Keywords
Key points
- •Transverse myelitis (TM) constitutes a pathobiologically heterogeneous syndrome that has significant neurologic implications and requires urgent attention.
- •Magnetic resonance imaging (MRI) evaluation of the entire spinal cord axis is mandatory in all myelopathic patients.
- •The length of the spinal cord lesion on MRI is an important discriminator with etiologic and prognostic significance; longitudinally extensive transverse myelitis (LETM) refers to lesions that extend over 3 or more vertebral segments.
- •Early and timely identification and immunotherapy are critical to minimize, or even prevent, future disability.
- •The long-term management should focus on neurorehabilitation and a multidisciplinary approach aimed at managing the various complications of spinal cord damage.
Introduction
Acute noncompressive myelopathies have been recognized since the nineteenth century. The terms myelitis and myelopathy are often used interchangeably, but have different connotations. Both suggest a lesion affecting the spinal cord. Whereas myelopathy is a broad, generic term (much like neuropathy or encephalopathy) that does not imply any particular etiology, myelitis refers to an inflammatory disease process.
Transverse myelitis (TM) includes a pathobiologically heterogeneous syndrome characterized by acute or subacute spinal cord dysfunction resulting in paresis, a sensory level, and autonomic (bladder, bowel, and sexual) impairment below the level of the lesion.
2
, 3
Etiologies for TM can be broadly classified as parainfectious, paraneoplastic, drug/toxin-induced, systemic autoimmune disorders (SAIDs), and acquired demyelinating diseases like multiple sclerosis (MS) or neuromyelitis optica (NMO).3
, 4
, 5
, 6
Patients with isolated TM present a diagnostic dilemma, as it is common in both MS and NMO, but may also be the initial manifestation of SAIDs. Also, there are noninflammatory etiologies (eg, vascular, metabolic) that may mimic the clinical and radiologic appearance of TM. Further complicating the diagnostic process is the frequent coexistence of systemic autoantibodies in NMO and, sometimes, MS. The implications of an incorrect diagnosis can be severe, as treatment may not only be ineffective, but may exacerbate the underlying disease process. The cause of TM remains unknown despite an extensive workup in about 15% to 30%4
of patients and is therefore referred to as “idiopathic” according to set criteria.7
Box 1 explains important terms related to TM.Box 1
Nosology of transverse myelitis
- Myelopathy: a broad, generic term referring to a lesion affecting the spinal cord
- Myelitis: refers to an inflammatory disease of the spinal cord
- Transverse myelitis (TM): classically describes a pathobiologically heterogeneous syndrome characterized by acute or subacute spinal cord dysfunction resulting in paresis, a sensory level, and autonomic impairment below the level of the lesion
- Acute Complete TM (ACTM): TM causing paresis of the lower and/or upper extremities, sensory dysfunction (characterized by a sensory level), and autonomic impairment below the level of the lesion. On magnetic resonance imaging (MRI), there is typically a single lesion spanning 1 or 2 vertebral segments; on axial sections, there is either full-thickness involvement, or the central portion of the spinal cord is maximally affected.
- Acute Partial TM (APTM): TM causing asymmetric neurologic impairment (localizable to the spinal cord) or deficits attributable to a specific anatomic tract. On MRI, it spans 1 or 2 vertebral segments; there is involvement of a small portion of the spinal cord on axial sections.
- Longitudinally-Extensive TM (LETM): a spinal cord lesion that extends over 3 or more vertebral segments on MRI. On axial sections, it typically involves the center of the cord over more than two-thirds of the spinal cord area.
- Secondary TM: TM related to a systemic inflammatory autoimmune disorder (eg, lupus, Sjögren syndrome, sarcoidosis). It is typically an ACTM.
- Idiopathic TM: TM without any clear etiology despite a thorough investigation. It should meet the criteria listed in Table 8.
The annual incidence of TM ranges from 1.34 to 4.60 cases per million,
8
, 9
, 10
but increases to 24.6 cases per million if acquired demyelinating diseases like MS are included.11
TM can occur at any age, although a bimodal peak in incidence occurs in the second and fourth decades of life.8
, 9
, 10
, 12
Half of patients have an antecedent infection.10
Case report
A 30-year-old white woman presents with 3 days of progressive paraparesis, constipation, and urinary incontinence. In addition, she reports a feeling a circumferential tightness around her abdomen (as though she was wearing a corset). Examination revealed spasticity, hyperreflexia with up-going plantar reflexes, and muscle strength of 3 in her lower extremities. Anal tone was decreased. A T8 sensory level was detected. Spine MRI revealed a T2/fluid-attenuated inversion recovery (FLAIR) hyperintense signal with associated contrast enhancement and cord swelling from T2 to 7 vertebral segments. What are the next steps in managing this patient?
Clinical presentation
It is important to consider the age and gender of the patient when evaluating myelopathic patients. Older patients (older than 50 years) are more likely to suffer spinal cord infarction. Female patients are at higher risk of having TM. Demographic features are otherwise not particularly useful in distinguishing the etiologic causes of myelopathy.
13
The temporal profile of the myelopathic features must be elucidated. TM typically has an acute to subacute onset, with neurologic deficits reaching a nadir within a few weeks. An apoplectic onset with deficits reaching the nadir in less than 4 hours indicates a vascular event. An insidious, progressive course in which the deficits continue to worsen beyond 4 weeks is uncharacteristic of TM. Clinically, TM may present as one of several syndromes of the spinal cord. Acute complete TM (ACTM) manifests as paresis/plegia, sensory dysfunction (characterized by numbness, paresthesias, or other manifestations in conjunction with a sensory level), and autonomic impairment below the level of the lesion. Acute partial TM (APTM) results in asymmetric manifestations or deficits specific to particular anatomic tracts; manifestations include the hemi-cord (Brown-Sequard), central cord, or posterior column syndrome, as well as selective tract impairment. Table 1 describes these syndromes. Distinguishing ACTM and APTM has etiologic and prognostic significance, as discussed later.
