epilepsy

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EPILEPSY:

EPILEPSY Presented by G.HANUMANTH (M.Pharmacy) 2 nd semester Department of pharmacology

CONTENTS:

CONTENTS Introduction Definition Etiology of seizures Classification of seizures Epilepsy syndrome Etiology of epilepsy and seizures Pathophysiology Drug treatment

INTRODUCTION:

INTRODUCTION The term EPILEPSY based on Greek word “ epilambanein ” ( “meaning to seize” ) was first used by Hippocrates. He described epilepsy as a disease of the brain , which should be treated with diet. Hippocrates provided the first classification on epilepsy.

DEFINITION:

DEFINITION  Seizure: The clinical manifestation of an abnormal and excessive “ synchronization” of a population of cortical neurons.  Epilepsy: A tendency toward recurrent seizures unprovoked by any systemic or acute neurologic insults.  Epileptogenesis: sequence of events that converts a normal neuronal network into a hyperexcitable network.

ETIOLOGY OF SEIZURES:

ETIOLOGY OF SEIZURES Seizures are either provoked or unprovoked. Provoked Seizures: Triggered by certain provoking factors in otherwise healthy brain. Metabolic abnormalities (hypoglycemia and hyperglycemia, hyponatremia, hypocalcemia). Alcohol withdrawal. Acute neurological insult (infection, stroke, trauma). Illicit drug intoxication and withdrawal. Prescribed medications that lower seizure threshold (theophylline, TCA). High fever in children. Unprovoked Seizures: Occur in the setting of persistent brain pathology. cont..

CLASSIFICATION OF EPILEPTIC SEIZURES:

CLASSIFICATION OF EPILEPTIC SEIZURES The International League Against Epilepsy (ILAE) developed an international classification of epileptic seizures that divides seizures into 2 major classes. partial-onset seizures and generalized-onset seizures. Partial-onset seizures begin in a focal area of the cerebral cortex, whereas generalized-onset seizures have an onset recorded simultaneously in both cerebral hemispheres.

Slide 7:

In 2001, the International League Against Epilepsy (ILAE) proposed that rather than revising the entire classifications of seizures (1981) or epilepsy syndromes (1989), a better strategy was to devise a 5-axis diagnostic scheme, as follows. Axis 1: Descriptive ictal terminology Axis 2: Seizure type, from the List of Epileptic Seizures with specific brain location, if known Axis 3: Syndrome, from the List of Epilepsy Syndromes, Axis 4: Etiology, including specific genetic defects or pathologic substrates Axis 5: Impairment, optional but useful parameter can be derived from the WHO ICIDH-2 impairment classification .

ILAE Classification of Seizures:

ILAE Classification of Seizures

SIMPLE PARTIAL SEIZURES:

SIMPLE PARTIAL SEIZURES

COMPLEX PARTIAL SEIZURES:

COMPLEX PARTIAL SEIZURES  Impaired consciousness  Clinical manifestations vary with site of origin and degree of spread Presence and nature of aura Automatisms Other motor activity  Duration typically < 2 minutes

SECONDARILY GENERALIZED SEIZURES:

SECONDARILY GENERALIZED SEIZURES Begins focally, with or without focal neurological symptoms  Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases Typical duration 1-3 minutes  Postictal confusion, somnolence, with or without transient focal deficit

EEG: Partial Seizure:

EEG: Partial Seizure Right temporal seizure with maximal phase reversal in the right sphenoidal electrode

ILAE Classification of Seizures:

ILAE Classification of Seizures

TYPICAL ABSENCE SEIZURES:

TYPICAL ABSENCE SEIZURES Brief staring spells (“petit mal”) with impairment of awareness 3-20 seconds. Sudden onset and sudden resolution. Onset typically between 4 and 14 years of age. Often resolve by 18 years of age.  N ormal development and intelligence.  EEG: Generalized 3 Hz spike-wave discharge.

EEG: Typical Absence Seizure:

EEG: Typical Absence Seizure

Atypical Absence Seizures:

Atypical Absence Seizures  Brief staring spells with variably reduced responsiveness 5-30 seconds Gradual (seconds) onset and resolution Onset typically after 6 years of age  Often in children with global cognitive impairment  EEG: Generalized slow spike-wave complexes (<2.5 Hz)  Patients often also have Atonic and Tonic seizures

ATYPICAL ABSENCE SEIZURES:

ATYPICAL ABSENCE SEIZURES

Myoclonic Seizures:

Myoclonic Seizures  Brief, shock-like jerk of a muscle or group of muscles.  Epileptic myoclonus . Typically bilaterally synchronous. Impairment of c onsciousness difficult to assess (seizures <1 second) Clonic seizure – repeated myoclonic seizures (may have impaired awareness).  Differentiate from b enign, nonepileptic myoclonus (e.g., while falling asleep).  EEG: Generalized 4-6 Hz polyspike -wave discharges.

