Seizure Disorders. 2 Definition of seizures Time-limited paroxysmal events that result from...

Seizure Disorders

2

Definition of seizures

Time-limited paroxysmal events that result from abnormal, involuntary, rhythmic neuronal discharges in the brain

Seizures are usually unpredictable

Seizures usually brief ( < 5 minutes) and stop spontaneously

Convulsion, ictus, event, spell, attack and fit are used to refer to seizures

Seizures that are prolonged or repetitive can be life-threatening

Definition of epilepsy

Epilepsy is a disorder which is a symptom of disturbed electrical activity in the brain, which may be caused by a wide variety of etiologies

A collection of many different types of seizures that vary widely in severity, appearance, cause, consequence, and management

Definition of epilepsy

Not uncommonly, patients have other comorbid disorders, including depression, anxiety, and potentially neuroendocrine disturbances.

Patients with epilepsy also may display neurodevelopmental delay, memory problems, and/or cognitive impairment

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Etiology of seizures Provoked Seizures: Triggered by certain provoking factors

in otherwise healthy brain

… Metabolic abnormalities (hypoglycemia and hyperglycemia, hyponatremia, hypocalcemia)

… Alcohol withdrawal

… Acute neurological insult (infection, stroke, trauma)

… Illicit drug intoxication and withdrawal

… Prescribed medications that lower seizure threshold (theophylline, TCA)

… High fever in children

Unprovoked Seizures: Occur in the setting of persistent brain pathology

TABLE 62.1 Common Causes of New-Onset Seizures

Primary or Acquired Neurological Disorders Alzheimer's disease or other neurodegenerative diseases Brain tumor Central nervous system infection Cerebrovascular disease Febrile seizures of childhood Genetic or developmental disorders Head trauma Idiopathic/genetic Systemic or Metabolic Disorders Alcohol abuse and withdrawal Anoxia or ischemia Drug overdose or toxicity Eclampsia Hepatic failure Hypocalcemia Hypoglycemia Hypomagnesemia Hyponatremia Porphyria Renal failure

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Etiology of seizures Many medical conditions can cause

epilepsy.

A genetic predisposition to seizures has been observed in many forms of primary generalized epilepsy.

Patients with mental retardation, cerebral palsy, head injury, or strokes are at an increased risk for seizures and epilepsy

In elderly, seizures are primarily of partial onset associated with the focal neuronal injury induced by strokes, neurodegenerative disorders

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Etiology of seizuresfactors that precipitate seizures in

susceptible individuals.

Hyperventilation can precipitate absence seizures.

Sleep, sleep deprivation, sensory stimuli, and emotional stress increase the frequency of seizures.

Hormonal changes occurring around the time of menses, puberty, or pregnancy.

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Etiology of seizuresfactors that precipitate seizures in

susceptible individuals.

theophylline, alcohol, high-dose phenothiazines, antidepressants (especially maprotiline or bupropion), and street drug use have been associated with provoking seizures.

Perinatal injuries and small gestational weight at birth are risk factors for partial-onset seizures.

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Etiology of Epilepsy Any process that alters structure or function

of the brain neurons can cause epilepsy

Processes that lead to structural alteration include:

Congenital malformation

Degenerative disease

Infectious disease

Trauma

Tumors

Vascular process

TABLE 62.2 Drugs That Have Been Associated With Provoking or Drugs That May Exacerbate Seizures

Antiarrhythmic agents (class 1B) Antimicrobials β-Lactams and related compounds Isoniazid Quinolones Antivirals Acyclovir Ganciclovir Drugs of abuse Amphetamine Cocaine Ephedra Methylphenidate Psychotropic agents Antidepressants Antipsychotics Lithium Sedative-hypnotic drug withdrawal Alcohol Barbiturates (short-acting) Benzodiazepines (short-acting) Miscellaneous Cyclosporine Lindane Flumazenil Metoclopramide Normeperdine (accumulation in renal failure) OKT3 Radiographic contrast agents Theophylline Tramadol

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Classification of seizures Traditionally divided into “ grand mal”

and “petit mal” seizures

ILAE classification of epileptic seizures in 1981 based on clinical observation and EEG findings

Seizures were divided into partial and generalized seizures based on loss of consciousness

Partial seizures were divided into simple partial and complex partial based on alteration of consciousness

CLASSIFICATION OF SEIZURES

Seizures

Loss of Consciousness?

Yes No

Generalized Seizures Partial Seizures

Alteration of Consciousness?

