Curr Treat Options Neurol (2015) 17:10 DOI 10.1007/s11940-014-0336-z
Pediatric Neurology (RM Boustany, Section Editor)
Treatment of Pediatric Multiple Sclerosis Sona Narula, MD* Sarah E. Hopkins, MD Brenda Banwell, MD Address * Division of Neurology, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, 3501 Civic Center Boulevard, Colket Translational Research Building, 10th floor, Philadelphia, PA 19104, USA Email: [email protected]
* Springer Science+Business Media New York 2015
This article is part of the Topical Collection on Pediatric Neurology Keywords Pediatric I Multiple sclerosis I Treatment I Glatiramer acetate I Interferon I Natalizumab I Fingolimod I Emerging therapies
Opinion statement The past 10 years have borne witness to increased recognition and diagnosis of pediatric multiple sclerosis (MS). Additionally, during this time period, the number of treatment options available for MS patients has increased significantly, as has the number of studies evaluating the use of these therapies in children. Though the U.S. Food and Drug Administration has not formally approved any of these therapies for use in pediatric MS, a number of injectable, oral, and intravenous treatments are currently being used off-label in these children. Disease modifying therapy should be initiated promptly following a diagnosis of MS. The patient and family should be engaged in the choice of therapy as this is likely to promote adherence. First-line options include any of the injectable therapies (glatiramer acetate, interferon beta), which have roughly similar efficacy (approximately 30 % reduction of clinical relapses). If a patient has breakthrough disease or persistent, unmanageable side effects, transition to a different first-line therapy or escalation to a second-line therapy, such as natalizumab, should be considered. Though the efficacy of second-line agents is higher, the potential risk of serious adverse effects also increases. New therapies, including oral agents, are now being rigorously studied with pediatric clinical trials and may provide safe alternatives for patients that are either unresponsive or intolerant to currently available medications. When necessary, acute exacerbations can be treated with corticosteroids. Intravenous methylprednisolone at a dosage of 30 mg/kg/day (maximum dose 1000 mg/day) for 3–5 days is recommended with severe attacks. If patients are unresponsive to corticosteroids, treatment with either intravenous immunoglobulin or plasma exchange may be required. Fatigue, spasticity, and pain can also occur in pediatric patients with MS. Medications are needed if symptoms are severe and impact quality of life.
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Introduction Though pediatric multiple sclerosis (MS) is an overall rare disease, between 2 % and 10 % of MS patients will have their first symptom in childhood [1–4]. Within the pediatric population, MS is more commonly diagnosed in postpubertal children though patients as young as 2 years old have been reported in the literature [5, 6]. MS follows a relapsing remitting disease course in childhood and pediatric patients tend to have a higher relapse rate in the first few years after diagnosis as compared with patients with adult-onset disease [2, 7]. Though children with MS do not tend to accrue physical disability unrelated to relapses, cognitive impairment is common. In fact, up to 35 % of pediatric MS patients have some identifiable cognitive dysfunction at the time of diagnosis, and at least one-half of children continue to accrue cognitive deficits within the first 5 years after disease onset [8–11]. Prior MS diagnostic criteria required clinical or magnetic resonance imaging (MRI) evidence of repeated attacks of central nervous system (CNS) inflammation separated in both time and space. The 2010 revisions to the McDonald criteria now allow for diagnosis of MS after a first clinical attack, if the event is consistent with a MS-related clinical event, and provided that specific MRI features are evident [12]. The MRI features require at least two clinically silent lesions, located in two of four areas typical for MS, and require that at least one clinically silent lesion enhance with gadolinium (while at least one other lesion does not). Patients can also meet the 2010 MS diagnostic criteria on the basis of further clinical attacks, or by MRI evidence of new lesions on serial imaging [12]. A diagnosis of MS can only be confirmed when disorders that mimic MS are excluded. Depending on the clinical scenario, some disorders to consider include acute disseminated encephalomyelitis (ADEM), small vessel CNS vasculitis, lupus, CNS infection, and neuromyelitis optica (NMO). Exclusion of MS mimics is especially important when considering selection of appropriate disease modifying therapy as patients with
different relapsing disorders may respond poorly to some of the approved MS therapies. For example, as it has been suggested that patients with neuromyelitis optica respond poorly to interferon-beta, it may be prudent to avoid this therapy in a patient in which this diagnosis is also being considered [13]. It is also important to exclude ADEM at the time of an initial attack, which can usually be done by evaluating a patient’s clinical history, as this is typically a monophasic disease that does not require chronic disease modifying therapy. This review discusses management of exacerbations, as well as disease modifying therapies and symptomatic management of pediatric MS. Studies have established that disease modifying therapy is efficacious in preventing relapses in children with MS. First-line disease modifying therapies include glatiramer acetate and interferon beta. To date, all studies of these medications in children have been retrospective or open-label observational studies. Second-line therapies, including natalizumab, cyclophosphamide, and rituximab, are also discussed and should be considered for use when breakthrough disease or intolerable side effects with first line therapies occur. Medications for acute clinical exacerbations and symptomatic management are also often required by pediatric patients. Details of these therapies and of their associated side effects are described below. Finally, with recent mandates by the European Medicines Agency and the U.S. Food and Drug Administration (FDA), pediatric investigation plans are required for all new therapeutics, and international clinical trials are now underway for some emerging therapies. Though prompt initiation of disease modifying therapy is of utmost importance in pediatric MS, discussion of adherence must concurrently occur as non-adherence has the potential to influence treatment effect and may pose risks to the patient, especially with some of the newer therapies. Multidisciplinary support is often required and can reinforce the need for preventative medication if needed.
Treatment Diet and lifestyle Vitamin D
Studies in children have associated low serum vitamin D levels with an increased risk of MS [14••] and an increased relapse rate in patients with
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Page 3 of 12 10 confirmed disease [15]. There are no studies that delineate optimal blood levels for vitamin D 25(OH) (the serum biomarker for vitamin D) specifically in MS. Dosing should be individualized, with most patients requiring 800–3000 IU oral vitamin D per day to achieve serum levels in the range determined by most labs as being normal (30–80 ng/mL).
Smoking
Observational studies suggest that smoking may increase MS risk in adults [16, 17]. In children, second-hand smoke, occurring via exposure to a parent smoking at home, has been associated with an increased risk for MS [18]. A longer duration of smoke exposure has also been associated with an elevated risk [18].
Body mass index
Studies have shown an association of adolescent obesity with an increased risk of subsequent adult-onset MS [19–21].
