INTRODUCTION — Acute transverse myelitis (TM) is a rare, acquired neuro-immune 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 neuro-inflammatory disorders that includes acute disseminated encephalomyelitis, multiple sclerosis, myelin oligodendrocyte glycoprotein antibody disease (MOGAD), neuromyelitis optica spectrum disorder (NMOSD), and acute flaccid myelitis (AFM). The clinical features, diagnostic work-up, and acute and chronic therapies differ between these forms of TM. It is important in the evaluation of patients with acute myelopathies to exclude compressive and noninflammatory causes of myelopathy as well as to distinguish various types of TM, since the prognosis, risk of recurrence, and treatment options may differ among these distinct entities.
This topic will review transverse myelitis. Related conditions are discussed elsewhere:
Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis
Acute disseminated encephalomyelitis (ADEM) in adults
Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis
Manifestations of multiple sclerosis in adults
Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis
Neuromyelitis optica spectrum disorders (NMOSD): Clinical features and diagnosis
Poliomyelitis and post-polio syndrome
Acute flaccid myelitis
ETIOLOGY
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 [1]. Axonal degeneration was also reported [1]. 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. TM has been reported after vaccination [2,3], and autopsy reports have described lymphocytic infiltration with demyelination and axonal loss [4]. Although these case reports describe TM in association with vaccination, causation has not been established based on the timing and sequence of events alone. 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 [5]. 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.
While TM can be a manifestation of recurring autoimmune conditions of the central nervous system, such as multiple sclerosis and neuromyelitis optica spectrum disorder, there are times when the cause of TM is not identified. In this situation, the TM is referred to as idiopathic TM. In 30 to 60 percent of the idiopathic TM cases, there is an antecedent respiratory, gastrointestinal, or systemic illness [6-12]. Nevertheless, these are considered idiopathic because the causative nature of the infection is seldom proven. 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, herpes virus, and Listeria monocytogenes (table 1 and table 2) [13], and only rarely with direct microbial infection of the central nervous system. Molecular mimicry and super antigen-mediated disease have also been described as potential mechanisms of autoimmunity [4]. 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 [14]. Microbial super antigens 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 [4,15-18], thereby triggering autoimmune disease by activating preexisting auto-reactive T cell clones [19,20].
The diverse pathology of disease-associated TM is evident from studies showing that lupus-associated TM could be associated with central nervous system vasculitis or thrombotic infarction of the spinal cord [4,21-25]. Other studies have also described the role of autoantibodies in patients with neuromyelitis optica spectrum disorder and recurrent TM [26-29]. 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 that cross-react with antibodies directed against infectious pathogens [4].
Associated and causative conditions — Idiopathic TM usually occurs as a postinfectious complication and appears to result from an autoimmune process. Alternatively, secondary TM can be directly associated with infectious, systemic inflammatory, or multifocal central nervous system disease. We use the term transverse myelitis 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 [30].
●Central nervous system autoimmune 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 [CIS]) 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 neuromyelitis optica spectrum disorder. However, neuromyelitis optica spectrum disorder 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 disorders (NMOSD): Clinical features and diagnosis", section on 'Transverse myelitis'.)
•Acute disseminated encephalomyelitis (ADEM) – TM may be seen in patients with ADEM, a demyelinating disease of the central nervous system 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".)
•Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) – This disorder is associated with a variety of manifestations related to central nervous system demyelination that include relapsing and bilateral optic neuritis, transverse myelitis, brainstem encephalitis, and 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'.)
●Systemic inflammatory autoimmune disorders have been associated with TM, but some conditions are more common than others.
