Version May 2024
INTRODUCTION — Acute transverse myelitis (TM) is a rare, acquired neuroimmune spinal cord disorder that can present with the rapid onset of weakness, sensory alterations, and bowel or bladder dysfunction. TM can occur as an independent entity, usually as a postinfectious complication, but TM also exists on a continuum of neuroinflammatory disorders that includes acute disseminated encephalomyelitis (ADEM), multiple sclerosis, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), neuromyelitis optica spectrum disorder (NMOSD), and acute flaccid myelitis (AFM).
This topic will review the etiology, clinical features, and diagnosis of TM. Treatment and prognosis are reviewed separately. (See "Transverse myelitis: Treatment and prognosis".)
Related conditions are discussed elsewhere:
● Acute disseminated encephalomyelitis (ADEM) in adults
● Evaluation and diagnosis of multiple sclerosis in adults
● Manifestations of multiple sclerosis in adults
● Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis
● Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis
TERMINOLOGY AND CLASSIFICATION
●Definitions
•Myelopathy – A clinical syndrome characterized by motor, sensory, or autonomic symptoms caused by spinal cord dysfunction [1].
•Myelitis – Inflammation of the spinal cord.
•Transverse myelitis (TM) – In the strictest sense, TM is defined as inflammation involving an entire transverse section of the spinal cord. However, TM is also used to refer to immune-mediated myelitis involving all or part of a transverse section of the spinal cord, also referred to as a segmental syndrome [2].
We use the term TM inclusively to comprise all causes of inflammatory myelopathy, regardless of the severity or degree of structural or functional interruption of pathways through a transverse spinal cord section [3].
•Idiopathic TM – When the cause of TM is not identified despite a comprehensive evaluation, the TM is referred to as idiopathic. (See 'Idiopathic' below.)
•Secondary (disease-related) TM – When TM is associated with other immune-mediated conditions (see 'Associated and causative conditions' below), it is considered secondary or disease-related TM. The clinical features, diagnostic work-up, and acute and chronic therapies differ between these forms of TM.
●Subtypes – Subtypes of TM are differentiated based upon the clinical severity, relative involvement of spinal cord gray matter, and longitudinal extent of the spinal cord lesion.
•Acute partial TM – Spinal cord dysfunction that is mild or grossly asymmetric with a magnetic resonance imaging (MRI) lesion extending one to two vertebral segments.
•Acute complete TM – Spinal cord dysfunction that causes symmetric, complete, or near complete neurologic deficits (paresis, sensory loss, and autonomic dysfunction) below the level of the lesion with a corresponding lesion on MRI that extends one to two vertebral segments.
•Longitudinally extensive transverse myelitis (LETM) – Complete or incomplete spinal cord dysfunction with a corresponding lesion on MRI that extends three or more vertebral segments.
These subtypes of TM, while imperfect, imply distinct differential diagnoses and prognoses.
IMMUNOPATHOGENESIS — The immunopathogenesis of TM is varied and reflects the rather diverse spectrum of this disease from idiopathic to disease-associated myelitis. (See 'Associated and causative conditions' below.)
Traditionally, the majority of TM cases were thought to be characterized by perivascular infiltration by monocytes and lymphocytes in the lesion [4]. Axonal degeneration was also reported [4]. Autopsy reports have described lymphocytic infiltration with demyelination and axonal loss [5]. Pathologic heterogeneity and the involvement of both gray and white matter suggest that TM is not a pure demyelinating disorder but rather a mixed inflammatory disorder that affects neurons, axons, and oligodendrocytes and myelin.
In parainfectious TM, the injury may be associated with the systemic response to infection by a variety of agents such as enteroviruses, varicella zoster virus (VZV), herpes virus, and Listeria monocytogenes (table 1 and table 2) [6],and only rarely with direct microbial infection of the central nervous system (CNS). Molecular mimicry and super antigen-mediated disease have also been described as potential mechanisms of autoimmunity [5]. Molecular mimicry in TM was postulated to be the cause of injury following infection with Enterobius vermicularis (pinworm) in a patient who had elevated titers of cross-reacting antibodies [7]. Microbial superantigens such as staphylococcal enterotoxins A through I, toxic shock syndrome toxin-1, and streptococcus pyogenes exotoxin, have also been purported to stimulate the immune system and are known to be capable of activating T-lymphocytes without costimulatory molecules [5,8-11], thereby triggering autoimmune disease by activating preexisting autoreactive T cell clones [12,13].
The diverse pathology of disease-associated TM is evident from studies showing that lupus-associated TM could be associated with CNS vasculitis or thrombotic infarction of the spinal cord [5,14-18]. Other studies have also described the role of autoantibodies in patients with neuromyelitis optica spectrum disorder (NMOSD) and recurrent TM [19-22]. Autoantibodies have been implicated in activating other components of the immune system after crossing the blood-brain barrier. It may also be that some autoantibodies initiate a direct and selective injury of neurons or glia that express antigens with epitopes, which cross-react with antibodies directed against infectious pathogens [5].
