Case record...Idiopathic postinfectious transverse myelitis


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Case record...Idiopathic postinfectious transverse myelitis

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Case record...Idiopathic postinfectious transverse myelitis

  1. 1. CASE OF THE WEEK PROFESSOR YASSER METWALLY CLINICAL PICTURE CLINICAL PICTURE A 35 years old female patient presented with paraplegia with a high dorsal sensory level of acute onset. The neurological disability occurred 10 days following rabies vaccination. RADIOLOGICAL FINDINGS RADIOLOGICAL FINDINGS Figure 1. MRI study of the cervico-dorsal region showing multisegmental (almost 8 spinal segments) T2 hyperintensity / precontrast T1 hypointensity (representing central cord edema) occupying centrally more than 2/3 of the cross section of the spinal cord and causing mild spinal cord enlargement at the affected zone.
  2. 2. Figure 2. (A, Precontrast MRI T1 image, B MRI T2 image) MRI study of the cervico-dorsal region in a case of acute idiopathic transverse myelitis showing multisegmental (almost 8 spinal segments) T2 hyperintensity / T1 hypointensity (representing central cord edema) occupying centrally more than 2/3 of the cross section of the spinal cord and causing mild spinal cord enlargement at the affected zone. Notice the peripheral enhancement on postcontrast MRI T1 image (C). Figure 3. MRI T2 cross sectional images showing central hyperintensity occupying more than 2/3 of the cross sections of the spinal cord with central dot sign seen on A.
  3. 3. Figure 4. MRI pre and post contrast images and MRI T2 images in a case of acute idiopathic transverse myelitis. Notice the central dot sign in the cross sectional T2 images, also notice that enhancement on the postcontrast MRI T1 image is peripherally located and outside the T2 central hyperintensity. Figure 5. (A, MRI T2 image and B, postcontrast MRI T1 image) Notice that enhancement on the postcontrast MRI T1 image is peripherally located and outside the T2 central hyperintensity.
  4. 4. Figure 6. A case with acute idiopathic 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.  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.
  5. 5. DIAGNOSIS: DIAGNOSIS: ACUTE IDIOPATHIC TRANSVERSE MYELITIS DISCUSSION DISCUSSION Transverse myelitis (TM) is a neurologic syndrome caused by inflammation of the spinal cord. TM is uncommon but not rare. Conservative estimates of incidence per year vary from 1 to 5 per million population (105). The term myelitis is a nonspecific term for inflammation of the spinal cord; transverse refers to involvement across one level of the spinal cord. It occurs in both adults and children. You may also hear the term myelopathy, which is a more general term for any disorder of the spinal cord. The term radiculomyelitis refers to inflammation of the spinal roots as they emerge from the spinal cord along with inflammation of the spinal cord itself. Myelitis probably rarely occurs without concomitant involvement of the emerging spinal roots in the inflamed spinal segments and in such a case a combination of upper and lower motor neuron manifestations is the usual clinical presentation.  Clinical symptoms TM symptoms develop rapidly over several hours to several weeks. Approximately 45% of patients worsen maximally within 24 hours (Ibid.). The spinal cord carries motor nerve fibers to the limbs and trunk and sensory fibers from the body back to the brain. Inflammation within the spinal cord interrupts these pathways and causes the common presenting symptoms of TM which include limb weakness, sensory disturbance, bowel and bladder dysfunction, back pain and radicular pain (pain in the distribution of a single spinal nerve). Almost all patients will develop leg weakness of varying degrees of severity. The arms are involved in a minority of cases and this is dependent upon the level of spinal cord involvement. Sensation is diminished below the level of spinal cord involvement in the majority of patients. Some experience tingling or numbness in the legs. Pain (ascertained as appreciation of pinprick by the neurologist) and temperature sensation are diminished in the majority of patients. Appreciation of vibration (as caused by a tuning fork) and joint position sense may also be decreased or spared. Bladder and bowel sphincter control are disturbed in the majority of patients. Many patients with TM report a tight banding or girdle-like sensation around the trunk and that area may be very sensitive to touch. Recovery may be absent, partial or complete and generally begins within 1 to 3 months. Significant recovery is unlikely, if no improvement occurs by 3 months. Most patients with TM show good to fair recovery. TM is generally a monophasic illness (one-time occurrence); however, a small percentage of patients may suffer a recurrence, especially if there is a predisposing underlying illness.  Causes of transverse myelopathy / myelitis or radiculomyelitis Transverse myelitis may occur in isolation or in the setting of another illness. When it occurs without apparent underlying cause, it is referred to as idiopathic. Idiopathic transverse myelitis is assumed to be a result of abnormal activation of the immune system against the spinal cord. A list of illnesses associated with TM includes: Table1: Diseases Associated with transverse myelitis transverse myelopathy or radiculomyelitis  Parainfectious (occurring at the time of and in association with an acute infection or an episode of infection).  Viral: herpes simplex, herpes zoster, cytomegalovirus, Epstein-Barr virus, enteroviruses (poliomyelitis, Coxsackie virus, echovirus), human T-cell, leukemia virus, human immunodeficiency virus, influenza, rabies  Bacterial: Pyogenic, Mycoplasma pneumoniae, Lyme borreliosis, syphilis, tuberculosis, Neuroschistosomiasis  Postvaccinal (rabies, cowpox)
