seizure treatment

 Pharmacological treatment of epileptic seizures



For Bola Adamolekun, MD, Clinical Professor of Neurology, University of Tennessee Health Science Center
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    Epilepsy
    Epilepsy
    Pharmacological treatment of epileptic seizures

No drug is able to control all types of seizures and different patients require different types of drugs. Some patients need polytherapy. (See also the American Academy of Neurology and the American Epilepsy Society.)
Principles of long-term treatment

There are some general principles for using anticonvulsants:

    One drug, usually the 1st or the 2nd used, controls epileptic fits in about 60% of patients.

    If crises are difficult to control from the beginning (30-40% of patients), a number ≥ 2 drugs may eventually be necessary.

    If the crises are untreatable (refractory to an adequate trial with ≥ 2 drugs), patients should be referred to an epilepsy center to determine if they are candidates for surgery.

Some drugs (eg, phenytoin, valproate), given either EV or PO, reach the target therapeutic range very rapidly. Others (eg, lamotrigine, topiramate) can be administered initially at low doses and gradually increased over several weeks until the standard therapeutic dose is reached, based on the patient's weight. The initial dose should be appropriate to the patient's tolerance to the drug. Some patients have symptoms of drug toxicity when blood levels are low; others tolerate high levels without any symptoms. If crises continue, the daily dose will be increased by small increments. The appropriate dose of any drug is the minimum dose that blocks all crises and has the least adverse effects, regardless of the level of drug in the blood. Blood levels of drugs are just guidelines. Once the response to the drug is known, following the clinical course is more useful than measuring blood levels.

If toxicity develops before the seizures are controlled, the dose should be reduced to the pre-toxic dose. Then another anti-epileptic is introduced at low doses, which are gradually increased until reaching crisis control. Patients should be tightly controlled because the 2 antiepileptics can interact, interfering with the rate of drug metabolism. The ineffective drug initially used is then slowly scaled and finally completely suspended. The use of multiple antiepileptics should, if possible, be avoided due to the incidence of adverse effects, poor adherence and the fact that drug interactions increase significantly. The addition of a 2nd drug helps about 10% of patients, but the incidence of adverse effects has more than doubled. The blood level of anticonvulsants is altered by many other drugs, and vice versa. Physicians should be aware of all potential drug interactions before prescribing a new drug.

Once the crises are controlled, the therapy must be continued without interruption up to a period free of crises of at least 2 years. At that point, the suspension of the drug can be considered. Most of these drugs can be decreased by 10% every 2 weeks. A relapse is more likely in patients who have had one of the following conditions:

    Epilepsy since childhood

    Need for> 1 drug to have a crisis remission

    Previous crises while taking antiepileptics

    Partial or myoclonic crisis

    Underlying static encephalopathy

    Abnormal EEG findings over the last year

Structural lesions (highlighted in imaging studies)

About 60% of patients with relapses do so within 1 year and 80% within 2 years. Patients who relapse during a withdrawal of anticonvulsant therapy should be treated indefinitely.
Pharmacological choice for long-term treatment

The preferable drugs vary according to the type of crisis (Choice of drugs for crises). For more detailed drug-specific information, Pharmacological treatment of epileptic seizures: Specific anticonvulsants. Traditionally, the drugs have been separated into older and newer groups, based on when they were made available. However, some so-called new drugs have been available for many years now.

The broad-spectrum antiepileptics (which are effective in partial seizures and in various types of generalized seizures) include lamotrigine, levetiracetam, topiramate, valproate and zonisamide.

For generalized partial and tonic-clonic seizures, the most recent antiepileptics (eg, clobazam, clonazepam, ezogabine, felbamate, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, zonisamide) are no more effective than drugs already established. However, the newer drugs tend to have less adverse effects and to be better tolerated.

Infantile spasms, atonic crises, and myoclonics are difficult to treat. Valproate or vigabatrine is usually preferred, followed by clonazepam. In infantile spasms the use of corticosteroids, for a period of 8-10 weeks, is often effective. The optimal dosage remains controversial. You can also use the ACTH 20-60 IM units 1 time / day. A ketogenic diet (a very high fat diet that induces ketosis) can help, but it is difficult to maintain.

For juvenile myoclonic epilepsy, treatment is generally recommended for life. Carbamazepine, oxcarbazepine or gabapentin can exacerbate crises.

