In the clinic. Multiple sclerosis.

Multiple Sclerosis

Physician Writer Daniel M. Harrison, MD Section Editors Deborah Cotton, MD, MPH Jaya K. Rao, MD, MHS Darren Taichman, MD, PhD Sankey Williams, MD

Diagnosis

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Treatment

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Tool Kit

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Patient Information

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CME Questions

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The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including ACP Smart Medicine and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP’s Medical Education and Publishing divisions and with the assistance of science writers and physician writers. Editorial consultants from ACP Smart Medicine and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://smartmedicine.acponline.org, http://www.acponline.org/products_services/ mksap/15/?pr31, and other resources referenced in each issue of In the Clinic. CME Objective: To review current evidence for diagnosis and treatment of multiple sclerosis. The information contained herein should never be used as a substitute for clinical judgment. © 2014 American College of Physicians

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In the Clinic

ultiple sclerosis (MS) is an autoimmune condition that results in inflammatory damage to the central nervous system (CNS). The pathologic hallmarks of MS are diffuse and focal areas of inflammation, demyelination, gliosis, and neuronal injury in the optic nerves, brain, and spinal cord. In addition to affecting white matter tracts, MS results in injury to the cortical and deep gray matter. The neurologic symptoms and disability that patients with MS experience are a direct consequence of these pathologic processes, resulting in acute and chronic disruption of white matter tracts and gray matter structures.

M

MS is the most common nontraumatic cause of neurologic disability in persons younger than 40 years, with an estimated prevalence of 400 000 in the United States (1). It occurs in a female–male ratio of 3 to 1 (1). The cause of MS is multifactorial and is probably the cumulative result of multiple genetic and environmental risk factors. Twin studies have shown concordance rates between 20% and 30% in monozygotic twins and between 2% and 3% in dizygotic twins (2). Genome-wide assays have identified risk alleles in genes for major histocompatibility complex, interleukin-2 receptor, and interleukin-7 receptor, among others (3, 4). Geographic location of residence before adolescence is also predictive of MS risk, with increased rates of the disease in northern and southern latitudes compared with equatorial countries. Reduced sunlight exposure in these regions may explain some of this distribution. Because ultraviolet radiation to the skin is the major source of vitamin D synthesis, living in regions with low levels of seasonal sunlight is associated with an increased risk for MS in individuals with vitamin D deficiency (5). Risk may also be influenced by exposure or lack of exposure to particular infectious agents because antibodies against certain viruses (such as Epstein–Barr virus) are more frequently seen in patients with MS than in those without it (6).

Diagnosis 1. Niedziela N, AdamczykSowa M, Pierzchala K. Epidemiology and clinical record of multiple sclerosis in selected countries: a systematic review. Int J Neurosci. 2013. [Epub ahead of print] [PMID: 23998938] 2. Islam T, Gauderman WJ, Cozen W, Hamilton AS, Burnett ME, Mack TM. Differential twin concordance for multiple sclerosis by latitude of birthplace. Ann Neurol. 2006;60:56-64. [PMID: 16685699] 3. Patsopoulos NA, Barcellos LF, Hintzen RQ, Schaefer C, van Duijn CM, Noble JA, et al; IMSGC. Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet. 2013;9:e1003926. [PMID: 24278027]

© 2014 American College of Physicians

What characteristic symptoms or physical findings should alert clinicians to the diagnosis of MS? MS symptoms typically occur as a consequence of focal inflammatory plaques that cause functional areas of neuronal loss or interruption of critical axonal tracts. In most patients, focal lesions occur intermittently and acutely, leading to a “relapse” or “flare” in which symptoms evolve over the course of days and may last for weeks or months before improving. Because MS can affect nearly any part of the CNS, clinical presentations vary widely. The most common clinical manifestations of a relapse are optic neuritis, myelitis, and brainstem or cerebellar symptoms. Optic neuritis, or inflammation of the optic nerve, often presents

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with subacute visual changes varying from central or centrocecal scotoma to blindness in 1 or both eyes along with pain with eye movement. Ocular examination usually reveals a reduction in visual acuity, a visual field deficit, and a decreased ability to differentiate colors. Examination of the pupil in patients with unilateral optic neuritis reveals an afferent pupillary defect in which there is paradoxical dilation of the pupil when light is rapidly shifted from the unaffected eye to the affected one. If the anterior portion of the optic nerve is involved, funduscopic examination may also reveal papillitis (inflammatory changes of the optic disc). Myelitis, or focal inflammation within the spinal cord, usually manifests as sensory or motor symptoms below

Annals of Internal Medicine

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the affected spinal level. Some patients may also have a tight, bandlike sensation around the chest or abdomen during the acute inflammatory process; Lhermitte sign (shock-like sensations radiating down the spine or limbs induced by neck movements); and urinary frequency, urgency, or retention. Unlike other spinal cord processes, MS tends to cause a partial myelitis, so symptoms similar to a full-cord transection are exceedingly rare. Examination will often reveal focal muscle weakness and reduced sensation below the affected spinal level. Muscle tone can be flaccid in the acute setting, but spasticity develops over time in patients who do not recover completely from the attack. Disruption of vestibular or cerebellar pathways can lead to ataxia and vertigo. Appendicular or truncal ataxia can be seen on examination, with dysmetria on finger-to-nose testing and tandem gait dysfunction. Brainstem involvement can cause eye movement abnormalities, causing symptoms of diplopia or oscillopsia (a sensation of jerking of the visual field). Disconjugate eye movements, nystagmus, or an internuclear ophthalmoplegia (inability to adduct one eye and nystagmus in the abducting eye) can be seen on oculomotor examination. In addition to the development of acute or subacute focal symptoms, patients with MS may have chronic symptoms due to widespread cortical demyelination and global brain atrophy. Common manifestations include cognitive dysfunction and mental and physical fatigue. Many patients with MS also have Uhthoff phenomenon, which is transient worsening of baseline neurologic symptoms in the setting of elevations in body temperature. Electrical messages travel more slowly in the context of increased temperature, a biological property that becomes clinically

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evident in patients with prior demyelination-related injury to key neural pathways. Uhthoff phenomenon events (sometimes termed “pseudorelapses”) are differentiated from relapses in that they do not represent new inflammatory events, do not require direct treatment, and typically are alleviated in cooler temperatures or after resolution of fever. What are the historical characteristics associated with each subtype of MS? The time course of the onset of symptoms and their evolution is critical to determining the clinical subtype of patients with MS. Identifying and categorizing MS by clinical subtype has important treatment implications because most treatments are specifically geared toward the relapsing– remitting form of MS (RRMS). Approximately 85% of patients with MS initially have RRMS, in which neurologic symptoms come in the form of repeated episodes of relapse followed by recovery. Patients who do not meet the full diagnostic criteria for MS at the time of a first relapsing event can be said to have had a clinically isolated syndrome (CIS). Because MS disease-modifying therapies (DMTs) can increase the time from first clinical relapse to a second attack, it is important to correctly identify patients who either meet the 2010 McDonald criteria at the time of the first attack (and thus can be diagnosed with MS) or have a high likelihood of having the diagnosis confirmed at a later date. Patients with brain lesions on magnetic resonance imaging (MRI) scans at the time of CIS have a 10-year risk of approximately 90% for meeting criteria for MS diagnosis on the basis of clinical or MRI evidence. Patients who have an acute demyelinating attack (such as optic neuritis or transverse myelitis) without brain

4. Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, Cotsapas C, et al; International Multiple Sclerosis Genetics Consortium (IMSGC). Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 2013;45:135360. [PMID: 24076602] 5. van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Simmons R, Taylor BV, et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ. 2003;327:316. [PMID: 12907484] 6. Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM; NeuroproMiSe EBV Working Group. Epstein-Barr virus in the multiple sclerosis brain: a controversial issue— report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain. 2011;134:2772-86. [PMID: 21846731]

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lesions have a risk of approximately 10% to 20% (7). Symptoms of an MS relapse tend to peak after a few days or weeks. A period of recovery follows that may last weeks or months. In the first few years, many patients experience significant recovery of previous functioning. However, as time passes, recovery diminishes and permanent disability can occur. In approximately 50% to 60% of patients with RRMS, relapses become infrequent or cease completely after a median of 10 to 15 years but neurologic deficits continue to accrue in a slowly progressive manner (8). This latter stage of MS is termed secondary progressive MS (SPMS).

7. O’Riordan JI, Thompson AJ, Kingsley DP, MacManus DG, Kendall BE, Rudge P, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up. Brain. 1998;121 (Pt 3):495-503. [PMID: 9549525] 8. Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112 (Pt 1):133-46. [PMID: 2917275] 9. Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers GC. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006;129:584-94. [PMID: 16401620] 10. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302. [PMID: 21387374]


Approximately 15% of patients with MS will never have a relapse but will have progressive disability accumulation from the time of disease onset. This clinical phenotype is termed primary progressive MS (PPMS). This subtype often presents later in life, with the first symptoms typically occurring in the fifth or sixth decade. Disability accumulation can occur rapidly. Early studies of the natural history of this disease type implicated sex and age at onset as predictors of rapid progression, but recent studies have only supported early disability accrual as a predictor of long-term progression rates (9). In addition to the classic MS subtypes, the recent increased availability of MRI has led to the occasional use of the term “radiologically isolated syndrome” to describe patients incidentally found to have changes on MRI scans that meet the diagnostic criteria for MS but who have no history or active symptoms suggestive of MS. Radiologically isolated syndrome is a controversial entity, and the long-term prognosis and recommendations for or against treatment are still being studied.

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What are the McDonald criteria, and how can they help clinicians diagnose MS? Given the lack of MS-specific diagnostic biomarkers, confirming the diagnosis of the condition requires a full assessment of clinical symptoms, ancillary testing, and ruling out other conditions in the differential diagnosis. The McDonald criteria are the official diagnostic criteria for MS, providing guidance on the proper integration of clinical and diagnostic evidence (10). For a diagnosis of RRMS, the McDonald criteria require clinical evidence of CNS demyelination disseminated in space and time, which may be obtained through documentation of present and previous relapses and of present and previous neurologic examination findings. MRI findings also can satisfy criteria for dissemination in time and space if clinical evidence does not suffice. In cases in which the clinical evidence is strong, less radiologic confirmation is necessary according to these criteria. In cases of early disease, in which the clinical evidence is sparse, greater radiologic confirmation is required. The McDonald criteria can also be used to make a diagnosis of PPMS. The PPMS criteria require at least 1 year of neurologic disability progression plus at least 2 of the following: evidence of dissemination in space on brain MRI scan, evidence of dissemination in space on spinal cord MRI scan, or cerebrospinal fluid (CSF) findings consistent with MS. Proper application of the McDonald criteria can also help differentiate MS from other conditions and can prevent unnecessary neurologic testing and referrals. This is especially true with various common conditions, such as migraine, microvascular ischemic disease, and head trauma, that can also cause white matter lesions on MRI scans but do not cause lesions that meet the McDonald criteria for location.


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What is the role of MRI in diagnosis? MRI is the primary diagnostic and prognostic tool in evaluation of patients with MS. The McDonald criteria require confirmation of the condition based on MRI findings for most cases. MS typically manifests on MRI scans with findings of lesions within white matter regions, which appear hyperintense on T2weighted images and hypointense on T1-weighted images. These lesions represent areas of demyelination and gliosis. In addition, lesions that are undergoing an active inflammatory process with breakdown of the blood–brain barrier will show enhancement with administration of gadolinium contrast. The Figure shows examples of each of the lesion locations emphasized by the McDonald criteria (10): periventricular, juxtacortical, infratentorial (brainstem and cerebellum), and spinal cord. A minimum of 2 lesions in 2 or more locations is necessary for evidence of dissemination in space. The presence of both an asymptomatic contrast-enhancing lesion and an asymptomatic nonenhancing T2bright lesion at baseline or the development of a new white matter lesion or new contrast enhancement on a

follow-up scan can satisfy requirements for dissemination in time. Although diagnostic criteria focus specifically on the presence of lesions in white matter, other MRI changes can be seen, including demyelinating lesions in the cortex, cortical and deep gray matter atrophy, white matter structure atrophy, and alterations in quantitative MRI measures (such as magnetization transfer imaging and diffusion tensor imaging) in lesions and normalappearing white matter (11). What role does lumbar puncture play in diagnosis? The McDonald criteria do not require confirmation of MS by CSF testing for RRMS. For the diagnosis of PPMS, spinal fluid testing is only necessary if MRI features do not meet criteria for dissemination in space. However, CSF testing can be a useful diagnostic tool in cases where the diagnosis is not clear. The presence of unique oligoclonal bands in the spinal fluid by isoelectric focusing is found in 90% to 95% of patients with MS (12). An elevation of the IgG index is also seen in 50% to 75% of cases, and mild pleocytosis is seen in about half of patients with

Figure. Examples of lesion locations emphasized by the McDonald criteria. The left image shows a sagittal, fluid-attenuated, inversion recovery brain sequence showing periventricular (top arrow), juxtacortical (right-hand arrow), and infratentorial (bottom arrow) lesions. The center image is a sagittal T1 image after administration of intravenous contrast. Lesions are typically either silent or dark on T1 imaging, but lesions that enhance with contrast (arrow) do so because of active inflammation in the lesion. The image on the right is a sagittal T2 scan of the cervical spine showing a lesion at approximately the C2 level (arrow).

