunohistochemistry for HSV-1, HSV-2, and CMV as well as by the polymerase chain reaction for viral DNA sequences (HSV1, HSV2, and CMV) (Jay et al 1995). They also assessed eight non-epileptic patients with pathologically-demonstrated or clinically-suspected encephalitis and five specimens from patients with epilepsy but without encephalitis. Using polymerase chain reaction, CMV was present in six and HSV-1 in two of ten epilepsy patients with chronic encephalitis. CMV was demonstrated by in situ hybridization in two of the six patients positive for CMV by polymerase chain reaction. Immunochemistry was negative for viral antigens in all cases. None of the patients without encephalitis were found to have viral sequences by polymerase chain reaction, whereas two of the eight patients with encephalitis but without epilepsy did show CMV sequences. The authors suggest that in situ hybridization might miss some cases. In contrast, Rasmussen reports negative standard viral studies (or positive reactions only to herpes simplex and measles virus in low dilution, which is of doubtful clinical significance) (Rasmussen 1978). And Mizuno and colleagues used immunoperoxidase stains against ten viral antigens on brain specimens from two patients with Rasmussen's syndrome and found all to be negative (Mizuno et al 1985). Furthermore, Farrell and associates were unable to detect CMV using immunostaining with anti-CMV antibodies in their three patients with Rasmussen's encephalitis (Farrell et al 1991). Vinters and colleagues studied brain tissue from epileptic children with chronic (usually Rasmussen-type) encephalitis (Vinters et al 1993). They extracted DNA from specimens of brain tissue and used polymerase chain reaction with primers specific for CMV, varicella zoster, herpes simplex, Epstein-Barr virus, and human herpes virus 6 genes. They found evidence of low levels of CMV and Epstein-Barr virus genes in most brain specimens from encephalitis patients, and in several brain specimens from patients without encephalitis. The signal strength for both CMV and Epstein-Barr virus was much lower in the brains of patients with epilepsy than in the brains of AIDS patients with CMV encephalitis or brain lymphoma. The authors conclude that the small amounts of Epstein-Barr virus and CMV genes suggest that herpes virus infection of the brain did not directly cause Rasmussen' s encephalitis. Atkins and colleagues studied ten biopsy and resection specimens from seven patients using biotinylated double-stranded DNA probes to CMV, herpes simplex virus, and Epstein-Barr www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 211
  • 215. virus (Atkins et al 1995). Electron microscopy was also carried out on two samples, and one was evaluated using standard immunoperoxidase techniques. However, they were unable to identify any evidence of viral material. The likely role of viruses in the pathogenesis of Rasmussen's encephalitis has been reviewed by Asher and Gajdusek (Asher and Gajdusek 1991). Andrews and colleagues suggest that immunopathogenetic mechanisms are important in Rasmussen's encephalitis (Andrews et al 1990). They carried out extensive studies on the hemispherectomy specimen from a child with Rasmussen's encephalitis and found widespread cerebral vasculitis with immunofluorescence staining for IgG, IgM, IgA, C3 and C1q. There was also ultrastructural evidence of vascular injury, in addition to severe cortical atrophy with marked neuronal loss. The child had elevated serum antinuclear antibody titres and cerebrospinal fluid oligoclonal bands. PATHOPHYSIOLOGY AND PATHOGENESIS Perhaps the most exciting recent development in our understanding of the etiology of Rasmussen's encephalitis has been the establishment by Rogers and colleagues of a link between circulating antibodies of a ligand-gated ion channel receptor of the central nervous system in rabbits and a progressive encephalopathy with epileptic seizures (Rogers et al 1994). These workers report that two out of four rabbits who were immunized with GluR3 fusion protein in order to generate subtype-specific antibodies to recombinant GluR proteins developed seizures. Microscopic examination of the rabbit brains demonstrated chronic inflammatory changes consisting of microglial nodules and perivascular lymphocytic infiltration mainly in the cerebral cortex, as well as lymphocytic infiltration of the meninges. Rogers and colleagues reasoned that these changes probably occurred as a result of an autoimmune process directed against GluR3 and went on to look for these antibodies in four patients with pathologically confirmed Rasmussen's encephalitis. For controls, they used age- and sex-matched children with epilepsy, age and sex-matched children without CNS disease, children with active CNS inflammation, other children with epilepsy, and normal children. Immunoreactivity to GluR3 fusion protein was found in sera from two children with Rasmussen's encephalitis, and one child also showed weak immunoreactivity to GluR2 fusion protein, but the fourth child did not show immunoreactivity to any tested antigen. Only one control showed weak immunoreactivity to GluR3 that was different from the serum GluR immunoreactivity seen in individuals with Rasmussen's encephalitis. The GluR immunoreactivity appeared to correlate with disease activity, in that the three children with immunoreactivity had progressive disease or ongoing seizures, whereas hemispherectomy had been performed several years earlier in the child with no immunoreactivity, resulting in clinical stability and freedom from seizures. As a result of these findings and the implication that the disease process might be related to circulating antibodies, Rogers and colleagues carried out plasma exchange in one of the children with Rasmussen's encephalitis who showed immunoreactivity and who was seriously ill (Rogers et al 1994). The result of the plasma exchange was a decrease in seizures and improvement in neurologic status, but the improvement was short-lived, with www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 212
