seizure disorder Flashcards
siezure
paroxysmal (sudden) disorder of the CNS characterized by abnormal cerebral neuronal discharges with or without loss of consciousness
some synchrony to them
result of disordered, synchronous, excessivem and rhythmic firing of a population of brain neurons
convulsion
specific seizure type where the attack is manifested by involuntary muscle contractions
epilepsy
repeated seizures due to damage, irritation and/or chemical imbalance in the brain which leads to a sudden, excessive, synchronous electrical discharge
seizure originates in the ___
gray matter of ant cortical or subcortical area of the brain (thalamus)
focal or partial seizures
60% activity starts in 1 area of the brain only part of the brain is affected usually due to a lesion can evolve to generalized seizure simple VS complex simple- no loss of consciousness or altered awareness, sensory disturbances complex - altered awareness
generalized seizures
40%
no focal point
both hemispheres involved
typically involve a loss of consciousness
referred to as “primary” or “idiopathic”
most presumed to be genetic
absence, tonic clonic, myoclonic, clonic, tonic, atonic
simple partial seizure pathophysiology
25% of partial seizures
limited convulsions (jerking limited to 1 body part)
limited sensory disturbance
NO loss of consciousness
subjective experiences (auras): abdominal discomfort, sense of fear, altered taste, unpleasant smell, result of abnormal electrical activity
complex partial seizure pathophysiology
75% of partial seizures
clouding of consciousness, altered awareness
staring
automatisms (repetitive motor behaviors): clicking, chewing, lip smacking with no memory
disturbances of visceral, emotional and autonomic systems
followed by confusion, fatigue and throbbing headache (postictal state)
aura is common*
postictal state
after seizure (complex), pt will not recover a normal level of consciousness immediately
may last seconds to hours depending on: area of brain affected, length of seizure, use of AEDs, age
Sxs: confusion, disorientation, anterograde amnesia
absence seizures pathophysigology
generalized seizure
typical or atypical
typical (petit-mal): *brief loss of consciousness, staring or eye flickering, begin abruptly, repetitive, *no convulsions, aura, or postictal period
(no consciousness, no convulsions)
atypical: slower onset, more difficult to control pharmacologically than typical
non-absence generalized seizures
myoclonic: shock-like contraction of the muscles, isolated jerking of head, trunk, body
tonic: children, rigidit as a result of increased tone in extensor muscles
clonic: babies and young children, rapid, repetitive motor activity
atonic: loss of muscle tone, fall of standing (drop attacks)
tonic-clonic: tonic immediately followed by clonic phase, “grand-mal”, characteristic of epilepsy
status epilepticus: single prolonged seizure
tonic-clonic seizure pathophysiology
generalized, “grand mal”
most dramatic of all epileptic seizures
first phase: tonic; begins abruptly often with diaphragm contraction, rigidity in all extremities (15-30 seconds), tonus is interrupted by a tremor that corresponds to relaxation
second phase: clonic; begins as relaxation becomes more prolonged, involves violent jerking (hyperpolarization and depolarization back and forth) that lasts 1-2 minutes
jerking followed by stuperous state
tongue or cheek may be bitten
urinary incontinence is common
primary have no evidence of localized onset
secondary start as partial seizure, could be an aura
status epilepticus pathophysiology
repetitive seizure activity in which the patient does not regain consciousness between seizures OR a continuous, single seizure episode lasting over 30 minutes
aka: greater than 5 minutes of continuous seizure activity OR recurrent seizure activity without return to baseline
therapeutic goal is to bring seizures under control within 60 minutes to minimize neurologic and CV complications, including: abnormal glucose utilization, compromised CNS blood flow (O2), lactic acid accumulation, CV collapse (arrhythmia), long term impact on cognitive function and worsening of seizure disorder
excitatory NTs
AMPA, NMDA, Ca
inhibitory NTs
GABA, K
epilepsy statistics
1-2% of population, 1/5 will experience some seizure activity in their lifetime, 50-75% of pts w epilepsy are successfully treated with therapeutic agents
**drug therapy can be gradually withdrawn in pts who have been clinically-free of seizures for 2-5 years
triggers of SE
