Neuroimmunology
Autoantibodies: mechanism and testing
Dec. 20, 2024
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Transverse myelitis …
- Updated 06.19.2024
- Released 05.08.1995
- Expires For CME 06.19.2027
Transverse myelitis
Introduction
Overview
Transverse myelitis is inflammation spanning both sides of at least one segment of the spinal cord. The inflammation injures the myelin that protects the nerve fibers. There are multiple etiologies for transverse myelitis. In this updated article, the author describes new developments in the diagnosis of subgroups of myelitis caused by myelin oligodendrocyte glycoprotein (MOG)-Ab and its comparison to multiple sclerosis and neuromyelitis optica.
Key points
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• Acute transverse myelitis, as defined here, is idiopathic. It excludes other forms of myelitis such as myelin oligodendrocyte glycoprotein-associated disease (MOGAD), neuromyelitis optica (NMO, Devic disease), multiple sclerosis, postinfectious and postvaccinal myelitis, etc. | |
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• Cord symptoms evolve over hours to days and then typically resolve over several weeks or months. | |
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• The pathology in the spinal cord is similar to lesions in multiple sclerosis, but only 40% will develop multiple sclerosis. | |
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• Cord lesions in MOGAD, NMO, and CNS Sjögren disease are longitudinal, down the center of the cord; in multiple sclerosis the lesions are shorter and acentric. | |
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• High-dose glucocorticosteroids hasten recovery from an attack but may have no long-term benefit. |
Historical note and terminology
Transverse lesions of the spinal cord were historically ascribed to thrombosis from arteriosclerosis, syphilis, and other infections (ie, Bastian in the 1880s) (49), and this concept persisted well into the next century. Foix and Alajouanine believed that transverse myelitis had a vascular etiology (48). They described two patients with subacute necrosis in the sacral or thoracolumbosacral cord associated with massive dilatation and endomysial hypertrophy of the extramedullary veins and similar but less marked changes in the intramedullary vessels. The lumens were not obliterated, and the arteries were not involved. The term "angiodysgenetic necrotizing myelopathy" is sometimes applied to this condition (49). A similar syndrome is believed to be caused by spinal dural arteriovenous fistulae (110). Paine and Byers were the first to report a large clinical series with follow-up exams and used the term “transverse myelopathy” (125). They postulated a vascular cause but presented no pathological evidence. In most of these early reports, one or two patients were studied, and the autopsies were performed months to years after the original illness (72).
Several large series describing idiopathic transverse myelitis appeared in the 1960s and 1970s and seldom showed vascular alterations (03; 101; 142; 18). Some assumed the condition was an inflammatory myelitis from an antigen-antibody reaction (133) or a hypersensitivity reaction to infection or vaccination (115). A consensus evolved that acute transverse myelitis was an inflammatory demyelinating disease of the cord. It sometimes followed infections but usually had no antecedent. In a series of 33 cases of acute or subacute noncompressive myelopathy, 46% were parainfectious, 12% were associated with cord ischemia, 21% were multiple sclerosis exacerbations, and 21% were idiopathic (75).
Acute transverse myelitis, as defined here, is an idiopathic disorder caused by inflammation of the spinal cord, associated with marked demyelination and often with significant axonal loss. The specific process that instigates the inflammation in transverse myelitis is unknown. (This includes the third of transverse myelitis patients with antecedent virus infections.)
Diagnostic criteria for transverse myelitis include (1) neurologic symptoms attributable solely to the spinal cord, negative brain MRI, and no clinical brain symptoms; (2) bilateral signs or symptoms; (3) clearly defined sensory level; (4) MRI exclusion of compression; (5) inflammation in the spinal cord (CSF white cells or elevated IgG index, or MRI gadolinium enhancement) seen within seven days of onset; (6) progressive worsening with maxima from 4 hours to 21 days after onset; and (7) no other etiology such as infection, neoplasm, compressive, trauma, embolus, degeneration, or vitamin deficiency (166). With these strict criteria, only 16% of 288 patients with acute transverse myelitis from all causes have idiopathic acute transverse myelitis (37). Scott and colleagues counter that inflammation is less severe in transverse myelitis than in multiple sclerosis and, thus, inflammation should not be used as a criterion (153). Acute transverse myelitis can be split into complete or partial transverse myelitis, each with a different outcome (150).
These definitions are undergoing revision. Subsets of transverse myelitis are now associated with antibodies against myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (“NMO-IgG”; neuromyelitis optica [NMO], Devic disease), partially overlapping with Sjögren disease (73). These differ markedly from multiple sclerosis. Unfortunately, many of the classic treatises on idiopathic transverse myelitis likely included patients with these disorders.
Clinical manifestations
Presentation and course
Symptoms of transverse myelitis evolve over hours or sometimes over a week or two, but rarely develop within minutes or stutter over a month (101; 142; 42; 166; 24). Before the onset of neurologic dysfunction, there can be nonspecific complaints such as fever or muscle aches. Although the clinical signs are bilateral (ie, from "transverse" or horizontal cord lesions), there is usually also longitudinal expansion of cord pathology. Ascending centripetal symptoms are presumably from a lesion expanding both rostrally and caudally. In theory, lesions spreading from the meninges inward through somatotopic layers of the long tracts could cause ascending symptoms, but this is unlikely because peripheral cord tracts are preserved compared to deeper fibers.
Complete transverse myelitis (the main subject of this article) and partial transverse myelitis differ. The spinal cord damage in acute complete transverse myelitis generally affects all cord functions, and the symptoms are typically more severe than in the patchy cord lesions of multiple sclerosis. Acute partial cord lesions often associated with multiple sclerosis cause unilateral or markedly asymmetric bilateral sensory and motor dysfunction, a Brown-Sequard syndrome (108; 50; 153; 150).
The first symptoms in transverse myelitis are ascending paresthesias or back pain at the level of the myelitis, plus leg weakness and sphincter dysfunction (03; 142; 42). Tingling or paresthesias in the feet soon progress to loss of pain, temperature, and vibration sensation, and then halt at a sensory level (approximately 80% are at T7). There is an encircling band of hyperesthesia at the dermatome right above the sensory loss in one third of cases. A unilateral of bilateral “MS hug” can be amplified by thoracic flexion, a thoracic crunch sign (136). Cervical levels are less commonly involved. There may be a dermatomal band of hyperesthesia two or three segments more rostrally, and pain is often interscapular. Chronic truncal pain can occur. Ninety-two percent of patients with neurogenic pruritus have pruritus within the dermatome innervated by the involved spinal cord area (64). Weakness is usually flaccid at onset ("spinal shock"). In two thirds of cases, weakness is severe, with inability to walk, and often evolves to total leg paralysis and spasticity. The arms are weak in one fourth of cases, occasionally before the legs. Deep tendon reflexes later become brisk. Tonic spasms can occur; late spinal dystonia has been reported. Five percent of patients have respiratory weakness. Damage to autonomic pathways can cause a sweat level, adynamic ileus, anorgasmia, paroxysms of hypertension and sweating or poikilothermia, autonomic dysreflexia with paroxysms of sympathetic output due to renal denervation, myocardial ischemia, and orthostatic hypotension, especially with higher level lesions. Association with acute motor axonal neuropathy has appeared several times and can be preceded by a thoracic sensory band/hug. Bladder and bowel function is frequently lost and is often heralded by urinary retention and anogenital sensory loss. Fifty eight percent of children had acute bladder retention requiring chronic intermittent cauterization (61). Forty two percent of those affected still required catheterization at 10 years.
Symptoms typically begin to resolve in 2 to 17 days, and recovery can be complete (42). The rate of resolution is most marked in the first few weeks after the symptoms have crested. Improvement is fastest in the first three months after disease onset but can continue for several years.
Recurrent transverse myelitis, without evidence of multiple sclerosis and with negative brain MRI and CSF studies, is considered to be rare (164). Recurrences range from 6% to 69%, depending on the reporting era, ethnic composition, and contamination by neuromyelitis optica cases. Recurrent myelitis is associated with brucellosis and hepatitis C infection and neuromyelitis optica (57). Risk of recurrence increases with African ancestry, female sex, high CSF IgG index, oligoclonal bands, and low vitamin D levels.
Prognosis and complications
The sequelae of transverse myelitis are variable, even after severe paralysis. One third recover completely, one third do not improve from their nadir, and one third have residual symptoms (101; 142; 18; 42). Some patients have lasting motor, sensory, or urologic complaints. Persistent genitourinary symptoms include detrusor hyperreflexia, detrusor-external sphincter dyssynergia, and erectile dysfunction (16). Patients with multiple sclerosis-like acute partial myelitis have a better short-term prognosis and are more likely to recover than patients with acute complete transverse myelitis. Recurrences are unusual in acute transverse myelitis compared to multiple sclerosis (164; 75).
