Acute Mielopathies

ORIGINAL ARTICLE

Diagnosis and Management of Acute Myelopathies Adam I. Kaplin, MD, PhD,* Chitra Krishnan, MHS,† Deepa M. Deshpande, MS,† Carlos A. Pardo, MD,† and Douglas A. Kerr, MD, PhD†

Background: Acute myelopathies represent a heterogeneous group of disorders with distinct etiologies, clinical and radiologic features, and prognoses. Transverse myelitis (TM) is a prototype member of this group in which an immune-mediated process causes neural injury to the spinal cord, resulting in varying degrees of weakness, sensory alterations, and autonomic dysfunction. TM may exist as part of a multifocal CNS disease (eg, MS), multisystemic disease (eg, systemic lupus erythematosus), or as an isolated, idiopathic entity. Review Summary: In this article, we summarize recent classification and diagnostic schemes, which provide a framework for the diagnosis and management of patients with acute myelopathy. Additionally, we review the state of current knowledge about the epidemiology, natural history, immunopathogenesis, and treatment strategies for patients with TM. Conclusions: Our understanding of the classification, diagnosis, pathogenesis, and treatment of TM has recently begun to expand dramatically. With more rigorous criteria applied to distinguish acute myelopathies and with an emerging understanding of immunopathogenic events that underlie TM, it may now be possible to effectively initiate treatments in many of these disorders. Through the investigation of TM, we are also gaining a broader appreciation of the mechanisms that lead to autoimmune neurologic diseases in general. Key Words: transverse myelitis, myelopathy, neuroinflammatory (The Neurologist 2005;11: 2–18)

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lthough several cases of “acute myelitis” were described as early as 1882, it was not until 1948 that Dr SuchettKaye,1 an English neurologist at St. Charles Hospital in London, first used the term acute transverse myelitis. Dr From the *Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland; and the †Department of Neurology, Johns Hopkins Transverse Myelitis Center, Baltimore, Maryland. Reprints: Adam I. Kaplin, MD, PhD, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Osler 320, 600 N. Wolfe Street, Baltimore, MD 21287-5371. E-mail: akaplin@ jhmi.edu. Copyright © 2005 by Lippincott Williams & Wilkins ISSN: 1074-7931/05/1101-0002 DOI: 10.1097/01.nrl.0000149975.39201.0b

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Suchett-Kaye used this term to designate a case of rapidly progressive paraparesis with a thoracic sensory level, occurring as a postinfectious complication of pneumonia. Several attempts at providing diagnostic criteria for acute transverse myelitis (TM) have been made over the past half-century, culminating in the nosology established by the International Transverse Myelitis Consortium Working Group in 2002.2 It is this set of criteria for TM that will be employed in this review article. TM is a rare syndrome with an incidence of between 1 and 8 new cases per million people per year.3 TM is characterized by focal inflammation within the spinal cord, and clinical manifestations are due to resultant neural dysfunction of motor, sensory, and autonomic pathways within and passing through the inflamed area. There is often a clearly defined rostral border of sensory dysfunction and evidence of acute inflammation demonstrated by a spinal MRI and lumbar puncture. 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% to 94% of patients have numbness, paresthesias, or bandlike dysesthesias.3– 8 Autonomic symptoms consist variably of increased urinary urgency, bowel or bladder incontinence, difficulty or inability to void, incomplete evacuation or bowel constipation, and sexual dysfunction.9 Like MS,10 TM is the clinical manifestation of a variety of disorders, with distinct presentations and pathologies.11 Recently, we proposed a diagnostic and classification scheme which has defined TM as either idiopathic or associated with a known inflammatory disease (ie, multiple sclerosis, systemic lupus erythematosus, Sjo¨gren syndrome, or neurosarcoidosis).2 Patients with TM should be offered immunomodulatory treatment such as steroids and plasmapheresis, though there is yet no consensus as to the most appropriate strategy. Most TM patients have monophasic disease, while up to 20% will have recurrent inflammatory episodes within the spinal cord (JHTMC case series).12,13 TM exists on a spectrum of neuroinflammatory CNS conditions (Table 1), characterized by abrupt neurologic deficits associated with inflammatory cell infiltrates and demyelination. This can occur as a single episode (eg, TM, optic neuritis 关ON兴, or acute disseminated encephalomyelitis The Neurologist • Volume 11, Number 1, January 2005

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TABLE 1. Spectrum of Neuroinflammatory Conditions of CNS CNS Conditions Transverse myelitis Optic neuritis Neuromyelitis optica Acute disseminated encephalomyelitis Multiple sclerosis

Region

Recurrence (%)

Spinal cord Optic nerve Spinal cord and optic nerve Brain and spinal cord

Yes (20) Yes (24) Yes (100)

Optic nerve, brain, and spinal cord

Yes (100)

No

关ADEM兴) or as a multiphasic condition (eg, recurrent TM, recurrent ON, neuromyelitis optica 关NMO兴, and MS). The pathophysiological cause of recurrence is not currently known but is of obvious clinical significance. This spectrum of neuroinflammatory CNS conditions also varies based on regional involvement of the CNS, ranging from monofocal involvement (eg, TM involving the spinal cord and isolated ON involving the optic nerve) to multifocal involvement (eg, ADEM involving the brain and spinal cord, NMO involving the optic nerve and spinal cord, and MS involving anywhere in the central neuraxis). What accounts for this regional specificity is a subject of considerable research interest, for which there is no current consensus explanation. Presumably, this regional specification could result from differences inherent in CNS tissue at different sites (such as varying threshold for injury or distinct localization of signal transduction machinery or antigens) or from differential access to distinct regions of the CNS by exogenous pathogenic mechanisms.

Acute Myelopathies

found to have TM have been studied at the JHTMC (unpublished data). Indeed, all patients who met criteria for the diagnosis of TM and had tissue sampling of the spinal cord (biopsy or autopsy) had inflammatory changes. These pathologic abnormalities invariably included focal infiltration by monocytes and lymphocytes into segments of the spinal cord and perivascular spaces and astroglial and microglial activation (Fig. 1). The magnitude and extension of these inflammatory features vary and are determined by the etiological factors and the temporal profile of the myelopathic changes. The presence of white matter changes, demyelination and axonal injury is prominent in postinfectious myelitis. However, involvement of the central compartment of the cord, gray matter, or neurons is also prominent in some cases, a finding that supports the view that in TM both gray and white matter compartments may be equally affected. In some biopsies obtained during the acute phases of myelitis, infiltration of CD4⫹ and CD8⫹ lymphocytes, along with an increased presence of monocytes, is quite prominent. In biopsies obtained during subacute phases of myelopathic lesions, prominent monocyte and phagocytic-macrophage infiltration is observed. In some cases, autoimmune disorders such as systemic lupus erythematosus (SLE) lead to vasculitic lesions that produce focal areas of spinal cord ischemia without prominent inflammation.17 These immunopathological obser-

We proposed a diagnostic and classification scheme which has defined transverse myelitis (TM) as either idiopathic or associated with a known inflammatory disease.

