Medications Used In Epilepsy – Part 2

EPILEPSY & SEIZURES SERIES • PART TWO BY BY PATRICIA MCGOLDRICK, NP & STEVEN M. WOLF, MD

The mainstay of treatment for epilepsy is medications. The goal of any therapy is to control seizures with minimal side effects and to achieve it by using as few medications as possible. When seizure control is not achieved, it is time to rethink the regimen and look at alternative treatments, including surgery and diet.

Seizures occur when there is a “burst of electricity in the brain,” or more, technically, when there is a disturbance in the balance between excitation and inhibition of the neurons. Epilepsy is diagnosed when a person has two or more unprovoked seizures—that is, seizures that are not caused by fevers, injuries, sleep deprivation, illness or drug or alcohol use. However, epilepsy may be diagnosed after one seizure when there is an abnormal EEG.

The International League Against Epilepsy (ILAE) has proposed a new definition for epilepsy which states that epilepsy be considered a disease of the brain defined by any of the following conditions:
1.At least two unprovoked seizures occurring more than 24 hours apart
2.One unprovoked seizure and a possibility of further seizures similar to the general recurrence risk after two unprovoked seizures (approximately 75% or more)
3.At least two seizures in a setting of reflex epilepsies

Epilepsy is treated, for the most part, with medication that works to sustain the balance between excitation and inhibition. Antiepileptic medications work to increase or decrease the levels of neurotransmitters or to affect the excitability of the neurons at a cellular level.

WHICH MEDICATION IS RIGHT?

When choosing medications to treat epilepsy, the clinician works to choose the correct medication for a specific type of seizures. In last month’s Exceptional Parent (EP) magazine the epilepsy article discussing the different type of Seizures. Being able to accurately describe and classify you loved one’s seizure type helps in picking the correct medications.

WHAT ARE SIDE EFFECTS?

The newer antiepileptic medications are generally considered to be better tolerated with fewer side effects. Examples of typical side effects are fatigue, dizziness, nausea, or even rash. Just because a medication has a potential side effect, does not mean that a patient will necessary experience it. “Potential side effects” just means there is a risk of experiencing those issues. Your doctor or nurse practitioner will discuss potential side effects, so you know the risks and what to potentially expect if something does not feel right. The patient or family’s job is to relate to the doctor or nurse practitioner what they are feeling on the medications.

All anti-epileptic medications carry an increased risk of suicidal behavior and ideation, in comparison to placebos. The diagnosis of epilepsy alone also increases the risk of suicidality.

FDA APPROVAL AND GENERIC MEDICATIONS

The American Academy of Neurology recommends the use of the newer medications and NOT to use generic medications. Generic medications may be bioequivalent to the brand name medication, but there is no generic-to-generic testing. Therefore, different brands of generic drugs are not bioequivalent and may result in increased seizure activity, although generic medications are usually much less expensive then the new medications. Have a discussion about this issue with your provider when picking medications, talking about cost and efficacy of medication. Many families feel comfortable starting with a generic and, if that fails, then switching to the name brand medications. Other families feel the opposite and do not want to take a chance using generic. Clearly ask your provider, “Why are you picking this medicine? Is it Generic or not and why?”

WHAT DOES “OFF LABEL USE” MEAN?

Medications used in the United States are approved by the Federal Drug Administration (FDA), usually initially in adults with partial seizures. If the pharmaceutical company goes on to petition for the FDA for additional approvals, they may later be approved for use in generalized seizures and in children. Often, however, the prohibitive expense results in the approval in children never being sought.

Meanwhile, clinicians typically use medications for “off-label” uses. The FDA states that “Good medical practice and the best interests of the patient require that physicians use legally available drugs and devices according to their best knowledge and judgment… If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale, and on sound medical evidence, and to maintain records of the use and effects.” i

CLASSIFYING THE MEDICINES – DESCRIBING THEM AS “FAMILIES”

It is very hard sometimes to understand how doctors and nurse practitioners jump from one medicine to another. We have tried here to group the medicines by “families,” based on their basic mechanism of action (meaning what receptor in the brain the drug works on). So, for example, if your loved one fails a medicine in the Sodium Channel family, your provider might switch them to a GABA family medicine or a Mixed Neurotransmitter family, since the Sodium Channel one did not work. Another is example is, if your loved one had good control on a Sodium Channel Medicine but has some side effects, then your provider might change them to another Sodium Channel Medicine with different or fewer side effects. Below we have attempted to categorize the medications to help you understand the big picture of the medicines and let you see where SOME of the logic of picking and choosing medicines come from.

