seizure/epilepsy Flashcards
what is a seizure
transient occurrence of S&s +/- symptoms due to abnormal excessive/synchronous neuronal activity in brain
what is epilepsy
disease of brain defined by any of
- at least 2 unprovoked seizures happening > 24h apart
- one unprovoked seizure and probability of further seizures similar to general recurrence risk after 2 unprovoked seizures occurring over the next 10 years
- diagnosis of epilepsy syndrome
what is acute symptomatic seizure
- immediately recognisable stimulus
- occur in presence/closely timely association with acute brain insult
what is remote symptomatic seizure
- absence of potentially responsible clinical condition
- occur 1 wk after disorder that incrase risk of developing epilepsy
what is unprovoked seizure
no direct stimulus or acute seizure that last longer than normal
what are non-epileptic events
- abnormal paroxysmal psychic, sensory, motor manifestations which resemble epileptic seizures but not abnormal epileptiform discharges
- types
1) psychogenic non-epileptic seizures (PNES)
- partial alteration in level of consciousness with partial preservation of awareness
- caused by stressful psychological experiences or emotional trauma
2) physiological non-epileptic event
- symptoms of paroxysmal systemic disorder
- examples: convulsive syncope, hypoglycemia, migraine order, intoxication, panic attack
risk for recurrent seizure
1) lower risk: single seizure normal EEG, normal brain scan
2) higher risk: previous seizure, epileptiform EEG, abnormal brain scan
pathophysiology of seizure
- synchronised paroxysmal discharges occuring in large population of neurons within cortex starting from defined regions (foci)
- unbalanced excitatory & inhibitory receptor/ion channel function which favour depolarisation = dysregulated discharge
- split into 2 components
1) hyperexcitability
2) hyper synchronisation
pathophysiology of seizure - hyperexcitability
- enhanced predisposition of neurons to depolarise
- causes
1) voltage gated K+, Na+, Ca2+, Cl- channels
2) abnormalities in intra/extracellular substances
3) excess excitatory neurotransmitters (e.g. glutamate bind to NMDA receptor -> open Ca2+ ion channel)
4) insufficient inhibitory neurotransmitters (GABA bind to GABA receptor = open Cl- ion channel)
pathophysiology of seizure - hyper synchronisation
hippocampal sclerosis
- intrinsic reorganisation of local circuits (hippocampus, neocortex, thalamus)
- contribute to synchronisation and promote generation of epileptiform activity
aetiology of acute seizure
1) metabolic
- low Na, Ca, Mg, FBG
2) toxic substances/drugs
- alcohol, drugs, benzodiazepine withdrawal
3) structural
- stroke, traumatic brain injury
4) seizure triggers
- hyperventilation, photo stimulation, physical/emotional stress, sleep deprivation, sensory stimuli, infection, hormonal change, drugs
classifications of seizures based on mode of onset
1) focal onset: 1 hemisphere
2) generalised onset: both hemisphere
3) secondary generalised: start with 1 hemisphere then spread to other
tldr phases of seizure onset
1) prodromal
2) early ictal (aura)
3) ictal
4) postictal
prodromal for seizure onset
- before seizure
- subjective feeling/sensation
- symptoms: confusion, anxiety, irritability, headache, tremor, mood disturbances
early ictal (Aura) for seizure onset
- not everyone w epilepsy experience aura
- common symptoms
** bitter acidic taste, dejavu, dizzy, hallucination, psych problems, numbness, ringing/buzzing sound, vision problems
ictal for seizure onset
symptoms
- stiffening, chewing, confusion, difficulty breathing, drooling, twitching in one direction, inability to move/speak, pupil dilation
postictal for seizure onset
- recovery period after seizure
- duration depends on seizure type, severity and regions of brain affected
- common symptoms: arm/leg weakness, body sore, confusion, malaise, memory loss, HTN, headache, nausea, thirst
clinical presentation of focal onset
1) motor symptoms
- clonic movement (twitch/jerk) of arm, shoulder, face, leg
- speech arrest
2) sensory
- numbness/tingling
- visual disturbances (flashing lights)
- rising epigastric sensation
3) autonomic symptoms
- sweating, salivating, pallor, BP, HR
4) psychic (somatosensory) symptoms
- flashback