IMMUNOPATHOGENESIS OF TM The pathology of acute myelopathies reflects the heterogeneous nature of these disorders. Few studies to date have described the pathology of acute myelitis, and the majority of these pathologic descriptions are clinicopathological case reports.14 –16 Pathologic data from autopsies and biopsies of suspicious spinal cord lesions from patients later © 2005 Lippincott Williams & Wilkins

FIGURE 1. Histology of transverse myelitis (TM). A, Myelin staining of cervical spinal cord section from a patient who died during a subacute stage of TM. There are a few myelinated areas left (asterisk) and foci of cystic degeneration in the anterior horns (arrow). The remaining spinal cord shows chronic inflammation and demyelination (LFB/HE stain). B, Perivascular infiltration by inflammatory cells in an area of active inflammation in a patient with TM. C, Infiltration by microglial cells in an area of inflammation (HLA-Dr immunostain). D, High-magnification view of few myelinated fibers left in areas of active inflammation (arrows) (LFB/HE stain).

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vations further confirm that TM is an immune-mediated disorder that involves cellular reactions and perhaps humoral factors that injure compartments of the spinal cord.

Overview of Immunopathogenesis of TM The immunopathogenesis of disease-associated TM is varied. For example, pathologic data confirm that many cases of lupus-associated TM are associated with a CNS vasculitis,18 –20 while others may be associated with thrombotic infarction of the spinal cord.21,22 Neurosarcoid is often associated with noncaseating granulomas within the spinal cord,23 while TM associated with MS often has perivascular lymphocytic cuffing and mononuclear cell infiltration with variable complement and antibody deposition.24 Since these diseases have such varied (albeit poorly understood) immunopathogenic and effector mechanisms, instances of disease-associated TM will not be further discussed here. Rather, the subsequent discussion will focus on findings potentially related to idiopathic TM.

In TM patients, it is likely that there is abnormal activation of the immune system resulting in inflammation and injury within the spinal cord.

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from these studies is that a vaccination may induce an autoimmune process resulting in TM. However, it should be noted that extensive data continue to overwhelmingly show that vaccinations are safe and are not associated with an increased incidence of neurologic complications.26 –32 Therefore, such case reports must be viewed with caution, as it is entirely possible that 2 events occurred in close proximity by chance alone or for reasons that are only incidentally related to the vaccination procedure.

Parainfectious TM In 30% to 60% of the idiopathic TM cases, there is an antecedent respiratory, GI, or systemic illness.4 – 6,8,11,25 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, including herpes viruses and Listeria monocytogenes, though in most of these cases, causality has not been established. Though in these cases the infectious agent is required within the CNS, other mechanisms of autoimmunity discussed below, such as molecular mimicry and superantigenmediated disease, require only peripheral immune activation and may account for other cases of TM.

Molecular Mimicry Most patients have CSF pleocytosis and blood-brain barrier breakdown within a focal area of the spinal cord, and conventional treatments are aimed at ameliorating immune activation. In 30% to 60% of idiopathic TM cases, there is an antecedent respiratory, gastrointestinal or systemic illness.3– 6,8,11,25 In TM patients, it is likely that there is abnormal activation of the immune system resulting in inflammation and injury within the spinal cord. Thus, an understanding of the immunopathogenesis of TM must account for abnormal or excessive incitement of immune activation, and effector mechanisms by which immune activation leads to CNS injury.

Putative Mechanisms of Immune Activation Postvaccination TM It is widely reported in neurology texts that TM is a postvaccination event, despite there being evidence of correlation but not causation at the present time. Several reports of TM following vaccination have been recently published, including following an influenza26 and booster hepatitis B vaccination.27 Autopsy evaluation of patients with postvaccination TM revealed lymphocytic infiltration of the spinal cord with axonal loss and demyelination. The suggestion

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Molecular mimicry as a mechanism to explain an inflammatory nervous system disorder has been best described in Guillain-Barré syndrome (GBS). First referred to as an “acute postinfectious polyneuritis” by W. Osler in 1892, GBS is preceded in 75% of cases by an acute infection.33–36 Campylobacter jejuni infection has emerged as the most important antecedent event in GBS, occurring in up to 41% of cases.37– 40 Human neural tissue contains several subtypes of ganglioside moieties within their cell walls.41,42 A characteristic component of human gangliosides, sialic acid,43 is also found as a surface antigen on C. jejuni within its lipopolysaccharide (LPS) outer coat.44 Antibodies against C. jejuni that cross-react with gangliosides have been found in serum from patients with GBS45– 47 and have been shown to bind peripheral nerves, fix complement and impair neural transmission in experimental conditions that mimic GBS.41,48 –50 Susceptibility to the development of GBS is also dependent on host genetic factors, which are at least partly mediated by HLA alleles.43,60 Molecular mimicry in TM may be associated with the development of autoantibodies in response to an antecedent infection. This etiology was postulated to be involved in the case of a patient who contracted TM following infection with © 2005 Lippincott Williams & Wilkins

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Enterobium vermicularis (perianal pinworm) and was found to have elevated titers of cross-reacting antibodies.61

Microbial Superantigen-Mediated Inflammation Another link between an antecedent infection and the development of TM 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 SAGs are staphylococcal enterotoxins A through I, toxic shock syndrome toxin-1 and Streptococcus pyogenes exotoxin, though many viruses encode SAGs as well.51–54 SAGs activate T-lymphocytes in a unique manner compared with conventional antigens: instead of binding to the highly variable peptide groove of the T cell receptor, SAGs interact with the more conserved V␤ region.55–58 Additionally, unlike conventional antigens, SAGs are capable of activating T lymphocytes in the absence of costimulatory molecules. As a result of these differences, a single SAG may activate between 2% and 20% of circulating T-lymphocytes compared with 0.001% and 0.01% with conventional antigens.59 – 61 Stimulation of large numbers of lymphocytes may trigger autoimmune disease by activating autoreactive T-cell clones.62,63

Humoral Derangements Either of the above processes may result in abnormal immune function with blurred distinction between self and nonself. 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 NMO64 – 68 and recurrent TM.12,13,69 The high prevalence of various autoantibodies seen in such patients suggests polyclonal derangement of the immune system. It may also be that some autoantibodies initiate a direct and selective injury of neurons that contain antigens that crossreact with antibodies directed against infectious pathogens. However, it may not just be autoantibodies, but high levels of even normal circulating antibodies that have a causative role in TM. A case of TM was described in a patient with extremely high serum and CSF antibody levels to hepatitis B surface antigen following booster immunization.70 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.71 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 TM were found to have much higher serum IgE levels than MS patients or controls (360 © 2005 Lippincott Williams & Wilkins

Acute Myelopathies

versus 52 versus 85 U/mL).72 Virtually all of the patients in this study had specific serum IgE to household mites (Dermatophagoides pteronyssinus or Dermatophagoides farinae), while less than one third of MS and control patients did. One potential mechanism to explain the TM in such patients is the deposition of IgE with subsequent recruitment of cellular elements. Indeed, biopsy specimens of 2 TM patients with elevated total and specific serum IgE revealed antibody deposition within the spinal cord, perivascular lymphocyte cuffing, and infiltration of eosinophils.73 It was postulated that eosinophils, recruited to the spinal cord, degranulated and induced the neural injury in these patients.

Putative Mechanisms of Immune-Mediated CNS Injury We recently have carried out a series of investigations that describe immune derangements in TM patients (Kaplin et al, unpublished data). We have found that interleukin 6 (IL-6) levels in the spinal fluid of TM patients were markedly elevated compared with control patients and to MS patients. While relatively low levels of IL-6 in MS patients did not correlate with disability, IL-6 levels in TM patients strongly correlated with and were highly predictive of disability. IL-6 levels in TM patients’ CSF correlated with nitric oxide (NO) metabolites, which also correlated with disability. We suggest, therefore, that marked up-regulation of IL-6 as a result of immune system activation correlates with increased NO production and that this elevation is etiologically related to tissue injury leading to clinical disability in TM.