ASSOCIATED AND CAUSATIVE CONDITIONS — TM exists on a continuum of neuroinflammatory disorders. In a retrospective report from a tertiary center that included 1193 patients referred between 2006 and 2021 for evaluation of TM, an inflammatory myelopathy was diagnosed in 772 patients (65 percent) and a noninflammatory myelopathy in 421 (35 percent) [23]. In the 772 patients with an inflammatory myelopathy, the most frequent diagnoses after a comprehensive work-up were multiple sclerosis or clinically isolated syndrome in 221 (29 percent), idiopathic myelitis in 149 (19 percent), and neuromyelitis optica spectrum disorder (NMOSD) in 132 (17 percent).
CNS demyelinating disorders — Central nervous system (CNS) demyelinating disorders that can cause TM include the following:
●Multiple sclerosis – TM can occur as part of the spectrum of multiple sclerosis. In some cases, TM is the initial demyelinating event (a clinically isolated syndrome) that precedes clinically definite multiple sclerosis. (See "Manifestations of multiple sclerosis in adults" and "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis".)
●Neuromyelitis optica spectrum disorder (NMOSD) – TM manifesting as a longitudinally extensive spinal cord lesion spanning three or more vertebral segments is one of the characteristic manifestations, along with optic neuritis, of NMOSD. However, NMOSD can also cause TM involving fewer segments. The most common autoantibody identified in NMOSD is the anti-aquaporin-4 (AQP4) antibody. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Transverse myelitis'.)
●Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) – This disorder is associated with a variety of manifestations related to CNS demyelination that include relapsing and bilateral optic neuritis, TM, brainstem encephalitis, and acute disseminated encephalomyelitis (ADEM). MOGAD is more common in children than adults and can mimic the NMOSD syndrome seen in patients with the anti-AQP4 antibody. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'Clinical features'.)
●Acute disseminated encephalomyelitis (ADEM) – TM may be seen in patients with ADEM, a demyelinating disease of the CNS that typically presents as a monophasic disorder with multifocal neurologic symptoms and encephalopathy. Brain involvement is required to make a diagnosis of ADEM. (See "Acute disseminated encephalomyelitis (ADEM) in adults" and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis".)
Systemic autoimmune disorders — The systemic inflammatory autoimmune disorders more commonly associated with TM include the following:
●Sarcoidosis [24-26] (see "Neurologic sarcoidosis", section on 'Brain and spinal cord involvement')
●Sjögren's disease [27-29] (see "Neurologic manifestations of Sjögren's disease", section on 'Focal or multifocal demyelination/inflammation')
●Systemic lupus erythematosus [27,30,31] (see "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Inflammatory and demyelinating disease')
Less commonly associated systemic inflammatory autoimmune disorders include:
●Ankylosing spondylitis [32] (see "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Neurologic manifestations')
●Antiphospholipid syndrome [27,33,34] (see "Clinical manifestations of antiphospholipid syndrome", section on 'Neurologic involvement')
●Behçet syndrome [35,36] (see "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Neurologic disease')
●Mixed connective tissue disease [37] (see "Mixed connective tissue disease")
●Rheumatoid arthritis [38] (see "Neurologic manifestations of rheumatoid arthritis")
●Systemic sclerosis [39] (see "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults")
Infections — Infections associated with TM include but are not limited to enteroviruses (commonly enterovirus D68 and EV71, and poliovirus), West Nile virus, herpes viruses, human immunodeficiency virus (HIV), human T-lymphotropic virus 1 (HTLV-1), Zika virus [40], neuroborreliosis (Lyme), Mycoplasma, and Treponema pallidum (table 1 and table 2).
Acute flaccid myelitis (AFM) is a specific neurologic condition recognized in biennial outbreaks in the United States and Europe associated with circulating enterovirus D68. AFM manifests as a clinical syndrome similar to poliomyelitis with a gray matter-centric myelitis and a lower motor neuron pattern of weakness (eg, reduced reflexes, decreased tone). Most cases have occurred in children; adults are rarely affected. (See "Acute flaccid myelitis".)
In general, infectious causes of spinal cord dysfunction are rare, but outbreaks of AFM serve as a reminder of the myelitis outbreaks seen during poliovirus outbreaks. (See "Poliomyelitis and post-polio syndrome".)
Paraneoplastic syndromes — Paraneoplastic myelopathy can present as a rapidly progressive spastic paresis with or without bowel and bladder dysfunction. It often occurs in association with involvement of other areas of the nervous system; examples include encephalitis, sensory neuronopathy, chorea, and optic neuropathy.
Paraneoplastic myelopathy can also occur as an isolated syndrome. The most commonly associated antibodies are anti-Hu, anti-collapsin-responsive mediator protein 5 (CRMP5), and, less frequently, anti-amphiphysin antibodies. The usual associated malignancy is small cell lung cancer (SCLC). (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Spinal cord syndromes'.)
Vaccinations — TM has been reported to occur in association with vaccination, but causation has not been established based on the timing and sequence of events alone [41-44]. In one retrospective study of 47 children with acute TM, vaccination within 30 days prior to the onset of TM symptoms was reported in 28 percent [44]. There were no patterns in the illness or vaccine history that correlated with the acute onset of disease.
In a database from the United States, with 64 million vaccine doses administered among children and adults from 2007 through 2012, there were only seven subjects with TM who were vaccinated during the primary exposure interval of 5 to 28 days prior to TM onset [43]. Comparing each TM case with all matched subjects in the exposure interval who received the same vaccination, there was no association of TM with prior vaccination.