Following is an overview of the currently available medications for treatment of epilepsy.

MEDICATIONS:

ACETAZOLAMIDE (DIAMOX)
(In a Novel Family of Medicine- Carbonic anhydrase Inhibitor)
• Approved as adjunctive treatment for refractory focal and generalized epilepsies, especially absence, and for catamenial (menstrual related) seizures
• Mechanism of action is carbonic anhydrase inhibitor
• Side effects include altered taste sensation, loss of appetite, drowsiness, tingling, renal stones, rash and muscle weakness
• Dosing: 250-1000mg/day

CARBAMAZEPINE (TEGRETOL, CARBATROL) (1964)
(In the Sodium Channel Family of Medicines)
• Approved by FDA for treatment of partial seizures, generalized seizures and mixed seizure types
• Most useful for treatment of partial seizures and can worsen certain types of generalized seizures, including atonic, absence and myoclonic
• Also used for trigeminal neuralgia and bipolar disorder
• Acts on sodium channels
• Therapeutic drug blood levels: 4-12

• Initially the medicine is started at a low dose then increased a week or two, later, as the body gets used to it. This is due to a process call autoinduction.
• Interactions: phenobarbital and phenytoin (Dilantin) can increase clearance and valproic acid can elevate carbamazepine levels and increase side effects
• Adverse effects worsen with higher doses and include- dizziness, double vision, nausea, vomiting, sedation (usually early on in  treatment), weight gain, severe rash, cardiac issues, hypertension, anemias and liver issues, as well as low sodium, jaundice and blood clots
• Reduces the effectiveness of oral contraceptives
• Pregnancy – can cause congenital malformations
• Dosing:200-800mg/day

CLOBEZAM (FRISIUM-ONFI) (2012)
(In Benzodiazepam family of Medicines)
• Approved as adjunctive therapy for generalized seizures, focal seizures and focal seizures with secondary generalization & patients with Lennox-Gastaut like seizures.
• Rapid onset – wide spectrum of effectiveness
• Enhances GABA (neurotransmitter)
• Rare side effects
• No Drug-Drug interactions
• Subject to low risk of tolerance (meaning needing a higher dose as the body could get “use to “ the medicine)
• Rare side effects include sleepiness, fatigue, behavioral issues, sedation, and cognitive impairment
• Does not interact with contraceptives
• Use with central nervous system depressants, such as alcohol and barbiturates
can worsen side effects- such as sedation and fatigue
• No negative indicators to date in pregnancy and breastfeeding
• Therapeutic blood levels not indicated
• Dosing 5mg-40mg/day

CLONAZEPAM
(In Benzodiazepam family of Medicines)
• FDA approved for use for seizures associated with Lennox-Gastault syndrome, for akinetic and myoclonic seizures and absence seizures that fail to respond to other medications
• Increases GABA
• Side effects- sedation behavioral and cognitive impairment, drowsiness, ataxia; personality and behavioral change in children- hyperactivity, blurred vision aggressiveness, and irritability (usually dose–related)
• Titrated slowly- larger dose at night to avoid side effects
• Dosing solely at night often effective for myoclonic jerks (and may be first choice)
• Drug monitoring not recommended in asymptomatic individuals (therapeutic range 20-0mg/L
• Withdrawal symptoms if a dose is missed may include increased pulse, tremor and general feeling of being unwell
• Do not use with glaucoma or liver dysfunction
• Benefits of breastfeeding thought to outweigh risks
• Pregnancy-data limited but no increase in major malformations in some small studies
• Dosing: 0.25-3mg/day

DIAZEPAM (VALIUM)
(In Benzodiazepam family of Medicines)
• Rescue medication – used in the community setting
• Soon to available in an “EPI-Pen like Device” for quick IM injection
• Available in oral, IV, IM, rectal gel
• Used in status epileptic and acute repetitive seizures
• Shorter duration of action than lorazepam but reaches brain more rapidly – IV lorazepam is first choice for status epilepticus when available
• Therapeutic drug monitoring not indicated
• Should be given immediately as a rescue medication, not as effective when administration is delayed
• Adverse reactions are common and include confusion, ataxia, dizziness, dysarthria, restlessness, irritability (paradoxical)
• Repeated administration can increase the risk of respiratory depression, sedation and hypotension
• Pregnancy- class D – use in the first trimester increases the risk of major malformations and cleft palate- use just before delivery places the infant at risk for respiratory depression, hypotonia, feeding difficulties, temperature instability and neonatal withdrawal syndrome
• Should not be used when breastfeeding because it causes feeding difficulties in the infant
• No effect on oral contraceptives but oral contraceptives reduce the clearance of diazepam
• Dosing: 2.5mg-20mg rectally; 1mg-10mg orally

