Multiple Sclerosis

Annals of Internal MedicineT

any groundbreaking advances have Diagnosis occurred in the field of multiple sclerosis Msince this series last reviewed the disorder in 2014. The U.S. Food and Drug Administration Treatment has approved 7 new medications for relapsing– remitting multiple sclerosis and approved the first medication for primary progressive multiple sclerosis. The McDonald criteria for diagnosing multiple COVID-19 and sclerosis were updated in 2017. New blood tests can now differentiate patients with multiple sclero- Multiple Sclerosis sis from those with neuromyelitis optica spectrum disorder, and 3 new medications have been approved specifically for the latter disorder. Also, new medications for treating the symptoms of multiple sclerosis have been introduced.

CME/MOC activity available at Annals.org.

Physician Writer doi:10.7326/AITC202106150 Michael J. Olek, DO Touro University Nevada, This article was published at Annals.org on 8 June 2021. Henderson, Nevada CME Objective: To review current evidence for diagnosis and treatment of multiple sclerosis. Funding Source: American College of Physicians. Acknowledgment: The author thanks Daniel M. Harrison, MD, author of the previous version of this In the Clinic. Disclosures: Dr. Olek, ACP Contributing Author, reports that he is the ﬁrst author of the chapter on multiple sclerosis in UpToDate. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConﬂictOfInterestForms.do?msNum=M21- 0830.

With the assistance of additional physician writers, the editors of Annals of Internal Medicine develop In the Clinic using MKSAP and other resources of the American College of Physicians. The patient information page was written by Monica Lizarraga from the Patient and Interprofessional Partnership Initiative at the American College of Physicians. In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical guidelines, please go to https://www.acponline.org/clinical_information/ guidelines/. © 2021 American College of Physicians Multiple sclerosis is an autoim- concordance rates between 20% 1. Wallin MT, Culpepper WJ, mune condition that results in and 30% in monozygotic twins Campbell JD, et al; US inflammatory damage to the cen- and between 2% and 3% in dizy- Multiple Sclerosis Prevalence Workgroup. The tral nervous system (CNS). The gotic twins (2). Genome-wide prevalence of MS in the fi United States: a popula- pathologic hallmarks are diffuse assays have identi ed risk alleles tion-based estimate using and focal areas of inflammation, in the genes for major histocom- health claims data. Neurology. 2019;92: demyelination, gliosis, and neuro- patibility complex, interleukin-2 e1029-e1040. [PMID: nal injury in the optic nerves, receptor, and interleukin-7 recep- 30770430] 2. Islam T, Gauderman WJ, brain, and spinal cord. In addition tor, among others (3,4). Geo- Cozen W, et al. Differential twin concordance for multi- to affecting white matter tracts, graphic location of residence ple sclerosis by latitude of multiple sclerosis results in injury birthplace. Ann Neurol. before adolescence also predicts 2006;60:56-64. [PMID: to the cortical and deep gray mat- risk, with increased rates in north- 16685699] ter. The neurologic symptoms and 3. Patsopoulos NA, Barcellos ern and southern latitudes com- LF, Hintzen RQ, et al; disability that patients experience pared with equatorial areas. This IMSGC. Fine-mapping the are a direct consequence of these genetic association of the may be related to the observation major histocompatibility pathologic processes, resulting in complex in multiple sclero- that persons with vitamin D defi- sis: HLA and non-HLA acute and chronic disruption of effects. PLoS Genet. white matter tracts and gray mat- ciency seem to have increased 2013;9:e1003926. [PMID: 24278027] ter structures. risk for multiple sclerosis. Because 4. Beecham AH, Patsopoulos ultraviolet radiation to the skin is NA, Xifara DK, et al; Multiple sclerosis is the most com- International Multiple the major source of vitamin D syn- Sclerosis Genetics mon nontraumatic cause of neuro- Consortium (IMSGC). thesis, vitamin D deficiency is Analysis of immune-related logic disability in persons younger loci identifies 48 new sus- than 40 years. In 2010, the esti- more common among persons ceptibility variants for multiple sclerosis. Nat Genet. mated prevalence in the United living in regions with low levels of 2013;45:1353-60. [PMID: seasonal sunlight (5). Risk may 24076602] States was 309.2 per 100 000 per- 5. Sintzel MB, Rametta M, sons, or 727 433 adults (1). It also be influenced by exposure or Reder AT. Vitamin D and – multiple sclerosis: a com- occurs in a female male ratio of lack of exposure to infectious prehensive review. Neurol 2.8 to 1 (1). agents because antibodies Ther. 2018;7:59-85. [PMID: 29243029] The cause of multiple sclerosis is against certain viruses, such as 6. Lassmann H, Niedobitek G, – Aloisi F, et al; multifactorial and is probably the Epstein Barr virus, are more fre- NeuroproMiSe EBV Working Group. Epstein– cumulative result of multiple quently seen in patients with mul- Barr virus in the multiple tiple sclerosis than in those sclerosis brain: a controver- genetic and environmental risk sial issue—report on a factors. Studies have shown without it (6). focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain. 2011;134:2772-86. [PMID: Diagnosis 21846731] 7. de la Cruz J, Kupersmith What characteristic symptoms clinical presentations vary widely. MJ.. Clinical profile of fi The most common initial clinical simultaneous bilateral or physical ndings should optic neuritis in adults. Br J alert clinicians to the diagnosis manifestations are the result of Ophthalmol. 2006;90:551- fl 4. [PMID: 16622084] of multiple sclerosis? in ammation of the optic nerve 8. Thompson AJ, Banwell BL, (optic neuritis), focal inflammation Barkhof F, et al. Diagnosis Symptoms typically occur as a within the spinal cord (myelitis), of multiple sclerosis: 2017 consequence of focal inflamma- revisions of the McDonald and brainstem or cerebellar criteria. Lancet Neurol. tory plaques that cause functional 2018;17:162-73. [PMID: lesions. Each of these is termed a 29275977] areas of neuronal loss or interrup- 9. O’Riordan JI, Thompson AJ, tion of critical axonal tracts. In clinically isolated syndrome (CIS). Kingsley DP, et al. The prognostic value of brain most patients, focal lesions occur Optic neuritis often presents with MRI in clinically isolated intermittently and acutely, leading subacute vision changes that vary syndromes of the CNS. A “ ” “fl ” 10-year follow-up. Brain. to a relapse or are in which from blindness to a central sco- 1998;121:495-503. [PMID: symptoms evolve over the course toma or a horizontal oval scotoma 9549525] of days and may last for weeks or 10. Weinshenker BG, Bass B, embracing both the fixation point Rice GP, et al. The natural months before improving, if they history of multiple sclero- do improve. and the blind spot (centrocecal sis: a geographically — based study. I. Clinical scotoma) predominantly in 1 eye course and disability. Because multiple sclerosis can (90%) and rarely in both eyes Brain. 1989;112:133-46. [PMID: 2917275] affect nearly any part of the CNS, (10%)—along with pain during eye

