The Evolution in Diagnosis and Treatment of Multiple Sclerosis

The Evolution in Dignosis nd Tretment of Multiple Sclerosis Tiffni Stroup, DO University of Chicgo Medicine, Chicgo, Illinois Abstrct Mngement of multiple sclerosis (MS) hs evolved significntly since the first disese-modifying therpy (DMT) ws introduced. With incresing demnd for mgnetic resonnce imging (MRI), MS often is on the differentil dignosis of nonspecific white-mtter lesions. Mking n ccurte dignosis remins crucil to select pproprite therpies. Red flgs in either the history or imging should rise suspicion tht n lterntive dignosis my be more likely. MRI is extremely useful to neurologists s they dignose ptients, monitor response to therpy, nd, potentilly, mesure trophy s mrker for disbility. Tretment decisions should be individulized, but certin fctors (eg, MRI evidence of cliniclly silent disese t dignosis) cn help physicins decide to use more ggressive therpies erlier. Trnsitioning to different DMTs cn be guided by blncing the risks nd benefits of such tretments. Tretment of symptoms due to MS cn improve qulity of life. Use of screening tools t follow-up visits cn help in the identifiction of MS-specific symptoms. A multidisciplinry pproch of incorporting ncillry services, ddressing polyphrmcy, nd strting specific medictions is most effective in combting common symptoms. M ngement of multiple sclerosis (MS) hs chnged significntly since mgnetic resonnce imging (MRI) nd the first disese-modifying therpies (DMTs) were introduced into clinicl prctice. Ptients re being dignosed erlier in the course of disese, nd they my be mintined on DMT for decdes. These developments hve led to incresed demnd for mking n ccurte dignosis nd recognizing potentil mimics of MS, becuse DMTs re expensive nd my cuse potentilly serious side effects. n ESTABLISHING AN ACCURATE DIAGNOSIS Bsed on presenttion by Hether Jen McLen, MD, Deprtment of Neurology, University of Ottw, nd Director, MS Clinic, The Ottw Hospitl, Ottw, Ontrio, Cnd. Since the 2010 McDonld criteri were introduced, there hs been n urgency to dignose MS erly. 1 These criteri llowed for dignosis bsed upon just one MRI scn. Becuse multiple relpses erly in the course of the disese led to more disbility, the focus of MS therpy remins prevention of ttcks. Unfortuntely, misdignosis occurs in pproximtely 5% 10% of cses nd is lrgely due to misinterprettion of MRI findings nd filure to recognize disorders tht mimic MS. Among the nerly 100 disorders tht cn mimic MS rdiologiclly re microvsculr disese, migrine hedches, nd psychogenic phenomen. 2 Tretment nd prognosis vry for these disorders, mking pproprite dignosis crucil. Certin red flgs in the history such s progression of symptoms, childhood or elderly onset, similr fmily history, or hering loss should prompt evlution for nother disese process. Similrly, red flgs relted to imging include lesions tht re tumefctive, longitudinlly extensive, or do not involve the corpus cllosum. When red flgs re detected, the physicin should crete differentil dignosis nd proceed with the pproprite workup, which my include contrst-enhnced imging of the neuroxis, lumbr puncture, nd evoked potentils. 3 If pproprite, tretment cn be strted, but working dignosis should be mintined. The prctitioner should keep high index of suspicion tht the cse my evolve nd tht tretment eventully my need to be djusted. Alterntively, it my be pproprite to dely tretment if the presenttion is reltively benign nd the dignosis is still uncler. However, in typicl cses, tretment should not be delyed, nd ncillry tests cn led to flse positives. 2 Specific Diseses nd Disorders Tht Mimic MS Susc s syndrome is rre condition tht typiclly occurs in people 20 40 yers of ge nd more commonly in women thn in men. This dignosis is chrcterized by the clssic trid of visul loss, hering loss, nd encephlopthy. Pthogenesis of Susc s syndrome is ttributed to microngiopthic chnges in the nervous system, with correltion of imging findings in the corpus cllosum nd white mtter. Notble findings long the corpus cllosum include T2 hyperintensities or T1 blck holes positioned round the midportion tht project s rdilly oriented icicle- or snowbll-shped lesions. Chrcteristic white-mtter lesions resemble string of perls in the internl cpsule Dr. Stroup is Multiple Sclerosis Fellow in the Deprtment of Neurology, University of Chicgo Medicine, Chicgo, Illinois. T H E N E U R O L O G Y R E P O R T S u m m e r 2 0 1 4 17

