Epilepsy- Krysiak

What is SUDEP?

Sudden Unexpected Death in Epilepsy—> sudden, unexpected death in a person with epilepsy, where underlying cause of injury/death unknown

T/F: pts. with epilepsy ALL experience seizures

T

T/F: all individuals who experience a seizure will be diagnosed with epilepsy.

F

A chronic disorder of brain function characterized by the recurrent and unpredictable occurrence of seizures is called…

epilepsy

Some seizures are provoked bc of systemic, toxic, or metabolic problems.

What’s a symptom of these problems?

fever (ex: febrile seizures)

Do febrile seizures qualify as epilepsy?

No –> they’re provoked by fever and don’t recur once the fever resolves

Most common cause of childhood onset and older-age onset epilepsy?

• childhood—> genetic issues

• older-age—> acquired structural injury (ex: stroke)

The etiologies of epilepsy can be classified into what 6 categories?

Which the most common?

1. genetics

2. structural

3. infectious- most common

4. metabolic

5. immune

6. unknown

note: many epilepsies can belong to 2+ categories

What are some triggers for epilepsy?

• hyperventilation

• photo stimulation (flashing lights)

• others: stress, sleep deprivation, hormones, drugs

What is the underlying general process of epilepsy? aka what happens to the neurons?

neuronal hyperexcitability + hyper synchronization

What can lead to hyperexcitability in the neuron?

• describe glutamate and GABA as inhibitory or excitatory

• neurotransmitter changes/imbalances

  • glutamate= excitatory

  • GABA= inhibitory

• others: alteration in ion channels, and ions in general

To reduce seizure generation, would we want to increase or decrease GABA and glutamate?

• INCREASE GABA (increase inhibition)

• DECREASE GLUTAMATE (decrease excitation)

Seizures are classified based on what 3 things?

(not that imp, more of an FYI)

1. where seizures start in the brain

2. level of awareness during seizure

3. other seizure features- nonmotor/motor symptoms

Describing WHERE a seizure starts helps to classify it.

What are the 3 categories and describe them?

1. focal seizures- one hemisphere of brain, unilateral, may or may not lose consciousness

2. generalized seizures- both hemispheres of brain, bilateral, loss of awareness/consciousness

3. unknown

Describing the motor symptoms of a seizure helps to classify it.

What are some examples of motor and non-motor symptoms?

(idk how imp)

• motor: rhythmical jerking (clonic), limp/weak muscles (atonic), twitches (myoclonus), rigid/tense muscles (tonic)

• non-motor: sensations, emotions, thinking, etc.

Most generalized seizures have __________ motor movement.

a. unilateral

b. bilateral

(idk how imp)

b.

How is epilepsy DIAGNOSED? WHAT are the conditions?

1. at least 2 unprovoked seizures occurring greater than 24 hours apart

2. 1 unprovoked seizure and a probability of further seizures—> similar to the general recurrence risk (at least 60%) after 2 unprovoked seizures over the next 10 years

   • aka if a pt. only had 1 seizure but they have high risk features

3. diagnosis of epilepsy syndrome

What are the diagnostic laboratory tests for epilepsy?

TRICK QUESTION—> THERE ARE NONE

Obtaining what serum levels may HELP (not diagnose) confirm seizures?

serum prolactin—> must be taken within 10-20 minutes of seizure

What scans can HELP (not diagnose) confirm a seizure? gold standard?

• electroencephalogram

  • video EEG gold standard

• CT

• MRI

Is pharm therapy for epilepsy curative or for symptoms?

(FYI)

for symptoms

Nonpharm therapy for epilepsy?

• keto diet

• vagus nerve stimulation (VNS)- device used as adjunctive therapy in pts. 12+ with focal seizures refractory to AEDs

• surgery

ALL anti-epileptic drugs have increased risk for what condition?

suicide

What drugs are 1st gen, 2nd gen, and 3rd gen AEDs? (Anti-epileptic drugs)

• FYI

1st gen	2nd gen	3rd gen
carbamazepine clonazepam ethosuximide phenobarbital phenytoin primidone valproate	felbamate gabapentin lamotrigine levetiracetam oxcarbazepine tiagabine topiramate zonisamide	brivaracetam cenobamate esliscarbazepine lacosamide perampanel pregabalin cannabidol

Answer the following about Carbamazepine (CBZ):

• drug interactions

• what’s unique about it’s metabolism?

