Transverse Myelitis (TM) is an inflammatory disorder of the spinal cord that may be idiopathic or related to other diseases.1,2 It is characterized by acute or subacute dysfunction of the spinal cord affecting the motor, sensory, and autonomic (bowel, bladder, sexual) systems below the lesion level.2
Consensus diagnostic criteria for idiopathic TM3:
- Bilateral (not necessarily symmetric) sensorimotor and autonomic spinal cord dysfunction.
- Clearly defined sensory level.
- Demonstration of spinal cord inflammation: cerebrospinal fluid pleocytosis of elevated immunoglobulin G index, or magnetic resonance imaging (MRI) revealing a gadolinium-enhancing cord lesion.
- Progression to nadir of clinical deficits between 4 hours and 21 days after symptom onset.
- Exclusion of compressive, post-radiation, neoplastic, and vascular causes.
Acute TM (ATM) occurs as an immune-mediated phenomenon or direct infection/invasion from viruses (20-40%), of which Coxsackie virus A7, A9 and A23 and B strains are most common; it can also occur from mycoplasma pneumoniae and schistosomiasis infection. It has been noted as a presenting symptom of systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS) in up to 39-50% of cases, but it can also be associated with other autoimmune or disease-associated causes such as multiple sclerosis (MS) and neuromyelitis optica (NMO). Despite thorough evaluation, 10-45% of the cases remain idiopathic.5
Epidemiology including risk factors and primary prevention
Annual incidence of TM in the United States is approximately 4.6 per million per year.2 Incidence in children is lower than in adults with up to 28% of the reported cases. There are three peaks of distribution occurring between 0-3 and 5-17 years old in the pediatric population4,5 and between 30-39 years old in adults. Idiopathic ATM has no racial, sex, familial, or geographical predilection, and there are no particular risk factors or method of primary prevention.
Histopathology of TM is characterized by lymphocytes and monocytes infiltrating focal areas of the cord with varying degrees of inflammation, demyelination, axonal injury, and astroglial and microglial activation. Necrosis and cavitation can result in more severe cases. The cord involvement in most cases of TM occurs in a central, uniform, and symmetric pattern in comparison with MS, which has patches of peripheral lesions. This may occur because of direct tissue damage or immune mediated infection-triggered tissue damage. The latter may involve mechanisms such as molecular mimicry, autoantibody development, or superantigen effect.2 Lesions may occur at any level of the spinal cord but more commonly at the thoracic level.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
- Onset of back pain,1 motor weakness, sensory deficits, and bladder or bowel dysfunction typically evolves over hours to days. Symptoms are usually bilateral, but are occasionally unilateral or asymmetric.2
- Progression to the nadir of clinical deficits is between 4 hours and 21 days after onset of symptoms (part of diagnostic criteria).2
- Clinically, it can present as a complete or partial spinal cord injury syndrome. Complete ATM characteristically results in paresis of lower and/or upper extremities and a sensory level, whereas a partial ATM would present with asymmetric neurological impairments.6 The course is typically monophasic but relapsing idiopathic TM may occur.2
- Most recovery occurs in the first 3 months after injury, but improvement may occur up to a year or longer.2
Specific secondary or associated conditions and complications
TM is a form of nontraumatic spinal cord injury (NTSCI), and thus has medical complications of NTSCI depending on the severity of injury to the cord. As with spinal cord injury (SCI), medical complications involving every organ system are common after TM. Medical management and complications are similar to SCI and should be managed in the same manner.7 It is crucial to determine the etiology, whether disease-associated or idiopathic, as this helps identify recurrence risk, appropriate treatment and surveillance that may be required to improve outcomes. 8
Specifically, secondary complications such as impaired mobility, and sensation, pressure ulcers, bowel and bladder dysfunction, sexual dysfunction, spasticity, movement disorders, autonomic dysregulation, and pain, should also be addressed.
2. ESSENTIALS OF ASSESSMENT
Signs of myelopathy, such as motor weakness, sensory abnormalities, pain, bowel or bladder dysfunction, as well as recent infections, vaccinations, travel, medical history, review of systems, social history, family medical history, and surgical history, should be considered in order to direct the investigation for a specific etiology.