on diffusion-weighted imging. Tretment is necdotl nd usully involves immunosuppression with corticosteroids, cyclophosphmide, mycophenolte mofetil, zthioprine, or intrvenous (IV) immunoglobulin. Prognosis vries gretly from miniml disbility to significnt cognitive nd hering deficits, but most cses re self-limited nd cn lst from 6 months to 5 yers. 3 Neurosrcoidosis. The pthogenesis of this rre disorder is relted to inflmmtory grnuloms ffecting multiple orgn systems, such s the lungs, skin, eyes, joints, nd nervous system. Neurologic involvement from srcoidosis my include optic neuritis, crnil neuropthies, peripherl neuropthy, myopthy, chronic meningitis, or hypothlmic dysfunction. Most cses re monophsic, but one third of cses my be relpsing nd remitting. In the United Sttes, this disese predominntly ffects Africn-Americns, wheres Cucsins re preferentilly ffected in Europe. Dignosis includes MRI signs of prenchyml or leptomeningel involvement, cerebrospinl fluid (CSF) findings of lymphocytic pleocytosis, imging of other involved systems, nd gllium scn tht my show chrcteristic pnd sign representing bilterl lcriml nd protid glnd uptke. 3 Acute disseminted encephlomyelitis my be difficult to distinguish from MS. Ptients present with fulminnt neurologic dysfunction hours to dys fter vccintion or infection nd typiclly re encephlopthic. Relpses cn occur, lthough rrely, nd new neurologic symptoms occurring within 3 months of the initil dignosis re still considered monophsic. The workup includes MRI showing lrge white-mtter lesions tht re similr in ge with vrible enhncement. Lumbr puncture findings typiclly re negtive for oligoclonl bnds. Nerly one hlf of ptients with this disese recover completely. 3,4 Hereditry leukodystrophies. A history of fmily members dying young with significnt neurologic disbility should prompt investigtion for hereditry leukodystrophies, which cn lso mimic MS. Most of these diseses present in childhood with progressive neurologic dysfunction nd re due to n utosomlrecessive or X-linked recessive defect in myelin production or mintennce. An exmple of hereditry leukodystrophy tht cn present in dulthood is dultonset utosoml-dominnt leukodystrophy, which rdiologiclly presents with confluent frontoprietl white-mtter lesions tht spre the periventriculr re nd involve the corticospinl trcts nd cerebellr peduncles. 3 Cerebrl utosoml-dominnt rteriopthy with subcorticl infrcts nd leukoencephlopthy should be considered in the differentil dignosis of MS. Clinicl fetures include subcorticl infrcts t young ge, migrine hedches with or without n ur, vsculr dementi, nd depression. Dignosis cn be mde with genetic testing for the NOTCH3 muttion on chromosome 19 or by skin biopsy showing deposits in vessel wlls tht test positive with periodic cid-schiff stining. Chrcteristic MRI findings include confluent white-mtter T2 hyperintensities in the temporl poles nd externl cpsules. 3 Neuromyelitis optic (NMO) is demyelinting disorder tht my be mistken for MS, but its distinct clinicl fetures include preferentil involvement of the optic nerves nd longitudinlly extensive trnsverse myelitis extending over three or more spinl cord segments (Tble 1). 5 Pthology of this disorder is necrotizing involvement of the prenchym, nd imging cn show swelling of the spinl cord. Other thn MRI orbits nd spinl imging to demonstrte T2 lesions with TABLE 1 Dignostic Criteri for Neuromyelitis Optic Optic neuritis + myelitis + two of the following: Longitudinlly extensive trnsverse myelitis (three or more vertebrl segments) noted on mgnetic resonnce imging (MRI) MRI nondignostic for multiple sclerosis Positive for serum neuromyelitis optic immunoglobulin G (NMO-IgG) Source: Sellner et l 5 vrible enhncement, the dignostic workup lso includes MRI of the brin, which my demonstrte some T2 hyperintensities round the third nd fourth ventricles but is otherwise unremrkble; CSF tht typiclly shows elevted protein nd neutrophilic pleocytosis nd tht tests negtive for oligoclonl bnds; nd serum positivity to NMO immunoglobulin G (IgG). Tretment is empiricl, consisting of immunosuppression with rituximb or zthioprine; however, prognosis is poor, s most ptients re left with residul disbility. 5 Progressive multifocl leukoencephlopthy (PML) mimics MS nd should be considered in immunosuppressed ptients. Ptients with PML present with subcute neurologic phenomen due to John Cunninghm virus (JCV) infection of the brin. Clssiclly, MRI shows lrge subcorticl T2 hyperintensities with irregulr borders, which cn involve the gry mtter, typiclly presenting in the temporl, prietl, nd occipitl regions nd extending to the U fibers; these lesions do not enhnce with contrst. Most ffected ptients undergo brin biopsy, which shows oligodendrocyte inclusions of JCV nd enlrged strocytes. 3 n THE USE AND MISUSE OF MRI IN DIAGNOSIS AND TREATMENT Bsed on presenttion by Nicol De Stefno, MD, Deprtment of Medicine, Surgery nd Neuroscience, University of Sien, Sien, Itly. In neurologic prctice, MRI is useful tool to dignose MS, monitor response to tretment, nd evlute possible side effects nd tissue loss. Over the pst 10 yers, the number of MRI scns ordered hs incresed in both the United Sttes nd Europe. 6 Thus, neurologists hve become incresingly fmilir with typicl MS brin lesions, which re ovoid, irregulrly shped, nd distributed symmetriclly. These lesions evolve in vrying ptterns nd occur in typicl loctions: periventriculr, juxtcorticl, infrtentoril, nd long the corpus cllosum. 7 Cliniclly Isolted Syndrome (CIS) Since the 2010 McDonld criteri were introduced (Tble 2), 1 ptients with 18 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