© 2021 American College of Physicians ITC2 In the Clinic Annals of Internal Medicine movement (7). Ocular examina- Oculomotor examination can also 11. Kremenchutzky M, Rice tion usually reveals a reduction in find disconjugate eye movements, GP, Baskerville J, et al. fi fi nystagmus, or an inability to The natural history of visual acuity, a visual eld de cit, multiple sclerosis: a and a decreased ability to differ- adduct 1 eye with nystagmus in geographically based study 9: observations on entiate colors. Examination of the the abducting eye (internuclear the progressive phase of ophthalmoplegia). the disease. Brain. pupil in patients with unilateral 2006;129:584-94. optic neuritis reveals paradoxical [PMID: 16401620] In addition to the development 12. Filippi M, Rocca MA, dilation of the pupil in the affected of acute or subacute focal symp- Ciccarelli O, et al; MAGNIMS Study Group. eye when light is rapidly and toms, patients with multiple scle- MRI criteria for the diag- repeatedly shifted from one eye nosis of multiple sclero- rosis may have chronic symptoms sis: MAGNIMS to the other (afferent pupillary due to widespread cortical demy- consensus guidelines. Lancet Neurol. defect). If the anterior portion of elination and global brain atro- 2016;15:292-303. the optic nerve is involved, fundu- [PMID: 26822746] phy. Common manifestations 13. Bakshi R, Thompson AJ, scopic examination may also include cognitive dysfunction and Rocca MA, et al. MRI in multiple sclerosis: cur- reveal inflammatory changes of mental and physical fatigue. rent status and future the optic disc (papillitis). prospects. Lancet Many patients with multiple scle- Neurol. 2008;7:615-25. [PMID: 18565455] Myelitis usually manifests as sen- rosis also have transient worsen- 14. Stangel M, Fredrikson S, Meinl E, et al. The utility sory or motor symptoms below ing of baseline neurologic of cerebrospinal fluid the affected spinal level, and ex- symptoms when body tempera- analysis in patients with multiple sclerosis. Nat amination often reveals focal mus- ture is elevated (Uhthoff phenom- Rev Neurol. enon) because electrical 2013;9:267-76. [PMID: cle weakness and reduced 23528543] sensation in the same distribution. messages travel more slowly over 15. Gronseth GS, Ashman EJ. Practice parameter: Muscles can be flaccid in the areas with demyelination-related the usefulness of evoked acute setting, but spasticity devel- injury when temperature is potentials in identifying clinically silent lesions ops over time in patients who do increased. These events are in patients with sus- “ pected multiple sclerosis not recover completely from the sometimes termed pseudo- (an evidence-based attack. Unlike other spinal cord relapses.” They must be differenti- review): report of the Quality Standards processes, multiple sclerosis ated from true relapses because Subcommittee of the they do not represent new inflam- American Academy of tends to cause a partial myelitis, Neurology. Neurology. so symptoms similar to a full-cord matory events; do not require 2000;54:1720-5. [PMID: 10802774] transection are exceedingly rare. direct treatment; and typically 16. Costello F, Burton JM. Some patients may also have a resolve in cooler temperatures or Retinal imaging with optical coherence tomogra- tight, band-like sensation around after resolution of fever and infec- phy: a biomarker in tion, which usually indicates an multiple sclerosis. Eye the chest or abdomen during the Brain. 2018;10:47-63. acute inflammatory process; asymptomatic urinary tract infec- [PMID: 30104912] 17. Garcia-Martin E, Pablo shock-like sensations radiating tion. If the elevated temperature is LE, Herrero R, et al. due to an infection, it is even more Diagnostic ability of a down the spine or limbs induced linear discriminant func- by neck movements (Lhermitte important to distinguish a pseudo- tion for spectral-domain optical coherence to- sign); and urinary frequency, uri- relapse from a true relapse mography in patients nary urgency, or urine retention. because antibiotics are indicated with multiple sclerosis. Ophthalmology. and steroids may make the infec- 2012;119:1705-11. Disruption of vestibular or cere- tion worse. [PMID: 22480742] 18. Solomon AJ, Naismith bellar pathways can lead to ataxia RT, Cross AH. and vertigo. Examination can also What are the characteristics Misdiagnosis of multiple sclerosis: impact of the find impaired ability to perform of each subtype of multiple 2017 McDonald criteria smoothly coordinated voluntary sclerosis? on clinical practice. Neurology. 2019;92:26- movements of the limbs or trunk Thetimecourseofsymptomonset 33. [PMID: 30381369] 19. Jarius S, Wildemann B. (appendicular or truncal ataxia), and the evolution of symptoms The history of neuromye- dysmetria on finger-to-nose test- determine the clinical subtype of litis optica. J Neuroinflammation. ing, and dysfunction during tan- multiple sclerosis, and this is im- 2013;10:8. [PMID: 23320783] dem gait. Brainstem involvement portant for choosing the correct 20. Wallach AI, Tremblay M, can lead to eye movement abnor- disease-modifying therapy (DMT). Kister I. Advances in the treatment of neuromye- malities that cause symptoms of For example, it is important to dif- litis optica spectrum dis- diplopia or a sensation of jerking ferentiate relapsing–remitting mul- order. Neurol Clin. 2021;39:35-49. [PMID: of the visual field (oscillopsia). tiple sclerosis (RRMS) from primary 33223088]

Annals of Internal Medicine In the Clinic ITC3 © 2021 American College of Physicians progressivemultiplesclerosis disability from the time of disease 21. Goldschmidt C, McGinley MP. Advances in the treat- (PPMS) and secondary progressive onset, with only a rare relapse. This ment of multiple sclerosis. multiple sclerosis (SPMS). subtype is termed primary pro- Neurol Clin. 2021;39:21- 33. [PMID: 33223085] gressive multiple sclerosis,andit 22. Amato MP, Fonderico M, Approximately 85% of patients Portaccio E, et al. Disease- often presents later in life, with the modifying drugs can with multiple sclerosis initially first symptoms typically occurring reduce disability progres- have RRMS, in which neurologic sion in relapsing multiple in the fifth or sixth decade. The symptoms appear as repeated sclerosis. Brain. accumulation of disability can 2020;143:3013-24. episodes of relapse followed by [PMID: 32935843] occur rapidly. Early studies of the 23. Buron MD, Chalmer TA, recovery. Patients who do not Sellebjerg F, et al. Initial meet the full criteria for multiple natural history of this subtype impli- high-efficacy disease-mod- fi cated sex and age at onset as pre- ifying therapy in multiple sclerosiswhentheyhavetheir rst sclerosis: a nationwide event are said to have had a CIS. dictors of rapid progression, but cohort study. Neurology. 2020;95:e1041-e1051. Because DMTs can extend the recent studies support only accrual [PMID: 32636328] time from the first clinical event to of early disability as a predictor of 24. Polman CH, O’Connor PW, Havrdova E, et al; the second event, it is important long-term progression rates (11). AFFIRM Investigators. A to correctly identify patients who randomized, placebo-con- What are the McDonald trolled trial of natalizumab have RRMS or have a high likeli- for relapsing multiple hood of having the diagnosis con- criteria, and how can they help sclerosis. N Engl J Med. firmed at a later date, which is why clinicians diagnose multiple 2006;354:899-910. fi [PMID: 16510744] speci c diagnostic criteria are so sclerosis? 25. Bloomgren G, Richman S, important (8). For example, peo- Hotermans C, et al. Risk Confirming the diagnosis of multi- of natalizumab-associated ple who have an acute demyeli- progressive multifocal leu- ple sclerosis requires a full assess- koencephalopathy. N Engl nating attack, such as optic J Med. 2012;366:1870- neuritis or partial myelitis with ment of clinical symptoms, 80. [PMID: 22591293] brain lesions on magnetic reso- physical examination, testing, and 26. Reuwer AQ, Heron M, van der Dussen D, et al. The nance imaging (MRI) scans, have a consideration of other conditions clinical utility of JC virus 10-year risk of approximately 90% in the differential diagnosis antibody index measure- ments in the context of for eventually meeting criteria for because diagnostic biomarkers progressive multifocal leu- multiple sclerosis. In contrast, koencephalopathy. Acta for this condition do not exist. The Neurol Scand. 2017;136 those who have a similar event 2017 McDonald criteria are widely Suppl 201:37-44. [PMID: without brain lesions have a risk of 29068484] accepted as the best way to inte- 27. Kolcava J, Hulova M, approximately 10% to 20% (9). Benesova Y, et al. The grate the different types of evi- value of anti-JCV antibody dence (8). For example, to index assessment in mul- The symptoms of an individual tiple sclerosis patients relapse tend to peak after a few establish a diagnosis of multiple treated with natalizumab sclerosis, the McDonald criteria with respect to demo- days or weeks. A period of recov- graphic, clinical and radio- eryfollowsthatmaylastweeksor may require 2 relapses plus 2 logical findings. Mult Scler Relat Disord. months. During the first few years, objective signs over time or 1 2019;30:187-91. [PMID: many patients experience signifi- relapse (as a CIS) plus 2 clinical 30785075] fi fi 28. Lee P, Plavina T, Castro A, cant recovery of previous function- signs plus speci cMRI ndings et al. A second-generation ELISA (STRATIFY JCVTM ing. However, as time passes and (12). There also must be no better TM DxSelect ) for detection more relapses occur, the amount explanation for the patient's of JC virus antibodies in fi human serum and plasma of recovery from each relapse symptoms, clinical ndings, and to support progressive MRI findings. The McDonald crite- multifocal leukoencephal- diminishes and permanent disabil- opathy risk stratification. J ity can occur. In approximately ria are readily available online (for Clin Virol. 2013;57:141- 6. [PMID: 23465394] 50% to 60% of patients with RRMS, example, at www.aan.com). 29. Gold R, Kappos L, Arnold Although clinical research studies DL, et al; DEFINE Study relapses become infrequent or Investigators. Placebo-con- cease completely after a median of usually adhere strictly to the trolled phase 3 study of McDonald criteria, many oral BG-12 for relapsing 10 to 15 years, but neurologic defi- multiple sclerosis. N Engl specialists use them in individual J Med. 2012;367:1098- cits continue to accrue in a slowly 107. [PMID: 22992073] progressive manner (10). This patients more as a guideline than 30. Freeman L, Kee A, Tian M, as strict criteria. For example, a et al. Evaluating treatment stageofmultiplesclerosisis patterns, relapses, health- termed secondary progressive clinician may diagnose possible care resource utilization, and costs associated with multiple sclerosis. multiple sclerosis and start a DMT disease-modifying treat- even though the patient does not ments for multiple sclerosis in DMT-naïve patients. Approximately 15% of patients meet criteria because the tradeoff Clinicoecon Outcomes with multiple sclerosis have steady between risk and benefit favors Res. 2021;13:65-75. [PMID: 33519217] accumulation of progressive early treatment.