Myoclonic Seizures:

Myoclonic Seizures

TONIC AND ATONIC SEIZURES:

TONIC AND ATONIC SEIZURES T onic seizures Symmetric, tonic muscle contraction of extremities with tonic flexion of waist and neck. Duration - 2-20 seconds. EEG – Sudden attenuation with generalized, low-voltage fast activity (most common) or generalized polyspike -wave. Atonic seizures Sudden loss of postural tone. When severe often results in falls. When milder produces head nods or jaw drops. Consciousness usually impaired. Duration - usually seconds, rarely more than 1 minute. EEG – sudden diffuse attenuation or generalized polyspike -wave.

TONIC AND ATONIC SEIZURES:

TONIC AND ATONIC SEIZURES

Generalized Tonic-Clonic Seizures:

Generalized Tonic-Clonic Seizures Associated with loss of consciousness and post- ictal confusion/lethargy Duration 30-120 seconds Tonic phase Stiffening and fall Often associated with ictal cry Clonic Phase Rhythmic extremity jerking EEG – generalized polyspikes

Epilepsy Syndromes:

Epilepsy Syndromes Epilepsy means a tendency to have seizures and is a symptom of brain rather then a disease.

Etiology of Seizures and Epilepsy:

Etiology of Seizures and Epilepsy  Infancy and childhood Prenatal or birth injury. Inborn error of metabolism. Congenital malformation.  Childhood and adolescence Idiopathic/genetic syndrome. CNS infection. Trauma.

Etiology of Seizures and Epilepsy:

Etiology of Seizures and Epilepsy  Adolescence and young adult Head trauma. Drug intoxication and withdrawal*.  Older adult Stroke. Brain tumor. Acute metabolic disturbances*. Neurodegenerative.

PATHOPHYSIOLOGY:

PATHOPHYSIOLOGY Seizures are paroxysmal manifestations of the electrical properties of the cerebral cortex. A seizure results when a sudden imbalance occurs between the excitatory and inhibitory forces within the network of cortical neurons in favor of a sudden-onset net excitation. If the affected cortical network is in the visual cortex, the clinical manifestations are visual phenomena. Other affected areas of primary cortex give rise to sensory, gustatory, or motor manifestations.

Basic Mechanisms Underlying Seizures and Epilepsy:

Basic Mechanisms Underlying Seizures and Epilepsy  Feedback and feed-forward inhibition, illustrated via cartoon and schematic of simplified hippocampal circuit

Epilepsy—Basic Neurophysiology:

Epilepsy—Basic Neurophysiology  Causes of Hyperexcitability : excitatory post synaptic potentials (EPSPs) inhibitory post synaptic potentials (IPSPs) changes in voltage gated ion channels alteration of local ion concentrations

Epilepsy—GABA:

Epilepsy—GABA  Major inhibitory neurotransmitter in the CNS  Two types of receptors GABA A —post-synaptic, specific recognition sites, linked to CI - channel GABA B —presynaptic autoreceptors that reduce transmitter release by decreasing calcium influx, postsynaptic coupled to G-proteins to increase K + current

Epilepsy—GABA:

Epilepsy—GABA GABA site Barbiturate site Benzodiazepine site Steroid site Picrotoxin site

Slide 31:

Diagram of the various glutamate receptor subtypes and locations

Cellular Mechanisms of Seizure Generation:

Cellular Mechanisms of Seizure Generation  Excitation (too much) Ionic—inward Na + , Ca ++ currents Neurotransmitter—glutamate, aspartate  Inhibition (too little) Ionic—inward CI - , outward K + currents Neurotransmitter—GABA

Normal CNS Function:

Normal CNS Function Excitation Inhibition Glutamate , Aspartate GABA

Hyperexcitability reflects both increased excitation and decreased inhibition:

Hyperexcitability reflects both increased excitation and decreased inhibition Glutamate, Aspartate Excitation Inhibition GABA

Neuronal (Intrinsic) Factors Modifying Neuronal Excitability:

Neuronal (Intrinsic) Factors Modifying Neuronal Excitability  Ion channel type, number, and distribution  Post-translational modification of channels (phosphorylation, etc).  Activation of second-messenger systems that affect channel function (e.g. G proteins)  Modulation of gene expression of ion channels

Epilepsy and Channelopathies:

