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, MD;B. Weinstock-Guttman, MD; and S. Tenembaum, MD; for the International Pediatric MS Study Group‡

Abstract—Studies in adult patients with multiple sclerosis (MS) suggest significant benefit of early treatment initiation.However, 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.

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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 age,individuals reaching any given level of impairmentwill be younger than individuals with adult onsetdisease.1,2

Disease-modifying therapies (DMT) for adult MSare now initiated soon after diagnosis based on sev-eral clinical trials that suggested benefits of earlytreatment.3-5 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 adults,6 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 patients.7-11 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)–approved 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 MS.17 Otherimmunosuppressive agents used empirically for pa-tients with aggressive MS include oral azathioprine,IV immunoglobulins (IVIg), oral methotrexate, oralmycophenolate mofetil, IV cyclophosphamide, andpulses of IV methylprednisolone (MP). Natalizumab,an anti-alpha 4 integrin, was granted FDA approval

*The first authors contributed equally to this work.‡Members of the International Pediatric MS Study Group are listed in the Appendix.From the Department of Pediatrics and Pediatric Neurology (D.P.), Georg-August-University Goettingen, Germany; Multiple Sclerosis Center at UCSF(E.W., D.C.), San Francisco, CA; Department of Pediatric Neurology (B.B.), The Hospital for Sick Children, University of Toronto, Canada; MassachusettsGeneral Hospital for Children (T.C.), Brigham & Women’s Hospital, Harvard Medical, Boston; Baird MS Center (B.W.-G.), Jacobs Neurological Institute,Buffalo, NY; and Department of Pediatric Neurology (S.T.), National Pediatric Hospital, Dr. J. P. Garrahan, Buenos Aires, Argentina.Disclosure: The authors report no conflicts of interest.Address correspondence and reprint requests to Dr. Emmanuelle Waubant, UCSF MS Center, 350 Parnassus Street, Suite 908, San Francisco, CA 94117;e-mail: [email protected]

S54 Copyright © 2007 by AAN Enterprises, Inc.

for relapsing forms of MS,18-20 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 (e.g., interfering withdaily function) are usually treated promptly withhigh doses of IV glucocorticosteroids in order toshorten relapse duration and hasten recovery.21-23

High doses of IV methylprednisolone (IVMP) (morethan 500 mg/day for at least 3 days in adults) seemsuperior to lower doses (IV or oral).24,25 Recent datasuggest that high doses of oral prednisone could sub-stitute for IV pulses in adult MS.26 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 children,growth 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 glucocorticosteroids.27

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 autoantibody.28

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 (0.4 g/kg daily for 5 daysfollowed by three single infusions monthly for 3months) was not found to improve visual recoveryafter optic neuritis,29 nor delay the time to progres-sion in secondary progressive (SP) MS (in a dosage of1g/kg monthly).30 Although IVIg treatment in combi-nation with high dose glucocorticosteroids does notappear superior to high dose glucocorticosteroidsalone to treat relapses,31,32 IVIg (in a dosage of 0.4g/kg daily for 5 days) has been somewhat helpful tochildren and adults with acute demyelinating at-tacks who do not improve after high dose MP.33-38

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-alanine,and L-tyrosine) Mitoxantrone

Production E coli Mammaliancells

Mammaliancells

Synthetic Synthetic

Glycosylated No Yes Yes NA NA

Mutation Met 1 deleted;Cys 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 mg/m2

Development of neutralizingantibodies

35% 2–5% 12–24% No No

Side effects Flu-like reaction,LFT increase,skin reaction

Flu-like reaction,LFT increase

Flu-like reaction,LFT increase,skin reaction

Systemic reaction,skin reaction

Infection, cardiotoxicity,early menopause,acute leukemia

LFT � liver function test.

