Treatment of pediatric multiple sclerosis and variants

Treatment of pediatric multiple sclerosisand variants

D Pohl MD E Waubant MD PhD B Banwell MD D Chabas MD PhD T Chitnis MDB Weinstock-Guttman MD and S Tenembaum MD for the International Pediatric MS Study GroupDagger

AbstractmdashStudies in adult patients with multiple sclerosis (MS) suggest significant benefit of early treatment initiationHowever there are no approved therapies for children and adolescents with MS For adult MS tolerability and efficacy ofseveral immunomodulatory and immunosuppressive drugs have been demonstrated Guidelines for the use of these MStherapies in children do not exist Several small cohort studies of the safety and tolerability of disease-modifying therapies(DMT) in children and adolescents with MS have been recently reported The side effects of interferon beta (IFNB) andglatiramer acetate (GA) appear to be similar to those reported by adults The long-term tolerability and safety have yet tobe established and efficacy data have yet to be studied In view of the potential for significant long-term physical andcognitive disability in children with MS and recent evidence that initiation of immunomodulatory therapy early in thecourse of MS improves long-term prognosis an increasing number of children and adolescents with MS are being offeredthe DMT approved for adults This review summarizes current knowledge of DMT in pediatric MS and experience inseveral centers treating pediatric MS and MS variants such as neuromyelitis optica or Devic disease Balo concentricsclerosis Marburg acute MS and Schilder disease (myelinoclastic diffuse sclerosis) Finally an overview of symptomaticMS therapies and experiences with these treatments in pediatric patients is provided

NEUROLOGY 200768(Suppl 2)S54ndashS65

Pediatric multiple sclerosis (MS) is often associatedwith a relatively high relapse rate early in the dis-ease However the conversion to a secondary pro-gressive course or long-term disability is thought tobe slower in children compared to adults Nonethe-less as a result of developing MS at an early ageindividuals reaching any given level of impairmentwill be younger than individuals with adult onsetdisease12

Disease-modifying therapies (DMT) for adult MSare now initiated soon after diagnosis based on sev-eral clinical trials that suggested benefits of earlytreatment3-5 Patients younger than 18 years werenot enrolled in pivotal trials of MS therapies andthus these therapies have not been officially ap-proved in the pediatric age group Since there ap-pears to be considerable overlap between MS inchildren adolescents and adults6 many young pa-tients are already receiving off label treatment withDMT approved for adult MS

Children and adolescents treated with immuno-modulating drugs seem to experience similar sideeffects as adult MS patients7-11 However because ofweight and body surface differences it is not clearhow the dosage should be adapted to maximize toler-ability and efficacy for individuals before they reach

adult size Furthermore general questions such asdrug effect on growth puberty or long-term adverseevents on the still immature immune system havenot yet been addressed In addition since all immu-nomodulating drugs are relatively new (maximumexperience of about 15 years in adults) unexpectedlong-term adverse events remain possible and couldbe of particular importance in younger patients

Current MS therapies The aim of drugs thatmodify the course of MS is to reduce the frequency ofclinical relapses and to prevent the progression ofdisability Current DMTs for MS modulate or sup-press the immune system (table 1) There are fourFood and Drug Administration (FDA)ndashapproved im-munomodulating agents for reducing MS relapses inadults three preparations of interferon beta (IFNB)and glatiramer acetate (GA)12-16 There is also oneFDA-approved immunosuppressive medication mi-toxantrone for patients with worsening MS17 Otherimmunosuppressive agents used empirically for pa-tients with aggressive MS include oral azathioprineIV immunoglobulins (IVIg) oral methotrexate oralmycophenolate mofetil IV cyclophosphamide andpulses of IV methylprednisolone (MP) Natalizumaban anti-alpha 4 integrin was granted FDA approval

The first authors contributed equally to this workDaggerMembers of the International Pediatric MS Study Group are listed in the AppendixFrom the Department of Pediatrics and Pediatric Neurology (DP) Georg-August-University Goettingen Germany Multiple Sclerosis Center at UCSF(EW DC) San Francisco CA Department of Pediatric Neurology (BB) The Hospital for Sick Children University of Toronto Canada MassachusettsGeneral Hospital for Children (TC) Brigham amp Womenrsquos Hospital Harvard Medical Boston Baird MS Center (BW-G) Jacobs Neurological InstituteBuffalo NY and Department of Pediatric Neurology (ST) National Pediatric Hospital Dr J P Garrahan Buenos Aires ArgentinaDisclosure The authors report no conflicts of interestAddress correspondence and reprint requests to Dr Emmanuelle Waubant UCSF MS Center 350 Parnassus Street Suite 908 San Francisco CA 94117e-mail EmmanuelleWaubantucsfedu

S54 Copyright copy 2007 by AAN Enterprises Inc

for relapsing forms of MS18-20 but safety concernsarising after three patients developed progressivemultifocal leukoencephalopathy (PML) led to its tem-porary removal from the market The FDA approvedits return in summer 2006 It is expected that thedrug will be used as a second line therapy in patientsintolerant to or failing on IFNB or GA

Treatment options and experience in pediatricMS and its variants Treatment for relapses Notherapeutic trial for relapses has yet been conductedin the pediatric MS population Therefore relapsetherapy is based on clinical experience and extrapo-lated from studies of acute relapse management inadult MS

Corticosteroids In adults mild relapses or re-lapses recovering spontaneously do not warrant highdose steroid treatment Relapses associated with sig-nificant neurologic impairment (eg interfering withdaily function) are usually treated promptly withhigh doses of IV glucocorticosteroids in order toshorten relapse duration and hasten recovery21-23

High doses of IV methylprednisolone (IVMP) (morethan 500 mgday for at least 3 days in adults) seemsuperior to lower doses (IV or oral)2425 Recent datasuggest that high doses of oral prednisone could sub-stitute for IV pulses in adult MS26 The typical regi-men in adults 1 g per day for 3 to 5 daysadministered IV is generally well tolerated23 exceptfor occasional insomnia mood changes and rarepsychosis

The most frequent side effects of high dose glu-cocorticosteroids are facial flushing sleep difficul-ties irritability and increased appetite In childrengrowth retardation is an additional concern with pro-longed corticotherapy Although side effects such ashigh blood pressure and hyperglycemia are rare es-

pecially in children treatment with corticosteroidsrequires careful monitoring of blood pressure urineglucose serum potassium and administration ofgastric protection The risk of side effects increaseswith prolonged use and total cumulative dose Corti-costeroids used in the doses reviewed are generallywell tolerated even when a short oral taper dose isgiven

Plasma exchange Plasma exchange has beenproposed to treat severe relapses in adult patientswith MS or NMO when they fail to recover aftertreatment with high-dose glucocorticosteroids27

Plasma exchange has also been proposed in childrento avoid side effects of frequent pulses of steroids asan alternative treatment for recurrent relapses oc-curring over a short period However the availableliterature in the pediatric population is restricted toa single case report of a 7-year-old patient with MSwith high titers of antinuclear autoantibody28

IV immunoglobulins The efficacy of IVIg hasnever been demonstrated as a preventative or cura-tive relapse therapy in MS or NMO In adult pa-tients IVIg therapy (04 gkg daily for 5 daysfollowed by three single infusions monthly for 3months) was not found to improve visual recoveryafter optic neuritis29 nor delay the time to progres-sion in secondary progressive (SP) MS (in a dosage of1gkg monthly)30 Although IVIg treatment in combi-nation with high dose glucocorticosteroids does notappear superior to high dose glucocorticosteroidsalone to treat relapses3132 IVIg (in a dosage of 04gkg daily for 5 days) has been somewhat helpful tochildren and adults with acute demyelinating at-tacks who do not improve after high dose MP33-38

Disease-modifying therapy Immunomodulatorytherapy Both GA and IFNB are immunomodula-tors and decrease relapse rate and MRI activity in

Table 1 Available approved therapies

Interferonbeta-1b

Interferonbeta-1a

Interferonbeta-1a

Random polypeptide(L-glutamic acid

L-lysine L-alanineand L-tyrosine) Mitoxantrone

Production E coli Mammaliancells

Mammaliancells

Synthetic Synthetic

Glycosylated No Yes Yes NA NA

Mutation Met 1 deletedCys 17 mutated

to a serine

No No NA NA

Administration SC every other day IM once a week SC threetimes a week

SC every day IV once every3 months up to

2 years

Dose per injection 250 g or 8 MIU 30 g 44 g 20 mg 12 mgm2

Development of neutralizingantibodies

35 2ndash5 12ndash24 No No

Side effects Flu-like reactionLFT increaseskin reaction

Flu-like reactionLFT increase

Flu-like reactionLFT increaseskin reaction

Systemic reactionskin reaction

Infection cardiotoxicityearly menopauseacute leukemia

LFT liver function test

April 17 2007 NEUROLOGY 68(Suppl 2) S55

adult patients with relapsing MS12-16 Two IFNB-1aand one IFNB-1b are FDA approved for RRMS (table1) IM IFNB-1a recently gained a label extension foradults experiencing an initial demyelinating attackalso termed a clinically isolated syndrome (CIS)None of these therapies has been approved for use inthe pediatric age group While there is some reportedexperience using these therapies in children withMS efficacy and tolerability data are extremely lim-ited especially in children under the age of 10 years

