Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Charles Locock commented in the Lancet on his use of potassium bromide in 15 cases of "hysterical" epilepsy in young women. The next development was the serendipitous discovery of the anticonvulsant properties of phenobarbital by Alfred Hauptmann in 1912. This predated by more than 20 years the screening of potential therapeutic agents against "electrical seizures" in cats by Houston Merritt and Tracy Putnam. The result was the launching of phenytoin in 1938. Next came primidone, ethosuximide, carbamazepine and valproic acid, all of which can be regarded as first generation antiepileptic drugs (AEDs). Shortly after their synthesis, the benzodiazepines were rapidly recognised as having anticonvulsant activity. The modern era focused on the systematic screening of many thousands of compounds against rodent seizure models under the Anticonvulsant Drug Development Program in the US. This resulted in the global licensing, in chronological order, of vigabatrin, zonisamide, oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam, pregabalin and lacosamide.
7. Clinical Pharmacology of Selected AEDs
• Hydantoins:
• Clinical indications: “broad-spectrum AED”
• May exacerbate absence seizures.
• Pharmacokinetics:
• Phenytoin is highly fat soluble, highly protein bound (98%), readily absorbed from the GI tract,
• metabolized in the liver by CYP2C9/10. It induces CYP2C/3A families.
• Oral bioavailability is variable due to first-pass metabolism.
• Arelatively small change in dosage can produce a marked change in blood levels.
• Valproic acid lowers phenytoin plasma levels because it displaces phenytoin from plasma protein binding
sites and increases availability for metabolism.
• The metabolism of phenytoin is enhanced in the presence of inducers of liver metabolism (e.g.,
phenobarbital) and inhibited other drugs (e.g., cimetidine).
– Phenytoin should be used with caution in liver disease.
• Adverse effects:
• Gingival hyperplasia (20-40% of patients, especially children), coarsening of facial features, hirsutism,
skin rash, mental confusion, altered vitamin D and calcium metabolism.
• Dizziness, ataxia (inability to coordinate voluntary movement), nystagmus (involuntary movement of
eye), diplopia (double vision).
• Teratogenic effects: cleft palate, congenital heart disease, slowed growth, and mental retardation (“fetal
hydantoin syndrome”).
• Contraindication: Sinus bradycardia and SA block
• Black box warnings: Cardiovascular risk with rapid infusion.
8. • Barbiturates :
• Clinical indications: “broad-spectrum AEDs”
• Generalized tonic/clonic (grand mal) seizures; partial seizures; status epilepticus. Although it is commonly used
in children, it has the major disadvantage of sedation and cognitive impairment.
• May exacerbate absence seizures.
• Pharmacokinetics:
• 40-60% is plasma protein bound, metabolized by hepatic microsomal enzymes (mainly by CYP2C9), also a
potent inducer of enzymes (CYP2C; 3A & UGT, uridine diphosphate- glucuronosyltransferase).
• Adverse effects:
• Sedation, ataxia, impaired cognitive function, withdrawal seizures (thus, withdraw slowly), osteomalacia
(softening of the bone due to deficiency of vitamin D and calcium).
• Paradoxical hyperactivity in some children, and agitation and confusion in some elderly patients.
• Suspected TERATOGEN.
Primidone can be used in some patients who are hypersensitive to barbiturates. 85% of primidone activity is
due to metabolism to phenobarbital. Its activity is considerably less then phenobarbital, and toxic levels may be
reached before full control of seizures is achieved. It is often used in combination with other drugs, namely
phenytoin and carbamazepine.
9. • Succinamides:
• Clinical indications:
• Primary agent for the treatment of absence seizures. Not effective in tonic-clonic
seizures.
• Pharmaokinetics:
• Not plasma protein bound, but is metabolized by hepatic microsomal enzymes
(does not induce these enzymes).
• Adverse effects:
• Nausea and vomiting (onset of treatment)
• Suspected TERATOGEN, most notably in combinations with barbiturates.
10. • Iminostilbenes:
• Clinical indications: “broad-spectrum AED”
• Used for generalized tonic/clonic (grand mal) seizures; partial seizures; status epilepticus.
