Transverse Myelitis (TM) is an acquired neuroinflammatory disorder of the spinal cord characterized by acute or subacute inflammation, leading to substantial motor, sensory, and autonomic dysfunction below the level of the lesion. While historically considered a single idiopathic entity, modern diagnostics have clarified that TM is often a clinical syndrome representing the initial presentation of specific underlying demyelinating diseases, such as Neuromyelitis Optica Spectrum Disorder (NMOSD) or Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD). Understanding the progression from initial cause to clinical presentation is essential for prompt, effective, and evidence-based management.
Aetiology (Causes and Classification)
The aetiology of Transverse Myelitis is heterogeneous, typically classified into idiopathic TM (where no clear underlying cause or subsequent systemic disease is identified) and associated TM (where the syndrome is linked to a specific autoimmune, infectious, or systemic disorder). Approximately 30-50% of cases remain idiopathic after comprehensive investigation, though this percentage continues to decrease with improved antibody testing.
1. Infectious and Post-Infectious Triggers
Infection is a common trigger, either directly invading the spinal cord or initiating a parainfectious autoimmune response.
- Direct Infections: Viruses such as Herpes Simplex Virus 1 and 2 (HSV), Varicella-Zoster Virus (VZV), Cytomegalovirus (CMV), and Human Immunodeficiency Virus (HIV) are known culprits. Bacterial causes include Mycoplasma pneumoniae, Lyme disease (Borrelia burgdorferi), and syphilis.
- Parainfectious: This form occurs following a systemic infection (often respiratory or gastrointestinal) and is thought to be mediated by molecular mimicry, where the immune system targets spinal cord antigens due to structural similarity with microbial epitopes. Acute Disseminated Encephalomyelitis (ADEM) is a key syndrome falling within this category.
2. Systemic Autoimmune Diseases
TM can represent a spinal cord manifestation of underlying systemic rheumatologic conditions, necessitating thorough screening for these disorders:
- Systemic Lupus Erythematosus (SLE)
- Sjögren’s Syndrome
- Sarcoidosis
- Behçet’s disease
3. High-Risk CNS Autoimmune Syndromes
The most critical workup involves differentiating idiopathic TM from TM associated with specific central nervous system (CNS) demyelinating diseases, as these require aggressive, long-term preventative maintenance therapy due to their high relapse rate and potential for severe disability.
- Neuromyelitis Optica Spectrum Disorder (NMOSD): Characterized by the IgG antibody targeting Aquaporin-4 (Aqp4), primarily damaging astrocytes in the spinal cord and optic nerves. TM in NMOSD is typically severe, often extensive longitudinally (involving three or more vertebral segments, known as Longitudinally Extensive Transverse Myelitis or LETM).
- Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): Characterized by the antibody targeting MOG, a component of the myelin sheath. TM related to MOGAD often presents with conus involvement and may be less destructive than Aqp4-positive TM, though relapse is common.
- Multiple Sclerosis (MS): While MS-related TM is usually short-segment (less than two vertebral bodies), TM can be the initial presentation of MS, requiring vigilant clinical and radiological follow-up.
Pathophysiology (Mechanism of Spinal Cord Damage)
The fundamental mechanism in TM involves an immune-mediated inflammatory attack on the spinal cord parenchyma, leading to demyelination, axonal injury, and subsequent neurological deficit.
1. Blood-Spinal Cord Barrier (BSCB) Disruption
The initial event involves the compromise of the BSCB, allowing inflammatory cells (T-lymphocytes, B-cells, and macrophages) and circulating antibodies to infiltrate the spinal cord tissue. This infiltration is often concentrated in the thoracic region, although any level can be affected.
2. Inflammatory Cascade and Demyelination
Once within the CNS, activated T-cells recognize specific myelin components or glial proteins as foreign targets. They release pro-inflammatory cytokines (e.g., TNF-α, interleukins) that amplify the attack.
- Cellular Damage: Macrophages are recruited and participate in the destruction of myelin sheaths surrounding the axons—a hallmark of demyelinating syndromes. In cases of severe inflammation, the axons themselves can be damaged (axonal loss), which is the primary predictor of poor long-term functional outcome.
3. Specific Immunopathology
The precise location and mechanism of damage vary based on the underlying antibody profile:
- Aqp4-TM (NMOSD): Aqp4 is highly expressed on astrocytes. The binding of Aqp4 IgG antibody recruits complement, leading to astrocytic injury, demyelination, and necrosis. This results in significant cavitation and inflammatory edema.
- MOG-TM (MOGAD): MOG is expressed on oligodendrocytes and the outer surface of the myelin sheath. MOG antibody binding leads to robust demyelination, often with less outright tissue destruction compared to NMOSD, potentially explaining why MOGAD patients often have better recovery profiles.
4. Secondary Damage: Edema and Ischemia
The acute inflammatory assault leads to profound swelling (edema) within the confined space of the vertebral canal. This swelling can compress surrounding blood vessels, resulting in secondary ischemic injury that significantly exacerbates neurological damage and tissue necrosis, contributing to the “transverse” (affecting the entire width) nature of the deficit.