Yes No

Complex Partial Simple Partial

ILAE CLASSIFICATION OF SEIZURES

Partial Seizures Generalized Seizures

Complex Partial Seizures (CPS)–With automatism

–Without automatism

Simple Partial Seizures (SPS)–Motor

oWith marchoWithout marchoVersiveoPosturaloPhonatory

–SensoryoSomatosensoryoOlfactory oVisualoAuditoryoGustatoryoVertiginous

–Autonomic

–PsychiatricoDysphasicoDéjà vu or jamais vuoCognitiveoAffectiveoIllusionsoStructured hallucinations

Secondary Generalized Tonic-Clonic

Tonic-Clonic (primary tonic-clonic)

Absence

Myoclonic

Clonic

Tonic

Atonic

Atypical Absence

Infantile Spasm

Clinical presentationSymptoms

CP seizures can include somatosensory or focal motor features.

CP seizures are associated with altered consciousness.

Absence seizures can be almost nondetectable with only very brief (seconds) periods of altered consciousness.

GTC seizures are major convulsive episodes and are always associated with a loss of consciousness.

Clinical presentation Signs

… between seizure episodes there are typically no objective

Laboratory Tests

… There are currently no diagnostic laboratory tests for epilepsy.

… In some cases, GTC or CP), serum prolactin levels can be transiently elevated.

… Lab tests done to rule out treatable causes of seizures.

Clinical PresentationOther Diagnostic Tests

EEG is very useful in the diagnosis

An epileptiform EEG is found in only approximately 50% of the patients who have epilepsy.

A prolactin level within 10 to 20 mins of a tonic-clonic seizure can be useful in differentiating seizure activity from pseudoseizure activity but not from syncope.

MRI is very useful (especially imaging of the temporal lobes)

CT scan typically is not helpful except in the initial evaluation for a brain tumor or cerebral bleeding.

Generalized tonic-clonic seizures

begin with tonic (rigid) flexion of the extremities followed by extension.

The tonic phase usually lasts 15 to 20 seconds and is quickly followed by the clonic (jerking) phase, during which there are spasms of the trunk and extremities and often biting of the tongue.


The clonic phase usually lasts 20 to 30 seconds and is followed by a postictal state, during which the patient may sleep or awaken confused and disoriented.

gradual return of consciousness and orientation over a period of 15 to 30 minutes, after which the patient has no recall of the event.


Increases in blood pressure and heart rate, incontinence of urine or feces, and a brief interruption of normal breathing with cyanosis commonly accompany this type of seizure.

Absence Seizures

Occur primarily during childhood

Characterized by an abrupt interruption of consciousness followed by a fixed stare.

Automatisms (coordinated involuntary movements such as lip smacking, chewing, or grimacing) or mild clonic movements may also occur.

Absence Seizures there is no loss of postural tone.

lasts several seconds and ends as abruptly

may also cluster and occur as frequently as hundreds of times a day.

Simple Partial Seizures Motor manifestations (e.g., clonic

jerking of one limb) or sensory symptoms (e.g., a foul odour or visual distortions).

Patients can respond to their environment throughout the attack.

Complex partial seizures impaired consciousness and a

heterogeneous group of abnormal symptoms or behaviours.

Auras precede complex partial seizures in many patients.

Unusual epigastric sensations are the most common, although various motor, sensory, or psychic symptoms (as described for simple partial seizures) may occur.

Complex Partial Seizures Consciousness is impaired for an

average of about 2 minutes.

During this time, patients may exhibit automatisms such as lip smacking, buttoning or unbuttoning of clothing, or wandering behaviour.

TREATMENT

Desired Outcome Accurately diagnose seizure type and

determine the etiology.

Identify and eliminate patient-specific seizure precipitants.

Select optimal AED based on seizure type, patient age, sex, and concomitant medical conditions.

Therapy should be individualized to attain best possible seizure control

General approach to treatment

identification of goals

assessment of seizure type and frequency

development of a care plan

a plan for follow-up evaluation

General approach to treatment Consider Patient characteristics such as age,

medical condition, ability to comply with a prescribed regimen

For new-onset seizures decide whether to use drug therapy or not.

If a decision is made to start AED therapy, monotherapy is preferred.

Patient education and assurance of patient understanding of the plan are essential.

… Detailed directions regarding titration, what to do in the event of a treatment-emergent side effect, and what to do if a seizure occurs

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Treatment of Seizures

Provoked Seizures

…Treatment directed to the provoking factor

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Treatment of Seizures Unprovoked Seizures

… First Seizure

Usually no treatment

Treatment initiated if risk of recurrence is high or if a 2nd seizure could be devastating

… Second Seizure

Diagnosis of epilepsy is established and risk of a third Seizure is high

In children, some may wait for a third seizure

When to start AED initiate prophylactic treatment following a

CNS insult likely to cause epilepsy (e.g., stroke or head trauma).