• Treatment of choice for partial seizures in pediatric patients. In controlled studies, it is similar to
phenytoin for focal and major motor seizures and has the least cognitive impairment.
• Pharmacokinetics:
• 80% is plasma protein bound.
• Metabolized to an epoxide that is as active as the parent compound by CYP3A4. Induces hepatic
microsomal enzymes CYP2C, CYP3A and UGT.
• Adverse effects:
• Diplopia, ataxia.
• May cause a rare but frequently fatal aplastic anemia (idiosyncratic).
• Suspected teratogen.
• Toxicity: Liver toxicity. Follow up with liver function test and CBC.
• Contraindications: MAO inhibitor use within 2 weeks.
• Black box warnings: Aplastic anemia/ agranulocytosis.
11. • Benzodiazepines:
• Clinical indications:
• Adjunct for absence seizures; myoclonic seizures; atonic seizures.
• Diazepam, lorazepam, and clorazepate are used for status epilepticus and as adjuncts for other
anticonvulsants.
• Rectal administration of diazepam gel (Diastat) is approved for intermittent use in adults as
treatment of increased seizure activity while taking other AEDs.
• Rectal diazepam (Diastat) in children may help terminate seizures activity (febrile seizures)
and reduce emergency room visits.
• Adverse effects:
• Use is limited due to 1) sedation and 2) tolerance.
• These drugs can also cause respiratory depression and bronchial hypersecretion. They should
be used with caution in patients with respiratory depression.
• In combination with sodium valproate, a suspected TERATOGEN.
12. • Carboxylic acid containing drugs
• Clinical indications: “broad-spectrum AED”
• Absence seizures, tonic-clonic seizures; myoclonic seizures, partial seizures.
• Pharmacokinetics:
• 70-90% plasma protein bound.
• Metabolized to a glucuronide conjugate by UGT enzymes and beta-oxidation. Inhibits UGT
enzyme.
• Inhibits metabolism of drugs that are substrates for CYP2C9 (phenytoin and phenobarbital)
Adverse effects:
• Nausea, vomiting.
• Hepatotoxicity (idiosyncratic).
• Can increase the blood levels of phenobarbital by as much as 40%.
• TERATOGEN: Neural tube defects, craniofacial, skeletal, cardiovascular, urogenital and cerebral
defects. Combination therapy including sodium valproate is thought to be the highest risk for
developmental effects.
• Toxicity: Hepatotoxicity. Follow up with liver function test. Adjust dose based on patient response
and desired serum levels.
• Contraindications: Hepatic impairment; pregnancy Black box warning: Hepatotoxicity, fetal risk
and pancreatitis.
13. • Gabapentin
• Clinical indications:
• Adjunct for partial and tonic-clonic seizures.
• Pharmacokinetics:
• Is not plasma protein bound and does not induce liver microsomal enzymes, therefore
producing no interactions with phenytoin, valproic acid, phenobarbital, or carbamazepine.
• Absorption in the GI tract shows saturability; increasing the dose does not
proportionately increase the amount absorbed.
• Adverse effects:
• Usually mild, but include somnolence, fatigue, ataxia, dizziness.
• Animal studies suggest that gabapentin is not teratogenic; however, the clinical data does
not have sufficient numbers to make a valid conclusion (Pregnancy category C).
14. • Lamotrigine
• Clinical indications:
• Adjunct therapy in patients with partial and tonic-clonic seizures with or without
secondary
•
generalization that are resistant to mono- therapy.
• Adverse effects:
• Dizziness, ataxia, somnolence/fatigue, and a rash in about 5% of patients (titrate drug).
• Elimination is more rapid in patients taking carbamazepine, phenytoin, and
phenobarbital. Half-life doubles in those taking valproic acid. Adverse effects are worse
in presence of enzyme inhibiting drugs (valproic acid and felbamate).
• Animal studies suggest that lamotrigine is not teratogenic; however, the clinical data
does not have sufficient numbers to make a valid conclusion despite the promising data.
15. • Oxcarbazepine
• Clinical indications:
• Partial seizures.