- visual, auditory, gustatory, olfactory hallucination
- affective symptoms: fear, depression, anger, irritability
types of generalised seizures
1) tonic clonic (GTC, grand mal)
2) clonic
3) tonic
4) myoclonic
5) absence (pepti mal)
6) atonic
7) partial seizure
tonic clonic (GTC, grand mal) clinical presentation
1) tonic phase
- stiffening of limbs
- decrease/lack of breathing
- cyanosis of nails/lips/face that returns during clonic phase
2) clonic phase
- last 1 min
- occur after brain hyperpolarised and insensitive to stimuli
- possible symptoms
** incontinence
** biting of tongue/inside mouth
** noisy/laboured breathing
3) after
- headache, lethargic, confused, sleepy
clonic clinical presentation
- clonic jerking (asymmetrical, irregular)
- most frequent in young
tonic clinical presentation
- sudden loss of consciousness & rigid posture of entire body (10 - 20s)
- characteristic of Lennox-Gaustat syndrome
myoclonic clinical presentation
rapid, brief contraction of bodily muscles (bilateral but can be unilateral)
absence (petit mal) clinical presentation
- abrupt lapse in awareness, triggered by physical exertion, less erratic
- mistaken as persistent staring
- more common in children
- only few seconds, no sfter effect
- not preceded by aura
- characteristic EEG pattern: 3Hz spike waves
partial seizure clinical presentation
- simple: consciousness not impaired
- complex: consciousness impaired
components of seizure diagnosis
1) history taking
2) neurologic examination
3) concomitant medical conditions
history taking for seizure diagnosis
- onset, duration, symptoms
neurologic examination for seizure diagnosis
1) scalp EEG
- epileptic discharges: generalised all regions affected, partial only some regions affected
- limitations
** normal EEG X exclude possibility of epilepsy
** normal person can have abnormal EEG
** Expensive, labour intensive
2) MRI w gadolinium
- indication: adult w first seizure, pt w focal neurologic deficit, suggestion of focal onset
3) biochemical/toxicology
- rule out electrolyte abnormality
- CK raised after GTC
tldr nonpharmaco for seizure treatment
1) ketogenic diet
2) vagus nerve stimulator (VNS)
3) responsive neurostimulator system (RNS)
4) epilepsy surgery
5) seizure diary
ketogenic diet for seizure treatment
1) indication
- X tolerate or X respond to ASM treatment
2) low carbohydrates, high fat diet
- induce ketosis, prevent seizures
3) limitations
- challenging to adhere long term
vagus nerve stimulator for seizure trearment
- indication: intractable focal seizure, X respond well to ASM
- stimulator send electrical stimulus
responsive neurostimulator system (RNS) for seizure treatment
- indication: pt w focal seizures who have
1) undergone testing that localised ≤ 2 epileptogenic foci -> 2 foci causing seizure
2) not responsive to ≥ 2 ASM
3) frequent and disabling symptoms - continuously monitor electrical activity in brain -> deliver brief pulses of electrical stimulation when it detects epileptiform activity that can lead to a seizure
epilepsy surgery
indication
- last line for focal seizure
- early therapy for epileptic syndrome
seizure diary for seizure treatment
- seizure frequency and type
- how long each seizure last
- changes in AED
- AED SE
- seizure triggers
first aid for GTC
- ease person to floor
- turn person gently to side for them to breath
- clear area of hards/sharps
- put something soft under head
- remove eyewear
- loosen anything around neck
- time seizure, call 995 if ≥ 5 mins
aetiology for epilepsy
1) Structural
- hippocampus sclerosis, brain tumour, vascular malformation, glial scarring (stroke, traumatic brain injury)
2) genetic/presumed genetic
- Dravet syndrome with SCN1A mutations
3) neurodegenerative
- Alzheimer
4) metabolic
5) infectious
types of epileptic syndromes
1) electroclinical syndromes
- infancy: West syndrome, Dravet syndrome
- childhood: febrile syndrome plus, Lennox-gaustat syndrome, childhood absence epilepsy
- adult: JME, PME, epilepsy w GTC seizures alone
2) distinctive constellation
- mesial temporal lobe epilepsy w hippocampal sclerosis
3) epilepsies attributed to and organised by structural metabolic causes
- malformation of cortical development tuberous sclerosis tumour trauma stroke
