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Ther Adv Neurol Disord. 2010 July; 3(4): 217–228.
PMCID: PMC3002659

Therapeutic strategies in childhood multiple sclerosis

Abstract

Multiple sclerosis (MS) in children and adolescents accounts for 3–10% of the whole MS population, and is characterized by a relapsing course in almost all cases. The frequency of relapses is higher than in adult onset MS, at least in the first years of evolution. The objective of treatment is to speed the recovery after a relapse, to prevent the occurrence of relapses, and to prevent disease progression and neurodegeneration. The use of drugs for MS in children and adolescents has not been studied in clinical trials, so their use is mainly based on results from trials in adults and from observational studies. There is a consensus to treat acute relapses with intravenous high-dose corticosteroids. The possibility of preventing relapses and disease progression is based on the use of immunomodulatory agents. Interferon-beta (IFNB) and glatiramer acetate (GA) have been demonstrated to be safe and well tolerated in pediatric MS patients, and also to reduce relapse rate and disease progression. Cyclophosphamide and natalizumab could be offered as second-line treatment in patients with a poor response to IFNB or GA. New oral and injectable drugs will be available in the near future: if safe and well tolerated in the long-term follow up of adults with MS, they could be tested in the pediatric MS population.

Keywords: adolescence, childhood, cyclophosphamide, glatiramer acetate, interferon beta, intravenous immunoglobulin, intravenous methylprednisolone, mitoxantrone, multiple sclerosis, natalizumab

Introduction

The onset of multiple sclerosis (MS) typically occurs in adults at about 30 years of age; however the onset before 18 years of age is being increasingly recognized worldwide, accounting for 3–10% of all individuals with MS [Banwell et al. 2007]. The clinical features of pediatric MS (Ped-MS) have been delineated in several retrospective, prospective and longitudinal studies. Overall, they are not different from those of the adult form, but some findings seem to be peculiar to Ped-MS, being more frequent in comparison with adult MS (A-MS):

  1. the onset with cerebellar and brainstem dysfunction [Banwell et al. 2007; Ghezzi et al. 2002];
  2. the polysymptomatic presentation, with fever, headache, lethargy, meningism, seizures (acute disseminated encephalomyelitis-like onset), especially in very young patients [Banwell et al. 2007];
  3. the evolution with a high number of relapses, specially in the first years of the disease, and an annualized relapse rate of 1–1.9, which is higher than in A-MS [Gorman et al. 2009; Renoux et al. 2007; Ghezzi et al. 2002; Gusev et al. 2002];
  4. the evolution, with a predominance of the relapsing–remitting (RR) course, in more than 90% of cases, and the very low frequency of the primary progressive course [Banwell et al. 2007];
  5. the progression, with a longer interval but a lower age to reach mild and severe disability.

In fact, the majority of Ped-MS patients develop mild and severe disability, as well as the shift to the secondary progressive phase of MS, after a longer disease interval but at a younger age, compared with A-MS [Renoux et al. 2007; Boiko et al. 2002]. So, at a given age, patients with onset in childhood are more disabled than those with a later onset.

The frequency of relapses (or the interattack interval) in the first few years after disease onset is a negative prognostic factor as it correlates with an increased disease severity and with an earlier entry into the secondary progressive phase of MS [Banwell et al. 2007].

Recent studies have demonstrated that approximately one third of children and adolescents with MS develop cognitive dysfunction early: processing speed, attention, language and working memory are involved, with a negative impact on academic functioning and on social relationships [Amato et al. 2008; Banwell and Anderson, 2005; MacAllister et al. 2005].

The high number of relapses in the first years of the disease, and the high frequency of patients with the RR course suggest that the inflammatory process is more pronounced in children with MS compared with adults. This pattern is also suggested by the frequent pleocytosis in the cerebrospinal fluid (CSF) [Pohl et al. 2004], and by the aspect of magnetic resonance imaging (MRI) lesions [Waubant et al. 2009; Chabas et al. 2008]. It seems reasonable to expect that drugs targeting the inflammatory process could have a positive beneficial effect in patients with Ped-MS. As in A-MS, the objective of the treatment is to prevent the occurrence of brain damage, and to limit the damage once it has occurred. In other words:

  1. to speed the recovery and prevent disability after a relapse;
  2. to prevent the occurrence of relapses;
  3. to prevent disease progression, disability and cognitive impairment.