• Pharmacokinetics:
• Rapidly absorbed from the GI tract; metabolized in the liver (but not by cytochrome P450). Its active
metabolite has a
• t1/2 of 8-10 hr.
• Adverse effects:
• Dizziness, ataxia, somnolence/fatigue, diplopia, nausea/vomiting, and rash; thought to be less
frequent/severe than carbamazepine.
• Levetiracetam
• Clinical indications:
• Approved only as adjunct therapy in adults with partial seizures.
• Also used in generalized seizure types, including myoclonic and absence seizures.
• Pharmacokinetics:
• Is not plasma protein bound and is not metabolized by cytochrome P450. T1/2 is 6-8 hr, 66% excreted as
parent compound in the urine.
• Adverse effects: Serious reactions, depression, aggressive behavior, and GIT distress.
16. • Topiramate
• Mechanism of action:
• It reduces voltage-gated Na+ channels, may act on inactivated state
• It activates K+ currents, and GABA-A receptor currents.
• It also limits activation of AMPA-kainate subtype receptors.
• Clinical indications:
• Partial seizures.
• Primary generalized (tonic-clonic) seizures.
•
Adverse effects:
• Somnolence, fatigue, weight loss, nervousness, memory impairment, kidney stones.
• Contraindications: Alcohol use within 6 hours.
17.
18.
19. • First line treatment – this refers to a drug that is tried first and usually used on its own. If more than one
AED is listed in this row, one AED will be chosen and tried on its own first. If it does not work, the another
may be tried, or a drug from the ‘alternative first line drug’ list might be used.
•
• Alternative first line treatment – this is the ‘second round’ of AEDs that are tried. Like the ‘first line
treatment’ they are usually tried on their own, although sometimes combinations might be used.
•
• Adjunctive treatment (or ‘add-on treatment’) – these are AEDs that might be added to a first line treatment
(so are used in combination). This happens if a first line treatment does not control the seizures or is not
tolerated (for example, has side effects which means that the person cannot continue on that AED).
•
• Action if adjunctive treatment is not effective or tolerated – this is guidance on what to do if adjunctive
treatment does not work. In some situations, referral back to a neurologist, or on to specialist neurological
services (or ‘tertiary services’) might be needed. It may be that the person’s diagnosis needs to be looked at,
or a more specialist combination of treatment is needed.
•
• Cautions – this includes situations where extra care is needed when prescribing AEDs. Some AEDs can
have specific side effects, or there may be AEDs that make some seizure types worse rather than better.
•
• Tertiary epilepsy services – these are specialist services in hospitals or units that focus on specific
conditions. You have to be referred to tertiary services, usually from secondary care (your local hospital).
26. WHEN TO START ANTISEIZURE DRUG
THERAPY
• First-time unprovoked seizure — The term unprovoked seizure refers to a seizure of unknown etiology as well as one that occurs in
relation to a preexisting brain lesion or progressive nervous system disorder (often referred to as a remote symptomatic
seizure). Unprovoked seizures are distinct from provoked seizures provoked seizures: These are due to an acute condition such as a
toxic or metabolic disturbance, head trauma, or acute stroke (ie, acute symptomatic seizures).
• The decision of whether or not to start antiseizure drug therapy at the time of a first unprovoked seizure in an adult should be
individualized. The main factors to consider in making the decision are:
• ●The risk for recurrent seizures, which varies based on clinical factors
• ●The approximate benefit that can be expected from immediate antiseizure drug therapy on the risk of recurrent seizure
• ●The side effect profiles of various antiseizure drug options, which vary based on individual patient comorbidities and age
• ●Patient values and preferences, particularly with regard to the social consequences of a recurrent seizure (eg, implications for
driving or employment)
• The guideline offers the following specific recommendations:
• ●Adults with an unprovoked first seizure should be informed that their seizure recurrence risk is greatest early within the first two
years (21 to 45 percent).
• ●Clinical variables associated with an increased risk may include a prior brain insult, an EEG with epileptiform abnormalities, a
significant brain imaging abnormality, and a nocturnal seizure.
