Multiple Sclerosis

Essentials of Diagnosis

• Episodic neurologic symptoms

• Usually under 55 years of age at onset

• Single pathologic lesion cannot explain clinical findings

• Multiple foci best visualized by MRI

General Considerations

• Should not be diagnosed unless there is evidence that two or more different regions of the central white matter (dissemination in space) have been affected at different times (dissemination in time)

• Diagnosis may be made in a patient with two or more typical attacks and

  • Objective evidence on clinical examination of two lesions (eg, optic disk atrophy and pyramidal weakness) or

  • Objective evidence of one lesion with clear-cut historical evidence the other attack was typical of multiple sclerosis and in a distinct neuroanatomic location

  • No alternative explanation for the patient's presentation has been found

• To fulfill the criterion of dissemination in space in a patient with only one lesion

  • Repeat imaging in a few months; at least one lesion should be demonstrated in at least two of four typical sites

    • Periventricular

    • Cortical or juxtacortical

    • Infratentorial

    • Spinal

  • Alternatively, another attack localized to a different site suffices

• To fulfill the criterion of dissemination in time in a patient with only one attack

  • Simultaneous presence of gadolinium-enhancing and nonenhancing lesions at any time (including at initial examination)

  • Presence of oligoclonal bands unique to the cerebrospinal fluid

  • A new lesion on follow-up MRI

  • A second attack

• Primary progressive disease requires at least a year of progressive disease, plus two of three of the following:

  • At least one typical brain lesion

  • At least two spinal lesions

  • Oligoclonal banding in the cerebrospinal fluid

• In patients with a single clinical event who do not satisfy criteria for multiple sclerosis, a diagnosis of a clinically isolated syndrome is made

• Vitamin D deficiency may be associated with an increased risk of developing multiple sclerosis

Demographics

• Common disorder, probably on an autoimmune basis, with its greatest incidence in young adults

• Much more common in persons of western European lineage who live in temperate zones

• No population with a high risk for multiple sclerosis exists between latitudes 40°N and 40°S

• A genetic susceptibility to the disease is likely

Symptoms and Signs

• Fatigue is common in all forms of the disease

• Common initial presentation

  • Weakness, numbness, tingling, or unsteadiness in a limb

  • Spastic paraparesis

  • Retrobulbar optic neuritis

  • Diplopia

  • Dysequilibrium

  • Sphincter disturbance, such as urinary urgency or hesitancy

• Symptoms may disappear after a few days or weeks, although examination often reveals a residual deficit

RELAPSING-REMITTING DISEASE

• Symptoms occur months or years after initial presentation

• Eventually relapses and usually incomplete remissions lead to increasing disability, with weakness, spasticity, and ataxia of the limbs, impaired vision, and urinary incontinence

• Findings on examination commonly include

  • Optic atrophy

  • Nystagmus

  • Dysarthria

  • Pyramidal, sensory, or cerebellar deficits in some or all of the limbs

SECONDARY PROGRESSIVE DISEASE

• In some of the relapsing-remitting patients, the clinical course changes to steady deterioration, unrelated to acute relapses

PRIMARY PROGRESSIVE DISEASE

• Less common

• Symptoms steadily progress from their onset, and disability develops at a relatively early stage

• The diagnosis cannot be made unless the total clinical picture indicates involvement of different parts of the CNS at different times

• A number of factors (eg, infection, trauma) may precipitate or trigger exacerbations

• Relapses are also more likely during the 2 or 3 months following pregnancy

Differential Diagnosis

• Acute disseminated encephalomyelitis

• Foramen magnum lesion (Arnold-Chiari malformation)

• Progressive multifocal leukoencephalopathy

• Subacute combined degeneration of the spinal cord (B₁₂ deficiency)

• Spinal cord tumor

• Vasculitis

• Neurosyphilis

• Lyme disease

• Syringomyelia

• HIV-associated myelopathy

• Human T cell lymphotropic virus-I myelopathy

Laboratory Tests

• A definitive diagnosis can never be based solely on the laboratory findings

• Cerebrospinal fluid may reveal

  • Mild lymphocytosis or a slightly increased protein concentration, especially after an acute relapse

  • Elevated IgG and discrete bands of IgG (oligoclonal bands), which are not specific, having been found in a variety of inflammatory neurologic disorders and occasionally in patients with vascular or neoplastic disorders of the nervous system

Imaging Studies

• MRI of the brain and cervical cord is often helpful in demonstrating the presence of multiple lesions

• Myelography or MRI

  • May be necessary in patients presenting with myelopathy alone and in whom there is no clinical or laboratory evidence of more widespread disease to exclude a congenital or acquired surgically treatable lesion

  • In patients with mixed pyramidal and cerebellar deficits in the limbs, the foramen magnum region must be visualized to exclude the possibility of Arnold-Chiari malformation, in which part of the cerebellum and lower brainstem are displaced into the cervical canal

