L1 - Pathophysiology of Seizure Disorders (8:19).pdf

Seizure Disorders Pathophysiology JASON ERIKSEN, PH.D. (Source)  Identify the characteristics and epidemiology of various seizure disorders. Compare the pathophysiologic mechanisms of seizure disorders. Lecture Lis...

Seizure Disorders Pathophysiology JASON ERIKSEN, PH.D. (Source)  Identify the characteristics and epidemiology of various seizure disorders. Compare the pathophysiologic mechanisms of seizure disorders. Lecture List the major classes and subclasses of Objectives epilepsy. Recognize the factors that trigger seizures in susceptible individuals. Identify the changes that occur in the seizure focus. Goodman and Gilman. The Pharmacological Basis of Therapeutics. Chapter 21. Pharmacotherapy of the Epilepsies. 2 A History of the Mechanisms of Seizures John Hughlings Jackson, the father of modern concepts of epilepsy, proposed the framework that seizures were caused by the spread of convulsive discharges from a seizure focus. Development of the electroencephalogram in the 1930s demonstrated that the epilepsies are disorders of neuronal excitability. The pivotal role of synapses in mediating communication among neurons in the mammalian brain suggested that defective synaptic function leads to seizure. 3 What is a Electroencephalogram? Electrical activity is recorded from the surface of the scalp from ensembles of neurons in the brain just underneath  Typically non- invasive, with the electrodes placed along the scalp. 4 Seizures contain a characteristic “fingerprint” Studies of populations of neurons (field potentials) show a sharp interictal (or between-seizures) depolarizing spike (DS) and a burst of action potentials, but no behavioral symptoms, always precedes a seizure. The DS can be used to identify the seizure focus. Seizure activity occurs only after the DS and a variable silent period have elapsed 5 Key Differences between Seizures and Epilepsy A seizure refers to the clinical manifestation of an abnormal and excessive synchronization of a population of cortical neurons Seizures are thought to arise from the cerebral cortex, and not from other central nervous system (CNS) structures. Epilepsy refers to an unprovoked tendency toward Patient Experiencing a Grand Mal Seizure (YouTube ) two or more recurrent seizures unprovoked by insults. 6 What Does a Seizure Look Like? OPSCEA Rashetta Higgings Visualization Source: UCSD 7  Epidemiology of Epilepsy Epilepsies are common and frequently devastating disorder, affecting 1.2%, or 3.5 million people in the U.S. Frequency of epilepsy is highest in the young and the elderly. Therapy is effective for symptoms in 70-80% of patients. Available drugs inhibit seizures, but neither effective prophylaxis nor cure is available. Compliance with medication is a Source: Epilepsy in Older People, The Lancet major problem because of the need for long-term therapy together with unwanted effects of many drugs. 8 Causes of Epilepsy Epileptic syndromes are classified according to a cluster of symptoms frequently occurring together that include seizure types, cause, age of onset, and other factors Focal (partial) epilepsies account for 60% of epilepsies. The cause (etiology) of these is frequently correlated with a lesion in some part of the cortex. Generalized epilepsies are usually genetic in origin and account for 40% of all epilepsies. Juvenile myoclonic epilepsy accounts for 10% of all epilepsy and is associated with by multiple familial susceptibility genes. 9 Seizures are categorized as focal or generalized. Focal seizures start in one part of the brain. They may cause staring, twitching of the hands or feet, or repeated movements on one side of the body. They may cause a loss of consciousness. Generalized seizures start and spread in both sides of the brain, with loss of consciousness. One type (tonic-clonic) can cause a person to become stiff, pass out, and shake all over. 10 Categories of Focal Seizures Seizure Type Features Conventional Anti-Seizure Drugs Focal Aware Diverse manifestations determined by Carbamazepine cortical region, lasting 20-60 seconds. A Phenytoin key feature is the preservation of Valproate consciousness. Focal Impaired consciousness lasting 30 Carbamazepine Impaired seconds to 2 minutes, often associated Phenytoin with purposeless movements. Valproate Focal to Simple or complex partial seizure evolves Carbamazepine Bilateral into a tonic-clonic seizure with loss