Treatment and prognosis of pediatric multiple sclerosis

INTRODUCTION — Multiple sclerosis (MS) is typically considered to be a disease of young adults. However, pediatric MS, defined as onset of MS before the age of 18, is increasingly recognized and accounts for approximately 5 percent of cases [1]. This disorder was previously known as early onset MS (EOMS) and juvenile MS.

The prognosis and treatments for children with MS are different from those of the more common adult form, and to a large extent are understudied. This topic will review the treatment and prognosis of pediatric MS. Some of the references on therapy refer to adults, since data are limited in pediatric MS and it is assumed that the disease response is likely to be similar.

The pathogenesis, clinical features, and diagnosis of pediatric MS are discussed separately. (See "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".)

TREATMENT OF ACUTE ATTACKS — Glucocorticoids are the mainstay for treatment of acute MS attacks [2]. They rapidly decrease inflammation and hasten recovery from an acute MS attack.

Pulse intravenous (IV) methylprednisolone 20 to 30 mg/kg given once daily for five days is a typical regimen used to treat an acute attack of MS [2]. No further glucocorticoids are given for patients who demonstrate complete recovery of their symptoms. However, a tapering oral prednisone course can be used for patients with residual disability, starting with prednisone 1 mg/kg per day and decreasing by 5 mg every two days. Evidence from adult studies suggests that oral glucocorticoids are equivalent to IV methylprednisolone and are a reasonable choice in patients who prefer this option or have poor venous access [3].

For children who relapse during a taper of glucocorticoids, we suggest either retreatment with IV methylprednisolone 20 to 30 mg/kg daily for five days, or intravenous immune globulin (IVIG) 400 mg/kg daily for five days.

Therapeutic plasma exchange is an alternative if IVIG is not an option. Typically, one plasma volume is exchanged every other day for a total of five to six exchanges [4]. MS is considered a class II indication for TPE (appropriate as second-line therapy). (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'ASFA therapeutic categories'.)

Adrenocorticotropic hormone injections are also another option for patients with persistent symptoms, though the cost of this medication makes it a second- or third-line option. (See "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Alternative therapy with ACTH'.)

APPROACH TO DISEASE-MODIFYING THERAPY

Initial therapy — We recommend treatment with a disease-modifying therapy (DMT) for children who develop relapsing-remitting MS.

The initial choice of DMT is highly influenced by patient and family preferences. The decision regarding the choice of therapy must include the child and family. Counseling the family on the benefits and risks of the medications and providing them with written information to review allows them to reach an educated decision.

●Preferred approach – Our preferred approach for initial therapy is to use a DMT considered to have high or intermediate efficacy, such as rituximab, fingolimod, or dimethyl fumarate. There is evidence that these DMTs are more effective than the older injectable platform DMTs (interferons and glatiramer) for reducing the relapse rate and the accumulation of new brain lesions [5], but at the cost of a higher rate of serious adverse events.

●Alternative approach – Another approach favored by some experts is to start treatment using an older injectable DMT for patients with relapsing forms of MS, particularly for those with a minimal disease burden or who are risk averse. Options include glatiramer acetate, interferon beta-1a (Avonex), interferon beta-1a (Rebif), interferon beta-1b (Betaseron), and peginterferon beta-1a. All of these agents appear to have similar effectiveness for MS. Escalation to intermediate efficacy oral DMT or high efficacy infusion DMT is then implemented only for patients who develop new MS attacks or evidence of new lesions on brain MRI. (See 'Treatment failure' below and 'Refractory disease' below.)

Among the older injectable DMTs (also known as platform therapies), interferon beta-1a (30 mcg intramuscular injection, Avonex) or peginterferon beta-1a (125 mcg subcutaneous injection) are often preferred by patients, since injections are limited to once per week or every 14 days, respectively. This is particularly helpful for patients with needle phobia. However, the intramuscular injection may be less well tolerated by some patients.

●Caveats

•Depression – Interferon beta drugs are generally avoided in adolescents who have comorbid depression. In adults, depression has been reported as a possible adverse effect of interferon beta, even though this association has not been confirmed [6,7]. Nevertheless, to be cautious, glatiramer acetate is the preferred drug in pediatric patients with comorbid depression.

•LFT abnormalities – Glatiramer acetate is suggested for patients who have persistent liver function test (LFT) abnormalities following initiation of an interferon.

