Youmans Neurological Surgery

1. Antiepileptic Medication
Principles of clinical use
Youmans Chapter 53

2. Older epileptic drug
Phenytoin Loading : Adult 18 mg/kg,Ped 20 mg/kg
Maintenance : Adult 200-500 mg/d (MDF=qD),
100 mg PO TID, Peds 4-7 mg/kg/d (MDF=BID)
Carbamazepine Oral dose
Adult 600-2000 mg/d
Peds 20-30 mg/kg/d
Valproate (Depakine) Dose (MDF = q d)
Adult 600-3000 mg/d
Ped 15-60 mg/kg/d
Phenobarbital and
Primidone
Adult : loading 20 mg/kg
maintenance 30-250 mg/d
Ped : loading 15-20 mg/kg
maintenance 30-250 mg/d

3. Older epileptic drug
• Phenytoin(Dilantin)
• Carbamazepine
• Valproate(Depakine)
• Phenobarbital and Primidone

4. Phenytoin(Dilantin)
• Dose
– Loading : Adult 18 mg/kg,Ped 20 mg/kg
– Maintenance : Adult 200-500 mg/d (MDF = q D)
– 100 mg PO TID, Peds 4-7 mg/kg/d (MDF = BID)
• First-order kinetic at low level
• Zero-order kinetic at therapeutic range
• Volume of distribution(Vd) : 0.75L/kg
• A dose of 7.5 mg/kg given intravenously raises the level
by 10 mg/L
• Adult : 15 mg/L, 5-6 mg/kg/day (350-450 mg/day)
– Common dose of 300 mg/day often result in levels of 10 mg/L

5. Phenytoin(Dilantin)
• Potent enzyme inducer  lower the level of many drug
– carbamazepine, valproate, felbamate, lamotrigine, topiramate,
zonisamide, and tiagabine
– warfarin, oral contraceptives, and cyclosporine
• Use
– partial seizures (simple or complex without or with secondary
generalization)
– generalized convulsive seizures
– status epilepticus
– neonatal seizures

6. Phenytoin(Dilantin)
• IV administration, 50 mg/min or 1 mg/kg/min
– bradyarrhythmia
– hypotension
– skin necrosis
• CNS side effect
– Nystagmus
– Ataxia
– lethargy.
• Delayes adverse effect
– gingival hyperplasia
– Hirsutism
– peripheral neuropathy
– bone demineralization secondary to reduced vitamin D levels.

7. Carbamazepine
• Dose oral route (MDF = BID)
• Adult 600-2000 mg/d
• Peds 20-30 mg/kg/d
• First-order kinetic
• Autoinduction : induce hepatic enzymes that result in
increased metabolism of itself
• USE
– Partial seizure without or with secondary generalized seizure
– Generalized tonic-clonic seizures

8. Carbamazepine
• Against partial and secondarily generalized seizures,
phenytoin, CBZ, phenobarbital, and primidone are about
equally effective in terms of seizure control
• no parenteral preparation
• Side effect
– Neutropenia
– Aplastic anemia
– Hyponatremia(SIADH like effect)
– movement disorders
– allergic rashes
– hypersensitivity syndrome

9. Valproate (Depakine)
• Dose (MDF = q d)
– Adult 600-3000 mg/d
– Ped 15-60 mg/kg/d
• USE
– Partial seizure
– Absence seizure
– GTC seizure
– Myoclonic seizure
– Infantile spasm
– Lennox-Gastaut syndrome
• Prolong the elimination(and raise the level) of other
drugs

10. Valproate(Depakine)
• Side effect
– Drowsiness
– Transient hair loss
– Dose-relates tremor
– Fatal hepatotoxicity (< 2 Yr and in combination with other drug)
– Pancreatitis
– Thrombocytopenia
– VPA-mediated disturbance of hemostasis  withdraw VPA
before elective surgery is recommend
– Women of childbearing age : neural tube defect(1-2 %),
polycystic ovaries and metabolic and endocrine disturbance

