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CME ARTICLE Multiple sclerosis: A comprehensive review for the physician assistant

Browning, Victoria PA‐C; Joseph, Michelle PA‐C; Sedrak, Mona PhD, PA‐C

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Victoria Browning and Michelle Joseph are graduates of the Seton Hal University PA program in South Orange, New Jersey. Victoria Browning practices in urgent care at Cape Regional Urgent Care, Cape May Court House, New Jersey. Mona Sedrak is associate dean of the School of Health and Medical Sciences of Seton Hall University. The authors have indicated no relationships to disclose relating to the content of this article.

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Abstract

Successful management of MS requires treating the debilitating symptoms to maximize function and counseling to address the psychological impact of the disease.

Multiple sclerosis (MS) is a chronic demyelinating neurologic disorder that affects 2.5 million people worldwide, 400,000 of whom are in the United States.1 Most people with MS are 20 to 50 years old, with rare cases occurring after age 65 years.2 MS is slightly more than twice as likely to develop in women than in men.2 Studies have shown that persons living above 40° latitude have a higher risk of MS, with the greatest risk among Northern Europeans. Risk increases with greater distance from the equator, and MS is much less common in Asian, African, Native American, and Inuit populations.2,3 The median survival time is 30 years from onset of symptoms; life expectancy is 5 to 10 years shorter in MS patients than in those without the disease.2 Studies show that first‐degree relatives of MS patients are at a sevenfold risk of developing the disease compared with the general population.2 Substantial variability in MS manifestations leads to a high number of misdiagnoses each year, but advances in technology and pharmaceuticals are leading to more accurate diagnosis and effective treatment.

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PATHOPHYSIOLOGY

Multiple sclerosis is associated with a spectrum of demyelination that depends on disease duration and clinical categorization. The disorder is characterized by plaques composed of demyelination, neuronal and axonal degeneration, and astrocytic scars (sclerosis). The inflammatory plaques that are the histopathologic hallmark of MS are believed to originate from a breach in the integrity of the blood‐brain barrier. The etiology of MS remains unclear. Some studies suggest a viral etiology, while others implicate environmental factors or exposures acting in conjunction with a coexisting immunodeficiency.

At the core of the inflammatory process are leukocytes that have entered the CNS. Lymphocytes programmed to recognize myelin antigens are thought to trigger a cascade of events resulting in the formation of an acute inflammatory, demyelinating lesion.2 These lesions typically develop in white matter through targeting of the myelin sheath and the myelinating cell (the oligodendrocyte), but gray matter lesions, also resulting from the targeting of myelin, can occur.2 Relentless inflammation attributable to the leukocytes, as well as a myriad of other inflammatory mediators, leads to the eventual destruction of myelin and the gradual progression of neurocognitive decline. The progression of MS is the result of a combination of factors, including the accumulative loss of axons due to a continued complex of inflammation responses. Patients predisposed to neurodegeneration will experience continuing changes as the brain tissues progressively degenerate.2

Figure. Demyelinatio...
Figure. Demyelinatio...
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CLASSIFICATION

Relapsing remitting MS (RRMS) is present in 85% to 90% of patients at diagnosis. This subtype is characterized by relapses and remissions that can last months to years without development of new symptoms. Approximately 65% of these patients will progress to secondary progressive MS. New episodes occur erratically, but the rate seldom exceeds 1 to 5 episodes per year.2

Secondary progressive MS (SPMS) is arguably not a classification of its own but rather the second stage of RRMS. The median time span between diagnosis of RRMS and progression to SPMS is 19 years, with men often experiencing more rapid progression than women; the older the patient is at presentation, the faster the progression. Also, motor or long‐tract symptoms have been associated with earlier conversion.4 The disease course includes distinct exacerbations with no symptom‐free remissions; instead, patients will experience progressive neurocognitive decline.