TABLE 2 2010 Revised McDonld Criteri for Dignosis of Multiple Sclerosis (MS) Clinicl presenttion Two or more ttcks ; objective clinicl evidence of two or more lesions or one lesion with resonble historic evidence of prior ttck b Two or more ttcks ; objective clinicl evidence of one lesion One ttck ; objective clinicl evidence of two or more lesions One ttck ; objective clinicl evidence of one lesion (cliniclly isolted syndrome) None c Additionl dt needed for MS dignosis Dissemintion in spce, demonstrted by: One or more T2 lesions in t lest two of four MS-typicl centrl nervous system (CNS) regions (periventriculr, juxtcorticl, infrtentoril, or spinl cord) d or Awit further clinicl ttck implicting different CNS site Dissemintion in time, demonstrted by: The simultneous presence of symptomtic gdolinium-enhncing nd nonenhncing lesions t ny time or A new T2 nd/or gdolinium-enhncing lesion(s) on follow-up MRI, irrespective of its timing with reference to bseline scn or Awit second clinicl ttck Dissemintion in spce nd time, demonstrted by: For dissemintion in spce: One or more T2 lesions in t lest two of four MS-typicl CNS regions (periventriculr, juxtcorticl, infrtentoril, or spinl cord) d or Awit second clinicl ttck implicting different CNS site nd For dissemintion in time: The simultneous presence of symptomtic gdolinium-enhncing nd nonenhncing lesions t ny time or A new T2 nd/or gdolinium-enhncing lesion(s) on follow-up MRI, irrespective of its timing with reference to bseline scn or Awit second clinicl ttck Insidious neurologic One yer of disese progression (retrospectively or prospectively determined) plus two of the following three criteri d : progression suggestive Evidence of dissemintion in spce in the brin bsed on one or more T2 lesions in MS-chrcteristic regions of MS (PPMS) (periventriculr, juxtcorticl, or infrtentoril) Evidence of dissemintion in spce in the spinl cord bsed on two or more T2 lesions in the cord Positive cerebrospinl fluid findings (isoelectric focusing evidence of oligoclonl bnds nd/or elevted IgG index) If the criteri re fulfilled nd there is no better explntion for the clinicl presenttion, the dignosis is MS ; if suspicious, but the criteri re not completely met, the dignosis is possible MS ; if nother dignosis rises during the evlution tht better explins the clinicl presenttion, then the dignosis is not MS. An ttck (relpse, excerbtion) is defined s ptient-reported or objectively observed events typicl of n cute inflmmtory demyelinting event in the CNS, current or historic, with durtion of t lest 24 hours, in the bsence of fever or infection. It should be documented by contemporneous neurologic exmintion, but some historic events with symptoms nd evolution chrcteristic for MS, but for which no objective neurologic findings re documented, cn provide resonble evidence of prior demyelinting event. Reports of proxysml symptoms (historic or current) should, however, consist of multiple episodes occurring over not less thn 24 hours. Before definite dignosis of MS cn be mde, t lest one ttck must be corroborted by findings on neurologic exmintion, visul evoked potentil response in ptients reporting prior visul disturbnce, or MRI findings consistent with demyelintion in the re of the CNS implicted in the historic report of neurologic symptoms. b Clinicl dignosis bsed on objective clinicl findings for two ttcks is most secure. Resonble historic evidence for one pst ttck, in the bsence of documented objective neurologic findings, cn include historic events with symptoms nd evolution chrcteristics of prior inflmmtory demyelinting event; t lest one ttck, however, must be supported by objective findings. c No dditionl tests re required. However, it is desirble tht ny dignosis of MS be mde with ccess to imging bsed on these criteri. If imging or other tests (for instnce, CSF exmintion) re undertken nd the results re negtive, extreme cution should be tken before mking dignosis of MS, nd lterntive dignoses must be considered. There must be no