of Phenobarbital Tonic-Clonic consciousness, typically lasting 1-2 Phenytoin minutes Valproate 11 12 Common Generalized Seizures Seizure Type Features Conventional Anti-Seizure Drugs Absence seizure Abrupt onset of impaired consciousness Ethosuximide (Petit mal) associated with staring and cessation of Valproate ongoing activities typically lasting less Clonazepam than 30 seconds. Myoclonic seizure A brief (perhaps a second), shocklike Valproate contraction of muscles that may be Clonazepam restricted to part of one extremity or may be generalized. Tonic-clonic seizure A generalized tonic-clonic seizure: Carbamazepine (Grand mal) resembles a focal seizure with secondary Phenobarbital generalization, but without an initial Phenytoin focal onset. Valproate 13 Generalized Convulsive Seizures Tonic-clonic seizures (Grand Mal): major convulsions proceeded by an aura and loss of consciousness. 14  Generalized Convulsive Seizures Myoclonic seizures: single or multiple rapid, shock- like contractions of a single muscle or a muscle group which may involve a single limb or the torso. Tonic seizures: convulsions are limited to pure tonic or sustained contractions in which opposing muscle groups contract at the same time. Clonic seizures: Convulsions are limited to a thrashing type of motor activity in which opposing muscle groups alternately relax and contract. Infantile spasm (West’s syndrome, jack-knife seizure) multi-symptoms in cluster. Juvenile Myoclonic Epilepsy: Most common of the generalized forms. Multi-epilepsies in cluster. Patient Experiencing a Myoclonic Seizure (YouTube ) 15 Generalized Convulsive Seizures Dravet Syndrome (Severe myoclonic epilepsy in infancy: SMEI): Is a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. Cognitive impairment, behavioral disorders and motor disorders. Lennox-Gastaut syndrome: A complex, rare, and severe childhood-onset epilepsy. It is characterized by multiple and concurrent seizure types, cognitive dysfunction. 16 Generalized Nonconvulsive Seizures Absence seizures (petit mal): brief, often repetitive periods of impaired consciousness; each episode is followed by some degree of post-seizure amnesia. Atonic seizures: a loss of consciousness and a sudden loss of skeletal muscle tone characterized by "head drop", jaw slackening or slumping to the ground (drop attacks). Akinetic seizures: a loss of consciousness and excessive inhibitory tone to motor systems to impair movements. 17 Febrile Seizures  Unclassified Seizure  Affects 1 in 25 children (6 mo – 5 years old)  Associated with fever 18 Status Epilepticus A seizure that lasts longer than 5 minutes or having more than 1 seizure within a 5 minutes period, without returning to a normal level of consciousness between episodes is called status epilepticus. Medical emergency (can be fatal) Many causes, including withdrawal from alcohol or barbiturates, electrolytes imbalance, hypoglycemia or hyperglycemia, drug overdose. Results: include progressive exhaustion, profound metabolic disturbances, brain damage, hyperthermia, CV & respiratory failure and death. Source: Irreversible brain injury following status epilepticus 19 What triggers seizures? Numerous factors can precipitate seizure in susceptible individuals: Hyperventilation (absence seizure) Sleep or sleep deprivation Sensory stimuli (flashing lights or other stimuli) Mental stress Hormonal changes (during menses, puberty, or pregnancy) High doses of drugs (theophylline, alcohol, phenothiazines, antidepressants Source: The Simpsons, “In Marge We Trust” (especially maprotiline or bupropion), and street drug use. Seizures occur due to hypersynchronized discharge of a group of cortical neurons. 20 The development of symptomatic epilepsy A conceptual time course of epileptogenesis, The role of different factors in the development clinical and subclinical seizures in acquired and maintenance of an epilepsy condition. symptomatic epilepsy. Source: The enigma of the latent period 21 Seizure Foci: The Epicenter of Epileptic Activity Seizure focus is an area in the cortex that functions as an abnormal pacemaker. Generalized epilepsies are associated with mutations in voltage-gated channels Focal epilepsies have changes in the numbers of localization of voltage-gated channels Changes found in Foci in epilepsies are associated with decreased inhibition (GABA), increased excitation (NMDA), decreased levels of adenosine (which typically inhibits activity). 22