Pathophysiology of Seizures PDF

Pathophysiology of Seizures JOSHUA MASTIN, MD SOUTH COLLEGE SCHOOL OF PHARMACY Introduction, Pathophysiology of Seizures As discussed in the previous unit regarding the modulation of motor coordination via the basal ganglia and - thalamus,...

Pathophysiology of Seizures JOSHUA MASTIN, MD SOUTH COLLEGE SCHOOL OF PHARMACY Introduction, Pathophysiology of Seizures As discussed in the previous unit regarding the modulation of motor coordination via the basal ganglia and - thalamus, both the CNS and PNS are highly reliant on electrochemical excitability. * The movement of electrolytes as it relates to the nerve action potential The transmission of neurotransmitters from the pre-synaptic neuron to a post-synaptic structure (neuron, muscle, gland, etc.) - The expression of receptors in the post-synaptic neuron, resulting in neurotransmitter binding The expression of regulatory/modulatory enzymes which are capable of biochemically inactivating neurotransmitters  * know the physiology of the nerve Review, Nerve Action Potential Ap ! The nerve action potential is a phenomenon by - which the entry of sodium (which leads to - depolarization) and the efflux of potassium (which leads- to repolarization) ultimately allows for the - transmission of electrochemical current down the - axon. This electrochemical current is responsible for the release of neurotransmitter through the activation - of voltage-gated calcium channels, which allow - for vesicular docking and release of - neurotransmitter.  & kNow Starred pointsa physiology of Ap ! Review, Nerve Action Potential Under normal conditions, the potential (voltage) of the vast majority of # neurons within the CNS and PNS is -70 mV (millivolts). This is known as the resting membrane potential (the voltage of the neuron at rest). ② In response to stimulation sodium ions enter the neuron (at the soma, - - or cell body). As sodium enters the cell, the cell becomes more positively charged, thus increasing the voltage (thus, depolarized). * - - IMPORTANT POINT: stimulation, on its own, does NOT lead to an - action potential! - C - If the amount of depolarization surpasses the neuron’s threshold potential (the “threshold” at which a full action potential can be fired), an action potential is successfully fired. - [ Action potentials are “all or nothing” phenomena; meaning, the amount of stimulation MUST be sufficient to surpass the threshold potential in order for the neuron to fire O - - kNor the value for RMP ! ↓ Rud - If the newsor is unable to achieve adequate depolarization , NOTHING HAPPENS ↑ -  kNow * Phases of nerve Ap ! Review, Nerve Action Potential do NOT open channels ated " unless a certain achieved ! -"Voltage-9 - Voltage is o If threshold potential is surpassed (usually around -55 mV) voltage-gated - sodium channels open. This allows for a HUGE influx of sodium into the neuron. 1 Peak where the positive electric- #efflux current has been completely fired. Once the peak is achieved, this marks the phase where the firing of the current is complete and, therefore, the neuron must return to its resting membrane potential in order flux ↑ to fire again.- # in -- - Repolarization Voltage gated sodium channels close; voltage gated Na - potassium channels OPEN. Since the VG-potassium channels are EFFLUX O & - channels, large amounts of potassium leave the neuron, thus rendering the neuron more negative! - Hyperpolarization - absolute refractory period (period in which no further AP’s - can be fired). Allows time for VG potassium channels to close and normal sodium - channels - to open; this is an-important “resetting” phase-for the neuron.  * KNOW Starred Points ! Neurophysiology of Neuronal Excitation in the CNS * When it comes to excitation within the CNS, glutamate is the primary neurotransmitter involved with excitation! - - Two Key receptors within the CNS: ** NMDA (should be review from last week) binds glutamate, Opromotes - calcium entry into the neuron; take longer to have full physiologic effect - # Magnesium blocks the NMDA channel under normal conditions = O (resting membrane potential); during depolarization, Mg is - displaced, allowing for influx of calcium - * Magnesium bound to the NMDA receptor = NEGATIVE FEEDBACK & - O O AMPA binds glutamate, promotes sodium entry into neuron; - RAPIDLY ACTING! Under normal conditions, both play critically important roles in synaptic plasticity and learning - In seizures ! 