For febrile convulsions, medications are not recommended unless children have a subsequent seizure in the absence of febrile illness. Many physicians prescribe phenobarbital or other antiepileptics to children with febrile convulsions complicated to prevent the development of non-febrile seizures, but this treatment does not seem effective and, in the long run, phenobarbital reduces learning ability.

For seizures due to alcohol withdrawal, medications are not recommended. In contrast, the treatment of abstinence syndrome tends to prevent seizures. Treatment usually includes a benzodiazepine.
Choice of drugs for crises

Guydrugs



Use

Primary-generalized tonic-clonic crises


valproate


First line monotherapy


Lamotrigine

Levetiracetam

Topiramate


2-line monotherapy or additional therapy


Zonisamide


Additional therapy


Phenobarbital


Although effective, it is often considered 2nd line in monotherapy because it is sedative and can cause behavioral problems and learning in children

Partial crises, with and without secondary generalization


Carbamazepine

Lamotrigine

Levetiracetam

Oxcarbazepine

Phenytoin

Topiramate


First line monotherapy


Gabapentin

lacosamide

Pregabalin

valproate

Zonisamide


2-line monotherapy or additional therapy


clobazam

Ezogabina

felbamate

Tiagabine

Vigabatrin


3rd line monotherapy or additional therapy


Phenobarbital


Although effective, it is often considered less appropriate because it is sedative and can cause behavioral problems in children

Typical absence crisis


ethosuximide

Lamotrigine

valproate


First line monotherapy


clobazam

Levetiracetam

Topiramate

Zonisamide


These are also effective

Crisis of atypical absence

Absence crisis associated with other types of crisis


felbamate

Lamotrigine

Topiramate

valproate


First line monotherapy


Clonazepam


Effective, but often there is development of tolerance


Acetazolamide


Reserved for refractory cases

Infantile spasms

Atonic crises

Myoclonic crises


valproate

Vigabatrin


First line monotherapy; risk of irreversible visual field defects


Clonazepam


2nd line

Tonic and / or atonic crises in Lennox-Gastaut syndrome


Lamotrigine

Topiramate

valproate


First line monotherapy


clobazam

felbamate

Zonisamide


Sometimes as an alternative or additional therapy for atonic crises

Juvenile myoclonic epilepsy


valproate
First line monotherapy


Lamotrigine

Levetiracetam

Topiramate

Zonisamide


2-line monotherapy or additional therapy

Unclassifiable crises


valproate


First line monotherapy


Lamotrigine


2nd line monotherapy


Levetiracetam

Topiramate

Zonisamide


3rd line monotherapy or additional therapy
Adverse effects

All anticonvulsants can cause a scarlattiniform or morbilliform allergic rash, and none are completely safe during pregnancy (convulsive disorders during pregnancy). Carbamazepine, phenytoin and valproate are drugs in category D in pregnancy (ie for which the teratogenicity occurs in animals and in human pregnancies). The risk of neural tube defects is somewhat higher with valproate than with other commonly used anticonvulsants. The most recent drugs are category C (ie for which teratogenicity is verified in animals, but the risk for humans is unknown).

Anti-epileptic fetal syndrome (cleft lip, cleft palate, cardiac anomalies, microencephaly, growth retardation, developmental delay, abnormal facies, digital hypoplasia or limbs) occurs in 4% of children of epileptic mothers who take anti-cancer drugs during pregnancy. However, since generalized uncontrolled crises during pregnancy can lead to fetal harm and death, protracted drug treatment (convulsive disorders in pregnancy) is generally recommended. The risk must be taken into account: alcohol is more toxic to fetal development than any anti-epileptic drug. Taking folic acid supplements before conception helps to reduce the risk of neural tube defects and should be recommended for all women who are of childbearing age and who take anticonvulsants.

Many anticonvulsants decrease serum folate and B12 levels; oral vitamin supplements can prevent this effect.

Other adverse effects vary according to the medication (Pharmacological treatment of epileptic seizures: Specific anticonvulsants).
Specific anticonvulsants

The dosage is based on a weight of 70 kg if not specified.
Acetazolamide

This drug is indicated for refractory absence crises.