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MS. Given the known sensitivity of these tests, a negative CSF result alone cannot be used to rule out the diagnosis of MS, but in cases in which clinical and radiologic suspicion is low, a normal CSF result helps reassure patients that they probably do not have MS and should prompt clinicians to explore other diagnoses.

11. Rocca MA, Messina R, Filippi M. Multiple sclerosis imaging: recent advances. J Neurol. 2013;260:929-35. [PMID: 23263475] 12. Stangel M, Fredrikson S, Meinl E, Petzold A, Stüve O, Tumani H. The utility of cerebrospinal fluid analysis in patients with multiple sclerosis. Nat Rev Neurol. 2013;9:26776. [PMID: 23528543] 13. Gronseth GS, Ashman EJ. Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;54:1720-5. [PMID: 10802774] 14. Parisi V, Manni G, Spadaro M, Colacino G, Restuccia R, Marchi S, et al. Correlation between morphological and functional retinal impairment in multiple sclerosis patients. Invest Ophthalmol Vis Sci. 1999;40:2520-7. [PMID: 10509645] 15. Garcia-Martin E, Pablo LE, Herrero R, Satue M, Polo V, Larrosa JM, et al. Diagnostic ability of a linear discriminant function for spectraldomain optical coherence tomography in patients with multiple sclerosis. Ophthalmology. 2012;119:1705-11. [PMID: 22480742]


When should clinicians consider obtaining evoked potentials? In cases where the clinical examination and MRI are unable to provide evidence of dissemination in space, obtaining evoked potentials can be useful in finding evidence of subclinical demyelinating lesions. Evoked potential tests are electrophysiologic measurements of the time it takes for nerves to respond to stimulation. Reduced evoked potential conduction velocity on visual-evoked potentials detects prior demyelination, even in patients who do not recall an episode of optic neuritis (13). Brainstem auditory–evoked potentials can provide evidence of a lesion along the acoustic and brainstem pathways. Somatosensory evoked potentials can provide evidence of lesions in spinal sensory pathways. Results of brainstem and spinal cord potentials are less likely to be abnormal than visual-evoked potentials in patients with MS, and care should be taken in interpreting the results (13).

neuromyelitis optica, and can occur in patients with compressive lesions of the optic nerve. Thus, it is not a specific test for MS but is useful in further documenting dissemination of MS disease activity in space in patients presenting with a first attack of nonoptic neuritis. In a study that compared OCT between 69 healthy volunteers and 69 patients with MS, RNFL measurements with a modern, fourth-generation spectral domain OCT scanner were shown to have a strong diagnostic discriminant function. OCT in this validation set had a sensitivity of 83% and specificity of 69% for differentiation of patients with MS from healthy control participants (15).

What are the differential diagnoses? Whenever the diagnosis of MS is being considered, conditions that mimic MS should be part of the differential diagnosis. The various rheumatologic, inflammatory, infectious, and metabolic disorders that can cause neurologic symptoms and changes on MRI scans that are sometimes incorrectly diagnosed as MS are listed in Table 1. A comprehensive review of the patient’s medical history, review of systems, and physical examination can be helpful in increasing or decreasing suspicion for any such condition. Knowledge of the other potential diagnoses in the differential and how to distinguish these from MS can help reduce misdiagnoses and inappropriate referrals.

When should clinicians consider obtaining optical coherence tomography? Optical coherence tomography (OCT) uses near-infrared light to measure the thickness of nerve fiber layers in the retina. The retinal nerve fiber layer (RNFL) is reduced after optic neuritis (14), and reductions in RNFL also can be seen in the eyes of patients with MS who have not had optic neuritis (15). It is important to note, however, that RNFL thinning is also a consequence of isolated optic neuritis, is seen in patients with

When should clinicians consider consulting with a neurologist or other specialist for diagnosis? Given the complexity of MS diagnosis, patients presenting with symptoms of a demyelinating disorder should have MRI. If findings suggest possible MS, a neurologist should evaluate the patient to confirm the diagnosis or facilitate further testing. For cases in which the diagnosis is unclear or in whom treatment has failed, second opinions can be obtained from MS specialty clinics.

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Differential Diagnosis of Multiple Sclerosis Disorder

Notes

Other demyelinating diseases ADEM Neuromyelitis optica (Devic disease)

Idiopathic transverse myelitis Systemic inflammatory disease SLE The Sjögren syndrome Sarcoidosis The Behçet syndrome Metabolic disorders Adult-onset leukodystrophy

Vitamin B12 deficiency Copper deficiency Zinc toxicity Vitamin E deficiency Infections HIV, Lyme disease, syphilis HTLV Vascular disorders Sporadic and genetic stroke syndromes (hypercoagulability disorders) CNS vasculitis The Susac syndrome Dural arteriovenous fistula Migraine

Neoplasia (i.e., primary CNS neoplasm (glioma or lymphoma) or metastatic disease) Paraneoplastic syndromes

Somatoform disorders

Monophasic, often postinfectious syndrome causing large, diffuse areas of inflammatory CNS demyelination, fever, and encephalopathy. More common in children, rare in adults. Antibody-mediated inflammation directed at aquaporin-4 channels in the CNS, resulting in inflammatory demyelination in the optic nerves and spinal cord. Can be differentiated from MS by NMO IgG antibody testing; lack of significant brain involvement; large, longitudinally extensive spinal cord lesions; and profound cerebrospinal fluid leukocytosis. Monophasic, often postinfectious syndrome causing spinal cord inflammation. Differentiated from MS by the presence of symptoms and findings unique to the underlying systemic disorder in addition to neurologic symptoms. Can present with white matter changes on MRI and encephalopathy. Can cause an NMO-like disorder with optic neuritis and myelitis. Also can cause multiple cranial neuropathies and small fiber neuropathy. Results in granulomatous inflammation in the parenchyma and meninges of the brain and spinal cord. Can cause brainstem abnormalities and encephalopathy and occasionally is associated with myelopathy. Rare, adult-onset forms of leukodystrophy, such as adrenoleukodystrophy or metachromatic leukodystrophy, may cause white matter changes and progressive neurologic symptoms. Family history typically present. Can cause optic neuropathy, cognitive changes, and subacute combined degeneration of the spinal cord (spasticity, weakness, and vibratory and proprioceptive sensory loss). Can cause myelopathy identical to B12 deficiency. Can cause an acquired copper deficiency. Can cause cerebellar ataxia. Can cause encephalopathy and myelopathy; can be diagnosed with appropriate serology and spinal fluid analysis. Causes slowly progressive myelopathy with thoracic cord atrophy. Sometimes termed “tropical spastic paraparesis” because it is more common in patients in equatorial latitudes. Microvascular ischemic disease can cause nonspecific white matter changes on MRI; age, other vascular risk factors, and findings on neurologic examination should help to distinguish it from MS. Can be diagnosed by catheter angiography or tissue biopsy. Can present with both stroke-like changes on MRI and meningeal contrast enhancement. Causes small-vessel arteriopathy, which causes dysfunction of the retina and cochlea and corpus callosum lesions on MRI. Can cause spinal cord infarction or vascular congestion with cord lesions that can be confused with MS lesions. Has a subacute clinical progression without remission or relapse. Subcortical white matter lesions can occur in patients with migraine and are often confused with MS lesions. CADASIL should be considered a possible diagnosis in patients with a familial syndrome of migraine, subcortical strokes, mood disorders, and early dementia. Has progressively worsening symptoms and neuroimaging findings. When imaging cannot differentiate neoplasms from demyelinating disease, brain biopsy is indicated. May cause progressive cerebellar ataxia or myeloneuropathy (neuropathy affecting the spinal cord and peripheral nerves). Paraneoplastic limbic encephalitis can cause personality and mental status changes in addition to seizures and movement disorders. Metastatic evaluation and antibody testing may lead to diagnosis. Psychiatric disorders can sometimes present with neurologic-like symptoms that are due to somatization, conversion, and similar conditions. Neurologic workup is normal.

