Summary
Multiple sclerosis (MS) is a chronic, degenerative disease of the CNS that is caused by an immune-mediated inflammatory process. This process results in demyelination and axonal degeneration 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 primarily in white matter. Differential diagnoses 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.
Epidemiology
- Sex: ♀ > ♂ (3:1) [1]
- Age of onset: 20–40 years of age
- Ethnicity: ↑ prevalence among the white population
- Prevalence: : 50-300 per 100 000 people (greater among people who live further from the equator)
References: [2]
Epidemiological data refers to the US, unless otherwise specified.
Etiology
The etiology of multiple sclerosis is unclear; it is believed to develop in genetically predisposed people who have been exposed to certain environmental factors.
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Genetic predisposition
- Presence of HLA-DRB1*15 allele increases the risk of MS. [3]
- Presence of HLA-A*02 allele appears to be protective against MS. [3]
- 35% disease concordance among monozygotic twins [4]
- 3–4% disease concordance among first-degree relatives [4]
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Environmental risk factors [2][5]
- Low vitamin D levels (insufficient intake, decreased exposure to UV radiation)
- Cigarette smoking
- Pathogens: EBV, HHV 6
- Obesity early in life
Pathophysiology
- Pathophysiology of MS is characterized by autoimmune 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
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B-lymphocyte dysfunction: The following suggests that B-lymphocytes play a role in the pathogenesis of MS, although the exact mechanism of their involvement is unclear.
- Anti-CD20 agents (ocrelizumab, ofatumumab, rituximab) are effective in preventing relapses.
- Presence of tertiary lymphoid organs in the meninges of individuals with secondary progressive MS [6]
- Intrathecal synthesis of IgG (oligoclonal bands; see “Diagnostics” section for more information)
- Progressive phenotypes (forms) of MS are characterized by [7]
- Chronic inflammation that occurs with an intact blood-brain barrier and is driven by immune cells compartmentalized in the leptomeninges and perivascular spaces
- Accelerated compared to relapsing-remitting phenotype brain atrophy
Clinical features
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Constitutional symptoms
- Fatigue
- Headache
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Optic neuritis [8][9][10]
- Most often the earliest manifestation
- Typically unilateral
- Can be painful
- Impaired vision and color blindness
- Relative afferent pupillary defect (Marcus Gunn pupil)
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Internuclear ophthalmoplegia (INO) as a result of a lesion in the medial longitudinal fasciculus (MLF)
- Ipsilateral medial rectus weakness but an intact convergence reflex
- Disconjugate, lateral gaze nystagmus in the contralateral eye
- More frequently bilateral than unilateral
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Demyelination of spinal cord tracts
- Lhermitte sign: a shooting electric sensation that travels down the spine upon flexion of the neck
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Pyramidal tract lesion: upper motor neuron weakness
- Spasticity
- Hyperreflexia
- Positive Babinski sign
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Involvement of the dorsal spinal column
- Loss of vibration and fine-touch sensation
- Numbness, paresthesias
- Sensory ataxia usually involving the trunk or one or more limbs
- Neuropathic pain
- Absent abdominal reflex [11]
- Cerebellar involvement: Charcot neurological triad
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Cranial nerve palsies [12]
- Diplopia
- Trigeminal sensory neuralgia
- Facial palsy
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Autonomic dysfunction
- Bowel and bladder neurogenic disorders
- Impaired sexual function
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Changes in mental state
- Depression, emotional changes
- Memory deficits, impaired concentration
- Uhthoff phenomenon: a reversible exacerbation of neurological symptoms following an increase in body temperature, e.g., physical exertion, a warm bath, or fever
Fundoscopy is normal in 60% of cases of optic neuritis. Neither the patient nor the doctor are able to see anything.
Uhthoff phenomenon triggered by a viral infection may mimic an exacerbation of MS.
Stages
Clinical course [13]
Clinical phenotypes of multiple sclerosis | ||
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Phenotype | Characteristics | Incidence at the time of diagnosis |
Relapsing-remitting MS (RR-MS) |
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Secondary progressive MS (SP-MS) |
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Primary progressive MS (PP-MS) |
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Definition of 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. |
Special forms of MS
- Radiologically isolated syndrome (RIS) [13][14]
- Clinically isolated syndrome (CIS): a constellation of neurological symptoms that, in hindsight, can be interpreted as the first episode of MS [13]
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Diffuse cerebral sclerosis (Schilder disease)
- Clinical course: primarily affects children; monophasic course with most patients dying within 1–2 years of disease onset
- Clinical features: large areas of demyelination leading to various neurological deficits and psychological changes depending on the location of the lesion
Diagnostics
For more detailed information about the MS diagnostics, see “Revised McDonald criteria.”
