A Comprehensive Review on Pharmacological Management of Paediatric Demyelinating Disorders

Edwin Dias^1,2*, Riya Fathima V³

1.         HOD and Professor, Department of Paediatrics, Srinivas institute of medical science and research centre, Manglore, Karnataka, India

2.         Adjunct Professor, Srinivas University, Director of research and publication, India                       

3.         Final year PharmD student, Srinivas college of pharmacy, Valachil, Manglore, Karnataka, India

*Correspondence: dredwindias@gmail.com Contact no: +918136908582

DOI: https://doi.org/10.71431/IJRPAS.2025.4606      

INTRODUCTION

Demyelinating diseases of the central nervous system in the pediatric population are rare, but their recognition has increased significantly due to advances in neuroimaging, immunological assays, and improved awareness among clinicians. These disorders involve immune-mediated damage to the myelin sheath, a protective layer surrounding nerve fibers, which leads to a disruption in neuronal signaling and consequent neurological dysfunction. Pediatric CNS demyelinating diseases include a spectrum of conditions such as acute disseminated encephalomyelitis (ADEM), pediatric-onset multiple sclerosis (POMS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Each of these conditions presents with distinct clinical, radiological, and immunological features, and yet shares a common underlying pathology of CNS inflammation and demyelination.

In contrast to adult-onset demyelinating diseases, pediatric cases often present with more aggressive inflammation, frequent relapses, and extensive lesion burdens on magnetic resonance imaging (MRI). These clinical distinctions necessitate tailored diagnostic criteria and management approaches ^[1]. A correct and timely diagnosis is vital to guide immediate treatment and also to differentiate between monophasic and chronic relapsing forms, which significantly differs in their prognoses and treatment strategies. ^[3]

The management of pediatric CNS demyelinating disorders relies heavily on immunomodulatory and immunosuppressive therapies. Acute episodes are typically treated with high-dose corticosteroids, intravenous immunoglobulin (IVIG), or plasma exchange. Long-term disease control is achieved with disease-modifying therapies (DMTs) such as interferons, fingolimod, rituximab, and others. However, the pediatric population presents unique pharmacological challenges, including age-related pharmacokinetics, drug tolerability, and long-term safety considerations.

This review aims to comprehensively explore the management of pediatric demyelinating CNS diseases where a tailored pharmacologic approach is essential considering their development and long-term safety.

DISCUSSION

Pediatric CNS demyelinating disorders are heterogeneous in presentation and pathophysiology. They can be broadly classified into monophasic and relapsing disorders. The four primary disorders discussed include Acute Disseminated Encephalomyelitis (ADEM), pediatric-onset multiple sclerosis (POMS), Neuromyelitis Optica Spectrum Disorder (NMOSD), and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD).

PHARMACOTHERAPY IN ACUTE MANAGEMENT

1.      ACUTE MANAGEMENT STRATEGIES

The acute management of pediatric demyelinating diseases focuses on addressing inflammatory attacks to minimize neurological damage and prevent long-term disability.

Corticosteroids, such as intravenous methylprednisolone, remain the first-line treatment during acute relapses. They act by rapidly suppressing immune responses, decreasing the permeability of the blood-brain barrier, and limiting axonal damage. In pediatric patients, the recommended dose is 20–30 mg/kg/day, with a maximum of 1 g/day, administered for 3 to 5 days. For adults, the dosage ranges from 500 to 1000 mg per day for the same duration ^[2]. Adverse reactions may include hypertension, mood disturbances, growth suppression in children, and hyperglycemia. Monitoring parameters include blood pressure, blood glucose levels, and growth tracking in children. Supportive lifestyle measures include calcium and vitamin D supplementation, stress minimization, and regular monitoring of weight and mood.

Intravenous immunoglobulin (IVIG), composed of pooled immunoglobulins from healthy donors, is used as an immunomodulatory therapy in cases where corticosteroids are ineffective or contraindicated, particularly in pediatric ADEM and NMOSD. It is typically administered at a dose of 0.4 g/kg/day for five consecutive days. The primary adverse effects include headache, renal dysfunction, and, less commonly, aseptic meningitis.