  6. 6.  Systemic autoimmune disease  Systemic lupus erythematosis and other connective tissue disease  Sjogren's syndrome  Sarcoidosis  Multiple Sclerosis  Paraneoplastic syndrome  Vascular  Thrombosis of spinal arteries  Vasculitis secondary to heroin abuse  Spinal arterio-venous malformation  Antiphospholipid syndrome  Radiation induced The cause of idiopathic transverse myelitis is unknown, but most evidence supports an autoimmune process. This means that the patient's own immune system is abnormally stimulated to attack the spinal cord and cause inflammation and tissue damage. Examples of autoimmune diseases which are more common include rheumatoid arthritis, in which the immune system attacks the joints, and multiple sclerosis, in which myelin, the insulating material for nerve cells in the brain, is the target of autoimmune attack. TM often develops in the setting of viral and bacterial infections, especially those which may be associated with a rash (e.g., rubeola, varicella, variola, rubella, influenza, and mumps). Approximately one third of patients with TM report a febrile illness (flu-like illness with fever) in close temporal relationship to the onset of neurologic symptoms. In some cases, there is evidence that there is a direct invasion and injury to the cord by the infectious agent itself (especially poliomyelitis, herpes zoster, and AIDS). A bacterial abscess can also develop around the spinal cord and injure the cord through compression, bacterial invasion and inflammation. However, experts believe that in many cases infection causes a derangement of the immune system which leads to an indirect autoimmune attack on the spinal cord, rather than a direct attack by the organism. One theory to explain this abnormal activation of the immune system toward human tissue is termed quot;molecular mimicry.quot; This theory postulates that an infectious agent may share a molecule which resembles or quot;mimicsquot; a molecule in the spinal cord. When the body mounts an immune response to the invading virus or bacterium, it also responds to the spinal cord molecule with which it shares structural characteristics. This leads to inflammation and injury within the spinal cord. Vaccination is well known to carry a risk of the development of acute disseminated encephalomyelitis (ADEM) which is an acute inflammation of the brain and spinal cord. This was particularly common with the older antirabies vaccine which was grown in animal spinal cord cultures; the use of the newer antirabies vaccine grown in human tissue culture has almost eradicated this complication. This is also thought to occur as an immune system response. Transverse myelitis may be a relatively uncommon manifestation of several autoimmune diseases including systemic lupus erythematosis (SLE), Sjogren's syndrome, and sarcoidosis. SLE is an autoimmune disease of unknown cause which affects multiple organs and tissues in the body. Features of this illness include arthralgias (joint pain) and arthritis (joint inflammation), rashes, kidney inflammation, low blood counts (including white and red blood cells, platelets), oral ulcers and the presence of abnormal autoantibodies (antibodies which are directed against the person's own tissues) in the blood. The fully developed syndrome of SLE is easy to recognize; however, this illness may begin with just one or two signs and is then more difficult to diagnose.
  7. 7. Sjogren's syndrome is another autoimmune disease characterized by invasion and infiltration of the tear and salivary glands by (lymphocytes) white blood cells with resultant decreased production of these fluids. Patients complain of dry mouth and dry eyes. Several tests can support this diagnosis: the presence of a SS-A antibody in the blood, ophthalmologic tests that confirm decreased tear production and the demonstration of lymphocytic infiltration in biopsy specimens of the small salivary glands (a minimally invasive procedure). Neurologic manifestations are unusual in Sjogren's syndrome, but TM can occur. Sarcoidosis is a multisystem inflammatory disorder of unknown cause manifested by enlarged lymph nodes, lung inflammation, various skin lesions, liver and other organ involvement. In the nervous system, various nerves, as well as the spinal cord, may be involved. Diagnosis is generally confirmed by biopsy demonstrating features of inflammation typical of sarcoidosis. Multiple sclerosis is an inflammatory autoimmune disease of the central nervous system (brain and spinal cord) which results in demyelination or loss of myelin (the insulating material on nerve fibers) with resultant neurologic dysfunction. A definite diagnosis of MS is not given until a patient has had at least two attacks of demyelination (hence, multiple) at two different sites in the central nervous system. The spinal cord is frequently affected in multiple sclerosis and may be the site of involvement of the first attack of MS. This presents the possibility that patients with acute transverse myelitis could later go on to have a second episode of demyelination and receive a diagnosis of MS. Just what percentage of patients with a first attack of acute transverse myelitis will go on to develop MS is unclear in the medical literature, ranging from 15 to 80%; however, the majority of studies show a low risk. We do know that patients who have abnormal MRI scans of the brain with lesions like those seen in MS are much more likely to go on to develop MS than those who have normal brain MRIs at the time of their myelitis (between 60 and 90% for those with abnormal brain scans, less than 20% for those with normal scans in one study). It is also suggested in the medical literature that patients with quot;completequot; transverse myelitis (which means severe