Bad prognostic indicators include catastrophic onset, severe weakness, initial lancinating pain, sensory disturbance at cervical levels, spinal shock, incontinence, no recovery after three months, long cord lesions, and presence of 14-3-3 protein in the CSF (71). Pain is more common in neuromyelitis optica. Favorable prognostic signs include subacute progression of sensory or motor symptoms over days or weeks, youth, retention of posterior column function and deep tendon reflexes, and early recovery (101; 142). In addition, the chance of recovery is poor when somatosensory evoked potentials show a conduction block, but good when somatosensory evoked potentials are normal or only slightly delayed (171; 78). CSF cells or protein do not predict outcome (03; 142).
Children comprise 20% of total cases of acute transverse myelitis (162). Paresthesias are less common, and recovery is more frequent than in adults (125; 42). Fifty-eight percent have pain, 28% motor symptoms, and 11% numbness; 61% had T2 MRI brain lesions (163). In 27 children with non-Devic acute transverse myelitis, lesions were in the center of the cord, with a median length of five segments. Forty-three percent had swelling. Recurrences were only 6% over five years. Cognition is normal. In 50 Japanese children, younger patients and those with hypotonia had a worse prognosis (113). Also ominous were need for respiratory support and high cord lesions (19). Many of these children (62%) had residual deficits. This contrasts with other studies with good functional outcomes in 50% to 62% (125), and 62% of children with myelitis (42).
The frequency of developing multiple sclerosis after transverse myelitis ranges from 0% to 45% in multiple large studies from 1963 to 2013: 0% over 6.5 years (35), 1% over 15 years (18), 5% over 8 years in children from Chongqing, China (27), 6% over 5 years (03), 3% after 5 years (101), 3% over 6 years (05), or 8% to 14% after an average of 5 years (142), 13% over 4.5 years—four fifths had brain lesions at presentation (163), 29% over 5 years (131), 40% of 20 patients over 12 to 30 months (33), or 45% over 6 years (34). The second attack, ie, multiple sclerosis, is most likely to occur within one year and unlikely if two years have passed (131).
Acute complete transverse myelitis, with short, acentric, asymmetric lesions evolves to multiple sclerosis more frequently than with long central lesions (153). Partial cord lesions with negative MRI will evolve to multiple sclerosis in 2% to 25%, partial myelitis with multiple sclerosis-like brain lesions evolves to multiple sclerosis in 44% to 85% (150; 131; 154). Compared to patients with partial cord lesions, those with complete transverse myelitis have fewer oligoclonal bands, relapses, and multiple sclerosis. In contrast, partial cervical myelopathy and transverse myelitis without initial brain MRI lesions often evolves into clinically definite multiple sclerosis, especially if evoked potentials and CSF are abnormal (14; 131).
The following features increase the risk of developing multiple sclerosis: (1) partial, rather than complete, transverse myelopathy and more than one cord lesion; (2) cranial MRI suggestive of multiple sclerosis after a transverse myelopathy; (3) CSF IgG or IgM oligoclonal bands; (4) abnormal visual or sensory evoked potentials (less helpful than MRI); (5) HLA-DR2 positive (14); and (6) family history of multiple sclerosis.
Unilateral patchy cord lesions are an entity separate from acute complete transverse myelitis. Over three years, 60% to 80% of patients with acute partial myelitis developed multiple sclerosis (108; 50; 32). Other predictors of multiple sclerosis in acute partial transverse myelitis include Black Afro-American descent, initial sensory symptoms, lateral-posterior lesions, Gd-positive cord lesions, abnormal brain MRI, and positive CSF oligoclonal bands.
In established multiple sclerosis, superimposed acute transverse myelitis appears is associated with later onset and optic neuritis, but with fewer brainstem, cerebral, or cerebellar symptoms and fewer MRI lesions (51). (Note: These are Japanese patients. A Devic-like syndrome is more common in Japanese than in European patients.) In another series, 15 out of 16 multiple sclerosis patients with acute myelopathy had asymmetric motor or sensory symptoms, but 19 out of 20 with acute transverse myelopathy had weakness and sensory symptoms (151).
Clinical vignette
A 30-year-old marathon runner and commodities broker developed a minor “cold,” and 10 days later noticed tingling in the middle of his trunk. The tingling was soon followed by paresthesias in his feet and then loss of sensation from below the mid-thoracic level with a 4 cm hyperesthetic band above. In conjunction, he developed profound weakness of both legs and urinary retention. He had no symptoms above the thoracic level. MRI scan of the brain was normal, but a spinal cord MRI showed swelling and diffuse abnormal T2 signal from the T-5 to the T-10 level. Spinal fluid had protein of 113 mg/100 ml, glucose of 66 mg/100 ml, 65 lymphocytes/mm3, and no oligoclonal bands. He refused therapy with glucocorticoids.
The symptoms lasted for three weeks and then began to resolve. Over the next two years, muscle strength gradually returned. He reported that improvements in a given muscle group were often heralded by muscle cramping and aches. At two years, sensation and bladder function was essentially normal, and he was running four miles per day.
Biological basis
Etiology and pathogenesis
Two thirds of acute transverse myelitis episodes are idiopathic. Virus infections trigger one third of the cases in adults and at least half of the cases in children (101; 18; 113; 163). Transverse myelitis typically develops 3 to 15 days after an upper respiratory infection (125; 109; 75; 90). There are occasional case reports of transverse myelitis following various immunizations, but a true disease association is not evident in controlled studies (below).
A virus could cause transverse myelitis through: (1) direct damage to parenchymal cells (eg, subacute sclerosing panencephalitis and possibly AIDS myelopathy); (2) a "bystander effect" damaging the cord during an immune response against the virus, or from release of virus-induced cytokines or superantigens that activate immune cells (eg, heat shock protein from mycoplasma); and (3) sensitization of the host to brain antigens during an inflammatory response, eg, release of damaged myelin (processed by antigen-presenting cells) or cross-reactivity between virus and myelin antigens. Examples of the latter include postinfectious encephalomyelitis (95) and postvaccinal encephalomyelitis, especially following rabies vaccination containing duck embryo CNS components. Viruses trigger most episodes of acute disseminated encephalomyelitis, which is an autoimmune, delayed-type hypersensitivity response against brain antigens. Postinfectious myelitis after measles infection is a clear host response to myelin basic protein, even when the virus is no longer present in the brain (76). Virus infections precede one third of multiple sclerosis relapses (127) and one third of episodes of transverse myelitis. The mechanism of the viral association with multiple sclerosis relapses is unknown and likely complex. Viruses vary hugely in their antigen composition, immune escape mechanisms, and cytokine induction.
Mycoplasma pneumoniae and, occasionally, pulmonary tuberculosis or Borrelia trigger acute transverse myelitis (90). Mycoplasma suppresses T cell function and can cause thrombosis, and also induces interferons and polyclonal B cell activation with antibodies to gangliosides (02), leading to anti-brain immune responses. The molecular mimicry between Campylobacter jejuni surface lipo-oligosaccharides and human gangliosides in the peripheral nervous system induce a cross-reactive immune response to cause Guillain-Barre syndrome. Cross-reactivity is less common in the central nervous system, but there are cases of transverse myelitis after Campylobacter jejuni enteritis with associated antiganglioside antibodies (102). Childhood acute transverse myelitis can coincide with positive anti-ganglioside GM1 antibodies (79).
In acute transverse myelitis, myelin loss exceeds axonal loss, but axons are usually destroyed along with the demyelination, and secondary demyelination may also result. In severe transverse myelitis, the lesions can be cavitary.
The pathological hallmark of transverse myelitis is the presence of lymphocytes and monocytes, plus astroglial and microglial activation in the spinal cord, with varying degrees of both axonal injury and demyelination. In transverse myelitis, monocytes spread out from veins, lymphocytes infiltrate focal areas of the cord, and astrocytes and microglia are activated. The pattern of spread is difficult to discern based on autopsy findings, but at autopsy and on MRI there is relative preservation of subpial parenchyma. In some cases of transverse myelitis, polymorphonuclear leukocytes and lymphocytes infiltrate the meninges, and macrophages infiltrate the parenchyma.
Scattered lesions are less common and suggest multiple sclerosis, where many axons are usually preserved, and the lesions are scattered (primary demyelination). MRI lesions in acute idiopathic transverse myelitis are bilateral, somewhat symmetrical, and typically central, with relative preservation of tissue at the periphery; in multiple sclerosis, lesions often begin at the pial surface. Partial cord lesions, or transverse myelitis plus scattered CNS lesions on MRI, frequently evolve into multiple sclerosis or are exacerbations of established multiple sclerosis.
