Lecture 49 Seizure Therapeutics Wong

GOALS OF THERAPY OF ANTIEPILEPTIC DRUGS (AEDs)

• Prevent seizure recurrence

• Improve quality of life

• Minimize adverse drug reactions

SEIZURE DISORDERS:

BEFORE STARTING AN AED, CONSIDER…

• Risk for seizure reoccurance

• Expected benefit from immediate therapy

• Prognosis

• Adverse effects of various AED options

• Patient’s preferences (sz recurrence, QOL)

SEIZURE ETIOLOGY Provoked Definition • Known etiology

• Usually secondary to an acute condition

Common causes • Metabolic disturbances: electrolytes, glucose, thyroid

• Alcohol & drug withdrawal

• Medications

• Fever

• Acute neurologic disorders: stroke, infection (encephalitis, meningitis), TBI

Febrile seizures Seizures in children who…

• An elevated temperature > 38 oC

• Absence of CNS infection or inflammation

• Absence of acute systemic metabolic abnormality that may produce convulsions

• No history of previous afebrile seizures

Simple (typical) Complex (atypical)

Duration? Short (<15 minutes) Longer (>15 minutes)

Seizure type? Generalized Focal or genrealized

Recurrence in 24 hours? No Yes

Long-term effects on brain function or intelligence?

No Variable (depends on etiology)

Treatment? • Risk of seizure recurrence o If <12 months: 50% o If >12 months: 30% o After 2nd febrile sz: 50%

• No demonstrated prevention of epilepsy

• Good prognosis w/o AED therapy (AED not recommend)

• Antipyretics DO NOT reduce recurrences but used to improve comfort if febrile

• Risk of recurrence, expected benefit of early AED therapy, and prognosis are variable (depends on etiology)

• Prompt investigations are usually done to determine necessity of treatment

Treatment • Presumption is seizure would not recur in absence of the provocation

• No expected benefit from AED therapy

• Good prognosis

• Adverse effects of various AED options

Unprovoked Definition • Unknown etiology

• Relation to a pre-existing brain lesion or progressive nervous system disorder

First unprovoked seizure

• Adults: risk of seizure recurrence – 21-45% first 2 years

• Children: risk of seizure recurrence – 24% in first year and 45% over next 14 years

• Factors associated with an increased risk for seizure recurrence: o EEG abnormalities o Prior brain insult o Brain-imaging abnormalities

• Immediate AED therapy is unlikely to improve prognosis as measured by sustained seizure remission

Two unprovoked seizures (24 h apart)

• Adults: risk of seizure recurrence – 73% within first 4 years (mostly in first year)

• Children: risk of seizure recurrence – 70% in first year

• The substantial increased risk for additional seizures warrant AED therapy

Other definition of epilepsy

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

Prolonged seizures

Definition • Occur from various etiologies

• Seizures lasting longer than 5 mins

• Low probability of spontaneous cessation neuronal injury

Treatment Children at risk may be prescribed seizure rescue medications for use at home:

• Intranasal or buccal midazolam = preferred treatments for prolonged seizures o No pre-loaded device available in Canada – injectable solution is used instead o Attachment of nasal atomizer recommended for intranasal route o Families are taught how to draw up dose

• Rectal diazepam = for use in infants < 3 months of age o Available in pre-loaded syringe gel at significantly higher cost; can also use the injectable solution rectally o Attachment of 3-4 inch feeding tube recommended if injectable solution used

Lecture 49 Seizure Therapeutics Wong

EPILEPSIES: DIAGNOSIS AND MANAGEMENT 1. Choose antiepileptic drug based on presenting epilepsy syndrome 2. If epilepsy syndrome not clear, base decision on presenting seizure type(s)

Syndrome Treatments

Absence ETX, VPA, LTG

Juvenile myoclonic VPA, LTG, LEV, TOP

Idiopathic generalized VPA, LTG, TOP

COMPARATIVE EFFICACY OF AEDs:

• No single AED is clearly most effective or best tolerated

• Alarmingly lack of well-designed, properly conducted RCTs

• Head-to-head comparison trials no significant differences

• Most randomized trials in epilepsy test new AEDs as “add-on” therapy

• Selection of AED remains highly individualized

SPECTRUM OF AEDS IN VARIOUS SEIZURE TYPES All seizures & syndromes Focal (partial) & generalized tonic-clonic Absence only Special syndromes

• Valproic acid

• Clobazam

• Clonazepam

• Lamotrigine (except Dravet)

• Phenobarbital (except absence)

• ? Ttopiramate

• ? Levetiracetam

• Carbamazepine

• Oxcarbazepine

• Eslicarbazepine

• Lacosamide

• Perampanel

• Ethosuximide • Stiripentol (Dravet)

• Vigabatrin (Infantile spasms -TS)

• Rufinamide (Lennox-Gastaut)

ADVERSE EFFECTS: AED Common adverse effects Rare/serious adverse effects

All AEDs • Drowsiness, ataxia, dizziness

• GI upset

Carbamazepine • Rash

• Leukopenia

• SJS, TEN (↑ risk in Asians with HLA-B*1502 allele)

• Aplastic anemia

• Hepatoxicity

• Hyponatremia

Phenobarbital • Rash

• ↓ cognition / concentration

• Paradoxical hyperactivity

• SJS

• Blood dyscrasia

• Hepatotoxicity

Phenytoin • Rash

• Gingival hyperplasia

• Facial coarsening

• SJS

Lamotrigine • Rash

• Insomnia

• SJS

Levetiracetam • Irritability

• Depression

• Psychosis

•

Topiramate • ↓ cognition / concentration

• Weight loss

• Renal stones

•

Valproic acid • Tremor

• Weight gain

• Hyperammonia

• Alopecia

• Thrombocytopenia

• Leukopenia

• Hepatoxicity

• Pancreatitis

COMORBIDITIES: Condition Use Avoid

Cognitive dysfunction Phenobarbital, topiramate

Migraine Topiramate, valproate

Mood disorders / ADHD Lamotrigine, valproate Levetiracetam, clobazam, phenobarbital

