L13-14 Epilepsy Flashcards
seizure vs epilepsy
- transient occurrence of signs and/or sx due to abnormal excessive or synchronous neuronal activity in the brain
vs - brain disorder, characterised by an enduring predisposition to generate epleptic seizures
key concept for the pathophysiolgy of seizure
hyperexcitability and hypersynchronisation
hyperexcitability
enhanced predispostion of a neuron to depolarise
- voltage or ligand-gated K+, Na+, Ca2+, Cl- ion channels: abnormalities in intra- and extracellular substances eg. Na+, K+, O2, glucose, etc.
- excessive excitatory neurotransmitters eg. glutamine, acetylcholine, histamine, cytokines, etc.
- insufficient inhibitory neurotransmitters eg GABA, dopamine
hypersynchronisation
(network disorder)
intrinsic organisation of local circuits: hippocampus, the neocortex and the thalamus
- contribute to synchronisation and promote generation of epileptiform activity
- reorganisation: new, sprouting fibers that intrude self-perpetuating excitatory circuits
simple partial seizures
focal onset seizures (without dyscognitive features) seizures
difference between absence seizures and complex partial seizures (4)
- absence seizures are never preceded by auras
- ’’ lasts seconds, rather than minutes
- ’’ begin frequently and end abruptly
- produce characteristic EEG pattern: 3Hz waves (specific for absence seizures)
epileptiform discharges on EEG ______ diagnosis
if diagnosis of seizures or epilepsy is considered
- a normal eeg does not excl possibility of epilepsy
investigations
scalp EEG, MRI with gadolinium, biochemical/toxicology
risk factors for seizure recurrence
- epileptiform abnormalities on EEG
- prior brain insult eg stroke, brain trauma
- structural abnormality in the brain imaging
- nocturnal seizure
do you start ASM after 1st seizure?
unlikely, unless there is a presence of risk factors
after a single unprovoked seizure, recurrence is
approx 30%
- 80-90% of which had a second seizure within 2 years
with 2 unprovoked nonfebrile seizures, the risk of recurrence is
approx 70%
- initiate tx
non pharmaco tx
- keto diet
- vagus nerve stimulation
- responsive neurostimulator system
- surgery
general principles of pharmaco tx
monotherapy preferred
- likely lower incidence of AE
- absence of DDI
- reduced risk of birth defects
- lower cost
- easier to correlate response and AE
- better adherance
drug resistant epilepsy
failure of adequate trials of 2 tolerated, appropriately chosen and used ASM drug schedule to achieve sustained seizure freedom
- whether as monotherapy or in combi
seizure triggers (9)
- hyperventilation
- photostimulation
- physical and emotional stress
- sleep deprivation
- electrolytes imbalance: hypoglycemia, hypo/hyperNa, hypoCa, hypoMg
- sensory stimuli
- infection
- hormonal changes: time of menses, puberty, or pregnancy
- drugs (decr seizure threshold) eg. theophylline, alc, high-dose phenothiazines, antidepressants esp bupropion, tramadol, carbapenems
appropriate seizure first aid: for generalised grand mal
- ease the person to the floor
- turn the person gently onto one side, help the person breathe
- clear the area around the person of anything hard or sharp, prevent injury
- put something soft and flat, like a folded jacket, under his or her head
- remove eyeglasses
- loosen ties or anything around the neck that may make it hard to breathe
- time the seizure, call 911 if the seizure lasts longer than 5 mins
migraine
consider topiramate, valproate
dep/anx
use levetiracetam with caution
women w child-bearing potential
avoid valproate, consider levetiracetam/lamotrigine
NICE 1st line agents for new onset, focal onset epilepsy
carbamazepine, levetiracetam, valproate, lamotrigine, oxcarbazepine
NICE 1st line agents for new onset, generalised tonic-clonic epilepsy
lamotrigine, valproate, carbamazepine, oxc?
tx option: refractory, focal onset epilepsy
clobazam, lacosamide, pregabalin, perampanel
tx option: refractory, generalised tonic clonic epilepsy
clobazam, levetiracetam
topiramate
possible cognitive adverse effect, possible teratogenicity
What ASMs are preferentially avoided for use in pregnancy?
valproate, topiramate, phenytoin
phenytoin
possible teratogenicity
1st ASM is predominantly cleared via the _____ route?
hepatic
Does 1st gen or 2nd gen ASM have more ddi?