Related syndromes show somewhat distinct pathology. In multiple sclerosis, lesions are recurrent and have different distributions. In acute disseminated encephalomyelitis and associated conditions (perivenous encephalomyelitis and postinfectious and postvaccinal encephalomyelitis), there is widespread perivenous lymphocytic-histiocytic inflammation, mostly within the white matter. There are small foci of demyelination (0.1 to 1 mm), but the contiguous demyelination of acute transverse myelitis is not seen (04).
Acute hemorrhagic leukoencephalitis, progressive necrotizing myelopathy, and Devic disease are often necrotizing. The clinical course, the histology, serum markers, and dissemination of lesions in space and time all differ.
Paraneoplastic necrotizing myelitis is acute or subacute. It causes a necrotic "carcinotoxic myelodegeneration," with patchy bilateral destruction of myelin, axons, and neurons. Necrosis is massive and hemorrhagic. Inflammation is mild. The blood vessel walls are thickened and sometimes contain fibrin thrombi (123).
ICSF IL-6 is elevated 300-fold in idiopathic transverse myelitis compared to mixed neurologic controls (80). IL-6 is secreted by astrocytes, and to a lesser extent by microglia. It binds to oligodendroglia and axons and also induces more IL-6 production by astrocytes. High levels of IL-6 in the spinal cord directly cause death and dysfunction of CNS cells, and induce nitric oxide synthetase in microglia, which elevates toxic nitric oxide. Brain cells are spared, in contrast, and low IL-6 doses are actually neuroprotective, possibly because the brain has higher levels of the soluble IL-6 receptor that blocks IL-6 toxicity (80). IL-6 is increased in CSF in multiple sclerosis and inflammatory neurologic diseases (104), along with IL-8, IL-10, and matrix metalloproteases-2 and -9. IL-6 and IL-17 are secreted by peripheral blood cells at high levels in transverse myelitis (55); cases of neuromyelitis optica may be included in this paper.
High IL-6 levels correlate with sustained clinical disability. IL-6 and other cytokines induced by interferon beta could enhance spasticity, especially in patients with preexisting cord lesions (20). In parallel, interferon-induced IL-6 levels correlate with fever (116). Interferon-beta also induces other members of the IL-6 superfamily, such as neurotrophic leukemia inhibitory factor and neuroprotective LIF (22). An “inverted U” effect of IL-6 induced by inflammation or interferon-beta could cause spinal cord repair, dysfunction, or damage depending on local IL-6 levels.
B cells are expanded in the blood and CSF in transverse myelitis. There is extensive editing of immunoglobulins in multiple sclerosis and in transverse myelitis, but not in optic neuritis, suggesting ongoing immune responses (99).
Epidemiology
The age at onset is typically in the mid-teens to the mid-40s. There is no seasonal variation. The annual incidence of transverse myelitis is 0.46 in 100,000 in the United States (75), at least 2.46 in New Zealand (175), and 0.13 in 100,000 in Israel (18). Ashkenazi (European-American born) and Sephardic (Afro-Asian) Jews born outside of Israel have an identical risk of developing transverse myelitis, but birth in Israel halves the eventual risk (18). Black African and Eastern Asian ancestry predispose to a Devic-like picture, with more frequent myelitis and more disability than with the Western form of multiple sclerosis.
Prevention
If upper respiratory tract infections could be avoided, perhaps one third of all cases of transverse myelitis would be prevented. For this reason, influenza vaccinations are reasonable prophylactic measures for transverse myelitis and multiple sclerosis. Sunlight and vitamin D prevent multiple sclerosis. Vitamin D enhances type I interferon function and perhaps prevents virus infections (45). Smoking and obesity provoke multiple sclerosis. Idiopathic transverse myelitis may be similarly affected by these modifiable risk factors.
Differential diagnosis
Confusing conditions
Transverse myelitis can be recurrent; other diseases also cause recurrent cord symptoms. These include hepatitis B with high-titer surface antigen (HBS Ag), systemic lupus erythematosus, antiphospholipid antibody syndrome, and other connective tissue disease (164; 100; 155; 126; 77). Recurrent transverse myelitis has been seen in Sjögren syndrome (see below) and in anti-Ro (SSA) and antinuclear antibody-positive patients.
Many processes can cause an acute transverse myelopathy and therapy differs (166; 97; 44).
Diseases causing transverse myelopathy include the following:
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• Abscess of the spinal cord. Intramedullary or epidural abscesses cause fever, systemic signs of infection, local pain, and neurologic deficits, and usually an enhancing MRI lesion. Agents are usually Staphylococcus aureus (36), and also streptococci, and gram-negative bacteria, plus Candida, Aspergillus, and Blastomyces dermatitidis. | |
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• Acute disseminated encephalomyelitis, postvaccinal encephalomyelitis, and postinfectious encephalomyelitis are monophasic. Transverse myelitis in children is more often purely sensory and areflexic; acute disseminated encephalomyelitis more often involves multiple cord segments and has more severe demyelination and sometimes necrosis (173). | |
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• Acute necrotizing hemorrhagic leukoencephalitis of Weston Hurst is a monophasic, possibly post-viral syndrome that affects the cord, hemispheres, and brainstem. It is usually seen in young adults, and occurs a few days after upper respiratory tract infection, occasionally after chickenpox or measles, and rarely after vaccination (rabies, smallpox) or drug exposure (arsphenamine, streptomycin, p-aminosalicylic acid, intra-arterial penicillin). The onset is explosive, with fever, peripheral leukocytosis, and hemispheral neurologic symptoms. Necrosis of the cord can cause spinal shock. There are mononuclear and polymorphonuclear leukocyte infiltrates in the cord, with fibrin deposition in blood vessels and demyelination around the vessels. Mononuclear cells appear first, followed by polymorphonuclear leukocytes. There are widespread perivascular cellular infiltrates, red blood cells in a ball and ring pattern, small perivascular hemorrhages, and necrosis, often to the point of liquefaction. The CSF contains elevated protein and up to 3000 mononuclear cells early on, and polymorphonuclear leukocytes later (65). | |
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• Acute flaccid paralysis in children is caused by enterovirus D68 affecting gray matter (see virus below). Children with acute flaccid myelitis (vs. transverse myelitis) are younger, and they have a prodromal illness, proximal weakness, and hyporeflexia, but fewer sensory, bowel, and bladder symptoms (66). They are more likely to have brainstem lesions on MRI. | |
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• Acute partial myelitis is more likely to progress to multiple sclerosis than complete transverse myelitis. | |
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• Adrenomyeloneuropathy or adrenoleukodystrophy, where variable MRI white matter abnormalities are seen in 14 of 16 patients (09). This hereditary myelopathy is slowly progressive and causes spastic paraparesis and loss of vibratory sense in the legs. | |
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• AIDS-related myelopathy (39). | |
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• Allogeneic hematopoietic cell (stem cell) transplant has induced acute transverse myelitis in three patients. Symptoms have paralleled what is possibly an immune-mediated pancytopenia, presumably causing immune dysregulation (130). | |
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• Amyloidosis, cerebral, shows MRI T2 white matter lesions, but iron on T2* images. | |
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• Ankylosing spondylitis can cause a cauda equina syndrome plus transverse myelitis. | |
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• Arachnoiditis is usually more gradual in onset and often painful. | |
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• Asthma with Hopkins syndrome: flaccid paralysis of one or more limbs 4 to 7 days after an asthma attack. Anterior cord lesions in 1- to 12-year-old children with onset over 1 to 2 days are followed by permanent paralysis. CSF typically contains 20 lymphocytes and 20 polymorphonuclear neutrophils (69). | |
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• Atopic myelitis (idiopathic eosinophilic myelitis, hyperIgEaemic myelitis). In Japan and Korea, this is associated with high concentrations of IgE directed against mite antigens and eosinophilic infiltration of the cord (86; 174). Sensory symptoms have subacute onset, elevated eosinophils are elevated in blood, and extensive multi-segmental, usually thoracic, lesions enhance at the cord margins (174). CSF is usually normal. Steroids reduce symptoms. | |
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• Barbotage of the cord during surgery (historical), after repeated injection and withdrawal of spinal fluid; possibly a mechanism for myelitis associated with intrathecal drug delivery systems. | |
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• Bariatric surgery can cause malabsorption of vitamins and other nutrients and a slowly progressive myelopathy. | |
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• Behçet disease causes recurring aphthous stomatitis, genital ulceration, arthropathy, and uveitis, plus lesions in brainstem, basal ganglia, and occasional myelitis (in 10% of CNS Behçet disease; “bagel sign” with dark center on MRI). It may respond to type I interferon (117) or glucocorticoid therapy. Hughes-Stovin syndrome (HSS) is a lymphocytic vasculitis that is a forme fruste of Behçet disease that can cause transverse myelitis. | |