better explntion for the clinicl presenttion, nd objective evidence must be present to support dignosis of MS. d Gdolinium-enhncing lesions re not required; symptomtic lesions re excluded from considertion in ptients with brinstem or spinl cord syndromes. Source: Polmn et l 1 CIS hve been dignosed with cliniclly definitive MS if the initil MRI findings fulfill the criteri for both dissemintion in spce nd time. Dissemintion in spce is defined s the presence of t lest one lesion in two or more chrcteristic res (periventriculr, juxtcorticl, infrtentoril, or spinl cord). In contrst, dissemintion in time requires either the presence of symptomtic gdoliniumenhncing nd non-enhncing lesions on one scn or new T2 lesion or gdolinium-enhncing lesion on repet MRI scn. 1 These criteri help to simplify the dignostic process by requiring less imging to dignose MS. Rdiologiclly Isolted Syndrome (RIS) RIS hs been defined in recent yers s incidentl MRI findings tht resemble MS lesions without ny clinicl correlte. Clinicl criteri proposed to dignose RIS (Tble 3) 7 require tht ptients hve no history of neurologic dysfunction nd tht other MS mimics hve been ruled out. At 5 yers fter initil dignosis, two thirds of ptients with RIS will show progression TABLE 3 Chrcteristics of T2 Hyperintensities in Rdiologiclly Isolted Syndrome Ovoid Well circumscribed Homogeneous My or my not involve the corpus cllosum Size > 3 mm Fulfills three of four criteri for dissemintion in spce Not consistent with vsculr distribution Source: Okud et l 7 T H E N E U R O L O G Y R E P O R T S u m m e r 2 0 1 4 19

of MRI findings, nd one third will hve clinicl mnifesttions. Certin risk fctors tht increse the odds of developing clinicl progression include cervicl spinl cord or infrtentoril loction, numerous lesions, younger ge, pregnncy, bnorml visul evoked potentils, the presence of oligoclonl bnds in the CSF, or elevted IgG index plus the presence of t lest 10 initil T2 lesions on MRI. 6 Use of MRI for Tretment Decisions For ptients lredy on DMT, progression of MRI lesions over prespecified period of time my help guide further tretment. Ptients tking interferon β who experience more thn one relpse or one relpse nd t lest four new T2 lesions within 1 yer of inititing therpy re likely to be nonresponders. 8,9 The Itlin Neurologicl nd Neurordiologicl Societies hve proposed tht ptients with CIS undergo MRI t bseline nd t 3 months nd 1 yer fter dignosis; for ptients with relpsing-remitting MS, MRI should be performed t 6, 12, 24, nd 36 months fter tretment begins nd, if ptients re cliniclly stble, every 2 yers therefter. 10 MRIs my be useful for detecting PML, which cn be deleterious side effect of ntlizumb therpy. In ptients who re nti-jcv ntibody positive, MRI should be repeted nnully fter ntlizumb therpy begins, nd discontinution of ntlizumb should be considered. 11 Certin chrcteristics, such s lck of mss effect for lrge lesions nd subcorticl loction, cn help distinguish PML from new MS lesion. 3 Assessment of Brin Tissue Loss Brin trophy cn be seen t ny stge of MS, but it tends to be more severe in secondry progressive MS nd correltes with clinicl disbility. Unfortuntely, lck of stndrdiztion limits the widespred use of brin trophy mesures in MS ptients. To further complicte this issue, pseudotrophy relted to resolution of inflmmtion cn be seen fter initition of DMT. 12 MRI findings my be useful in guiding dignosis, prognosis, nd sfety of MS tretment. For comprison purposes, ptients should hve repet imging done on the sme MRI scnner with stndrdized MS protocols. 12 n TREATMENT OPTIMIZATION FOR RELAPSING MS Bsed on presenttion by Mrk S. Freedmn, MD, MSc, Professor of Neurology nd Director, Multiple Sclerosis Reserch Unit, University of Ottw, Ottw, Ontrio, Cnd. Tretment of MS should be individulized for ech ptient. However, certin fctors, such s estimted risk of disese progression nd mediction sfety profile, my help guide such decisions. Relpses erly in the course of MS decrese the functionl reserve of the brin nd contribute to xonl loss. With the dignostic criteri for CIS, physicins my intervene t the first neurologic presenttion of MS. The type of tretment initilly provided my vry if the ptient is presenting erly, with reltively mild disese burden on MRI, or lter, with high rdiologic burden of previously silent disese. 