Clinical Review Multiple Sclerosis: A Review of the Disease and Treatment Options Daniel Sturm, Samuel L. Gurevitz, Amelia Turner Objective: To provide a review of the etiology, epidemiology,
clinical features, diagnostic findings, and treatment options for multiple sclerosis (MS). Data Sources: A PubMed search of English language articles using a combination of words: elderly; multiple sclerosis*, late onset multiple sclerosis*, etiology; screening; diagnosis; or treatment to identify original studies, guidelines, and reviews on multiple sclerosis and late-onset multiple sclerosis, published 2002 to 2013. Primary sources were then used to search for additional relevant material. Study Selection and Data Extraction: Original studies, clinical reviews, references, and guidelines were obtained and evaluated for their clinical relevance. Data Synthesis: The literature included guidelines and considerations for the etiology, diagnosis, screening, and management of MS. Conclusion: MS is a chronic autoimmune disease characterized by inflammation, demyelination, and local axonal injury. It typically presents between ages 20 and 40 and largely affects women. However, 2% to 10% of individuals are diagnosed after 50 years of age. Diagnosis is based on presentation of clinical symptoms and the McDonald criteria for diagnosing MS. Management focuses on suppression of the immune system and prevention of relapses. Key Words: Elderly, Geriatrics, Late-onset multiple sclerosis, Multiple sclerosis, Treatment. Abbreviations: CBC = Complete blood count, CIS = Clinically isolated syndrome, CNS = Central nervous system, DIS = Disseminated in space, DIT = Disseminated in time, LFTs = Liver function tests, LOMS = Late-onset multiple sclerosis, MRI = Magnetic resonance imaging, MS = Multiple sclerosis, PPMS = Primary-progressive multiple sclerosis, PRMS = Progressive-relapsing multiple sclerosis, RRMS = Relapsingremitting multiple sclerosis, SPMS = Secondary-progressive multiple sclerosis, YOMS = Young-onset multiple sclerosis. Consult Pharm 2014;29:469-79.
Introduction There are many chronic diseases of the central nervous system (CNS) that can destroy the myelin sheaths that encircle the nerves. The myelin sheath is a protective covering composed of lipids that insulate nerves, thereby allowing electrical impulses to be transmitted more quickly and efficiently down the length of the axon. If the myelin sheath surrounding the nerves is damaged, electrical conduction slows down. This process is called demyelination.1 The most common chronic demyelinating disease of the CNS is multiple sclerosis (MS).2 MS is a neurological disorder that affects the CNS and is capable of causing a great amount of disability in those diagnosed with the disease.3 MS can affect all aspects of life. Patients commonly suffer from visual changes, muscle weakness, ataxia leading to falls, paroxysms such as tonic spasms and seizures, cognitive impairments, and fatigue. These symptoms impact activities of daily living, which include dressing and bathing, as well as their instrumental activities of daily living, which include driving, cooking, and shopping. It is estimated that 2.5 million individuals worldwide are affected by MS, and approximately 400,000 of those cases are in the United States.4 The purpose of this review article is to provide information regarding the etiology, epidemiology, clinical features, diagnostic findings, and treatment options for MS.
Epidemiology The prevalence of MS varies geographically.5 Areas of higher prevalence (60 cases per 100,000 people) include Europe, Russia, southern Canada, northern United States, New Zealand, and southeast Australia. In the United States, the prevalence is estimated to be 100 cases per 100,000 people.2 Presentation of symptoms in MS usually begins between 20 and 40 years of age. When a patient is diagnosed with MS after the age of 50, the diagnosis is termed late-onset multiple sclerosis (LOMS). It is estimated that between 2% and 10% of patients diagnosed with MS fall into this category.6,7 MS typically affects women more than men. In addition, it is more commonly seen in Caucasians of Northern European decent as compared with other ethnic groups,
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Clinical Review including African-Americans, Asians, and Hispanics/ Latinos.8 However, there was recently a study that found the risk of developing MS was higher in African-American women when compared with Caucasian American women and men.9 In addition to the ethnic disparities of the disease, there are also geographic disparities with regard to latitude. Studies have shown that there are fewer cases of MS diagnosed closer to the equator, while people living north of 40° latitude have a higher risk of developing the disease.4 The risk of developing MS also seems to be affected by relocation from one geographic area to another. Individuals who relocate after puberty (around age 15) retain the risk level for developing MS of the place from which they moved. However, those who relocate prior to puberty assume the risk level of the area to which they moved.2 These findings along with other evidence have led some researchers to theorize that there is a relationship between the amount of exposure to sunlight and vitamin D and the risk of developing MS.10 In addition, other environmental factors, such as smoking or viral infections, have been shown to increase the risk of developing MS.2,4,5,10 The risk of developing MS may be related to genetic components as well as environmental factors. Studies have shown that there is a 2% to 4% increased risk of developing MS if a first-degree relative has been diagnosed with the disease.4 Twin studies have demonstrated that the risk of developing MS for dizygotic twins is similar to that of siblings, which is approximately 3% to 5%. The risk of developing MS for monozygotic twins, on the other hand, is significantly higher. It is estimated to be between 20% and 40%.2,4
Pathophysiology Although the exact cause of MS is controversial, evidence suggests it may be the result of the interaction among the immune system, genetics, and environmental factors.3 Some research suggests that the autoimmune component of MS is initiated by exposure to an infectious stimulant.4,11 Another hypothesis suggests that autoimmunity is triggered by dysregulation of the immune system. Studies propose that activated T-cells and other lymphocytes cross the blood-brain barrier. Once in the CNS, these cells recognize
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antigens on the myelin sheaths of the axons. After recognition, the lymphocytes attack the myelin sheath, causing inflammation resulting in the formation of plaques.2-4 The plaques and the ongoing destruction of the myelin slow conduction of the nerve impulses between neurons. Loss of axons and conduction can lead to the progression of the disabling symptoms associated with MS.2
Classifications MS primarily affects women younger than 50 years of age. The clinical course of MS varies extensively. Furthermore, there is not a single laboratory test or clinical finding that is uniquely specific for MS. This has caused confusion among researchers and clinicians. The results of an international survey conducted by Lublin and Reingold has helped by categorizing MS into four types (Table 1).12 Regardless of the type, most patients will follow one of three clinical patterns: episodic attacks followed by complete or incomplete recovery, gradual deterioration of function, or a combination of both. Relapsing-remitting MS (RRMS) is characterized by periods of relapses and remissions without disease progression between relapses. These patients tend to be younger. About 85% of patients will present with RRMS.13 Primary-progressive MS (PPMS) is a continuously progressive disease that worsens over time, but never clearly falls into a remission or relapse stage. These patients never return to their baseline. Secondaryprogressive MS (SPMS) is defined as initial RRMS disease that has evolved into a progressive pattern. In SPMS, there may be some minor relapses and remissions, but the patient no longer returns to baseline. SPMS is considered the long-term outcome of RRMS. Progressive-relapsing MS (PRMS) is uncommon and characterized by progressive MS from the onset with clearly identifiable relapses. Recovery may or may not be complete with progression between relapses.12
MS Clinical Presentation MS patients typically present with neurologic abnormalities such as optic neuritis, brainstem symptoms, and/or acute myelitis. The first neurological event that lasts at
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Table 1. Clinical Classifications of Multiple Sclerosis MS Classifications
Characteristics
Relapsing-remitting (RRMS)
Clearly defined relapses and remissions with full- or near-full-recovery periods No disease progression in between relapses
Primary-progressive
Disease progression from outset without relapses or remissions Plateaus or minor improvements may be seen but baseline status never returns
Secondary-progressive
Initial RRMS that becomes progressive Relapses and remissions may occur
Progressive-relapsing
No history or RRMS Progressive disease with defined relapses and variable remissions Continuous progression between relapses
Source: Reference 12.
