Seizures / Epilepsy

Question 1

Common Examples of Medications Which Can Precipitate Seizures

Answer 1

– Tramadol
– Bupropion
– Theophylline
– Sympathomimetics
– Stimulants (Amphetamines, Methylphenidate, Cocaine)
– Imipenem
– Lithium
– Excessive doses of penicillins or cephalosporins

Question 2

Inhibitory neurotransmitters

Answer 2

GABA (gamma-amino butyric acid) acts on ion channels.
It allows chloride to flow into the neuron and decreases the chances of action potential formation

Question 3

Excitatory neurotransmitters

Answer 3

aspartate, glutamate: allow sodium and calcium influx, which paves the way for action potential formation

Question 4

GOAL OF ANTI-SEIZURE MEDICATIONS (ASMs)

Answer 4

Regulate neuronal firing by achieving balance between excitatory factors and inhibitory factors

Question 5

ASM Mechanism of Action: Major Categories

Answer 5

1. Modulation of sodium, potassium, or calcium ion channels.
2. Enhancement of γ-aminobutyric acid (GABA) neurotransmission
3. Modulation of synaptic neurotransmitter release
4. Diminishing excitation mediated by ionotropic glutamate receptors

Question 6

In general, ASMs recommended in focal-onset epilepsy have comparable efficacy. Which medication is the exception?

Answer 6

Gabapentin - considered “weaker”

Question 7

When a total daily dose is increased, how long should be allowed for the serum drug level to reach a new steady-state?

Answer 7

About 5 half-lives

Question 8

Carbamazepine

Answer 8

First gen
WORSENS absence seizures bc metabolite
Forms epoxide metabolite
MANY DDI
AUTO-INDUCTION CYP3A4
Inducer of 3A4, 1A2, 2B6, 2C9/19
80% Protein bound - watch in conditions of decreased albumin
BBW: Agranulocytosis; aplastic anemia; SJS/TEN (Higher with risk of HLA-B-1502 positive)
AEs: blood dyscrasias (rare, serious) ; Hyponatremia due to SIADH, elevated LFTs (common)
Teratogenic - don’t use in WOCBP if possible

Question 9

Clonazepam

Answer 9

First gen
CYP3A4 substrate, long t1/2 (30-40 hrs)
BBW: use with opiates can increase death and other compl.
AEs (common): pronounced sedation, paradoxical agitation, tolerance; severe withdrawal symptoms

Question 10

Ethosuximide

Answer 10

First gen
MOA: Inhibition of T-type calcium channels (unique MoA for first gen)
Medication of choice for Absence seizures (mono/adjunct), hardly other seizure type use
Narrow therapeutic index
CYP3A4 and 2E1 substrate

Question 11

Phenobarbital

Answer 11

First gen
MOA: GABA Agonist (Barbiturate)
Indication: Not FDA-approved; used off-label for focal onset and generalized seizures
Long t1/2 = 53-180 hours, Inducer of CYP 3A4/2C9/2C19/1A2, Substrate of CYP3A4 and CYP2C19
BBW w/opiates
Prominent CNS depression/sedation
Contraindicated: respiratory disease with evidence of dyspnea or obstruction
Used ACUTELY

Question 12

Phenytoin

Answer 12

First gen
MOA: Sodium Channel Blocker/Modulator
Indication includes status epilepticus (IV) and focal onset plus tonic-clinic
Narrow therapeutic index
Highly protein bound (80-90%)
Potent inducer of CYP3A and CYP2C; Substrate of CYP2C9; CYP2C19
Exhibits Michaelis-Menten PK: metabolism is saturable. t1/2 increases as dose increases
AEs (rare, serious): SJS/TEN, Blood dyscrasias, (“purple glove syndrome”)
Common AE: Gingival Hyperplasia (50% with long-term use)

Question 13

Primidone

Answer 13

First gen
MOA: Prodrug converted to phenobarbital and another active metabolite, phenylethylmalonamide (PEMA)
Like phenobarbital- Long t1/2 = 53-180 hours, Inducer of CYP 3A4/2C9/2C19/1A2, Substrate of CYP3A4 and CYP2C19
Acute use