ADEM = acute disseminated encephalomyelitis; CNS = central nervous system; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy; HTLV = human T-lymphotropic virus; MRI = magnetic resonance imaging; MS = multiple sclerosis; NMO = neuromyelitis optica; SLE = systemic lupus erythematosus.

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Diagnosis... MS is an autoimmune disease that can result in neurologic disability. Patients with RRMS have relapsing symptoms, whereas those with PPMS and SPMS experience progressive disability accumulation. The diagnosis of MS is made by application of the revised 2010 McDonald criteria, which use a combination of clinical history, physical examination findings, and radiologic findings to show dissemination in disease activity over space and time. Additional testing, such as lumbar puncture, evoked potentials, and OCT, is not required by diagnostic criteria but can be helpful in evaluating for this diagnosis and in separating it from other disorders in the differential diagnosis.

CLINICAL BOTTOM LINE

Treatment 16. Langer-Gould AM, Anderson WE, Armstrong MJ, Cohen AB, Eccher MA, Iverson DJ, et al. The American Academy of Neurology’s top five choosing wisely recommendations. Neurology. 2013;81:1004-11. [PMID: 23430685] 17. Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, et al; BENEFIT Study Group. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8:987-97. [PMID: 19748319] 18. Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A, et al; PreCISe study group. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, doubleblind, placebocontrolled trial. Lancet. 2009;374:1503-11. [PMID: 19815268] 19. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating-remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients. Multiple Sclerosis Collaborative Research Group (MSCRG). Mult Scler. 1995;1:118-35. [PMID: 9345462]

What is the overall approach to treatment of patients with MS? The care of patients with MS requires a multidisciplinary approach and a comprehensive strategy for relapse management, prevention of relapses, medication and nonmedical approaches to management of fatigue, and assessment of cognitive functioning. It should also include consideration of means to assist patients in maximizing daily function. An increasing number of medications can reduce relapse rate, and some may delay disease progression. Symptomatic management of acute relapses and treatments for fatigue, spasticity, and bladder dysfunction are also available. Use of all of these tools has led to significant improvements in the quality of life of patients with MS. Although it is hoped that reduction in inflammatory disease activity early in RRMS will reduce risk for secondary disease progression, alleviation of tissue injury through enhanced repair and prevention of neurodegeneration are key priorities for ongoing research.


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What role does clinical subtype play in guiding treatment decisions? As discussed in the Diagnosis section, assigning a clinical subtype for MS is a critical first step before initiation of any drug therapy. The U.S. Food and Drug Administration (FDA) has approved many medications for CIS and RRMS,

In the Clinic


but treatment options for SPMS and PPMS are limited. Because of the lack of data supporting the use of immunotherapy in patients with progressive disease and because of a poor cost–benefit ratio for these patients, recent clinical guidelines recommend against using immunomodulatory drugs in patients with progressive MS (16). Initiation of immunotherapy is indicated for most patients with RRMS. All of the immunomodulatory drugs approved by the FDA for use in MS have a designation for treatment of RRMS. Initiation of such therapies at the time of a first MS attack is approved for glatiramer acetate and interferon-β products in patients who do not yet meet the 2010 McDonald criteria for MS diagnosis at the inciting event but who are considered highly likely to have future confirmation. Data from formal trials are lacking on the use of newer therapies, but such evidence will probably emerge as the newer therapies are studied at this early time point in MS. What medications are typically used? What are their benefits, potential harms, and costs? First-line DMTs include immunomodulatory and immunosuppressive medications that have been shown to reduce the risk for relapse and new lesion formation on MRI scans. The first-line therapies of interferon-β


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and glatiramer acetate have been shown to delay the time from a first clinical attack to confirmation of clinically definite MS (17, 18). The FDA has approved 10 DMTs (Table 2), each differing in its route of administration, mechanism of action, and potential adverse effects. Choosing an appropriate therapy from these options depends on patient tolerability, risk stratification, and disease activity. Given the

efficacy of the immunomodulatory drugs for reducing relapse rates and new lesion formation on MRI scans and for preventing disability accumulation, immunomodulatory drugs should be initiated at the time of diagnosis. Interferon-β

The interferon-β preparations (β1a and β1b) are immunomodulatory cytokines that shift immune

Disease-Modifying Therapies for Multiple Sclerosis Medication

Route of Administration

Potential Adverse Effects

Recommended Monitoring

Pregnancy Category*

Interferon β-1a (2 formulations) and interferon β-1b (2 formulations)

Intramuscular or subcutaneous injection

CBC and liver function testing every 6 mo

C

Glatiramer acetate

Subcutaneous injection

None

B

Natalizumab

Intravenous

Rigorous, regimented, industry-sponsored monitoring (TOUCHE program). JC virus antibody testing.

