Epilepsy Disorders of Brain Function PDF

Epilepsy SCOTT HANES, PHARMD ASSOCIATE PROFESSOR COLLEGE OF PHARMACY AT ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE Learning Objectives 1. Identify co...

Epilepsy SCOTT HANES, PHARMD ASSOCIATE PROFESSOR COLLEGE OF PHARMACY AT ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE Learning Objectives 1. Identify common etiologies and precipitating factors for seizures. 2. Differentiate seizure vs epilepsy 3. Differentiate various seizure disorders based on clinical signs and symptoms 4. Provide examples of automatisms, motor manifestations, and non-motor manifestations 5. Describe pathophysiologic processes for epilepsy and status epilepticus including key mediators and the balance between excitatory and inhibitory neuronal processes 6. Correlate new seizure nomenclature with previously used nomenclature 7. Identify established generalized convulsive status epilepticus based on definition provided 8. Identify common etiologies of pediatric and adult status epilepticus 9. Recognize common complications of status epilepticus Epilepsy Seizure defined as abnormal electrical neuronal discharge resulting in motor , sensory, autonomic, and/or psychic changes Seizure ≠ Epilepsy Epilepsy is chronic condition of recurrent seizure activity (or potential for) ○ Due to chronic, underlying condition ○ At least 2 unprovoked seizures separated by 24 hours  Epilepsy Chronic underlying condition that predisposes to epilepsy General relationships by age ○ Infants/children C  Genetic abnormalities N  Developmental (structural) abnormalities S ○ Adults  Cerebrovascular disease  Brain tumor T  Degenerative CNS diseases r abnormal neuronal wiring a (or rewiring) of neuronal circuits u m a Epilepsy Common precipitating factors ○ Metabolic derangements  Hyponatremia, hypocalcemia, hypoglycemia, hypoxia  Kidney failure, liver failure ○ Toxins/medication overdose  Alcohol/heroin/benzodiazepine withdrawal, stimulant drug abuse  B-lactam antibiotics ○ CNS infection (meningitis) ○ Fever (neonates/infants) Epilepsy Pathophysiology Normal neuronal activity coordinated sequentially via cell excitation/inhibition Seizure: ○ Simultaneous firing of cortical neurons with long duration of depolarization due to calcium followed by sodium intracellular influx ○  stimulates more action potentials Imbalance between cortical neuronal cell excitation and inhibition ○ Pathologically excitable neurons (hyperexcitable) Neuronal excitation spreads until inhibition mechanism predominate (i.e. GABA)  Epilepsy Pathophysiology Mechanisms: ○ Neuronal hyperexcitability ○ Na, Ca, K, and Cl ion channel alterations promote hyperexcitability Activation of Ca influx voltage gated channels and N-methyl-D- aspartate (NMDA) receptors  Na influx Glutamate stimulates NMDA opening of Ca and Na channels (depolarization) ○ Diminished neuronal inhibitory mechanisms  *Deficiency of gamma aminobutyric acid (GABA)  GABA ↑ Cl ion conduction and inhibits neuronal action potentials Epilepsy Clinical Presentation Epilepsy Common Terms Aura (“internal” sensory events) Prodrome Actually a simple focal seizure Ictal Seizure activity Seizure activity terminated Post-Ictal Confusion, anterograde amnesia, transient neurological deficits  Seizure Classifications Based on ○ Onset Focal Generalized ○ Awareness ○ Motor activity Intact Impaired Impaired Awareness Awareness Awareness Non- Non- Motor Motor Motor motor Focal to Generalized Epilepsy Manifestations Motor ○ Automatisms  Non-purposeful, repetitive movements: Lip smacking, chewing, picking at objects ○ Common general motor terms  Tonic – sudden hypertonia  Clonic – rhythmic jerking/twitching  Tonic-clonic (most common)  Myoclonic – limb jerking movements  Atonic – sudden hypotonia (head droop, postural collapse) and no postictal phase  Absence – nonconvulsive; impaired consciousness Consciousness/Awareness (thalamic/brainstem involvement) Epilepsy Manifestations Non-Motor ○ Other ○ Sensory  Cognitive  Paresthesias ○ Familiarity with unfamiliar ○ tingling or crawling feeling events/situations ○ Unfamiliarity with familiar  Visual events/situations ○ flashing lights ○ Sensation of falling/vertigo  Auditory (ringing/buzzing) ○ Hallucinations, Objects growing  Gustatory (altered taste) smaller/larger  Olfactory (altered smell) ○ Language problems ○ Autonomic Nervous System (via  Emotional thalamic/brainstem involvement) ○ Overwhelming feeling of fear,  Flushing flooding of ideas, detachment,  Tachycardia depersonalization  Diaphoresis (sweating)  Behavioral ○ Pausing, freezing  Salivation  BP changes  