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• Biotinidase deficiency. | |
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• Cancer--see neoplastic. | |
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• Celiac disease—case reports. | |
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• Chemotherapy (CAR-T cell therapy, immune enhancer, and immune checkpoint inhibitors such as abatacept [anti-CTLA-4], atezolizumab [anti-PD-L1], ipilimumab/nivolumab, pembrolizumab) causes toxic myelopathy and inflammatory myelopathy. Many of these links are case reports. | |
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• Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). In addition to brainstem lesions, two thirds of patients have spinal cord lesions (160). | |
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• Compression of the spinal cord from abscess, ankylosing spondylitis, giant cell arteritis, epidural or subdural hematoma (spontaneous or after lumbar puncture or trauma), herniated disc, ossification of the ligamentum flavum, surfer myelopathy from prolonged back hyperextension, rheumatoid arthritis with cervical spondylosis or atlantoaxial dislocation, synovial cyst, tuberculoma, tumor, or T2 MRI lesions are common at the site of disc herniation (30% to 41%), where they can form an enhancing “pancake sign” at or right below the compression. Those without T1 lesions have better prognoses. Thirty-two percent to 52% of T2 lesions improve after surgery, some during surgery (159; 106). | |
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• Congenital and developmental defects (spina bifida, syrinx). | |
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• Connective tissue disease (lupoid sclerosis; lupus myelopathy; lupus myelitis). Transverse myelitis is seen with systemic lupus erythematous (SLE), especially in association with anticardiolipin and antiphospholipid antibodies; mixed connective tissue disease, periarteritis nodosa, primary biliary sclerosis, scleroderma and systemic sclerosis (sometimes with conus lesions), and Sjögren disease (65; 01; 13; 90; 91; 70; 176). Motor and sphincter dysfunction is typical in this spectrum, and outcome is poor. These diseases may cause recurrent longitudinal myelitis spanning several or many cord segments (96). With lupus, the sometimes devastating lesions are usually thoracic but are much less frequent than the small white matter brain lesions in 50%, seen on T2 MRI. Patients with SLE myelopathy are often females and African Americans, have elevated sedimentation rate and CSF IgG, and have longer hospital stays. Rituximab has been used successfully in lupus myelopathy and Sjögren myelopathy (73). | |
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• Sjögren disease is somewhat similar to lupus--CSF cell counts are sometimes more than 30 per ml, and oligoclonal bands are rare, but the large centromedullary lesions on MRI are usually in the cervical cord. CNS Sjögren lesions can be restricted to the cord (26). | |
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• Connective tissue disease linkage to cord demyelination (and associated autoimmune disease and organ-specific antibodies) has been clarified (74). Sjögren disease is usually defined by serologic tests (SSA and SSB). However, it is better detected with a clinical history of sicca biopsies of minor salivary gland of mouth) that show 4+/4 inflammation in minor salivary glands of the oral mucosa, even when serologic tests are negative. These patients have high serum interferon-alpha/beta levels and excessive response to interferon stimulation; both features are reduced in multiple sclerosis (44). Transverse myelitis has not been studied. Approximately 5% of transverse myelitis cases have NMO and CNS Sjögren disease. They respond to anti-CD20 therapy but are worsened with interferon or glatiramer therapy (74). | |
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• Copper deficiency, seen after gastric, colon, and bariatric surgery, is often associated with high zinc consumption and low plasma ceruloplasmin. Hypocupric myelopathy causes progressive cervical myelopathy with gait ataxia, leg spasticity, sensory ataxia from dorsal column dysfunction, occasional optic neuropathy, neutropenia, and microcytic anemia. Copper deficiency myelopathy is a human analogue of “swayback” in ruminants (92) and, possibly, cuprizone-induced demyelination. | |
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• Cytomegalovirus can cause a radiculomyelitis that evolves over days to weeks. | |
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• Decompression sickness (dysbarism). | |
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• Devic disease (neuromyelitis optica, NMO) may have initial cord lesions similar to acute idiopathic transverse myelitis. Axons and myelin are destroyed in the center of the cord; there is some preservation of subpial areas, but lesions are >3 segments long. In contrast to multiple sclerosis, in both Devic disease and transverse myelitis, the CSF contains elevated protein and tends to have transient or no oligoclonal bands. The optica component requires optic nerve involvement, abnormal visual evoked potentials, or a subsequent episode of optic neuritis. Optic nerve and cord involvement develops simultaneously or sequentially over months or years. It is not a form of multiple sclerosis, but a distinct variant with associated autoimmune features and excessive responses to interferon beta (44). | |
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• Recurrent myelitis is typical in neuromyelitis optica. A United Kingdom study on neuromyelitis optica found a subgroup of 20 patients with relapsing myelitis without optic nerve involvement that included fewer females, less disability, more oligoclonal bands, and smaller acentric cord lesions. NMO-IgG positivity is rare with short cord lesions in the United States; only one of 22 in acute partial transverse myelitis, but three of four in Devic disease, and none of six in multiple sclerosis (152). Thus, there may be three related entities that cause transverse myelitis: (1) pure relapsing transverse myelitis; (2) neuromyelitis optica with initial cord damage, but later optic nerve involvement and autoantibodies to aquaporin-4; and (3) a spinal variant of multiple sclerosis with longer lesions and positive CSF oligoclonal bands. Elevated CSF polymorphonuclear leukocytes in NMO suggests high levels of IL-17 and a different immune etiology than in idiopathic acute transverse myelitis. | |
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• Japanese had the “oriental form” of multiple sclerosis, four times more prevalent than the “Western form” 50 years ago (120). The ratio has now flipped to 1:2, suggesting environmental changes have altered forms of multiple sclerosis. Fifteen Korean patients with recurrent cord symptoms were often male, presented with acute transverse myelitis, and had normal CSF indices (87). The male predominance is unexpected in multiple sclerosis and NMO. Twenty of 32 Taiwanese patients with nonrecurrent transverse myelitis were evenly divided between women and men, with mean length of damage = 1.6 vertebral segments. The remaining 12 cases were recurrent. All were women and were later categorized as connective tissue disease (3), Devic variant (5), or idiopathic (3), with an average of 3.4 involved vertebral cord segments. | |
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• Neuromyelitis optica is marked by an antibody to aquaporin-4 on astrocyte foot processes (NMO-IgG) in 60% to 75% of cases; in multiple sclerosis, less than 10% were defined as antibody-positive (97); multiple sclerosis is now considered NMO-antibody-negative. Aquaporin-4 is the most abundant water-channel protein in the central nervous system. Other serum autoantibodies and other autoimmune diseases are frequent. Immunologically, there is more Th2 predominance, leading to the autoantibodies. | |
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• CSF oligoclonal bands are infrequently positive (approximately 25%) and disappear over time. NMO-IgG levels correlate with recurrent attacks. Some patients with CNS Sjögren disease and long cervical cord lesions are NMO-IgG negative | |
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• Fifteen percent of NMO-positive patients have short cord lesions; 92%, however, also develop longitudinal lesions (24). | |
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• Steroids and plasma exchange are used for the treatment of an acute attack. Therapy differs between multiple sclerosis (interferon-beta, glatiramer, natalizumab, S1P1 modulators, dimethylfumarate, and teriflunomide) and Devic disease. Approved drugs are anti-CD19, anti-IL-6, and anti-complement antibodies; other therapies include rituximab, mycophenolate mofetil, and cyclophosphamide. Interferon triggers exacerbations, especially in the CNS Sjögren variant characterized by high pretreatment serum interferon levels (44). | |
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• Diskitis can cause local pain (36). | |
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• Down syndrome with severe acute neuromyelitis optica may be linked to intrinsic Down abnormalities (23), such as hyperactive interferon responses. | |
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• Drugs. Based on clinical experience and the multiple sclerosis literature, there are theoretical reasons to avoid several drugs. Cimetidine, H2 blockers (07), and melatonin (31) enhance immune function. Beta-adrenergic blockers inhibit suppressor cell function (81). Fluoroquinolone antibiotics (ie, ciprofloxacin), which induce inflammatory cytokines, can worsen demyelinating disease (Reder, unpublished 1985-2023, and similar FDA black box warning for worsening inflammatory peripheral neuropathy). Sulfamethazine, used to treat pneumonia in the mid-1900s, was implicated, but pneumonia was the likely trigger. Cigarette smoking is probably a risk factor. | |
