Pediatric Neurology Use of Biologic and Chemotherapeutic Agents Pediatric Neurology Use of Biologic and Chemotherapeutic Agents

STATISTICS 400,000 Adults have MS in the US 8,000-10,000 children have MS in the US Another 10,000-15,000 children in the US experience disorders that may be related to MS Studies suggest 2 to 5% of all people with MS have a history of symptom onset before age 18.

MULTIPLE SCLEROSIS Multiple sclerosis (or MS) is a chronic, often disabling disease that attacks the central nervous system (CNS), which is made up of the brain, spinal cord, and optic nerves. Symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. The progress, severity, and specific symptoms of MS are unpredictable and vary from one person to another

PEDIATRIC MULTIPLE SCLEROSIS Onset occurs before age 16 Disease progresses slower than it does in adults, however permanent disability occurs at a younger age Progressive course at diagnosis and having more relapses during the first 2 years increases the rate of disability

CAUSES OF MULTIPLE SCLEROSIS MS is an autoimmune disease Genetics Gender * Less than age 10 < males * Adolescent presentation > females Environmental Triggers * Infectious * Sunlight Exposure & Vitamin D

ABNORMALITIES WHICH OCCUR IN MS Patches of inflammation begin to occur in areas of the brain and spinal cord. Demyelination – myelin sheaths around the cells affected by inflammation begin to deteriorate. The nerve fibers or axons which are stripped of protective myelin are destroyed. After the myelin sheaths are destroyed, the cells in the CNS are unable to communicate vital information to the rest of the body which results in symptoms of MS.

DIAGRAM OF DEMYLINATION

DAMAGED NERVE

FOUR COURSES OF MS Relapsing-Remitting MS * Attacks followed by recovery * 85% of adults initially * 93-95% of children initially Primary-Progressive MS * Slowly worsening neurologic function from the * Approximately 10% of adult patients Secondary – Progressive MS * Conversion to progressive phase Progressive –Relapsing MS * Steady worsening of disease from onset * Less than 5% of adults

SYMPTOMS Sensory and Motor Symptoms Spasticity / Tremors / Ataxia Visual Problems Bladder and Sexual Dysfunction Fatigue Dysarthria Pain / L’Hermittee’s Phenomeno Depression Paroxysmal symptoms Seizures Many of the symptoms they experience are “invisible”, vary in intensity and come and go randomly.

DIAGNOSTIC WORKUP Complete Medical History Nervous System Functioning: Reflexes/ coordination/ balance/ vision Diagnostic Tests: * MRI – locates areas of inflamation, demylination and size of brain * Evoked Potential Tests – demylination cause nerves to conduct impulses slower * Spinal Tap - presence of protein – oligoclonal bands – (present in > 90% of children with MS)

MRI FINDINGS

TREATMENT Divided into three categories: 1. Treatment of acute attacks 2. Treatments to reduce the number of attacks and attack severity 3. Treatment of intermittent or persistent MS symptoms

TREATMENT ACUTE MS RELAPSES Corticosteroids - help to prompt recovery during MS relapses by reducing inflammation. Intravenous methylprednisone – mg/kg/day (maximum of 1 gram) as single dose for 3 to 5 days Children with complete resolution receive no further corticosteroids Incomplete recovery following IV steroids - oral prednisone starting at 1mg/kg/day followed by a tapering schedule with reduction by 5 mg every 2 to 3 days Intravenous Immunoglobulins – used when sufficient clinical recovery does not occur after corticosteroids IVIg – 2 gms/kg over 2-5 days Plasma Exchange – adults for severe relapses not responsive to steroids – 5 exchanges over 8 to 10 days

TREATMENT REDUCE NUMBER OF ATTACKS Immunomodulatory therapy – decrease the relapse rate and MRI accrual of new lesions Interferon beta – Ib (Betaseron/ Betaferon) Interferon beta – Ia IM (Avonex) Interferon beta – Ia (Rebif) Glatiramer acetate (Copaxone)

TREATMENT REDUCE NUMBER OF ATTACKS Immunosuppressive Drugs -- Drugs to suppress or control the immune system * Azathioprine * Cyclophosphamide -significant risks * Methotrexate – low dose orally - well tolerated

TREATMENT OPTIONS CURRENTLY IN ADULTS WHEN TRADITIONAL TREATMENT FAILS Natalizumab (Tysabri) – Monoclonal antibody – prevents inflammatory cells from entering the brain (IV infusion every 28 days) FDA approved for MS in patients over 18 years old who have failed conventional treatments although long term safety data unknown Cases of Progressive multifocal leukoencephalopathy (PML), liver dysfunction and skin cancer have been reported All patients on this medication must participate in the TOUCH program which monitors their current status and side effect profile (Medical exam/ MRI/ Lab work at least every 6 months)

TREATMENT OPTIONS CURRENTLY IN ADULTS WHEN TRADITIONAL TREATMENT FAILS Mitazantrone (recommended for aggressive forms of MS which do not respond to first line therapy – cardiotoxicity limits duration of therapy) Methotrexate (experimental – low dose orally well tolerated) Cyclophosphamide (experimental – significant risks) Cladarabine (experimental– significant risks) Acyclovir (experimental)

References Ahorro, J. (2009). Multiple Sclerosis in Children. Multiple Sclerosis Quartely Report. Volume 28, Number 1. Ascherio, A. & Munger, K. (2007). Environmental risk factors for multilpe sclerosis. Part I: the role of infection. Annals of Neurology, 61 (4), Blckstone, M. (2003). The First Year – Multiple Sclerosis: An Essential Guide for the Newly Diagnosed. New York: Marlowe & Company. Holland, N, Murray, T, & Reingold, S. (2002). Multiple Sclerosis: A Guide for the Newly Diagnosed. Second Edition. New York: Demos Medical Printing. Polman, C., Thompson, A., Murray,t. Bowling, A., & Noseworthy, J. (2006). Mutiple sclerosis: The Guide to Treatment and Management. Sixth Edition. New York: Demos Medical Publishing. Schapiro, R. (2003). Managing the Symptoms of Multiple Sclerosis. Fourth Edition. New York: Demos Medical Printing. National Multiple Sclerosis Society at