Pupillary changes  Overview Epilepsy Types Focal Seizure Intact awareness (without impaired consciousness) ○ Formerly – simple partial seizure ○ Typically mono-hemispheric ○ Peripheral manifestations are contralateral to involved hemisphere ○ Motor involvement  Can begin distally (i.e in fingers) and progress (“march”) to proximal portion of limb ○ = Jacksonian march Focal Seizure Impaired Awareness (With impaired consciousness) ○ Formerly – complex partial seizure ○ Commonly involve temporal lobe ○ Aura is common and stereotypical for patient ○ May begin as mono-hemispheric but can spread to both hemispheres  May progress to generalized (tonic-clonic) ○ May be difficult to differentiate rapid progression of focal to generalized vs. generalized ○ Automatisms are common  Repetitive, non-purposeful movements ○ Lip-smacking, chewing ○ Rubbing/patting ○ Grimacing  Generalized Seizures Most common type Typically ○ Bilateral hemispheric involvement ○ Impaired consciousness Generalized Absence Seizure Characteristics ○ Non-convulsive ○ Impaired consciousness  Blank stare , “daydreaming”  Unresponsive  Motionless ○ May have automatisms Types ○ Typical – short duration (seconds); return to normal activity immediately; no post-ictal phase ○ Atypical – associated with alterations in muscle tone and more gradual onset/offset Formally called “petit mal” Video Generalized Tonic-Clonic Most common motor presentation Formerly called “gran mal” Characteristics ○ Sudden tonic muscle contraction, extension of extremities  Respiratory muscle and larynx (vocal cords) contraction – moan (“ictal cry”) ○ Brief interruption of breathing - cyanosis  Mandibular contraction – risk of biting tongue  Secretions pool in oropharynx  ↑sympathetic tone ○ ↑HR, BP, mydriasis (pupillary dilation) ○ Immediate loss of consciousness ○ Followed by bilateral rhythmic, clonic movements ○ Typical duration 1-2 minutes ○ Post-ictal phase  May take hours to fully resolve/regain consciousness  Bladder/bowel incontinence is common  Excessive salivation common  Flaccid muscles Video  Status Epilepticus Prolonged seizure activity Main types ○ Generalized convulsive status epilepticus, GCSE (75%) ○ Non-convulsive status epilepticus (25%) Stages (For GCSE) Stage (duration) Stage Description Definition 1 (0-30 minutes) Impending GCSE Continuous seizure ≥ 5 min or 2 seizures w/o recovery between 2 (30-60 minutes) Established GCSE Continuous seizure ≥ 30 min or intermittent seizures for 30 min without recovery 3 (> 120 minutes) Refractory GCSE Continuous despite 2-3 AEDs 4 (> 24 hours) Super-refractory GCSE ≥ 24 hours despite anesthesia AEDs = antiepileptic drugs Status Epilepticus > 30 minutes of GCSE associated with poor neurologic outcomes and increased mortality ○ More prone to epilepsy; fewer remissions ○ More cognitive, memory, neurologic deficits  Hippocampus particularly susceptible ○ Mortality 16-20%  ? If due to GCSE or underlying disorder Common Etiologies Common etiologies  Congenital/genetic  Substance withdrawal  Head trauma  CNS infection  Subtherapeutic anti-epileptic drug therapy ○ Sudden withdrawal of therapy  Cerebrovascular disease ○ Stroke, tumor ○ Especially for onset > 60 years of age  Drugs (including illicit)  Head trauma  GCSE Pathophysiology Excitation>>>inhibition mechanisms ○ Unabated, self-sustaining neuronal excitation Glutamate stimulates NMDA receptors opening of Ca and Na channels (depolarization) ○ NMDA receptors recruited to synaptic membrane Prolonged seizures leads to endocytosis of GABA receptors thus limiting their inhibitory function (via chloride channel opening) ○ Not necessarily due to ↓ GABA concentrations GCSE Complications Activation of SNS ↑BP, HR to preserve cerebral perfusion pressure (CPP) ○ CPP = MAP-ICP SNS + hypoxemia ↑ risk of arrhythmias Hypoxemia  lactic acidosis Sustained muscle contractions ○ Risk of rhabdomyolysis  Acute kidney injury and hyperkalemia Seizure/Epilepsy Diagnostic Approach Clinical presentation ○ Witness history important Family history Electroencephalography (EEG) ○ Useful during active seizure activity Laboratory ○ Not directly useful  Can see elevated prolactin concentration immediately post seizure ○ Most diagnostic workup related to assessing etiology (MRI, CT, spinal (CSF) tap  Medication Therapy Inhibition of Na dependent action potentials ○ Phenytoin, carbamazepine, lamotrigine, topiramate Inhibition of Ca voltage gated channels ○ Phenytoin Attenuation of glutamate ○ Lamotrigine, topiramate Augmentation of GABA ○ Benzodiazepines (diazepam, lorazepam) ○ Barbiturates (phenobarbital) ○ Valproic acid