underlying conditions: prenatal injury, cerebrovascular Dx, brain tumors, head trauma, infection, hemorrhage, anoxia
general perturbations: metabolic disturbances (hyperventiliation, blood gas, pH, hypoglycemia), sleep deprivation, stress, alcohol withdrawl, *AED withdrawl (sudden discontinuation), repetitive light stimulation
drugs that aggravate or inc risk of seizure
alcohol, theophylline, CNS stimulants, bupropion, OCs, withdrawl from depressants, clozapine
4 MOAs of anticonvulsant drugs
- inhibition Na influx, prolong inactivation of Na channels
- inhibition of Ca influx (critical for absence seizures)
- stimulation of GABA-mediated neuronal inhibition
- inhibition of excitatory transmitters (glutamate)
phenytoin
***Strong P450 and UGT inducer; teratogen – pregnancy category D, therapeutic serum conc 10 – 20 mcg/mL (calculate free phenytoin with albumin); boxed warning – cardiovascular events; decreased bone mineral density, SJS/TEN, nystagmus, ataxia, double vision, hepatotoxicy, hirsutism, gingival hyperplasia, alteration of Vitamin D metabolism; osteoporosis; status epilepticus – fosphenytoin dosed in phenytoin equivalents preferred to reduce risk of arrhythmias, hypotension, purple glove syndrome
carbamazepine
**Partial/generalized seizures, P450 inducer (including auto‐inducing own metabolism), hyponatremia, aplastic anemia, SJS/TEN (HLA‐B1502 testing in patients of Asian descent), DRESS syndrome (HLA‐ A*3101 testing – Northern European descent (not required, suggested), therapeutic range *4 – 12 mcg/ml, electrolytes, CBC w/platelets, decreased efficacy of OCs, teratogen – category D (some generics available)
drugs that inhibit Na presynaptic Na channels
phenytoin, carbamazepine, lacosamide, lamotrigine, valproate
barbituates
used to treat partial seizures and generalized tonic-clonic
phenobarbital: drug of choice in infants up to 2 months of age (sedative)
MOA: binds to an allosteric regulatory site on the GABAa receptor, increases duration* of Cl- channel-opening events (and thus enhances GABA inhibitory signaling)
DI: induces liver cytochrome P450 enzymes
toxicity: sedation, physical dependence
benzodiazepines
used to treat partial seizures and generalized tonic-clonic
diazepam: especially useful for tonic-clonic status epilepticus; often administered as a rectal gel for acute control of seizure activity
MOA: binds to an allosteric regulatory site on the GABAa receptor, increases frequency* of Cl- channel-opening events (and thus enhances GABA inhibitory signaling
toxicity: sedation, physical dependence (tolreance), not for chronic treatment
clonazepam: useful for acute Tx of epilepsy and absence seizures*
drugs that inhibit post-synaptic GABAa receptors
phenobarbital, benzodiazepines
gabapentin MOA
increases GABA release
NMDA and AMPA receptors
used to treat partial seizures and generalized tonic-clonic
NMDA: glutamate binding triggers an influx of Na and *Ca and and efflux of K
AMPA: glutatamte binding triggers an influx of Na and and efflux of K
succinimides
used to treat absence seizures
MOA: blocks T-type Ca channels in thalamic neurons, T=type Ca channels are thought to be involved in generating the rhythmic cortical discharge of an absence attack
toxicity: GI distress, sedation
drugs that inhibit Ca channels in the presynaptic neuron
ethosuximide, lamotrigine, levetiracetam, valproate
levetiracetam MOA
MOA: binds the synaptic vesicular protein SV2A and thus interferes with synaptic vesicle release and neurotransmission, also appears to interfere with Ca entry through Ca channels and with intraneuronal calcium singaling
drugs that inhibit NMDA receptors
felbamate
drugs that inhibit AMPA receptors
topiramate
drugs that inhibit GABA transporter
tiagabine
drugs that inhibit GABA transaminase
vigabatrim
always counsel on the interaction between anticonvulsants and ___
oral contraceptives
common co-morbidity to seizures
depression
most common treatment of SE
IV benzodiazepines i.e. lorazepam
levetiracetam valproate lacosamide phenobarbital topiramate (PO only)
successful anticonvulsant withdrawl my occur after a seizure free period of ___
2-5 years
urgent control of SE
used after emergent initial for rapid attainment therapeutic serum conc of AED
IV fosphenytoin/phenytoin, valproate, levetiracetam
cont. infusion midazolam
consider re-initiation of prior effective anti-epileptic drug (why did status occur?)
