Epilepsy & Seizures 5

Question 1

On which factors does selection of first AED depend

Answer 1

1) the classification of seizure type and epilepsy syndrome
2) age
3) gender
4) comorbid conditions
5) individual circumstances (specific pharmacological properties in relation to the patient’s specific needs)

Question 2

Which AEDs have no indication in focal onset seizures

Answer 2

Ethosuximide
Rufinamide (Class I trials - not FDA approved)
Clobazam (not proven in trials)

Question 3

Which AEDs have indication for Lennox Gastaut syndrome

Answer 3

Class I trials:
Felbamate
Lamotrigine
Topiramate
Rufinamide
Clobazam
Cannabidiol

Valproate (Suggested, but not proven in Class I trials)

++ Fenfluramine!

Question 4

Common medication or other interactions that may lower antiseizure medication levels

Answer 4

Estrogen/ Phenytoin/ Carbamazepine –> lower level of Lamotrigine

Tobacoo –> lower levels of Phenytoin

ginkgo biloba –> lower levels of phenytoin and valproate

Question 5

Drug-Drug Interactions That Depress Antiseizure Medication Levels

1) Brivaracetam
2) Clonazepam, other benzodiazepines
3) Enzyme-inducing antiseizure medications
(eg, phenytoin, carbamazepine, primidone)
4) Eslicarbazepine acetate, oxcarbazepine
5) Felbamate
6) Lamotrigine
7) Primidone
8) Perampanel
9) Rufinamide
10) Tiagabine
11) Topiramate
12) Valproate/valproic acid
13) Zonisamide

Answer 5

1) Rifampin
2) Rifampin, enzyme-inducing antiseizure medications
3) Enzyme-inducing antiseizure medications
4) Enzyme-inducing antiseizure medications
5) Enzyme-inducing antiseizure medications
6) Rifampin, estrogen, lopinavir/ritonavir, enzyme-inducing antiseizure medications
7) Diuretics
8) Enzyme-inducing antiseizure medications (not primidone)
9) Enzyme-inducing antiseizure medications
10) Enzyme-inducing antiseizure medications
11) Phenytoin, carbamazepine
12) Carbapenem antibiotics
13) Enzyme-inducing antiseizure medications

Question 6

Which is the only combination of AEDs proved to be synergistic

Answer 6

the combination of lamotrigine and valproate

Question 7

In the case of lack of efficcacy of the first AED, what is in favor of

1) substitution monotherapy
2) Add-on therapy

Answer 7

1) Substitution monotherapy is favored when the first AED was not well tolerated or was totally ineffective. Substitution monotherapy would also be preferable in elderly patients who already take other medications, in women of childbearing potential contemplating pregnancy, in patients with compliance challenges, and when financial restrictions exist

2) Add-on therapy would be preferred if the first
AED was well tolerated and partially effective or if the projected add-on agent has not been tested in monotherapy. The add-on therapy should not have negative pharmacokinetic interactions with the first AED or other concomitant medications (For example, the use of an enzyme inducer with an AED whose metabolism can be induced will reduce its efficacy. Enzyme inhibition is less of a problem as long as dosing accommodations are made)

Question 8

Which AEDs can be used as an initial treatment for focal onset seizures

Answer 8

For focal-onset seizures, carbamazepine or phenytoin may be used first, but newer drugs have clear pharmacokinetic advantages, particularly absence of enzyme induction.

clinical trial evidence supporting their use as initial monotherapy:
Lamotrigine
gabapentin
levetiracetam
zonisamide
lacosamide
eslicarbazepine acetate

A large community-based study found that lamotrigine was significantly better than carbamazepine, gabapentin, and topiramate and had a nonsignificant advantage compared to oxcarbazepine with respect to time to treatment failure.
However, lamotrigine requires slow titration and would not be an appropriate first choice when a rapid onset of action is needed.
When rapid therapeutic effect is required, oxcarbazepine and levetiracetam may be the drugs of choice because they can be started at an effective dose.
Topiramate also requires slow titration. Because of its cognitive adverse effects, it is not generally the first drug of choice unless comorbidities (e.g., migraine, obesity) favor its use.