Idiopathic — TM is considered idiopathic when the cause is not identified despite a comprehensive evaluation. Idiopathic TM accounts for 15 to 30 percent of TM cases [23,45-47]. These wide discrepancies in the frequency of idiopathic TM may reflect variation in catchment area populations, disease definitions, and the evolution of diagnostic methods.
There is an antecedent respiratory, gastrointestinal, or systemic illness in 30 to 60 percent of idiopathic TM cases [48-54]. Nevertheless, these are considered idiopathic because the causative nature of the infection is seldom proven.
EPIDEMIOLOGY — TM is a rare disorder with a reported incidence between one and nine cases per million people per year [55-57]; this is probably an underestimate. These numbers imply that approximately 1400 new cases occur in the United States per year and that approximately 34,000 people have chronic morbidity from TM at any time [48-50].
A bimodal peak between the ages of 10 and 19 years and between 30 and 39 years has been reported [48-50]. Approximately 20 percent of cases are under the age of 18 years [44]. One report of acute TM in children found a bimodal distribution by age even among patients younger than 18 years of age, and a higher peak under the age of 3, with no sex predisposition [44].
There is no sex or familial predisposition to TM, although females predominate among the cases that are associated with multiple sclerosis [58].
CLINICAL FEATURES
Acute myelopathy — TM affects spinal cord function at one or more levels and causes a segmental syndrome. The head and face are not affected. There is loss of sensory modalities and/or weakness below the affected spinal cord level with associated bladder dysfunction. Loss of function may be total or incomplete. (See "Anatomy and localization of spinal cord disorders", section on 'Segmental syndrome'.)
Onset and progression
●Presenting symptoms – The onset of TM is characterized by acute or subacute development of neurologic signs and symptoms consisting of motor, sensory, and/or autonomic dysfunction. In a survey with data for over 470 individuals with idiopathic TM, the most common initial symptoms were [59]:
•Sensory change – 39 percent
•Weakness – 25 percent
•Pain (mainly back pain) – 22 percent
Bladder and bowel symptoms and balance problems were less frequent first symptoms [59]. Presentation with pain or weakness was more common in children (n = 70) than in adults.
●Progression to nadir – In most patients with idiopathic or secondary TM, the time to the maximal neurologic deficit before improvement or plateau (ie, the nadir) is within 1 to 21 days [1,2,46,60]. In a retrospective series of 47 children with TM, the mean time to nadir from the onset of acute symptoms was approximately two days [44].
●Maximal deficits – In a series of 47 children with TM, symptoms of sensory loss or numbness, weakness, urinary dysfunction, or pain were present in 91, 89, 85, and 75 percent of children, respectively [44]. Most (89 percent) of the children required a wheelchair or were confined to bed in the initial phase of TM; note that this series was published in 2007 before myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) antibody testing was generally available. Symptoms at nadir tend to be less severe with multiple sclerosis-associated TM, while symptoms tend to be moderate to severe (eg, requiring an ambulatory aid) with seropositive neuromyelitis optica spectrum disorder (NMOSD)- or MOG antibody-associated disease (MOGAD)-associated TM [2].
●Outcomes – Most patients experience variable degrees of subsequent improvement, as discussed separately. (See "Transverse myelitis: Treatment and prognosis", section on 'Recovery'.)
Motor symptoms — Motor symptoms include a rapidly progressing paraparesis or quadriparesis, depending on location of the lesion within the spinal cord [4,5,52]. Accompanying symptoms may include paroxysmal tonic spasms of the trunk or extremities (especially with seropositive NMOSD-associated TM) [2].
In most cases caused by white matter damage, there is initial flaccidity followed by spasticity. Gray matter involvement leads to persistent flaccid weakness.
Sensory symptoms — Most patients have a sensory level (a dermatomal level at which sensation is normal above and reduced or absent below). In one series of 170 patients with idiopathic TM, a thoracic clinical sensory level was identified in 63 percent of the patients. Another series of 47 children with acute TM reported a thoracic clinical sensory level in 53 percent [44]. In addition to sensory loss, other typical sensory symptoms include pain, dysesthesia, and paresthesias, although paresthesias are uncommon in children [4,61]. Some patients have Lhermitte sign (a transient electric sensation radiating down the spine or into the limbs with neck flexion) [2].
Autonomic symptoms — Autonomic symptoms include increased urinary urgency, bladder and bowel incontinence, difficulty with voiding or inability to void, bowel constipation, and sexual dysfunction [4,62-64].
IMAGING FEATURES
Spine imaging — In patients with TM, MRI of the spinal cord typically shows a gadolinium-enhancing signal abnormality (image 1), usually extending over one or more cord segments [44,48,65,66]. The cord often appears swollen at the affected levels. In an adult case series of 170 patients with idiopathic TM, MRI T2-weighted imaging showed a cervical signal abnormality in 44 percent and a thoracic signal abnormality in 37 percent; the rostral-caudal extent of the lesion ranged from one vertebral segment in many to the entire spinal cord in two patients [67]. A similar pattern was seen in children, with the average lesion spanning six segments [44]. Since these reports [44,67] predate the widespread use of anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin-4 (AQP4) antibody testing, it is not possible to confirm if all included patients truly had idiopathic TM.
The extent and pattern of enhancement of the spinal cord lesion on MRI (image 2) can suggest the underlying cause of TM.