AED may not be indicated in patients whose seizures have minimal impact on their lives.

a careful individual risk–benefit assessment.

treatment is recommended in all persons with a high risk of seizure recurrence

the side effects of AEDs need to be considered.

When to start AEDHigh-risk features for seizure recurrence

symptomatic epilepsy with generalized tonic–clonic seizures

complex or simple partial seizures,

idiopathic generalized epilepsies.

Early treatment after a first GTCS has not been shown to improve long-term prognosis or lower mortality or the risk of injury

When to start AED

Good prognoses who may not even require drug treatment

uncomplicated febrile seizures

benign idiopathic partial epilepsies

Table 58-2 Recurrence Risk for Patients Experiencing One Unprovoked Seizure

Type of Patient First-Year Risk (%) Fifth-Year Risk (%)

Adults with single unproved seizure 34

No CNS insult 10 29

Influence of family history

Sibling with seizure 29 46

No sibling with seizures 7 27

EEG patterns GSW on EEG 15 58 Normal EEG 9 26

Occurrence of previous seizure 10 39

Caused by an illness or childhood febrile seizure

Remote symptomatic with Todd paresis 26 48

41 75

Status epilepticus at onset 37 56

Prior acute seizure 60 80 Idiopathic 10 29

Nonpharmacologic therapy

Diet

Surgery

vagus nerve stimulation (VNS).

Nonpharmacologic therapy Diet

… ketogenic diet devised in1920s.

… high in fat and low in CHO/ protein

… leads to acidosis and ketosis

… It requires strict control and parent compliance.

… poorly tolerated by patients.

… Long-term effects have included kidney stones, increased bone fractures, and adverse effects on growth.

Nonpharmacologic therapy Surgery

… treatment of choice in selected patients with refractory focal epilepsy.

… success rate 80% and 90% in properly selected patients.

… surgery reduces the risk of epilepsy-associated death, and it may also improve depression and anxiety in refractory epilepsy patients.

… Learning and memory can be impaired postoperatively, and general intellectual abilities are also affected in a small number of patients.

Nonpharmacologic therapy Surgery

A National Institutes of Health Consensus Conference identified three absolute requirements for surgery.

… an absolute diagnosis of epilepsy

… failure on an adequate trial of drug therapy

… definition of the electroclinical syndrome.

… Surgery may be particularly useful in children with intractable epilepsy. Patients may need to continue to receive AED therapy for a period of time

Nonpharmacologic therapy vagus nerve stimulation (VNS).

… An implanted device approved as an adjunctive for partial-onset seizures refractory to AEDs.

… It is also used off-label in the treatment of generalized epilepsy.

… The mechanisms of antiseizure actions of VNS are unknown in the human.

… 23% to 50%of patients achieve > 50% reduction in their seizure frequency

Nonpharmacologic therapy vagus nerve stimulation (VNS).

… The most common side effect are hoarseness, voice alteration, increased cough, pharyngitis, dyspnea, dyspepsia, and nausea.

… Serious adverse effects reported include infection, nerve paralysis, hypoesthesia, facial paresis, left vocal cord paralysis, left facial paralysis, left recurrent laryngeal nerve injury, urinary retention, and low-grade fever.

FIGURE 58-1.

Drug Therapy

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ANTIEPILEPTIC DRUGS (AED)

First Generation Second Generation

Unconventional

Carbamazepine (Tegretol)

Clonazepam (Klonopin)

Clorazepate (Tranxene)

Ethosuximide (Zarontin)

Phenobarbital

Phenytoin (Dilantin)

Primidone (Mysoline)

Valproic acid (Depakote)

Felbamate (Felbatol)

Gabapentin (Neurontin)

Lamotrigine (Lamictal)

Levetiracetam (Keppra)

Oxcarbazepine (Trileptal) Pregabalin (Lyrica)

Tiagabine (Gabitril)

Topiramate (Topamax)

Zonisamide (Zonegran)

Adrenocorticotropic hormone (ACTH )

Acetazolamide (Diamox)

Amantadine (Symmetrel)

Bromides

Clomiphene (Clomid)

Ethotoin (Peganone)

Mephenytoin (Mesantoin)

Mephobarbital (Mebaral)

Methsuximide (Celontin)

Trimethadione (Tridione)

Choice of antiepileptic drug

the choice of first-line agents is based on

efficacy for the seizure or epilepsy syndrome,

Tolerability and safety,

ease of use,

pharmacokinetics (including current or likely future need for concomitant medication for comorbidity),

cost

TABLE 62.6 Antiepileptic Drugs of Choice Based on Seizure Classification

Partial Seizuresa Generalized Seizures Generalized Tonic-Clonic Absence Myoclonic, Atonic, Atypical Absence

Drugs of choice Carbamazepine Phenytoin Lamotrigine Oxcarbazepine Topiramateb

Valproate Carbamazepine Phenytoin Topiramate Lamotrigine

Ethosuximide Lamotrigine Valproate

Valproate Lamotrigine

Alternatives Gabapentinb Levetiracetam Phenobarbital Pregabalin Primidone Tiagabineb Valproate

Levetiracetam Phenobarbital Phenytoin Primidone

Clonazepam Clonazepam Topiramate Felbamate

aSimple-partial, complex-partial, and secondarily generalized tonic-clonic seizures. bUsed primarily as adjunctive therapy.