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• Therapeutic antibodies that modify immunity are occasionally associated with transverse myelitis, but rare reactions could be due to chance. Reports include efalizumab (anti-CD11a for psoriasis) and imatinib (protein-tyrosine kinase inhibitor for Philadelphia chromosome abnormality in chronic myeloid leukemia). Etanercept (TNF receptor-immunoglobulin fusion protein that blocks TNF) is associated with transverse myelitis and other demyelinating diseases. Discontinuation prevents recurrences (62). Anti-TNF-alpha agents create an imbalance between immune cell proliferation, regulation, and cell death, which can lead to a paradoxical activation of lymphocytes, macrophages, and microglia. This change in activation leads to inflammation and demyelination (139). | |
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• Some patients are extremely sensitive to low doses of carbamazepine (25 mg). It causes weakness, probably by blocking Na+ channels in demyelinated axons. | |
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• Epstein-Barr virus can cause an acute or subacute encephalomyeloradiculitis. | |
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• Fibrocartilaginous emboli. Retrograde flow of emboli from a herniated nucleus pulposus into the anterior spinal artery or spinal veins during straining causes an anterior spinal artery syndrome (170). There is back or neck pain but often no history of trauma, followed by sudden (minutes to hours) onset of weakness and incontinence. This is more common in women than men. It is associated with anterior cord lesions on MRI and anterior horn cell fallout on electrophysiological testing. Cord swelling on MRI is associated with a collapsed disc at the level of the cord deficit, usually in the cervical region (“pancake sign”) (165). The CSF is normal. There is no associated viral syndrome. Recovery is unlikely. | |
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• Foix-Alajouanine syndrome, subacute necrotic myelitis of presumed vascular etiology (48); angiodysgenetic myelomalacia. These may have been lupus myelopathy. | |
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• Fungal infections with mass effect or thrombosis (36). | |
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• Genetic disorders with myelopathy include Friedreich ataxia (cerebellar symptoms), hereditary spastic paraparesis (predominantly motor, with bladder and dorsal column damage), leukodystrophies, and adrenomyelopathy (myelopathy, sometimes with affected cognition, vision, hearing, and cerebellar symptoms). There is a case report of Leber hereditary optic neuropathy with extensive myelopathy resembling longitudinally extensive transverse myelitis (21). | |
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• Glial fibrillary acidic protein (GFAP) encephalopathy is an astrocytopathy. Fifty percent have longitudinal cord lesions. | |
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• Granulocyte-colony stimulating factor given for immune reconstitution after autologous non-myeloablative stem cell transplantation for lupus is linked to recurrent transverse myelitis with neutrophil infiltration in one case and is in association with irradiation and high-dose chemotherapy in two others. | |
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• Granulomatous meningomyelitis (eg, tuberculosis). | |
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• Guillain-Barré syndrome (acute ascending polyradiculopathy, acute inflammatory demyelinating polyradiculopathy), which is largely a peripheral nerve disease, is more likely to cause autonomic damage, arm paresis, lost deep tendon reflexes, and cranial nerve weakness. Concomitant transverse myelitis has been reported. | |
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• Hematomyelia and hemorrhage are associated with clotting deficiencies or trauma. | |
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• Heroin myelopathy (hypersensitivity) (138; 54; 58; 65; 43). Immune effects of opiates and generation of autoantibodies as part of this myelitis have not been evaluated. | |
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• Herpes simplex virus myeloradiculitis (lumbosacral and bladder symptoms are prominent; myelitis may be recurrent and associated with genital Herpes lesions). Transverse myelopathy is more common with HSV-1 (119); HSV-2 has an ascending pattern. Sacral radiculomyelitis can be triggered by HSV-2 infections (Elsberg syndrome). | |
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• Herpes zoster myelitis (varicella-zoster virus). | |
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• HTLV-I–associated myelopathy (HAM), or tropical spastic paraparesis (TSP), is a slowly progressive myelopathy, often sparing the brain. It is typically ascending, but cervical cord lesions can predominate. The bladder is often hypotonic, legs are spastic, and vibration sense is lost. | |
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• Human immunodeficiency virus (HIV) causes (1) HIV-associated vacuolar myelopathy (a painless slowly progressive spastic paraparesis without a discrete sensory level, with sensory ataxia and a neurogenic bladder), (2) direct infection causing a transverse myelitis, or (3) associated opportunistic infections from other viruses, mycobacteria, or fungi. Immune restoration with effective HIV therapy can provoke transverse myelitis (immune reconstitution inflammatory syndrome; IRIS), sometimes in association with connective tissue disease. | |
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• Human herpesvirus 6 (HHV6) causes progressive spastic paraparesis or acute multiple sclerosis-like episodes. There has been a case that was in addition to transverse myelitis opso-myoclonus syndrome. | |
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• IgG4-related disease typically presents with pachymeningitis and hypophysitis. Spinal cord involvement is rare, but there is a documented case of longitudinally extensive transverse myelitis (167). | |
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• Infection. Bacteria, abscess, acute meningitis with Borrelia, brucellosis, cat-scratch disease (Bartonella henselae), Campylobacter jejuni (see the “Pathogenesis and pathophysiology” section), chlamydia, erythema infectiosum (118; 90), Legionella pneumophila, leptospirosis, Lyme disease (neuroborreliosis), psittacosis (Chlamydia psittoci), rickettsia such as Coxiella burnetii (Q fever), R diaporica, R orienta, and R tsutsugamushi (scrub typhus—a mite-borne disease from chiggers that feed on rodents), Rochalimaea, Salmonella paratyphi B, non-typhi Salmonella, syphilis (especially tabes dorsalis problems), and Whipple disease (Tropheryma whipplei). | |
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• Mycoses: histoplasmosis, cryptococcosis in immunocompetent patient. | |
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• Mycoplasma pneumoniae, the most frequent etiology of autoimmune neuroinflammation, is associated with antineuronal antibodies that appear 2 to 4 weeks after the infection. Tuberculous meningitis, tuberculoma (see “Parasites and virus infections,” below). | |
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• M pneumoniae, M tuberculosis, mumps, and nonspecific respiratory infections may cause rapid onset of severe, progressive necrotizing myelopathy. Bacterial meningitis can present with hyperintensities of the central cord (82; 140). Many of these are case reports, so spurious associations and amplification of preexisting symptoms by fever, are possible. | |
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• Intermittent claudication of the cauda equina is caused by narrowing of the lumbar spinal cord. Rarely, claudication of the cord is caused by spinal AVM, atherosclerosis, thrombosis of terminal aorta, syphilitic arteritis, or lumbar spondylosis with disc protrusion. | |
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• Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency (28). | |
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• Lupus myelopathy. See connective tissue disease. | |
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• Lyme disease (borreliosis, erythema chronicum migrans; Bannwarth syndrome, lymphocytic meningoradiculitis) in both acute and chronic stages of infection. A lymphocytic meningitis is associated with myelitis alone or with acute radiculoneuritis. | |
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• Metabolic and nutritional (chronic liver disease or hepatic shunt myelopathy, diabetes mellitus, vitamin B12 or vitamin E deficiency, pellagra). | |
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• Metachromatic leukodystrophy causes slowly progressive peripheral nervous system and supratentorial signs. | |
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• Myelin oligodendrocyte glycoprotein autoantibody (MOG-IgG)-associated myelitis (MOGAD) is seen in “12%-56%” (24); 12% of children and 26% of adults nave cord lesions; 70% of the lesions are longitudinally extensive. The median age of onset is within the fourth decade of life with either a monophasic or relapsing course. Clinical features favoring MOG-IgG myelitis over AQP4-IgG myelitis include prodromal symptoms of optic neuritis and concurrent acute disseminated encephalomyelitis, with lack of enhancement on MRI. MOG-IgG-associated myelitis has MRI T2-signal abnormalities confined to the grey matter (H sign on T2 MRI) and multiple longitudinally extensive T2 cord lesions, often thoracic and in conus (169). Recovery after attacks is more common than in multiple sclerosis. In an early study, antibodies to myelin-associated glycoprotein (MAG) were present in all cases of neuromyelitis optica (60). | |
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• Myasthenia gravis (see thymectomy, below) | |