●Short acute lesions, less than three vertebral segments, are suggestive of multiple sclerosis, especially when associated with multiple short T2 hyperintense peripheral lesions within the spinal cord. Acute lesions are usually enhancing. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Spinal cord MRI'.)
Short lesions are less common with neuromyelitis optica spectrum disorder (NMOSD) or MOG antibody-associated disease (MOGAD). (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Spinal cord MRI' and "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'MRI spinal cord'.)
●Longitudinally extensive transverse myelitis (LETM), with lesions extending three or more vertebral segments, is typical in NMOSD, is common in MOGAD, and is more common than short lesions in acute disseminated encephalomyelitis (ADEM), particularly with MOGAD-associated ADEM. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Spinal cord MRI' and "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'MRI spinal cord' and "Acute disseminated encephalomyelitis (ADEM) in adults", section on 'Neuroimaging' and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Neuroimaging'.)
Long spinal cord lesions may also be seen in myelitis due to sarcoidosis and paraneoplastic syndromes [2]. (See "Neurologic sarcoidosis" and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Myelopathy'.)
Brain imaging — In appropriate clinical settings, brain MRI findings can help distinguish the different central nervous system (CNS) demyelinating disorders. The pattern of lesions with these disorders is described in detail separately:
●With multiple sclerosis, brain lesions are typically found in the periventricular region, corpus callosum, centrum semiovale, brainstem, cerebellum, spinal cord, and, to a lesser extent, deep white matter structures and basal ganglia. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Magnetic resonance imaging' and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis", section on 'MRI'.)
●With NMOSD, MRI of the brain on presentation is often normal, aside from optic nerve enhancement. Over time, however, brain involvement develops in many, with lesions in the central medulla, hypothalamus, diencephalon, and/or subcortical white matter. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'MRI of the brain and orbits'.)
●With MOGAD, different phenotypes have different patterns of lesions on MRI. With optic neuritis, orbital MRI typically shows unilateral or bilateral optic nerve enhancement. With an ADEM phenotype, brain MRI typically shows multiple large, poorly demarcated T2 hyperintense lesions in white matter, deep gray matter, the brainstem, and/or middle cerebellar peduncles. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'MRI orbits' and "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'MRI brain'.)
●With ADEM, with or without seropositivity for MOG immunoglobulin G (IgG) autoantibody, brain MRI typically shows bilateral, asymmetric, poorly demarcated T2 hyperintense lesions in white matter, deep gray matter, the brainstem, and/or middle cerebellar peduncles. (See "Acute disseminated encephalomyelitis (ADEM) in adults", section on 'Neuroimaging' and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Neuroimaging'.)
INITIAL EVALUATION
When to suspect the diagnosis — The diagnosis of TM is suspected when there are acute or subacute signs and symptoms of motor, sensory, and/or autonomic dysfunction that localize to one or more contiguous spinal cord segments in patients with no evidence of a compressive cord lesion on imaging.
History — The first step is to determine from the history and examination (see 'Clinical features' above) whether the condition is likely to be a myelopathy.
Symptoms that should cause a clinician to consider a myelopathy include weakness and sensory loss in a myelopathic distribution, accompanied by bowel/bladder incontinence and urinary retention. Any of these symptoms should at least raise the possibility of a myelopathy and a consideration for MRI of the spine.
The history should be explored for important preceding factors such as systemic or central nervous system (CNS) autoimmune disorders and antecedent respiratory, gastrointestinal (especially chronic liver disease), or systemic illness. Additional factors to question include prior treatments (eg, methotrexate, immune checkpoint inhibitors, tumor necrosis factor-alpha inhibitors, radiotherapy) or substance use (eg, heroin, nitrous oxide) that may cause myelopathy [68].
Examination — On examination, localization of neurologic dysfunction is always important; a spinal cord lesion may be suspected when there are motor and/or sensory signs or symptoms that do not involve the head or face. CNS motor deficits are characterized by weakness and long tract signs (eg, spasticity, increased reflexes, Babinski sign). A spinal cord sensory level, with normal sensation above and reduced or absent sensation below, can also often be identified and should be specifically sought. Any patient with a reported or identified sensory level should be considered to have a myelopathy until proven otherwise. (See "Anatomy and localization of spinal cord disorders", section on 'Clinical localization'.)
When the pathology is localized, these findings will be present in muscle groups innervated below the corresponding spinal cord level and will be normal above that level. Gray matter involvement of the cord can lead to a lower motor neuron pattern of weakness (flaccid weakness, lost reflexes).
Clinically, it is impossible to differentiate a peripheral motor neuropathy leading to weakness from an anterior horn cell pathology leading to motor weakness. Thus, in the right setting, imaging must be considered in all patients with weakness.
Urgent spine imaging — When myelopathy is suspected, urgent spinal imaging is warranted to exclude a compressive lesion and to distinguish between different types of myelopathy. Imaging of the entire spinal cord is indicated, even in patients with paraplegia, due to the potential for cervical cord lesions to cause isolated lower extremity symptoms.
●MRI of the entire spine – MRI of the entire spine, with and without gadolinium, is the preferred diagnostic study for suspected TM (algorithm 1).
In addition, diffusion-weighted imaging (DWI) of the spine should be added for patients with hyperacute (<12 hours) or acute onset of myelopathic symptoms to look for evidence of spinal cord infarction [2]. (See "Spinal cord infarction: Clinical presentation and diagnosis", section on 'Diagnostic evaluation'.)