Interferon betandash1b (BetaseronBetaferon) A ret-rospective review of safety and tolerability ofIFNB-1b in a cohort of 43 children and adolescentswith MS was recently reported by an internationalworking group11 Eight medical centers worldwidewith expertise in the care of pediatric MS patientsparticipated in the study Treatment was initiated ata mean age of 13 years (eight children were less than11 years old at first injection) for a mean of 30months All but two children (both under age 10)received the full adult dose (8 million internationalunits [MIU]) 26 of them after an escalation from aninitial dose of 25 to 50 of full dose No serious orunexpected adverse events (AE) were reported Mostcommon AE included flu-like symptoms (35) ab-normal liver function test (LFT) (26) and injectionsite reactions (21) There was a trend to higherLFT changes in patients under 10 years of age Thissmall study and case reports of IFNB-1b treatmentin pediatric patients suggest a reasonable short-termsafety profile113940

Long-term efficacy studies are not available how-ever a case report of a 7-year-old boy treated withIFNB-1b (4 MIU SC every other day) did not showeither a significant clinical relapse or new lesions onfollow-up MRIs over a 3-year period39 In anotherreport a 15-year-old patient with SPMS treated withIFNB-1b (8 MIU SC three times per week) showedimproved neurologic status40

Interferon betandash1a IM (Avonex) Data on tolera-bility of weekly IM IFNB-1a for treatment of relaps-ing remitting MS (RRMS) in nine children 16 yearsof age was reported in a retrospective study7 Meanduration of therapy was 17 months (range 5 to 36months) One patient initiated therapy at one thirdof the dose (10 g weekly) two patients at one halfthe dose (15 g weekly) and six patients at full dose(30 g weekly) all but the youngest child (8 yearsold) were escalated to full dose within 1 month AEincluded flu-like symptoms (44) headaches (44)fever (22) and injection site soreness (11) Nopatient discontinued therapy due to AE

In another retrospective study 13 of 16 RRMSpatients below 18 years of age were treated withIFNB-1a IM41 All but the youngest patient (10 yearsold) were treated with full dose IFNB-1a side effectswere reported to be mild and included frequent flu-like symptoms and rare injection site erythemaTreatment was discontinued in 4 cases (31) be-cause of frequent relapses

Preliminary results of an Italian multicenter

study (The Immunomodulatory Treatment of Early-onset MS [ITEMS] study) reported 22 patients underthe age of 16 years who received IFNB-1a IM (30 gonce a week) for a mean duration of 191 months Areduction of annualized relapse rate from 31 (pre-treatment) to 03 and stable EDSS were reportedHowever in the absence of a randomized doubleblind control design efficacy data must be consid-ered with caution42

Interferon betandash1a (Rebif) In a cohort of 46 pa-tients with pediatric MS 22 g SC of IFNB-1a treat-ment was initiated three times weekly In fiveadditional patients with very active disease treat-ment was started at 44 g three times weekly Themean age of the participants was 146 years (range81 to 179 years)10 The mean duration of therapywas 18 years (range 1 month to 44 years) Sideeffects were similar to those described for adult pa-tients injection site reactions (71) flu-like symp-toms (65) gastrointestinal symptoms (10) andblood count (39) and LFT abnormalities (35) Twoof the 51 patients experienced serious AE A 12-year-old boy developed a systemic reaction including gen-eralized edema weakness fatigue and mild pleuraleffusion 4 weeks after initiating therapy with 22 gIFNB-1a three times a week Therapy was discontin-ued and his symptoms resolved within 2 weeks with-out any sequelae In the second case a 12-year-oldboy developed a depressive mood disorder after 13months of treatment (5 months after increasing thedose to 44 g three times weekly) Seven other pa-tients discontinued treatment due to various rea-sons headache (1) needle phobia (2) inefficacy (1)injection site necrosis (1) nausea (1) and fatigue (1)All but one of the patients could be treated with theadult recommended dose (22 to 44 g three timesweekly) Only a young patient of 8 years of age hadto be switched to 22 g IFNB-1a twice a week injec-tions due to liver enzyme elevation

In a 6-year prospective single-center open-labelstudy IFNB-1a treatment was initiated in 24 pa-tients of two treatment groups43 The mean age ofstudy participants was 127 years (range 38 to 179years) In the first treatment group IFNB-1a wasinitiated in eight children with a tentative dose cal-culated as 33 to 50 of the adult dose of 22 g threetimes weekly After a mean treatment of 29 months(18 to 48 months) the annual relapse rate had in-creased up to twofold compared to pretreatment val-ues and a planned dose escalation was subsequentlyperformed Twenty-three children tolerated the 22g tiw dose 16 of them from the beginning andseven after the dose-escalation phase The mean ex-posure to treatment was 444 months (range 12 to 89months) Tolerability was similar to that reported inpatients with adult-onset MS However two possibleserious AE were observed one patient developed adepressive mood disorder and attempted suicide af-ter 1 year of treatment and another developedtreatment-associated polyarthritis after 3 months onIFNB Therapy was discontinued permanently in

S56 NEUROLOGY 68(Suppl 2) April 17 2007

only one of the 24 patients due to concomitant poly-arthritis During the 6-year follow-up a significantreduction in the relapse rate compared to pretreat-ment values was observed but only in the relapsingremitting subgroup receiving IFNB-1a 22 g tiw

Additionally there is one case report of a 7-year-old child with RRMS treated with IFNb-1a SC whowas started at a dose of 2 MIU tiw44 The patientexperienced three minor relapses during the firstyear and a severe exacerbation during the secondtreatment year The dose was then increased to 6MIU (22 g) tiw Further follow-up is not available

None of the aforementioned studies was designedto objectively evaluate treatment efficacy Howeverone study reported increased annualized relapserates (ARR) at doses lower than 22 g tiw whereas22 g tiw was associated with decreased ARR (18pretreatment compared to 014 on drug) and disabil-ity compared to baseline43 In another study meanARR decreased on drug (19 pretreatment comparedto 08 on treatment with IFNB-1a SC 22-44 g tiw)10

The preliminary results of the ITEMS study includ-ing eight patients treated with IFNB-1a 22 g tiwshow a decrease of ARR from 41 pretreatment to 07after a mean treatment duration of 486 months42

Glatiramer acetate (Copaxone) GA appeared tobe safe and well tolerated in seven children withRRMS at the daily adult dose of 20 mg daily admin-istered SQ for 24 months45 Treatment was initiatedin children with a median age of 166 years Re-ported AE included injection site pain or induration(27) and transient systemic reaction (17) Althoughno patient discontinued therapy due to AE three ofseven children discontinued treatment due to fre-quent relapses and disability progression

A Web-based survey of 43 patients treated withGA under the age of 18 reported only one patientdiscontinuing therapy because of side effects9

Preliminary results of the Italian ITEMS studyincluded seven patients treated with GA under theage of 16 years After a mean treatment duration of147 months there was a reduced ARR from a base-line of 25 to 01 on drug and stable EDSS werereported42

IV immunoglobulins IVIg has been proposed forpediatric MS patients whose symptoms relapsewithin days or weeks of discontinuation of steroids9The reported regimen was 04 gkg initially givendaily for 5 days followed by subsequent IVIg pulseeither every other month or every 3 months for aduration ranging from 6 months to 1 year9 An alter-native regimen based on a study in adult MS pa-tients46 consists of monthly IVIg 1 gkgday on twoconsecutive days and appears to be well tolerated inthe pediatric age group (personal communication)

Immunosuppressive therapy Azathioprine Oralazathioprine in a dose of 25 to 3 mgkgday has beenused in MS to prevent exacerbations Data regardingits clinical benefits are available in adult MSpatients47-49 whereas MRI effects have only beenstudied in small groups of patients5051 Side effects

include cytopenia gastrointestinal intolerance livertoxicity and skin rashes The risk to develop canceron long-term therapy is unclear The drug remains areasonable alternative for patients refusing in-jectables tolerating poorly IFNB or GA or notresponding to these drugs but close monitoring ofthe complete blood count (CBC) and LFTs isrecommended

Management of poor responders As in adultswith MS some children fail treatment with IFNB orGA eg continue to present acute relapses and pro-gression of disability 6 to 12 months after initiatingappropriate regimen of various DMT There is noaccepted definition of MS treatment failure in adultsand children Anecdotal evidence from severalgroups indicates that a variety of treatments can beused as escalation therapy for children with MS in-cluding the addition of pulse IV steroid treatments toapproved DMT or a switch to chemotherapeuticagents including cyclophosphamide mitoxantronemethotrexate or mycophenolate mofetil Howeverthere is little experience with these medications inchildren and toxicities may limit their use in thepediatric population The experience with immuno-suppressive agents in adults is summarized belowOnly a small number of children received betweenone and three infusions of natalizumab 300 mg be-fore it was pulled off the market in February 2005Therefore no conclusion regarding its safety and ef-ficacy in children with MS can be made at this time

Cyclophosphamide The efficacy of cyclophospha-mide in advanced forms of SPMS is unclear52-54 al-though younger adult patients with relapsing MS54

or earlier stages of the disease55 may derive somebenefit In adults with relapsing disease doing poorlyon IFNB monthly pulses for 6 months have beenassociated with reduction of disease activity on serialMRI scans compared to monthly IVMP5657 Pulse cy-clophosphamide therapy is started at 800 mgm2

given every 4 weeks Dose should be titrated for atarget WBC nadir of 1500 to 2000mm3 obtained 10to 12 days after the infusion IVMP may be given asconcomitant treatment