Table 1Spinal cord syndromes
| Syndrome | Tracts Involved | Clinical Manifestations |
|---|---|---|
| Complete transverse myelitis | All | Paresis, sensory loss, and autonomic impairment below the level of the lesion |
| Hemicord (Brown-Sequard) | Ipsilateral corticospinal; Ipsilateral dorsal columns; contralateral spinothalamic | Ipsilateral paresis and impaired dorsal column sensation; contralateral pain and temperature loss |
| Dorsal column | Bilateral dorsal columns | Bilateral loss of vibratory and proprioceptive sensation; Lhermitte phenomenon |
| Subacute Combined Degeneration | Bilateral dorsal columns and corticospinal tracts | Bilateral dorsal column dysfunction; paresis and upper motor neuron signs below the level of the lesion |
| Central cord | Crossing spinothalamic fibers, and corticospinal tracts | Dissociated sensory loss (diminished pain and temperature with normal dorsal column function) in a shawl-like pattern. Saddle-sparing sensory loss. Upper motor neuron weakness below the level of the lesion. |
| Conus medullaris | Sacral autonomic fibers | Early and prominent sphincter and sexual impairment; saddle pattern sensory loss; mild weakness |
| Tract-specific dysfunction | Depending on involved tract |
Acutely, limb tone and muscle stretch reflexes may be diminished and even absent (“spinal shock syndrome”) leading to possible diagnostic confusion with Guillain-Barre syndrome (GBS). Clinically, spinal shock may persist for days to weeks, with a mean duration of 4 to 6 weeks following an insult.
14
Over time, spasticity, hyper-reflexia, and extensor plantar responses (ie, classic features of the upper motor neuron [UMN] syndrome) become evident.Sensory symptoms (both positive and negative) are common in TM. Some patients report a circumferential band of dysesthesia, attributable to the dermatomes just rostral to the sensory level, around their trunk. In some cases, this may be associated with a constricting sensation (colloquially referred to as the “MS hug”) that ranges from mild discomfort to a severe spasmodic or burning pain. In the authors' experience, this symptom may be so distressing that it may be more appropriately called the “anaconda squeeze”! TM-related pain may be a central, deep aching pain or radicular in nature.
3
Exacerbation of spinal pain with recumbency may indicate a neoplastic lesion involving the spinal cord.15
Phantom limb phenomenon has been observed.16
Lhermitte phenomenon (paresthesia traveling down the limbs and trunk with neck flexion) suggests an intrinsic cervical spinal cord lesion, typically affecting the dorsal columns. A reverse Lhermitte phenomenon (paresthesia with neck extension) usually indicates a compressive extra-axial cervical lesion.17
Inverse Lhermitte phenomenon (paresthesia traveling upward) is another reported variation.18
Autonomic dysfunction is almost always present in the form of perturbations of bladder, sexual, gastrointestinal, cardiovascular, and thermoregulatory functions. Priapism is a rare acute manifestation.
19
, 20
These features are discussed later.Certain clinical signs can aid in localizing the level of the lesion and are described in Table 2.
Table 2Clinical signs with useful localizing value in myelopathic patients
| Clinical Sign | Description | References |
|---|---|---|
| Beevor sign | Describes the upward migration of the umbilicus during the act of sitting up from supine position owing to weakness of the lower half of the rectus abdominis (because the upper rectus segments pull in a direction opposite of the lower segments, the movement of the abdomen is upward). In some cases, downward migration of the umbilicus may be observed. This sign indicates a lesion at the level of the T10–12 spinal cord and/or roots. | |
| Superficial abdominal reflexes | A lesion above T6 segmental cord level will abolish all superficial abdominal reflexes. A lesion at or below T10 spares the upper and middle abdominal reflexes. All the reflexes are present with a lesion below T12. | 23 |
| Cremasteric reflex | Lost in lesions at or above L2 segmental cord level. | 23 |
| Bulbocavernous reflex | Mediated by S2–4 nerve roots; hence, is abolished in lesions above S2 segmental cord level. | 24 |
| Anal wink reflex | Mediated by S2–4 nerve roots; hence, is abolished in lesions above S2 segmental cord level | 24 |
The list of differential diagnoses of TM is long; hence, a meticulous history and detailed physical examination are indispensible. A systematic and careful history may help exclude other mimics of TM (these are discussed in Box 2). An antecedent infection or prior vaccination may implicate acute disseminated encephalomyelitis (ADEM) or parainfectious TM. Travel abroad may indicate more exotic infectious causes of TM, such as schistosomiasis. Risk factors for or concomitant existence of malignancy may implicate a paraneoplastic etiology.
Box 2
Red flags arguing against TM in myelopathic patients
- 1.Apoplectic onset (reaching the nadir less than 4 hours from onset).
- 2.Insidious progressive course.
- 3.Older age of onset.
- 4.Preceding trauma, pain, and/or vertebral tenderness would suggest traumatic myelopathy.
- 5.Vascular instrumentation (in particular, aortic and cardiac surgery) or maneuvers that increase intra-abdominal pressure (eg, weight-lifting or straining) before the acute/subacute appearance of myelopathic features may implicate spinal cord infarction.
- 6.Prior bariatric surgical procedures, malabsorption syndromes, dietary restrictions, malnutrition, use of zinc supplements, excessive use of zinc-containing denture cream, alcoholism, and/or drug/toxin exposure may implicate a metabolic or toxic etiology.
- 7.Prior radiation therapy.
