Topic of the month...Transverse myelitis

Topic of the month...Transverse myelitis

1. INDEX
INTRODUCTION
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
INTRODUCTION
ACUTE IDIOPATHIC TRANSVERSE
MYELITIS

2. 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)
Systemic autoimmune disease
Systemic lupus erythematosis and other connective tissue disease
Sjogren's syndrome
Sarcoidosis
Multiple Sclerosis
Paraneoplastic syndrome
Vascular

3. 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 "molecular
mimicry." This theory postulates that an infectious agent may share a molecule which resembles or "mimics"
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.
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.

4. 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 "complete" 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 1. 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 "stroke" of the spinal cord.
Myelopathy as a complication of heroin toxicitycommonly has an acute onset often within hours of drug
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

5. 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.
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 2. Heroin myelopathy Increased T2 signal (Arrow) in cervical spinal cord

6. Figure 3. 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 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
Disease entity
T2
hyperintensity
Number
of
segments
involved
Contrast element Pathology
Idiopathic transverse
myelitis
Central,
multisegmental
4-8 In transverse myelitis
enhancement is peripheral to
the centrally located area of
Nonspecific necrosis that
affects gray and white
matter indiscriminately and

7. Figure 4. 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.
high T2 signal intensity rather
than in the very same area.
destroys axons and cell
bodies as well as myelin.
Spinal multiple
sclerosis
 
Peripheral1-2 In contrast to transverse
myelitis, enhancement in MS
occurs in the same location of
high-signal-intensity lesions
seen on T2-weighted images.
White matter demyelination
only.

8. Figure 5. 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.
Figure 6. 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 7. A, Transverse Myelitis. B, Myelitis in ADEM

9. Figure 8. 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.
Figure 9. MS-myelitis is more peripheral and more likely to involve less than half of the cross-sectional cord
area.

10. 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 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

11. 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

 Classification of acute 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
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)

12. 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
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 lymphocytic cuffing and mononuclear cell infiltration immunopathogenic and with
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.

13. 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] .

14. 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] .
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

15. [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.
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] .

16. 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 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

17. 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)
Reference1 Bastian HC. Thrombotic softening of the spinal cord. A case of so-called "acute myelitis". 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.
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

18. 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.
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

19. 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.
32 Ropper AH, Poskanzer DC. The prognosis of acute and subacute transverse myelopathy based on early
signs and symptoms. Ann Neurol 1978; 4(1):51-59.
33 Salgado CD, Weisse ME. Transverse myelitis associated with probable cat-scratch disease in a previously
healthy pediatric patient. Clin Infect Dis 2000; 31(2):609-611.
34 Giobbia M, Carniato A, Scotton PG, Marchiori GC, Vaglia A. Cytomegalovirus-associated transverse
myelitis in a non- immunocompromised patient. Infection 1999; 27(3):228-230.
35 Baig SM, Khan MA. Cytomegalovirus-associated transverse myelitis in a non- immunocompromised
patient. J Neurol Sci 1995; 134(1-2):210-211.
36 Antal EA, Loberg EM, Bracht P, Melby KK, Maehlen J. Evidence for intraaxonal spread of Listeria
monocytogenes from the periphery to the central nervous system. Brain Pathol 2001; 11(4):432-438.
An excellent report showing a potential mechanism for bacteria to gain access to the CNS: via intraxonal
transport. By such a mechanism, Listeria causes a focal encephalitis or Myelitis depending on the route of
entry.
37 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.
38 Sanders EA, Peters AC, Gratana JW, Hughes RA. Guillain-Barre syndrome after varicella-zoster infection.
Report of two cases. J Neurol 1987; 234(6):437-439.
39 Tsukada N, Koh CS, Inoue A, Yanagisawa N. Demyelinating neuropathy associated with hepatitis B virus
infection. Detection of immune complexes composed of hepatitis B virus surface antigen. J Neurol Sci 1987; 77
(2-3):203-216.
40 Thornton CA, Latif AS, Emmanuel JC. Guillain-Barre syndrome associated with human immunodeficiency
virus infection in Zimbabwe. Neurology 1991; 41(6):812-815.
41 Rees JH, Soudain SE, Gregson NA, Hughes RA. Campylobacter jejuni infection and Guillain-Barre
syndrome. N Engl J Med 1995; 333(21):1374-1379.

