• Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS).
• Diagnosis is secured from having repeated CNS demyelinating attacks and/or new CNS demyelinating lesions on magnetic resonance imaging (MRI) or progressive neurologic dysfunction consistent with MS with no better alternative explanation.
• Acute attacks of multiple sclerosis (MS) are treated with high-dose corticosteroids and, in severe cases, plasma exchange.
• Therapy is directed at relapsing–remitting disease with interferon β1, glatiramer acetate (Copaxone), fingolimod, teriflunomide, dimethyl fumarate, and natalizumab (Tysabri). Therapy for secondary progressive MS (typically with ongoing relapses) is mitoxantrone (Novantrone).
• Novel MS medications, including further oral medications, and infusion-based monoclonal antibodies, are currently under scientific evaluation.
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) that affects approximately 400,000 people in the United States alone.
Women are at least twice as likely to develop MS as are men. Other known risk factors for developing MS include ethnicity, genetic background, and environmental exposures. Persons of European ethnicity, particularly those born and reared in extreme northern or southern latitudes, are particularly susceptible to MS. African Americans are less likely to be diagnosed with MS than European Americans, but they have a more severe clinical course. Genetic susceptibility is associated with the major histocompatibility (MHC) allele HLA-DRB1 as well as interleukin-2 and interleukin-7 receptors. Low serum vitamin D levels are associated with an increased risk of development of MS in whites but are of unclear significance in the severity of its clinical course. There are intriguing but as yet unproven associations with infection with Epstein-Barr virus (infectious mononucleosis), particularly if this is contracted later in adolescence. Exposure to Epstein-Barr virus may be necessary but insufficient for developing MS. Cigarette smoking is associated with an increased risk of development of MS and likely is associated with an increased severity and clinical course of MS, including that of cognitive impairment.
The etiology and pathophysiology of MS as a whole remains uncertain. However, most evidence supports an inflammatory demyelinating disease induced by uncertain environmental factors in a genetically susceptible host. Animal studies including experimental allergic encephalomyelitis and Theiler’s murine encephalomyelitis virus also point to an autoimmune inflammatory demyelinating etiology, possibly associated with viral infection. Studies that suggest chronic cerebrospinal vascular insufficiency has an important association with MS remain unconfirmed.
Pathophysiology likely varies among individual patients with MS. Four distinct pathologies in active demyelinating MS lesions have been described. Pattern 1 displays marked macrophage infiltration without humoral abnormalities. Pattern 2 shows distinct humoral abnormalities with complement activation and immunoglobulin (Ig) deposition. Pattern 3 involves primary oligodendrocyte degeneration and early loss of myelin-associated glycoprotein. Pattern 4 reveals oligodendrocyte dystrophy in periplaque white matter. Early studies suggest there could be a therapeutic advantage with different therapies for different types of demyelinating disease.
Currently, there is no known way to prevent the development of MS. Patients with a single clinical attack of demyelination and abnormal magnetic resonance imaging (MRI) (“high-risk” clinically isolated syndrome) have a delayed onset to MS diagnosis with immunomodulatory therapy; however, there is no evidence to support that this prevents the eventual development of MS.
The clinical course of MS is varied. Approximately 85% of patients present with a relapsing–remitting course. This entails an acute impairment within the CNS, depending on the area of inflammation. A demyelinating cause of a focal neurologic symptom is suggested by an onset over hours to days, with a plateau of impairment over a few weeks. Symptoms then improve either spontaneously or with the use of corticosteroids over a number of days to weeks or longer.
Following this, however, symptoms might not completely resolve. Inflammation within the optic nerve (optic neuritis) is heralded by painful, unilateral, central monocular visual deficit (central scotoma). Symptoms of brain stem dysfunction include binocular diplopia, sensory deficits unilaterally on the face and contralaterally on the arm and leg, significant dysarthria, and vertigo. Cerebellar dysfunction is seen with pure ataxia that is typically unilateral. Spinal cord inflammation is indicated by a distinctive, usually gradually rising sensory level of deficit that commonly is accompanied by bowel and bladder impairment and paraparesis or quadriparesis, depending on a thoracic versus cervical level of the lesion.
