11 Transverse Myelitis Clinical Manifestations, Pathogenesis, and Management Chitra Krishnan, Adam I. Kaplin, Deepa M. Deshpande, Carlos A. Pardo, and Douglas A. Kerr 1. INTRODUCTION First described in 1882, and termed acute transverse myelitis (TM) in 1948 (1), TM is a rare syndrome with an incidence of between one and eight new cases per million people per year (2). TM is characterized by focal inflammation within the spinal cord and clinical manifestations are caused by 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 dys- function and evidence of acute inflammation demonstrated by a spinal magnetic resonance imaging (MRI) and lumbar puncture. When the maximal level of deficit is reached, approx 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 band-like dysesthesias (2–7). 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 (8). Like mul- tiple sclerosis (MS) (9), TM is the clinical manifestation of a variety of disorders with distinct presen- tations and pathologies (10). Recently, we proposed a diagnostic and classification scheme that has defined TM as either idiopathic or associated with a known inflammatory disease (i.e., MS, systemic lupus erythematosus [SLE], Sjogren’s syndrome, or neurosarcoidosis) (11). Most TM patients have monophasic disease, although up to 20% will have recurrent inflammatory episodes within the spinal cord (Johns Hopkins Transverse Myelitis Center [JHTMC] case series, unpublished data) (12,13). 2. DIAGNOSTIC CLASSIFICATION OF TRANSVERSE MYELITIS TM exists in a series of neuroinflammatory central nervous system (CNS) conditions, charac- terized by abrupt neurological deficits associated with inflammatory cell infiltrates and demyeli- nation. This can occur as a single episode (e.g., TM, optic neuritis [ON], or acute disseminated encephalomyelitis [ADEM]) or as a multiphasic condition (e.g., recurrent TM, recurrent ON, neuromyelitis optica [NMO], and MS). The pathophysiological cause of recurrence is unknown but of obvious clinical significance. This spectrum of neuroinflammatory CNS conditions also varies based on regional involvement of the CNS, ranging from monofocal involvement (e.g., TM involving the spinal cord, isolated ON involving the optic nerve, and ADEM involving the brain and spinal cord) to multifocal involvement (e.g., NMO involving the optic nerve and spinal cord and MS involving any area in the central neuraxis). Because there is no consensus From: Current Clinical Neurology: Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management Edited by: A. Minagar and J. S. Alexander © Humana Press Inc., Totowa, NJ 217 218 Krishnan et al. Table 1 Diagnostic Criteria for Transverse Myelitis Inclusion criteria • Motor, sensory, 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 h and 21 d Exclusion criteria • Radiation to spine in the past 10 yr • Clear arterial distribution clinical deficit consistent with thrombosis of the anterior spinal artery • Extra-axial compressive etiology by neuroimaging • Abnormal flow voids on the surface of the spinal cord consistent with AVM • Serologic or clinical evidence of connective tissue disease, such as sarcoidosis, Behcet’s disease, Sjogren’s syndrome, SLE, and mixed connective tissue disorder (diagnostic of connective-tissue-associated TM) • History of clinically apparent optic neuritis (diagnostic of neuromyelitis optica) • CNS manifestations of syphilis, Lyme disease, HIV, HTLV-1, mycoplasma, or other viral infection such as HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, and enteroviruses (diagnostic of infectious myelitis) • Brain and spinal cord MRI abnormalities suggestive of MS and presence of oligoclonal bands in CSF (suggestive of TM associated with MS. Apply McDonald criteria to define MS) CSF, cerebrospinal fluid; IgG, immunoglobulin-G; AVM, arteriovenous malformation; SLE, systemic lupus erythematosus; TM, transverse myelitis; HIV, human immunodeficiency virus; HTLV-1, human T-cell lymphotropic virus-1; HSV, herpes simplex virus; VZV, varicella zoster virus; EBV, Epstein-Barr virus; CMV, cytomegalovirus; HHV, human herpes virus; MRI, magnetic resonance imaging; MS, multiple sclerosis. explanation, the cause for this regional specificity is a subject of considerable research interest. We speculate that this regional specification could result from differences inherent in CNS tissue at different sites (e.g., 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 transverse myelopathy (which includes noninflammatory causes) and TM have often been used interchangeably throughout the published literature. Most recently, we proposed diagnostic criteria for distinguishing TM from noninflammatory myelopathies and for distinguishing idiopathic TM from TM associated with multifocal CNS and multisystemic inflammatory disorders. These criteria are summarized in Table 1. A diagnosis of TM requires confirmation of inflammation within the spinal cord by MRI and lumbar puncture. Markers of inflammation include gadolinium- enhanced spinal MRI, cerebrospinal fluid (CSF) pleocytosis and/or elevated immunoglobulin-G (IgG) index (11). If none of the inflammatory criteria are met at symptom onset, MRI and lumbar puncture evaluation should be repeated between 2 and 7 d following symptom onset. IgG synthesis rate is a less specific indicator of CNS inflammation than is CSF IgG index (14,15) and should not be used in diagnosis. Vascular myelopathies can be differentiated from TM by a progression of symptoms to maximal severity in less than 4 h and the lack of inflammation as defined above; however, these criteria do not completely distinguish vascular myelopathies from TM, because myelopathies associated with venous infarcts or vascular malformations may progress more slowly and may meet the other criteria for TM. Differentiating idiopathic TM from TM attributed to an underlying disease is also impor- tant. Many systemic inflammatory disorders (e.g., sarcoidosis, SLE, Behçet’s disease, Sjögren’s 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 Transverse Myelitis 219 regarding the presence of rashes, night sweats, oral or genital ulcers, sicca symptoms, short- ness of breath, pleuritic pain, and hematuria. Examination should attempt to detect the pres- ence of uveitis or retinitis, decreased lacrimation or salivation, skin rash (malar, livedo reticularis, erythema nodosum), oral or genital ulcers, adenopathy, pleuritic or pericardial fric- tion rub, and organomegaly. Laboratory studies should include a complete blood count with differential and smear, antinuclear antibodies (ANA), SS-A, SS-B, erythrocyte sedimenta- tion rate , and complement. Additional laboratory testing may be required if signs of systemic vasculitis are detected. From this evaluation, it may be possible to distinguish idiopathic TM from disease-associ- ated TM (i.e., TM associated with multifocal CNS disease or systemic inflammatory disease). This distinction is important because patients at high risk of developing MS may be evaluated more closely or may be offered immunomodulatory treatment (16). Similarly, patients with disease-associated TM may need to be closely followed for recurrent systemic and neurological complications and should be offered immunosuppressive treatment to decrease the risk of recurrence. 3. CLINICAL MANIFESTATIONS OF TM 3.1.Epidemiology TM affects individuals of all ages with bimodal peaks between the ages of 10 and 19 yr and 30 and 39 yr (2–5). There are approx 1400 new cases diagnosed in the United States each year, and approx 34,000 people have chronic morbidity from TM at any given time. About 28% of reported TM cases are in children (JHTMC case series). There is no gender or familial predis- position 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 wk of the onset of the disorder (17,18,JHTMC). Thirty percent of pediatric TM cases referred to an academic center had a history of an immunization with 1 mo of the onset of symptoms (JHTMC case series). Although a history of an immunization preceding the onset of TM is commonly reported, there is insufficient information about the relationship between immunization and TM. 3.2.Clinical Symptoms TM is characterized clinically by acute or subacute signs of neurological 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 and occasionally progresses to involve the arms. Flaccidity may be noted initially with gradually appearing pyramidal signs by the second