IL-6 levels in TM patients strongly correlated with and were highly predictive of disability.

DEFINING TM Historical Classifications of TM Acute transverse myelopathy (which includes noninflammatory causes) and TM have often been used interchangeably throughout the published literature. One report established the following criteria for transverse myelopathy: bilateral spinal cord dysfunction developing over a period of ⬍ 4 weeks with a well-defined upper sensory level, no antecedent illness, and exclusion of compressive etiologies.11 Subsequently, these criteria were altered to include only those patients who developed motor, sensory, and sphincter dysfunction acutely over ⬍ 14 days, whereas patients with other neurologic disease or underlying systemic diseases were excluded.5 Other authors then defined TM as acutely developing paraparesis (no specification of a time to maximum deficit) with bilateral sensory findings and

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impaired sphincteric function, a spinal segmental level of sensory disturbance, a stable nonprogressive course (to distinguish from progressive spastic paraparesis), and no clinical or laboratory evidence of spinal cord compression.3 Patients were excluded if they had progressive spastic paraparesis, a patchy sensory deficit or hemicord syndrome, syphilis, severe back trauma, metastatic cancer, or encephalitis. To further separate diseases with distinct etiologies, suggested criteria for TM were revised to include only those patients who progressed to maximum deficit within 4 weeks and to exclude other known diseases including arteriovenous malformations of the spinal cord, human T-cell lymphotropic virus-1 infection, and sarcoidosis.4 With use of these criteria, cases of TM were classified as parainfectious, related to MS, spinal cord ischemia, or idiopathic. Most recently, acute noncompressive myelopathies were classified according to an etiologic scheme74: (1) those related to MS; (2) systemic disease (eg, SLE, antiphospholipid syndrome, Sjo¨gren disease); (3) postinfectious; (4) delayed radiation myelopathy; (5) spinal cord infarct; and (6) idiopathic myelopathy. The presence of MS or systemic disease was determined by standard criteria,75–77 whereas parainfectious myelopathies were diagnosed on the basis of positive IgM serology or a 4-fold or greater increase in IgG levels on 2 successive tests to a specific candidate/infectious agent. Delayed radiation myelopathy was diagnosed according to clinical history, and spinal cord infarction was diagnosed on the basis of appropriate clinical and imaging findings in the absence of other likely etiologies. Idiopathic transverse myelopathy was defined in those individuals that could not be otherwise categorized and constituted 16.5% of this series. We recently proposed a set of diagnostic criteria that served to distinguish TM from noninflammatory myelopathies and to distinguish idiopathic TM from TM associated with multifocal CNS and multisystemic inflammatory disorders. These criteria are summarized in Table 2. A diagnosis of TM requires evidence of inflammation within the spinal cord. Because spinal cord biopsy is not a practical option in the routine evaluation of these patients, spinal MRI and CSF analysis are the only tools currently available to determine the presence of inflammation within the involved lesion. Gado-

TABLE 2. Diagnostic Criteria for Transverse Myelitis Diagnostic criteria Sensory, motor, or autonomic dysfunction attributable to the spinal cord Bilateral signs and/or symptoms Clearly defined sensory level Inflammation defined by CSF pleocytosis or elevated IgG index or gadolinium enhancement Progression to nadir between 4 hours and 21 days

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linium-enhanced spinal MRI and a lumbar puncture are mandatory in the evaluation of suspected TM, and we proposed that abnormal gadolinium enhancement of the spinal cord or CSF pleocytosis or elevated CSF IgG index be required for a diagnosis of TM.2 If none of the inflammatory criteria are met at symptom onset, MRI and lumbar puncture evaluation should be repeated between 2 and 7 days following symptom onset to determine if these inflammatory criteria are met. IgG synthesis rate is a less specific indicator of CNS inflammation than is CSF IgG index78,79 and should not be used in the diagnosis. Vascular myelopathies can be differentiated from TM by a progression of symptoms to maximal severity in less than 4 hours and the lack of inflammation as defined above. However, these criteria do not completely distinguish vascular myelopathies from TM, since myelopathies associated with venous infarcts or with vascular malformations may be more slowly progressive and may meet the other criteria for TM (though not an elevated IgG index). Differentiating idiopathic TM from TM attributed to an underlying disease is also important. Many systemic inflammatory disorders (eg, sarcoidosis, SLE, Behc¸et disease, Sjo¨gren syndrome) may involve the nervous system and TM may be one of the possible presentations. Therefore, all patients presenting with TM should be investigated for the presence of systemic inflammatory disease. Important historical information should be obtained from the patient regarding the presence of rashes, night sweats, oral or genital ulcers, sicca symptoms, shortness of breath, pleuritic pain, or hematuria. Examination should attempt to detect the presence of uveitis or retinitis, decreased lacrimation or salivation, skin rash (malar, livedo reticularis, erythema nodosum), oral or genital ulcers, adenopathy, pleuritic or pericardial friction rub, or organomegaly. Laboratory studies should include the following: CBC with differential and smear, ANA, SS-A, SS-B, ESR, ACE, and complement. Additional laboratory testing may be required if signs of a systemic vasculitis are detected. From this evaluation, it may be possible to distinguish idiopathic TM from disease-associated TM (ie, TM associated with multifocal CNS disease or systemic inflammatory disease). This distinction is important since patients at high risk of developing MS may be evaluated more closely or may be offered immunomodulatory treatment.80 Similarly, patients with disease-associated TM may need to be closely followed for recurrent systemic and neurologic complications and should be offered immunosuppressive treatment to decrease the risk of recurrence.

NATURAL HISTORY OF TM Epidemiology and Clinical Presentation of TM TM affects individuals of all ages, with bimodal peaks between the ages of 10 and 19 years and 30 and 39 years.3– 6 There are approximately 1400 new cases diagnosed in the © 2005 Lippincott Williams & Wilkins

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United States per year, and approximately 34,000 people have chronic morbidity from TM at any given time. Approximately 28% of reported TM cases are in children (JHTMC case series). There is no sex or familial predisposition to TM. A preceding illness including nonspecific symptoms such as fever, nausea, and muscle pain has been reported in about 40% of pediatric cases within 3 weeks of the onset of the disorder (JHTMC case series).25,81 Thirty percent of all cases of pediatric TM cases referred to an academic center had a history of an immunization within 1 month of the onset of symptoms (JHTMC case series). Although a history of an immunization preceding the onset of TM is commonly reported, the relationship to this event is unclear because of insufficient data. TM is characterized clinically by acutely or subacutely developing symptoms and signs of neurologic dysfunction in motor, sensory and autonomic nerves, and nerve tracts of the spinal cord. Weakness is described as a rapidly progressive paraparesis starting with the legs that occasionally progresses to involve the arms as well. Flaccidity maybe noted initially, with gradually appearing pyramidal signs by the second week of the illness. A sensory level can be documented in most cases. The most common sensory level in adults is the midthoracic region, though children may have a higher frequency of cervical spinal cord involvement and a cervical sensory level.82 Pain may occur in the back, extremities, or abdomen. Paresthesias are a common initial symptom in adults with TM but are unusual for children.83 Autonomic symptoms consist variably of increased urinary urgency, bowel or bladder incontinence, difficulty or inability to void, incomplete evacuation, or bowel constipation.9 Also commonly the result of sensory and autonomic nervous system involvement in TM is sexual dysfunction.84,85 Genital anesthesia from pudendal nerve involvement (S2-S4) results in impaired sensation in men and women. Additional male sexual problems with parasympathetic (S2-S4) and sympathetic (T10-L2) dysfunction in TM patients include erectile dysfunction, ejaculatory disorders and difficulty reaching orgasm. Corresponding female sexual problems include reduced lubrication and difficulty reaching orgasm. In addition to the signs and symptoms of direct spinal cord involvement by the immune system in TM, there also appears to be indirect effects manifested as depression and selective cognitive impairment that are reminiscent of what has been described in MS (unpublished observations).86 This depression or cognitive impairment does not correlate significantly with the patient’s degree of physical disability and can have lethal consequences, resulting in suicide in severe cases if left untreated. In fact, in our case series depression resulting in suicide is the leading cause of mortality, accounting for 60% of the deaths we have seen in our clinic (unpublished observations). © 2005 Lippincott Williams & Wilkins