Progressive forms of MS include secondary progressive MS and primary progressive MS. These are heralded by a slow (months to years) but steady and insidious, progressive neurologic deficit, usually a progressive myelopathy of upper motor neuron gait disorder with spasticity, neurogenic bladder and bowel impairment, and progressive weakness. Occasionally, patients with progressive MS have insidious cerebellar ataxia or dementia in isolation or in association with the myelopathy. Secondary progressive MS is diagnosed when a patient has had a history of at least one clinical attack (relapse) with improvement in the past. Primary progressive MS is diagnosed in the entire absence of any prior relapse but with progressive CNS disease consistent with MS and typical MRI brain or spinal lesions, often with cerebrospinal fluid (CSF) or visual evoked potential abnormalities that support the diagnosis.
The diagnosis of MS is formalized by the revised McDonald criteria. This entails having two or more clinical attacks (relapses) in the accompaniment of two or more objective lesions seen on clinical examination or with evidence for dissemination in space and time diagnosed by further development of new MRI lesions. Additionally, patients with a single clinical attack who have both the presence of MRI gadolinium enhancing lesions (indicative of prior MS lesions) and nongadolinium enhancing lesions (indicative of acute MS lesions) may now be diagnosed with MS. Progressive MS is diagnosed when there is progressive disease for at least 1 year and abnormal MRI scan of the brain and abnormal MRI scan of the spinal cord, with or without abnormal CSF and visual evoked potentials (Figure 1). An abnormal CSF examination is defined as elevated oligoclonal IgG bands within CSF that are not present in serum with or without elevations in the IgG index. Occasionally, visual evoked potentials and somatosensory evoked potentials are used to further document dissemination of MS within the CNS. Serologic investigations are done primarily to rule out MS mimickers depending on and directed by any accompanying systemic symptoms and the clinical setting in individual patients. These may include antinuclear antibodies (ANA for lupus), erythrocyte sedimentation rate, anticardiolipin antibodies, vitamin B12, Lyme serology, and chest imaging for CNS sarcoidosis.
FIGURE 1 Magnetic resonance image showing brain T1 gadolinium- enhancing lesions (A) and T2 thoracic spine (B) typical of multiple sclerosis.
Other CNS demyelinating diseases can mimic relapsing or progressive MS. Acute disseminating encephalomyelitis is an acute, typically monophasic, and postinfectious CNS inflammatory demyelinating disease. It may be severe; however, if recurrent episodes occur separated by at least 3 months, a diagnosis of relapsing–remitting MS is by far more likely.
Neuromyelitis optica is an autoimmune disease with severe acute attacks but is relatively restricted to the optic nerves and spinal cord. Other brainstem and deep cerebral structures, such as the area postrema, cerebral white matter, and hypothalamus, can also be affected by neuromyelitis optica. Brain MRI scan is usually not consistent with MS, at least early on in the disease, and a specific autoantibody (neuromyelitis optica IgG) directed against the aquaporin 4 water channel is found in more than 70% of cases.
Progressive myelopathies that mimic primary progressive MS or secondary progressive MS include a compressive myelopathy from cervical spondylosis, disk disease, or neoplastic infiltration; nutritional deficiencies (such as vitamin B12 or copper deficiencies); paraneoplastic disease (usually associated with CRMP-5 auto- antibodies); or a vascular progressive cause due to dural arteriovenous fistula.
Optic neuritis may be mimicked by acute ischemic optic neuropathy. This condition is typically painless, occurs suddenly, and occurs in patients with advanced age and preexisting vascular risk factors.
Acute demyelinating MS attacks (relapses) may be treated with high doses of corticosteroids. These may be given orally or intravenously; however, high doses of corticosteroids are necessary and are superior to low doses. For example, a typical regimen is intravenous methylprednisolone (Solu-Medrol) 1000 mg once daily for 3 to 5 days without oral corticosteroid tapering doses. The oral equivalent to this intravenous regimen is prednisone 1250 mg orally once daily for 5 days with no oral corticosteroid taper following. Gastrointestinal intolerance occurs in some patients, and concomitant use of stomach- protecting agents such proton pump inhibitors may be recommended. Typical acute corticosteroid side effects include insomnia, irritability, and increased appetite as well as an extremely rare association with avascular hip necrosis. Chronic corticosteroid side effects such as diabetes mellitus, cataracts, and weight gain and cushingoid habitus are more associated with chronic corticosteroid use and not short courses of steroids.
