Annals of Internal MedicineT In the ClinicT Multiple Sclerosis 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 sclero- sis. 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 app- roved 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 mul- tiple 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