- 8.Immunocompromised state (HIV/AIDS or immunosuppressive therapy).
- 9.Features of infection: fever, meningismus, rash, leukocytosis, burning dermatomal pain.
- 10.Paralysis with dissociated sensory loss (loss of pinprick and temperature but preserved dorsal column function) indicates an anterior spinal artery infarction.
- 11.The exacerbation of spinal pain with recumbency suggests malignancy.
- 12.Foix-Alajouanine syndrome (congestive venous myelopathy) is characterized by exacerbation of myelopathic features with exercise and relief with rest.
Women of reproductive age are at higher risk of acquired demyelinating diseases and SAIDs with the exception of Behcet disease (BD) and ankylosing spondylitis (AS). A history of relapsing-remitting attacks of neurologic deficits, eg, acute optic neuritis (AON) or internuclear ophthalmoparesis (INO), would suggest MS. Uhthoff phenomenon (discussed later) may be present in demyelinating diseases. A thorough neurologic examination may reveal evidence of prior neurologic impairments suggestive of MS exacerbations disseminated in time and space. NMO usually causes attacks of severe AON (sometimes bilateral) and brainstem lesions resulting in intractable nausea, vomiting, or hiccups.
21
, , 23
, 24
Although the manifestations of NMO may be similar to MS, attacks are typically more devastating.25
In cases of NMO mistakenly diagnosed as MS, treatment with interferon beta-1a would dramatically increase attacks.26
Autoimmune disorders, in particular systemic lupus erythematosus (SLE), BD, AS, Sjögren's syndrome (SS), and antiphospholipid syndrome (APS), are known causes of TM. In some, TM may be the initial clinical manifestation of such a disorder. Fatigue and constitutional complaints are common in patients with autoimmune disorders. A thorough integumentary examination may offer valuable clinical signs. Systemic (eg, renal, cardiac) and nonmyelopathic neurologic manifestations (eg, mononeuritis multiplex, myositis, cerebellar ataxia) may occur in some SAIDs. The presence of peripheral nervous system deficits rules out MS and NMO, unless there are concomitant disorders in the same patient (eg, diabetic peripheral neuropathy). Table 3 describes some salient manifestations of selected systemic autoimmune disorders.
Table 3Systemic manifestations of autoimmune disorders
| Disorder | Clinical Sign/Symptom |
|---|---|
| Sjögren syndrome | Xerophthalmia, xerostomia, parotid gland enlargement, Raynaud phenomenon, dysphagia, and dry cough (owing to xerotrachea). A positive Schirmer test detects deficient tear production. |
| Systemic lupus erythematosus | Joint pains, morning stiffness, myalgias, and integumentary manifestations (alopecia, unguium mutilans, perniotic lesions, leuconychia, splinter hemorrhages, nail-fold hyperkeratosis, ragged cuticles, malar rash, Raynaud phenomenon, photosensitivity, and/or discoid lupus). |
| Antiphospholipid syndrome | History of deep vein thromboses, pulmonary embolism, multiple miscarriages, and/or young-onset stroke. |
| Behcet disease | Classic triad of recurrent aphthous ulcers, genital ulcers, and uveitis. Other manifestations: ophthalmic (hypopyon and retinal vasculitis) and cutaneous (pseudofolliculitis, erythema nodosumlike lesions, or acneiform lesions). Positive pathergy test. |
| Ankylosing spondylitis | Back pain, enthesitis, and limited spinal flexion. |
Evaluation and diagnosis
Magnetic resonance imaging (MRI) of the complete spinal axis is mandatory in any patient with myelopathic features to exclude structural lesions, particularly those amenable to emergent neurosurgical intervention. The spinal cord cephalad to the suspected level of the lesion should always be imaged owing to possibly misleading signs, eg, paraparesis attributable to cervical lesions. The most sensitive MRI sequence for detecting spinal cord lesions (especially MS plaques) are short-tau inversion recovery (STIR) fast spin-echo and T2-weighted fast spin-echo sequences.
27
, 28
The location and length of the cord lesion on MRI may also provide clues about the underlying disease. Based on clinical and radiologic data, TM can first be dichotomized into longitudinally limited and longitudinally extensive TM (LETM). Longitudinally limited TM can be further classified as ACTM or APTM. ACTM and APTM span 1 or 2 vertebral segments. ACTM causes a complete spinal cord syndrome; on axial sections, there is either full-thickness involvement, or the central portion of the spinal cord is maximally affected.
29
APTM results in asymmetric spinal cord involvement or neurologic deficits attributable to a specific anatomic tract; on axial sections, there is involvement of a portion of the spinal cord. Patients with APTM are at increased risk of recurrence and transition to MS.13
, 29
, 30
Conversely, ACTM carries a lower risk of transition to clinically definite multiple sclerosis (CDMS) and is usually related to other causes (eg, SAIDs). LETM refers to lesions that extend over 3 or more vertebral segments; on axial sections, it typically involves more than two-thirds of the spinal cord thickness (maximally affecting the central portion).3
, 29
Box 3 summarizes the differential diagnoses of LETM. The unique radiologic features of different etiologies are explored later.Box 3
Differential diagnosis of LETM
- 1.Neuromyelitis optica (NMO) or NMO-spectrum disorders
- 2.Acute disseminated encephalomyelitis (ADEM)
- 3.Systemic autoimmune disorders: systemic lupus erythematosus (SLE), Sjögren syndrome (SS), neurosarcoidosis, neuro-Behcet disease
- 4.Parainfectious TM: Borrelia burgdorferi, Chlamydia psittaci, mumps virus, cytomegalovirus, coxsackie virus, Mycobacterium tuberculosis, Mycoplasma pneumoniae, enterovirus 71, hepatitis C virus, Brucella melitensis, Epstein-Barr virus, echovirus type 30, Ascaris suum, Toxocara canis, and Schistosoma species.