Generally, only MS attacks that are associated with functional impairment (vision loss, diplopia, motor weakness, ataxia) are treated because clinical recovery is hastened but final clinical recovery is not found to be altered by this therapy. Rarely, patients have very severe acute attacks of MS or other demyelinating disease that does not improve with use of high-dose corticosteroids. In these rare patients, the use of plasma exchange (seven exchanges over approximately 14 days) is recommended. Approximately 45% of patients experience functional recovery within 1 month following plasma exchange. Side effects of plasma exchange therapy include paresthesias related to hypocalcemia, anemia, thrombocytopenia, or complications of central venous access that is required for many patients. Intravenous immunoglobulin (Gammagard)1 has not yet been shown to improve severe clinical attacks of demyelinating disease.
Chronic therapy for relapsing–remitting MS includes the use of β1 interferon (IFN-β1), glatiramer acetate (Copaxone), natalizumab (Tysabri), alemtuzumab (Lemtrada), or, for secondary progressive MS (typically with ongoing attacks or new inflammatory lesions on MRI), mitoxantrone (Novantrone) (Table 1). First-line therapy for patients with relapsing–remitting MS is by injectable therapies with preparations of IFN-β1 or, alternatively, glatiramer acetate and with oral therapy with fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera). The side-effect profile is well known for traditional injectable agents such as interferons and glatiramer acetate (see Table 1), and they have been safely used for many years.
The short-term safety profile for oral therapies seemed satisfactory, but the long-term side-effect profile is still being assessed. For fingolimod, new federal FDA labeling was required in 2012 after the sudden death of a patient within 24 hours of first fingolimod dose and the occurrence of other unexplained deaths following initiation of fingolimod. Teriflunomide may be associated with liver disease and teratogenicity. Dimethyl fumarate is associated with flushing gastrointestinal discomfort, and rare patients treated for psoriasis with a related agent, fumaric acid, have developed PML as has one MS patient treated with dimethyl fumarate. Second-line therapy, if first- line medications are intolerable or if therapeutic response is suboptimal (continued MS attacks or marked ongoing and new inflammatory disease on MRI), includes agents such as natalizumab or mitoxantrone. The goal of chronic immunomodulatory therapy for MS is a reduction in clinical attacks of MS (somewhere between 30% and 60%, depending on the agent) and reduction in new inflammatory MRI lesions (somewhere between 40% and 90%, depending on the agent). Patients and health care professionals should realize that the medications are not a cure or for symptomatic benefit (making people feel better) but specifically for reduction in relapse-related disease.
Approved Immunomodulatory Therapy for Relapsing–Remitting Multiple Sclerosis
Abbreviations: Ab = antibody; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; AV = atrioventricular; BUN = blood urea nitrogen; CBC = complete blood count; CHF = congestive heart failure; CSF = cerebrospinal fluid; ECG = electrocardiogram; FDA = U.S. Food and Drug Administration; JCV = JC virus; MI = myocardial infarction; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; PLEX = plasma exchange; PML = progressive multifocal leukoencephalopathy; PPD = purified protein derivative; SPMS = secondary progressive multiple sclerosis; SSS = sick sinus syndrome; TIA = transient ischemic attack; TOUCH = Tysabri Outreach: Unified Commitment to Health; VZV-IgG = varicella zoster virus immunoglobulin G.
Second-line immunomodulatory agents are effective in reducing MS attacks; however, they are rarely associated with serious side effects. Natalizumab, as monotherapy or in combination with other medications, is associated with the development of progressive multifocal leukoencephalopathy, a severely impairing, and often fatal, opportunistic brain infection caused by reactivation of dormant JC virus. In North America, natalizumab is only available through the TOUCH (Tysabri outreach: unified commitment to health) prescribing program. Risk factors for PML in natalizumab-treated patients include the presence of JC virus serum antibody (AB), duration of therapy of at least 2 years, and history of immunosuppressive medication therapy (e.g., methotrexate, azathioprine). Seropositivity of MS patients for JC virus antibody is approximately 56%. Seroconversion rate from JC virus Ab negativity to positivity is approximately 2% per year, and false-negative results are rare (less than 3%). Currently, no cases of PML have been found in patients persistently seronegative for JCV antibodies. Risk prevalence estimation after 2 years of treatment in JCV Ab positive patients range from 1:250 for those without history of immunosuppression to 1:90 in those with history of prior immunosuppressive therapy. Mitoxantrone is a chemotherapy agent that is the only approved medication for secondary progressive MS. It may be associated with pulmonary and urinary tract infections, alopecia, and cardiotoxicity. The lifetime cumulative dosing of mitoxantrone is restricted to no more than approximately 100 mg/m2. Cases of acute myelogenous leukemia as well as acute or delayed cardiotoxicity are additional concerns associated with the use of mitoxantrone in MS patients, and close clinical and investigational (e.g., measuring ejection fraction by echocardiography) follow-up is needed.