As diagnosis of MS has a major impact on patients and their families, psychological and social support should be offered to reduce the emotional impact of MS, to face the physical and psychological limitations in family, school and social activities, and to strengthen the compliance with medication. In addition to pharmacological treatment, the care of children and adolescents with MS requires a multidisciplinary team, with occupational and physiotherapists, psychologists and social workers, in addition to pediatric or adult neurologists [Banwell et al. 2007].

The effects of drugs in Ped-MS have not been formally evaluated in clinical trials, so their use is based on results in A-MS, experts’ opinion, case reports, and data from observational studies. There are no approved guidelines for the treatment of Ped-MS, but recently a proposal has been published by a group of adult and child neurologists, with the objective of defining a shared approach for the treatment of children and adolescents with MS [Ghezzi et al. 2010].

In the present review, the most relevant studies related to the treatment of Ped-MS are presented, with a hint to possible future therapeutic strategies.

Management of acute MS relapses

Corticosteroids remain a mainstay of treatment for relapses in MS of adults, with class I and class II evidence of speeding functional recovery after acute attacks [Goodin et al. 2002]. Based on the evidence from A-MS studies, there is a general consensus to treat acute relapses of MS in children and adolescents with intravenous methylprednisolone 10–30 mg/kg for 3–5 days [Ghezzi et al. 2010; Banwell, 2005; Ghezzi 2005], although the effectiveness of corticosteroids has not been clearly demonstrated by specific studies. In adults with MS, oral corticosteroids [Morrow et al. 2004; Barnes et al. 1997] have a similar effectiveness and the benefit of a more practical route of administration, but this schedule of administration has not been tested in pediatric patients.

The treatment of acute relapses with corticosteroids hastens the recovery but does not modify the long-term evolution of the disease [Compston and Coles, 2002; Optic Neuritis Study Group, 1997]. Only a single class II study [Zivadinov et al. 2001] has shown that regular pulsed corticosteroids are useful in the long-term management: in a cohort of 88 adult MS randomly assigned to pulses of methylprednisolone (MP) (5 g over 5 consecutive days every 4 months for 3 years, subsequently every 6 months for 2 years) or MP at the same dose schedule only for relapses, the relapse rate was equivalent but disability was less in subjects treated with pulsed MP.

In patients with a severe attack and/or an incomplete recovery after high-dose corticosteroids, a second pulse of corticosteroids can be offered [Banwell, 2005]. Alternatively, intravenous immunoglobulins can be administered, usually 2 g/kg over 2–5 days. This treatment does not have proven efficacy in treating acute relapses, and only has beneficial effects in preventing some relapses in adults with RRMS, demonstrated by studies with methodological limitations and small size [Elovaara et al. 2008; Banwell, 2005; Goodin et al. 2002].

For patients suffering from severe steroid-resistant relapses, plasma exchange can be offered as a therapeutic option, based on results of randomized studies in adults and sporadic use in single MS pediatric cases [Lehmann et al. 2006; Weinshenker et al. 1999; Takahashi et al. 1997].

Treatment to prevent relapses and disease progression

First-line disease-modifying treatment of Ped-MS

Three beta-interferons (Avonex® 30 µg given intramuscularly [i.m.] once a week, Rebif® 22 µg or 44 µg given subcutaneously [s.c.] three times a week, Betaferon® 250 µg given s.c. every other day) and glatiramer acetate (GA; Copaxone®, 20 mg given s.c. every day) are licensed for the treatment of RRMS, and one beta-interferon (Betaferon® 250 µg given s.c. every other day) for the treatment of secondary progressive MS.

There is a large body of evidence, based on results of randomized, double-blind, placebo-controlled trials with class I evidence, that these immunomodulatory agents (IAs):

  1. delay the time to a second MS attack [Comi et al. 2009, 2001; Kappos et al. 2006; Jacobs et al. 2000] and the risk of confirmed disability [Kappos et al. 2007b], if given in subjects at their first demyelinating episode;
  2. have a profound effect on MRI lesions and activity [Soriani et al. 2009]; in patients treated with interferon-beta (IFNB)-1a 22 µg weekly, this drug reduced cerebral atrophy, compared with placebo [Filippi et al. 2004].