© 2021 American College of Physicians ITC4 In the Clinic Annals of Internal Medicine The McDonald criteria can also be demonstrated by the simultane- 31. Boffa G, Massacesi L, Inglese M, et al; Italian used to diagnose PPMS. These cri- ous presence of a gadolinium- BMT-MS study group. Long-term clinical out- teria require at least 1 year of pro- enhancing lesion and a nonen- comes of hematopoietic gressive neurologic disability plus hancing lesion or by a new T2- stem cell transplantation in multiple sclerosis. at least 2 of the following: dissemi- hyperintense or gadolinium- Neurology. 2021. [PMID: 33472915] nation in space on a brain MRI enhancing lesion not present on a 32. Correale J, Ysrraelit MC, scan, dissemination in space on a baseline scan, regardless of the Gaitán MI. Gender dif- ferences in 1,25 dihy- spinal cord MRI scan, or cerebro- timing of the baseline scan. droxyvitamin D3 fl fi immunomodulatory spinal uid (CSF) ndings consist- effects in multiple scle- ent with multiple sclerosis. Although diagnostic criteria focus rosis patients and fi healthy subjects. J speci cally on the presence of Immunol. Proper application of the lesions in white matter, other MRI 2010;185:4948-58. [PMID: 20855882] McDonald criteria can also help changes can be seen, including 33. Mowry EM, Waubant E, differentiate multiple sclerosis McCulloch CE, et al. demyelinating lesions in the cor- Vitamin D status predicts from other conditions and thus tex; atrophy of cortical and deep new brain magnetic res- prevent unnecessary neurologic onance imaging activity gray matter; atrophy of white mat- in multiple sclerosis. testing and referrals. This is espe- Ann Neurol. ter structure; and alterations in 2012;72:234-40. cially true for common conditions, lesions and normal-appearing [PMID: 22926855] such as migraine, microvascular is- 34. Simpson S Jr, Taylor B, white matter indicated by magnet- Blizzard L, et al.. Higher chemic disease, and head trauma, 25-hydroxyvitamin D is ization transfer, diffusion tensor associated with lower which can cause white matter imaging, and other quantitative relapse risk in multiple lesions on MRI scans but do not sclerosis. Ann Neurol. MRI measures (13). 2010;68:193-203. cause lesions that meet the [PMID: 20695012] 35. Soilu-Hänninen M, Aivo McDonald criteria for location. What role does lumbar J, Lindström BM, et al. A puncture play in diagnosis? randomised, double What is the role of MRI in blind, placebo controlled trial with vitamin diagnosis? The McDonald criteria do not D3 as an add on treat- fi ment to interferon b-1b MRI is the primary diagnostic and require testing of CSF to con rm in patients with multiple prognostic tool for the evaluation the diagnosis of RRMS. For the di- sclerosis. J Neurol Neurosurg Psychiatry. of patients with multiple sclerosis. agnosis of PPMS, CSF testing is 2012;83:565-71. fi [PMID: 22362918] For most patients, the McDonald necessary only if MRI ndings do 36. Miclea A, Bagnoud M, criteria require confirmation with not meet criteria for dissemination Chan A, et al. A brief fi fi review of the effects of MRI ndings. Typical MRI ndings in space. However, CSF testing vitamin D on multiple are lesions in white matter regions sclerosis. Front can be a useful diagnostic tool in Immunol. 2020;11:781. that appear hyperintense on T2- cases where the diagnosis is not [PMID: 32435244] fl 37. Runia TF, Hop WC, de weighted and uid-attenuated clear. CSF testing with isoelectric Rijke YB, et al. Lower se- inversion recovery images and fi rum vitamin D levels are focusing nds unique oligoclonal associated with a higher hypointense on T1-weighted bands in 90% to 95% of patients relapse risk in multiple images. These lesions are areas of sclerosis. Neurology. with multiple sclerosis (14). An 2012;79:261-6. [PMID: demyelination and gliosis. In addi- 22700811] elevation of the IgG index is seen 38. Ramo-Tello C, Grau- tion, administration of gadolinium in 50% to 75% of patients, and López L, Tintore M, et al. contrast will enhance lesions that A randomized clinical mild pleocytosis is seen in about trial of oral versus intra- are undergoing an active inflam- venous methylpredniso- half of patients. Given the sensitiv- matory process with breakdown lone for relapse of MS. ity and specificity of these tests, Mult Scler. of the blood–brain barrier. The 2014;20:717-25. negative CSF test results by them- [PMID: 24144876] Figure shows examples of lesions 39. Morrow SA, Stoian CA, in each of the 4 locations empha- selves cannot rule out the diagno- Dmitrovic J, et al. The bi- sis of multiple sclerosis. However, oavailability of IV meth- sized by the McDonald criteria: ylprednisolone and oral when negative CSF test results prednisone in multiple periventricular, juxtacortical, sclerosis. Neurology. brainstem and cerebellum (infra- occur in patients with a low suspi- 2004;63:1079-80. [PMID: 15452302] tentorial), and spinal cord. cion for multiple sclerosis based 40. Trebst C, Reising A, on clinical and radiologic findings, Kielstein JT, et al. Dissemination in space can be Plasma exchange ther- demonstrated by characteristic clinicians should consider other apy in steroid-unrespon- sive relapses in patients T2-hyperintense lesions that are possible diagnoses and advise with multiple sclerosis. in2ormoreofthe4locations. patients that they probably do not Blood Purif. 2009;28:108-15. Dissemination in time can be have multiple sclerosis. [PMID: 19521072]

Left. Sagittal, ﬂuid-attenuated, inversion recovery brain sequence showing periventricular (top arrow), juxtacortical (right-hand arrow), and infratentorial (bottom arrow)lesions.Middle. 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. Right. Sagittal T2 scan of the cervical spine showing a lesion at approximately the C2 level (arrow).

