Multiple sclerosis

Multiple sclerosis (MS) is a chronic degenerative disease of the CNS characterized by demyelination and axonal degeneration in the brain and spinal cord, which are caused by an immune-mediated inflammatory process. The prevalence of MS is higher 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 MS; other neurological deficits appear as the disease progresses. The most common clinical course is characterized by exacerbations followed by periods of complete or incomplete remission. Diagnosis is made using clinical and MRI findings to identify the dissemination of CNS lesions in time and space. Characteristic MRI findings are demyelinated sclerotic plaques primarily located in white matter. Differential diagnoses of MS include other chronic demyelinating diseases and neurological infections (e.g., borreliosis, neurosyphilis). Acute exacerbations of MS are usually treated with high-dose glucocorticoids. Between exacerbations, patients may be treated with disease-modifying drugs (e.g., interferon beta, glatiramer acetate, natalizumab). There is currently no definitive treatment for MS.

• Sex: : ♀ > ♂ (3:1) ^[1]
• Age of onset: : 20–40 years of age ^[2]
• Ethnicity: ↑ prevalence among the white and black population ^[3]
• Prevalence: 50-300 per 100 000 people (greater among people who live further from the equator) ^[2]

Epidemiological data refers to the US, unless otherwise specified.

The etiology of multiple sclerosis is unclear; it is believed to develop in genetically predisposed people who have been exposed to certain environmental factors.

• Genetic predisposition
  • Presence of HLA-DRB1*15 allele increases the risk of MS. ^[4]
  • Presence of HLA-A*02 allele appears to be protective against MS. ^[4]
  • 35% disease concordance among monozygotic twins ^[5]
  • 3–4% disease concordance among first-degree relatives ^[5]
• Environmental risk factors ^[2][6]
  • Low vitamin D levels (insufficient intake, decreased exposure to UV radiation)
  • Cigarette smoking
  • Pathogens: EBV, HHV 6
  • Obesity early in life

Definitions ^[7][8]

• Exacerbation
  • New symptoms or significant worsening of symptoms caused by CNS demyelination that last at least 24 hours and are not accompanied by fever or infection
  • Also referred to as an attack, relapse, or flare
• Remission: a period of recovery after an exacerbation during which clinical symptoms resolve completely or almost completely
• Pseudorelapse: recurrence or significant worsening of existing symptoms due to stressors (e.g., infection, heat)
• Radiologically isolated syndrome (RIS) ^[9]
  • The presence of demyelinating lesions characteristic of MS in an asymptomatic individual
  • Not considered an MS phenotype but may progress to MS
• Clinically isolated syndrome (CIS)
  • A single episode of neurological symptoms resulting from CNS demyelination
  • A second episode of such symptoms increases the likelihood that the symptoms are not clinically isolated and that the patient meets the diagnostic criteria for MS.
• Diffuse cerebral sclerosis (Schilder disease) ^[10][11]
  • A rare inflammatory demyelinating CNS condition that affects children and young adults
  • Large areas of demyelination lead to various neurological deficits and psychological changes.

Clinical course ^[7][12][13]

• 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
• 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 exacerbations.
  • Presence of tertiary lymphoid organs in the meninges of individuals with secondary progressive MS ^[14]
  • Intrathecal synthesis of IgG (oligoclonal bands; see “Diagnostics” section for more information)
• Progressive phenotypes (forms) of MS are characterized by ^[15]
  • 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

• Constitutional symptoms: fatigue, headache
• Optic neuritis ; ^[16][17][18]
  • Most often the earliest manifestation
  • Typically unilateral
  • Can be painful
  • Impaired vision and color blindness
  • Relative afferent pupillary defect (Marcus Gunn pupil)
• 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
• Demyelination of spinal cord tracts
  • Lhermitte sign: a shooting electric sensation that travels down the spine upon flexion of the neck
  • Pyramidal tract lesion: upper motor neuron weakness, spasticity, hyperreflexia, positive Babinski sign, impaired gait
  • Dorsal spinal column lesion: 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 ^[19]
• Cerebellar involvement: poor postural control, imbalance, gait dysfunction, Charcot neurological triad: of scanning speech, nystagmus, and intention tremors
• Transverse myelitis
  • Asymmetric paraplegia, unilateral sensory loss, bladder dysfunction
  • Partial transverse myelitis is a common early manifestation of MS, causing asymmetric neurologic dysfunction below the lesion.
• Cranial nerve palsies: diplopia, facial palsy, trigeminal neuralgia (can be bilateral) ; ^[20][21]
  • Trigeminal neuralgia (TN) typically manifests unilaterally.
  • Bilateral TN should raise concern for MS, especially in younger patients.
• Autonomic dysfunction: bowel and bladder neurogenic disorders (e.g., urinary incontinence), impaired sexual function
• 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.