Short- and long-term safety of cyclophosphamidehas not been established in the pediatric populationand common potential side effects may include nau-sea and vomiting following infusion risk of infectiontransient alopecia as well as menstrual irregulari-ties and gonadal failure Oral contraceptives or Lu-pron may provide some protection against gonadalfailure in girls and sperm banking should be consid-ered in boys Fluid loading prior to and after treat-ment helps prevent hemorrhagic cystitis The lengthof treatment varies from a few months to up to 3years with the maximum duration limited by thepotential risk of hemorrhagic cystitis bladder can-cer and hematologic malignancies

Mitoxantrone A phase III study in worseningadult MS demonstrated that recipients of mitox-antrone compared to placebo experienced significantbenefits at 24 months on disability progression


number of treated relapses and number of new T2-weighted MRI lesions17 Mitoxantrone 12 mgm2 isusually administered IV every 3 months up to 2years Above a cumulative dose of 120 mgm2 there isan increased risk of cardiotoxicity For this reasonmonitoring ventricular ejection fraction with cardiacecho or multigated angiocardiography (MUGA) isnow recommended before each infusion Other sideeffects include increased risk of infection earlymenopause and very rare therapy-induced leuke-mia The experience in children is limited

Oral methotrexate Oral methotrexate 75 mgper week may slow progression of disability in pa-tients with progressive MS as measured by a com-posite measure of disability ambulation handfunction and MRI5859 Methotrexate up to 20 mg perweek in association with folic acid (1 mgday) is cur-rently used occasionally in adult patients Therapycan result in macrocytic anemia that responds wellto folate supplement Other side effects include bonemarrow depletion gastrointestinal disturbancesliver toxicity and interstitial pneumonitis

Natalizumab Natalizumab treatment (300 mginfused monthly) decreases relapse rate by up to 68and reduces progression of disability by 42 over 2years18-20 Natalizumab reduces MRI activity in adultpatients with relapsing MS by up to 92 at year 1and 218-20 Safety concerns arising after three pa-tients developed PML led to a suspension of its usein February 2005 In summer 2006 the FDA ap-proved its return on the market as a monotherapywith a special restricted distribution program

Treatment for progressive forms of MS There isno approved therapy for primary progressive MS orsecondary progressive MS without relapses The ef-fect of IFNB on pure progression in SPMS isunclear60-63 Several phase II and III clinical trialshave failed to show a beneficial effect of IFNB-1a mi-toxantrone IVIg and GA on progression of disability inPPMS64-66 and SPMS30 Several drugs are used arbi-trarily off-label to attempt preventing progression inpatients with SPMS without superimposed exacerba-tion or PPMS that include pulses of IVMP67 oral meth-otrexate and IV cyclophosphamide

Taking into consideration the rarity of progressiveforms of MS in children it is unlikely that any clini-cal trials will be feasible in the future Treatmentdecisions will therefore have to rely on findings andrecommendations in adult MS patients

Experimental treatments Recent advances in thetreatment of adult MS include the evaluation of newimmunomodulatory agents and exploration of neuro-protective agents A subset of novel MS therapeuticshave been previously used for other disorders bothin adults and children and have an establishedsafety profile Included in this category are themonoclonal antibodies Daclizumab and rituximabAlthough efficacy of some drugs in the adult MSpopulation has been established strict safety profilesshould be established prior to use in pediatricpatients

General recommendations for the treatment ofpediatric MS Relapse therapy As in adults re-lapses associated with significant neurologic impair-ment warrant high-dose steroid treatment A typicalregimen used by child neurologists is IVMP 20 to 30mgkgday as 1 to 2 hour infusion in the morning for3 to 5 consecutive days In view of potential sideeffects of prolonged steroid treatment in pediatricpatients a subsequent oral taper should be re-stricted to patients with insufficient resolution ofsymptoms after IVMP or those patients who experi-ence recurrence of symptoms after IVMP discontinu-ation Steroid taper should be kept as short aspossible usually not exceeding 2 to 3 weeks (egprednisone 1 mgkgday as a single-morning doseduring the first 3 days after IVMP followed by pro-gressive dose reduction every 2 to 3 days) Althoughhigh doses of oral glucocorticosteroids (eg MP 10mgkgday as a single morning dose) are an alterna-tive to IVMP treatment there are no tolerability andefficacy data (apart from personal communications)for children and adolescents with MS Children withsevere relapses not improving after high-dose IVMPpulse or with contraindications to glucocorticoste-roids might benefit from a treatment with plasmaexchange

IVIg may be an option for children with contrain-dications to corticosteroids and mild to moderate at-tacks although efficacy has not been formallyinvestigated IVIg doses up to 1 gkgday on 2 consec-utive days might be administered

In children with frequent attacks despite exces-sive glucocorticosteroid exposure or with steroid de-pendency (eg recurrence of symptoms during orafter glucocorticosteroid taper) plasma exchange orIVIg treatment may be considered

Disease-modifying therapy Initiation The In-ternational Pediatric MS Study Group agreed thatimmunomodulatory treatment should be started inchildren and adolescents with active RR disease (de-fined clinically or by MRI scans) after MS is diag-nosed More than one exacerbation in a period of 1 to2 years and new T2-bright lesions or gadolinium-enhancing lesions on repeat brain MRI scans overthe same time frame warrant DMT In patients witha recent clinical exacerbation any MRI change orenhancement on a follow-up brain MRI 3 to 6months after the exacerbation would suggest diseaseactivity In patients whose initial episode includesencephalopathy the use of DMT should be delayeduntil a second or third attack with more typical MSfeatures has occurred to avoid giving DMT to a childwith ADEM or its variants

Choice of drug First-line MS therapies includeapproved drugs for adult MS IFNB-1a and -1b andGA The drug should be chosen after discussionswith the child and parents that include issues re-lated to compliance efficacy and tolerability In pa-tients with needle phobia or who cannot tolerateDMT a secondary option is azathioprine Alterna-tively IVIg treatment could be considered especially


for very young children (6 years and younger) givenlimited knowledge of tolerability of IFNB and GA inthis age group

Dosage Dose adjustment for IFNB in childrenyounger than 10 years or with a corresponding lowbody weight might be necessary especially at initia-tion of treatment The initial IFNB dose might bedecreased to 25 to 50 of the recommended full dosefor adults with MS followed by a stepwise escalationevery 2 to 4 weeks up to full or highest tolerateddose Use of acetaminophen (15 mgkg) or ibuprofen(10 mgkg) at the time of injections and if necessary4 to 6 hours thereafter will lessen frequency andseverity of flu-like symptoms during the first monthsof therapy GA regimen in children and adolescentsis similar to adult regimen No dose escalation isneeded For second line therapies such as azathio-prine and IVIg the dosage should be weight ad-justed as done in adult MS

Follow-up evaluations Both tolerability and effi-cacy should be evaluated during follow-up evalua-tions Interferon therapy requires laboratorymonitoring especially in the first months after initi-ation The authors recommend obtaining CBC withdifferential AST and ALT monthly until the fulldosage is reached every 3 months thereafter andwhenever the patientrsquos well-being is impaired Forpatients on azathioprine CBC every 3 to 6 monthswill guide decisions regarding the dose and checkingAST and ALT every 6 months will monitor liverfunction

One approach to evaluate treatment efficacy in anindividual patient is to perform neurologic examina-tions at baseline and at 1 3 and 6 months andevery 6 months thereafter In case of a stable diseasewithout attacks yearly follow-up may be sufficientlater on A repeat brain MRI scan with and withoutgadolinium should be obtained 6 to 12 months afterinitiating DMT This scan should be compared to thebaseline scan obtained around the time of treatmentinitiation After the first year of therapy in stablepatients (no clinical attacks no new T2-bright areason treatment at month 12) brain MRI scans can beobtained yearly

Change of treatment Change of DMT should beconsidered in the presence of severe side effects poorcompliance or in patients who appear to be poorresponders

Compliance To maximize compliance young pa-tients and their parents need regular support by fre-quent follow-up by the clinical team eg clinicvisits phone calls and a support network Adoles-cents are advised to learn to inject themselves andare encouraged to take control of their treatment Asnoted elsewhere in this conference report compli-ance is generally much better when children haveparticipated in their treatment decisions (see McAl-lister et al)67b

Management of poor responders and progressiveforms Addition of IVMP pulses (up to 1 gday on 3consecutive days monthly) or switch to mitox-

antrone (up to 12 mgm2 every 3 months) cyclophos-phamide (starting at 700 mgm2 monthly) ormethotrexate (up to 20 mg weekly) have been usedin a few pediatric MS patients who continued topresent significant numbers of clinical exacerbationsor new MRI lesions while on appropriate regimen ofIFNB or GA treated by members of the InternationalPediatric MS Study Group Meticulous follow-up pro-tocols are mandatory for all these treatments Na-talizumab therapy is restricted by the FDA topatients over 18 years of age There are currently toolittle safety data to consider its use in children