The systemic inflammatory autoimmune disorders more commonly associated with TM include the following:
•Sarcoidosis [31-33] (see "Neurologic sarcoidosis", section on 'Brain and spinal cord involvement')
•Sjögren syndrome [34-36] (see "Neurologic manifestations of Sjögren's syndrome", section on 'Focal or multifocal demyelination/inflammation')
•Systemic lupus erythematosus [34,37,38] (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 [39,40] (see "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults")
•Antiphospholipid antibody syndrome [34,41,42] (see "Clinical manifestations of antiphospholipid syndrome", section on 'Neurologic involvement')
•Behçet disease [43,44] (see "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Neurologic disease')
•Mixed connective tissue disease [45] (see "Clinical manifestations and diagnosis of mixed connective tissue disease")
•Rheumatoid arthritis [46] (see "Neurologic manifestations of rheumatoid arthritis")
•Systemic sclerosis [47] (see "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults")
●Infections including but not limited to enteroviruses (commonly enterovirus D68 and EV71), West Nile virus, herpes viruses, HIV, human T-cell leukemia virus type 1 (HTLV-1), Zika virus [48], neuroborreliosis (Lyme), Mycoplasma, and Treponema pallidum (table 1 and table 2). In general, infectious causes of spinal cord dysfunction are rare, but outbreaks of acute flaccid myelitis (AFM) serve as a reminder of the myelitis outbreaks seen during poliovirus outbreaks. (See "Acute flaccid myelitis".)
●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. However, 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, antiamphiphysin antibodies (table 3). The usual culprit is small cell lung cancer (SCLC). (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Spinal cord syndromes'.)
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 refers to spinal cord dysfunction that is mild or grossly asymmetric with an MRI lesion extending one to two vertebral segments.
●Acute complete TM refers to 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 magnetic resonance imaging (MRI) lesion extending one to two vertebral segments.
●Longitudinally extensive transverse myelitis (LETM) refers to complete or incomplete spinal cord dysfunction with a lesion on MRI that extends three or more vertebral segments.
●Gray matter-centric myelitis is the pattern that is seen in acute flaccid myelitis (AFM). Clinically, patients with this pattern of involvement will suffer from lower motor neuron patterns of weakness (eg, reduced reflexes, decreased tone). (See "Acute flaccid myelitis".)
These subtypes of TM, while imperfect, imply distinct differential diagnoses and prognoses.
EPIDEMIOLOGY — Although TM is a rare disorder, the reported incidence between one to eight new cases per million people per year [49,50] is probably an underestimate. These numbers would imply that approximately 1400 new cases occur in the United States per year and that about 34,000 people have chronic morbidity from TM at any time [6-8].
A bimodal peak between the ages of 10 to 19 years and 30 to 39 years has been reported [6-8]. Approximately 20 percent of cases are under the age of 18 years [51]. One report 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 gender predisposition [51]. In the 30 days prior to the onset of TM symptoms, there was a preceding illness in 47 percent of the children and vaccination in 28 percent. There were no patterns in the illness or vaccine history that correlated with the acute onset of disease.
There is no gender or familial predisposition to TM, although women predominate among the cases that are associated with multiple sclerosis [52].
In one series of 354 patients with TM, approximately 64 percent of cases were idiopathic and 36 percent were disease-associated (secondary TM) [1]. In other reports, idiopathic TM accounts for 15 to 30 percent of cases [53-55]. These wide discrepancies in the frequency of idiopathic TM may reflect variation in catchment area populations, disease definitions, and the evolution of diagnostic methods.
CLINICAL FEATURES
Onset and progression — 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 first symptoms were sensory change, weakness, and pain in 39 percent, 25 percent, and 22 percent, respectively [56]. Bladder and bowel symptoms and balance problems were less frequent first symptoms. Among children (n = 70), presentation with pain or weakness was more common in comparison with adults.
In a retrospective series of 47 children with TM, the mean time to nadir from the onset of acute symptoms was approximately two days [51]. Symptoms of sensory loss or numbness, weakness, urinary dysfunction, or pain were present in 91, 89, 85, and 75 percent of children, respectively [51]. Most (89 percent) of the children were bed bound or wheelchair bound in the initial phase of TM.
Motor symptoms — Motor symptoms include a rapidly progressing paraparesis that can involve the upper extremities (depending on location of the lesion within the spinal cord), with initial flaccidity followed by spasticity if caused by white matter damage [1,4,10]. Gray matter involvement would lead to persistent flaccid weakness.
