Seizures Flashcards
What is a seizure?
a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain
What is epilepsy?
disorder of the brain characterized by an enduring predisposition to generate epileptic seizures
How does the epilepsy diagnosis differ now compared to 2015?
2015: diagnosis required pt to have a min of 2 seizures 24h apart
now: diagnosis expanded to include pts with only 1 unprovoked seizure but at significant risk of sz recurrence
-EEG with epileptiform abnormalities, brain injury, structural brain abnormalities, nocturnal seizures
What is an unprovoked seizure?
one which occurs in the absence of an acute brain injury (e.g. stroke, head trauma, infection, metabolic/toxic insult)
What is the 2nd most common neurological disorder in the world?
seizures/epilepsy
What is the etiology of seizures?
largely unknown, variable causes
-metabolic
-immune
-infection
-genetics
-structural lesions in the brain (acquired or genetic)
anything that disturbs the normal functioning of the cerebral cortex can cause seizures, and if this abnormality is enduring, it can result in epilepsy
Describe the pathophysiology of seizures.
synchronous hyperexcitability of szs may be due to:
-increased excitatory synaptic neurotransmission
-decreased inhibitory synaptic neurotransmission
-alteration of voltage-gated ion channels
-alteration of intra or extracellular ion []’s
-hypersynchrony (recruitment of neighboring neurons into abnormal firing mode)
many ASMs target +1 of these possible causes
What are the impacts of seizures on patients lives?
stigma
fear of seizures
injuries
hospitalizations
mortality
MDD and anxiety
lost productivity
What is a critical aspect with regards to selecting the most appropriate ASM?
accurate seizure classification
not all ASMs treat all seizure types and some drugs can lead to seizure worsening when used for the incorrect seizure type
How are seizures differentiated according to onset?
focal:
-originate within networks limited to one hemisphere
generalized:
-originate at some point within, and rapidly engaging, bilaterally distributed networks
unknown:
-reflects the difficulty to classify unwitnessed seizures and those that occur while the patient is asleep
What can focal seizures progress to?
bilateral tonic clonic
What is status epilepticus?
medical emergency
any recurrent or continuous seizure activity lasting > 30 mins in which the patient does not regain baseline mental status
-or a cluster of seizures that does not return to baseline for > 30 mins
any seizure that does not stop within 5 min should be treated as impending status epilepticus
What is the main class of drugs used to treat status epilepticus?
BZDs: IV midazolam or lorazepam
What is the strategy that is often done to reduce the risk of progression to status epilepticus?
pts are often given “on demand” BZDs to use “prn” at the onset of seizures to decrease risk of progression to SE
-adults commonly: lorazepam 1-2 mg SL
-pediatrics: intranasal or buccal midazolam
-infants < 3 mo: rectal diazepam
What are post ictal symptoms?
an array of symptoms that can occur after a seizure
-confusion
-tired
-memory problems
-cognitive problems
-depression and anxiety
-headaches
Describe proper seizure first aid.
time it, longer than 5 mins = call an ambulance
-most seizures are over in 2-3 mins
explain what is going on, ask to be given space
cushion head and neck with something soft
do NOT restrain
do NOT put anything in their mouth
roll the person to their side to prevent choking
clear the area of dangers
speak gently, be kind during and after the seizure
What are some drugs that can lower the seizure threshold?
analgesics:
-opioids (especially meperidine, tramadol)
anticancer drugs
psychiatric drugs:
-SSRI, SNRI, TCA, bupropion, buspirone, lithium, APs (<clozapine), MAOI, atomoxetine
immunosuppressants:
-tacrolimus, cyclosporine, azathioprine, mycophenolate
stimulants:
-MPH, amphetamines
sympathomimetics and decongestants:
-PSE, PE, anorexiants
What are the many different aspects involved in the diagnosis of epilepsy?
based on combo of clinical history and physical/neuro exam
-not always possible to make a definitive diagnosis
clear, detailed, and accurate history is important
-reliable source of info is crucial (pt may forget!!)
diagnostics: EEG, CT +/- MRI, labwork
medication review
-identify high risk drugs
What is the role of EEG in the diagnosis of epilepsy?