• ●Immediate antiseizure drug therapy, as compared with delay of treatment pending a second seizure, is likely to reduce recurrence
risk within the first two years but may not improve quality of life. Over a longer term (>3 years), immediate temporary antiseizure
drug treatment is unlikely to improve prognosis as measured by sustained seizure remission.
• In patients with a first unprovoked seizure who are found to have a CNS abnormality on neuroimaging (such as a brain tumor or
scar tissue from an old head injury or CNS infection), the risk of seizure recurrence is high. In this instance, most clinicians
would start treatment after the first unprovoked seizure. In fact, such patients likely have a sufficiently high risk of seizure
recurrence to meet criteria for epilepsy according to International League Against Epilepsy (ILAE) guidelines
27. • Risk of seizure recurrence — In prospective, randomized trials of individuals with a first unprovoked seizure,
the estimated two-year recurrence risk in untreated patients ranges from 40 to 50 percent . The risk of recurrence is highest
in the first year after the seizure and diminishes with time; 80 to 90 percent of patients who have recurrent seizures do
so within two years.
• The most replicated clinical factors associated with an increased risk for seizure recurrence after a first unprovoked
seizure include
• ●Epileptiform abnormalities on EEG
• ●Remote symptomatic cause, as identified by clinical history or neuroimaging (eg, brain tumor, brain malformation, head
injury with loss of consciousness, prior central nervous system infection)
• ●Abnormal neurologic examination, including focal findings and intellectual disability
• ●A first seizure that occurs during sleep (ie, a nocturnal seizure)
• Each of these factors has been associated with an approximately 2- to 2.5-fold increased risk for recurrent seizure in
studies
• Other potential risk factors for seizure recurrence have been investigated and remain more uncertain. As an example,
patients who have a first presentation with status epilepticus or with multiple seizures within a single day are more
likely to be treated with antiseizure drugs than are those with a single short-duration seizure. However, limited data
suggest that presentation with status epilepticus, in the absence of other risk factors, does not increase the risk of
seizure recurrence
• Similarly, whether a history of prior febrile seizures is associated with an increased risk of seizure recurrence after a
first unprovoked afebrile seizure is uncertain.
• Study results have conflicted as to whether a family history of epilepsy impacts recurrence risk . This varies according
to the epilepsy syndrome
28. • Benefit of early versus deferred treatment
• For adults presenting with an unprovoked first seizure, immediate antiseizure drug treatment reduces
the risk of seizure recurrence by about 35 percent over the next one to two years.
• However, studies suggest that starting an antiseizure drug has little impact on long-term outcome. At four
and five years after the first seizure, patients have similar rates of complete seizure remission whether
antiseizure drug treatment was initiated immediately after the first seizure or deferred until a second seizure
occurred.
• Second unprovoked seizure — Patients presenting with a second unprovoked seizure should be
started on antiseizure drug therapy, since seizure recurrence indicates that the patient has a
substantially increased risk for additional seizures (ie, epilepsy).
• Acute symptomatic seizure — Acute symptomatic seizures have a lower risk for subsequent
epilepsy compared with remote symptomatic seizures . Early management decisions, including whether
or not to start an antiseizure drug, depend upon multiple factors, including the severity of the
underlying illness, the cause and duration of the seizure, the expected risk of early recurrence, and
the risks associated with a recurrent seizure.
• Short-term antiseizure drug therapy may be indicated if the metabolic disturbance is expected to
persist or if the initial seizure is prolonged (as in the instance of status epilepticus).
29.
30. • Side effect profiles
• ●Neurocognitive side effects – Most antiseizure drugs are associated with a negative impact on cognition, but some are
more problematic than others .
• Among the older antiseizure drugs, studies suggest that phenobarbital is associated with greater impairments compared
with carbamazepine, valproate, and phenytoin, which have similar, but more modest negative effects.
• Among the newer antiseizure drugs, gabapentin and lamotrigine have been found to be less problematic than
carbamazepine in their effects on cognition. Negative cognitive effects are similar with oxcarbazepine and carbamazepine
.
• Finally, a significant minority of patients taking topiramate discontinue the drug because of clinically apparent cognitive
difficulties. In direct comparison studies, cognitive profiles in patients taking topiramate were worse than those taking
valproate, lamotrigine, or gabapentin .