least 24 hours is frequently termed a “clinically isolated syndrome” (CIS). A CIS may be classified as monofocal, consisting of a single neurological symptom from a single centrally located lesion, or multifocal if more than one lesion from two separate locations causes multiple symptoms.14 MS symptoms may include: • Sensory symptoms: pain, paresthesia, diminished sensation, trigeminal neuralgia, Lhermitte’s sign (pain radiating into arm with neck flexion)15 • Motor symptoms: spasticity, muscle weakness, paraparesis • Bladder dysfunction: urinary urgency, frequency, incontinence, or retention • Bowel dysfunction: constipation, incontinence • Cerebellar dysfunction: gait abnormalities, coordination, tremor • Neuropsychiatric disorders: impaired concentration, anxiety, insomnia, depression • Sexual dysfunction: erectile dysfunction, decreased libido • Fatigue: a prominent symptom, worse in progressive MS and when ambulation becomes affected16 The typical presentation of MS is that of a young patient with more than one CNS event that improves over
a period of 24 to 48 hours. A positive family history and imaging help support the diagnosis. Other differential diagnoses should be considered if the patient is older than 60 or younger than 15 years of age.
MS Diagnosis The diagnosis of MS is based on clinical suspicion, laboratory evaluation, and imaging studies of the brain and spinal cord. A cerebrospinal fluid analysis with elevated IgG immunoglobulins or oligoclonal bands is consistent with a diagnosis of MS in a patient who presents with a CIS.17 Since MS is a chronic demyelinating disease, MRI findings will change over the course of time. The McDonald criteria have been used to document these changes and help support the diagnosis of MS.18 According to the McDonald criteria, the diagnosis of MS is supported in patients who present with a CIS and meet specific MRI requirements.13 The diagnostic requirements for MS on an MRI must include the documentation of lesions disseminated in space (DIS) and disseminated in time (DIT). DIS requires one or more T2 lesions in two or more MS locations of the CNS. The MS typical locations are periventricular, juxctacortical, infratentorial, and spinal cord. DIT can be established by the presence of a new
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Clinical Review lesion compared with a previous scan or the simultaneous presence of an asymptomatic enhanced lesion plus a T2 nonenhancing lesion on the same scan. The McDonald criteria have undergone several revisions since they were introduced in 2001. The purpose of the latest revision in 2010 was to simplify the diagnosis while maintaining sensitivity and specificity and to make them applicable to a broader population, including pediatrics, Asians, and Hispanics (Table 2).13,17,19
Late-Onset MS MS is often perceived as a young person’s disease and is most commonly diagnosed between the ages of 20-40.6,7 This is not always the case. A minority of MS patients are diagnosed into the fifth and sixth decades. LOMS is defined as the first episode after the age of 50.6 LOMS makes up a special subset of MS patients, who often present a diagnostic challenge in part because clinicians often do not suspect MS because they have atypical presentations.7 Several studies have examined the presentation and clinical course of LOMS versus young-onset MS (YOMS). LOMS is more likely to be PPMS rather than RRMS.6,20 A possible explanation is that genetic differences and the slowly declining immune system in the elderly population play a role.7 Misdiagnosis and delayed diagnosis of MS is
more common in LOMS.21 YOMS patients are more likely to present with visual symptoms, cerebrospinal fluid pleocytosis, and contrast-enhanced lesions on an MRI during their initial attack compared with those with LOMS. On the other hand, LOMS patients more commonly complain of motor symptoms. Spinal-cord lesions are more common in LOMS, and cerebellar lesions are more common in YOMS (Table 3).20 MRI specificity for the diagnosis of MS declines with age because of the coexistence of microcalcifications in this age group, further complicating the diagnosis.20
MS Treatment Treatment of MS in the elderly patients is guided by comorbidities and clinical judgment. Until more evidencebased information becomes available, elderly patients and patients with late-onset MS should be managed according to the same algorithms as those used for younger individuals, but with more caution.7 Currently there is no cure for MS. Management focuses on suppression of the immune system and prevention of relapses. Goals of treatment include decreasing symptoms, preventing progression, reducing the number of relapses, and reducing long-term disabilities. There are three general approaches to treatment:
Table 2. 2010 McDonald MRI Criteria for Meeting the Requirement of DIS and DIT DIS can be demonstrated by ≥ 1 T2* lesion in at least 2 of 4 multiple sclerosis typical areas of the central nervous system: Periventricular Juxtacortical Infratentorial Spinal cord
DIT can be demonstrated by: A new T2 and/or gadolinium-enhancing lesion(s) on followup MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI Simultaneous presence of asymptomatic gadoliniumenhancing and nonenhancing lesions at any time
*T2 refers to a bright lesion on MRI that does not require gadolinium enhancement. Abbreviations: DIS = Lesion dissemination in space, DIT = Lesion dissemination in time. Source: References 13, 17, 19.
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Table 3. Comparison of Symptoms Commonly Seen in YOMS Compared with Those Seen in LOMS YOMS Characteristics
LOMS Characteristics
Visual symptoms upon presentation Contrast-enhanced lesions on MRI common
Motor symptoms upon presentation
Cerebrospinal pleocytosis more frequent
Cerebrospinal pleocytosis less frequent
Cerebellar lesions more frequent MRI specificity higher
Spinal cord lesions more frequent
Contrast-enhanced lesions on MRI rare
MRI specificity lower
Abbreviations: LOMS = Late-onset multiple sclerosis, YOMS = Young-onset multiple sclerosis. Source: Reference 20.
• Treat acute relapses with corticosteroids. • Treat with disease-modifying therapies to decrease the number of relapses, prevent permanent neurological damage, and prevent disability. • Treat MS-associated symptoms to minimize the impact on quality of life (Table 4).22,23 Exacerbations of MS are episodes of neurological dysfunction that occur spontaneously. The established and substantiated treatment options are injectable steroids, generally methylprednisolone, sometimes followed by an oral corticosteroid taper.24 They reduce inflammation by decreasing the migration of inflammatory cells into the CNS and hasten recovery from an acute exacerbation of MS. Plasmapheresis can be used short-term for severe attacks if steroids are contraindicated or ineffective. The 2011 American Academy of Neurology guideline for plasmapheresis in neurological diseases categorizes plasmapheresis as “probably effective” as second-line treatment for relapsing MS exacerbations that do not respond to steroids.24,25 Current therapies target the immune dysfunction in MS. The National Clinical Advisory Board of the National Multiple Sclerosis Society recommends everyone with a definite diagnosis of MS should begin therapy with a disease-modifying agent as soon as possible, with the goal of terminating inflammation and reducing axonal
damage.26 Table 5 lists all of the disease-modifying therapies approved for MS, their adverse effects, monitoring, and selected drug interactions.27-33 The mainstay of MS therapy has been the betainterferons and glatiramer acetate. Beta-interferon is available as beta-1a or beta-1b. Although the exact mechanism of action of beta-interferons is unknown, it may be related to suppression of T-helper cell response.29,34 In separate pivotal trials, they reduced clinical exacerbations by up to 30% and decreased the development of new inflammatory lesions on MRI by 50% to 65%.35-37 As a class, the beta-interferons share similar side effects of worsening depression, possible liver toxicity, and flulike symptoms following injections.27-29,34 The flulike symptoms may be treated with acetaminophen or nonsteroidal antiinflammatory drugs and may diminish over time. Liver function tests (LFTs) should be monitored periodically while on therapy.38 Glatiramer acetate is a subcutaneous daily injection that is thought to work by a different mechanism. It mimics myelin basic protein, a major component of the myelin sheath, and may induce T-helper type-2 cells.34,39 The mechanism of action is yet to be fully elucidated. Glatiramer acetate has been shown to have roughly the same efficacy of the beta-interferons.29,40-43 The side effect profile of glatiramer acetate includes acute injection-site reactions such as pain and inflammation, and systemic
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Clinical Review Table 4. Treatment Options for Common Symptoms of Multiple Sclerosis Symptom
Nonpharmacologic
Pharmacologic
Bladder dysfunction
Reduce fluid intake
Failure-to-empty dysfunction • Intermittent self-catheterization • α1-blockers
Pelvic floor exercises Regular bladder emptying
Bowel dysfunction
Bladder overactivity: • Antimuscarinics (first-line) • Intravesical botulinum toxin A
Review drug side effects Maintenance of physical activity Timed bowel evacuation Increase dietary fiber
Constipation • Bulk-forming agents • Stool softeners • Laxatives Fecal incontinence: • Antidiarrheal agents
Adequate hydration Biofeedback Fatigue
Occupational therapy: simplify tasks at work and home
Amantadine
Physical therapy: learn energy-saving ways of walking and performing daily tasks, and regular exercise program
Methylphenidate
Modafinil
Impaired gait
Not applicable
Dalfampridine extended-release
Mood disorders
Cognitive behavior therapy
Depression • Selective serotonin reuptake inhibitors • Tricyclic antidepressants and duloxetine (may be useful in comorbid neuropathic pain) Pseudobulbar affect • Dextromethorphan/quinidine
Pain
Trigeminal neuralgia • Carbamazepine, oxcarbazepine
Massage, stress reduction
Lhermitte’s sign • Gabapentin Neuropathic pain • Tricyclic antidepressant Sexual dysfunction
Men: Phosphodiesterase-5 inhibitors
Men: Vacuum-device Women: Vaginal lubricants
Spasticity
Physiotherapy, stretching, splinting
Baclofen Tizanidine Botulinum toxin A
Source: References 22, 23.