ESLICARBAZEPINE ACETATE
(In the Sodium Channel Family of Medicines)
• Not yet available in the US
• Adjunctive therapy for complex partial seizures in adults
• Inhibits sodium channels
• No therapeutic range established yet
• Adverse effects: headache, dizziness, double vision, nausea and vomiting
• No serious reactions noted yet
• Reduces efficacy of oral contraceptives

ETHOSUXIMIDE (ZARONTIN) (1958)
(In the Mixed Neurotransmitter Family of Medicine)
•Indicated for childhood absence seizures – not effective for generalized tonic -clonic or partial seizures
• Works on T-calcium channels, NMDA and GABA
• Adverse effects usually mild and dose-dependent but gastrointestinal side effects are fairly common
• Blood levels 40-100 mcg/mL but routine monitoring is not useful

FELBAMATE (FELBATOL) (1993)
(In the Mixed Neurotransmitter Family of Medicine)
• Indicated in patients with Lennox-Gastault syndrome whose seizures are not controlled with other medications
• Also used for refractory partial seizures with or without secondary generalization
• Works on sodium channels, NMDA and GABA
• Show significant effects in seizure reduction
• Severe adverse reactions include life-threatening aplastic anemia and liver failure – this is common if the patient has a history of allergy or anemia on previous anti-epileptic medications or has a history of immune disorders, especially lupus
• Common side effects include anorexia, nausea, vomiting, and weight loss, insomnia and irritability in children; and are most likely to occur within the first 3 months of treatment
• Medication should be given at 8 am and noon to avoid side effect of insomnia
• If patient is on the ketogenic diet, tablet should be used instead of liquid because there is a large amount of sorbitol in liquid
• Bloods should be checked before initiating treatment and monitored at regular intervals
• Felbamate Increases phenytoin levels
• Dosing 1600-3600mg/day

GABAPENTIN (NEURONTIN) (1993)
(In a Novel Family of Medicine- Calcium Channel Drug)
• Indicated for adjunctive therapy in adults and children over 3 years old for partial seizures
• Works on calcium channels
• Side effects include central nervous system depression (drowsiness, sedation) and are generally short-lived; other side effects include emotional lability and hostility and a rare rash
• No drug to drug interaction, including oral contraceptives and antiepileptic medications
• No need for therapeutic drug monitoring of blood
• Not to be used in pregnancy
• Limit use while breastfeeding
• Seems to increase GABA and decrease glutamate but mechanism not fully understood
• Dosing 3600-4200mg/day

LACOSAMIDE (VIMPAT) (2008)
(In the Sodium Channel Family of Medicines)
• Approved as adjunctive treatment for partial onset seizures in patients over 16 years old
• Advantages- works in refractory patients
• Mechanism of action- works on slow sodium channels
• Low potential for interactions with other drugs
• No rashes or weight changes in clinical trials
• Side effects- dizziness
• No need for drug level monitoring
• Can cause EKG changes in patients with cardiac conduction problems or cardiac issues
• Should not be used in pregnancy or breastfeeding
• Does not interact with oral contraceptives
• Dosing: 200-400mg/day

LAMOTRIGINE (LAMICTAL) (1994)
(In the Sodium Channel Family of Medicines)
• Indicated for adjunctive therapy for partial onset seizures in adults and children; monotherapy in partial onset seizures, monotherapy for generalized seizures associated with Lennox-Gastault syndrome and tonic-clonic seizures in generalized epilepsy
• Frequently used to treat absence seizures in children and adolescents
• Acts on sodium channels thereby blocking release of glutamate (excitatory neurotransmitter)
• Advantages- well-tolerated, does not worsen cognition, synergistic with valproic acid
• Disadvantages- risk of severe rash (lower risk with slow initiation and titration)
• Levels reduced by tegretol, phenytoin and other enzyme inducing antiepileptic drugs
• Rare indications for following blood levels, except in pregnancy
• Common side effects- dizziness, ataxia, somnolence, headache, double vision, blurred vision, nausea, vomiting, insomnia
• Use in pregnancy – slight increase in risk of congenital malformations, including oral clefts
• Breastfeeding- no adverse effects
• Can lower efficacy of oral contraceptives
• Dosing 200-400mg/day (and higher)