00 NMDA- - generalized tori - clonic seizures (last longer) AMPA - focal - seizures (more rapid)  * know starred points ! Regulation/Inhibition of Excitatory Activity in the CNS - * GABA, or gamma-aminobutyric acid, is the primary inhibitory neurotransmitter within the CNS. Two primary receptors: ** GABA  ion channel; A -allows for entry of chloride, which hyperpolarizes the neuron, making it more difficult for the neuron - to fire & GABA  Bdiverse functions, depending on the subtype; can be expressed on EITHER the presynaptic OR post-synaptic neuron! Both are G-protein coupled, meaning that they rely on the cAMP- PKA pathway! F Pre-synaptic GABA receptor blocks activation of voltage- gated calcium channel in the presynaptic terminal prevents vesicular docking +neurotransmitter release Can prevent EITHER glutamate (mostly) OR GABA release! -& Post-synaptic GABA receptor GPCR which mediates potassium efflux (which hyperpolarizes the cell) this ! Focus on one Biochemical Etiology of Seizures * Excessive Excitation excessive glutamatergic transmission, resulting in hyperexcitability - Increased glutamatergic release from pre-synaptic neurons - Increased expression of post-synaptic AMPA, NMDA receptors location! - ↑ common *- Decreased Inhibition downregulation of GABA neurons, resulting in decreased hyperpolarization -mos- A lobe temporal - Keep in mind - - anything that decreases hyperpolarization will INCREASE excitability and, therefore, promote seizure/epileptiform activity! Synchronization (Firing Together) of Nerves usually occurs in locations of the brain where neurons typically fire in asynchronous patterns Neurons firing together significantly increase the likelihood that other nerve networks within the brain are depolarized simultaneously, resulting in seizure-like activity -- - - Usually a synergistic effect of both excitation (increased physiologic effect of glutamate) and inhibition (decreased physiologic effect of GABA) * Metabolic/Electrolyte Abnormalities alteration in electrolyte concentration (e.g., Na, Ca, glucose) can affect concentration gradient, which affects water distribution extracellularly and intracellularly. The O most important of these is SODIUM. - [ What effect does hyponatremia have on seizure threshold? Hyponatremia (low sodium) decreased extracellular sodium, increased intracellular sodium relative to the outside - G water movement to the inside of the neuron, resulting in neuronal edema. This neuronal edema can induce changes in the neuronal membrane which make it more easy to depolarize,promoting seizure activity - Acute hyponatremia is more likely to lead to seizure activity! & Hypoxia +/- Mitochondrial Dysfunction membrane, resulting in seizure both increase the likelihood of reversion to anaerobic metabolism, which increases oxidative stress of neurons and results in a more highly depolarizable ↑ of newrond * PORTANT : ↑ oxidative stress leads to sensitivity membrace to Nat ; therefore , neurons become excitable in more response to hypoxial oxidative damage !  # KNOW general roles of lobes & notes below ! Important Neuroanatomical Locations to Consider with Seizure/Epileptiform Activity When evaluating the diffusion of seizure/epileptiform activity across the brain, there are a multitude of areas involved with the propagation of abnormal electrochemical discharge: focal localized motor abnormalities ↳ Frontal Lobe primary motor cortex, supplemental motor areas ~ , (numbness/tingling burning) - - ↳ sensory abnormalities Parietal Lobe Primary somatosensory cortex - , - ↳ Occipital Lobe Primary Visual Cortex - visual arrad visual abnormalities with depth perception W - , Temporal Lobe most common epileptiform focus! - - Deep to the temporal lobe the hippocampus is the most highly affected subcortical area involved with seizures! * - co Subcortical areas Thalamus, Amygdala (subcortical area primarily responsible for induction of fear, aggression) X Brainstem primarily responsible for the loss of consciousness that many experience in severe, generalized seizures Often, clinical symptoms can provide “clues” into which portion(s) of the brain are involved with a seizure! brain ; therefore , thats - Thalamus