Primary progressive MS (PPMS) is responsible for 10% to 15% of cases. Unlike patients with SPMS, who have a period of RRMS and recovery phases, those with PPMS steadily decline from diagnosis, with no remission.

Progressive relapsing MS (PRMS) is the least common subtype. Patients experience a constant decline that includes exacerbations without any symptom‐free remissions.

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KEY POINTS

* MS is characterized by plaques composed of demyelination, neuronal and axonal degeneration, and astrocytic scars (sclerosis) thought to result from a breach in the blood‐brain barrier.

* The most common symptoms are optic neuritis; fatigue; difficulties with gait and balance; spasticity; and Uthoff phenomenon.

* The McDonald Criteria sought to simplify the demonstration of dissemination in time and dissemination in space with fewer MRI evaluations, make it easier to distinguish MS from the commonly misdiagnosed neuromyelitis optica (NMO) and its spectrum disorders, improve the specificity and sensitivity of the original criteria, and make the diagnosis more uniform to allow for widespread use.

* Disease‐modifying agents‐that is, beta‐interferons and glatiramer acetate‐are the mainstay of MS treatment.

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CLINICAL PRESENTATION

A variety of other serious and potentially life‐threatening conditions must be ruled out in patients with possible MS. Depending on symptoms at presentation, a working differential diagnosis includes spinal cord neoplasm, vasculitis, acute disseminated encephalomyelitis, spinal cord infarction, arteriovenous fistula, sarcoidosis, small‐vessel ischemia, and transverse myelitis.

Signs and symptoms Patients with MS may experience a variety of symptoms (Table 1).5 The most common symptoms are diplopia, pain with eye movement, sudden vision loss, and blurry vision (commonly grouped together as optic neuritis); fatigue; difficulties with gait and balance; spasticity; and Uthoff phenomenon, a syndrome characterized by symptom exacerbation with exposure to increases in temperature.6,7

Table 1
Table 1
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Approximately 66% of patients present initially with symptoms of acute optic neuritis (AON), a condition characterized by loss of visual acuity, reduced perception of light, and poor color vision.6 Patients typically exhibit nystagmus, internuclear ophthalmoparesis, and slowed eye adduction. Symptoms may be exacerbated by exercise, stress, and heat7 and usually resolve within 4 to 12 weeks.8

Fatigue, the most common symptom of MS, affects 80% of patients.9 Those with progressive disease states and those experiencing difficulties with gait are the most affected by debilitating fatigue, which is a substantial source of morbidity even in nonambulatory patients.9 Nonpharmacologic approaches to management include analysis of sleep patterns and modification of daily activities to reduce exertion and minimize fatigue. Other causes of fatigue, such as depression, anemia, and hypothyroidism, should be ruled out or, if identified, managed appropriately. Pharmacologic measures may also be used for symptom relief. Modafinil, aminopyridines, and levocarnitine have shown promising results, along with glatiramer acetate and natalizumab in reducing fatigue.5 Neurologic referral is in order for all patients suspected of having MS, especially those with new or worsening symptoms or limitations in activity or mobility.

Eighty percent of patients with MS also experience ataxia and tremor.5 Patients may have difficulties in gait, balance, and coordination. These symptoms are often treated with propranolol, clonazepam, levetiracetam, and isonizaid.5 Patients with localized tremor and minimum disability may be candidates for surgical therapy, including stereotactic thalamotomy and deep brain stimulation.5 Those experiencing impaired ambulation have shown improvement with fampridine.5 Treatment decisions may require consultation with a neurosurgical team.