  • 216. further deterioration over the following 4 weeks. The same team later reported the finding that the antibodies found in Rasmussen's encephalitis actually activate the receptor, raising the possibility that the antibodies might directly trigger seizures by overstimulating the glutamate receptors (Twyman et al 1995). The fact that Rasmussen's encephalitis sometimes appears to follow a blow to the head or systemic illness has led to their proposition of a model for the development of Rasmussen's encephalitis. In their model, the insult causes a breach in the blood-brain barrier, which, in individuals with autoantibodies to GluR3, could allow the entry of these antibodies to the brain, causing activation of the receptors and subsequent seizures. The result is a vicious circle in which more rifts would be caused in the blood-brain barrier as a result of the seizures. Alternatively, the GluR3 antibodies may arise as a result of the initial central nervous system damage, thus leading to further damage. EPIDEMIOLOGY Rasmussen's syndrome is a rare disorder which, as far as is known, is not more prevalent in any population group. Diagnosis is dependent on the degree of neurologic sophistication in the country or area where the patients live. DIFFERENTIAL DIAGNOSIS The clinical changes of Rasmussen's encephalitis, like the pathological changes, are non- specific, particularly in the early stages, and several other conditions can present in a rather similar manner. MELAS is one such condition, with the clinical features of episodic vomiting, recurrent strokes, and partial seizures that are frequently associated with prolonged migrainous manifestations and often develop into epilepsia partialis continua (Dvorkin et al 1987). Cortical dysplasia may cause intractable partial epilepsy (Andermann et al 1987), though only occasionally with epilepsia partialis continua. Tuberous sclerosis may cause similar symptoms (Andermann et al 1987), as may tumors (Rich et al 1985), cerebral vasculitis (Mackworth-Young and Hughes 1985), and Russian spring-summer encephalitis (Kozhevnikov 1991). DIAGNOSTIC WORK-UP Non-specific abnormalities of the cerebrospinal fluid have been found in 50% of patients with Rasmussen's syndrome. These include minor increases of the white cell count, a modest increase in the protein content of the spinal fluid, and a first-zone or mid-zone abnormality in the colloidal gold curve (Rasmussen and Andermann 1991). Oligoclonal or, occasionally, monoclonal bands have been found in some patients, but again this has not been consistent (Dulac et al 1991; Grenier et al 1991).  Radiology The earliest patients to be reported with focal seizures due to chronic localized encephalitis were studied using pneumoencephalography (Rasmussen et al 1958). One of the patients, www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 213
  • 217. studied 5 months after the onset, had a normal pneumoencephalography. The second child, who presented with right-sided focal seizures followed by the development of a right hemiparesis, also had a normal pneumoencephalography early in the disease, but by 2 years after the onset, there was definite enlargement of the left lateral ventricle. Another pneumoencephalography performed 3 years later showed more marked evidence of atrophy of the left cerebral hemisphere, and by the following year, there was marked destruction of the left hemisphere with slight enlargement of the right lateral ventricle. The third patient described in the paper similarly had a normal pneumoencephalography early in the disease, with evidence of worsening hemispheric atrophy as the disease progressed. With the development of more sophisticated methods of imaging the brain, it has become possible to examine the changes is more detail. The advent of CT scanning confirmed the development of progressive hemiatrophy, usually beginning in the temporoinsular region, causing enlargement of the temporal horn and Sylvian fissure and eventually progressing to involve the remainder of the hemisphere in the majority of patients (Tampieri et al 1991). These authors examined the CT scans of 15 patients diagnosed since 1974 and found hemiatrophy of variable severity in 11, diffuse cerebral atrophy in 2, and normal scans in 2 who were examined early in the course of the disease. They noted that the progression of the hemiatrophy could be very rapid, becoming severe in less that 24 months. They also noted that the contralateral ventricle could become enlarged in time. This may be due to Wallerian changes and perhaps to the effect of seizures and trauma. The contralateral atrophy was never comparable to that involving the affected hemisphere. Figure 5. CT scan showing right hemispherical atrophy with ventricular dilation There have also now been several reports of MRI findings in patients with Rasmussen's encephalitis. Tampieri and colleagues describe two patients who both showed hemiatrophy and abnormal, high-intensity signal on proton density and T2-weighted images in accordance with gliosis in one child (Tampieri et al 1991). www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 214