Details of DMT administration are presented below. (See 'Disease-modifying therapies' below.)

Monitoring response — Both clinical and neuroimaging parameters can be used to monitor response to DMT. The International Pediatric MS Study Group suggests neurologic examinations at baseline; one, three, and six months after initiating therapy; and every six months thereafter [8]. In clinically stable children without attacks, yearly follow-up and neurologic examination may be sufficient.

Independent of the patient's clinical status, ongoing disease activity on brain magnetic resonance imaging (MRI) may suggest the need for an alternate immunomodulatory agent or more aggressive treatment. The International Pediatric MS Study Group suggests obtaining repeat brain MRI scans 6 to 12 months after the initiation of an immunomodulatory agent [8]. The repeat scan is compared with the baseline scan performed prior to treatment.

●For clinically stable patients with no more than one new T2 lesion or lesion with gadolinium enhancement, the MRI can be repeated yearly.

●For patients with several new T2 lesions and/or several lesions with gadolinium enhancement on follow-up imaging, repeat MRI should be performed again in six months. Changing DMT can be considered if the MRI continues to demonstrate a significantly increasing burden of disease, as discussed in the following section.

Treatment failure — Patients are considered to have an inadequate response (treatment failure) to DMT when one or more of the following conditions are present despite ongoing therapy (ie, minimum six months on full-dose therapy and fully adherent to treatment) [9]:

●Two or more relapses in a 12-month period based upon clinical or MRI data

●Two or more new T2 or contrast-enhancing brain lesions on MRI compared with pre-treatment period

Refractory disease — For patients with treatment failure, one reasonable strategy is to change therapy:

●Patients who have a poor response to interferon beta drugs or glatiramer acetate can be switched to an intermediate efficacy oral DMT, such as fingolimod or dimethyl fumarate, or high efficacy infusion DMT, such as rituximab. (See 'Other disease-modifying therapies' below.)

●Patients who have a poor response to recombinant human interferon beta-1a (Avonex) and remain risk-adverse can be switched to higher-dose interferon (recombinant human interferon beta-1b [Betaseron] or recombinant human interferon beta-1a [Rebif]) or to glatiramer acetate.

●Natalizumab is the primary agent suggested for refractory multiple sclerosis that has not responded to the high-efficacy agents previously noted. Its use is limited by its associated risk for PML in those patients with high-index seropositive status for JC virus. (See 'Natalizumab' below.)

Risks with pregnancy — All sexually active females should be counseled on the importance of contraception because of concern that some DMTs used to treat MS are associated with a risk of teratogenicity or other fetal harm. This is particularly true for patients treated with fingolimod or teriflunomide, though limited data for pregnancy outcomes among patients treated with teriflunomide have not shown evidence of fetal harm [10].

For adolescents and women with MS of child-bearing age who are planning a pregnancy or who become pregnant, many experts suggest stopping treatment with DMT. However, there is no clear consensus about this approach. The decision must weigh uncertain risks to the fetus posed by most DMTs for MS against clear benefits to the mother. This issue is discussed in greater detail separately. (See "Multiple sclerosis: Pregnancy planning".)

DISEASE-MODIFYING THERAPIES — A number of immunomodulatory agents have important beneficial effects for patients with MS, including decreased relapse rate and a slower accumulation of brain lesions on magnetic resonance imaging (MRI).

Rituximab — Rituximab has been widely used off-label to treat MS in some centers for years. Data from randomized controlled trials supporting the effectiveness of rituximab for relapsing forms of MS are limited, but nonrandomized studies in children [5,11,12] and the positive trials for ocrelizumab (another monoclonal antibody that targets CD20) in adults increase confidence that rituximab is beneficial [13]. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Ocrelizumab'.)

Rituximab is given by intravenous infusion every six months. Dosing of rituximab is 750 mg/m² per dose (maximum of 1000 mg/dose). For induction, two doses are given, separated by 14 days. A single maintenance dose of 750 mg/m² is then given every six months. An alternative induction schedule is to give four doses of 325 mg/m² with each dose separated by seven days.

Methylprednisolone 100 mg intravenously is typically given as a premedication with each dosing.

Infusion reactions (eg, skin flushing, coughing, or throat irritation) with rituximab are common, especially with the initial dosing. These can often be managed by stopping the infusion for 30 minutes, giving diphenhydramine, and restarting at a slower infusion rate.