Spasticity is seen in 60% of MS patients. A disorder of increased muscle resistance to an externally imposed stretch across a musculotendinous unit,5 spasticity can be debilitating and may lead to pain, spasms, reduced mobility, limited range of motion, and contractures. Spasticity may also mask underlying weakness and ataxia. Patients should be questioned about the extent to which spasticity is affecting their daily function, aggravating and alleviating factors, and pain. Management should focus on physiotherapy if available. However, many refractory or severe cases often require pharmacologic intervention. Oral baclofen is commonly used as a first‐line agent, followed by tizanidine.5 The rule of “start low and go slow” applies here. Clonazepam can also be used, either alone or in conjunction with these medications. Second‐line treatments are gabapentin and dantrolene.5 Cannabinoids are being studied as a treatment option for spasticity.5 Patients with refractory spasticity may be candidates for intrathecal baclofen or phenol.5 At times, botulinum toxin type A is recommended to induce muscle relaxation and to prevent contractures in distal muscles and selected proximal muscles.5 If severe pain persists, addition of morphine may be considered but only in patients with refractory spasticity.

First described in 1890 as blurred vision caused by increased body temperature, Uthoff phenomenon is present in 60% to 80% of MS patients.1 Patients with MS often report that high temperatures worsen their symptoms, especially fatigue,7 as well as decreased concentration, weakness, urinary urgency, electriclike sensations radiating down the back and limbs when bending the neck (Lhermitte sign), and pain.7

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DIAGNOSTIC APPROACH

McDonald Criteria First developed in 2001 by the International Panel on MS,10 the McDonald Criteria were most recently revised in 2010.11 The criteria comprise five distinct possible presentations, as well as the additional information needed to illustrate the hallmark characteristic of MS, dissemination in time (DIT) and/or dissemination in space (DIS):11

* Two or more attacks (events typical of an acute demyelinating event in the CNS lasting at least 24 hours) with objective clinical evidence of two or more lesions or objective clinical evidence of one lesion with reasonable historical evidence of a prior attack

* Two or more attacks with objective clinical evidence of one lesion plus

- Evidence of DIS

- One or more T2‐weighted lesions in at least two regions of the CNS typically affected by MS or

- Await another clinical attack implicating a different site

* One attack with objective clinical evidence of two or more lesions plus

- Evidence of DIT

- Simultaneous presence of asymptomatic gadolinium (Gd)‐enhancing and nonenhancing lesion at any time or

- New T2‐weighted and/or Gd‐enhancing lesion(s) on follow‐up MRI, irrespective of its timing with reference to a baseline scan or

- Await a second clinical attack

* One attack with objective clinical evidence of one lesion (clinically isolated syndrome) plus

- Evidence of DIS and DIT as previously described

* Insidious neurologic progression suggestive of PPMS

- One year of disease progression plus two of the following:

- Evidence of DIS in the brain based on one or more T2‐weighted lesion(s) in MS‐characteristic regions

- Evidence of DIS in the spinal cord based on two or more T2‐weighted lesions in the cord

- Positive CSF findings (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index).

The goal of the McDonald Criteria is to enable early diagnosis and prompt treatment. The criteria also simplify the demonstration of DIT and DIS with fewer MRI evaluations. In addition, the panel aimed to make MS easier to distinguish from the commonly misdiagnosed differential of neuromyelitis optica (NMO) and its spectrum disorders. The new criteria also improve the specificity and sensitivity of the original criteria and make the diagnosis more uniform to allow for widespread use.10

Neuroimaging MRI has emerged as the single most useful imaging tool in the diagnosis of MS.12 According to the Consortium of Multiple Sclerosis Centers, the current imaging protocol includes axial proton density/T2‐weighted, axial fluid‐attenuated inversion recovery (FLAIR), sagittal FLAIR, and axial precontrast and postcontrast T1‐weighted sequences.13 T2‐weighted sequences have a high detection rate for lesions in the infratentorial region, while FLAIR sequences have a high sensitivity for lesions in the juxtacortical and periventricular white matter.14 Gadolinium‐enhancing lesions can be found in approximately 60% of patients in the early stages of MS but usually decrease during the prolonged progressive phases.15 Gd‐enhancing lesions, which represent a breach in the blood‐brain barrier, indicate a new active lesion and usually disappear within 2 months. Note that new enhancing lesions are often seen before a clinical relapse.15 In 95% of patients, MRI will illustrate focal or confluent abnormalities in the white matter.2