Instrument-based diagnostics
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Plain MRI (brain and spine): investigation of choice
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Multiple sclerotic plaques (most commonly seen in periventricular white matter) ; with finger-like radial extensions (Dawson fingers) related to demyelination and reactive gliosis
- In T1: hypo-/isointense; severe demyelination and axonal destruction → black hole lesions
- In T2 and FLAIR: hyperintense
- Contrast MRI (with gadolinium): enhancement of active lesion during and up to 6 weeks after the exacerbation
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Multiple sclerotic plaques (most commonly seen in periventricular white matter) ; with finger-like radial extensions (Dawson fingers) related to demyelination and reactive gliosis
- Visual evoked potentials: slowed optic nerve conduction → increased latency
CSF examination
- Lymphocytic pleocytosis
- Oligoclonal bands (↑ production of IgG subfractions): the presence of multiple oligoclonal bands in CSF and their absence in the blood is highly suggestive of MS.
- ↑ myelin basic protein
The appearance of oligoclonal bands in the early stages of the disease indicates a poor prognosis!
References:[15][16][17][18]
Revised McDonald criteria
The McDonald criteria are used to diagnose MS based on the dissemination of the CNS lesions in time and space.
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Dissemination in time (DIT): defined as the appearance of new lesions over time that can be confirmed by one of the following:
- Two or more exacerbations occurring at least 30 days apart
- MRI demonstrates the presence of both gadolinium-enhancing and nonenhancing lesions at any time or a new hyperintense T2 or enhancing lesion on follow-up MRI
- Alternatively to DIT: positive CSF oligoclonal bands with no serum oligoclonal bands (indicate ongoing intrathecal inflammation)
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Dissemination in space (DIS): defined as the presence of lesions in different regions of the CNS that can be confirmed by one of the following:
- Presence of two or more lesions with objective clinical evidence
- Objective clinical evidence of a lesion refers to the correlation between the symptoms reported by a patient and corresponding objective findings (e.g., T2 hyperintensities in the regions corresponding to somatosensory tracts on MRI or abnormal somatosensory evoked potentials in a patient who reports sensory loss)
- Presence of one or more hyperintense lesions on MRI in T2 sequence in at least 2 of the following regions: periventricular, juxtacortical, infratentorial, spinal
- Presence of two or more lesions with objective clinical evidence
McDonald criteria (2017) for the diagnosis of multiple sclerosis [19] | |||
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Dissemination in space (DIS) | |||
Criterion met (≥ 2 lesions with objective clinical evidence) | Criterion not met (1 lesion with objective clinical evidence) | ||
Dissemination in time (DIT) | Criterion met ≥ 2 exacerbations) |
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Criterion not met (1 exacerbation) |
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Differential diagnoses
Autoimmune diseases associated with inflammatory demyelination
Neuromyelitis optica spectrum disorders (NMOSD; previously known as Devic disease or neuromyelitis optica) [20][21]
- Definition: immune-mediated, chronic inflammatory disorders of the CNS that primarily affect the optic nerve and spinal cord
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Epidemiology
- Incidence: 0.3-4.4 per 100,000
- More prevalent in individuals of African and Asian descent than in white populations
- Peak onset: 40-60 years
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Pathophysiology
- Not fully understood but is thought to be an autoimmune process
- Anti-aquaporin-4 (an autoantibody that targets aquaporin-4 in the membrane of astrocytes) is involved in a humoral immune response
- Process characterized by demyelination and axonal damage of the optic nerve and spinal cord
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Clinical features
- Closely resembles the clinical appearance of MS
- Recurrent acute attacks with rapid stepwise deterioration, but no progression in between the attacks
- Optic neuritis (often bilateral): impaired vision, retrobulbar pain
- Transverse myelitis: symmetric paraplegia, sensory loss, bladder dysfunction
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Diagnosis: based on
- Serological evidence of anti-aquaporin-4 (AQP4)
- The presence of clinical characteristics
- Optic neuritis
- Acute myelitis
- Area postrema syndrome (episodes of intractable nausea, vomiting, and/or hiccups)
- Acute brainstem syndrome
- Narcolepsy or acute diencephalic syndrome with typical MRI lesions
- Cerebral syndrome with typical brain lesions
- Typical MRI findings (see clinical criteria for NMOSD with negative AQP4-IgG or unknown status below)
Diagnostic criteria of NMOSD based on AQP4-IgG status | ||
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Serological criteria | Clinical criteria | Additional criteria |