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Table 5. Summary of Adverse Effects, Recommended Monitoring, and Selected Drug Interactions for MS Medications Medication
Adverse Effects
Monitoring
Beta-interferons
Flulike symptoms, depression, liver toxicity, hypothyroid
Monitor LFTs, thyroid Injection-site reactions test, CBC
Glatiramer acetate
Injection-site reactions, immediate postinjection systemic reactions
No laboratory monitoring needed
Lipoatrophy at injection site rare but thought to be permanent
Fingolimod
Skin malignancies, first-dose bradycardia, macular edema, dyspnea, increased liver enzymes
Monitor heart rate, signs of infection, LFTs, blood pressure, CBC, annual eye exam
Patients should be amply immunized
Comments
Avoid live vaccines during and 2 months after treatment, in patients with recent myocardial infarction, angina, stroke/ transient ischemic attack, or severe heart failure Drug interactions: Class Ia or Class III antiarrhythmic drugs are contraindicated; drugs that prolong QTinterval or slow heart rate use with caution
Teriflunomide
Acute renal failure, alopecia, blood pressure, infections hyperkalemia, peripheral neuropathy gastrointestinal symptoms, increased liver enzymes
CBC, blood pressure, LFTs, bilirubin, potassium, signs of infection, serum creatinine, blood urea nitrogen
Avoid live vaccines
Dimethyl fumarate
Gastrointestinal symptoms, flushing, lymphopenia
CBC, monitor signs of infection
Taking with food may decrease flushing
Mitoxantrone
Alopecia, cardiac toxicity, Monitor CBC, LFTs, infections, secondary leukemia heart function infections, bone marrow suppression
Blue-green urine 24 hours after infusion Cumulative lifetime dose = 140 mg/m2 because of cardiotoxicity
Natalizumab
Urinary tract infections, lower respiratory tract infections, joint pain Progressive multifocal leukoencephalopathy
Peripheral neuropathy (60 years of age and older with diabetes) Drug interactions: Increased ethinyl estradiol and levonorgesterol concentrations Inhibits 2C8 (repaglinide) and induces 1A2 (duloxetine, tizanidine), warfarin (decreases INR)
Not considered first-line therapy unless LFTs patient has risk of severe disease Progressive multifocal leukoencephalopathy
Abbreviations: CBC = Complete blood cell, INR = International Normalized Ratio, LFTs = Liver function tests, MS = Multiple sclerosis. Source: References 27-33.
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Clinical Review immediate postinjection reactions. The acute injection-site reactions may be reduced by applying warm compresses or ice to the site before injecting. The postinjection reaction is characterized by a variable combination of symptoms, such as facial flushing, chest tightness, dyspnea, palpitations, tachycardia, and/or anxiety, which usually occurs within the first few seconds to minutes after drug administration and lasts up to 30 minutes. Although this reaction is not harmful, the patient should be informed. The majority of these events require no additional treatment.34,39 The armamentarium for the treatment of MS is increasing rapidly. Three new oral treatments, fingolimod, teriflunomide, and dimethyl fumarate, have shown benefit and convenience of such administration. The first available oral disease-modifying therapy for MS was fingolimod. It is an oral sphingosine-1-phosphate analogue that works to block egress of lymphocytes out of secondary lymphoid tissues.43 In a two-year placebo-controlled trial, fingolimod decreased relapses by 54% compared with placebo. It decreased disability progression and new and enlarging T2 lesions.45 When compared with intramuscular interferon beta-1a, there was a significant relative treatment benefit with fingolimod, but no effect on disability over the 12-month study.46 Fingolimod is associated with first-dose bradycardia, dyspnea, macular edema, and elevated LFTs.30,47 Teriflunomide is the active metabolite of leflunomide. It is a dihydroorotate dehydrogenase inhibitor, a mitochondrial membrane protein that blocks pyrimidine synthesis.31 By altering pyrimidine synthesis, it decreases T- and B-cell proliferation.31,48,49 In a two-year, randomized, placebo-controlled trial, teriflunomide reduced annualized relapse rates by 31.2% in the 7-mg group and 31.5% in the 14-group.50 The most common adverse effects are alopecia, gastrointestinal symptoms, and elevation of liver enzymes.51,52 Discontinuation and initiation of an accelerated elimination procedure should be considered if patients develop liver injury or peripheral neuropathy. The accelerated elimination procedure consists of 11 days of treatment with cholestyramine 8 grams every 8 hours or activated charcoal 50 g every 12 hours.31 Dimethyl fumarate and its primary metabolite, monomethyl fumarate, inhibit proinflammatory cytokines
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and increase anti-inflammatory cytokines. Additionally, dimethyl fumarate exerts neuroprotective properties by activating the nuclear factor (erythroid-derived 2)-like 2 pathway. This pathway is thought to be the primary cellular defense against oxidative stress.49,52,53 In two large phase 3 trials, dimethyl fumarate reduced annualized relapse rates by 44% to 53%.54,55 During the first year of treatment with dimethyl fumarate, the mean lymphocyte count decreased by 30%. Six percent of patients experienced lymphopenia.33 GI symptoms and flushing seem to be the two most common adverse effects.49,52,53 Flushing and GI symptoms usually dissipate after the first month. Taking with food may also help. Mitoxantrone and natalizumab are efficacious, but should be reserved for patients with progression of symptoms, intolerant or nonresponsive to first-line therapies. Mitoxantrone carries a risk of cardiotoxicity at cumulative doses above 140 mg/m2, and long-term use has been associated with a 2% to 3% risk of developing acute myeloid leukemia. Natalizumab can cause progressive multifocal leukoencephalopathy.29,32 There is no consensus on the best agent for initial therapy, except for mitoxantrone. Mitoxantrone may be considered for patients with rapidly advancing disease who have failed other therapies.29 The beta-interferons and glatiramer acetate have been the foundation of initial treatment. The advantage of these agents is the considerable knowledge of their long-term safety and efficacy. Until long-term safety data become available for the oral agents, the first-line therapy may continue to be beta-interferons and glatiramer acetate. The oral agents will likely be used when the patient is nonresponsive to the injectable disease-modifying agents.56 Because of the risk of progressive, multifocal leukoencephalopathy, natalizumab will be primarily used in patients with more active disease or those who do not respond to beta-interferons or glatiramer acetate. This may change with the approval of the Stratify John Cunningham virus antibody ELISA test. The health care provider using this test and other clinical information from the patient can help determine the risk for developing PML in MS. The Food and Drug Administration (FDA) safety announcement emphasizes that patients who