(Bradley)

Question 9

Which AEDs can be used as an initial treatment for generalized onset seizures 1) Absence 2) generalized tonic clonic 3) Myoclonic

Answer 9

For generalized-onset seizures, the initial ASM is dependent on the seizure type

1) Pure generalized absence seizures: ethosuximide is the first drug of choice, based on a comparative trial with valproate and lamotrigine, in which it had the best balance of efficacy and tolerability.
Valproate was equally effective and may be the best choice if there are concomitant GTC seizures or generalized myoclonic seizures because ethosuximide efficacy is limited to generalized absence seizures.

2) Generalized tonic-clonic seizures: valproate was significantly better than both lamotrigine and topiramate for time to treatment failure and may be the first drug of choice for men, in the absence of prohibitive comorbidities.
However, valproate is teratogenic, with dose-related increased risk of major congenital malformation, permanent cognitive impairment, and increased risk of autism in the exposed fetus.
Other choices are lamotrigine, topiramate, levetiracetam.

3) Generalized myoclonic seizures: While no ASM has official FDA initial monotherapy indication, valproate is clearly effective, and levetiracetam, which has FDA approval as adjunctive therapy for generalized myoclonic seizures, may also be effective in monotherapy.
Weaker evidence exists for efficacy of topiramate, zonisamide, and lamotrigine (lamotrigine may even aggravate myoclonic seizures in some individuals). The newest drugs perampanel and brivaracetam also have anecdotal evidence of efficacy.

(Bradley)

Question 10

AEDs titration

Answer 10

For all epilepsy indications, treatment is initiated with an
AED monotherapy.
In the absence of urgency, it is preferable to start at a low dose and titrate slowly, even for AEDs that can be started at a higher effective dose.
The initial target dose is often the minimal effective dose that has been demonstrated in clinical trials, keeping in mind that the pivotal clinical trials may have underestimated or overestimated that dose in some instances. If the initial target dose is not sufficient, the AED dose can then be titrated gradually until efficacy is established.
For patients with infrequent seizures, it may take a long time to determine when an effective dose has been reached. Therefore it is wise for the initial target dose to be an average rather than a minimum effective dose. Before a medication can be considered ineffective, it usually has to be titrated to the highest tolerated dose

Question 11

Failure of initial AED monotherapy

Answer 11

If a medication fails due to lack of efficacy, the neurologist may choose either replacement monotherapy or adjunctive therapy with another medication. The available evidence is that the two options do not differ significantly in either efficacy or tolerability.

• If the initial therapy has been completely ineffective, then replacement monotherapy is the best choice.
• If the initial therapy was partially effective, adjunctive therapy may be a consideration.
• If medication failure is due to lack of tolerability, then replacement monotherapy is the clearly preferable option.
  Replacement monotherapy usually requires initially adding the new AED before withdrawing the old agent. However, overnight switch is possible for some AEDs such as carbamazepine and oxcarbazepine

Question 12

Which AEDs are approved for adjunctive therapy

Answer 12

All AEDs are approved for adjunctive therapy

Question 13

Which factors have to be taken into consideration in adjunctive therapy selection

Answer 13

Adjunctive therapy should take into consideration any
possible pharmacodynamic or pharmacokinetic interactions between the medications in question. Ideally, the added medication should not have adverse pharmacokinetic or pharmacodynamic interactions

Question 14

How mechanism of action affect AED selection

Answer 14

At present, the AED mechanism of action is not crucial for AED selection, although there is a suggestion that combining two AEDs with different mechanisms may have a greater chance of efficacy than combining two AEDs with the same mechanism.
On the other hand, mechanism of action may be a predictor of adverse effects from pharmacodynamic interactions. For example, dizziness, ataxia, and diplopia are more likely when combining lacosamide with another agent that acts on the sodium channel.
The neurologist will often need to reduce the dose of the initial AED when adding a second AED with a similar mechanism of action

Question 15

Which side effects of AEDs are more likely and which less likely in childhood

Answer 15

More likely:
Serious rashes from lamotrigine
behavioral adverse effects from levetiracetam
oligohidrosis from topiramate and zonisamide
Valproate-induced liver failure (in children younger than 2 years of age)

Less likely:
hyponatremia from oxcarbazepine
aplastic anemia from felbamate

Question 16

What is important in AED selection in women of childbearing age

Answer 16

1) certain AEDs may reduce the efficacy of oral
contraception

2) valproate is to be avoided for two important reasons:
-higher risk of congenital malformations in the
exposed fetus
-increased risk of polycystic ovaries and hyperandrogenism