Sensory symptoms — Typical sensory symptoms are pain, dysesthesia, and paresthesia, although paresthesia are uncommon in children [1,57]. In one series of 170 patients with idiopathic TM, spinal magnetic resonance imaging (MRI) T2-weighted imaging showed a cervical signal abnormality in 44 percent and a thoracic signal abnormality in 37 percent [58].
Most patients have a sensory level. 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 noted that a thoracic clinical sensory level was present in 53 percent [51].
Autonomic symptoms — Autonomic symptoms include increased urinary urgency, bladder and bowel incontinence, difficulty with voiding or inability to void, bowel constipation, and sexual dysfunction [1,59-61].
EVALUATION AND DIAGNOSIS
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.
Diagnostic criteria — Although a set of diagnostic criteria for TM (table 4) has been developed for research purposes, not all are necessarily required to make the diagnosis in clinical practice [54,62]:
●Sensory, motor, or autonomic dysfunction attributable to the spinal cord
●T2 hyperintense signal change on spinal magnetic resonance imaging (MRI)
●No evidence of compressive cord lesion
●Bilateral signs and/or symptoms
●Clearly defined sensory level
●Inflammation defined by cerebrospinal fluid pleocytosis, elevated immunoglobulin G (IgG) index, or gadolinium enhancement on MRI
●Progression to 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 [34]. Furthermore, some mimics of TM, specifically vascular myelopathies, can have signal change on MRI and pleocytosis within the cerebrospinal fluid (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.
History and examination — 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, sensory loss, bowel/bladder incontinence, and urinary retention. The onset of urinary retention may be the first sign of myelitis. Any of these symptoms should at least raise the possibility of a myelopathy and a consideration for MRI imaging of the spine. The history should be explored for important preceding factors such as systemic or central nervous system autoimmune disorders, and antecedent respiratory, gastrointestinal, or systemic illness. Even in the absence of antecedent illness, consideration for myelitis is imperative.
On examination, localization of neurologic dysfunction is always an important objective; 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. Central nervous system motor deficits are characterized by weakness and long tract signs (eg, spasticity, increased reflexes, Babinski sign). 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. 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 and an anterior horn cell pathology leading to motor weakness. Thus, in the right setting, imaging must be considered in all patients with weakness. A spinal cord sensory level, with normal sensation above and reduced or absent 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 to a myelopathy until proven otherwise.
Urgent spine imaging — When myelopathy is suspected, urgent spinal imaging is warranted to exclude a compressive etiology. An MRI of the spine is the preferred diagnostic study for suspected TM, but a spine computed tomography (CT) or CT myelogram are reasonable alternatives to exclude spinal cord compression if an MRI is contraindicated or if an MRI cannot be obtained immediately. A normal CT does not rule out an intrinsic cord lesion.
Determining if the myelopathy is inflammatory — If a compressive myelopathy is ruled out, the clinician should determine whether the myelopathy is inflammatory or noninflammatory. The best surrogate markers for inflammation are an inflammatory cerebrospinal fluid (ie, with pleocytosis and/or an elevated IgG index) or a spinal MRI demonstrating active breakdown of the blood-brain barrier (ie, with a gadolinium enhancing lesion). However, postcontrast enhancement and a 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 cerebrospinal fluid findings must all be considered when determining if the presentation fits best for TM.
●Spine MRI – MRI of the entire spine, with and without gadolinium, is the best study to evaluate for parenchymal spinal cord lesions. MRI of the spinal cord in patients with TM typically shows a gadolinium-enhancing signal abnormality (image 1), usually extending over one or more cord segments [6,51,63,64]. The cord often appears swollen at the affected levels. In an adult case series of 170 patients with idiopathic TM [58], the rostral-caudal extent of the lesion ranged from one vertebral segment in many to the entire spinal cord in two patients. A similar pattern was seen in children, with the average lesion spanning six segments [51].