- 5.Paraneoplastic TM (in particular, anti-collapsin response-mediator protein [CRMP]-5 antibodies)
- 6.Mimics of TM
- a.Neoplasms: primary intramedullary spinal cord tumors, metastatic intramedullary tumors, lymphoma
- b.Radiation myelitis
- c.Metabolic myelopathies: B12 deficiency, copper deficiency, nitrous oxide toxicity
- d.Vascular myelopathies: anterior spinal artery infarction, spinal dural arteriovenous fistula
- a.
A brain MRI with and without gadolinium administration should also be obtained on all patients to look for evidence of concomitant or prior lesions that may provide clues about the etiology. The presence of MS-like brain lesions in patients with partial TM portends an 80% risk of transition to clinically definite MS at 3 to 5 years.
13
Serum vitamin B12 level, thyroid function tests, syphilis, and HIV serologies always should be obtained to evaluate for potentially treatable causes of myelopathy. Vitamin E, serum copper, and ceruloplasmin levels are checked in those at risk of deficiency (see later in this article for further details). Serum aquaporin-4–specific autoantibodies (NMO-immunoglobulin [Ig]G) should be checked on all patients with TM because of its high specificity for NMO or NMO spectrum disorders (NMOSD).
31
, 32
NMO-IgG seropositivity is rarely found in patients with APTM30
but its presence would have profound implications on treatment. Inflammatory markers (please see Box 4) should be checked if SAID is suspected. In suspected parainfectious TM, serologic evidence of recent infection (eg, Mycoplasma antibody titers) should be sought. Serum paraneoplastic profiles should be performed in suspected cases of paraneoplastic TM; additionally, in such cases, appropriate investigations should be undertaken to search for the occult malignancy, the identification of which can have profound ramifications for the patient; even a cure if a malignancy can be confirmed and eradicated before pathologic dissemination.Box 4
Investigations into suspected TM
- 1.Magnetic resonance image (MRI) of the spine
- 2.Brain MRI
- 3.Cerebrospinal fluid (CSF): cells, differential, protein, glucose, Venereal Disease Research Laboratory (VDRL), immunoglobulin (Ig)G index, oligoclonal bands, cytologic analysis
- 4.Serum: B12, methylmalonic acid, HIV antibodies, syphilis serologies, thyroid stimulating hormone (TSH), Free T4, 25-hydroxyvitamin D
Must be obtained on all patients:
- 1.Serum NMO-IgG
- 2.Serum erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, antibodies to extractable nuclear antigen, rheumatoid factor, antiphospholipid antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA)
- 3.Visual-evoked potentials
Must be obtained on all patients with LETM:
- 1.Neuro-ophthalmological evaluation
- 2.Paraneoplastic panel
- 3.Infectious serologies and CSF studies (cultures and viral polymerase chain reaction)
- 4.Serum copper and ceruloplasmin
- 5.Serum vitamin E level
- 6.Computed tomography of the chest
- 7.Nerve conduction studies and electromyography
- 8.Minor salivary gland biopsy
May need to be obtained:
Cerebrospinal fluid (CSF) analysis is essential in the evaluation of TM. CSF cell count, differential, protein, glucose, oligoclonal bands (OCBs) and IgG index should be checked on all patients with TM. Isoelectric focusing is the superior method for the detection of OCBs, providing a much higher yield and specificity.
33
OCBs are useful in predicting conversion to MS, as OCBs are present in 85% to 90% of patients with MS, in 20% to 30% of patients with NMO or SAIDs, and rarely in other causes of TM.13
Bear in mind that their mere presence clearly does not militate against being reflective of a myriad of inflammatory, infectious, and neoplastic or paraneoplastic processes.A neuro-ophthalmological evaluation is warranted to look for ophthalmic manifestations that may provide valuable diagnostic clues, especially when radiologic and laboratory investigations are unremarkable. For example, different subtypes of uveitis are associated with unique etiologic underpinnings.
34
Demyelinating diseases affecting the brainstem and/or cerebellum commonly cause ocular motor manifestations.35
Electrophysiologic tests may be very useful in assessing patients with TM. Nerve conduction studies and electromyography (EMG) may reveal and help characterize any peripheral nervous pathology, the exclusion of which would lend compelling support for a spinal cord process. This latter principle is especially salient in that acute TM can present as a spinal shock variant, one that may mimic a polyneuropathic process like GBS. In early TM, F-waves may be absent,
36
an observation that can serve to misguide even the most experienced neurologic consultant (especially when the MRI is unremarkable) to localize the disease process to the peripheral nervous system. EMG-evidence of anterior horn cell dysfunction may portend a poor prognosis for recovery.37
Somatosensory evoked potentials may offer evidence of a myelopathy in the presence of a normal spinal cord MRI. In addition, conventional and multifocal visual-evoked potentials (VEP) may provide evidence of subclinical demyelination along the afferent visual pathways not clearly identified on imaging. Evidence of such disruption may support the diagnosis of MS or NMO but are by no means specific for these disease entities (discussed in greater detail later).A list of investigations into TM is provided in Box 4.
Causes of TM
Box 5 summarizes the causes of TM.
Box 5
Summary of reported causes of TM
- 1.Acquired demyelinating disorders
- a.Multiple sclerosis
- b.NMO
- c.ADEM
- a.
- 2.Systemic inflammatory autoimmune disorders
- a.SLE
- b.SS
- c.Antiphospholipid syndrome
- d.Behcet disease
- e.Vogt-Koyanagi Harada disease
- f.Ankylosing spondylitis
- g.Mixed connective tissue disease
- h.Others: systemic sclerosis, anti-Jo-1 antibody, urticarial vasculitis, psoriatic arthritis, perinuclear ANCA systemic vasculitis, graft-versus-host disease, common variable immunodeficiency, celiac disease
- a.