Pharmacologic treatment: therapies for acute exacerbations Treatment of acute exacerbations in pediatric MS is largely based on experience in adults as there are few studies in children. Treatment is considered when an exacerbation causes symptoms that are associated with impairment, such as limited mobility or vision. Glucocorticoids
Standard dosage
Treatment with corticosteroids has been shown to decrease the duration of symptoms associated with acute exacerbations in adult patients with MS [22], and reduces the number of enhancing lesions seen on MRI [23]. Although formal studies have not been done in children, glucocorticoids are standard first-line treatment, usually with intravenous (IV) methylprednisolone [24•]. Our practice is to use IV methylprednisolone for 3 to 5 days. Treatment is stopped at 3 days if there has been resolution of symptoms, and continued for 5 days with possible use of an oral taper if symptoms persist. Methylprednisolone IV, 30 mg/kg/day (maximum daily dose of 1000 mg) for 3–5 days. A taper is not required for all patients and should be reserved for patients with partial recovery who demonstrate an ongoing response to IV corticosteroids. If an oral prednisone taper is used, the starting dose is typically 1 mg/kg/day (maximum dose of 60 mg/day), with a taper over 1–2 weeks.
Main side effects
The most common side effects include change in appetite and behavior, irritability, and difficulty sleeping. The dose may be given once a day, in the morning to minimize effects on sleep. Potentially serious side effects include gastrointestinal bleeding, hypertension, glaucoma, and hyperglycemia. Patients should receive gastrointestinal prophylaxis with an antacid, and blood pressure and glucose should be monitored. Patients requiring long- term or frequent treatment with steroids are at risk for further adverse effects, including avascular necrosis, osteoporosis, edema, and obesity.
Special considerations
While IV methylprednisolone is effective in treating relapses, treatment with an IV medication for several days can be inconvenient for families. Data suggests that an equivalent dose of oral corticosteroid may be equally efficacious [25, 26], although there are no reports in children.
Cost
$28.22 for 1000 mg in the United States of America (USA)
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Intravenous immunoglobulin
Standard dosage
Main side effects
Cost
Intravenous immunoglobulin (IVIG) may be considered in pediatric MS patients if steroids are contraindicated, or in an attempt to reduce dependence on glucocorticoids for those with frequent exacerbations. IVIG is believed to impact inflammation by decreasing levels of cytokines and binding antibodies against myelin as well as blocking Fc receptors [27], and it may promote remyelination [28]. There is some evidence that IVIG may decrease disease activity, including the frequency of relapses, in adults with MS [29]. While there have been pediatric case reports of successful treatment of acute demyelinating syndromes (MS, ADEM) using IVIG [30–32], there have been no controlled studies. 2 grams/kg, divided over 1–5 days. The infusion should be initiated at a slow rate and increased as tolerated, as per institutional protocols. Dose and concentration may require adjustment in renal impairment. Headache, myalgia, and fever are common adverse reactions, and some patients may develop aseptic meningitis. There is the potential for a severe allergic reaction in patients with IgA deficiency, and there is a risk for hemolytic anemia along with the usual risks associated with the use of a blood product. Patients should be premedicated with acetaminophen and diphenhydramine to minimize side effects Thromboembolism is another rare but serious adverse effect. Care should be used in patients with impaired renal function because of the influx of hyperosmolar fluid. The majority of more serious complications may be limited by adequate hydration and a slow infusion rate. $14,929 for IVIG 10 % 100 g in the USA.
Plasma exchange
Administration Special considerations
Plasma exchange may be considered in patients with fulminant demyelination unresponsive to corticosteroids [33, 34], especially when there is significant functional disability. Plasma exchange is presumed to work by washing autoantibodies and pro-inflammatory cytokines from the blood, and is particularly useful for demyelinating diseases with a major humoral component, such as NMO. A typical course consists of five to seven exchanges over the course of 2 weeks. Plasma exchange requires an indwelling catheter and may be associated with depletion of coagulation factors and electrolytes as a result of the large fluid shifts. These risks can be minimized by careful monitoring and repletion following exchanges. Furthermore, many medications, including anti-epileptic drugs, may require additional doses following treatments.
Pharmacologic treatment: disease modifying therapies First-line disease modifying therapy Glatiramer acetate and interferon beta have been routinely used in adults with MS for the past 15–20 years. Initial studies of these medications in adult MS patients revealed similar efficacy in terms of reduction of relapse rates (approximately 30 %) and accrual of new lesions on MRI [35–38]. Though there have not been any randomized controlled trials of these medications in the pediatric MS population, there have been a number of retrospective studies
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evaluating the off-label use of these therapies in children. In this section, we briefly review the currently accepted dosing and administration for these medications and the evidence for their use in children. Glatiramer acetate
Standard dosage
Glatiramer acetate is an acetate salt of a mixture of synthetic polypeptides composed of four amino acids (L-alanine, L-glutamic acid, L-lysine, and Ltyrosine), which resembles myelin basic protein [38]. Though its mechanism of action is still not fully understood, it is thought that glatiramer acetate has some of its effect on the immune system by modulating the functioning of antigen-presenting cells and by effecting the cytokine secretion of CD4+ T helper cells [39]. Retrospective studies done in children have shown glatiramer acetate to be well tolerated with a clinical efficacy (reduction in relapse rate) similar to that previously reported in adult trials [40–42]. 20 mg via subcutaneous injection daily or 40 mg via subcutaneous injection three times per week (with injections being at least 48 hours apart). Injection sites should be rotated.
Contraindications
Hypersensitivity to glatiramer acetate, mannitol, or any other component of the formulation
Main side effects
Local injection site reactions characterized by pain, erythema, and swelling are the most common side effects [41–43]. A postinjection reaction can occur and manifests with immediate anxiety, chest pain, dyspnea, flushing, and palpitations after an injection. The reaction lasts between 30 seconds and 30 minutes and resolves without intervention [38]. Other reported side effects include lipoatrophy at injection sites and chest pain (independent of the immediate postinjection reaction).
Cost
$4500–$5500 per month (estimate based on wholesale cost from a single manufacturer) in the USA
Interferon beta Interferon beta acts as immune-modulator via several different mechanisms. These include inhibiting autoreactive T cells, increasing production of anti-inflammatory cytokines, reducing proinflammatory cytokines, and decreasing migration of proinflammatory leukocytes into the CNS [44]. Over the past 10 years, several observational studies have evaluated the safety and efficacy of interferon beta in children with MS and have found its tolerability and efficacy to parallel that seen in adults [40, 41, 45–47].
Dosing and formulations Interferon beta 1a Subcutaneous standard dosage Intramuscular standard dosage Interferon beta 1b standard dosage Contraindications (all formulations)
22 mcg or 44 mcg via subcutaneous injection 3 times weekly with doses separated by at least 48 hours. 30 mcg via intramuscular injection once weekly. 0.25 mg via subcutaneous injection every other day. Hypersensitivity to natural or recombinant interferon or a component of the formulation. Interferons should be avoided in pregnant patients (pregnancy risk category C, Class III evidence) [48].