Other potential adverse effects of rituximab include hypogammaglobulinemia, infection, reactivation of hepatitis B, and neutropenia. Rare cases of PML have been reported in patients treated with rituximab for other indications. However, it is unknown if rituximab increases the risk of PML, since rituximab is often used to treat patients who have an underlying risk factor for PML. For hypogammaglobulinemia in patients with otherwise good disease control, reduced maintenance doses of rituximab can be considered.

Rituximab monitoring and adverse effects are discussed in detail separately. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Rituximab'.)

Fingolimod — There is high-quality evidence that oral fingolimod is more effective than interferon beta-1a for treating pediatric MS. The PARADIGMS randomized controlled trial of 215 children with relapsing-remitting MS compared oral fingolimod (0.5 mg daily, or 0.25 mg daily for children ≤40 kg) with intramuscular interferon beta-1a (30 mcg per week) [14]. At two years, the annualized relapse rate was lower with fingolimod (0.12, versus 0.67 with interferon beta-1a, absolute difference 0.55, 95% CI 0.36-0.74), as was the annualized rate of new or newly enlarged brain lesions on T2-weighted MRI (4.39, versus 9.27 with interferon beta-1a, absolute difference 4.88, 95% CI 2.91-6.84). However, there was a higher rate of serious adverse events with fingolimod (16.8 percent, versus 6.5 percent with interferon beta-1a). Based upon these data, fingolimod was approved by the US Food and Drug Administration (FDA) for the treatment of MS in children age 10 years and older [15]. It is the only disease-modifying therapy with an FDA approval in pediatric MS.

In adults and pediatric patients 10 years of age and older weighing >40 kg, the recommended dosage of fingolimod is 0.5 mg orally once daily [16]. In pediatric patients 10 years of age and older weighing ≤40 kg, the recommended dosage is 0.25 mg orally once daily.

Prior to dosing, the patient should have a baseline electrocardiogram (ECG). The first dose of fingolimod should be given in a setting where symptomatic bradycardia can be managed. The ECG is repeated after six hours of observation for signs and symptoms of bradycardia along with hourly pulse and blood pressure monitoring [16].

The most common adverse effects associated with fingolimod include headache, influenza, diarrhea, back pain, elevated liver enzymes, and cough. Less common but potentially serious adverse events include bradyarrhythmia and atrioventricular block (potentially fatal), macular edema, diminished respiratory function, and tumor development.

Fingolimod dosing, monitoring, and adverse effects are discussed in detail separately. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Fingolimod'.)

Dimethyl fumarate — Evidence from observational studies suggests that dimethyl fumarate is safe and effective for treating relapsing-remitting MS in children [5,17,18]. Evidence from randomized controlled trials in adults established the efficacy of dimethyl fumarate for the treatment of relapsing forms of MS, as reviewed elsewhere. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Dimethyl fumarate'.)

The starting dose for oral dimethyl fumarate is 120 mg given twice daily. After seven days, the dose should be increased to 240 mg given twice daily. It is available in 120 and 240 mg preparations.

The most common side effects of dimethyl fumarate are flushing and gastrointestinal symptoms, including diarrhea, nausea, and abdominal pain. There are case reports of patients taking dimethyl fumarate for MS or psoriasis who developed progressive multifocal leukoencephalopathy (PML), including those with and without lymphocytopenia.

Dimethyl fumarate dosing, monitoring, and adverse effects are discussed in detail separately. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Dimethyl fumarate'.)

Interferon beta drugs — Injectable interferon beta drugs (interferon beta-1a and interferon beta-1b) reduce the frequency of clinical relapses in adults with the relapsing form of MS by approximately 30 percent [19]. They also decrease inflammatory lesion activity on MRI as well as prevent brain atrophy. (See "Overview of disease-modifying therapies for multiple sclerosis", section on 'Interferons'.)

With the exception of a randomized trial that compared interferon beta-1a with fingolimod (see 'Fingolimod' above), the literature describing the effectiveness and tolerability of interferon beta drugs in children is mainly limited observational studies [8,20-23].