- 3.Neurosarcoidosis
- 4.Parainfectious TM
- a.Viral: hepatitis A, hepatitis B, hepatitis C, hepatitis E, measles, mumps, rubella, varicella zoster, Epstein-Barr, cytomegalovirus, herpes simplex, influenza A/B, lymphocytic choriomeningitis virus, chikungunya, Hanta virus, HIV, human T-cell lymphotropic virus, human herpes virus 6, Japanese encephalitis, Murray Valley encephalitis, St Louis encephalitis, tick-borne encephalitis, vaccinia, Rocky Mountain spotted fever, dengue virus, enterovirus 71, coxsackievirus A and B, West Nile virus, parvovirus B19, human corona virus, and echovirus
- b.Bacterial: Mycoplasma pneumoniae, Campylobacter jejuni, Borrelia burgdorferi, Acinetobacter baumanii, Coxiella burnetii, Bartonella henselae, Chlamydia psittaci, Leptospira, Chlamydia pneumoniae, Legionella pneumonia, Orientia tsutsugamushi (scrub typhus), Salmonella paratyphi B, Mycobacterium tuberculosis, Treponema pallidum, Brucellosis melitensis, and groups A and B streptococci
- c.Fungal: Actinomyces, Blastomyces, Coccidioides, Aspergillus, Cryptococcus, and Cladophialophora bantiana
- d.Parasitic: Toxocara species, Schistosoma species, Gnasthostoma spinigerum, Echinococcus granulosus, Taenia solium, Toxoplasma gondii, Acanthamoeba species, Paragonimus westermani, and Trypanosoma brucei
- a.
- 5.Paraneoplastic syndromes
- a.Anti-Ri (ANNA-2) antibody
- b.CRMP-5-IgG antibody
- c.Anti-amphiphysin IgG antibody
- d.Anti-GAD65 antibody
- e.NMDAR antibody
- a.
- 6.Atopic myelitis
- 7.Drugs and toxins
- a.Tumor necrosis factor-alpha inhibitors
- b.Sulfasalazine
- c.Epidural anesthesia
- d.Chemotherapeutic agents: gemcitabine, cytarabine, cisplatin
- e.Heroin
- f.Benzene
- g.Brown recluse spider toxin
- a.
- 8.Idiopathic TM
Multiple Sclerosis
MS is a disabling progressive neurologic disorder affecting approximately 400,000 people in the United States.
38
First attacks of MS, called clinically isolated syndrome (CIS), usually consist of AON, brainstem syndromes, or APTM. The probability for APTM to transition to CDMS ranges from 10% to 62%.30
, 39
, 40
, 41
, 42
, 43
APTM may be a CIS with a higher risk of conversion to MS.43
TM in MS most commonly presents with sensory phenomena. Spine MRI typically reveals an asymmetrically placed lesion (usually occurring in the posterolateral or lateral portion of the spinal cord) less than 2 segments in length (ie, APTM) with a predilection for the cervicothoracic cord.
3
, 30
, 39
, 42
, 43
The most important investigation that helps determine the risk of conversion to CDMS is the brain MRI. If it is normal, only 10% of patients with APTM will develop CDMS at 61 months
30
; this increases to 21% risk of progression at 20 years follow-up according to another study of CIS.44
White matter lesions predict higher risk of conversion to MS (with rates of up to 88% reported).43
, 44
If the lesions meet at least 3 of the Barkhof criteria45
this risk is increased substantially.43
Another important factor that helps predict the risk of transition to CDMS is CSF OCBs. In the setting of TM, OCBs have been shown to have a robust predictive value of for predicting conversion to MS.
43
, 46
, 47
, 48
In patients with TM with normal brain MRIs, the presence of OCBs and/or an elevated IgG index portends a higher risk of developing MS.49
The risk of developing MS is less than 10% with a normal brain MRI and CSF findings.43
Longitudinally extensive lesions in the context of TM is actually quite rare in MS and, when present, is significantly shorter than those seen in NMO. When MS is confirmed, spinal lesions tend to favor a cervical localization, and tend to have less cord swelling and gadolinium-enhancement.
50
In general, patients with LETM have been shown to have a conspicuously low risk of developing MS.30
Neuromyelitis Optica
NMO is diagnosed on the basis of the revised Wingerchuk criteria
51
requiring the presence of optic neuritis and TM as well as 2 of 3 of the following: NMO antibodies, LETM, and/or brain MRI lesions inconsistent with MS. NMOSDs include Asian optic-spinal MS, recurrent LETM, recurrent AON, and AON or TM in the context of certain organ-specific and non–organ-specific autoimmune disease. The article on NMO by Sahraian, MA, elsewhere in this issue discusses this disease in detail. Here, we underscore the important features of NMO that give rise to diagnostic confusion.Diagnostic confusion may arise with SAIDs, as patients with NMO/NMOSD often have accompanying autoimmune diseases and multiple non–organ-specific autoantibodies. Autoimmune diseases observed to coexist with NMO include SS, SLE, autoimmune thyroid disease, type 1 diabetes mellitus, ulcerative colitis, idiopathic thrombocytopenic purpura, myasthenia gravis, rheumatoid arthritis, polymyositis, celiac disease, and Raynaud phenomenon.