Positive AQP4-IgG |
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Negative AQP4-IgG or unknown status |
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Treatment
- First line: high-dose glucocorticoid therapy for 3–5 days followed by a taper for 2–8 weeks
- Plasmapheresis in severe, refractory cases
- The following biological agents are approved for use in patients with positive AQP4-IgG
- Eculizumab: antibody against C5 complement component
- Inebilizumab: antibody against CD19
- Satralizumab: antibody against IL-6 receptor
- Immune modulators used off-label (azathioprine, rituximab) may also reduce the risk of acute attacks
- Natalizumab and IFN-β (effective MS treatment options) can trigger NMOSD exacerbations
Acute disseminated encephalomyelitis (ADEM, acute demyelinating encephalomyelitis) [22]
- Definition: an immune-mediated, demyelinating CNS disease of parainfectious origin (e.g., measles) or after vaccinations (less common)
- Epidemiology: mostly affects children and young adults
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Clinical features: rapidly progressing, usually monophasic, course with multifocal symptoms
- Evidence of motor, sensory, cranial nerve, and/or brainstem impairment
- Altered mental status (loss of consciousness is possible)
- Optic neuritis: impaired vision, retrobulbar pain
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Diagnosis
- Lumbar puncture: lymphocytic pleocytosis and elevated protein
- Spinal and/or brain MRI (with and without contrast): typically multiple, bilateral lesions
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Treatment
- High-dose IV corticosteroid therapy for 3–5 days
- IV immune globulin therapy or plasma exchange in patients who do not respond to corticosteroids
- Acyclovir (empiric therapy until infectious etiology is identified)
Other conditions
- Vasculitis resulting from connective tissue disorders (e.g., SLE, polyarteritis nodosa, granulomatosis with polyangiitis, Behcet disease)
- Infections
- 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.
Treatment
Summary of therapy for multiple sclerosis [23]
The goal is to begin treatment as early as possible to treat the primary exacerbation, prevent further exacerbations, and slow down the disease process.
Summary of multiple sclerosis therapy | ||||
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Indication | Clinically isolated syndrome (CIS) | Relapsing remitting MS (RR-MS) | Secondary progressive MS (SP-MS) | Primary progressive MS (PP-MS) |
Treatment of acute exacerbation |
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Prevention of exacerbations |
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Treatment of acute exacerbations
- First line: high-dose glucocorticoid therapy for 3–5 days
- Prophylaxis against side effects of corticosteroids: proton pump inhibitors to prevent gastritis and LMW heparin for thromboprophylaxis
- Second line: plasmapheresis
Disease-modifying MS therapy
Disease-modifying drugs (DMDs) | ||||
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Medication | Mechanism of action | Route of application | Indications | Side effects |
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Glatiramer acetate (copolymer-1) |
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Mitoxantrone |
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Dimethyl fumarate |
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Teriflunomide |
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Fingolimod |
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Siponimod |
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Ozanimod | ||||
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Natalizumab |
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Ocrelizumab |
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Ofatumumab |
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Supportive therapy
- Spasticity: dantrolene, baclofen (centrally acting GABA agonist); , tizanidine; (α2-receptor agonist), physiotherapy
- Tremors: carbamazepine, primidone, propranolol
- Painful paresthesias: anticonvulsants (e.g., carbamazepine), tricyclic antidepressants (e.g., amitriptyline)
- Urinary retention: intermittent catheterization and parasympathomimetic drugs
- Urinary incontinence: parasympatholytic agents (e.g., oxybutynin)
- Walking impairment: dalfampridine (blockage of potassium channels → increased duration of action potentials)
- Erectile dysfunction: sildenafil
- Depression: antidepressants
References:[24][25][26][27][28][29][30][31][32][33][34][35][36][37]
Prognosis
Prognostic factors for disease progression [38][39]
- Male sex
- Age at MS onset > 40 years
- Multiple symptoms with early motor and cerebellar involvement
- Incomplete recovery after relapses
- High relapse rate in the first 2 years after MS onset
Special patient groups
Multiple sclerosis in pregnancy [40]
- Effect of pregnancy on MS:
- Decreased relapse rate of MS during pregnancy
- Increased relapse rate in the postpartum period
- The long-term clinical course of MS remains unchanged.
- Effect of MS on pregnancy: ↑ rate of caesarean sections and ↓ birth weights when compared to mothers without MS