Question 14

Valproate

Answer 14

First gen
Available as valproic acid and divalproex (sodium valproate + valproic acid in 1:1 ratio)
Potent Inhibitor of CYP2C9; GT epoxide hydrolase. Substrate of UGT hepatic metabolism.
NB: Valproate does not decrease efficacy of oral contraceptives, but oral contraceptives may cause increased valproate metabolism and subsequent increased risk in seizures.
Black Box Warning: Hepatotoxicity, teratogenicity, patients with mitochondrial disease, pancreatitis
AEs (rare, serious): Hyperammonemia and encephalopathy (higher risk when used with topiramate), thrombocytopenia
AEs: (common) Tremor, weight gain, alopecia or hair texture changes, nail and nail bed disorders, hormone changes, osteomalacia/osteoporosis
Contraindications: Hepatic disease, urea cycle disorders
Clinical Pearls: Broad spectrum and highly effective for both focal and generalized onset seizure types, so it is commonly used despite several unique AEs. Should be avoided in WOCBP if at all possible due to teratogenicity.
Per PI don’t give with phenobarbital or lamotrigine

Question 15

Felbamate

Answer 15

Second gen
~50% renally eliminated
BBW: Irreversible, fatal aplastic anemia, hepatic failure
Reserved for severe refractory epilepsy due to potential serious AEs

Question 16

Gabapentin (Neurontin)

Answer 16

Second gen
MOA: Calcium channel modulator
Indication: Adjunctive therapy for focal onset seizures (NOT mono therapy)
100% renally eliminated
Widely used for other indications (i.e. neuropathic pain)
Inferior efficacy

Question 17

Lamotrigine (Lamictal)

Answer 17

Second gen
Sodium channel modulator/blocker, broad spectrum ASM
Slow titration required to mitigate risk of SJS – see package insert
Dose recommendations differ if on valproate, carbamazepine, phenobarbital, phenytoin, or primidone - see package insert
Estrogen OCs may decrease lamotrigine levels by 50%
BBW: SJS/TEN with increased risk when given with valproate or rapid dose escalation
Clinical Pearls: Widely used due to efficacy in a range of different seizure types, relatively good tolerability; main disadvantage is risk of SJS and need for slow titration (not desirable when rapid symptom control is needed)

Question 18

Pause for a minute and visit Lamotrigine dosing chart

Answer 18

Notice valproate is the first gen inhibitor
The remainder are inducers and thus dose is higher to compensate

Question 19

Levetiracetam (Keppra)

Answer 19

Second gen
MOA: Glutamate Blocker
Commonly used off-label as monotherapy
66% renally eliminated
AEs: Common: Mood-related: Irritability,agitation,anger,depression,or other mood disturbance (“Kepp-Rage”). Can worsen pre-existing psychiatric comorbidities.
Clinical Pearls: Widely used due to efficacy in a range of different seizure types, relatively less sedation/cognitive impairment and idiosyncratic AEs, ability to escalate dose quickly (no slow titration needed), and lack of drug interactions. Mood-related AEs can be difficult to tolerate.

Question 20

Oxcarbazepine (Trileptal)

Answer 20

Second gen
Developed in an attempt to maintain the benefits of carbamazepine while avoiding auto-induction and drug interactions
Induces CYP3A4, CYP3A5, and GT; Inhibits CYP2C19
– Does not produce epoxide metabolite —> better tolerability than carbamazepine
AEs: Rare but serious: Agranulocytosis, SJS/TEN (higher risk in HLA-B*1502 positive)

Question 21

Tiagabine (Gabitril)

Answer 21

Second gen
MOA: GABA modulator
AEs (rare, serious): new onset seizures,status epilepticus, exacerbation of EEG abnormalities
Generally reserved for refractory epilepsies due to risk of serious AEs

Question 22

Topiramate (Topamax)

Answer 22

Second gen
70% renally eliminated. Induces CYP3A at high doses; Inhibits CYP2C19
AEs (common): Notable cognitive impairment (“Dope-Amax”), bilateral paresthesias, weight loss, hypohidrosis (can rarely lead to hypo/hyperthermia), kidney stones
Contraindications: Alcohol use for the ER formulation (within 6 h prior to and 6 h after administration)
Clinical Pearls: Widely used, although cognitive AEs can be difficult to tolerate. Can be useful in patients with comorbid migraine or obesity.

