New Antiepileptic Drugs and Treatments

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New Antiepileptic Drugs and Treatments

• Josiane LaJoie, MD
• Assistant Professor of Neurology and Pediatrics
• NYU Comprehensive
• Epilepsy Center

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History of AEDs
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New AEDs

• Felbamate-1993
• Gabapentin-1994
• Lamotrigine-1995
• Topiramate-1995
• Tiagabine-1996
• Oxcarbazepine-1998
• Levetiracetam-1999
• Zonisamide-1999

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GABAPENTIN

• Indications
• Partial seizures /- secondary generalization
• Benign Rolandic Epilepsy
• Not effective for generalized epilepsies
• Mechanism of Action
• Multimodal/Unknown

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Gabapentin Dosing

• Adults
• 900 mg/day-3600 mg/day
• Children
• 10mg/kg/day to 100 mg/kg/day

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Gabapentin Side Effects

• Behavioral changes
• Lethargy
• Dizziness
• Weight gain
• No interactions with other AEDs

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FELBAMATE

• Indications
• Partial seizures /-secondary generalization
• Lennox-Gastaut Syndrome
• Not first line medication
• Mechanism of Action
• Unknown
• Major risks
• Aplastic anemia, fatal hepatotoxicity

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FBM Dosing

• Adults
• 1200 mg per day to 3600 mg per day
• TID,QID
• Children
• 15-45 mg/kg/day

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FBM-Common Side Effects

• Anorexia
• Nausea/Vomiting
• Insomnia
• Headache/Dizziness
• Lethargy

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Aplastic Anemia and Hepatotoxicity with Felbamate

• Aplastic Anemia
• 31 cases
• 13 deaths
• 11 FBM likely cause
• Hepatotoxicity
• 23 cases
• 10 deaths
• 10 FBM likely cause ( 5 deaths)

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Risks of Felbamate

• Overall risk Risk of death
• Aplastic Anemia 17,900 112,000
• Genl population 1500,000
• Hepatotoxicity 111,000 122,000
• Combined risk 14,600 19,300
• NO cases of FBM associated aplastic anemia in
  children 13 years

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Fatal Hepatotoxicity of VPA

• Age(yrs) Monotherapy Polytherapy
• 0-2 0 1618
• 3-10 116,000 18,000
• 11-20 0 110,000
• 21-40 1230,000 131,000
• 41 0 1107,000

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FBM Interactions

• Increases Phenytoin, VPA, Phenobarbital levels
• Decreased by Phenytoin, Phenobarbital,
• No effect by VPA

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LAMOTRIGINE

• Indications
• Partial seizures /- secondary generalization
• Lennox-Gastaut Syndrome
• Also used in primary generalized epilepsy
  (absence, myoclonic)
• Mechanism of Action
• Unknown
• Favorable cognitive and behavioral profile

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Lamotrigine Side Effects

• Headache
• Lethargy
• Dizziness/Ataxia/Diplopia
• GI upset
• RASH/Stevens-Johnson Syndrome

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Lamictal and SJS

• Rates decreasing with new dosing schedules
• 0.01 to 0.12
• Usually between first 2-8 weeks of treatment

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Lamictal Dosing-Adults

• With VPA
• 25 mg po QOD for 2 weeks then 25 mg po q day
• Usual maintenance100-400 mg/day
• Without VPA
• 50 mg/day for 2 weeks then 100 mg/day
• Usual maintenance300-500 mg/day

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Lamictal Dosing-Children

• With VPA
• 0.15 mg/kg/day for 2 weeks then 0.3 mg/kg/day
• Usual maintenance1-5 mg/kg/day
• Without VPA
• 0.6 mg/kg/day for 2 weeks then 1.2 mg/kg/day
• Usual maintenance5-15 mg/kg/day

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Lamotrigine and AEDs

• Decreases VPA
• No effect on Phenytoin, Carbamazepine
• Decreased by Phenytoin, CBZ
• Increased by VPA

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TOPIRAMATE

• Indications
• Partial seizures /- secondary generalization
• GTC seizures
• Lennox-Gastaut Syndrome
• Juvenile Myoclonic Epilepsy

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Topiramate

• Mechanism of Action
• Unknown, may activate GABA receptors, block
  voltage dependent Na channel, glutamate
  antagonist
• Dosing
• Adults 200-400 mg/day
• Children 1-10 mg/kg/day

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Topiramate SE

• Psychomotor slowing
• Altered verbal fluency
• Altered behavior, attention
• Fatigue
• Decreased appetite
• Lethargy
• Kidney Stones