leg paralysis and sensory loss) are less likely to develop MS than those who had a partial or less severe case. The literature also suggests that patients who have abnormal antibodies in their spinal fluid, called oligoclonal bands, are at higher risk to develop MS subsequently. Myelitis related to cancer (paraneoplastic syndrome) is uncommon. There are several reports in the medical literature of a severe myelitis occurring in association with a malignancy. In addition, there are a growing number of reports of cases of myelopathy associated with cancer in which the immune system produces an antibody to fight off the cancer and this cross-reacts with the molecules in the spinal cord neurons. It should be emphasized that this is an unusual cause of myelitis. Figure 7. A case with acute idiopathic 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. Vascular causes are listed because they present with the same problems as transverse myelitis; however this is really a distinct problem primarily due to inadequate blood flow to the spinal cord instead of actual inflammation. The blood vessels to the spinal cord can close up with blood clots or atherosclerosis or burst and bleed; this is essentially a quot;strokequot; of the spinal cord. Myelopathy as a complication of heroin toxicity commonly has an acute onset often within hours of drug
  8. 8. administration (Often related to single dose after period of abstinence ) with weakness (Paraplegia or Quadriplegia) and urinary retention. Prominent recovery may occur over weeks to months. CSF analysis is usually normal with occasional pleocytosis or increased protein. The mechanism of disease could be due to hypersensitivity or vasculitis. Corticosteroids or plasma exchange might be tried for treatment during the acute phase. MRI examination commonly shows transverse myelitis-like findings with intramedullary T2 hyperintensity and cord swelling. Enhancement is often patchy, over several levels. Figure 8. Heroin myelopathy Increased T2 signal (Arrow) in cervical spinal cord  Diagnosis The general history and physical examination are first performed, but often do not give clues about the cause of spinal cord injury. The first concern of the physician who evaluates a patient with complaints and examination suggestive of a spinal cord disorder is to rule out a mass-occupying lesion which might be compressing the spinal cord. Potential lesions which might compress the cord include tumor, herniated disc, stenosis (a narrowed canal for the cord), and abscess. This is important because early surgery to remove the compression may sometimes reverse neurologic injury to the spinal cord. The easiest test to rule out such a compressive lesion is magnetic resonance imaging of the appropriate levels of the cord. Figure 9. MRI T2 showing a case of acute idiopathic transverse myelitis. Notice cord swelling and the multisegmental, central increased cord signal intensity at the cervicodorsal region If the MRI shows no mass lesion outside or within the spinal cord, then the patient with spinal cord dysfunction is
  9. 9. thought to have transverse myelitis or vascular problems. The MRI can sometimes show an inflammatory lesion within the cord. It is difficult to get to the cause of the inflammation, because biopsy is rarely done on the spinal cord because of the damage this would cause. The physician would next send blood for general bloodwork and studies for SLE and Sjogren's syndrome, HIV infection, vitamin B12 level to rule out deficiency and a test for syphilis. The next test which is commonly performed is a lumbar puncture to obtain fluid for studies, including white cell count and protein to look for inflammation, cultures to look for infections of various types, and tests to examine for abnormal activation of the immune system (immunoglobulin level and protein electrophoresis). A MRI of the brain is often performed to screen for lesions suggestive of MS. If none of these tests are suggestive of a specific cause, the patient is presumed to have idiopathic transverse myelitis or parainfectious transverse myelitis, if there are other symptoms to suggest an infection.  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. (See Fig. 9) Table 2. Differences between idiopathic transverse myelitis and spinal multiple sclerosis Number T2 of Disease entity Contrast element Pathology hyperintensity segments involved Idiopathic transverse Central, 4-8 In transverse myelitis Nonspecific necrosis that affects myelitis multisegmental enhancement is peripheral to the gray and white matter centrally located area of high T2 indiscriminately and destroys signal intensity rather than in axons and cell bodies as well as 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.
  10. 10. Figure 10. MRI T1 precontrast (A,B,C,D) and postcontrast (E,F,G) and MRI T2 image (H) showing a case of acute idiopathic transverse myelitis, notice cord swelling in the cervico dorsal region with patchy irregular and peripheral contrast enhancement. Also notice the central T2 hyperintensity. Peripheral contrast enhancement is outside and peripheral to the central T2 hyperintensity. MRIs are uninformative in a large number of patients with acute transverse myelitis. There is a relatively good differentiation on MRI between MS-associated acute transverse myelitis and parainfectious-associated acute transverse myelitis. Patients with MS-associated acute transverse myelitis show small plaque-like lesions (partial myelopathy), and those patients with parainfectious acute transverse myelitis show swelling of the spinal cord if they have abnormalities on MRI. Figure 11. A case with acute idiopathic transverse myelitis. Notice spinal cord swelling and the MRI T2 central hyperintensity. Also notice the involvement of the complete cross section of the spinal cord.