Diagnostic Procedures

• Visual, brainstem auditory, and somatosensory evoked potentials are helpful, but other disorders may also be characterized by multifocal electrophysiologic abnormalities reflecting disease of central white matter

Medications

ACUTE EPISODE, INCLUDING RELAPSE

• Dexamethasone, 160 mg/day orally for 3–5 days

• Methylprednisolone, 1 g/day intravenously for 3–5 days

• Prednisone, 1000 mg/day orally for 3–5 days

PRIMARY PROGRESSIVE

• Ocrelizumab (Ocrevus), humanized anti-CD20 monoclonal antibody

  • Dose: 300 mg intravenously infusion once, then again as 300 mg intravenously 2 weeks later, then subsequent doses of 600 mg are given as a single infusion every 6 months

  • The only medication effective in slowing disability progression in primary progressive multiple sclerosis

  • Approved for this indication by the FDA

RELAPSE PREVENTION, FIRST-LINE TREATMENT

• Dimethyl fumarate (Techfidera)

  • Dose: 240 mg orally twice daily

  • Progressive multifocal leukoencephalopathy (PML) has developed in several patients

  • Fingolimod (Gilenya)

    • Dose: 0.5 mg/day orally

    • Heart rate should be monitored for 6 hours after the first dose or if restarted after an interval of ≤ 2 weeks

    • Associated with fatal disseminated varicella zoster infection; immunity must be demonstrated prior to treatment initiation

  • Glatiramer acetate (Copaxone), 20 mg subcutaneously daily

  • Interferon beta-1a (Rebif), 44 mcg subcutaneously three times per week

  • Interferon beta-1a (Aconex), 30 mcg intramuscularly once per week

  • Interferon beta-1b (Betaseron, Extavia), 0.25 mg subcutaneously on alternate days

  • High-dose high-frequency interferons, fingolimod, and glatiramer acetate more efficacious than once weekly interferon

  • Teriflunomide (Aubagio)

    • Dose: 14 mg/day orally

    • Pregnancy category X

    • If patient becomes pregnant, need to wash out drug; monitor for hepatotoxicity

  • Ocrelizumab (Ocrevus) 300 mg intravenously on day 1 and day 15, followed by 600 mg every 6 months

Relapse prevention for disease activity despite use of first-line treatment

• Alemtuzumab (Lemtrada)

  • Dose: 12 mg intravenously daily for 5 days; 3-day course given 1 year later

  • Associated with disseminated zoster as well as development of autoimmune disease and malignancy

• Dimethyl fumarate (Techfidera)

  • Dose: 240 mg orally twice daily

  • PML has developed in several patients

• Fingolimod (Gilenya)

  • Dose: 0.5 mg/day orally

  • Heart rate should be monitored for 6 hours after the first dose or if restarted after an interval of ≤ 2 weeks

  • Associated with fatal disseminated varicella zoster infection; varicella immunity must be demonstrated prior to treatment initiation

• Mitoxantrone (Novantrone)

  • Dosage: 12 mg/m² intravenously every 3 months

  • Maximum lifetime dose: 140 mg/m²

• Natalizumab (Tysabri)

  • Dosage: 300 mg intravenously monthly

  • Highly effective but increases the risk of developing PML

  • Need to monitor JC antibody status every 6 months

• Ocrelizumab (Ocrevus) 300 mg intravenously on day 1 and day 15, followed by 600 mg every 6 months

• Teriflunomide (Aubagio)

  • Dose: 14 mg/day orally

  • Pregnancy category X

  • If patient becomes pregnant, need to wash out drug; monitor for hepatotoxicity

High disease activity (typically with multiple gadolinium-enhancing lesions on MRI)

• Alemtuzumab (Lemtrada)

  • Dose: 12 mg intravenously daily for 5 days; 3-day course given 1 year later

  • Associated with disseminated zoster as well as development of autoimmune disease and malignancy

• Natalizumab (Tysabri)

  • Dose: 300 mg intravenously monthly

  • Highly effective but increases the risk of developing PML

  • Need to monitor JC antibody status every 6 months

• Ocrelizumab (Ocrevus) 300 mg intravenously on day 1 and day 15, followed by 600 mg every 6 months

Therapeutic Procedures

• For corticosteroid-refractory relapses, plasmapheresis may be used

• Treatment for spasticity and for neurogenic bladder may be needed in advanced cases

• Excessive fatigue must be avoided, and patients should rest during periods of acute relapse

Follow-Up

• Consider MRI 6–12 months after patients have clinically isolated syndrome to assess for presence of any new lesion

Prognosis

• At least partial recovery from acute exacerbations can reasonably be expected

• Relapses may occur without warning

• There is no means of preventing progression of the disorder

• Some disability is likely to result eventually

• About half of all patients are without significant disability even 10 years after onset of symptoms

When to Refer

• All patients, but especially those with progressive disease despite standard therapy, should be referred

When to Admit

• Patients requiring plasma exchange for severe relapses unresponsive to corticosteroids

• During severe relapses

• Patient unable to manage at home