1st gen, significant protein binding
which of the 2nd gen ASMs experience DDI?
LEV (few, 55%), TPM (dose dependent, 15%), CLB (80-90%)
Are 2nd gen ASMs usually cleared renally/hepatically?
renally
Which of the 2nd gen ASMs are eliminated hepatically?
LTG (100%)
for patients who require >200mg/day of TPM
potentially significant DDI
what kind of interaction is easily overlooked, since it is not captured by most CPOE platforms or pharmacy system?
deinduction interactions
- when enzyme-inducing ASM is discontinued, activity of affected enzymes will return to baseline
- drugs that are metabolised by the affected enzymes may required dose adjustment
what is usually the main limiting factor in the tx of epilepsy?
adverse effects
Chronic adverse effect of gingival hyperplasia is usually observed in patients receiving what therapy?
phenytoin
Chronic adverse effect of hirsutism is usually observed in patients receiving what therapy?
phenytoin
Chronic adverse effect of alopecia is usually observed in patients receiving what therapy?
valproate
Chronic adverse effect of encephalopathy is usually observed in patients receiving what therapy?
phenytoin at high doses, or phenobarbitone
Chronic adverse effect of peripheral neuropathy is usually observed in patients receiving what therapy?
phenytoin at high doses, also a/w cbz and pb
How to reverse chronic adverse effect peripheral neuropathy?
May or may not improve with decrease in ASM doses
How can peripheral neuropathy be reversed?
May respond to folate supplementation
Is chronic adverse effect increased weight gain reversible?
Gradually reverses spontaneously with discontinuation of treatment
Which ASM is indicated as a possible pharmacological agent for weight loss?
Topiramate
Chronic adverse effect of increased weight gain is usually observed in patients receiving what therapy?
val
Chronic adverse effect of anorexia and weight loss is usually observed in patients receiving what therapy?
topiramate and felbamate
Is chronic adverse effect increased weight loss and anorexia reversible?
reversible with discontinuation of drug
Chronic adverse effect of osteomalaccia is usually observed in patients receiving what therapy?
phenytoin, phenobarbitone, cbz, maybe val
Chronic adverse effect of blood dyscrasis is usually observed in patients receiving what therapy?
isolated cases associated with nearly all ASMs
Chronic adverse effect of megaloblastic anaemia is usually observed in patients receiving what therapy?
phenytoin (predominantly), also a/w cbz and phenobarbitone
Chronic adverse effect of neonatal congenital defects is usually observed in patients receiving what therapy?
- a/w phenytoin, pb, tpm (malformation risks)
- val (cognition)
What is the main hypothesis for the mechanism by which ASM induce skin reactions?
Unclear: ASM with an aromatic ring can form an arene-oxide intermediate
- become immunogenic through interactions with proteins or cellular macromolecules
indications for ASM TDM
- To establish an individual’s ‘therapeutic range’
- To assess lack of efficacy
- To assess potential toxicity
- To assess loss of efficacy (breakthrough seizures)
ref range of phenytoin
10-20mg/L
ref range of val
50-100mg/L
ref range of cbz
4-12mg/L
ref range of pb
15-40mg/L
epilepsy is considred to be resolved for
indiv who had an age-dependent epilepsy syndrome
- but now part the applicable age
who have remained seizure-free for the last 10 years
- w no seizure meds for the last 5 years
status epilepticus
condition resulting either from
- failure of the mech responsible for seizure termination
- from the initiation of mech which lead to abnormally prolonged seizures
tonic clonic SE: operational dimension 1
5 min
- when a seizure is likely to be prolonged leading to continuous seizure activity
tonic clonic SE: operational dimension 2
30 mins
- when a seizure may cause LT consequences (incl neuronal injury, neuronal death, alteration of neuronal networks and functional deficits)
5-20 mins: initial therapy phase
benzodiazepine, first line:
- im midazolam
- iv lorazepam
- iv diazepam
others: iv pb, rectal diazepam, intranasal midazolam (not avail in sg)
20-40 min: sec therapy phase
single dose:
- iv fosphenytoin
- iv valproic acid
- iv levetiracetam
otherwise, iv pb
40-60min: third therapy phase
no clear evidence to guide therapy in this phase
- repeat second line therapy or anesthetic doses of: thiopental, midazolam, pb, profolol (all w cont EEG monitoring)
