- Clinical science
Multiple sclerosis (MS) is a chronic, degenerative disease of the CNS that is caused by an immune-mediated inflammatory process. This process results in the demyelination of white matter in the brain and spinal cord. MS has a higher prevalence among women and people in temperate regions such as Europe and North America. Impaired vision (due to retrobulbar neuritis) is usually the first manifestation of the disease. Other neurological deficits also appear as the disease progresses. The most common clinical course is characterized by exacerbations (relapses) followed by periods of complete/incomplete remission. MRI, which is the investigation of choice, reveals demyelinated sclerotic plaques in white matter. Differential diagnosis of MS includes other chronic demyelinating diseases and neurological infections (e.g., borreliosis, neurosyphilis). Acute exacerbations of MS are treated with high-dose glucocorticoids. Between relapses, patients may be treated with disease-modifying drugs (e.g., β-interferon, glatiramer acetate). No definitive therapy is available for MS.
- Exact cause remains unknown
- Characterized by inflammation, demyelination, and axonal degeneration
- Most commonly accepted theory: Activation of autoreactive T-lymphocytes → inflammatory processes → focal demyelination with partial preservation of axons (acute plaques) → loss of axons and atrophy of oligodendrocytes (chronic plaques) → gliosis → inadequate remyelination
- There is evidence for Th1 immune response involving myelin basic proteins
- Most common sites of demyelination in MS
- Optic neuritis (most often the earliest manifestation): impaired vision and color blindness
- INO) as a result of a lesion in the medial longitudinal fasciculus (MLF) (
Demyelination of spinal cord tracts
- Lhermitte's sign: a shooting electric sensation that travels down the spine when the patient flexes his/her neck
- Absent abdominal reflex
- Pyramidal tract lesion: upper motor neuron weakness characterized by spasticity, hyperreflexia, and a positive Babinski's sign (see )
- Involvement of the dorsal spinal column; : loss of vibration and fine touch sensations, numbness, paresthesias, sensory ataxia
Cerebellar involvement → Charcot's neurological triad
- Scanning speech
- Intention tremors
- Cranial nerve palsies
- Autonomic dysfunction: bowel and bladder disorders, impaired sexual activity
- Change in mental state: memory deficits, impaired concentration, and/or depression
- Uhthoff's phenomenon: a reversible exacerbation of neurological symptoms following physical exertion, a warm bath, or fever
In 60% of cases of optic neuritis, fundoscopy is normal. Neither the patient nor doctor are able to see anything!
Uhthoff's phenomenon triggered by a viral infection can be confused with an exacerbation of MS!
|Characteristics||Incidence at the time of diagnosis|
|Relapsing-remitting MS (RR-MS)|| || |
|Secondary progressive MS (SP-MS)|| || |
|Primary progressive MS (PP-MS)|| || |
|Definition of relapse/exacerbation: new symptoms or significant worsening of existing symptoms, both of which last at least 24 hours and are preceded by at least 30 days of relative clinical stability.|
Plain MRI (brain and spine): investigation of choice
- Multiple sclerotic plaques (most commonly seen in periventricular white matter) with finger-like radial extensions (Dawson's fingers)
- Contrast MRI (with gadolinium): enhancement of active lesion during and up to 6 weeks after the exacerbation
- Electrophysiological studies: slowed nerve conduction → increased latency of visually evoked potentials (VEP)
- For more detailed information, see .
Lumbar puncture for CSF examination
- Only indicated if MRI is inconclusive
The appearance of oligoclonal bands in the early stages of the disease indicates a poor prognosis!
- Other causes of inflammatory demyelination
- Vasculitis resulting from connective tissue disorders (e.g., SLE, polyarteritis nodosa, granulomatosis with polyangiitis, Behcet's disease)
- Neuroborreliosis: diagnosed by CSF examination (intrathecal Borrelia-specific antibodies, lymphocytosis)
- Neurosyphilis: diagnosed by a TPHA screening test
- Progressive multifocal leukoencephalopathy (PML): perform an HIV test
- HIV-encephalopathy: perform an HIV test
The differential diagnoses listed here are not exhaustive.
Summary of step-wise therapy for multiple sclerosis
- The goal is to begin treatment as early as possible to treat the primary exacerbation, prevent further exacerbations, and slow down the disease process.
- Therapeutic strategies include
- Escalation therapy: Patients who do not respond to first-line therapy with disease-modifying drugs (DMDs), are switched to second-line DMDs.
- Induction therapy: Patients with severe disease activity at onset, first receive strong immunosuppressant drugs , followed by long-term maintenance therapy with DMDs.
|Summary of multiple sclerosis therapy|
|Indication||Relapsing remitting MS (RR-MS)||Secondary progressive MS (SP-MS)||Primary progressive MS (PP-MS)|
|Treatment of acute exacerbation|| |
|Prevention of exacerbations|| || |
Treatment of acute exacerbations
- First line: high-dose glucocorticoid therapy for 3–5 days (methylprednisolone 500–1000 mg/d IV or PO)
- Second line: plasmapheresis
Disease-modifying MS therapy (prevention of exacerbations)
|Disease-modifying drugs (DMDs)|
|Medication||Mechanism of action||Indications||Side effects|
|Glatiramer acetate (copolymer-1)|| |
|Mitoxantrone|| || |
|Fingolimod|| || |
| || |
- Spasticity: dantrolene, ,physiotherapy
- Painful paresthesias: carbamazepine; , amitriptyline
- Urinary retention: intermittent catheterization and
- Urinary incontinence: (e.g.,
- Erectile dysfunction: sildenafil
Multiple sclerosis in pregnancy
- Effect of pregnancy on MS:
- Effect of MS on pregnancy: ↑ rate of and ↓ birth weights when compared to mothers without MS