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Main side effects (all formulations)
Cost (all interferons)
The most common side effects are flu-like symptoms (myalgias, fatigue, headache, fever, or chills). These symptoms are often mitigated by administration of antipyretics on the day of injection. For all interferons, the dose is often titrated to goal over 4-6 weeks for better tolerability. Transient transaminase elevation and bone marrow suppression (primarily leukopenia) can also occur and merit intermittent surveillance [45–47]. Typically, blood counts and liver function tests are checked monthly for the first 6 months of therapy and then every 6 months thereafter. Thyroid function should be checked yearly. Most interferon-associated lab abnormalities are clinically asymptomatic [47]. Other reported side effects include a worsening of underlying depression, development of concurrent autoimmune disorders (idiopathic thrombocytopenia, hyper and hypothyroidism), local injection site reactions, and allergic reactions. Injection sites should be rotated. $4000–$5400 per month (estimate based on wholesale cost) in the USA.
Second-line disease modifying therapy Natalizumab Natalizumab is humanized monoclonal antibody that targets the α4 subunit of α4β1 and α4β7 integrins, which are molecules expressed on the surface of lymphocytes, which allow for their adhesion to vascular endothelium and subsequent transmigration into the CNS. Natalizumab is the most effective medication for relapsing remitting multiple sclerosis and has been shown to decrease relapses by about 70 % (compared with placebo) in adults [49]. However, because of its potential side effects, namely progressive multifocal leukoencephalopathy (PML), its use is typically limited to children who have refractory disease or poor tolerance to first line medications. There have been few studies describing the effect of natalizumab in children with MS. The largest study to date is of 55 active MS patients who received a median of 26 infusions. Most patients were found to have clinical and radiologic benefit as evidenced by the reduction in the mean Expanded Disability Status Scale scores (decreased from 2.7 to 1.9) and the percentage of patients who remained free of new MRI activity (74 %–83 %) while on treatment [50•]. Other studies of smaller pediatric cohorts have shown similar results [51–54]. PML is a severe opportunistic brain infection caused by the JC virus, a polyomavirus. PML has the potential to occur in all natalizumab-treated patients who have been exposed to JC virus (as evidenced by JC virus antibody positivity), though the risk is substantially higher in patients with prior exposure to immunosuppressive medication and with increased time on therapy. The seroprevalence of JC virus has been previously reported to be low (21 %) in healthy children [55], yet a recent study of a large pediatric MS cohort found about one-half of the patients to be positive for JC virus antibodies when tested within 6 months of initial diagnosis [56]. The authors also report an annual seroconversion rate of 4.37 % in patients who were initially JC virus antibody negative. As a result, frequent testing of JC virus antibodies and risk stratification is recommended when natalizumab is used.
Curr Treat Options Neurol (2015) 17:10 Standard dosage
Page 7 of 12 10 300 mg intravenously every 4 weeks.
Contraindications
Prior to initiating treatment, the risks and benefits of natalizumab should be discussed in all patients who have been exposed to JC virus or have been treated previously with immunosuppression. JC virus antibody testing should be repeated every 3 months while on therapy and risks should be re-discussed if a patient seroconverts and as their treatment duration increases. Natalizumab is contraindicated in pregnant patients (Pregnancy class C) [48].
Main side effects
Hypersenstivity reactions, headache, and mild hematologic abnormalities (elevated white blood cell count; anemia) have been reported in children [51, 52, 54]. PML is the most concerning potential side effect though there have not been any cases of natalizumab-associated PML in the pediatric MS population thus far.
Cost
$5600 per dose (300 mg) in the USA (estimate based on wholesale cost)
Cyclophosphamide
Standard dosage
Cyclophosphamide is an alkylating agent with powerful and varied immunosuppressant properties, including lymphocytotoxicity, which may be considered as a second line treatment in MS. Studies in adults have shown conflicting results with regard to efficacy, and suggest that it may be more effective in younger patients with aggressive disease [57]. One retrospective study of 17 patients suggested that it may decrease relapse rate and limit short-term disability progression in pediatric MS patients with aggressive disease [58]. Therapy is generally administered monthly, but an induction protocol is sometimes used. 600–1000 mg/m2 intravenously, administered monthly with the minimum dose required to decrease white blood cell counts to less than 3000/mm3 (measured at days 7, 14, and 28 postinfusion) [59].
Contraindications
Prior to initiating treatment, the risks and benefits of cyclophosphamide should be discussed in all patients, and with their parents or legal guardians. Cyclophosphamide is contraindicated in pregnant patients (Pregnancy class D).
Main side effects
Common side effects include nausea and vomiting, susceptibility to infection, amenorrhea, and alopecia. Nausea and vomiting may be decreased by premedication with glucocorticoids and ondansetron, which is an antiemetic. More severe adverse effects include hemorrhagic cystitis, infertility, and longterm risks of bladder cancer and hematologic malignancies. Risk for bladder cancer may be mitigated by the use of mesna, vigorous hydration, and limiting the lifetime cyclophosphamide dose to less than 100 g [60].
Monitoring
Pregnancy screening in women of childbearing age should be done before initiation of cyclophosphamide. A complete blood count with differential should be done on the day of infusion and then again measured at day 7, 14, and 28 postinfusion [59]. Urinalysis should be done with each infusion.
Special considerations Cyclophosphamide is a potent immunosuppressant with potentially serious adverse effects. Vaccinations should be updated prior to initiation when possible. Follow-up complete blood count (with differential) and urinalysis should be performed yearly, even after cessation of treatment, to monitor for hematologic or bladder malignancies. Prior immunosuppressant use is a risk factor for
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PML in patients treated with natalizumab, and this should be considered when choosing to use cyclophosphamide in patients who may require natalizumab in the future. Cost $527.40 for cyclophosphamide powder for a 600 mg injection, $879 for a 1000 mg injection in the USA Rituximab
Standard dosage
Rituximab is a monoclonal antibody targeting CD20+ B lymphocytes. Originally developed as a treatment for B cell lymphoma, it is also effective in antibody-medicated diseases, including NMO. MS is not an FDAapproved indication for rituximab use. However, there is evidence for B cell involvement in MS, and evidence from adult studies suggests that rituximab may decrease relapses by as much as 50 % [61]. Retrospective studies and case reports in pediatric autoimmune inflammatory and demyelinating disease suggest that rituximab is well tolerated, and may have efficacy in pediatric multiple sclerosis [62–64]. Clinically, it is a useful treatment to consider in cases where the differential includes NMO as well as MS. 750 mg/m2/dose, maximum of 1000 mg, administered as two doses 2 weeks apart. Infusion should be started slowly and increased according to institutional protocol or the manufacturer’s instructions. Rituximab is typically readministered when a patient’s B cell panel demonstrates reconstitution of CD19+/CD20+ B cells.
