Your SlideShare is downloading. ×
Topic of the month.... Postinfectious monophasic demyelinating disorders of the CNS
Upcoming SlideShare
Loading in...5

Thanks for flagging this SlideShare!

Oops! An error has occurred.

Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

Topic of the month.... Postinfectious monophasic demyelinating disorders of the CNS


Published on

Topic of the month.... Postinfectious monophasic demyelinating disorders of the CNS

Topic of the month.... Postinfectious monophasic demyelinating disorders of the CNS

Published in: Education, Health & Medicine
  • Be the first to comment

  • Be the first to like this

No Downloads
Total Views
On Slideshare
From Embeds
Number of Embeds
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

No notes for slide


  • 1. INDEX  INTRODUCTION INTRODUCTION Benign regressive postinfectious demyelinating neurological disorders (BRPIND) are a group of neurological disorders that are characteristically postinfectious /postvaccination in nature, they are a white matter demyelinating monophasic pathological process that has a regressive, benign and self-limiting course. They must be differentiated them from the more malignant and progressive postinfectious neurological disorders such as SSPE (subacute sclerosing panencephalomyelitis) and rubella panencephalitis. Neurological diseases related to the benign regressive postinfectious neurological disorders (BRPIND) are listed in box 1. Box 1. Benign regressive postinfectious neurological disorders (BRPIND) include Central demyelinative disorders 1. Postinfectious encephalomyelitis (acute disseminated encephalomyelitis., ADEM) 2. Postinfectious cerebellitis (?variant of acute disseminated encephalomyelitis) 3. Postinfectious transverse myelitis 4. Postinfectious optic neuritis in children 5. Postinfectious neuromyelitis optica Peripheral demyelinative disorders 1. Guillain-Barré syndrome
  • 2. Benign regressive postinfectious demyelinating neurological disorders have the following main characteristics. 1. These disorders are commonly postinfectious of post vaccination in origin (Developing within 5 says to 3-5 weeks after infection or vaccination). 2. They are inflammatory demyelinating white matter diseases in nature characterized pathologically by autoimmune demyelination, breakdown of blood brain barrier with the development of vasogenic edema and contrast enhancement in the acute stage. The MRI signal changes (mainly MRI T2 hyperintensities) observed in these disorders are mainly due to the development of vasogenic edema. 3. Vasogenic edema is a very common characteristic of these disorders and they are responsible for the MRI T2 and FLAIR white matter hyperintensities frequently observed in these disorders. The existence of gross white matter edema separates these disorders from multiple sclerosis in which edema is not as gross and as severe as the postinfectious neurological disorders (BRPIND). 4. They commonly have an acute onset and a regressive course. 5. They commonly have a benign course with good prognosis and full functional recovery should be expected in most cases. It is quite apparent that postinfectious neurological disorders have protean clinical presentations depending upon the site(s) involved in the central or peripheral nervous system. Postinfectious neurological disorders might involve the brain and spinal cord (postinfectious encephalomyelitis), the cerebellar only (postinfectious cerebellitis), The spinal cord only (postinfectious acute idiopathic transverse myelitis), The optic nerve only (optic neuritis in children) or the optic nerve and spinal cord (neuromyelitis optica). It is not known whether these disorders represent a single disease with different clinical presentations or different diseases. Pathologically spinal cord involvement in neuromyelitis optica and acute disseminated encephalomyelitis is a transverse myelitic process identical to that of isolated acute idiopathic postinfectious transverse myelitis. Bilateral optic neuritis is characteristically present in acute disseminated encephalomyelitis. It looks like that the division between these postinfectious demyelinating disorders is indistinct, which is suggestive of a clinical continuum. Benign regressive postinfectious neurological disorders (BRPIND) comprises a group of poorly understood inflammatory/demyelinating white matter disorders of cerebrum, cerebellum and spinal cord that is characteristically postinfectious in nature. It is unclear what are the triggers and effector mechanisms resulting in white matter insult, though tantalizing clues have emerged. These disorders exist on a continuum of postinfectious neuroinflammatory and white matter demyelinative background that includes Guillain-Barre syndrome (GBS), acute disseminated encephalomyelitis (ADEM), Neuromyelitis Optica (NMO), optic neuritis, transverse myelitis and postinfectious cerebellitis. Each of these disorders differs in the spatial and temporal restriction of inflammation within the nervous system. However, clinical and pathologic studies support the notion that there are many common features of the inflammation and white matter demyelination that is postinfectious or postvaccinal in nature. The disease is better termed cerebral ADEM (Acute disseminated encephalitis), Spinal ADEM (acute postinfectious transverse myelitis), Cerebellar ADEM (acute postinfectious cerebellitis), Optic ADEM (Optic neuritis in children)...etc. ADEM is probably the clinico-pathological category under which all other subtypes are filed. ADEM is a collective pathological terminology that can involve the cerebrum only (Acute disseminated encephalitis or much better termed acute disseminated cerebritis), the spinal cord only (acute postinfectious transverse myelitis), The cerebellum only (acute postinfectious cerebellitis), The optic nerves and the spinal cord (neuromyelitis optic), or the optic nerves only (optic neuritis in children) [139]. Other terminologies might even be suggested like ataxic ADEM (acute postinfectious cerebellitis), myelitic ADEM (acute postinfectious transverse myelitis)...etc. Predominantly brainstem presentation with features suggesting Miller-Fisher syndrome might occasionally be encountered (? brain stem ADEM). Miller-Fisher syndrome can occasionally be postinfectious in nature. These disorders might coexist in various combinations in the same patient or might present clinically as an isolated disease. It looks like that the division between these postinfectious disorders is indistinct, which is suggestive of a clinical continuum. These disorders simply represent a single disease with different clinical presentations. Myelin basic protein (which is the main antigen that is targeted in the immune mechanism that end in myelin destruction) is different in different parts of the CNS. The myelin basic protein in the peripheral nerves is different from that of the CNS and this might explain why the demyelinative process may preferentially involves some parts of the CNS and spare other parts in different patients (depending upon the antigenic properties of the myelin basic protein of the involved sites) resulting in a protean clinical presentations of the same disease in different patients. Different areas of the white matter within the CNS and the peripheral nervous system are targeted by the inflammatory demyelinating pathological process in various combinations in different patients depending upon the antigenic properties of the myelin basic protein in these areas resulting in some patients having their optic nerves, cerebrum,
  • 3. and spinal cord involved (acute disseminated encephalomyelitis), other patients having their optic nerves and spinal cord involved (neuromyelitis optica) and so on. [139] Although almost any portion of the CNS may be clinically involved, certain systems appear to be particularly prone to dysfunction; thus, the descending white matter motor tracts (the corticospinal tract, pyramidal tract), optic nerves, and spinal cord are particularly commonly involved. In particular postinfectious isolated transverse myelitis is the most common clinical presentation of this disorder in the author experience, probably this signifies the selective involvement of the descending corticospinal and pyramidal tract fibers. Myelin destruction and inflammatory white matter demyelination is an immune-mediated mechanism in Benign regressive postinfectious neurological disorders (BRPIND) that is triggered by antecedent infection. The immune mechanisms include antibody-mediated complement dependant myelinolysis, T-cell mediated lysis of Schwann cells and T -cell mediated induction of an immune reaction with release of cytokines and recruitment of inflammatory cells including macrophages. The description of these immune mediated mechanisms are beyond the scope of This chapter. [139] Benign regressive postinfectious neurological disorders (BRPIND) most commonly occur after smallpox and measles infections. In recent years, the disease has been associated with various viral and bacterial infections. Patients may have a history of an exanthem or a nonspecific respiratory or gastrointestinal illness 1 to 3 weeks before onset of neurologic symptoms. Acute cerebellar ataxia is a form of acute postinfectious encephalomyelitis following varicella infection. [139] Post-immunization BRPIND occur most frequently following measles, rubella, or mumps vaccination. Many vaccines have been implicated in the causation of BRPIND [Table - 1]. In countries where neural tissue-based vaccines are still used, antirabies immunization with either BPL (betapropionolactone inactivated) or Semple (phenol inactivated) vaccines are important causes for BRPIND. [139] Table 1. Infections alleged to cause BRPIND [139] Viral Measles, Mumps, Varicella, Rubella, Influenza, A,B Hepatitis, A,B Coxsackie, Epstein-Barr, Dengue [16]and HIV [17] Bacterial Mycoplasma pneumoniae, Borrelia burgdorferi, Mycobacterium tuberculosis, Brucella, Chlamydia, Legionella, Salmonella typhi, and Leptospira, Campylobacter, Streptococcus pyogenes Vaccination Rabies, Measles, Rubella, Smallpox, Diphtheria, Mumps, Tetanus, antitoxin, Pertussis, Japanese encephalitis, Polio, Hepatitis B, Influenza, and Meningococcal A, and C Drugs Gold, Arsenical compounds, Sulfonamides, streptomycin/PAS Miscellaneous Allogenic bone marrow transplantation , Heart-lung transplantation Herbal extracts, Ventriculo- atrial shunts, Stings, Leprosy type I reaction CLINICAL SUBTYPES OF THE ACUTE POSTINFECTIOUS REGRESSIVE NEUROLOGICAL DISORDERS  Acute disseminated encephalomyelitis (ADEM) (Postinfectious cerebritis) Acute disseminated encephalomyelitis (ADEM) is an immune-mediated disorder of the central nervous system (CNS). Disease typically starts with an abrupt onset of neurologic symptoms and signs within days to weeks after a viral infection or immunization. Neuropathological examination of the CNS in ADEM reveals involvement of white matter, with infiltration of monocytoid cells and perivenous demyelination. Acute disseminated encephalomyelitis (ADEM) is an immune-mediated disorder of the central nervous system (CNS). Disease typically starts with an abrupt onset of neurologic symptoms and signs within days to weeks after a viral infection or immunization. ADEM is also known as “postinfectious,” “parainfectious,” “postexanthematous,” or “postvaccinal” encephalomyelitis. Although many viral agents associated with ADEM also cause acute viral encephalitis, ADEM usually occurs much later after the onset of infection and differs clinically by virtue of greater white matter involvement with respective neurologic symptoms. Contrary to acute viral encephalitis, attempts to isolate the virus from postmortem ADEM brains have often failed, implying mechanisms other than direct invasion of CNS by the infectious agent. Neuropathologic examination of ADEM consistently discloses widespread perivenular inflammation and myelin disruption, giving rise to the pathologically derived terms “perivascular myelinoclasis,” “perivenous encephalitis,” and “acute demyelinating encephalomyelitis”. [139] The first clues to the possible pathogenic mechanisms underlying ADEM came from studies on demyelinating encephalomyelitis cases that occasionally complicated smallpox vaccination [127]. Rivers and Schwentker [128] reported histologic similarities between postvaccinal encephalomyelitis brains and fatal neuroparalytic accidents
  • 4. following rabies vaccination. Perivenular inflammation and demyelination were obvious in both cases. To examine the contribution of brain-derived proteins present in rabies vaccine to the induction of lesions, Rivers and Schwentker [128] repeatedly injected homogenates of normal rabbit brains into monkeys. Several monkeys receiving the virus-free brain homogenates developed an inflammatory, demyelinating brain disease, closely resembling clinical and pathologic features of postvaccinal encephalomyelitis [129]. Indeed, this was the first example of “experimental autoimmune encephalomyelitis” (EAE), which came to be studied extensively in the ensuing decades as a prototype autoimmune disease model, particularly multiple sclerosis (MS) [131,132,133]. EAE was later shown to be inducible by single injections of homologous brain tissue (ie, brain tissue removed from the same animal) when it was emulsified in complete Freund's adjuvant. The myelin protein antigens able to induce disease were subsequently identified and shown to have common sequences across species. Interestingly, disease was later shown to be passively transferable to healthy animals by injecting CD4+ T lymphocytes from immunized animals [133]. EAE signs vary depending on species; strain (genetic background); age; gender; and the immunization protocol. Disease typically starts with weakness and paralysis, 7 to 21 days after inoculation of brain homogenate or myelin components. On neuropathologic analysis, mononuclear cell infiltrates consisting of lymphocytes and monocytoid cells are seen in meninges and in perivenular areas in the white matter. These findings are accompanied by activation of resident microglia and are followed by demyelination and axonal injury. Although mainly considered a disease of the CNS, inflammatory demyelinating lesions have also been described in the peripheral nervous system (ie, dorsal root ganglia in rabbits induced with EAE) [134,135]. Repair of demyelinated foci with recurrent inflammation and demyelination gives rise to a relapsing-remitting disease course in some species. A pathogenically similar but clinically distinct disease termed “experimental autoimmune neuritis” can be induced in the peripheral nervous system. Reported by Waksman and Adams [136] in 1955, rabbits receiving peripheral nerve emulsions in adjuvant develop an acute demyelinating neuropathy after a period of about 2 weeks. Similar to EAE, experimental autoimmune neuritis is characterized by mononuclear cells infiltrating out of endoneural venules followed by demyelination. [139] The presence of brain-derived components in rabies vaccines at the time, the striking histologic similarities between vaccine-induced encephalomyelitis and EAE, and similar latency times and clinical disease course after immunizations led to the belief that postvaccinal encephalomyelitis was a disease of an autoimmune nature. This assumption was reinforced by the observation that lymphocytes from post–rabies vaccine encephalomyelitis patients could be stimulated in vitro with myelin antigens, a feature similar to the lymphocytes isolated from EAE animals. Indeed, the incidence of postvaccinal encephalomyelitis dramatically decreased with the introduction of rabies vaccines devoid of myelin components (ie, virus grown in embryonated eggs or cell cultures, rather than infected rabbit or sheep brain) [137]. Growing rabies virus in newborn mice brains, however, which are largely unmyelinated, failed completely to eliminate neurologic complications of vaccine [138]. Nevertheless, many of the patients receiving these vaccines developed polyradicular neuropathies with cranial nerve involvement, which have been attributed to the presence of peripheral nerve myelin components in the cranial nerves isolated with newborn mice brains [138]. In the author experience the condition is much better termed acute disseminated cerebritis rather than acute disseminated encephalitis or encephalomyelitis as the disease was only restricted to the cerebrum in the author experience and the cerebellum, the brain stem and the spinal cord were never seen involved in the ADEM cases seen by the author. The word encephalitis simply means involvement of the cerebrum, the brain stem and the cerebellum by the inflammatory process, while encephalomyelitis means, in addition, involvement of the spinal cord which has never been the case in the author experience. In ADEM cases seen by the author, the cerebrum was involved in isolation by the inflammatory process and the cerebellum, the brain stem and the spinal cord were spared both clinically and by MRI examination. ADEM is more common in the winter months, with as many as 65- 85% of cases occurring between October and March.