  11. 11. Figure 12. A case with acute idiopathic transverse myelitis. Notice spinal cord swelling and the MRI T2 central signal changes. Also notice the involvement of the complete cross section of the spinal cord. Figure 13. A, Transverse Myelitis. B, Myelitis in ADEM
  12. 12. Figure 14. MS-myelitis is more peripheral and more likely to involve less than half of the cross-sectional cord area. ACUTE IDIOPATHIC TRANSVERSE MYELITIS  Introduction Acute transverse myelitis (ATM) 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 pathologic substrate-injury and dysfunction of neural cells within the spinal cord- may be caused by a variety of immunologic 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 and/or perivascular cellular influx into the spinal cord resulting in 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 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 (ADEM), Guillain-Barre syndrome (GBS) and Neuromyelitis Optica (NMO). Developing further understanding of how the immune system induces neural injury will depend upon confirmation and extension of these findings and will require multicenter collaborative efforts. Acute transverse myelitis (ATM) is 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, though tantalizing clues have emerged. acute Transverse Myelitis exists on a continuum of neuroinflammatory disorders that also includes Guillain-Barre syndrome (GBS), multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM) and Neuromyelitis Optica (NMO). 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 neural injury. In the current review, we will examine recent evidence that shed light on the immunopathogenesis of acute Transverse Myelitis and, where applicable, related neuroinflammatory disorders. These 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 acute Transverse Myelitis will require controlled studies with epidemiologic and clinical-pathologic correlation. It is only then that we will be able to establish rational intervention strategies designed to improve the outcome of patients with acute Transverse Myelitis.  History of acute transverse myelitis Several cases of “acute myelitis” were described in 1882, and pathologic analysis revealed that some were due to
  13. 13. vascular lesions and others to 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 post-vaccinal encephalomyelitis, over 200 cases were reported in those two years alone. Pathologic analyses of fatal cases revealed inflammatory cells and demyelination.” In 1928, it was first postulated that many cases of acute myelitis are “post-infectious rather than infectious in cause” since for many patients, the “fever had fallen and the rash had begun to fade” when the myelitis symptoms began [4] . It was proposed, therefore, that the myelitis was an “allergic” response to a virus rather than the virus itself that caused the spinal cord damage. It was in 1948 that the term “acute transverse myelitis” was utilized in reporting a case of fulminant inflammatory myelopathy complicating pneumonia [5] .  Diagnosis of acute transverse myelitis 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 MRI and lumbar puncture shows evidence of acute inflammation (CSF culture and sensitivity should always be carried out to rule out bacterial, fungal, parasitic infections, see table 1). 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 [6-8,9,10,11] . Autonomic symptoms consist variably of increased urinary urgency, bowel or bladder incontinence, difficulty voiding, or bowel constipation [12]. MRI characteristics of acute idiopathic transverse myelitis  Involvement of the whole cross section of the spinal cord. Partial myelopathy (either on clinical examination or on MRI imaging) should rule out acute idiopathic transverse myelitis.  The lesion induces swelling of the spinal cord in the involved segments in the acute stage  The lesion has the following MRI characteristics (see above for MRI characteristics of transverse myelitis)  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.  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.  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.  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.  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. (See Fig. 9)  Intramedullary lesions that can simulate acute idiopathic transverse myelitis on clinical background can easily be ruled out by MRI
  14. 14.  In the author experience, acute idiopathic transverse myelitis occurred exclusively in the lower cervical and/or the upper dorsal spinal cord regions. Evolvement of other regions of the spinal cord should direct the attention to disease - associated transverse myelopathy. (See table 1)   Classification of acute transverse myelitis Recently, a diagnostic and nosology scheme has been proposed which defines acute Transverse Myelitis according to the inclusion and exclusion criteria set forth in Table 3 [13] . These criteria have attempted to define acute Transverse Myelitis 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 acute Transverse Myelitis. Thus, two diagnostic categories of “idiopathic acute Transverse Myelitis” and “disease-associated acute Transverse Myelitis” (i.e. SLE associated acute Transverse Myelitis) are proposed, provided that other criteria are met. Disease-associated acute Transverse Myelitis is diagnosed when the patient meets standard criteria for other known inflammatory diseases (e.g. multiple sclerosis, sarcoidosis, systemic lupus erythematosus, Sjogren’s syndrome) or direct infection of the spinal cord. When an extensive search fails to determine such a cause, idiopathic acute Transverse Myelitis is defined. Table 3: Idiopathic acute transverse myelitis criteria Inclusion criteria  Development of sensory, motor or autonomic dysfunction attributable to the spinal cord  Bilateral signs and/or symptoms (though not necessarily symmetric)  Clearly-defined sensory level  Exclusion of extra-axial compressive etiology by neuroimaging (MRI)  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- 7 days following symptom onset meets criteria  Progression to nadir between 4 hours to 21 days following the onset of symptoms (if patient awakens with symptoms, symptoms must become more pronounced from point of awakening) Exclusion criteria  History