Seizure Type First-Line Drugs Alternative Drugsa CommentsPartial seizures (newly diagnosed) U.S. guidelines25,26

Adults & adolescents: FDA approved:

CarbamazepineCarbamazepine OxcarbazepineGabapentin PhenobarbitalLamotrigine PhenytoinOxcarbazepine TopiramatePhenobarbital Valproic acidPhenytoin Topiramate Valproic acid

U.K. guidelines27,28

Carbamazepine LamotrigineOxcarbazepineTopiramateValproic acid

ILAE guidelines29

Adults: Adults: Carbamazepine Gabapentin Phenytoin Lamotrigine Valproic acid Oxcarbazepine Phenobarbital Topiramate Children: Children: Oxcarbazepine Carbamazepine Phenobarbital Phenytoin Topiramate Valproic acid Elderly: Elderly: Gabapentin Carbamazepine Lamotrigine

U.S. Expert Panel 200530

Carbamazepine Levetiracetam Lamotrigine Oxcarbazepine

Partial seizures (refractory monotherapy)

U.S. guidelines25,26

Lamotrigine FDA approved:

Oxcarbazepine Carbamazepine

Topiramate Lamotrigine

Oxcarbazepine

Phenobarbital

Phenytoin

Valproic acid


Lamotrigine

Oxcarbazepine

Topiramate

Partial seizures (refractory adjunct) U.S. guidelines25,26

Adults: FDA approved:

Gabapentin Carbamazepine

Lamotrigine GabapentinLevetiracetam LamotrigineOxcarbazepine Levetiracetam

Tiagabine Oxcarbazepine

Topiramate PhenobarbitalZonisamide PhenytoinChildren: PregabalinGabapentin TiagabineLamotrigine Valproic acidOxcarbazepine Zonisamide


Gabapentin

Lamotrigine

Levetiracetam

Oxcarbazepine

Tiagabine

Topiramate

http://www.accesspharmacy.com/content.aspx?aID=3203733


Generalized seizures absence (newly diagnosed)


Lamotrigine FDA approved: Ethosuximide

Valproic acidU.K. guidelines27,28

Lamotrigine

ILAE guidelines29

None Ethosuximide Lamotrigine Valproic acid


Ethosuximide Lamotrigine Valproic acid

Primary generalized (tonic-clonic)


Topiramate FDA approved: Lamotrigine Topiramate


Lamotrigine Topiramate

ILAE guidelines29

None Adults: Carbamazepine Lamotrigine Oxcarbazepine Phenobarbital Phenytoin Topiramate Valproic acid Children: Carbamazepine Phenobarbital Phenytoin Topiramate Valproic acid


Valproic acid Lamotrigine Topiramate













Juvenile myoclonic epilepsy

FDA approved:

Levetiracetam (myoclonic seizures)

ILAE29

None Clonazepam

Lamotrigine

Levetiracetam

Topiramate

Valproic acid

Zonisamide


Valproic acid Levetiracetam

Topiramate

Zonisamide



PARTIAL SEIZURES partial seizures do not respond to

treatment as well as seizures that are generalized.

Carbamazepine, phenytoin, phenobarbital, and primidone are equally effective for the treatment of partial seizures

carbamazepine and phenytoin are usually tolerated better.

Phenytoin has a long half-life that allows for once-daily dosing

PARTIAL SEIZURES

phenytoin is associated with cosmetic

changes that make it less desirable for the

treatment of epilepsy in children,

adolescents, and women.

Valproate is also useful for the treatment of

partial seizures, but carbamazepine

provides better seizure control and fewer

long-term adverse effects.

PARTIAL SEIZURES

Felbamate, gabapentin, lamotrigine,

tiagabine, topiramate, levetiracetam,

oxcarbazepine, zonisamide, and pregabalin

are also effective for treating partial seizures.

Lamotrigine and topiramate are effective as

monotherapy and appear to be better

tolerated than carbamazepine monotherapy

particularly in elderly patients.