Question 17

Examples of AED side effects that are more likely in the elderly

Answer 17

• Reversible parkinsonism and cognitive impairment from valproate
• hyponatremia from oxcarbazepine, particularly when combined with diuretics or other agents that may lower sodium

Question 18

Which AEDs are best tolerated in new onset geriatric epilepsy

Answer 18

Lamotrigine and gabapentin are better tolerated than
immediate-release carbamazepine in new-onset geriatric epilepsy, but no difference is found between lamotrigine and extended-release carbamazepine

Question 19

Causes of persistance of seizures despite AED therapy

Answer 19

1) misdiagnosis of nonepileptic psychogenic seizures
2) breakthrough seizures related to noncompliance
3) sleep deprivation (particularly in genetic generalized epilepsy)
4) alcohol or drug abuse
5) co-medications that reduce the seizure threshold
6) incorrect AED selection or inadequate AED use

Question 20

Definition of drug resistant epilepsy

Answer 20

failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom

Question 21

Seizure aggravation and AEDs

Answer 21

Seizure aggravation may occur with a number of medications.

• This is most common in generalized epilepsy, where AEDs such as carbamazepine, oxcarbazepine, phenytoin, tiagabine, gabapentin, or vigabatrin may increase the number of seizures or provoke the appearance of new seizure types (myoclonic or absence seizures) at a therapeutic level.
• AED may cause a paradoxical increase in seizures in some patients. This phenomenon has been documented with levetiracetam. A number of AEDs have been reported to increase seizure frequency or severity as a manifestation of toxicity, with AED serum levels above “therapeutic” range. This is well documented for phenytoin but may also occur with other agents
• seizure exacerbation may occur in the setting of AED-induced encephalopathy or with sedation. For example, seizures may be exacerbated with valproate-induced encephalopathy, and sedative AEDs may exacerbate tonic seizures in patients with Lennox-Gastaut syndrome

Question 22

Common long term AED adverse effects

Answer 22

• Barbiturate chronic use may be associated with frozen shoulder and Dupuytren contractures
• Reduction in bone mineral density most likely with chronic use of enzyme-inducing AEDs but has also been associated with valproate and other nonenzyme-inducing agents. It is therefore advisable to monitor bone density with chronic AED therapy, and to supplement vitamin D and calcium
• the enzyme inducing AEDs, carbamazepine and phenytoin, have been associated with serological markers of vascular risk, ameliorated upon switching to lamotrigine or levetiracetam
• Another long-term adverse effect of AEDs is potential for teratogenicity as well as reduced IQ in exposed infants. This adverse effect is most pronounced with valproate

Question 23

Dose dependent AED adverse effects management

Answer 23

The most common adverse effects are dose dependent and will predictably occur if titration continues. Their appearance indicates that the dose should be reduced. These adverse effects are most likely to occur at the time of greatest serum concentration following medication intake, in which case they could be alleviated without dose reduction by splitting the dose, taking the medication with food, or using an extended release preparation. In general, dose-dependent adverse effects are reversible with dose reduction or medication discontinuation. Cognitive and behavioral adverse effects of AEDs could be considered in the category of dose-dependent adverse effects, although some individuals may be predisposed by virtue of genetic or other factors.

Question 24

Most common dose-dependent adverse effects with medications acting on the sodium channel (phenytoin, carbamazepine, oxcarbazepine, lamotrigine)

Answer 24

dizziness, ataxia, and diplopia

Question 25

Most common adverse effect with benzodiazepines and barbiturates (GABA receptor)

Answer 25

Sedation

Question 26

AEDs that may affect cognition

Answer 26

Barbiturates and benzodiazepines are best known to affect cognition, but any AED can cause impairment of concentration and memory
Among the new AEDs, topiramate and zonisamide are the most likely to impair cognition, while lamotrigine is the least likely

Question 27

AEDs that can cause depression or psychosis

Answer 27

Depression may occur with any AED
Psychosis is an uncommon adverse effect of many AEDs but seems more likely associated with topiramate, vigabatrin, and levetiracetam

Question 28

AEDs that can cause weight gain or weight loss

Answer 28

weight gain with valproate and pregabalin
weight loss with topiramate and zonisamide

Question 29

Idiosyncratic and predictors of adverse effects

Answer 29

Idiosyncratic adverse effects:
they are not dose dependent and include
1) hepatotoxicity, which may occur with valproate and felbamate
2)Stevens-Johnson syndrome, which may occur with several AEDs including phenytoin, carbamazepine, and lamotrigine
3) aplastic anemia, which may occur with felbamate and (more rarely) carbamazepine.