20. 42 Mishu B, Ilyas AA, Koski CL, Vriesendorp F, Cook SD, Mithen FA et al. Serologic evidence of previous
Campylobacter jejuni infection in patients with the Guillain-Barre syndrome. Ann Intern Med 1993; 118
(12):947-953.
43 Hariharan H, Naseema K, Kumaran C, Shanmugam J, Nair MD, Radhakrishnan K. Detection of
Campylobacter jejuni/C.coli infection in patients with Guillain-Barre syndrome by serology and culture. New
Microbiol 1996; 19(3):267-271.
44 Jacobs BC, Endtz H, Van der Meche FG, Hazenberg MP, Achtereekte HA, Van Doorn PA. Serum anti-
GQ1b IgG antibodies recognize surface epitopes on Campylobacter jejuni from patients with Miller Fisher
syndrome. Ann Neurol 1995; 37(2):260-264.
45 Kusunoki S, Shiina M, Kanazawa I. Anti-Gal-C antibodies in GBS subsequent to mycoplasma infection:
evidence of molecular mimicry. Neurology 2001; 57(4):736-738.
46 Jacobs BC, Endtz HP, Van der Meche FG, Hazenberg MP, de Klerk MA, Van Doorn PA. Humoral immune
response against Campylobacter jejuni lipopolysaccharides in Guillain-Barre and Miller Fisher syndrome. J
Neuroimmunol 1997; 79(1):62-68.
47 Lee WM, Westrick MA, Macher BA. High-performance liquid chromatography of long-chain neutral
glycosphingolipids and gangliosides. Biochim Biophys Acta 1982; 712(3):498-504.
48 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(2):618-626.
49 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(1-2):28-36.
50 Jacobs BC, Hazenberg MP, Van Doorn PA, Endtz HP, Van der Meche FG. Cross-reactive antibodies
against gangliosides and Campylobacter jejuni lipopolysaccharides in patients with Guillain-Barre or Miller
Fisher syndrome. J Infect Dis 1997; 175(3):729-733.
51 Hao Q, Saida T, Kuroki S, Nishimura M, Nukina M, Obayashi H 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(1-2):116-126.
52 Goodyear CS, O'Hanlon GM, Plomp JJ, Wagner ER, Morrison I, Veitch J 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(6):697-708.
53 Plomp JJ, Molenaar PC, O'Hanlon GM, Jacobs BC, Veitch J, Daha MR et al. Miller Fisher anti-GQ1b
antibodies: alpha-latrotoxin-like effects on motor end plates. Ann Neurol 1999; 45(2):189-199.
An important study which shows how autoantibodies, generated through a molecular mimicry mechanism,
have the potential to diminish neuronal conduction
54 O'Hanlon GM, Paterson GJ, Veitch J, Wilson G, Willison HJ. Mapping immunoreactive epitopes in the
human peripheral nervous system using human monoclonal anti-GM1 ganglioside antibodies. Acta
Neuropathol (Berl) 1998; 95(6):605-616.
55 Sheikh KA, Nachamkin I, Ho TW, Willison HJ, Veitch J, Ung H et al. Campylobacter jejuni
lipopolysaccharides in Guillain-Barre syndrome: molecular mimicry and host susceptibility. Neurology 1998;
51(2):371-378.

21. 56 Yuki N, Taki T, Takahashi M, Saito K, Tai T, Miyatake T 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(5):2101-2103.
57 Ang CW, Van Doorn PA, Endtz HP, Merkies IS, Jacobs BC, de Klerk MA et al. A case of Guillain-Barre
syndrome following a family outbreak of Campylobacter jejuni enteritis. J Neuroimmunol 2000; 111(1-2):229-
233.
58 Koga M, Yuki N, Kashiwase K, Tadokoro K, Juji T, Hirata K. 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 1998; 88(1-2):62-66.
59 Drulovic J, Dujmovic I, Stojsavlevic N, Tripkovic I, Apostolski S, Levic Z et al. Transverse myelopathy in
the antiphospholipid antibody syndrome: pinworm infestation as a trigger? J Neurol Neurosurg Psychiatry
2000; 68(2):249.
60 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(4):251-272.
61 Bohach GA. Staphylococcal enterotoxins B and C. Structural requirements for superantigenic and
entertoxigenic activities. Prep Biochem Biotechnol 1997; 27(2-3):79-110.
62 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.
63 Zhang J, Vandevyver C, Stinissen P, Mertens N, Berg-Loonen E, Raus J. Activation and clonal expansion of
human myelin basic protein-reactive T cells by bacterial superantigens. J Autoimmun 1995; 8(4):615-632.
64 Kappler J, Kotzin B, Herron L, Gelfand EW, Bigler RD, Boylston A et al. V beta-specific stimulation of
human T cells by staphylococcal toxins. Science 1989; 244(4906):811-813.
One of the earliest reports of the unique potential of superantigens to induce immune system derangements.
65 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(4):1437-1446.
66 Webb SR, Gascoigne NR. T-cell activation by superantigens. Curr Opin Immunol 1994; 6(3):467-475.
67 Acha-Orbea H, MacDonald HR. Superantigens of mouse mammary tumor virus. Annu Rev Immunol 1995;
13:459-486.
68 Brocke S, Gaur A, Piercy C, Gautam A, Gijbels K, Fathman CG et al. Induction of relapsing paralysis in
experimental autoimmune encephalomyelitis by bacterial superantigen. Nature 1993; 365(6447):642-644.
69 Racke MK, Quigley L, Cannella B, Raine CS, McFarlin DE, Scott DE. Superantigen modulation of
experimental allergic encephalomyelitis: activation of anergy determines outcome. J Immunol 1994; 152
(4):2051-2059.
70 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(1):57-67.
71 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(9):3785-3792.