Treatment options and experience in pediatricpatients with MS variants Devic disease or neu-romyelitis optica NMO is the main MS variant inadults Due to the small number of patients therehas been no randomized clinical trial in this popula-tion Arbitrarily physicians have used approved oroff-label MS drugs Review of the published litera-ture suggests that IVMP (30 mgkgday [under 30 kgof body weight] to 1 gday [over 30 kg of body weight]for 3 to 5 days) and plasma exchanges for severeexacerbations insufficiently responding to IVMPmight help recovery2768 Long-term therapy with oralazathioprine or IV rituximab may decrease relapserate6970 The effect of IFNB and GA is unclear withonly isolated reports71 In three children with NMOwho were corticosteroid dependent combined ther-apy with monthly IV cyclophosphamide and oralmethylprednisolone (1 to 2 mgkgday) was well tol-erated Combination treatment seemed to reduce re-lapse rate and improve disability in two childrenwhereas the third one remained stable72 There areno published data regarding long-term immunosup-pressive therapy in children with NMO

Balo concentric sclerosis There has been notherapeutic trial for Balo concentric sclerosis due tosmall numbers of patients In adults treatmentswith corticosteroids73-82 mitoxantrone75 immunosup-pressants7580 and plasmapheresis79 have been re-ported to have various efficacy

To date only four Balo concentric sclerosis caseswith an early onset before the age of 18 years havebeen published8183-85 A 4-year-old boy and a 15-year-old girl were treated with high dose corticosteroidsand showed subsequent remission for the reportedfollow-up periods of 5 and 6 months8184 On the con-trary the effect of corticosteroids in a 13-year-oldgirl and a 16-year-old boy was questionable and ofshort duration8385 Azathioprine treatment did notprevent further attacks in the 16-year-old boy83

whereas IVIg treatment was followed by a long-lasting remission during a 30-month follow-up in the13-year-old girl85 In view of the sparse data on ther-apy for Balo disease no specific treatment recommen-dations can be made

Marburg acute MS Marburgrsquos variant of MS israre and there are no reports of pediatric cases inthe recent literature No controlled clinical trialshave been done and there are few reports on thera-


peutic interventions Treatment with steroids is of-ten unsuccessful86-91 Plasma exchange has beendescribed to be effective in single cases and in somepatients in a blinded clinical trial279092 Mitoxantronewas reported to maintain remission after plasma ex-changes in two patients9091 The treatment of pediat-ric patients with Marburg disease will have to relyon the experience in adult patients in whom plasmaexchange and immunosuppressive treatment seem tobe beneficial

Schilder myelinoclastic diffuse sclerosis Most re-ported cases of pediatric Schilder disease weretreated with high dose and often long coursecorticosteroids93-110 This treatment was followed bysome improvement in the majority of patients IVIgwas used in one patient with questionable effect101

and in two patients without effect101106 A 12-year-oldboy was treated with cyclophosphamide followed byazathioprine and was reported to be stable on thisregimen103 whereas azathioprine did not preventprogressive decline in a 12-year-old girl101 Cyclo-phosphamide treatment in combination with ACTHwas followed by complete recovery in another patientwho had failed to respond to ACTH alone111 Therapyof pediatric patients with myelinoclastic diffuse scle-rosis is based on both anecdotal reports of treatmentand recommendations for classic MS

Symptomatic therapy There are little publisheddata outlining the frequency of common MS symp-toms such as spasticity fatigue bladder dysfunc-tion and depression in the pediatric MS populationThe DMT available today and presented earlier inthis article benefit MS by decreasing the number ofrelapses and delaying the progression of physical dis-ability However these therapies often do not restorealready established impairment Symptomatic ther-apy plays a role in reducing the physical and emo-tional consequences of the disease

Spasticity The goal of spasticity treatment is toimprove mobility reduce pain and control painfulmuscle spasms In severely affected patients careinvolves positioning in order to prevent contracturesand pressure sores The treatments offered to reducespasticity in children with MS are very similar tomethods used in children with severe spastic cere-bral palsy Prior to initiation of any therapeutic pro-gram a careful review of systems is indicated toexclude confounding contributions to spasticity suchas urinary tract infection or pain due to musculoskel-etal or bone injury Initial management of spasticityutilizes daily stretching and physical therapy withparticular focus on range-of-motion exercises Ifstretching exercises are insufficient progressive ti-tration of antispastic medication can be consideredBaclofen a GABA agonist is the drug of choice formonotherapy It is particularly useful for reducingthe flexor or extensor spasms and increased flexortone Starting dose is usually 25 mg daily which canbe titrated up gradually to a maximum of 20 to 60mgday based on the response112113 Tizanidine a

central alpha-adrenergic agonist can be consideredas monotherapy for patients who do not tolerate ba-clofen Tizanidine is started usually at a dose of 1 mggiven at bedtime for children under 10 years and canbe initiated as 2 mg for children of 10 years or moremaintenance dose is 03 to 05 mgkgday dividedfour times daily114 Diazepam and clonazepam alsofacilitate GABA-mediated synaptic inhibition andmay be of value in selected patients However ben-zodiazepines have significant sedative side effectsand exhibit tolerance over time which often limitstheir utility Relatively low evening doses may beeffective for nocturnal stiffness and spasms espe-cially in combination with baclofen or tizanidine Di-azepam has been used in the dosage range from 1 to10 mg per dose it could be administered up to threeto four times per day115 Clonazepam is rapidly ab-sorbed after oral administration has a half-life of 18to 28 hours and has been used to reduce nighttimemuscle spasms Typical dosage in children is 001 to003 mgkgday divided BID or TID116 In cases ofmedically intractable spasticity or intolerance to oralmedications implantation of a pump placed in thelower abdomen with an intrathecal catheter (intra-thecal baclofen ITB) can deliver continuously ba-clofen with remarkable efficacy already proven in theadult MS population but also in a significant numberof children with cerebral palsy117 For patients resis-tant to the previously mentioned antispasticity inter-ventions selective botulinum toxin type A injectionscan be also considered Botulinum toxin has success-fully relieved severe leg adductor spasticity in somepatients but its high cost restricted muscle area ofbenefit and short lasting effect requiring repeatedadministrations limit its use Destructive proceduresincluding surgical neurectomy and rhizotomy areless frequently used since the introduction of the ITBpump and are of limited applicability

Fatigue Many children with MS complain of fa-tigue Patients who experience fatigue that is suffi-ciently severe to interfere with school performance orsocial activities may benefit from pharmacologictherapy When evaluating a complaint of fatigue it isimportant to exclude depression sleep disturbancesinappropriate dietary interventions or exhaustionrelated to physical disability and exposure to heatwhich should be diagnosed and appropriatelytreated

Pharmacologic management of fatigue in childrenis based on strategies utilized in the management ofadults with MS fatigue Amantadine 100 to 200 mgqd is the most commonly used antifatigue medicationin adult MS118 Amantadine is an NMDA receptorantagonist with antiviral neuroprotective and anti-parkinsonian effects A recent study showed amanta-dine to be safe and efficient in treating behavioralchanges associated with brain injury in children119

The dosage used as per pediatric recommendationswere as follows for age 6 to 9 years (weight 40 kg)5 mgkgday up to maximum dose of 150 mgday for


age 10 years or older and weight 40 kg 200mgday

If amantadine is not effective modafinil awakefulness-promoting agent should be consid-ered120121 The safety of modafinil 50 to 100 mg in themorning in the pediatric population was recentlyevaluated in a small group of children with spasticity

related to cerebral palsy122 Its effect on fatigue inpediatric MS is unknown Methylphenidate 10 to 40mg qd and its extended-release form methylpheni-date HCl SR are occasionally used to treat fatigue inadult MS The potassium channel blockers representa new approach for treatment of MS symptoms suchas weakness and fatigue This group of drugs includ-

Table 2 Medication data

Medication Dosing information Class Beneficial effects Common side effectsStrategies to reduce

side effects

Interferon beta

Interferonbeta-1b

8 MIU or 250 gevery other daysubcutaneously

Recombinantinterferon beta

ExacerbationsReduced by 30

Flu-like symptoms Begin with lower thantherapeutic dose andgradually escalate

Interferonbeta-1a

30 g onceper weekintramuscular


MRI Reduces theformation of new andenhancing lesions

Disability progressionAll DMT likely to haveeffect in delayingprogression ofdisability on MS-specificrating scales

Headache lymphopenialiver toxicity potentialfor spontaneous abortionor teratogenicityunknown

Premedicate withacetaminophen orNSAIDs

Interferonbeta-1a

22 or 44 g 3times per weeksubcutaneous


Fewer patients withclinically isolatedsyndromes of earlyMS and MRI abnormalitiestypical of MSdeveloped clinicallydefinite MS on interferonbeta over a 2-yearperiod

Production of neutralizingantibodies may renderagent ineffective in somecases neutralizingantibodies cross react toall interferon beta forms

Monitor laboratoryparameters (CBC andLFT) use ice andanesthetic cream forpainful injectionsites evening injectionto minimize sideeffects during theday use birth control

Other DMT

Glatirameracetateinjections

20 mg dailysubcutaneous

Syntheticpolymer

Reduces the number ofattacks by 30 fewernew lesions appear onMRI scan may haveneuroprotectiveproperties

Injection site reactions(mild) ldquosystemicrdquo panicattack-like reactionlipoatrophy noneutralizing antibodiespotential for spontaneousabortion or teratogenicityunknown

Use birth control

Mitoxantrone 12 mgm2 given IVevery 3 mo to alifetime maximumof 144 mgm2 notsure if shouldbe used incombination withthe other DMTagents

Cytotoxicantracenedione

FDA approved for usein worsening MSreduces the number ofattacks and progressionof disability MRIReduces the formationof new and enhancinglesions

