Seizures (Midterm II) Flashcards
seizures
- associated with abnormal episodic high frequency discharge of a group of neurons (the focus) and can be spontaneous or caused by damage (such as high blood sugar)
- begin in one area but spread
- while the cause of initial triggering events isn’t understood, the site of primary discharge and extent of spread determine symptoms (ex involvement of motor cortex and brain stem lead to convulsions and loss of consciousness respectively)
- approx 66% are drug responsive, the remaining are either fully or partially resistant
epilepsy
- umbrella term encompassing a number of disorders characterized by unprovoked recurring seizures with different origins, causes, and symptoms
- emphasis on unprovoked, ie they aren’t bc of low blood sugar, injury, etc
what happens to neuronal activity during a seizure?
- note than in an intact brain, activity in one part is often mirrored in the other part; this is not necessarily true of seizure brains
- seizures of display abnormal, often synchronized depolarization over several brain regions
- generalized seizures typically involve the whole cortex
- clonic seizures involved rapid relaxation and contraction of muscles
- tonic seizures involve loss of consciousness and muscle rigidity
generalized tonic/clonic seizure
- obvious physical effects via muscle contraction followed by relaxation; severe, can last minutes and result in loss of consciousness
1. preseizure phase: brain activity is fairly normal
2. tonic phase: abnormal discharges in rapid succession, typically leading to a loss of consciousness along with muscle rigidity; clenching may be tight enough to cause structural damage, tongue biting, etc
3. clonic phase: more rhythmic depolarization as the muscles cycle through rapid contracting and decontraction
4. aftereffects: the person is unconscious, and now looks to be in a…coma-like state? - called generalized bc there’s abnormal discharge spread thr/out the brain
generalized absence seizure
- can be very short, sometimes lasting only seconds, but affects consciousness
- see a different sort of abnormal but very rhythmic firing paralleled in all parts of the brain
- typically involves brief dissociation events and vary in intensity (can look like daydreaming to the ppl around them, might manifest in slightly strange verbalization or action)
partial seizure
- confined to specific regions with minimal spread (might even be localized to one hemi or even 1-2 lobes)
- although it may be altered, consciousness is generally retained, and the episode can last minutes
LGICs relevant for seizure
- ligand-gated ion channels play a role in modulating neuronal depolarization by selectively allowing certain ions to cross the membrane, modifying charge
- AMPA and NMDA (Glu) and GABA-A receptors contribute to these processes
- seizure disorders likely related to some imbalance in this system (either too much excitation Glu-induced cation influx or not enough inhibitory GABA induced anion influx)
what can be altered to decrease neuronal excitability?
- increase inhibitory influences by increasing the effects of GABA
- inhibit action potentials from spreading and reaching ohter neurons by blocking voltage-gated sodium influx
- decrease the spread of neuronal discharge by blocking low-voltage activated ca channels
- decrease excitatory influences by decreasing Glu LGIC receptor activity (nip in the bud by preventing depolarization)
* a common side effect of most of these drugs is sedation, because even when you aren’t actively seizing, it will still decrease neuronal activation)
enhancement of GABA action for seizure treatment
- in the nerve ending, gaba in synthesized from Glu by GAD (glutamic acid decarboxylase); soon after release, GABA transporters remove it from the cleft for repackaging or metabolism by GABA-T (transaminase) in the presyn terminal and astrocytes
- we can boost gaba signaling by blocking gabatransaminase or by inhibiting gaba transport
Vigabatrin
- drug with good efficacy for treating partial seizures
- an irreversible inhibitor of GABA-transaminase; effects are long lasting because the body will need to recycle and synthesize a new protein to recover function
- may also partially inhibit the gaba transporter
- can cause tunnel vision and blindness (these side effects are idiosyncratic, meaning we don’t know why they occur and therefore can’t predict them, which limits utlilty)
tiagabine
inhibits GAT (the gaba transporter) from removing synaptic gaba after a depolarization, allowing it to accumulate and enhancing inhibitory effects
-usually an add-on therapy (in addition to 1st line treatment) for partial seizures
-sometimes used off label to treat fibromyalgia (a constant pain that seems to involve gaba neurotransmission), anxiety/panic disorder (as boosting gaba signaling can partially ameliorate symptoms)
BUT hard to find drugs that bind to only one transporter
pharmacological inhibition of action potentials
- voltage gated sodium channels (VGSC) are closed in resting state, and open rapidly when the protein senses change in voltage across the membrane, allowing Na to rush in; the inactivation gate will then migrate to plug the channel, inactivating it briefly to prevent inappropriate retrograde signaling
- a blocker drug will migrate slowly into the channel after activation and essentially lock the protein into the closed, inactive conformation, preventing ion passage
use-dependent block
- term used to describe drugs that preferentially bind to channels that have been opened, likely bc the drug only has access due to the binding site if the channel is in the open state and as frequency of firing increases, the drug has greater access and produces a greater block (preferentially blocking excitation of cells that fire repetitively)
- they lock the channels in an inactive state and at high abnormal rates, there isn’t enough time between firing events for the drug to leave the channel, protecting against seizures without impairing normal functioning (doesn’t affect initial depolarization, but will prevent subsequent inappropriate depol)
carbamazepine
-a widely used antiepileptic drug and use-dependent VGSC blocker; effective in treating most forms of epilepsy but actually seems to make absence seizures worse (hence importance or diagnosing the kind before treating)
-chemically derived from tricyclic antidepressants (no effects there though)
side effects:
-severe mental and motor disturbances
-powerful induction of hepatic microsomal enzymes (speeding up its own metabolism if given repeatedly, dropping half life from 30 to 15 hrs)
-hyponatremia (dilution of Na in blood from severe water retention, which can lead to brain swelling and death)
-severe bone marrow (and therefore immune system) depression in ppl of Asian descent (which can lead to opportunistic infection, cancer)
Ca channel blockers
- Ethosuximide and all other effective drugs for treatment of absence seizures block T-type low-voltage-activated Ca channels
- in healthy brains, these Ca channels play central role in depolarizing neurons and creating action potentials, establishing rhythmic patterns that happen mostly in sleep
- these patterns are seen in wakefulness during absence seizures (hence loss of consc), displaying a specific pattern of abnormal thalamocortical discharge (a 3 hz pattern that can look like stage 3 sleep)
- note that these drugs are NOT use-dependent, but DO dampen abnormal firing