  • 218. Tien and colleagues report the results of neuroimaging in four young patients who had undergone various combinations of CT, xenon CT, and MR scans, and PET (Tien et al 1992). Two patients had rather unremarkable CT studies but had xenon CT scans showing selectively decreased cerebral blood flow to the affected hemisphere. A third patient had CT and MRI scans showing marked atrophy of the affected hemisphere, with decreased fluorodeoxyglucose tracer uptake in that hemisphere. The fourth patient's CT and MR scans showed severe hemispheric atrophy, with appearance of gliosis in the basal ganglia region and the periventricular area. Zupanc and colleagues describe a patient with typical features of Rasmussen's encephalitis in whom repeated MRI scans, with and without gadolinium, were normal, except one that was carried out approximately 5 months after seizure onset (Zupanc et al 1990). This MRI demonstrated increased signal intensity in the white and grey matter of the left temporal lobe and a small cortical area of the left parietal lobe on the T2-weighted images, which is suggestive of edema. Similar findings of hemispheric atrophy and signal change have been reported by other authors (Aguilar et al 1996; Yacubian et al 1997). Figure 6. Rasmussen's encephalitis with hemiatrophy and ventricular dilatation Nakasu and colleagues report serial MRI findings of Rasmussen's encephalitis in a 12-year- old boy who underwent biopsy and treatment with immunoglobulins (Nakasu et al 1997). No abnormality was seen on the initial scans carried out 1 year after the onset of seizures. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 215
  • 219. But 11 months later, a high intensity lesion was seen in the left frontal cortex; this lesion rapidly spread into the white matter and then gradually regressed after biopsy and immunoglobulin therapy. Five months after the biopsy, another high intensity lesion was seen adjacent to the previous one, despite good seizure control at the time. Radiologists who are not aware of the clinical problem often interpret the signal changes observed in the MRI as being due to vascular abnormalities; therefore, it is essential to present the history and findings to the radiologist before the images are analyzed. Cendes and colleagues performed MRS in three patients with Rasmussen's syndrome (Cendes et al 1995). They measured the relative resonance intensity of N-acetylaspartate to creatine, an index of neuronal loss or damage, for various regions in the brain. They demonstrated decreased relative N-acetylaspartate signal intensity over the entire affected hemisphere, including both cortex and white matter; the decrease in intensity was most prominent in the anterior periventricular region. There was a tendency for the signal loss to be worse in patients with longer duration of disease. Follow-up scans after 1 year showed progression of the changes. The authors also note that the changes on MRS were more widespread than the structural changes seen on MRI but did not affect the contralateral hemisphere. Two of the patients had epilepsia partialis continua during the follow-up scans only; these patients showed increase in lactate resonance intensity, suggesting that the lactate accumulation resulted from repetitive seizures rather than from the disease process itself. Peeling and Sutherland performed MRS on tissue from patients undergoing surgical treatment for Rasmussen's encephalitis (Peeling and Sutherland 1993). They found that the metabolite concentrations varied with the severity and extent of the encephalitis, with the markedly abnormal tissues having decreased N-acetylaspartate, glutamate, cholines, and inositol. The decrease in the levels of N-acetylaspartate and glutamate was greater than in gliotic hippocampal tissue, suggesting the possibility that in vivo MRS might be helpful in diagnosis and in the assessment of results for various forms of immunological treatment. Figure 7. Rasmussen's encephalitis Several authors have reported the results of functional imaging in patients with Rasmussen's encephalitis. English and colleagues describe five children with Rasmussen's encephalitis in whom SPECT imaging demonstrated an area of hypoperfusion and hypometabolism corresponding to the anatomical localization of the epileptogenic foci www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 216
  • 220. found by clinical assessment, EEG, and CT (English et al 1989). In all cases, the SPECT showed a more extensive area of abnormality than CT, and in two patients undergoing sequential studies, the SPECT reflected the patients' changing clinical condition. Figure 8. Rasmussen's encephalitis. Coronal FLAIR image demonstrates encephalomalacia in the left frontoparietal region with abnormal signal in the left paracentral lobule and exvacuo dilatation of the left lateral ventricle in a patient with pathologically proven Rasmussen's encephalitis. Hwang and associates report PET and SPECT studies in patients with Rasmussen's encephalitis (Hwang et al 1991). One child was studied with 99Tc-HMPAO SPECT, showing an increase in cerebral blood flow in the left temporal lobe ictally and a wider decrease interictally in the left temporal, frontal, and parietal lobes. Five patients underwent 18-FDG-PET scanning, which usually showed a regional decrease in the local cerebral metabolic rate in the utilization of glucose, widely distributed over the affected hemisphere and extending beyond the frontal and temporal lobes. However, within the regional hypometabolic zone were one or two more foci of localized increase in metabolic rate, which, in some cases, coincided with focal epileptogenic activity as determined by electrocorticography at surgery. Figure 9. Focal decrease of FDG uptake in the right frontal cortex (arrows) in the early stage of Rasmussen's syndrome. An MR image was normal at this time. The diagnosis was later confirmed by histology. Burke and colleagues describe a patient with Rasmussen's syndrome in whom Tc-99m HMPAO SPECT produced grossly abnormal results at a time when the MRI scan showed no structural abnormality, suggesting that Tc-99m HMPAO SPECT might be helpful in early diagnosis of the condition (Burke et al 1992). Aguilar and associates describe an 8- year-old girl with epilepsia partialis continua due to Rasmussen's encephalitis involving the left side of the body who underwent ictal and interictal 99mTc HMPAO-SPECT (Aguilar et al 1996). In the ictal period this showed increased cerebral blood flow in the right www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 217