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Topiramate Interactions

• No significant changes on other AEDs
• Minimal increase in phenytoin, minimal decrease
  in VPA
• Decreased by Phenytoin, CBZ
• Minimal decrease by VPA

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TIAGABINE

• Indications
• Partial seizures /- secondary generalization
• Mechanism of Action-inhibits the reuptake of GABA

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Tiagabine Dosing

• Adults
• 32-56 mg/day
• Children
• Start 0.1 mg/kg/day

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Tiagabine Side Effects

• Dizziness
• Asthenia/lack of energy
• Nausea
• Irritability
• Abdominal pain
• Nervousness
• Difficulty with attention/concentration
• Tremor
• Depression
• Aphasia

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Tiagabine Interactions

• No effect on Phenytoin, CBZ
• Probably no effect on Phenobarb
• Decreases VPA slightly
• Decreased by CBZ, Phenytoin,Phenobarb
• No effect by VPA

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LEVETIRACETAM

• Indications
• Partial seizures /- secondary generalization
• ?JME
• Mechanism of Action-unknown
• Dose 1000-3000mg/day

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Levetiracetam

• Side Effects
• Neurobehavioral changes
• Lethargy
• Unsteadiness
• Does not interact with medications

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ZONISAMIDE

• Indications
• Partial seizure /- secondary generalization
• Myoclonic Epilepsy
• Mechanism of Action-unknown

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Zonisamide

• Dosing
• 100-400 mg/day
• Can be given once a day
• Side Effects
• Rash, SJS (sulfonamide)
• Lethargy/Mental slowing
• Headache
• Weight loss
• Kidney stones

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New Treatments

• Devices
• Vagus Nerve Stimulator
• Deep Brain Stimulation
• Gamma Knife
• Neuropace
• Ketogenic Diet
• Epilepsy Surgery
• Alternative Medicine
• Neurofeedback
• Melatonin

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Vagus Nerve Stimulator (VNS)

• Is an FDA approved device
• Provides chronic intermittent electrical
  stimulation of the vagus nerve
• Exact mechanism is unknown

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VNS candidates

• Patients with refractory epilepsy
• Partial or generalized
• Lennox-Gastaut Syndrome
• Poor surgical candidates
• Contraindicated in
• Patients with left or bilateral vagotomy

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VNS Implantation

• Short surgical procedure under general anesthesia
• Less than 24 hour hospital stay

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The VNS System
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VNS Function

• Chronic intermittent pulses
• Patient can use own magnet to give additional
  stimulation

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Effects

• No immediate effect
• Decreases seizures over time
• At one year
• 31-57 have gt50 reduction
• 20-30 have gt90 reduction

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Side Effects

• Pain/Discomfort
• Alteration in voice
• Cough
• Surgical/Anesthesia risks

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Deep Brain Stimulation

• Based on stimulating widespread inhibitory
  pathways
• Thalamus
• Anterior Thalamic Nucleus
• Centromedian Nucleus of the Thalamus
• Cerebellum

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Cerebellar Stimulation

• Has Gaba-ergic output
• Difficulties
• Stimulation of target
• Equipment

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Brain Stimulation

• Pros
• Minimal invasive
• Safe, Well tolerated
• Cons
• Malfunction
• Unknown long term benefits/complications

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Brain Stimulation-Future

• Open loop vs. Closed loop
• Reactive
• Direct Stimulation

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Functional Radiosurgery

• Began in 1951
• Used for intractable pain, Parkinsons,
  Psychiatric conditions

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Gamma Knife-Limitations

• Unknown long term results
• Lack of consistent approaches

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Neuropace

• Investigational Device
• Clinical Trials Ongoing
• Implantable device designed to detect abnormal
  brain signals and abort any possible seizure
  activity

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Melatonin

• Alternative treatment
• Used in conjunction with standard medical therapy

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What is Melatonin?

• Naturally produced hormone
• Involved in sleep promotion
• Used in a variety of neurological conditions

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How does it work?

• Regulates sleep
• Anti-seizure properties

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Seizure

• Due to imbalances in neurochemicals
• Results in production of free radicals

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Melatonins Effects

• Anti-oxidant
• Blocks effects of Glutamate
• Enhances Gaba actions

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Evidence-Basic Science

• Multiple studies show that Melatonin
• Blocks seizures
• Protects the brain from damage
• Potentiates the effect of carbamazepine and
  phenobarbital

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Animal study

• Control
• Melatonin
• Kainic acid
• Kainic acid melatonin

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Evidence-Clinical Studies

• Human studies have so far shown significant
  improvement in seizure control

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How is Melatonin used?

• Given orally 30 minutes to one hour before
  bedtime
• Dose ranges from 3-10 mg