April 17, 2007 NEUROLOGY 68(Suppl 2) S55

adult patients with relapsing MS.12-16 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 attack,also 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 beta–1b (Betaseron/Betaferon). 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 group.11 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 profile.11,39,40

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 period.39 In anotherreport, a 15-year-old patient with SPMS treated withIFNB-1b (8 MIU SC three times per week) showedimproved neurologic status.40

Interferon beta–1a 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 study.7 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 IM.41 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 erythema.Treatment 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 19.1 months. Areduction of annualized relapse rate from 3.1 (pre-treatment) to 0.3 and stable EDSS were reported.However, in the absence of a randomized doubleblind control design, efficacy data must be consid-ered with caution.42

Interferon beta–1a (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 14.6 years (range8.1 to 17.9 years).10 The mean duration of therapywas 1.8 years (range 1 month to 4.4 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 groups.43 The mean age ofstudy participants was 12.7 years (range 3.8 to 17.9years). 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 22�g tiw dose, 16 of them from the beginning andseven after the dose-escalation phase. The mean ex-posure to treatment was 44.4 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 tiw.44 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. However,one study reported increased annualized relapserates (ARR) at doses lower than 22 �g tiw, whereas22 �g tiw was associated with decreased ARR (1.8pretreatment compared to 0.14 on drug) and disabil-ity compared to baseline.43 In another study, meanARR decreased on drug (1.9 pretreatment comparedto 0.8 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 4.1 pretreatment to 0.7after a mean treatment duration of 48.6 months.42

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 months.45 Treatment was initiatedin children with a median age of 16.6 years. Re-ported AE included injection site pain or induration(2/7) and transient systemic reaction (1/7). 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 effects.9

Preliminary results of the Italian ITEMS studyincluded seven patients treated with GA under theage of 16 years. After a mean treatment duration of14.7 months, there was a reduced ARR from a base-line of 2.5 to 0.1 on drug and stable EDSS werereported.42

IV immunoglobulins. IVIg has been proposed forpediatric MS patients whose symptoms relapsewithin days or weeks of discontinuation of steroids.9The reported regimen was 0.4 g/kg 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 year.9 An alter-native regimen based on a study in adult MS pa-tients46 consists of monthly IVIg 1 g/kg/day on twoconsecutive days and appears to be well tolerated inthe pediatric age group (personal communication).

Immunosuppressive therapy. Azathioprine. Oralazathioprine in a dose of 2.5 to 3 mg/kg/day has beenused in MS to prevent exacerbations. Data regardingits clinical benefits are available in adult MSpatients,47-49 whereas MRI effects have only beenstudied in small groups of patients.50,51 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, e.g., 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, mitoxantrone,methotrexate, or mycophenolate mofetil. However,there 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 below.Only a small number of children received betweenone and three infusions of natalizumab 300 mg be-fore it was pulled off the market in February 2005.Therefore, 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 IVMP.56,57 Pulse cy-clophosphamide therapy is started at 800 mg/m2

given every 4 weeks. Dose should be titrated for atarget WBC nadir of 1,500 to 2,000/mm3 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 population,and common potential side effects may include nau-sea and vomiting following infusion, risk of infection,transient 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 lesions.17 Mitoxantrone 12 mg/m2 isusually administered IV every 3 months up to 2years. Above a cumulative dose of 120 mg/m2 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 7.5 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 MRI.58,59 Methotrexate up to 20 mg perweek in association with folic acid (1 mg/day) 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 disturbances,liver toxicity, and interstitial pneumonitis.

Natalizumab. Natalizumab treatment (300 mginfused monthly) decreases relapse rate by up to 68%and reduces progression of disability by 42% over 2years.18-20 Natalizumab reduces MRI activity in adultpatients with relapsing MS by up to 92% at year 1and 2.18-20 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 isunclear.60-63 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 SPMS.30 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 IVMP,67 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 rituximab.Although 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 30mg/kg/day 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 (e.g.,prednisone 1 mg/kg/day 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 (e.g., MP 10mg/kg/day 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 g/kg/day on 2 consec-utive days might be administered.