11. Phenobarbital and Primidone
• Dose
– Adult : loading 20 mg/kg, maintenance 30-250 mg/d
– Peds : loading 15-20 mg/kg, maintenance 30-250 mg/d
• Use
– Partial and secondary generalized
• Decline because their central nervous effect
• More sedative than other AED
• Side effect
– Cognitive impairment
– Sedation
– Allergic reaction
– Libido(Primidone)

12. Newer epileptic drug
• Felbamate
• Gabapentin
• Lamotrigine
• Topiramate
• Tiagabine
• Oxcarbazepine
• Levetiracetam
• Pregabalin

13. Newer epileptic drugFelbamate 1200 mg/d BID,TID,QID and reduced other AED by about a third
increase biweekly in 600 mg to usual dose of 1600-3600 mg/d
Gabapentin
(Neurontin)
Adult 300 mg PO x 1 day; 300 mg PO BID day 2;
300 mg PO TID day 3; then increase rapidly up to usual dose of 800-
1800 mg/day
Lamotrigine
(Lamictal)
Receiveing enzyme-enzyme inducing AED (PHT,CBZ,Phenobarbital)
: 50 mg PO q d x 2 wk,then 50 mg BID x 2 wk, then increase by 100
mg/d q wk unitl 200-700 mg/d
VA : maintainace dose 100-200 mg/d
Topiramate Adult : start with 25-50 mg/d(0.5-1 mg/kg/d) and increase slowly up
up to 200-400 mg/d(5-6 mg/kg/d)
Oxcarbazepine Adult : 300 mg twice daily, increase weekly, target 1200-1800 mg
Ped : 5-10 mg/kg per day in children, target 20-30 mg/kg
Levetiracetam
(Keppra)
Adult : 250-500 mg twice dialy(500-1000 mg/day), maintenace dose
1000-3000 mg/day
Ped : 20 mg/kg per day, maintenance 30-40 mg/kg per day
Pregabalin
(Lyrica)
Adult : 150 mg/day the first week, 300 mg/day the second week, 450
mg/day the third week, and 600 mg/day thereafter

14. Felbamate
• Dose
– 1200 mg/d BID,TID,QID and reduced other AED by about a third
– increase biweekly in 600 mg to usual dose of 1600-3600 mg/d
• Use
– Partial seizure(complex and secondary generalized)
• Not to be used in 1st
line drug
• Side effect
– Aplastic anemia
– Hepatic failure
– Insomnia
– Anorexia
– N/V
– H/A

15. Gabapentin(Neurontin)
• Dose :
– Adult 300 mg PO x 1 day; 300 mg PO BID day 2; 300 mg PO
TID day 3; then increase rapidly up to usual dose of 800-1800
mg/day
• Eliminated entirely by the kidneys  no pharmacokinetic
interaction
• Side effect
– Somnolence
– Dizziness
– Ataxia
– Fatigue
– Nystagmus
– Increase appetite

16. Lamotrigine(Lamictal)
• Dose
– Receiveing enzyme-enzyme inducing AED
(PHT,CBZ,Phenobarbital) : 50 mg PO q d x 2 wk,then 50 mg
BID x 2 wk, then increase by 100 mg/d q wk unitl 200-700 mg/d
– VA : maintainace dose 100-200 mg/d
– Ped : not indicated for use in patients < 16 Yr
• Use
– Partial seizure
– Lennox-Gastaut syndrome
• Side effect
– Somnolence,dizziness,diplopia
– Steven-Johnson symdrome,TEN

17. Topiramate
• Dose
– Adult : start with 25-50 mg/d(0.5-1 mg/kg/d) and increase slowly
up up to 200-400 mg/d(5-6 mg/kg/d)
• Use
– GTC
– Lennox-Gastaut syndrome
• Side effect
– Somnolence
– Impaired concentration
– Confusion
– Abnormal thinking
– Impaired verbal memory

18. Tiagabine
• Not found widely use
• Use
– Partial seizure without or with secondary generalized
• Side effect
– Dizziness
– Tremor
– Difficulty with concentration
– Nervousness
– Emotional lability