PARTIAL SEIZURES

Phenobarbital and primidone are also useful in partial seizures, but sedation and cognitive adverse effects limit their utility.

PARTIAL SEIZURES The first AED leads to complete seizure

control in about 50-65%% of patients

Subsequent combination or substitution achieve control in up to 10–15%.

1 in 3 patients remains with uncontrolled partial seizures.

The other new agents are primarily used as adjunctive therapy if monotherapy has failed or for patients who are intolerant of standard AEDs (e.g., carbamazepine, phenytoin, and valproate).

PARTIAL SEIZURES If several single-drug or combination

regimens with these drugs have failed, surgical options should be considered.

If not, third-line agents are available; these are clobazam, phenobarbital, phenytoin, primidone, and tiagabine.

Less often used agents with either tolerability or safety problems or no Class I evidence for efficacy (acetazolamide, bromide, felbamate, sulthiame, vigabatrin) should be used as a last resort.

GENERALIZED SEIZURES Valproate, lamotrigine, and topiramate are

the drugs of choice for the treatment of primary generalized tonic-clonic seizures.

insufficient data to support the use of any of the new AEDs as monotherapy in newly diagnosed primary generalized tonic-clonic seizures

topiramate was recently approved as initial monotherapy for primary generalized seizures in those older than 10 years of age.

GENERALIZED SEIZURES 75% to 85% of patients achieve complete

seizure control during monotherapy with VPA

Lamotrigine and topiramate are emerging as more often used therapies in children younger than 2 years of age because of the higher risk of valproate-associated hepatotoxicity in this population.

Phenobarbital and primidone are also effective, but because of their potential for adverse effects, they are usually reserved for second-line or third-line agents.

GENERALIZED SEIZURES Carbamazepine, phenytoin, and

oxcarbazepine can rarely exacerbate seizures in patients with primary generalized epilepsy syndromes.

Absence seizures Ethosuximide, VPA and lamotrigine are

effective for the treatment of absence seizures.

Ethosuximide may be preferred over VPA when only absence seizures are involved because of the potential for fewer serious adverse effects.

Ethosuximide is not effective against GTC seizures; therefore, valproate and lamotrigine are preferred if this seizure type is also present.

Absence seizures 70% to 90% of patients who were treated

with ethosuximide or valproate experienced cessation or a dramatic reduction in absence seizures.

The combination of ethosuximide and valproate is often effective when monotherapy fails to yield adequate results

Absence seizures Clonazepam is also effective against

absence seizures.

it should be reserved for patients in whom ethosuximide and valproate fail because of frequent dose-related adverse effects and the development of tolerance

Carbamazepine , phenobarbital, and phenytoin are ineffective for the treatment of absence seizures and may even exacerbate it

Myoclonic, atonic, and atypical absence seizures VPA is effective for the treatment of

myoclonic, atonic, and atypical absence seizures and is the initial drug of choice for patients with mixed seizure types.

It controls myoclonic seizures in 75% to 90% of patients with generalized idiopathic and juvenile myoclonic epilepsy.

Myoclonic, atonic, and atypical absence seizures Clonazepam is also effective as

monotherapy or in combination with VPA when either drug alone does not provide adequate seizure control.

Lamotrigine, topiramate, zonisamide, and felbamate are also effective against myoclonic, atonic, and atypical absence seizures.

Advantages of modern AEDs less enzyme inducing than CBZ, PHT or r

barbiturates

less enzyme inhibiting than VPA, or do not influence hepatic enzyme systems at all.

causes fewer adverse drug interactions.

fewer hormona metabolic disturbances

Advantages of modern AEDs malformation rate associated with LTG is

similar to CBZ or untreated women with epilepsy and is lower than VPA.

the absence of hypersensitivity reactions.

a modern AED should be preferred over a classic AED when starting drug treatment in a patient with new-onset epilepsy.

Finding the optimal dose of AED The drug is titrated to the lowest effective

dose.

If seizures continue, the daily dose is increased by small increments to the average effective dose

Most AEDs work within several days to a week of starting treatment.

Finding the optimal dose of AED If seizure control cannot be achieved with

the maximum tolerated dose, a dose reduction

to the previous average dose is recommended. If toxic symptoms or high plasma concentrations indicate an increased risk of toxicity before seizures are controlled, a second AED is added.

Monitoring treatment with antiepileptic drugs Target plasma AED concentrations are

available for a number of drugs.

Plasma concentrations are less useful than the clinical course.

Some patients have toxic symptoms at low concentrations, whereas others tolerate higher concentrations without apparent clinical symptoms.

Monitoring treatment with antiepileptic drugs If treatment is ineffective, monitoring of

concentration may unmask irregular drug compliance

Except for PHT, for which monitoring is strongly recommended because of the nonlinear saturation dose kinetics, monitoring of other AED plasma concentrations is optional and should be individualized (e.g., poor drug compliance or adverse events).