Predictors of adverse effects:

1) Valproate hepatotoxicity is more likely in children younger than 2 years, particularly those with mitochondrial disease
2) Prior immune disorder and prior cytopenia are risk factors for felbamate-associated aplastic anemia

Question 30

Causes of low serum values of AEDs

Answer 30

1) Non-compliance
2) Fast metabolism, either due to genetic factors or due to enzyme induction by concomitant medication

Question 31

Discontinuation of Antiepileptic Drug Therapy

Answer 31

After a two- to four-year seizure-free interval, it is reasonable to begin a discussion about continued antiseizure medication therapy versus a trial of discontinuation.

independent predictors of seizure recurrence:
● Epilepsy duration before remission (longer duration associated with higher risk)
● Seizure-free interval before ASM withdrawal (shorter interval associated with higher risk)
● Age at onset of epilepsy (onset in adulthood associated with higher risk)
● History of febrile seizures
● Number of seizures before remission (≥10 associated with higher risk)
● Absence of a self-limiting epilepsy syndrome (eg, absence epilepsy, benign epilepsy with centrotemporal spikes)
● Epileptiform abnormality on EEG before withdrawal

Question 32

Juvenile myoclonic epilepsy treatment

Answer 32

initial treatment with a broad spectrum antiseizure medication (eg, valproate, levetiracetam, lamotrigine, topiramate)

Valproate has the best established efficacy and results in seizure control in 80 percent of patients.

Patients generally respond quickly and completely to antiseizure medication therapy, but many require long-term treatment.
Some patients require combination therapy after two single-agent treatment failures. Rare patients have drug-resistant epilepsy.

Question 33

Juvenile myoclonic epilepsy and childhood absence epilepsy difference in treatment duration

Answer 33

In contrast to CAE patients, those with JME generally do not have remission of their seizures and require anticonvulsant treatment
throughout their lives

Question 34

Antiepileptics that can cause chorea

Answer 34

Antiepileptic medications such as
* gabapentin
* carbamazepine
* phenytoin
* valproic acid

can cause chorea

Question 35

1) When should the doctor monitor antiseizure medication and 2) how must the results be interpreted

Answer 35

1) Once a treatment regimen is deemed effective, a trough antiseizure medication concentration can establish a proper baseline by which to judge future problems such as toxicities or changes in effectiveness, such as breakthrough seizures or suspected nonadherence.
Antiseizure medication levels can be obtained either in anticipation of or in the face of changes in health or development that may perturb steady-state levels, such as in children when they are rapidly growing, changes in clearance as the result of aging or hepatic-renal disease, or pregnancy.
2) Drug levels may be helpful when encountering possible formulation variability or pharmacokinetic interactions when coinciding medications change.
The interpretation of normal should be done cautiously because there can be considerable variability of reference ranges across different laboratories. Most importantly, what is normal for one patient may be toxic or ineffective for another. In short, serum concentrations are only part of the story; dose adjustments should not be made on the basis of levels alone but should be performed when guided by the patient’s clinical state

Question 36

Which are the AEDs with FDA approved indications outside of epilepsy

Answer 36

• clonazepam (panic attacks)
• carbamazepine (trigeminal neuralgia)
• valproate (migraine prophylaxis, acute treatment and maintenance for mania/bipolar disorder)
• gabapentin (postherpetic neuralgia)
• lamotrigine (maintenance for bipolar disorder)
• topiramate (migraine prophylaxis)
• pregabalin (diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia)

Question 37

What is bioavailability

Answer 37

The fraction of an administered dose of unchanged drug that reaches the systemic circulation
It is one of the principal pharmacokinetic properties of drugs

Question 38

Protein binding meaning

Answer 38

Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug’s efficiency may be affected by the degree to which it binds.
The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse.
Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, and α, β‚ and γ globulins

Question 39

Teratogenic risk profiles of antiseizure medications

Answer 39