In the pediatric population 50-100% of the cases are preceded by a mild febrile illness 3 weeks prior to onset of symptoms.8
The physical exam will likely change as the neurologic deficits progress or improve depending on the patient’s individual course. Serial exams will help identify the nadir of clinical findings.
Initial physical exams should evaluate the following:
- Muscle strength, tone, and muscle stretch reflexes.
- Sensory reflexes, including abdominal and bulbocavernosus reflexes.
- Rectal exam.
- Detailed sensory exam of dermatomes. Sensory loss is often described in a band-like or transverse level, with decreased sensation distally. 8
- Autonomic instability or dysfunction.
- Consider using the American Spinal Injury Association (ASIA) exam to classify completeness of the SCI.
- Skin evaluation for pressure ulcers, especially over insensate areas and bony prominences such as the occiput, sacrum, ischia, and heels.
- The Functional Independence Measure (FIM) and WeeFIM (for children) are commonly used tools to measure motor and cognitive functional status.9
- Spinal Cord Independence Measure (SCIM) are an alternative to the FIM to assess 16 categories of functional independence.
- Walking Index for Spinal Cord Injury (WISCI) assesses the amount of physical assistance and devices needed for ambulation.
- The SCIM and WISCI can be used for traumatic and nontraumatic and acute and chronic SCI for ages 13 to >65 years.
Lab studies focus on determining the etiology of the TM syndrome. This includes serology, cerebrospinal fluid, polymerase chain reaction, or specific markers to assess for:
- Central nervous system (CNS) manifestations of infections, for example syphilis, Lyme disease, human immunodeficiency virus, human T-lymphotropic virus type I, mycoplasma, herpes viruses, and enteroviruses.
- Connective tissue disease, for example sarcoidosis, Behcet disease, Sjogren disease, SLE, APS, and mixed connective tissue disease.
- Paraneoplastic causes
- Acquired CNS demyelinating disease: presence of CSF oligoclonal bands in multiple sclerosis; aquaporin-4 specific autoantibodies (NMO-immunoglobulin G) for neuromyelitis optica.
- Postinfectious or postvaccination causes.2,5
- Endocrinopathies such as thyroid disease.6
- Other: serum vitamin B12 and E, serum copper and ceruloplasmin in those at risk.6
MRI of the spine with gadolinium is required as the initial workup for acute myelopathy and to rule out conditions such as extrinsic spinal cord compression, ischemia, tumor, arteriovenous malformation and toxicities such as Vitamin 12 deficiency, or post-radiation myelopathy.
Acute partial and complete TM would commonly present on MRI as a single lesion spanning 1 or 2 vertebral levels. The differentiating feature is that in complete ATM there is full-thickness involvement of the spinal cord or its central portion is maximally affected, whereas in partial ATM the involvement is limited to a small portion of the spinal cord in axial sections. If the lesion extends over 3 or more vertebral segments, it is classified as a longitudinally extensive transverse myelitis (LETM),6 which is the most common finding in idiopathic monophasic ATM in children.4,10
MRI of the brain may be done as part of the initial investigation to evaluate for MS, NMO or a concomitant encephalopathy (e.g., Acute Disseminated Encephalomyelitis or ADEM).
Other imaging during the initial evaluation should include:
- Venous Doppler if there is concern for deep venous thrombosis.
- Renal ultrasound for possible renal parenchymal damage.
- Voiding Cystourethrogram for possible urinary reflux.
- Subsequent imaging needs are dependent on the patient’s clinical presentation and response to treatment.
Supplemental assessment tools
Urodynamic studies will allow optimization of a bladder management program.
Electrodiagnostic studies may play an important role in distinguishing peripheral from central lesions. For instance, nerve conduction studies can aid in distinguishing acute inflammatory demyelinating polyneuropathy (AIDP) from ATM. In the former, prolonged distal latencies & late responses, slowing of conduction velocities, and conduction block/temporal dispersion are characteristic findings. In ATM, such findings of peripheral demyelination would not be present.