Contraindications
Rituximab should not be used in patients with a history of Hepatitis B because of the risk of fulminant reactivation of disease. It also should not be used in pregnant patients (pregnancy category C).
Main side effects
Rituximab is generally well tolerated, but may be associated with mild infusion reactions. It is associated with fulminant reactivation of hepatitis B. Rituximab has been associated with PML in patients with hematologic malignancies or autoimmune conditions other than MS, but only in the presence of an additional history of immunosuppression.
Special considerations
Immunizations should be updated prior to initiation of rituximab when possible, and immunity to hepatitis B should be documented. Because of the risk of allergic reaction patients are typically premedicated with glucocorticoids, acetaminophen, and diphenhydramine. Prior immunosuppressant use is a risk factor for PML in patients treated with natalizumab, and, as with cyclophosphamide, this should be considered when choosing to use rituximab in patients who may require natalizumab in the future.
Cost
$8459 for 1000 mg in the USA.
Other treatments Fatigue
MS-related fatigue has been described as an overwhelming sense of tiredness, lack of energy, and a feeling of exhaustion, which often interferes with functionality [65]. Fatigue has been reported in 9 %–76 % [66–68] of children with MS, with varying percentages attributed to differences in measurement scales and whether the patient or the parent reports. Fatigue in MS patients is multifactorial and can be a result of comorbid mood disorders, irregular sleep, physical deconditioning, or from ongoing inflammation involving key parts of the central nervous system [68]. Nonpharmacologic interventions, such as routine exercise, are typically the first line treatments for fatigue. If symptoms
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Page 9 of 12 10 persist, use of medications such as modafinil or amantadine can be considered. Neither modafinil nor amantadine has been approved by the FDA for MSassociated fatigue. Modafinil has been studied in the adult MS population with both open label and placebo-controlled trials [69–72]. Results from these studies have been equivocal with some benefit noted in the open-label and single-blind phase II studies, but no significant differences found with modafinil in the double-blind, placebo-controlled study.
Spasticity
Though treatment of spasticity has not been formally studied in pediatric MS (largely because of the fact that relatively few pediatric MS patients develop severe motor impairment early in the disease), it has been evaluated in children with cerebral palsy [73]. For generalized spasticity in cerebral palsy, medications such as diazepam, baclofen, and tizanidine have been used in this population. If focal spasticity is severe, botulinum toxin A is recommended [73]. Baclofen has been studied in adult MS patients and is generally well tolerated. Potential benefits from this medication include a reduction in spasms and their associated pain, and improvement in range of motion. Abrupt discontinuation of baclofen can result in seizures, hallucinations, and hyperthermia [74–76]. Baclofen can also result in muscle weakness and somnolence, especially upon initiation and with dose increases.
Neuropathic pain
Neuropathic pain is one of the most commonly reported symptoms in adults with MS. This type of pain is often described as a burning sensation affecting one or more limbs, typically distally more than proximally. Gabapentin is the most commonly used medication for this indication. Gabapentin has not been formally studied in pediatric MS but has been studied in a small open label study of 22 adult MS patients [77]. In this study, 68 % of subjects experienced excellent to moderate pain relief at a dose of 600 mg per day; 50 % of the cohort reported some adverse side effect though only five patients discontinued treatment. Mental cloudiness, somnolence, and gastrointestinal complaints were the most commonly reported side effects [77].
Emerging therapies Several oral medications have recently been approved for MS in adults. These include fingolimod, teriflunomide, and dimethyl fumarate. Some adverse effects have been reported in adults, teratogenicity and hepatic failure with teriflunomide, bradycardia with the initial dose of fingolimod, and leukopenia with all three medications. Given the limited data regarding the safety and efficacy of these treatments in pediatric patients, they are not routinely being used in pediatric patients at this time. Recent FDA regulations mandate a pediatric investigation plan for all newly approved drugs, and clinical trials to investigate the safety and efficacy of these medications in the pediatric population are now underway.
Conclusions As more medications are studied and approved for use in pediatric MS, the number of available treatment options that are both tolerable and effective will increase, as will therapies with different mechanisms of action. Factors including medication side effects, aggressiveness of disease, and ease of monitoring may impact selection of therapy in a particular patient, and should be discussed prior to initiation. Compliance is likely to improve if medications either have
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greater tolerability, or are given at predefined and relatively infrequent intervals (i.e. infusions given every month or every 6 months). As medications increase in efficacy, it is hoped that mitigation of long-term consequences of MS will be achieved. We are hopeful that multicenter international collaboration will enable clinical trials to succeed, given that pediatric MS is a rare disease.
Compliance with Ethics Guidelines Conflict of Interest Sona Narula, Sarah E. Hopkins, and Brenda Banwell declare no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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Sahlas D, Miller S, Guerin M, et al. Treatment of acute disseminated encephalomyelitis with intravenous immunoglobulin. Neurology. 2000;54(6):1370–2. Weinshenker B, O’Brien P, Petterson T, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol. 1999;46:878–86. Cortese I, Chaudhry V, So YT, et al. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011;76(3):294–300. The INFB, Group MSS. Interferon beta-1b is effective in realpsing-remiting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebocontrolled trial. Neurology. 1993;43(4):655–61. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39(3):285–94. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneoulsy in Multiple Sclerosis) Study Group. Randomized double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498–504. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45(7):1268–76. Lalive PH, Neuhaus O, Benkhoucha M, et al. Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs. 2011;25(5):401–14. Ghezzi A, Amato MP, Capoblanco M, et al. Diseasemodifying drugs in childhood-juvenile multiple sclerosis: results of an Italian co-operative study. Mult Scler. 2005;11(4):420–4. Ghezzi A, Immunomodulatory Treatment of Early Onset MS (ITEMS) Group. Immunomodulatory treatment of early onset multiple sclerosis: results of an Italian Co-operative study. Neurol Sci. 2005;26 Suppl 4:S183–6. Kornek B, Bernert G, Balassy C, et al. Glatirmaer acetate treatment in patients with childhood and juvenille onset multiple sclerosis. Neuropediatrics. 2003;34(3):120–6. Giovannoni G, Southam E, Waubant E. Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence. Mult Scler. 2012;18(7):932–46. McGraw CA, Lublin FD. Interferon beta and glatiramer acetate therapy. Neurotherapeutics. 2013;10(1):2–18. Mikaeloff Y, Moreau T, Debouverie M, et al. Interferonbeta treatment in patients with childhood-onset multiple sclerosis. J Pediatr. 2001;139(3):443–6.