●CSF analysis – We perform a lumbar puncture for CSF analysis including (at a minimum) cell count and differential, protein, glucose, Venereal Disease Research Laboratory test (VDRL), oligoclonal bands, IgG index, and cytology. Additional CSF studies are warranted if there is suspicion for an infectious etiology, as indicated in the table (table 5).
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/mm3 and mean protein level was 75 mg/dL (0.75 g/L) [58]. 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) [51].
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 inflammatory demyelinating disease, a rare infection of the nervous system, a systemic rheumatologic disease, or a paraneoplastic syndrome (table 5). 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, risk of recurrence, and prognoses [54,62].
CNS inflammatory demyelinating disorders — Clinical and imaging evidence of multifocal involvement within the central nervous system (CNS) raise suspicion for TM associated with multiple sclerosis, neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody disease (MOGAD), or acute disseminated encephalomyelitis (ADEM) (table 5).
●Brain MRI – Brain MRI with and without gadolinium is recommended to evaluate for the presence of brain and/or optic nerve lesions suggestive of multiple sclerosis, NMOSD, MOG antibody disorders, or ADEM.
●Autoantibody testing – For patients with suspected TM of unknown etiology, we test for serum anti-aquaporin-4 (AQP4) IgG autoantibodies (associated with NMOSD) and anti-MOG IgG autoantibodies (associated with MOGAD).
●CSF findings – Oligoclonal bands in CSF are found in 85 to 95 percent of patients with multiple sclerosis but are more frequently absent in patients with anti-AQP4 antibody-mediated NMOSD or ADEM.
The evaluation and diagnosis of these disorders is reviewed in detail separately. (See "Evaluation and diagnosis of multiple sclerosis in adults" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis" and "Neuromyelitis optica spectrum disorders (NMOSD): Clinical features and diagnosis" and "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis" and "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 syndrome, 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 (table 5). MRI findings can be instructive as sarcoidosis often causes meningeal inflammation at the level of parenchymal involvement in the spinal cord.
Studies are useful to evaluate for systemic autoimmune disorders include (table 5):
●Anti-AQP4 antibodies
●Anti-MOG antibodies
●Serum antinuclear antibodies (ANA), ds DNA
●Antibodies to extractable nuclear antigen (Ro/SSA, and La/SSB antibodies)
●Rheumatoid factor
●Antiphospholipid antibodies
●Antineutrophil cytoplasmic antibodies
●Serum erythrocyte sedimentation rate
●C reactive protein
●Chest CT scan to evaluate for evidence of sarcoidosis
●Salivary gland biopsy (if high suspicion for Sjögren syndrome but negative SSA/SSB antibody)
●Paraneoplastic antibodies (see 'Paraneoplastic syndromes' below)
Infectious causes — Although rare, a central nervous system 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 (table 5). Examples of tests for infectious etiologies that may be warranted (table 5) include:
●Enterovirus testing
●HIV testing
●Syphilis serologies
Paraneoplastic syndromes — Paraneoplastic myelopathies are often associated with longitudinally extensive transverse myelitis on spine MRI that is tract-specific [65,66]. The most common antibodies include anti-Hu and anti-collapsin-responsive mediator protein 5 (CRMP5), and, less frequently, antiamphiphysin antibodies (table 3). The usual culprit is small cell lung cancer. (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. In some cases, however, 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'.)
Deficiency syndromes — Metabolic myelopathies may mimic TM, including copper deficiency, vitamin B12 deficiency, and vitamin E deficiency [53]. The following studies should always be obtained to exclude these potentially treatable disorders:
●Serum copper and ceruloplasmin
●Serum vitamin B12 and methylmalonic acid
●Serum vitamin E
Additional testing — Select patients may need additional testing [53]:
●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)
●Prothrombotic evaluation
DIFFERENTIAL DIAGNOSIS — The main considerations in the differential diagnosis of idiopathic TM are conditions that cause other types of myelopathy (eg, compressive or noninflammatory), the various disorders that cause secondary TM, and nonmyelopathic disorders that may mimic TM (eg, Guillain-Barré syndrome).
