Anticonvulsant Therapy

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Anticonvulsant Therapy

• Directed By Dr. Afaf Al-Arini
• Presented By Dr. Y. Abu-zanouna

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Anticonvulsant Therapy

• Principles of epilepsy treatment
• Anti Epileptic Drugs
• Ketogenic diet
• Surgery for epilepsy

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To Treat or Not to Treat that is the Question ?

• Prognosis after the 1st seizure in 1 yr
• 25 risk of having another seizure
  neurologically normal, -ve family
  history,unprovoked siezure.
• 37 risk prior neurological insult (e.g. CP)
• After the 2nd seizure
• 70 risk of recurrence .

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Anticonvulsant therapy

• Withholding treatment until after the second
  seizure dose not alter the long term prognosis of
  epilepsy.
• Study randomizing 419 patients with 1st
  tonic-clonic seizure to immediate AED or
  treatment after a 2nd seizure
• Anticonvulsant therapy reduced the short term
  relapse rate, but at 1 2 yrs , the number of
  seizure- free patients in both groups was similar.

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Anticonvulsant therapy

• In children with an idiopathic seizure,EEG is the
  most valuable predictor of recurrence41 vs. 15
  .
• Initial presentation as status epilepticus The
  risk of recurrence of any type of seizure is not
  increased in those with status epilepticus.

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To Treat or Not to Treat that is the Question ?

• Individualized decision.
• No treatment
• Another seizure , with the risk of injury ,
  stigma , status epilepticus.
• Treatment
• Chronic AED
• Cost Of treatment

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Anticonvulsant therapy

• Practice of most neurologists is to refrain from
  treatment in 1st idiopathic seizure.In
  symptomatic seizures treatment is more
  problematic.
• Parents elect to avoid therapy if seizures are
  infrequent /or mild.
• Absence seizures, drop attacks , infantile spasm
  are always treated they usually present with an
  established disorder.

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Basic principles of AED therapy

• Initiation of therapy
• Adding a second drug
• Monotherapy vs. Polytherapy
• Drug-Drug interaction
• Anticonvulsant level monitoring

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Monitoring serum levels

• Onset of treatment
• Non-compliant patients families
• At the time of status epilepticus
• Patients on polytherapy D-D
• Symptoms Signs of toxicity
• Hepatic or renal disease
• Children with cognitive or physical disabilities

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Before treatment

• Routine blood investigations ?
• Family History
• Neurological disease
• Consanguinity
• Adverse reactions hematological, cutaneous
• Autoimmune disorders
• Renal stones

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Antiepileptic Drugs

• Drugs that block voltage- dependant sodium
  channels
• Carbamazepine
• Phenytoin
• Lamotrigine
• Oxcarbazine

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Carbamazepine

• Indications
• Used in Generalized tonic-clonic partial
  seizures.
• Affective disorders Bipolar disorder
• Chronic pain syndromes trigeminal neuralgia.
• Dose
• Begin 10mg/kg/24h
• Increase to 20-30mg/kg/24hr tid

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Carbamazepine

• Pharmacokinetics
• Absorbed slowly after oral administration
• Eliminated by hepatic cyt p450, main metabolite
  carbamazepine epoxide
• Enzyme inducer
• Plasma levels are increased by erythromycin ,
  clarithromycin , diltiazem , INH

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Side Effects

• Dose relatedDiplopia ,dizziness, ataxia esp in
  1st week,GI upset ,tremors, fatigue.
• Worsening of myoclonic, atonic absence
  seizures,may ppt drop attacks in pts with L-G
  Syndrome.
• Allergic
• Skin rash 5-15
• TEN in 1st 8 weeks
• Drug induced lupus

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Carbamazepine

• On chronic use
• Leucopoenia.
• Hyponatremia (SIADH)
• Heart conduction disturbances.
• Advantages
• Twice daily extended release forms.
• Less teratogenic ( 0.5-1 )

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phenytoin

• Used generalized tonic clonic , partial
  seizures , in status epilepticus.
• Dose 3-9 mg/kg/24h bid,oral
• Pharmacokineticswell absorbed,long t1/2 life,
  peaks in 4-8 hrs
• Enzyme inducer
• To be adjusted in renal failure

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Side effects

• Dose related Nystagmus,drowsiness, fatigue,
  dysarthria,tremors,impaired concentration,encephal
  opathy.
• Idiosyncratic skin allergy 5-10 Vasculitis.
• Chronic peripheral neuropathy, behavior
  changes,coarse facial features, gingival
  hyperplasia,pulmonary fibrosis,acne,hirsutism,fola
  te deficiency, neonatal coagulation
  defects,endocrine impairment.
• teratogenic

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Lamotrigine

• Affects neurons that synthesize glutamate
  aspartate.
• Uses broad spectrum ,adjunct treatment in
  generalized seizures partial seizures,mixed
  seizures,absence,Lennox-Gestaut
• Dose individualized, based on age additional
  anticonvulsants.

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Lamotrigine

• Side effects
• Dose related fatigue, ataxia ,drowsiness,nystagmu
  s,insomnia,may cause myoclonic seizures in high
  doses.
• Allergic TEN,SJS,angioedema(main side effect)
• Advantages
• Broad spectrum
• Once or twice daily
• Not an enzyme inducer
• Low teratogenic potential

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Oxcarbazepine

• Uses
• Polytherapy
• Partial seizures
• Tonic-clonic seizures
• Side effects
• Dizziness ,ataxia,headache ,fatigue
• Less hyponatremia than carbamazepine
• Teratogenic potential not known

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Antiepileptic Drugs

• Drugs that Affect Calcium Currents
• Ethosuximide
• Absence ( typical better than atypical)
• May increase tonic- clonic seizures
• Side effects mainly well tolerated GI upset,
  sleep disturbance , pancytopenia ,lupus-like
  syndrome.