At time of the IV Urineand sclera may turn bluefor hours mild nauseaday 14 after IV Dramatictransient white blood cellcount drop can worsenconcomitant infectionslong-term side effectsinfertility prematuremenopause cardiactoxicity more likelyat doses aboverecommended veryrare leukemia inducedcomplicationteratogenicity

Check CBC ESRand urinalysis withmicrobiology if neededbefore each infusionif chronic neutropeniaoccurs reduce thedoses or discontinueinterferon checkechocardiogram orMUGA scans atbaseline and beforeeach infusion potentialbenefit of usingLupron every 3 monthsto preserve fertilityin women

ContinuedThese effects apply to all Interferon beta therapies

ESR erythrocyte sedimentation rate


ing 4-aminopyridine and 3 4-diaminopyridine hasbeen tested in MS clinical trials showing benefit instrength and ambulation123 The side effect of mostconcern has been seizures and thus any child with ahistory of seizures should not be offered thesemedications

Tremor and ataxia Cerebellar tremor andataxia are among the most disabling neurologicsymptoms of MS and respond poorly to most thera-pies Fortunately although ataxia and tremor arecommon features of acute MS relapse in the authorsrsquoexperience most children show spontaneous improve-ment of these symptoms Occupational and physicaltherapy can be helpful in providing adaptive equip-ment (eg wrist weights Rollator peripheral cool-ing) for safe walking and other daily activities Inour experience clonazepam is the most effective

treatment for MS intention tremor (table 2) Anothertreatment option is primidone (initiated as 25 to 50mg hs and increased every 2 to 3 weeks up to 250 mgif tolerated)124 In adults stimulation of the ventralintermediate thalamic nucleus (deep brain stimula-tion DBS) is a promising new technique that hasbeen demonstrated to be effective in parkinsonianessential and intention tremor Preliminary resultsin adult MS patients have demonstrated consider-able success in tremor control The procedure is be-ing recommended only for carefully selected patientswith relatively stable disease in whom upper ex-tremity tremor is the most disabling symptom125

There is no published experience in children withMS

Paroxysmal symptoms Paroxysmal symptomsoccur abruptly during exacerbations of MS spread

Table 2 Continued

Symptomagenthowsupplied Mechanism of action Common side effects

Spasticity

Baclofen10 20 mg tab Agonist of GABA-B (inhibitory) receptor Dizziness weakness drowsiness mental confusion rapidwithdrawal should be avoided

Tizanidine2 4 mg tab Alpha-2 receptor agonist acts on polysynapticreflex arc

Sedation liver function abnormalities orthostatic hypotension

Diazepam2 510 mg tab

Enhance the GABAergic transmission Sedation addiction

Clonazepam051 2 mg tab


Dantrolene25 50100 mg

Direct action on skeletal muscle(decreasing the calcium releasefrom ER)

Weakness hepatotoxicity fatigue

Fatigue

Amantadine100 mg N-methyl-D aspartate antagonist Nausea unusual dreams peripheral edema livedo reticularis

Methylphenidate HCl1020 mg methylphenidateHCl SR20 mg

Central nervous stimulant Insomnia agitation

Modafinil100 mg Alpha-1 adrenergic agonistnoradrenalin reuptake inhibitor

Headache insomnia restlessness

Bladder disturbance

Oxybutinin5 mg andin the sustainedrelease formulation10 mg 15 mg

Anticholinergic agent Constipation dry mouth increased risk of urinary retention

Tolterodine2 mgDetrol LA 4 mg


Hyoscyamine0125 orthe sustained releaseformulation 0375 mg


TCA10 25 50 75 mg Tricyclic antidepressant withanticholinergic properties

Constipation dry mouth increased risk of urinary retentionconfusion orthostatic hypotension

DMT disease-modifying therapy MS multiple sclerosis NSAID nonsteroidal anti-inflammatory drug CBC complete bloodcount LFT liver function tests FDA Food and Drug Administration ESR erythrocyte sedimentation rate


within seconds and last for seconds to minutes withno enduring deficit They may present as motor tonicspasms or sensory paresthesias occur repeatedlyare promoted by hyperventilation and can be pain-ful Treatment with IVMP (500 mg to 1000 mgday)for 3 to 5 days may be sufficient to treat the relapsebut sometimes symptoms last several weeks and re-quire short-term symptomatic treatment Acetazol-amide can be initiated at the full dose (250 mg BIDndashTID in adults) with the advantage of not beingsedative contrarily to anticonvulsants Carbamaz-epine is also useful even in usually subtherapeuticanticonvulsant dosages

Cognitive impairment Cognitive impairmentoccurs in up to 50 of MS adult patients even inthe first stages of the disease and recent pediatricMS studies have called attention to similar defi-cits126127 Recent studies in adult MS suggest func-tional improvement using donepezil therapy128129

At this point a more in-depth understanding ofthe scope severity and consequences of cognitiveimpairment in pediatric MS patients is urgentlyrequired before pharmacologic intervention can beconsidered

Urologic and bowel disorders Disruption ofbladder function is a common and distressing prob-lem in adult MS patients but appears to be rela-tively infrequent in children with MS Neurogenicdisorders of the bladder include detrusor hyperre-flexia with urge incontinence frequently associ-ated with sphincter dyssynergia and areflexia withurinary retention A more exact evaluation is ob-tained using videourodynamic studies Early rec-ognition of abnormal urodynamic parameters canprevent serious urologic complications

Urinary tract infections are frequent in adultMS patients (40 to 60) and should be the firstconcern at the time of initial inquiry about bladderdisturbances Detrusor hyperreflexia (without sig-nificant post-voided urine residual [PVR] eg PVRbelow 100 mL) usually responds to anticholinergicagents The most commonly used are oxybutynintolterodine and hyoscyamine A recent study thatevaluated the effectiveness and tolerability oftolterodine (01 mgkgday for patients under 5years and 2 mgday for older children divided intotwo doses) and oxybutynin (04 mgkgday dividedinto three doses) in children with detrusor insta-bility showed that although the reductions in theurge urinary incontinence episodes were similarwith tolterodine and oxybutynin tolterodineshowed significantly better tolerability130 Anticho-linergic treatment overdose can result in urinaryretention Detrusor-sphincter dyssynergia (withsignificant urine residual PVR above 100 to 150mL) responds to combination of anticholinergicagents with intermittent straight catheterization(ISC) Severe nocturia unresponsive to eveningfluid restriction anticholinergic medication andISC might respond to desmopressin acetate nasalspray 01 to 02 mL (10 to 20 g) given at bedtime

Similar to bladder dysfunction bowel dysfunctionis rare in children with MS Constipation is morecommon than bowel incontinence but some pa-tients experience an alternating pattern Main-taining a good fluid intake scheduled defecation30 to 60 minutes after eating bulk-forming agents(bran and psyllium) and stool softeners such asdocusate sodium are often helpful

Summary Given the goal of inhibiting diseaseprogression and disability the Study Group sug-gests that children with MS be treated with theDMTs approved for use in adults Given the lim-ited experience and the lack of approved drugs inthe pediatric population the group strongly recom-mends that treatment is initiated and supervisedby practitioners experienced in pediatric MS Inview of the potential severe long-term conse-quences of pediatric MS treatment should not bedelayed into adulthood but started early in thedisease course

AppendixThe International Pediatric MS Study Group Lauren Krupp MD (chair)Brenda L Banwell MD Anita Belman MD Dorothee Chabas MD PhDTanuja Chitnis MD Peter Dunne MD Andrew Goodman MD Jin SHahn MD Deborah P Hertz MPH Nancy J Holland EdD RN MSCNDouglas Jeffery MD PhD William MacAllister PhD Raul Mandler MDMaria Milazzo RN MS CPNP Jayne Ness MD PhD Jorge OksenbergPhD Trena L Pelham MD Daniela Pohl MD PhD Kottil RammohanMD Mary R Rensel MD Christel Renoux MD Dessa Sadovnick PhDSteven Robert Schwid MD Silvia Tenembaum MD Cristina Toporas Em-manuelle Waubant MD PhD Bianca Weinstock-Guttman MD

References1 Boiko A Vorobeychik G Paty D Devonshire V Sadovnick D UBC MS

Clinic Neurologists Early onset multiple sclerosis A longitudinalstudy Neurology 2002591006ndash1010

2 Simone IL Carrara D Tortorella C et al Course and prognosis inearly-onset MS Comparison with adult-onset forms Neurology 2002591922ndash1928

3 Jacobs LD Beck RW Simon JH et al Intramuscular interferonbeta-1a therapy initiated during a first demyelinating event in multi-ple sclerosis N Engl J Med 2000343898ndash904

4 Comi G Filippi M Barkhof F et al Effect of early interferon treat-ment on conversion to definite multiple sclerosis a randomized studyLancet 20013571576ndash1582

5 PRISMS Study Group and the University of British Columbia MSMRIAnalysis Group PRISMS-4 Long-term efficacy of interferon-beta-1a inrelapsing MS Neurology 2001561628ndash1636

6 Hanefeld F Multiple sclerosis in childhood Curr Opin Neurol Neuro-surg 19925359ndash363

7 Waubant E Hieptas J Stewart T et al Interferon beta-1a in childrenwith multiple sclerosis is well tolerated Neuropediatrics 200132211ndash213

8 Banwell B Treatment of children and adolescents with multiple scle-rosis Exp Rev Neurother 20055391ndash401

9 Krupp LB Macallister WS Treatment of pediatric multiple sclerosisCurr Treat Options Neurol 20057191ndash199

10 Pohl D Rostasy K Gartner J Hanefeld F Treatment of early onsetmultiple sclerosis with subcutaneous interferon beta-1a Neurology200565888ndash890