LEVETIRACETEM (KEPPRA) (1999)
(In a New Family of Medicine- SV2A Receptor Drug)
• Indicated for monotherapy in the treatment of partial onset seizures in adults and children over 6 years old
• Adjunctive therapy for partial onset seizures in adults and children over 1 month old
• Used for myoclonic seizures, photosensitive seizures, status epilepticus and neonatal seizures
• Works on modulating the activity of the SV2A protein
• Well tolerated when used with steroids (as in patients with brain tumors)
• Side effects- sleepiness, irritability, nausea, headaches, depression, emotional lability (mostly with higher doses and previous history of behavioral problems or psychiatric diagnosis)– no effect on cognition
• Pregnancy – decreases blood concentration- after delivery, maternal serum concentrations increase rapidly, so blood levels should be monitored during pregnancy and dose decreased soon after delivery
• Few observations of major congenital defects
• Breastfeeding- concentrations are low in neonate but elimination is longer
• Oral contraceptives- no interactions
• Dosing- 1000-3000mg/day

LORAZEPAM (ATIVAN)
(In Benzodiazepam family of Medicines)
• Indicated as first line treatment for status epilepticus – usually given IV or IM
• Also used in adults for anxiety and sedation
• Enhances action of GABA
• Less risk of hypotension than with diazepam (which is also used for status epilepticus)
• Tendency for development of tolerance
• Common reactions- respiratory depression, sedation, dizziness, vertigo, weakness and unsteadiness
• Less common- disorientation, depression,
• Pregnancy use – only in life-threatening situations
• Not to be used in breastfeeding
• Oral contraceptives- may need to increase dose
• Dosing:0.5-6mg/day

MIDAZOLAM
(In Benzodiazepam family of Medicines)
• Licensed in the United States for conscious sedation, anesthesia and sedation in intensive care units
• Benzodiazepine that is used for treatment of status epilepticus and given nasally, intravenously or through buccal mucosa
• Alternative to Diastat (rectal valium)
• Short-lasting
• Rescue medication- used in the community setting -fewer relapses in one hour than with diazepam
• Easier to use inpatients in wheelchairs than rectal valium
• Most pediatric neurologists do not recommend a test dose administered in patient
• Severe adverse reactions of respiratory depression and variations in blood pressure and pulse are only reported with intravenous use in an inpatient settings
• Side effects include gastrointestinal disturbances, jaundice, anaphylaxis, drowsiness, hallucinations, laryngospasm, drowsiness, ataxia, amnesia, fatigue, dizziness and vertigo,
• Pregnancy – no specific evidence of fetal malformations
• Breastfeeding – readily crosses into breast milk but no evidence of harm
• No interaction with oral contraceptives
• Dosing: 5-10mg

OXCARBAZEPINE (TRILEPTAL) (1991)
(In the Sodium Channel Family of Medicines)
• Indications- monotherapy and adjunctive therapy for partial-onset seizures
• Multiple mechanisms of action including acting on sodium, potassium and calcium channels
• Not associated with serious anemia and agranulocytosis as with carbamazepine
• No cognitive impairment in drug trials- fewer drug interactions due to low protein binding
• Side effects- drowsiness and low sodium (more in adults)
• Serious reactions include anaphylaxis, angioedema, rash, and anemia
• Major congenital malformation rates are comparable to rate in pregnancies in women with epilepsy on or off antiepileptic medications
• Blood levels should be monitored with renal impairment, to rule out non-compliance and during pregnancy because levels increase and increased markedly after delivery so doses may need to be changed
• Breastfeeding – effects are unknown
• Oral contraceptives reduce the efficacy of oxcarbazepine
• Recently released in extended release formulation- Oxtellar
• Dosing 150mg-3000mg/day

PERAMPANEL (VICAMPA) (2013)
(In New Family of Medicines- AMPA Channel Drug)
• Works on AMPA channels
• Indicated for adjunctive treatment of partial complex seizures
• Dosing- 4-12mg/day