C

Fingolimod

Oral

Cardiac monitoring for administration of first dose; ophthalmologic screening; liver function testing and CBC

C

Dimethyl fumarate

Oral

Oral

Mitoxantrone

Intravenous

Monitor CBC frequently in the first 6 mo, every 6 mo thereafter Monitor CBC, hepatic panel, amylase, lipase, and blood pressure frequently in the first 6 mo, every 6 mo thereafter Required monitoring of cardiac function by echocardiography or multigated radionucleotide angiography before each infusion and regular CBC

C

Teriflunomide

Flu-like symptoms, fatigue, depression, increased spasticity, transaminitis, and injection site reactions Injection site reactions, lipoatrophy of skin at injection sites, and rare systemic panic attack– like syndrome Black-box warning of increased risk for PML. Common adverse effects of headache and chest discomfort. Rare hepatotoxicity, infusion reactions, and anaphylaxis Transaminitis, lymphopenia, increased risk for serious herpesvirus infection, hypertension, bradycardia (usually only with the first dose), and macular edema Diarrhea, nausea, abdominal cramping, flushing, lymphopenia Alopecia, respiratory infections (including tuberculosis), pancreatitis, transaminitis, lymphopenia, hypertension, peripheral neuropathy Black-box warnings for cardiotoxicity and acute myeloid leukemia. Other adverse effects include infection, nausea, oral sores, alopecia, menstrual irregularties, and blue discoloration of urine

X

D

CBC = complete blood count; PML = progressive multifocal leukoencephalopathy. *Pregnancy category definitions: B = fetal risk in animal studies but no adequate human studies or fetal risk in animal studies but adequate human studies with no risk; C = fetal risk in animal studies and no adequate human studies, but potential benefit to pregnant women may outweigh risk; D = fetal risk in human studies, but potential benefit to pregnant women may outweigh risk, X = Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

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20. Interferon beta-1b is effective in relapsingremitting multiple sclerosis. I. Clinical results of a multicenter, randomized, doubleblind, placebocontrolled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:655-61. [PMID: 8469318] 21. Flechter S, Vardi J, Pollak L, Rabey JM. Comparison of glatiramer acetate (Copaxone) and interferon beta-1b (Betaferon) in multiple sclerosis patients: an open-label 2-year follow-up. J Neurol Sci. 2002;197:51-5. [PMID: 11997066] 22. Lublin FD, Cofield SS, Cutter GR, Conwit R, Narayana PA, Nelson F, et al; CombiRx Investigators. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73:327-40. [PMID: 23424159] 23. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899-910. [PMID: 16510744] 24. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870-80. [PMID: 22591293] 25. Lee P, Plavina T, Castro A, Berman M, Jaiswal D, Rivas S, et al. A second-generation ELISA (STRATIFY JCVE DxSelectE) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol. 2013;57:141-6. [PMID: 23465394] 26. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362: 387-401. [PMID: 20089952]


responses toward a less autoimmune phenotype and reduce the levels of the matrix metalloproteinases used by immune cells to break down the blood–brain barrier. Interferon-β1a is administered either once weekly by intramuscular injection or 3 times weekly by subcutaneous injection. Interferon-β1b is administered every other day by subcutaneous injection. The interferons reduce relapse rates by approximately one third compared with placebo and have positive effects on disability progression and MRI findings (19, 20). Glatiramer Acetate

Glatiramer acetate, a copolymer of 4 amino acids, is administered daily by subcutaneous injection. This medication probably has several mechanisms of action, including modifying the binding activity of major histocompatibility complex molecules and altering the balance of T-helper cell types. Glatiramer acetate also reduces relapse rates by one third compared with placebo and is equivalent to the high-dose interferons in head-to-head studies (21). A recent combination trial of glatiramer acetate added to interferon-β did not provide added benefit above either therapy alone (22). Natalizumab

Natalizumab is a monoclonal antibody that is administered by oncemonthly intravenous infusion. Its antibody target is the α4-integrin cellular adhesion molecule on activated T cells, which inhibits binding to the vascular endothelium, thus reducing activated immune cell entry through the blood–brain barrier into the CNS. Natalizumab is a highly effective medication, reducing relapse rates by approximately two thirds compared with placebo and slowing disability progression by approximately 40% (23). Despite its efficacy, natalizumab is limited to use as a second-line agent because of the risk for progressive multifocal leukoencephalopathy (PML), a potentially

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fatal demyelinating infection caused by reactivation of the JC virus in the CNS. This is more likely to occur in patients with low CD4 T-cell counts (such as occurs in patients treated with natalizumab, those on longterm immunosuppressive regimens, or those with AIDS). The estimated initial risk for PML in patients with MS commencing treatment with natalizumab is approximately 1 in 1000 but is significantly higher in those who have previous exposure to immunosuppressants or chemotherapy and those with elevated serum titers of antibodies against the JC virus. In patients without either of these risk factors, natalizumab confers a risk for PML of less than 1 in 10 000 (24). A 2-step enzyme-linked immunosorbent assay serum test for JC virus antibodies is an effective risk stratification tool for assessing the viability of treating patients with MS with natalizumab and for monitoring PML risk while the patient is receiving the medication. An assessment of the sera of more than 1300 patients with MS receiving natalizumab showed a seroprevalence of 50% to 60% positivity on this assay. In an assessment of the sera of 63 patients who developed PML while receiving natalizumab, antibodies to the JC virus were present before PML diagnosis in all cases. In those with a positive antibody on screening or during treatment, the risk for PML increased to approximately 3 cases per 1000 patients and to 13 cases per 1000 patients if there was a history of immunosuppression (25).

Fingolimod

Fingolimod is a once-daily pill that sequesters activated lymphocytes in lymph nodes by modulating the sphingosine-1–phosphate receptor. It reduces relapse rates by approximately one half compared with placebo and also reduces the risk for disability progression and the accumulation of new lesions on MRI scans (26). Fingolimod requires first-dose monitoring because of first-dose bradycardia that occurs in most patients. It should not be used in those with known heart block or those receiving


1 April 2014

β-blockers. Ophthalmologic examinations are required because of a risk for retinal macular edema. Caution should be used when considering fingolimod in patients with diabetes or in those with preexisting macular disease. An increased risk for herpetic infection has been reported, and all patients should receive varicella vaccination before treatment onset if they are not serologically shown to be varicella-immune. Teriflunomide

Teriflunomide is a once-daily pill that exerts an immunosuppressive effect by inhibiting a mitochondrial enzyme involved in pyrimidine synthesis in rapidly dividing cells. Compared with placebo, teriflunomide reduces relapse rates by one third, in addition to reducing the risk for disability and the accumulation of lesions on MRI (27). Teriflunomide is a class X medication due to teratogenicity; thus, contraception counseling is essential for all female patients. Procedures for “washing out” teriflunomide in patients who conceive or those with toxicity require oral lavage with activated charcoal. Dimethyl Fumarate

Oral dimethyl fumarate exerts its immunomodulatory effects by modulating the nuclear factor– like 2-transcriptional pathway. In a recent clinical trial, the annualized relapse rate of patients receiving dimethyl fumarate, 240 mg twice daily, was 0.17 compared with 0.36 for placebo (P < 0.001). The relative risk reduction for disability progression was 38% compared with placebo (P = 0.005), and new lesions on MRI scans were reduced compared with placebo. On the basis of these data, this dosing regimen was approved by the FDA for use in patients with RRMS (28).

Mitoxantrone

Mitoxantrone is an anthracenedione chemotherapy that exerts an immunosuppressive effect by reducing lymphocyte proliferation. It has been shown to reduce relapse rates

1 April 2014


and is the only drug ever to show success in reducing the rate of disability accumulation in patients with SPMS. However, the risks for cardiac toxicity and secondary leukemia have significantly limited its use (29).