Multiple characteristic lesions of MS can be identified by shape and location on MRI (Figures 1–5), although these lesions are not always specific to MS. The characteristic lesions of MS found in the deep white matter are ovoid or have a perpendicular trajectory, called Dawson fingers, along the long axis of the ventricles. Spinal cord lesions are usually ovoid or cigar‐shaped, with the majority located in the dorsal column. These lesions are found more commonly in the cervical than thoracic spine (Figure 6). New imaging techniques, such as direct inversion recovery (DIR), magnetization‐prepared rapid gradient‐echo (MPRAGE), and high Tesla field imaging, have discovered that lesions once believed to occur exclusively in white matter are found in gray matter as well.1

Figure 1
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Figure 5
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Figure 6
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Serial MRIs are performed in order to document the extent of the disease, mark the progression, and determine response to treatment. These techniques monitor ongoing inflammation, degeneration, and CNS atrophy.15

CSF evaluation Findings on CSF analysis have long been the standard for supporting the diagnosis of MS.2 Oligoclonal bands, which are seen in approximately 90% of MS patients2 after protein electrophoresis, have proved to be the most sensitive laboratory test in the diagnosis of MS.12 However, this technique does not reflect disease activity or any treatment the patient has received.12

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TREATMENT

Goals of treatment include treating acute exacerbations, preventing progression, and reducing the number of relapses. Patients may require evaluation and treatment by physical therapists, occupational therapists, nutritionists, and counselors throughout the course of their disease. Helping patients and their families identify and become involved in local support groups is essential to avoiding feelings of isolation.

An important aspect of MS is the psychological impact it has on patients and everyone involved in their care. Many patients will require counseling on how the diagnosis will impact their quality of life (QOL). Special attention should be paid to relatively younger patients who find themselves afflicted with an incurable, progressive disease. Open communication is key when dealing with patients and family members. Primary care providers should take the lead in educating the patient about MS, its symptoms, and what can be done to achieve and maintain a good QOL. Family members should be encouraged to attend appointments, ask questions, and become an integral part of the patient's treatment. Emphasize to family members the importance of staying well‐rested and maintaining participation in outside activities in order to reduce stress. Be prepared to offer referrals to counseling services as the disease progresses.1

Disease‐modifying agents The mainstay of treatment of multiple sclerosis comprises the disease‐modifying beta‐interferons and glatiramer acetate (Table 2).1 Medications are not curative but can delay disease progression and severity; maintain or improve QOL; and lessen CNS atrophy.16 Beta‐interferons reduce clinical exacerbations by up to 30% and decrease the occurrence of new MRI enhancing lesions by 70% to 90%.1 Glatiramer acetate reduces the number and severity of exacerbations and the occurrence of new MRI enhancing lesions.1

Table 2
Table 2
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Other FDA‐approved drugs for MS include mitoxantrone, natalizumab, methotrexate, dalfampridine, and fingolimod.1 Mitoxantrone is a powerful anti‐inflammatory medication, but because it has dangerous side effects (increased incidence of leukemia and cardiotoxicity), it is used only in extreme cases to induce remission and then it is discontinued. Along with natalizumab, mitoxantrone is considered second‐line treatment for worsening RRMS.16 Natalizumab blocks the transmigration of inflammatory cells into the brain and spinal cord. It reduces exacerbations by 70% and can slow disease progression by 50%.1 Mitoxantrone is used when patients fail to respond to disease‐modifying drugs, have difficulty tolerating IM injections, or have extremely active disease. Associated side effects include life‐threatening immunosuppression and risk of developing progressive multifocal leukoencephalopathy.