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test negative for anti-John Cunningham virus antibodies are still at risk for the development of PML because of the potential for new John Cunningham virus infection or a false-negative test result.57 Further trials are needed before combination therapy is an option for patients with insufficient response to the injectable disease-modifying agent.56 There is increasing interest in an association between MS and vitamin D. Evidence suggests that vitamin D deficiency is recognized as a risk for MS. Other studies show an inverse correlation between serum vitamin D levels and MRI disease activity or relapse rate in MS patients.58-60 Randomized trials are needed to translate the effect of vitamin D into evidence-based guidelines. Given the current evidence of the potential benefit of vitamin D, it appears to be reasonable and safe to consider vitamin D supplementation at dosing adequate to achieve normal levels in patients with MS. Pharmacists have a critical role in facilitating optimal use of medications in multiple sclerosis. Among these are to: • Make treatment recommendations and monitor laboratory results, drug interactions, adverse reactions, and therapeutic responses • Ensure the patient is current with all vaccinations • Consider avoiding live vaccines because live-virus vaccines can precipitate an increase in disease activity61 • Ensure proper injection technique and daily rotation of injection sites • Confirm and make recommendations to ensure medications are administered correctly in regard to meals and in relation to other medications
Conclusion MS is a chronic neurologic, demyelinating disease that causes a great amount of disability in those patients diagnosed with the disease. It typically presents between 20 and 40 years of age and affects a greater number of women than men. However, 2% to 10% are diagnosed after 50 years of age. This diagnosis is termed LOMS. Although the exact etiology of MS is unknown, research suggests that MS is autoimmune in nature. The leading theory to support the autoimmunity of MS is that activated T-cells cross the blood-brain barrier, recognize antigens on the myelin sheaths of axons, and destroy the myelin, causing inflammation, which results in the formation of plaques. The diagnosis of MS is based on the presentation of clinical symptoms and the McDonald criteria. Management is individualized and focuses on suppression of the immune system, prevention of relapses, and symptomatic treatment to minimize the impact on quality of life. Currently, research is focused on finding effective new treatments that are able to modify the disease. There are several products in the pipeline. Alemtuzumab, an anti-CD52 monoclonal antibody, has been approved in Canada and by the European Medicines Agency. FDA declined approval in December 2013.
Daniel Sturm, MMS, PA-C, is assistant professor, Physician Assistant Program, College of Pharmacy and Health Sciences, Butler University, Indianapolis, Indiana. Samuel L. Gurevitz, PharmD, CGP, is assistant professor, Physician Assistant Program, College of Pharmacy and Health Sciences, Butler University. Amelia Turner, MS, PA-S, is physician assistant student, College of Pharmacy and Health Sciences, Butler University. For correspondence: Daniel Sturm, MMS, PA-C, College of Pharmacy and Health Sciences, Butler University, 4600 Sunset Avenue, Indianapolis, IN 46208; Phone: 317-940-8564; Fax: 317-940-6172; E-mail: [email protected]. Disclosures: No funding was received for this study or the development of the manuscript. The authors report no potential conflicts of interest. © 2014 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2014.469.
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Clinical Review References 1. Sherwood L. Principles of Neural and Hormonal Communication. In Adams P, Arbogast M, eds. Human Physiology: From Cells to Systems. 6th ed. Belmont, CA: Thomson Brooks/Cole; 2007:98-100. 2. Olek MJ. Epidemiology and clinical features of multiple sclerosis in adults. UpToDate 2013. Available at http://www.uptodate.com/contents/ epidemiology-and-clinical-features-of-multiple-sclerosis-in-adults. Accessed May 14, 2013. 3. Srivastava R, Aslam M, Kalluri SR et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med 2012;367:115-23. 4. Frohman TC, O’Donoghue DL, Northrop D. Multiple sclerosis for the physician assistant. Available at www.nationalmssociety.org/download. aspx?id=32262. Accessed May 22, 2013. 5. Ebers GC. Environmental factors and multiple sclerosis. Lancet Neurol 2008;7:268-77. 6. Polliack ML, Barak Y, Achiron A. Late-onset multiple sclerosis. J Am Geriatr Soc 2001;49:168-71. 7. Awad A, Stüve O. Multiple sclerosis in the elderly patient. Drug Aging 2010;27:283-94. 8. Who gets MS? National Multiple Sclerosis Society. Available at http:// www.nationalmssociety.org/about-multiple-sclerosis/what-we-knowabout-ms/who-gets-ms/index.aspx. Accessed May 23, 2013. 9. Langer-Gould A, Brara SM, Beaber BE et al. Incidence of multiple sclerosis in multiple racial and ethnic groups. Neurology 2013;80:1734-9. 10. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Ann Neurol 2007;61:504-13. 11. Rutschmann OT, McCrory DC, Matchar DB, Immunization panel of the Multiple Sclerosis Council for Clinical Practice Guidelines. Immunization and MS: a summary of published evidence and recommendations. Neurology 2002;59:1837-43. 12. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996;46:907-11. 13. Montalban X, Tintoré M, Swanton J et al. MRI criteria for MS in patients with clinically isolated syndromes. Neurology 2010;74:427-34. 14. Clinically Isolated Syndrome. National Multiple Sclerosis Society. Available at http://www.nationalmssociety.org/about-multiple-sclerosis/ what-we-know-about-ms/diagnosing-ms/cis/index.aspx. Accessed June 19, 2013. 15. Kanchandani R, Howe JG. Lhermitte’s sign in multiple sclerosis: a clinical survey and review of the literature. J Neurol Neurosurg Psychiatry 1982;45:308-12. 16. Mills RJ, Young CA. The relationship between fatigue and other clinical features of multiple sclerosis. Mult Scler 2010;17:604-12. 17. Polman CH, Reingold SC, Banwell B et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292-302. 18. Rovira A, Swanton J, Tintoré M et al. A single, early magnetic resonance imaging study in the diagnosis of multiple sclerosis. Arch Neurol 2009;66:587-92. 19. Swanton JK, Rovira A, Tintoré M et al. MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicenter retrospective study. Lancet Neurol 2007;6:677-86. 20. Kis B, Rumberg B, Berlit P. Clinical characteristics of patients with lateonset multiple sclerosis. J Neurol 2008;255:697-702.