What is the role of vitamin D? Links between vitamin D deficiency and the pathophysiology of MS have been clearly established. Immunoregulatory vitamin D receptors are present on T cells, and vitamin D interacts with the immunomodulatory

27. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al; TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293303. [PMID: 21991951] 28. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098-107. [PMID: 22992073] 29. Marriott JJ, Miyasaki JM, Gronseth G, O’Connor PW; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2010;74:1463-70. [PMID: 20439849] 30. Hauser SL, Johnston SC. Multiple sclerosis drugs: sticker shock [Editorial]. Ann Neurol. 2012;71:A5-6. [PMID: 22522488] 31. Noyes K, Bajorska A, Chappel A, Schwid SR, Mehta LR, Weinstock-Guttman B, et al. Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study. Neurology. 2011;77:355-63. [PMID: 21775734] 32. Comi G, Martinelli V, Rodegher M, Moiola L, Leocani L, Bajenaru O, et al. Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome. Mult Scler. 2013;19:1074-83. [PMID: 23234810] 33. Correale J, Ysrraelit MC, Gaitán MI. Gender differences in 1,25 dihydroxyvitamin D3 immunomodulatory effects in multiple sclerosis patients and healthy subjects. J Immunol. 2010;185:4948-58. [PMID: 20855882]

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The cost of MS treatment has skyrocketed in the past decade. As of 2010, MS therapies cost between $37 000 and $48 000 per year in the United States (30). Prescription drug plans have mostly absorbed this heavy cost burden, and the pharmaceutical industry has sponsored copay reduction and free drug programs for low-income and uninsured individuals. Regardless, the high cost of these medications has called into question the cost– benefit ratio of MS treatment (31). When should clinicians consider immunomodulatory therapy? Given the efficacy of the immunomodulatory drugs for reducing relapse rates and new lesion formation on MRI scans and preventing disability accumulation, these drugs should be initiated at the time of diagnosis. In the past, clinicians were encouraged to wait until a clinically definite diagnosis of MS could be established. However, given the high risk for conversion to a definite diagnosis of MS in patients with CIS and periventricular brain lesions on MRI scans and the data previously discussed showing the efficacy of treatment in this population, guidelines now recommend initiating immunomodulatory treatment at the time of first clinical symptoms for those with RRMS and CIS with risk factors for later conversion to a definite diagnosis of MS (32).

In the Clinic


34. Mowry EM, Waubant E, McCulloch CE, Okuda DT, Evangelista AA, Lincoln RR, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72:234-40. [PMID: 22926855] 35. Simpson S Jr, Taylor B, Blizzard L, Ponsonby AL, Pittas F, Tremlett H, et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol. 2010;68:193-203. [PMID: 20695012] 36. Soilu-Hänninen M, Aivo J, Lindström BM, Elovaara I, Sumelahti ML, Färkkilä M, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83:565-71. [PMID: 22362918] 37. Runia TF, Hop WC, de Rijke YB, Buljevac D, Hintzen RQ. Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis. Neurology. 2012;79:261-6. [PMID: 22700811] 38. Beck RW, Cleary PA, Anderson MM Jr, Keltner JL, Shults WT, Kaufman DI, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326:581-8. [PMID: 1734247] 39. Ramo-Tello C, GrauLópez L, Tintoré M, Rovira A, Ramió I Torrenta L, Brieva L, et al. A randomized clinical trial of oral versus intravenous methylpredisolone for relapse of MS. Mult Scler. 2013. Epub ahead of print. [PMID: 24144876] 40. Morrow SA, Stoian CA, Dmitrovic J, Chan SC, Metz LM. The bioavailability of IV methylprednisolone and oral prednisone in multiple sclerosis. Neurology. 2004;63:1079-80. [PMID: 15452302]


effects of estrogen and testosterone (33). Reduced serum vitamin D levels have been shown to predict accumulation of new lesions on MRI scans, and high vitamin D levels are associated with decreased relapse risk (34, 35). Recently, a randomized trial of addition of vitamin D supplements to interferon-β treatment showed that vitamin D supplementation reduces lesion accumulation on MRI scans compared with placebo (36). Although the ideal dosing and 25hydroxyvitamin D serum levels are still unknown, most studies have shown benefit for serum levels of 50 nmol/L or greater (37). How should clinicians choose therapy for patients who are having an acute relapse? MS relapses are defined by the development of new or worsening neurologic symptoms that have lasted for 24 hours or more without any clear underlying triggers of pseudorelapse (for example, infection or change in body temperature). When a relapse has been confirmed, the standard treatment is high-dose corticosteroids. These are typically administered as an intravenous infusion of methylprednisolone, 1 g once per day for 3 to 5 days. This dosing regimen was initially shown to be efficacious in the original optic neuritis treatment trial in 1992, in which patients with optic neuritis were randomly assigned to high-dose intravenous methylprednisolone, low-dose oral prednisone, or placebo (38). Patients in the high-dose intravenous group had faster visual recovery and fewer recurrences than those in the placebo group, and patients in the oral prednisone group had worse visual outcomes than those in the placebo group.

For relapses that do not respond to treatment with steroids, plasma exchange has shown efficacy as a rescue treatment (41). Other alternative rescue treatments are 5 days of intramuscular or subcutaneous adrenocorticotrophic hormone gel (42) or pulse-dose intravenous cyclophosphamide (43). When should a patient with MS be hospitalized? Most MS relapses do not require hospitalization. Oral steroid treatment does not require observation in the hospital, and most insurance plans cover home nursing services for intravenous infusions of corticosteroids because this is more cost-effective than hospitalization for the procedure. Hospitalization may be beneficial for severe relapses causing complete loss of mobility or impaired bladder or bowel control (which can lead to serious infection risks). Patients who have marked worsening during relapse require nursing and rehabilitation services, care that is often beyond the capacity of their family. Hospitalization may also be beneficial for patients who require special monitoring while receiving relapse treatment (such as blood glucose monitoring for steroid administration in a patient with diabetes). Rescue treatment for steroidrefractory relapses with adrenocorticotrophic hormone gel does not require hospitalization, but plasma exchange or pulse-dose cyclophosphamide therapy should probably be done in the hospital.

Recent trials have shown equivalent efficacy for MS relapses between intravenous methylprednisolone, 1 g/d for 5 days, and oral methylprednisolone, 1 g/d for 5 days (39), or oral prednisone, 1250 mg/d for 5 days (40).