Nevertheless, as in adults, interferon beta drugs appear to reduce relapse rates and possibly reduce the progression of disability in pediatric patients with MS [9,24]. As an example, one study evaluated 65 patients with MS who were treated during childhood or adolescence at 15 centers in Italy [20]. The mean age at onset of MS was 12 years. There were three treatment groups: 38 children received intramuscular interferon beta-1a (Avonex), 18 received subcutaneous interferon beta-1a (Rebif) or subcutaneous interferon beta-1b (Betaferon), and 9 received subcutaneous glatiramer acetate. The mean treatment duration was 23, 41, and 33 months, respectively. The mean annualized relapse rate decreased from initial to final assessment to a similar degree in each group:

●Interferon beta-1a: From 2.4 to 0.4

●Interferon beta-1b: From 3.2 to 0.8

●Glatiramer: From 2.8 to 0.25

The mean expanded disability status scale (EDSS) scores from initial to final assessment showed little or no change in each group.

Adolescents are usually prescribed the full adult dose:

●Recombinant human interferon beta-1a (Avonex): 30 mcg intramuscular injection once weekly

●Recombinant human interferon beta-1a (Rebif): 22 mcg or 44 mcg subcutaneous injection three times weekly

●Pegylated interferon beta-1a: 125 mcg subcutaneous injection every 14 days

●Recombinant human interferon beta-1b (Betaseron; Betaferon): 8 million international units subcutaneous injection every other day

For children <10 years of age, the dose of these drugs is calculated using the child's weight in kilograms divided by 50 kg and multiplying this fraction by the adult dose. A full dose is given to children weighing ≥50 kg.

The most common side effects of interferons include flu-like symptoms and headache. Transient elevations of liver aminotransferases, leukopenia, and thyroid function abnormalities (hypothyroidism more often than hyperthyroidism) can occur at the initiation of therapy. These laboratory tests should be serially monitored early in the treatment course and intermittently thereafter. Abnormalities will often resolve with transient reduction in dosing.

Glatiramer — Glatiramer acetate reduces the frequency of clinical relapses in adults with the relapsing form of MS by approximately 30 percent [19]. (See "Overview of disease-modifying therapies for multiple sclerosis", section on 'Glatiramer acetate'.)

As with the interferon beta drugs, the literature describing the effectiveness and tolerability of glatiramer in children is mainly limited observational studies [8,20]. Nevertheless, glatiramer appears to reduce relapse rates and possibly reduce the progression of disability in pediatric patients with MS [9,24].

For adolescents, the dose of glatiramer acetate is 20 mg subcutaneous injection daily or 40 mg subcutaneous injection three times per week administered at least 48 hours apart. For children under the age of 10 years, the dose is calculated using the child's weight in kilograms divided by 50 kg and multiplying this fraction by the adult dose. A full dose is given to children weighing ≥50 kg.

The most common side effect of glatiramer acetate is an erythematous skin reaction localized to the injection site. This is usually transient and resolves with continued treatment. Patients should be warned about alarming but transient idiosyncratic reactions consisting of chest pain and flushing that may occur immediately after injection.

Natalizumab — Natalizumab is the primary agent suggested for refractory MS that has not responded to the high or intermediate efficacy agents, such as rituximab, fingolimod, or dimethyl fumarate. The use or natalizumab is limited by its associated risk for PML in those patients with high-index seropositive status for JC virus.

Randomized controlled trials in adults with relapsing forms of MS established the effectiveness of natalizumab. However, its use is rarely associated with the development of progressive multifocal leukoencephalopathy (PML), a potentially fatal complication. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis" and "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Natalizumab'.)

Natalizumab is approved as monotherapy for adults with relapsing-remitting MS. Data are limited regarding natalizumab in pediatric MS [25-27]. One study from a center in Italy reported 101 children with MS (mean age 14.7 years) who were treated with intravenous natalizumab (300 mg) every 28 days for severe active MS [27]. Over a mean treatment duration of 34 months, the annualized relapse rate decreased from 2.3 in the year prior to therapy to 0.1 at last natalizumab infusion, and no evidence of disease activity was achieved in 58 percent of patients.

The manufacturer's prescribing information states that natalizumab is not indicated for pediatric patients [28]. However, some pediatric MS experts note that the risk profile of natalizumab must be balanced with the potential benefits; these should be discussed in detail with the patient and family when deciding on this therapy for children with an inadequate treatment response to first-line agents for MS [9].

The dose of natalizumab for adults and adolescents is 300 mg by intravenous infusion every four weeks. Dosing in younger children has not been established [29].