The effect of IAs to reduce relapse rate and disease progression has been confirmed in postmarketing studies, with a clear demonstration that IAs are also more effective in everyday clinical practice if started earlier [Trojano et al. 2009, 2007].

There is also some evidence that IFNB improves cognitive functioning [Patti et al. 2010; Kappos et al. 2009; Fisher et al. 2000].

These positive clinical effects of IAs in adults, and their overall positive safety profile, have encouraged the use of these drugs in Ped-MS patients. At present, there have been no formal clinical trials of IAs in the Ped-MS population; the effect of these medications has been evaluated in some preliminary studies on a small number of cases [Mikaeloff et al. 2001; Waubant et al. 2001], mainly addressed to evaluate their safety, and subsequently in studies including a larger number of cases [Ghezzi et al. 2009a, 2005; Banwell et al. 2006; Tenembaum and Segura, 2006; Pohl et al. 2005; Kornek et al. 2003], also providing data on the clinical effects.

In two studies, the data of patients treated with IAs were compared with those of an untreated group. In a study of 16 patients randomly assigned to IFNB-1a 30 µg i.m. weekly or placebo, the active treatment reduced relapse rate, disability progression and MRI measures [Pakdaman et al. 2006]. In a cohort of 197 Ped-MS patients, 24 patients treated with IFNB showed a significant reduction in relapse rate compared with subjects who did not receive any therapy [Mikaeloff et al. 2008].

The main demographic and clinical findings of the cohorts of Ped-MS patients treated with IAs are summarized in Table 1. In comparison with the pretreatment phase, a reduction of relapse rate is reported in almost all studies, as well as a stabilization of disability, assessed by means of Expanded Disability Status Scale (EDSS) score, confirming the positive effect on disease evolution observed in A-MS patients.

Table 1.
Main demographic and clinical data of patients treated with interferon-beta (IFNB) and glatiramer acetate, according to literature data.

The frequency of adverse events reported in these studies is similar to those observed in a meta-analysis of A-MS patients [Filippini et al. 2003] (Table 2). The wide range of frequency of adverse events, summarized in Table 2, is likely to be due to the use of different methods of evaluation and IFNB types.

Table 2.
Frequency of adverse events in pediatric multiple sclerosis (Ped-MS) patients treated with interferon beta, according to the studies reported in Table 1, compared to the frequency observed in adults [Filippini et al. 2003].

Data in children are less consistent: Tenembaum and Segura [2006] treated eight children under 10 years of age with Rebif, and observed a statistically significant reduction of relapse rate. Ghezzi et al. [2009a] treated 23 patients under 12 years of age with IAs, finding a reduction of relapse rate and a stabilization of EDSS at the end of follow up. IAs were well tolerated, with a frequency of adverse events similar to those observed in the whole cohort of adolescents.

The available literature on the treatment with Copaxone is limited to a small case series [Ghezzi et al. 2009a; Kornek et al. 2003]. A reduction of relapses has been shown, together with a stabilization of disability. No major clinical adverse events and laboratory abnormalities were reported during the treatment with GA. Dyspnea, chest pain, transient systemic reaction (flushing, dizziness) and fatigue have been observed in 7–14% of pediatric patients treated with GA. Hematological and hepatic abnormalities are not reported in patients treated with GA.

The overall positive results of IFNB and GA in Ped-MS has led the European Regulatory Agency to modify the label of drugs including the following statement: “limited published data suggest that safety profile in adolescents from 12 to 16 years of age receiving IFNB or GA is similar to that seen in adults (… )”, whereas there is not enough information on the use of IFNB or GA in children below 12 years of age.

Clinical results have also been confirmed after a long-term follow up of more than 4 years (Table 3) [Ghezzi et al. 2009a].

Table 3.
Clinical data of a cohort of pediatric multiple sclerosis (MS) patients treated with immunomodulatory agents, after a long-term follow up [Ghezzi et al. 2009a].