Methotrexate is postulated to reduce the number of relapses of RRMS and slow neurologic deterioration.16 It is less effective than beta‐interferon and may be used as an adjunct therapy in the treatment of RRMS. Dalfampridine, a potassium channel blocker that improves conduction through demyelinated fibers, is a newly approved drug that is indicated for the symptomatic treatment of gait disturbance in MS patients. It is currently the only drug marketed with this indication but has yet to be proven cost‐effective.17 Fingolimod, also recently approved by the FDA, is the first oral agent for MS. It acts by promoting redistribution of lymphocytes back into the circulation, thereby reducing immunomodulated axonal attack.1

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CONCLUSION

The degree of disability and overall course of MS varies from patient to patient. There are no reliable predictors, but favorable prognostic indicators include good functional recovery from neurologic attacks, sensory symptoms predominating over motor/cerebellar symptoms, and infrequent exacerbation in the first year.12 Early diagnosis and treatment is important in reducing the severity of relapses and progression.1 Available pharmacologic and nonpharmacologic treatment options not only treat the symptoms of MS but also impact the course of the disease.

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REFERENCES

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1. Frohman TC, O'Donoghue DL, Northrop D. A Practical Primer: Multiple Sclerosis for the Physician Assistant. Dallas, TX: Southwestern Medical Center; 2011.

2. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359(313);1221-1231.

3. Rosati G. The prevalence of multiple sclerosis in the world; an update. Neurol Sci. 2001;22(2):117-139.

4. Koch M, Kingwell E, Rieckmann P, et al. The natural history of secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2010;81(9):1039-1043.

5. Thompson AJ, Toosy AT, Ciccarelli O. Pharmacological management of symptoms in multiple sclerosis: current approaches and future directions. Lancet Neurology. 2010;9(12):1182-1199.

6. National Multiple Sclerosis Society. About MS: Who gets MS? http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-gets-ms/index.aspx. Accessed July 1, 2012.

7. Flensner G, Ek AC, Söderhamn O, Landtblom AM. Sensitivity to heat in MS patients: a factor strongly influencing symptomatology-an explorative survey. BMC Neurol. 2011;11:27.

8. Matti AI, Keane MC, McCarl H, et al. Patients' knowledge and perception on optic neuritis management before and after an information session. BMC Ophthalmol. 2010;10:7.

9. Mills RJ, Young CA, Pallant JF, Tennant A. Development of a patient reported outcome scale for fatigue in multiple sclerosis: The Neurological Fatigue Index (NFI-MS). Health Qual Life Outcomes. 2010;8:22.

10. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50(1):121-127.

11. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.

12. Arya, A. Multiple sclerosis: a review. Int J Pharm Sci Res. 2010;1(2):13-23.

13. Borazanci AP, Harris MK, Schwendimann RN, et al. Multiple sclerosis: clinical features, pathophysiology, neuroimaging, and future therapies. Future Neurol. 2009;4(2):229-246.

14. Wattjes MP, Barkhof F. High field MRI in the diagnosis of multiple sclerosis: high field-high yield? Neuroradiology. 2009;51(5):279-292.

15. Tomassini V, Palace J. Multiple sclerosis lesions: insights from imaging techniques. Expert Rev Neurother. 2009;9(9):1341-1359.

16. Ashtari F, Savoj MR. Effects of low dose methotrexate on relapsing-remitting multiple sclerosis in comparison to Interferon Ð-1Ð: A randomized controlled trial. J Res Med Sci. 2011;16(4):457-462.

17. Tam S, Lopez A, Shek A, Yeh J. Multiple sclerosis: a paradigm change with oral agents? Formulary. 2011;46(6):228-232, 237-240.

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Section Description

EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 46 and successfully completing the posttest on page 51. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of August 2012.

LEARNING OBJECTIVES

* Discuss the incidence, prevalence, and pathogenesis of multiple sclerosis (MS)

* Recognize the common signs and symptoms of MS

* Apply the McDonald Criteria for diagnosing MS

* Discuss pharmacologic and nonpharmacologic treatment options for MS

© 2012 Lippincott Williams & Wilkins, Inc.

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