The dose is

    Adults: 4-15 mg / kg PO bid (do not exceed 1g / day)

    Children: 4-15 mg / kg bid PO (do not exceed 1g / day)

Therapeutic and toxic levels are

    Therapeutic levels: 8 to 14 μg / mL (34 to 59 μg / mL)

    Toxic levels:> 25 μg / mL (> 106 μmol / L)

Adverse effects include kidney stones, dehydration and metabolic acidosis.
Carbamazepine

This drug is indicated for partial, generalized and mixed seizures but not for myoclonic absences or crises.

The dose isAdults: 200-600 mg PO bid (the initial dose is the same for both normal and prolonged-release tablets)

    Children <6 years: from 5 to 10 mg / kg PO bid (tablets) or from 2.5 to 5 mg / kg PO qid (suspension)

    Children from 6 to 12 years: 100 mg PO bid (tablets) or 2.5 mL (50 mg) PO qid (suspension)

    Children> 12 years: 200 mg PO bid (tablets) or 5 mL (100 mg) PO qid (suspension)

Therapeutic and toxic levels are

    Therapeutic levels: 4-12 μg / mL (17-51 μmol / L)

    Toxic levels:> 14 μg / mL (> 59 μmol / L)

Adverse effects include diplopia, dizziness, nystagmus, gastrointestinal disorders, dysarthria, lethargy, leukopenia (3000-4000 / μL), severe rash (in 5%). The idiosyncratic adverse effects include granulocytopenia, thrombocytopenia, liver toxicity and medullary aplasia.

If the subjects are carriers of the HLA-B * 1502 allele, particularly Asians, the risk of severe rash (Stevens-Johnson syndrome or toxic epidermal necrolysis) is higher than the usual 5% frequency. Thus, before prescribing carbamazepine, doctors must evaluate HLA, at least in Asians.

The blood count should be routinely monitored during the 1st year of therapy. Decreases in GB counts and dose-dependent neutropenia (neutrophils <1000 / μL) are frequent. Sometimes, if the drug can not easily be replaced with another, decreasing the dose can handle these effects. However, if erythrocytes and GBs decrease rapidly, carbamazepine will be stopped immediately.
clobazam

This drug is indicated for absence crisis; it is indicated as additional therapy for tonic or atomic crises in Lennox-Gastaut syndrome and for refractory partial epileptic seizures with or without secondary generalization.

The dose isAdults: 5 mg to 20 mg PO bid

    Children: 5 to 10 mg PO bid (up to 20 mg PO bid in children> 30 kg)

Therapeutic levels are not clearly defined.

Side effects include drowsiness, sedation, constipation, ataxia, suicidal ideation, drug addiction, irritability and dysphagia.
Clonazepam

This drug is indicated for the atypical absence crises in Lennox-Gastaut syndrome, atonic and myoclonic seizures, infantile spasms, and, possibly, for the absence of refractory episodes in the etosuccimide.

The dose is

    Adults: initially, 0.5 mg PO tid, up to 5-7 mg PO tid for maintenance (maximum: 20 mg / day)

    Children: initially, 0.01 mg / kg PO from bid to tid (maximum: 0.05 mg / kg / day), increasing 0.25-0.5 mg every 3 days until seizure control or the onset of adverse events (usual maintenance dose: 0.03-0.06 mg / kg PO tid)

Therapeutic and toxic levels are

    Therapeutic levels: 25-30 ng / mL

    Toxic levels:> 80 ng / mL

Adverse effects include somnolence, ataxia, behavioral abnormalities, and partial or complete tolerance to beneficial effects (usually in 1-6 months); rare series reactions.
Divalproato

This drug has the same indications as the valproproate; that is, it is indicated by absence (typical and atypical), partial seizures, tonic-clonic seizures, myoclonic seizures, juvenile myoclonic epilepsy, infantile spasms, and neonatal or febrile convulsions. It is also indicated for tonic or atonic seizures in Lennox-Gastaut syndrome.

The dose is

    Adults: 5 mg / kg PO tid to be increased slowly, eg, from 1.67 to 3.33 mg / kg PO tid at weekly intervals, especially if other drugs have been used (maximum: 20 mg / kg tid)

    Children: initially, 5 mg / kg PO from bid to tid increasing 5-10 mg / kg / day every week (usual maintenance dose: 10-20 mg / kg PO tid)

Children may take delayed (slow) release tablets 1 time / day. The total daily dose is 8 to 20% higher than normal tablets. Valproate-delayed valvedrate release may have fewer side effects, improving therapeutic adherence.