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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% to 94% of patients have numbness, paresthesias, or bandlike dysesthesias.3– 8 In more than 80% of cases, patients reach their clinical nadir within 10 days of the onset of symptoms.81 Although the temporal course may vary, neurologic function usually progressively worsens during the acute phase from between 4 and 21 days.2 A spinal MRI and lumbar puncture often show evidence of acute inflammation.3–5,8,11,87,88 In our case series of 170 idiopathic TM cases, spinal MRI showed a cervical T2 signal abnormality in 44% and a thoracic T2 signal abnormality in 37% of cases. Five percent of patients had multifocal lesions and 6% showed a T1 hypointense lesion. This corresponded to the following clinical sensory levels: 22% cervical, 63% thoracic, 9% lumbar, 6% sacral, and no sensory level in 7%. The rostral-caudal extent of the lesion ranged from 1 vertebral segment in many to spanning the entire spinal cord in 2 patients. In 74% of patients, the lesion also enhanced with gadolinium. Forty-two percent of patients had a CSF pleocytosis, with a mean WBC count of 38 ⫾ 13 cells (range 0 –950 cells). Fifty percent of the patients revealed an elevated protein level (mean protein level 75 ⫾ 14 mg/dL). Table 3 lists some of the radiologic features that distinguish various acute myelopathies.

Seventy-five percent to 90% of TM patients experience monophasic disease and have no evidence of multisystemic or multiphasic disease.

Monophasic Versus Recurrent TM Seventy-five percent to 90% of TM patients experience monophasic disease and have no evidence of multisystemic or multiphasic disease. Most commonly, symptoms will stop progressing after 2 to 3 weeks, and spinal fluid and MRI abnormalities will stabilize and then begin to resolve. There are several features, however, that predict recurrent disease (Table 4). Patients with multifocal lesions within the spinal cord, demyelinating lesions in the brain, oligoclonal bands in the spinal fluid, mixed connective tissue disorder, or serum autoantibodies (most notably SS-A) are at a greater risk of recurrence.89 Preliminary studies suggest that patients who have persistently abnormal CSF cytokine profiles (notably IL-6) may also be at increased risk for recurrent TM, though these findings must be validated before they are used clini-

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TABLE 3. Suggestive Imaging Features to Diagnose Acute Myelopathies Imaging Features

Potential Diagnosis

Blood within the spinal cord (bright and dark T1 and T2 signal) Flow voids within spinal cord Central T2 signal abnormality Ring-enhancing lesion Acute loss of vertical intervertebral disc height and corresponding T2 signal abnormality Fusiform lesion extending over ⬎ 3 spinal cord segments T2 bright lesion in white matter occupying less than 2 spinal cord segments in rostral-caudal extent and less than 50% of the cord diameter T2 spinal cord lesion adjacent to disk herniation or spondylitic ridge but lack of spinal cord compression

Vascular malformation such as cavernous angioma or dural AV fistula Dural AV fistula or AVM Venous hypertension Infection or tumor (but consider course of IV steroids to rule out inflammatory process before progressing to biopsy) Consider fibrocartilaginous embolism Consider neuromyelitis optica or disease-associated TM Consider MS

Consider dynamic spinal cord compression only during flexion or extension (flexion-extension x-ray to determine the presence of abnormal spinal column mobility; MRI in flexion or extended position instead of in neutral position)

TABLE 4. Distinguishing Features Between Recurrent and Monophasic Transverse Myelitis Characteristics

Monophasic

Spinal MRI

Single T2 lesion

Brain MRI Blood serology SS-A CSF oligoclonal bands Systemic disease Optic nerve involvement

Normal Normal Negative Negative None No

cally (Kaplin et al, unpublished data). At the current time, we do not understand the relative contribution of these factors to gauge whether chronic immunomodulatory treatment is warranted in high-risk patients.

Prognosis Some patients with TM may experience recovery in neurologic function, regardless of whether specific therapy is instituted. Recovery, if it occurs, should begin within 6 months, and most patients show some restoration of neurologic function within 8 weeks (JHTMC case series).83 Recovery may be rapid during months 3 to 6 after symptom onset and may continue, albeit at a slower rate, for up to 2 years.81,82 Longitudinal case series of TM reveal that approximately one third of patients recover with little to no sequelae, one third are left with moderate degree of permanent disability, and one third have severe disabilities.5,6,11,25,81 Knebusch et al81 estimated that a good outcome with normal gait, mild urinary symptoms, and minimal sensory and upper motor

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Recurrent Multiple distinct lesions or fusiform lesion extending over ⬎ 3 spinal cord segments T2/FLAIR abnormalities ⬎ 1 autoantibody (ANA, dsDNA, phospholipid, c-ANCA) Positive Positive Connective tissue disorder Likely

neuron signs occurred in 44%. A fair outcome with mild spasticity but independent ambulation, urgency and/or constipation, and some sensory signs occurred in 33%, and a poor outcome with the inability to walk or severe gait disturbance, absence of sphincter control, and sensory deficit in 23%. The patient cohort we follow at Johns Hopkins is more severe, with only 20% experiencing a good outcome by those definitions, likely a reflection of referral bias to a tertiary-care center. Symptoms associated with poor outcome include back pain as an initial complaint, rapid progression to maximal symptoms within hours of onset, spinal shock, and sensory disturbance up to the cervical level.83 The presence of 14-3-3 protein, a marker of neuronal injury, in the CSF during the acute phase may also predict a poor outcome.90 Our recent studies suggest that CSF IL-6 levels at acute presentation are proportional to, and highly predictive of, long-term disability (Kaplin et al, unpublished data). If confirmed by future studies, the finding that IL-6 © 2005 Lippincott Williams & Wilkins

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levels are proportional to disability in subjects prior to treatment could provide a much-needed biomarker to help guide the aggressiveness of interventions employed in treating patients presenting with acute TM.