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21. Martinelli V, Rodegher M, Moiola L et al. Late onset multiple sclerosis: clinical characteristics, prognostic factors and differential diagnosis. Neurol Sci 2004;25:S350-5. 22. Thompson AJ, Toosy AT, Ciccarelli O. Pharmacological management of symptoms in multiple sclerosis: current approaches and future directions. Lancet Neurol 2010;9:1182-99. 23. Samkoff LM, Goodman AD. Symptomatic management in multiple sclerosis. Neurol Clin 2011;29:449-63. 24. Berkovich R. Treatment of acute relapses in multiple sclerosis. Neurotherapeutics 2013;1:97-105. 25. Cortese I, Chaudhry V, So YT et al. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2011;76:294-300. 26. Miller A, Lisak R, Bohen R et al. National Multiple Sclerosis Society. Disease management consensus statement: expert opinion paper. New York, NY: National Multiple Sclerosis Society; 2008. 27. Avonex (Interferon beta-1a) prescribing information. Cambridge, MA: Biogen Idec; 2013. 28. Betaseron (interferon beta-1b) prescribing information. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2013. 29. Gawronski KM, Rainka MM, Patel MJ et al. Treatment options for multiple sclerosis: current and emerging therapies. Pharmacotherapy 2010;30:916-27. 30. Gilenya (fingolimod) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. 31. Cada DJ, Demaris K, Levien TL et al. Formulary drug review Teriflunomide. Hosp Pharm 2013;48:231-40. 32. New Drugs for Multiple Sclerosis. Med Lett Drugs Ther 2012;54:89. 33. Dimethyl fumarate (tecfidera) for multiple sclerosis. Med Lett Drugs Ther 2013;55:45 34. McGraw CA, Lublin FD. Interferon beta and glatiramer acetate therapy. Neurotherapeutics 2013;10:2-18. 35. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebocontrolled trial. The IFNB Multiple Sclerosis Study Group. Neurology 1993;43:655-61. 36. Jacobs LD, Cookfair DL, Rudick RA et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996;39:285-94. 37. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998;352:1498-504. 38. Bayas A, Rieckman P. Managing the adverse effects of interferon-β therapy in multiple sclerosis. Drug Safety 2000;2:149-59. 39. Carter NJ, Keating GM. Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis. Drugs 2010;70:1545-77. 40. Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging—measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001;49:290-7.
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41. Comi G, Martinelli V, Rodegher M et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 2009;374:1503-11. 42. Mikol DD, Barkhof F, Chang P et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs. Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, openlabel trial. Lancet Neurol 2008;7:903-14. 43. O’Connor P, Filippi M, Arnason B et al. 250 microg or 500 microg interferon beta-1b versus 20 milligram glatiramer acetate in relapsingremitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol 2009;8:889-97. 44. Singer B, Ross AP, Tobias K. Oral fingolimod for the treatment of patients with relapsing forms of multiple sclerosis. Int J Clin Pract 2011;65:887-95. 45. Kappos JM, Radue E-W, O’Connor P et al. A placebo controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401. 46. Cohen JA, Barkof F, Comi G et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402-15. 47. Scott LJ. Fingolimod: a review of its use in the management of relapsing-remitting multiple sclerosis. CNS Drugs 2011;25:673-98. 48. Claussen MC, Korn T. Immune mechanisms of new therapeutic strategies in MS – Teriflunomide. Clin Immunol 2012;142:49-56. 49. Thone J, Ellrichmann G. Oral available agents in the treatment of relapsing remitting multiple sclerosis: an overview of merits and culprits. Drug Healthc Patient Saf 2013;5:37-47. 50. O’Connor P, Wolinsky JS, Confavreux C et al. Randomized trial of teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-303. 51. Tanasescu R, Evangelou N, Constantinescu CS. Role of oral teriflunomide in the management of multiple sclerosis. Neuropsychiatr Dis Treat 2013;9:539-53.
52. Jeffery DR. Recent advances in treating multiple sclerosis: efficacy, risks, and place in therapy. Ther Adv Chronic Dis 2013;4:45-51. 53. Perumal J, Khan O. Emerging disease-modifying therapies in multiple sclerosis. Curr Treat Options Neurol 2012;14:256-63. 54. Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107. 55. Fox RJ, Miller DH, Phillips JT et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in relapsing multiple sclerosis. N Engl J Med 2012;367:1087-97. 56. Hartung HP, Montalban X, Sorensen PS et al. Principles of a new treatment algorithm in multiple sclerosis. Expert Rev Neurother 2011;11:351-62. 57. FDA Drug Safety Communication: New risk factor for progressive multifocal leukoencephalopathy (PML) associated with Tysabri (natalizumab). Available at http://www.fda.gov/Drugs/DrugSafety/ ucm288186.htm#hcp. Accessed October 19, 2013. 58. Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance activity in multiple sclerosis. Ann Neurol 2012;72:234-40. 59. Runia TF, Hop WC, de Rijke YB et al. Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis. Neurology 2012;79:261-6. 60. Simpson S, Taylor B, Blizzard L et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol 2010;68:193-203. 61. Vaccinations. National Multiple Sclerosis Society. Available at http:// www.nationalmssociety.org/living-with-multiple-sclerosis/healthy-living/ vaccinations/index.aspx. Accessed May 9, 2013.
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clinical features, diagnostic findings, and treatment options for multiple sclerosis (MS). Data Sources: A PubMed search of English language articles using a combination of words: elderly; multiple sclerosis*, late onset multiple sclerosis*, etiology; screening; diagnosis; or treatment to identify original studies, guidelines, and reviews on multiple sclerosis and late-onset multiple sclerosis, published 2002 to 2013. Primary sources were then used to search for additional relevant material. Study Selection and Data Extraction: Original studies, clinical reviews, references, and guidelines were obtained and evaluated for their clinical relevance. Data Synthesis: The literature included guidelines and considerations for the etiology, diagnosis, screening, and management of MS. Conclusion: MS is a chronic autoimmune disease characterized by inflammation, demyelination, and local axonal injury. It typically presents between ages 20 and 40 and largely affects women. However, 2% to 10% of individuals are diagnosed after 50 years of age. Diagnosis is based on presentation of clinical symptoms and the McDonald criteria for diagnosing MS. Management focuses on suppression of the immune system and prevention of relapses. Key Words: Elderly, Geriatrics, Late-onset multiple sclerosis, Multiple sclerosis, Treatment. Abbreviations: CBC = Complete blood count, CIS = Clinically isolated syndrome, CNS = Central nervous system, DIS = Disseminated in space, DIT = Disseminated in time, LFTs = Liver function tests, LOMS = Late-onset multiple sclerosis, MRI = Magnetic resonance imaging, MS = Multiple sclerosis, PPMS = Primary-progressive multiple sclerosis, PRMS = Progressive-relapsing multiple sclerosis, RRMS = Relapsingremitting multiple sclerosis, SPMS = Secondary-progressive multiple sclerosis, YOMS = Young-onset multiple sclerosis. Consult Pharm 2014;29:469-79.
Introduction There are many chronic diseases of the central nervous system (CNS) that can destroy the myelin sheaths that encircle the nerves. The myelin sheath is a protective covering composed of lipids that insulate nerves, thereby allowing electrical impulses to be transmitted more quickly and efficiently down the length of the axon. If the myelin sheath surrounding the nerves is damaged, electrical conduction slows down. This process is called demyelination.1 The most common chronic demyelinating disease of the CNS is multiple sclerosis (MS).2 MS is a neurological disorder that affects the CNS and is capable of causing a great amount of disability in those diagnosed with the disease.3 MS can affect all aspects of life. Patients commonly suffer from visual changes, muscle weakness, ataxia leading to falls, paroxysms such as tonic spasms and seizures, cognitive impairments, and fatigue. These symptoms impact activities of daily living, which include dressing and bathing, as well as their instrumental activities of daily living, which include driving, cooking, and shopping. It is estimated that 2.5 million individuals worldwide are affected by MS, and approximately 400,000 of those cases are in the United States.4 The purpose of this review article is to provide information regarding the etiology, epidemiology, clinical features, diagnostic findings, and treatment options for MS.