• ●Hypersensitivity reactions – Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with
eosinophilia and systemic symptoms (DRESS) are rare but severe idiosyncratic reactions, characterized by fever and
mucocutaneous lesions are common.
• SJS and TEN have been most often associated with the use of carbamazepine, oxcarbazepine, phenytoin, lamotrigine,
and phenobarbital and less commonly with valproate and topiramate; however, they have been described with almost all
antiseizure drugs. The period of highest risk is within the first two months of use.
• For carbamazepine (and possibly phenytoin and oxcarbazepine), the risk may be higher in patients with the HLA-B*1502 or
HLA-A*3101 alleles. The former occurs almost exclusively in patients of Asian ancestry, including South Asian Indians. The
US Food and Drug Administration (FDA) recommends screening such patients for the HLA-B*1502 allele prior to starting
carbamazepine and possibly phenytoin.
• ●Suicidality – Antiseizure drugs as a class have been associated with an approximately twofold increased relative risk of
suicidal behavior . Some experts advise screening for depression at diagnosis of epilepsy and at each follow-up visit .
31. • ●Weight gain or loss – Weight gain is associated with valproate, gabapentin, carbamazepine, vigabatrin, pregabalin,
and perampanel. Weight loss has been reported with felbamate, topiramate, and zonisamide.
• Comorbid medical conditions — Medical comorbidities are important to consider when selecting an antiseizure drug.
Many antiseizure drugs are either metabolized by the liver, excreted by the kidneys, or both When a person has hepatic
or renal disease, it may be necessary to avoid certain antiseizure drugs or to adjust the dose. Other comorbidities can be
problematic because of potential drug side effects or drug interactions, while others may represent an opportunity to choose
an antiseizure drug that has efficacy in both conditions.
• Renal disease — Renally excreted drugs
include gabapentin, topiramate, zonisamide, lacosamide, levetiracetam, oxcarbazepine, and pregabalin (R PT LOG)
• The dose of these drugs should be adjusted based on the severity of renal impairment .
• In patients on hemodialysis, antiseizure drug regimens should be individualized based on drug levels and clinical response.
The renally excreted drugs and some others (eg, phenobarbital, lamotrigine) are removed by hemodialysis, and a low dose
should be supplemented after dialysis to maintain therapeutic levels. The effects of peritoneal dialysis on antiseizure
drug metabolism are not well studied, and antiseizure drug treatment in such patients may require additional
monitoring.
• Albuminuria (causing low serum albumin) and acidosis reduce protein binding fractions and binding affinity, leading to
increased fractions of free drug . For highly protein-bound antiseizure drugs, sub therapeutic total drug levels may be
sufficient , have efficacy as required and may also avoid toxicity in this setting
• Topiramate and zonisamide are associated with nephrolithiasis and should probably be avoided in patients with a history
of or who are prone to this condition. Renal tubular acidosis can also occur with these antiseizure drugs; patients with
preexisting conditions that make them prone to metabolic acidosis (eg, severe respiratory disorders, diarrhea) should also
consider avoiding these drugs or have more frequent monitoring of serum bicarbonate levels.
• In the setting of renal transplantation, potential drug interactions between antiseizure drugs and immunosuppressive therapy
should be considered. Enzyme-inducing antiseizure drugs may lower serum immunosuppressant levels, while enzyme-
inhibitors may increase levels.
32. • Hepatic disease — Some antiseizure drugs are associated with hepatic toxicity and should be avoided in
patients with preexisting liver disease. These include valproate and felbamate, and to a lesser
extent, phenytoin and carbamazepine
• Many other antiseizure drugs are metabolized fully or partially in the liver with caution and dose
adjustment when used in patients with chronic liver disease. These include carbamazepine, lamotrigine,
phenytoin, phenobarbital, clobazam, valproate,
felbamate, zonisamide, topiramate, oxcarbazepine, eslicarbazepine, and brivaracetam.
• Levetiracetam, gabapentin, pregabalin, and vigabatrin do not undergo hepatic metabolism and are less
problematic for use in patients with chronic liver disease.
