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Epilepsy treatment optionsNew, alternative, and experimentalOlgica Laban-Grant, MDNortheast Regional Epilepsy Group

Seizures are defined as abnormal discharge of electrical activity of brain resulting in transient impairment of motor, sensory or mental function.

Epilepsy: two episodes of unprovoked seizures

Epilepsy treatmentMedications

SurgeryDietNew (FDA approved) treatmentPreclinical testingin laboratory animals

Clinical Trials - Drug studies in humans can begin only after treatment is reviewed by the FDA and a local institutional review board (IRB). The board is a panel of scientists and non-scientists in hospitals and research institutions that oversees clinical research.

New (FDA approved) treatmentPhase 1 safety - usually conducted in healthy volunteers.

Phase 2 effectiveness - - usually conducted in patients with certain disease/condition.

Clinical trialsControlled trials - patients receiving the drug are compared with similar patients receiving a different treatment-usually an inactive substance (placebo), or a different drug. Randomized-subjects are randomly allocated to receive one or other of the alternative treatments under study (like tossing a coin)Blinded - both tester and subject are blinded

New (FDA approved) treatmentPhase 3 - more information about safety and effectiveness, studying different populations and different dosages and using the drug in combination with other drugs.

Post-market requirement and commitment studies

AlternativeAny practice that is presented as having the healing effects but is not based on evidence gathered by the scientific method.

Complementary medicine is alternative medicine used together with conventional medical treatment (not proven by scientific method)

ExperimentalTreatments that are still being studied to see if they are effective or safe.

Treatment is not part of established treatment practice, or has not yet been subject to extensive clinical studies

ExperimentalHow to find open studies:

http://www.clinicaltrials.govhttp://epilepsygroup.comClinical servicesopen clinical studies

Antiepileptic Drugs

1850: Bromides1910: Phenobarbital1940: Phenytoin1950: Ethosuximide1968: Carbamazepine1974: Depakote

1990s: newer AEDs were developed.Good efficacy,Fewer toxic effects, Better tolerabilityNo blood level monitoring.

New MedicationsVimpat (lacosamide) 2008Banzel (rufinamide) 2008Sabril (vigabatrin) 2009Onfi (clobazam) 2011Fycompa (perampanel) 2012

Lacosamide (Vimpat)Approved in 2008Epilepsy treatment for partial-onset seizures in patients who are 17years and older.It is a medication that can be added to any other antiepilepsy medications

Lacosamide (Vimpat)Approximately 40% of patients in clinical studies had their partial-onset seizures reduced by half or more.

More seizure-free days

Lacosamide (Vimpat)Mechanism of actionEnhances the number of sodium channels entering into the slow inactivated state Does not affect activity mediated by fast inactivation

DilantinTegretolTrileptalZonegran

Vimpat

Lacosamide (Vimpat)Side effectsDepression 1:500Dizziness, double vision, sleepiness, problems with coordinationIrregular heartbeat (may prolong PR interval on EKG)No effect on weightNo effect on memory

Banzel (Rufinamide)Approved in 2008Indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children 4 years and older and adults.

Lennox-Gastaut syndrome1-4% of childhood epilepsiesDifferent types of seizuresMental retardationDifficult to treatSpecific EEG patternBanzel (Rufinamide)reduction in total number of seizures 42.5% median percentage reduction in tonic-atonic seizure(drop attacksignificant improvement in seizure severity

Banzel (Rufinamide)Reports on decrease of frequency of partial seizures medication is not approved for this indication

Banzel (Rufinamide)The exact mechanism of action is unknown. Modulates the activity of sodium channels and, in particular, prolongation of the inactive state of the channel.

Banzel (Rufinamide)Side effectsDepression 1:500Dizziness, double vision, sleepiness, problems with coordinationMay make the contraception less effectiveIt is contraindicated in familial short QT syndrome-EKG prior to starting it

Sabril (Vigabatrin))Approved in 2009Refractory complex partial seizuresInfantile spasms (IS) - babies between the ages of 1 month and 2 years

Infantile spasmsOnset typically 4-8 monthsinfantile spasmsdevelopmental regressionspecific pattern on EEG called hypsarrhythmia (chaotic brain waves)Sabril (Vigabatrin))Mechanism of actionPreventing breaking down of GABA. GABA is chemical that suppresses activity in neurons.

Sabril (Vigabatrin))Side effectsIt may permanently damage the vision. The most noticeable loss is in the ability to see to the side when looking straight ahead (peripheral vision). Occurred in 30% or more of patient.

Ezogabine (Potiga)FDA approved in 2011

Adjunctive therapy in partial-onset seizures uncontrolled by current medications in adults

Ezogabine (Potiga)Novel mechanism of action

Potassium channel opener

Ezogabine (Potiga)Side effectsdizziness, fatigue, tremor, problems with coordination, double visionmemory impairmentlack of strength.urinary retentionconfusion, hallucinationsdepression

Ezogabine (Potiga)New FDA warning in 2013

can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retinaIt is unknown if this is reversiblePatients should have a baseline eye exam and periodic eye exams that should include visual acuity testing

Clobazam (Onfi)FDA approved in 2011Approved for add on treatment for Lennox Gastaut Syndrome.Variable efficacy in partial onset seizures.