What treatments are used to alleviate chronic symptoms? To adequately treat a patient with MS, it is important to use DMTs and to address and alleviate the effect of symptoms that remain chronic after previous relapses or progression. These pharmacologic and nonpharmacologic interventions have the ability to increase the quality of life of patients with MS. Table 3

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provides a comprehensive review of symptomatic management in MS. How should clinicians monitor patients being treated for MS? Monitoring patients with MS should involve regular assessments of safety and efficacy of DMT. There are no clear guidelines for monitoring treatment efficacy; however, clinical trials provide indirect guidance. In these trials, DMTs have been shown to reduce the chance of relapse, new lesion formation on MRI, and disability accumulation. Clinical efficacy assessment should involve cataloguing relapses, regular MRI scanning, and neurologic examination. Clinicians should consider a change in immunomodulatory treatment in patients who have regular relapses, lesion formation on MRI, or disability accumulation. Safety assessments are geared toward the known adverse effects of the immunomodulatory treatment

being used. Recommended monitoring tests are listed for each medication in Table 2. What should clinicians do about immunizations in patients with MS? The American Academy of Neurology clinical practice guidelines recommend regular immunizations for patients with MS (44). This is based on strong evidence that the risk for MS relapses is significantly increased in the weeks surrounding infectious episodes. Furthermore, there is no evidence that MS worsens as a consequence of immunization with any vaccines, including the influenza, hepatitis B, varicella, tetanus, and bacille Calmette–Guérin vaccines (45). Special considerations should be given, however, when using fingolimod. Because fingolimod decreases the ability to combat viral infections, the manufacturer has recommended that patients avoid the use of live viral vaccines while receiving the drug.

Symptomatic Management in Multiple Sclerosis Symptom

Nonpharmacologic Management

Pharmacologic Management

Spasticity

Physical therapy, stretching, massage therapy

Neuropathic pain

Not applicable

Fatigue

Proper sleep hygiene, regular exercise Individual or group counseling

Baclofen (oral or intrathecal pump), tizanidine, cyclobenzaprine, gabapentin, benzodiazepines, carisoprodol, botulinum toxin Gabapentin, pregabalin, duloxetine, tricyclic antidepressants, tramadol, carbamazepine, topiramate, capsaicin patch Modafinil, armodafinil, amantadine, or amphetamine stimulants Antidepressants (such as SSRIs, SNRIs, tricyclic antidepressants, antipsychotics) No proven therapy

Depression Cognitive dysfunction Mobility

Urinary urgency/frequency Urine retention Heat Intolerance

Pseudobulbar affect Limb tremor

Cognitive rehabilitation and accommodation strategies Physical and occupational therapy, use of braces, canes, rolling walkers, electrostimulatory walk-assist devices Timed voids, avoidance of caffeine Manual pelvic pressure, intermittent catheterization Avoidance of hot weather, hot tubs, etc. cooling equipment, such as fans or cooling vests None Occupational therapy

Dalfampridine

Oxybutynin, tolterodine None None

Dextromethorphan/quinidine Botulinum toxin

SNRIs = serotonin noradrenaline reuptake inhibitors; SSRIs = selective serotonin reuptake inhibitors

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41. Trebst C, Reising A, Kielstein JT, Hafer C, Stangel M. Plasma exchange therapy in steroid-unresponsive relapses in patients with multiple sclerosis. Blood Purif. 2009;28:108-15. [PMID: 19521072] 42. Simsarian JP, Saunders C, Smith DM. Five-day regimen of intramuscular or subcutaneous selfadministered adrenocorticotropic hormone gel for acute exacerbations of multiple sclerosis: a prospective, randomized, open-label pilot trial. Drug Des Devel Ther. 2011;5:381-9. [PMID: 21792296] 43. Greenberg BM, Thomas KP, Krishnan C, Kaplin AI, Calabresi PA, Kerr DA. Idiopathic transverse myelitis: corticosteroids, plasma exchange, or cyclophosphamide. Neurology. 2007;68:1614-7. [PMID: 17485649] 44. 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. [PMID: 12499473] 45. Farez MF, Correale J. Immunizations and risk of multiple sclerosis: systematic review and metaanalysis. J Neurol. 2011;258:1197-206. [PMID: 21431896]


Treatment... Treatment of patients with MS involves prevention of relapses by use of DMTs and vitamin D supplementation, use of acute treatments at the time of relapses, and management of symptoms. DMTs are only approved for use in patients with CIS and RRMS because there is poor evidence for any benefit for those with SPMS or PPMS. High-dose corticosteroids are the standard choice for acute relapse treatment, although plasma exchange, adrenocorticotrophic hormone gel, and cyclophosphamide can also be used in certain situations. Symptoms are managed on an individual basis through combined use of pharmacologic and nonpharmacologic means.

In the Clinic

Tool Kit

ACP Smart Medicine module http://smartmedicine.acponline.org/content.aspx?gbosId=256&result Click=3&ClientActionType=SOLR%20Direct%20to%20Content &ClientActionData=multiple Access the American College of Physicians Smart Medicine module.

Patient Information

Multiple Sclerosis

www.nlm.nih.gov/medlineplus/multiplesclerosis.html www.nlm.nih.gov/medlineplus/tutorials/multiplesclerosis/htm/index .htm www.nlm.nih.gov/medlineplus/spanish/tutorials/multiplesclerosis spanish/htm/index.htm Information on multiple sclerosis from the National Institutes of Health MedlinePlus, including an interactive tutorial in English and Spanish. www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple _sclerosis.htm http://espanol.ninds.nih.gov/trastornos/esclerosis_multiple.htm Information on multiple sclerosis, in English and Spanish from the National Institute of Neurological Disorders and Stroke (NINDS).

Clinical Guidelines www.neurology.org/content/76/3/294.full.pdf Evidence-based guideline update on plasmapheresis in neurologic disorders from the American Academy of Neurology in 2011. http://onlinelibrary.wiley.com/doi/10.1002/ana.22366/full Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria from the International Panel on Diagnosis of MS.

Diagnostic Tests and Criteria www.ninds.nih.gov/disorders/misc/diagnostic_tests.htm Fact sheet on neurologic diagnosis and testing from the NINDS. http://smartmedicine.acponline.org/content.aspx?gbosId=256&result Click=3&ClientActionType=SOLR%20Direct%20to%20Content &ClientActionData=mult List of laboratory and other studies for multiple sclerosis from ACP Smart Medicine.


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In the Clinic


In the Clinic

CLINICAL BOTTOM LINE


1 April 2014

WHAT YOU SHOULD KNOW ABOUT MULTIPLE SCLEROSIS

In the Clinic Annals of Internal Medicine

What is multiple sclerosis (MS)? • A chronic disease that affects the central nervous system (brain, spinal cord, and optic nerves). • MS causes the immune system to attack the protective covering that surrounds nerve cells (called the myelin sheath). • When myelin is damaged or destroyed, nerves can’t function properly to deliver signals back and forth from the brain to different parts of the body.