Adverse events most commonly associated with natalizumab treatment include headache, infections (mainly urinary tract infection and pneumonia), arthralgia, gastroenteritis, vaginitis, depression, extremity pain, abdominal discomfort, diarrhea, and rash. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Natalizumab'.)

The most feared complication of natalizumab therapy is PML. Patients receiving natalizumab must be followed in a risk management program to monitor for symptoms or signs suggestive of PML. This risk of PML varies according to the patient's anti-JC virus antibody status, history of prior immunosuppressant treatment, and the duration of natalizumab exposure. Other opportunistic infections rarely associated with natalizumab therapy include herpes simplex and varicella zoster infections. These issues are discussed in detail separately. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Natalizumab'.)

Teriflunomide — Oral teriflunomide is approved in the Europe Union for children ≥10 years of age for the treatment of relapsing forms of MS [30], but it is not approved in the United States for treating pediatric patients [31]. In our experience, it is not often used for children, due in part to concerns for lower efficacy (see "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults", section on 'Comparative efficacy') and risk of teratogenicity.

The multicenter TERIKIDS trial randomly assigned 166 patients aged 10 to 17 years with relapsing MS to treatment in a 2:1 ratio with teriflunomide (dose equivalent to 14 mg in adults) or placebo [32]. At 96 weeks, the cumulative probability of confirmed relapse was lower in the teriflunomide group compared with the placebo group (39 versus 53 percent); this difference was similar to the statistically significant effect observed in the much larger adult trials [33,34] but did not reach statistical significance in TERIKIDS (hazard ratio [HR] 0.66, 95% CI 0.39-1.11) [32], possibly due to small patient numbers [35]. The benefit of teriflunomide in TERIKIDS was statistically significant for the composite outcome of first relapse or high MRI activity (51 versus 72 percent, HR 0.57, 95% CI 0.37-0.87) and for two imaging endpoints: the number of new or enlarged T2 lesions per MRI scan was lower with teriflunomide compared with the placebo (4.7 versus 10.5, relative risk [RR] 0.45, 95% CI 0.29-0.71), as was the number of gadolinium-enhancing lesions (1.9 versus 7.5, RR 0.25, 95% CI 0.13-0.51) [32].

The dose of teriflunomide approved in the European Union is 14 mg daily for children with body weight ≥40 kg and 7 mg daily for children <40 kg [30].

Due to the risk of teratogenicity, women and adolescents of childbearing age must have a negative pregnancy test before starting the drug. Teriflunomide use in children has been associated with a risk of pancreatitis, which was observed in approximately 2 percent of patients in an earlier pediatric clinical trial [31]. Teriflunomide has a number of other uncommon but potentially serious adverse effects; monitoring and adverse effects are discussed in detail separately. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Teriflunomide'.)

Other disease-modifying therapies — A number of DMTs are effective for the treatment of relapsing forms of MS in adults and are approved in the United States for clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Oral DMTs include the following:

●Fumarates, a group of DMTs that includes dimethyl fumarate (see 'Dimethyl fumarate' above) and two others: diroximel fumarate and monomethyl fumarate (see "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Fumarates')

●Sphingosine 1-phosphate (S1P) receptor modulators, a group of DMTs that includes fingolimod (see 'Fingolimod' above) and three others: siponimod, ozanimod, and ponesimod (see "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'S1PR modulators')

●Cladribine (see "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Cladribine')

Monoclonal antibody DMTs include rituximab (see 'Rituximab' above), natalizumab (see 'Natalizumab' above), ocrelizumab, ofatumumab, and alemtuzumab (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis".)

Few of these DMTs have been systematically evaluated for the treatment of children with MS [9,36,37], but their use in the management of pediatric MS is increasing [38]. As noted previously, limited data suggest that rituximab, fingolimod, and dimethyl fumarate are safe and effective in pediatric MS (See 'Rituximab' above and 'Fingolimod' above and 'Dimethyl fumarate' above.)

SYMPTOMATIC MANAGEMENT — While disease-modifying therapies (DMTs) have dramatically altered the long-term treatment strategy for MS, management of daily symptoms remains a cornerstone to improving quality of life in these patients. Symptoms directly related to demyelination and its effects require a comprehensive evaluation.

Fatigue — Fatigue is one of the most common complaints of patients with MS (see "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis", section on 'Fatigue and depression'). Recognition of depression as causative for fatigue is important in this patient population and requires consultation with a psychiatrist experienced with MS [39]. (See 'Depression' below.)