Epidemiology The prevalence of MS varies geographically.5 Areas of higher prevalence (60 cases per 100,000 people) include Europe, Russia, southern Canada, northern United States, New Zealand, and southeast Australia. In the United States, the prevalence is estimated to be 100 cases per 100,000 people.2 Presentation of symptoms in MS usually begins between 20 and 40 years of age. When a patient is diagnosed with MS after the age of 50, the diagnosis is termed late-onset multiple sclerosis (LOMS). It is estimated that between 2% and 10% of patients diagnosed with MS fall into this category.6,7 MS typically affects women more than men. In addition, it is more commonly seen in Caucasians of Northern European decent as compared with other ethnic groups,
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Clinical Review including African-Americans, Asians, and Hispanics/ Latinos.8 However, there was recently a study that found the risk of developing MS was higher in African-American women when compared with Caucasian American women and men.9 In addition to the ethnic disparities of the disease, there are also geographic disparities with regard to latitude. Studies have shown that there are fewer cases of MS diagnosed closer to the equator, while people living north of 40° latitude have a higher risk of developing the disease.4 The risk of developing MS also seems to be affected by relocation from one geographic area to another. Individuals who relocate after puberty (around age 15) retain the risk level for developing MS of the place from which they moved. However, those who relocate prior to puberty assume the risk level of the area to which they moved.2 These findings along with other evidence have led some researchers to theorize that there is a relationship between the amount of exposure to sunlight and vitamin D and the risk of developing MS.10 In addition, other environmental factors, such as smoking or viral infections, have been shown to increase the risk of developing MS.2,4,5,10 The risk of developing MS may be related to genetic components as well as environmental factors. Studies have shown that there is a 2% to 4% increased risk of developing MS if a first-degree relative has been diagnosed with the disease.4 Twin studies have demonstrated that the risk of developing MS for dizygotic twins is similar to that of siblings, which is approximately 3% to 5%. The risk of developing MS for monozygotic twins, on the other hand, is significantly higher. It is estimated to be between 20% and 40%.2,4
Pathophysiology Although the exact cause of MS is controversial, evidence suggests it may be the result of the interaction among the immune system, genetics, and environmental factors.3 Some research suggests that the autoimmune component of MS is initiated by exposure to an infectious stimulant.4,11 Another hypothesis suggests that autoimmunity is triggered by dysregulation of the immune system. Studies propose that activated T-cells and other lymphocytes cross the blood-brain barrier. Once in the CNS, these cells recognize
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antigens on the myelin sheaths of the axons. After recognition, the lymphocytes attack the myelin sheath, causing inflammation resulting in the formation of plaques.2-4 The plaques and the ongoing destruction of the myelin slow conduction of the nerve impulses between neurons. Loss of axons and conduction can lead to the progression of the disabling symptoms associated with MS.2
Classifications MS primarily affects women younger than 50 years of age. The clinical course of MS varies extensively. Furthermore, there is not a single laboratory test or clinical finding that is uniquely specific for MS. This has caused confusion among researchers and clinicians. The results of an international survey conducted by Lublin and Reingold has helped by categorizing MS into four types (Table 1).12 Regardless of the type, most patients will follow one of three clinical patterns: episodic attacks followed by complete or incomplete recovery, gradual deterioration of function, or a combination of both. Relapsing-remitting MS (RRMS) is characterized by periods of relapses and remissions without disease progression between relapses. These patients tend to be younger. About 85% of patients will present with RRMS.13 Primary-progressive MS (PPMS) is a continuously progressive disease that worsens over time, but never clearly falls into a remission or relapse stage. These patients never return to their baseline. Secondaryprogressive MS (SPMS) is defined as initial RRMS disease that has evolved into a progressive pattern. In SPMS, there may be some minor relapses and remissions, but the patient no longer returns to baseline. SPMS is considered the long-term outcome of RRMS. Progressive-relapsing MS (PRMS) is uncommon and characterized by progressive MS from the onset with clearly identifiable relapses. Recovery may or may not be complete with progression between relapses.12
MS Clinical Presentation MS patients typically present with neurologic abnormalities such as optic neuritis, brainstem symptoms, and/or acute myelitis. The first neurological event that lasts at
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Table 1. Clinical Classifications of Multiple Sclerosis MS Classifications
Characteristics
Relapsing-remitting (RRMS)
Clearly defined relapses and remissions with full- or near-full-recovery periods No disease progression in between relapses
Primary-progressive
Disease progression from outset without relapses or remissions Plateaus or minor improvements may be seen but baseline status never returns
Secondary-progressive
Initial RRMS that becomes progressive Relapses and remissions may occur
Progressive-relapsing
No history or RRMS Progressive disease with defined relapses and variable remissions Continuous progression between relapses
Source: Reference 12.
least 24 hours is frequently termed a “clinically isolated syndrome” (CIS). A CIS may be classified as monofocal, consisting of a single neurological symptom from a single centrally located lesion, or multifocal if more than one lesion from two separate locations causes multiple symptoms.14 MS symptoms may include: • Sensory symptoms: pain, paresthesia, diminished sensation, trigeminal neuralgia, Lhermitte’s sign (pain radiating into arm with neck flexion)15 • Motor symptoms: spasticity, muscle weakness, paraparesis • Bladder dysfunction: urinary urgency, frequency, incontinence, or retention • Bowel dysfunction: constipation, incontinence • Cerebellar dysfunction: gait abnormalities, coordination, tremor • Neuropsychiatric disorders: impaired concentration, anxiety, insomnia, depression • Sexual dysfunction: erectile dysfunction, decreased libido • Fatigue: a prominent symptom, worse in progressive MS and when ambulation becomes affected16 The typical presentation of MS is that of a young patient with more than one CNS event that improves over
a period of 24 to 48 hours. A positive family history and imaging help support the diagnosis. Other differential diagnoses should be considered if the patient is older than 60 or younger than 15 years of age.
MS Diagnosis The diagnosis of MS is based on clinical suspicion, laboratory evaluation, and imaging studies of the brain and spinal cord. A cerebrospinal fluid analysis with elevated IgG immunoglobulins or oligoclonal bands is consistent with a diagnosis of MS in a patient who presents with a CIS.17 Since MS is a chronic demyelinating disease, MRI findings will change over the course of time. The McDonald criteria have been used to document these changes and help support the diagnosis of MS.18 According to the McDonald criteria, the diagnosis of MS is supported in patients who present with a CIS and meet specific MRI requirements.13 The diagnostic requirements for MS on an MRI must include the documentation of lesions disseminated in space (DIS) and disseminated in time (DIT). DIS requires one or more T2 lesions in two or more MS locations of the CNS. The MS typical locations are periventricular, juxctacortical, infratentorial, and spinal cord. DIT can be established by the presence of a new
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Clinical Review lesion compared with a previous scan or the simultaneous presence of an asymptomatic enhanced lesion plus a T2 nonenhancing lesion on the same scan. The McDonald criteria have undergone several revisions since they were introduced in 2001. The purpose of the latest revision in 2010 was to simplify the diagnosis while maintaining sensitivity and specificity and to make them applicable to a broader population, including pediatrics, Asians, and Hispanics (Table 2).13,17,19
Late-Onset MS MS is often perceived as a young person’s disease and is most commonly diagnosed between the ages of 20-40.6,7 This is not always the case. A minority of MS patients are diagnosed into the fifth and sixth decades. LOMS is defined as the first episode after the age of 50.6 LOMS makes up a special subset of MS patients, who often present a diagnostic challenge in part because clinicians often do not suspect MS because they have atypical presentations.7 Several studies have examined the presentation and clinical course of LOMS versus young-onset MS (YOMS). LOMS is more likely to be PPMS rather than RRMS.6,20 A possible explanation is that genetic differences and the slowly declining immune system in the elderly population play a role.7 Misdiagnosis and delayed diagnosis of MS is
more common in LOMS.21 YOMS patients are more likely to present with visual symptoms, cerebrospinal fluid pleocytosis, and contrast-enhanced lesions on an MRI during their initial attack compared with those with LOMS. On the other hand, LOMS patients more commonly complain of motor symptoms. Spinal-cord lesions are more common in LOMS, and cerebellar lesions are more common in YOMS (Table 3).20 MRI specificity for the diagnosis of MS declines with age because of the coexistence of microcalcifications in this age group, further complicating the diagnosis.20
MS Treatment Treatment of MS in the elderly patients is guided by comorbidities and clinical judgment. Until more evidencebased information becomes available, elderly patients and patients with late-onset MS should be managed according to the same algorithms as those used for younger individuals, but with more caution.7 Currently there is no cure for MS. Management focuses on suppression of the immune system and prevention of relapses. Goals of treatment include decreasing symptoms, preventing progression, reducing the number of relapses, and reducing long-term disabilities. There are three general approaches to treatment:
Table 2. 2010 McDonald MRI Criteria for Meeting the Requirement of DIS and DIT DIS can be demonstrated by ≥ 1 T2* lesion in at least 2 of 4 multiple sclerosis typical areas of the central nervous system: Periventricular Juxtacortical Infratentorial Spinal cord
DIT can be demonstrated by: A new T2 and/or gadolinium-enhancing lesion(s) on followup MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI Simultaneous presence of asymptomatic gadoliniumenhancing and nonenhancing lesions at any time
*T2 refers to a bright lesion on MRI that does not require gadolinium enhancement. Abbreviations: DIS = Lesion dissemination in space, DIT = Lesion dissemination in time. Source: References 13, 17, 19.