Question 23

Zonisamide (Zonegran)

Answer 23

Second gen
Adjunctive therapy for focal onset seizures
Cyp3A4 Substrate
AEs (common): Notable cognitive impairment, weight loss, hypohidrosis (can rarely lead to
hypo/hyperthermia), kidney stones
Contraindications: Sulfa allergy
Clinical Pearls: Cognitive impairment limits use, but useful for patients who have issues with medication adherence (long t1/2, dosed once daily)

Question 24

Brivaracetam (Briviact)

Answer 24

Third gen
MOA: SV2A Inhibitor, chemical analog of levetiracetam
Substrate of CYP2C19
AEs (common): Mood and behavioral similar to levetiracetam,but some evidence suggests they may be less common than with levetiracetam
Brand only, Controlled V

Question 25

Cenobamate (Xcopri)

Answer 25

Third gen Induces CYP2B6, CYP2C,; CYP3A4; Inhibits CYP 2B6, CYP2C19, CYP3A; Substrate for UGT2B7/B4, CYP2E1, CYP2A6, CYP2B6, CYP2C19, CYP3A4/5 Should be titrated no more quickly than every 2 weeks due to risk of DRESS BBW: Psychiatric, behavioral, mood, or personality changes which may be life-threatening Federal CV, no generic

Question 26

Eslicarbazepine (Aptiom)

Answer 26

Similar to oxcarbazepine, developed in an attempt to maintain the benefits of carbamazepine while avoiding auto-induction and drug interactions MOA: Sodium channel blocker/modulator; Prodrug to lizcarbazepine and carbamazepine 67% Renal Elimination, Inducer of GT, Inhibitor of CYP2C19 No epoxide metabolite AEs: Rare but serious: SJS, DRESS, angioedema, cardiac effects including long PR interval and AV block, hepatotoxicity, blood dyscrasias Common: Tremor, hyponatremia due to SIADH, rash **Dosed QD**

Question 27

Lacosamide (Vimpat)

Answer 27

Third gen MOA: Sodium Channel Blocker/Modulator Inhibits: CYP2C19 Substrate: CYP2C9/19; CYP3A4 AEs (rare, serious): Cardiac Arrhythmias, syncope, DRESS, neutropenia and anemia Clinical Pearls: Schedule V controlled Substance. **Of the third-generation ASMs, has become a drug of choice among providers due to ease of use, tolerability, availability of IV loading and lack of DIs. Generic available.**

Question 28

Perampanel (Fycompa)

Answer 28

Third gen MOA: Glutamate blocker Indication: Mono-or adjunctive therapy for focal-onset seizures with or without secondarily generalized; *adjunctive* therapy in primary generalized TC seizures **96% protein-bound**, Induces CYP3A4/5, CYP2B6, GT; Inhibits CYPA3A4/5, CYP2C8, GT Substrate CYP3A4/5; CYP1A2; CYP2B6 BBW: Aggression, hostility, irritability, anger, and homicidal ideation AEs (common): Mood-related, weight gain Clinical Pearls: Schedule III Controlled Substance. No generic available. Mood- related AEs can be difficult to tolerate. Numerous drug interactions

Question 29

Pregabalin (Lyrica)

Answer 29

Third gen MOA: Calcium channel modulator, similar to gabapentin Indication: *Adjunctive* therapy for focal onset seizures 90% renal elimination AEs (serious): Potential for misuse when taken with opiates AEs (common): Notable cognitive impairment, edema, weight gain Clinical Pearls: Schedule V Controlled Substance. Like gabapentin, widely used for other indications (i.e. neuropathic pain); less commonly used as a primary treatment for epilepsy. Generic available

Question 30

Vigabatrin (Sabril)

Answer 30

Third gen MOA: Binds to and irreversibly inhibits GABA transaminase Indication: *Adjunctive* treatment of *refractory* focal seizures, and ***infantile spasms*** Almost 100% renally eliminated, Induces CYP2C9 ***BBW WITH REMS PROGRAM: Progressive and permanent vision loss*** AEs (rare, serious): Can aggravate seizures (particularly absence and myoclonic seizures in generalized epilepsies) AEs (common): Pronounced CNS depressive effects, weight gain, edema, peripheral neuropathy, neuropsychiatric AEs (depression, psychosis, behavioral disturbance), vision loss Clinical pearls: Renally cleared and relatively few DIs, but use greatly limited due to risk of vision loss and seizure exacarbation, **reserved for refractory patients**. No generic available.