Other types of myelopathy — Patients with acute myelopathy may be recognized by a constellation of motor, sensory, and autonomic dysfunction, usually with myelopathic signs such as changes in urinary function and/or a sensory level (table 6). Magnetic resonance imaging (MRI) of the entire spine is important in the evaluation and diagnosis of acute myelopathy and in the distinction between different types of myelopathy (table 7), particularly for distinguishing a noncompressive inflammatory lesion from a structural abnormality or mass lesion causing spinal cord compression. 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.
Disc herniations, epidural masses or blood, 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 spinal cord imaging is indicated. Tuberculosis of the spine is another potential cause of compressive myelopathy and is more common in developing countries than in the United States.
Noninflammatory conditions that may mimic TM include the following [53]:
●Vascular myelopathies
•Anterior spinal artery infarction
•Spinal-dural arteriovenous fistula
•Fibrocartilaginous embolism
●Metabolic and nutritional myelopathies [67]
•Vitamin B12 deficiency
•Vitamin E deficiency
•Copper deficiency
•Nitrous oxide toxicity
•Neurolathyrism and neurocassavism
●Neoplasms
•Intramedullary primary spinal cord tumor
•Primary central nervous system lymphoma
•Intravascular lymphoma
●Radiation myelopathy (see "Complications of spinal cord irradiation")
Secondary transverse myelitis — Distinguishing idiopathic TM from secondary (disease-associated) TM is reviewed above. (See 'Determining the cause of TM' above.)
Acute flaccid myelitis — 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 with a clinical syndrome similar to poliomyelitis. Most cases have occurred in children; adults are rarely affected. (See "Acute flaccid myelitis", section on 'Pathogenesis and etiology' and "Acute flaccid myelitis", section on 'Epidemiology'.)
The initial presentation of AFM can mimic inflammatory causes of acute TM [68]. 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'.)
Standard testing of patients suspected of AFM includes MRI of the cervical and thoracic spine with and without contrast, MRI of the brain with and without contrast, cerebrospinal fluid (CSF) analysis, nasopharyngeal swabs for viral testing, fecal samples for viral testing, serum testing for potential mimics, and, in some cases, electrophysiology. (See "Acute flaccid myelitis", section on 'Diagnostic approach'.)
Guillain-Barré syndrome — Patients with acute inflammatory demyelinating polyneuropathy (AIDP; Guillain-Barré syndrome) may also present with progressive sensory and motor dysfunction [69]. However, several clinical and paraclinical features may be used to rapidly discriminate patients with AIDP from those with acute myelopathies (table 8).
●First, 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 between patients with AIDP and myelopathy. 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.
●Cerebrospinal fluid analysis in AIDP usually shows an elevated protein with few white cells (ie, cytoalbuminologic dissociation) whereas patients with TM may have an inflammatory cerebrospinal fluid with an elevated number of white blood cells and immunoglobulin G (IgG) index.
●Spinal MRI imaging often shows a discrete cord lesion in myelopathy, whereas spinal MRI may be normal in AIDP. Some reports indicate that spinal MRI in patients with Guillain-Barré syndrome 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
●Finally, electrodiagnostic studies may show conduction block or slowed conduction of peripheral nerves in AIDP and are usually (though not always) normal in myelopathies.
Guillain-Barré syndrome is reviewed in greater detail separately. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)
TREATMENT
Acute idiopathic TM — We suggest high-dose intravenous glucocorticoid treatment for patients with acute idiopathic TM. Glucocorticoid treatment should be initiated as soon as possible; there are relatively few contraindications. Thus, a clinician does not need to wait for the workup to be complete before initiating therapy. Our preferred regimens are methylprednisolone (30 mg/kg up to 1000 mg daily) or dexamethasone (120 to 200 mg daily for adults) for three to five days. Continued treatment with glucocorticoids or more aggressive regimens is based upon the clinical course and radiologic parameters.