52
, 53
We propose that all patients with a known SAID (eg, SS or SLE) who present with TM undergo serologic testing for NMO-IgG. The high specificity of NMO-IgG seropositivity
31
, 54
will establish the additional diagnosis of NMO coexisting with the systemic autoimmune disorder. In patients with NMO or TM, the isolated presence of systemic non–organ-specific antibodies should not be used to make a diagnosis of any particular rheumatic disease; instead, these assays can lend support in corroborating such conditions, when the established clinical criteria for each respective disorder has been fulfilled.Sjögren Syndrome
SS is a chronic, protean, progressive, systemic autoimmune disorder characterized by mononuclear infiltration and destruction of the salivary and lacrimal glands, leading to keratoconjunctivitis sicca, typically affecting middle-aged to elderly women. SS may appear alone (primary SS) or exist with another autoimmune disease (secondary SS).
55
, 56
, 57
A wide range of central nervous system (CNS) manifestations may occur, including AON and TM.
56
, 58
, 59
The precise prevalence of neurologic manifestations in SS is unclear, and has been reported to range from 8.5% to 70.0%57
; this large discrepancy may be related to the inclusion or exclusion of psychiatric and cognitive impairment. Neurologic deficits may be the initial presentation in as many as 57% of patients with SS.57
Spinal cord involvement (either acute TM or progressive myelopathy) may occur in 20% to 35% of patients with SS and may constitute the initial presentation of the disease in up to about 20%.55
, 57
The lesions tend to affect the cervical cord and may be longitudinally extensive.57
, 60
CSF typically reveals pleocytosis, mildly increased protein, and a mildly elevated IgG index.
56
, 60
Cytologic analysis may reveal small round lymphocytes, reactive lymphoid cells, plasma cells, and atypical mononuclear cells.56
OCBs have been reported in about 30% of patients with SS.57
SS-A or SS-B antibody seropositivity is not mandatory for the diagnosis of SS, because only 21% of patients with primary SS and neurologic manifestations demonstrate such seropositivity.57
Although other CNS manifestations of SS are corticosteroid-responsive,
56
spinal cord involvement is often refractory to steroids.60
Intravenous (IV) cyclophosphamide is effective56
, 57
; there is anecdotal evidence supporting the use of plasmapheresis61
and IV gammaglobulin.62
Maintenance immunosuppressive therapy with monthly pulse IV cyclophosphamide may be considered.56
Rituximab is another promising agent63
and may be a suitable agent for patients with coexisting NMO or MS, or where there is diagnostic confusion with these diseases.Careful longitudinal follow-up is important in SS, as recurrent attacks of TM or AON can culminate in substantial disability, and may ultimately lead to a confirmed diagnosis of NMO or MS.
Systemic Lupus Erythematosus
SLE is a chronic, systemic, autoimmune disease. The diagnosis of SLE requires at least 4 of 11 features, as outlined by the American College of Rheumatology.
64
Although neuropsychiatric manifestations of SLE are common, TM accounts for only 1% to 2% of patients, but constitutes the most devastating complication of SLE and one that often portends a poor prognosis.66
SLE-related TM tends to occur within the first 5 years from diagnosis, is the initial clinical manifestation in almost half of patients, and recurs in 21% to 55% of cases.67
, 68
, 69
AON and brainstem manifestations may accompany TM in SLE,70
, 71
mimicking MS and representing a significant source of diagnostic confusion.A short period of prodromal symptoms (eg, headache, fever, nausea) typically heralds the onset of thoracic myelopathy with prominent bladder dysfunction.
69
, 71
In a large series of SLE-related TM, 2 different clinical patterns at presentation were observed: gray and white matter myelitis. Gray matter myelitis demonstrated lower motor neuron (LMN) features, urinary retention, and a more devastating but monophasic course. White matter myelitis demonstrated UMN features and a more indolent but recurrent course.72
An earlier study suggested that EMG evidence of anterior horn cell dysfunction in patients with TM predicts a poor prognosis for recovery.37
The features of gray and white matter myelitis are summarized in Table 4.Table 4The differences between gray and white matter myelitis in SLE
Data from Birnbaum J, Petri M, Thompson R, et al. Distinct subtypes of myelitis in systemic lupus erythematosus. Arthritis Rheum 2009;60(11):3378–87.
| Gray Matter Myelitis | White Matter Myelitis | |
|---|---|---|
| Presentation | Lower motor neuron features with urinary retention (urinary retention always heralds paraplegia) | Upper motor neuron features |
| Prodrome (fever, nausea, vomiting) | Very frequent | Infrequent |
| Clinical course | More rapid deterioration; more severe weakness at nadir. Lower motor neuron features persist beyond the time expected for spinal shock. More aggressive immunosuppression needed. | Less severe clinical deterioration; longer time to reach nadir; less severe weakness at nadir. |
| Long-term Disability | Greater | Less |
| CSF | Neutrophilic pleocytosis; higher protein; hypoglycorrachia | Mild pleocytosis; mildly elevated protein; normal glucose |
| MRI | Cord swelling; frequent LETM; less frequent gadolinium-enhancement | Infrequent cord swelling; less frequent LETM; More frequent gadolinium-enhancement |
| Recurrence | Very rare | More than 70% of patients |
| Prior optic neuritis | Absent | Frequent |
| Coexisting NMO and/or NMO-IgG seropositivity | None | Frequent |
| Higher SLE disease activity | Frequent | Infrequent |
Abbreviations: CSF, cerebrospinal fluid; LETM, longitudinally extensive transverse myelitis; NMO, neuromyelitis optica; NMO-IgG, aquaporin-4-antibody; SLE, systemic lupus erythematosus.
Although low-titer positive antinuclear antibodies (ANA) in idiopathic TM (ITM) cases are similar to that of the general population, much higher serum ANA titers, anti–double-stranded DNA antibodies, and hypocomplementemia are found in SLE-related TM.