●Alternatives if urgent MRI not available – Computed tomography (CT) or CT myelogram of the spine are reasonable alternatives to exclude spinal cord compression if an MRI is contraindicated or if an MRI cannot be obtained immediately. However, a normal CT does not rule out an intrinsic spinal cord lesion.
Patients with imaging evidence of acute spinal cord compression require urgent definitive treatment to prevent further deterioration.
DIAGNOSIS
Is the myelopathy inflammatory? — If a compressive myelopathy is ruled out, the clinician should determine whether the myelopathy is inflammatory or noninflammatory. (See 'Additional studies for the cause of myelopathy' below.)
The best surrogate markers for inflammation are an inflammatory cerebrospinal fluid (ie, with pleocytosis and/or an elevated immunoglobulin G [IgG] index) or a spinal MRI demonstrating active breakdown of the blood-brain barrier (ie, with a gadolinium-enhancing lesion).
However, postcontrast enhancement and cerebrospinal fluid (CSF) pleocytosis can be seen in the setting of vascular myelopathies and hence are not specific for TM. Thus, the patient's history, MRI findings, and CSF findings must all be considered when determining if the presentation fits best for TM.
Diagnostic criteria for TM — Although a set of diagnostic criteria for TM (table 3) has been developed for research purposes, not all are necessarily required to make the diagnosis in clinical practice [46,69]:
●Sensory, motor, or autonomic dysfunction attributable to the spinal cord
●T2 hyperintense signal change on spinal MRI
●No evidence of compressive cord lesion
●Bilateral signs and/or symptoms
●Clearly defined sensory level
●Inflammation defined by CSF pleocytosis, elevated IgG index, or gadolinium enhancement on MRI
●Progression to maximal neurologic deficit (nadir) between 4 hours and 21 days
The most critical of these are the first three. The diagnosis of TM requires exclusion of a compressive cord lesion, usually by MRI.
The diagnosis is supported by the presence of inflammation as determined by either gadolinium-enhanced MRI or lumbar puncture. However, some patients presenting with TM may not fulfill all of the above criteria. As an example, a significant percentage of individuals with a clinical pattern that otherwise resembles TM do not meet the inflammatory features; therefore, the absence of inflammatory markers does not rule out TM [27]. Furthermore, some mimics of TM, specifically vascular myelopathies, can have signal change on MRI and pleocytosis within the CSF.
Thus, a clinical history is critical for narrowing down the diagnosis. For example, patients with a history of rapid symptom progression (<6 hours) should be suspected of having a vascular etiology (although some nonvascular pathologies can present acutely). A prior history of other inflammatory events (eg, optic neuritis) is suggestive of systemic autoimmune diseases such as multiple sclerosis or neuromyelitis optica spectrum disorder (NMOSD).
DETERMINING THE CAUSE OF TM — When an inflammatory myelopathy (ie, TM) is confirmed, it is important to distinguish idiopathic TM from secondary (disease-associated) TM, such as a multifocal central nervous system (CNS) inflammatory demyelinating disease, a rare infection of the nervous system, a systemic rheumatologic disease, or a paraneoplastic syndrome.
Idiopathic TM is defined by its occurrence without a definitive etiology despite a thorough work-up.
The diagnostic approach to noncompressive myelopathy (algorithm 1), including TM, emphasizes the determination of distinct entities that are likely to have different treatment options, recurrence risks, and prognoses [46,69].
Additional studies for the cause of myelopathy — For patients without a compressive cord lesion on spine imaging, additional studies are warranted to determine the cause of myelopathy and evaluate for inflammatory conditions that can cause TM.
Lumbar puncture — For patients without a compressive cord lesion on spine imaging, we perform a lumbar puncture for cerebrospinal fluid (CSF) analysis including (at a minimum) cell count and differential, protein, glucose, Venereal Disease Research Laboratory (VDRL) test, oligoclonal bands, immunoglobulin G (IgG) index, and cytology. Additional CSF studies are warranted if there is suspicion for an infectious etiology.
CSF is abnormal in approximately one-half of patients, with a moderate lymphocytosis (typically <100/microL) and an elevated protein level (usually 100 to 120 mg/dL). Glucose levels are normal. In a case series of 170 adult patients with idiopathic TM, the mean CSF white blood cell count was 38/microL and mean protein level was 75 mg/dL (0.75 g/L) [67]. However, higher levels were observed in a pediatric case series, where the mean white cell count was 136/microL and the mean protein level was 173 mg/dL (1.73 g/L) [44].
Oligoclonal bands in CSF are found in 85 to 95 percent of patients with multiple sclerosis but are typically absent in patients with anti-aquaporin-4 (AQP4) antibody-mediated neuromyelitis optica spectrum disorder (NMOSD) or acute disseminated encephalomyelitis (ADEM).
Brain MRI — For patients with suspected myelopathy of undetermined cause in whom a compressive or other structural spinal cord lesion has been ruled out by initial imaging, we obtain a brain MRI, with and without gadolinium, to evaluate for the presence of brain and/or optic nerve lesions suggestive of multiple sclerosis, NMOSD, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), ADEM, or systemic inflammatory disorders that can involve the CNS.
Serologic tests and autoantibodies — Serologic studies are indicated when the cause of myelopathy remains undetermined [2,60,70].