  • 5. Figure 1. A case of acute disseminated encephalomyelitis. Notice that the multifocal cortical / subcortical hyperintense foci are sparing the periventricular region, and this is the classic pattern in ADEM. The foci, although of large size they have mild mass effect. 1. Postinfectious transverse myelitis Acute transverse myelitis (ATM) is a common clinical presentation of postinfectious or postvaccinal ADEM that is characterized by focal inflammation of the spinal cord with subsequent neural injury leading to sensory, motor, and autonomic dysfunction. In the author experience postinfectious transverse myelitis is the most common clinical presentation of postinfectious benign monophasic demyelinating disorders. About one third of patients have pain in the distribution of the involved segments of the spinal cord, before the development of sensory-motor or autonomic symptoms. At the peak of the disease about 50% of patients with ATM are paraplegic; 80% to 94% have been reported to have paresthesia, dysesthesia, or numbness; with almost all the patients suffering from bladder dysfunction. Although ATM can occur in the context of multifocal CNS disease or as a part of multisystemic autoimmune disorders (eg, systemic lupus erythematosus or sarcoidosis), it can also present as an isolated idiopathic entity. The initial events leading to detrimental autoimmune responses targeting spinal cord are still a matter of debate, but disease has been pathogenically linked to postinfectious demyelinating disorders. Indeed, in 30% to 60% of idiopathic cases there is a preceding respiratory, gastrointestinal, or systemic illness. Like cerebral ADEM, ATM has also been reported following measles, rubella, influenza, and hepatitis B vaccinations. In about 5% of cases, transverse myelitis represents the first attack of MS. Unlike ATM, however, sensory-motor impairments following myelopathic MS are usually asymmetric, making the two entities distinguishable. Moreover, monosegmental involvement of the spinal cord is more commonly seen in myelopathic MS, compared with other ATM etiologies. Cerebrospinal fluid (CSF) pleocytosis and abnormal IgG index can be observed in both MS and ATM. Initial severity of weakness and evidence of denervation on electromyography has been considered poor prognostic indicators for ATM. Approximately one third of patients with ATM recover completely, one third show partial recovery with moderate disabilities, and the rest of the cases lead to permanent severe disabilities. [139]
  • 6. Figure 2. A case with acute idiopathic postinfectious transverse myelitis. Notice spinal cord swelling and the MRI T2 central hyperintensity and the central dot sign. Also notice the involvement of the complete cross section of the spinal cord. Table 2. The MRI picture characteristic of idiopathic transverse myelitis 1. A centrally located multisegmental (3 to 8 spinal segments) MRI T2 hyperintensity that occupies more than two thirds of the cross-sectional area of the cord is characteristic of transverse myelitis. The MRI T2 hyperintensity commonly shows a slow regression with clinical improvement. The central spinal cord MRI T2 hyperintensity represents evenly distributed central cord edema. MRI T1 Hypointensity might be present in the same spinal segments that show T2 hyperintensity although to a lesser extent. The MRI T2 hyperintensity is central, bilateral, more or less symmetrical and multisegmental. 2. MRI T2 central isointensity, or dot (within and in the core of the MRI T2 hyperintensity) might be present and is believed to represent central gray matter squeezed by the uniform, evenly distributed edematous changes of the cord. (central dot sign). It might not be of any clinical significance. 3. Contrast enhancement is commonly focal or peripheral and maximal at or near the segmental MRI T2 hyperintensity. In idiopathic transverse myelitis enhancement is peripheral to the centrally located area of high T2 signal intensity rather than in the very same area. The prevalence of cord enhancement is significantly higher in patients with cord expansion. 4. Spinal cord expansion might or might not be present and when present is usually multisegmental and better appreciated on the sagittal MRI T1 images. Spinal cord expansion tapers smoothly to the normal cord, and is of lesser extent than the high T2 signal abnormality. 5. Multiple sclerosis plaques (and subsequent T2 hyperintensity) are located peripherally, are less than 2 vertebral segments in length, and occupies less than half the cross-sectional area of the cord. In contrast to transverse myelitis, enhancement in MS occurs in the same location of high-signal-intensity lesions seen on T2-weighted images. Table 3. Differences between idiopathic transverse myelitis and spinal multiple sclerosis T2 Number Disease entity Contrast element Pathology hyperintensity of segments
  • 7. involved Idiopathic transverse Central, 4-8 In transverse myelitis Nonspecific necrosis that myelitis multisegmental enhancement is peripheral to affects gray and white matter the centrally located area of indiscriminately and destroys high T2 signal intensity rather axons and cell bodies as well as than in the very same area. myelin. Spinal multiple Peripheral 1-2 In contrast to transverse White matter demyelination sclerosis myelitis, enhancement in MS only. occurs in the same location of high-signal-intensity lesions seen on T2-weighted images.  Postinfectious cerebellitis Postinfectious cerebellitis (acute cerebellar ataxia) is an inflammatory syndrome resulting in acute cerebellar dysfunction, which may occur as a primary infectious, postinfectious, or post-vaccination disorder. Also known as acute cerebellar ataxia, cerebellitis occurs most commonly in young children and may be difficult to diagnose on routine clinical and laboratory studies. An encephalitis largely restricted to the cerebellum, called cerebellitis. Cerebellitis may occur due to a host of viral agents, including enteroviruses, herpesviruses, HIV, and rabies. Bacterial infections have also been associated with cerebellitis, including Borrelia burgdorferi (Lyme disease), Mycoplasma pneumoniae, Legionella, and Coxiella burnettii (Q fever). In addition, cerebellitis may follow immunizations such as hepatitis, smallpox, and measles vaccination, or may occur without evidence for an antecedent or concurrent factor. In many cases, however, the precise causative agent is not isolated. [139] The MRI C-shaped cerebellar white matter T2 hyperintensity demonstrated in post infectious cerebellitis is mainly due to cerebellar white matter vasogenic edema that totally disappeared on MRI follow-up studies following complete clinical recovery. Any involvement of the cerebellar gray matter in postinfectious cerebellitis is probably secondary to white matter edema and is due to spreading of edema to the nearby neurons. Vasogenic edema fluid is retained outside the vasculature, mostly in the white matter of the brain, and within the bundles of myelinated axons of long tracts and commissural fibers. This is because axons run in parallel bundles of fibres with loose extracellular space (that offer low resistance and facilitates the extension of vasogenic edema along myelinated axons which are spreaded apart by the edema) as opposed to gray matter, which has high cell density and is enmeshed in an interwoven network of connecting fibres that offer high resistance to the formation and spread of edema. Although the cerebellar MRI signal changes are commonly bilateral and symmetrical, cases with unilateral cerebellar abnormalities are reported. [139] Figure 3. A,B postcontrast CT scan and C, MRI T2 image showing bilateral more or less symmetrical C- shaped CT hypodensity and MRI T2 hyperintensity involving the cerebellar white matter. The 4th ventricle is compressed and anteriorly displaced. Mild hydrocephalic changes can also be demonstrated in the form of mildly dilated temporal horns of the lateral ventricles. The obstructive hydrocephalic changes are mainly due to cerebellar swelling by the effect of vasogenic edema.
  • 8. Figure 4. MRI T2 images showing bilateral more or less symmetrical C- shaped MRI T2 hyperintensity involving the cerebellar white matter. The 4th ventricle is compressed and anteriorly displaced. Figure 5. MRI FLAIR images showing the bilateral, symmetrical hyperintense C- shaped white matter cerebellar lesions and the mild hydrocephalic changes.
  • 9. Figure 6. A, Postmortem section through the cerebellum and the brain stem at the level of the 4th ventricle., B, MRI T2 image at the same level of the postmortem cut. Notice that the MRI T2 hyperintensity is taking the characteristic C- shaped because it is exactly mapping the cerebellar white matter and taking its shape. The MRI T2 C- shaped hyperintensity most probably representing vasogenic white matter edema that is spreading along the white matter tracts and association fibers of the cerebellum. Figure 7. A, Postmortem section through the cerebellum and the brain stem at the level of the 4th ventricle., B, MRI T2 image at the same level of the postmortem cut. Notice that the MRI T2 hyperintensity is taking the characteristic C- shaped because it is exactly mapping the cerebellar white matter and taking its shape. The MRI T2 C- shaped hyperintensity most probably representing vasogenic white matter edema that is spreading along the white matter tracts and association fibers of the cerebellum.