Newly FDA approved for relapsing MS is alemtuzumab (Lemtrada) a monoclonal antibody (anti-CD52; T and B cells). Given the safety precautions that include autoimmune thyroid disease, immune thrombocytopenia and anti-glomerular basement membrane disease it is generally reserved for patients with inadequate response to other MS immunomodulatory medications.
Novel medications for MS are under therapeutic investigation.
These include intravenous monoclonal antibodies that have a direct effect on inflammatory mediators such as daclizumab (Zenapax)1 (anti-CD25, IL2 receptor), and ocrelizumab1 (anti-CD20 B cells; humanized form).
Most, if not all, MS patients should be followed by a neurologist at least occasionally. Recommendations for clinical assessment range from 6 to 18 months, depending on clinical activity of relapses and disability. The ideal scheduling of repeat brain MRI scans is controversial and varies depending on MS clinical activity, but general recommendations are every 1 to 2 years.
MS is one of the main causes for impairment at a young age and trails only acute trauma. Often patients need gait assistance when impairment becomes more severe. This includes the use of a single gait aid, such as a cane or walking stick, or an ankle-foot orthosis for symptomatic foot drop.
Patients often experience symptoms of neurogenic bladder dysfunction. This includes symptoms of urgency and urge-related incontinence. Bladder stimulants such as caffeine need to be avoided. Patients with this symptom should be investigated for completeness of bladder emptying. If there is severe impairment in bladder emptying, urinary catheterization often is recommended. If bladder emptying is complete or only mildly impaired (<100 mL postvoid residual), use of medications such as oxybutynin (Ditropan) or tolterodine (Detrol) may be recommended for urge-related symptoms; however, ongoing monitoring of bladder emptying is recommended. Some patients require formal urodynamic evaluation for complex bladder symptoms.
Fatigue is a common MS-related symptom. A complete sleep history to ensure appropriate sleep hygiene is imperative. This includes initiating sleep promptly, maintaining sleep throughout the night, and awakening feeling refreshed. Encouragement of a formal exercise program to facilitate restful sleep and daytime vigor is important. Obstructive sleep apnea, restless legs syndrome, and other parasomnias need to be ruled out as additional contributing factors to fatigue. If sleep hygiene is entirely normal and late afternoon fatigue remains a problem, pharmacologic therapy for MS-related fatigue can proceed. Pharmacologic recommendations are limited but include amantadine hydrochloride (Symmetrel)1 100 mg by mouth twice daily. Modafinil (Provigil)1 has been shown in some studies to have an effect on MS-related fatigue at a dose of 200 mg by mouth once daily.
Spasticity associated with upper motor neuron weakness in the lower extremities may be treated with an active daily exercise program directed by physical therapists and physiatrists. Judicious use of baclofen (Lioresal) is helpful (starting at 10 mg once to three times by mouth daily no more than a maximum of 80 mg per day). Baclofen side effects include drowsiness and liver enzyme elevations. Some patients with significant lower extremity weakness are assisted in their gait by the leg support provided by spasticity, and if spasticity is reduced pharmacologically, this can in fact worsen their gait.
Alternatives to baclofen include tizanidine (Zanaflex) and clonidine (Catapres).1
MS is a common CNS inflammatory demyelinating disease with heterogenous presentation and prognosis. Relapsing–remitting or attack-related MS is treated with corticosteroids to hasten resolution of acute relapses and chronic immunomodulatory medications such as IFN-β,1 glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, and natalizumab to reduce the number of future clinical attacks and new MRI lesions. Mitoxantrone is the only medication approved for secondary progressive MS, but is appears to improve primarily those with ongoing attacks or continued inflammatory lesions, and concerns regarding short- and long-term side effects have limited its use. Purely progressive forms of primary progressive MS and secondary progressive MS are not responsive to immunomodulatory or immunosuppressive medications.
Symptomatic care is important in those patients, including the treatment of gait disorder, spasticity, neurogenic bladder dysfunction, and fatigue.
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1 Not FDA approved for this indication