both interictal and ictal recordings are informative
used to determine if focal vs generalized onset and estimating risk of recurrence
only a snapshot in time: may require multiple EEGs or admission
What is the role of brain imaging in the diagnosis of epilepsy?
used to identify structural brain abnormalities
NOT to observe seizure activity
Why does the diagnosis of epilepsy have to be approached with care?
misdiagnosis has life-altering implications
-driving restrictions
-social functioning
-AE from meds
-effects of long-term tx exposure
-employability
What are the goals of therapy for epilepsy?
complete seizure control (within min if SE, then ongoing)
-achievable in 60-70% of patients with epilepsy
decrease seizure frequency, severity, type (ongoing)
-in the 30-40% of patients that do not achieve control
improve QoL (ongoing)
minimize ADEs
reduce morbidity and mortality (ongoing)
Describe a general approach to treatment of seizures/epilepsy.
epilepsy diagnosis –>epilepsy classification–>care plan focused on:
-goals of therapy
-risk of seizure recurrence
-type of seizure/epilepsy
-prognosis
-available ASMs
-ADRs
What are the two main options for treatment of epilepsy?
pharmacotherapy or surgery
-epilepsy generally well controlled with drugs or surgery
-pharmacotherapy is pivotal to treatment
-surgery is an option for refractory cases (not all eligible)
What is the role of pharmacotherapy in acute seizures due to metabolic/toxic/infectious causes?
ASMs used in the short term but these are generally not continued once the patients medical problem has been resolved
When do we consider long-term treatment for seizures?
once diagnosis of epilepsy is made
-recall risk of recurrence is ~50% if pt has 1 unprovoked seizure and 60-90% if patient meets epilepsy diagnosis
-thus as 1/2 of pts who have 1 unprovoked seizure will not experience another seizure, long-term tx not started until pt meets epilepsy diagnosis
What are the general principles for initiating ASM therapy?
start with monotherapy
titrate slowly
-start at 1/4 to 1/3 of initial dose and increase q1-2wks
-minimizes risk of dose-dependent AEs
What is an example of an exception where we would not slowly titrate ASM therapy?
status epilepticus or high risk of harm from seizures –> loading doses
What are the potential approaches to take when there has been an inadequate response to initial ASM therapy?
inquire about medication adherence
if at a moderate dose with few AE –> titrate up to max dose
if continuing to experience seizures at maximum tolerable dose, consider:
-initiate a different 1st line ASM monotherapy (start new, taper old)
-initiate combination therapy by adding a 2nd ASM
What is the best approach to take when there has been an inadequate response to initial ASM therapy?
no single correct approach
When do we move towards polytherapy for inadequate responses to initial ASM therapy?
usually reserved for patients that have failed monotherapy with 2-3 drugs
-typically select an ASM with a different or complimentary MOA
What are the advantages of ASM monotherapy?
fewer idiosyncratic reactions
increases probability of adherence
more cost effective
What are the advantages of ASM polytherapy?
may have fewer side effects with lower doses of 2 concomitant ASMs
unclear if increases efficacy
True or false: all patients require lifelong ASM therapy
false
What is the risk vs benefit of discontinuing ASM therapy?
benefit:
-decreases polypharmacy, may decrease AE, improve cognition
risk:
-recurrent seizures and long-term seizure control may be lost
What are the factors favouring successful discontinuation of ASMs?
- seizure free (2yrs for children, 2-5yrs for adults)
- normal neurologic exam
- normalized EEG with treatment
- history of single type of focal seizure or generalized tonic-clonic seizures
How should ASMs be discontinued in non-emergency situations?
slow and gradual taper is best to prevent relapses and status epilepticus
-if on > 1 ASM, each one should be withdrawn separately
-no optimal rate identified, at least 6 weeks seems safe
What are the different non-pharm treatments for epilepsy?
ketogenic diet
surgery
vagus nerve stimulation
Describe the ketogenic diet as an approach to epilepsy.
high fat, low carb, adequate protein diet mimics state of starvation
-required strict compliance
-poorly tolerated by patients
may reduce seizure frequency
consider if have not responded to appropriate ASM therapy
Describe surgery as a treatment approach to epilepsy.