CLINICAL EVALUATION AND TREATMENT OF PATIENTS WITH TM Evaluation of Patients With Acute Myelopathies We recently proposed a systematic diagnostic approach for evaluating patients with acute myelopathies.2 The algorithm is shown in Figure 2. The first priority is to rule out a compressive lesion. If a myelopathy is suspected based on history and physical examination, a gadolinium-enhanced MRI of the spinal

Acute Myelopathies

cord should be obtained as soon as possible. If there is no structural lesion such as epidural blood or a spinal mass, then the presence or absence of spinal cord inflammation should be documented with a lumbar puncture. The absence of pleocytosis would lead to consideration of noninflammatory causes of myelopathy such as arteriovenous malformations, epidural lipomatosis, fibrocartilaginous embolism, or possibly early inflammatory myelopathy (ie, a false-negative CSF). In the presence of an inflammatory process (defined by gadolinium enhancement, CSF WBC pleocytosis, or elevated CSF immunoglobulin index), one should determine whether there is an infectious cause. Viral polymerase chain reaction assays should be performed to determine whether there is the presence of viral particles within the CNS (herpes simplex 1 and 2, varicella zoster, cytomegalo-

FIGURE 2. Acute myelopathies: a diagnostic approach. © 2005 Lippincott Williams & Wilkins

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virus, Epstein-Barr virus, and enterovirus). Detection of Lyme disease of the CNS typically is based on antibody detection methods (ELISA with confirmatory Western blot) and the CSF/ serum index is often helpful in determining whether there is true neuroborreliosis.91 Evidence of M. pneumoniae infection may be determined by seroconversion, which is defined by a 4-fold increase in titer or a single titer of ⱖ 1:128.

Recovery may be rapid during months 3 to 6 after symptom onset and may continue, albeit at a slower rate, for up to 2 years.

The next priority is to define the regional distribution of demyelination within the CNS, since several disorders (ie, multiple sclerosis or ADEM) may present with TM as the initial manifestation of disease or in the setting of multifocal disease. A gadolinium-enhanced brain MRI and visual evoked potential should be ordered to look for these entities. The absence of multifocal areas of demyelination would suggest the diagnosis of isolated TM and lead to appropriate treatment measures.2 TM is often misdiagnosed as acute inflammatory demyelinating polyradiculoneuropathy (AIDP) or GuillainBarre´ syndrome (GBS), because both conditions may present with rapidly progressive sensory and motor loss involving principally the lower extremities. Table 5 illustrates key differential points between these 2 conditions. A pure paraplegia or paraparesis with a corresponding distribution of sensory loss may favor TM, while GBS may present with a

gradient of motor and sensory loss involving the lower extremities greater than the upper extremities. When weakness and sensory loss involves both the upper and lower extremities equally with a distinct spinal cord level, then TM involving the cervical region is more likely. Pathologically brisk deep tendon reflexes are supportive of TM. However, patients with fulminant cases of TM that includes significant destruction of spinal cord gray matter may present with hypotonia and have decreased or absent deep tendon reflexes. Urinary urgency or retention is a common early finding in TM and is less common in GBS. In GBS, dysesthetic pain, involvement of the upper extremity and cranial nerve 7, and absent deep tendon reflexes involving the upper extremities are more common findings. An MRI of the spinal cord may show an area of inflammation in TM but not in GBS. Although cerebrospinal fluid findings in TM are not consistent and an elevated cell count may be absent, there is usually a moderate lymphocytic pleocytosis and elevated protein level. This is in contrast to the albuminocytologic dissociation of the CSF seen in GBS.81

Differential Diagnoses/Noninflammatory Myelopathies As indicated above, the suggested diagnostic algorithm and criteria first distinguish inflammatory from noninflammatory myelopathies. If the history and evaluation do not suggest a systemic or a CNS inflammatory process, then consideration should be given to ischemic, metabolic, or structural causes of myelopathy. Vascular myelopathy may be fairly easy to recognize in the setting of an anterior spinal artery infarct (sudden onset of symptoms with relative preservation of posterior column function). Or it may be more difficult to recognize in the setting of a venous infarct or a

TABLE 5. Distinguishing Features Between Guillain-Barré Syndrome and Transverse Myelitis Characteristics

Transverse Myelitis

Motor findings Sensory findings

Paraparesis or quadriparesis Usually can diagnose a spinal cord level

Autonomic findings

Early loss of bowel and bladder control

Cranial nerve findings Electrophysiologic findings

None EMG/NCV findings may be normal or may implicate the spinal cord: prolonged central conduction on somatosensory evoked potential (SEP) latencies or missing SEP in conjunction with normal sensory nerve action potentials Usually a focal area of increased T2 signal with or without gadolinium enhancement Usually, CSF pleocytosis and/or increased IgG index

MRI findings CSF

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Guillain-Barré Syndrome Ascending weakness LE ⬎ UE in the early stages Ascending sensory loss LE ⬎ UE in the early stages Autonomic dysfunction of the cardiovascular (CV) system EOM palsies or facial weakness EMG/NCV findings confined to the PNS: motor and/or sensory nerve conduction velocity reduced, distal latencies prolonged; conduction block; reduced H reflex usually present Normal Usually, elevated protein in the absence of CSF pleocytosis

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vascular malformation. Venous infarction may be suspected when a clinical history and serologic studies are suggestive of a prothrombotic state (deep venous thrombosis, pulmonary embolus, livedo reticularis, antiphospholipid antibodies, factor V Leiden mutation, APC resistance, or prothrombin gene mutation). A vascular malformation (dural AV fistula, AVM, cavernous angioma) may be suspected if the imaging suggests the presence of flow voids or bleeding into the spinal cord. A dural AV fistula is most likely to occur in men older than 40 years old and may present with a “stuttering” or progressive myelopathy. Patients with a dural AV fistula may report a postural dependence of symptoms and pain is usually a prominent feature. Spinal angiography is the diagnostic study of choice to define the presence of a vascular malformation. Surgical or endovascular treatment may result in stabilization or clinical improvement in a substantial proportion of patients.92–94 Fibrocartilaginous embolism is a rare (though likely underreported) cause of acute myelopathy.95–98 In most reported cases, there has been a sudden increase in intrathoracic or intraabdominal pressure prior to the onset of symptoms, and in several autopsies, fibrocartilaginous material was found to have embolized to the spinal cord. The most likely explanation for these findings is that the nucleus pulposus herniated vertically into the vertebral body sinusoids in response to markedly elevated pressure, followed by further herniation through vascular channels into the spinal cord parenchyma. Fibrocartilaginous embolism should be suspected in a patient with a sudden onset of myelopathy that reaches its maximal severity within hours in a patient with an antecedent elevation of intraabdominal or intrathoracic pressure. Imaging may show acute loss of intervertebral disk height and vertebral body end-plate changes adjacent to an area of T2 signal abnormality within the spinal cord. Radiation myelopathy may develop at any time up to 15 years following ionizing radiation. Pathologic studies show preferential involvement of myelinated tissue and blood vessels and it is likely that cellular death of oligodendrocytes and endothelial cells contributes to the clinical disorder.99 Patients may present with slowly progressive spasticity, weakness, hyperreflexia and urinary urgency. There is often a corresponding T2 signal abnormality that is nonenhancing and preferentially affects the more superficial spinal cord white matter. Though anticoagulation100,101 or hyperbaric oxygen102–104 has been proposed as a treatment option, neither has been clearly shown to be effective in patients with radiation myelopathy.