  • 10. Figure 8. Same as in figure 7, however the cerebellar white matter color is changes into white to show that the MRI T2 hyperintensity is predominately white matter in location and taking the shape of the cerebellar white matter (C- shaped) and represents vasogenic edema along the cerebellar white matte myelinated axons.  Devic's neuromyelitis optica (DNMO) Devic's neuromyelitis optica (DNMO) is a demyelinating disease characterized by bilateral visual disturbance and transverse myelopathy. Pathologically, lesions are restricted to the optic nerves and spinal cord, with areas of necrosis of gray and white matter, cavitations, lack of inflammatory infiltrate, vascular hyalinization, and fibrosis. Clinically, the disease may have a mono- or multiphasic course. The nosology is not clear, and the reports from the literature are confusing. Historically, the disease was defined as a monophasic disorder consisting of fulminant bilateral optic neuritis and myelitis, occurring in close temporal association. Cases of DNMO that followed in the literature described more extensive findings, with a relapsing course, which raised the question of whether DNMO represents a separate syndrome or a variant of MS. The most common abnormality observed on MR images of the spinal cord is longitudinal, confluent lesions extending across five or more vertebral segments, with a hyperintensity on T2-weighted images. Cord swelling and enhancement might be present. MR imaging findings can be used to differentiate between DNMO and MS: In DNMO, no cerebral white matter lesions are present; spinal cord lesions are confluent and extend to multiple segments in DNMO, which is uncommon in MS; spinal cord atrophy is present in MS but is often described as part of the course of DNMO; and cranial nerves or cerebellar involvement are common in MS but are not present in DNMO. The discovery of a novel serum autoantibody, NMO-IgG, with high sensitivity and specificity for DNMO, has significantly improved the early diagnosis of this severe demyelinating syndrome. Clinical findings that favor DNMO are higher age at onset and severe course. [139]  Optic neuritis in children Optic neuritis implies an inflammatory process involving the optic nerve. In children, most cases are due to an immune-mediated process. These cases may be associated with a viral or other infection or with immunization. Less commonly, optic neuritis may be the first manifestation of multiple sclerosis (MS) or part of a more diffuse demyelinating disorder, including acute disseminated encephalomyelitis or Devic disease. Possible mechanisms of inflammation in immune-mediated optic neuritis are the cross-reaction of viral epitopes and host epitopes and the persistence of a virus in central nervous system (CNS) glial cells. Children with optic neuritis have a good prognosis, but a minority of patients experience persistent visual loss. When optic neuritis is associated with other CNS diseases, the morbidity and mortality of those disorders contribute substantially to the final outcome. [139] Table 4. Comparison of features of optic neuritis in adults and children Adult Optic Neuritis Pediatric Optic Neuritis Unilateral Bilateral
  • 11. Retrobulbar optic neuritis Papillitis Commonly associated with pain on eye Commonly associated with headache movements Most often postinfectious or Most often idiopathic postimmunization High probability of recurrent inflammatory Low probability of recurrent demyelinating demyelinating events and a events in the CNS and a diagnosis of MS diagnosis of MS IMPORTANT ISSUES IN THE ACUTE POSTINFECTIOUS REGRESSIVE NEUROLOGICAL DISORDERS  General classification of encephalitis/myelitis (Infectious versus postinfectious) In general encephalitis/myelitis is an acute inflammatory process that affects brain or spinal cord tissue and is almost always accompanied by inflammation of the adjacent meninges. The disease is most commonly caused by viral infection. Encephalitis resulting from viral infection manifests as either acute viral encephalitis or postinfectious encephalomyelitis. Acute viral encephalitis is caused by direct viral infection of neural cells with associated perivascular inflammation and destruction of gray matter. Postinfectious encephalomyelitis follows infection with various viral or bacterial agents; the primary pathologic finding is demyelination of white matter. Postinfectious encephalitis/myelitis is an immunological disorders in which peripheral blood lymphocytes cross- react against myelin basic protein resulting in myelinolysis and inflammatory demyelination of the white matter. Breakdown of the blood brain barrier results in the formation of vasogenic edema that migrate along white matter tracts and is probably responsible for the MRI T2 hyperintensity observed in these disorders. Vasogenic edema is probably responsible for the multisegmental MRI T2 hyperintensity that are commonly seen in postinfectious transverse myelitis that apparently spare gray matter (gray matter is commonly seen as the central dot sign which represents the gray matter squeezed by edema). In postinfectious transverse myelitis vasogenic edema travel up and down along white matter tracts resulting in the multisegmental involvement of the spinal cord that is characteristic of postinfectious transverse myelitis.  Pathology and pathogenesis of postinfectious regressive demyelinating neurological disorders Encephalitis is an acute inflammatory process that affects brain tissue and is almost always accompanied by inflammation of the adjacent meninges. The disease is most commonly caused by viral infection. Encephalitis resulting from viral infection manifests as either acute viral encephalitis or postinfectious encephalomyelitis. Acute viral encephalitis is caused by direct viral infection of neural cells with associated perivascular inflammation and destruction of gray matter. Postinfectious encephalomyelitis follows infection with various viral or bacterial agents; the primary pathologic finding is demyelination of white matter. Direct viral infection of the brain and spinal cord involves mainly the gray matter (neurons), while Postinfectious or parainfectious neurological disorders is simply a white matter disease in which there is immune mediated demyelination of the white matter long tracts and the association fibers in the cerebrum, cerebellum, brain stem and spinal cord. Postinfectious neurological disorders might involve the peripheral nerves in Guillain barre syndrome (acute infectious demyelination polyradiculoneuropathy) The distinction between infective (neuronal) and postinfectious (immune -mediated demyelinative white matter disease) might be difficult or even impossible on clinical background, however table 5 demonstrates the main differences between the two pathologies. [139] Table 5. Differences between infectious and postinfectious encephalitis/myelitis [139] Parameter Infectious Postinfectious Site of involvement Cortical gray Demyelinative, white matter matter disease Mental state Impaired Less impaired, might be clear The interval between the first sign of infection and the onset of  Briefer (Few  Prolonged (7-21 days) neurological disorders days) CSF examination Abnormal May be normal
  • 12. Postinfectious regressive demyelinative white matter diseases (BRPIND) are characterized by perivenular inflammation and demyelination of brain/spinal cord tissue. In this disorder, peripheral blood lymphocytes cross- react against myelin basic protein. Before widespread vaccination, postinfectious encephalomyelitis most commonly occurred after smallpox and measles infections. In recent years, the disease has been associated with various viral and bacterial infections. Patients may have a history of an exanthem or a nonspecific respiratory or gastrointestinal illness 1 to 3 weeks before onset of neurologic symptoms. Acute cerebellar ataxia is a form of acute postinfectious encephalomyelitis following varicella infection. [139] Postinfectious regressive demyelinative white matter diseases represent an autoimmune response to proteins, most probably myelin- basic proteins, in the CNS with perivenous inflammation and demyelination found in autopsy and biopsy studies. Demyelination may not be present in the first few days of the disease. The strongest evidence for the auto- immune nature of postinfectious neurological disorders is that a similar pathology is seen in experimental allergic encephalitis (EAE). EAE is induced in animals by inoculating them with brain tissue or myelin basic protein. Although EAE now is used as an experimental model for ADEM, the occurrence of ADEM in afflicted humans exposed to rabies vaccine contaminated with brain tissue proves the validity of this model. Further support for the autoimmune nature of ADEM comes from the reactivity of T cells against myelin basic protein found in children with ADEM and the increase in proinflammatory cytokines and anti-inflammatory cytokines in the cerebrospinal fluid (CSF) of children with ADEM, even in the absence of ongoing infection. Even in the laboratory model of EAE, what is found in one strain of animals does not always apply to others. Autoimmunity can be triggered by several mechanisms, including molecular mimicry, bystander activation, epitope spreading, and mistaken self. The role of of these different mechanisms is unknown. [139] Figure 9. Histopathology studies In ADEM have demonstrated perivenous cuffing with inflammatory cells, especially lymphocytes and macrophages, and loss of myelin Histologically, the acute lesions in BRPIND are characterized by an extensive loss of myelin (perivenous cuffing with inflammatory cells, especially lymphocytes and macrophages, and loss of myelin). This may be in the form of a well-demarcated area of demyelination, although in the acute situation, the edges of the demyelinated lesions often are less well defined, and the demyelination and attendant cellular processes extend into the surrounding rim. Demyelinated fibers may be recognized by an axon devoid of a sheath, as seen histochemically, or immunohistochemically, or on electron microscopy by the presence of naked axons. In addition, thinly myelinated fibers may be seen within the lesion, suggesting partially demyelinated or remyelinated fibers. The presence of oligodendrocytes showing the re-expression of myelination proteins suggests the latter event is occurring in a least a significant number of these fibers. Vasogenic edema (due to breakdown of blood brain barrier) may be severe, and is seen as an expansion of the extracellular space, spreading apart both fibers and cells.
  • 13. Accompanying the myelin loss is a large infiltrate of foamy or debris- filled macrophages lying in sheets that appear to have replaced the normal neuropil. They also may be around the blood vessels, or infiltrating the more preserved areas of tissue as single cells. Depending on the age of the lesion, the macrophages may contain some or none of the myelin proteins described above, or may be LFB positive. The macrophages will stain for general markers such as KPI but depending on the patient's age, early (MRP14) or late (27ElO) markers also may be present to help date lesions. The inflammatory infiltrate varies, but in most acute cases will be of some significance. Lymphocytes staining with the leukocyte common antigen comprise most cells, although polymorphonuclear leukocytes, eosinophils, plasma cells, and even mast cells have been found, together with less well-characterized monocytes. Although they may be present throughout the tissue, they are particularly prominent around the blood vessels, and at times may be so severe as to mimic a vasculitis. Both CD4 helper cells and CD8 suppressor cells may be found in the lesions. In the past, there have been suggestions that CD4 cells predominate in early lesions, with CD8 cells taking over at later stages, but this is variable, and a fixed pattern has not been defined. Many workers also have described the occurrence of gamma-delta lymphocytes in these lesions, and their association with acute phase reactant or stress proteins such as heat shock protein on oligodendrocytes has been well recognized. (MS) [139] Demyelination of the white matter is associated with breakdown of the blood brain barrier and the development of vasogenic edema. Vasogenic edema is the most common type of edema results from local disruption of the blood brain barrier. This leads to extravasation of protein-rich filtrate of plasma into the interstitial space, with subsequent accumulation of vascular fluid. This disruption results from loosening of the tight junctions between endothelial cells, and the neoformation of pinocytic vesicles. Once the barrier is breached, hydrostatic and osmotic forces work together to extravasate intravascular fluid. Once extravasated, fluid is retained outside the vasculature, mostly in the white matter of the brain, and within the bundles of myelinated axons of long tracts and commissural fibers. This is because axons run in parallel bundles of fibres with loose extracellular space (that offer low resistance and facilitates the extension of vasogenic edema along myelinated axons which are spreaded apart by the edema) as opposed to gray matter, which has high cell density and is enmeshed in an interwoven network of connecting fibres that offer high resistance to the formation and spread of edema. By definition, this type of edema is confined to the extracellular space. Vasogenic edema is responsible for the MRI T2 hyperintensity and MRI T1 hypointensity and The MRI T1 contrast enhancement frequently observed in these disorders. [139]  Immunology The lesions of BRPIND are due to autoimmune-mediated inflammation of the CNS, and the absence of viral or bacterial antigens in the CNS is nearly universal. [139] T-cells have been shown to play an important role, possibly through molecular mimicry or by nonspecific activation of autoreactive T-cell clones. Interleukin-6 may be associated with proliferation of B-lymphocytes and immunoglobulin G synthesis. Anti-basal ganglia antibodies have been demonstrated in children with classical features of ADEM following streptococcal infection. A complex interplay between cytokines and adhesion molecules is responsible for the cellular events of inflammatory encephalomyelitis and oligodendrocyte death. An association has been established between ADEM and certain class II HLA alleles, indicating that genetic factors may play a role in immunoregulation and progression from infection/vaccination to ADEM. It is quite apparent that Benign regressive postinfectious neurological disorders (BRPIND) comprises a group of neurological disorders which represent a clinical continuum rather that separate diseases entities. They share a common aetiopathogenic factors (antecedent viral infection that invokes antibodies that cross react with the myelin basic protein of the peripheral and central nervous system). They also share a common pathological picture (demyelination of the white matter of the CNS and demyelinating polyneuropathy) and a common prognosis (They all have a very good prognosis with full functional recovery in most cases). [139]  BRPIND or multiple sclerosis? In a patient presenting with neurological dysfunction and MRI showing multiple white matter lesions, the most important differential diagnosis is MS. Distinguishing between ADEM and MS is a diagnostic challenge and has important therapeutic and prognostic implications. There are several clinical, imaging, and laboratory parameters that may be useful to distinguish between the two [Table - 6]. CSF electrophoresis has shown a significant reduction in the beta-1 globulin fraction in patients with MS as compared to those with BRPIND and this may be a potential CSF marker. Features that strongly favor BRPIND include a history of preceding infection, polysymptomatic neurological dysfunction, encephalopathy, grey matter involvement (mainly due to extension of the white matter edema to the nearby neurons in the grey matter rather than due to direct involvement of the grey matter ) on MRI, and absence of oligoclonal bands in CSF. Often, distinction between these two conditions cannot be made with certainty and follow-up with serial MRI may be necessary to establish the diagnosis. In general ADEM is an autoimmune meningo-encephalitic process that is associated with disturbed level of consciousness, seizures and meningeal irritation signs (multiple sclerosis is not an encephalitic process) Table 6. Differences between BRPIND and multiple sclerosis [139]