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Table 3. Comparison of Symptoms Commonly Seen in YOMS Compared with Those Seen in LOMS YOMS Characteristics
LOMS Characteristics
Visual symptoms upon presentation Contrast-enhanced lesions on MRI common
Motor symptoms upon presentation
Cerebrospinal pleocytosis more frequent
Cerebrospinal pleocytosis less frequent
Cerebellar lesions more frequent MRI specificity higher
Spinal cord lesions more frequent
Contrast-enhanced lesions on MRI rare
MRI specificity lower
Abbreviations: LOMS = Late-onset multiple sclerosis, YOMS = Young-onset multiple sclerosis. Source: Reference 20.
• Treat acute relapses with corticosteroids. • Treat with disease-modifying therapies to decrease the number of relapses, prevent permanent neurological damage, and prevent disability. • Treat MS-associated symptoms to minimize the impact on quality of life (Table 4).22,23 Exacerbations of MS are episodes of neurological dysfunction that occur spontaneously. The established and substantiated treatment options are injectable steroids, generally methylprednisolone, sometimes followed by an oral corticosteroid taper.24 They reduce inflammation by decreasing the migration of inflammatory cells into the CNS and hasten recovery from an acute exacerbation of MS. Plasmapheresis can be used short-term for severe attacks if steroids are contraindicated or ineffective. The 2011 American Academy of Neurology guideline for plasmapheresis in neurological diseases categorizes plasmapheresis as “probably effective” as second-line treatment for relapsing MS exacerbations that do not respond to steroids.24,25 Current therapies target the immune dysfunction in MS. The National Clinical Advisory Board of the National Multiple Sclerosis Society recommends everyone with a definite diagnosis of MS should begin therapy with a disease-modifying agent as soon as possible, with the goal of terminating inflammation and reducing axonal
damage.26 Table 5 lists all of the disease-modifying therapies approved for MS, their adverse effects, monitoring, and selected drug interactions.27-33 The mainstay of MS therapy has been the betainterferons and glatiramer acetate. Beta-interferon is available as beta-1a or beta-1b. Although the exact mechanism of action of beta-interferons is unknown, it may be related to suppression of T-helper cell response.29,34 In separate pivotal trials, they reduced clinical exacerbations by up to 30% and decreased the development of new inflammatory lesions on MRI by 50% to 65%.35-37 As a class, the beta-interferons share similar side effects of worsening depression, possible liver toxicity, and flulike symptoms following injections.27-29,34 The flulike symptoms may be treated with acetaminophen or nonsteroidal antiinflammatory drugs and may diminish over time. Liver function tests (LFTs) should be monitored periodically while on therapy.38 Glatiramer acetate is a subcutaneous daily injection that is thought to work by a different mechanism. It mimics myelin basic protein, a major component of the myelin sheath, and may induce T-helper type-2 cells.34,39 The mechanism of action is yet to be fully elucidated. Glatiramer acetate has been shown to have roughly the same efficacy of the beta-interferons.29,40-43 The side effect profile of glatiramer acetate includes acute injection-site reactions such as pain and inflammation, and systemic
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Clinical Review Table 4. Treatment Options for Common Symptoms of Multiple Sclerosis Symptom
Nonpharmacologic
Pharmacologic
Bladder dysfunction
Reduce fluid intake
Failure-to-empty dysfunction • Intermittent self-catheterization • α1-blockers
Pelvic floor exercises Regular bladder emptying
Bowel dysfunction
Bladder overactivity: • Antimuscarinics (first-line) • Intravesical botulinum toxin A
Review drug side effects Maintenance of physical activity Timed bowel evacuation Increase dietary fiber
Constipation • Bulk-forming agents • Stool softeners • Laxatives Fecal incontinence: • Antidiarrheal agents
Adequate hydration Biofeedback Fatigue
Occupational therapy: simplify tasks at work and home
Amantadine
Physical therapy: learn energy-saving ways of walking and performing daily tasks, and regular exercise program
Methylphenidate
Modafinil
Impaired gait
Not applicable
Dalfampridine extended-release
Mood disorders
Cognitive behavior therapy
Depression • Selective serotonin reuptake inhibitors • Tricyclic antidepressants and duloxetine (may be useful in comorbid neuropathic pain) Pseudobulbar affect • Dextromethorphan/quinidine
Pain
Trigeminal neuralgia • Carbamazepine, oxcarbazepine
Massage, stress reduction
Lhermitte’s sign • Gabapentin Neuropathic pain • Tricyclic antidepressant Sexual dysfunction
Men: Phosphodiesterase-5 inhibitors
Men: Vacuum-device Women: Vaginal lubricants
Spasticity
Physiotherapy, stretching, splinting
Baclofen Tizanidine Botulinum toxin A
Source: References 22, 23.
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Table 5. Summary of Adverse Effects, Recommended Monitoring, and Selected Drug Interactions for MS Medications Medication
Adverse Effects
Monitoring
Beta-interferons
Flulike symptoms, depression, liver toxicity, hypothyroid
Monitor LFTs, thyroid Injection-site reactions test, CBC
Glatiramer acetate
Injection-site reactions, immediate postinjection systemic reactions
No laboratory monitoring needed
Lipoatrophy at injection site rare but thought to be permanent
Fingolimod
Skin malignancies, first-dose bradycardia, macular edema, dyspnea, increased liver enzymes
Monitor heart rate, signs of infection, LFTs, blood pressure, CBC, annual eye exam
Patients should be amply immunized
Comments
Avoid live vaccines during and 2 months after treatment, in patients with recent myocardial infarction, angina, stroke/ transient ischemic attack, or severe heart failure Drug interactions: Class Ia or Class III antiarrhythmic drugs are contraindicated; drugs that prolong QTinterval or slow heart rate use with caution
Teriflunomide
Acute renal failure, alopecia, blood pressure, infections hyperkalemia, peripheral neuropathy gastrointestinal symptoms, increased liver enzymes
CBC, blood pressure, LFTs, bilirubin, potassium, signs of infection, serum creatinine, blood urea nitrogen
Avoid live vaccines
Dimethyl fumarate
Gastrointestinal symptoms, flushing, lymphopenia
CBC, monitor signs of infection
Taking with food may decrease flushing
Mitoxantrone
Alopecia, cardiac toxicity, Monitor CBC, LFTs, infections, secondary leukemia heart function infections, bone marrow suppression
Blue-green urine 24 hours after infusion Cumulative lifetime dose = 140 mg/m2 because of cardiotoxicity
Natalizumab
Urinary tract infections, lower respiratory tract infections, joint pain Progressive multifocal leukoencephalopathy
Peripheral neuropathy (60 years of age and older with diabetes) Drug interactions: Increased ethinyl estradiol and levonorgesterol concentrations Inhibits 2C8 (repaglinide) and induces 1A2 (duloxetine, tizanidine), warfarin (decreases INR)
Not considered first-line therapy unless LFTs patient has risk of severe disease Progressive multifocal leukoencephalopathy
Abbreviations: CBC = Complete blood cell, INR = International Normalized Ratio, LFTs = Liver function tests, MS = Multiple sclerosis. Source: References 27-33.