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Banwell B, Reder AT, Krupp L, et al. Safety and toleratibility of interferon beta-1b in pediatric multiple sclerosis. Neurology. 2006;66(4):472–6. 47. Pohl D, Rostasy K, Gartner J, Hanefeld F. Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a. Neurology. 2005;64(5):888–90. 48. Lu E, Wang BW, Guimond C, et al. Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. Neurology. 2012;79(11):1130–5. 49. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899–910. 50.• Ghezzi A, Pozzilli C, Grimaldi LM, et al. Natalizumab in pediatric multiple sclerosis: results of a cohort of 55 cases. Mult Scler. 2013;19D8]:1106–12. This study describes the safety and efficacy of natalizumab in a large pediatric MS cohort. 51. Yeh EA, Weinstock-Guttmann B. Natalizumab in pediatric multiple sclerosis patients. Ther Adv Neurol Disord. 2010;3(5):293–9. 52. Ghezzi A, Pozzilli C, Grimaldi LM, et al. Safety and efficacy of natalizumab in children with multiple sclerosis. Neurology. 2010;75(10):912–7. 53. Huppke P, Stark W, Zurcher C, et al. Natalizumab use in pediatric multiple sclerosis. Arch Neurol. 2008;65(12):1655–8. 54. Arnal-Garcia C, Garcia-Montero MR, Malaga I, et al. Natalizumab use in pediatric patients with relapsingremitting multiple sclerosis. Eur J Paediatr Neurol. 2013;17(1):50–4. 55. Kean JM, Rao S, Wang M, Garcea RL. Seroepidemioogy of human polyomaviruses. PLoS Pathog. 2009;5(3):e1000363. 56. Huppke P, Hummel H, Ellenberger D, et al. JC virus antibody status in a pediatric multiple sclerosis cohort: prevalance, conversion rate and influence rate on disease severity. Mult Scler. 2014 July 28. 57. Okuda D. Immunosuppressive treatments in multiple sclerosis. Handbook of Clinical Neurology 2014. p 122. 58. Makhani N, Gorman MP, Branson HM, et al. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology. 2009;72:2076–82. 59. Banwell B, Bar-Or A, Giovannoni G, et al. Therapies for multiple sclerosis: considerations in the pediatric patient. Nat Rev Neurol. 2011;7(2):109–22. 60. Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124(5):477–84. 61. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358:676–88.
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Pediatric Neurology (RM Boustany, Section Editor)
Treatment of Pediatric Multiple Sclerosis Sona Narula, MD* Sarah E. Hopkins, MD Brenda Banwell, MD Address * Division of Neurology, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, 3501 Civic Center Boulevard, Colket Translational Research Building, 10th floor, Philadelphia, PA 19104, USA Email: [email protected]
* Springer Science+Business Media New York 2015
This article is part of the Topical Collection on Pediatric Neurology Keywords Pediatric I Multiple sclerosis I Treatment I Glatiramer acetate I Interferon I Natalizumab I Fingolimod I Emerging therapies
Opinion statement The past 10 years have borne witness to increased recognition and diagnosis of pediatric multiple sclerosis (MS). Additionally, during this time period, the number of treatment options available for MS patients has increased significantly, as has the number of studies evaluating the use of these therapies in children. Though the U.S. Food and Drug Administration has not formally approved any of these therapies for use in pediatric MS, a number of injectable, oral, and intravenous treatments are currently being used off-label in these children. Disease modifying therapy should be initiated promptly following a diagnosis of MS. The patient and family should be engaged in the choice of therapy as this is likely to promote adherence. First-line options include any of the injectable therapies (glatiramer acetate, interferon beta), which have roughly similar efficacy (approximately 30 % reduction of clinical relapses). If a patient has breakthrough disease or persistent, unmanageable side effects, transition to a different first-line therapy or escalation to a second-line therapy, such as natalizumab, should be considered. Though the efficacy of second-line agents is higher, the potential risk of serious adverse effects also increases. New therapies, including oral agents, are now being rigorously studied with pediatric clinical trials and may provide safe alternatives for patients that are either unresponsive or intolerant to currently available medications. When necessary, acute exacerbations can be treated with corticosteroids. Intravenous methylprednisolone at a dosage of 30 mg/kg/day (maximum dose 1000 mg/day) for 3–5 days is recommended with severe attacks. If patients are unresponsive to corticosteroids, treatment with either intravenous immunoglobulin or plasma exchange may be required. Fatigue, spasticity, and pain can also occur in pediatric patients with MS. Medications are needed if symptoms are severe and impact quality of life.
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Introduction Though pediatric multiple sclerosis (MS) is an overall rare disease, between 2 % and 10 % of MS patients will have their first symptom in childhood [1–4]. Within the pediatric population, MS is more commonly diagnosed in postpubertal children though patients as young as 2 years old have been reported in the literature [5, 6]. MS follows a relapsing remitting disease course in childhood and pediatric patients tend to have a higher relapse rate in the first few years after diagnosis as compared with patients with adult-onset disease [2, 7]. Though children with MS do not tend to accrue physical disability unrelated to relapses, cognitive impairment is common. In fact, up to 35 % of pediatric MS patients have some identifiable cognitive dysfunction at the time of diagnosis, and at least one-half of children continue to accrue cognitive deficits within the first 5 years after disease onset [8–11]. Prior MS diagnostic criteria required clinical or magnetic resonance imaging (MRI) evidence of repeated attacks of central nervous system (CNS) inflammation separated in both time and space. The 2010 revisions to the McDonald criteria now allow for diagnosis of MS after a first clinical attack, if the event is consistent with a MS-related clinical event, and provided that specific MRI features are evident [12]. The MRI features require at least two clinically silent lesions, located in two of four areas typical for MS, and require that at least one clinically silent lesion enhance with gadolinium (while at least one other lesion does not). Patients can also meet the 2010 MS diagnostic criteria on the basis of further clinical attacks, or by MRI evidence of new lesions on serial imaging [12]. A diagnosis of MS can only be confirmed when disorders that mimic MS are excluded. Depending on the clinical scenario, some disorders to consider include acute disseminated encephalomyelitis (ADEM), small vessel CNS vasculitis, lupus, CNS infection, and neuromyelitis optica (NMO). Exclusion of MS mimics is especially important when considering selection of appropriate disease modifying therapy as patients with
different relapsing disorders may respond poorly to some of the approved MS therapies. For example, as it has been suggested that patients with neuromyelitis optica respond poorly to interferon-beta, it may be prudent to avoid this therapy in a patient in which this diagnosis is also being considered [13]. It is also important to exclude ADEM at the time of an initial attack, which can usually be done by evaluating a patient’s clinical history, as this is typically a monophasic disease that does not require chronic disease modifying therapy. This review discusses management of exacerbations, as well as disease modifying therapies and symptomatic management of pediatric MS. Studies have established that disease modifying therapy is efficacious in preventing relapses in children with MS. First-line disease modifying therapies include glatiramer acetate and interferon beta. To date, all studies of these medications in children have been retrospective or open-label observational studies. Second-line therapies, including natalizumab, cyclophosphamide, and rituximab, are also discussed and should be considered for use when breakthrough disease or intolerable side effects with first line therapies occur. Medications for acute clinical exacerbations and symptomatic management are also often required by pediatric patients. Details of these therapies and of their associated side effects are described below. Finally, with recent mandates by the European Medicines Agency and the U.S. Food and Drug Administration (FDA), pediatric investigation plans are required for all new therapeutics, and international clinical trials are now underway for some emerging therapies. Though prompt initiation of disease modifying therapy is of utmost importance in pediatric MS, discussion of adherence must concurrently occur as non-adherence has the potential to influence treatment effect and may pose risks to the patient, especially with some of the newer therapies. Multidisciplinary support is often required and can reinforce the need for preventative medication if needed.