Therapeutic and toxic levels are

    Therapeutic levels: 50-100 μg / mL (347-693 μmol / L) before the dose in the morning

    Toxic levels:> 150 μg / mL (> 1041 μmol / L)

Adverse effects include: nausea and vomiting, gastrointestinal intolerance, weight gain, reversible alopecia (in 5%), transient somnolence, transient neutropenia and tremor. It is idiosyncratic to have a hyperammonaemic encephalopathy. Fatal hepatic necrosis occurs rarely, particularly in young children with neurologic deficits treated with multiple antiepileptic drugs. The risk of neural tube defects is somewhat higher with valproate than with other commonly used anticonvulsants.

Because it is possible to have liver side effects, patients taking divalproate must perform liver function tests every 3 months for 1 year; if there is a significant increase in transaminases or ammonia (> 2 times the normal value), the drug should be discontinued. Upgrades of ammonia can be tolerated up to 1.5 times the upper normal limit without danger to the patient.
ethosuximide

This drug is indicated for absence crises.

The dose isAdults: 250 mg PO bid increasing of 250 mg \ every 4-7 days (maximum: 1500 mg / day)

    Children from 3 to 6 years: 250 mg PO 1 time / day (maximum: 20 to 40 mg / kg / day)

    Children> 6 years: initially, 250 mg PO bid, increasing of 250 mg / day, if necessary every 4-7 days (maximum: 1500 mg / day)

Therapeutic and toxic levels are

    Therapeutic levels: 40-100 μg / mL (283-708 μmol / L)

    Toxic levels:> 100 μg / mL (> 708 μmol / L)

Toxic levels have not been well established.

Side effects include nausea, lethargy, dizziness and headache. Idiosyncratic adverse reactions include leucopenia or pancytopenia, dermatitis and systemic lupus erythematosus.
Ezogabina

This drug is indicated for partial seizures, as a third line in monotherapy or additional therapy for patients ≥ 18 years.

The dose is

    Adults: 200 to 400 mg PO tid

No significant correlation between blood levels and pharmacological effect was observed.

Adverse effects include urinary retention, neuropsychiatric symptoms (eg, confusion, psychosis, hallucinations, suicidal ideation), QT interval elongation, dizziness and somnolence.
felbamate

This drug is indicated for refractory partial seizures and atypical absences in Lennox-Gastaut syndrome.

The dose is

    Adults: initially, 400 mg PO tid (maximum: 3600 mg / day)

    Children: initially, 15 mg / kg / day PO (maximum: 45 mg / kg / day)

Therapeutic and toxic levels are

    Therapeutic levels: 30-60 μg / mL (125-250 μmol / L)

    Toxic levels: not defined

Side effects include headache, fatigue, liver failure, and rarely medullary aplasia. Written informed consent is required for the patient.
fosphenytoin

This drug is indicated for the status of epileptic disease. It also has the same indications as phenytoin IV. They include tonic-clonic seizures, complex partial seizures, the prevention of secondary seizures at head injuries and the convulsive epileptic status.

The dose is

    Adults: 10 to 20 equivalents of phenytoin (PE) / kg EV or IM 1 time (maximum infusion rate: 150 PE / min)

    Children: as for adults

Heart rate and blood pressure should be monitored if the maximum infusion rate is used, but not at slower rates.

Therapeutic and toxic levels are

    Therapeutic levels: 10-20 μg / mL (40 to 80 μmol / L)

    Toxic levels:> 25 μg / mL (> 99 μmol / L)

Adverse effects include ataxia, dizziness, somnolence, headache, itching, and paresthesia.
GabapentinThis drug is indicated as adjunctive therapy for partial seizures in patients aged 3 to 12 years and as adjunctive therapy for partial seizures, with or without secondarily generalized tonic-clonic seizures in patients ≥ 12 years old.

La Dose is

    Adults: 300 mg PO tid (maximum: 1200 mg tid)

    Children from 3 to 12 years: 12.5-20 mg / kg PO bid (maximum: 50 mg / kg bid)

    Children ≥ 12 years: 300 mg PO tid (maximum: 1200 mg tid)

Toxic and therapeutic levels have not yet been determined.

Side effects include drowsiness, dizziness, weight gain, and headaches and, in patients aged 3 to 12, drowsiness, aggressive behavior, moodiness and hyperactivity.
lacosamide

This drug is indicated as second-line monotherapy or adjunctive therapy for partial seizures in patients ≥ 17 years.