MS is a chronic condition that typically manifests in a relapsing-remitting form characterized by episodic CNS dysfunction (exacerbations) with at least partial recovery between episodes.

General principles ^[7][22]

• Diagnosis of MS depends on a combination of clinical findings (e.g., optic neuritis, Lhermitte sign, sensory abnormalities, cerebellar signs), imaging, and laboratory results.
• Consider early specialist (i.e., neurology) consultation for patients with history and clinical features suggestive of MS.
• The McDonald Criteria for both DIT and DIS must both be met to confirm a diagnosis of MS: ^[7]
  • Dissemination in time (DIT): the appearance of new CNS lesions over time that can be confirmed clinically, with imaging, or with CSF analysis
  • Dissemination in space (DIS): the presence of lesions in different regions of the CNS that can be confirmed clinically or in MRI
• In some cases, electrophysiological, CSF, and laboratory studies may be necessary to support the diagnosis and exclude differential diagnoses. ^[23]

Clinical evidence or MRI findings consistent with the presence of CNS lesions that are disseminated in both time and space confirm the diagnosis of MS.

Imaging ^[7][13]

MRI is the imaging study of choice for the diagnosis and monitoring of MS.

• Indications
  • MRI brain (with and without gadolinium): all patients with suspected MS
  • MRI spinal cord (with and without gadolinium): to increase diagnostic yield (e.g., in patients with nondiagnostic brain MRI or symptoms of partial myelitis ) ^[24]
• Typical findings on MRI
  • Multiple sclerotic plaques (most commonly found in the periventricular white matter) ; with finger-like radial extensions (Dawson fingers) related to demyelination and reactive gliosis ^[13][23]
    • In T1: hypointense or isointense lesions (i.e., black hole lesions) due to severe demyelination and axonal destruction ^[25]
    • In T2 and FLAIR: hyperintense lesions, typically round or oval in shape and found in both hemispheres ^[26]
  • Contrast-enhancement of active lesions; usually resolves after 2–8 weeks ^[26]

Additional studies

Consider further testing for patients with nondiagnostic MRI and to rule out differential diagnoses.

• CSF examination: commonly performed to support MS diagnosis and rule out other conditions ^[1][27][28]
  • Oligoclonal bands ^[23]
    • Oligoclonal bands in the CSF but not in blood support diagnosis of MS.
    • Oligoclonal bands manifest due to increased production of multiple nonspecific IgG sub-fractions in the CSF, which are caused by intrathecal inflammation.
    • Detected using electrophoresis or isoelectric focusing of CSF
  • Other common findings: moderate lymphocytic pleocytosis, increased myelin basic protein ^[28]
• Evoked potentials: Consider visual evoked potentials for patients with symptoms related to vision. ^[13]
  • Can provide objective evidence of lesions
  • May show evidence of increased latency, which occurs due to slowed optic nerve conduction.
• Laboratory studies: to rule out other diagnoses, based on clinical suspicion ^[13]
  • Commonly ordered: CBC, vitamin B12, TSH, ESR, ANA, RPR, serologic testing for Lyme disease
  • Others: specific autoantibodies (e.g., antiphospholipid antibodies, anti-SSA, anti-SSB), HIV testing
• Physical examination: downwards pronator drift in pronator drift test
  • An examination finding of asymmetric pronation and drifting movement of the arms when the patient stands with outstretched arms and closed eyes
  • Cerebellar lesions typically cause pronation and upwards drift; upper motor neuron lesions typically cause pronation and downwards drift.

The presence of multiple oligoclonal bands in CSF and their absence in the blood is highly suggestive of MS. ^[27][29]

Autoimmune diseases associated with inflammatory demyelination

Neuromyelitis optica spectrum disorders (NMOSD; previously known as Devic disease or neuromyelitis optica) ^[30][31]

• Definition: immune-mediated, chronic inflammatory disorders of the CNS that primarily affect the optic nerve and spinal cord
• 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
• 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
• 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
• 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)

• 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) ^[32]

• 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
• 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
• Diagnosis
  • Lumbar puncture: lymphocytic pleocytosis and elevated protein
  • Spinal and/or brain MRI (with and without contrast): typically multiple, bilateral lesions
• 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

Transverse myelitis ^[33]