22. 72 Kotzin BL, Leung DY, Kappler J, Marrack P. Superantigens and their potential role in human disease. Adv
Immunol 1993; 54:99-166.
73 Vanderlugt CL, Begolka WS, Neville KL, Katz-Levy Y, Howard LM, Eagar TN et al. The functional
significance of epitope spreading and its regulation by co-stimulatory molecules. Immunol Rev 1998; 164:63-
72.
74 Renno T, Acha-Orbea H. Superantigens in autoimmune diseases: still more shades of gray. Immunol Rev
1996; 154:175-191.
75 Paliard X, West SG, Lafferty JA, Clements JR, Kappler JW, Marrack P et al. Evidence for the effects of a
superantigen in rheumatoid arthritis. Science 1991; 253(5017):325-329.
76 Eugster HP, Frei K, Winkler F, Koedel U, Pfister W, Lassmann H et al. Superantigen overcomes resistance
of IL-6-deficient mice towards MOG- induced EAE by a TNFR1 controlled pathway. Eur J Immunol 2001; 31
(8):2302-2312.
77 Jorens PG, VanderBorght A, Ceulemans B, Van Bever HP, Bossaert LL, Ieven M et al. Encephalomyelitis-
associated antimyelin autoreactivity induced by streptococcal exotoxins. Neurology 2000; 54(7):1433-1441.
A case report which describes a patient with severe acute disseminated encephalomyelitis due to a
streptococcal superantigen
78 Fukazawa T, Hamada T, Kikuchi S, Sasaki H, Tashiro K, Maguchi S. Antineutrophil cytoplasmic
antibodies and the optic-spinal form of multiple sclerosis in Japan. J Neurol Neurosurg Psychiatry 1996; 61
(2):203-204.
79 Leonardi A, Arata L, Farinelli M, Cocito L, Schenone A, Tabaton M et al. Cerebrospinal fluid and
neuropathological study in Devic's syndrome. Evidence of intrathecal immune activation. J Neurol Sci 1987;
82(1-3):281-290.
80 O'Riordan JI, Gallagher HL, Thompson AJ, Howard RS, Kingsley DP, Thompson EJ et al. Clinical, CSF,
and MRI findings in Devic's neuromyelitis optica. J Neurol Neurosurg Psychiatry 1996; 60(4):382-387.
81 Reindl M, Linington C, Brehm U, Egg R, Dilitz E, Deisenhammer F 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 ( Pt 11):2047-2056.
82 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
(2):131-133.
83 Tippett DS, Fishman PS, Panitch HS. Relapsing transverse myelitis. Neurology 1991; 41(5):703-706.
84 Pandit L, Rao S. Recurrent myelitis. J Neurol Neurosurg Psychiatry 1996; 60(3):336-338.
85 Garcia-Merino A, Blasco MR. Recurrent transverse myelitis with unusual long-standing Gd-DTPA
enhancement. J Neurol 2000; 247(7):550-551.
86 Renard JL, Guillamo JS, Ramirez JM, Taillia H, Felten D, Buisson Y. [Acute transverse cervical myelitis
following hepatitis B vaccination. Evolution of anti-HBs antibodies]. Presse Med 1999; 28(24):1290-1292.
87 Matsui M, Kakigi R, Watanabe S, Kuroda Y. Recurrent demyelinating transverse myelitis in a high titer
HBs-antigen carrier. J Neurol Sci 1996; 139(2):235-237.