• Psychiatric disorders —
• Some antiseizure drugs (valproate, lamotrigine, carbamazepine, oxcarbazepine) appear to have mood
stabilizing properties. Their efficacy in this regard is best established for bipolar disorder. However, many
physicians view these medications appropriate in patients with comorbid anxiety and depression.
• In contrast, some antiseizure drugs, in particular those that potentiate gamma-aminobutyric acid (GABA)
neurotransmission (phenobarbital, tiagabine, vigabatrin, topiramate), have been reported to cause or
exacerbate a depressed mood and perhaps should be avoided in patients with comorbid depression.
Similarly, drugs that have been reported to provoke psychosis (levetiracetam, topiramate,
vigabatrin, zonisamide, ethosuximide, and perampanel) may be less desirable in patients with that
history.
• Drug interactions are also a potential concern in patients with psychiatric disorders. Enzyme-inducing
antiseizure drugs can decrease the plasma concentration of many antidepressants including tricyclic
agents and selective serotonin reuptake inhibitors, as well as antipsychotic drugs and benzodiazepines
33. • Migraine — Some studies suggest that migraine may be more prevalent in patients with
epilepsy and vice versa Valproate, gabapentin, and topiramate are antiseizure drugs that
have demonstrated efficacy for migraine prevention in placebo-controlled trials .This
may provide an opportunity to limit polypharmacy in individuals with both migraine and
epilepsy.
• Osteoporosis risk — Antiseizure drugs in chronic use have been associated with bone loss.
Initially this association was observed for enzyme-inducing antiseizure drugs , but later
was found to extend to valproate as well as to some of the newer nonenzyme-inducing
antiseizure drugs . The evidence associating osteoporosis and antiseizure drug therapy may be
strongest for phenytoin. Osteoporosis is particularly problematic for patients with epilepsy,
as seizures are associated with falls and bone fractures
• While phenytoin should perhaps be avoided in patients in whom there is concern for bone
loss, there are insufficient data to recommend avoiding or choosing any other specific
antiseizure drug in order to limit the risk of osteoporosis
• Rather, monitoring of bone density, routine supplementation of calcium and vitamin D, and a
consistent exercise regimen are suggested for all patients on chronic antiseizure drug therapy.
34. • Others
• ●Diabetes – Because of its association with weight gain, insulin resistance, and polycystic ovarian syndrome, use
of valproate in individuals with diabetes or obesity should be carefully considered
• . Carbamazepine, vigabatrin, gabapentin, and pregabalin are also, but less frequently, associated with weight gain.
• Some antiseizure drugs (gabapentin, pregabalin, and possibly carbamazepine and topiramate) have efficacy in
treating pain associated with diabetic neuropathy valproate , gabapentin, and pregabalin.
• ●Thyroid disease – While many antiseizure drugs, in particular the enzyme-inducing agents, can alter thyroid hormone
levels, this is generally subclinical and should not impact drug choice . Enzyme-inducing agents should probably be avoided
in patients with severe thyroid dysfunction.
• ●Cancer – valproate may increase the toxicity of certain cancer chemotherapy agents. There also may be an increased
potential for allergic cutaneous reactions when antiseizure drugs are used during radiotherapy.
• ●HIV – Enzyme-inducing antiseizure drugs and those that are highly protein-bound may interact with antiretroviral therapy
of particular concern is that these drug interactions may cause minor reductions in the levels of protease inhibitors that could
lead to loss of viral suppression and the emergence of drug resistance. There are also concerns that phenytoin-associated
skin rash may be more common in HIV-positive patients. Lamotrigine doses may need to be increased with certain
medications including ritonavir and atazanavir. While early in vitro studies suggested that valproate might increase viral
replication, a series of patients treated with valproate maintained excellent control of both seizures and HIV.
35. • ●Cardiovascular disease – Should consider potential drug interactions between enzyme-inducing
antiseizure drugs and statins, calcium channel blockers, and warfarin . While, carbamazepine has been
associated with heart block and other bradyarrhythmias in susceptible individuals , clinically
significant ECG changes are uncommon with carbamazepine in older adult patients who do not have a
preexisting conduction defect .