Neuropathic pain Carbamazepine, gabapentin, pregabalin

Obesity Topiramate Clobazam, gabapentin, pregabalin, valproic acid

Polycystic ovarian syndrome Valproic acid

DRUG INTERACTIONS:

• AEDs can affect other medications and vice versa

• Particularly medications affected by: CYP450, UGT o Examples: other AEDs, contraceptives,

chemothera[y/immunosuppresants, anti-infective, anticoagulants, lipid-lowering drugs, GI medications

• Contraception: o ↑ failure of OCs with enzyme-inducing AEDs

▪ Use non enzyme-inducing AEDs (ex// levetiracetam)

▪ Use alternative/back-up method ▪ Select oral contraceptive with 50 mcg EE

o ↑ failure of AEDs in women taking contraceptives ▪ Use continuous dosing oral contraceptive to

avoid significant increase in AED levels during 7-day pill free week

TERATOGENICITY

• ↑ risk of malformations in fetuses exposed to certain AEDs

Valproic acid Neural-tube defects, spina bifida

Carbamazepine

Topiramate Cleft palate, low birth weight

Phenytoin Cleft palate

• Lamotrigine risk appears conflicting, but appears reassuring

• Levetiracetam associated with a low risk of malformations

AGE CONSIDERATIONS:

Pediatric Geriatric

• Valproic acid contraindicated in <2 yr and ↑ risk of hepatoxicity

• Paradoxical reactions (BZDs)

• Hypoalbuminemia (neonates)

• Higher doses due to enhanced renal clearance

• Inability to swallow whole tablets (compound solution)

• Polypharmacy (drug interactions)

• Hypoalbuminemia (altered protein binding)

• Declining renal & hepatic function (reduced drug clearance)

• ↑ in fat to lean body mass (altered Vd)

• Pharmacodynamic response (neurocognitive effects)

Lecture 49 Seizure Therapeutics Wong

TREATMENT WITH AEDS: 1. Monotherapy with AED: most ideal in treatment of epilepsy (reduces toxicities, eliminates risk of drug interactions, improves compliance, minimize cost)

o 50% of patients seizure-free for at least one year on monotherapy o Initiation of an AED:

1) Start single AED at a fraction of target dose and titrate 2) Evaluate once target maintenance dose is achieved 3) Adjust dose according to clinical response up to maximum

2. If seizures not well controlled:

a. Option 1: alternative monotherapy i. Start second AED at a fraction of target dose and titrate ii. Evaluate once target maintenance dose is achieved iii. Adjust dose according to clinical response up to maximum iv. Taper off first AED – an additional 13% of pts seizure-free on a second monotherapy

b. Option 2: add-on therapy i. Start second AED at a fraction of target dose and titrate ii. Evaluate once target maintenance dose is achieved iii. Adjust dose according to clinical response up to maximum

3. Rational polytherapy:

• Intentional choice of a second AED to enhance seizure control

• Application of AEDs with different mechanisms of action for synergism

• Considered in difficult-to-treat epilepsy

• Enhanced seizure control at expense of increased risk of adverse effects and drug interactions

4. Discontinuation of an AED

• Reasonable to consider after a 2-4 year seizure free interval

• Consider risks and benefits

• Reasons to discontinue: o Offers a sense of being “cured” o Eliminates chronic adverse effects o Eliminates financial burden

• Some risk factors for sz recurrence after D/C o Multiple sz types o Poor initial response to txt o Combo therapy at time of withdrawal

EVALUATING CLINICAL RESPONSE:

Efficacy Safety

• Seizure logs (# seizures, duration, time of day)

• Impact of seizures on daily life

• Hospital admissions required?

• EEG findings

• Adverse effects o Acute vs. chronic o Dose-related vs idiosyncratic o Serious adverse effects

THERAPEUTIC DRUG MONITORING IN AEDS

• Measuring serum drug levels can be valuable in guiding management of patient’s AED therapy

• Drug levels may be particularly useful in older generation of AEDs that have complex pharmacokinetic profiles: o Highly protein bound o Narrow therapeutic index o Non-linear kinetics o Significant drug interactions (ex// carbamazepine, phenobarbital, phenytoin)

• A drug level can be drawn to assess:

Examples

1) Efficacy • Uncontrolled seizures

• Dose optimization to preselected target

• “individual therapeutic range”

• Individual dose-dependent response

2) Safety • Change in formulations/generic substitutions

• Change in PK (ex// pregnancy, gaining population, drug interactions)

• Suspected toxicities

3) Adherence • Suspected poor compliance

• Remember to treat the patient, not the level!

• Phenytoin = 𝑪𝒑 𝒏𝒐𝒓𝒏𝒂𝒍 = 𝑪𝒑 𝒐𝒃𝒔𝒆𝒓𝒗𝒆𝒅

[(𝟎.𝟎𝟐 𝒙 𝒂𝒍𝒃𝒖𝒎𝒊𝒏) + 𝟎.𝟏 Cpss target: 40-80 umol Albumin normal range: 35-50 g/L

NON-PHARMACOLOGICAL STRATEGIES (REFRACTORY SEIZURES)

• Vagal nerve stimulation (VNS)

• Surgery

• Ketogenic diet: high fat, adequate protein, low CHO diet (requires minimal CHO contributions from medications) o Stimulates ketosis of starvation to control seizures o Used mainly in pediatric patients