an option for some patients with refractory partial onset epilepsy resistant to multiple ASMs
the majority of patients achieve seizure-freedom
Describe vagus nerve stimulation as an approach to epilepsy.
surgical procedure to implant an electrical pulse generator in the chest and attach electrodes to the vagus nerve in the neck
pulse generator stimulates the vagus nerve on a regularly scheduled basis
may reduce seizure frequency
option in refractory focal onset or generalized seizures
What are some general non-pharm measures to take for epilepsy in all patients?
adequate sleep/nutrition
reduce alcohol intake
reduce stress/anxiety
avoid triggers
What are the many different MOAs of ASMs?
- modulation of voltage-gated ion channels (Na, K, Ca)
- increased inhibitory effect of GABA
- modulation of synaptic release
- inhibition of synaptic excitation
- glutamate receptor activity
- AMPA receptor activity
ASMs target 1 or more
What is a big contributor to treatment failure of ASMs?
ADEs
-due to non-adherence because of AEs
What can be said about the most common ADEs in relation to dose of ASMs?
most common ADEs are dose-dependent and reversible
Describe the acute dose-related toxicities of ASMs.
common (1-10%) or very common (>10%)
dose-dependent, predictable, reversible
CNS:
-sedation, dizziness, diplopia, blurred vision, ataxia, difficulty concentrating
GI:
-nausea, vomiting
Describe the idiosyncratic reactions of ASMs.
usually not concentration-dependent
uncommon (0.1-1%) to rare (<0.1%)
usually develop within first few weeks of treatment
unpredictable
often mild, but can be serious or life-threatening
Which hypersensitivity reactions are we concerned about with ASMs?
SJS and TENS
Which ASMs are the most likely to cause hypersensitivity reactions?
phenytoin
carbamazepine
lamotrigine
? lacosamide
What is a key thing to keep in mind when switching ASMs due to a hypersensitivity reaction caused by an ASM?
cross-sensitivity between agents is possible
-due to aromatic hydrocarbon ring
Which ASMs show cross-sensitivity amongst themselves?
carbamazepine
oxcarbazepine
esclicarbazepine
phenobarbital
primidone
phenytoin
lamotrigine
What is the risk of ASMs in women of childbearing years?
teratogenicity
What are general measures to take with ASMS in women of childbearing years?
discuss pregnancy plan prior to conception
ensure adequate folic acid supplementation
consider teratogenic effect of ASMs for all women of reproductive age
aim for seizure-freedom for 9-12 months prior to pregnancy
How can we try and prevent teratogenicity due to ASMs?
if possible avoid VA in women of childbearing years
-if used: IUD/Depo/implant
possible preferences: levetiracetam, lamotrigine
avoid polytherapy: withdraw least helpful ASM
use lowest effective dose
avoid stopping ASMs or switching meds during pregnancy
Which ASMS are strong CYP inducers?
phenytoin
carbamazepine
phenobarbital
Which ASMs are CYP inhibitors?
valproic acid
What is the significance regarding the use of ASMs with hormonal contraceptives?
many enzyme-inducing ASMS decrease efficacy of combined hormonal contraceptives
-ex: phenytoin, CBZ, primidone, phenobarbital
estrogen containing OCP reduces lamotrigine levels
Which contraceptives are preferred in combo with ASMs?
LNG IUD/copper IUD/implant
depo
COC with > 30 mcg EE taken continuously
What is the key message regarding therapeutic drug monitoring and ASMs?
treat the patient, not the number
-poor correlation between levels and clinical efficacy
When do we draw drug levels for ASMs?