  • 221. hemisphere, particularly the Rolandic area and the temporal lobe, whereas in the interictal period a decreased flow was seen in the same regions. Yacubian and colleagues also report a focal increase in regional cerebral blood flow in four patients presenting with epilepsia partialis continua at the time of the HMPAO injection, and extensive cortical hypoperfusion in four other patients who received the injection during the interictal state (Yacubian et al 1997). These authors report abnormalities of cerebellar function in six patients, two of them with structural damage.  EEG changes Several authors have studied EEG changes in Rasmussen's encephalitis. The largest study to date has been that of So and Gloor, who describe the findings in 339 EEGs and 58 electrocorticograms carried out in 49 patients with Rasmussen's encephalitis (So and Gloor 1991). Analysis of all the preoperative EEGs showed a variety of abnormalities. All but one of the 47 patients for whom preoperative EEGs were available had some abnormality of background activity (either slowing beyond age-adjusted limits or irregularities in the morphology and frequency of waveforms), usually asymmetrical. In the later EEGs, the majority showed some abnormality bilaterally, but predominant on one side. All EEGs showed abnormal slow wave activity, and 44 of the 47 patients had evidence of interictal epileptiform discharges. Frequently, there were multiple independent foci lateralized over one hemisphere. Bilateral multiple independent discharges were seen in one third of patients but were usually predominant over one side. Almost half of the patients showed bilaterally synchronous spike and wave or sharp and slow wave discharges. Clinical or subclinical seizures were recorded in 32 patients, but although the onset could usually be lateralized to one hemisphere, it was rare for seizures to have a strictly localized electrographic onset. Electrocorticography usually showed widespread regions involved in interictal epileptiform activity, and if several seizures were studied, it was common to find multiple independent sites of seizure onset. The evolution of the EEG during the course of the disease process was also studied. Those patients with early disease who had not yet developed hemiparesis were more likely to show unilateral disturbance of background activity. As the disease progressed bilateral abnormalities became more common. EEG epileptiform abnormalities generally became more widespread with time, and some patients showed the development of independent epileptiform abnormalities over the contralateral hemisphere. Capovilla and colleagues also studied the evolution of the EEG from the onset of the disease in a single patient (Capovilla et al 1997). They noted focal delta activity over the left temporal region without spikes, at a time when the MRI was normal, and ongoing seizure activity was absent. They hypothesize that the presence of such changes in the absence of structural abnormality on imaging should prompt consideration of the diagnosis of Rasmussen's encephalitis even before the development of the classical clinical features. Andrews and colleagues studied two patients with pathologically confirmed Rasmussen's encephalitis and circulating GluR3 antibodies (Andrews et al 1997). The two patients were treated with plasma exchange and immunosuppressive treatment with intravenous immunoglobulins; high-dose steroids were also given to one patient. Repeated EEG monitoring showed that the EEG abnormalities present before plasma exchange improved during plasma exchange but worsened afterwards, apparently reflecting the change in clinical status. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 218
  • 222. PROGNOSIS AND COMPLICATIONS The initial course of Rasmussen's encephalitis is frequently characterized by rather non- specific clinical features, and it may be months or even years before the diagnosis becomes apparent. Oguni and colleagues divide the clinical course into three stages (Oguni et al 1992). In the first stage, seizures are mainly simple partial attacks with somatosensory or motor signs, and complex partial seizures without automatisms (with or without epilepsia partialis continua in each case). During the later part of the first stage, they note that seizures gradually become more frequent, and that the hemiparesis, initially postictal and transient, slowly becomes more permanent. In the second stage, there is a further increase in seizures with the development of more apparent fixed neurologic signs and increasing disability. Eventually, there seems to be a tendency for the disease activity to burn itself out, so that in the third stage there is a diminution in seizure frequency and severity, without further progression of the neurologic signs (which by this time would commonly include moderate to severe hemiparesis, a visual field defect, and a variable degree of intellectual and language impairment that ranged from mild to severe). The relentless progression of Rasmussen's encephalitis at the onset has led to the introduction of various medical treatments (Dulac et al 1991; DeToledo and Smith 1994; Hart et al 1994; Andrews et al 1996; McLachlan et al 1996), none of which have been entirely successful, and the suggestion that surgical treatment (particularly hemispherectomy, which does appear to halt the disease process in the majority of patients) should be carried out sooner rather than later (Vining et al 1993). MANAGEMENT In their protocol of high-dose steroid and immunoglobulin treatment for children with Rasmussen's encephalitis, Hart and colleagues suggest the diagnosis of chronic encephalitis in children who develop epilepsia partialis continua and meet at least