40

Transverse Myelitis

Isabella Strozzi and Michael Levy

INTRODUCTION

TM is a rare neuro-immune disease characterized by focal inflammation of the spinal cord, leading to acute or subacute onset of motor, and sensory and/or autonomic dysfunction (1). TM may occur independently or as a component of other diseases, such as MS, NMO, infections, and vasculitic disorders.

Descriptions of this disease have been present since 1882, initially mentioned as “acute myelitis” by British neurologist Henry Charlton Bastion in the section of Diseases of Spinal Cord of Quain’s Dictionary of Medicine (2) and later on with a series of cases of “softening” of the spinal cord caused by either inflammation or vascular events, such as thrombosis (3). Other authors in the early 1900s published accounts of infectious, postinfectious, and postvaccine etiologies of acute 373myelitis (4,5). The actual term “acute transverse myelitis” was first used in 1948, in a case report of pneumonia evolving to weakness and loss of sensation of lower limbs with urinary retention (6). Other names used to refer to this disease were “acute myelomalacia” and “acute necrotic myelopathy” among others (7,8). Since 1953, the term “transverse myelopathy” has been ascribed to focal spinal cord lesions of multiple etiologies (9), whereas “transverse myelitis” is reserved for those attributed to inflammatory disease.

The most recent criteria for diagnosis of TM were proposed by the Transverse Myelitis Consortium Working Group, as described in Table 40.1. A diagnosis of idiopathic, monophasic acute TM requires the fulfilment of every inclusion criteria and none of the exclusion criteria. Conversely, for disease-associated TM, a patient must meet all of the inclusion and one of the exclusion criteria (1). The application of these proposed criteria has been validated by other groups; however, about a third of patients do not show confirmatory evidence of inflammation by CSF analysis or gadolinium enhancement on MRI (10). Some authors propose that when these signs are not present at symptom onset, patients should be reevaluated after 2 to 7 days to determine if these criteria are fulfilled (8).

TABLE 40.1    Diagnostic Criteria for Idiopathic Acute Transverse Myelitis

CSF, cerebrospinal fluid; HTLV-1, human T-lymphotropic virus, type 1; MS, multiple sclerosis.

^aDiagnosis is still considered possible if patient meets all the inclusion criteria except for inflammatory findings in CSF analysis or spinal cord MRI.

Source: Adapted from Table 1 in Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002;59:499-505 and http://n.neurology.org/content/59/4/499.long.

EPIDEMIOLOGY

Incidence of acute TM is reported at 1.34 to 4.6 new cases per million annually (11). This incidence increases to 24.6 per million per year within populations with acquired demyelinating diseases such as MS (12). It is estimated that there are about 1,400 new cases in the United States every year (13) and 300 new cases per year in the United Kingdom (14). In children, the incidence is lower, at 0.4 per million per year (11). Out of all cases of TM, about 21% are of idiopathic etiology (15).

Although there are no records of incidence of TM by state, the Transverse Myelitis Association conducted an informal survey among its members from 1997 to 2001. They included 454 U.S. residents in their sample, distributed through the states as shown in Figure 40.1, where each state is colored according to the number of patients per 1,000,000 inhabitants. They did not find any difference among the states through statistical testing (16). Currently, there is no evidence of hereditary or ethnic predisposition for acute TM (17).

Although the disease affects individuals of any age, there is a bimodal distribution with peaks at 15 to 19 years and between 30 and 39 years (1,11,18), and about 20% of patients are under 18 years old (19). There also appears to be a peak within the pediatric patient group before the age of 3 (19). Through the same survey mentioned earlier, the Transverse Myelitis Association gathered information on the age at onset of TM patients based on the United States. The data are presented in Figure 40.2.

There are some reports of a slight predominance of the female sex, from 1.9:1 to 2.6:1 female/male ratio although not as pronounced as other autoimmune diseases (11,20–22), whereas other sources affirm there is no sex predominance in this disease (1,19). In the published literature, there is no difference in incidence among ethnic groups (13).

PATHOPHYSIOLOGY

The mechanism of TM, although still unknown, is presumed to be an immune-mediated attack of the spinal cord. This is based on inflammatory signs in the CSF, such as lymphocytosis and elevated IgG index, and gadolinium enhancement by MRI which suggests breakdown of the blood–brain barrier of the spinal cord (23). One theory proposes that there is molecular mimicry and consequently stimulation of T cells and autoantibodies involved, similar to the pathogenesis of Guillain–Barré syndrome (23). Another theory involves the overactivation of lymphocytes by nonspecific superantigens (23).

Much of the speculation around the pathophysiology of TM comes from related diseases, such as MS and NMO, and animal models, particularly with experimental autoimmune encephalomyelitis (EAE). In EAE, mice are injected with a myelin antigen that causes the animal’s immune system to react against its own central nervous system (CNS), reproducing some of the features of MS or TM. Myelin antigens that are used include myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG) (24). These antigens stimulate the proliferation and invasion of CD4⁺ T cells and macrophages, which consequently promote an immune response within the CNS. The role of B cells is still unclear, although there are higher circulating levels in EAE induced by anti-MOG antibodies (24).

Pathology of TM depends on the etiology, stratified by the type of lesion: demyelinating, necrotizing, or a mass lesion. Common causes for each category are listed in Table 40.2.

Demyelinating lesions are seen in animal models and autopsy from patients with TM through Luxol fast blue staining, combined with Cresyl violet acetate (see Figure 40.3), solochrome cyanin, black gold staining, or immunofluorescence through anti-MBP antibodies (26–28). Loss of myelin is typically accompanied by lymphocytic infiltration, axonal degeneration, edema, and gliosis (29).

375TABLE 40.2    Types of Spinal Cord Pathology in TM

ADEM, acute disseminated encephalomyelitis; HTLV-1, human T-lymphotropic virus, type 1; JC, John Cunningham; TM, transverse myelitis.

Most common causes are in bold.

Source: Adapted from Table 6.4 found in Levy M, Kerr DA. Transverse myelitis. In Dale RC, Vincent A, eds. Inflammatory and Autoimmune Disorders of the Nervous System in Children. London, UK: Mac Keith Press; 2010:97–107. (25)

Studies have shown increased interleukin 6 (IL-6) levels within the CSF and correlation between markedly elevated IL-6 levels with worsening neurological disability. IL-6, synthesized mainly by astrocytes in response to inflammatory cytokines, may worsen spinal cord demyelination and axonal degeneration by activating the Janus kinase (JAK)/Signal Transducer and Activator of Transcription proteins (STAT) pathway and increasing inducible nitric oxide synthase (iNOS) activity. This results in high nitric oxide levels and free-radical production, causing cell membrane discontinuity and altered neurotransmitter production (30). It is also suggested that IL-17 might induce focal inflammation through the production of IL-6 (31).

ANATOMICAL AND CLINICAL FEATURES

Signs and symptoms of TM are diverse since they are determined by the location of the lesion within the spinal cord (see Table 40.3). In both adult and pediatric populations, the most common levels affected are from T7 to T12 (50 – 85), followed by the cervical region, and the lumbar spine is mostly preserved (8,18,19,21,32). Although this disease is called “transverse” myelitis, it does not necessarily affect the whole width of the spinal cord and may also involve more than one vertebral segment. In fact, some studies show that the median range of spinal involvement is 1.6 to 2 vertebral segments, ranging from zero to eight (33,34).

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