sends fibers to multiple locations throughout hyperexcitability results in generalized seizures instability - - If thalamic projections to brainster affected - > autonomic  Subtypes of Seizures become ! CAN generalized ↑ u #Focal Seizures - abnormal hyperexcitability begins in one location; can either remain localized or spread to other - - - areas over time, and may cause motor +/- nonmotor symptoms. Don’t always result in loss of consciousness/ - - awareness of seizure activity * - - Usually due to frontal lobe seizures which affect the frontal lobe (motor cortex), parietal lobe -- (somatosensory cortex), or hippocampus - Frontal Lobe seizures - motor deficits (mostly clonic jerking) depending on which portion of the motor cortex is affected ~ Parietal Lobe seizures sensory deficits (numbness/tingling, burning sensation) depending on which - portion of the somatosensory cortex is affected - Multiple subtypes, but all have the potential to dissipate spontaneously OR revert to generalized seizures  Subtypes of Seizures X - Generalized seizures often involve both hemispheres, without one specific focus of epileptiform activity; usually - affects subcortical areas (thalamus, neuronal projections from the thalamus/basal ganglia to cerebral lobes of the brain, brainstem) - consciousness. Often followed by - - a post-ictal state (post-seizure state where patient feels fatigued and confused) o result in loss of X - - Generalized tonic-clonic seizures initially, patients are tonic (muscles become stiff), and patient falls to the ground with complete - - loss of consciousness; after approximately 45 -60 seconds, the patient’s muscles become clonic (jerking, uncontrollable movements). -- Usually last 2-5 minutes, after which the patient has no recollection of what transpired during the seizure. Respiratory muscles are commonly affected - could result in strenuous hypoventilation, cyanosis -- - Pupils become dilated and unresponsive to light - - Excessive salivation occurs, along with jaw clonus may increase the risk of tongue biting I - - Absence Seizures Generalized, but rarely presents with significant clonus/tonic movements; rather, patients appear to be -- staring into space. No post-ictal state present. ↳ C More common in childhood of > pediatric patients out them - may grow ~ / Absence seizures > - - no post-intal state !  S Benzodiazepine (Lorazepam ① Status Epilepticus , Diatepan , or Midazolam) ② Long-acting anticonvulsant (Phenytoin - , Valproin Acid , or Levitiracetam) ③ Phenobarbital - ④ General Anesthesia * - - Status Epilepticus pathophysiologic state where continuous seizure activity is seen for longer than 5 -minutes OR there are recurrent seizures without recovery of consciousness between them. Can result in hemodynamic instability, possibly permanent neurologic damage, and death; therefore, status epilepticus is a - - - MEDICAL EMERGENCY! & I Three primary subtypes: * Generalized Convulsive Status Epilepticus oo c seizure, hyperthermia, hypertension,- - MOST COMMON; presents as persistent tonic-clonic tachycardia - - Non-Convulsive Status Epilepticus no motor manifestations, but EEG (electro-encephalogram) proven - - epileptiform activity; prominent staring into space, unresponsiveness can be seen -- Focal Status Epilepticus Predictable focal motor/sensory/visual symptoms, depending on which lobe is affected; CAN progress to generalized seizure - ! the following tiered approach * Management- airway support > + - -  * encircled items ! only discussing Pathophysiologic Etiologies of Seizures O V - The pathophysiologic causes of seizures can be recalled via the mnemonic “VITAMIN D”! Vascular (Hemorrhagic/Ischemic Stroke, Post-Stroke Syndromes) - - O I Infectious (HIV-associated illnesses, Lyme Disease, TB, Herpesviruses, bacterial abscesses) - - O T Trauma O A Autoimmune (Most commonly, SLE) O M Metabolic (Hyperbilirubinemia secondary to hepatic failure, Uremia secondary to renal failure, Hypoglycemia, Hyponatremia, Hypocalcemia, Hypomagnesemia) I Idiopathic (Epilepsy) N Neoplastic (glioblastoma multiforme, metastatic brain cancers) O D Drugs (Prescribed/Pharmacologic, Illicits)  Pathophysiologic Etiologies of Seizures - Vascular Causes of Seizure o lead to hypoxia, which promotes increased neuronal excitability, - oxidative stress - Ischemic strokes (due