- once the desired clinical response has been achieved, to establish “individual therapeutic range”
- to assist the clinician in determining the magnitude of a dose increase, particularly with ASMs showing dose-dependent PK
- when there are uncertainties in differential diagnosis of signs and symptoms suggestive of concentration-related ASM toxicity
- when seizures persist despite an apparently adequate dosage
- alteration in PK suspected (age/pregnancy/disease/DDI)
- assess changes in SS when formulation is changed
- change in clinical response
- poor compliance is suspected
What are examples of conventional ASMs?
phenytoin
benzodiazepines
carbamazepine
barbiturates
valproate
What are examples of newer ASMs?
levetiracetam
gabapentin
pregabalin
topiramate
lacosamide
lamotrigine
What are examples of narrow spectrum ASMs?
phenytoin
carbamazepine
oxcarbazepine
phenobarbital
pregabalin
gabapentin
generally effective for focal seizures, less effective for and may exacerbate idiopathic epilepsy syndromes
What are examples of broad spectrum ASMs?
levetiracetam
topiramate
lamotrigine
valproate
generally effective against all seizure types
What is the most common MOA for ASMs?
Na+ channel blockade
-blocking Na+ ion flow in neurons alters signal transduction
What are examples of meds that target Na+ channels?
phenytoin
carbamazepine
esclicarbazepine
lacosamide
lamotrigine
rufinamide
What is the place in therapy for phenytoin?
“narrow spectrum” ASM
treating status epilepticus
4th line for focal seizures
NOT used for absence or myoclonic seizures
Why is phenytoin no longer used as 1st line therapy?
number of limitations
similar efficacy to other Na+ channel blockers
no longer listed for generalized motor seizures
What are the advantages of phenytoin?
daily or BID dosing
cheap
extensive experience
defined therapeutic serum concentration range
parenteral and other dosage forms available
What are the disadvantages of phenytoin?
substrate AND broad spectrum inducer of many CYP enzymes and glucuronidation = many DDIs
dosing complicated by saturable kinetics
long-term cosmetic AEs (ex: gingival hyperplasia)
Why are we concerned about the saturable kinetics of phenytoin?
at a higher SS concentration, the same change in dose produces a much larger increase in concentration
What is the maximum amount you should increase a dose of phenytoin by?
no more than 50-100 mg due to zero-order kinetics
What are the adverse effects of phenytoin?
dose related:
-nystagmus, drowsiness, ataxia, confusion, slurred speech
non-dose related:
-gingival hyperplasia, osteomalacia, hypersensitivity, folate deficiency, acne, hirsutism
What is the place in therapy for carbamazepine?
“narrow spectrum” ASM
1st line for focal onset seizures
3rd line for GTC
NOT for absence or myoclonic seizures
Where is the role of carbamazepine trending?
becoming less favourable as new drugs enter the market
What are the advantages of carbamazepine?
CR/XR tabs bioequivalent with BID dosing vs QID dosing with IR tabs
-may improve adherence
-CR/XR: lower peaks + higher troughs = decreased dose related AEs and improved seizure control
can be used in bipolar and neuropathy
What needs to be done if switching formulations of carbamazepine?
therapeutic drug monitoring
What are the disadvantages of carbamazepine?
substrate and broad-spectrum inducer of CYP enzymes = many DDIs
risk of SJS and TENS
Which patients are at increased risk of SJS/TENS from carbamazepine?
Asian + HLA-B1502
Caucasian + HLA-A3101
Describe the autoinduction of carbamazepine.
induces its own metabolism (complicates dose adjustments)
onset within 24 hours
time to completion is 1-5 weeks
dose related (each dose increase results in further autoinduction)
results in increased clearance and decrease t1/2
What are the dose-related side effects of carbamazepine?
GI: nausea, vomiting, anorexia
CNS: lethargy, dizziness, drowsiness, HA, incoordination, ataxia, blurred vision, diploplia, sedation
What are the idiosyncratic reactions of carbamazepine?
SIADH/hyponatremia
blood dyscrasias
hepatic: increased GGT, hepatitis
decreased free T3/T4
lupus like reaction
cardiac conduction abnormalities
rash
hypersensitivity reactions (SJS)
What are the chronic side effects of carbamazepine?
osteomalacia
vitamin D deficiency
Describe appropriate monitoring parameters for carbamazepine.
sedation: ongoing
ocular exam: baseline, q1yr
ECG: baseline
renal/LFTs/elytes/platelets/CBC:
-baseline, q1-2wks till stable, q2mo x 3, then q6mo
TSH/T3/T4: baseline, q3-6mo
rash: ongoing
What are the drugs reported to increase carbamazepine levels?