Ophthalmological examination, ideally with patterned visual evoked potentials and ocular coherence tomography, to evaluate for optic neuritis even if the patient is asymptomatic, as this has important diagnostic implications for disease-associated transverse myelitis and recurrence risk.8
The differential diagnosis for TM can be extensive, encompassing conditions that present as acute myelopathy such as those mentioned above. Guillain Barré Syndrome (GBS) and acute TM may be indistinguishable in the acute phase. Both may present similarly with depressed reflexes, weakness, bladder and bowel dysfunction and autonomic dysregulation. With GBS, there is a lack of prominent sensory symptoms and involvement of cranial nerves, excluding the optic nerve. Spine MRI will demonstrate enhancement of spinal nerve roots and absence of intramedullary disease. CSF studies will show elevated protein in both conditions, but only ATM will demonstrate pleocytosis. In more obscure cases, a nerve conduction study may assist by demonstrating an acquired neuropathy in GBS. Although rare, there have been reports of ATM and GBS occurring together.8
Once a diagnosis of TM is made, further differentiation is needed whether it is idiopathic or disease-related.
Table 1. Differentiating factors in Idiopathic and Disease-associated TM:8
|Idiopathic TM||Elevated CSF protein and pleocytosis||Central, uniform, symmetric lesions, LETM (common in children)|
|Neuromyelitis Optica (NMO)||Serum & CSF Aquaporin 4 IgG||LETM|
|Multiple Sclerosis||CSF Oligoclonal bands||Patchy, peripheral lesions; segmental: < 3 vertebral segment involvement;|
Brain MRI with MS-like lesions
|Connective Tissue Disease||ANA, anti–double-stranded DNA antibody, antiphospholipid antibodies, anti–Ro/La antibody, complement 3 and 4 (low in SLE), SS antibodies|
Early predictions of outcomes
According to the National Institute of Health data on idiopathic TM, ultimately one-third of patients have full recovery with the ability to walk, one-third have a fair recovery with some deficits, and one-third have poor recovery with significant neurologic deficits. Most cases of TM are singular events; however, relapses or recurrences can happen. Prognosis in children is not clear cut, but data suggest 30-50% make a fully recovery, and a significant portion remain to have residual debilitating motor sequela.8
Good prognosis is seen in older children4 and young adult with subacute progression of symptoms, recovery begins early and when posterior column function and deep tendon reflex are preserved,11 lower sensory and anatomic levels of spinal injury, absence of T1 hypointensity on spinal MRI obtained during the acute period, lack of white blood cells in the CSF, and fewer affected spinal cord segments.4
Poor recovery has been associated with rapid onset/progression of symptoms, severe neurological deficits, sensory disturbances at cervical level, incontinence, lack of improvement in the first 3-6 months, presence of protein 14-3-3 in CSF11, LETM12 and ATM associated with NMO. Infants tend to have worse outcomes, postulated due to their immature nervous system and impaired ability to recover after a fulminant inflammatory attack. 8
Although ATM can be the initial manifestation of MS, it is a rare presenting symptom in pediatric MS. 8
Information about the patient’s home, school, or work environment is important in determining appropriate adaptive devices and equipment. Depending on the degree of impairment, environmental modifications may be needed for wheelchair use at home and work/school, use of ramps and door width adjustments to ensure safe mobility. Attendants/aids, bath and toilet equipment, assistive and adaptive devices, and technology can be adjunctive support for people with SCI to promote as much functional independence as possible.
Social role and social support system
Information about the patient’s family, friends, home, work/school situations, and other support systems will be helpful in guiding treatment and rehabilitation. Those with chronic neurologic disability are at higher risk for depression, anxiety and cognitive-behavioral impairment, thus will need to be monitored closely to provide appropriate counseling intervention and support.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
- Treatment begins with intensive surveillance for acute life-threatening respiratory and autonomic complications.
- High-dose intravenous methylprednisolone (30mg/kg/d – 1 g/d for 5-7 days) as the first line of treatment, followed by oral corticosteroid taper over 3-4 weeks.5,8
- Plasma exchange may be offered to those who fail to improve or worsen with 24-48 hours of beginning high-dose corticosteroid treatment. 5,8
- Immunosuppressive therapy with rituximab may be considered in patients with suspected TM because of NMO. Azathioprine, cyclophosphamide, and intravenous immunoglobulin have been used for prevention of recurrent TM attacks; however, evidence is insufficient with regard to its efficacy.5
At different disease stages
Acute and chronic disease management includes the following:
- Motor deficits: patients will likely have impaired function in mobility, ambulation, and activities of daily living (ADLs). Working with physical and occupational therapists, along with the use of orthoses and assistive/adaptive devices can help increase independence with mobility, ADLs, and vocational skills.