11 Banwell B Reder AT Krupp L et al Safety and tolerability of inter-feron beta-1b in pediatric multiple sclerosis Neurology 200666472ndash476

12 The IFNB Multiple Sclerosis Study Group Interferon beta-1b is effec-tive in relapsing-remitting multiple sclerosis I Clinical results of amulticenter randomized double-blind placebo-controlled trial Neu-rology 199343655ndash661

13 Johnson KP and the Copolymer 1 Multiple Sclerosis Study GroupCopolymer 1 reduces relapse rate and improves disability in relapsingremitting multiple sclerosis results of a phase III multicenter doubleblind placebo-controlled trial Neurology 1995451268ndash1276

14 Jacobs LD Cookfair D Rudick R et al Intramuscular interferonbeta-1a for disease progression in relapsing multiple sclerosis AnnNeurol 199639285ndash294


15 PRISMS study group Randomised double-blind placebo-controlledstudy of interferon beta-1a in relapsing remitting multiple sclerosisLancet 19983521498ndash1504

16 Comi G Filippi M Wolinsky JS and the EuropeanCanadian Glati-ramer Acetate Study Group EuropeanCanadian multicenter double-blind randomized placebo-controlled study of the effect of glatirameracetate on magnetic resonance imaging-measured disease activity andburden in patients with relapsing multiple sclerosis Ann Neurol 200149290ndash297

17 Hartung HP Gonsette R Konig N et al Mitoxantrone in progressivemultiple sclerosis a placebo-controlled double-blind randomisedmulticentre trial Lancet 20023602018ndash2025

18 Miller DH Khan OA Sheremata WA et al A controlled trial of natali-zumab for relapsing multiple sclerosis N Engl J Med 200334815ndash23

19 Polman C OrsquoConnor P Havrdova E et al A randomized placebo-controlled trial of natalizumab for relapsing multiple sclerosis N EnglJ Med 2006354899ndash910

20 Rudick R Stuart W Calabresi P et al Natalizumab plus interferonbeta-1a for relapsing multiple sclerosis N Engl J Med 2006354911ndash923

21 Goodin DS Frohman EM Garmany GP et al Disease modifying ther-apies in multiple sclerosis report of the Therapeutics and TechnologyAssessment Subcommittee of the American Academy of Neurology andthe MS Council for Clinical Practice Guidelines Neurology 200258169ndash178

22 Andersson PB Goodkin DE Glucocorticosteroid therapy for multiplesclerosis a critical review J Neurol Sci 199816016ndash25

23 Brusaferri F Candelise L Steroids for multiple sclerosis and opticneuritis a meta-analysis of randomized controlled clinical trialsJ Neurol 2000247435ndash442

24 Beck RW The optic neuritis treatment trial three-year follow-up re-sults Arch Ophthalmol 1995113136ndash137

25 Oliveri RL Valentino P Russo C et al Randomized trial comparingtwo different high doses of methylprednisolone in MS a clinical andMRI study Neurology 1998501833ndash1836

26 Miller DM Weinstock-Guttman B Bethoux F et al A meta-analysisof methylprednisolone in recovery from multiple sclerosis exacerba-tions Mult Scler 20006267ndash273

27 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trialof plasma exchange in acute central nervous system inflammatorydemyelinating disease Ann Neurol 199946878ndash886

28 Takahashi I Sawaishi Y Takeda O Enoki M Takada G Childhoodmultiple sclerosis treated with plasmapheresis Pediatr Neurol 19971783ndash87

29 Noseworthy JH OrsquoBrien PC Petterson TM et al A randomized trialof intravenous immunoglobulin in inflammatory demyelinating opticneuritis Neurology 2001561514ndash1522

30 Hommes OR Sorensen PS Fazekas F et al Intravenous immunoglob-ulin in secondary progressive multiple sclerosis randomised placebo-controlled trial Lancet 20043641149ndash1156

31 Visser LH Beekman R Tijssen CC et al A randomized double-blindplacebo-controlled pilot study of iv immune globulins in combinationwith iv methylprednisolone in the treatment of relapses in patientswith MS Mult Scler 20041089ndash91

32 Sorensen PS Haas J Sellebjerg F Olsson T Ravnborg M IV immu-noglobulins as add-on treatment to methylprednisolone for acute re-lapses in MS Neurology 2004632028ndash2033

33 Finsterer J Grass R Stollberger C Mamoli B Immunoglobulins inacute parainfectious disseminated encephalo-myelitis Clin Neurop-harmacol 199821258ndash261

34 Nishikawa M Ichiyama T Hayashi T Ouchi K Furukawa S Intrave-nous immunoglobulin therapy in acute disseminated encephalomyeli-tis Pediatr Neurol 199921583ndash586

35 Apak RA Anlar B Saatci I A case of relapsing acute disseminatedencephalomyelitis with high dose corticosteroid treatment Brain Dev199921279ndash282

36 Pradhan S Gupta RP Shashank S Pandey N Intravenous immuno-globulin therapy in acute disseminated encephalomyelitis J NeurolSci 199916556ndash61

37 Sahlas DJ Miller SP Guerin M Veilleux M Francis G Treatment ofacute disseminated encephalomyelitis with intravenous immunoglobu-lin Neurology 2000541370ndash1372

38 Murthy SN Faden HS Cohen ME Bakshi R Acute disseminatedencephalomyelitis in children Pediatrics 2002110e21

39 Adams A Tyor W Holden K Interferon beta-1b and childhood multi-ple sclerosis Pediatr Neurol 199921481ndash483

40 Schilling S Haertel C Sperner J Follow-up of interferon beta-1btreatment in a 15-year-old patient with secondary progressive multi-ple sclerosis Neuropediatrics 200233A31

41 Mikaeloff Y Moreau T Debouverie M et al Interferon treatment inpatients with childhood-onset multiple sclerosis J Pediatr 2001139443ndash446

42 Ghezzi A Ruggieri M Trojano M Filippi M and the ITEMS StudyGroup Italian studies on early-onset multiple sclerosis the presentand the future Neurol Sci 2004 24S346ndashS349

43 Tenembaum SN Segura MJ Interferon beta-1a treatment in child-hood and juvenile-onset multiple sclerosis Neurology 200667511ndash513

44 Etheridge LJ Beverley DW Ferrie C McManus E The use of inter-feron beta in relapsing-remitting multiple sclerosis Arch Dis Child200489789ndash791

45 Kornek B Bernert G Balassy C Geldner J Prayer D Feucht MGlatiramer acetate treatment in patients with childhood and juvenileonset multiple sclerosis Neuropediatrics 200334120ndash126

46 Sorensen PS Wanscher B Jensen CV et al Intravenous immunoglob-ulin G reduces MRI activity in relapsing multiple sclerosis Neurology1998501273ndash1281

47 Goodkin DE Baily RC Teetzen ML Hertsgaard D Beatty WW Theefficacy of azathioprine in relapsing-remitting multiple sclerosis Neu-rology 19914120ndash25

48 Yudkin PL Ellsion GW Ghezzi A et al Overview of azathioprinetreatment in multiple sclerosis Lancet 19913381051ndash1055

49 Palace J Rothwell P New treatments and azathioprine in multiplesclerosis Lancet 1997350261

50 Cavazzuti M Merelli E Tassone G Mavilla L Lesion load quantifica-tion in serial MR of early relapsing multiple sclerosis patients inazathioprine treatment A retrospective study Eur Neurol 199738284ndash290

51 Massacesi L Parigi A Barilaro A et al Efficacy of azathioprine onmultiple sclerosis new brain lesions evaluated using magnetic reso-nance imaging Arch Neurol 2005621843ndash1847

52 Hauser SL Dawson DM Lehrich JR et al Intensive immunosuppres-sion in progressive multiple sclerosis a randomised three-arm studyof high-dose intravenous cyclophosphamide plasma exchange andACTH N Engl J Med 1983308173ndash180

53 Canadian Cooperative Multiple Sclerosis Study Group The Canadianco-operative trial of cyclophosphamide and plasma exchange in pro-gressive multiple sclerosis Lancet 1991337441ndash446

54 Weiner H Mackin G Orav E et al Intermittent cyclophosphamidepulse therapy in progressive multiple sclerosis final report of theNortheast Cooperative Multiple Sclerosis Treatment Group Neurol-ogy 199343910ndash918

55 Hohol MJ Olek MJ Orav EJ et al Treatment of progressive multiplesclerosis with pulse cyclophosphamidemethylprednisolone responseto therapy is linked to the duration of progressive disease Mult Scler19995403ndash409

56 Gobbini MI Smith ME Richert ND Frank JA McFarland HF Effectof open label pulse cyclophosphamide therapy on MRI measures ofdisease activity in five patients with refractory relapsing-remittingmultiple sclerosis J Neuroimmunol 199999142ndash149

57 Smith DR Weinstok-Guttman B Cohen J et al Randomized trial ofpulse cyclophosphamide in IFNB resistant active MS Neurology 2002A455 (suppl 3)

58 Goodkin DE Rudick RA VanderBrug Medendorp S Low-dose (75 mg)oral methotrexate reduces the rate of progression in chronic progres-sive multiple sclerosis Ann Neurol 19953730ndash40

