Demyelinating & Neuroinflammatory Disease
From McDonald criteria and oligoclonal bands to steroids, DMTs, and the AQP4 mimic
Multiple sclerosis: the disease and its attacks
Lesions in space and time. Multiple sclerosis (MS) is autoimmune demyelination of the CNS, classically in women aged 20–40. The unifying concept is dissemination in space and in time: separate CNS lesions occurring at separate times. Prevalence rises with distance from the equator; vitamin D deficiency, prior EBV infection, and smoking are risk factors.
Typical attacks. Relapses develop over days and include:
- Optic neuritis, often the first presentation.
- Internuclear ophthalmoplegia (INO): a medial longitudinal fasciculus lesion causing impaired adduction of one eye with nystagmus of the abducting eye; bilateral INO in a young adult strongly suggests MS.
- Sensory loss, weakness, cerebellar ataxia (scanning speech, intention tremor, nystagmus), and bladder dysfunction.
Characteristic signs. Uhthoff phenomenon: heat (a hot shower, exercise, fever) transiently worsens symptoms. Lhermitte sign: neck flexion sends an electric sensation down the spine.
Optic neuritis. Subacute monocular vision loss with pain on eye movement, reduced color vision (red desaturation), and a relative afferent pupillary defect (Marcus Gunn pupil). Treat with IV steroids and obtain a brain MRI to gauge future MS risk. Steroids speed visual recovery but do not change the final visual outcome; oral prednisone alone was linked to more recurrences and is avoided.
Course. The relapsing-remitting form is most common and can transition to secondary-progressive disease. Primary-progressive MS accumulates disability from onset without relapses. A first single attack is a clinically isolated syndrome; typical MRI lesions found incidentally in someone without symptoms are a radiologically isolated syndrome. Early disease-modifying therapy reduces long-term disability.
Diagnosis: McDonald criteria, MRI, and CSF
MRI is the key test. The McDonald criteria require dissemination in space and time, shown mainly with MRI T2 white-matter plaques in periventricular, juxtacortical, infratentorial, and spinal cord locations. Periventricular ovoid lesions perpendicular to the ventricles are Dawson fingers. A new lesion on follow-up, or enhancing and nonenhancing lesions on the same scan, demonstrates dissemination in time.
- Clinical attackOptic neuritis, myelitis, or a brainstem syndrome.
- MRI plaquesLesions in separate CNS regions show dissemination in space.
- New or enhancing lesions over timeShow dissemination in time.
- Supportive CSFOligoclonal bands; helpful but not required.
CSF. Oligoclonal bands and an elevated IgG index present in CSF but not in paired serum indicate intrathecal antibody production. They support the diagnosis (and under the 2017 revision can substitute for dissemination in time), but MRI remains the key test and bands are not required.
Matching bands in serum and CSF point to a systemic process rather than intrathecal synthesis.
Treating MS: relapses, disease modification, symptoms
Acute relapse. Give high-dose IV methylprednisolone to speed recovery; use plasma exchange for severe, steroid-refractory attacks. Steroids shorten attacks but do not change long-term disability. First exclude a pseudo-relapse, in which infection (often a UTI) or heat unmasks old deficits.
Disease-modifying therapy (DMT) reduces relapse rate and new lesions.
| Drug | Mechanism | Key toxicity or note |
|---|---|---|
| Interferon-β | Immunomodulatory cytokine | Flu-like symptoms, depression, elevated transaminases |
| Glatiramer acetate | Myelin basic protein mimic | Injection-site reactions, transient flushing |
| Dimethyl fumarate | Oral immunomodulator | Flushing, GI upset, lymphopenia |
| Fingolimod | S1P receptor modulator; traps lymphocytes in nodes | First-dose bradycardia, macular edema |
| Natalizumab | Anti-α4-integrin; blocks lymphocyte entry into CNS | PML in JC-virus-positive patients |
| Ocrelizumab | Anti-CD20 B-cell depletion | Infusion reactions, infection, hepatitis B reactivation; approved for primary-progressive MS |
Symptom management.
- Spasticity: baclofen or tizanidine.
- Fatigue: amantadine or modafinil.
- Bladder urgency: oxybutynin.
- Neuropathic pain: gabapentin or a TCA.
- Walking speed: dalfampridine.
- Depression is common; screen for and treat it.
Neuromyelitis optica and transverse myelitis
NMO spectrum disorder (NMOSD) combines optic neuritis with longitudinally extensive transverse myelitis (a spinal lesion spanning 3 or more vertebral segments), driven by antibodies against aquaporin-4 (AQP4-IgG), the astrocyte water channel. Area postrema attacks (intractable hiccups, nausea, vomiting) also occur. It is distinct from MS: treat attacks with steroids or plasma exchange, prevent relapses with an FDA-approved agent (eculizumab, ravulizumab, inebilizumab, or satralizumab) or off-label rituximab, and avoid MS drugs that can worsen it. If AQP4-IgG is negative, test for MOG-IgG (MOG antibody-associated disease).
| Feature | Multiple sclerosis | NMOSD |
|---|---|---|
| Target | CNS myelin (T- and B-cell autoimmunity) | Aquaporin-4 on astrocytes (AQP4-IgG) |
| Cord lesions | Short, fewer than 3 segments | Longitudinally extensive, 3 or more segments |
| CSF oligoclonal bands | Common | Usually absent |
| Prevention | DMTs (e.g., ocrelizumab, interferon-β) | Eculizumab, ravulizumab, inebilizumab, satralizumab, or off-label rituximab |
| Caution | Natalizumab PML risk | Interferon-β, natalizumab, fingolimod can worsen disease |
Transverse myelitis is an acute inflammatory spinal cord lesion with bilateral motor and sensory deficits, a sensory level, and bladder dysfunction. Causes include MS, NMO, and post-infectious or autoimmune disease. Obtain an emergent spine MRI to exclude compression, treat with IV corticosteroids, and evaluate for MS and NMO.
A sensory level on the trunk is the clue that the lesion is in the spinal cord rather than a peripheral nerve.