one of the following criteria (Hart et al 1994): (1) Progressive neurologic deficit at the beginning or after the onset of epilepsia partialis continua but before the start of treatment (2) Progressive hemispheric atrophy on CT, MRI, or both, with or without density or signal abnormalities (3) Presence of oligoclonal or monoclonal banding on CSF examination (4) Biopsy evidence of chronic encephalitis Children without epilepsia partialis continua but with focal epilepsy and biopsy evidence of chronic encephalitis (who might in addition meet criteria 1, 2 or 3) were also considered to have the diagnosis. Because of the relentless progression of Rasmussen's encephalitis in the majority of patients and because of the rarity of the condition, which makes clinical trials difficult, clinicians have tried a variety of treatments on an empirical basis. Although hemispherectomy appears to be successful in arresting the disease process in the majority www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 219
  • 223. of patients, the consequent neurologic deficits cause reluctance to carry out this procedure until a hemiparesis already exists. There has long been debate as to whether the progressive neurologic deficits in Rasmussen's encephalitis are secondary to ongoing seizure activity or if they are an independent effect of the encephalitic process. The initial attempts at treating Rasmussen's encephalitis concentrated on the quest for seizure control. The pharmacological treatment of 25 patients with Rasmussen's encephalitis at the Montreal Neurological Institute was analyzed by Dubeau and Sherwin who found that all had received polytherapy, often at the expense of significant morbidity as a result of toxic or other adverse effects (Dubeau and Sherwin 1991). Of the seizure types most commonly seen in patients with Rasmussen's encephalitis (partial motor, complex partial, and secondarily generalized tonic-clonic seizures), the secondarily generalized tonic-clonic seizures were most likely to respond to treatment. Most other treatments directed at aborting the disease have relied on the assumption that the cause is either infective, probably viral, or the result of an autoimmune process. Examples of such treatments include antiviral treatments including the use of ganciclovir, zidovudine, high-dose interferon, high-dose steroids and immunoglobulins, and plasma exchange. DeToledo and Smith used zidovudine to treat a 4-year-old child with epilepsia partialis continua, progressive aphasia, and right hemiparesis after the seizures had failed to respond to conventional antiepileptic drugs and ACTH (DeToledo and Smith 1994). Zidovudine was given for 62 days but was eventually discontinued because of granulocytopenia. Seizures stopped and neurologic deterioration was arrested for approximately 21 months within 6 weeks of the onset of treatment. Unfortunately when the patient relapsed, with seizures affecting the previously uninvolved left hemibody, side- effects prevented further treatment with zidovudine. Zidovudine was also used in three patients by Shorvon and colleagues (Shorvon, personal communication). But the improvement was, unfortunately, short-lived and unsustained. Because of the fact that CMV had been implicated in the pathogenesis of Rasmussen's syndrome, the effect of ganciclovir was assessed in four patients by McLachlan and colleagues (McLachlan et al 1996). The CMV genome was sought in three of these patients and found in two. One child with very frequent seizures, which developed over 3 months, became seizure-free 5 days after the onset of treatment; there was also resolution of focal neurologic signs, cognitive function, and EEG changes. Two other patients treated 34 and 72 months after disease onset showed some improvement, whereas in the fourth patient there was no benefit. Early reports of the use of corticosteroids (including dexamethasone, prednisone, and ACTH) in Rasmussen's encephalitis were not encouraging (Gupta et al 1984; Piatt et al 1988). However, Dulac and colleagues, who were among the first to try high-dose steroids in children with Rasmussen's encephalitis, produced some promising results (Dulac et al 1991). They treated five children with three intravenous infusions of 400mg/m2 of www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 220
  • 224. methylprednisolone, one every other day, followed by oral prednisone (2mg/kg per day) or hydrocortisone (10 mg/kg per day) tapered off over 3 to 24 months. epilepsia partialis continua ceased in three cases within 1 month of the start of treatment, with the EEG improving dramatically in two of the three plus one other child. Progression of motor and cognitive impairment stopped in all of the children, though only one showed a clear improvement, from a state in which she was bedridden and mute to one in which she could walk and talk. However, two of the patients relapsed within a few months of the cessation of treatment. As a result of this success, other authors tried this and other immunosuppressive treatments (Walsh 1991; Hart et al 1994). Several reports have documented improvement in intractable epilepsy of other etiologies treated with gamma-globulin (Pechadre et al 1977; Laffont et al 1979; Ariizumi et al 1983). Furthermore, Walsh describes a 12-year-old boy with Rasmussen's syndrome in whom treatment with six infusions (200 mg/kg) of intravenous immunoglobulin over a period of 3 months showed improvement both in neurologic dysfunction and also in seizure control during the course of the treatment and for several months afterwards (Walsh 1991). Hart and colleagues describe 19 patients treated with high-dose steroids, immunoglobulins, or both (Hart et al 1994). Two (both biopsy-proven) had developed Rasmussen's syndrome in adulthood, whereas the rest were children. The diagnosis was confirmed by biopsy in all but three of the