Clinical Features and Diagnosis
TM typically presents as an acute or subacute monophasic event, evolving rapidly over hours to four weeks. The clinical syndrome is defined by a characteristic triad of symptoms: motor, sensory, and autonomic dysfunction.
1. Clinical Features
- Motor Dysfunction: The most common symptom, manifesting as weakness starting acutely in the legs (paraparesis or paraplegia). Severity can range from subtle gait issues to complete paralysis. Deep tendon reflexes may initially be absent (spinal shock) but often become hyperreflexive over time.
- Sensory Symptoms: Often precede motor symptoms. Patients report ascending paresthesias (tingling, numbness) and dysesthesias (unpleasant, burning sensations). A crucial diagnostic sign is the sensory level—a distinct horizontal line on the torso below which all sensation (pain, temperature, vibration) is diminished or lost.
- Autonomic Dysfunction: This is a hallmark of TM, indicating involvement of the central pathways. Symptoms include sphincter dysfunction (urinary urgency, retention, or incontinence), obstipation (severe constipation), and sometimes sexual dysfunction or blood pressure lability.
2. Diagnostic Criteria and Investigations
Diagnosis is based on the clinical presentation, radiological evidence, and the rigorous exclusion of compressive causes (e.g., tumor, abscess, herniated disc).
- Winger Criteria (TM Diagnosis): Key elements include motor, sensory, or autonomic dysfunction attributable to the spinal cord; bilateral signs/symptoms; a clearly defined sensory level; progression to maximal deficit between 4 hours and 21 days; and exclusion of overt spinal cord compression.
- Magnetic Resonance Imaging (MRI): The gold standard.
- Spinal Cord: Typically reveals T2-weighted hyperintensity (inflammation/edema) within the spinal cord. Contrast (Gadolinium) enhancement indicates active inflammation. The length of the lesion is vital: short-segment TM (SS-TM, less than two vertebral segments) is often associated with MS, while LETM (three or more segments) is highly suggestive of NMOSD or MOGAD.
- Brain: Must be included to rule out MS, which often involves dissemination in space (DIT).
- Lumbar Puncture (LP): Cerebrospinal fluid (CSF) analysis often shows mild-to-moderate pleocytosis (increased white blood cell count, usually mononuclear cells) and elevated protein levels. The presence of oligoclonal bands (OCBs) is less common in TM than in MS, but OCBs are found in a significant minority of TM patients.
- Serology: Mandatory testing for Aqp4 IgG and MOG IgG antibodies is required to classify the TM syndrome and guide maintenance therapy. Further serological workup for systemic autoimmunity (ANA, anti-Ro/La, ESR, CRP) and infectious agents is also essential.
Management (Acute Treatment and Long-Term Strategy)
The management of TM is multi-faceted, focusing on halting the acute inflammatory attack, preventing complications, managing residual symptoms, and initiating relapse prevention therapy if an associated high-risk syndrome is identified.
1. Acute Phase Treatment (Inflammation Control)
Treatment must begin immediately upon diagnosis to maximize the chance of functional recovery.
- High-Dose Intravenous Methylprednisolone (IVMP): This is the first-line therapy. IVMP (typically 1 gram daily for 3–7 days) suppresses the acute inflammatory response, dampens T-cell activation, and reduces edema.
- Plasma Exchange (PLEX): Used for patients who fail to show significant improvement after 3–5 days of IVMP, or for severe presentations. PLEX physically removes pathogenic antibodies, immune complexes, and inflammatory mediators from the circulation, proving highly effective in severe Aqp4-positive TM.
- Intravenous Immunoglobulin (IVIg): Less studied than PLEX, IVIg may be considered an alternative, particularly in pediatric or post-infectious cases, though evidence is less robust than for IVMP or PLEX.
2. Long-Term Maintenance Therapy (Relapse Prevention)
For patients diagnosed with NMOSD or MOGAD, ongoing immune suppression is mandatory to prevent devastating future spinal cord or optic nerve attacks.
- NMOSD: Requires continuous, highly effective immunosuppression (e.g., Rituximab, Satralizumab, Inebilizumab, or Azathioprine).
- MOGAD: While some patients are managed with a slow steroid taper, many require maintenance therapy (e.g., Rituximab, Azathioprine, or Mycophenolate Mofetil) depending on clinical factors and relapse history.
- Idiopathic TM: Does not generally require long-term immune suppression, but patients must be monitored for progression to MS.
3. Supportive Care and Rehabilitation
This phase is crucial for maximizing functional recovery and quality of life. Recovery is often slow and can continue for weeks to years.
- Rehabilitation: Intensive physical therapy, occupational therapy, and gait training are essential to restore mobility and strength.
- Pain Management: Neuropathic pain (often chronic) is common and requires specialized agents (Gabapentinoids, tricyclic antidepressants).
- Spasticity Management: Baclofen or Tizanidine are used to manage muscle stiffness and involuntary movements.
- Autonomic Management: Careful bladder management (intermittent catheterization, medications) and bowel regimens are necessary to prevent urinary tract infections and severe constipation. Psychological support is also often required given the major impact on daily function.
References
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