- Sensory deficits: impaired sensation combined with impaired mobility may predispose patient to skin abrasions and pressure wounds. Patients and caregivers are educated on routinely doing pressure relief strategies and skin inspections for any pressure or irritation.
- Bladder dysfunction: urinary tract infections are common as with SCI patients. This may predispose patients to urinary stones, renal parenchymal damage, and bladder cancer. Bladder dysfunction persists in about 90% of patients despite apparent motor recovery. Urodynamic findings include detrusor over activity, detrusor-sphincter dyssynergia, low bladder compliance, and increased detrusor leak point pressure. Prolonged indwelling catheter use may predispose the patient to infections and may cause a small increase risk of bladder cancer. Clean intermittent catheterization program and/or anticholinergic medications should be instituted as soon as deemed necessary.
- Bowel dysfunction: constipation, fecal impaction, incontinence, and rectal prolapse are common consequences of neurogenic bowel. A bowel program is highly important, which may include diet modifications, the use of laxatives, stool softeners, suppositories, or enemas. The goal is to promote bowel continence and prevent complications.
- Autonomic Dysreflexia risk for lesions above T6: This potential life-threatening complication is due to the uninhibited sympathetic outflow manifested as hypertension, reflex bradycardia, sweating, headache, visual impairment due to cerebral vasodilatation. Common triggers include over distended bladder, severe constipation, ingrown toenail and pressure ulcers. Treatment includes avoidance/removal of noxious stimuli such as prophylactic intermittent urinary catheterization, bowel decompression, spasticity management, elevation of head and trunk, sublingual nifedipine or nitropaste application may be used as abortive agents for hypertension, patient/caregiver education.
- Spasticity: increased muscle tone may be beneficial to some patients with spasticity to aid with standing or bed mobility. However, it may also interfere with ADL’s and transfers. Treatment is focused on symptom relief and goals, ranging from physical modalities such as stretching or bracing, to pharmacologic management including oral baclofen, tizanidine, benzodiazepines, focal chemodenervation with botulinum toxin, alcohol or phenol; or intrathecal baclofen pump therapy.
- Pain: neuropathic pain is common and may arise at the level of injury or in areas that are partially innervated. Pain is reported in up to 50% of cases in children.4,10 Gabapentin, pregabalin, and amitriptylline are commonly used and may require dose titration over time. Nociceptive pain may be caused by wounds, deep vein thrombosis, and musculoskeletal conditions such as heterotopic ossification and sprain/strain injuries.
Coordination of care
As with SCI, TM treatment benefits from a coordinated rehabilitation team including physical therapy, occupational therapy, care management, social work, rehabilitation nursing, neurology, physiatry, the patient, and family. This way, appropriate and feasible goals can be decided on and executed. Medical care as well as outpatient and/or school therapies should be well-coordinated to maximize recovery, improve function, and prevent secondary complications.
Patient & family education
The patient and family must be well versed in this new life-changing event. As previously described, TM is highly variable in its course. Emphasizing the importance of prevention of secondary complications is paramount, and coordinated efforts that promote education will help with understanding and coping.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Patients presenting with longitudinally extensive type of ATM and who are seropositive for NMO-IgG have been seen to experience high relapse rate or eventually develop NMO.11 Paraneoplastic associated ATM has been reported in association with some serological markers, such as the collapsing response mediator protein (CRMP)-5-IgG associated with small cell lung carcinoma and amphiphysin-IgG associated with women with breast cancer.11
A novel therapeutic option of microsurgical nerve transfer surgery has been proposed in the literature. The techniques may vary, but in general the procedure aims at “neurotizing” the affected (target) nerve by transferring axons from a functioning (donor) nerve. In one case report the procedure resulted in improved strength and motor function of the affected upper extremity of a child.13
Clinicians should be aware of the emergence of acute flaccid paralysis (AFP) as a disorder that can often be misdiagnoses of ATM. Differentiating these two entities is important in directing evaluation, testing, and treatment as well as establishing prognosis. Classically associated with poliovirus infection, AFP can result from other pathogens such as West Nile Virus and nonpolio enterovirus. In contrast to ATM, which presents with weakness and sensory loss, often with a discernible spinal level, AFP manifest with prominent motor involvement, and limited or no sensory deficits. Imaging studies in AFP will reveal T2 hyperintensities in the spinal gray matter or brainstem whereas in ATM, involvement of gray and white matter is often noted. Treatment is similar to that of ATM. However, the probability for residual motor deficits is higher than in other flaccid paralysis.14
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
There is controversy regarding whether immunization is a causal agent for acute transverse myelitis. Some researchers have found a history of immunization 30 days prior the onset of symptoms4. However, a causation between immunization and ATM has not been established.