In children with frequent attacks despite exces-sive glucocorticosteroid exposure or with steroid de-pendency (e.g., 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 mg/kg) or ibuprofen(10 mg/kg) at the time of injections and, if necessary,4 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 patient’s 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, e.g., 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 g/day on 3consecutive days monthly), or switch to mitox-

antrone (up to 12 mg/m2 every 3 months), cyclophos-phamide (starting at 700 mg/m2 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 mg/kg/day [under 30 kgof body weight] to 1 g/day [over 30 kg of body weight]for 3 to 5 days) and plasma exchanges for severeexacerbations insufficiently responding to IVMPmight help recovery.27,68 Long-term therapy with oralazathioprine or IV rituximab may decrease relapserate.69,70 The effect of IFNB and GA is unclear, withonly isolated reports.71 In three children with NMOwho were corticosteroid dependent, combined ther-apy with monthly IV cyclophosphamide and oralmethylprednisolone (1 to 2 mg/kg/day) was well tol-erated. Combination treatment seemed to reduce re-lapse rate and improve disability in two children,whereas the third one remained stable.72 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 corticosteroids,73-82 mitoxantrone,75 immunosup-pressants,75,80 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 published.81,83-85 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 months.81,84 On the con-trary, the effect of corticosteroids in a 13-year-oldgirl and a 16-year-old boy was questionable and ofshort duration.83,85 Azathioprine treatment did notprevent further attacks in the 16-year-old boy,83

whereas IVIg treatment was followed by a long-lasting remission during a 30-month follow-up in the13-year-old girl.85 In view of the sparse data on ther-apy for Balo disease no specific treatment recommen-dations can be made.

Marburg acute MS. Marburg’s 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 unsuccessful.86-91 Plasma exchange has beendescribed to be effective in single cases and in somepatients in a blinded clinical trial.27,90,92 Mitoxantronewas reported to maintain remission after plasma ex-changes in two patients.90,91 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 coursecorticosteroids.93-110 This treatment was followed bysome improvement in the majority of patients. IVIgwas used in one patient with questionable effect,101

and in two patients without effect.101,106 A 12-year-oldboy was treated with cyclophosphamide followed byazathioprine, and was reported to be stable on thisregimen,103 whereas azathioprine did not preventprogressive decline in a 12-year-old girl.101 Cyclo-phosphamide treatment in combination with ACTHwas followed by complete recovery in another patientwho had failed to respond to ACTH alone.111 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 population.The 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 considered.Baclofen, 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 2.5 mg daily, which canbe titrated up gradually to a maximum of 20 to 60mg/day, based on the response.112,113 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 more;maintenance dose is 0.3 to 0.5 mg/kg/day dividedfour times daily.114 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 day.115 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 0.01 to0.03 mg/kg/day divided BID or TID.116 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 palsy.117 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 disturbances,inappropriate dietary interventions, or exhaustionrelated to physical disability and exposure to heat,which 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 MS.118 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 children.119

The dosage used as per pediatric recommendationswere as follows: for age 6 to 9 years (weight �40 kg)5 mg/kg/day up to maximum dose of 150 mg/day; for


age 10 years or older and weight �40 kg, 200mg/day.

If amantadine is not effective, modafinil, awakefulness-promoting agent, should be consid-ered.120,121 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 palsy.122 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 �g,every other daysubcutaneously

Recombinantinterferon beta

Exacerbations:Reduced by 30%*

Flu-like symptoms* Begin with lower thantherapeutic dose andgradually escalate*

Interferonbeta-1a

30 �g onceper week,intramuscular


MRI: Reduces theformation of new andenhancing lesions*

Disability progression:All DMT likely to haveeffect in delayingprogression ofdisability on MS-specificrating scales*

Headache, lymphopenia,liver 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 daily,subcutaneous

Syntheticpolymer

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

Injection site reactions(mild); “systemic” panicattack-like reaction;lipoatrophy; noneutralizing antibodies;potential for spontaneousabortion or teratogenicityunknown

Use birth control

Mitoxantrone 12 mg/m2 given IVevery 3 mo to alifetime maximumof 144 mg/m2; notsure if shouldbe used incombination withthe other DMTagents

Cytotoxic;antracenedione

FDA approved for usein worsening MS;reduces the number ofattacks and progressionof disability; MRI:Reduces the formationof new and enhancinglesions