  • 14. Feature BRPIND MS Onset Abrupt Subacute Triggering events Preceding infection or vaccination in Uncommon 70 % of cases Age group More common in children More common in young adult Temporal profile Monophasic, rarely relapsing Relapsing Clinical features Altered sensorium More common Rare Seizures More common Rare Neurological deficit Multifocal Usually single deficit Optic neuritis Bilateral Unilateral Myelitis Complete, transverse myelitis Partial myelopathy Lower motor neuron signs More common Rare Headache More common Rare Meningismus More common Rare Neuroimaging findings Distribution of the lesions Bilateral extensive lesions Scattered asymmetric lesions White matter lesions Confluent, ill-defined periventricular Well-defined, with periventricular and subcortical white matter lesions preponderance Corpus callosum lesions Rare Common grey matter involvement* Thalamic and basal ganglionic lesions Uncommon are common Edema and mass effect May be present Uncommon Follow-up MRI No new lesions New lesions with dissemination in time and place Cerebrospinal fluid Cell count Mild to moderate pleocytosis Normal to mild pleocytosis Protein Increased Normal Oligoclonal bands Uncommon, transient Common and persistent Mortality 10-25 Uncommon * Mainly due to extension of the white matter edema to the nearby neurons in the grey matter rather than due to direct involvement of the grey matter TRANSVERSE MYELITIS AS A PROTOTYPE OF THE ACUTE POSTINFECTIOUS REGRESSIVE NEUROLOGICAL DISORDERS  Immunopathogenesis of acute transverse myelitis. Acute transverse myelitis is a group of disorders characterized by focal inflammation of the spinal cord and resultant neural injury. Acute transverse myelitis may be an isolated entity or may occur in the context of multifocal or even multisystemic disease. It is clear that the pathological substrate - injury and dysfunction of neural cells within the spinal cord - may be caused by a variety of immunological mechanisms. For example, in acute transverse myelitis associated with systemic disease (i.e. systemic lupus erythematosus or sarcoidosis), a vasculitic or granulomatous process can often be identified. In idiopathic acute transverse myelitis, there is an intraparenchymal or perivascular cellular influx into the spinal cord, resulting in the breakdown of the blood-brain barrier and variable demyelination and neuronal injury. There are several critical questions that must be answered before we truly understand acute transverse myelitis: (1) What are the various triggers for the inflammatory process that induces neural injury in the spinal cord? (2) What are the cellular and humoral factors that induce this neural injury? and (3) Is there a way to modulate the inflammatory response in order to improve patient outcome? Although much remains to be elucidated about the causes of acute transverse myelitis, tantalizing clues as to the potential immunopathogenic mechanisms in acute transverse myelitis and related inflammatory disorders of the spinal cord have recently emerged. It is the purpose of this review to illustrate recent discoveries that shed light on this topic, relying when necessary on data from related diseases such as acute disseminated encephalomyelitis, Guillain-Barre syndrome and neuromyelitis optica. Developing a further understanding of how the immune system
  • 15. induces neural injury will depend upon confirmation and extension of these findings and will require multicenter collaborative efforts. Acute transverse myelitis (ATM) is a group of poorly understood inflammatory disorders resulting in neural injury to the spinal cord. It is unclear what are the triggers and effector mechanisms resulting in neural injury, although tantalizing clues have emerged. ATM exists on a continuum of neuroinflammatory disorders that also includes Guillain-Barre syndrome (GBS), multiple sclerosis (MS), acute disseminated encephalomyelitis and neuromyelitis optica (NMO). Each of these disorders differs in the spatial and temporal restriction of inflammation within the nervous system. However, clinical and pathological studies support the notion that there are many common features of the inflammation and neural injury. In the current review, we will examine recent evidence that shed light on the immunopathogenesis of ATM and, where applicable, related neuroinflammatory disorders. Such studies point to a variety of humoral and cellular immune derangements that potentially result in neuronal injury and demyelination. Further advances in understanding the immunopathogenesis of ATM will require controlled studies with epidemiological and clinical-pathological correlation. It is only then that we will be able to establish rational intervention strategies designed to improve the outcome of patients with ATM.  History of acute transverse myelitis Several cases of quot;acute myelitisquot; were described in 1882, and pathological analysis revealed that some were caused by vascular lesions and others by acute inflammation [1,2]. In 1922 and 1923, physicians in England and Holland became aware of a rare complication of smallpox vaccination: inflammation of the spinal cord and brain [3]. Given the term quot;post-vaccinal encephalomyelitisquot;, over 200 cases were reported in those 2 years alone. Pathological analyses of fatal cases revealed inflammatory cells and demyelination. In 1928, it was first postulated that many cases of acute myelitis are quot;postinfectious rather than infectious in causequot; because for many patients the `fever had fallen and the rash had begun to fadequot; when the myelitis symptoms began [4]. It was proposed, therefore, that the myelitis was an `allergicquot; response to a virus rather than the virus itself that caused the spinal cord damage. It was in 1948 that the term quot;acute transverse myelitisquot; was utilized in reporting a case of fulminant inflammatory myelopathy complicating pneumonia [5].  Diagnosis of acute transverse myelitis ATM is an inflammatory process affecting a restricted area of the spinal cord. It is characterized clinically by acutely or subacutely developing symptoms and signs of neurological dysfunction in motor, sensory and autonomic nerves and nerve tracts of the spinal cord. There is often a clearly defined rostral border of sensory dysfunction and a spinal magnetic resonance imaging (MRI) and lumbar puncture shows evidence of acute inflammation. When the maximal level of deficit is reached, approximately 50% of patients have lost all movements of their legs, virtually all patients have some degree of bladder dysfunction, and 80-94% of patients have numbness, paresthesias or band- like dysesthesias [6-11]. Autonomic symptoms consist variably of increased urinary urgency, bowel or bladder incontinence, difficulty voiding, or bowel constipation [12].  Classification of acute transverse myelitis Recently, a diagnostic and nosology scheme has been proposed that defines ATM according to the inclusion and exclusion criteria set forth in Table 7 (The Transverse Myelitis Consortium Working Group, 2002, in preparation). These criteria have attempted to define ATM as a monofocal inflammatory process of the spinal cord and to distinguish it from non-inflammatory myelopathies (i.e. radiation-induced myelopathy or ischemic vascular myelopathy). It further attempts to distinguish various etiologies for ATM. Two diagnostic categories of quot;idiopathic ATMquot; and quot;disease-associated ATMquot; [i.e. systemic lupus erythematosus (SLE)-associated ATM] are thus proposed, provided that other criteria are met. Disease-associated ATM is diagnosed when the patient meets standard criteria for other known inflammatory diseases (e.g. MS, sarcoidosis, SLE, Sjogren's syndrome) or direct infection of the spinal cord. When an extensive search fails to determine such a cause, idiopathic ATM is defined. Table 7. Idiopathic acute transverse myelitis criteria. Inclusion criteria (1) Development of sensory, motor or autonomic dysfunction attributable to the spinal cord (2) Bilateral signs or symptoms (although not necessarily symmetric) (3) Clearly-defined sensory level (4) Exclusion of extra-axial compressive etiology by neuroimaging (MRI or myelography; CT of spine not adequate)
  • 16. (5) Inflammation within the spinal cord demonstrated by CSF pleocytosis or elevated IgG index or gadolinium enhancement. If none of the inflammatory criteria is met at symptom onset, repeat MRI and LP evaluation between 2 and 7 days after symptom onset meets criteria (6) Progression to nadir between 4 h and 21 days after the onset of symptoms (if patient awakens with symptoms, symptoms must become more pronounced from point of awakening)  Exclusion criteria (1) History of previous radiation to the spine within the past 10 years (2) Clear arterial distribution clinical deficit consistent with thrombosis of the anterior spinal artery (3) Abnormal flow voids on the surface of the spinal cord consistent with AVM (4) Serological or clinical evidence of connective tissue disease (sarcoidosis, Behcet's disease, Sjogren's syndrome, SLE, mixed connective tissue disorder, etc.)a (5) CNS manifestations of syphilis, Lyme disease, HIV, HTLV-1, mycoplasma, other viral infection (e.g. HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, enteroviruses)a (a) Brain MRI abnormalities suggestive of MSa (b) History of clinically apparent optic neuritisa a AVM, Arteriovenous malformation; CMV, cytomegalovirus; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; EBV, Epstein-Barr virus; HHV, human herpesvirus; HSV, herpes simplex virus; HTLV, human T cell leukemia virus; LP, lumbar puncture; MRI, a magnetic resonance imaging; MS, multiple sclerosis; SLE, systemic lupus erythematosus. Do not exclude disease-associated acute transverse myelitis.  Immunopathogenesis of acute transverse myelitis  Disease-associated acute transverse myelitis The immunopathogenesis of disease-associated ATM is varied. For example, pathological data confirm that many cases of lupus-associated transverse myelitis are associated with central nervous system (CNS) vasculitis [13- 15], whereas others may be associated with thrombotic infarction of the spinal cord [16,17]. Neurosarcoid is often pathologically associated with non-caseating granulomas within the spinal cord [18], whereas transverse myelitis associated with MS often has perivascular lymphocytic cuffing and mononuclear cell infiltration immunopathogenically and with variable complement and antibody deposition [19]. As these diseases have such varied (albeit poorly understood) immunopathogenic and effector mechanisms, they will not be discussed further here. Rather, the subsequent discussion will focus on findings potentially related to idiopathic ATM.  Post-vaccination acute transverse myelitis Several reports of ATM following vaccination have recently been published. Indeed, it is widely reported in neurology texts that ATM is a post-vaccination event. One publication reports a case of post flu vaccine myelitis in which a 42-year-old man with a history of bilateral optic neuritis developed ATM 2 days after an influenza vaccination [20]. A separate study [21] reported a 36-year-old individual who developed a progressive and ultimately fatal, inflammatory myelopathy/polyradiculopathy 9 days after a booster hepatitis B vaccination. The patient had no fever or systemic illness and did not respond to extensive immunotherapy. Autopsy evaluation of the spinal cord revealed severe axonal loss with mild demyelination and a mononuclear infiltrate, predominantly T lymphocytes in nerve roots and spinal ganglia. The spinal cord had perivascular and parenchymal lymphocytic cell infiltrates in the grey matter, especially the anterior horns. The suggestion from such studies is that a vaccination may induce an autoimmune process resulting in ATM. However, it should be noted that extensive data continue to show overwhelmingly that vaccinations are safe and are not associated with an increased incidence of neurological complications [22- 29]. Therefore, such case reports must be viewed with caution, as it is entirely possible that two events occurred in close proximity by chance alone.  Parainfectious acute transverse myelitis In 30-60% of the idiopathic ATM cases, there is an antecedent respiratory, gastrointestinal or systemic illness [6- 10,30,31]. The term quot;parainfectiousquot; has been used to suggest that the neurological injury may be associated with
  • 17. direct microbial infection and injury as a result of the infection, direct microbial infection with immune-mediated damage against the agent, or remote infection followed by a systemic response that induces neural injury. An expanding list of antecedent infections is now recognized, although in the vast majority of these cases causality cannot be established. Several of the herpes viruses have been associated with myelitis, and are probably caused by direct infection of neural cells within the spinal cord [32-34]. Other agents, such as Listeria monocytogenes may be transported intra-axonally to neurons in the spinal cord [35.]. By using such a strategy, an agent may be able to gain access to a relatively immune privileged site, avoiding the immune surveillance present in other organs. Such a mechanism may also explain the limited inflammation to a focal region of the spinal cord seen in some patients with ATM. Although the infectious agent in these cases is required within the CNS, other mechanisms of autoimmunity, such as molecular mimicry and superantigen-mediated disease, require only peripheral immune activation and may account for other cases of ATM.  Molecular mimicry Molecular mimicry as a mechanism to explain an inflammatory nervous system disorder has been best described in GBS. First referred to as an quot;acute postinfectious polyneuritisquot; by Osler in 1892, GBS is preceded in 75% of cases by an acute infection [36- 39]. Campylobacter jejuni infection has emerged as the most important antecedent event in GBS, occurring in up to 41% of cases [40-43]. Human neural tissue contains several subtypes of ganglioside moieties such as GM1, GM2 and GQ1b within their cell walls [44,45]. A characteristic component of human gangliosides, sialic acid [46], is also found as a surface antigen on C. jejuni within its lipopolysaccharide outer coat [47]. Antibodies that crossreact with gangliosides from C. jejuni have been found in serum from patients with GBS [48-50], and have been shown to bind peripheral nerves, fix complement and impair neural transmission in experimental conditions that mimic GBS [44,51-53]. Susceptibility to the development of GBS is dependent upon both strain-specific features of the C. jejuni and host genetic factors. Enterogenic strains of C. jejuni differ from strains likely to induce GBS [43,45,54,55]. However, the susceptibility to develop GBS also depends on host genetic factors. In a recent study, several members of the same family became infected with a single strain of C. jejuni, yet only one patient developed a humoral response against the lipopolysaccharide extract, and that patient was the only one to develop GBS [56]. In addition, recent studies have suggested a predominance of certain HLA alleles - HLA-B35, HLA-B54, HLA-Cwl and HLA-DQB1*0 - in GBS patients, suggesting a genetic restriction [40,57]. Molecular mimicry in ATM may also occur and may be associated with the development of autoantibodies in response to an antecedent infection. One ATM patient developed elevated titers of lupus anticoagulant IgG, antisulfatide antibodies (1 : 6400) and anti-GM1 antibodies (1 : 600 IgG and 1 : 3200 IgM) after Enterobium vermicularis (perianal pinworm) infection [58]. As E. vermicularis has been shown to contain cardiolipin, ganglioside GM1, and sulfatides within their lipid composition, it was postulated that in the proper genetic and hormonal background, the infection triggered the pathogenic antibodies. Several additional studies have suggested how this process could cause neural injury. Box 2. The Molecular mimicry Molecular mimicry is defined as the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient enough to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the promiscuity of several peptide sequences which can be both foreign and self in nature, a single antibody or TCR (T cell receptor) can be activated by even a few crucial residues which stresses the importance of structural homology in the theory of molecular mimicry. Upon the activation of B or T cells, it is believed that these “peptide mimic” specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity).[104] Molecular mimicry is a phenomenon that has been just recently discovered as one of several ways in which autoimmunity can be evoked. A molecular mimicking event is, however, more than an epiphenomenon despite its low statistical probability of occurring and these events have serious implications in the onset of many human autoimmune disorders. In the past decade, the study of autoimmunity, the failure to recognize self antigens as “self”, has grown immensely. Autoimmunity is a result of a loss of immunological tolerance which is the ability for an individual to discriminate between self and non-self. Growth in the study of autoimmunity has resulted in more and more people being diagnosed with an autoimmune disease which affects approximately 1 in 31 people within the general population.[105] Growth has also led to a greater characterization of what autoimmunity is and how it can be studied and treated. Also, with an increased amount of research being performed, there has been tremendous growth in the study of the several different ways in which autoimmunity can occur; one of which is molecular mimicry. The mechanism by which pathogens have evolved, or obtained by chance, similar amino acid sequences or the homologous three-dimensional crystal structure of immunodominant epitopes remains a mystery.