Discrimination from Multiple Sclerosis TM can be the presenting feature of MS. Patients who are ultimately diagnosed with MS are more likely to have asymmetric clinical findings, predominant sensory symptoms with relative sparing of motor systems, MR lesions extending © 2005 Lippincott Williams & Wilkins

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over fewer than 2 spinal segments, abnormal brain MRI, and oligoclonal bands in the CSF.74,87,105–108 A patient with monofocal CNS demyelination (TM or ON) whose brain MRI shows lesions consistent with demyelination109 has an 83% chance of meeting clinical criteria for MS over the subsequent decade compared with 11% of such patients with normal brain MRI.110

MANAGEMENT OF TM Intravenous Steroids Intravenous steroid treatment is often instituted for patients with acute TM. Corticosteroids have multiple mechanisms of action including antiinflammatory activity, immunosuppressive properties, and antiproliferative actions.111,112 Though there is no randomized double-blind placebo-controlled study that supports this approach, evidence from related disorders and clinical experience support this treatment.113–117 Additionally, there are several small studies which support the administration of corticosteroids in patients with TM.118 –121 A study of 5 children with severe TM who received methylprednisolone (1 g/1.73 m2/d) for 3 or 5 consecutive days followed by oral prednisone for 14 days reported beneficial effects compared with 10 historic controls.120 In the steroid-treated group, the median time to walking was 23 days versus 97 days, full recovery occurred in 80% versus 10%, and full motor recovery at 1 year was present in 100% versus 20%. No serious adverse effects from the steroid treatments occurred.

The available evidence suggests that intravenous steroids are somewhat effective if given in the acute phase of TM.

Other investigations have suggested that intravenous steroid administration may not be effective in TM patients.81,83,122 The most significant of these manuscripts122 compared 12 TM patients seen between 1992 and 1994 who did not get steroids with 9 patients seen between 1995 and 1997 who did. Although the authors claimed that there was no statistically significant difference in the outcomes between the groups, it is evident that the TM patients who received steroids were more likely to recover, and fewer had a poor outcome on the Barthel Index (33% versus 67%). Therefore, the available evidence suggests that intravenous steroids are somewhat effective if given in the acute phase of TM. However, these studies did not rigorously define TM and

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therefore likely included patients with noninflammatory myelopathies. At our center, we routinely offer intravenous methylprednisolone (1000 mg) or dexamethasone (200 mg) for 3 to 5 days unless there are compelling reasons to avoid this therapy. The decision to offer continued steroids or add a new treatment is often based on the clinical course and MRI appearance at the end of 5 days of steroids.

Plasma Exchange (PLEX) PLEX is often initiated if a patient has moderate to severe TM (ie, inability to walk, markedly impaired autonomic function, and sensory loss in the lower extremities) and exhibits little clinical improvement after instituting 5 to 7 days of intravenous steroids. PLEX is believed to work in autoimmune CNS diseases through the removal of specific or nonspecific soluble factors likely to mediate, be responsible for, or contribute to inflammatory-mediated target organ damage. PLEX has been shown to be effective in adults with TM and other inflammatory disorders of the CNS.123–125 Predictors of good response to PLEX include early treatment (less than 20 days from symptom onset), male sex, and a clinically incomplete lesion (ie, some motor function in the lower extremities, intact or brisk reflexes).126 It is our experience that PLEX may significantly improve outcomes of patients with severe (though incomplete) TM and who have not significantly improved on intravenous steroids.

It is our experience that plasma exchange (PLEX) may significantly improve outcomes of patients with severe (though incomplete) TM and who have not significantly improved on intravenous steroids.

Other Immunomodulatory Treatment No controlled information currently exists regarding the use of other treatment strategies in patients with acute TM. Some clinicians consider pulse dose intravenous cyclophosphamide (500 –1000 mg/m2) for patients with TM that continues to progress despite intravenous steroid therapy. Cyclophosphamide, a bifunctional alkylating agent, forms reactive metabolites that cross-link DNA. This results in apoptosis of rapidly dividing immune cells and is believed to underlie the immunosuppressive properties of this medication. It is the experience at our center that some patients will respond significantly to intravenous cyclophosphamide, and this treatment is worthy of consideration while we await

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double-blinded placebo trials. However, cyclophosphamide should be administered under the auspices of an experienced oncology team, and caregivers should monitor the patient carefully for hemorrhagic cystitis and cytopenias. CSF filtration is a new therapy, not yet available in the United States, in which spinal fluid is filtered for inflammatory factors (including cells, complement, cytokines, and antibodies) prior to being reinfused into the patient. In a randomized trial of CSF filtration versus PLEX for AIDP, CSF filtration was better tolerated and was at least as effective.127 Clinical trials for CSF filtration are currently being initiated. Chronic immunomodulatory therapy should be considered for the small subgroup of patients with recurrent TM. Although the ideal treatment regimen is not known, we consider a 2-year course of oral immunomodulatory treatment in patients with 2 or more distinct episodes of TM. We most commonly treat patients with azathioprine (150 –200 mg/d), methotrexate (15–20 mg/wk) or mycophenolate (2–3 g/d), though oral cyclophosphamide (2 g/kg/d) may also be used in patients with systemic inflammatory disease. On any of these medicines, patients must be followed for transaminitis or leukopenias.

Long-Term Management Many patients with TM will require rehabilitative care to prevent secondary complications of immobility and to improve their functional skills. It is important to begin occupational and physical therapies early during the course of recovery to prevent the inactivity related problems of skin breakdown and soft tissue contractures that lead to loss of range of motion. The principles of rehabilitation in the early and chronic phases after TM are summarized in Table 6. During the early recovery period, family education is essential to develop a strategic plan for dealing with the challenges to independence following return to the community. Assessment and fitting for splints designed to passively maintain an optimal position for limbs that cannot be actively moved is an important part of the management at this stage. The long-term management of TM requires attention to a number of issues. These are the residual effects of any spinal cord injury including TM. In addition to chronic medical problems, there are the ongoing issues of ordering the appropriate equipment, reentry into the school for children and community, and coping with the psychologic effects of this condition by the patients and their families. Patients with TM should be educated about the effect of TM on mood regulation and routinely screened for the development of symptoms consistent with clinical depression. Patient warning signs that should prompt a complete evaluation for depression include failure to progress with rehabilitation and self-care, worsening fixed low mood or pervasive decreased interest, and social and professional withdrawal. A preoccupa© 2005 Lippincott Williams & Wilkins

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tion with death or suicidal thoughts constitutes a true psychiatric emergency and should lead to prompt evaluation and treatment. All patients should be educated about 3 main points related to depression. First, patients should be educated that depression in TM is similar to other neurologic symptoms patients endure, being mediated by the effects of the immune system on the brain. Depression is remarkably prevalent in TM, occurring in up to 25% of patients at any given time, and is largely independent of the patient’s degree of physical disability. Depression is not due to personal weakness or the inability to “cope.” Second, depression in TM can have devastating consequences; not only can depression worsen physical disability (such as fatigue, pain, and decreased concentration) but it can have lethal consequences. Suicide is the leading cause of death in TM, accounting for 60% of the deaths in the JHTMC since its inception. Third, despite the severity of the clinical presentation of depression in many patients with TM, these patients generally show a very robust response to combined aggressive psychopharmacologic and psychotherapeutic interventions. Complete symptom remission is the rule rather than the exception with appropriate recognition and treatment of TM depression. Spasticity is often a very difficult problem to manage. The goal is to maintain flexibility with a stretching routine using exercises for active stretching and a bracing program with splints for a prolonged stretch. These splints are commonly used at the ankles, wrists, or elbows. An appropriate strengthening program for the weaker of the spastic muscle acting on a joint and an aerobic conditioning regimen are also recommended. These interventions are supported by adjunctive measures that include antispasticity drugs (eg, diazepam, baclofen, dantrolene, tizanidine, and tiagabine), therapeutic botulinum toxin injections, and serial casting. The therapeutic goal is to improve the function of the patient in performing specific activities of daily living (ie, feeding, dressing, bathing, hygiene, mobility) through improving the available joint range of motion, teaching effective compensatory strategies, and relieving pain. Another major area of concern is effective management of bowel function. A high-fiber diet, adequate and timely fluid intake, and medications to regulate bowel evacuations are the basic components to success. Regular evaluations by medical specialists for adjustment of the bowel program are recommended to prevent potentially serious complications. Bladder function is almost always at least transiently impaired in patients with TM. Immediately after the onset of TM, as in the aftermath of traumatic spinal cord injury, there is frequently a period of transient loss or depression of neural activity below the involved spinal cord lesion. This phenomenon is often referred to as “spinal shock,” which lasts about 3 weeks, during which there is an interruption of descending excitatory influence with resultant bladder flaccidity. Following this period, bladder dysfunction can be classified into 2 syndromes involving either upper motor neurons (UMN) or lower motor neurons (LMN). © 2005 Lippincott Williams & Wilkins