macrolides:
-use alt ABX if possible, monitor CBZ lvs before + after
anticonvulsants:
-VA and lamotrigine
azoles:
-monitor CBZ lvls before + after
non-DHP CCBs:
-use alt agent if possible, monitor CBZ lvls before + after
grapefruit juice:
-dont ingest or dont alter ingestion lvl
What are the drugs reported to decrease carbamazepine levels?
phenytoin, phenobarbital, primidone
-avoid if possible
What are some drugs whos level is decreased by carbamazepine?
warfarin: monitor INR during CBZ initiation/dose adj/dc
ASMS: PHT, LTG, VA, topiramate
antifungals: caspofungin, itraconazole
DHP CCB: use alt agent, monitor for decreased effect
estrogens: use nonhormonal contraception, 50mcg EE
methadone: monitor for withdrawal
immunosuppressants: avoid CBZ
What are the indications for esclicarbazepine?
monotherapy for adult epilepsy patients with focal seizures
adjunctive tx for focal seizures (>6yo)
What are the drug interactions of esclicarbazepine?
induces 3A4 (moderate)
substrate of UGT2B4
no autoinduction
What is a con of esclicarbazepine?
$$$
What are the adverse effects of esclicarbazepine?
CNS: drowsy, dizzy, fatigue, diplopia, HA, ataxia
GI: NVD
rash, SJS/DRESS
hyponatremia
tremor
SERIOUS: prolonged PR interval
-CI if 2nd or 3rd degree AV block
Describe the pharmacology of oxcarbazepine.
structurally related to carbamazepine
prodrug that is immediately converted to licarbazepine
the S-enantiomer (eslicarbazepine) is the active form
like CBZ it binds to voltage-gated Na+ channels
induces 3A4 (weak), no autoinduction
What is the MOA of lamotrigine?
binds to voltage-gated Na+ channels
reduces release of glutamate
weak 5-Ht3 receptor inhibitory effects
What is the place in therapy for lamotrigine?
“broad spectrum” ASM
1st line for focal onset seizures
3rd line for generalized motor seizures
2nd line for absence seizures
2nd line for Lennox-Gastaut Syndrome
NOT myoclonic seizures
What are the advantages of lamotrigine?
generally well-tolerated
-pts are more alert, weight neutral
broad spectrum of seizure activity
one of the safest ASMs in pregnancy
NOT a broad spectrum enzyme inducer (fewer DDIs)
excellent option if concomitant bipolar disorder
What are the disadvantages of lamotrigine?
DDI with COC = decreased LTG ~50%
risk of SJS/TENS
very slow titration required
-not good if therapeutic lvls required quickly
DDI with other ASMs
-VA inhibits metabolism of LTG = decreased LTG dose 50%
What needs to happen if 5 days of therapy are missed during lamotrigine titration?
must restart titration
What are the adverse effects of lamotrigine?
more common:
-nausea, chest pain, peripheral edema, insomnia, drowsy, fatigue, dizzy, non serious rash
rare:
-SJS, aseptic meningitis, blood dyscrasias, aplastic anemia
What is the risk with titrating lamotrigine too quickly?
SJS
What is the therapeutic level of lamotrigine?
no established level
What are monitoring parameters for lamotrigine?
CBC
LFTs
SCr (to decrease dose, if necessary)
routine TDM not required
adherence
-if miss > 5d of treatment = restart titration
rash
What is the place in therapy of lacosamide?
“narrow spectrum” (but maybe broad spectrum) ASM
-controversial how broad it is
What are the approved indications for lacosamide?
2010: adjunctive tx of focal seizures (adults)
2017: mono tx of focal seizures (adults)
What is the MOA of lacosamide?
slow inactivation of voltage gated Na+ channels
decrease hyperexcitability of neuronal membranes
inhibits repetitive neuronal firing
What are the drug interactions of lacosamide?
few DDIs
no contraceptive interactions
antiarrhythmics: bradycardia, vtac, prolonged PR interval
What are the adverse effects of lacosamide?