refractory SE
*identified by continuous EEG, not serum conc
use EEG to guide therapy
bolus intermittent treatment - doses of AED given every few hours based on individualized dose
IV dosing - valproate, levetiracetam, phenytoin/fosphenytoin, lacosamide
cont. infusion - usually given if history of refractory SE or breakthrough seizures when using blous intermittent
IV dosing - midazolam, propofol, pentobarbital
phenytoin/fosphenytoin loading dose
phenytoin (hypotension limits infusion rate): 20 mg/kg IV, up to 50 mg/minute IV infusion
*fosphenytoin: 20 mg PE/kg IV, up to 150 mg PE/minute IV infusion
oral phenytoin dosing considerations
use if calculating a new oral dose based on obtained serum conc after loading doses and seizure control
**must obtain phenytoin serum conc and serum albumin in the same blood draw
adjusted conc = observed/((0.25 x albumin) + 0.1)
therapeutic range: 10-20 mcg/ml
valproate loading dose
IV: 15-30 mg/kg IV to PO conversion is 1mg:1mg loading calc: Vd x (desired conc) x kg Vd = 0.2 usual desired conc = 80 mcg/mL
lamotrigine in seizures
**Broad spectrum anticonvulsant – 1st line agent, SJS/TEN* – dose titration required to minimize risk; may decrease efficacy of OCs at higher doses of lamotrigine; blurred vision, drowsiness, dizziness, decreased coordination (generic available – IR dosage form)
Levetiracetam in seizures
**Broad spectrum anticonvulsant; IV dosing available for status epilepticus; 1st line agent; renal dosing for CrCl under 50 mL/min; ESRD – 500 – 1000 mg q24hr max, supplement 250 – 500 mg after dialysis; adults with partial seizures – ataxia, abnormal gait; adolescents (most commonly) – psychosis, worsening depression, unusual mood changes (generic available)
valproate in seizures
***Broad spectrum; use not recommended in pregnancy – neural tube defects/lower IQ in offspring; serum concentration range – 50 – 125 mcg/mL; status epilepticus dosing available, including loading dose; may cause *hyperammonemia, thrombocytopenia, weight gain, nausea, vomiting, sedation, alopecia, polycystic ovarian syndrome (PCOS) – monitor CBC w differential/platelets, *LFTs, serum concentration; watch dispensing – IR capsules, DR tablets, ER tablets, sprinkle capsules (some are generic)
zonisamide in seizures
***Contraindicated in sulfa allergy; partial/generalized tonic clonic; metabolic acidosis, renal calculi, ? DRESS syndrome?, drowsiness, tremor, weight loss
Clobazam in seizures
partial and generalized tonic-clonic
**C‐IV controlled substance; 3A4 substrate, weak 3A4 inducer – possible decreased efficacy of OCs; 1, 5 – benzodiazepine (theoretically less abuse potential); significant withdrawal symptoms if stopped abruptly; indicated only as adjunct for Lennox‐Gastaut syndrome
clonazepam in seizures
partial and generalized tonic-clonic
**C‐IV controlled substance; 3A4 substrate; pregnancy category D, indicated for myoclonic seizures; side effects – anterograde amnesia, paradoxical disinhibited behavior, significant withdrawal symptoms if stopped abruptly, respiratory depression, CNS depression; contraindicated in severe hepatic
dysfunction; generic available
eslicarbazepine in seizures
partial and generalized tonic-clonic
-
Active metabolite of oxcarbazepine; prodrug metabolized to active form; 2C19 inhibitor; SJS/TEN (HLA‐B1502 testing in patients of Asian descent (required) and HLA‐A*3101 testing of patients of Northern European descent (not required), hyponatremia, blood dyscrasias (not as severe as carbamazepine)
monitor: electrolytes
ezobagine in seizures
**C‐IV controlled substance; CrCl under 50 mL/min = 600 mg max daily dose; boxed warning retinal abnormalities progressing to vision loss – eye exam baseline & every 6 months; QTc prolongation; urinary retention; gray/blue skin – sign of toxicity; memory impairment, hallucinations; UGT major substrate; partial/generalized tonic clonic
felbamate in seizures
**Boxed warnings – aplastic anemia, hepatic failure – LFTs baseline and frequently thereafter (at least every 3 months), warn patients about signs of hepatic dysfunction, CBC w differential/platelets baseline and every 3 months – d/c if signs of bone marrow suppression; most commonly used for Lennox‐Gastaut syndrome (generic available)
gabapentin in seizures
**Abuse potential although not a controlled substance; 100% renal clearance; CrCl 30 – 60 mL/min – max dose 1800 mg/day; not recommended CrCl under 30 mL/min; monitor renal function; sedation, peripheral edema; first‐line agent partial/generalized tonic clonic; also used for neuropathic pain (generic available)
LACOSAMIDE in seizures