The dose is

    Adults: 100 to 200 mg PO bid

Therapeutic and toxic levels are

    Therapeutic levels: from 5 to 10 ug / mL

    Toxic levels: not well established

Side effects include dizziness, diplopia, and suicidal ideation.
Lamotrigine

This drug is indicated as adjunctive therapy for partial seizures in patients ≥ 2 years, generalized seizures in Lennox-Gastaut syndrome and primary generalized tonic-clonic seizures. In patients ≥ 16 years, lamotrigine is used as monotherapy for partial or secondarily generalized seizures after suspending a concomitant use of enzyme-inducing anticonvulsants (eg, carbamazepine, phenytoin, phenobarbital) or valproate.

The metabolism of lamotrigine is increased by enzyme-inducing antiepileptics and decreased by antiepileptic enzymes-inhibitors (eg, valproate). Valproate inhibits a broad spectrum of liver enzymes. Lamotrigine may have a particular synergistic effect when used in association with valproate.

The dosage in adults is

    With anti-epileptic enzymes-inducers and without valproate: 50 mg PO 1 time / day for 2 weeks, followed by 50 mg PO bid for 2 weeks, then increasing of 100 mg / day every 1-2 weeks until the usual maintenance dose (150 -250 mg PO bid)

    With valproate and with or without anti-epileptic enzymes-inducers: 25 mg PO every other day for 2 weeks, followed by 25 mg PO 1 v / day for 2 weeks, then increasing by 25-50 mg / day every 1-2 weeks until usual maintenance dose (100 mg PO 1 time / day to 200 mg PO bid)

The dosage in patients <16 years is

    With anti-epileptic enzymes-inducers and without valproate: initially, 1 mg / kg PO bid for 2 weeks, followed by 2.5 mg / kg PO bid for 2 weeks, then 5 mg / kg PO bid (maximum: 15 mg / kg o 250 mg / day)

    With anti-epileptic enzymes-inducers and valproate: initially, 0.1 mg / kg PO bid for 2 weeks, followed by 0.2 mg / kg PO bid for 2 weeks, then 0.5 mg / kg PO bid (maximum: 5 mg / kg or 250 mg / day)

    With valproate and without anti-epileptic enzyme inducers: initially, 0.1-0.2 mg / kg PO bid for 2 weeks, followed by 0.1-0.25 mg / kg PO bid for 2 weeks, then 0.25-0 , 5 mg / kg PO bid (maximum: 2 mg / kg or 150 mg / day)

No significant correlation between blood levels and pharmacological effect was observed.

Common adverse effects include headache, dizziness, somnolence, insomnia, fatigue, nausea, vomiting, diplopia, ataxia, tremor, menstrual abnormalities, and rash (2 to 3%), which sometimes progress to Stevens-Johnson syndrome (in 1 / 50-100 children and 1/1000 adults). The risk of skin rash can be reduced by increasing the dose more slowly, especially if lamotrigine is added to valproate.
Levetiracetam

This drug is indicated as adjunctive therapy for the following types of seizures: partial seizures in patients ≥ 4 years, tonic-clonic seizures in patients> 6 years, myoclonic seizures in patients> 12 years old, and juvenile myoclonic epilepsy.

The dose isAdults: 500 mg PO bid (maximum: 2000 mg 2 bid)

    Children: 250 mg PO bid (maximum: 1500 mg bid)

No significant correlation between blood levels and pharmacological effect was observed.

Adverse effects include fatigue, weakness, ataxia, mood changes and behavioral changes.
Oxcarbazepine

This drug is indicated for partial seizures in patients aged 4-16 years as adjunctive therapy and for partial seizures in adults.

The dose is

    Adults: 300 mg PO bid, increasing 300 mg 2 v / day at weekly intervals based on needs up to 1200 mg PO bid

    Children: initially, 4 to 15 mg / kg PO bid, increasing after 2 weeks to 15 mg / kg PO 2 v / day (usual maintenance dose)

The therapeutic level is

    from 15 to 25 μg / mL

Adverse effects include: fatigue, nausea, abdominal pain, headache, dizziness, somnolence, leukopenia, diplopia and hyponatraemia (in 2.5%).
Phenobarbital

This drug is indicated for generalized tonic-clinical seizures, partial seizures, status epilepticus, and neonatal seizures.