CNS: dizzy, HA, ataxia, fatigue, diplopia, nystagmus
GI: NVD
tremor, DRESS
SERIOUS: dose-dependent prolongation PR interval, asymptomatic AV block
-CI: 2nd or 3rd degree AV block
What are examples of ASMs that target calcium or potassium channels?
ethosuximide
pregabalin
gabapentin
carbamazepine
oxcarbazepine
esclicarbazepine
valproic acid
What are examples of ASMs that impact GABA activity?
benzodiazepines: clobazam
barbiturates: phenobarbital, primidone
topiramate
What are the different MOAs of ASMs that impact GABA activity?
reducing GABA breakdown
increasing GABA availability
mimicking GABA action on receptors
What is the MOA of clobazam?
BZDs bind to GABA receptors to facilitate increased endogenous GABA binding
What is the place in therapy for clobazam?
“broad spectrum” ASM
used 3rd or 4th line or as adjunct for most seizure types and Lennox-Gastaut syndrome
What are the advantages of clobazam?
less likely to develop tolerance vs other BZDs
broad-spectrum activity
rapid onset
daily or BID dosing
cheap
few drug interactions
What are the disadvantages of clobazam?
tolerance is possible
potential for abuse and dependence
must be weaned off to avoid withdrawal symptoms
What are the adverse effects of clobazam?
CNS effect
-tolerance develops to some
increased traffic accidents
What are monitoring parameters for clobazam?
sedation
respiratory depression
What is the MOA of phenobarbital?
binds to GABA receptors to prolong the activity of GABA
What is the place in therapy for phenobarbital?
“narrow spectrum” ASM
4th line for focal seizures
3rd line GTC seizures
declining use due to AE and DDI
What are the advantages of phenobarbital?
once daily dosing due to long t1/2
cheap
What are the disadvantages of phenobarbital?
substrate and broad-spectrum inducer of various CYP enzymes and glucuronidation = many DDI
sedation is prominent
lethality
What are the adverse effects of phenobarbital?
CNS effects
sedation (often significant)
rash (rarely serious)
decreased vitamin D and folic acid
hepatotoxicity
What are some monitoring parameters for phenobarbital?
serum levels
LFTs
CBC
renal function
What is the MOA of topiramate?
combination of mechanisms
blocks Na+ channels, enhances GABA, antagonizes AMPA glutamate receptors, weakly inhibit CA
What is the place in therapy for topiramate?
“broad spectrum” ASM
4th line for focal seizures
3rd line for GTC seizures
2nd line for myoclonic seizures
3rd line for absence seizures
What are the advantages of topiramate?
may assist with migraine prophylaxis, weight loss, and alcohol dependence
What are the disadvantages of topiramate?
generally not well tolerated due to CNS AE
nausea, diarrhea
renal stones (increase fluid intake)
weight loss (4kg, dose dependent)
rare: metabolic acidosis, increased LFTs, reduced sweating
What is the MOA of perampanel?
AMPA receptor antagonist
What are the approved indications for perampanel?
2014: adjunctive tx of PGTC seizures in adults
2018: expansion to focal seizures & PGTC
What are the drug interactions of perampanel?
substrate of 1A2 (minor), 2B6 (minor), and 3A4 (major)
What is a major con of perampanel?
expensive
What is the spectrum of activity of perampanel?
“broad spectrum” ASM
What are the adverse effects of perampanel?
CNS:
-dizzy, drowsy, fatigue, HA, ataxia, irritable, abnormal gait
GI:
-vomiting, nausea
hyponatremia
weight gain
MSK:
-arthralgia, myalgia, back pain, MSK pain
SERIOUS:
-psychiatric and behavioral rxns (homicidal, aggressive)
What are some ASM’s with “other MOAs”?
valproic acid
levetiracetam
brivaracetam
others: topiramate, felbamate
What is the MOA of valproic acid?
increases GABA activity through several mechanisms
modulates Na, Ca, and K channels
What is the difference between valproic acid and divalproex?
DVP dissociates to VA in the GI tract
-not interchangeable but doses are equivalent
-check lvls if changing between VA and DVP
DVP has better GI tolerance than VA
What is the place in therapy for valproic acid?
“broad spectrum” ASM
option for practically all seizure types
2nd line for focal seizures
3rd line for GTC seizures
3rd line for myoclonic seizures
1st line for absence seizures
What are the advantages of valproic acid?