C‐V controlled substance; partial/generalized tonic clonic; IV dosing available for status epilepticus; 2C19 substrate and inhibitor; caution in cardiac conduction abnormalities – prolongs PR interval – visual disturbances; dizziness, ataxia, somnolence, double vision; idiosyncratic – hepatic impairment, 1st degree heart block
oxcarbazepine in siezures
**3A4 substrate/inducer; 2C19 inhibitor; SJS/TEN (HLA‐B1502 testing in patients of Asian descent (required)), DRESS syndrome (HLA‐A*3101 testing in patients of Northern European descent – not required), hyponatremia (more common than with carbamazepine), blood dyscrasias (less common than with carbamazepine, NOT aplastic anemia); CBC w/differential/platelets, electrolytes (generic)
Perampanel in seizures
***C‐III controlled substance; 3A4 major substrate, dosing adjustments if given with 3A4 inducers; boxed warning for serious/life‐threatening neuropsychiatric events; use with caution in patients with psychosis; gait disturbance, somnolence
Phenobarbital in seizures
***C‐IV controlled substance; not commonly used in oral dosing in adults for seizure maintenance, may see in children; status epilepticus dosing for refractory status; pregnancy category D; 2C9 substrate; P450 and UGT strong inducer; LONG half‐life; somnolence, cognitive impairment; impaired calcium absorption; can be fatal in overdose (generic available)
pregabalin in seizures
**C‐V controlled substance; partial/generalized tonic clonic; 100% renal elimination – dose adjustments in CrCl under 60 mL/min; angioedema, PR interval prolongation; dizziness, sedation, peripheral edema; monitor renal function; more commonly used for neuropathic pain and generalized anxiety disorder
primidone in seizures
***Metabolized to phenobarbital; Pregnancy category D; strong P450 and UGT inducer; more commonly used to treat essential tremor; monitor LFTs and CBC with differential/platelets (generic)
rufinamide in seizures
***Lennox‐Gastaut or refractory seizures; contraindicated in familial short QT syndrome; DRESS; SJS/TEN; somnolence, fatigue, ataxia, nausea
tiagabine in seizures
***3A4 substrate – dose adjustments required for use with strong 3A4 inducers or inhibitors; may cause cognitive impairment; somnolence, tremor; use with caution off‐label for patient without seizure disorder (ie, as a mood stabilizer for bipolar disorder) and with hepatic dysfunction – may trigger seizures
topiramate in seizures
“dopamax”
***3A4 substrate/inducer – may decrease efficacy of OCs, pregnancy category D, status epilepticus dosing – but is only PO dosing; warnings/precautions – nephrolithiasis, CNS depression, metabolic acidosis, oligohydrosis/hyperthermia; secondary angle‐closure gluacome; visual field defects; *cognitive impairment,, hyperchloremic non‐anion gap metabolic acidosis; monitor urinalysis, basic metabolic profile (for bicarbonate) every 6 months; dose titrate slowly (generic)
vigabatrin in seizures
***35% renally cleared, otherwise UGT metabolism; renal dosing for CrCl under 80 mL/min; contraindicated in patients with other risk factors for irreversible vision loss (boxed warning), warnings for peripheral neuropathy, edema, anemia, neurotoxicity; side effects – depression, insomnia, weight gain, permanent loss of peripheral vision
ethosuximide in seizures
**Indicated only for absence seizures; avoid in renal/hepatic dysfunction; 3A4 substrate; CBC
w/differential/platelets, basic metabolic profile – leukopenia, eosinophilia, psychiatric/sleep
disturbances, aggression; systemic lupus erythematosus, SJS/TEN (generic available)
partial onset* seizures first line treatments
carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, valproate, lacosemide
tonic-clonic* seizures first line treatments
carbamazepine, lamotrigine, oxcarbazepine, valproate
absence* seizures first line treatments
ethosuximide, lamotrigine, valproate
myoclonic* seizures first line treatments
levetiracetam, topiramate, valproate
lennox-gastaut* syndrome seizures first line treatments
valproate, lamotrigine
1A2, 2C9, 2C19 inducers
carbamazepine, phenobarbital, phenytoin, primidone
3A4 inducers*
CHILD SUPPORT carbamazepine clobazam eslicarbamazepine felbamate lamotrigine oxcarbazepine phenobarbital phenytoin primidone rufinamide topiramate first line agents that *DO NOT interact: levetiracetam, valproate, ethosuximide others that do not interact: Zonisamide, Clonazepam, Ezobagine, Gabapentin, Lacosamide, Perampenel, Pregabalin, Tiagabine, Vigabatrin
contraceptives and AEDs
can use progestin only contraceptives - depo provera
higher dose estrogen contraceptives
SJS/TEN and pharmacogenomics
associated with carbamazepine, oxcarbazepine, eslicarbazepine
