Chapter 18. Transverse Myelitis

Acute transverse myelopathy is a clinical syndrome consisting of progressive symptoms and signs reflecting sensory, motor, or autonomic dysfunction attributable to the spinal cord. This syndrome can be caused by a heterogeneous group of disorders, including acute transverse myelitis (ATM). Definitions of ATM have varied significantly in the literature.1,2 To address this nonuniformity, the criteria proposed by the Transverse Myelitis Consortium Working Group3 (Table 18–1) should be used to establish the diagnosis and guide the differential diagnosis and workup. The diagnosis of ATM can be further refined by determining whether there is partial or complete involvement of the spinal cord in the axial plane. Complete ATM is characterized by moderate to severe symmetric symptoms, while partial ATM is marked by milder, asymmetric symptoms.4

ATM can be associated with more diffuse central nervous system (CNS) demyelinating disorders, systemic autoimmune disorders, or specific associated infections. Idiopathic ATM is associated with a nonspecific preceding infection or no apparent cause and constitutes the most common subgroup of pediatric ATM.

Idiopathic ATM afflicts approximately 1.34 persons per million.5 In the pediatric age group, patients present at a mean age of 8 years with an equal gender ratio.1,2,4,6–9 Approximately 280 cases of ATM occur in pediatric patients in the United States per year.10,11

Infectious agents can cause spinal cord dysfunction by directly infecting the spinal cord parenchyma (infectious myelopathy)12 or by triggering postinfectious, immune-mediated processes. In some cases, such as human T-cell lymphotropic virus (HTLV) associated myelitis, damage to the spinal cord may be produced by direct infection as well as the immune response to the microbe. Several agents, including cytomegalovirus (CMV) and varicella-zoster virus (VZV), are associated with direct CNS infection in certain patients (many of whom are immunocompromised) and postinfectious ATM in others.

Among all cases of ATM, the preceding infection is most commonly a nonspecific upper respiratory tract infection.1,5,9 Approximately 50% of patients report a preceding infection with an intervening symptom-free interval of 5–11 days.1,5,9,10 Some cases of ATM are associated with recent vaccination, although causality is difficult to prove given the paucity of cases and the frequency with which children are vaccinated.1,6,10,13–15

Although the precise pathophysiology of ATM is uncertain, the frequent association with preceding infections and accumulating immunological data support an inflammatory cause for the disorder.1,5,16,17 Increased peripheral blood lymphocyte responses to myelin basic protein have been demonstrated in the research setting in patients with ATM.18 None of the six patients who were tested in the recovery stage in this study showed significant responses to myelin basic protein, suggesting that the cellular autoimmune reaction is short-lived. In addition, the production of interleukin-6 (IL-6) by astrocytes appears to lead to nitric oxide-induced injury to spinal cord oligodendrocytes and axons in patients with idiopathic ATM. IL-6 levels are markedly elevated in the cerebrospinal fluid (CSF) of patients with ATM and correlate with long-term disability.16

In a specific form of ATM which also includes optic neuritis, termed neuromyelitis optica (NMO),19 a novel biomarker (NMO-IgG) has been detected in 73% of adult patients and several pediatric patients.20–22 This auto-antibody targets the predominant CNS water channel protein aquaporin-4, which is concentrated in astrocytic foot processes in the blood–brain barrier. The role of NMO-IgG and aquaporin-4 in the more common, idiopathic form of ATM is uncertain.