At time of the IV: Urineand sclera may turn bluefor hours; mild nausea;day 14 after IV: Dramatictransient white blood cellcount drop; can worsenconcomitant infections;long-term side effects:infertility, prematuremenopause, cardiactoxicity more likelyat doses aboverecommended, veryrare leukemia inducedcomplication,teratogenicity

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

Continued*These 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 ambulation.123 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 authors’experience most children show spontaneous improve-ment of these symptoms. Occupational and physicaltherapy can be helpful in providing adaptive equip-ment (e.g., 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 parkinsonian,essential, 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 symptom.125

There is no published experience in children withMS.

Paroxysmal symptoms. Paroxysmal symptomsoccur abruptly during exacerbations of MS, spread

Table 2 Continued

Symptom/agent/howsupplied Mechanism of action Common side effects

Spasticity

Baclofen/10, 20 mg tab Agonist of GABA-B (inhibitory) receptor Dizziness, weakness, drowsiness, mental confusion; rapidwithdrawal should be avoided

Tizanidine/2, 4 mg tab Alpha-2 receptor agonist: acts on polysynapticreflex arc

Sedation, liver function abnormalities, orthostatic hypotension

Diazepam/2, 5,10 mg tab

Enhance the GABAergic transmission Sedation, addiction

Clonazepam/0.5,1, 2 mg tab

Enhance the GABAergic transmission Sedation, addiction

Dantrolene/25, 50,100 mg

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

Weakness, hepatotoxicity, fatigue

Fatigue

Amantadine/100 mg N-methyl-D aspartate antagonist Nausea, unusual dreams, peripheral edema, livedo reticularis

Methylphenidate HCl/10,20 mg; methylphenidateHCl SR/20 mg

Central nervous stimulant Insomnia, agitation

Modafinil/100 mg Alpha-1 adrenergic agonist,noradrenalin reuptake inhibitor

Headache, insomnia, restlessness

Bladder disturbance

Oxybutinin/5 mg, andin the sustainedrelease formulation10 mg, 15 mg

Anticholinergic agent Constipation, dry mouth, increased risk of urinary retention

Tolterodine/2 mg,Detrol LA 4 mg


Hyoscyamine/0.125 orthe sustained releaseformulation 0.375 mg


TCA/10, 25, 50, 75 mg Tricyclic antidepressant withanticholinergic properties

Constipation, dry mouth, increased risk of urinary retention,confusion, 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 repeatedly,are promoted by hyperventilation, and can be pain-ful. Treatment with IVMP (500 mg to 1000 mg/day)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 BID–TID 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-cits.126,127 Recent studies in adult MS suggest func-tional improvement using donepezil therapy.128,129

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], e.g. PVRbelow 100 mL) usually responds to anticholinergicagents. The most commonly used are oxybutynin,tolterodine, and hyoscyamine. A recent study thatevaluated the effectiveness and tolerability oftolterodine (0.1 mg/kg/day for patients under 5years and 2 mg/day for older children, divided intotwo doses) and oxybutynin (0.4 mg/kg/day, 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 tolerability.130 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 0.1 to 0.2 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, PhD,Tanuja Chitnis, MD, Peter Dunne, MD, Andrew Goodman, MD, Jin S.Hahn, MD, Deborah P. Hertz, MPH, Nancy J. Holland, EdD, RN, MSCN,Douglas Jeffery, MD, PhD, William MacAllister, PhD, Raul Mandler, MD,Maria Milazzo, RN, MS, CPNP, Jayne Ness, MD, PhD, Jorge Oksenberg,PhD, Trena L. Pelham, MD, Daniela Pohl, MD, PhD, Kottil Rammohan,MD, Mary R. Rensel, MD, Christel Renoux, MD, Dessa Sadovnick, PhD,Steven Robert Schwid, MD, Silvia Tenembaum, MD, Cristina Toporas, Em-manuelle Waubant, MD, PhD, Bianca Weinstock-Guttman, MD.

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Treatment of pediatric multiple sclerosis and variants

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