●Autoantibodies:
•Serum AQP4-IgG and MOG-IgG by cell-based assay
•Antinuclear antibodies (ANA), double-stranded deoxyribonucleic acid (ds-DNA)
•Antibodies to extractable nuclear antigen (Ro/SSA, and La/SSB antibodies)
•Rheumatoid factor
•Antiphospholipid antibodies
•Antineutrophil cytoplasmic antibodies
•Paraneoplastic antibodies (table 4)
●Inflammatory markers:
•Erythrocyte sedimentation rate
•C-reactive protein
●Metabolic work-up:
•Serum copper and ceruloplasmin levels
•Serum cobalamin (vitamin B12), folate, methylmalonic acid, and homocysteine levels
•Serum alpha tocopherol (vitamin E) level
●Infectious work-up:
•Enterovirus serologies including D68
•HIV serology
•Syphilis serologies
•Lyme disease serology
•Varicella zoster virus (VZV) serology
•Human T-lymphotropic virus 1 (HTLV-1) serology
•Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test
Other studies in select patients — Select patients may need additional testing [45]:
●Chest CT scan to evaluate for evidence of sarcoidosis
●Salivary gland biopsy if high suspicion for Sjögren's disease but negative SSA/SSB antibody
●Neuro-ophthalmologic evaluation to look for evidence of optic neuritis
●Spinal angiogram in the setting of hyperacute myelopathies that are thought to be consistent with vascular myelopathies
●Evaluation for occult malignancy (see "Overview of paraneoplastic syndromes of the nervous system", section on 'Search for occult malignancy')
Clues to specific inflammatory causes
●CNS inflammatory demyelinating disorders – Clinical and imaging evidence (see 'Imaging features' above) of multifocal involvement within the CNS raise suspicion for TM associated with the following inflammatory demyelinating disorders:
•Multiple sclerosis (see "Evaluation and diagnosis of multiple sclerosis in adults" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis")
•Neuromyelitis optica spectrum disorder (NMOSD) (see "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis")
•Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (see "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis")
•Acute disseminated encephalomyelitis (ADEM) (see "Acute disseminated encephalomyelitis (ADEM) in adults" and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis")
●Systemic inflammatory disorders – Conditions that cause systemic inflammation, such as systemic lupus erythematosus, sarcoidosis, or Sjögren's disease, can present with TM as an initial event. Suspicion for a systemic inflammatory disorder is increased if the patient has certain clinical or paraclinical findings such as malar rash, livedo reticularis, serositis, night sweats, oral ulcers, or autoimmune antibodies. MRI findings can be instructive, as sarcoidosis often causes meningeal inflammation at the level of parenchymal involvement in the spinal cord.
Note that NMOSD is frequently associated with systemic autoimmune disorders, including systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren's disease, and may be associated with cancer. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis".)
●Paraneoplastic syndromes – Paraneoplastic myelopathies are often associated with longitudinally extensive transverse myelitis (LETM) on spine MRI that is tract-specific [71,72]. The most common antibodies include anti-Hu and anti-collapsin-responsive mediator protein 5 (CRMP5), and, less frequently, anti-amphiphysin antibodies (table 4). The usual associated malignancy is small cell lung cancer (SCLC). (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Spinal cord syndromes'.)
Patients suspected of having a paraneoplastic neurologic syndrome should be examined for paraneoplastic antibodies, and an evaluation for underlying malignancy should be performed (see "Overview of paraneoplastic syndromes of the nervous system", section on 'Search for occult malignancy'). In some cases, however, the paraneoplastic syndrome may precede the diagnosis of underlying malignancy.
The evaluation and diagnosis of paraneoplastic syndromes is reviewed in detail elsewhere. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Diagnostic evaluation'.)
●Infectious causes – Although rare, a CNS infection (table 1 and table 2) may be suspected with certain clinical or paraclinical factors, such as fever, meningismus, vesicular rash, adenopathy, or serologic or molecular identification of an infectious agent. (See 'Serologic tests and autoantibodies' above.)
The initial presentation of acute flaccid myelitis (AFM) can mimic inflammatory causes of acute TM [73]. Characteristic features of AFM include a febrile or respiratory illness before the onset of neurologic symptoms followed by acute flaccid limb weakness with evolution of weakness over hours to days. MRI of the spine shows evidence of predominantly gray matter involvement in the spinal cord. (See "Acute flaccid myelitis", section on 'Clinical features' and "Acute flaccid myelitis", section on 'Diagnostic approach'.)
Paralytic polio consists of acute flaccid weakness with pain due to anterior horn cell injury. The onset of weakness and pain may either coincide with or follow onset of severe illness. Paralytic polio develops in approximately 0.5 to 0.05 percent (1 in 200 to 1 in 2000) of individuals infected with poliovirus. The acute flaccid weakness ranges from one muscle or group of muscles to quadriplegia and respiratory failure. Proximal muscles usually are affected more than distal muscles, and legs more commonly than arms. Reflexes are decreased or absent. (See "Poliomyelitis and post-polio syndrome".)
DIFFERENTIAL DIAGNOSIS — The main considerations in the differential diagnosis of TM are conditions that cause other types of myelopathy (eg, compressive or noninflammatory) and nonmyelopathic disorders that may mimic TM (eg, Guillain-Barré syndrome). The prognosis, risk of recurrence, and treatment options differ between these distinct entities.