Monitoring treatment with antiepileptic drugs The therapeutic range for AEDs can be

different for different seizure types.

… higher to control CP seizures than to control tonic-clonic seizures.

Patients should be monitored chronically for seizure control, comorbid conditions, social adjustment (including quality-of-life assessments), drug interactions, compliance, and adverse effects.

.

Monitoring treatment with antiepileptic drugs Periodic screening for comorbid

neuropsychiatric disorders such as depression and anxiety is also important

Clinical monitoring involves identifying the number and type of seizures.

…a seizure diary.

…

ADVERSE EFFECTS Acute effects

… dose/serum concentration–related or idiosyncratic.

… Neurotoxic adverse effects

sedation, dizziness, blurred or double vision, difficulty with concentration, and ataxia.

can be alleviated by decreasing drug dose or avoided in some cases by increasing the drug very slowly.

… Most idiosyncratic reactions are mild, but they can be more serious including hepatitis or blood dyscrasias are serious but rare.

ADVERSE EFFECTS Acute effects

… Acute organ failure, generally occurs within the first 6 months.

… laboratory evaluations are not helpful in predicting or detecting the early stages and not recommended in asymptomatic patients.

… WBC and LFTs if the patient reports an unexplained illness (e.g., lethargy, vomiting, fever, or rash).

… adverse effects can occur despite serum concentrations within therapeutic range

ADVERSE EFFECTS Chronic effects

… osteomalacia and osteoporosis.

… ranging from asymptomatic high-turnover disease, with normal BMD, to markedly decreased bone BMD (osteoporosis)

… Etiology uncertain

… hypothesized that phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and valproic acid, may interfere with vitamin D metabolism.

ADVERSE EFFECTSChronic effects

osteomalacia and osteoporosis.

… ranging from asymptomatic high-turnover disease, with normal BMD, to markedly decreased bone BMD (osteoporosis)

… Etiology uncertain

… hypothesized that phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and valproic acid, may interfere with vitamin D metabolism.


cognition impairment

… No large differences between the older drugs

… phenobarbital and primidone appear to cause more cognitive impairment

… Phenytoin, particularly when serum concentrations are above the commonly accepted therapeutic range

… valproic acid may cause less impairment of cognition.


cognition impairment

… Patients changed from polytherapy to monotherapy also may demonstrate improvement

… newer agents believed to cause fewer neurobehavioral or cognitive effects.

… gabapentin and lamotrigine have been shown cause fewer cognitive impairments as compared with older agents

… topiramate may cause substantial cognitive impairment, when used at high doses or during rapid dose escalation.


worsening of seizures

… can result from either improper selection of an AED for a specific seizure type

… can represent a paradoxical toxic effect of the drug

Antiepileptic drug interactions

Older AEDs such as phenytoin, carbamazepine, phenobarbital and valproic acid can significantly interfere not only with each other and other AEDs, but also with other treatments.

Although newer AEDs have a more favourable pharmacokinetic profile, they are not entirely exempt from interactions andthey are also commonly administered in combination with older AEDs.


The AEDs that most commonly cause interactions with each other and with other drugs are older AEDs:

phenytoin, carbamazepine, phenobarbital, primidone and valproic acid.

Pharmacokinetic characteristics: they have high protein-binding capacity, exclusively or predominantly hepatic metabolism, potent enzyme induction and inhibition, and active intermediate metabolites.


In certain groups of patients, failure to anticipate potential interactions of AEDs with each other and with other drugs could lead to a major management problem

Patients with refractory epilepsy and elderly people are sections of the population in whom polypharmacy is the norm.

The interaction of AEDs with contraceptives is an aspect that must be taken into consideration in young women.


Cancer patients, patients undergoing treatment with immunosuppressants and those who are HIV positive or have a psychiatric disorder, often take drugs that interact with AEDs.

Antiepileptics are becoming increasingly widely used in other common conditions such as neuropathic pain and migraine.

Therapeutic considerations in the elderly and young Avoidance of AEDs that interact with other

medications that the elderly are taking.

… Many of the drugs are inducers or inhibitors of the CYP450 system,

Hypoalbuminemia is common in elderly, which can make monitoring and adjustment of serum drug levels of highly albumin-bound AEDs, such as phenytoin, valproic acid, and tiagabine, problematic.

increase in fat to lean body mass or decrease in body water, can affect the volume of distribution of some drugs, and therefore possibly the elimination half-life

Therapeutic considerations in the elderly and young declining renal and/or hepatic function require a

lower dose of the AED.

the pharmacodynamic response to AEDs can change as the patient ages because elderly patients may be more sensitive to various neurocognitive adverse effects of these drugs.