of previous radiation to the spine within the past 10 years, history of drug abuse especially heroin  Clear arterial distribution clinical deficit consistent with thrombosis of the anterior spinal artery  Abnormal flow voids on the surface of the spinal cord c/w AVM  *Serologic or clinical evidence of connective tissue disease (sarcoidosis, Behcet’s disease, Sjogren’s syndrome, SLE, mixed connective tissue disorder etc)  *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),  CNS manifestations of vasculitis, schistosomiasis  *Brain MRI abnormalities suggestive of MS  *History of clinically apparent optic neuritis *Do not exclude disease-associated ATM ACUTE TRANSVERSE MYELITIS / MYELOPATHY IS A TERMINOLOGY THAT HAS NO AETIOLOGICAL IMPLICATIONS, IT IS SIMPLY A CLINICAL DIAGNOSIS WHICH MEANS COMPLETE TRANS- SECTIONAL PATHOLOGICAL INVOLVEMENT OF THE SPINAL CORD WITH AN ACUTE ONSET. ALWAYS LOOK FOR AN AETIOLOGICAL FACTOR. ACUTE IDIOPATHIC TRANSVERSE MYELITIS IS A DIAGNOSIS BY EXCLUSION.  Immunopathogenesis of acute transverse myelitis. The immunopathogenesis of disease-associated acute Transverse Myelitis is varied. For example, pathologic data confirms that many cases of lupus-associated TM are associated with a CNS vasculitis [14-16] while others may be associated with thrombotic infarction of the spinal cord [17,18] . Neurosarcoid is often pathologically associated with non-caseating granulomas within the spinal cord [19] , while TM associated with MS often has perivascular
  15. 15. lymphocytic cuffing and mononuclear cell infiltration immunopathogenic and with variable complement and antibody deposition [20] . Since these diseases have such varied (albeit poorly understood) immunopathogenic and effector mechanisms, these diseases will not be further discussed here. Rather, the subsequent discussion will focus on findings potentially related to idiopathic acute Transverse Myelitis.  Post-vaccination acute transverse myelitis Several reports of acute Transverse Myelitis following vaccination have been recently published. Indeed, it is widely reported in neurology texts that acute Transverse Myelitis is a post-vaccination event. One publication reports a case of post flu vaccine myelitis in which a 42 year-old male with a history of bilateral optic neuritis developed acute Transverse Myelitis 2 days following an influenza vaccine [21] . A separate study reports a 36 year old male who developed a progressive and ultimately fatal, inflammatory myelopathy/polyradiculopathy 9 days following a booster Hepatitis B vaccination [22] . 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 these studies is that a vaccination may induce an autoimmune process resulting in acute Transverse Myelitis. However, it should be noted that extensive data continues to overwhelmingly show that vaccinations are safe and are not associated with an increased incidence of neurologic complications [23-30] . 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 acute Transverse Myelitis cases, there is an antecedent respiratory, GI or systemic illness [6-10,31,32] . The term “parainfectious” has been used to suggest that the neurologic injury may be associated with 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, though in the vast majority of these cases, causality cannot be established. Several of the herpes viruses have been associated with myelitis and are likely due to direct infection of neural cells within the spinal cord [33-35] . Other agents, such as Listeria monocytogenes may be transported intraaxonally to neurons in the spinal cord [36] . 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 acute Transverse Myelitis. Though in these cases, the infectious agent 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 acute Transverse Myelitis.  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 “acute post-infectious polyneuritis” by W. Osler in 1892, GBS is preceded in 75% of cases by an acute infection [37-40] . Campylobacter jejuni infection has emerged as the most important antecedent event in GBS, occurring in up to 41% of cases [41-44] . Human neural tissue contains several subtypes of ganglioside moieties such as GM1, GM2 and GQ1b within their cell walls [45,46] . A characteristic component of human gangliosides, sialic acid [47] , is also found as a surface antigen on C. jejuni within its lipopolysaccharide (LPS) outer coat [48] . Antibodies that cross-react with gangliosides from C. jejuni have been found in serum from patients with GBS [49-51] and have been shown to bind peripheral nerves, fix complement and impair neural transmission in experimental conditions that mimic GBS [45,52,53,54] . 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 [44,46,55,56] . 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 LPS extract and that patient was the only one to develop GBS [57] . Additionally, 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 [41,58] .
  16. 16. Molecular mimicry in acute Transverse Myelitis may also occur and may be associated with the development of autoantibodies in response to an antecedent infection. One acute Transverse Myelitis patient developed elevated titers of lupus anticoagulant IgG, antisulfatide antibodies (1:6400) and anti-GM1 antibodies (1:600 IgG and 1:3200 IgM) following Enterobium vermicularis (perianal pinworm) infection [59] . Since 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 and will be discussed below.  