Based on the evidence that:

  1. IAs are safe and well tolerated in children and adolescents with MS;
  2. IAs have confirmed an effect in reducing relapse rate and disease progression in this population;
  3. IAs are more advantageous in A-MS if administered in early phases of the disease;

a panel of experts [Ghezzi et al. 2010] has recommended to start early the therapy with IAs in children and adolescents with relapsing MS, to prevent the occurrence of relapses, to prevent the accumulation of disability and to reduce brain damage. Subjects at the first demyelinating episode must be monitored clinically and with MRI study; a second MRI is strongly recommended 3–6 months later. Treatment should be offered if a new clinical episode occurs or a second MRI shows disease activity (new T2 or gadolinium-enhanced [Gd+] lesions). There is no agreement on the use of IAs in Ped-MS patients after the first demyelinating episode, but it could be considered in some selected cases with an aggressive onset (many/large MRI lesions, Gd+ lesions).

In almost all patients, full doses of IAs are administered. Most authors suggest initiation of IFNB at one quarter to one half of the recommended adult dose, reaching the full dose within 1–3 months if it is well tolerated. Hematological tests (blood cell count, liver enzymes, bilirubin, thyroid function) should be performed at months 0, 1, 3, and every 3 months in the first year, and then successively every 3–6 months [Ghezzi et al. 2010]. In a cohort of patients treated before 12 years of age, 16 of them were treated with Avonex, 5 with Rebif, 2 with GA, with the same dose used in adolescents and adults. Adverse events and tolerability were similar to those observed in the whole cohort of pediatric patients [Ghezzi et al. 2009a].

Failure of first-line treatment

Relapses and disease progression can occur in spite of treatment with IAs. As no medication prevents the risk of a new attack by 100%, in clinical practice it is not simple to decide whether to continue the treatment with the same drug in a patient who continues to have relapses. Clinical findings (number or relapses, frequency of relapses during the treatment compared to the pretreatment phase, increase of EDSS score), and MRI data (new T2 lesions, Gd+ lesions) have been included as criteria to define treatment failure, but at present no consensus has been reached on the use of clinical or MRI markers [Portaccio et al. 2006; Rio et al. 2006; Freedman et al. 2004].

A panel of experts [Ghezzi et al. 2010] has suggested that patients may be deemed as failing to show an adequate response to a given medication if they meet one or more of the following criteria:

  1. relapse frequency, evaluated for 12 months of sustained, compliant therapy, is maintained at, or exceeds, the pretreatment relapse rate (assuming an annualized relapse rate of >1);
  2. severity of relapses on treatment is such that rescue therapy (intravenous immunoglobulins, plasma exchange) is consistently required for the management of acute relapses;
  3. physical disability accrual exceeds at least 2 points on the EDSS, sustained for more than 3 months.

The presence of two or more new T2 lesions or one Gd+ lesion on MRI scans obtained at least 1 year after sustained therapy with IFNB is indicative of a likelihood of further relapses in A-MS [Rio et al.2009, 2008; Tomassini et al. 2006; Rudick et al. 2004], but this finding was not included as proof of treatment failure in Ped-MS as data are not available regarding the natural history of lesion accrual in treated and untreated patients.

For patients treated with IFNB, there is evidence that the presence and persistence of neutralizing antibodies (NABs) to IFNB is related to a lack of biological activity of IFNB [Farrell et al. 2008; Malucchi et al. 2008; Sørensen et al. 2006, 2005]. Patients failing IFNB or demonstrating IFNB NABs can be offered therapy with GA [Capobianco et al. 2008]; an increase of IFNB dosage can also be considered for patients without NABs. Patients failing GA therapy can be considered for treatment with IFNB.

In a study of 130 Ped-MS patients, approximately 30% of cases altered treatment between IFNB and GA: the change of treatment regimen appeared to be advantageous, as the relapse rate continued to be lower with respect to the pretreatment value [Ghezzi et al. 2009a].

For patients with a very active form of MS, treatment with second-line drugs should be considered.

Second-line treatments in Ped-MS

Natalizumab (NA), mitoxantrone and cyclophosphamide (Cy) can be offered as options for adults with very active/rapidly progressing RRMS and poor response despite treatment with IFNB or GA.