Seven published case series ranging in size from 9 to 50 patients disclose common symptoms in pediatric patients with ATM.1,2,6–10 Patients universally report acute to subacute, bilateral leg weakness, which is symmetric in approximately 67% of patients.1 Involvement of the arms occurs in about 40% of patients. Approximately 90% of patients complain of bowel and bladder dysfunction. A similar percentage of patients report sensory symptoms, including paresthesias and numbness. Back pain and fever afflict nearly 50% of patients and may prompt consideration of primary infectious etiologies, such as an epidural abscess. The symptoms of ATM develop rapidly, peaking at an average of 2 and 5 days, in two respective studies.1,10

The general examination, although usually unremarkable, may reveal signs suggestive of an underlying systemic infection or autoimmune disorder. Abdominal examination may reveal a distended bladder. On the neurological examination, the presence of any mental status changes suggests that the myelitis is a component of a more diffuse process, such as acute disseminated encephalomyelitis (ADEM). In the acute stages, muscle tone is flaccid in affected limbs. All sensory modalities should be carefully assessed. A spinal cord sensory level is usually located in the thoracic region (80%) and less commonly in the cervical (10%) or lumbar (10%) area.5 In the acute phase, deep tendon reflexes are depressed in approximately 70% of patients and later become hyperactive. Similarly, Babinski responses may be negative early in the acute phase, but soon become positive, indicating upper motor neuron dysfunction.

Numerous disorders can affect the spinal cord and produce identical symptoms and signs that mimic idiopathic ATM (Table 18–2). Such conditions must be ruled out through a combination of history, physical examination, neuroimaging, and laboratory evaluation (Figure 18–1).

Isolated Spinal Cord Dysfunction

Extramedullary compressive lesions, including spinal epidural abscesses,23 spinal epidural hematomas,24 and tumors,25 are neurosurgical emergencies that must be diagnosed rapidly for effective treatment. Intramedullary lesions that can mimic ATM include primary spinal cord tumors (most commonly astrocytomas and ependymomas),26–28 radiation injury,29 spinal cord infarction, and vascular malformations.30 Direct infections of the spinal cord, typically viral in etiology, can also occur.

The initial clinical presentation of ATM can be very similar to that of Guillain–Barré syndrome. Both can present with back pain, paraparesis, and sensory abnormalities. Although typically absent in both disorders acutely, the presence of deep tendon reflexes would point strongly toward ATM. When deep tendon reflexes are absent, the presence of a spinal cord sensory level and bowel and bladder involvement is suggestive of ATM.

Spinal Cord Dysfunction Plus Additional Neurological or Systemic Symptoms and Signs

The presence of mental status changes and cerebral white matter magnetic resonance imaging (MRI) abnormalities point toward ADEM as the correct diagnosis. Mild, asymmetric spinal cord symptoms, previous episodes of transient neurological symptoms attributable to locations other than the spinal cord, and subclinical brain MRI lesions point toward multiple sclerosis.31 Concurrent or preceding optic neuritis suggests NMO as a possible diagnosis.19

ATM can also be secondary to a variety of systemic autoimmune disorders. Involvement of other organ systems, particularly the skin, lungs, kidneys, and joints, may point to a particular diagnosis, such as systemic lupus erythematosus or sarcoidosis.

Neuroimaging

Every patient with suspected ATM should undergo emergent gadolinium-enhanced MRI of the entire spine in order to confirm the diagnosis and rule out alternative diagnoses, particularly compressive lesions. T1- and T2-weighted sagittal imaging of the entire spine can serve as an initial screen followed by axial imaging in areas of suspected pathology.32 All patients with ATM should also undergo gadolinium-enhanced MRI of the brain to assess for additional demyelinating lesions suggestive of ADEM or multiple sclerosis.

Spinal MRI in ATM typically reveals T1 isointense and T2 hyperintense signal over several contiguous spinal cord segments,1 and may involve the entire spine.32 Spinal cord swelling with effacement of the surrounding CSF spaces may be present in severe cases. Contrast enhancement is present in as many as 74% of patients.10 In some patients with very suggestive clinical features, the initial spine MRI may be normal and should be repeated several days later.1,2,6 In some cases, the MRI remains normal, but does not rule out the diagnosis.10 Higher rostral levels and number of overall spinal segments predicts worse outcome.10

Lumbar Puncture

Unless a specific contraindication exists, all patients with ATM should undergo lumbar puncture. Approximately 50% of pediatric patients with ATM have CSF pleocytosis, typically with a lymphocytic predominance.10 Elevated CSF protein levels, either in isolation or in conjunction with pleocytosis, are also detected in about 50% of patients.10 Glucose is typically normal. A normal CSF profile does not rule out ATM, as this pattern is seen in approximately 25% of patients.