59 Goodkin DE Rudick RA VanderBrug Medendorp S Daughtry MMVan Dyke CD Low-dose oral methotrexate in chronic progressive mul-tiple sclerosis analyses of serial MRIrsquos Neurology 1996471153ndash1157

60 Kappos L Polman C Pozzilli C et al Final analysis of the Europeanmulticenter trial on IFNbeta-1b in secondary-progressive MS Neurol-ogy 2001571969ndash1975

61 Li DK Zhao GJ Paty DW University of British Columbia MSMRIAnalysis Research Group The SPECTRIMS Study Group Random-ized controlled trial of interferon-beta-1a in secondary progressive MSMRI results Neurology 2001561505ndash1513

62 Secondary Progressive Efficacy Clinical Trial of RecombinantInterferon-beta-1a in MS (SPECTRIMS) Study Group Randomizedcontrolled trial of interferon-beta-1a in secondary progressive MS clin-ical results Neurology 2001561496ndash1504

63 Cohen JA Cutter GR Fischer JS et al Benefit of interferon beta-1aon MSFC progression in secondary progressive MS Neurology 200259679ndash687

64 Leary SM Miller DH Stevenson VL Brex PA Chard DT ThompsonAJ Interferon beta-1a in primary progressive MS An exploratoryrandomized controlled trial Neurology 20036044ndash51

65 Kita M Cohen J Fox B A phase II trial of mitoxantrone in patientswith primary progressive multiple sclerosis Neurology 200462(suppl5)A99

66 Wolinsky J Pardo L Stark Y et al Effect of glatiramer acetate onprimary progressive multiple sclerosis initial analysis of the com-pleted PROMiSe trial Neurology 200462(suppl 5)A97

67 Goodkin DE Kinkel RP Weinstock-Guttman B et al A phase II studyof iv methylprednisolone in secondary-progressive multiple sclerosisNeurology 199851239ndash245

67b Macallister WS Boyd JR Holland NJ et al for the InternationalPediatric MS Study Group The psychosocial consequences of pediat-ric multiple sclerosis Neurology 200768(suppl 2)S66ndashS69

68 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Wein-shenker BG Plasma exchange for severe attacks of CNS demyelina-tion predictors of response Neurology 200258143ndash146


69 Mandler RN Ahmed W Dencoff JE Devicrsquos neuromyelitis optica aprospective study of seven patients treated with prednisone and aza-thioprine Neurology 1998511219ndash1220

70 Cree BAC Lamb S Morgan K Chen A Waubant E Genain C Anopen label study of the effects of rituximab in neuromyelitis opticaNeurology 2005641270ndash1272

71 Wingerchuk DM Neuromyelitis optica current concepts Front Biosci20049834ndash840

72 Tenembaum S Segura MJ Astorino F Rios V Katsicas MM Russo RNeuromyelitis optica in children clinical course and preliminary re-sults of immunosuppressive treatment Neurology 2003 60(suppl 1)A480

73 Moore GR Neumann PE Suzuki K et al Balous concentric sclerosisnew observations on lesion development Ann Neurol 198517604ndash611

74 Spiegel M Kruger H Hofmann E Kappos L MRI study of Balorsquosconcentric sclerosis before and after immunosuppressive therapy JNeurol 1989236487ndash488

75 Hanemann CO Kleinschmidt A Reifenberger G Freund HJ Seitz RJBalorsquos concentric sclerosis followed by MRI and positron emission to-mography Neuroradiology 199335578ndash580

76 Gharagozloo AM Poe LB Collins GH Antemortem diagnosis of Baloconcentric sclerosis correlative MR imaging and pathologic featuresRadiology 1994191817ndash819

77 Korte JH Bom EP Vos LD Breuer TJM Wondergem JHM Baloconcentric sclerosis MR diagnosis Am J Neuroradiol 1994151284ndash1285

78 Kim MO Lee SA Choi CG Huh JR Lee MC Balorsquos concentric sclero-sis a clinical case study of brain MRI biopsy and proton magneticresonance spectroscopic findings J Neurol Neurosurg Psychiatry 199762655ndash658

79 Sekijima Y Tokuda T Hashimoto T et al Serial magnetic resonanceimaging (MRI) study of a patient with Balorsquos concentric sclerosistreated with immunoadsorption plasmapheresis Mult Scler 19972291ndash294

80 Moore GRW Berry K Oger JJF et al Balorsquos concentric sclerosissurviving normal myelin in a patient with a relapsing-remitting clini-cal course Mult Scler 20017375ndash382

81 Karaarslan E Altintas A Senol U et al Balorsquos concentric sclerosisclinical and radiologic features of five cases Am J Neuroradiol 2001221362ndash1367

82 Kastrup O Stude P Limmroth V Balorsquos concentric sclerosis Evolu-tion of active demyelination demonstrated by serial contrast-enhancedMRI J Neurol 2002249811ndash814

83 Louboutin JP Elie B Treatment of Balorsquos concentric sclerosis withimmunosuppressive drugs followed by multimodality evoked poten-tials and MRI Muscle Nerve 1995181478ndash1480

84 Murakami Y Matsuishi T Shimizu T et al Balorsquos concentric sclerosisin a 4-year-old Japanese infant Brain Dev 199820250ndash252

85 Pohl D Rostasy K Krone K Hanefeld F Balorsquos concentric sclerosisassociated with primary human herpesvirus 6 infection J Neurol Neu-rosurg Psychiatry 2005761723ndash1725

86 Lebow S Anderson DC Mastri A Larson D Acute multiple sclerosiswith contrast-enhancing plaques Arch Neurol 197835435ndash439

87 Mendez MF Pogacar S Malignant monophasic multiple sclerosis orldquoMarburgrsquos diseaserdquo Neurology 1988381153ndash1155

88 Johnson MD Lavin P Whetsell WO Jr Fulminant monophasic mul-tiple sclerosis Marburgrsquos type J Neurol Neurosurg Psychiatry 199053918ndash921

89 Wood DD Bilbao JM OrsquoConnors P Moscarello MA Acute multiplesclerosis (Marburg type) is associated with developmentally immaturemyelin basic protein Ann Neurol 19964018ndash24

90 Jacquerye P Ossemann M Laloux P Dive A DeCoene B Acute fulmi-nant multiple sclerosis and plasma exchange Eur Neurol 199941174ndash175

91 Jeffery DR Lefkowitz DS Crittenden JP Treatment of Marburg vari-ant multiple sclerosis with mitoxantrone J Neuroimaging 20041458ndash62

92 Rodriguez M Karnes WE Bartleson JD Pineda AA Plasmapheresisin acute episodes of fulminant CNS inflammatory demyelination Neu-rology 1993431100ndash1104

93 Poser CM Goutieres F Carpentier MA Aicardi J Schilderrsquos myelino-clastic diffuse sclerosis Pediatrics 198677107ndash112

94 Mehler MF Rabinowich L Inflammatory myelinoclastic diffuse sclero-sis Ann Neurol 198823413ndash415

95 Rodesch G Avni EF Parizel P et al Schilderrsquos disease neuroradio-logical findings J Neuroradiol 198815386ndash393

96 Lana-Peixoto MA dos Santos EC Schilderrsquos myelinoclastic diffusesclerosis J Clin Neuroophthalmol 19899236ndash240

97 Barth PG Derix MM de Krom MC Valk J Theunissen PM Schilderrsquosdiffuse sclerosis case study with three yearsrsquo follow-up and neuro-imaging Neuropediatrics 198920230ndash233

98 Eblen F Poremba M Grodd W Opitz H Roggendorf W Dichgans JMyelinoclastic diffuse sclerosis (Schilderrsquos disease) cliniconeuroradio-logic correlations Neurology 199141589ndash591

99 Afifi AK Bell WE Menezes AH Moore SA Myelinoclastic diffusesclerosis (Schilderrsquos disease) report of a case and review of the litera-ture J Child Neurol 19949398ndash403

100 Stachniak JB Mickle JP Ellis T Quisling R Rojiani AM Myelino-clastic diffuse sclerosis presenting as a mass lesion in a child withTurnerrsquos syndrome Pediatr Neurosurg 199522266ndash269

101 Garell PC Menezes AH Baumbach G et al Presentation manage-ment and follow-up of Schilderrsquos disease Pediatr Neurosurg 19982986ndash91

102 Pretorius ML Loock DB Ravenscroft A Schoeman JF Demyelinatingdisease of Schilder type in three young South African children dra-matic response to corticosteroids J Child Neurol 199813197ndash201

103 Leuzzi V Lyon G Cilio MR et al Childhood demyelinating diseaseswith a prolonged remitting course and their relation to Schilderrsquosdisease report of two cases J Neurol Neurosurg Psychiatry 199966407ndash408

104 Fitzgerald MJ Coleman LT Recurrent myelinoclastic diffuse sclero-sis a case report of a child with Schilderrsquos variant of multiple sclero-sis Pediatr Radiol 200030861ndash865

105 Afifi AK Follett KA Greenlee J Scott WE Moore SA Optic neuritis anovel presentation of Schilderrsquos disease J Child Neurol 200116693ndash696

106 Poppe M Bruck W Hahn G et al Fulminant course in a case ofdiffuse myelinoclastic encephalitis a case report Neuropediatrics20013241ndash44

107 Nejat F Eftekhar B Decompressive aspiration in myelinoclastic dif-fuse sclerosis or Schilder disease J Neurosurg 2002971447ndash1449