PHENOBARBITOL (1912)
(In GABA Family of Medicines)
• Used for febrile seizures, tonic-clonic seizures, status epilepticus and eclampsia
• First line for treatment of partial and generalized tonic-clonic seizures in developing countries because of its low cost and ability to administer once daily
• Increases GABA and glutamate
• Blood levels 15-40mcg/mL

• Common side effects include drowsiness, mood changes, impairment of cognition and memory- at high doses may develop nystagmus, ataxia, slurred speech, disinhibition, anemias and tolerance with long-term use
• Serious reaction – respiratory depression
• Pregnancy – baby may experience withdrawal and trouble breathing; risk of congenital malformation
• Should not be taken when breastfeeding
• Interacts with oral contraceptives, causing contraceptive failure and breakthrough bleeding
• Valproate increases phenobarbitol concentration
• Interacts with a variety of medications, including steroids, warfarin, some antibiotics and antihistamines
• Blood level monitoring is recommended when the patient is on multiple anti-epileptic medications
• Dosing 30mg-300mg/day

PHENYTOIN (DILANTIN-FOSPHENYTOIN-CEREBYX) (1938)
(In the Sodium Channel Family of Medicines)
• Used for partial onset and generalized seizures and for status epilepticus (phosphenytoin and cerebyx)
• Blocks sodium channels
• Advantage-inexpensive, long half-life
• Must closely monitor blood levels, although levels often fluctuate – therapeutic level is 10-20 mcg/mL
• Side effects- gum hyperplasia, hirsutism, ataxia, slurred speech anemias, impotence; long-term use can lead to peripheral neuropathy and osteoporosis
• Pregnancy-preferably should not be on phenytoin- if needed, lowest dose possible should be used
• Usually considered safe in breastfeeding
• Multiple drug interactions including (but NOT limited to) psychiatric medications, calcium channel blockers, digoxin, cholesterol-lowering agents, warfarin, antifungals, antibiotics, felbamate, INH, topiramate, carbamazepine, phenobarbitol and vigabatrin
• Phenytoin increases blood levels of felbamate, oxcarbazepine, and topiramate
• Phenytoin lowers blood levels of benzodiazepines
• Carbamazepine , phenobarbitol and vigabatrin increase the blood levels of phenobarbital
• Dosing 200-400mg/day

POTIGA (EZOGABINE) (2012)
(In a New Family of Medicine – Potassium Channel Drug)
• Indications- FDA approved as add-on therapy for partial onset seizures with or without secondary generalization in patients 17 and older
• Mechanism of action : enhances transmembrane potassium currents, stabilizing resting membrane potential and reducing brain excitability
• Side effects include urinary retention, hallucination at higher doses, psychosis at higher doses,
• Most common side effects were dizziness, confusional state, fatigue and somnolence – less common in studies and in Europe were double vision, blurred vision, nausea, constipation, dyspepsia, fatigue and weight gain. With long term use skin and retina discoloration may occur.
• Interacts with digoxin – may increase Dilantin levels and use of alcohol increased the incidence of adverse reactions
• The dose of potiga should be increased when phenytoin (Dilantin) or carbamazepine (tegretol, carbatrol) are added
• Seems not to interfere with oral contraceptives
• Can increase QT interval (cardiac)
• Increased risk urinary retention first 6 months
• Dosing: three times a day 150mg-600mg/day

PREGABALIN (2005)
(In the Calcium Channel Family of Medicine)
• Indicated as adjunctive treatment for focal epilepsies in adults and children over 12 years old
• Also used for neuropathic pain
• Works on calcium channels
• Adverse reactions are mild to moderate and include sedation, dizziness, weight gain, gastrointestinal side effects and myoclonus (should not be used in generalized epilepsies)
• Not recommended for use in pregnancy
• Should be cautious in breastfeeding, as no studies are available
• Does not interact with oral contraceptives
• Low interaction with other meds except for carbamazepine, which may lower pregabalin blood concentrations
• Dosing: 150-600mg/day