Microbial superantigen-mediated inflammation Another link between an antecedent infection and the development of acute Transverse Myelitis may be the fulminant activation of lymphocytes by microbial superantigens (SAGs). SAGs 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 through I, toxic shock syndrome toxin-1 and Streptococcus pyogenes exotoxin, though many viruses encode superantigens as well [60-63] . SAGs activate T-lymphocytes in a unique manner compared to conventional antigens: instead of binding to the highly variable peptide groove of the T cell receptor (TCR), SAGs interact with the more conserved Vb region [64,65-67] . Additionally, unlike conventional antigens, SAGs 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 2-20% of circulating T-lymphocytes compared to 0.001-0.01% with conventional antigens [68-70] . Interestingly, SAGs often cause expansion followed by deletion of T lymphocyte clones with particular Vß regions resulting in “holes” in the T lymphocyte repertoire for some time following the activation [64-67,71] . Therefore, patients can often be tested for presumptive evidence of previous superantigen exposure through TCR Vß usage frequencies. Stimulation of large numbers of lymphocytes may trigger autoimmune disease by activating autoreactive T-cell clones [72,73] . In humans, there are multiple reports of expansion of selected Vß families in patients with autoimmune diseases suggesting a previous superantigen exposure [72,74] . Since this limited expansion was not seen in serum and non-inflamed tissues, it was proposed that SAG activated previously quiescent autoreactive T cells which then entered a tissue and were retained in that tissue by repeat exposure to the autoantigen [75] . In the central nervous system, SAG isolated from Staphlococcus induced paralysis in mice with experimental autoimmune encephalomyelitis (EAE) through its ability to directly stimulate Vb8-expressing T-cells specific for the MBP peptide Ac1-11 [68,69,76] . In humans, a patient with ADEM and necrotizing myelopathy was found to have Strep pyogenes SAG-induced T cell activation against myelin basic protein [77] .  Humoral derangements Either of the above processes may result in abnormal immune function with blurred distinction between self and non- self. The development of abnormal antibodies potentially may then activate other components of the immune system and/or recruit additional cellular elements to the spinal cord. Recent studies have emphasized distinct autoantibodies in patients with NMO [78-82] and recurrent acute Transverse Myelitis [83-85] . 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 have a causative role in acute Transverse Myelitis. A case of acute Transverse Myelitis was described in a patient with extremely high serum and CSF antibody levels to hepatitis B surface antigen following booster immunization [86] . 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 TM and high titers of hepatitis B surface antigen [87] . Circulating immune complexes containing HbsAg were detected in the serum and CSF during the acute phase and the disappearance of these complexes following treatment correlated with functional recovery.  Several Japanese patients with acute Transverse Myelitis were found to have much higher serum IgE levels than MS  patients or controls (360 vs. 52 vs. 85 U/ml) [88] . Virtually all of the patients in this study had specific serum IgE to household mites (Dermatophagoides pteronyssinus or Dermatophagoides farinae), while less than 1/3 of MS and control patients did. One potential mechanism to explain the acute Transverse Myelitis in such patients is the deposition of IgE with subsequent recruitment of cellular elements. Indeed, biopsy specimens of two acute Transverse Myelitis patients with elevated total and specific serum IgE revealed antibody deposition within the spinal cord, perivascular lymphocyte cuffing and infiltration of eosinophils [89] . It was postulated that eosinophils, recruited to the spinal cord degranulated and induced the neural injury in these patients.
  17. 17. Recently, several reports have suggested that elevated prolactin levels occur in some patients with NMO [90,91] . The elevated prolactin was limited to Asian and black women and correlated with involvement of the optic nerve. It therefore may be that extension of inflammation to the hypothalamus results in diminished hypothalamic dopamine and increased pituitary secretion of prolactin. Further, since prolactin is a potent immune stimulant for Th1 responses, it is possible that the enhanced prolactin leads to 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 dsDNA, and antibodies raised against this sequence react against dsDNA [92] . 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 MS brain and from B cells from the CSF of a patient with MS are comprised of anti DNA antibodies [93] . These antibodies bind to the surface of neuronal cells and oliogdendrocytes. Hence, molecular mimicry may cause the development of antibodies that interact with neuronal surface proteins and induce neural injury through the activation of neural pathways.  Potential treatment options in acute transverse myelitis There currently is no treatment that has been clearly shown to modulate outcome in patients with acute Transverse Myelitis. Indeed, with such varied immunopathogenesis, it may be that distinct treatment options need be employed for different subsets of acute Transverse Myelitis patients. Recent studies that have investigated potential strategies to modulate neural injury associated with acute Transverse Myelitis will be reviewed.  Methylprednisolone Based on the presumptive immunopathogenic mechanisms in acute Transverse Myelitis, several recent studies have investigated a role for intravenous methylprednisolone (MP) in the acute phase. Both studies evaluated a series of patients with acute Transverse Myelitis treated with methylprednisolone in open-label studies [94,95,96] . Two of these studies suggested a role for methylprednisolone in small, open label trials [94,96] , while one suggested no improvement in outcome [95] . In one study, 12 children with severe acute Transverse Myelitis were treated with MP and were compared with a historical group of 17 patients. Follow up evaluation revealed the following in the MP vs. non-MP group: 66% vs. 17.6% walking independently at one month; 54.6 vs. 11.7 % full recovery at one year; and 25 days vs. 120 days median time to independent walking. Subsequently, in a multicenter open label study of 12 children with severe acute Transverse Myelitis, outcome measures were compared to historical controls and suggested a beneficial outcome at one month and one year [94] . However, in a prospective, hospital-based study, outcome evaluations and electrophysiologic studies were used to evaluate a potential effect of methylprednisolone in 21 acute Transverse Myelitis patients [95] . It was found that patients in both groups with positive physiologic studies (recordable central conduction time on evoked potential and absent denervation) improved, while those with negative physiologic studies did not. There was no observed difference in the outcome due to methylprednisolone both in patients with mild and severe symptoms.  