Overview
Definition:
Pediatric multiple sclerosis (MS) is a chronic, autoimmune, inflammatory, and demyelinating disease of the central nervous system (CNS) that affects children and adolescents, characterized by distinct neurological deficits, often with relapsing-remitting courses.
Epidemiology:
Pediatric MS accounts for approximately 0.4% to 5% of all MS cases
Incidence varies geographically, with higher rates reported in Caucasian populations
Peak onset is typically in adolescence (10-19 years), with a female predominance similar to adult MS.
Clinical Significance:
Early diagnosis and prompt initiation of appropriate disease-modifying therapies (DMTs) are crucial in pediatric MS to reduce lesion burden, minimize relapses, slow disease progression, and improve long-term functional outcomes, thereby impacting quality of life and preventing long-term disability.
Clinical Presentation
Symptoms:
Common initial symptoms include unilateral optic neuritis (visual loss, pain with eye movement)
Motor deficits (weakness, spasticity)
Sensory disturbances (numbness, tingling)
Cerebellar signs (ataxia, tremor)
Brainstem dysfunction (diplopia, vertigo, dysarthria)
Acute disseminated encephalomyelitis (ADEM)-like presentations (altered consciousness, seizures) can mimic early MS, especially in younger children.
Signs:
Neurological examination may reveal optic nerve pallor (late finding), nystagmus, cranial nerve palsies, hemiparesis or paraparesis, hyperreflexia, positive Babinski sign, ataxia, impaired gait, and sensory level abnormalities
Uhthoff's phenomenon (worsening of symptoms with heat) and Lhermitte's sign (electric shock sensation down the spine with neck flexion) may be present.
Diagnostic Criteria:
Diagnosis relies on McDonald criteria, adapted for pediatric use
Key elements include dissemination in space (DIS) and dissemination in time (DIT) of demyelinating lesions in the CNS, supported by MRI, cerebrospinal fluid (CSF) analysis (oligoclonal bands, IgG index), and exclusion of other causes
Pediatric MS often has a higher likelihood of initial ADEM-like presentations or monophasic illness, necessitating careful follow-up to meet DIT criteria.
Diagnostic Approach
History Taking:
Detailed history of neurological symptoms, their onset, duration, progression, and any preceding infections or vaccinations is vital
Inquire about visual disturbances, motor weakness, sensory changes, coordination issues, and cognitive/behavioral changes
Family history of autoimmune diseases, especially MS, is important
Rule out acute disseminated encephalomyelitis (ADEM) and other inflammatory CNS disorders.
Physical Examination:
Comprehensive neurological examination focusing on cranial nerves, motor strength, tone, reflexes, sensation, coordination, gait, and balance
Assessment of visual acuity, visual fields, and fundoscopy
Assess for Uhthoff's and Lhermitte's signs.
Investigations:
Brain and spinal cord MRI with gadolinium contrast is essential to identify demyelinating lesions (periventricular, juxtacortical, infratentorial, spinal cord)
MRI demonstrates dissemination in space and time
CSF analysis: oligoclonal bands (OCBs) are present in ~90% of pediatric MS cases
elevated IgG index can also be seen
Evoked potentials (visual, brainstem auditory, somatosensory) can detect subclinical lesions
Blood tests to rule out other causes of CNS inflammation/demyelination (e.g., AQP4-IgG, MOG-IgG, ANCA, SLE workup, metabolic screens).
Differential Diagnosis:
Acute disseminated encephalomyelitis (ADEM) is a major consideration, especially in younger children, and is often monophasic
Other differentials include neuromyelitis optica spectrum disorder (NMOSD, particularly MOG-AD), central nervous system infections (viral encephalitis, Lyme disease), metabolic disorders, mitochondrial disorders, genetic leukodystrophies, vasculitis, and autoimmune conditions like SLE
MOG-IgG serology is crucial to differentiate MOG-AD from MS.
Management
Initial Management:
For acute relapses, intravenous methylprednisolone (IVMP) 10-30 mg/kg/day for 3-5 days (max 1000 mg/day) is the standard of care to reduce inflammation and hasten recovery
If unresponsive to IVMP or severe, plasma exchange (PLEX) or intravenous immunoglobulin (IVIG) may be considered.