The dosage is generally 1 time / day, but separate doses can be used. For all indications, except for the status epilepticus, the dose is

    Adults: 1,5-4 mg / kg PO before bedtime

    Infants: 3-4 mg / kg PO 1 time / day, then increase (based on clinical response and blood levels)

    Infants: 5-8 mg / kg PO 1 time / day

    Children between 1 and 5 years: from 3 to 5 mg / kg PO 1 time / day

    Children between 6-12 years: 4-6 mg / kg PO 1 time / day

The dosage for the status of evil epilepticus is

    Adults: 15-20 mg / kg EV (maximum infusion rate: 60 mg / min or 2 mg / kg / min)

    Children: 10-20 mg / kg EV (maximum infusion rate: 100 mg / min or 2 mg / kg / min)

Therapeutic and toxic levels are

    Therapeutic levels: 10-40 μg / mL (43-129 μmol / L)

    Toxic levels:> 40 μg / mL (> 151 μmol / L)

Adverse effects include drowsiness, nystagmus, ataxia, learning disabilities and, in children, paradoxical hyperactivity. The idiosyncratic negative effects include anemia and rash.
Phenytoin

This drug is indicated for generalized tonic-clonic secondary seizures, complex partial seizures and convulsive status epilepticus. It is also used to prevent secondary head trauma crises.

The dosage for all indications, except for the status epilepticus, is

    Adults: 4-7 mg / kg PO before going to bed

    Infants: initially, 2.5 mg / kg PO bid (usual maintenance dose: 2.5-4 mg / kg PO bid)

The dosage for the status of evil epilepticus is

    Adults: from 15 to 20 mg / kg EV

    Children from 6 months to 3 years: from 8 to 10 mg / kg EV

    Children from 4 to 6 years: from 7.5 to 9 mg / kg EV

    Children from 7 to 9 years: from 7 to 8 mg / kg EV

    Children from 10 to 16 years: from 6 to 7 mg / kg EVThe maximum infusion rate is 1 to 3 mg / kg / min for children (up to 16 years) and 50 mg / min for adults.

Therapeutic and toxic levels are

    Therapeutic levels: 10-20 μg / mL (40 to 80 μmol / L)

    Toxic levels:> 25 μg / mL (> 99 μmol / L)

Adverse effects include megaloblastic anemia, gingival hyperplasia, hirsutism, adenopathy, and osteoporosis. Folic acid supplements (0.5 mg / day) can markedly reduce gingival hyperplasia. At elevated blood levels, phenytoin may cause nystagmus, ataxia, dysarthria, lethargy, irritability, nausea, vomiting, and confusion. The idiosyncratic negative effects include rash, exfoliative dermatitis, and, rarely, exacerbation of epileptic seizures.
Pregabalin

This drug is indicated as an adjunctive therapy for partial seizures.

The dose is

    Adults: initially, 50 mg PO tid or 75 mg PO bid increasing according to need and tolerance up to 200 mg PO tid or 300 mg PO bid (maximum: 600 mg / day)

No significant correlation between blood levels and pharmacological effect was observed.

Adverse effects include dizziness, somnolence, ataxia, blurred vision, diplopia, tremors, weight gain.
primidone

This drug is indicated for generalized partial and tonic-clonic seizures.

The dose is

    Adults and children> 8 years old: initially, from 100 to 125 mg PO at bedtime, followed by 100 to 125 mg PO bid from the fourth to the sixth day and from 100 to 125 mg PO tid from the week to the ninth day, then 250 mg PO tid

    Children <8 years: initially, 50 to 125 mg PO before bedtime, increased from 50 to 125 mg / day every 3-7 days (usual maintenance dose: 3 to 8 mg / kg tid)

Therapeutic and toxic levels are

    Therapeutic levels: 5-12 μg / mL (23-55 μmol / L)

    Toxic levels:> 15 μg / mL (> 69 μmol / L)

The adverse effects are the same as phenobarbital: somnolence, nystagmus, ataxia, learning difficulties and, in children, paradoxical hyperactivity. The idiosyncratic negative effects include anemia and rash.
Tiagabine

This drug is indicated as adjunctive therapy for partial seizures in patients ≥ 12 years.