23. 88 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(5):676-679.
89 Kikuchi H, Osoegawa M, Ochi H, Murai H, Horiuchi I, Takahashi 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(1):73-78.
This is the second in a series of reports from this group that proposes a pathogenic role for IgE and eosinophils
in acute Transverse Myelitis. This report presents biopsy specimens from two patients, thereby providing a
unique look into immunopathogenesis.
90 Yamasaki K, Horiuchi I, Minohara M, Osoegawa M, Kawano Y, Ohyagi Y et al. Hyperprolactinemia in
optico-spinal multiple sclerosis. Intern Med 2000; 39(4):296-299.
91 Vernant JC, Cabre P, Smadja D, Merle H, Caubarrere I, Mikol J et al. Recurrent optic neuromyelitis with
endocrinopathies: a new syndrome. Neurology 1997; 48(1):58-64.
92 DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B. A subset of lupus anti-DNA
antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 2001; 7
(11):1189-1193.
93 Williamson RA, Burgoon MP, Owens GP, Ghausi O, Leclerc E, Firme L 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
(4):1793-1798.
94 Defresne P, Meyer L, Tardieu M, Scalais E, Nuttin C, De Bont B et al. Efficacy of high dose steroid therapy
in children with severe acute transverse myelitis. J Neurol Neurosurg Psychiatry 2001; 71(2):272-274.
This non-controlled study showed a role for intravenous methylprednisolone in children with acute Transverse
Myelitis. It is suggestive, but I disagree with the authors that the data supporting a beneficial effect is so strong
that consideration of a randomized, placebo-controlled trial is not warranted.
95 Kalita J, Misra UK. Is methyl prednisolone useful in acute transverse myelitis? Spinal Cord 2001; 39
(9):471-476.
A better study of a potential role for methylprednisoloine in that it incorporated electrophysiologic studies at
entry and at follow-up.
96 Lahat E, Pillar G, Ravid S, Barzilai A, Etzioni A, Shahar E. Rapid recovery from transverse myelopathy in
children treated with methylprednisolone. Pediatr Neurol 1998; 19(4):279-282.
97 Mok CC, Lau CS, Chan EY, Wong RW. Acute transverse myelopathy in systemic lupus erythematosus:
clinical presentation, treatment, and outcome. J Rheumatol 1998; 25(3):467-473.
98 Neuwelt CM, Lacks S, Kaye BR, Ellman JB, Borenstein DG. Role of intravenous cyclophosphamide in the
treatment of severe neuropsychiatric systemic lupus erythematosus. Am J Med 1995; 98(1):32-41.
99 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(4):456-459.
100 Weinshenker BG, O'Brien PC, Petterson TM, Noseworthy JH, Lucchinetti CF, Dodick DW et al. A
randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease.
Ann Neurol 1999; 46(6):878-886.
This was a courageous study in that it was randomized and sham-controlled, meaning that some patients with

24. severe demyelination received sham plasma exchange. This was a very difficult study to do. The results, though
involving relatively small numbers of patients, are believable because of the cross-over design and sham
control. The experience at our hospital is in agreement with the findings of this study.
101 Celik Y, Tabak F, Mert A, Celik AD, Aktu&gbreve, lu Y. Transverse myelitis caused by Varicella. Clin
Neurol Neurosurg 2001; 103(4):260-261.
102 Wollinsky KH, Hulser PJ, Brinkmeier H, Aulkemeyer P, Bossenecker W, Huber-Hartmann KH et al. CSF
filtration is an effective treatment of Guillain-Barre syndrome: a randomized clinical trial. Neurology 2001; 57
(5):774-780.
103 Hauben E, Agranov E, Gothilf A, Nevo U, Cohen A, Smirnov I et al. Posttraumatic therapeutic vaccination
with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J Clin
Invest 2001; 108(4):591-599.
104 Hauben E, Butovsky O, Nevo U, Yoles E, Moalem G, Agranov E et al. Passive or active immunization with
myelin basic protein promotes recovery from spinal cord contusion. J Neurosci 2000; 20(17):6421-6430.
105. 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.
106. Berman M, Feldman S, Alter M, et. al. "Acute transverse myelitis: incidence and etiological
considerations." Neurology, 1981; 31:966.
107. Stone LA. "Transverse Myelitis" in Rolak LA and Harati Y (eds.) Neuroimmunology for the Clinician.
Boston, MA: Butterworth-Heinemann, 1997; 155-165.