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Sympathetic input to the bladder, which promotes urine storage, originates at levels T10-L2 of the spinal cord and travels via the hypogastric nerve. Afferent input to the urinary tract is provided by the sacral (S2-S4) spinal cord through the pelvic nerve. Efferent parasympathetic input to the bladder, which mediates detrusor contractions, is carried by the pelvic nerve (S2-S4). UMN bladder dysfunction results from lesions above S1-S2 and is characterized by reflexive emptying with bladder filling if the injury is complete and urge incontinence if the neurologic involvement is incomplete. In addition, detrusor-sphincter dyssynergia results from impaired communication between the sacral and brain stem micturition centers. In the case of UMN dysfunction, anticholinergic medications, ␣-blockers, or electric stimulation is used to restore adequate bladder storage and drainage. LMN bladder dysfunction with either direct involvement of S2-S4 or indirect involvement including the conus medullaris and cauda equina results in detrusor areflexia and requires clean intermittent self-catheterization. TM-induced sexual dysfunction involves similar innervation and analogous syndromes as those found in bladder dysfunction. Spinal cord segments S2-S4 relay afferent sensory fibers from the genitalia via the pudendal nerves and supply parasympathetic input via the pelvic nerves. Parasympathetic stimulation initiates and maintains penile erection in men and clitoral and labial engorgement and vaginal lubrication in women. Sympathetic fibers from T10-L2 provide the major stimulus for ejaculation and orgasm but can also mediate erections through mechanisms that are less well understood. Reflex erections in response to tactile stimulation are parasympathetically mediated through a local sacral (S2S4) reflex arc and tend to occur in patients with UMN lesions. Psychogenic erections are sympathetically mediated through sympathetic pathways that exit the spinal cord at T10-T12 and allow many patients with LMN lesions of the sacral reflex arc to achieve erections through psychogenic stimulation. Treatment of sexual dysfunction should take into account baseline function before the onset of TM and begins, with adequate education and counseling about the known physical and neurologic changes that TM has on sexual functioning. Patients should be encouraged to discuss their concerns with their doctors, as well as their partners. Because of the similarities in innervation between sexual and bladder function, patients with UMN-mediated sexual dysfunction should be encouraged to empty their bladders before sexual stimulation to prevent untimely incontinence. The mainstays of treatment of erectile dysfunction in men are inhibitors of cGMP phosphodiesterase, type 5, which will allow most of men with TM to achieve adequate erections for success in intercourse through a combination of reflex and/or psychogenic mechanisms. Although less effective in women, these same types of medications have been shown capable of enhancing sexual functioning in women.

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TABLE 6. Chronic Management of Patients with Transverse Myelitis Early Rehabilitation General Consider inpatient rehabilitation Daily land-based and/or water-based therapy for 8–12 wk Daily weight bearing for 45–90 min Bone densitometry: vitamin D, Ca Screen for depression Demoralization Individual and group support. Useful resource is TM Association (TMA) (www.myelitis.org) Development of problem-focused coping skills. All members of medical care providers could contribute (neurologist, physiatrist, PT, OT, psychiatrist, psychologist, SW, etc) Depression Education about depression as a manifestation of brain involvement in conjunction with stressful circumstance Warning about the lethality of depression (with suicide being one of the leading causes of death in TM) Treatment of depression with antidepressants and talk therapy. SSRIs are common first-line agents, but consider TCA if there is the possibility of simultaneously treating depression, incontinence, and neuropathic pain with a single agent. Bladder dysfunction If postvoid residual is ⬎ 80 mL, consider clean intermittent catheterization Anticholinergic Rx if urgency Cranberry juice for urine acidification Bowel dysfunction High-fiber diet, increased fluid intake Digital disimpaction Bowel program: colace, Senokot, Dulcolax, docusate PR, bisacodyl in water base, MiraLax, enemas PRN Weakness Passive and active ROM Splinting or orthoses when necessary

Pain or dysesthesias ROM exercises Gabapentin, carbamazepine, nortriptyline, tramadol Avoid narcotics if possible

Late Rehabilitation

Examine for scoliosis Serial flexion/extension x-ray of back to follow angle Fatigue: Amantadine, Methylphenidate, Modafinil, CoQ10 Bone densitometry: vitamin D, Ca, Bisphosphonate therapy Screen for depression Biannual national TM symposiums organized through the JHTMC and TMA Establish local TMA support group if none exists

Referral to psychiatrist if diagnosis is in doubt, initial trials of antidepressant treatment is unsuccessful, or if there is concern about suicide potential Ensure caregiver is receiving sufficient support to prevent burnout

Urodynamics study for irritative or obstructive symptoms Anticholinergic drug if detrusor hyperactive; adrenergic blocker if sphincter dysfunction Cranberry juice/vitamin C for urine acidification Consider sacral nerve stimulation High-fiber diet, increased fluid intake Digital disimpaction Bowel program: colace, Senokot, Dulcolax, docusate PR, bisacodyl in water base, MiraLax, enemas PRN Passive and active ROM Splinting or orthoses if needed Continued land and water therapy Ambulation devices Daily weightbearing for 45–90 minutes Orthopedics evaluation if joint imbalance ROM exercises Gabapentin, carbamazepine, nortriptyline, tramadol Topical lidocaine (patch or cream) Intrathecal baclofen or opioids (Continued)

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TABLE 6. (Continued) Early Rehabilitation Spasticity ROM exercises Aquatherapy Baclofen, tizanidine, diazepam, botulinum toxin, tiagabine

Late Rehabilitation

ROM exercises Aquatherapy Baclofen, tizanidine, diazepam, botulinum toxin, tiagabine Intrathecal baclofen trial

Sexual dysfunction Phosphodiesterase V inhibitors

SPECULATIONS ON FUTURE TREATMENTS OF TM Work over the last few years has begun to reveal fundamental immune abnormalities in patients with TM and related neuroimmunologic disorders. The generation of autoantibodies and the presence of abnormally elevated cytokine levels in the spinal fluid are likely to be important immunopathogenic events in many patients with TM. Though TM is a heterogeneous syndrome that is associated with distinct pathologies, recent classification strategies have attempted to identify patients with likely similar immunopathogenic events. While current therapies are largely nonspecific, future therapies will be more specifically targeted to those critical immunopathogenic events in TM. For example, evolving strategies will more effectively identify autoantibodies and the antigen to which they respond,128,129 making it possible to develop specific targets to block the effects of these autoantibodies. Additionally, several strategies exist and more are currently being developed that specifically alter cytokine profiles or the effects of these cytokines within the nervous system. However, a cautionary note exists from recent studies examining TNF-␣ modulation in patients with multiple sclerosis or systemic rheumatologic disease: paradoxical demyelination may be triggered by TNF-␣ reduction in the blood.130 These findings may suggest that secondary alterations in immune system function may occur in response to blockade of any single pathway and that a “cocktail approach” aimed at halting multiple proinflammatory pathways may be ideal. Future research will attempt to elucidate individual predispositions and environmental triggers to immune overactivation. A more comprehensive understanding of the mechanisms of tissue insult will lead to the development of rational therapeutics geared to intervene at various steps of the signal transduction pathways leading to injury. For those patients who have already undergone extensive neurologic injury as a result of TM, neurorestorative treatments (perhaps involving stem cells) offer the best hope for meaningful functional recovery. © 2005 Lippincott Williams & Wilkins