PRIMIDONE (MYSOLINE) (1954)
(In GABA Family of Medicines)
• Treatment of generalized tonic-clonic seizures and complex partial seizures – second line treatment for juvenile myoclonic epilepsy
• Partially metabolized to phenobarbitol
• Plasma levels 5-12 mcg/mL
• Common (but usually transient) side effects of drowsiness, listlessness, visual disturbances, nausea, headaches, dizziness, vomiting, nystagmus and ataxia
• Serious reactions include anemias, elevated liver enzymes, arthralgia and osteomalacia
• Pregnancy – can cause low folate levels and coagulation disorders in neonates and there is some evidence for congenital malformations
• Breastfeeding – can cause somnolence and drowsiness in nursing newborns
• Interacts with oral contraceptives – causing breakthrough bleeding and failure of contraceptive therapy
• Interacts with numerous medications, similarly to phenobarbital
• Dosing- 50-2000mg/day

RUFINAMIDE (BANZEL) (2009)
(In the Mixed Neurotransmitter Family of Medicine)
• Adjunctive treatment for partial onset seizures and seizures associated with Lennox-Gastault syndrome
• Main mechanism of action is GABA and sodium channels
• Common side effects are dizziness, fatigue, nausea, vomiting, double vision and somnolence
• Can cause shortening of QT interval (cardiac)
• Valproic acid increases rufinamide concentration
• Does not decrease seizure activity when used with carbamazepine
• Rufinamide increases the serum concentration of carbamazepine, lamotrigine, and phenobarbital
• Decreases efficacy of oral contraceptives
• No need for blood level monitoring
• Not indicated for use during pregnancy
• Should not be taken when breastfeeding
• Dosing 400-3200mg/day

STIRIPENTOL
(In GABA Family of Medicines)
• Not available in the United States
• Used in severe myoclonic epilepsy in infancy (Dravet’s syndrome)
• Enhances GABA
• May need to decrease dosing of clobezam and should decrease dose of carbamazepine
• No indication for blood monitoring
• Common side effects are anorexia, weight loss, drowsiness, ataxia, nausea, lethargy, vomiting, tremor and in rare cases aplastic anemia
• Complete blood count and liver functions should be checked before treatment and every 6 months during treatment
• No studies on use in pregnancy and breastfeeding
• Dosing: 50mg-4gm

TIAGABINE (GABATRIL)
(In GABA Family of Medicines)
• Indicated for adjunctive therapy for partial seizures with or without secondary generalization in adults and children over 12
• Increases GABA levels
• Disadvantages- requires slow titration because of potential adverse side effects and can aggravate generalized seizures
• No evidence to recommend routine monitoring of blood levels but patients seem to respond best with trough levels greater than 20 mcg/mL and even better at trough levels of 40 mcg/mL

• Side effects- dizziness, weakness, nervousness, tremor, diarrhea, depression and emotional lability- usually can be managed by slow titration and dosing multiple times per day
• Not recommended in pregnancy
• Women who are taking tiagibine and breastfeeding should monitor their infants for adverse events
• Does not interact with oral contraceptives
• Minimal interaction with other anti-epileptic drugs
• Dosing:32-56mg/day

TOPIRAMATE (TOPAMAX) (1997)
(In the Mixed Neurotransmitter Family of Medicine)
• Indicated as monotherapy for partial onset and primary generalized tonic-clonic seizures in patients 10 years of age and older; adjunctive therapy for partial seizures in adults and pediatric patients 2-16 years old; adjunctive therapy in primary generalized tonic-clonic seizures in adults and pediatric patients 2-16 years old and seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older
• Several mechanisms of action include actions on sodium channels, calcium channels, inhibition of carbonic anhydrase and decrease in glutamate activity
• Side effects- cognitive dulling (word finding difficulties and memory disturbances,) somnolence, dizziness, ataxia, nervousness, and fatigue- tend to be worse while titrating and reduce over time
• Minimal drug interactions although phenytoin and carbamazepine may increase topiramate elvels
• Increased rate of congenital malformations (cleft palate) when used in pregnancy
• Excreted in high concentrations in breast milk if taken at doses higher than 200mg/day
• Dosing 200-400mg/day
• Newly available in extended release for once daily dosing (Trokendi XR)