When should clinicians sclerosis, these results are less consider obtaining evoked likely to be abnormal than the

41. Simsarian JP, Saunders C, potentials? results of visual-evoked potentials Smith DM. Five-day regi- (15). men of intramuscular or Evoked potentials can be useful subcutaneous self-administered adrenocorticotropic when the clinical examination and When should clinicians hormone gel for acute MRI are unable to provide evi- consider obtaining optical exacerbations of multiple sclerosis: a prospective, dence of dissemination in space coherence tomography? randomized, open-label pilot trial. Drug Des Devel because they can provide evi- Optical coherence tomography Ther. 2011;5:381-9. dence of subclinical demyelinat- [PMID: 21792296] uses near-infrared light to mea- 42. Gómez-Figueroa E, ing lesions. Evoked potential tests sure the thickness of the different Gutierrez-Lanz E, Alvarado-Bolaños A, et al. measure the time it takes for the layers that make up the retina. Cyclophosphamide treat- brain to respond to sensory stimu- ment in active multiple Patients with multiple sclerosis sclerosis. Neurol Sci. lation, and the results are report- have reductions in the thickness 2021. [PMID: 33452657] 43. Rutschmann OT, McCrory ed as conduction velocities. For of the retinal nerve fiber layer af- DC, Matchar DB; example, reduced conduction ve- Immunization Panel of ter optic neuritis (16), and this the Multiple Sclerosis locity after visual stimuli can alsocanbeseeninpatientswith Council for Clinical Practice Guidelines. detect prior demyelination in an multiple sclerosis who have not Immunization and MS: a optic nerve even in patients who summary of published had optic neuritis (17). However, evidence and recommen- cannot recall an episode of optic thinning of this layer also occurs dations. Neurology. 2002;59:1837-43. [PMID: neuritis (15). Reduced conduction after isolated optic neuritis with- 12499473] 44. Farez MF, Correale J. velocity measured in the brain- out other manifestations of multi- Immunizations and risk of stem after auditory stimuli can ple sclerosis, in patients with multiple sclerosis: systematic review and meta-anal- detect a lesion along the acoustic neuromyelitis optica, and in ysis. J Neurol. 2011;258:1197-206. and brainstem pathways, and patients with compressive [PMID: 21431896] reduced conduction velocity after lesions of the optic nerve. Thus, 45. Costa-Frossard L, Moreno- Torres I, Meca-Lallana V, somatosensory stimuli can detect optical coherence tomography is et al. [EMCAM (Multiple fi Sclerosis Autonomous lesions in spinal sensory pathways. not a de nitive test for multiple Community of Madrid) Care should be taken in interpret- sclerosis, but it can be useful for document for the management of patients with ing all of these results but espe- documenting dissemination in multiple sclerosis during fi the SARS-CoV-2 pan- cially the results of tests involving space for patients having a rst demic]. Rev Neurol. the brainstem and spinal cord attack that does not include 2020;70:329-40. [PMID: 32329046] because in patients with multiple optic neuritis.

Other Demyelinating Diseases Notes Acute disseminated encephalomyelitis Monophasic, often postinfectious syndrome causing large, diffuse areas of inflammatory CNS demyelination, fever, and encephalopathy More common in children; rare in adults NMO-SD 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 Idiopathic transverse myelitis Monophasic, often postinfectious syndrome causing spinal cord inflammation Systemic inflammatory disease Differentiated from MS by the presence of symptoms and findings unique to the underlying systemic disorder in addition to neurologic symptoms Systemic lupus erythematosus Can present with encephalopathy and white matter changes on MRI Sjögren syndrome Can cause an NMO-SD–like disorder with optic neuritis and myelitis Also can cause multiple cranial neuropathies and small-fiber neuropathy Sarcoidosis Results in granulomatous inflammation in the parenchyma and meninges of the brain and spinal cord Behçet syndrome Can cause brainstem abnormalities and encephalopathy and is occasionally associated with myelopathy Metabolic disorders Adult-onset leukodystrophy 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

Vitamin B12 deﬁciency Can cause optic neuropathy, cognitive changes, and subacute combined degeneration of the spinal cord (spasticity, weakness, and vibratory and proprioceptive sensory loss)

Copper deficiency Can cause a myelopathy identical to B12 deficiency Zinc toxicity Can cause an acquired copper deficiency Vitamin E deficiency Can cause cerebellar ataxia Infections: HIV, Lyme disease, syphilis, HTLV These disorders (except HTLV) can cause encephalopathy and myelopathy and can be diagnosed with appropriate serologic testing and spinal fluid analysis HTLV-1 causes a slowly progressive myelopathy with thoracic cord atrophy; it is sometimes termed tropical spastic paraparesis because it is more common in patients in equatorial latitudes Vascular disorders Sporadic and genetic stroke syndromes Microvascular ischemic disease can cause nonspecific white matter changes on MRI (hypercoagulability disorders) Age, other vascular risk factors, and neurologic examination findings help to distinguish it from MS CNS vasculitis Primary CNS vasculitis, which can be diagnosed by catheter angiography or tissue biopsy, can present with both stroke-like changes on MRI and meningeal contrast enhancement Susac syndrome Causes a small-vessel arteriopathy, which leads to dysfunction of the retina and cochlea and to corpus callosum lesions on MRI Dural arteriovenous fistula Can result in spinal cord infarction or vascular congestion with cord lesions that can be confused with MS lesions Subacute clinical progression without remission or relapse Migraine Subcortical white matter lesions can occur in patients with migraine and can often be confused with MS lesions Cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) should be considered in patients with a familial syndrome of migraine, subcortical strokes, mood disorders, and early dementia Neoplasia (i.e., primary CNS neoplasm [glioma or Neoplasms have progressively worsening symptoms and neuroimaging findings lymphoma] or metastatic disease) When imaging cannot differentiate neoplasms from demyelinating disease, brain biopsy is indicated Paraneoplastic syndromes 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 Somatoform disorders Psychiatric disorders can sometimes present with neurologic-like symptoms that are due to somatization, conversion, and similar conditions Neurologic work-up will be normal

CNS = central nervous system; HTLV = human T-lymphotropic virus; MRI = magnetic resonance imaging; MS = multiple sclerosis; NMO-SD = neuromyelitis optica spectrum disorder.