5) epilepsies of unknown causes
treatment algorithm
1) diagnosis -> begin treatment with 1st ASD based on seizure type, comorbidities, SE
2) evaluate if seizure is controlled
2.1) if seizure is controlled check if can control SE
- if can control SE then assess if optimal QoL
** optimal QoL: continue treatment, re-evaluate again in 2 yrs, if controlled then can consider removing ASD, if not controlled then (2)
** not optimal QoL: explore QoL issue, if cmi then (2) - if cannot control SE then decrease ASD dose and (2)
2.2) if seizure not controlled then check if can tolerate SE
2.2.a) can: increase ASD dose then repeat (2)
2.2.b) cannot: decrease 1st ASD dose then add 2nd ASD -> re-evaluate again if seizure free
- if controlled: then remove 1st ASD and repeat (2)
- if not controlled then check if can tolerate SE
** can tolerate SE: increase dose of 2nd ASD, check for interactions and compliance then (2.2b)
** cannot tolerate SE: remove least effective ASD, add another ASD and evaluate if seizure free, if seizure free then continue or (2.2.b), if not seizure free then check diagnosis/change treatment options
phenytoin general
- high interindividual variability
- narrow therapeutic range so need TDM
phenytoin indication
focal seizure
phenytoin MOA
inhibit voltage gated Na+ channel
phenytoin PK - absorption
completely absorbed (F=1) but slow
- reduce F by
1) high dose > 400mg/dose
2) interaction with enteral feeds (nasogastric tube for delivery)
- 2 hrs apart between enteral feed and phenytoin
phenytoin PK - distribution
- Vd = 0.7 L/kg
- highly albumin bound
** increase phenytoin concentration when
1) low albumin
2) displace by drugs that are highly protein bound
phenytoin PK - metabolism
CYP2C, CYP3A, UGT
phenytoin PK - elimination
1) zero order kinetics
- concentration increment not proportionate to dose increment
2) capacity limited clearance
- CI inversely proportionate to concentration
phenytoin serum concentration measurement
corrected phenytoin levels
- corrected = observed/[albumin coefficient (albumin level/10) + 0.1]
- albumin coefficient
** CrCl ≥ 10: x = 0.275
** CrCl > 10: x = 0.2
phenytoin AE
1) dose/plasma concentration related
- CNS: fatigue, headache, blurred vision, diplopia, ataxia
- nystagmus
2) idiopathic/hypersensitivity related
- SJS, TEN, rash
- first few months of therapy
3) chronic/systemic
- gingival hyperplasia, hirsutism
- peripheral neuropathy: folate supplement
- osteomalacia
** enzyme induced -> increased Vit D clearance -> secondary hyperparathryoidism -> increased bone turnover -> reduced bone density - hepatotox, macrocytic anemia
4) others
- N/V, dyskinesia, teratogenic, suicidal
phenytoin DDI
potent inducer of CYP2C, CYP3A, UGT
- pharmacological classes affected: antidepressant, antipsychotic, immunosuppression, antiretroviral, chemo
- potential physiological effect
1) women: reproductive hormones, sexual function, OC effectivness
2) men: sexual function, fertility
3) bone health
4) vascular risk
phenytoin pharmacogenomic testing
HLA-B*1502 for hypersensitivity testing
valproate indication
1st line for everything
valproate MOA
1) reduce neuronal firing
- inhibit voltage-gated Na+ channel
- inhibit T-type Ca2+ channel
2) inhibit GABA transaminase -> increase inhibitory GABA concentrationva
valproate PK
1) Absorption
- F almost 1
2) Distribution
- Vd = 0.15 L/kg
- highly albumin bound
** saturable protein binding within therapeutic range (higher concentration = reduced protein binding)
3) metabolism
- CYP2C9, UGT
valproate AE
1) dose/plasma related
- ataxia, tremor, hepatotoxicity, thrombocytopenia, pancreatitis, hyperammonemia
2) chronic/systemic
- weight gain, alopecia, major malformation risk, affect neonatal cognition
valproate DDI
potent inhibitor of CYP2C9, UGT
carbamazepine MOA
inhibit voltage gated Na+ channel
carbamazepine indication
focal, GTC
carbamazpine PK
1) absorption
- bioavailability about 0.8
2) distribution
- Vd = 1.4 Lkg
- highly albumin bound (low albumin = increase carbamazepine concentration)
3) metabolism, elimination
- CYP3A4
- autoinduction
** induce own metabolism
** increase clearance, shorter t1/2
** max autoinduction 2 - 3 wks after dose titration
** X start w desired dose at first, need titrate to initial dose
carbamazepine AE