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• Multiple sclerosis. These patients are typically younger and have patchy disseminated demyelination (11). Transverse myelitis can be the first sign of an exacerbation of multiple sclerosis. The incidence of this overlap syndrome of acute transverse myelitis in multiple sclerosis dropped from 60% to 5% in Japan over 30 years, strongly suggesting that environment influences the clinical profile of these demyelinating diseases (120). The cord lesion in multiple sclerosis is more often patchy with skipped, normal segments (not contiguous over many segments), partial (not transverse and bilateral), round or wedge-shaped in dorsal, lateral, and ventral cord. CSF oligoclonal bands are more common in multiple sclerosis. A slowly evolving myelopathy is typical in primary progressive multiple sclerosis. Autoimmune disease and connective tissue disease are seldom if ever associated with multiple sclerosis; associations in many older studies are likely from epidemiologic contamination with Devic or Sjögren variants. | |
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• Neoplastic. Extramedullary tumors are often painful and easily seen with MRI (meningeal spread from melanoma, lung, breast, gastrointestinal tract, or renal; metastatic invasion or compression of the cord). An intramedullary tumor can mimic transverse myelitis (astrocytoma, dermoid, ependymoma, intramedullary glioma, hemangioblastoma, B cell lymphoma, intravascular lymphomatosis, schwannoma). A tumor typically has symptoms lasting weeks to months, enhances after Gd infusion on MRI, and less frequently causes CSF pleocytosis. (See below--paraneoplastic) | |
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• Neuromyelitis optica (NMO) see Devic disease. | |
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• Neurosarcoidosis chronic evolution of a transverse myelitis picture and also cauda equina syndrome, radiculopathy, syringomyelia, and arachnoiditis. Cord lesions can precede brain lesions but are less common than brain lesions. Spinal cord involvement occurs in less than 1% of all sarcoidosis cases. MRI often demonstrates hyperintense T2-weighted images, sometimes longitudinally extensive, and Gd enhancement that can last for months. Dorsal subpial enhancement forms a “trident sign.” With systemic sarcoidosis, hilar adenopathy may be present, along with constitutional symptoms. CSF lymphocytic pleocytosis, hypoglycorrhachia, and elevated angiotensin-converting enzyme are more common in neurosarcoid than in multiple sclerosis or neuromyelitis optica. The gold standard for diagnosis is biopsy of neurologic or non-neurologic tissue to detect noncaseating granulomas. | |
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• Paraneoplastic myelopathy, on a background of lymphoma, oat cell, non-small cell lung cancer, or other tumors, causes subacute necrotizing encephalomyelopathy. Also called necrotic myelitis, spinal necrosis, and myelomalacia. The course is acute or subacute, and the ascending paraplegia is followed by rapid deterioration and death (123; 145). Onset in the center of the thoracic cord progresses rostrally and caudally over days to weeks. Some cases have associated hypertrophy of the cauda equina. | |
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• Anti-Ri (ANNA2) is associated with paraneoplastic myelitis. Antibodies to collapsin response-mediator protein-5 (CRMP-5-IgG, aka CV2) are associated with a constellation of optic neuritis, vitreous inflammation with CD4 lymphocytes, CSF oligoclonal bands, and occasionally with extensive or patchy cord lesions (132) and underlying small cell lung cancer. Twenty-seven percent of patients with antibodies to amphiphysin IgG have inflammatory transverse myelitis (132). Antibodies to amphiphysin syndrome are associated with breast cancer and stiff-man syndrome. | |
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• Parasitic. Schistosomiasis, typically S mansoni or S haematobium, causes myelopathy with lumbar pain, lower limb radicular pain, muscle weakness, sensory loss and bladder dysfunction, and lesions at T12-L1 and the conus (143); a mechanism for this localization is of interest. Rarely causing cord symptoms are Ascaris suum, cysticercosis, echinococcosis, gnathostomiasis, malaria, paragonimiasis, Taenia solium, Toxocara canis (visceral larva migrans; leg sensory, motor, and autonomic signs; cord lesions are several segments long), toxoplasmosis (90; 36; 157), and trypanosomiasis. | |
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• Pelizaeus-Merzbacher disease has early onset, slow progression, supratentorial symptoms, and a family history). | |
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• Postinfectious encephalomyelitis is autoimmune and parainfectious, and not a primary virus infection. It is seen in children and young adults after measles (incidence = 3 in 100,000), chickenpox/varicella, dengue, rubella, mumps, scarlet fever (109), and other virus infections (below) and after mycoplasma pneumoniae. Many of these viruses also cause primary invasion. | |
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• Postvaccinal encephalomyelitis (seen with rabies, especially with brain antigens in the vaccine preparation; smallpox) (46). It is most common in older subjects; young adults are affected more than infants (04). There are reports of an association with recombinant hepatitis B vaccine (161); larger epidemiologic studies dispute this (08). Pertussis and influenza vaccination do not appear to cause acute transverse myelitis (46). There are scattered reports following millions of vaccinations for cholera, influenza, Japanese encephalitis, DPT, measles, mumps, rubella, polio, and typhoid. However, epidemiologic studies have not established a causal link. | |
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• Radiation myelopathy (with exposure over 50 Gy). Damage can be delayed up to 15 years after exposure but typically appears 10 to 16 weeks later (172). Radiation myelopathy causes vasculopathic, and sometimes anterior horn cell, changes with high T2 signal, and swelling on MRI. | |
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• Referred pain (cervical rib, brachial plexus tumor or plexitis, visceral mass, myocardial ischemia). | |
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• Sarcoid—see neurosarcoid. | |
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• Serum sickness (anti-tetanus serum or others). Local neuritis or polyneuritis is much more common than acute transverse myelitis. | |
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• Sjögren disease (see connective tissue disease and Devic). | |
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• Spider bite (brown recluse). | |
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• Stiff-person (Stiff-man) syndrome, most common in women, is lowly progressive spasticity, stiffness, and cramps described by Moersch and Woltman in 1956. It is associated with antibodies to glutamic acid decarboxylase (GAD65) on a background of diabetes mellitus, or occasionally with antibodies to amphiphysin on a background of breast adenocarcinoma. | |
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• Subacute combined degeneration; funicular myelopathy—European terminology for long tract degeneration. Affects dorsal columns, corticospinal tact, and peripheral nerves. Serum B12 levels are usually low, but confirmation may be necessary with elevated serum homocysteine and methylmalonic acid, which are more specific. | |
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• Subacute myelo-opticoneuropathy (SMON); iodochlorohydroxyquinoline toxicity (40). | |
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• SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) has occurred in association with Devic disease. | |
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• Syphilis. A classic cord syndrome is tabes dorsalis, but tertiary syphilis (meningomyelitis) can cause acute paraparesis (68). | |
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• Syrinx. Syringomyelia can cause slowly evolving symptoms. Extensive central cord demyelination and necrosis could evolve into a transient or chronic syrinx. | |
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• Systemic lupus erythematosus--see connective tissue disease. | |
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• Tetanus causes spasticity. | |
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• Thymectomy for myasthenia gravis increases the risk of neuromyelitis optica by 150-fold (89). This may be due to the underlying disease and not the thymectomy. Four women--two black, one white, and one Chinese--developed Devic disease 1, 5, 2, and 10 years after thymectomy. Longitudinal lesions were 5.5 cord segments at onset and at least 10.5 segments later. NMO-IgG was positive in two of three, ANA in two of four, anti-acetylcholine receptor in four of four, and stiff-man syndrome appeared in one. Interferon beta may have exacerbated disease in one. Because one in eight thymectomized patients develop autoimmune diseases, it is postulated that elimination of thymic suppressor cells leads to overactive T and B cell responses. | |
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• TNF-alpha inhibitors (see drugs). | |
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• Toxins include arsenic, clioquinol, diethylene glycol (Sterno) with delayed ascending paralysis 8 days after injection, intrathecal chemotherapy, intrathecal radiological contrast media, and orthocresol phosphate. Nitrous oxide abuse inactivates methylcobalamin. In medical and dental settings, “anesthesia paresthetica” can develop weeks after exposure to nitrous oxide. Chronic nitrous oxide use inactivates vitamin B12, causing demyelination of the dorsal columns of the spinal cord (98). A case of methanol intoxication with a clinical picture similar to transverse myelitis was from spinal cord necrosis. | |