Intravenous glucocorticoids have long been considered the standard of care and first-line therapy in acute idiopathic TM. Even without placebo-controlled trials evaluating glucocorticoids specifically in TM [52], there is good evidence that intravenous glucocorticoids are effective in acute inflammatory central nervous system diseases like TM, such as multiple sclerosis. (See "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Initial therapy with glucocorticoids'.)
Plasma exchange may be effective for acute central nervous system demyelinating diseases that fail to respond to high-dose glucocorticoid treatment [70-72]. Thus, in addition to high-dose glucocorticoid therapy, we suggest treatment with plasma exchange for patients who have acute TM with motor impairment [73]. Our preferred regimen is five treatments, each with exchanges of 1.1 to 1.5 plasma volumes, every other day for 10 days; alternatively, the first two plasma exchange treatments can be given on successive days, with the remaining three treatments given every other day [74]. For patients with significant deficits, waiting until glucocorticoid treatments are completed is not necessary. Clinical judgment must be used, and some patients may benefit from earlier intervention with plasma exchange. Most patients can be exchanged with albumin instead of plasma, but fibrinogen levels should be monitored. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology" and "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)
In the clinical experience of the authors, intravenous cyclophosphamide (800 to 1200 mg/m2 administered as a single pulse dose) for patients with aggressive TM has been associated with good outcomes, but this was most notable in patients with systemic lupus erythematosus. In a retrospective study, all 122 patients with idiopathic TM were treated with three to five days of intravenous methylprednisolone, either alone (n = 66) or in combination with plasma exchange (n = 32), cyclophosphamide (n = 13), or both plasma exchange and cyclophosphamide (n = 11) [75]. In a subset of patients with systemic autoimmune disease (eg, systemic lupus erythematosus), the addition of cyclophosphamide to the treatment regimen improved outcomes. In the absence of systemic autoimmune disease, plasma exchange plus methylprednisolone was superior to methylprednisolone alone. Given the methodologic limitations of this small, uncontrolled observational study, these findings require confirmation in randomized controlled trials.
Recurrent idiopathic TM — For patients with recurrent idiopathic TM, chronic immunomodulatory therapy is a reasonable treatment option. We most commonly treat patients with mycophenolate (2 to 3 g daily) or intravenous rituximab (1000 mg every six months), but other immunosuppressive regimens may be used in patients with systemic inflammatory disease [4].
Acute and recurrent secondary TM — Acute attacks of TM in patients with most types of central nervous system (CNS) or systemic inflammatory disorders are typically treated with high-dose intravenous glucocorticoids, similar to acute idiopathic TM. (See "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Initial therapy with glucocorticoids' and "Acute disseminated encephalomyelitis (ADEM) in adults", section on 'Initial therapy' and "Neuromyelitis optica spectrum disorders (NMOSD): Treatment and prognosis", section on 'Acute attacks'.)
Acute attacks of TM in rare patients with an infectious cause varies according to the specific infectious agent. Glucocorticoids and antiviral agents are often used for secondary TM associated with viral infections, but there is no high-quality evidence or consensus about management and the use of anti-inflammatory therapies is controversial. In the setting of AFM, for example, it is unclear if glucocorticoids, plasma exchange (PLEX), or intravenous immunoglobulin (IVIG) have any benefit. There are theoretical concerns about the use of glucocorticoids in these patients, but clinical data are mixed.