1) dose/plasma related
- CNS: lethargy, headache, blurred vision, diplopia, unsteady, ataxia, incoordination
- nystagmus
- N/V
2) idiopathic/hypersensitivity related
- rash, SJS, TEN
3) chronic (systemic)
- hyponatremia, leukopenia, aplastic anemia, hepatotox, osteopenia/osteoporosis/osteomalacia, neuropathy
carbamazepine DDI
potent inducer of CYP (1A2, 2C, 3A4), UGT
- pharmacological classes to look out for: antidepressant, antipsychotic, immunosuppression, antiretroviral, chemotherapy
- potential physiological effect
** women: reproductive hormone, sexual function, OC ineffective
** men: sexual function, fertility
** bone health
** vascular risk
pharmacogenomic testing for carbamazepine
test HLA-B*1502 for hypersensitivity reaction
types of benzodiazepine
clonazepam, diazepam, lorazepam
benzodiazepine indication
status epilepticus
benzodiazepine MOA
potentiate GABA binding to GABA receptor -> potentiate influx of Cl- ions into neuron -> hyperpolarisation -> more difficulty to reach threshold membrane potential
benzodiazepine PK
long acting
benzodiazepine AE
addictive
- cause acute toxicity/overdose
- respiratory depression +/- alcohol
- drowsiness, confusion, anemia
- impaired muscle coordination
- tolerance & dependence
management of dose/plasma related AE
1) monotherapy vs combination
- monotherapy: higher concentration = more prominent
- combination therapy: lower plasma concentration = more prominent (additive effect during initiation)
2) management
- low dose -> titrate slowly
- avoid large dose change
- avoid combination if possible
- adjust administration schedule
** largest dose at bedtime
** smaller, more frequent dose
** sustained release
** reduce total daily dose if clinically safe
ASM choice for paediatric/neonatal
phenobarbital
- IV loading dose +/- IV or oral maintenance
- MOA: potentiate GABA mediated Cl- current at site distinct from benzodiazepine
- disadvantages: severe withdrawal and tolerance, dose dependent CNS depression
which drug choices for pregnant
1) lamotrigine
2) levetiracetam
3) NO VALPROATE
lamotrigine for pregnant - indication
absent, GTC
lamotrigine for pregnant - MOA
1) block voltage gated Na+ channel and high voltage gated Ca2+ channel
2) inhibit release of glutamate
3) impede sustained repetitive neuronal depolarisation
lamotrigine for pregnant - PK
- linear
- t1/2
** shorter in children
** significantly reduced when + carbamazepine/phenytoin
** significantly increased w valproate
lamotrigine for pregnant - AE
- CNS: dizzy, headache, incoordination, tremor, somnolence
- asthenia, N/V
- rash, SJS, TEN, DRESS
lamotrigine for pregnant - risk management for hypersensitivity reaction
avoid
1) high starting dose
2) rapid dose escalation
3) use with valproate
levetiracetam for pregnant - indication
myoclonic
levetiracetam for pregnant - MOA
bind to SV2A vesicles that contain glutamate in presynaptic neuron
levetiracetam for pregnant - PK
linear, low intra/inter individual variability
levetiracetam for pregnant - AE
- CNS: somnolence, dizzy, coordination difficulties (4 wks after initiation, irritability, aggression)
- asthenia
lactation and ASM
safe
indication for TDM
1) establish individual therapeutic range
2) assess lack of efficacy, potential toxicity, loss of efficacy
what to monitor for TDM
1) seizure diary
2) SE, DDI
3) check and manage seizure trigger
4) be careful when swimming/driving
treatment discontinuation for seizure
1) min 2 yrs wo seizure
- longer if higher risk of recurrence or low frequency of seizure before remission
2) discuss risk benefit
what is status epilepticus
- failure of mechanism responsible for seizure termination or from initiation of mechanisms that lead to abnormally prolonged seizure
** prolonged seizure: GTC ≥ 5 mins
** long term consequences when GTC ≥ 30 mins
treatment for status epilepticus
1) stabilisation phase: 0 - 5 mins
- stabilise pt (ABC)
- give O2, ECG monitoring
- replenish glucose if glucose < 60 mg/dL (IV dextrose)
- supportive care
2) initial therapy phase: 5 - 20 mins
- if still seizure then IV lorazepam or diazepam
3) second therapy phase: 20 - 40 mins
- if still seizure then IV phenytoin, valproic acid, levetiracetam
4) third therapy phase: 40 - 60 mins
- if still seizure then repeat second therapy