• Definition: an acute or subacute inflammatory myelopathy that results in motor, sensory, and autonomic symptoms below the level of the affected segment
• Epidemiology
  • Rare condition (< 5 cases per million)
  • Bimodal incidence: peak in the 2^nd and 4^th decade of life
• Etiology
  • Most often idiopathic
  • Parainfectious (e.g., enteroviruses, EBV, CMV, Listeria monocytogenes, B. burgdorferi)
  • CNS demyelinating disorders (e.g., multiple sclerosis, neuromyelitis optica spectrum disorders)
  • Systemic inflammatory autoimmune disorders (e.g., SLE, sarcoidosis)
  • Paraneoplastic syndromes
  • Drug-induced (e.g., TNF-α inhibitors, chemotherapeutic agents)
• Clinical features
  • Course of the disease
    • Acute or subacute onset: symptoms may reach their peak between 4 hours and 21 days after onset
    • Acute spinal shock may be present at onset
    • Later, spasticity, hyperreflexia, and signs of upper motor neuron involvement (e.g., positive Babinski sign) may develop
  • Neurologic dysfunction
    • Motor dysfunction (e.g., paresis, paraplegia)
    • Sensory dysfunction (e.g., numbness, paresthesias, circumferential dysesthesia directly above the sensory level)
    • Autonomic dysfunction (e.g., bladder and/or bowel incontinence, sexual dysfunction)

• Diagnostics
  • MRI of the brain and spine with and without gadolinium: investigation of choice
    • Finding: focal, gadolinium-enhancing lesion in the spinal cord (T2-weighted sequence)
    • Brain MRI with and without gadolinium should also be performed to rule out CNS demyelinating disorders (e.g., MS)
  • Laboratory studies
    • Serological testing for viral infections, syphilis, and HIV antibodies
    • Inflammatory markers (ESR, CRP)
    • Serum autoimmune antibody testing: antinuclear antibodies, rheumatoid factor, antiphospholipid antibodies, NMO IgG (anti-aquaporin-4)
    • Serum levels of vitamin B₁₂ and methylmalonic acid
    • Thyroid function tests
  • CSF analysis ^[34]
    • Inflammatory markers: pleocytosis and/or elevated IgG index
    • Oligoclonal bands: helpful in diagnosing MS
    • Cultures and viral PCR
    • VDRL to rule out syphilis
  • Further investigations based on clinical presentation and suspected underlying cause, e.g., paraneoplastic profile to rule out paraneoplastic syndrome, CT chest to rule out sarcoidosis, nerve conduction studies to help rule out GBS and peripheral neuropathies
• Differential diagnoses
  • Anterior spinal artery infarction
  • Guillain-Barré syndrome (GBS)
  • Compressive myelopathy (e.g., due to intramedullary spinal cord tumors)
  • Radiation myelitis
  • Metabolic myelopathy (e.g., due to vitamin B₁₂ deficiency, copper deficiency)
• Treatment
  • Acute management
    • First-line: immediate high-dose IV corticosteroids
    • Second-line
      • Plasmapheresis if response to corticosteroids is insufficient
      • Cyclophosphamide
    • Supportive care: prevent decubitus ulcer and/or thrombosis, manage urinary retention, gastroparesis, constipation, and respiratory failure in patients with high cervical cord lesions
  • Long-term management
    • Neurological rehabilitation
    • Ongoing treatment of underlying causes (e.g., long-term immunomodulatory therapies for systemic autoimmune conditions or demyelinating disease)

Other

• 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.

General principles ^[35]

• All patients: Refer to a neurologist for specialized management.
• Acute exacerbations: Treat all acute exacerbations that affect physical functioning.
  • First line: high-dose IV or PO glucocorticoids (e.g., methylprednisolone)
  • Alternatives: plasmapheresis or adrenocorticotropic hormone (ACTH) gel ^[36]
• Long-term management: Combine pharmacological and nonpharmacological measures to prevent exacerbations and improve quality of life.
  • Disease-modifying MS therapy
  • Lifestyle modifications (e.g., exercise, smoking cessation) and management of comorbidities (e.g., cardiovascular disease, sleep disorders)
  • Vitamin D supplementation may be beneficial. ^[37]
  • Management of symptoms (e.g., spasticity, pain, bowel and bladder dysfunction)

Treatment should be initiated as early as possible; the goals of treatment are to manage the primary exacerbation, prevent further exacerbations, and slow disease progression.

Management of acute exacerbations ^[7][38]

If an acute exacerbation of MS is suspected, a specialist should be consulted immediately for management.