patients. Because the patients were treated at different centers, the treatment protocols varied. Seventeen patients received treatment with steroids, usually oral steroids, although six patients received intravenous methylprednisolone at some stage, and one child received ACTH injections over 4 weeks. Two patients received intravenous immunoglobulins alone, whereas seven patients received both high dose steroids and intravenous immunoglobulins. Seven patients showed no improvement in seizure frequency following treatment with steroids. Two patients showed an improvement of 25% or less, whereas eight showed at least a 50% reduction in seizure frequency. With the exception of two patients, the frequency of seizures increased within days or weeks of steroid withdrawal. Side effects were common and often prominent. Seven of the nine patients treated with intravenous immunoglobulin showed definite improvement in seizure control, at least initially. This was not maintained in three patients. Any improvement in neurologic deficit in these patients was only transient and accompanied improved seizure control, except in one instance wherein the hemiparesis improved disproportionately to the improvement in seizure control. It seems likely that treatments such as these might have maximum effect early in the onset of disease. In this study a considerable proportion of the patients had been ill for several years before treatment (fourteen already had mild hemiparesis and another four had evidence of intellectual deterioration), and this may be responsible for the rather poor results. Hart and colleagues suggest protocols for the treatment of patients with intravenous immunoglobulins or high-dose steroids (Hart et al 1994). With respect to intravenous immunoglobulin, the recommended treatment is 400 mg/kg per day by intravenous infusion on 3 successive days, with a single further infusion of 400 mg/kg at monthly intervals if improvement occurs. If no improvement is seen, treatment with steroids is www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 221
  • 225. recommended, with the initial course consisting of intravenous methylprednisolone (400 mg/m2 of body surface) given as three consecutive infusions on alternate days. Subsequent infusions consist of single infusions at monthly intervals for the first year, bi-monthly intervals for the second year, and tri-monthly intervals for the third year, unless serious side-effects supervene. The treatment is accompanied by oral prednisolone starting at 2 mg/kg per day, reducing very gradually over a period of months depending on clinical response, with the total duration of oral steroid treatment usually being 1 to 2 years. Another patient with symptoms highly responsive to repeated courses of immunosuppressant treatment is described by Krauss and colleagues (Krauss et al 1996). They describe a woman who had developed her first symptoms, partial and secondarily generalized seizures, at the age of 15, and had gone on to develop typical features of Rasmussen's encephalitis. Brain biopsy was also consistent with this diagnosis. Treatment with immunoglobulins at the age of 29 produced no change in her seizure control or aphasia, but intravenous methylprednisolone brought about a dramatic improvement in her seizures and neurologic deficits. Oral steroids were ineffective, and treatment with intermittent cyclophosphamide was insufficient to contain her symptoms. She was also treated with plasmapheresis, though the effect was unclear. Her serum and CSF were negative to antibodies to GluR3 by both immunoblot and immunocytochemical analysis of cells transfected with GluR3 cDNA, suggesting an alternative immune-mediated process in some patients with chronic encephalitis. Intraventricular alpha-interferon has also been tried in Rasmussen's encephalitis (Maria et al 1993; Dabbagh et al 1997), on the basis that not only do interferons have immunomodulating activity, such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, but they also inhibit virus replication in virus-infected cells. The 3 year old child described by Dabbagh and colleagues had epilepsia partialis continua and a right hemiparesis and was mute at the time of treatment (Dabbagh et al 1997). She was given three doses of 3,000,000 units of INF-alpha through an Omaya reservoir in the first week on alternate days, two doses per week in the second and third weeks, and weekly doses for the fourth through sixth weeks. She had a significant reduction in seizures but relapsed to baseline 3 weeks after stopping treatment. However, she did respond to further courses of treatment, and at the time of the report, more than 12 months after the onset of treatment, she remained seizure-free with treatments every third week. The patient described by Maria and colleagues also showed improvement in the control of his epilepsy and neurologic deficit with INF-alpha in the short term (Maria et al 1993). Andrews and colleagues describe the use of plasma exchange in four patients with clinical and pathological features of Rasmussen's encephalitis, two of them previously described by Rogers and colleagues (Rogers et al 1994; Andrews et al 1996). Three of the patients had repeated, dramatic, transient clinical improvements shown by reduced seizure frequency, rapid control of status epilepticus, and improved neurologic function. Two of these patients had evidence of active inflammation on pathological examination; the third had chronic changes (though autoantibodies were present). The fourth patient, who also had pathological evidence of active inflammation, had a more muted response to repeated www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 222