13 Wht Fctors Should Be Considered Before Inititing Tretment? TABLE 4 Tiers of Tretment in Multiple Sclerosis First-line Injectble: interferon β-1, interferon β-1b, gltirmer cette Orl: teriflunomide, dimethyl fumrte, fingolimod Second-line Intrvenous: ntlizumb, lemtuzumb (not pproved in the US) Orl: fingolimod Third-line Intrvenous: mitoxntrone, cldribine, cyclophosphmide Source: Freedmn et l 13 During the first 5 yers fter dignosis, fctors relted to poor prognosis with risk for fster disese progression include non-cucsin descent; initil presenttion with multiple neurologic deficits; incresed numbers of ttcks; shortened time between ttcks; evidence of disbility; high lesion lod on MRI; nd erly involvement of disese ffecting motor, cerebellr, or bowel nd bldder function. High disese burden on MRI is defined by two or more gdolinium-enhncing lesions with t lest nine T2 hyperintensities. 13 Individuliztion of MS tretment should ccount for the current severity of the disese, the ptient s experience with other therpies, medicl comorbidities, nd desired onset of therpeutic effect. Determintion of estimted disese progression soon fter dignosis cn be chllenging, but this cn be key fctor in deciding whether first-line or more ggressive therpies should be strted. Ptients with low risk of imminent disese progression should be plced on first-line gents with proven long-term sfety. Alterntively, ptients with the previously mentioned risk fctors for poor prognosis t disese onset cn be considered t high risk for imminent disese progression nd my be cndidtes for more ggressive immunosuppressnt medictions tht hve nrrow sfety profile. 13 Clinicl trils of DMT hve shown vrible relpse rtes for MS. However, cler definition of tretment tiers is complicted by lck of comprison trils. Moreover, the use of older gents in newer studies hs been ssocited with lower relpse rtes thn previously noted, perhps s result of tril ptients entering trils erly in the course of disese or fter they hve received DMT. 13 Lstly, tretment should be individulized, s tril dt re not necessrily pplicble to ll ptients. In the low-risk ptient, initition of first-line therpy with interferons, gltirmer cette, or ny of the orl gents is resonble (Tble 4). 13 Key fctors to further individulize therpy include sfety bsed on medicl comorbidities nd tolerbility, since this mediction is intended to be used for long period. In the high-risk ptient, escltion of therpy to second-tier gents nd bove my be considered with the trde-off of more serious sfety concerns. Escltion of therpy cn be temporry; for exmple, in induction, second-line or bove gent is used to chieve desired response gol, nd then therpy is switched to sfer first-line gent when the disese is reltively quiescent. An lterntive pproch involves the use of permnent escltion, 20 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

TABLE 5 Level of Concern Bsed on the Number nd Timing of Relpses, Disbility Progression, nd Number of Lesions Detected on Mgnetic Resonnce Imging Relpses nd Level of Concern Level of concern Criterion Low Medium High Rte One relpse in the second yer of One relpse in the first yer of More thn one relpse in the first tretment tretment yer of tretment Severity Mild Moderte Severe Steroids not required Steroids not required Steroids nd/or hospitliztion Miniml effect on ctivities of dily Moderte effect on ctivities of dily required living living Severe effect on ctivities of dily One functionl domin ffected More thn one functionl domin living No or mild motor nd/or cerebellr ffected More thn one functionl domin involvement Moderte motor nd/or cerebellr ffected involvement Severe motor nd/or cerebellr involvement Recovery (durtion) Prompt recovery Incomplete recovery t 3 months Incomplete recovery t 6 months No functionl deficit Some functionl impirment Functionl impirment Level of concern determined by meeting t lest one criterion Disbility Progression nd Level of Concern Level of concern Criterion Low Medium High EDSS score 3.5 1 point 2 points t 6 months > 2 points t 6 months or 2 points t 12 months 4.0 5.0 < 1 point 1 point t 6 months > 1 point t 6 months or 1 point t 12 months 5.5 0.5 point t 6 months > 0.5 point t 6 months Cliniclly No motor involvement Some motor, cerebellr, or cognitive Pronounced motor, cerebellr, or documented Minor sensory involvement involvement cognitive involvement progression Multiple EDSS domins ffected Multiple EDSS domins ffected Chnge in Timed 20% increse confirmed t > 20% nd < 100% increse confirmed 100% increse confirmed t 25-Foot Wlk Test b 6 months t 6 months 6 months EDSS = Expnded Disbility Sttus Scle If EDSS progression lone is used to ssess response to tretment, ny chnge requires subsequent confirmtion t 3 6 months. b From bseline (estblished with wlking id, if needed) Annul MRI Findings nd Level of Concern Level of concern Criterion Low Medium High Number of new gdolinium-enhncing lesions per yer or nnul ccumultion of new T2 lesions 1 lesion 2 lesions 3 lesions MRI = mgnetic resonnce imging Routine follow-up MRI with gdolinium is recommended 6 12 months fter inititing therpy for relpsing-remitting multiple sclerosis (or in cliniclly isolted syndrome if therpy is not initited). New T2 lesions tht re lso enhncing on the sme scn re counted only once s unique ctive lesions. The presence of gdolinium-enhncing lesions is more relible thn new T2 lesion counts. New T2 lesion counts require high-qulity comprble MRI scns nd interprettion by highly qulified individuls. Source: Freedmn et l 13 during which second-line gent is initited nd mintined for the best efficcy. 