108 Obara S Takeshima H Awa R et al Tumefactive myelinoclasticdiffuse sclerosis Neurol Med Chir 200343563ndash566

109 Kurul S Cakmakci H Dirik E Kovanlikaya A Schilderrsquos disease casestudy with serial neuroimaging J Child Neurol 20031858ndash61

110 Garrido C Levy-Gomes A Teixeira J Temudo T Schilderrsquos diseasetwo new cases and a review of the literature Rev Neurol 200439734ndash738

111 Konkol RJ Bousounis D Kuban KC Schilderrsquos disease additionalaspects and a therapeutic option Neuropediatrics 198718149ndash152

112 Goldstein EM Spasticity management an overview J Child Neurol20011616ndash23

113 Krach LE Pharmacotherapy of spasticity oral medications and intra-thecal baclofen J Child Neurol 20011631ndash36

114 Wagstaff AJ Bryson HM Tizanidine A review of its pharmacologyclinical efficacy and tolerability in the management of spasticity asso-ciated with cerebral and spinal disorders Drugs 199753435ndash452

115 Patel DR Soyode O Pharmacologic interventions for reducing spastic-ity in cerebral palsy Ind J Pediatr 200572869ndash872

116 Matthews DJ Wilson P Cerebral palsy In Molnar GE AlexanderMA eds Pediatric rehabilitation 3rd ed Philadelphia Hanley amp Bel-fus 1999193ndash218

117 Gooch JL Oberg WA Grams B Ward LA Walker ML Care providerassessment of intrathecal baclofen in children Dev Med Child Neurol200446548ndash552

118 Krupp LB Coyle PK Doscher C et al Fatigue therapy in multiplesclerosis results of a double-blind randomized parallel trial of aman-tadine pemoline and placebo Neurology 1995451956ndash1961

119 Beers SR Skold A Dixon CE Adelson PD Neurobehavioral effects ofamantadine after pediatric traumatic brain injury a preliminary re-port J Head Trauma Rehabil 200520450ndash463

120 Rammohan KW Rosenberg JH Lynn DJ Blumenfeld AM NagarajaHN Efficacy and safety of modafinil (Provigil) for the treatment offatigue in multiple sclerosis a two centre phase 2 study J NeurolNeurosurg Psychiatry 200272179ndash183

121 Stankoff B Waubant E Confavreux C et al Modafinil for fatigue inMS a randomized placebo-controlled double-blind study Neurology2005641139ndash1143

122 Hurst DL Lajara-Nanson W Use of modafinil in spastic cerebralpalsy J Child Neurol 200217169ndash172

123 Schwid SR Petrie MD McDermott MP et al Quantitative assessmentof sustained-release 4-aminopyridine for symptomatic treatment ofmultiple sclerosis Neurology 199748817ndash821

124 Anouti A Koller WC Tremor disorders Diagnosis and managementWest J Med 1995162510ndash513

125 Schulder M Sernas TJ Karimi R Thalamic stimulation in patientswith multiple sclerosis long-term follow-up Stereotact Funct Neuro-surg 20038048ndash55

126 Mac Allister WS Belman AL Milazzo M et al Cognitive functioningin children and adolescents with multiple sclerosis Neurology 2005641422ndash1425

127 Banwell BL Anderson PE The cognitive burden of multiple sclerosisin children Neurology 200564891ndash894

128 Greene YM Tariot PN Wishart H et al A 12-week open trial of donepe-zil hydrochloride in patients with multiple sclerosis and associated cogni-tive impairments J Clin Psychopharmacol 200020350ndash356

129 Krupp LB Christodoulou C Melville P Scherl WF MacAllister WSElkins LE Donepezil improved memory in multiple sclerosis in arandomized clinical trial Neurology 2004631579ndash1585

130 Kilic N Balkan E Akgoz S Comparison of the effectiveness andside-effects of tolterodine and oxybutynin in children with detrusorinstability Int J Urol 200613105ndash108


DOI 10121201wnl000025940740023ab200768S54-S65 Neurology

D Pohl E Waubant B Banwell et al Treatment of pediatric multiple sclerosis and variants

This information is current as of April 16 2007

ServicesUpdated Information amp

httpwwwneurologyorgcontent6816_suppl_2S54fullhtmlincluding high resolution figures can be found at

References

st-1httpwwwneurologyorgcontent6816_suppl_2S54fullhtmlref-liThis article cites 129 articles 57 of which you can access for free at

Citations

articleshttpwwwneurologyorgcontent6816_suppl_2S54fullhtmlotherThis article has been cited by 12 HighWire-hosted articles

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httpwwwneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

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Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

for relapsing forms of MS18-20 but safety concernsarising after three patients developed progressivemultifocal leukoencephalopathy (PML) led to its tem-porary removal from the market The FDA approvedits return in summer 2006 It is expected that thedrug will be used as a second line therapy in patientsintolerant to or failing on IFNB or GA

Treatment options and experience in pediatricMS and its variants Treatment for relapses Notherapeutic trial for relapses has yet been conductedin the pediatric MS population Therefore relapsetherapy is based on clinical experience and extrapo-lated from studies of acute relapse management inadult MS

Corticosteroids In adults mild relapses or re-lapses recovering spontaneously do not warrant highdose steroid treatment Relapses associated with sig-nificant neurologic impairment (eg interfering withdaily function) are usually treated promptly withhigh doses of IV glucocorticosteroids in order toshorten relapse duration and hasten recovery21-23

High doses of IV methylprednisolone (IVMP) (morethan 500 mgday for at least 3 days in adults) seemsuperior to lower doses (IV or oral)2425 Recent datasuggest that high doses of oral prednisone could sub-stitute for IV pulses in adult MS26 The typical regi-men in adults 1 g per day for 3 to 5 daysadministered IV is generally well tolerated23 exceptfor occasional insomnia mood changes and rarepsychosis

The most frequent side effects of high dose glu-cocorticosteroids are facial flushing sleep difficul-ties irritability and increased appetite In childrengrowth retardation is an additional concern with pro-longed corticotherapy Although side effects such ashigh blood pressure and hyperglycemia are rare es-

pecially in children treatment with corticosteroidsrequires careful monitoring of blood pressure urineglucose serum potassium and administration ofgastric protection The risk of side effects increaseswith prolonged use and total cumulative dose Corti-costeroids used in the doses reviewed are generallywell tolerated even when a short oral taper dose isgiven

Plasma exchange Plasma exchange has beenproposed to treat severe relapses in adult patientswith MS or NMO when they fail to recover aftertreatment with high-dose glucocorticosteroids27

Plasma exchange has also been proposed in childrento avoid side effects of frequent pulses of steroids asan alternative treatment for recurrent relapses oc-curring over a short period However the availableliterature in the pediatric population is restricted toa single case report of a 7-year-old patient with MSwith high titers of antinuclear autoantibody28

IV immunoglobulins The efficacy of IVIg hasnever been demonstrated as a preventative or cura-tive relapse therapy in MS or NMO In adult pa-tients IVIg therapy (04 gkg daily for 5 daysfollowed by three single infusions monthly for 3months) was not found to improve visual recoveryafter optic neuritis29 nor delay the time to progres-sion in secondary progressive (SP) MS (in a dosage of1gkg monthly)30 Although IVIg treatment in combi-nation with high dose glucocorticosteroids does notappear superior to high dose glucocorticosteroidsalone to treat relapses3132 IVIg (in a dosage of 04gkg daily for 5 days) has been somewhat helpful tochildren and adults with acute demyelinating at-tacks who do not improve after high dose MP33-38

Disease-modifying therapy Immunomodulatorytherapy Both GA and IFNB are immunomodula-tors and decrease relapse rate and MRI activity in

Table 1 Available approved therapies

Interferonbeta-1b

Interferonbeta-1a

Interferonbeta-1a

Random polypeptide(L-glutamic acid

L-lysine L-alanineand L-tyrosine) Mitoxantrone

Production E coli Mammaliancells

Mammaliancells

Synthetic Synthetic

Glycosylated No Yes Yes NA NA

Mutation Met 1 deletedCys 17 mutated

to a serine

No No NA NA

Administration SC every other day IM once a week SC threetimes a week

SC every day IV once every3 months up to

2 years

Dose per injection 250 g or 8 MIU 30 g 44 g 20 mg 12 mgm2

Development of neutralizingantibodies

35 2ndash5 12ndash24 No No

Side effects Flu-like reactionLFT increaseskin reaction

Flu-like reactionLFT increase

Flu-like reactionLFT increaseskin reaction

Systemic reactionskin reaction

Infection cardiotoxicityearly menopauseacute leukemia

LFT liver function test






































































side effects

Interferon beta

Interferonbeta-1b





Interferonbeta-1a







Interferonbeta-1a






Other DMT



Syntheticpolymer



Use birth control














Table 2 Continued


Spasticity











Fatigue






Bladder disturbance































































































































































References


Citations




Reprints








































































side effects

Interferon beta

Interferonbeta-1b





Interferonbeta-1a







Interferonbeta-1a






Other DMT



Syntheticpolymer



Use birth control














Table 2 Continued


Spasticity











Fatigue






Bladder disturbance































































































































































References


Citations




Reprints









Table 2 Continued


Spasticity











Fatigue






Bladder disturbance































































































































































References


Citations




Reprints
























































































































































References


Citations




Reprints




Treatment of pediatric multiple sclerosis and variants

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Transcript of Treatment of pediatric multiple sclerosis and variants