• BBW

• ADRs

  • common

  • serious/rare

  • long term

• inducer of CYP3A4, 1A2, 2B6, 2C9/19

• auto-inducer (aka induces its own metabolism)

• BBW—> increased risk of SJS/TEN with HLA-B*1502, aplastic anemia, and agranulocytosis

• ADRs

  • common: CNS effects

  • serious/rare: blood dyscrasias, hepatotoxicity, DRESS rxns

  • long term: hyponatremia from SIADH, metabolic bone disease

What are the advantages/DISADVANTAGES of using Carbamazepine?

• advantages: useful in comorbid bipolar disorder and trigeminal neuralgia

• disadvantages

  • avoid in absence seizures

  • screen for HLA-B*1502 allele

  • fetal harm

Answer the following about Oxcarbazepine (CBZ):

• drug interactions

• is it metabolized like carbamazepine?

• ADRs

  • common

  • serious/rare

• D/I

  • inducer of CYP3A4, inhibits CYP2C19

  • may decrease lamotrigine levels, increase phenytoin levels

• not the same metabolism as carb—> not auto-inducer

• ADRs

  • common: CNS effects, GI, hyponatremia, rash

  • serious/rare: SJS, TEN, DRESS, blood dyscrasias

What are the advantages/disadvantages to using oxcarbazepine?

(idk how imp really)

• advantages: useful in bipolar disorder, ER useful

• disadvantages

  • hyponatremia

  • HLA-B*1502

Phenytoin uses what kind of pharmacokinetics?

michaelis-menten kinetics (saturates metabolizing enzymes at higher doses)

Having low what may cause phenytoin levels to be falsely low or normal?

low albumin (<3.5 g/dl)

What are the ADRs of phenytoin?

• BBW

• common

• serious/rare

• long term

• BBW- phenytoin IV admin rate should NOT exceed 50mg/min

• common: nystagmus (eyes moving a lot), decreased coordination, mental confusion, dizzy, insomnia, HA

• serious/rare: blood dyscrasias, rash, DRESS, angioedema, hepatotoxicity, purple glove syndrome with IV admin, extravasation

• long term: connective tissue changes and skin thickening, HIRSUTISM, GINGIVAL HYPERPLASIA, HEPATOTOXICITY

What are the advantages/disadvantages of phenytoin?

• FYI

• advantages: oral or IV available, ER formulations

• disadvantages:

  • avoid in absence seizures

  • can increase BS in DM

  • HLA-B*1502 risk factor

  • dose adjustments and monitoring

What is the prodrug of phenytoin?

Fosphenytoin

For administration of fosphenytoin it cannot exceed ________ PE/minute.

150mg

What are the ADRs of lamotrigine?

• BBW

• common

• serious/rare

• BBW: serious skin reactions including SJS/TEN, increase risk with high dosing, quick dose escalation OR when used w/ valproic acid

• common: n/v, somnolence, tremor, ataxia, diplopia, alopecia

• serious/rare: DRESS, blood dyscrasias, HLH

Ethosuxamide is the DOC for __________________.

absence seizures

ADRs of Ethosuxamide?

serious skin rxns (SJS/TEN), blood dyscrasias, DRESS, psychiatric abnormalities

ADRs of Gabapentin?

weight gain, sedation, dizzy, angioedema

List the AEDs that belong to each MOA:

MOA	drugs
sodium channel blockers
calcium channel blockers
GABA enhancers
Glutamate inhibitors/ synaptic vesicle modulators

MOA	drugs
sodium channel blockers	phenytoin carbamazepine oxcarbazepine lamotrigine
calcium channel blockers	ethosuximide gabapentin
GABA enhancers	benzos phenobarbital tiagabine vigabatrin
Glutamate inhibitors/ synaptic vesicle modulators	levetiracetam valproate

Benzos (clonazepam, clobazam) have what BBW? What long-term ADRs?

• concurrent use with opioids may result in profound sedation, respiratory depression, and death

• long term ADRs: dependence/tolerance

ADRs of phenobarbital?

• common

• serious/rare

• long term

• common: CNS effects, dependence, tolerance, hangover effect

• serious/rare: respiratory depression, apnea, bradycardia, hypotension (IV), hepatotoxicity

• long term: metabolic bone disease, folate deficiency, behavior changes

If albumin is low, the true valproic acid level will be _______than it appears.

a. higher

b. lower

a.

Answer the following about valproic acid:

• drug interactions?

• ADRs

  • BBW

  • common

  • serious/rare

• D/I:

  • CYP2C9 inhibitor

• ADRs:

  • BBW: hepatic failure, fetal harm, pancreatitis

  • common: GI, weight gain, alopecia, thrombocytopenia, POCS, blurred vision

  • serious/rare: hyperammonemia, DRESS, bleeding

Advantages/disadvantages of using valproic acid?