In a retrospective report from a tertiary center of 1193 patients referred between 2006 and 2021 for evaluation of TM, there were 421 with a noninflammatory myelopathy; among these, the most frequent diagnoses were spinal cord infarction in 47 percent and structural myelopathy (eg, cervical spondylosis, disc herniation, spinal cord syrinx) in 26 percent [23].
Time to nadir — The time from onset of symptoms to maximal neurologic deficit (nadir) is useful in narrowing the differential diagnosis.
●With idiopathic or secondary TM, the time to nadir is typically within 1 to 21 days.
●With spinal cord infarction, the time to nadir is usually within 1 to 12 hours.
Other types of myelopathy may continue to progress beyond 21 days; examples include cervical spondylotic myelopathy, dural arteriovenous fistula, paraneoplastic myelopathy, metabolic myelopathy, and primary progressive multiple sclerosis [2]. (See "Disorders affecting the spinal cord".)
Compressive myelopathy — Disc herniations, vertebral body compression fractures, and spondylosis are among the most common causes of compressive myelopathy. They may present without overt evidence or history of trauma. Identifying these disorders is critical since immobilization to prevent further injury, neurosurgical intervention, and/or high-dose methylprednisolone may be warranted in certain cases. Therefore, urgent imaging of the entire spine with MRI is indicated. (See 'Urgent spine imaging' above.)
●Cervical spondylotic myelopathy – The diagnosis of cervical spondylotic myelopathy is made by correlating the clinical features with evidence of cervical spondylosis and cord compression on MRI. (See "Cervical spondylotic myelopathy", section on 'Diagnosis'.)
●Tuberculosis arachnoiditis – Tuberculosis arachnoiditis of the spine is another potential cause of compressive myelopathy and is more common in developing countries than in the United States. The diagnosis should be suspected in patients with subacute onset of nerve root and cord compression signs who have a history of prior tuberculosis (TB) infection or disease, known or possible TB exposure, and/or past or present residence in or travel to an area where TB is endemic. A presumptive diagnosis may be made in the setting of spinal MRI with nodular arachnoiditis and unusually high cerebrospinal fluid (CSF) protein levels, with or without pleocytosis, particularly if a definitive diagnosis of TB has been established from an extraneural site of disease. (See "Central nervous system tuberculosis: An overview", section on 'Spinal arachnoiditis'.)
Vascular myelopathies — Vascular conditions that may present acutely (over hours) include spinal cord infarction (anterior or posterior spinal artery), spinal dural arteriovenous fistula, and hemorrhage (hematomyelia, epidural hematoma) [2].
●Spinal cord infarction – The diagnosis of spinal cord infarction is made in the setting of a compatible clinical syndrome, typically with rapidly developing myelopathic deficits in the absence of another identifiable etiology. Spine MRI findings have imperfect sensitivity and specificity for ischemia. However, diffusion-weighted images (DWI-MRI) improve the sensitivity of MRI to detect acute spinal ischemia. (See "Spinal cord infarction: Clinical presentation and diagnosis".)
●Dural arteriovenous fistula – Spinal-dural arteriovenous fistula predominately occurs in men 60 years of age and older, and typically presents with a progressive, stepwise myeloradiculopathy. MRI with contrast-enhanced magnetic resonance angiography (MRA) can identify a dural arteriovenous fistula but has imperfect sensitivity. (See "Disorders affecting the spinal cord", section on 'Vascular malformations'.)
●Epidural hematoma – Spinal epidural hematoma typically presents with local and/or radicular pain, followed by loss of sensory, motor, and bladder and bowel function. MRI is a sensitive imaging modality for these lesions. MRI findings vary according to the age of the clot, as described separately. (See "Disorders affecting the spinal cord", section on 'Spinal epidural hematoma'.)
Metabolic and toxic myelopathies — These disorders generally present with a chronic progressive course but may have a subacute onset or worsening [2].
●Metabolic – Metabolic myelopathies include copper deficiency myeloneuropathy, subacute combined degeneration due to vitamin B12 deficiency, and vitamin E deficiency [68,74]. Testing (serum copper and ceruloplasmin levels; cobalamin [vitamin B12], folate, methylmalonic acid, and homocysteine levels; and alpha tocopherol [vitamin E] level) should be obtained to exclude these potentially treatable disorders. These conditions are reviewed separately. (See "Copper deficiency myeloneuropathy" and "Disorders affecting the spinal cord", section on 'Subacute combined degeneration' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)
●Toxic – Toxic myelopathies include those caused by methotrexate, tumor necrosis factor-alpha medications, immune checkpoint inhibitors, radiation therapy, hepatic myelopathy leading to accumulation of toxins, substance use (nitrous oxide toxicity, heroin), and decompression myelopathy due to prolonged-duration diving with rapid ascent.
Radiation myelopathy is discussed in detail elsewhere. (See "Complications of spinal cord irradiation".)
Rare toxic myelopathies caused by diet include neurolathyrism due to neurotoxins in diets consisting mainly of Lathyrus species, as well as konzo due to cyanogens in diets consisting mainly of bitter cassava. (See "Disorders affecting the spinal cord", section on 'Lathyrism and konzo'.)