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• Trauma to the cord. | |
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• Tropical ataxic neuropathy. In Mozambique, this is from ingestions of cyanide-rich cassava roots. | |
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• Tuberculosis. Compression arises from a dural tuberculoma, intramedullary tuberculoma, tuberculous spondylitis (Pott disease), spinal cord infarction, or tuberculous myelitis. | |
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• Tumor--see neoplastic. | |
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• Ulcerative colitis associated with transverse myelitis. | |
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• Vaccinations (see postvaccinal encephalomyelitis, above). | |
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• Vascular lesions from arterial occlusion, especially anterior spinal artery of Adamkiewicz, rarely posterior spinal artery, and acute occlusion of terminal aorta; arteriovenous malformation (AVM), spinal dural arteriovenous fistula, CADASIL, cavernoma of conus medullaris, venous thrombosis, impaired venous drainage by a disc herniation or fibrocartilaginous embolism from a ruptured disc, percutaneous embolization; or postsurgical—aortic reconstruction with hypotension during surgery). Cobb syndrome, with skin and spinal cord angiomas. | |
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• An ischemic or hemorrhagic vascular etiology is likely if symptoms peak within 4 hours or stepwise (166). Occlusion of the anterior cerebral artery mimics acute myelitis; loss of sphincter function, but no loss of pain sensation augurs a poor outcome. AVMs are rare but can lead to subarachnoid hemorrhage or focal cord lesions. A case of spinal subarachnoid hemorrhage appeared in the setting of lupus vasculitis (52). Hemorrhage into the cord or subarachnoid space presents with sudden severe back pain, spreading to different levels and nerve roots, with meningeal irritation. Chronic AVM damage is slowly progressive, occasionally stepwise. Venous congestion causes diffuse high T2 MRI signal and flow voids in dorsal cord vessels. Central or transverse infarcts are linked to peripheral vascular disease and arterial hypotension (122). Oligoclonal bands are usually negative, and patients often are older than 50. MRI shows an “owl sign” or “snake eyes sign.” | |
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• Virus infections are associated with myelitis, often without direct invasion. The most common viruses causing myelitis are enterovirus, HSV-2, and varicella-zoster. There are scattered case reports of associations with adenovirus; cat scratch fever; COVID-19; coxsackie strains A and B; cytomegalovirus; chikungunya; dengue 2 virus; echovirus types 2, 5, 6, 11, 18, 19, 25, and 30; enterovirus 71; Epstein-Barr virus; familial Mediterranean fever, hand, foot, and mouth disease; hepatitis A, B, C, and E (158); HIV; HTLV 1 and 2; herpes simplex (HSV) types 1, 2, and 6; herpes zoster with or without shingles; influenza; Japanese encephalitis virus; lymphocytic choriomeningitis virus (LCMV); monkeypox; mumps; Murray Valley encephalitis virus; parvovirus b19; poliovirus 1, 2, and 3; rubeola; rubella; Russian spring-summer encephalitis; St Louis encephalitis virus; acute varicella (VZV; primary or reactivation); West Nile flavivirus; and Zika virus (109; 30; 90). | |
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• Coxsackie, enterovirus D68, (a picornavirus), poliovirus, and West Nile virus can cause acute flaccid paralysis. The latter three viruses affect gray matter, with myalgia, low back pain, and a “railroad track sign” highlighting inflamed gray matter on sagittal cord MRI (AT Reder) related to “snake eyes” or “owl eyes” from focal anterior horn lesions. HSV-2 can cause sacral radiculomyelitis sometimes associated with genital lesions; HSV-1 can cause recurrent ascending myelitis (155). Hepatitis viruses appear to cause an autoimmune myelitis, probably not from direct invasion. Parainfectious conus myelitis causes bladder hesitancy and retention, occasional sacral and lumbar sensory loss, and motor weakness (135). SARS-CoV/COVID-19 is associated with encephalopathy, stroke, seizures, Guillain-Barre syndrome, meningoencephalitis, and acute necrotizing hemorrhagic encephalopathy (121). Recent infection, rash, stiff neck, acute onset, and elevated CSF cell count are suggestive of a virus infection. MRI appearance is a major tool in the diagnosis (114). | |
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• Vitamin deficiency. Low vitamin B12 causes subacute combined degeneration (see above). Low folate causes systemic symptoms similar to B12 deficiency but is often not associated with neurologic problems. Vitamin E deficiency causes progressive spinocerebellar problems and damages dorsal columns, corticospinal tract, and peripheral nerves. | |
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• Vogt-Koyanagi-Harada disease, uveomeningoencephalitis, is a disorder of melanin-forming cells (103). CNS symptoms coexist with iridocyclitis, uveitis, and cutaneous abnormalities. |
Diagnostic workup
Transverse myelitis is a clinical syndrome with many inflammatory and noninflammatory causes. The first step is to rapidly rule out cord compression (MRI), then vascular or connective tissue disease (serology), and then define whether the inflammation is restricted to the cord (brain MRI). The history and exam should exclude connective tissue disease and Behçet disease by focusing on rashes, joint pain, pleuritis, night sweats, shortness of breath, hematuria, anemia, adenopathy, orogenital ulcers, organomegaly, uveitis, and retinitis. Labs should include CBC and differential cell count, CRP, ANA, and other infectious workups (ie, QuantiFERON-TB gold) to differentiate disease-related from idiopathic transverse myelitis.
Serum markers of axonal and neuronal damage (sNFL, neurofilament light chains) and astrocyte damage (GFAP) increase in transverse myelitis and multiple sclerosis. Levels are even higher in neuromyelitis optica (88).
Spinal cord inflammation is a sine qua non for idiopathic acute transverse myelitis, so a Gd-enhanced MRI and CSF analysis strengthen the diagnosis. With acute transverse myelitis, an MRI of the spinal cord shows increased signal density on T2-weighted images in 50% to 90% of adults (107; 10; 78) and 50% to 83% of children (90; 113). T1-weighted MRI scans are isointense or mildly hypointense, with swelling of the cord over several segments. Normal MRIs occur in some patients with devastating, localized cord symptoms. Moreover, extensive cord involvement often does not correlate with clinical severity or outcome (06).
The abnormal MRI T2 or FLAIR signal is centrally located or holocord and extends over multiple cord segments (161; 53). It may reach several segments above the clinically determined sensory level (12; 29). The thoracic cord is typically involved, but some series show cervical predominance (74% of lesions in 20 young French patients). Lupus myelopathy is typically thoracic; Sjögren myelopathy is cervical. Lesions restricted to the conus medullaris can follow virus infections. The spinal cord is sometimes swollen in transverse myelitis (40%), but rarely seen in multiple sclerosis (75). MRI lesions are all of the same age in acute transverse myelitis, but the signal resolves in some areas before others. More extensive MRI lesions and persistent enhancement after gadolinium infusion herald residual clinical deficits (147; 128), but MRI severity does not always correlate with clinical deficits (134). Diffusion tensor imaging shows abnormalities in distal, normal-appearing white matter. Associated brain lesions suggest acute disseminated encephalomyelitis or multiple sclerosis. However, there is one report of brain MRI abnormalities in 17 of 30 patients and oligoclonal bands in 12 of 25 patients who had "acute transverse myelitis" without clinical signs above the foramen magnum (107). Patients with CSF abnormalities and heterogeneous spinal cord and brain lesions on MRI are more likely to eventually develop multiple sclerosis (156).
The spinal fluid has elevated protein (often 100 to 120 mg/100 ml; normal less than 50 mg) and moderate pleocytosis (50 to 100 lymphocytes/mm3) in one third to one half of adult patients (03; 101; 18; 164; 10; 75) and in up to 80% of children (113). Glucose and opening pressure are normal (03; 142). Seventy percent of children have elevated spinal fluid myelin basic protein (113). The spinal fluid in transverse myelitis typically lacks oligoclonal bands. The bands, if present, do not persist (85). IgG (35% to 52%), IgG index (42%, the most specific of these measures of inflammation), and immunoglobulin synthesis rate (33%) are sometimes increased, but not as frequently as in multiple sclerosis. Axonal 14-3-3 protein is present in only 10% of patients with transverse myelitis and multiple sclerosis (38). In seven patients with acute transverse myelitis, the four that had 14-3-3 in their CSF did poorly (71). In 19 Japanese patients with multiple sclerosis, 14-3-3 is linked to more damage, progression, and optico-spinal disease (148). In another series, none of the six patients with transverse myelitis were positive (38). High CSF IL-6 predicted recurrent transverse myelitis and disability (94; 80). Nonspecific enolase (NSE), myelin basic protein, and S-100 are predictors of severity. NMO-IgG, MOG-IgG, angiotensin-converting enzyme, and serum tests for connective tissue disease are important, especially if cord lesions are contiguous or extend for more than two segments.
Related syndromes have a different MRI and CSF picture. In acute necrotizing hemorrhagic leukoencephalomyelitis, there is fever and peripheral blood neutrophilia. The CSF is xanthochromic, and it contains variable amounts of protein and often red blood cells and up to 2000 polymorphonuclear lymphocytes. In milder cases the cell count is lower and largely mononuclear.