What are the symptoms? • • • • • •

Blurred vision or other vision problems. Loss of balance and poor coordination. Tremors, numbness, or slurred speech. Partial or complete paralysis. Fatigue and problems with memory and concentration. Symptoms vary depending on the area of the body where the myelin sheath is damaged. • Symptoms may be permanent, or they may come and go.

• Your doctor will perform a careful examination and ask you about your medical history. • No single test is available to prove or rule out MS. • Blood tests may show signs of other illnesses that cause symptoms similar to MS. • Neurologic tests that check eye movements, speech, muscles, balance, reflexes, and sensation can show how well your nervous system is working. • Spinal fluid from a spinal tap may show signs of MS or rule out infection or other possible conditions. • Magnetic resonance imaging takes a detailed picture of your brain and spinal cord, where lesions that suggest MS may be present.

How is it treated? • Your doctor may prescribe medicine to relieve specific symptoms, such as pain, muscle stiffness and spasms, fatigue, and bladder problems.

• Steroids, such as prednisone, can help reduce nerve inflammation during flare-ups. • Disease-modifying drugs, such as interferons or glatiramer acetates, can slow disease progression. • Physical therapy, occupational therapy, and speech therapy can also help reduce symptoms. • Lifestyle changes, including a healthy diet, being physically active, and getting enough sleep, may also be beneficial.

For More Information www.nationalmssociety.org/about-multiple-sclerosis/newly-diagnosed/ index.aspx

Information and resources for patients with newly diagnosed MS from the National Multiple Sclerosis Society. www.nationalmssociety.org/about-multiple-sclerosis/what-we-know -about-ms/treatments/index.aspx www.nationalmssociety.org/about-multiple-sclerosis/what-we-know -about-ms/treatments/medications/plasmapheresis-plasma-exchange/ index.aspx www.nationalmssociety.org/about-multiple-sclerosis/what-we-know -about-ms/treatments/rehabilitation/index.aspx

Information on the role of different treatments and rehabilitation in managing MS.


Patient Information

How is it diagnosed?

CME Questions

1. A 45-year-old woman is evaluated for a 6-month history of severe, often disabling, fatigue in the afternoon. The patient has a 15-year history of multiple sclerosis (MS). She states that her mood is good and that she is not feeling depressed or sad. She describes no problems with her sleep, and her partner reports no unusual movements or apnea spells. In the morning, she feels well rested. Medications are glatiramer acetate, low-dose baclofen, and a daily multivitamin. Physical and neurologic examination findings, including vital signs, are normal. Results of laboratory studies show a hemoglobin level of 12.9 g/dL (129 g/L), a normal mean corpuscular volume, and a serum thyroid-stimulating hormone level of 1.3 µU/mL (1.3 mU/L). Which of the following is the most appropriate treatment of her fatigue?

A. Amantadine B. Iron supplementation C. Levothyroxine D. Memantine E. Substitution of an interferon beta for glatiramer acetate 2. A 40-year-old woman is evaluated for worsening MS. She has had three relapses in the past year that were treated with corticosteroids. A recent MRI showed additional ovoid lesions since diagnosis. The patient also has a history of major depression treated with paroxetine. She has taken glatiramer acetate since MS was diagnosed 1 year ago. The decision is made to change the patient’s MS medication from glatiramer acetate to natalizumab.

A. Dose-dependent cardiotoxicity B. Flu-like symptoms C. Progressive multifocal leukoencephalopathy D. Skin lipoatrophy E. Worsening of her underlying depression 3. A 29-year-old woman is evaluated in the emergency department for a 3-day history of a shooting, electrical sensation radiating down her back with neck movements; a 1-week history of progressively worsening numbness and weakness of the right arm and leg; and a 3-month history of significant daytime fatigue. Twelve years ago she had ocular pain and blurry vision in the right eye for 1 week but never sought medical attention. Her father had two strokes and diabetes mellitus and her mother had hypertension. The patient takes no medication. On physical examination, blood pressure is 105/50 mm Hg, pulse rate is 80/min, and respiration rate is 14/min. Weakness of the right arm and leg is observed. Testing of reflexes shows hyperreflexia on the right side with an upturned toe. Sensory testing reveals a loss of pinprick sensation on the right side below the C5 dermatome. No visual field or language deficits are noted.

4. A 45-year-old woman is evaluated in the emergency department for a 3-day history of worsening leg spasms and pain and urinary frequency and urgency. She has a 10-year history of multiple sclerosis characterized by mild leg spasms and pain and started using a cane 4 years ago. Medications are interferon beta-1a, baclofen, pregabalin, and extended-release oxybutynin. On physical examination, temperature is 38.4°C (101.1°F), blood pressure is 105/65 mm Hg, and pulse rate is 108/min. Muscle spasticity and hyperreflexia are noted bilaterally in the lower extremities. The patient walks with a slow, stiff-legged gait and needs the assistance of a cane. A urine dipstick test is positive for leukocytes, leukocyte esterase, and nitrite. An ultrasound of the bladder shows a postvoid residual volume of 200 mL. Which of the following is the most appropriate treatment?

A. A 3-day course of methylprednisolone B. A 7-day course of ciprofloxacin C. Decrease the baclofen dosage D. Increase the oxybutynin dosage

On the basis of her history and clinical findings, which of the following is the most likely diagnosis?

A. Cardioembolic stroke B. Cervical disk herniation C. Complex migraine D. Multiple sclerosis

Physical examination findings, including vital signs, are normal. Results of laboratory studies are normal. Which of the following is a potential complication of her new therapy?

Questions are largely from the ACP’s Medical Knowledge Self-Assessment Program (MKSAP, accessed at http://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/ to complete the quiz and earn up to 1.5 CME credits, or to purchase the complete MKSAP program.


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1 April 2014

How to run a multiple sclerosis relapse clinic.

The aetiology of acute neurological decline in multiple sclerosis: experience from an open-access clinic.

Experience with long-term rituximab use in a multiple sclerosis clinic.

Multiple sclerosis: Drug-enhanced remyelination in a multiple sclerosis model.

Multiple sclerosis: Atacicept increases relapse rates in multiple sclerosis.

The multiple sclerosis microbiome?

Multiple sclerosis: A clinically useful genetic variant in multiple sclerosis?

Multiple sclerosis in children.

Pregnancy in multiple sclerosis.

Multiple sclerosis in Chile.

Metamemory in multiple sclerosis.

Caregiving in multiple sclerosis.

Exercise in multiple sclerosis.

Demyelination in multiple sclerosis.

Relapse in multiple sclerosis.

Geography in multiple sclerosis.

Parkinsonism in multiple sclerosis.

Epilepsy in multiple sclerosis.

Multiple sclerosis.

Multiple sclerosis in children.

Remyelination in multiple sclerosis.

Diet in multiple sclerosis.

Multiple sclerosis.

Multiple sclerosis.