Treatment Diet and lifestyle Vitamin D
Studies in children have associated low serum vitamin D levels with an increased risk of MS [14••] and an increased relapse rate in patients with
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Page 3 of 12 10 confirmed disease [15]. There are no studies that delineate optimal blood levels for vitamin D 25(OH) (the serum biomarker for vitamin D) specifically in MS. Dosing should be individualized, with most patients requiring 800–3000 IU oral vitamin D per day to achieve serum levels in the range determined by most labs as being normal (30–80 ng/mL).
Smoking
Observational studies suggest that smoking may increase MS risk in adults [16, 17]. In children, second-hand smoke, occurring via exposure to a parent smoking at home, has been associated with an increased risk for MS [18]. A longer duration of smoke exposure has also been associated with an elevated risk [18].
Body mass index
Studies have shown an association of adolescent obesity with an increased risk of subsequent adult-onset MS [19–21].
Pharmacologic treatment: therapies for acute exacerbations Treatment of acute exacerbations in pediatric MS is largely based on experience in adults as there are few studies in children. Treatment is considered when an exacerbation causes symptoms that are associated with impairment, such as limited mobility or vision. Glucocorticoids
Standard dosage
Treatment with corticosteroids has been shown to decrease the duration of symptoms associated with acute exacerbations in adult patients with MS [22], and reduces the number of enhancing lesions seen on MRI [23]. Although formal studies have not been done in children, glucocorticoids are standard first-line treatment, usually with intravenous (IV) methylprednisolone [24•]. Our practice is to use IV methylprednisolone for 3 to 5 days. Treatment is stopped at 3 days if there has been resolution of symptoms, and continued for 5 days with possible use of an oral taper if symptoms persist. Methylprednisolone IV, 30 mg/kg/day (maximum daily dose of 1000 mg) for 3–5 days. A taper is not required for all patients and should be reserved for patients with partial recovery who demonstrate an ongoing response to IV corticosteroids. If an oral prednisone taper is used, the starting dose is typically 1 mg/kg/day (maximum dose of 60 mg/day), with a taper over 1–2 weeks.
Main side effects
The most common side effects include change in appetite and behavior, irritability, and difficulty sleeping. The dose may be given once a day, in the morning to minimize effects on sleep. Potentially serious side effects include gastrointestinal bleeding, hypertension, glaucoma, and hyperglycemia. Patients should receive gastrointestinal prophylaxis with an antacid, and blood pressure and glucose should be monitored. Patients requiring long- term or frequent treatment with steroids are at risk for further adverse effects, including avascular necrosis, osteoporosis, edema, and obesity.
Special considerations
While IV methylprednisolone is effective in treating relapses, treatment with an IV medication for several days can be inconvenient for families. Data suggests that an equivalent dose of oral corticosteroid may be equally efficacious [25, 26], although there are no reports in children.
Cost
$28.22 for 1000 mg in the United States of America (USA)
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Intravenous immunoglobulin
Standard dosage
Main side effects
Cost
Intravenous immunoglobulin (IVIG) may be considered in pediatric MS patients if steroids are contraindicated, or in an attempt to reduce dependence on glucocorticoids for those with frequent exacerbations. IVIG is believed to impact inflammation by decreasing levels of cytokines and binding antibodies against myelin as well as blocking Fc receptors [27], and it may promote remyelination [28]. There is some evidence that IVIG may decrease disease activity, including the frequency of relapses, in adults with MS [29]. While there have been pediatric case reports of successful treatment of acute demyelinating syndromes (MS, ADEM) using IVIG [30–32], there have been no controlled studies. 2 grams/kg, divided over 1–5 days. The infusion should be initiated at a slow rate and increased as tolerated, as per institutional protocols. Dose and concentration may require adjustment in renal impairment. Headache, myalgia, and fever are common adverse reactions, and some patients may develop aseptic meningitis. There is the potential for a severe allergic reaction in patients with IgA deficiency, and there is a risk for hemolytic anemia along with the usual risks associated with the use of a blood product. Patients should be premedicated with acetaminophen and diphenhydramine to minimize side effects Thromboembolism is another rare but serious adverse effect. Care should be used in patients with impaired renal function because of the influx of hyperosmolar fluid. The majority of more serious complications may be limited by adequate hydration and a slow infusion rate. $14,929 for IVIG 10 % 100 g in the USA.
Plasma exchange
Administration Special considerations
Plasma exchange may be considered in patients with fulminant demyelination unresponsive to corticosteroids [33, 34], especially when there is significant functional disability. Plasma exchange is presumed to work by washing autoantibodies and pro-inflammatory cytokines from the blood, and is particularly useful for demyelinating diseases with a major humoral component, such as NMO. A typical course consists of five to seven exchanges over the course of 2 weeks. Plasma exchange requires an indwelling catheter and may be associated with depletion of coagulation factors and electrolytes as a result of the large fluid shifts. These risks can be minimized by careful monitoring and repletion following exchanges. Furthermore, many medications, including anti-epileptic drugs, may require additional doses following treatments.
Pharmacologic treatment: disease modifying therapies First-line disease modifying therapy Glatiramer acetate and interferon beta have been routinely used in adults with MS for the past 15–20 years. Initial studies of these medications in adult MS patients revealed similar efficacy in terms of reduction of relapse rates (approximately 30 %) and accrual of new lesions on MRI [35–38]. Though there have not been any randomized controlled trials of these medications in the pediatric MS population, there have been a number of retrospective studies
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evaluating the off-label use of these therapies in children. In this section, we briefly review the currently accepted dosing and administration for these medications and the evidence for their use in children. Glatiramer acetate
Standard dosage
Glatiramer acetate is an acetate salt of a mixture of synthetic polypeptides composed of four amino acids (L-alanine, L-glutamic acid, L-lysine, and Ltyrosine), which resembles myelin basic protein [38]. Though its mechanism of action is still not fully understood, it is thought that glatiramer acetate has some of its effect on the immune system by modulating the functioning of antigen-presenting cells and by effecting the cytokine secretion of CD4+ T helper cells [39]. Retrospective studies done in children have shown glatiramer acetate to be well tolerated with a clinical efficacy (reduction in relapse rate) similar to that previously reported in adult trials [40–42]. 20 mg via subcutaneous injection daily or 40 mg via subcutaneous injection three times per week (with injections being at least 48 hours apart). Injection sites should be rotated.