  • 226. plasma exchange. The authors draw attention to the known complications of plasma exchange (infection, anaemia, coagulopathy, etc.) and to its expense. They also suggest certain situations in which plasma exchange might prove particularly helpful, as in, for example, status epilepticus in Rasmussen's encephalitis and the evaluation of patients prior to surgery, when residual function may be unmasked by the reduction in seizure frequency brought about by the plasma exchange. Andrews and colleagues also suggest a protocol, advocating five to six single volumes of plasma exchange initially, with albumin and saline replacement, spread over 10 to 12 days, with an infusion of 1g/kg of intravenous immunoglobulin being given to the patient the day after (Andrews et al 1996). They recommend that subsequent plasma exchange be given on the basis of clinical need because of recurrent seizures, perhaps every 2 to 3 months on average. They believe that interval treatment with immunosuppressive agents might limit expense in addition to prolonging the improvement after each plasma exchange. Despite the promise shown by these treatments in a few patients, at present none has shown itself to reliably affect the course of the disease. Surgical treatment has been tried in a number of patients. Limited focal resection carried out early in the disease appears to be of little lasting benefit (Rasmussen and McCann 1968). There seems to be a consensus of opinion that functional hemispherectomy is a reasonable option when the patient has developed hemiparesis and homonymous hemianopia (Rasmussen 1983). However, some groups believe that since hemispherectomy is the only procedure that apparently stops progression of the disease, it should be considered as an early option, without awaiting the development of maximal hemiparesis (Vining et al 1993). References 1. Aguilar Rebolledo F, Rojas Bautista JC, Villanueva Perez R, Morales Hernandez S. [SPECT-99mTc-HMPAO in a case of epilepsia partialis continua and focal encephalitis] [Spanish]. Rev Invest Clin 1996;48:199-205. 2. Andermann F, Olivier A, Melanson D, Robitaille Y. Epilepsy due to focal cortical dysplasia with macrogyria and the forme fruste of tuberous sclerosis: a study of 15 patients. In: Wolf P, Dam M, Janz D, Dreifuss F, editors. Advances in epileptology: the 16th Epilepsy International Symposium. New York: Raven Press, 1987:35-8. 3. Andrews JM, Thompson JA, Pysher TJ, Walker ML, Hammond ME. Chronic encephalitis, epilepsy, and cerebrovascular immune complex deposits. Ann Neurol 1990;28:88-90. 4. Andrews PI, Dichter MA, Berkovic SF, Newton MR, McNamara JO. Plasmapheresis in Rasmussen's encephalitis. Neurology 1996;46:242-6. 5. Andrews PI, McNamara JO, Lewis DV. Clinical and electroencephalographic correlates in Rasmussen's encephalitis. Epilepsia 1997;38:189-94. 6. Antel JP, Rasmussen T. Rasmussen's encephalitis and the new hat. Neurology 1996;46:9-11. 7. Ariizumi M, Baba K, Shiihara H, et al. High dose gamma-globulin for intractable childhood epilepsy. Lancet 1983;2:162-3. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 223
  • 227. 8. Asher DM, Gajdusek DC. Virologic studies in chronic encephalitis. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth-Heinemann, 1991:147-58. 9. Atkins MR, Terrell W, Hulette CM. Rasmussen's syndrome: a study of potential viral etiology. Clin Neuropathol 1995;14:7-12. 10. Burke GJ, Fifer SA, Yoder J. Early detection of Rasmussen's syndrome by brain SPECT imaging. Clin Nucl Med 1992;17:730-1. 11. Capovilla G, Paladin F, Bernardina BD. Rasmussen's syndrome: longitudinal EEG study from the first seizure to epilepsia partialis continua. Epilepsia 1997;38:483-8. 12. Cendes F, Andermann F, Silver K, Arnold DL. Imaging of axonal damage in vivo in Rasmussen's syndrome. Brain 1995;118:753-8. 13. Dabbagh O, Gascon G, Crowell J, Bamoggadam F. Intraventricular interferon- alpha stops seizures in Rasmussen's encephalitis: a case report. Epilepsia 1997;38:1045-9. 14. DeToledo JC, Smith DB. Partially successful treatment of Rasmussen's encephalitis with zidovudine: symptomatic improvement followed by involvement of the contralateral hemisphere. Epilepsia 1994;35:352-5. 15. Dubeau F, Sherwin A. Pharmacologic principles in the management of chronic encephalitis. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth-Heinemann, 1991:179-92. 16. Dulac O, Robain O, Chiron C, et al. High-dose steroid treatment of epilepsia partialis continua due to chronic focal encephalitis. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth- Heinemann, 1991:79-110. 17. Dvorkin GS, Andermann F, Carpenter S, et al. Classical migraine, intractable epilepsy, and multiple strokes: a syndrome related to mitochondrial encephalomyopathy. In: Andermann F, Lugaresi E, editors. Migraine and epilepsy. Boston: Butterworths, 1987:202-32. 18. English R, Soper N, Shepstone BJ, Hockaday JM, Stores G. Five patients with Rasmussen's syndrome investigated by single-photon-emission computed tomography. Nucl Med Commun 1989;10:5-14. 19. Farrell M, Cheng L, Cornford ME, Grody WW, Vinters HV. Cytomegalovirus and Rasmussen's encephalitis. Lancet 1991;337:1551-2. 20. Friedman H, Ch'ien L, Parham D. Virus in brain of child with hemiplegia, hemiconvulsions, and epilepsy. Lancet 1977;2:666. 21. Gilden DH, Lipton H. Cytomegalovirus and Rasmussen's encephalitis. Lancet 1991;337:239. 22. Grenier Y, Antel JP, Osterland CK. Immunologic studies in chronic encephalitis of Rasmussen. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth-Heinemann, 1991:125-34. 23. Gupta PC, Rapin I, Houroupian DS, Roy S, Llena JF, Tandon PN. Smouldering encephalitis in children. Neuropediatrics 1984;15:191-7. 24. Hart YM, Cortez M, Andermann F, et al. Medical treatment of Rasmussen's syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or immunoglobulins in 19 patients. Neurology 1994;44:1030-6. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 224