• Preferred therapy:
  • High-dose glucocorticoid pulse therapy (e.g., methylprednisolone ) ^[38][39][40]
  • Start measures to prevent complications of glucocorticoid therapy (e.g., PPIs, monitoring for hyperglycemia).
• Alternatives: plasmapheresis, ACTH gel ^[38][41]
• Additional considerations
  • Perform a thorough neurological examination and compare with the patient's baseline.
  • Evaluate for possible infectious triggers. ^[42]
  • Consider hospital admission for patients with disabling symptoms (e.g., loss of vision, difficulty with ambulation, dysphagia). ^[43]
  • Supportive care: physical therapy, occupational therapy, and/or speech and swallow evaluations

Mild exacerbations that do not impact physical functioning may not require medical treatment.

Disease-modifying MS therapy

• There are multiple disease-modifying drugs available to treat MS.
• The decision about agent requires careful consideration of:
  • Individual patient's characteristics (e.g., clinical phenotype, comorbidities)
  • Medication side effects
  • Other factors (e.g., medication availability, route of administration)
• All patients receiving disease-modifying therapy for MS should use birth control.

Disease-modifying therapy for MS is generally not recommended for pregnant and breastfeeding patients. ^[44]

Monoclonal antibodies (e.g., natalizumab, ocrelizumab) have the highest efficacy for reducing exacerbations, but lower efficacy medications (e.g., interferon beta, glatiramer acetate) often have fewer side effects. ^[7]

Supportive care and symptom management ^[7][59][60]

Consider any of the following measures in a management plan tailored to the individual patient:

• General measures
  • Encourage physical activity.
  • Close follow-up with neurology and primary care
  • Ancillary referral as needed (e.g., physical therapists, occupational therapists, psychologists)
  • Screen for major depression and start therapy with antidepressants as needed (see also “Treatment” in “Major depression disorder”).
• Urinary and bowel dysfunction
  • Urinary frequency: pelvic floor physical therapy, bladder training; Consider anticholinergics (e.g., oxybutynin) and antimuscarinics (e.g., tolterodine).
  • Urinary retention: Consider intermittent catheterization and parasympathomimetic drugs (e.g., bethanechol). ^[61]
  • Bowel dysfunction: dietary fiber and fluid intake; laxatives (e.g., senna) and stool softeners (e.g., docusate) as needed
• Spasticity
  • Stretching, avoidance of triggers (e.g., certain positions, pain, constipation)
  • Medications: baclofen (centrally acting GABA agonist), tizanidine (α₂-receptor agonist), gabapentin, dantrolene, botulinum toxin.
• Tremors: deep brain stimulation techniques, beta blockers (e.g., propranolol), gabapentin
• Neuropathic pain: tricyclic antidepressants (e.g., amitriptyline): , other antidepressants (e.g., duloxetine), anticonvulsants (e.g., carbamazepine, gabapentin), transcutaneous electrical nerve stimulation (see also “Treatment” in “Trigeminal Neuralgia”)
• Walking difficulties: mobility aids (e.g., canes, walkers), consider dalfampridine ^[62]
• Others
  • Fatigue: Consider medications such as amantadine or modafinil.
  • Sexual dysfunction: Consider medications for erectile dysfunction (e.g., sildenafil) and nonpharmacological measures (e.g., vaginal lubricants, intracavernous injection therapy) as needed.
  • Psychotherapy: to reduce potential psychological issues (e.g., depression)

Physical therapy, occupational therapy, and psychotherapy are safe, nonpharmacological options that can improve multiple symptoms in patients with MS, including spasticity, fatigue, walking difficulties, and neuropathic pain.

Prognostic factors for disease progression ^[63][64]

• Male sex
• Age at MS onset > 40 years
• Multiple symptoms with early motor and cerebellar involvement
• Incomplete recovery after exacerbations
• High relapse rate in the first 2 years after MS onset

Multiple sclerosis in pregnancy ^[7][44]

Prognosis

• Effect of pregnancy on MS
  • Decreased exacerbation risk during pregnancy
  • Increased risk of exacerbation in the postpartum period
  • The long-term clinical course of MS remains unchanged.
• Effect of MS on pregnancy
  • Increased rate of elective cesarean sections
  • Decreased birth weights ^[65]

Management

• Most disease-modifying therapy for MS should be discontinued ≥ 4 months prior to conception. ^[66]
• Avoid steroids for the treatment of exacerbations in the first trimester of pregnancy. ^[44]
• Breastfeeding is generally not recommended for patients receiving disease-modifying therapy for MS.
• Avoid MRI with gadolinium in pregnant patients.