Neoplastic myelopathies — Both benign and malignant tumors can produce a myelopathy because of external spinal cord compression or intramedullary growth. Tumor types include primary spinal cord astrocytoma, ependymoma, primary intramedullary spinal cord lymphoma, and metastatic disease. Progression is often chronic (beyond 21 days), but subacute onset or worsening can occur. MRI of the entire spine with contrast can identify extradural tumors causing cord compression and intramedullary spinal cord tumors causing myelopathy. (See "Disorders affecting the spinal cord", section on 'Neoplasms'.)
Guillain-Barré syndrome — Patients with acute inflammatory demyelinating polyneuropathy (AIDP), the most common form of Guillain-Barré syndrome (GBS), may also present with progressive sensory and motor dysfunction [75]. However, several clinical and paraclinical features may be used to rapidly discriminate patients with AIDP from those with acute myelopathies (table 5).
●Patients with AIDP often have both upper and lower extremity involvement, though the lower extremity involvement is usually more severe. By contrast, patients with myelopathy may have only lower extremity involvement if the myelopathy is thoracic, or equivalent upper and lower extremity involvement if the myelopathy is cervical.
●Autonomic involvement differs. Patients with myelopathy are more likely to have urinary or bowel urgency or retention, while those with AIDP are more likely to have cardiovascular instability.
●Every attempt should be made to determine a neuropathic versus myelopathic pattern of sensory loss, since a sensory level is often definable in patients with acute myelopathy but is never present in AIDP.
●CSF analysis in AIDP usually shows an elevated protein with few white cells (ie, cytoalbuminologic dissociation), whereas patients with TM may have an inflammatory CSF with an elevated number of white blood cells and immunoglobulin G (IgG) index.
●Spinal MRI often shows a discrete cord lesion in myelopathy, whereas spinal MRI may be normal in AIDP. Spinal MRI in patients with GBS may reveal thickening and enhancement of the intrathecal spinal nerve roots and cauda equina. This may involve only the anterior spinal nerve roots or both the anterior and posterior spinal nerve roots. In exceptional cases of Miller Fisher syndrome, abnormalities of the spinal cord posterior columns have been described. However, these findings may have occurred in patients with variants of myelitis that were misinterpreted as peripheral inflammatory neuropathy.
●Electrodiagnostic studies may show conduction block or slowed conduction of peripheral nerves in AIDP and are usually (though not always) normal in myelopathies.
GBS is reviewed in greater detail separately. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)
SUMMARY AND RECOMMENDATIONS
●Definitions – Acute transverse myelitis (TM) is a neuroinflammatory spinal cord disorder that presents with the rapid onset of weakness, sensory alterations, and/or bowel and bladder dysfunction. Idiopathic TM is defined by its occurrence without a definitive etiology despite a thorough work-up. Secondary (disease-associated) TM is most often related to a systemic inflammatory autoimmune condition. (See 'Immunopathogenesis' above and 'Terminology and classification' above.)
TM is rare, with an annual incidence of one to nine new cases per million. (See 'Epidemiology' above.)
●Causes – Idiopathic TM often occurs as a postinfectious complication and presumably results from an autoimmune process. Alternatively, TM can be associated with infectious (table 1 and table 2), systemic inflammatory, or multifocal central nervous system (CNS) disease.
Acquired CNS demyelinating disorders that can cause TM include multiple sclerosis, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), neuromyelitis optica spectrum disorder (NMOSD), and acute disseminated encephalomyelitis (ADEM). (See 'Associated and causative conditions' above.)
●Clinical features – The onset of TM is characterized by acute or subacute development of myelopathic signs and symptoms consisting of the following (see 'Clinical features' above):
•Motor symptoms include a rapidly progressing paraparesis that can progress to quadriparesis. Initial flaccidity is followed by spasticity. The head and face are spared.
•Most patients have a sensory level (a dermatomal level at which sensation is normal above and reduce or absent below). Sensory symptoms may also include pain, dysesthesia, and paresthesia.
•Autonomic symptoms involve increased urinary urgency, bladder and bowel incontinence, difficulty or inability to void, incomplete evacuation and bowel constipation, and sexual dysfunction.
●Evaluation and diagnosis – The diagnosis of TM is suspected when there are acute or subacute signs and symptoms of motor, sensory, and/or autonomic dysfunction that localize to one or more contiguous spinal cord segments in patients with no evidence of a compressive cord lesion.
Thus, the diagnosis of TM requires exclusion of a compressive cord lesion, usually by MRI, and confirmation of inflammation by either gadolinium-enhanced MRI or lumbar puncture (algorithm 1). When inflammation is present in the absence of cord compression, the criteria for TM (table 3) have been met.
The evaluation next investigates the presence of infection, systemic inflammation, and the extent and sites of CNS inflammation (table 6). (See 'Initial evaluation' above.)
●Differential diagnosis – The main considerations in the differential diagnosis of idiopathic TM and secondary (disease-related) TM are conditions that cause noninflammatory types of myelopathy (eg, compressive, vascular, metabolic, toxic myelopathies) and nonmyelopathic disorders that may mimic TM (eg, Guillain-Barré syndrome). (See 'Differential diagnosis' above.)
●Treatment and prognosis – These issues are reviewed elsewhere. (See "Transverse myelitis: Treatment and prognosis".)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Douglas Kerr, MD, and Chitra Krishnan, MHS, who contributed to earlier versions of this topic review.
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