“broad spectrum” ASM and useful for other psychiatric and neurologic conditions
-useful if > 1 indication for VA (bipolar/migraine/pain + seizure)
low risk of rash
-does not cross react with aromatic hydrocarbons
does NOT reduce the effectiveness of COC
should be dosed BID or TID for seizures
What are the disadvantages of valproic acid?
inhibits CYP enzymes
-increases LTG lvls by 30-50%
well-known teratogen
-least desirable option in women of childbearing potential
-AVOID if possible
can contribute to metabolic syndrome
What are the dose related side effects of valproic acid?
GI: NV, anorexia (reported to be lower with DVP_
CNS: tremor, sedation, ataxia
thrombocytopenia
thinning or hair loss, weight gain, amenorrhea
What are the idiosyncratic side effects of valproic acid?
increased transaminases and LDH
leukopenia
PCOS
lupus like reaction
hepatotoxicity
pancreatitis
hyperammonemia
rare: SJS (increased risk with LTG)
What are the chronic side effects of valproic acid?
weight gain (mean 8-14 kg)
menstrual disturbances, polycystic ovaries
alopecia
Describe appropriate monitoring parameters for valproic acid.
sedation: ongoing
rash: ongoing
CBC diff/elytes/LFTs: baseline, q1-2 wks till stable, then q1-2 mo x 6 mo, then q6mo
ammonia: unexplained lethargy/vomiting/confusion
VA level: 2-4d after dose change or DDI, then in 1-2 wks to ensure stable then q1-6 mo or as needed
What is the MOA of levetiracetam?
considerably different than other ASMs
full mechanism unclear
binds to synaptic vesicle protein SV2A in the presynaptic terminal to modulate neurotransmitter release
What is the place in therapy for levetiracetam?
“broad spectrum” ASM
2nd line for focal seizures
3rd line for GTC seizures
4th line adjunct for myoclonic seizures
What are the advantages of levetiracetam?
novel MOA
no significant DDI
very well tolerated
low risk of rash
allows rapid dose titrations & loading doses
dosed BID
What are the disadvantages of levetiracetam?
psychiatric/behavioral problems might limit therapy
renal dosing adjustments
What are the adverse effects of levetiracetam?
CNS (sedation is most common)
GI
behavioral/psychiatric symptoms (up to 30% of pts)
-mood swings are common
-agitation, aggression, anxiety, depression
rare: decreased WBCs, SJS/TENS
What are monitoring parameters for levetiracetam?
CBC: if clinically indicated
renal function: requires renal dose adjustments
TDM not required
What is the MOA of brivaracetam?
binds to SV2A protein
What are the approved indications for brivaracetam?
adjunctive tx for partial onset seizures in adults not controlled with conventional ASMs
What are the drug interactions of brivaracetam?
substrate of 2C19 (major)
inhibitor of 2C19 (weak)
What are the adverse effects of brivaracetam?
CNS:
-drowsy, fatigue, lethargy, ataxia, nystagmus
GI:
-NV
decreased WBC
SERIOUS:
-psychiatric disturbances, bronchospasm, angioedema
Summarize the recommendations for focal seizures.
1st line:
-CBZ, lamotrigine
2nd line:
-valproate, levetiracetam, oxacarbazepine, zonisamide
3rd line:
-NA
4th line:
-gabapentin, topiramate, phenytoin
as per AAN 2018
Summarize the recommendations for generalized motor (tonic-clonic) seizures.
1st line:
-NA
2nd line:
-NA
3rd line;
-carbamazepine, lamotrigine, topiramate, valproate, levetiracetam
4th line:
-NA
as per AAN 2018
Summarize the recommendations for generalized motor (myoclonic) seizures.
1st line:
-valproate
2nd line:
-topiramate, levetiracetam
as per NICE 2012
Summarize the recommendations for absence seizures.
1st line:
-ethosuximide, valproate
2nd line:
-lamotrigine
as per AAN 2018
Which ASMs should be avoided in myoclonic and absence seizures?
carbamazepine
phenytoin
oxcarbazepine
gabapentin
pregabalin