Epilepsy and Channelopathies Inherited Voltage-gated ion channel mutations Ligand-gated ion channel (neurotransmitter receptor) mutations Different mutations in the same gene can result in radically different types of seizures and epilepsy Acquired Auto-immune (anti-potassium channel antibodies) Changes in channel expression after seizures

Ion Channel & Neurotransmitter Receptors Mutated in Epilepsy - I:

Ion Channel & Neurotransmitter Receptors Mutated in Epilepsy - I Voltage-gated Sodium Channel Gene Mutations SCN1A Generalized Epilepsy & Febrile Seizures Plus (GEFS+) type 2 Severe Myoclonic Epilepsy of Infancy (SMEI) SCN1B GEFS+ type 1 SCN2A1 GEFS+ Benign Familial Neonatal-Infantile Seizures (BFNIS)

Ion Channel & Neurotransmitter Receptors Mutated in Epilepsy - II:

Ion Channel & Neurotransmitter Receptors Mutated in Epilepsy - II Voltage-gated Chloride Channel Gene Mutations CLCN2A Juvenile Absence Epilepsy (JAE) Juvenile Myoclonic Epilepsy (JME) Epilepsy with Grand Mal upon Awakening (EGMA)

Mechanisms of Generating Hyperexcitable Networks :

Mechanisms of Generating Hyperexcitable Networks  Loss of inhibitory neurons Loss of excitatory neurons “driving” inhibitory neurons Change in neuronal firing properties ( channelopathies )

Drug treatment:

Drug treatment Choosing Antiepileptic Drugs  Seizure type  Epilepsy syndrome  Pharmacokinetic profile  Interactions/other medical conditions  Efficacy  Expected adverse effects  Cost

Guidelines for choice of AED:

Guidelines for choice of AED Epilepsy type First-line Second-line Third-line Partial/secondary tonic clonic seizures Carbamazepine Valproate Lamotrigine Topiramate Gabapentin Tiagabine Levetiracetam Clobazam Phenytoin Primidone Phenobarbital Oxcarazepine Vigabatrin Acetazoleamide Primary GTCS Sodium valproate Lamotrigine Topiramate Carbamazepine Phenytoin Primidone Gabapentin Phenobarbital Tiagabine Acetazoleamide Absence Ethosuximide Sodium valproate Lamotrigine Clonazepam Acetazoleamide Myoclonic Sodium valproate Clonazepam Piractem Lamotrigine Phenobarbital

Antiepileptic Drug Interactions :

Antiepileptic Drug Interactions Drugs that may induce metabolism of other drugs: carbamazepine, phenytoin, phenobarbital, primidone Drugs that inhibit metabolism of other drugs: valproate, felbamate Drugs that are highly protein bound: valproate, phenytoin, tiagabine carbamazepine, oxcarbazepine topiramate is moderately protein bound Other drugs may alter metabolism or protein binding of antiepileptic drugs (especially antibiotics, chemotherapeutic agents and antidepressants)

Adverse Effects of AEDs: Common:

Adverse Effects of AEDs: Common Often dose-related: Dizziness Fatigue Ataxia Diplopia Irritability levetiracetam Word-finding difficulty topiramate Weight loss/anorexia topiramate, zonisamide, felbamate Weight gain valproate (also associated with polycystic ovarian syndrome in young women) carbamazepine, gabapentin, pregabalin

Adverse Effects of AEDs: Serious:

Adverse Effects of AEDs: Serious Typically idiosyncratic: Renal stones topiramate, zonisamide Hyponatremia carbamazepine, oxcarbazepine Aplastic anemia felbamate, zonisamide, valproate, carbamazepine Agranulocytosis carabamazepine Hepatic Failure valproate, felbamate, lamotrigine, phenobarbital Anhydrosis , heat stroke topiramate Acute closed-angle glaucoma topiramate

Slide 45:

THANK YOU….

BIBLIOGRAPHY:

BIBLIOGRAPHY Joseph Dipiro T, et al. Pharmacotherapy, A pathophysiologic approach: seventh edition;2008: 927-948. Nicholas Boon A, Nicki Colledge R, Brian walker R. Davidson’s principles and practice of medicine: 20 th edition; 2006:1169-1176. Laurence Brunton L, John Lazo S, Keith Parker L. Goodman and Gilman’s, The pharmacological basis of therapeutics: eleventh edition; 2006: 501-524. Dennis Kasper L, Eugene Braunwald , Anthony Fanci S. Harrison’s, principles of internal medicine: 16 th edition; 2005: 2357-2372 Thomas Lemke L, David Williams A, Victoria Roche F, William Zito S. Foye’s , principles of medicinal chemistry: 6 th edition; 2008: 521-544.