NA has shown a strong effect on disease activity in a double-blind, placebo-controlled trial [Polman et al. 2006] reducing the relapse rate by 68% and slowing disease progression by 54% after 2 years of treatment. In a post-hoc study, disease activity was suppressed completely in 29.5% of cases and they remained free of clinical and radiological activity (defined by the criteria of new/enlarged lesions, or Gd+ lesions) after 2 years of treatment [Havrdova et al. 2009].

NA is administered i.v. every 28 days and is well tolerated; however, the occurrence of JC-virus-mediated progressive multifocal leukoencephalopathy (PML), with a risk of about 1:1000, the possible increased risk of melanoma, the potential hepatotoxicity must be taken into account [Kappos et al. 2007a; Yousry et al. 2006]. Many postmarketing studies are ongoing in adults to establish these risks in clinical practice.

NA was demonstrated to be effective in two single cases with very active MS and failure to first line treatments [Appleton and Boggild, 2009; Boriell et al. 2009], and in three MS patients with many relapses and MRI activity who were treated with NA 3-5 mg/kg every 28 days, obtaining a suppression of disease activity [Huppke et al. 2008]. NA was safe and well tolerated in a cohort of 38 subjects with juvenile Crohn’s disease, treated with this drug [Hyams et al. 2007].

Preliminary data of a cohort of 17 cases with active MS (3.1 relapses in the previous year) and MRI activity (2.3 Gd+ lesions at baseline), a mean age of 14.2 years, and a mean of 10 NA infusions have been presented recently [Ghezzi et al. 2009b]. Following NA treatment, the relapse rate decreased from 3.1 to 0.1, EDSS from 2.7 to 2 at the last observation, and no subject developed Gd+ lesions during the treatment. NA was well tolerated and the dose was the same as used in adults.

Data are not available on long-term follow up of NA, and further studies are necessary to better define the role of NA as a second-line treatment of Ped-MS, although these preliminary data show that NA is very effective and well tolerated in Ped-MS.

Mitoxantrone is approved for the treatment of active MS in adults, and it could also be offered as a second-line therapy in selected Ped-MS patients with active MS, but the increased risk of severe adverse events such as leukemia, cardiomyopathy, infections and infertility, in addition to side effects such as nausea, vomiting and hair loss, strongly limit the use of this drug. In particular, some recent studies have shown a high risk of leukemia, 1:333 in a study including 5472 cases [Ellis and Boggild, 2009] and 1:140 in an Italian multicenter survey of 2854 cases [Martinelli et al. 2009]. There are no data on the use of mitoxantrone in Ped-MS.

Cy is not licensed for MS treatment, but it has a powerful effect of reducing disease activity in A-MS. In a recent paper Cy has been used in a group of 17 Ped-MS patients with a mean age of 15 years and evidence of disease activity, as they received a mean of 2.5 steroid courses in the previous year, in spite of other first- (14 cases) and second-line (9 cases) treatments [Makhani et al. 2009]. Three different treatment regimens were used: induction therapy alone, induction therapy with pulse maintenance therapy, and pulse maintenance therapy alone. The dose ranged from 500 to 1000 mg/m2. EDSS score was reduced in most cases after 1 year. Three children remained relapse free, 12 reduced their annualized relapse rate from 3.8 to 1.6. Adverse events were frequent (nausea and vomiting in 15 patients, lymphopenia in 16, anemia in 10, alopecia in 10, menstrual disorders in 5 out of 10 girls; in rare cases thrombocytopenia, hematuria, infections, fatigue, urticaria, myalgias); they were severe in a few patients (amenorrhea in 3, sterility in 1, osteoporosis in 2, bladder cancer in 1). For these reasons the authors concluded that Cy should be considered a second-line treatment for carefully selected and monitored children with aggressive MS refractory to first-line therapies.

To conclude, limited published data seem to suggest that NA and Cy are effective in Ped-MS with active course. Further studies are necessary to define the dose, the treatment duration, and the occurrence of short- and long-term adverse effects.