13 Defining Response to Tretment Nonresponse to tretment cn be defined s continued disese ctivity despite the use of DMT. Within the first yer of dignosis, ptients should be followed every 3 or 4 months, encourged to contct the office with mediction side effects or relpses, hve neuroimging t bseline nd surveillnce t 1 yer, nd hve lbortory prmeters monitored bsed on the therpy used. 13 Bseline neuroimging should be ccomplished when the drug is effective, which mens t lest 3 months fter strting drug tht ffects lymphocytes; these cells must undergo one life cycle before the full effect of the drug is seen. Mrkers for disese progression include the number of clinicl relpses, disbility progression, nd MRI findings. The Cndin Tretment Optimiztion Model hs been proposed s guide to switching therpy bsed on low, medium, or high risk of disese progression (Tble 5). 13 Ptients t low risk of disese progression hve up to one ttck by 2 yers of tretment, less thn 20% chnge noted in the Timed 25-Foot Wlk Test (T25FWT) t 6 months, nd fewer thn two new T2 lesions on MRI. Conversely, high-risk ptients hve more thn one ttck in the first yer of tretment, greter thn 100% chnge in the T25FWT t 6 months, nd three or more new T2 lesions on MRI. 13 T H E N E U R O L O G Y R E P O R T S u m m e r 2 0 1 4 21

Approching Disese Brekthrough A suboptiml response to tretment my result from poor tolernce to the DMT prescribed, finncil issues, or disese brekthrough. A chnge to new gent my be ccomplished by lterl switch to similrly effective DMT, induction therpy, or escltion mintennce. Ptients considered t low risk of imminent disese progression cn be switched vi lterl move, nd high-risk ptients typiclly require either temporry or permnent escltion. The lterl pproch cn be used with first-line medictions ptients re monitored in mnner similr to tht used during the first yer of tretment, with therpy esclted if further disese ctivity is noted. For ptients with more ggressive disese, n induction strtegy using second-line gent (eg, ntlizumb) my be given for 1 2 yers; use of the first-line gent then my be resumed with more cceptble sfety profile. In even more ggressive cses, escltion mintennce my be used, such tht second-line or higher-tier mediction is used indefinitely, since first-line gents my no longer be effective in this popultion. The long-term sfety profile of these gents is not well defined. Tretment with ntlizumb for more thn 2 yers in ptients who re positive for nti-jcv ntibody increses the risk of PML, nd use of mitoxntrone is limited by lifetime mximum exposure. As with ny tretment decision, switching should be bsed on risk-benefit profile, lthough newer gents do not hve clerly defined longterm sfety profile outside of clinicl trils. Individuliztion of tretment pln should be bsed on the perceived risk of disese progression, with use of more ggressive tretments reserved for ptients with lrge burden of silent lesions t initil presenttion or erly disese progression. 13 Erly on, pln should be in plce for switching mediction if the ptient hs erly disese progression or cnnot tolerte therpy with prticulr gent. n SYMPTOMATIC MANAGEMENT Bsed on presenttion by Stephen Krieger, MD, Assistnt Professor of Neurology, Mount Sini Medicl Center, New York, New York. Mnging MS ptients entils comprehensive evlution of symptoms tht my ffect them s result of the disese. At ech visit, ddressing these components cn help improve ptient functioning nd qulity of life. Often, ddressing the symptoms of disese involves multidisciplinry pproch nd, in some cses, is chieved by reducing polyphrmcy. Common symptoms ffecting MS ptients include ftigue, spsticity, wekness, blnce, mobility, tremor, proxysml symptoms, bldder issues, pin, nd depression. Ftigue Ftigue my be the most common MS symptom. Assessment of ftigue involves screening for depression, common medicl problems (eg, hypothyroidism), polyphrmcy, nd sleeping difficulty. The pthophysiology of ftigue in MS is multifctoril nd likely includes combintion of cytokines nd neurochemicls secreted throughout the nervous system. Underlying disbility my require extr energy expenditure, nd ftigue my be most prominent in excessively wrm wether or t the end of the dy. 14 Fctors tht cn contribute to poor sleep in ptients with MS include poorly treted pin or spsticity, restless legs syndrome, nd nxiety. The Epworth Sleepiness Scle is simple questionnire tht cn be completed by ptients to clrify whether poor sleeping hbits re contributing to ftigue. Affected ptients my be referred to sleep disorders clinic, since mngement of sleeping problems cn significntly improve ftigue. 