  • 18.  Immunological tolerance Tolerance is a fundamental property of the immune system. Tolerance involves non-self discrimination which is the ability of the normal immune system to recognize and respond to foreign antigens, but not self antigens. Autoimmunity is evoked when this tolerance to self antigen is broken.[106] Tolerance within an individual is normally evoked as a fetus. This is known as maternal-fetal tolerance where T cells expressing receptors specific for a particular antigen enters the circulation of the developing fetus via the placenta.[107] After pre-T cells leave the bone marrow where they are synthesized, they are moved to the thymus where the maturation of T cells occurs. It is here where the first wave of T cell tolerance arises. Within the thymus, pre-T cells will encounter various self and foreign antigens present in the thymus that enter the thymus from peripheral sites via the circulatory system. Within the thymus, pre-T cells undergo a selection process where they are positively or negatively selected for maturation. T cells that have an interaction with foreign antigen within the thymus are positively selected for maturation. These cells will express the appropriate T cell receptor and co-receptor (either CD4 or CD8) after a period of about three weeks. Conversely, T cells that interact with self antigen or do not react to antigen at all are negatively selected for apoptosis. This negative selection is known as clonal deletion, one of the mechanisms for T cell tolerance. Approximately 99 percent of pre-T cells within the thymus are negatively selected. Only approximately 1 percent are positively selected for maturity.[108] However, there is only a limited repertoire of antigen that T cells can encounter within the thymus. T cell tolerance then must occur within the periphery after the induction of T cell tolerance within the thymus as a more diverse group of antigens can be encountered in peripheral tissues. This same positive and negative selection mechanism, but in peripheral tissues, is known as clonal anergy. The mechanism of clonal anergy is important to maintain tolerance to many autologous antigens. Active suppression is the other known mechanism of T cell tolerance. Active suppression involves the injection of large amounts of foreign antigen in the absence of an adjuvant with leads to a state of unresponsiveness. This unresponsive state is then transferred to a naïve recipient from the injected donor to induce a state of tolerance within the recipient.[109] Tolerance is also produced in B cells. There are also various processes which lead to B cell tolerance. Just as in T cells, clonal deletion and clonal anergy can physically eliminate autoreactive B cell clones. Receptor editing is another mechanism for B cell tolerance. This involves the reactivation or maintenance of V(D)J gene recombination in the cell which leads to the expression of novel receptor specificity through V region gene rearrangements which will create variation in the heavy and light immunoglobulin (Ig) chains.[109]  Autoimmunity Autoimmunity can thus be defined simply as exceptions to the tolerance quot;rules.quot; By doing this, an immune response is generated against self-tissue and cells. These mechanisms are known by many to be intrinsic. However, there are pathogenic mechanisms for the generation of autoimmune disease. Pathogens can induce autoimmunity by polyclonal activation of B or T cells, or increased expression of major histocompatibility complex (MHC) class I or II molecules. There are several ways in which a pathogen can cause an autoimmune response. A pathogen may contain a protein that acts as a mitogen to encourage cell division, thus causing more B or T cell clones to be produced. Similarly, a pathogenic protein may act as a superantigen which causes rapid polyclonal activation of B or T cells. Pathogens can also cause the release of cytokines resulting in the activation of B or T cells, or they can alter macrophage function. Finally, pathogens may also expose B or T cells to cryptic determinants which are self antigen determinants which have not been processed and presented sufficiently to tolerize the developing T cells in the thymus and are presented at the periphery where the infection occurs.[110] Molecular mimicry has been characterized as recently as the 1970’s as another mechanism by which a pathogen can generate autoimmunity. Molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products. Either the linear amino acid sequence or the conformational fit of the immunodominant epitope may be shared between the pathogen and host. This is also known as “cross-reactivity” between self antigen of the host and immunodominant epitopes of the pathogen. An autoimmune response is then generated against the epitope. Due to similar sequence homology in the epitope between the pathogen and the host, cells and tissues of the host associated with the protein are destroyed as a result of the autoimmune response.[110]  Probability of mimicry events The prerequisite for molecular mimicry to occur is thus the sharing of the immunodominant epitope between the pathogen and the immunodominant self sequence that is generated by a cell or tissue. However, due to the amino acid variation between different proteins, molecular mimicry should not happen from a probability standpoint. Assuming five to six amino acid residues are used to induce a monoclonal antibody response, the probability of 20 amino acids occurring in six identical residues between two proteins is 206 or 1 in 64,000,000. However, there has been evidence shown and documented of many molecular mimicry events.[111]
  • 19. To determine which epitopes are shared between pathogen and self, large protein databases are used. The largest protein database in the world, known as the SWISS-PROT database, has shown reports of molecular mimicry becoming more common with expansion of the database. The database currently contains 1.5 X 107 residues. The probability of finding a perfect match with a motif of 5 amino acids in length is 1 in 3.7 X 10-7 (0.055). Therefore, within the SWISS-PROT database, one would expect to find 1.5 X 107 X 3.7 X 10-7 = 5 matches. However, there are sequence motifs within the database that are overrepresented and are found more than 5 times. For example, the QKRAA sequence is an amino acid motif in the third hypervariable region of HLA-DRB1*0401. This motif is also expressed on numerous other proteins, such as on gp110 of the Epstein-Barr virus and in E. coli. This motif occurs 37 times in the database.[112] This would suggest that the linear amino acid sequence may not be an underlying cause of molecular mimicry since it can be found numerous times within the database. The possibility exists, then, for variability within amino acid sequence, but similarity in three-dimensional structure between two peptides can be recognized by T cell clones. This, therefore, uncovers a flaw of such large databases. They may be able to give a hint to relationships between epitopes, but the important three-dimensional structure cannot yet be searched for in such a database.[113]  Structural mimicry Despite no obvious amino acid sequence similarity from pathogen to host factors, structural studies have revealed that mimicry can still occur at the host level. In some cases, pathogenic mimics can possess a structural architecture that differs markedly from that of the functional homologues. Therefore, proteins of dissimilar sequence may have a common structure which elicits an autoimmune response. It has been hypothesized that these virulent proteins display their mimicry through molecular surfaces that mimic host protein surfaces (protein fold or three-dimensional conformation), which have been obtained by convergent evolution. It has also been theorized that these similar protein folds have been obtained by horizontal gene transfer, most likely from a eukaryotic host. This further supports the theory that microbial organisms have evolved a mechanism of concealment similar to that of higher organisms such as the African praying mantis or chameleon who camouflage themselves so that they can mimic their background as not to be recognized by others.[114] Despite dissimilar sequence homology between self and foreign peptide, weak electrostatic interactions between foreign peptide and the MHC can also mimic self peptide to elicit an autoimmune response within the host. For example, charged residues can explain the enhanced on-rate and reduced off-rate of a particular antigen or can contribute to a higher affinity and activity for a particular antigen that can perhaps mimic that of the host. Similarly, prominent ridges on the floor of peptide-binding grooves can do such things as create C-terminal bulges in particular peptides that can greatly increase the interaction between foreign and self peptide on the MHC.[115]. Similarly, there has been evidence that even gross features such as acidic/basic and hydrophobic/hydrophilic interactions have allowed foreign peptides to interact with an antibody or MHC and TCR. It is now apparent that sequence similarity considerations are not sufficient when evaluating potential mimic epitopes and the underlying mechanisms of molecular mimicry. Molecular mimicry, from these examples, has therefore been shown to occur in the absence of any true sequence homology.[104] There has been increasing evidence for mimicking events caused not only by amino acid similarities but also in similarities in binding motifs to the MHC. Molecular mimicry is thus occurring between two recognized peptides that have similar antigenic surfaces in the absence of primary sequence homology. For example, specific single amino acid residues such as cysteine (creates di-sulfide bonds), arginine or lysine (form multiple hydrogen bonds), could be essential for T cell cross-reactivity. These single residues may be the only residues conserved between self and foreign antigen that allow the structurally similar but sequence non-specific peptides to bind to the MHC.[116]  Epitope spreading Epitope spreading is another common way in which autoimmunity can occur which uses the molecular mimicry mechanism. This inducer of autoimmunity causes autoreactive T cells to be activated de novo by self epitopes released secondary to pathogen-specific T cell-mediated bystander damage. T cell responses to progressively less dominant epitopes are activated as a consequence of the release of other antigens secondary to the destruction of the pathogen with a homologous immunodominant sequence. Thus, inflammatory responses induced by specific pathogens that trigger pro- inflammatory Th1 responses have the ability to persist in genetically susceptible hosts. This may lead to organ-specific autoimmune disease.[117] Conversely, epitope spreading could be due to target antigens being physically linked intracellularly as members of a complex to self antigen. The result of this is an autoimmune response that is triggered by exogenous antigen that progresses to a truly autoimmune response against mimicked self antigen and other antigens.[118] From these examples, it is clear that the search for candidate mimic epitopes must extend beyond the immunodominant epitopes of a given autoimmune response.[104]  Implications in human disease  Diseases of the central nervous system The HIV-1 virus has been shown to cause diseases of the central nervous system (CNS) in humans through a molecular
  • 20. mimicry apparatus. HIV-1 gp41 is used to bind chemokines on the cell surface of the host so that the virion may gain entrance into the host. Astrocytes are cells of the CNS which are used to regulate the concentrations of K+ and neurotransmitter which enter the cerebrospinal fluid (CSF) to contribute to the blood brain barrier. A twelve amino acid sequence (Leu-Gly-Ile-Trp-Gly-Cys-Ser-Gly-Lys-Leu-Ile-Cys) on gp41 of the HIV-1 virus (immunodominant region) shows sequence homology with a twelve amino acid protein on the surface of human astrocytes. Antibodies are produced for the HIV-1 gp41 protein. These antibodies can cross-react with astrocytes within human CNS tissue and act as autoantibodies. This contributes to many CNS complications found in AIDS patients.[119] Theiler’s murine encephalomyelitis virus (TMEV) leads to the development of a progressive CD4+ T cell-mediated response after these cells have infiltrated the CNS. This virus has been shown to cause multiple sclerosis, which is another autoimmune disease. It results in the gradual destruction of the myelin sheath coating axons of the CNS. TMEV shares a thirteen amino acid sequence (His-Cys-Leu-Gly-Lys-Trp-Leu-Gly-His-Pro-Asp-Lys-Phe) (PLP (proteolipid protein) 139-151 epitope) with that of a human myelin-specific epitope. Bystander myelin damage is caused by virus specific Th1 cells that cross react with this self epitope. To test the efficacy in which TMEV uses molecular mimicry to its advantage, a sequence of the human myelin-specific epitope was inserted into a non-pathogenic TMEV variant. As a result, there was a CD4+ T cell response and autoimmune demyelination was initiated by infection with a TMEV peptide ligand.[120] In humans, it has recently been shown that there are other possible targets for molecular mimicry in patients with multiple sclerosis. These involve the hepatitis B virus mimicking the human proteolipid protein (myelin protein) and the Epstein-Barr virus mimicking anti-myelin oligodendrocyte glycoprotein (contributes to a ring of myelin around blood vessels).