• advantages: useful in bipolar disorder, migraines

• disadvantages:

  • C/I in severe hepatic dysfunction, mitochondrial disorders, urea cycle disorders

  • caution pancreatitis, bleeding disorders

  • C/I in pregnancy when treated for migraine prophylaxis

Advantages/disadvantages to using Levetiracetam?

• advantages: NO SIGNIFICANT DRUG INTERACTIONS, XR useful

• disadvantages: may worsen depression, PTSD, anxiety, thought disorders

What are the ADRs of Levetiracetam?

• common

• serious/rare

• common: CNS effects, agitation, aggression, depersonalization, hostility

• serious/rare: psychosis, hallucinations

Answer the following about Lacosamide:

• ADRs

• Interactions

• advantages/disadvantages

• ADRs: prolongs PR interval, increased risk of arrhythmias (obtain ECG prior)

  • common: n/v, diplopia, blurred vision, euphoria

• Interactions: caution with medications that prolong PR interval (B blockers, CCB, digoxin) due to risk of AV block and bradycardia

• advantages/disadvantages

  • advantages: minimal interactions

  • disadvantages: ECG prior to use, not rec in severe renal/hepatic impairment, fetal harm

When is topiramate C/I?

trokendi XR only: alcohol use 6 hrs before or after dose— pts. with metabolic acidosis who are taking metformin

What are the ADRs of topiramate?

• common

• serious/rare

• long term

• common: CNS effects

• serious/rare: kidney stones, hypo/hyperthermia, oligohidrosis, metabolic acidosis, hyperammonemia with valproate, fetal harm

• long term: weight loss/anorexia, renal stones

(lowkey: Zonisamide has similar ADRs)

When is Zonisamide C/I?

sulfa hypersensitivity

When is cannabidiol used?

oral solution useful for tx of refractory seizures in LGS and Dravet syndrome

BBW of Felbamate?

hepatic failure, aplastic anemia

Vigabatrin has a REMS program bc of what side effect?

vision loss

Eslicarbazepine is a major active metabolite of ___________________.

oxcarbazepine

T/F: The efficacy of newer AEDs is considered comparable to older AEDs.

true

What medications require SLOW titration?

Lamotrigine, topiramate, clobazam, phenobarbital

When starting AEDs, is mono or combination therapy preferred?

start with monotherapy

What is the definition of drug resistance in epilepsy?

basically failure to control seizures after 2 medications

Is concentration monitoring a therapeutic endpoint or a tool to optimize therapy?

tool to optimize therapy, NOT a therapeutic endpoint

ALL AEDs act on the same part of the body so have a risk of what side effects?

• act on brain—> so CNS side effects are a risk (sedation, dizzy, blurred vision, double vision, ataxia)

• also have a risk of suicidal thoughts/behaviors

Review:

Hypersensitivity reactions (SJS/TEN/DRESS) are most associated with aromatic anticonvulsants such as…

• Carbamazepine

• oxcarbazepine

• ethosuximide

• lamotrigine

• phenobarbital

• phenytoin

• primidone

Review:

What AEDs have a increased risk of osteoporosis/osteomalacia?

• phenytoin

• phenobarbital

• Carbamazepine

• oxcarbazepine

• felbamate

• valproic acid

What are the main counseling points with AEDs?

• can cause suicidal thoughts/actions

• do not stop taking this medication without consulting your healthcare provider

• seizure meds can impair judgement, thinking, coordination

• avoid drugs that lower seizure threshold

• use caution with generic substitutions

• avoid st. johns wort with ALL anticonvulsants

According to guidelines, when can AED withdrawal be considered?

• seizure free 2-5 yrs

• history of single type of focal seizure or generalized seizure

• normal neuro exam/IQ

• normal EEG

T/F: When discontinuing AEDs, it should be done abruptly.

FALSE—> gradually

In the elderly what is the DOC for focal onset seizures?

Lamotrigine

What AEDs can decrease efficacy of oral contraceptives?

• Carbamazepine

• oxcarbazepine

• topiramate

• rufinamide

• lamotrigine

• clobazam

• felbamate

What should be supplemented in any women of childbearing age who is taking an AED?

folic acid

In pregnancy, what AEDs have increased clearance?

LAMOTRIGINE, carbamazepine, phenytoin, levetiracetam

What AEDs should NOT be used in pregnancy?

• valproic acid

• topiramate (cleft palate)