• Because the cytochrome P450 enzymes are involved in cholesterol synthesis, it is possible that enzyme-
inducing antiseizure drugs may thereby affect vascular risk. In one small series, switching patients
from carbamazepine or phenytoin to noninducing antiseizure drugs levetiracetam or lamotrigine was
associated with improvements in serologic markers of vascular risk (eg, total cholesterol, triglycerides,
C-reactive protein) . Some studies have found that long-term monotherapy with carbamazepine,
phenytoin, or valproate, is associated with markers of increased cardiovascular risk, such as carotid
intimal thickening, abnormal cholesterol, homocysteine, and folate metabolism, and elevated levels of
C-reactive protein . However, no studies have clearly linked any specific antiseizure drugs to a higher or
lower risk of vascular events.
• ●Blood disorders – Certain antiseizure drugs (carbamazepine, phenytoin, ethosuximide, valproate) are
associated with neutropenia and agranulocytosis, and should be avoided in patients with blood
disorders.
• Similarly, drugs associated with thrombocytopenia (eg, carbamazepine, valproate, phenytoin) should be
avoided in patients with a low platelet count or a history of other bleeding diatheses and dengue .
• Women of childbearing age — A number of issues are important in women of childbearing age, especially
if they are considering becoming or are already pregnant.
• Folate should be prescribed to all women of childbearing age who are taking antiseizure drugs. Patients
taking valproate or carbamazepine should receive daily folic acid supplementation (4 mg/day) for one
to three months prior to conception. Women who are taking other antiseizure drugs should take the
dose of folic acid (0.4 to 0.8 mg per day).
36. • Hormonal contraception — Women should be informed about the interactions between antiseizure drug
therapies and hormonal pill, patch, or ring contraception and the availability of long-acting reversible
contraception (LARC), which is highly effective and avoids most if not all drug-drug interactions,
depending on the specific method.
• The expected contraceptive failure rate of 0.7 per 100 woman using oral contraceptives is increased to
3.1 per 100 woman-years in patients who concomitantly take enzyme-inducing antiseizure drugs
• While vigabatrin is not an enzyme inducer, lower levels of ethinyl estradiol have been reported in
volunteers taking this antiseizure drug.
• In addition to the effect of antiseizure drugs on hormonal contraceptive metabolism, combined hormonal
contraceptives can increase the metabolism of lamotrigine, thereby reducing the plasma drug
concentration. In other words, higher doses of lamotrigine may be needed in women taking combined
estrogen-progesterone contraception, and continuous dosing may be preferable to avoid increased
lamotrigine levels during pill-free intervals.
• Catamenial epilepsy — Many women with epilepsy report an association between the occurrence of their
seizures and certain phases of their menstrual cycle . Catamenial seizure clustering can occur in women
with any seizure type and epilepsy syndrome but may be more common among women with focal
compared with generalized epilepsy and among those with left-sided temporal epilepsy compared
with right-sided, multifocal, or extratemporal epilepsy .
• In general, research suggests that catamenial seizure patterns result from cyclic changes in hormone levels
during the menstrual cycle; changes in antiseizure drug levels due to endogenous metabolic effects may
also contribute. Estrogen levels peak mid-cycle and then, in women who do not conceive, fall through the
onset of menses. It is during the late part of the menstrual cycle (just before the onset of menses), during a
relative drop in estrogen levels, that seizures most often cluster . Periovulatory (mid-cycle) seizure
clustering can also occur.
37. • The mainstay of treatment of catamenial seizures is an antiseizure drug that is most effective for the
woman's epilepsy syndrome. However, when catamenial seizures are not controlled with antiseizure
drugs, clinicians may consider use of a continuous estrogen-progestin contraceptive on the theoretical
basis that suppressing estrogen fluctuations will lead to better seizure control. The rationale and use of
hormonal prophylaxis for catamenial epilepsy is similar to that in estrogen-associated migraine.
• Intermittent benzodiazepine treatment timed according to the vulnerable phase of the menstrual cycle is
also a common strategy.