The most common type of fatigue encountered in MS is related directly to the disease and is often called lassitude or MS-related fatigue. It is described as an overwhelming feeling of tiredness in those who have done little and are not depressed [40]. Occupational therapy assessment can be useful to improve any circumstances contributing to the fatigue. It is also important to optimize patients' sleep hygiene.

Pharmacologic agents for fatigue include amantadine, modafinil, fluoxetine, and methylphenidate. Amantadine or modafinil are typically used as first-line treatment.

●Amantadine is given at 2.5 mg/kg two times a day (maximum 150 mg/day) for children under 40 kg or younger than 10 years of age. Older children and adults are prescribed 100 mg twice daily.

●Modafinil is started at 50 to 100 mg once a day for children under 10 years. Older children begin with 100 mg daily and the dose is increased as needed up to 300 mg daily.

●Methylphenidate and similar amphetamines are prescribed at doses typically used for the treatment of attention deficit disorder. Long-acting preparations of these medications are preferred. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulants'.)

●Fluoxetine is usually started at 10 mg every other day for two weeks and then increased up to a maximum dose of 20 mg/day for children under age 10 years and up to 40 mg/day for adolescents.

Fluoxetine and other antidepressants must be used with caution, given concern of increased suicidal ideation following initiation of these agents in children and adolescents treated for major depression. In addition, fatigue may be a presenting feature of major depression, and this possibility must be thoroughly investigated. Consultation with a child psychiatrist should be obtained before starting these agents if there is evidence of a mood disorder.

Depression — Some children with MS develop depression (see "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis", section on 'Fatigue and depression') and require consultation and treatment by a pediatric psychiatrist. MS profoundly affects all aspects of the child's life and has significant effects on families and caregivers. It is potentially a life-long diagnosis with implications of progressive disability.

In addition, children with MS must often handle the considerable burden of daily to weekly treatment with immunomodulatory agents, often given by injection.

Nevertheless, many children seem to cope with the diagnosis fairly well, while their parents, other family members, and caregivers often have greater difficulty. This may relate to the "invincible" attitude of most adolescents. The clinician should carefully note changing psychosocial dynamics of the patient, family, and other individuals involved in the patient's care and social life.

The evaluation and treatment of pediatric depression is discussed in detail separately. (See "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis" and "Overview of prevention and treatment for pediatric depression".)

Cognitive impairment — Cognitive deficits in children with MS may include problems with general cognition, language, visuomotor integration, and verbal and visual memory. (See "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis", section on 'Cognitive impairment'.).

For children who are having problems with school, annual neuropsychological assessment may be useful.

Other problems — Other major problems encountered in patients with MS are muscle spasticity, pain, and bladder issues. Treatment for these conditions includes pharmaceutical intervention as well as consultation with physical and occupational therapists.

PROGNOSIS — Progression of disability due to MS is highly variable.

Although not definitive, some data suggest that individuals with pediatric-onset MS have a paradoxically higher annualized relapse rate than those with adult-onset MS [41-43].

By contrast, compared with MS onset at older ages, a younger age at MS onset is associated with slower disease progression (figure 1) [1,44-47]. Despite the slower progression, because of their earlier onset, patients with pediatric-onset MS historically reached disability landmarks at younger ages than those with adult onset MS [46,47]. One of the largest natural history studies of pediatric MS followed a cohort of 394 patients from France and Belgium who were 16 years old or younger at MS onset [46]. These were compared with 1775 patients who were older than 16 at MS onset. The following results were reported for patients with pediatric-onset MS:

●The estimated median time from disease onset to the assignment of a Kurtzke Disability Status Score of 6 (ie, assistance needed for walking) was 29 years (95% CI 27-33), and the corresponding median age was 42 years (approximately 10 years younger than the estimated median age for adult onset MS)

●The estimated median time from disease onset to conversion to secondary progression was 28 years (approximately 10 years longer than adult onset MS), and the corresponding median age was 41 years (approximately 10 years younger than adult onset MS)

●A higher relapse rate during the first two years of disease was associated with an increased rate of disability

●A progressive course at MS onset occurred in only 2 percent of children, and was associated with a shorter time to reach irreversible disability

The risk of persistent disability may be improving over time. A retrospective study analyzed data from a registry of patients with pediatric-onset MS onset and compared time to reach disability milestones by epoch of MS diagnosis (before 1993, 1993 to 1999, 2000 to 2006, and 2007 to 2013) and found that the risk of persistent disability declined by 50 to 70 percent in later diagnosis epochs [48]. This improvement was attributed to an increase over time in the number of patients treated with disease-modifying therapies. (See 'Disease-modifying therapies' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (See "Patient education: Multiple sclerosis in adults (The Basics)" and "Patient education: Multiple sclerosis in children (The Basics)".)