15 After sleeping problems nd polyphrmcy hve been ddressed, ptients with continued ftigue cn try phrmcologic therpies. Vrious medictions such s mntdine, modfinil, nd methylphenidte hve been used to combt ftigue in ptients with MS with limited success nd should be selected on cse-by-cse bsis. 14 Spsticity On physicl exm, signs suggesting tht ptient is strting to develop spsticity my include wekness, pin, nd hyperreflexi. Identifying the type of spsticity s phsic or tonic my help guide further tretment decisions. Phsic spsticity is defined s pinful muscle spsms tht occur intermittently. Conversely, tonic spsticity is long-lsting nd is ssocited with stiffness nd restricted mobility. 16 The Modified Ashworth Spsticity Scle cn help quntify tonic spsticity nd my llow comprison cross visits. 17 Effective mngement of spsticity cn id in pin control, hygiene, prevention of contrctures, mobility, nd functionl independence. The most criticl portion of spsticity tretment is to remove ny contributing noxious stimuli. Spsticity initilly should be ddressed by physicl therpists. Beyond physicl therpy nd stretching, medictions cn be useful. First-line orl medictions (eg, bclofen, tiznidine, nd benzodizepines) cn be helpful, but their use often is limited by sedtion. Certin ntiepileptics (eg, gbpentin, crbmzepine, nd levetircetm) re useful for mnging phsic spsticity, prticulrly to brek the cycle of pin nd spsticity. Injection with botulinum toxin my improve focl spsticity, prticulrly in distl muscles, but it cuses wekness of the injected muscle. For ptients with generlized spsticity tht requires high doses of orl medictions, n intrthecl bclofen pump is nother tretment option. 18 Limited Mobility Mobility cn be limited due to wekness, dorsl column sensory loss, visul impirment, edem, or txi in MS. 19,20 Externl fctors such s socil ttitudes, ccessibility of businesses, nd climte lso contribute to limited mobility. Incorportion of physicl therpy for git ssessment nd evlution for ssistive devices cn be importnt in improving mobility in these ptients. Specific interventions such s nkle-foot orthosis, electricl stimultion, nd compression stockings lso my be beneficil. The T25FWT is useful screening tool for wlking impirment nd my be used s comprison tool cross visits to ssess chnges. Tretment with dlfmpridine cn improve performnce on the T25FWT but my cuse dizziness, 22 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

gstrointestinl upset, nd insomni. At higher doses, there is risk of seizures. Blnce nd coordintion often is ffected in MS ptients. Once gin, physicl therpy hs significnt role in teching blnce-trining exercises to ptients. 20 Bldder Difficulties Bldder difficulties cn occur in MS ptients due to either spstic (storge) or hypotonic (emptying) dysfunction. Differentiting between the types of dysfunction is crucil to guide tretment. Ptients with spstic bldder typiclly complin of urinry frequency nd urge incontinence, which re best treted with medictions such s oxybutynin. However, ptients with hypotonic bldders typiclly complin of urinry hesitncy, which is treted with α-drenergic 1 ntgonists or intermittent ctheteriztion. Initil evlution of bldder disorders should include screening for urinry trct infection, post-void residuls, nd occsionl referrl to urologist for urodynmic testing or cystometry. 21 Episodic Symptoms Episodic symptoms in MS cn lso be disturbing. Proxysml symptoms include pin, tonic spsms cusing intermittent dysrthri, myokymi, sensory phenomen (eg, trigeminl neurlgi, Lhermitte s phenomenon, nd numbness), or Uhthoff s phenomenon, which cuses trnsient visul impirment. Tretment should be directed t the type of complint, but pin nd sensory symptoms hve improved with use of either ntidepressnts or nticonvulsnts (eg, crbmzepine or gbpentin). Ptients with trigeminl neurlgi who do not respond to phrmcologic intervention my be referred to neurosurgeon for surgicl intervention. A course of IV corticosteroids is resonble option if the sensory or visul complints re new nd signify relpse. 