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

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

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.

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 toxicity commonly 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

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 hyperintensityand 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

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

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

 

Peripheral 1-2 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.

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

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.

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

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)

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.

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] .

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.

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 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)

Reference

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An amazing discussion which proposes the still current belief that non-compressive myelopathies may be vascular or “allergic”, meaning post-infectious in nature.

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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)

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One of the earliest reports of the unique potential of superantigens to induce immune system derangements.

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A case report which describes a patient with severe acute disseminated encephalomyelitis due to a streptococcal superantigen

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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.

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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.

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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

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.

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