68
, 71
The presence of antiphospholipid antibodies (APLA) in SLE has been suggested to increase the risk of developing TM73
but this association has been challenged.67
, 69
CSF pleocytosis with elevated protein and intrathecal IgG synthesis are typically detected, particularly in LETM68
, 69
, 71
, 74
; interestingly, OCBs, although unusual, have been observed in APLA-seropositive patients.69
The most common MRI finding in SLE-related TM is a longitudinally extensive, T2-hyperintense lesion (accompanied by cord swelling).
68
, 69
, 71
, 74
, 75
, 76
, 77
, 78
In severe cases, the lesion involves the entire spinal cord and extends into the medulla.79
, 80
Radiologic findings may not correlate with the clinical course.68
Almost a third of patients with SLE-related TM do not have any detectable MRI abnormalities at presentation.67
On brain MRI, subcortical lesions predominate in APS and SLE, whereas periventricular and callosal lesions are more common in MS.81
In a randomized controlled trial, IV cyclophosphamide was found to be more efficacious in treating neuropsychiatric manifestations of SLE compared with IV methylprednisolone.
82
The combination of high-dose IV methylprednisolone and IV cyclophosphamide may be effective in SLE-related TM if instituted promptly, resulting in improvement in a few days to 3 weeks.67
, 70
, 83
, 84
Relapses are common (50%–60%) during corticosteroid dose taper, emphasizing the need for maintenance immunosuppression.70
Plasmapheresis has been used in severe cases.67
, 71
, 85
, 86
There is anecdotal evidence for using intravenous immunoglobulin and rituximab.71
, 87
, 88
Anticoagulation therapy is indicated only in those with a history of thrombotic phenomena.69
, 71
, 73
, 74
Long-term aspirin use has anecdotal support.74
Factors associated with severe neurologic deficits include extensive cord MRI lesions, LMN features and sphincteric dysfunction at onset, APLA, and delayed (>2 weeks) initiation of therapy.
67
, 72
, 89
Antiphospholipid Syndrome
APS is a systemic, autoimmune disorder characterized by recurrent thrombotic events and/or miscarriages, as well as APLA seropositivity (2 or more occasions at least 6 weeks apart) (ie, anticardiolipin, lupus anticoagulant, and anti-beta-2-glycoprotein I antibodies).
90
In secondary APS, the disease coexists with another autoimmune disorder.TM is an unusual complication of APS, with a prevalence of less than 1%.
91
, 92
, 93
Although typically monophasic, recurrent corticosteroid-responsive LETM has also been observed.92
Characteristically, acute thoracic cord dysfunction occurs with sphincter involvement.93
Spine MRI may be normal on presentation in up to 40% of patients, underscoring the importance of repeat imaging in suspected cases.94
It is hypothesized that interactions between APLA and spinal cord phospholipids are responsible for APS-related TM,95
explaining the efficacy of and justifying the use of early high-dose corticosteroid therapy.93
In corticosteroid-refractory patients, cyclophosphamide, plasmapheresis, and rituximab may be needed.93
A higher prevalence of APLA seropositivity has been reported in patients with MS and appears to rise with disease duration.
96
, 97
, 98
, 99
, 100
Although diagnostic confusion may arise in APLA-positive patients with TM, the presence of CSF OCBs and the absence of prior miscarriages or thrombotic phenomena would favor MS rather than APS.Behcet Disease
BD is a relapsing multisystem inflammatory disorder of unclear etiology resulting in oral aphthous ulcers, genital ulcers, uveitis, cutaneous manifestations, and involvement of other organ systems.
101
Neurologic involvement in BD (neuro-BD) may follow or precede the onset of systemic manifestations.
102
Neuro-BD typically occurs in the third to fourth decade of life, is more common in men, and is usually associated with ocular involvement.102
, 103
, 104
The frequency of neuro-BD varies greatly, from 1.3% to 59.0%, with a pooled average of 9.4%.102
, 104
Neuro-BD can be classified as parenchymal or nonparenchymal (vascular). Parenchymal neuro-BD commonly manifests as a meningoencephalitic syndrome with headaches and focal neurologic deficits.102
The manifestations of vascular BD stem from cerebral venous thrombosis (often with subsequent increased intracranial hypertension) and/or rarely, arterial infarctions.105
Spinal cord involvement ranges between 2.5% and 30.0%, with a predilection for the cervical and thoracic cord segments (in particular the posterolateral cord), and carries a poor prognosis.102
, 103
, 106
, 107
, 108
, 109
Isolated TM in neuro-BD is distinctly unusual.102
, 105
Spinal cord lesions are usually longitudinally extensive and involve multiple noncontiguous segments, or even involve the entire cord. Cord swelling and T2-hyperintense, nonenhancing lesions are present in the acute or subacute phase.
106
, 107
, 109
, 110
, 111
, 112
, 113
, 114
An unusual report of TM (extending from T9 to the conus) following CT-guided L2 nerve root injection, may be a florid demonstration of the pathergic reaction in the spinal cord.115
Brain MRI may reveal T1-hypo/isointense and T2-hyperintense lesions that may or may not show gadolinium enhancement acutely. Characteristically, an upper pontomesencephalic lesion with thalamic, hypothalamic, and basal ganglial extension on one side is seen.
102
, 105
, 107
, 109
, 116
, 117
Interestingly, the red nucleus is almost always spared.107
, 109
Striking brainstem atrophy, as well as the rarity of periventricular lesions, optic neuropathy, cortical atrophy, and gray matter lesions in neuro-BD,102
, 109
, 117
, 118
distinguish it from MS.CSF typically reveals normal glucose, increased protein, and neutrophilic pleocytosis; the IgG index may be elevated, and OCBs are rare.