Therefore,  there remains  uncertainty  as to the  beneficial effect  of steroids  in  acute  Transverse Myelitis, though  this  treatment is widely offered to patients in the acute phase. The limitations in these studies - heterogeneous patient population, small study size, open label and the use of historical control population-necessitate the conclusion that further definition of a role for steroids in acute Transverse Myelitis will require controlled studies on more defined patient populations.  Cyclophosphamide Several reports have suggested a role for cyclophosphamide and steroids in lupus-associated acute Transverse Myelitis [97-99] . However, the role for immunomodulatory treatments in other forms of acute Transverse Myelitis remains unclear.  Plasma exchange Plasma exchange (PE) was recently shown to be effective in patients with severe, isolated CNS demyelination [100,101] . In this randomized, sham-controlled, crossover-design study, 44% of patients with severe inflammatory
  18. 18. demyelination who had not responded to steroids improved following plasma exchange. It has been reasoned that the plasma exchange may remove humoral factors (including antibodies, endotoxins and/or cytokines) contributing to the inflammation.  CSF filtration CSF filtration (CSFF) was recently proposed and investigated for patients with the related monophasic inflammatory disease GBS [102] . In this study 37 patients were randomized to receive CSFF or plasma exchange during the acute phase of GBS. CSFF consisted of placement of a spinal catheter then 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 comprised several such cycles (5-6 times, each of 30-50 cc), repeated daily for 5-15 consecutive days compared to standard PE regimen for GBS. CSFF showed equal effectiveness compared to PE with fewer complications. The rationale for this treatment-that cellular or humoral factors in the CSF may be contributing to dysfunction and injury of peripheral nerves and nerve roots-is even stronger in acute Transverse Myelitis patients in which the inflammation is largely or entirely within the central nervous system. Therefore, it is worthwhile of further investigation in such patients.  Protective Autoimmunity Though 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 recovery from spinal cord injury [103,104] . In these studies, active or passive immunization of animals against central nervous system antigens resulted in improved functional status and diminished neuronal death following spinal cord contusion. The benefit was mediated by T lymphocytes and may indicate that removal of damaged neural tissue facilitates enhanced recovery.  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. 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 deposition of immune complexes within the spinal cord. It is our current challenge to define clinical, genetic and serologic characteristics which predict this pathologic heterogeneity. Only then can rational, targeted therapies be envisioned. Before diagnosis of acute idiopathic transverse myelitis, you should consider the following points (see table 1)  Try to rule out disease - associated transverse myelopathy that might have a clinical picture similar to the clinical picture of acute idiopathic transverse myelitis  MRI should be carries out to rule out non- inflammatory causes of acute myelopathy such as ischemic, arterial, venous, watershed or arteriovenous malformation, arteriovenous fistula, radiation myelopathy, tumor infiltration or intramedullary inflammatory process with abscess formation.  CSF culture and sensitivity should always be carried out to rule out bacterial, fungal, parasitic infections, always consider early inflammatory myelopathy with early false negative result (repeat Lumbar culture in 2-7 days)  Serological evidence of collagen disease, vasculitis, should be looked for (see table 1)  Diseases like antiphospholipid syndrome, sarcoidosis, bilharziasis etc. should be ruled out (see table 1)  Demyelinating diseases like multiple sclerosis, acute disseminated encephalomyelitis, or neuromyelitis optica should be ruled out by brain MRI
  19. 19. SUMMARY SUMMARY Over the past decade, researchers and clinicians have gained new insights into the core of demyelinating diseases of the spinal cord, and much progress has been made in the management of these diseases. Although we are starting to uncover some of the structural and physiologic substrates of demyelination of the CNS, we are far from understanding what causes many of these demyelinating disorders and how to prevent their progression. With further development of new techniques, such as DTI and more potent MR units, spinal cord diseases may be distinguished from each other, and effective therapeutic strategies may be initiated before any cord damage occurs (Fig. 17). In particular MRI is very helpful in differentiation between Spinal multiple sclerosis and transverse myelitis In the series reported by Choi et al, [59] the centrally located MRI T2 high signal intensity occupied more than two thirds of the cross-sectional area of the cord in transverse myelitis. In multiple sclerosis, plaques are usually located peripherally and occupy less than half the cross-sectional area of the cord. The central isointensity, or dot (commonly seen in transverse myelitis), represents central gray matter squeezed by the uniform, evenly distributed oedematous changes of the cord. Choi and colleagues [59] have demonstrated the role of contrast media in differentiating transverse myelitis from multiple sclerosis. In transverse myelitis, enhancement is in the periphery of a centrally located area of high T2 weighted images. In multiple sclerosis, the lesions show enhancement in the central zone of peripherally located high signal intensity on T2 weighted images. [74] In conclusion, certain MRI characteristics help in differentiating acute transverse myelitis from spinal form of multiple sclerosis. These include: 1) centrally located high intensity signal extending over 3 to 4 segments and occupying more than two thirds of the cord cross-sectional area and 2) peripheral contrast enhancement of high intensity signal.