• Clobazam is the only benzodiazepine studied systematically for this purpose. In a double-blind cross-
over study, clobazam (20 to 30 mg/day) was administered for 10 days in the high risk phase of the
menstrual cycle in 18 women with catamenial epilepsy. Fourteen patients reported better seizure control
with clobazam than placebo. Long term follow-up of patients who continued to use this treatment
strategy revealed seizure remission and/or significant reduction of seizures in five of nine patients .
These limited data support a fairly common practice of treating catamenial seizure exacerbations
with intermittent benzodiazepines with a long-acting agent such as lorazepam. A reasonable dose of
lorazepam in this setting is 0.5 to 1 mg two to three times daily.
• Very limited data suggest that appropriately timed acetazolamide may have some benefit in catamenial
epilepsy. Although cyclic natural progesterone has been reported to reduce seizure frequency in
observational studies, a randomized trial failed to confirm a benefit in 294 women with poorly
controlled seizures.
• Pregnancy and postpartum — Treatment of epilepsy during pregnancy must balance competing risks.
Both major and minor malformations are more common in fetuses exposed to antiseizure drugs in utero
compared with offspring of untreated women with epilepsy and women without epilepsy. The overall risk
of major malformations is 4 to 6 percent in exposed infants; valproate is a major contributor to this risk.
38. Dietary therapy (Ketogenic Diet)
• The ketogenic diet (KD) is an established, effective nonpharmacological treatment for
intractable childhood epilepsy
• The KD is a carefully prescribed, high fat, low carbohydrate, adequate protein diet that has
been employed in the treatment of medically refractory epilepsy since the early 20th century.
• The KD is considered when surgery is not an option and medications are either
ineffective or problematic in people with medically refractory epilepsy. The classic KD is
based on a ratio of fats to carbohydrates and protein; typically a ratio of 4:1 (fats to
carbohydrates and protein, respectively) is used. By limiting the dietary intake of
carbohydrates, ketone bodies (e.g., b-hydroxy- butyrate) produced via the breakdown of fatty
acids become the body’s primary fuel. Although the mechanism responsible for the diet’s
antiepileptic effects are not completely understood, the degree of ketosis often correlates with
the diet’s effectiveness. Successful use of the KD requires that it be prescribed and monitored
by physicians and dieticians who are well-trained in its use.
39. • A good intake of vitamin D (found in fortified milk, egg yolks, oily fish, sunlight)
• Calcium (dairy foods, leafy greens, broccoli, canned fish with bones)
• Folic acid (fresh fruits, vegetables, grains) should offset medication effects
• Consider vitamin D and calcium supplements if on long-term epilepsy treatment
• Excess Folic acid supplements should not be used because overly high blood
levels may decrease anticonvulsant efficacy.
40. • Antiepileptic drugs (AEDs) are increasingly used for the treatment of several non-epileptic
neurological conditions and psychiatric disorders.
•
• With regard to neurological conditions other than epilepsy, experimental evidence for the efficacy
of AEDs is only available for the treatment of patients with trigeminal neuralgia, neuropathic
pain syndromes, migraine and essential tremor. Carbamazepine is commonly prescribed as first-
line therapy for patients with trigeminal neuralgia.
• Gabapentin has been recently marketed for the management of neuropathic pain syndromes,
particularly diabetic neuropathy and postherpetic neuralgia.
• Valproic acid (sodium valproate), in the form of divalproex sodium, is approved for migraine
prophylaxis.
• Primidone can be considered a valuable option for the treatment of essential tremor.
• AEDs are also used to treat psychiatric conditions, in particular bipolar disorder. So far, the most
commonly utilized AEDs in the treatment of this disorder have been carbamazepine and valproic
acid, which have showed an antimanic efficacy and a probable long-term, mood-stabilizing effect in
many bipolar patients, including those refractory or intolerant to lithium.
• The availability of a new generation of AEDs has broadened the therapeutic options in bipolar
disorder. Lamotrigine, oxcarbazepine, gabapentin and topiramate appear to be promising in the
treatment of refractory bipolar disorder, as a monotherapy as well as in combination with traditional
mood stabilizers.
• In addition, newer AEDs appear to have a more favorable tolerability and less drug interaction
profile as compared to older compounds, thus improving compliance to treatment.