Contraindications
Hypersensitivity to glatiramer acetate, mannitol, or any other component of the formulation
Main side effects
Local injection site reactions characterized by pain, erythema, and swelling are the most common side effects [41–43]. A postinjection reaction can occur and manifests with immediate anxiety, chest pain, dyspnea, flushing, and palpitations after an injection. The reaction lasts between 30 seconds and 30 minutes and resolves without intervention [38]. Other reported side effects include lipoatrophy at injection sites and chest pain (independent of the immediate postinjection reaction).
Cost
$4500–$5500 per month (estimate based on wholesale cost from a single manufacturer) in the USA
Interferon beta Interferon beta acts as immune-modulator via several different mechanisms. These include inhibiting autoreactive T cells, increasing production of anti-inflammatory cytokines, reducing proinflammatory cytokines, and decreasing migration of proinflammatory leukocytes into the CNS [44]. Over the past 10 years, several observational studies have evaluated the safety and efficacy of interferon beta in children with MS and have found its tolerability and efficacy to parallel that seen in adults [40, 41, 45–47].
Dosing and formulations Interferon beta 1a Subcutaneous standard dosage Intramuscular standard dosage Interferon beta 1b standard dosage Contraindications (all formulations)
22 mcg or 44 mcg via subcutaneous injection 3 times weekly with doses separated by at least 48 hours. 30 mcg via intramuscular injection once weekly. 0.25 mg via subcutaneous injection every other day. Hypersensitivity to natural or recombinant interferon or a component of the formulation. Interferons should be avoided in pregnant patients (pregnancy risk category C, Class III evidence) [48].
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Main side effects (all formulations)
Cost (all interferons)
The most common side effects are flu-like symptoms (myalgias, fatigue, headache, fever, or chills). These symptoms are often mitigated by administration of antipyretics on the day of injection. For all interferons, the dose is often titrated to goal over 4-6 weeks for better tolerability. Transient transaminase elevation and bone marrow suppression (primarily leukopenia) can also occur and merit intermittent surveillance [45–47]. Typically, blood counts and liver function tests are checked monthly for the first 6 months of therapy and then every 6 months thereafter. Thyroid function should be checked yearly. Most interferon-associated lab abnormalities are clinically asymptomatic [47]. Other reported side effects include a worsening of underlying depression, development of concurrent autoimmune disorders (idiopathic thrombocytopenia, hyper and hypothyroidism), local injection site reactions, and allergic reactions. Injection sites should be rotated. $4000–$5400 per month (estimate based on wholesale cost) in the USA.
Second-line disease modifying therapy Natalizumab Natalizumab is humanized monoclonal antibody that targets the α4 subunit of α4β1 and α4β7 integrins, which are molecules expressed on the surface of lymphocytes, which allow for their adhesion to vascular endothelium and subsequent transmigration into the CNS. Natalizumab is the most effective medication for relapsing remitting multiple sclerosis and has been shown to decrease relapses by about 70 % (compared with placebo) in adults [49]. However, because of its potential side effects, namely progressive multifocal leukoencephalopathy (PML), its use is typically limited to children who have refractory disease or poor tolerance to first line medications. There have been few studies describing the effect of natalizumab in children with MS. The largest study to date is of 55 active MS patients who received a median of 26 infusions. Most patients were found to have clinical and radiologic benefit as evidenced by the reduction in the mean Expanded Disability Status Scale scores (decreased from 2.7 to 1.9) and the percentage of patients who remained free of new MRI activity (74 %–83 %) while on treatment [50•]. Other studies of smaller pediatric cohorts have shown similar results [51–54]. PML is a severe opportunistic brain infection caused by the JC virus, a polyomavirus. PML has the potential to occur in all natalizumab-treated patients who have been exposed to JC virus (as evidenced by JC virus antibody positivity), though the risk is substantially higher in patients with prior exposure to immunosuppressive medication and with increased time on therapy. The seroprevalence of JC virus has been previously reported to be low (21 %) in healthy children [55], yet a recent study of a large pediatric MS cohort found about one-half of the patients to be positive for JC virus antibodies when tested within 6 months of initial diagnosis [56]. The authors also report an annual seroconversion rate of 4.37 % in patients who were initially JC virus antibody negative. As a result, frequent testing of JC virus antibodies and risk stratification is recommended when natalizumab is used.
Curr Treat Options Neurol (2015) 17:10 Standard dosage
Page 7 of 12 10 300 mg intravenously every 4 weeks.
Contraindications
Prior to initiating treatment, the risks and benefits of natalizumab should be discussed in all patients who have been exposed to JC virus or have been treated previously with immunosuppression. JC virus antibody testing should be repeated every 3 months while on therapy and risks should be re-discussed if a patient seroconverts and as their treatment duration increases. Natalizumab is contraindicated in pregnant patients (Pregnancy class C) [48].
Main side effects
Hypersenstivity reactions, headache, and mild hematologic abnormalities (elevated white blood cell count; anemia) have been reported in children [51, 52, 54]. PML is the most concerning potential side effect though there have not been any cases of natalizumab-associated PML in the pediatric MS population thus far.
Cost
$5600 per dose (300 mg) in the USA (estimate based on wholesale cost)
Cyclophosphamide
Standard dosage
Cyclophosphamide is an alkylating agent with powerful and varied immunosuppressant properties, including lymphocytotoxicity, which may be considered as a second line treatment in MS. Studies in adults have shown conflicting results with regard to efficacy, and suggest that it may be more effective in younger patients with aggressive disease [57]. One retrospective study of 17 patients suggested that it may decrease relapse rate and limit short-term disability progression in pediatric MS patients with aggressive disease [58]. Therapy is generally administered monthly, but an induction protocol is sometimes used. 600–1000 mg/m2 intravenously, administered monthly with the minimum dose required to decrease white blood cell counts to less than 3000/mm3 (measured at days 7, 14, and 28 postinfusion) [59].
Contraindications
Prior to initiating treatment, the risks and benefits of cyclophosphamide should be discussed in all patients, and with their parents or legal guardians. Cyclophosphamide is contraindicated in pregnant patients (Pregnancy class D).