103
, 104
, 105
, 106
, 108
, 117
Acutely, administration of high-dose corticosteroids results in improvement in most patients
103
, 104
, 108
, 110
, 111
, 113
, 119
; corticosteroid therapy also improved pleocytosis.117
Infliximab, cyclophosphamide, and intravenous immunoglobulin have been used with some success.104
, 120
No randomized controlled trials have been conducted into the treatment of neuro-BD. Azathioprine, mycophenolate mofetil, and methotrexate have been used as initial immunosuppressive therapy. In more aggressive disease, tumor necrosis factor-antagonists or monthly infusions of cyclophosphamide have been used. Colchicine, thalidomide, and pentoxifylline may be used for mucocutaneous lesions.
102
, 103
, 104
Cyclosporin A has been used to treat ophthalmic manifestations but may be neurotoxic and worsen neurologic manifestations.121
, 122
, 123
, 124
TM in Other Rheumatologic Diseases
TM has been reported in AS, psoriatic arthritis, mixed connective tissue disease, and systemic sclerosis (please refer to Table 5).
Table 5Other dysimmune disorders associated with TM
| Disorder | Comment | References |
|---|---|---|
| Ankylosing spondylitis | Neurologic involvement is rare and is almost always attributable to compressive myelopathy. Noncompressive myelopathy is exceptionally rare with only 2 clearly documented cases of TM. | 368 , 369 , 370 |
| Psoriatic arthritis | 371 | |
| Mixed connective tissue disease | Female preponderance; predilection for the thoracic cord. | 372 , 373 , 374 , 375 , 376 , 377 |
| Systemic sclerosis | Rare and typically compressive in etiology. Progressive myelopathy, subacute TM, and NMO-IgG positive LETM have been reported. | 378 , 379 , 380 , 381 |
| Anti-Jo-1 antibody | A single report of TM preceding the development of polymyositis and pulmonary fibrosis in a patient with anti-Jo-1 antibody. | 382 |
| Urticarial vasculitis | Urticarial vasculitis may be primary disorder or coexist with other autoimmune diseases. | 383 |
| pANCA seropositivity | Perinuclear antineutrophil cytoplasmic antibody (pANCA) seropositivity has been reported to cause TM associated with CSF pleocytosis and increased protein with typically absent OCBs. | 384 , 385 |
| Celiac disease | Celiac disease is an immune-mediated disorder characterized by intolerance to dietary gluten. | 386 |
| Thymic follicular hyperplasia | Recurrent multifocal TM associated with thymic follicular hyperplasia that resolved following thymectomy. | 387 |
| Graft-vs-host disease | TM may be a rare manifestation of graft-vs-host disease following hematopoietic cell transplantation. | 388 , 389 , 390 |
| Common variable immunodeficiency | A primary immune deficiency disorder characterized by hypogammaglobulinemia, antibody deficiency, and recurrent infections. | 391 , 392 |
Abbreviations: CSF, cerebrospinal fluid; LETM, longitudinally extensive transverse myelitis; NMO-IgG, aquaporin-4-antibody; OCB, oligoclonal bands; SLE, systemic lupus erythematosus.
Neurosarcoidosis
Sarcoidosis is a multisystem granulomatous disease with protean manifestations that may affect any organ. Neurologic involvement (neurosarcoidosis) is reported in 5% to 13% of patients with sarcoidosis
125
, 126
, 127
, 128
but may be as high as 26%.129
The usual age of onset is the fourth decade.127
, 130
Spinal cord neurosarcoidosis appears to be more common in men.131
, 132
CNS features are the initial manifestation of neurosarcoidosis in up to 70% of patients.
130
Although unusual, spinal cord involvement portends a poor outcome, and may be related to intramedullary, intradural extramedullary, or extradural lesions; cauda equina syndrome; or arachnoiditis.130
, 131
, 133
Although isolated myelopathy has been observed, half of patients with spinal cord neurosarcoidosis demonstrate systemic manifestations.129
, 133
, 134
Neurosarcoidosis has a predilection for the cervical and thoracic cord
131
, 132
, 135
, 136
, 137
and is frequently associated with back pain and radicular symptoms.131
, 138
, 139
, 140
Intramedullary disease typically appears as a longitudinally extensive, T1-hypointense, T2-hyperintense, heterogeneously enhancing lesion with fusiform cord enlargement or myelomalacia.131
, 141
Spinal cord lesions may be multifocal; gadolinium enhancement may be nodular or predominate at the periphery of the lesion.129
, 131
, 132
Neurosarcoidosis should be suspected in any infiltrating intramedullary cord lesion with leptomeningeal enhancement. Half of patients with spinal neurosarcoidosis have concomitant intracranial lesions.131
, 141
The diagnosis of spinal cord neurosarcoidosis is challenging, particularly if systemic manifestations are absent. When clinical suspicion is high, even in the absence of systemic symptoms, it is worthwhile performing a high-resolution chest CT, positron emission tomography, ophthalmic examination, or a gallium-67 scan to identify extraneural granulomas that may be amenable to biopsy.
66
, 140
, 142
CSF findings reveal elevated protein, lymphocytic pleocytosis, occasional hypoglycorrachia, and infrequent OCBs. CSF angiotensin-converting enzyme levels are normal in more than half of patients. Hypoglycorrachia is specific and can distinguish neurosarcoidosis from other inflammatory etiologies.
130
, 131
, 140
, 143
Early corticosteroid therapy results in remarkable recovery but delayed treatment leads to only partial resolution of myelopathic manifestations.
132
A high index of suspicion for the diagnosis is required because early intervention is associated with a favorable outcome.Vogt-Koyanagi-Harada Syndrome
Vogt-Koyanagi-Harada syndrome (VKH), also known as uveomeningoencephalitis, is a systemic inflammatory disorder affecting the melanin-forming cells in different organs.
144
TM is an infrequent complication of VKH,145
, 146
and bilateral AON with papilitis has been reported.147</