Week 1 - Role of ion channels in epilepsy Flashcards
definition of a seizure
abnormal excessive and synchronous electrical discharges of brain neuronal network
-paroxysmal events characterized by clinical signs and/or symptoms
aura
ictal; very short part of seizure (symptoms)
prodrome
pre-ictal; feeling that a seizure is coming, but not part of a seizure yet
ictal
seizure period or events due to seizure
interictal
period between 2 seizures (symptom-free)
post-ictal
when seizure is over (symptoms like fatigue, temporary loss of function)
ILAE classification of epileptic seizures
- partial/focal (one hemisphere, size doesn’t matter)
- simple (no loss or impaired consciousness, but motor symptoms present)
- complex (impaired consciousness)
- both may lead to secondary generalized (start from one hemisphere and spread to another - generalized (both hemispheres)
- convulsive (most common)
- non-convulsive (no clinical manifestations except unconsciousness)
types of simple partial seizures
- motor signs
- somatosensory or special sensory symptoms
- autonomic symptoms or signs
- psychic symptoms
types of complex partial seizures
- simple partial onset followed by impairment of consciousness
- with impairment of consciousness at onset
types of partial seizures evolving to secondarily generalized seizures
- simple partial seizures evolving to generalized seizures
- complex partial seizures evolving to generalized seizures
- simple partial seizures evolving to complex partial seizures evolving to generalized seizures
types of generalized seizures
- absence seizures (most common in kids via behavioral arrest for a few seconds, then resume)
- typical or atypical absence - myoclonic seizures
- clonic seizures
- tonic seizures
- tonic-clonic seizures
- atonic seizures
- unclassified epileptic seizures
what is epilepsy?
disease of brain characterized by enduring predisposition to generate epileptic seizures (acute change in electrolytes)
what is an epilepsy syndrome?
an electroclinical syndrome
-complex of clinical features, signs, and symptoms that together define a distinctive, recognizable clinical disorder
ILAE classification for epileptic syndromes
- idiopathic - presumed genetic etiology
- symptomatic - consequence of a known or suspected disorder of CNS
- cryptogenic - unknown cause
epileptic channelopathies
lowered seizure threshold based on mutation causing changes in current carried by channel
- enhanced (gain of ion channel function) or reduced (loss)
- majority are autosomal dominant or de novo mutations
- rarely autosomal recessive
variations of alpha subunit of Na+ channels
9 variations, mostly in CNS
- Nav1.1 and Nav1.3 in cell bodies
- Nav1.2 in unmyelinated axons and dendrites
- Nav1.6 in myelinated axons and dendrites
severe myoclonic epilepsy of infancy
SMEI or Dravet syndrome; due to Nav1.1 mutation
- 1st year of life: seizures associated with elevated body temp (fever or bathing)
- -progressively prolonged and cluster seizures
- -status epilepticus
- 2nd year of life: psychomotor delay, ataxia, and cognitive impairment
pathophysiology of SMEI
- loss of high-frequency APs
- loss of inhibitory function of GABA-ergic cortical interneurons (leads to seizures) and Purkinje cells (leads to ataxia)
pharmacological transcription for SMEI
try to re-establish GABA-ergic transmission
- tiagabine –> decrease reuptake of GABA
- benzodiazepine (clonazepam) –> increase in response of post-synaptic GABA receptors
generalized epilepsy with febrile seizures plus
GEFS+; milder than SMEI, usually no cognitive impairment
- first mutation was found in SCN1B (encoding B-1 subunit)
- later SCN1A mutations were found
pathophysiology of GEFS+
mutations (usually missense) –> loss of function of fast inactivation –> gain of function of Na+ channel –> persistent Na+ current
treatment of GEFS+
antiepileptic medications that can potentially bind to mutant channels and stabilize folding of PRO
ILAE definition of febrile seizures
seizure occuring in childhood after 1 month of age
- associated with febrile illness not caused by infection of CNS
- w/o previous neonatal seizures or previous unprovoked seizure
what causes febrile seizures?
mutations in Nav1.1
- reduction of peak Na+ currents
- positive shift in voltage dependence of activation
Nav1.1 mutation severity (from mild to severe to truncation)
febrile seizures –> GEFS+ –> SMEI
2 types of K+ channelopathies in epilepsy
- Kv7.2 and Kv7.3 subunit, mostly in cells with M current
- M current is close to the resting potential, and is regulated by muscarinic and other G-PRO coupled receptors
- missense mutation –> impaired flux of K+ (loss of function) –> decreased M current - pore-forming subunit encoded by KCNMA1
- mutation –> larger K+ flux (gain of function)
- generalized epilepsy and paroxysmal dyskinesia
benign familial neonatal convulsion (BFNC)
missense mutation causing decreased M current (impaired flux of K+)
- normal development and behavior
- brief generalized and partial seizures resolve by age 6 weeks
Ca++ channelopathies in epilepsy
T-type Ca++ channels
- can have rhythmic burst-firing b/c
- -activated with small depolarization
- -inactivated with maintained depolarization
- mostly in thalamic cells
- subtypes are Cav3.1/2/3 encoded by CACNA1G/H/1l
- mutations –> gain of function –> excessive synchronous rhythmic burst firing –> idiopathic generalized epilepsy
Cl0 channelopathies in epilepsy
12 trans-membrane segments
- maintain Cl- gradient required for GABAergic synapses and hyperpolarization
- mutations in CLCN2 gene can lead to idiopathic generalized epilepsy
antiepileptic drugs
AED; decrease hyperexcitability of neurons
- Na+ channel blockers/stabilizers
- -prevent return of channels to active state by prolonging inactive/refractory state
- increasing inhibitory function of neurons
- -GABA-ergic medication
epilepsy surgery
not all seizures are channelopathies, so surgery considered in localization related epilepsy that is medically refractory
- given if fail to respond to 2 medications
- if seizure onset zone can be identified, and is not in eloquent cortex