to thrombi/thromboembolic disease) - Hemorrhagic Strokes Trauma, Vascular malformation, or ischemic-to-hemorrhagic conversion - * - higher risk of seizures than ischemic strokes! Due to the direct leakage of pro-inflammatory cytokines onto neurons, resulting in oxidative - stress and increased neuronal excitability - Strokes in terms of * Hemorrhagic - > Ischemic ! seizure potential  * know pathogensa associations ! Pathophysiologic Etiologies of Seizures Infectious Causes * E Meningitis - Streptococcus Pneumoniae think COPD patients # Neisseria Meningitidis college-age students, military barracks, prisons -- Cryptococcal Meningitis most common cause of meningitis in HIV/AIDS patients * E Encephalitis - Borrelia Burgdorferi Lyme Disease (Ixodes Deer Tick) - ②Herpesviruses (mostly HSV-1, HSV-2) bitemporal encephalitis - - Mosquito-borne infections (Zika, West Nile) & -- Widespread Demyelination O JC Virus progressive multifocal leukoencephalopathy (PML) - Pathophysiologic Etiologies of Seizures - Trauma-Induced Seizures can either be acute or chronic - Acute due to neuronal hyperexcitability, increased glutamate release Chronic due to neurogliosis (scarring), abnormal neuronal remodeling of CNS neurons, resulting in an increased risk of synchronous firing and, therefore, decreased seizure threshold ↳ ONLY Frow Acute ! => Pathophysiologic Etiologies of Seizures increased inflammation, resulting- w Autoimmune in increased neuronal hyperexcitability, - neuronal damage, and increased NMDA + AMPA receptor activity ** SLE is the most common autoimmune disease associated with seizures 3 - Cases of molecular mimicry (e.g., post-viral syndromes which follow RSV, the common cold, influenza) can also result in seizures! - FYI ! only immune Disease -both AMPA can NMDA receptor activity & - SLE is the most common  * know the starred items ! Pathophysiologic Etiologies of Seizures Metabolic Y Hypoglycemia - due to decreased aerobic metabolism within neurons, resulting in increased reversion to anaerobic - - metabolism - + oxidative stress, resulting in increased excitability of neuronal membranes # - Classically seen in those who enter fasting/starvation stages after 5-7 days without dietary sources of glucose; rates of gluconeogenesis + beta oxidation cannot keep up with metabolic demands of the body * - Hyponatremia - most common; hyponatremia results in decreased extracellular sodium concentration outside of the neuron. This facilitates the- movement of water to the inside of the neuron (higher tonicity), resulting in neuronal swelling/ Oedema. This- alters the electrochemical gradients of sodium and potassium intracellularly and, therefore,- promotes - increased neuronal excitability and, thus, seizure activity * Classically seen in- marathon runners/athletes who consume excessive amounts of water (primary polydipsia) - ALSO seen in patients with central/nephrogenic diabetes insipidus. Why? Y KNOW THIS ! ** Lithium- > used M in I bipolar & DIS ↑ serum osmolarity , I water content > - disorder ; can cause nephroganic 3 constant thirst DI- ↑ Seizure risk !  * ONLY know starred items ! Pathophysiologic Etiologies of Seizures - -- Because some drugs can affect synaptic transmission, electrolyte homeostasis, or induce damage to the nervous system, they can lower the seizure threshold and, therefore, significantly increase - the risk of seizures. Drugs which Commonly Lower Seizure Threshold: Illicit drugs * - Amphetamines, Cocaine, MDMA (ecstasy, Molly) increase glutamate release, resulting in hyperexcitability * THIS ! * - Ketamine * paradoxical increase in excitability! NMDA-independent mechanism!- > know - - Ketamine is NORMALLY an NMDA receptor ANTAGONIST; however, ketamine ALSO potentiates (promotes) increased norepinephrine and dopamine release from subcortical areas, - especially the thalamus, resulting in hyperexcitability of cortical neurons SEIZURES! - - - IMPORTANT TO KNOW The excitation produced by ketamine is NOT due to glutamate, but rather NE + dopamine! threshold blockade ↓ Prescribed Drugs -- Not - potential ! Antidepressants Bupropion (Welbutrin) is the most common! SSRI’s can also do this, though not as commonly as Welbutrin! ---- BupropionDNRI (dopamine-norepinephrine reuptake inhibitor) also has sodium blockade effects, which increases membrane excitability - -- Flumazenil emergency intervention for benzodiazepine overdose; competitive GABA antagonist decreased inhibitory effect on neurons, which increases the risk of seizures! A Antibiotics (Penicillins, Cefepime, Isoniazid) direct neuronal damage, resulting in increased neuronal excitability * Antipsychotics Clozapine causes agranulocytosis (decreased WBC count affecting neutrophils, eosinophils, basophils, mast cells) + seizure Pathophysiologic Etiologies of Seizures * Drugs (Continued) The withdrawal of some drugs can also lower seizure threshold and increase risk of seizures! * Benzodiazepine Withdrawal - in patients who have abused benzodiazepines chronically, acute cessation of benzodiazepines results in decreased GABA transmission CNS hyper-excitability due to - - relative increase in glutamatergic activity - Short-acting benzodiazepines (Alprazolam, Lorazepam) more rapid onset of symptoms Long-acting benzodiazepines (Chlordiazepoxide, Diazepam) symptoms can last for WEEKS * - & Early symptoms Anxiety, Insomnia, Sweating, Tremors, Heart palpitations/tachycardia - Late symptoms (CAN BE LETHAL) Seizures (usually generalized tonic-clonic, hallucinations (visual more common than auditory; may have tactile hallucinations too); Paranoia which may evolve into frank o aggression; severe autonomic instability featuring hypertension, tachycardia which may evolve to cardiac arrest, hyperthermia - - Management: Manage individual symptoms with appropriate pharmacotherapy for seizures, autonomic instability; some seizures may require general anethesia ↑ - -- Alcohol Withdrawal, Delirium Tremens usually occurs 48-96 hours after the patient’s last alcoholic drink; can be life threatening! - &- Alcohol commonly potentiates GABAA transmission, promoting hyperpolarization. Over time, chronic alcohol use leads to downregulation of available GABAA receptors, resulting in desensitization. Alcohol withdrawal which is sudden CNS hyper-reactivity! - acute loss of GABA transmission through decreased receptor sensitivity significantly decreased inhibition, relative increase in glutamatergic activity, anxiety, tremors, insomnia, heart palpitations; in chronic alcoholics,- Initially 000 severe nausea and abdominal pain (due to underlying chronic pancreatitis) present ↳-20 - Delirium Tremens life-threatening manifestations of alcohol withdrawal (seizure, autonomic instability, paranoia + aggression); occurs 48-96 hours after last drink C - - SEVERE agitation (worse than BZ withdrawal), AGGRESSION, Hallucinations (visual and tactile most common), life threatening autonomic instability with high risk for cardiac arrest *- - Management: IV Lorazepam for acute agitation, long-acting benzodiazepines (Chlordiazepoxide) to help restore GABA sensitivity, physiologic response; general anesthesia in severe cases  DRUGS * KNOW THESE & mechanisms Pharmacologic Management of Seizures glutament t - > blockade Su2A T GABA, release - Voltage-Gated Sodium Channel Blockade slows depolarization rate of neurons, thereby decreasing neuronal excitability through action potential inhibition Carbamazepine, Oxcarbazepine & [ ↑ Phenytoin Lamotrigine A -o - Synaptic Vesicle Blockade (SV2A inhibitor) SV2A is a protein involved with packaging glutamate and GABA into presynaptic vesicles; blockade of SV2A can lead to a “balancing” effect between the two neurotransmitters (less packaging of glutamate, more packaging of GABA) - - & Levitiracetam (Keppra) * - Topiramate 3-headed mechanism of anti-seizure activity: - Blockade of voltage-gated sodium channel activity diministed action potential propagation ↳ - Blockade of voltage-gated calcium channel activity decreased NT transmission of glutamatergic neurons - - Blockade of AMPA receptors decreased glutamatergic activity Potentiation of GABAA receptor activity increased GABA effect - passive effect &- Valproic Acid 3-headed mechanism of anti-seizure activity: E Blockade of voltage-gated sodium channel activity diministed action potential propagation Potentiation of GABAA receptor activity increased GABA effect - Blockade of calcium channels in the thalamus decreased hyperexcitability of neurons going to areas of the cortices ↑e - Ethosuximide blockade of calcium channels in the thalamus; FIRST LINE MANAGEMENT FOR ABSENCE SEIZURES (due to effects in thalamus) ! - Y know THIS