Plasma exchange (PLEX) is reserved for severe, steroid-refractory cases of multiple sclerosis and NMOSD ^[4]. This procedure removes circulating autoantibodies and immune complexes from plasma. It typically involves 5 to 7 sessions administered on alternate days. While effective, it carries risks such as hypotension, electrolyte imbalances, and bleeding ^{[7] [8]}.

2.      DISEASE-MODIFYING THERAPIES (DMTs)

Disease-modifying therapies are designed to reduce relapse rates, delay disease progression, and prevent the development of new lesions.

Interferon beta, which modulates the immune response by reducing antigen presentation and T-cell activation, is one of the earliest approved agents for pediatric MS in children aged 10 years or older. Interferon beta comes in two forms: IFN-β1a (Avonex, Rebif) and IFN-β1b (Betaseron), and is administered either intramuscularly or subcutaneously. Common adverse effects include flu-like symptoms, depression, and elevated liver enzymes ^[5]. Monitoring includes complete blood count (CBC), liver function tests (LFTs), and thyroid profiles.

Glatiramer acetate, another immunomodulatory agent, mimics myelin basic protein and helps divert immune responses away from CNS myelin. It is administered subcutaneously, either as 20 mg daily or 40 mg three times per week. This medication is typically used for relapsing-remitting MS (RRMS). Side effects may include injection site reactions, chest tightness, and flushing ^[6].

Fingolimod, an oral sphingosine-1-phosphate receptor modulator, functions by trapping lymphocytes in lymph nodes, thereby reducing CNS infiltration. Pediatric dosing is weight-based: 0.25 mg/day for those under 40 kg and 0.5 mg/day for those above. Adults receive a standard dose of 0.5 mg/day. Adverse effects include bradycardia, macular edema, and increased susceptibility to infections. Monitoring involves ECG, ophthalmologic examination, CBC, and LFTs.

Dimethyl fumarate activates the Nrf2 transcription pathway and exerts both antioxidant and anti-inflammatory effects. It is given orally with an initial dose of 120 mg twice daily, followed by a maintenance dose of 240 mg twice daily. Side effects include flushing, gastrointestinal upset, and lymphopenia, necessitating monitoring of CBC and LFTs.

Teriflunomide inhibits pyrimidine synthesis by blocking the mitochondrial enzyme dihydroorotate dehydrogenase, thereby reducing T and B cell proliferation. It is administered orally at a dose of 7 mg or 14 mg once daily and is associated with hepatotoxicity, requiring liver function monitoring. ^[10]

Natalizumab works by preventing leukocyte migration across the blood-brain barrier through α4-integrin inhibition. It is administered intravenously every four weeks and is used in highly active MS. While effective, it carries a risk of progressive multifocal leukoencephalopathy (PML) and hypersensitivity reactions, making JC virus antibody testing and regular MRI monitoring essential. ^[9]

Ocrelizumab, an anti-CD20 monoclonal antibody, depletes B cells that contribute to antigen presentation and cytokine release. It is administered via IV infusion every six months following an initial loading dose. Adverse effects include infusion reactions and infections.

Rituximab, though not FDA-approved for pediatric MS or NMOSD, is widely used off-label. It targets CD20+ B cells and is typically administered at a dose of 375 mg/m² weekly for four weeks or 500–1000 mg every six months. Indications include NMOSD, pediatric MS, and ADEM. It is associated with risks like hypogammaglobulinemia and neutropenia.

Cyclophosphamide, an alkylating agent with broad immunosuppressive activity, is reserved for severe, refractory cases. It is administered intravenously at 750 mg/m² monthly and can cause hemorrhagic cystitis, infertility, and neutropenia. Preventive measures include mesna administration and aggressive hydration.

Eculizumab inhibits complement C5, thereby preventing membrane attack complex formation. It is particularly effective in NMOSD patients with AQP4 antibodies. The dosing regimen begins with 900 mg weekly for four weeks, followed by 1200 mg every two weeks. It increases the risk of meningococcal infections, so vaccination is mandatory before initiating treatment.