18,22 Mood Impirment Mood impirment cn be disbling symptom of MS. Depression is common; its exct cuse is not known, but it my be rection to the dignosis, sign of the unpredictbility of the disese, or side effect of interferon therpy. Unfortuntely, ptients with untreted depression cn experience worsening of other MS symptoms. Screening for depression includes dministering simple two-question test recommended by the US Preventive Services Tsk Force, which screens for depressed feelings or nhedoni over the previous 2 weeks. Common side effects of ntidepressnt therpy include nticholinergic effects, sexul dysfunction, nd weight gin. 23,24 Pseudobulbr ffect chrcterized by outbursts of inpproprite lughing or crying lso my occur in MS ptients. A US Food nd Drug Administrtion pproved mediction tht combines dextromethorphn nd quinidine my significntly reduce the frequency nd severity of outbursts due to pseudobulbr ffect. 24 Summry Incorporting ncillry services, referrls to other specilists, nd pproprite phrmcologic interventions my improve the qulity of life of MS ptients significntly. Too often, ptients my express hopelessness due to the dignosis of chronic, potentilly disbling disese. Mngement of secondry symptoms is s vluble s prevention of further relpses. REFERENCES 1. Polmn CH, Reingold SC, Bnwell B, et l. Dignostic criteri for multiple sclerosis: 2010 revisions to the McDonld criteri. Ann Neurol. 2011; 69:292 302. 2. Rolk LA, Fleming JO. The differentil dignosis of multiple sclerosis. Neurologist. 2007;13:57 72. 3. Chril A, Yousry TA, Rovris M, et l. MRI nd the dignosis of multiple sclerosis: expnding the concept of no better explntion. Lncet Neurol. 2006;5:841 852. 4. Miller DH, Weinshenker BG, Filippi M, et l. Differentil dignosis of suspected multiple sclerosis: consensus pproch. Mult Scler. 2008;14:1157 1174. 5. Sellner J, Boggild M, Clnet M, et l. EFNS guidelines on dignosis nd mngement of neuromyelitis optic. Eur J Neurol. 2010;17:1019 1032. 6. Grnberg T, Mrtol J, Kristoffersen-Wiberg M, Aspelin P, Fredrikson S. Rdiologiclly isolted syndrome-incidentl mgnetic resonnce imging findings suggestive of multiple sclerosis: systemtic review. Mult Scler. 2013;19:271 280. 7. Okud DT, Mowry EM, Beheshtin A, et l. Incidentl MRI nomlies suggestive of multiple sclerosis: the rdiologiclly isolted syndrome. Neurology. 2009;72:800 805. 8. Rio J, Cstillo J, Rovir A, et l. Mesures in the first yer of therpy predict the response to interferon bet in MS. Mult Scler. 2009;15:848 853. 9. Sormni MP, De Stefno N. Defining nd scoring response to IFN-β in multiple sclerosis. Nt Rev Neurol. 2013;9:504 512. 10. Filippi M, Rocc MA, Bstinello S, et l. Guidelines from the Itlin Neurologicl nd Neurordiologicl Societies for the use of mgnetic resonnce imging in dily life clinicl prctice of multiple sclerosis ptients. Neurol Sci. 2013;34:2085 2093. 11. SØrenson PS, Bertolotto A, Edn G, et l. Risk strtifiction for progressive multifocl leukoencephlopthy in ptients treted with ntlizumb. Mult Scler. 2012;18:143 152. 12. Simon JH, Li D, Trboulsee A, et l. Stndrdized MR imging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. AJNR Am J Neurordiol. 2006;27:455 461. 13. Freedmn MS, Selchen D, Arnold DL, et l. Tretment optimiztion in MS: Cndin MS working group updted recommendtions. Cn J Neurol Sci. 2013;40:307 323. 14. Lpierre Y, Hum S. Treting ftigue. Int MS J. 2007;14:64 71. 15. Brss SD, Duquette P, Proulx-Therrien J, Auerbch S. Sleep disorders in ptients with multiple sclerosis. Sleep Med Rev. 2010;14:121 129. 16. Hwker K, Frohmn E, Rcke M. Levetircetm for phsic spsticity in multiple sclerosis. Arch Neurol. 2003;60:1772 1774. 17. Ghotbi N, Nkhostin AN, Nghdi S, et l. Mesurement of lower-limb muscle spsticity: intrrter relibility of Modified Ashworth Scle. J Rehbil Res Dev. 2011;48:83 88. 18. Pollmnn W, Feneberg W. Current mngement of pin ssocited with multiple sclerosis. CNS Drugs. 2008;22:291 324. 19. Olggiti R, Burgunder JM, Mumenthler M. Incresed energy cost of wlking in multiple sclerosis: effect of spsticity, txi, nd wekness. Arch Phys Med Rehbil. 1988;69;846 849. 20. Bethoux F. Git disorders in multiple sclerosis. Continuum. 2013;19:1007 1022. 21. DsGupt R, Fowler CJ. Bldder, bowel nd sexul dysfunction in multiple sclerosis: mngement strtegies. Drugs. 2003;63:153 166. 22. O Connor AB, Schwid SR, Herrmnn DN, et l. Pin ssocited with multiple sclerosis: systemtic review nd proposed clssifiction. Pin. 2008;137:96 111. 23. Frgoso YD, Adoni T, Ancleto A, et l. Recommendtions on dignosis nd tretment of depression in ptients with multiple sclerosis. Prct Neurol. 2014;14:206 209. 24. Minden SL, Feinstein A, Klb RC, et l. Evidence-bsed guideline: ssessment nd mngement of psychitric disorders in individuls with MS: report of the Guideline Development Subcommittee of the Americn Acdemy of Neurology. Neurology. 2014;8:174 181. T H E N E U R O L O G Y R E P O R T S u m m e r 2 0 1 4 23