The dose isAdults: 4 mg 1 time / day PO, increased from 4 to 8 mg / day at weekly intervals up to 28 mg PO bid or 14 mg PO qid (maximum: 56 mg / day)

    Children ≥ 12 years: 4 mg PO 1 time / day, increased 4 mg / day, if necessary at weekly intervals up to 16 mg PO bid or 8 mg PO qid (maximum: 32 mg / day)

No significant correlation between blood levels and pharmacological effect was observed.

Adverse effects include dizziness, lightheadedness, confusion, slowed thinking, asthenia, tremor, sedation, nausea and abdominal pain.
Topiramate

This drug is indicated for partial seizures in patients ≥ 2 years, due to atypical absence crisis and as second-line monotherapy or adjunctive therapy for primary generalized tonic-clonic seizures.

The dose is

    Adults: 50 mg PO 1 time / day, increasing from 25 to 50 mg / day every 1-2 weeks (maximum: 200 mg bid)

    Children from 2 to 16 years: 0.5-1.5 mg / kg PO bid (maximum: 25 mg / day)

The therapeutic levels are

    5-20 mg / mL (probably)

Adverse effects include: decreased concentration, paresthesia, fatigue, language dysfunction, confusion, anorexia, weight loss, decreased sweating, metabolic acidosis, nephrolithiasis (1 to 5% of cases) and psychosis (1%).
valproate

This drug is indicated for absence (typical and atypical), partial seizures, tonic-clonic seizures, myoclonic seizures, juvenile myoclonic epilepsy, infantile spasms and neonatal or febrile convulsions. It is also indicated for tonic or atonic seizures in Lennox-Gastaut syndrome. Valproate inhibits a broad spectrum of liver enzymes.

The dose is

    Adults: 5 mg / kg PO tid, to be slowly increased, eg, from 1.67 to 3.33 mg / kg tid at weekly intervals, especially if other drugs have been used (maximum: 20 mg / kg tid)

    Children: initially, 5 mg / kg PO bid or tid, increased by 5-10 mg / kg / day every week (usual maintenance dose: 10-20 mg / kg tid)

Therapeutic and toxic levels are

    Therapeutic levels: 50-100 μg / mL (347-693 μmol / L) before the dose in the morning

    Toxic levels:> 150 μg / mL (> 1041 μmol / L)

Adverse effects include nausea and vomiting, gastrointestinal intolerance, weight gain, reversible alopecia (in 5%), transient somnolence, transient neutropenia and tremor. It is idiosyncratic to have a hyperammonaemic encephalopathy. Fatal hepatic necrosis occurs rarely, particularly in young children with neurologic deficits treated with multiple antiepileptic drugs. The risk of neural tube defects is somewhat higher with valproate than with other commonly used anticonvulsants.

Because it is possible to have adverse liver effects, patients taking valproate should perform liver function tests every 3 months for 1 year; if there is a significant increase in transaminases or ammonia (> 2 times the normal value), the drug should be discontinued. Upgrades of ammonia can be tolerated up to 1.5 times the upper normal limit without danger to the patient.
vigabatrin

This drug is indicated as an adjunctive therapy for partial seizures; it is also indicated for infantile spasms.

The dose is

    Adults: initially, 0.5-1.0 g / day PO, increased by 0.5-1.0 g every 1-2 weeks until the usual maintenance dose of 2-4 g / day

    Children: increase to 100 mg / kg / day PO in 1 week, then usual maintenance dose of 100-150 mg / kg / day

No significant correlation between blood levels and pharmacological effect was observed.

Adverse effects include drowsiness, dizziness, headache, fatigue and irreversible visual field defects (requires periodic visual field assessments).
Zonisamide

This drug is indicated as adjunctive therapy for partial seizures in patients aged ≥ 16 years; it is also indicated as an alternative or additional therapy for tonic or atonic seizures in Lennox-Gastaut syndrome.

The dose is

    Adults: 100 mg PO 1 time / day, up to 100 mg / day every 2 weeks (maximum: 300 mg bid)

Therapeutic and toxic levels are

    Therapeutic levels: 15 to 40 μg / mL (for levels> 30 μg / mL, adverse effects on the central nervous system are likely to increase)

    Toxic levels:> 40 μg / mLAdverse effects include sedation, exhaustion, dizziness, ataxia, confusion, cognitive impairment (eg difficulty in finding words), weight loss, loss of appetite, and nausea. Less commonly, zonisamide can cause depression, psychosis, urolithiasis and oligoidrosis.