Disease Modifying Therapies:
The goal of DMTs is to reduce relapse frequency and severity, new lesion formation, and disability accumulation
Options are broadly categorized into injectable and oral/infusion therapies, mirroring adult MS treatments, but with specific pediatric considerations and evidence
Injectable Therapies:
Interferon-beta (IFN-β) preparations (e.g., Avonex, Betaseron, Rebif): Subcutaneous or intramuscular injections
Generally considered for younger children or those with milder disease
Evidence in pediatric MS is primarily extrapolated from adult studies and registry data
Dosing: typically based on body weight or BSA
Side effects include injection site reactions, flu-like symptoms, and potential for depression
Glatiramer acetate (GA): Subcutaneous injections
Also considered a first-line option, especially if IFN-β is not tolerated
Registry data supports its efficacy and safety in children
Dosing: typically 20 mg daily or 40 mg three times weekly
Side effects include injection site reactions and post-injection flushing/chest tightness
Oral Therapies:
Fingolimod: Sphingosine-1-phosphate (S1P) receptor modulator
Approved for pediatric MS in some regions
Reduces lymphocyte trafficking to the CNS
Dosing: typically weight-based (e.g., 0.25 to 0.5 mg daily)
Requires cardiac monitoring due to potential for bradycardia, and monitoring for infections (especially JC virus), lymphopenia, and macular edema
Teriflunomide: Pyrimidine synthesis inhibitor
May be considered in older adolescents
Evidence in pediatric MS is limited
Infusion Therapies (Highly Effective DMTs - HEDMTs):
Natalizumab: Monoclonal antibody targeting alpha-4 integrin
Highly effective, but carries a risk of progressive multifocal leukoencephalopathy (PML) and John Cunningham virus (JCV) infection
Used cautiously in children, often after failure of other agents, with strict JCV monitoring
Rituximab: Anti-CD20 monoclonal antibody
Used off-label in pediatric MS, particularly for MOG-AD or B-cell mediated MS
Effective in reducing relapses
Requires monitoring for infusion reactions, infections, and potential for B-cell depletion
Ocrelizumab: Anti-CD20 monoclonal antibody
Approved for relapsing forms of MS in adults, and emerging data in pediatric MS
Similar efficacy to rituximab with a more predictable dosing schedule.
Supportive Care:
Symptomatic management includes addressing fatigue (energy conservation techniques, sometimes medications like modafinil), spasticity (baclofen, tizanidine), pain (analgesics, gabapentin), depression (SSRIs, counseling), and bladder/bowel dysfunction
Rehabilitation services (physical, occupational, speech therapy) are crucial for maintaining function
Nutritional support and psychological support for the child and family are essential.
Complications
Early Complications:
Acute relapse-related neurological deficits (e.g., optic neuritis leading to vision loss, hemiparesis impacting mobility, severe ataxia affecting independence)
Treatment-related side effects: infections (especially with immunosuppressive DMTs), injection site reactions, infusion reactions.
Late Complications:
Accumulation of disability leading to chronic motor and sensory impairments, cognitive decline, emotional lability, and fatigue, impacting educational attainment and social integration
Development of treatment-resistant disease
Irreversible optic nerve damage
Increased risk of secondary progressive MS (less common in pediatrics but possible).
Prevention Strategies:
Adherence to prescribed DMTs is paramount
Regular monitoring for efficacy and adverse events
Prompt treatment of relapses
Proactive management of symptoms
Encouraging a healthy lifestyle with adequate nutrition and exercise
Genetic counseling may be considered in families with a strong history.
Prognosis
Factors Affecting Prognosis:
Factors influencing prognosis include early diagnosis and initiation of effective DMTs, disease severity at onset, frequency and severity of relapses, extent of MRI lesion burden, adherence to treatment, and presence of MOG-AD versus MS
Children with a more ADEM-like onset and fewer relapses may have a better initial prognosis but long-term outcomes can vary.
Outcomes:
With modern DMTs, the prognosis for pediatric MS has improved significantly, with many children achieving prolonged periods of remission and good functional recovery
However, MS remains a chronic condition, and some degree of disability progression or superimposed relapses can occur over time
Long-term follow-up is essential.
Follow Up:
Regular clinical evaluations (every 3-6 months) are necessary to assess for new symptoms, monitor disease activity, and evaluate treatment adherence and tolerance
Annual MRI with gadolinium contrast is recommended to assess lesion activity, unless higher frequency monitoring is indicated by the specific DMT or disease activity
Regular blood tests to monitor for side effects (e.g., CBC, LFTs, JC virus antibodies for natalizumab) and adherence to vaccination schedules are important.
Key Points
Exam Focus:
DMT choices in pediatric MS are guided by efficacy, safety, and tolerability, often mirroring adult guidelines but with specific pediatric data
Fingolimod is the first oral DMT approved for pediatric MS
MOG-IgG testing is critical to differentiate MOG-AD from MS
MRI criteria for DIS and DIT are central to diagnosis.
Clinical Pearls:
Always consider pediatric MS in children presenting with new-onset focal neurological deficits, especially if recurrent
Differentiate from ADEM and MOG-AD early
Weight-based dosing for pediatric DMTs is often crucial
Educate families thoroughly on DMT risks and benefits, emphasizing adherence and monitoring schedules.
Common Mistakes:
Delaying diagnosis by attributing symptoms to common childhood ailments
Failing to differentiate MS from MOG-AD or ADEM
Inadequate MRI protocol or interpretation
Inappropriate selection of DMT without considering the child's age, disease severity, and potential side effects
Insufficient patient and family education regarding long-term management and monitoring requirements.