The treatment of secondary TM due to autoimmune etiologies is primarily directed at the underlying condition, as reviewed separately:
●Multiple sclerosis (see "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis" and "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults" and "Treatment of secondary progressive multiple sclerosis in adults" and "Treatment and prognosis of pediatric multiple sclerosis")
●Aquaporin-4 (AQP4) antibody-associated NMOSD (see "Neuromyelitis optica spectrum disorders (NMOSD): Treatment and prognosis", section on 'Attack prevention')
●Acute disseminated encephalomyelitis (ADEM) (see "Acute disseminated encephalomyelitis (ADEM) in adults", section on 'Treatment' and "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis")
●Ankylosing spondylitis (see "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults")
●Antiphospholipid antibody syndrome (see "Management of antiphospholipid syndrome", section on 'Central nervous system manifestations')
●Behçet disease (see "Treatment of Behçet syndrome", section on 'Neurologic disease')
●Mixed connective tissue disease (see "Prognosis and treatment of mixed connective tissue disease", section on 'Treatment')
●Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (see "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Treatment and prognosis")
●Neurologic sarcoidosis (see "Neurologic sarcoidosis", section on 'Treatment')
●Sjögren syndrome (see "Neurologic manifestations of Sjögren's syndrome", section on 'Treatment')
●Systemic lupus erythematosus (see "Neurologic manifestations of Sjögren's syndrome", section on 'Treatment')
Treatment for TM due to a paraneoplastic etiology is directed at the underlying malignancy [65].
PROGNOSIS
Recovery — Most patients with idiopathic TM have at least a partial recovery, which usually begins within one to three months, and continues with exercise and rehabilitation therapy [76]. Recovery can proceed over years. Some degree of persistent disability is common, occurring in about 40 percent [51,76]. A very rapid onset with complete paraplegia and spinal shock has been associated with poorer outcomes [34,76-78].
Research is needed to define biomarkers of disease that predict outcome and risk of recurrence. Ongoing aggressive rehabilitation with activity-based therapy is recommended in these patients.
Recurrence — The majority of patients with idiopathic TM experience a monophasic disease. Recurrence has been reported in 25 to 33 percent of patients with idiopathic TM [79-81], but these studies include cohorts that predated the widespread use of anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin-4 (AQP4) testing. In addition, TM can recur in a subset of patients with a history of systemic autoimmune disease. With disease-associated TM, the recurrence rate may be as high as 70 percent [6,49,55].
Features present at the time of initial acute onset that may predict recurrence (table 9) include the following [1,81]:
●Multifocal or longitudinally extensive lesions in the spinal cord on magnetic resonance imaging (MRI)
●Brain lesions on MRI
●Presence of one or more autoantibodies (antinuclear antibody [ANA], double stranded DNA [dsDNA], phospholipid, cytoplasmic anti-neutrophil cytoplasmic antibodies [c-ANCA])
●Underlying mixed connective tissue disease
●Presence of oligoclonal bands in the cerebrospinal fluid
●Seropositivity for neuromyelitis optica immunoglobulin G (NMO-IgG; AQP4) antibody
●Persistent seropositivity for the anti-MOG-IgG antibody (see "Evaluation and diagnosis of multiple sclerosis in adults", section on 'MOGAD')
In patients with severe complete acute TM, brain MRI is almost always normal. These patients are less likely to present with oligoclonal bands, less likely to relapse with a second bout of myelitis, and less likely to transition to clinically definite multiple sclerosis. (See 'Progression to multiple sclerosis' below.)
Progression to multiple sclerosis — Patients presenting with acute complete TM (complete or near complete clinical deficits below the lesion) have a generally cited risk of multiple sclerosis of only 5 to 10 percent [77,82], although some reports suggest a higher conversion rate [83]. However, partial or incomplete myelitis with mild or grossly asymmetric spinal cord dysfunction is a more common clinical entity and bears greater relevance to multiple sclerosis. Patients who have acute partial myelitis as an initial presentation and cranial MRI abnormalities showing lesions typical for multiple sclerosis have a transition rate to multiple sclerosis over three to five years of 60 to 90 percent [83-85]. In contrast, patients with acute partial myelitis who have a normal brain MRI develop multiple sclerosis at a rate of only 10 to 30 percent over a similar time period [86].
The length of the spinal cord lesion is also associated with the risk of progression to multiple sclerosis. In a retrospective report of patients with isolated myelitis and no evidence of inflammation or demyelination elsewhere in the central nervous system, progression to MS with short-segment myelitis (less than three vertebral segments) occurred in 25 of 77 patients (32 percent), while progression to MS with longitudinally extensive myelitis occurred in none of 23 patients (0 percent) [87].