Question 31

Third-Generation ASMs Indicated For Specific Syndromes (not sure this is tested)

Answer 31

• Epidiolex (cannabidiol): Indicated for Lennox-Gastaut Syndrome and Dravet Syndrome • Clobazam: Benzodiazepine indicated for Lennox-Gastaut Syndrome • Stiripentol: Indicated for Dravet Syndrome • Rufinamide: Indicated for Lennox-Gastaut Syndrome

Question 32

Rescue Therapies

Answer 32

Used to stop a *cluster* of repeated seizures. – Diazepam Rectal Gel (Diastat) – Diazepam Nasal Spray (Valtoco) – Midazolam Nasal Spray (Nayzilam)

Question 33

Non-Pharmacologic Treatments

Answer 33

Ketogenic diet Vagus Nerve Stimulator (VNS): FDA-approved implantable device Surgery

Question 34

Special populations: Children

Answer 34

Weight-based dosing with **higher** mg/kg compared to adults due to high metabolic rates in children May be more susceptible to neuropsychiatric adverse effects

Question 35

Special Populations: Older Adults

Answer 35

• Use extra caution in ASMs with pronounced adverse cognitive effects – I.E. benzodiazepines, phenobarbital • Extra monitoring and attention should be paid to PK/PD changes that can occur in older adults – I.E. reduced renal and hepatic clearance, body mass changes – Hypoalbuminemia is common in older adults —> impacts protein-bound drugs

Question 36

Special Populations: Patients with Comorbid Conditions

Answer 36

Some ASMs can be useful for synergystic treatment of comorbid conditions – Treatment-ResistantDepression:VNS – Migraine: Topiramate, valproate, zonisamide – Bipolar disorder: Lamotrigine, valproate, carbamazepine, oxcarbazepine – Neuropathy: Gabapentin or pregabalin – Trigeminal neuralgia: Carbamazepine – Essential tremor: Primidone, topiramate, gabapentin

Question 37

Special Populations: Race and Ethnicity

Answer 37

Asian, South Asian and Southeast Asian populations have higher incidence of HLA-B*1502 gene – Increased susceptibility to idiosyncratic reactions such as Stevens- Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) – Genetic testing is recommended before prescribing carbamazepine, phenytoin, oxcarbazepine, eslicarbazepine, or lamotrigine

Question 38

Special Populations: WOCBP, Pregnant and Postpartum

Answer 38

• Many enzyme-inducing ASMs decrease the effectiveness of hormonal contraceptives. – Carbamazepine,oxcarbazepine,primidone/phenobarbital,phenytoin,topiramate, felbamate, parempanel • Several ASMs have been associated with teratogenicity: - **Valproicacid**: neural tube defects(spinabifida) – **Carbamazepine**: neural tube defects (spina bifida) – **Topiramate**: cleft palate, low birthweight, hypospadias • Polytherapy has shown worse outcomes compared to monotherapy (however, this is primarily driven by older ASMs such as valproate and carbamazepine) • ***Levetiracetam and lamotrigine are often preferred medications in pregnancy*** due to no strong evidence of teratogenicity in humans

Question 39

Special Populations: WOCBP, Pregnant and Postpartum Part 2

Answer 39

General recommendations for pregnancy and postpartum: – Give supplemental folic acid 1-4 mg daily to all WOCBP – Monitor ASMs serum concentrations at start of pregnancy, monthly thereafter – Administer supplemental Vitamin K during 8th month of pregnancy to women receiving enzyme-inducing AEDs – Many ASMs pass into breast milk; those with low protein binding accumulate more – Monitor nursing infant for poor feeding, sedation, irritability – With a few exceptions (i.e. benzodiazepines, phenobarbital), ASM treatment is not normally a reason to discourage breastfeeding

Question 40

Seizure Safety

Answer 40

Every state restricts driving until 3-12 months seizure-free (duration varies) for people who have seizures with loss of consciousness. • Water safety: Drowning can occur in a matter of seconds. – Never swim or take baths alone. Showers are safer than baths; consider using a shower chair or sitting in shower in case of falls. – When swimming, advise those who are with you to call 911 if a seizure occurs in water. – Wear a life jacket (preferably a Coast Guard Class 1 or Class 2 rated, which will turn most unconscious users onto their back). • Fire/Burn safety – Sit far back from open flames, i.e. campfires – Electric stoves may be safer than gas. Try to cook on the back burners. – Set the maximum hot water temp in your house to 110 degrees F. – Consider placing common items on both floors of the house to avoid going up and down stairs frequently. • Arrange home for safety – Pad sharp corners; safety-proof heights, railings, and pools; use non-slip carpet • Climbing heights – Avoid ladders or unprotected heights (safety harness could be an acceptable safety aid depending on seizure type) • Avoid using power tools when possible, use automatic safety stop switches, consider wearing protective gear • Use common sense/consult doctor to select appropriate recreational activities • Wearable devices may be able to alert caregivers of convulsive seizures or falls – Empatica Embrace watch: FDA approved for this purpose