SUMMARY AND RECOMMENDATIONS

●Acute attack

•Initial treatment – For acute attacks of MS in children, we suggest intravenous (IV) methylprednisolone 20 to 30 mg/kg given once daily for five days (Grade 2B). Glucocorticoids can be stopped without a taper in children who demonstrate complete recovery, while a tapering oral prednisone regimen can be used for patients with residual disability. We taper by starting oral prednisone at 1 mg/kg per day and decreasing by 5 mg every two days. (See 'Treatment of acute attacks' above.)

•Recurrence – For children with acute exacerbation of MS that fails to respond to IV glucocorticoid therapy, we suggest intravenous immune globulin (IVIG) 400 mg/kg daily for five days (Grade 2C). For children who relapse during a taper of glucocorticoids, we suggest either retreatment with IV methylprednisolone 20 to 30 mg/kg daily for five days (Grade 2C), or IVIG 400 mg/kg daily for five days (Grade 2C). Therapeutic plasma exchange (one total volume exchange every other day for five to six sessions) is an alternative if IVIG is not an option. (See 'Treatment of acute attacks' above.)

●Disease-modifying therapy – For children who develop relapsing-remitting MS, we recommend treatment with a disease-modifying therapy (DMT) (Grade 1B). The initial choice of DMT is highly influenced by patient and family preferences. (See 'Approach to disease-modifying therapy' above and 'Disease-modifying therapies' above.)

•Preferred approach – Our preferred approach for initial therapy is to choose a DMT with high or intermediate efficacy, such as rituximab, fingolimod, or dimethyl fumarate. These DMTs appear to be more effective than the older injectable platform DMTs (ie, interferons and glatiramer) for reducing the relapse rate and the accumulation of new brain lesions, but at the cost of a higher rate of serious adverse events.

•Alternative approach – Another approach favored by some experts is to start treatment using an older platform DMT for patients with relapsing forms of MS, particularly for those with a minimal disease burden or those who are risk averse; options include glatiramer acetate, interferon beta-1a (Avonex), interferon beta-1a (Rebif), interferon beta-1b (Betaseron), or peginterferon beta-1a.

•Monitoring – Response to DMT is monitored by neurologic examinations at one, three, and six months after initiation of the DMT, along with brain magnetic resonance imaging (MRI) scans 6 to 12 months after initiation. Thereafter, follow-up intervals are determined by the level of disease activity. (See 'Monitoring response' above.)

●Treatment failure

•Definition – Patients are considered to have an inadequate response to DMT (ie, minimum six months on full-dose therapy and fully compliant with treatment) if they develop two or more relapses in a 12-month period or two or more new T2 or contrast-enhancing brain lesions on MRI compared with the pre-treatment period. (See 'Treatment failure' above.)

•Management – For patients with treatment failure, DMT should be switched. Patients who have a poor response to interferon beta drugs or glatiramer acetate can be switched to an intermediate- or high-efficacy DMT, such as fingolimod or rituximab; patients who have a poor response to oral agents can be switched to a high-efficacy infusion DMT (rituximab or natalizumab). (See 'Refractory disease' above.)

●Symptom management – Symptomatic treatment of daily symptoms remains a cornerstone to improving quality of life in patients with MS.

•Fatigue – Fatigue is the most common complaint of patients with MS. Typical pharmacologic treatments include amantadine and modafinil. (See 'Fatigue' above.)

•Other symptoms – Other prominent issues that can affect children with MS include depression, cognitive impairment, muscle spasticity, pain, and bladder problems. (See 'Depression' above and 'Cognitive impairment' above and 'Other problems' above.)

●Prognosis – Compared with MS onset at older ages, a younger age at MS onset is associated with slower disease progression. Despite the slower progression, because of their earlier onset, patients with pediatric-onset MS historically reached disability landmarks at younger ages than those with adult-onset MS (figure 1). (See 'Prognosis' above.)