1 I. HISTORY Ancient Times:, epilepsy was called the Asacred disease@, due to presumed cause by a deity or demon. AEpilepsy@ is derived from the Greek Aepilambanein@ meaning Ato seize or attack.@ 1850 : Bromides discovered to be effective; use of bromides persisted into the mid 1900s. 1870: John Hughlings Jackson proposed that seizures were caused by Aoccasional, sudden, excessive, rapid and local discharges of gray matter.@ 1912: The first clinical use of phenobarbital to treat epilepsy was reported 1929 - 1938: Hans Berger discovered the EEG and showed the relationship between discharges in the brain and the clinical manifestations of epileptic seizures. 1938: Merritt and Putnam screened 746 compounds in a cat model discovered phenytoin. II. INTRODUCTION A. Seizures: result from abnormal neuronal discharge in the central nervous system produced by either focal or generalized disturbances of brain tissue. B. Causes: a wide variety of disorders can result in seizures: head trauma, birth and perinatal injuries, congenital malformations, metabolic disturbances (blood sodium, glucose, calcium, urea), drugs or alcohol, drug withdrawal, vascular insults (anoxia), infections, neoplasia, genetic defects, fever. All people are capable of experiencing a seizure, given the appropriate conditions. In many cases (e.g., metabolic disturbances) if the condition is corrected, seizures do not recur. D. Definition of epilepsy: "...chronic central nervous system (CNS) disorder having in common the occurrence of sudden and transitory episodes (seizures) of abnormal phenomena of motor (convulsion), sensory, autonomic, or psychic origin. The seizures are nearly always correlated with abnormal and excessive EEG discharges." Incidence: between 1/100 and 1/300 in the general population. III. CLASSIFICATION OF SEIZURES The classification of seizures is based on the degree of central nervous system involvement and is divided into two main groups: partial and generalized (See Table). ANTISEIZURE DRUGS Dental Pharmacology Randal A. Skidgel, Ph.D. Dept. of Pharmacology 412 CSN, 6-91792 Classification of Seizures Seizure Type Frequency Loss of Consciousness Duration Features PARTIAL (FOCAL) Simple partial 10 % No 20 - 60 sec Focal motor (specific muscle groups), sensory (e.g., tingling, hot or cold sensations) or speech disturbances Complex partial 35 % Impaired 30 sec to 2 min Complex symptoms; confused behavior, dreamy state, amnesia; often associated with automatisms (purposeless movements). Partial with secondarily generalized tonic-clonic seizure 10 % Yes 1 - 2 min Simple or complex partial seizure evolves into loss of consciousness, rigid extension of trunk and limbs (tonic), then rhythmic contraction of arms and legs (clonic). GENERALIZED Tonic-Clonic (grand mal) 30 % Yes 1 - 5 min Loss of consciousness; massive contraction of skeletal muscle; rigid extension of trunk and limbs (tonic; posture called opisthotonos), then rhythmic contraction of arms and legs (clonic). Absence (petit mal) 10 % Impaired < 30 sec Abrupt brief onset of impaired consciousness, cessation of activities and staring. Characteristic 3 per second spike and wave pattern on EEG. Commonly in children (3 - 15 years old). Myoclonic < 3 % No 1 - 5 sec Brief, shocklike contraction of muscles; may be restricted to part of extremity or may be generalized. Can occur in clusters for several min. Atonic/Akinetic < 2 % Yes 5 sec - mins Sudden loss of postural tone leading to sagging of the head or falling. Sudden freezing of motion (called “akinetic”) Status Epilepticus 7% Yes >5 min A state of continuous generalized tonic-clonic seizure of > 5 min or 2 or more discrete seizures between which baseline consciousness is not regained. This is a medical emergency that can be fatal up to 35% of the time.3Mechanisms: hyperexcitability of neurons can be caused by: 1. Increased activity of voltage-gated ion channels (e.g., Na+ & Ca++ channels) 2. Decreased inhibitory (i.e., GABA) neurotransmission 3. Increased excitatory neurotransmission (i.e., glutamate receptors) 4. Alteration of extracellular ion concentration (e.g., potassium, calcium). Etiology: Epileptic seizures are caused by hyperexcitable neurons 1. Seizures usually originate at a site of damage called an "epileptogenic" focus. 2. The manifestations of the seizure depend on the location of the focus. 3. The abnormal electrical discharge of the focus can spread to normal neuronal tissue during a seizure, causing generalized symptoms. Figure 1. Pathways of seizure spread. A, Focal seizure with spread to adjacent and contralateral cortical regions. B, Focal seizure with secondary generalization. Seizure discharge activates subcortical centers (A), which then activate entire cortex (B). C, Primary generalized absence seizure in which thalamocortical relays are believed to act on a diffusely hyperexcitable cortex.4 Figure 2. Relationship between cortical EEG, extracellular and intracellular recordings in a seizure focus. A, Seizure was induced by local application of a convulsant agent. The extracellular recording was made through a high-pass filter. Note the high-frequency firing of the neuron evident in both extracellular and intracellular recording during the paroxysmal depolarization shift (PDS). This seizure would is representative of a partial with secondarily generalized tonic-clonic seizure. B, Recording during an absence seizure, demonstrating the characteristic generalized spike and wave discharges at a frequency of 3 per second. IV. DRUG THERAPY OF EPILEPSY AND SEIZURES Mechanisms of action of antiseizure drugs: The mechanisms below likely underlie clinically relevant antiseizure effects of the drugs used to treat seizures, but probably do not completely explain their mechanisms of action. Identified mechanisms by which antiseizure drugs work are: 1. Inactivation of voltage-dependent Na+ channels in a use-dependent fashion. 2. Increase the effectiveness of inhibitory GABA transmission via the GABAA receptor. 3. Inhibition of Ca++ currents through T-type Ca++ channels. 4. Inhibition of excitatory glutamate transmission via ionotropic receptors.5 Figure 3. Enhancement of Na+ channel inactivation by antiseizure drugs. A, resting state in which Na+ channel activation gate (A) is closed. B, Arrival of an action potential causes