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Antiepileptic Drugs

• Drugs that affect GABA metabolism
• Phenobarbital
• Clonazepam
• Gabapentin
• Tiagabine
• Vigabatrin

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Phenobarbital

• Uses
• Generalized tonic clonic
• Partial seizures
• Neonatal seizures
• Status epilepticus

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Phenobarbital

• Pharmacokinetics
• T ½ life 25 150 hrs, level is relatively
  stable , no need for peak trough levels , no
  difference.
• Serum levels should be checked 3-4 weeks after
  initial dose ( therapeutic level 10-40 mcg/ml)
• Drug Drug interaction
• Advantages
• Low cost
• Once daily
• Broad spectrum
• IV form

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Side Effects

• Dose related Drowsiness, blurred vision ,
  ataxia, fatigue , depression.
• Chronic
• Cognitive ,memory behavioral changes
• Megaloblastic changes
• Affects vitamin D calcium metabolism
• Withdrawal symptoms on abrupt discontinuation
• Coagulation defects in fetus

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Clonazepam

• Uses
• Absence ,myoclonic, infantile spasm, partial,
  Lennox- Gastaut , akinetic.
• Side effects
• Tolerated in up to 50 of patients
• Drowsiness, ataxia, behavioral personality
  changes, excessive salivation.

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Gabapentin

• Uses
• Add-on-therapy for refractory partial seizures.
• Pharmacokinetics
• Excreted unchanged in urine.
• Not necessary to monitor serum levels
• No drug interactions 2 hrs after antacids.
• Side effects
• Sedation,Dizziness , headache,tremor, nystagmus,
  weight gain.

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Tiagabine

• Uses Infantile spasm,Adjunctive therapy for
  complex partial seizures.
• Side effects
• Idiosyncratic psychosis or severe depression in
  1-2
• Chronic Irreversible concentric visual field
  defect, weight gain
• Visual field testing before treatment every 6
  months.

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Drugs with multiple mechanisms of action

• Valproate
• Mechanism of action
• Blocks voltage dependant Na channels.
• Enhances GABA synthesis
• Acts against Ca currents.
• Uses
• Broad spectrum AED used alone in combination
  for partial seizures several types of
  generalized seizures.

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VALPROATE

• Pharmacokinetics
• Food delays absorption
• Drug interactions at protein binding sites
• Decreased protein binding in pregnancy ,hepatic
  renal disease.
• Intravenous preparations now available
• Therapeutic levels 50 150 mcg/ml to be
  checked after 1-2 weeks.

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Side Effects

• Fatigue ,tremor,Encephalopathy, alopecia, GI
  upset.
• Idiosyncratic BM suppression ,pancreatitis,throm
  bocytopenia.
• Hepatotoxicity higher fatality in children lt 2
  yrs, those receiving polytherapy.
• Reye like syndrome
• Chronic use weight gain, polycystic ovary.
• Teratogenic NTD in 1st trimester 1-2

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Topiramate

• Mode of action
• Voltage gated Na channels
• GABA
• Antagonizes glutamate receptors
• Week inhibitor of carbonic anhydrase in CNS.
• Uses
• Adjuvant therapy for poorly controlled seizures
• L-G syndrome

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Topiramate

• Pharmacokinetics
• Excreted unchanged in urine
• Not an enzyme inducer
• Therapeutic levels not established
• Side effects
• Dizziness , parethesias ,headache.
• Chronic use Wt loss 10 , nephrolethiasis1-5
  .
• May increase levels of phenytoin

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Stopping antiepileptic treatment

• After 2 years with no seizers.
• Likelihood of recurrence after 2 years of control
  30-40
• Overall rate of recurrence in idiopathic epilepsy
  is 29 .
• In symptomatic epilepsy 47
• Slow EEG on diagnosis 45
• 28 with normal EEG

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Life long treatment

• Juvenile myoclonic epilepsy
• Progressive myoclonic epilepsy
• Atypical absence seizures
• Lennox-Gastaut

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Higher rates of recurrence

• Older age at the outset
• Syndromes
• Symptomatic epilepsy
• Poor initial control of seizures
• Change in the type of seizures during treatment

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Intractable ??

• Consider the following
• Wrong diagnosis.
• Inadequate drug level
• Inattention to life style factors ( sleep
  deprivation,alcohol,stress)
• Underlying progressive brain disease or metabolic
  disease.
• Intrinsic intractable syndrome.
• Wrong drug

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Ketogenic Diet

• For children with complex myoclonic epilepsy
  tonic- clonic convulsions.
• Continued for at least two years.
• Pyrovate Dehydrogenase deficiency glucose
  transport protein deficiency.
• Safe for children younger than 2 yrs .
• May be unpleasant for older children
• ¾ parts fat , 1 part CHO protein.
• Mechanism of action not well known .

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Ketogenioc diet

• Levels of Ketone bodies to be monitored in serum
  urine.
• Valproate is contraindicated with this diet.
• Suppresses seizure activity by at least 50 in
  40 of patients.
• Side effects
• Decreased bone mass
• Renal stones
• Hypoprotenemia
• Metabolic Encephalopathy
• Hyperuricemia

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Epilepsy surgery

• Considered, regardless of age , in children with
  persistent , frequent , refractory seizures ,
  with adverse impact on their lives interfering
  with their cognitive , behavioral psychosocial
  development.
• Focal seizures , with focality documented by
  EEG,SPECT,PET , fMRI ,MEG.

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Epilepsy surgery

• Relatively non invasive
• Vagal nerve stimulation
• Invasive
• Local resection
• Hemispherectomy
• Temporal lobectomy
• Corpus callosectomy ( drop attacks )