Satralizumab and inebilizumab are biologics used in NMOSD. Satralizumab inhibits IL-6 receptor signaling, reducing B-cell survival and CNS inflammation. Inebilizumab depletes CD19+ B cells, offering broader B-cell targeting than rituximab. Satralizumab is administered subcutaneously at 120 mg every two weeks for three doses, then monthly. Inebilizumab is given as 300 mg intravenously twice (two weeks apart), then every six months.

Tolebrutinib, currently under investigation in phase III trials, is a Bruton's tyrosine kinase (BTK) inhibitor that modulates B-cell receptor signaling and microglial activation. It is taken orally at a dose of 60 mg daily. Potential adverse effects include headache, elevated liver enzymes, and infection risk, requiring monitoring of hepatic function and blood counts. ^[12]

Ublituximab, a glycoengineered anti-CD20 monoclonal antibody, induces potent B-cell depletion and was FDA-approved in December 2022 for relapsing MS. It is administered via IV infusion: 150 mg on day 1, 450 mg on day 15, and 450 mg every 24 weeks thereafter. Side effects include infusion-related reactions and infections, with recommended monitoring of CBC and immunoglobulin levels. ^[13]

Ofatumumab is a fully human anti-CD20 monoclonal antibody administered subcutaneously. The initial dose is 20 mg weekly for three weeks, followed by 20 mg monthly. It is used in relapsing MS and may cause injection site reactions, infections, and headaches. Monitoring includes CBC, serum immunoglobulin levels, and signs of infection.

PAEDIATRIC CONSIDERATIONS

Clinical trial data for pediatric demyelinating disorders is limited, which necessitates the extrapolation of treatment efficacy and safety from adult studies. Dosing in pediatric patients must be carefully weight-based to minimize the risk of toxicity. The psychosocial impact of these chronic neurological diseases in children is significant, making family education and mental health support crucial components of comprehensive care. Long-term monitoring is necessary to assess growth, progression through puberty, cognitive development, and school performance outcomes.

MONITORING AND SAFETY CONSIDERATIONS

Ongoing monitoring is essential to ensure both treatment efficacy and patient safety. Liver function tests are required for patients receiving interferons and azathioprine, as these drugs may cause hepatotoxicity. Lymphocyte counts must be monitored, especially in patients being treated with fingolimod, due to its immunosuppressive effects. Before initiating therapy with natalizumab, testing for JC virus antibodies is mandatory to assess the risk of progressive multifocal leukoencephalopathy (PML). Because certain immunosuppressive agents, such as rituximab and eculizumab, increase the risk of infections, patients must be screened for hepatitis, tuberculosis, and other relevant infections prior to treatment initiation. Additionally, all vaccinations, particularly live vaccines should be updated before beginning immunosuppressive therapy. ^[11]

ROLE OF CLINICAL PHARMACISTS

Clinical pharmacists play a critical role in optimizing pharmacotherapy for pediatric patients with demyelinating diseases. They are responsible for ensuring age- and weight-appropriate dosing and for the continuous monitoring of laboratory parameters to detect and manage adverse effects early. Pharmacists are also essential in educating families about the importance of medication adherence, recognizing signs of relapse, and understanding each drug's purpose. Furthermore, they coordinate vaccination schedules and provide guidance on infection prophylaxis where needed. In complex or comorbid cases, clinical pharmacists help manage polypharmacy to avoid harmful drug interactions and ensure therapeutic effectiveness.

CONCLUSION

Pharmacological management of demyelinating diseases has expanded significantly, offering diverse therapeutic options for both pediatric and adult patients. Acute strategies aim to minimize neurological injury during relapses, while DMTs prevent disease progression and relapses. In pediatric populations, the balance between efficacy and long-term safety is critical. Innovations in biologics and targeted therapies offer hope, but ongoing research and pediatric-specific trials remain essential. A multidisciplinary approach that incorporates pharmacologic treatment, lifestyle support, and psychosocial care is key to achieving optimal outcomes.

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