Phosphodiesterase V inhibitors

CONCLUSION TM is a clinical syndrome caused by focal inflammation of the spinal cord. Many cases are postinfectious and are thought to be due to a transient abnormality in the immune system that results in injury to a focal area of the spinal cord. Recent studies have emphasized the need to classify TM according to whether there is evidence of systemic disease or multifocal CNS disease. The importance of this may be that distinct treatment strategies are offered to patients with distinct forms of TM. Though the causes of TM remain unknown, recent advances have suggested specific cytokine derangements that likely contribute to sustained disability due to injury of motor, sensory, or autonomic neurons within the spinal cord. Future research will attempt to define triggers for the immune system derangements, effector mechanisms that propagate the abnormal immune response, and cellular injury pathways initiated by the inflammatory response within the spinal cord. Ultimately, this may allow us to identify patients at risk for developing TM, specifically treat the injurious aspects of the immune response, and/or offer neuroprotective treatments which minimize the neural injury that occurs in response to the inflammation.

ACKNOWLEDGMENT We acknowledge the support and efforts of the Transverse Myelitis Association (TMA) and its president Sanford Siegel. The TMA serves a critical role to the TM community and to researchers striving to understand and treat this disorder. We also acknowledge financial support of the Katie Sandler Fund for TM research and the Claddagh Foundation to the Johns Hopkins TM Center. We thank the Noel P. Rahn Fellowship for support (AIK). REFERENCES 1. Suchett-Kaye AI. Acute transverse myelitis complicating pneumonia. Lancet. 1948;255:417. 2. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002;59: 499 –505. 3. Berman M, Feldman S, Alter M, et al. Acute transverse myelitis:

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incidence and etiologic considerations. Neurology. 1981;31:966 –971. 4. Jeffery DR, Mandler RN, Davis LE. Transverse myelitis: retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events. Arch Neurol. 1993;50:532–535. 5. Christensen PB, Wermuth L, Hinge HH, et al. Clinical course and long-term prognosis of acute transverse myelopathy. Acta Neurol Scand. 1990;81:431– 435. 6. Altrocchi PH. Acute transverse myelopathy. Arch Neurol. 1963;9:21–29. 7. Misra UK, Kalita J, Kumar S. A clinical, MRI and neurophysiological study of acute transverse myelitis. J Neurol Sci. 1996;138:150 –156. 8. Lipton HL, Teasdall RD. Acute transverse myelopathy in adults: a follow-up study. Arch Neurol. 1973;28:252–257. 9. Sakakibara R, Hattori T, Yasuda K, et al. Micturition disturbance in acute transverse myelitis. Spinal Cord. 1996;34:481– 485. 10. Lucchinetti CF, Brueck W, Rodriguez M, et al. Multiple sclerosis: lessons from neuropathology. Semin Neurol. 1998;18:337–349. 11. Ropper AH, Poskanzer DC. The prognosis of acute and subacute transverse myelopathy based on early signs and symptoms. Ann Neurol. 1978;4:51–59. 12. Tippett DS, Fishman PS, Panitch HS. Relapsing transverse myelitis. Neurology. 1991;41:703–706. 13. Pandit L, Rao S. Recurrent myelitis. J Neurol Neurosurg Psychiatry. 1996;60:336 –338. 14. Nagaswami S, Kepes J, Foster DB, et al. Necrotizing myelitis: a clinico-pathologic report of two cases associated with diplococcus pneumoniae and mycoplasma pneumoniae infections. Trans Am Neurol Assoc. 1973;98:290 –292. 15. Mirich DR, Kucharczyk W, Keller MA, et al. Subacute necrotizing myelopathy: MR imaging in four pathologically proved cases. AJNR Am J Neuroradiol. 1991;12:1077–1083. 16. Katz JD, Ropper AH. Progressive necrotic myelopathy: clinical course in 9 patients. Arch Neurol. 2000;57:355–361. 17. de Macedo DD, de Mattos JP, Borges TM. 关Transverse myelopathy and systemic lupus erythematosus: report of a case and review of the literature兴. Ar Qneuropsiquiatr. 1979;37:76 – 84. 18. Piper PG. Disseminated lupus erythematosus with involvement of the spinal cord. JAMA. 1953;153:215–217. 19. Adrianakos AA, Duffy J, Suzuki M, et al. Transverse myelitis in systemic lupus erythematosus: report of three cases and review of the literature. Ann Intern Med. 1975;83:616 – 624. 20. Nakano I, Mannen T, Mizutani T, et al. Peripheral white matter lesions of the spinal cord with changes in small arachnoid arteries in systemic lupus erythematosus. Clin Neuropathol. 1989;8:102–108. 21. 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. 22. Weil MH. Disseminated lupus erythematosus with massive hemorrhagic manifestations and paraplegia. Lancet. 1955;75:353–360. 23. Ayala L, Barber DB, Lomba MR, et al. Intramedullary sarcoidosis presenting as incomplete paraplegia: case report and literature review. J Spinal Cord Med. 2000;23:96 –99. 24. Garcia-Zozaya IA. Acute transverse myelitis in a 7-month-old boy. J Spinal Cord Med. 2001;24:114 –118. 25. Paine RS, Byers RK. Transverse myelopathy in childhood. Am J Dis Child. 1968;85:151–163. 26. Patja A, Paunio M, Kinnunen E, et al. Risk of Guillain-Barre´ syndrome after measles-mumps-rubella vaccination. J Pediatr. 2001;138:250 –254. 27. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barre´ syndrome following vaccination in the National Influenza Immunization Program, United States, 1976 –1977. Am J Epidemiol. 1979;110:105–123. 28. Langmuir AD, Bregman DJ, Kurland LT, et al. An epidemiologic and clinical evaluation of Guillain-Barre syndrome reported in association with the administration of swine influenza vaccines. Am J Epidemiol. 1984;119:841– 879. 29. 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. 30. Ascherio A, Zhang SM, Hernan MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med. 2001;344:327–332.

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84 BILLION IN 150,000 ⴙ/- YEARS* Reliable Ways to Get Down to a Healthy, Peaceful, Worldly One Billion: Drive 50 on the 65 MPH beltway. Eat bacon, butter, and eggs each breakfast. “Entertain” your neighbor’s wife when he is out of town. Leave loaded rifles in the grandchildren’s closet. Repair the rain spouts on your three-story house. Volunteer to look for that elusive water on the moon. Negotiate the intra-uterine onset week of personhood & humanness. Agree that the persistent vegetative state arrives earlier in Republicans. Truly patriotic seniors will stop eating at age 75, or maybe 73. Bomb uncivilized nations with contraceptives and Krispy-Kremes. Sell your stairstepper. Ed Spudis, MD *NEWSWEEK, JAN. 2003

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