Elderly patients may demonstrate efficacy (e.g., control of seizures) at relatively lower serum concentrations as well.

Therapeutic considerations in the elderly and young For neonates and infants, an increase in the total

body water to body fat ratio and a decrease in serum albumin and -acid glycoprotein can result in volume of distribution changes that can affect the elimination half-life of the AEDs.

newborns up to the age of 2 to 3 years display decreased efficiency in renal elimination, with the newborn having the most significant impairment.

Hepatic activity is also reduced in this population.

by age 2 to 3 years, hepatic activity is more robust than in adults. Therefore, children require higher doses than adults, whereas neonates and infants require lower doses.

THERAPEUTIC CONSIDERATIONS IN WOMEN Estrogen has a seizure-activating effect

progesterone exerts a seizure-protective effect.

Hepatic enzyme inducers, increase the metabolism of steroid hormones and induce the production of sex hormone–binding globulin.

…decreases in the unbound fraction of the hormone.

… topiramate and oxcarbazepine at higher doses, can cause treatment failures in women taking oral contraceptives.

THERAPEUTIC CONSIDERATIONS IN WOMEN

…Valproic acid, benzodiazepines, and most of the newer AEDs, such as gabapentin, levetiracetam, tiagabine, and zonisamide, are not enzyme inducers and have not been associated with this effect.

THERAPEUTIC CONSIDERATIONS IN WOMEN In some women, vulnerability to seizures

is highest just before and during the menstrual flow and time of ovulation.

This can be related to progesterone withdrawal and changes in the estrogen-to-progesterone ratio.

Conventional AEDs should be tried first in these women.

THERAPEUTIC CONSIDERATIONS IN WOMEN Intermittent acetazolamide also

has been used but with variable and limited success.

Hormonal therapy with progestational agents also can be effective.

THERAPEUTIC CONSIDERATIONS IN PREGNANCY the possibility of increased maternal

seizures, pregnancy complications, and adverse fetal outcome.

Approximately 25% to 30% ↓and ↑

Increased seizure activity may result from either a direct effect on seizure threshold or a reduction in AED concentration.

THERAPEUTIC CONSIDERATIONS IN PREGNANCY An increase in clearance has been

reported for phenytoin, carbamazepine, phenobarbital, ethosuximide, lamotrigine, oxcarbazepine, and clorazepate.

Protein binding also may be altered.

… as early as the first 10 weeks of pregnancy and can take up to 4 weeks postpartum to return to normal.

THERAPEUTIC CONSIDERATIONS IN PREGNANCY There is a higher incidence of adverse

pregnancy outcomes in women with epilepsy(4% to 6%)

barbiturates and phenytoin are associated with congenital heart malformations, orofacial clefts, and other malformations.

Valproic acid and carbamazepine are associated with spina bifida (neural tube defect) and hypospadias.

THERAPEUTIC CONSIDERATIONS IN PREGNANCY the risk of neural tube defect

appears to be related to drug exposure during gestational days 0 to 28.

Other adverse outcomes associated with maternal seizures, but not necessarily caused by AEDs, are growth, psychomotor, and mental retardation.

THERAPEUTIC CONSIDERATIONS IN PREGNANCY Women with epilepsy are also more

likely to have miscarriages

Many of these teratogenic effects can be prevented by adequate folate intake;

Higher folate doses should be used in women with a history of a previous pregnancy with a neural tube defect.

THERAPEUTIC CONSIDERATIONS IN PREGNANCY New AEDs are reported to be less

teratogenic,

clinical data are still limited, and more experience is needed.

Some AEDs also can lead to neonatal hemorrhagic disorder, which can be prevented by the administration of vitamin K 10 mg orally, given to the mother daily during the last month of pregnancy.

THERAPEUTIC CONSIDERATIONS IN PREGNANCY Although AEDs pass into the breast

milk, the concentrations are very low, and the infant receives a subtherapeutic dose.

Taking AEDs with less protein binding results in more accumulation in breast milk.

THERAPEUTIC CONSIDERATIONS IN PREGNANCY The perimenopausal period can be

associated with worsening of seizures, possibly owing to fluctuations in sex hormones.

At menopause, seizures actually can improve

The effect of hormone-replacement therapy on seizure control is still unclear.

CLINICAL CONSIDERATIONS WITH SPECIFIC DRUGS

CARBAMAZEPINE

Advantages

Oral immediate- and extended-release solid and liquid dosage forms are available

The sustained- and controlled-release dosage forms allow for twice-daily dosing to reduce the peak-to-trough fluctuations.