[121]  Muscle disorders Myasthenia gravis is another common autoimmune disease. This disease causes fluctuating muscle weakness and fatigue. The disease occurs due to detectable antibodies produced against the human acetylcholine receptor. The receptor contains a seven amino acid sequence (Trp-Thr-Tyr-Asp-Gly-Thr-Lys)[121] in the a-subunit that demonstrates immunological cross-reactivity with a shared immunodominant domain of gpD of the herpes simplex virus (HSV). Similar to HIV-1, gpD also aids in binding to chemokines on the cell surface of the host to gain entry into the host. Cross-reactivity of the self epitope (a-subunit of the receptor) with antibodies produced against HSV suggests that the virus is associated with the initiation of myasthenia gravis. Not only does HSV cause immunologic cross-reactivity, but the gpD peptide also competitively inhibits the binding of antibody made against the a-subunit to its corresponding peptide on the a-subunit. Despite this, an autoimmune response still occurs. This further shows an immunologically significant sequence homology to the biologically active site of the human acetylcholine receptor.[122]  The postinfectious benign demyelinating neurological disorders Molecular mimicry in ATM may also occur and may be associated with the development of autoantibodies in response to an antecedent infection. One ATM patient developed elevated titers of lupus anticoagulant IgG, antisulfatide antibodies (1 : 6400) and anti-GM1 antibodies (1 : 600 IgG and 1 : 3200 IgM) after Enterobium vermicularis (perianal pinworm) infection [58]. As E. vermicularis has been shown to contain cardiolipin, ganglioside GM1, and sulfatides within their lipid composition, it was postulated that in the proper genetic and hormonal background, the infection triggered the pathogenic antibodies. Several additional studies have suggested how this process could cause neural injury.  Control of molecular mimicry There are ways in which autoimmunity caused by molecular mimicry can be avoided. Control of the initiating factor (pathogen) via vaccination seems to be the most common method to avoid autoimmunity. Inducing tolerance to the host autoantigen in this way may also be the most stable factor. The development of a downregulating immune response to the shared epitope between pathogen and host may be the best way of treating an autoimmune disease caused by molecular mimicry.[122] Alternatively, treatment with immunosuppressive drugs such as cyclosporin A and azathioprine has also been used as a possible solution. However, in many cases this has been shown to be ineffective because cells and tissues have already been destroyed at the onset of the infection.[106]  Conclusion The concept of molecular mimicry is a useful tool in understanding the etiology, pathogenesis, treatment, and prevention of autoimmune disorders. Molecular mimicry is, however, only one mechanism by which an autoimmune disease can occur in association with a pathogen. Understanding the mechanisms of molecular mimicry may allow future research to be directed toward uncovering the initiating infectious agent as well as recognizing the self determinant. This way, future research may be able to design strategies for treatment and prevention of autoimmune disorders. The use of transgenic models such as those used for discovery of the mimicry events leading to diseases of the CNS and muscle disorders has helped evaluate the sequence of events leading to molecular mimicry.  Microbial superantigen-mediated inflammation
  • 21. Another link between an antecedent infection and the development of ATM may be the fulminant activation of lymphocytes by microbial superantigens. Superantigens are microbial peptides that have a unique capacity to stimulate the immune system, and may contribute to a variety of autoimmune diseases. The best-studied superantigens are staphylococcal enterotoxins A to I, toxic shock syndrome toxin-1 and Streptococcus pyogenes exotoxin, although many viruses also encode superantigens [59-62]. Superantigens activate T lymphocytes in a unique manner compared with conventional antigens: instead of binding to the highly variable peptide groove of the T cell receptor, superantigens interact with the more conserved V. region [63-66]. In addition, unlike conventional antigens, superantigens are capable of activating T lymphocytes in the absence of co-stimulatory molecules. As a result of these differences, a single superantigen may activate between 2 and 20% of circulating T lymphocytes compared with 0.001- 0.01% with conventional antigens [67-69]. Interestingly, superantigens often cause expansion followed by deletion of T lymphocyte clones with particular V. regions resulting in `holes' in the T lymphocyte repertoire for some time after the activation [63-66,70]. Therefore, patients can often be tested for presumptive evidence of previous superantigen exposure through T cell receptor Vb usage frequencies. The stimulation of large numbers of lymphocytes may trigger autoimmune disease by activating autoreactive T cell clones [71,72]. In humans, there are many reports of the expansion of selected V. families in patients with autoimmune diseases, suggesting a previous superantigen exposure [71,73]. As this limited expansion was not seen in serum and non-inflamed tissues, it was proposed that superantigens activated previously quiescent autoreactive T cells, which then entered a tissue and were retained in that tissue by repeated exposure to the autoantigen [74]. In the CNS, superantigens isolated from Staphylococcus induced paralysis in mice with experimental autoimmune encephalomyelitis through its ability directly to stimulate Vb8-expressing T cells specific for the myelin basic protein peptide Ac 1-11 [67,68,75]. In humans, a patient with acute disseminated encephalomyelitis and necrotizing myelopathy was found to have Streptococcus pyogenes superantigen-induced T cell activation against myelin basic protein [76].  Humoral derangements Either of the above processes may result in abnormal immune function, with a blurred distinction between self and non-self. The development of abnormal antibodies may then potentially activate other components of the immune system or recruit additional cellular elements to the spinal cord. Recent studies have emphasized distinct autoantibodies in patients with NMO [77-81] and recurrent ATM [82-84]. The high prevalence of various autoantibodies seen in such patients suggests polyclonal derangement of the immune system. However, it may not just be autoantibodies, but high levels of even normal circulating antibodies that play a causative role in ATM. A case of ATM was described in a patient with extremely high serum and cerebrospinal fluid (CSF) antibody levels to hepatitis B surface antigen after booster immunization [85]. Such circulating antibodies may form immune complexes that deposit in focal areas of the spinal cord. Such a mechanism has been proposed to describe a patient with recurrent transverse myelitis and high titers of hepatitis B surface antigen [86]. Circulating immune complexes containing hepatitis B surface antigen were detected in the serum and CSF during the acute phase, and the disappearance of these complexes after treatment correlated with functional recovery. Several Japanese patients with ATM were found to have much higher serum IgE levels than MS patients or controls (360 versus 52 versus 85 U/ml) [87]. Virtually all the patients in that study had specific serum IgE to household mites (Dermatophagoides pteronyssinus or Dermatophagoides farinae), whereas fewer than a third of MS and control patients did. One potential mechanism to explain ATM in such patients is the deposition of IgE with the subsequent recruitment of cellular elements. Indeed, biopsy specimens of two ATM patients with elevated total and specific serum IgE revealed antibody deposition within the spinal cord, perivascular lymphocyte cuffing and the infiltration of eosinophils [88]. It was postulated that eosinophils recruited to the spinal cord degranulated and induced the neural injury in these patients. Recently, several reports have suggested that elevated prolactin levels occur in some patients with NMO [89,90]. The elevated prolactin levels were limited to Asian and black women and correlated with involvement of the optic nerve. It may therefore be that the extension of inflammation to the hypothalamus results in diminished hypothalamic dopamine and increased pituitary secretion of prolactin. Furthermore, as prolactin is a potent immune stimulant for T helper cell type 1 responses, it is possible that the enhanced prolactin leads to an augmentation of disease activity elsewhere in the neuraxis. It may even be that autoantibodies initiate a direct injury of neurons. A particular pentapeptide sequence found on microbial agents is a molecular mimic of double-stranded DNA, and antibodies raised against this sequence react against dsDNA [91]. This pentapeptide sequence is also present in the extracellular region of the glutamate receptor subunits NR2a and NR2b, present on neurons in the CNS. dsDNA antibodies recognize glutamate receptors in vitro and in vivo, and can induce neuronal death. Other studies have shown that the IgG repertoire from active plaque and periplaque regions in the MS brain and from B cells from the CSF of a patient with MS consisted of anti-DNA antibodies [92]. These antibodies bind to the surface of neuronal cells and oligodendrocytes. Therefore, molecular mimicry may cause the development of antibodies that interact with neuronal surface proteins and induce neural
  • 22. injury through the activation of neural pathways.  Potential treatment options in acute transverse myelitis There is currently no treatment that has been clearly shown to modulate the outcome in patients with ATM. Indeed, with such varied immunopathogenesis, it may be that distinct treatment options need to be employed for different subsets of ATM patients. Recent studies that have investigated potential strategies to modulate neural injury associated with ATM will be reviewed.  Methylprednisolone On the basis of the presumptive immunopathogenic mechanisms in ATM, several recent studies have investigated a role for intravenous methylprednisolone in the acute phase. All studies evaluated a series of patients with ATM treated with methylprednisolone in open-label studies [93,94,95]. Two of the studies suggested a role for methylprednisolone in small, open label trials [93,95], whereas one suggested no improvement in outcome [94]. In one study [95], 12 children with severe ATM were treated with methylprednisolone and were compared with a historical group of 17 patients. Follow-up evaluation revealed the following in the methylprednisolone versus the non-methylprednisolone group: 66 versus 17.6% were walking independently at one month; 54.6 versus 11.7% had made a full recovery at one year; and 25 versus 120 days was the median time to independent walking. Subsequently, in a multicenter open label study of 12 children with severe ATM [93], outcome measures were compared with historical controls and suggested a beneficial outcome at one month and one year. However, in a prospective, hospital-based study [94], outcome evaluations and electrophysiological studies were used to evaluate a potential effect of methylprednisolone in 21 ATM patients. It was found that patients in both groups with positive physiological studies (recordable central conduction time on evoked potential and absent denervation) improved, whereas those with negative physiological studies did not. There was no observed difference in the outcome caused by methylprednisolone either in patients with mild or with severe symptoms. Therefore, there remains uncertainty as to the beneficial effect of steroids in ATM, although this treatment is widely offered to patients in the acute phase. The limitations in such studies - heterogeneous patient population, small study size, open label, and the use of a historical control population - led to the conclusion that the further definition of a role for steroids in ATM will require controlled studies on more defined patient populations.  Cyclophosphamide Several reports have suggested a role for cyclophosphamide and steroids in lupus-associated ATM [96-98]. However, the role of immunomodulatory treatments in other forms of ATM remains unclear.  Plasma exchange Plasma exchange was recently shown to be effective in patients with severe, isolated CNS demyelination [99,100]. In a randomized, sham-controlled, crossover-design study, 44% of patients with severe inflammatory demyelination who had not responded to steroids improved after plasma exchange. It was reasoned that plasma exchange may remove humoral factors (including antibodies, endotoxins or cytokines) contributing to inflammation.  Cerebrospinal fluid filtration CSF filtration was recently proposed and investigated for patients with the related monophasic inflammatory disease GBS [101]. In that study 37 patients were randomly selected to receive CSF filtration or plasma exchange during the acute phase of GBS. CSF filtration consisted of the placement of a spinal catheter and the removal of 30- 50 cc of CSF via a filter bypass designed for the elimination of cells, bacteria, endotoxins, immunoglobulins and inflammatory mediators. A filtration session consisted of several such cycles (five to six times, of 30-50 cc each), repeated daily for 5-15 consecutive days compared with a standard plasma exchange regimen for GBS. CSF filtration showed equal effectiveness compared with plasma exchange, with fewer complications. The rationale for this treatment - that cellular or humoral factors in the CSF may contribute to the dysfunction and injury of peripheral nerves and nerve roots - is even stronger in ATM patients in whom the inflammation is largely or entirely within the CNS. Therefore, it is worthy of further investigation in such patients.  Protective autoimmunity Although this review has focused on how the immune system may damage the neural system, recent evidence suggests that in certain situations, the immune system may play a role in the recovery from spinal cord injury [102,103]. In those studies, active or passive immunization of animals against CNS antigens resulted in improved functional status and diminished neuronal death after spinal cord contusion. The benefit was mediated by T lymphocytes, and may indicate that the removal of damaged neural tissue facilitates enhanced recovery.
