EPILEPSY

What is Epilepsy?
Epilepsy is a seizure disorder resulting from sudden bursts of electrical energy in the brain. These electrical discharges produce seizures which vary from one person to another in frequency and form. Sometimes the electrical signal only reaches part of the brain where a part of the body, like an arm or a leg may move on its own. If the signal goes through all of the brain, the person may shake all over, fall and lose consciousness.

Etiology
Identifiable Causes of Epilepsy in Children: Brain injury to the fetus during pregnancy Birth trauma lack of oxygen Head trauma, e.g., car accident Brain tumor and stroke Infection e.g., meningitis Poisoning from substance abuse or environmental contaminants, e.g., lead poisoning.

Characteristics
The characteristics and frequency of seizures vary greatly. Some known characteristics are:

Uncontrolled movements such as shaking of arms or legs Loss of consciousness Falling Staring into space (absences) mostly in children Appearing dazed, confused

Types of Seizures
There are many different kinds of seizures. Two main types are: partial and generalized.

Simple partial seizure sudden jerky movements distortion in sight or smell sudden sense of fear, stomach discomfort, dizziness sensations above are called an aura Strategy: Reassure the person

Partial seizures continued

Complex partial seizure loses awareness appears dazed and confused random walking, head turning and pulling at clothes person does not remember these behaviours after the seizure 2/3 of people have this type of seizure Strategy: do not restrain the person stay with the person until he/she is out danger.

Generalized seizures
Generalized seizures affect the whole body. They are generalized absence or tonic-clonic. Generalized absence seizure staring into space eyes may roll forward 5 to 15 second lapses of consciousness person does not recall this lapse occur in childhood and disappear in adolescence Strategy: Talk gently to the person, be comforting as it may take time for the person to become re-oriented.

Generalized seizures continued

Tonic-clonic seizure (grand mal) occurs in two phases Tonic phase: loses consciousness and falls Clonic phase: muscles stiffen, body jerks and twitches bladder control may be lost consciousness returns slowly Strategy: Require First Aid Treatment plus immediate medical attention if the seizure lasts more than 5 minutes.

Incidence of Seizure Types

Based on information from: Epilepsy A Comprehensive Textbook, 1997

Evidence for the Pathophysiology of Seizures

Increased EAA

Increased Excitatory Amino Acid Transmission Increased sensitivity to EAA Progressive increase in glutamate release during kindling Increased glutamate and aspartate at start of seizure Upregulation of NMDA receptors in kindled rats

Decreased GABA Decreased binding of GABA and benzodiazepines Decreased Cl- currents in response to GABA Decreased glutamate decarboxylase activity (synthesizes GABA) Interfere with GABA causes seizures

Strategies in Treatment
Stabilize

membrane and prevent depolarization by action on ion channels

GABAergic transmission EAA transmission

Increase

Decrease

Classification of Anticonvulsants
Action on Ion Channels
Na+: Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid Ca++: Ethosuximide Valproic acid

Enhance GABA Transmission

Benzodiazepines (diazepam, clonazepam) Barbiturates (phenobarbital) Valproic acid Gabapentin Vigabatrin Topiramate Felbamate

Inhibit EAA Transmission

Felbamate Topiramate

Na+: For general tonic-clonic and partial seizures Ca++: For Absence seizures

Most effective in myoclonic but also in tonic-clonic and partial Clonazepam: for Absence

Classification of Anticonvulsants
Classical

Newer

Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproic Acid Trimethadione

Lamotrigine Felbamate Topiramate Gabapentin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin Others

R1 R2

X
R3

Phenytoin

Ethosuximide

Trimethadione

Phenobarbital

Carbamazepine

Valproic Acid

Phenytoin or Diphenylhydantoin

Limited water solubility not given i.m. Slow, incomplete and variable absorption. Extensive binding to plasma protein. Metabolized by hepatic ER by hydroxylation. Chance for drug interactions. Therapeutic plasma concentration: 10-20 g/ml

Phenytoin Toxicity and Adverse Events

Acute Toxicity

High i.v. rate: cardiac arrhythmias hypotension; CNS depression.

Fosphenytoin
A Prodrug. Given i.v. or i.m. and rapidly converted to phenytoin in the body. Avoids local complications associated with phenytoin: vein irritation, tissue damage, pain and burning at site, muscle necrosis with i.m. injection, need for large fluid volumes. Otherwise similar toxicities to phenytoin.

Other Na Channel Blockers

Carbamazepine: Serious hematological toxicity: aplastic anemia. Antidiuretic effect (anti ADH). Lamotrigine: possible other mechanisms. Effective in Absence seizures and has antidepressant effects in bipolar depression. No chronic associated effects.

Inhibitors of Calcium Channels Ethosuximide

Drug of choice for Absence. Blocks Ca++ currents (T-currents) in the thalamus. Not effective in other seizure types GI complaints most common CNS effects: drowsiness lethargy

Enhancers of GABA Transmission

Phenobarbital

The only barbiturate with selective anticonvulsant effect. Bind at site on GABA receptor and duration of opening of Cl channel. Ca-dependent release of neurotransmitters at high doses. Inducer of microsomal enzymes drug interactions. Toxic effects: sedation (early; tolerance develops); nystagmus & ataxia at higher dose; osteomalacia, folate deficiency and vit. K deficiency.

Enhancers of GABA Transmission

Benzodiazepines

Sedative - hypnotic- anxiolytic drugs. Bind to another site on GABA receptor. Other mechanisms may contribute. frequency of opening of Cl channel. Clonazepam and clorazepate for long term treatment of some epilepsies. Diazepam and lorazepam: for control of status epilepticus. Disadvantage: short acting. Toxicities: chronic: lethargy drowsiness. in status epilepticus: iv administration: respiratory and cardiovascular depression. Phenytoin and PB also used.

GABA-A Receptor Binding Sites

Cl-

Enhancers of GABA Transmission

Gabapentin: Developed as GABA analogue. Mechanism: Increases release of GABA by unknown mechanism. Vigabatrin: Irreversible inhibitor of GABA transaminase. Potential to cause psychiatric disorders (depression and psychosis). Tiagabine: decreases GABA uptake by neuronal and extraneuronal tissues.

Valproic Acid

Effective in multiple seizure types. Blocks Na and Ca channels. Inhibits GABA transaminase. Increases GABA synthesis. Toxicity: most serious: fulminant hepatitis. More common if antiepileptic polytherapy in children < 2 years old. (?) Toxic metabolites involved. Drug interactions: inhibits phenobarbital and phenytoin metabolism.

Other Drugs

Topiramate; multiple mechanisms of action (Na channel, GABA enhancement like BZD, antagonist at AMPA subtype of glutamate receptors (not NMDA). Felbamate: multiple mechanisms: Na channel block; modulates glutamate transmission interacts with glycine site. Serious hematological and hepatic toxicities.

Treatment of Epilepsy
Start with a single agent. Raise to maximum tolerated dose before shifting to another. If therapy fails may use combination of drugs. Frequent physician visits early on and therapeutic drug monitoring. Importance of compliance. Aim and duration of therapy.