19. Oxcarbazepine
• Dose
– Adult : 300 mg twice daily, increase weekly, target 1200-1800
mg
– Ped : 5-10 mg/kg per day in children, target 20-30 mg/kg
• Derivative of carbamazepine
• Enzyme inducer
• Use
– Partial seizure
– Secondary generalized seizure
• Side effect
– Somnolence,Dizziness
– hyponatremia
– Ataxia

20. Levetiracetam(Keppra)
• Dose
– Adult : 250-500 mg twice dialy(500-1000 mg/day), maintenace
dose 1000-3000 mg/day
– Ped : 20 mg/kg per day, maintenance 30-40 mg/kg per day
• No drug-drug interaction,protein binding is low
• No level monitoring need
• Side effect
– somnolence, asthenia, dizziness, emotional lability, depression,
and psychosis
– Behavioral problems are particularly common in children and
include agitation, hostility, oppositional behavior, anxiety, and
aggression
– Allergic reactions, liver failure, and bone marrow suppression
are exceedingly rare.

21. Levetiracetam(Keppra)
• Use, broad spectrum AED
– partial and secondarily generalized seizures
– primarily generalized tonic-clonic seizures in idiopathic general
epilepsies
– myoclonic seizures in juvenile myoclonic epilepsy
– absence seizures
– severe myoclonic epilepsy in infancy
– progressive myoclonic epilepsy (Unverricht-Lundborg)
– rolandic epilepsy
– posthypoxic and postencephalitic myoclonus

22. Pregabalin(Lyrica)
• Dose
– Adult : 150 mg/day the first week, 300 mg/day the second week,
450 mg/day the third week, and 600 mg/day thereafter
• Use,narrow spectrum activity
– Focal onset seizure
– Secondarily generalized seizure
• Side effect
– Dizziness,somnolence
– dry mouth
– peripheral edema
– blurred vision
– excessive weight gain
– difficulty with concentration

23. Principle of treatment
• Decision to initiate antiepileptic drug therapy
– risk for recurrence seizure, potential risk associated with seizure
recurrence, chronic AED therapy associated
– Not indicated routine treatment,patient own preference
– Risk factor for recurrence
• Remote symptomatic seizure
• Focal onset seizure
• History of previous acute symptomatic seizures
• Epileptiform abnormalities on electroencephalography (EEG)
• First seizure manifested as status epilepticus
• First seizure followed by Todd’s paralysis
– Low risk for recurrence
• idiopathic generalized tonic-clonic seizure
• absence of epileptiform abnormalities on EEG

24. Principle of treatment
• Antiepileptic Drug Selection by Seizure Type or Epilepsy
Syndrome
– AED is based first on the seizure type or on the epileptic
syndrome
– Adverse effect, Patient’s age, gender and preference

26. Principle of treatment
• Basic Principles of Antiepileptic Drug Use
– Initial target dose
– Further increase in dose, seizure control, side effect by the drug
– Children higher clearance,Elderly lower clearance
– The drug not fail,if maximal tolerated dose has been reached
– If the first drug fail to control the seizure at maximal tolerated
dose  second drug
– When a therapeutic dose or level of the second drug has been
reached, the first drug should be tapered

27. Principle of treatment
• Discontinuation of Antiepileptic Drug Therapy
– Risk versus benefit analysis
– Factor for seizure recurrence after stopping AED
• known remote cause
• seizure onset after the age of 12 years
• a family history of epilepsy in patients with idiopathic epilepsy
• focal or generalized slowing on EEG before discontinuation
• a history of atypical febrile seizures
• IQ of less than 50
– The 2-year risk for recurrence after drug discontinuation may
vary from about 10% in patients with none of these risk factors to
about 80% in patients with remote symptomatic seizures and
three risk factors

28. Principle of treatment
• Discontinuation of Antiepileptic Drug Therapy
– decision to discontinue an AED is made after 2 years without
seizures,taper slowy over at least 3 month
– In patient who have become free of seizures after epilepsy
surgery : reduce the number of AED after 1 year and to
discontinue all drug after 2 years