**pts of asain descent are more likely if they carry the HLA-B1502 allele
recommend to test for it before initiating treatment
therapy w these drugs is *CI in any patient who tests positive
DRESS syndrome
drug reaction with eosinophilia and systemic symptoms or drug induced hypersensitivity syndrome
potentially life-threatening
dermatologic rxn
systemic multi-organ involvement
**associated with carbamazepine, lamotrigine, phenobarbital, phenytoin, valproate, zonisamide
HLA-A*3101 (usually asian or northern european)
anticonvulsants and pregnancy
serum conc may change due to changes in Vd
category D - carbamazepine, clonazepam, fosphenytoin, phenobarbital, phenytoin, primidone, topiramate
**valproate is D or X - neural tube defects and decreased IQ (D for seizures)
CV AE with AEDs
QTc prolongationg: ezogabine QTc shortening: rufinamide PR interval changes: lacosamide, pregabalin (peripheral edema, caution in HF) heart block: lacosamide arrythmia: pheytoin/fosphenytoin
natural seizure remedies
ketogenic diet
3:1 or 4:1 fats:carbs/proteins
non-drug seizure interventions
vagus nerve stimulation: coil around vagus nerve, helps reduce depression
deep brain stimulation
responsive neurostimulation
surgery - separate hemispheres
lorazepam
**Not commonly used as an oral dose for maintenance control of seizures (abuse potential); common 1st line agent for status epilepticus; significant withdrawal symptoms if taken orally for maintenance treatment and abruptly stopped; CAN be used in hepatic dysfunction
risk factors for recurrence
under 2 years seizure free *Onset of seizure after age 12 2-6 years before good seizure control in treatment *Partial seizures (most common) *Abnormal EEG throughout treatment
lamotrigine dosing*
UGT substrate with risk of SJS, with other drugs effecting UGT, must be dosed differently none: 25 mg QD x 14 50 mg QD x 14 100 mg QD x 7 200 mg QD concomitant inducer (carbamazepine, phenytoin): 50 mg QD x 14 100 mg QD x 14 200 mg QD x 7 400 mg QD concomitant inhibitor (valproate): 25 mg QOD x 14 25 mg QD x 14 50 mg QD x 7 100 mg QD
anticonvulsant withdrawal syndromes
Associated with abrupt discontinuation of anticonvulsant drug therapy
May cause recurrence of seizures, so doses of anticonvulsants should always be tapered for discontinuation
Worst offenders: clobazam, clonazepam, ezogabine, perampanel, Phenobarbital, pregabalin, gabapentin
Tapers can be over 6 months, if seizures recur, put back on the last dose of the taper regimen
depression in epilepsy
Patients with epilepsy have a high-risk of co-morbid depression
Antidepressants also have P450 isoenzyme metabolism, requires careful evaluation of anticonvulsant therapy and use of appropriate antidepressants
**Use of bupropion should be avoided in patients with uncontrolled seizure disorders, as it can increase the risk of seizures and seizure frequency, May be can be tried if seizures are controlled and it’s the best therapy, but should be monitored carefully
cardio vascular adverse events
QTc prolongation: ezobagine QTc shortening: rufinamide PR interval changes: lacosamide, pregabalin Heart block: lacosamide Arrhythmia: phenytoin, fosphenytoin
electrolyte abnormalities/metabolic acidosis/mineral metabolism
SIADH (hyponatremia): carbamazepine, eslicarbazepine, oxcarbazepine
Metabolic acidosis, renal calculi: zonisamide
**Altered Vit D metabolism and decreased calcium concentrations leading to osteoporosis with long-term use: phenytoin
Decreased serum bicarbonate leading to metabolic acidosis, nephrolithiasis: topiramate
Psychiatric Side Effects of Anticonvulsants
Levetiracetam: behavior abnormalities, including psychosis, suicidal thoughts/behaviors, unusual mood changes, worsening of depression
Perampanel: boxed warning for dose-related serious and/or life-threatening neuropsychiatric events
Valproate: acute mental status changes
Tiagabine: risk of seizures if used off-label
Topiramate: cognitive dysfunction if dose is increased too rapidly
Visual Abnormalities
Phenytoin: associated with nystagmus
Ezobagine: retinal abnormalities that may lead to visual loss
Topiramate: labeling for vision loss, monitor closely
**Vigabatrin: contraindicated in patients who have other risk of factors for irreversible vision loss; vision assessments should be performed prior to initiation of therapy and every 3-6 months
drug related information**
Ezobagine: warning of urinary retention, grey-blue/brown skin discoloration (sign of toxicity), QTc prolongation
Phenytoin: risk of osteoporosis
Topiramate: Adverse effect of cognitive dysfunction
Vigabatrin: contraindicated in patients with other risk factors for irreversible vision loss