  • 23.  Conclusion In summary, emerging evidence suggests that a variety of immune stimuli, through such processes as molecular mimicry or superantigen-mediated immune activation, may trigger the immune system to injure the nervous system. The activation of previously quiescent autoreactive T lymphocytes or the generation of humoral derangements may be effector mechanisms in this process. Several recent studies have highlighted the importance of specific immune system components in inducing neural injury: IgE and hypereosinophilia, autoantibodies, complement fixation, and the deposition of immune complexes within the spinal cord. It is our current challenge to define clinical, genetic and serological characteristics that predict this pathological heterogeneity. Only then can rational, targeted therapies be envisioned.  Abbreviations ATM acute transverse myelitis. GBS Guillain-Barre syndrome. MS multiple sclerosis. NMO neuromyelitis optica. SLE systemic lupus erythematosus . References 1. Bastian HC. Thrombotic softening of the spinal cord. A case of so-called `acute myelitis'. Lancet 1910; ii:1531- 1534. 2. Bastian HC. Special diseases of the spinal cord. In: Quain R, editor. A dictionary of medicine: including general pathology, general therapeutics, hygiene, and the diseases peculiar to women and children/by various writers. London: Longmans, Green and Co.; 1882. pp. 1479-1483. 3. Rivers TM. Viruses. JAMA 1929; 92:1147-1152. 4. Ford FR. The nervous complications of measles: with a summary of literature and publications of 12 additional case reports. Bull Johns Hopkins Hosp 1928; 43:140-184. 5 . Suchett-Kaye AI. Acute transverse myelitis complicating pneumonia. Lancet 1948; 255:417. 6. Altrocchi PH. Acute transverse myelopathy. Arch Neurol 1963; 9:21-29. 7. Berman M, Feldman S, Alter M, et al. Acute transverse myelitis: incidence and etiologic considerations. Neurology 1981; 31:966-971. Immunopathogenesis of acute transverse myelitis Kerr and Ayetey 345 8. Christensen PB, Wermuth L, Hinge HH, Bomers K. Clinical course and longterm prognosis of acute transverse myelopathy. Acta Neurol Scand 1990; 81:431-435. 9. Jeffery DR, Mandler RN, Davis LE. Transverse myelitis. Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events. Arch Neurol 1993; 50:532-535. 10. Lipton HL, Teasdall RD. Acute transverse myelopathy in adults. A follow-up study. Arch Neurol 1973; 28:252- 257. 11. Misra UK, Kalita J, Kumar S. A clinical, MRI and neurophysiological study of acute transverse myelitis. J Neurol Sci 1996; 138:150-156. 12. Sakakibara R, Hattori T, Yasuda K, Yamanishi T. Micturition disturbance in acute transverse myelitis. Spinal Cord 1996; 34:481-485. 13. Piper PG. Disseminated lupus erythematosus with involvement of the spinal cord. JAMA 1953; 153:215-217. 14. Adrianakos AA, Duffy J, Suzuki M, Sharp JT. Transverse myelitis in systemic lupus erythematosus: report of three cases and review of the literature. Ann Intern Med 1975; 83:616-624. 15. Nakano I, Mannen T, Mizutani T, Yokohari R. Peripheral white matter lesions of the spinal cord with changes in small arachnoid arteries in systemic lupus erythematosus. Clin Neuropathol 1989; 8:102-108. 16. Sinkovics JG, Gyorkey F, Thoma GW. A rapidly fatal case of systemic lupus erythematosus: structure resembling viral nucleoprotein strands in the kidney and activities of lymphocytes in culture. Texas Rep Biol Med
  • 24. 1969; 27:887- 908. 17. Weil MH. Disseminated lupus erythematosus with massive hemorrhagic manifestations and paraplegia. Lancet 1955; 75:353-360. 18. Ayala L, Barber DB, Lomba MR, Able AC. Intramedullary sarcoidosis presenting as incomplete paraplegia: case report and literature review. J Spinal Cord Med 2000; 23:96-99. 19. Garcia-Zozaya IA. Acute transverse myelitis in a 7-month-old boy. J Spinal Cord Med 2001; 24:114-118. 20. Larner AJ, Farmer SF. Myelopathy following influenza vaccination in inflammatory CNS disorder treated with chronic immunosuppression. Eur J Neurol 2000; 7:731-733. 21 Sindern E, Schroder JM, Krismann M, Malin JP. Inflammatory polyradiculoneuropathy with spinal cord involvement and lethal [correction of letal] outcome after hepatitis B vaccination. J Neurol Sci 2001; 186:81-85. 22 Patja A, Paunio M, Kinnunen E, et al. Risk of Guillain-Barre syndrome after measles-mumps-rubella vaccination. J Pediatr 2001; 138:250-254. 23 Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976-1977. Am J Epidemiol 1979; 110:105-123. 24. Langmuir AD, Bregman DJ, Kurland LT, et al. An epidemiologic and clinical evaluation of Guillain-Barre syndrome reported in association with the administration of swine influenza vaccines. Am J Epidemiol 1984; 119:841- 879. 25. Monteyne P, Andre FE. Is there a causal link between hepatitis B vaccination and multiple sclerosis? Vaccine 2000; 18:1994-2001. 26. Merelli E, Casoni F. Prognostic factors in multiple sclerosis: role of intercurrent infections and vaccinations against influenza and hepatitis B. Neurol Sci 2000; 21 (4 Suppl 2):S853-S856. 27 . Ascherio A, Zhang SM, Hernan MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001; 344:327-332. 28. Confavreux C, Suissa S, Saddier P, et al. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med 2001; 344:319-326. 29. Moriabadi NF, Niewiesk S, Kruse N, et al. Influenza vaccination in MS: absence of T-cell response against white matter proteins. Neurology 2001; 56:938-943. 30 Paine RS, Byers RK. Transverse myelopathy in childhood. AMA Am J Dis Children 1968; 85:151-163. 31. Ropper AH, Poskanzer DC. The prognosis of acute and subacute transverse myelopathy based on early signs and symptoms. Ann Neurol 1978; 4:51-59. 32. Salgado CD, Weisse ME. Transverse myelitis associated with probable cat-scratch disease in a previously healthy pediatric patient. Clin Infect Dis 2000; 31:609-611. 33, Giobbia M, Carniato A, Scotton PG, et al. Cytomegalovirus-associated transverse myelitis in a non- immunocompromised patient. Infection 1999; 27:228-230. 34. Baig SM, Khan MA. Cytomegalovirus-associated transverse myelitis in a nonimmunocompromised patient. J Neurol Sci 1995; 134:210-211. 35. Antal EA, Loberg EM, Bracht P, et al. Evidence for intra-axonal spread of Listeria monocytogenes from the periphery to the central nervous system. Brain Pathol 2001; 11:432-438. 36. Dowling PC, Cook SD. Role of infection in Guillain-Barre syndrome: laboratory confirmation of herpesviruses in 41 cases. Ann Neurol 1981; 9 (Suppl.):44-55. 37. Sanders EA, Peters AC, Gratana JW, Hughes RA. Guillain-Barre syndrome after varicella-zoster infection. Report of two cases. J Neurol 1987; 234:437- 439. 38. Tsukada N, Koh CS, Inoue A, Yanagisawa N. Demyelinating neuropathy associated with hepatitis B virus
  • 25. infection. Detection of immune complexes composed of hepatitis B virus surface antigen. J Neurol Sci 1987; 77:203- 39. Thornton CA, Latif AS, Emmanuel JC. Guillain-Barre syndrome associated with human immunodeficiency virus infection in Zimbabwe. Neurology 1991; 41:812-815. 40. Rees JH, Soudain SE, Gregson NA, Hughes RA. Campylobacter jejuni infection and Guillain-Barre syndrome. N Engl J Med 1995; 333:1374-1379. 41 Mishu B, Ilyas AA, Koski CL, et al. Serologic evidence of previous Campylobacter jejuni infection in patients with the Guillain-Barre syndrome. Ann Intern Med 1993; 118:947-953. 42. Hariharan H, Naseema K, Kumaran C, et al. Detection of Campylobacter jejuni/C. coli infection in patients with Guillain-Barre syndrome by serology and culture. N Microbiol 1996; 19:267-271. 43. Jacobs BC, Endtz H, Van der Meche FG, et al. Serum anti-GQ1b IgG antibodies recognize surface epitopes on Campylobacter jejuni from patients with Miller Fisher syndrome. Ann Neurol 1995; 37:260-264. 44. Kusunoki S, Shiina M, Kanazawa I. Anti-Gal-C antibodies in GBS subsequent to mycoplasma infection: evidence of molecular mimicry. Neurology 2001; 57:736-738. 45 Jacobs BC, Endtz HP, Van der Meche FG, et al. Humoral immune response against Campylobacter jejuni lipopolysaccharides in Guillain-Barre and Miller Fisher syndrome. J Neuroimmunol 1997; 79:62-68. 46. Lee WM, Westrick MA, Macher BA. High-performance liquid chromatography of long-chain neutral glycosphingolipids and gangliosides. Biochim Biophys Acta 1982; 712:498-504. 47. Moran AP, Rietschel ET, Kosunen TU, Zahringer U. Chemical characterization of Campylobacter jejuni lipopolysaccharides containing N-acetylneuraminic acid and 2,3-diamino-2,3-dideoxy-D-glucose. J Bacteriol 1991; 173:618-626. 48. Gregson NA, Rees JH, Hughes RA. Reactivity of serum IgG anti-GM1 ganglioside antibodies with the lipopolysaccharide fractions of Campylobacter jejuni isolates from patients with Guillain-Barre syndrome (GBS). J Neuroimmunol 1997; 73:28-36. 49. Jacobs BC, Hazenberg MP, Van Doorn PA, et al. Cross-reactive antibodies against gangliosides and Campylobacter jejuni lipopolysaccharides in patients with Guillain-Barre or Miller Fisher syndrome. J Infect Dis 1997; 175:729-733. 50. Hao Q, Saida T, Kuroki S, et al. Antibodies to gangliosides and galactocerebroside in patients with Guillain- Barre syndrome with preceding Campylobacter jejuni and other identified infections. J Neuroimmunol 1998; 81:116-126. 51. Goodyear CS, O'Hanlon GM, Plomp JJ, et al. Monoclonal antibodies raised against Guillain-Barre syndrome- associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle-nerve preparations. J Clin Invest 1999; 104:697-708. 52, Plomp JJ, Molenaar PC, O'Hanlon GM, et al. Miller Fisher anti-GQ1b antibodies: alpha-latrotoxin-like effects on motor end plates. Ann Neurol 1999; 45:189-199. 53. O'Hanlon GM, Paterson GJ, Veitch J, et al. Mapping immunoreactive epitopes in the human peripheral nervous system using human monoclonal anti-GM1 ganglioside antibodies. Acta Neuropathol (Berl) 1998; 95:605- 616. 54. Sheikh KA, Nachamkin I, Ho TW, et al. Campylobacter jejuni lipopolysaccharides in Guillain-Barre syndrome: molecular mimicry and host susceptibility. Neurology 1998; 51:371-378. 55. Yuki N, Taki T, Takahashi M, et al. Penner's serotype 4 of Campylobacter jejuni has a lipopolysaccharide that bears a GM1 ganglioside epitope as well as one that bears a GD1 a epitope. Infect Immun 1994; 62:2101-2103. 56. Ang CW, Van Doorn PA, Endtz HP, et al. A case of Guillain-Barre syndrome following a family outbreak of Campylobacter jejuni enteritis. J Neuroimmunol 2000; 111:229-233. 57. Koga M, Yuki N, Kashiwase K, et al. Guillain-Barre and Fisher's syndromes subsequent to Campylobacter jejuni enteritis are associated with HLA-B54 and Cw1 independent of anti-ganglioside antibodies. J Neuroimmunol
  • 26. 1998; 88:62-66. 58. Drulovic J, Dujmovic I, Stojsavlevic N, et al. Transverse myelopathy in the antiphospholipid antibody syndrome: pinworm infestation as a trigger? J Neurol Neurosurg Psychiatry 2000; 68:249. 59. Bohach GA, Fast DJ, Nelson RD, Schlievert PM. Staphylococcal and streptococcal pyrogenic toxins involved in toxic shock syndrome and related illnesses. Crit Rev Microbiol 1990; 17:251-272. 60. Bohach GA. Staphylococcal enterotoxins B and C. Structural requirements for superantigenic and entertoxigenic activities. Prep Biochem Biotechnol 1997; 27:79-110. 61. Betley MJ, Borst DW, Regassa LB. Staphylococcal enterotoxins, toxic shock syndrome toxin and streptococcal pyrogenic exotoxins: a comparative study of their molecular biology. Chem Immunol 1992; 55:1-35. 62. Zhang J, Vandevyver C, Stinissen P, et al. Activation and clonal expansion of human myelin basic protein- reactive T cells by bacterial superantigens. J Autoimmun 1995; 8:615-632. 63. Kappler J, Kotzin B, Herron L, et al. V beta-specific stimulation of human T cells by staphylococcal toxins. Science 1989; 244:811-813. 64. Hong SC, Waterbury G, Janeway CA Jr. Different superantigens interact with distinct sites in the Vbeta domain of a single T cell receptor. J Exp Med 1996; 183:1437-1446. 65. Webb SR, Gascoigne NR. T-cell activation by superantigens. Curr Opin Immunol 1994; 6:467-475. 66 Acha- Orbea H, MacDonald HR. Superantigens of mouse mammary tumor virus. Annu Rev Immunol 1995; 13:459-486. 67. Brocke S, Gaur A, Piercy C, et al. Induction of relapsing paralysis in experimental autoimmune encephalomyelitis by bacterial superantigen. Nature 1993; 365:642-644. 68. Racke MK, Quigley L, Cannella B, et al. Superantigen modulation of experimental allergic encephalomyelitis: activation of anergy determines outcome. J Immunol 1994; 152:2051-2059. 69. Brocke S, Hausmann S, Steinman L, Wucherpfennig KW. Microbial peptides and superantigens in the pathogenesis of autoimmune diseases of the central nervous system. Semin Immunol 1998; 10:57-67. 70. McCormack JE, Callahan JE, Kappler J, Marrack PC. Profound deletion of mature T cells in vivo by chronic exposure to exogenous superantigen. J Immunol 1993; 150:3785-3792. 71. Kotzin BL, Leung DY, Kappler J, Marrack P. Superantigens and their potential role in human disease. Adv Immunol 1993; 54:99-166. 72 Vanderlugt CL, Begolka WS, Neville KL, et al. The functional significance of epitope spreading and its regulation by co-stimulatory molecules. Immunol Rev 1998; 164:63-72. 73 Renno T, Acha-Orbea H. Superantigens in autoimmune diseases: still more shades of gray. Immunol Rev 1996; 154:175-191. 74. Paliard X, West SG, Lafferty JA, et al. Evidence for the effects of a superantigen in rheumatoid arthritis. Science 1991; 253:325-329. 75, Eugster HP, Frei K, Winkler F, et al. Superantigen overcomes resistance of IL-6-deficient mice towards MOG- induced EAE by a TNFR1 controlled pathway. Eur J Immunol 2001; 31:2302-2312. 76. Jorens PG, VanderBorght A, Ceulemans B, et al. Encephalomyelitis -associated antimyelin autoreactivity induced by streptococcal exotoxins. Neurology 2000; 54:1433-1441. 77. Fukazawa T, Hamada T, Kikuchi S, et al. Antineutrophil cytoplasmic antibodies and the optic-spinal form of multiple sclerosis in Japan. J Neurol Neurosurg Psychiatry 1996; 61:203-204. 78. Leonardi A, Arata L, Farinelli M, et al. Cerebrospinal fluid and neuropathological study in Devic's syndrome. Evidence of intrathecal immune activation. J Neurol Sci 1987; 82:281-290. 79. O'Riordan JI, Gallagher HL, Thompson AJ, et al. Clinical, CSF, and MRI findings in Devic's neuromyelitis optica. J Neurol Neurosurg Psychiatry 1996; 60:382-387.