  20. 20. Figure 15. Differential diagnoses of intramedullary lesions based on their location at the cross-sectional area of the cord. (A) MS: Dorsally located wedge-shaped lesion involving less then two thirds of the cross-sectional area of the spinal cord seen on axial T2-Wi MR image. (B) Poliomyelitis: Bilateral enhancing anterior nerve roots demonstrated on postcontrast T1-Wi MR image. (C) Vacuolar myelopathy: Bilateral, symmetrical, high-signal-intensity abnormality located dorsally in the spinal cord in an HIV-positive patient. DD: Subacute combined degeneration. (D) ATM: On axial T2-Wi, a high-signal-intensity lesion involving more than two thirds of cross-sectional area of the spinal cord is observed. (E) Herpes-simplex-virus myelitis: Postcontrast T1-Wi axial MR image showing nodular enhancing lesion located in the lateral part of the cervical spinal cord. DD: active MS plaque. (F) Spinal cord infarction: Swelling of the anterior parts of the spinal cord is shown on axial T2-Wi MR images, indicating vulnerability of the anterior portions of the spinal cord to ischemia.  Addendum  A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday.)
  21. 21.  To download the current version follow the link quot;;.  You can also download the current version from my web site at quot;http://yassermetwally.comquot;.  To download the software version of the publication (crow.exe) follow the link:  The case is also presented as a short case in PDF format, to download the short case follow the link:  At the end of each year, all the publications are compiled on a single CD-ROM, please contact the 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 reported cases go to, then under pages in the right panel, scroll down and click on the text entry quot;downloadable case records in PDF formatquot; REFERENCES References 1 Bastian HC. Thrombotic softening of the spinal cord. A case of so-called quot;acute myelitisquot;. The Lancet 1910; ii (4552):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: 1479-1483. 3 Rivers TM. Viruses. JAMA 1929; 92(14):1147-1152. 4 Ford FR. The nervous complications of measles: with a summary of literature and publications of 12 additional case reports. Bulletin of Johns Hopkins Hospital 1928; 43(3):140-184. An amazing discussion which proposes the still current belief that non-compressive myelopathies may be vascular or “allergic”, meaning post-infectious in nature. 5 Suchett-Kaye AI. Acute transverse myelitis complicating pneumonia. The Lancet 1948; 255(6524):417. 6 Altrocchi PH. Acute Transverse Myelopathy. Arch Neurol 1963; 9:21-29. 7 Berman M, Feldman S, Alter M, Zilber N, Kahana E. Acute transverse myelitis: incidence and etiologic considerations. Neurology 1981; 31(8):966-971. 8 Christensen PB, Wermuth L, Hinge HH, Bomers K. Clinical course and long-term prognosis of acute transverse myelopathy. Acta Neurol Scand 1990; 81(5):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(5):532-535. One of only two papers to establish an incidence of TAM in the United States, this article also served categorize acute Transverse Myelitis into various subtypes. 10 Lipton HL, Teasdall RD. Acute transverse myelopathy in adults. A follow-up study. Arch Neurol 1973; 28(4):252- 257. 11 Misra UK, Kalita J, Kumar S. A clinical, MRI and neurophysiological study of acute transverse myelitis. J Neurol Sci 1996; 138(1-2):150-156. 12 Sakakibara R, Hattori T, Yasuda K, Yamanishi T. Micturition disturbance in acute transverse myelitis. Spinal Cord 1996; 34(8):481-485.
  22. 22. 13 The Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Manuscript submitted to Neurology 2002. 14 Piper PG. Disseminated lupus erythematosus with involvement of the spinal cord. JAMA 1953; 153:215-217. 15 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. 16 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. 17 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 Reports Biol Med 1969; 27:887-908. 18 Weil MH. Disseminated lupus erythematosus with massive hemorrhagic manifestations and paraplegia. Lancet 1955; 75:353-360. 19 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(2):96-99. 20 Garcia-Zozaya IA. Acute transverse myelitis in a 7-month-old boy. J Spinal Cord Med 2001; 24(2):114-118. 21 Larner AJ, Farmer SF. Myelopathy following influenza vaccination in inflammatory CNS disorder treated with chronic immunosuppression. Eur J Neurol 2000; 7(6):731-733. 22 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(1-2):81-85. 23 Patja A, Paunio M, Kinnunen E, Junttila O, Hovi T, Peltola H. Risk of Guillain-Barre syndrome after measles- mumps-rubella vaccination. J Pediatr 2001; 138(2):250-254. 24 Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, Keenlyside RA, Ziegler DW, Retailliau HF et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976--1977. Am J Epidemiol 1979; 110(2):105-123. 25 Langmuir AD, Bregman DJ, Kurland LT, Nathanson N, Victor M. An epidemiologic and clinical evaluation of Guillain-Barre syndrome reported in association with the administration of swine influenza vaccines. Am J Epidemiol 1984; 119(6):841-879. 26 Monteyne P, Andre FE. Is there a causal link between hepatitis B vaccination and multiple sclerosis? Vaccine 2000; 18(19):1994-2001. 27 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. 28 Ascherio A, Zhang SM, Hernan MA, Olek MJ, Coplan PM, Brodovicz K et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001; 344(5):327-332. 29 Confavreux C, Suissa S, Saddier P, Bourdes V, Vukusic S. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med 2001; 344(5):319-326. 30 Moriabadi NF, Niewiesk S, Kruse N, Jung S, Weissbrich B, ter M, V et al. Influenza vaccination in MS: absence of T-cell response against white matter proteins. Neurology 2001; 56(7):938-943. 31 Paine RS, Byers RK. Transverse myelopathy in childhood. AMA American Journal of Diseases of Children 1968; 85:151-163.
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