VALPROATE (DEPAKOTE, DEPAKENE, STAVZOR
(In the Mixed Neurotransmitter Family of Medicine)
• FDA approved for monotherapy and adjunctive therapy for partial seizures, simple and complex absence seizures and as adjunctive therapy for multiple seizures types including absence, photosensitive and generalized tonic-clonic, absence and myoclonic status epilepticus, status epilepticus
• Enhances GABA, works on sodium and calcium channels and works on stabilizing mood by its action on dopamine and serotonin neurotransmitters
• Severe (rare) adverse events-pancreatitis, hepatic (liver) dysfunction, Parkinsons
• Side effects- weight gain, nausea, vomiting, diarrhea, anorexia, abdominal pain, tremors, dizziness, agitation, hair loss, osteomalacia • Pregnancy –increased risk of major congenital malformations, delayed intellectual development in children, craniofacial abnormalities (fetal valproate syndrome,) neuronal tube defects- must have folic acid supplementation
• Breastfeeding –not contraindicated
• Valproate has no effect on oral contraceptives
• Dosing -250-3000mg/day

VIGABATRIN (SABRIL) (2009)
(In GABA Family of Medicines)
• FDA approved as monotherapy for infantile spasms and adjunctive therapy for refractory complex partial seizures
• Inhibitor of transaminase – increases GABA
• Advantages- very effective for two severe types of seizures— infantile spasms and refractory partial seizures
• Adverse effects – visual field loss (of peripheral vision, worse towards the nose)
• Side effects- rare cognitive issues, may worsen myoclonic and absence epilepsy, MRI changes in deep gray and white matter, usually transient and asymptomatic, weight gain, fatigue, somnolence, irritability, behavioral changes, psychosis, depression, ataxia; hyperactivity and agitation in children
• Pregnancy – studies in animals have shown intrauterine growth retardation, minor congenital malformations and delays in skeletal development
• Breastfeeding – secreted in breast milk in low quantities
• No interaction with oral contraceptives
• Dosing: 500-3000mg/day

ZONISAMIDE (ZONEGRAN) (2000)
(In the Mixed Neurotransmitter Family of Medicine)
• FDA approved for adjunctive treatment of partial seizures – widely used for generalized seizures, Lennox-Gastault syndrome and infantile spasms
• Works on sodium and calcium channels
• Adverse effects- cognitive side effects, risk of renal stones, rash (rare)
• Side effects- ataxia, dizziness, nausea, weight loss, fatigue, somnolence, agitation, irritability and anorexia (dose-related, titrate slowly)
• Not to be used if allergic to sulfa drugs
• Advantages- once daily dosing, does not interact with other anti-epileptic drugs
• Pregnancy-limited data but no higher risk than with other anti-epileptic medsshould be used only if potential benefits outweigh the risks
• Breastfeeding – extensively secreted in breast milk but limited data, so infant should be closely monitored for sedation or irritability
• Oral contraceptives- no clinically significant interactions
• Dosing 100-600mg/day

There are other medications that are not strictly anti-epileptic drugs but are widely used for certain syndromes and hard to control seizures. They are briefly mentioned here:

ACTH (ADRENOCORTICOTROPIC HORMONE) & PREDNISONE (STEROIDS)
• Used for infantile spasms and Landau-Kleffer syndrome, Lennox-Gastault syndrome, absence epilepsy, progressive myoclonic epilepsy, Rasmussen’s syndrome, epilepsia partialis continua IVIG
• Used in epilepsy syndromes with a presumed immune-mediated pathogenesis.
• Initiated inpatient- given intravenously and then dosed usually monthly at home, with premedication of Tylenol and Benadryl Other treatments include surgery, ketogenic diet, and devices such as vagal nerve stimulators and deep brain stimulators, all of which will be discussed in future issues of EP magazine, so stay tuned!

In conclusion, the mainstay of treatment for epilepsy is medications. The goal of any therapy is to control seizures with minimal side effects and to achieve it by using as few medications as possible. When seizure control is not achieved, it is time to rethink the regimen and look at alternative treatments, including surgery and diet.•

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ABOUT THE AUTHORS:
Steven M. Wolf, M.D., is a Pediatric Neurologist at Ferncliff Manor, and Director of the  Developmental Disability Center at Roosevelt Hospital and the Director of Pediatric Epilepsy at Beth Israel Medical Center and EEG Lab at St. Luke’s-Roosevelt Hospital Center. His practice is in collaboration with Patricia McGoldrick, NP.

Patricia Engel-McGoldrick, NP, is a Nurse Practitioner and a Medical Physician Assistant, she is also Associate Director of the  Developmental Disability Center at St. Luke’s Roosevelt Hospital and Co-director of the Tuberous Sclerosis Clinic at Beth Israel Medical Center.


 

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