In acute disseminated encephalomyelitis, MRI lesions are all of the same age and are widespread in brain and cord, often with bilateral optic nerve or basal ganglia lesions. These disappear with the passage of time (177; 85). There is moderate pleocytosis, moderately increased protein, and occasional but transient oligoclonal bands. In chronic progressive myelopathy, 44% have oligoclonal bands, and 44% have abnormal visual evoked potentials (129), suggesting that many of these patients have multiple sclerosis. In 20 patients with "myelopathy" developing over days to years, 65% had T2-weighted MRIs compatible with multiple sclerosis, and an additional 25% had abnormal visual evoked potentials or CSF oligoclonal bands (111). In progressive necrotizing myelopathy, from spinal vascular malformations (48; 110) or from a remote effect of cancer (49), the cord is swollen on myelography and the CSF is xanthochromic with high protein (144), a normal cell count or a few lymphocytes or polymorphonuclear lymphocytes, and no oligoclonal bands.
MRI and lumbar puncture, which are sensitive and specific, have largely obviated other tests. Myelograms are usually normal (101; 18), although cord swelling may be present on CT myelography (144) or MRI (12).
Electrophysiologic tests of spinal cord function are sensitive for detecting spinal cord damage. Visual and brainstem evoked potentials help exclude CNS dissemination (which would suggest multiple sclerosis).
Somatosensory evoked potentials are abnormal in up to 85% (141; 171; 78); normal potentials suggest a better prognosis. Absent or reduced sensory action potentials could also indicate peripheral nervous system damage. F waves may be absent on electrodiagnostic testing, and this raises the possibility of Guillain-Barré syndrome. Electromyography of the lower limb muscles showing neuropathic potentials suggests demyelination in the ventral root zone. These indicate a poor outcome (112), as do abnormalities of peripheral nervous function (63). In parainfectious and idiopathic transverse myelitis, one-fourth of patients have evidence of peripheral damage (eg, abnormal motor unit action potentials, sensory nerve action potentials, and nerve conduction velocities) (63), unlike multiple sclerosis.
There is slowed central motor conduction time to the lower limbs (abnormal in 90%) after magnetic stimulation. Electrically-induced motor evoked potentials are even more sensitive, but this test can be painful. Painless transcranial magnetic stimulation is abnormal in 96% of children with myelitis (168).
Management
Transverse myelitis is a diagnosis of exclusion. Potentially treatable diseases such as cord compression, local tumor, paraneoplastic disease, infection, vascular causes, and connective tissue diseases must be ruled out.
Symptom management. Most patients with transverse myelitis will have paraplegia of the lower limbs for weeks or months. In some the paresis is permanent. Prevention of deep vein thrombosis and decubitus ulcers is essential. Spastic legs can be relaxed with physical therapy using active and passive range of motion exercises and stretching. Drugs include baclofen, tizanidine, Mg++, cannabidiol (CBD), and sometimes benzodiazepines, or dantrolene (removed from some markets including the United States). Intrathecal baclofen is useful for severe spasticity unrelieved by oral drugs. Weakness may be improved with 4-aminopyridine, 3,4-diaminopyridine (fampridine), amantadine, and methylphenidate. In idiopathic acute transverse myelitis, extended-release dalfampridine (D-ER) improved walking speed in 85% of the treated arm compared to 69% of the placebo group (149).
Central neuropathic pain in multiple sclerosis, and presumably in some cases of transverse myelitis, is strongly linked to T1-T6 cord lesions. These lesions disrupt the longitudinally extensive intermediomedial nucleus that surrounds the midthoracic central canal (124). Pain is usually not a problem after the initial symptoms resolve, but persisting pain may be relieved with muscle stretching or by therapy with gabapentin, carbamazepine, phenytoin, amitriptyline, CBD, or oral or intrathecal baclofen (67). Orthostatic hypotension can be treated with compression stockings, hydration, salt supplementation, and fludrocortisone or midodrine.
Anticholinergics can reduce urinary frequency caused by a spastic bladder but also cause or worsen urinary retention. Self-catheterization is far superior to indwelling catheters for treatment of incontinence. Recurrent urinary tract infections should be investigated. They can arise from a second insult from multiple sclerosis.
Acute and chronic rehabilitation is helpful for recovery from transverse myelitis Techniques are maximization of load bearing in affected limbs, optimization of sensory cues, and patterned nonspecific training, as well as functional electrical stimulation and neurotrophin induction (94; 146).
Treating the underlying disease process. Transverse myelitis has traditionally been treated with oral or intravenous glucocorticoids or intravenous adrenocorticotropic hormone. The aim of initial immunotherapy is to stop disease progression. High-dose intravenous steroid therapy usually causes prompt clinical improvement (41; 84). Intravenous immunoglobulin or plasma exchange are the second line of immunotherapy (47). Oral and intravenous steroids and IVIG had no effect on eventual outcome in a retrospective study of 50 Japanese children (113). Lessons from the treatment of other demyelinating diseases may also be relevant. In multiple sclerosis, glucocorticoids shorten the duration of symptoms but do not change the long-term outlook. In optic neuritis, high-dose intravenous methylprednisolone improves vision and appears to prevent recurrences compared to oral prednisone alone (15). A more prolonged steroid taper than that described by Beck and colleagues may be advisable based on a rat model of postvaccinal encephalomyelitis (137). Taper is not needed in multiple sclerosis. Similarly, acute disseminated encephalomyelitis responds dramatically to glucocorticoids, but symptoms flare up on sudden withdrawal (177), so a taper is advised. Idiopathic transverse myelitis is presumably more like multiple sclerosis.
A number of studies from the Mayo Clinic and other case reports suggest that plasma exchange has benefits in severe attacks of CNS demyelination (83; 56). Anecdotal evidence suggests azathioprine or cyclophosphamide therapy is helpful (56), but this sample included many cases of other autoimmune diseases that cause transverse myelitis (93). Cyclophosphamide, mycophenolate, azathioprine, and rituximab have been used for chronic disease or because of resistance to multiple other treatments.
Recurrent transverse myelitis appears to be a form of multiple sclerosis, although it seldom develops into multiple sclerosis when the brain MRI is negative (150). Disease-modifying drugs for multiple sclerosis could prevent further attacks in transverse myelitis.
Neuromyelitis optica with serum NMO-IgG antibodies is different from multiple sclerosis or idiopathic transverse myelitis. Treatment of the initial attack includes intravenous high-dose corticosteroids and plasma exchange. Because of the likelihood of recurrence, maintenance therapy is recommended to suppress the immune system. The following medications are FDA-approved for NMO-IgG neuromyelitis optica spectrum disorder: eculizumab (complement inhibitor), inebilizumab (anti-CD19), and satrilizumab (anti-IL6). Rituximab and other anti-CD20 antibodies are effective. Mycophenolate mofetil, azathioprine, and repeated intravenous immunoglobulin infusions have some benefit.
Tumor necrosis factor blockers, effective in rheumatoid arthritis, have precipitated transverse myelitis and other demyelinating syndromes. Interferon beta is unhelpful or dangerous in patients with positive NMO-IgG or CNS Sjögren disease because they already have high endogenous type I interferon levels (73).
Outcomes
In pediatric transverse myelitis, motor function and urinary dysfunction improve the most when there is minimal delay from symptom onset to initiation of immunotherapy and rehabilitation (25). Outcomes are discussed in the “Clinical manifestations” section.
Special considerations
Pregnancy
No epidemiologic studies have been done. It would be expected that just as in multiple sclerosis, normal biological immunosuppression would make transverse myelitis less likely during pregnancy, but more likely for a few months after delivery.
Women with preexisting transverse myelitis can have successful deliveries but are subject to complications such as skeletal muscle fatigue, which depends on the severity of their neurologic disease (17). Systemic lupus erythematosus and neuromyelitis optica can mimic transverse myelitis, and exacerbations of systemic lupus erythematosus sometimes occur during pregnancy (105).
Drugs used for in vitro fertilization trigger attacks of multiple sclerosis. Buserelin, a gonadotropin-releasing hormone agonist, decreases the release of luteinizing hormone and follicular stimulating hormone. It induced an attack of acute transverse myelitis two weeks after injections.
Anesthesia
Transverse myelitis following general anesthesia is unlikely (59). Direct needle trauma to the spinal cord during spinal anesthesia, however, can cause hemorrhage. A patient with Behçet disease developed local myelitis near a lumbar root steroid injection. Cord trauma should be avoided in necrotic myelopathies and probably in transverse myelitis.
Media
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Anthony T Reder MD
Dr. Reder of the University of Chicago received honorariums from Biogen Idec, Genentech, Genzyme, and TG Therapeutics for service on advisory boards and as a consultant as well as stock options from NKMax America for advisory work and an unrestricted lab research grant from BMS.
See Profile
Former Authors
- Sara Klein MD
Patient Profile
- Age range of presentation
-
- 1 monthto 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- none
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Encephalitis, myelitis and encephalomyelitis, unspecified: G04.9
- ICD-11
-
- Transverse myelitis: 8A41.0
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