Annals of Internal Medicine In the Clinic ITC7 © 2021 American College of Physicians What is the differential diagnosis? of systems, and physical examina- (eculizumab, inebilizumab, and Whenever the diagnosis of multi- tion. Knowledge about other satralizumab-mwge) (20). potential diagnoses that might be ple sclerosis is being considered, When should clinicians conditions that mimic it (Table 1) confused with multiple sclerosis is should be part of the differential di- also useful. consider consulting with agnosis. These include disorders a neurologist or another that can cause neurologic symp- One condition that may be con- specialist for diagnosis? fused with multiple sclerosis is toms and changes in MRI scans that Given the complexity of the diag- are sometimes incorrectly diag- neuromyelitis optica spectrum nosis, if initial ﬁndings suggest nosed as multiple sclerosis. For disorder (Table 1). Since 2004, it multiple sclerosis, the clinician example, a recent study found that has been possible to diagnose approximately 30% of patients this disorder by testing for a novel should refer the patient to a neu- referred to a tertiary multiple sclero- serum autoantibody termed neurologist for further evaluation and sis center had an incorrect diagno- romyelitis optica IgG or AQP4-Ab testing. For cases in which the di- sis (18). The best way to distinguish (19). An important reason to diag- agnosis is unclear or if initial treat- patients with multiple sclerosis from nose this disorder is that the U.S. ment has failed, clinicians should those with other diagnoses is to Food and Drug Administration consider obtaining a second opin- conduct a comprehensive review of (FDA) has approved 3 medica- ion from 1 or more multiple scle- the patient's medical history, review tions to treat it in the past 2 years rosis specialty clinics.

Diagnosis... Patients presenting with symptoms of a demyelinating disorder should have a thorough review of their medical history and physical examination, with special attention to the possibility of optic neuritis, myelitis, and brainstem or cerebellar lesions, and they should have an MRI scan of their brain and spinal cord. The diagnosis of multiple sclerosis is made by applying the revised 2017 McDonald criteria, which use a combination of ﬁnd- ings to show dissemination of disease activity over space and time. Early referral to a neurologist is encouraged. Additional testing, such as lumbar puncture, evoked potentials, optical coherence tomography, and serum markers for other diseases, is not required but can be helpful in some patients for separating multiple sclerosis from other disorders. CLINICAL BOTTOM LINE

Treatment What is the overall approach to progression currently focuses on considered; if the patient is declin- fl treating patients with multiple controlling in ammatory disease ing slowly, general immunosup- sclerosis? activity early in RRMS, ongoing pressive agents may be used. research provides hope for allevi- The care of patients with multiple ating tissue injury through What medications are typically sclerosis requires a multidiscipli- enhanced repair and the preven- used, and what are their nary approach and a comprehen- tion of neurodegeneration. benefits, potential harms, sive strategy with medication and and costs? nonmedical approaches for What role does clinical subtype relapse management; prevention play in guiding treatment First-line DMTs include immuno- of relapses and delay of disease decisions? modulatory and immunosuppres- progression; and management of Assigning a clinical subtype is a sive medications that have been fatigue, cognitive function, spas- critical first step before starting shown on MRI scans to reduce risk ticity, bladder dysfunction, and any drug therapy. Most of the for relapse, disease progression, other symptoms. An increasing FDA's approvals for DMTs have and new lesion formation (22). In number of effective medications been for CISs, RRMS, and active addition, recent evidence sup- are available for these purposes. SPMS, but 1 new medication has ports the idea that some DMTs Treatment should also include been approved for PPMS (21). assisting patients in maximizing provide real-world clinical daily function. Use of all of these Immunotherapy is indicated as benefits. tools has led to significant soon as the diagnosis is established improvements in quality of life for for most patients with CISs, RRMS, A Danish registry compared 194 many patients with multiple scle- or PPMS. If patients with SPMS are patients started on high-efficacy rosis. Although reducing disease having relapses, a DMT should be DMTs (natalizumab, fingolimod,

© 2021 American College of Physicians ITC8 In the Clinic Annals of Internal Medicine alemtuzumab, cladribine, and approximately 40% (24). Another natalizumab, antibodies to the JC ocrelizumab) with 194 patients advantage is adherence, given virus were present before PML di- receiving medium-efficacy DMTs. that the medication is adminis- agnosis in all cases. The risk for The high-efficacy patients had tered once monthly by infusion in PML increased to approximately lower rates of clinical worsening a clinical setting rather than by the 3 cases per 1000 patients in those with a positive antibody result at and fewer on-treatment relapses. patient as an oral or injectable fi screening or during treatment and In addition, an Italian registry con- medication. Despite its ef cacy, to 13 cases per 1000 patients if cluded that starting patients within natalizumab is limited by its risk there was a history of immunosup- 2 years of diagnosis on a high- for progressive multifocal leu- pression (28). efficacy DMT (rituximab, ocrelizu- koencephalopathy (PML), a poten- Dimethyl fumarate mab, mitoxantrone, alemtuzumab, tially fatal demyelinating infection or natalizumab) was associated caused by reactivation of the John Oral dimethyl fumarate exerts its with less disability 6 to 10 years Cunningham (JC) virus in the immunomodulatory effects by – after disease onset (23). CNS. This is more likely to occur in modulating the nuclear factor like patients with low CD4 T-cell 2 transcriptional pathway. Before 1993, there were no FDA- counts, such as those treated with approved medications for multi- In the pivotal clinical trial of di- natalizumab, those on long-term ple sclerosis. Since then, the FDA methyl fumarate, the annualized immunosuppressive regimens, or has approved 23 DMTs (Table 2) relapse rate in patients receiving those with AIDS. The estimated with different routes of administra- 240 mg twice daily was 0.17 com- initial risk for PML in patients be- pared with 0.36 for placebo (P< tion, mechanisms of action, and ginning treatment with natalizu- 0.001). The relative risk reduction potential adverse effects. A com- mab is approximately 1 in 1000 for disability progression was 38% prehensive review of all DMTs by but is significantly higher in those compared with placebo (P = nonpartisan groups may be found with previous exposure to immu- at https://ms-coalition.org/wp- 0.005), and new lesions on MRI nosuppressants or chemotherapy content/uploads/2019/06/MSC_ scans were reduced compared and those with elevated serum DMTPaper_062019.pdf. This with placebo. titers of antibodies against the JC document provides the route of virus (25). The results of tests for These data led to FDA approval administration, mechanism of antibodies against JC virus may for use of this medication in action, adverse effects, warnings, be reported as direct antibody patients with RRMS (29). The pack- and clinical and MRI data for all levels or as an index (the age insert has been updated to DMTs and is updated on a regular include CISs, RRMS, and SPMS STRATIFY or JC antibody index), basis. The Appendix Figure with relapses. which is a ratio of direct antibody (available at Annals.org) shows levels to levels in a calibrator sam- the current understanding of the The cost of multiple sclerosis ple (26). An index value below 0.2 pathophysiology of multiple scle- treatment has skyrocketed in the is regarded as evidence of sero- past decade, and this is being rosis as well as the mechanisms of negativity, between 0.2 and 0.4 as increasingly questioned by action of the major medications. indeterminate, and above 0.4 as patients and analysts. A 2021 arti- The following sections provide evidence of seropositivity. A se- cle that examined cost data from information on 2 frequently used rum test for JC virus antibodies is 5906 patients with multiple sclero- medications. sis reported that the yearly range an effective risk stratification tool for DMTs was $70 000 to $82 000 Natalizumab before starting use of natalizumab (30). Natalizumab is a monoclonal anti- and for monitoring risk during body that is administered by use. For example, a positive base- Current treatment varies greatly, monthly intravenous infusion. It line anti–JC virus antibody index with different specialists using dif- reduces entry of activated T cells above 0.90 predicts stable posi- ferent medications for different through the blood–brain barrier tive JC virus serostatus (27) and is stages of the disease. One into the CNS by inhibiting the a reason to use a DMT other than approach is as follows: a 4-integrin cellular adhesion mol- natalizumab. ecule on these immune cells and For patients with a newly diag- An assessment of the sera of more nosed CIS or RRMS, start intrave- thus interfering with binding to than 1300 patients with multiple nous natalizumab and perform the vascular endothelium. sclerosis receiving natalizumab tests for JC virus antibodies and Natalizumab is highly effective; showed a seroprevalence of 50% their index. If the results are pos- it reduces relapse rates by 68% to 60% positivity. In an assessment itive, continue natalizumab for compared with placebo and slows oftheseraof63patientswho 1 year and then switch to oral disability progression by developed PML while receiving dimethyl fumarate.