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Clinical Review immediate postinjection reactions. The acute injection-site reactions may be reduced by applying warm compresses or ice to the site before injecting. The postinjection reaction is characterized by a variable combination of symptoms, such as facial flushing, chest tightness, dyspnea, palpitations, tachycardia, and/or anxiety, which usually occurs within the first few seconds to minutes after drug administration and lasts up to 30 minutes. Although this reaction is not harmful, the patient should be informed. The majority of these events require no additional treatment.34,39 The armamentarium for the treatment of MS is increasing rapidly. Three new oral treatments, fingolimod, teriflunomide, and dimethyl fumarate, have shown benefit and convenience of such administration. The first available oral disease-modifying therapy for MS was fingolimod. It is an oral sphingosine-1-phosphate analogue that works to block egress of lymphocytes out of secondary lymphoid tissues.43 In a two-year placebo-controlled trial, fingolimod decreased relapses by 54% compared with placebo. It decreased disability progression and new and enlarging T2 lesions.45 When compared with intramuscular interferon beta-1a, there was a significant relative treatment benefit with fingolimod, but no effect on disability over the 12-month study.46 Fingolimod is associated with first-dose bradycardia, dyspnea, macular edema, and elevated LFTs.30,47 Teriflunomide is the active metabolite of leflunomide. It is a dihydroorotate dehydrogenase inhibitor, a mitochondrial membrane protein that blocks pyrimidine synthesis.31 By altering pyrimidine synthesis, it decreases T- and B-cell proliferation.31,48,49 In a two-year, randomized, placebo-controlled trial, teriflunomide reduced annualized relapse rates by 31.2% in the 7-mg group and 31.5% in the 14-group.50 The most common adverse effects are alopecia, gastrointestinal symptoms, and elevation of liver enzymes.51,52 Discontinuation and initiation of an accelerated elimination procedure should be considered if patients develop liver injury or peripheral neuropathy. The accelerated elimination procedure consists of 11 days of treatment with cholestyramine 8 grams every 8 hours or activated charcoal 50 g every 12 hours.31 Dimethyl fumarate and its primary metabolite, monomethyl fumarate, inhibit proinflammatory cytokines
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and increase anti-inflammatory cytokines. Additionally, dimethyl fumarate exerts neuroprotective properties by activating the nuclear factor (erythroid-derived 2)-like 2 pathway. This pathway is thought to be the primary cellular defense against oxidative stress.49,52,53 In two large phase 3 trials, dimethyl fumarate reduced annualized relapse rates by 44% to 53%.54,55 During the first year of treatment with dimethyl fumarate, the mean lymphocyte count decreased by 30%. Six percent of patients experienced lymphopenia.33 GI symptoms and flushing seem to be the two most common adverse effects.49,52,53 Flushing and GI symptoms usually dissipate after the first month. Taking with food may also help. Mitoxantrone and natalizumab are efficacious, but should be reserved for patients with progression of symptoms, intolerant or nonresponsive to first-line therapies. Mitoxantrone carries a risk of cardiotoxicity at cumulative doses above 140 mg/m2, and long-term use has been associated with a 2% to 3% risk of developing acute myeloid leukemia. Natalizumab can cause progressive multifocal leukoencephalopathy.29,32 There is no consensus on the best agent for initial therapy, except for mitoxantrone. Mitoxantrone may be considered for patients with rapidly advancing disease who have failed other therapies.29 The beta-interferons and glatiramer acetate have been the foundation of initial treatment. The advantage of these agents is the considerable knowledge of their long-term safety and efficacy. Until long-term safety data become available for the oral agents, the first-line therapy may continue to be beta-interferons and glatiramer acetate. The oral agents will likely be used when the patient is nonresponsive to the injectable disease-modifying agents.56 Because of the risk of progressive, multifocal leukoencephalopathy, natalizumab will be primarily used in patients with more active disease or those who do not respond to beta-interferons or glatiramer acetate. This may change with the approval of the Stratify John Cunningham virus antibody ELISA test. The health care provider using this test and other clinical information from the patient can help determine the risk for developing PML in MS. The Food and Drug Administration (FDA) safety announcement emphasizes that patients who
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test negative for anti-John Cunningham virus antibodies are still at risk for the development of PML because of the potential for new John Cunningham virus infection or a false-negative test result.57 Further trials are needed before combination therapy is an option for patients with insufficient response to the injectable disease-modifying agent.56 There is increasing interest in an association between MS and vitamin D. Evidence suggests that vitamin D deficiency is recognized as a risk for MS. Other studies show an inverse correlation between serum vitamin D levels and MRI disease activity or relapse rate in MS patients.58-60 Randomized trials are needed to translate the effect of vitamin D into evidence-based guidelines. Given the current evidence of the potential benefit of vitamin D, it appears to be reasonable and safe to consider vitamin D supplementation at dosing adequate to achieve normal levels in patients with MS. Pharmacists have a critical role in facilitating optimal use of medications in multiple sclerosis. Among these are to: • Make treatment recommendations and monitor laboratory results, drug interactions, adverse reactions, and therapeutic responses • Ensure the patient is current with all vaccinations • Consider avoiding live vaccines because live-virus vaccines can precipitate an increase in disease activity61 • Ensure proper injection technique and daily rotation of injection sites • Confirm and make recommendations to ensure medications are administered correctly in regard to meals and in relation to other medications
Conclusion MS is a chronic neurologic, demyelinating disease that causes a great amount of disability in those patients diagnosed with the disease. It typically presents between 20 and 40 years of age and affects a greater number of women than men. However, 2% to 10% are diagnosed after 50 years of age. This diagnosis is termed LOMS. Although the exact etiology of MS is unknown, research suggests that MS is autoimmune in nature. The leading theory to support the autoimmunity of MS is that activated T-cells cross the blood-brain barrier, recognize antigens on the myelin sheaths of axons, and destroy the myelin, causing inflammation, which results in the formation of plaques. The diagnosis of MS is based on the presentation of clinical symptoms and the McDonald criteria. Management is individualized and focuses on suppression of the immune system, prevention of relapses, and symptomatic treatment to minimize the impact on quality of life. Currently, research is focused on finding effective new treatments that are able to modify the disease. There are several products in the pipeline. Alemtuzumab, an anti-CD52 monoclonal antibody, has been approved in Canada and by the European Medicines Agency. FDA declined approval in December 2013.
Daniel Sturm, MMS, PA-C, is assistant professor, Physician Assistant Program, College of Pharmacy and Health Sciences, Butler University, Indianapolis, Indiana. Samuel L. Gurevitz, PharmD, CGP, is assistant professor, Physician Assistant Program, College of Pharmacy and Health Sciences, Butler University. Amelia Turner, MS, PA-S, is physician assistant student, College of Pharmacy and Health Sciences, Butler University. For correspondence: Daniel Sturm, MMS, PA-C, College of Pharmacy and Health Sciences, Butler University, 4600 Sunset Avenue, Indianapolis, IN 46208; Phone: 317-940-8564; Fax: 317-940-6172; E-mail: [email protected]. Disclosures: No funding was received for this study or the development of the manuscript. The authors report no potential conflicts of interest. © 2014 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2014.469.
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