Cerebrospinal fluid studies suggest that in patients with monosymptomatic disease, those with positive oligoclonal bands have a higher risk of evolution to multiple sclerosis than those without oligoclonal bands [88]. However, cerebrospinal fluid results do not help further in prognosis when compared with MRI alone.
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 neuro-inflammatory 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 'Introduction' above and 'Etiology' above.)
●Causes – Idiopathic TM usually 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 disease. Acquired central nervous system demyelinating disorders that can cause TM include multiple sclerosis, myelin oligodendrocyte glycoprotein (MOG) antibody disease, neuromyelitis optica spectrum disorder (NMOSD), and acute disseminated encephalomyelitis. (See 'Associated and causative conditions' above and 'Subtypes' above.)
●Epidemiology – TM is rare, with an annual incidence of one to eight new cases per million. (See 'Epidemiology' above.)
●Clinical features – The onset of TM is characterized by acute or subacute development of neurologic signs and symptoms consisting of motor, sensory, and/or autonomic dysfunction. Motor symptoms include a rapidly progressing paraparesis that can involve the upper extremities, with initial flaccidity followed by spasticity. In most patients, a sensory level can be identified. Sensory symptoms 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. (See 'Clinical features' above.)
●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 magnetic resonance imaging (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, then the criteria for TM (table 4) have been met, and it is necessary to evaluate for the presence of infection, systemic inflammation, and the extent and sites central nervous system inflammation (table 5). (See 'Evaluation and diagnosis' above.)
●Differential diagnosis – The main considerations in the differential diagnosis of idiopathic TM are conditions that cause other types of myelopathy (eg, compressive or noninflammatory or vascular), the various disorders that cause secondary TM, and nonmyelopathic disorders that may mimic TM (eg, Guillain-Barré syndrome). (See 'Differential diagnosis' above.)
●Treatment – For patients with acute idiopathic TM, we suggest high-dose intravenous glucocorticoid treatment (Grade 2C). Our preferred regimens are methylprednisolone (30 mg/kg up to 1000 mg daily) or dexamethasone (up to 200 mg daily for adults) for three to five days. For patients with acute TM complicated by motor impairment, we suggest additional treatment with plasma exchange (Grade 2C). Our preferred regimen is five treatments, each with exchanges of 1.1 to 1.5 plasma volumes, every other day for 10 days; alternatively, the first two plasma exchange treatments can be given on successive days, with the remaining three treatments given every other day. (See 'Treatment' above.)
●Prognosis
•Degree of recovery – Most patients with idiopathic TM have at least a partial recovery, which usually begins within one to three months and continues with exercise and rehabilitation therapy. Some degree of persistent disability is common, occurring in about 40 percent. A very rapid onset with complete paraplegia and spinal shock has been associated with poorer outcomes. Recovery can proceed over years. (See 'Recovery' above.)
•Risk of recurrence – The majority of patients with TM experience monophasic disease. Recurrence has been reported in approximately 25 to 33 percent of patients with idiopathic TM, although this usually signals a systemic condition. With disease-associated (secondary) TM, the recurrence rate may be as high as 70 percent. (See 'Recurrence' above.)
•Risk of multiple sclerosis – Patients presenting with acute complete transverse myelitis have a generally cited risk of multiple sclerosis of only 5 to 10 percent. However, for patients with partial myelitis as an initial presentation and cranial MRI abnormalities showing lesions typical for multiple sclerosis, the transition rate to multiple sclerosis over three to five years is 60 to 90 percent. In contrast, patients with acute partial myelitis who have a normal brain MRI develop multiple sclerosis at a rate of only 10 to 30 percent over a similar time period. (See 'Progression to multiple sclerosis' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Douglas Kerr, MD, and Chitra Krishnan, MHS, who contributed to earlier versions of this topic review.