  • 228. 25. Hwang PA, Gilday DL, Spire JP, et al. Chronic focal encephalitis of Rasmussen: functional neuroimaging studies with positron emission tomography and single- photon emission computed tomography scanning. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth- Heinemann, 1991:61-72. 26. Jay V, Becker LE, Otsubo H, et al. Chronic encephalitis and epilepsy (Rasmussen's encephalitis): detection of cytomegalovirus and herpes simplex virus 1 by the polymerase chain reaction and in situ hybridization. Neurology 1995;45:108-17. 27. Kozhevnikov AY. A particular type of cortical epilepsy (epilepsia corticalis sive partialis continua). Asher DM, trans. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth-Heinemann, 1991:245- 65. 28. Krauss GL, Campbell ML, Roche KW, Huganir RL, Niedermeyer E. Chronic steroid-responsive encephalitis without autoantibodies to glutamate receptor GluR3. Neurology 1996;46:247-9. 29. Laffont F, Esnaults S, Gilbert A, Peytour MA, Cathala HP, Eygonnet JP. Effet des hammaglobulines sur des Žpilepsies rebelles. Etude prŽliminaire. Ann Med Interne (Paris) 1979;130:307-12. 30. Mackworth-Young CG, Hughes GR. Epilepsy: an early symptom of systemic lupus erythematosus (letter). J Neurol Neurosurg Psychiatry 1985;48:185. 31. Maria BL, Ringdahl DM, Mickle JP, et al. Intraventricular alpha interferon therapy for Rasmussen's syndrome. Can J Neurol Sci 1993;20:333-6. 32. McLachlan RS, Girvin JP, Blume WT, Reichman H. Rasmussen's chronic encephalitis in adults. Arch Neurol 1993;50:269-74. 33. McLachlan RS, Levin S, Blume WT. Treatment of Rasmussen's syndrome with ganciclovir. Neurology 1996;47:925-8. 34. Mizuno Y, Chou SM, Estes ML, Erenberg G, Cruse RP, Rothner AD. Chronic localized encephalitis (Rasmussen's) with focal cerebral seizures revisited. J Neuropathol Exp Neurol 1985;44:351. 35. Nakasu S, Isozumi T, Yamamoto A, Okada K, Takano T, Nakasu Y. Serial magnetic resonance imaging findings of Rasmussen's encephalitis: a case report. Neurol Med Chir (Tokyo) 1997;37:924-8. 36. Oguni H, Andermann F, Rasmussen TB. The natural history of the syndrome of chronic encephalitis and epilepsy: a study of the MNI series of forty-eight cases. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth-Heinemann, 1991:7-35. 37. Oguni H, Andermann F, Rasmussen TB. The syndrome of chronic encephalitis and epilepsy: a study based on the MNI series of 48 cases. Adv Neurol 1992;57:419-33. 38. Pechadre JC, Sauvezie B, Osier C, Gilbert J. Traitement des encŽphalopathies de l'enfant par les gammaglobulines. RŽsultats prŽliminaires. Rev Electroencephalogr Neuropsysiol Clin 1977;7:443-7. 39. Peeling J, Sutherland G. 1 H magnetic resonance spectroscopy of extracts of human epileptic neocortex and hippocampus. Neurology 1993;43:589-94. 40. Piatt JH, Hwang PA, Armstrong DC, Becker LE, Hoffman HJ. Chronic focal encephalitis (Rasmussen syndrome): six cases. Epilepsia 1988;29:268-79. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 225
  • 229. 41. Power C, Poland SD, Blume WT, Girvin JP, Rice GP. Cytomegalovirus and Rasmussen's encephalitis. Lancet 1990;336:1282-4. 42. Rasmussen T. Further observations on the syndrome of chronic encephalitis and epilepsy. Appl Neurophysiol 1978;41:1-12. 43. Rasmussen T. Hemispherectomy for seizures revisited. Can J Neurol Sci 1983;10(2):71-8. 44. Rasmussen T, Andermann F. Rasmussen's syndrome: symptomatology of the syndrome of chronic encephalitis and seizures: 35-year experience with 51 cases. In: Luders HO, editor. Epilepsy surgery. New York: Raven Press, 1991:173-82. 45. Rasmussen T, McCann W. Clinical studies of patients with focal epilepsy due to "chronic encephalitis". Trans Am Neurol Assoc 1968;93:89-94. 46. Rasmussen T, Olszewski J, Lloyd-Smith D. Focal seizures due to chronic localized encephalitis. Neurology 1958;8:435-45. 47. Rich KM, Goldring S, Gado M. Computed tomography in chronic seizure disorder caused by glioma. Arch Neurol 1985;42:26-7. 48. Robitaille Y. Neuropathologic aspects of chronic encephalitis. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth-Heinemann, 1991:79-110. 49. Rogers SW, Andrews PI, Gahring LC, et al. Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 1994;265:648-51. 50. Root-Bernstein RS. Cytomegalovirus and Rasmussen's encephalitis. Lancet 1991:239-40. 51. So NK, Gloor P. Electroencephalographic and electrocorticographic findings in chronic encephalitis of the Rasmussen type. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth- Heinemann, 1991:37-45. 52. Tampieri D, Melanson D, Ethier R. Imaging of chronic encephalitis. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth-Heinemann. 1991;47-60. 53. Tien RD, Ashdown BC, Lewis DV, Atkins MR, Burger PC. Rasmussen's encephalitis: neuroimaging findings in four patients. AJR Am J Roentgenol 1992;158:1329-32. 54. Twyman RE, Gahring LC, Spiess J, Rogers SW. Glutamate receptor antibodies activate a subset of receptors and reveal an agonist binding site. Neuron 1995;14:755-62. 55. Vining EP, Freeman JM, Brandt J, Carson BS, Uematsu S. Progressive unilateral encephalopathy of childhood (Rasmussen's syndrome): a reappraisal. Epilepsia 1993;34:639-50. 56. Vinters HV, Wang R, Wiley CA. Herpes viruses in chronic encephalitis associated with intractable childhood epilepsy. Hum Pathol 1993;24:871-9. 57. Walsh PJ. Treatment of Rasmussen's syndrome with intravenous gammaglobulin. In: Andermann F, editor. Chronic encephalitis and epilepsy: Rasmussen's syndrome. Boston: Butterworth-Heinemann, 1991:201-204. 58. Walter GF, Renella RR. Epstein-Barr virus in brain and Rasmussen's encephalitis. Lancet 1989;1:279-80. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 226
  • 230. 59. Yacubian EM, Marie SK, Valerio RM, Jorge CL, Yamaga L, Buchpiguel CA. Neuroimaging findings in Rasmussen's syndrome. J Neuroimaging 1997;7:16-22. 60. Zupanc ML, Handler EG, Levine RL, et al. Rasmussen encephalitis: epilepsia partialis continua secondary to chronic encephalitis. Pediatr Neurol 1990;6:397-401. www.yassermetwally.com Professor Yasser Metwally www.yassermetwally.com 227