Immunopathogenesis of Acute Transverse Myelitis

Douglas A. Kerr, MD/PhD^a and Harold Ayetey, BSc Hons (Lond)^b

^aDepartment of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD

^bGuy’s, King’s and St. Thomas’ School of Medicine, University of London, London, UK.

Please send correspondence to:

Dr. Douglas A. Kerr, MD/PhD

Assistant Professor,

Department of Neurology,

Johns Hopkins Hospital,

Pathology 627 C

600 N. Wolfe Street,

Baltimore, MD 21287-6965

Tel: (410) 502 7099

Fax: (410) 502 6736

Email: dkerr@jhmi.edu

Abstract

Acute transverse myelitis (ATM) is a group of disorders characterized by focal inflammation of the spinal cord and resultant neural injury.  ATM 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 ATM associated with systemic disease (i.e. systemic lupus erythematosus or sarcoidosis), a vasculitic or granulomatous process can often be identified.  In idiopathic ATM, 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 ATM: 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 ATM, tantalizing clues as to potential immunopathogenic mechanisms in ATM 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.  

Introduction

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.  ATM 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 ATM 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 ATM 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 ATM.

History of ATM

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 ATM

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.  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] . 

Classification of ATM

Recently, a diagnostic and nosology scheme has been proposed which defines ATM according to the inclusion and exclusion criteria set forth in Table 1 [13] .  These criteria have attempted to define ATM as a monofocal inflammatory process of the spinal cord and to distinguish it from non-inflammatory myelopathies (i.e. radiation-induced myelopathy or ischemic vascular myelopathy). It further attempts to distinguish various etiologies for ATM.  Thus, two diagnostic categories of “idiopathic ATM” and “disease-associated ATM” (i.e. SLE associated ATM) are proposed, provided that other criteria are met.  Disease-associated ATM is diagnosed when the patient meets standard criteria for other known inflammatory diseases (e.g. 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 ATM is defined.  Based on these criteria, an algorithm has been proposed to guide clinical management research protocols for individuals with suspected ATM (Figure 1). 

Immunopathogenesis of ATM.

The immunopathogenesis of disease-associated ATM 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 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 ATM.

Post-Vaccination ATM

Several reports of ATM following vaccination have been recently published.  Indeed, it is widely reported in neurology texts that ATM is a post-vaccination event. One publication reports a case of post flu vaccine myelitis in which a 42 year-old male with a history of bilateral optic neuritis developed ATM 2 days following an influenza vaccine [21] .  A separate study reports a 36 year old 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 ATM.  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 ATM

In 30-60% of the idiopathic ATM 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 ATM. 

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 ATM.

Molecular Mimicry

Molecular mimicry as a mechanism to explain an inflammatory nervous system disorder has been best described in GBS.  First referred to as an “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 ATM may also occur and may be associated with the development of autoantibodies in response to an antecedent infection. One ATM patient developed elevated titers of lupus anticoagulant IgG, antisulfatide antibodies (1:6400) and anti-GM1 antibodies (1:600 IgG and 1:3200 IgM) 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 ATM 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 Vβ 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 Vβ 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 Vβ 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 ATM [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 ATM.  A case of ATM 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 ATM 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 ATM in such patients is the deposition of IgE with subsequent recruitment of cellular elements.  Indeed, biopsy specimens of two ATM patients with elevated total and specific serum IgE revealed antibody deposition within the spinal cord, perivascular lymphocyte cuffing and 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 ATM

There currently is no treatment that has been clearly shown to modulate outcome in patients with ATM.  Indeed, with such varied immunopathogenesis, it may be that distinct treatment options need be employed for different subsets of ATM patients.  Recent studies that have investigated potential strategies to modulate neural injury associated with ATM will be reviewed.

Methylprednisolone

Based on the presumptive immunopathogenic mechanisms in ATM, several recent studies have investigated a role for intravenous methylprednisolone (MP) in the acute phase.  Both studies evaluated a series of patients with ATM 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 ATM 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 ATM, 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 ATM 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 ATM, 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 ATM will require controlled studies on more defined patient populations. 

Cyclophosphamide

Several reports have suggested a role for cyclophosphamide and steroids in lupus-associated ATM [97-99] .  However, the role for immunomodulatory treatments in other forms of ATM 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 ATM 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.

References and Recommended Reading

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    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.

    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.

    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.

    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 ATM.  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 ATM.  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 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.

This is a novel study examining CSF filtration in patients with GBS compared to the accepted therapy, PE.  The exciting finding was that CSF filtration- accomplished by repeated exchange through a filter designed to remove cells, bacteria, endotoxins, immunoglobulins and inflammatory mediators- is as effective as PE.  If confirmed in larger studies, this would represent a major advance.  Conceptually, this treatment would potentially be even more effective in ATM patients. 

—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.

One of several studies from the same group, this report shows a potential protective role for the immune system in traumatic spinal cord injury.  Vaccination of rats after severe, incomplete spinal cord injury with myelin basic protein peptides resulted in improved behavioural and pathologic outcomes.  The authors suggest that regulatory T lymphocytes may enhance the endogenous reparative strategies invoked following such an injury.

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.

Table 1:

Idiopathic ATM Criteria