Additional Tests

The long list of infectious, demyelinating, and rheumatologic disorders potentially associated with ATM precludes diagnostic testing for every possible disorder (Table 18–3). The etiology of a direct infectious myelopathy is usually established by positive CSF culture or polymerase chain reaction results. In postinfectious ATM, a specific etiology can be suggested by elevated acute or rising convalescent serum titers and/or isolation of the agent from systemic sources in the setting of a suggestive clinical picture. The infectious disease workup should be focused on pathogens that are common, treatable, or suggested by particular clues in the history or examination, such as environmental exposures and immune status.

There have been no randomized, controlled treatment trials in ATM. On the basis of case reports and series which have suggested a beneficial effect,7,33,34 high-dose corticosteroids have become the standard of care in ATM. In one series of 12 children with severe ATM compared to a historical control group of 17 patients, the use of high-dose intravenous methylprednisolone significantly increased the proportion of children walking independently at 1 month (66% compared to 18%) and with full recovery at 1 year (55% compared to 12%).7 Although a variety of agents and courses have been used, we use intravenous methylprednisolone 30 mg/kg/dose once a day for 5 days (maximum daily dose 1 g). The need for a prednisone taper is controversial and may be based on whether full or partial recovery is achieved with the intravenous steroids. For patients who do not adequately improve with intravenous methylprednisolone, intravenous immunoglobulins (IVIG)35 or plasmapheresis can be used (Figure 18–2).

As most cases are attributed to secondary, immune-mediated mechanisms, antimicrobial treatment is not likely to have significant benefit. However, antimicrobial therapy should be considered in cases with highly suspected or proven associated infections, such as aeithromycin, doxycycline or levofloxacin for Mycoplasma pneumoniae,36 ganciclovir for CMV,37 and acyclovir for HSV and VZV.38 When antimicrobials are used, agents with good CSF penetration are preferred as direct CNS invasion may be present in some cases.

Additional treatment includes pain management, urinary bladder catheterization, bowel regimens, peptic ulcer and deep venous thrombosis prophylaxis, physical therapy, and psychosocial support. Mechanical ventilation is required in approximately 5% of patients.

Disability

Although the variable definitions of recovery reported in the literature preclude a definitive assessment, the prognosis for pediatric patients with ATM is generally favorable.39 Paine and Byers’ degree of recovery categories have been the most widely reported outcome scale but are limited by vague terminology.9 Based on this scale, approximately 80% of pediatric patients who receive high-dose intravenous methylprednisolone achieve full or good recovery and 20% have a fair or poor outcome.7,33 Among patients not treated with high-dose intravenous methylprednisolone, 60% have a full or good recovery, while 40% have a fair or poor outcome.9

One large, tertiary-referral, center-based study of 47 children with ATM, of whom 70% were treated with intravenous steroids, has cast doubt on the favorable prognosis of the disorder in childhood.10 In this study, approximately 40% of patients were nonambulatory and 50% required bladder catheterization at a median follow-up of 3.2 years. These results may have been influenced by a high percentage of patients younger than 3 years and patients with cervical involvement compared to other studies. Multicenter and/or population-based studies are needed to further clarify the prognosis of ATM in childhood.

During recovery, motor function returns first, with an average time to independent ambulation of 56 days in one study1 and 25 days in a group of patients treated with high-dose intravenous methylprednisolone.7 Bowel/bladder control recovers more slowly with an average time to recovery of normal urinary function of 7 months in those patients with complete recovery.1

Recurrences

The overwhelming majority of pediatric patients with idiopathic ATM do not have any recurrences. In a series of 24 pediatric patients with a mean follow-up of 7 years, there were no recurrences.1 In another study of children with a variety of initial acute demyelinating events, only 2 of 29 (7%) patients with transverse myelitis had a later demyelinating event.40,41