Medication Route of Warnings, Contraindications, Recommended Pregnancy Administration and Potential AEs Monitoring Category* Interferon-b1a and Intramuscular or AEs: Flu-like symptoms, fatigue, CBC and liver function test- C interferon-b1b subcutaneous injection depression, increased spasticity, ing every 6 mo transaminitis, injection site reactions, seizures, congestive heart failure, leukopenia, autoimmune disorders Glatiramer acetate Subcutaneous injection AEs: Injection site reactions, None B lipoatrophy of skin at injection sites, rare systemic panic attack–like syndrome Daclizumab Subcutaneous injection Black box warning: Hepatic injury, Liver function testing every No adequate data; see full including autoimmune hepatitis and 3–6mo prescribing information other immune-mediated disorders Contraindications: Preexisting hepatic disease or hepatic impairment, including alanine aminotransferase or aspartate aminotransferase level ≥2 times the upper limit of normal and history of autoimmune hepatitis or other autoimmune condition involving the liver AEs: Injection site reactions, upper respiratory infections, depression, transaminitis Ofatumumab Subcutaneous injection Contraindication: Active HBV infec- Must have HBV screening No adequate data; see full tion and serum immunoglobu- prescribing information AEs: Upper respiratory tract infec- lins before use tions, headache, injection-related reactions, reduction in immunoglo- bulins, local injection site reactions Fingolimod Oral Contraindications: Cardiac monitoring for C Recent myocardial infarction, administration of first unstable angina, stroke, transient dose; ophthalmologic ischemic attack, decompensated screening; liver function heart failure with hospitalization, testing and CBC; yearly or class III/IV heart failure skin examinations History of Mobitz type II second- or third-degree AV block or sick sinus syndrome, unless patient has pacemaker Baseline QTc interval ≥500 ms Treatment with class Ia or class III antiarrhythmic drugs AEs: Transaminitis, lymphopenia, increased risk for serious herpesvirus infection, hypertension, PML, poste- rior reversible encephalopathy syndrome, cutaneous tumors, bradycardia (usually only with the first dose), macular edema Dimethyl fumarate Oral AEs: Diarrhea, nausea, abdominal Monitor CBC frequently in C cramping, flushing, lymphopenia the first 6 mo, every 6 mo thereafter as well as for infections Diroximel fumarate Oral Same as dimethyl fumarate, plus PML Same as dimethyl fumarate C and transaminitis plus liver function tests before start Monomethyl fumarate Oral Same as diroximel fumarate Same as diroximel fumarate C Teriflunomide Oral Black box warnings: Hepatotoxicity Monitor CBC, hepatic X and risk for teratogenicity panel, amylase, lipase, Contraindications: Severe hepatic and blood pressure fre- impairment, pregnancy, hypersensi- quently in the first 6 mo, tivity, current leflunomide treatment every 6 mo thereafter AEs: Alopecia, respiratory infections (including tuberculosis), pancreatitis, transaminitis, lymphopenia, hypertension, peripheral neuropathy

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Medication Route of Warnings, Contraindications, Recommended Pregnancy Administration and Potential AEs Monitoring Category*

Cladribine Oral Black box warnings: Cancer and risk CBC every 3–6 mo; screen D for teratogenicity for TB, hepatitis, shingles, Contraindications: or other infections as Patients with current cancer appropriate Pregnant women and adults of reproductive potential who do not plan to use effective contraception during cladribine dosing and for 6 mo after the last dose in each treatment course HIV infection Active chronic infections (e.g., hepatitis or tuberculosis) History of hypersensitivity to cladribine Women intending to breastfeed on a cladribine treatment day and for 10 d after the last dose AEs: Upper respiratory infection, headache, lymphopenia, liver injury Siponimod Oral Contraindications: Obtain CBC, liver function No adequate data; see full Patients with a CYP2C9*3/*3 tests, electrocardiogram, prescribing information genotype and ophthalmologic Patients with myocardial infarc- assessment before initiat- tion, unstable angina, stroke, TIA, ing treatment decompensated heart failure Monitor for infection during requiring hospitalization, or class treatment III/IV heart failure in the past 6 mo Do not start in patients with Presence of Mobitz type II second- active infection or third-degree AV block or sick Other warnings include mac- sinus syndrome, unless patient has ular edema, bradyarrhyth- functioning pacemaker mia, respiratory effects, AEs: Headache, hypertension, transa- liver injury, increased blood minitis, infection pressure, and fetal risk Ozanimod Oral Same as siponimod, plus contraindi- Same as siponimod Same as siponimod cation for severe untreated sleep apnea Alemtuzumab Intravenous Black box warnings: Autoimmunity, Available only through re- C infusion reactions, tumors stricted distribution under a Contraindication: HIV infection Risk Evaluation Mitigation AEs: >90% of patients in clinical trials Strategy program experienced infusion reactions (rash; fever; headache; muscle aches; temporary recurrence of previous neurologic symptoms; and, rarely, anaphylaxis and heart rhythm abnormalities) Serious AEs: Autoimmunity, infusion reactions, tumors, immune thrombo- cytopenia, glomerular nephropa- thies, thyroid disorder, other autoimmune cytopenias, infections, pneumonitis, immediate and signiﬁ- cant depletion of lymphocytes; her- pes simplex and zoster infections more common in patients who received alemtuzumab in clinical trials, especially soon after infusions; prophylaxis with antiviral agent is recommended for ≥2 mo or until CD4 count is >0.200 Â 109 cells/L Natalizumab Intravenous Black box warning: Increased risk for Rigorous, regimented, C PML industry-sponsored moni- AEs: headache, chest discomfort toring (TOUCH program) (common); hepatotoxicity, infusion JC virus antibody and index reactions, anaphylaxis (rare) testing

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Medication Route of Warnings, Contraindications, Recommended Pregnancy Administration and Potential AEs Monitoring Category*

Ocrelizumab Intravenous Contraindication: Active HBV infec- Prescreen for hepatitis B No adequate data; see full tion prescribing information AEs: Infusion reactions (possibly life- threatening), infections, possible increase in tumors Mitoxantrone Intravenous Black box warnings: Cardiotoxicity Required monitoring of car- D and acute myeloid leukemia diac function by echocar- AEs: Infection, nausea, oral sores, alo- diography or multigated pecia, menstrual irregularities, blue radio-nucleotide angiog- discoloration of urine raphy before each infusion and regular CBC

AE = adverse effect; AV = atrioventricular; CBC = complete blood count; HBV = hepatitis B virus; JC = John Cunningham; PML = progressive multifocal leukoencephalopathy. * 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.

