Isabella Strozzi and Michael Levy
KEY POINTS FOR CLINICIANS
• Incidence of acute transverse myelitis (TM) is reported at 1.34 to 4.6 new cases per million annually. It is estimated that there are about 1,400 new cases in the United States every year. Around 21% of all cases of TM are idiopathic. Other causes include multiple sclerosis (MS), neuromyelitis optica (NMO), and vascular lesions.
• The mechanism of TM, although still unknown, is presumed to be an immune-mediated attack of the spinal cord.
• Patients with TM usually present with paresis of the lower limbs that progresses from flaccid to spastic. Sensory deficits are typically loss of pain and temperature in the level of lesion and hyperesthesia in upper segments. Patients also commonly report preceding symptoms of infection and back pain.
• Diagnosis of TM begins with a comprehensive history and neurological exam, but it must be confirmed by MRI with gadolinium contrast, ideally within the first hours of presentation, and analysis of cerebrospinal fluid (CSF) cell count, oligoclonal bands (OCBs), and immunoglobulin G (IgG) index.
• Differential diagnoses include spinal cord trauma or compression, subacute combined degeneration (vitamin B12 deficiency), neurosyphilis, anterior spinal artery insufficiency, progressive MS, hereditary spastic paraplegia, and radiation myelitis.
• The first-line treatment for TM attacks is the administration of high-dose intravenous methylprednisolone. Plasma exchange is usually offered for patients with more severe presentations of TM or if the disease is unresponsive to steroid therapy.
• Classically, it is considered that about one-third of patients have a good outcome, another third has a fair outcome, and the other third have poor prognosis. Poor outcome is associated with back pain in adults, spinal shock, severe neurological deficits, longer duration of acute phase, and shorter interval between symptom onset and its peak.
• Recurrence of idiopathic TM varies in different international studies from 24% to 61%.
• Currently, mortality is around 5% to 10% and is more common in younger children or older adults, and with high cervical lesions, sepsis, respiratory failure, and pulmonary embolism.
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).
• Development of sensory, motor, or autonomic dysfunction attributable to the spinal cord
• History of previous radiation to the spine within the last 10 y
• Bilateral signs and/or symptoms (though not necessarily symmetric)
• Clear arterial distribution clinical deficit consistent with thrombosis of the anterior spinal artery
• Clearly defined sensory level
• Abnormal flow voids on the surface of the spinal cord
• Exclusion of extra-axial compressive etiology by MRI or myelography (CT of spine is NOT adequate)
• Serologic or clinical evidence of connective tissue disease
• Inflammation within the spinal cord demonstrated by CSF or MRI findingsa
• CNS manifestations of syphilis, Lyme disease, HIV, HTLV-1, Mycoplasma or other viral infections
• Progression to nadir between 4 hr and 21 d following the onset of symptoms
• Brain MRI abnormalities suggestive of MS
• History of clinically apparent optic neuritis
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 n.neurology.org/content/59/4/499.long.
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).
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).
TM, transverse myelitis.
Source: Created based on data found in siegel S, Wang D. The TMA study of transverse myelitis. J For TR Myelitis Assoc. 2001;4(2):24–29.
TM, transverse myelitis.
Source: Created based on data found in Siegel S, Wang D. The TMA study of transverse myelitis. J TR Myelitis Assoc. 2001;4(2):24–29.
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).
TYPE OF LESION
Demyelinating (most common)
• Multiple sclerosis
• Idiopathic transverse myelitis
• HIV vacuolar myelopathy
• Tropical spastic paraparesis (HTLV-1)
• Progressive multifocal leukoencephalopathy (JC virus)
• Systemic lupus erythematosus
• Sjögren’s syndrome
• Enteroviral infection
• Behçet’s disease
• Mixed connective tissue disorder
• Lyme disease
• Other viral infections (e.g., varicellazoster virus, cytomegalovirus, Epstein–Barr virus, West Nile virus, Coxsackievirus)
• Neuromyelitis optica
• Herpes simplex virus acute necrotizing myelitis
• Progressive necrotic myelopathy
• Bacterial abscess
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).
Source: Adapted from Figure 3 in Cox A, Coles A, Antoun N, et al. Recurrent myelitis and optic neuritis in a 29-year-old woman. Lancet Neurol. 2005;4(8):510–516. doi:10.1016/S1474-4422(05)70143-5.