1 I. HISTORY Ancient Times:, epilepsy was called the Asacred disease@, due to presumed cause by a deity or demon. The term Aseizure@ may have originated from the belief that epileptics were Aseized by the devil.@ The word 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 systematically studied 746 compounds in a cat model of epilepsy and discovered phenytoin. Introduced the new concept that antiseizure drugs did not have to be sedatives. Phenytoin is still widely used today. 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. C. Seizures can take many form such as: motor convulsions; abnormal sensory perceptions; abnormal emotional responses; abnormal pain (trigeminal neuralgia). 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. ANTISEIZURE DRUGS Medical Pharmacology Randal A. Skidgel, Ph.D. Dept. of Pharmacology 412 CSN, 6-91792D. Epilepsy: the most common chronic seizure disorders, characterized by recurrent seizures of a particular pattern. There are between 1 in 100 and 1 in 300 epileptic patients in the general population. E. 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." F. Epileptic Syndromes: A cluster of symptoms frequently occurring together, including seizure types (see below), etiology, age of onset, etc.. More than 40 syndromes have been identified. Primarily useful in clinical assessment and management. Choice of drug dependent on particular seizure type (see below). G. 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. H. Mechanisms: 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). 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).3 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.4 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. Figure 2. Cellular and synaptic mechanisms of seizures. A seizure can be divided into three phases: (1) focal epileptogenesis (initiation), (2) synchronization of the surrounding neurons, and (3) propagation of the seizure discharge to other areas of the brain. Arrows indicate where each of the mechanisms on the left participates in the three phases involved in seizure generation.5 Figure 3. 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
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