For patients with RRMS who al- respond to therapy and those Immunoregulatory vitamin D ready are receiving a DMT and with SPMS. receptors are present on T cells, are doing well—meaning that and vitamin D interacts with the In a recent study of autologous he- they can tolerate the medication, immunomodulatory effects of matopoietic stem cell transplant have had no relapses in 1 to 2 estrogen and testosterone (32). patients, 210 with RRMS or SPMS years, and have had no changes Reduced serum vitamin D levels underwent this procedure. For on their MRI scans for 1 year— have been shown to predict accu- patients with RRMS, 85% had no maintain them on that therapy. mulation of new lesions on MRI worsening of disability at 5 years For those who are not doing scans, and high levels are associ- and 71.3% had no worsening at well, switch to a different DMT. ated with decreased risk for 10 years. For patients with SPMS, relapse (33, 34). For patients with newly diag- 71% showed no worsening of dis- nosed PPMS, start ocrelizumab. ability at 5 years and 57.2% A randomized, double-blind, pla- showed no worsening at 10 years cebo-controlled trial of the addi- For patients with SPMS who are (31). tion of vitamin D supplements stable with no medication, maxi- When should clinicians (14 007 IU/d) to interferon-b treat- mize physical therapy and symp- consider immunomodulatory ment found that vitamin D supple- tomatic medications. Do not therapy? mentation reduced lesion start a DMT because of the risk accumulation on MRI scans com- for infection. Immunomodulatory drugs should be initiated at the time of diagno- pared with placebo (35). Another trial found that the number of new For patients with SPMS who are sis. In the past, clinicians were using a DMT but continue to encouraged to wait until a clini- gadolinium-enhancing lesions or have relapses, add an immuno- cally definite diagnosis of multiple T2 lesions that were new or enlarg- suppressant agent or consider sclerosis could be established. ing was reduced by 32% in switching to a different DMT. Guidelines now recommend ini- patients supplemented with chole- tiating immunomodulatory treat- calciferol compared with placebo For patients with SPMS who con- ment at the time of first clinical (36). tinue to have attacks despite symptoms for those with RRMS having used multiple different Although the ideal serum 25- and for those with a CIS and risk hydroxyvitamin D levels are still DMTs, start intravenous cyclo- factors for later conversion to a unknown, most studies have phosphamide. diagnosis of multiple sclerosis. shown benefit for levels of 50 nmol/L or greater (37), so some What is the role of vitamin D? Bone marrow transplant, a more multiple sclerosis specialists mea- aggressive approach that is not Researchers have established sure vitamin D levels in all of their FDA approved for multiple sclero- clear links between vitamin D defi- patients and prescribe supple- sis, has been used as a rescue ciency and the pathophysiology ments if the values are less than therapy for patients who do not of multiple sclerosis. 50 nmol/L.

© 2021 American College of Physicians ITC12 In the Clinic Annals of Internal Medicine How should clinicians choose intramuscular or subcutaneous can lead to serious infection risks. therapy for patients having an adrenocorticotrophic hormone Patients who have marked worsen- acute relapse? gel (41), and pulse-dose intrave- ing during relapse require nursing nous cyclophosphamide (42) are and rehabilitation services, which Relapses are defined by the de- available rescue treatments. are often beyond the capacity of velopment of new or worsening their family. Hospitalization may neurologic symptoms lasting 24 When should a patient with also be beneficial for patients who hours or more without an increase multiple sclerosis be fi require special monitoring while in body temperature, identi able hospitalized? infection, or another trigger for a receiving relapse treatment, such pseudo-relapse. When a relapse Most relapses do not require hos- as blood glucose monitoring for has been confirmed, the standard pitalization. Oral steroid treatment steroid administration in a patient treatment is high-dose corticoste- does not require observation in with diabetes. Rescue treatment roids, which are typically adminis- the hospital, and most insurance for steroid-refractory relapses with tered as an intravenous infusion of plans cover home nursing services adrenocorticotrophic hormone gel methylprednisolone, 1 g/d for 3 for intravenous infusions of cortico- does not require hospitalization, to 5 days, with no oral taper. steroids because this is more cost- but plasma exchange or pulse- Recent trials have shown that oral effective than hospitalization and dose cyclophosphamide therapy methylprednisolone, 1 g/d for 5 decreases the chance of infection. should be done in the hospital. days (38), and oral prednisone, What treatments are used to 1250 mg/d for 5 days (39), have Hospitalization may be beneficial alleviate chronic symptoms? equivalent efficacy. For relapses for severe relapses causing com- that do not respond to steroids, plete loss of mobility or impaired To adequately treat a patient with plasma exchange (40), 5 days of bladder or bowel control, which multiple sclerosis, it is important

Table 3. Symptom Management in Multiple Sclerosis

Symptom Nonpharmacologic Management Pharmacologic Management Spasticity Physical therapy, stretching, massage Baclofen (oral or intrathecal pump), tizani- therapy dine, cyclobenzaprine, dantrolene, gabapentin, benzodiazepines, carisoprodol, botulinum toxin Neuropathic pain Not applicable Gabapentin, pregabalin, duloxetine, tricyclic antidepressants, tramadol, carbamazepine, topiramate, capsaicin patch Fatigue Proper sleep hygiene, regular exercise Modafinil, armodafinil, amantadine, fluoxetine or amphetamine stimulants Depression Individual or group counseling Antidepressants (such as SSRIs, SNRIs, tricyclic antidepressants, antipsychotics) Cognitive dysfunction Cognitive rehabilitation and accommoda- No proven therapy tion strategies Mobility Physical and occupational therapy; use of bra- Dalfampridine ces, canes, rolling walkers, electrostimulatory walk-assist devices Urinary urgency/frequency Timed voids, avoidance of caffeine Oxybutynin, tolterodine, desmopressin, darifenacin, tamsulosin, mirabegron, imipramine, solifenacin, botulinum toxin, implantable bladder stimulators Urine retention Manual pelvic pressure, intermittent Antibiotics for urinary tract infection catheterization Consider BPH, which can be treated with a-blocker and/or 5-a reductase inhibitor Bowel dysfunction None Metamucil, docusate, bisacodyl, milk of magnesia, mineral oil, enemas or suppositories Erectile dysfunction Vacuum pump Sildenafil, tadalafil, vardenafil, alprostadil, avanafil Heat intolerance Avoidance of hot weather and hot tubs None Cooling equipment (fans, cooling vests) Pseudobulbar affect None Dextromethorphan/quinidine Limb tremor Occupational therapy Isoniazid, clonazepam, botulinum toxin, tha- lamic stimulation via deep-brain stimulator

BPH = benign prostatic hypertrophy; SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.

Annals of Internal Medicine In the Clinic ITC13 © 2021 American College of Physicians to use DMTs and to address cies of relapse and new MRI guidelines recommend the same symptoms that remain chronic lesions and to reduce the accumu- immunizations for patients with after a previous relapse or pro- lation of disability. Therefore, clini- multiple sclerosis that are recom- fi gression. Table 3 provides a com- cal assessment of ef cacy should mended for others (43). One rea- prehensive review of symptom include documentation of relap- son is that the risk for relapses management. It is important to ses, periodic neurologic examina- increases during the weeks sur- recognize the usefulness of these tions, and regular MRI scans. rounding infectious episodes. In interventions for increasing quality Clinicians should consider chang- of life in patients with multiple ing immunomodulatory treatment addition, there is no evidence sclerosis. for patients with recurrent relap- that multiple sclerosis worsens as ses, new lesion formation on MRI, a consequence of immunization How should clinicians monitor or progressive accumulation of with any vaccines, including those patients being treated for disability. Safety assessments are against influenza, hepatitis B, multiple sclerosis? targeted toward the known varicella, tetanus, and tuberculosis Monitoring should involve regular adverse effects of the immunomo- (bacille Calmette–Guerin vaccine) assessments of the efficacy and dulatory treatment being used. (44). However, fingolimod safety of DMTs. There are no clini- Recommended monitoring tests decreases a patient's ability to cal guidelines for monitoring are listed in Table 2. treatment efficacy, but the prac- recover from viral infections, and tices developed for clinical trials Should patients with multiple the manufacturer recommends can provide indirect guidance. In sclerosis receive immunizations? that patients avoid live viral these trials, DMTs have been The American Academy of vaccines while receiving the shown to decrease the frequen- Neurology clinical practice drug.