  • 27. 80. Reindl M, Linington C, Brehm U, et al. Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: a comparative study. Brain 1999; 122:2047-2056. 81. Haase CG, Schmidt S. Detection of brain-specific autoantibodies to myelin oligodendrocyte glycoprotein, S100beta and myelin basic protein in patients with Devic's neuromyelitis optica. Neurosci Lett 2001; 307:131-133. 82. Tippett DS, Fishman PS, Panitch HS. Relapsing transverse myelitis. Neurology 1991; 41:703-706. 83. Pandit L, Rao S. Recurrent myelitis. J Neurol Neurosurg Psychiatry 1996; 60:336-338. 84. Garcia-Merino A, Blasco MR. Recurrent transverse myelitis with unusual long-standing Gd-DTPA enhancement. J Neurol 2000; 247:550-551. 85. Renard JL, Guillamo JS, Ramirez JM, et al. Acute transverse cervical myelitis following hepatitis B vaccination. Evolution of anti-HBs antibodies [in French]. Presse Med 1999; 28:1290-1292. 86. Matsui M, Kakigi R, Watanabe S, Kuroda Y. Recurrent demyelinating transverse myelitis in a high titer HBs- antigen carrier. J Neurol Sci 1996; 139:235-237. 87. Kira J, Kawano Y, Yamasaki K, Tobimatsu S. Acute myelitis with hyperIgEaemia and mite antigen specific IgE: atopic myelitis. J Neurol Neurosurg Psychiatry 1998; 64:676-679. 88. Kikuchi H, Osoegawa M, Ochi H, et al. Spinal cord lesions of myelitis with . hyperIgEemia and mite antigen specific IgE (atopic myelitis) manifest eosinophilic inflammation. J Neurol Sci 2001; 183:73-78. 89. Yamasaki K, Horiuchi I, Minohara M, et al. Hyperprolactinemia in opticospinal multiple sclerosis. Intern Med 2000; 39:296-299. 90. Vernant JC, Cabre P, Smadja D, et al. Recurrent optic neuromyelitis with endocrinopathies: a new syndrome. Neurology 1997; 48:58-64. 91. DeGiorgio LA, Konstantinov KN, Lee SC, et al. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 2001; 7:1189-1193. 92. Williamson RA, Burgoon MP, Owens GP, et al. Anti-DNA antibodies are a major component of the intrathecal B cell response in multiple sclerosis. Proc Natl Acad Sci U S A 2001; 98:1793-1798. 93. Defresne P, Meyer L, Tardieu M, et al. Efficacy of high dose steroid therapy in children with severe acute transverse myelitis. J Neurol Neurosurg Psychiatry 2001; 71:272-274. 94. Kalita J, Misra UK. Is methyl prednisolone useful in acute transverse myelitis? . Spinal Cord 2001; 39:471-476. A better study of a potential role for methylprednisoloine in that it incorporate. electrophysiological studies at entry and at follow-up. 95. Lahat E, Pillar G, Ravid S, et al. Rapid recovery from transverse myelopathy in children treated with methylprednisolone. Pediatr Neurol 1998; 19:279- 282. 96. Mok CC, Lau CS, Chan EY, Wong RW. Acute transverse myelopathy in systemic lupus erythematosus: clinical presentation, treatment, and outcome. J Rheumatol 1998; 25:467-473. 97. Neuwelt CM, Lacks S, Kaye BR, et al. Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus. Am J Med 1995; 98:32-41. 98 . Inslicht DV, Stein AB, Pomerantz F, Ragnarsson KT. Three women with lupus transverse myelitis: case reports and differential diagnosis. Arch Phys Med Rehabil 1998; 79:456-459. 99. Weinshenker BG, O'Brien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999; 46:878-886. 100. Celik Y, Tabak F, Mert A, et al. Transverse myelitis caused by Varicella. Clin Neurol Neurosurg 2001; 103:260-261. 101. Wollinsky KH, Hulser PJ, Brinkmeier H, et al. CSF filtration is an effective treatment of Guillain-Barre
  • 28. syndrome: a randomized clinical trial. Neurology 2001; 57:774-780. 102. Hauben E, Agranov E, Gothilf A, et al. Posttraumatic therapeutic vaccination with modified myelin self- antigen prevents complete paralysis while avoiding autoimmune disease. J Clin Invest 2001; 108:591-599. 103. Hauben E, Butovsky O, Nevo U, et al. Passive or active immunization with myelin basic protein promotes recovery from spinal cord contusion. J Neurosci 2000; 20:6421-6430. 104. Kohm, A.P., Fuller, K.G. and Miller, S.D. (2003). quot;Mimicking the way to autoimmunity: an evolving theory of sequence and structural homology.quot;. TRENDS in Microbiology 11: 101–105. doi:10.1016/S0966-842X(03)00006-4. 105. Shoenfeld, Y. and Gershwin, M.E. (2002). quot;Autoimmunity at a glance.quot;. Autoimmune Reviews 1: 1. 106. Abbas, A.K. and Lichtman, A.H. (2005).. Cellular and Molecular Immunology: Updated edition. Elsevier. Philadelphia, PA, 216-217. 107. Trowsdale, J. and Betz, A.G. (2006). quot;Mother's little helpers: mechanisms of maternal-fetal tolerance.quot;. Nature Immunology 7: 241–246. doi:10.1038/ni1317. 108. Leech, S. (1998). quot;Molecular mimicry in autoimmune disease.quot;. Archives of Disease in Childhood 79: 448-451. 109. Pelanda, R., Schwers, S., Sonoda, E., Torres, R.M., Nemazee, D. and Rajewsky, K. (1997). quot;Receptor editing in a transgenic mouse model: site, efficiency, and role in B cell tolerance and antibody diversification.quot;. Immunity 7: 765–775. doi:10.1016/S1074-7613(00)80395-7. 110. Karlsen, A.E. and Dyrberg, T. (1998). quot;Molecular mimicry between non-self, modified self and self in autoimmunity.quot;. Seminars in Immunology 10: 25–34. doi:10.1006/smim.1997.0102. 111. Oldstone, M.B.A. (1998). quot;Molecular mimicry and immune-mediated diseases.quot;. Journal of the Federation of American Societies for Experimental Biology 12: 1255–1265. 112. Roudier, C., Auger, I. and Roudier, J. (1996). quot;Molecular mimicry reflected through database screening: serendipity or survival strategy?quot;. Immunology Today 17: 357–358. doi:10.1016/0167-5699(96)30021-2. 113.Wildner, G. and Thurau, S.R. (1997). quot;Database screening for molecular mimicry.quot;. Immunology Today 18: 252–253. doi:10.1016/S0167-5699(97)90086-4. 114. Stebbins, C.E. and Galan, J.E. (2001). quot;Structural mimicry in bacterial virulence.quot;. Nature 412: 701–705. doi:10.1038/35089000. 115. Speir, J.A., Garcia, K.C., Brunmark, A., Degano, M., Peterson, P.A., Teyton, L. and Wilson, I.A. (1998). quot;Structural basis of 2C TCR allorecognition of H-2Ld peptide complexes.quot;. Immunity 8: 553–562. doi:10.1016/S1074-7613(00)80560-9. 116. Quartino, S., Thorpe, C.J., Travers, P.J. and Londei, M. (1995). quot;Similar antigenic surfaces, rather than sequence homology dictate T-cell epitope molecular mimicry.quot;. Proceedings of the National Academy of Sciences, USA 92: 10398–10402. doi:10.1073/pnas.92.22.10398. 117. Miller, S.D., Vanderlugt, C.L., Begolka, W.S., Pao, W., Yauch, R.L., Neville, K.L., Katz-Levy, Y., Carrizosa, A. and Kim, B.S. (1997). quot;Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading.quot;. Nature Medicine 3:1133-1136. 118. Davies, J.M. (2000). quot;Introduction: epitope mimicry as a component cause of autoimmune disease.quot;. Cellular and Molecular Life Sciences 57: 523–526. doi:10.1007/PL00000713. 119. Yamada, M., Zurbriggen, A., Oldstone, M.B.A. and Fujinami, R.S. (1991). quot;Common immunologic determinant between human immunodeficiency virus type 1 gp41 and astrocytes.quot;. Journal of Virology 65: 1370– 1376. 120. Olson, J.K, Croxford, J.L., Calenoff, M.A., Dal Canto, M.C. and Miller, S.D. (2001). quot;A virus-induced molecular mimicry model of multiple sclerosis.quot;. Journal of Clinical Investigation 108: 311–318. 121. Oleszak, E.L., Chang, J.R., Friedman, H., Katsetos, C.D. and Platsoucas, C.D. (2004). quot;Theiler's virus infection: a model for multiple sclerosis.quot;. Clinical Microbiology Reviews 17: 174–207. doi:10.1128/CMR.17.1.174-
  • 29. 207.2004. 122. Schwimmbeck, P.L., Dyrberg, T., Drachman, D.B. and Oldstone, M.B.A. (1989). quot;Molecular mimicry and myasthenia gravis.quot;. Journal of Clinical Investigation 84: 1174–1180. 123. Barnett, L.A. and Fujinami, R.S. (1992). quot;Molecular mimicry: a mechanism for autoimmunity.quot;. Federation of American Societies for Experimental Biology 6: 840–844. 124. Johnson RT. The pathogenesis of acute viral encephalitis and postinfectious encephalomyelitis. J Infect Dis. 1987;155(3):359–364. 125. Hartung HP, Grossman RI. ADEM: distinct disease or part of the MS spectrum?. Neurology. 2001;56 (10):1257–1260. 126. Johnson RT, Griffin DE. Postinfectious encephalomyelitis. In: Infections of the nervous system. London: Butterworth; 1987;p. 209–226. 127. Gurvich EB, Vilesova IS. Vaccinia virus in postvaccinal encephalitis. Acta Virol. 1983;27(2):154–159. 128. Rivers T, Schwentker F. Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys. J Exp Med. 1935;61:689–702. 129. Johnson RT. Postinfectious demyelinating diseases. In: Johnson RT, editor. Viral infections of the nervous system. 2nd ed. Philadelphia: Raven-Lippincott; p. 181–210. 130. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol. 2005;23:683–747. 131. Steinman L, Zamvil SS. How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann Neurol. 2006;60(1):12–21. 132. Steinman L, Zamvil SS. Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol. 2005;26(11):565–571. 133. Whitacre CC, Paterson PY. Transfer of experimental allergic encephalomyelitis in Lewis rats using supernates of incubated sensitized lymph node cells. J Exp Med. 1977;145(5):1405–1410. 134. Pender MP, Sears TA. Vulnerability of the dorsal root ganglion in experimental allergic encephalomyelitis. Clin Exp Neurol. 1985;21:211–223. 135. Pender MP, Sears TA. The pathophysiology of acute experimental allergic encephalomyelitis in the rabbit. Brain. 1984;107(Pt 3):699–726. 136. Waksman BH, Adams RD. Allergic neuritis: an experimental disease of rabbits induced by the injection of peripheral nervous tissue and adjuvants. J Exp Med. 1955;102(2):213–236. 137. Dreesen DW. A global review of rabies vaccines for human use. Vaccine. 1997;15(Suppl):S2–S6. 138. Cabrera J, Griffin DE, Johnson RT. Unusual features of the Guillain-Barré syndrome after rabies vaccine prepared in suckling mouse brain. J Neurol Sci. 1987;81(2–3):239–245. 139. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2009 Addendum   A new version of topic of the month publication is uploaded in my web site every month (it remains for a month and  is changed with the monthly update of the neurology bulletin at:.  To download the current version of topic of the month publication follow the link quot;;  You can also download the current version of topic of the month publication from within the publication or go to my web site at: quot;http://yassermetwally.comquot; to download it.
  • 30.  At the end of each year, all the publications are compiled on a single CD-ROM, please author to know more details.  Screen resolution is better set at 1024*768 pixel screen area for optimum display  For an archive of the previously published topics in downloadable PDF format go to, then under pages in the right panel, scroll down and click on the text entry quot;topic of the monthquot;  In order to view a list of the previously published topics in downloadable PDF format, follow the link: The author: Professor Yasser Metwally, professor of neurology, Ain Shams university, Cairo, Egypt