New treatments

Many new oral drugs are under evaluation in phase II or phase III trials [Gasperini and Ruggieri, 2009]:

  1. Cladribine is a new oral immunosuppressant with a strong effect in reducing clinical relapses, disease progression, and MRI activity. A phase III trial has randomized 1326 patients to receive two different cumulative doses of cladribine or placebo in a 1:1:1 ratio [Giovannoni et al. 2010]; the active treatment significantly reduced the annualized relapse rate (0.14 and 0.15, respectively, versus 0.33), the risk of disease progression, and brain lesion count on MRI. A phase III trial evaluating the effect of cladribine to delay the conversion to MS after a first demyelinating episode is ongoing.
  2. Fingolimod is another powerful oral immunomodulating agent; in a phase III trial including 1292 patients, oral fingolimod at a dose of either 1.25 or 0.5 mg significantly reduced annualized relapse rate compared with IFNB-1a 30 µg weekly (0.20 and 0.16, respectively, versus 0.33) [Cohen et al. 2010]. In another study [Kappos et al. 2010] the same doses of fingolimod were compared with placebo after 24 months of treatment. Both doses of fingolimod reduced relapse rate (0.16 and 0.18, respectively, versus 0.40), the probability of disease progression (16.6% and 17.7%, respectively, versus 24.1%), and MRI measures.
  3. Teriflunomide has been demonstrated to reduce MRI activity in a phase II study, together with some positive clinical outcome measures [O’Connor et al. 2006]; a phase III trial is ongoing.
  4. Fumarate reduced several measures of MRI activity and reduced relapse rate by 32% in a phase II study [Kappos et al. 2008]; a phase III study is ongoing.
  5. Laquinimod has shown an effect on MRI and clinical measures given at the dose of 0.6 mg in a phase II study enrolling 306 patients [Comi et al. 2008]; a phase III trial is ongoing.

Monoclonal antibodies targeting cells involved in the immunopathological process of MS (CD20+ B cells, Rituximab; CD25+ B cells, Daclizumab; CD52 on lymphocytes and monocytes, Alentuzumab) are promising drugs for the treatment of MS. Rituximab was effective in a phase I study including RRMS [Bar-Or et al. 2008], and partially effective in primary progressive MS patients with evidence of MRI activity [Hawker et al. 2009]. It was effective in an adolescent with a severe evolution of MS [Karenfort et al. 2009]. Daclizumab reduced disease activity in RRMS patients who experienced persistent MS disease activity with IFNB therapy in a phase II study [Bielekova et al. 2009].

Alentuzumab strongly reduced the rate of sustained accumulation of disability and the annualized relapse rate in comparison with Rebif in a phase II trial [The CAMMS223 Trial Investigators, 2008]. A phase III trial is ongoing. The major risk of monoclonal antibodies is related to the development of PML [Carson et al. 2009].

Conclusions

At present, no formal clinical trials of IAs have been performed in Ped-MS patients, and the use of medications is mainly based on results on clinical trials in adults. IAs such as IFNB and GA appear to be safe and well tolerated in children and adolescents with MS.

According to the suggestions of a panel of experts, IAs should be given to children and adolescents with active RRMS to reduce the risk of relapses and the risk of disease progression. A careful clinical follow up of patients must be planned to prevent and minimize adverse effects, and to adapt the treatment according to the clinical evolution of MS.

In cases that have a poor response to a drug, clinicians can consider the option to increase the dose (if possible) or to switch subjects to other first-line or second-line treatments. Cy and NA can be offered to patients with an active evolution and a poor response to first-line treatments. Further studies are needed to better evaluate their safety.

In the future many oral or injectable agents will become available for the treatment of adults with MS. Most of them seem to have a stronger clinical effect compared with currently available drugs, others will probably have an equal clinical effect but with the advantage of an oral administration. The extension of a new drug to Ped-MS needs careful demonstration of its safety in adults and careful evaluation of potentially negative effects in children given its mechanism of action. In particular, the risk of infections should be carefully considered, owing to the greater exposure to infections in young subjects, of cancer, and the potential effects on reproductive function and physical development, with careful surveillance of short- and long-term safety and tolerability. Further studies will define their possible use in Ped-MS. It will become possible to select the most useful and best-tolerated drug for each patient.

Conflict of interest statement

Dr. Angelo Ghezzi received honoraria for speaking from Bayer Schering, Biogen-Dompé, Merck-Serono, and Novartis, for consultancy from Actelion, Merck-Serono, and Novartis, received support for participation to National and International Congresses from Bayer Schering, Biogen-Dompé, Merck-Serono Novartis, Sanofi-Aventis.

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