Main side effects
Common side effects include nausea and vomiting, susceptibility to infection, amenorrhea, and alopecia. Nausea and vomiting may be decreased by premedication with glucocorticoids and ondansetron, which is an antiemetic. More severe adverse effects include hemorrhagic cystitis, infertility, and longterm risks of bladder cancer and hematologic malignancies. Risk for bladder cancer may be mitigated by the use of mesna, vigorous hydration, and limiting the lifetime cyclophosphamide dose to less than 100 g [60].
Monitoring
Pregnancy screening in women of childbearing age should be done before initiation of cyclophosphamide. A complete blood count with differential should be done on the day of infusion and then again measured at day 7, 14, and 28 postinfusion [59]. Urinalysis should be done with each infusion.
Special considerations Cyclophosphamide is a potent immunosuppressant with potentially serious adverse effects. Vaccinations should be updated prior to initiation when possible. Follow-up complete blood count (with differential) and urinalysis should be performed yearly, even after cessation of treatment, to monitor for hematologic or bladder malignancies. Prior immunosuppressant use is a risk factor for
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PML in patients treated with natalizumab, and this should be considered when choosing to use cyclophosphamide in patients who may require natalizumab in the future. Cost $527.40 for cyclophosphamide powder for a 600 mg injection, $879 for a 1000 mg injection in the USA Rituximab
Standard dosage
Rituximab is a monoclonal antibody targeting CD20+ B lymphocytes. Originally developed as a treatment for B cell lymphoma, it is also effective in antibody-medicated diseases, including NMO. MS is not an FDAapproved indication for rituximab use. However, there is evidence for B cell involvement in MS, and evidence from adult studies suggests that rituximab may decrease relapses by as much as 50 % [61]. Retrospective studies and case reports in pediatric autoimmune inflammatory and demyelinating disease suggest that rituximab is well tolerated, and may have efficacy in pediatric multiple sclerosis [62–64]. Clinically, it is a useful treatment to consider in cases where the differential includes NMO as well as MS. 750 mg/m2/dose, maximum of 1000 mg, administered as two doses 2 weeks apart. Infusion should be started slowly and increased according to institutional protocol or the manufacturer’s instructions. Rituximab is typically readministered when a patient’s B cell panel demonstrates reconstitution of CD19+/CD20+ B cells.
Contraindications
Rituximab should not be used in patients with a history of Hepatitis B because of the risk of fulminant reactivation of disease. It also should not be used in pregnant patients (pregnancy category C).
Main side effects
Rituximab is generally well tolerated, but may be associated with mild infusion reactions. It is associated with fulminant reactivation of hepatitis B. Rituximab has been associated with PML in patients with hematologic malignancies or autoimmune conditions other than MS, but only in the presence of an additional history of immunosuppression.
Special considerations
Immunizations should be updated prior to initiation of rituximab when possible, and immunity to hepatitis B should be documented. Because of the risk of allergic reaction patients are typically premedicated with glucocorticoids, acetaminophen, and diphenhydramine. Prior immunosuppressant use is a risk factor for PML in patients treated with natalizumab, and, as with cyclophosphamide, this should be considered when choosing to use rituximab in patients who may require natalizumab in the future.
Cost
$8459 for 1000 mg in the USA.
Other treatments Fatigue
MS-related fatigue has been described as an overwhelming sense of tiredness, lack of energy, and a feeling of exhaustion, which often interferes with functionality [65]. Fatigue has been reported in 9 %–76 % [66–68] of children with MS, with varying percentages attributed to differences in measurement scales and whether the patient or the parent reports. Fatigue in MS patients is multifactorial and can be a result of comorbid mood disorders, irregular sleep, physical deconditioning, or from ongoing inflammation involving key parts of the central nervous system [68]. Nonpharmacologic interventions, such as routine exercise, are typically the first line treatments for fatigue. If symptoms
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Page 9 of 12 10 persist, use of medications such as modafinil or amantadine can be considered. Neither modafinil nor amantadine has been approved by the FDA for MSassociated fatigue. Modafinil has been studied in the adult MS population with both open label and placebo-controlled trials [69–72]. Results from these studies have been equivocal with some benefit noted in the open-label and single-blind phase II studies, but no significant differences found with modafinil in the double-blind, placebo-controlled study.
Spasticity
Though treatment of spasticity has not been formally studied in pediatric MS (largely because of the fact that relatively few pediatric MS patients develop severe motor impairment early in the disease), it has been evaluated in children with cerebral palsy [73]. For generalized spasticity in cerebral palsy, medications such as diazepam, baclofen, and tizanidine have been used in this population. If focal spasticity is severe, botulinum toxin A is recommended [73]. Baclofen has been studied in adult MS patients and is generally well tolerated. Potential benefits from this medication include a reduction in spasms and their associated pain, and improvement in range of motion. Abrupt discontinuation of baclofen can result in seizures, hallucinations, and hyperthermia [74–76]. Baclofen can also result in muscle weakness and somnolence, especially upon initiation and with dose increases.
Neuropathic pain
Neuropathic pain is one of the most commonly reported symptoms in adults with MS. This type of pain is often described as a burning sensation affecting one or more limbs, typically distally more than proximally. Gabapentin is the most commonly used medication for this indication. Gabapentin has not been formally studied in pediatric MS but has been studied in a small open label study of 22 adult MS patients [77]. In this study, 68 % of subjects experienced excellent to moderate pain relief at a dose of 600 mg per day; 50 % of the cohort reported some adverse side effect though only five patients discontinued treatment. Mental cloudiness, somnolence, and gastrointestinal complaints were the most commonly reported side effects [77].
Emerging therapies Several oral medications have recently been approved for MS in adults. These include fingolimod, teriflunomide, and dimethyl fumarate. Some adverse effects have been reported in adults, teratogenicity and hepatic failure with teriflunomide, bradycardia with the initial dose of fingolimod, and leukopenia with all three medications. Given the limited data regarding the safety and efficacy of these treatments in pediatric patients, they are not routinely being used in pediatric patients at this time. Recent FDA regulations mandate a pediatric investigation plan for all newly approved drugs, and clinical trials to investigate the safety and efficacy of these medications in the pediatric population are now underway.
Conclusions As more medications are studied and approved for use in pediatric MS, the number of available treatment options that are both tolerable and effective will increase, as will therapies with different mechanisms of action. Factors including medication side effects, aggressiveness of disease, and ease of monitoring may impact selection of therapy in a particular patient, and should be discussed prior to initiation. Compliance is likely to improve if medications either have
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greater tolerability, or are given at predefined and relatively infrequent intervals (i.e. infusions given every month or every 6 months). As medications increase in efficacy, it is hoped that mitigation of long-term consequences of MS will be achieved. We are hopeful that multicenter international collaboration will enable clinical trials to succeed, given that pediatric MS is a rare disease.
Compliance with Ethics Guidelines Conflict of Interest Sona Narula, Sarah E. Hopkins, and Brenda Banwell declare no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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