Treatment... Treatment includes medications to prevent relapses, additional medications during acute relapses, and other medications and nonmedication treatments for symptom management. DMTs are approved to prevent relapses in patients with CISs, RRMS, and PPMS and in those with SPMS who have recurrent relapses. Less disability over time has been associated with high-efﬁcacy DMTs (natalizumab, ﬁngolimod, alemtuzumab, cladribine, ocrelizumab, rituximab, and mitoxantrone). Vitamin D supplementation may also be helpful when serum levels are low. High-dose corticosteroids are the standard treatment for acute relapses, although plasma exchange, adrenocorticotrophic hormone gel, and cyclophosphamide can be used. Symptoms are managed on an individual basis through combined use of pharmacologic and nonpharmacologic means. CLINICAL BOTTOM LINE

COVID-19 and Multiple Sclerosis The COVID-19 Neurology the latest developments practice is to continue DMTs in Resource Center (www.aan. regarding the interaction patients with multiple sclerosis com/tools-and-resources/covid- between SARS-CoV-2 and neu- because these therapies and 19-neurology-resource-center) rologic conditions, including COVID-19 do not seem to affect keeps practitioners updated on multiple sclerosis. Current each other (45).

© 2021 American College of Physicians ITC14 In the Clinic Annals of Internal Medicine In the Clinic Patient Information https://medlineplus.gov/multiplesclerosis.html https://medlineplus.gov/spanish/multiplesclerosis.html Information and handouts in English and Spanish from Tool Kit the National Institutes of Health's MedlinePlus. www.ninds.nih.gov/disorders/all-disorders/multiplesclerosis-information-page https://espanol.ninds.nih.gov/trastornos/esclerosis_ Multiple Sclerosis multiple.htm Information in English and Spanish from the National Institute of Neurological Disorders and Stroke.

www.nationalmssociety.org/What-is-MS www.nationalmssociety.org/Resources-Support/ Library-Education-Programs/Informacion-en-Espanol Resources in English and Spanish from the National Multiple Sclerosis Society. Information for Health Professionals www.thelancet.com/journals/laneur/article/PIIS1474- 4422(17)30470-2/fulltext 2017 revisions of the McDonald criteria for diagnosis of multiple sclerosis.

www.aan.com/Guidelines/home/GuidelineDetail/899 2018 practice guideline systematic review summary on disease-modifying therapies for adults with multiple sclerosis from the American Academy of Neurology.

www.aan.com/Guidelines/home/GuidelineDetail/974 2019 practice guideline update summary on vaccine- preventable infections and immunization in multiple sclerosis from the American Academy of Neurology.

www.nationalmssociety.org/For-Professionals/Clinical- Care Resources from the National Multiple Sclerosis Society. In the Clinic

What Is Multiple Sclerosis? Multiple sclerosis is a progressive, chronic disease that affects the central nervous system. It causes the immune system to attack cells in the brain, spinal cord, and optic nerves. It is important to diagnose and treat multiple sclerosis early to prevent relapse, delay disease progression, and maximize quality of life. Doctors don't know for sure what causes multiple sclerosis, but it is most likely a combination of environmental and genetic factors. It affects women more than men. What Are the Symptoms? How Is It Treated? Symptoms differ depending on where the nerve • You and your neurologist will come up with a cells are damaged. Symptoms may come and go, treatment plan that is best for you based on the or they may be permanent. They can include: type of multiple sclerosis you have. • Changes in vision (1 eye more common than • Early treatment with immunotherapy is very both eyes) important and has been shown to lower risk for • Muscle weakness relapse, disease progression, and development • Fatigue of new lesions in many patients. • Loss of balance or trouble with coordination • A multidisciplinary approach to care that includes • Tremors, numbness, or slurred speech nondrug therapies (physical, occupational, and • Partial or total paralysis speech therapy) and symptom management • Thinking or memory problems (pain, muscle stiffness and spasms, fatigue, and • Frequent urge to urinate bladder problems) may help preserve function and quality of life. Many patients with multiple sclerosis experience • “flares” or “relapses” when symptoms suddenly Steroids, such as prednisone, can reduce nerve inflammation during a relapse or flare. get worse or new ones appear and last more • than 24 hours. Low levels of vitamin D are common in patients with multiple sclerosis and are associated with How Is It Diagnosed? increased risk for relapse. You may be instructed • No single test is available to diagnose multiple to take a vitamin D supplement. sclerosis. Your doctor will ask about your medical • Lifestyle changes, including a healthy diet, being history, do a physical examination, and run a physically active, and getting enough sleep, may combination of other tests. also help symptoms. • Blood tests may show signs of other illnesses that Questions for My Doctor cause symptoms similar to those of multiple sclerosis. • What kind of multiple sclerosis do I have? • Magnetic resonance imaging is essential for diag- • What can I do to manage my symptoms? nosis. It takes a detailed picture of your brain and • Will my symptoms get worse over time? spinal cord, where lesions that suggest multiple • What treatments are available to me? sclerosis may be present. • What are the risks and side effects of the • More specialized testing may be needed if the di- treatment? agnosis is unclear. • How often should I have follow-up visits?

For More Information MedlinePlus https://medlineplus.gov/multiplesclerosis.html National Multiple Sclerosis Society www.nationalmssociety.org/What-is-MS Patient Information

© 2021 American College of Physicians ITC16 In the Clinic Annals of Internal Medicine Appendix Figure. Overview of the components of the immune system that are involved in pathogenesis of MS and where various medications exert their actions.

Immunopathogenesis of the MS Lesion

K-channel T CD8 Ab+C Oligo Pl blockers

NO Memantine B Riluzole Minocycline IFN Th2 TNF IL-10 Th3 Glutamate TGF B7 CD28 Trl MCP-1 MIP-1 Thl Thl7 IP-10 Microglia RANTES B CD40L GA Foxp3 BBB CD40 Steroids

Minocycline Plasmapheresis Statins, E2 VCAM-1 MMP-2/9 VCAM-1 Mitoxantrone IFN- IL-4 Th2 IL-5 Alemtuzumab Antegren Th3 VLA-4 VLA-4 B IL-6 IL-13 Trl Fingolimod Thl Rituximab TGF Laquininmod IFN Thl7 IL-6/TGF Teriflunomide TNF IL-4 & IL-10 IL-12 B7CD28 Cladribine APC Thp Rapamycin Thp APC Sade 27 CD4 Daclizumab CD4 CD40 CD40L

5-HT = 5-hydroxytryptamine; Ab+C = antibody plus complement; APC = antigen-presenting cell; APRIL = a proliferation-inducing ligand; ATP = adenosine triphosphate; B = B cell; BAFF = B-cell–activating factor; CTL = cytotoxic T lymphocytes; FcR = Fc receptor; GA = glatiramer acetate; ICAM-1 = intercellular adhesion molecule 1; IFN = interferon; IL = interleukin; IP-10 = interferon c-inducible protein-10; LFA-1 = lymphocyte function-associated antigen 1; MCP = monocyte chemotactic protein; MIP = macrophage inﬂamma- tory protein; MMP = matrix metalloproteinase; MS = multiple sclerosis; NAA =N-acetyl aspartate; NO = nitric oxide; Oi = free oxygen radicals; Pl = plasma cell; RANTES = regulated on activation, normal T cell expressed and secreted; TACI = transmembrane activator and calcium-modulating cyclophilin ligand; TGFb =transforminggrowthfactorb; Th = T helper; Thp = T-helper precursor; TNFa = tumor necrosis factor a; VCAM-1 = vascular cell adhesion molecule 1; VLA-4 = very late antigen 4. Reprinted from Journal of Neuroimmunology, vol. 176, Dhib-Jalbut S, Arnold DL, Cleveland DW, et al, “Neurodegeneration and Neuroprotection in MS and Other Neurodegenerative Diseases,” pp. 198-215, copyright 2006, with permission from Elsevier.