There is some research data that suggest a possible higher risk of “conversion” to Multiple Sclerosis in 3-5 years for those patients with TM, particularly acute partial TM, who present with Multiple Sclerosis-like brain abnormalities in MRI.5
There are no placebo controlled randomized studies to support efficacy of high-dose steroids, despite it being the first line of treatment offered. There is also insufficient evidence to determine the efficacy of immunosuppresive therapy.5
- Awad A, Stüve O. Idiopathic transverse myelitis and neuromyelitis optica: clinical profiles, pathophysiology and therapeutic choices. Curr Neuropharmacol. 2011;9:417-428.
- Frohman EM, Wingerchuk DM. Clinical practice. Transverse myelitis. N Engl J Med. 2010;363:564-572.
- Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. 2002;59:499-505.
- Pidcock FS, Krishnan C, Crawford TO, Salorio CF, Trovato M, Kerr DA. Acute transverse myelitis in childhood: center-based analysis of 47 cases. 2007;68:1474-1480.
- Scott T, Frohman E, De Seze J, Gronseth G, Weinshenker B. Evidence-based guideline: clinical evaluation and treatment of transverse myelitis. 2011;77:2128–2134.
- Beh, SC, Greenberg, BM. Transverse Myelitis. Neurol Clin. 2013; 31 (1): 79-138.
- Gupta A, Taly AB, Srivastava A, Murali T. Non-traumatic spinal cord lesions: epidemiology, complications, neurological and functional outcome of rehabilitation. Spinal Cord. 2009;47:307-311.
- Wolf V, Lupo P and Lotze T. Pediatric acute transverse myelitis: overview and differential diagnosis. J Child Neurol. 2012;27(11):I426-436.
- Calis M, Kirnap M, Calis H, Mistik S, Demir H. Rehabilitation results of patients with acute transverse myelitis. Bratisl Lek Listy. 2011;112:154-156.
- Thomas T, Branson HM, Verhey LH, et al. The demographic, clinical, and magnetic resonance imaging (MRI) features of transverse myelitis in children. J Child Neurol. 2012;27:11-21.
- Sá, MJ. Acute transverse myelitis: a practical reappraisal. Autoimmunity Reviews. 2009; 9(2):128-131.
- Sepúlveda M, Blanco Y, Rovira A, Rio J, Mendibe M, Llufriu S, Gabilondo I, Villoslada P, Castilló J, Corral J, Ayuso T, Iñiguez C, Santos S, Guijarro C, Ramió-Torrentà L, Sempere AP, Olascoaga J, Graus F, Montalban X, Saiz A. Analysis of prognostic factors associated with longitudinally extensive transverse myelitis. Multiple Sclerosis. 2013;19(6):742-748.
- Dorsi MJ, Belzberg AJ. Nerve transfer for restoration of upper extremity motor function in a child with upper extremity motor deficits due to transverse myelitis: case report. Microsurgery. 2012; 32(1): 64-67.
- Nelson GR, Bonkowsky JL, Doll E, Green M, Hedlund GL, Moore KR, Bale JF Jr. Recognition and Management of Acute Flaccid Myelitis in Children. Pediatr Neurol. 2016;55:17-21.
Original Version of the Topic:
Rochelle T. Dy, MD, Anand Allam, MD. Transverse Myelitis. Publication Date:2012/08/09.
Rochelle T. Dy, MD
Nothing to Disclose
Mariella Hillebrand, MD
Nothing to Disclose