Compared with other first-generation AEDs, carbamazepine causes minimal cognitive impairment.

CARBAMAZEPINE has an active metabolite that can

contribute to efficacy and toxicity.

Other drugs can alter the concentration of this metabolite without changing the concentration of the parent carbamazepine.

It induces its own metabolism, which requires careful dosage titration.

It also induces the metabolism of other medications, and other drugs may interact with it and/or the active metabolite

CARBAMAZEPINE

no parenteral formulation.

clinically meaningful CNS side effects including sedation and nausea.

Chronic carbamazepine use also has been associated with alterations in bone mineral density in some studies and decreases in 25-hydoxy (OH) vitamin D.

CARBAMAZEPINE

Place in Therapy

first-line therapy for patients with newly diagnosed partial seizures and for patients with primary generalized convulsive seizures who are not in an emergent situation

GABAPENTIN

Advantages

has multiple mechanisms of action and is mechanistically different from first-generation AEDs.

It is not metabolized and is excreted unchanged by the kidney.

Has a broad therapeutic index with minimal CNS adverse effects and no drug interactions.

Doses can be escalated rapidly.

GABAPENTIN

Disadvantages

absorbed by an active process that saturates at higher doses.

This may require more frequent daily dosing for patients who need doses greater than 3,600 mg/day.

Doses >3,600 mg/day may be required in some patients to achieve seizure remission.

There is no parenteral formulation.

GABAPENTIN

Place in Therapy

second-line agent for patients with partial seizures who have failed initial treatment

may be a role in patients with less severe seizure disorders, such as new-onset partial epilepsy, particularly in the elderly patient.

has been shown to be useful in the treatment of chronic pain and other nonepileptic conditions.

LEVETIRACETAM

Advantages

not metabolized by the cytochrome P450 system and no significant drug interactions,

Well tolerated, with transient sedation

LEVETIRACETAM

Disadvantages

Dose adjustments are needed for patients with decreased renal function

Slower dose escalation may be needed to avoid CNS adverse effects.

Behavioral problems can limit therapy in some patients.

LEVETIRACETAM

Place in Therapy

indicated for patients with partial seizures who have failed initial therapy.

recently approved as adjunctive treatment for myoclonic seizures in patients with juvenile myoclonic epilepsy.

PHENYTOIN

Advantages

Phenytoin has been used for more than 65 years

It is available in multiple dosage forms, allowing flexibility in dosing and use in emergent situations.

PHENYTOIN

Disadvantages

metabolism saturates at doses given clinically. This makes phenytoin a challenging drug to dose.

Phenytoin is an inducer of cytochrome P450 isozymes, is metabolized by cytochrome P450 enzymes, and is highly protein bound.

Phenytoin is associated with multiple significant adverse effects.

PHENYTOIN

Place in Therapy

a first-line AED for primary generalized convulsive and partial seizures.

Its use in therapy may be reevaluated as more experience is gained with newer AEDs.

TOPIRAMATE

Advantages

Topiramate has multiple mechanisms of action and is a broad-spectrum AED.

The kidney mainly eliminates it, although some liver metabolism occurs, especially if given concomitantly with enzyme inducers.

It has liner pharmacokinetics and few drug interactions.

TOPIRAMATE

Disadvantages

With rapid dosage escalation, topiramate can compromise cognitive functioning, including impaired word finding and short-term memory.

Renal stones and weight loss also have been associated with topiramate use.

There is no parenteral formulation.

TOPIRAMATE

Place in Therapy

Topiramate is a first-line AED for patients with partial seizures.

The drug is also approved for the treatment of tonic-clonic seizures in primary generalized epilepsy.

VALPROIC ACID/DIVALPROEX SODIUMAdvantages

available in multiple dosage formulations. The IV formulation is especially well tolerated.

It has a wide therapeutic index and can be considered a broad-spectrum AED.

It can be useful in other neurologic or psychiatric disorders, including migraine headache and bipolar disorder.

VALPROIC ACID/DIVALPROEX SODIUMDisadvantages

Some patients report significant weight gain which s can limit compliance.

Associated with alopecia, tremor, pancreatitis, polycystic ovary disease, and thrombocytopenia.

It has been associated with hepatic necrosis in young children.

It is an enzyme inhibitor and is involved in multiple drug-drug interactions

VALPROIC ACID/DIVALPROEX SODIUMPlace in Therapy

Valproic acid is first-line therapy for primary generalized seizures such as myoclonic, atonic, and absence seizures.

It can be used as both monotherapy and adjunctive therapy for partial seizures

it can be very useful in patients with mixed seizure disorders.

Seizure Disorders. 2 Definition of seizures Time-limited paroxysmal events that result from...

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