Mechanism of action: GABA

Clobazam (Onfi)Side effectsCommonsleepinessunsteadinessAggressionDouble visionNausea ,Vomiting

Withdrawal symptoms on abrupt discontinuation.

Perampanel (Fycompa)Approved in 2012

Epilepsy treatment for partial onset seizures in patients with epilepsy ages 12 years and older.

Perampanel (Fycompa)Mechanism of action: selective, non-competitive AMPA receptor antagonist (glutamate receptor)Glutamate is the main excitatory neurotransmitter in the brain

novel mechanism of action

Perampanel (Fycompa)Approximately 19-35% (depending on dose) of patients in clinical studies had their partial-onset seizures reduced by half or more.

Perampanel (Fycompa)Side effectsrisk of serious neuropsychiatric events (including irritability, aggression, anger, anxiety, paranoia, euphoric mood, agitation, and mental status changes.)Common: dizziness, drowsiness, fatigue, irritability, falls, upper respiratory tract infection, weight increase, vertigo, loss of muscle coordination, gait disturbance, balance disorder, anxiety, blurred vision, weakness.

Candidate Antiepileptic drugs Eslicarbazepine (approved in Europe in 2009)prodrug for the major active metabolite of oxcarbazepine (Trileptal)Supposed to be better tolerated

Brivarecetamanalog of levetiracetam (Keppra)Supposed to be more potent

Candidate Antiepileptic drugs GanaxoloneNeurosteroid (metabolized from pogesterone), modulation of GABA receptorsGood safety profile

Surgical Treatment OptionsSurgical resectiveLobectomyHemispherectomyCorpus callosotomyMultiple subpial rescectionsSurgical Non-resectiveVNS (Vagal nerve stimulator)Brain stimulatorsDBS - Deep Brain Stimulators.RNS- Responsive neurostimulator ( Neuropace)r TMS ( repetitive transcranial magnetic stimulator)TNS trigeminal nerve stimulator

ExperimentalSurgical Treatment OptionsSurgical resectionFocal radiation (gamma knife) vs. temporal lobectomyPhase 3

Visualase Thermal Therapy System - MR-guided laser induced thermal therapy in patients diagnosed with focal lesional epilepsyPhase 1Other treatments: DevicesDBS - Deep Brain StimulatorRNS- Responsive neuro stimulator (Neuropace)r TMS - repetitive transcranial magnetic stimulator.TNS trigeminal nerve stimulatorDeep brain stimulator anterior thalamusApproved in Europe and in Canada.FDA did not approve it in 2010No safety issues no sufficient time to evaluateBilateral stimulation of the anterior nucleus of the thalamus. New data - 69% median reduction in seizure frequency at 5 years

RNS (Neuropace)It is now being considered for FDA approval.

treatment option for patients with bilateral independent seizure foci or with an epileptogenic zone in eloquent cortex not suitable for surgical resection.

The generator is implanted in the skull and connected to either depth or subdural strip electrodes to deliver stimulation directly to one or two seizure onset zones.

The reduction in seizure frequency was 37.9% in the treatment group compared to 17.3% in the sham stimulation group.

rTMS

A noninvasive cortical stimulation methodThe device modulates cortical excitability. Most studies used daily rTMS sessions for about 1 week, then evaluated efficacy 2 to 4 weeks later. Studies show variable results. Relatively more significant improvement was noted in patients who have more superficial seizure foci.

Trigeminal Nerve Stimulation

A noninvasive stimulation methodAvailable in EuropePending phase 3 study in USAExternal stimulation of the trigeminal nerve by wearing a gel electrode on the forehead for 12 hours

Alternative treatment

Dietary TherapyPossible option in patients with drug resistant epilepsy and epilepsy surgery may not be an option.

Dietary TherapyKetogenic Diet: Modified Atkins dietLow glycemic diet

Ketogenic dietVery low carbohydrate, high fat, and low to adequate protein diet.

The onset of action is very fast. In one study the median time to first improvement was 5 days, with a range of 1 to 65 days. Improvement was unlikely if no benefit had been seen by 2 months.

Efficacy of the ketogenic diet in children was confirmed in a randomized controlled but unblinded trial: 38% of children who received the diet had a greater than 50% seizure reduction versus only 6% of controls, 7% had a greater than 90% reduction versus none of the controls .

Ketogenic diet Can be effective All patients with refractory epilepsies.Could be first-line therapy for children with glucose transporter deficiency and pyruvate dehydrogenase deficiency. Myoclonic-astatic epilepsy, tuberous sclerosis, Rett syndrome, Dravet syndrome, and infantile spasms .

Absolute contraindications include mitochondrial disorders, pyruvate carboxylase deficiency, and -oxidation defects.

Modified Atkins DietIt is more palatable and less restrictive than the ketogenic diet. It only restricts carbohydrates (10 g/day for children and 15 g/day for adults), not protein, fat, or calories.In one pediatric study, 65% of children had a greater than 50% reduction in seizures, and In an adult study, 47% had greater than 50% reduction at 3 months and 33% at 6 months, but 33% discontinued the diet before 3 months.

Low glycemic dietThe diet allows only low glycemic index carbohydrates, with an overall carbohydrate intake of 40 to 60 g/day. There was a greater than 90% improvement in seizure control in about 25% at 3 months, with another 25% experiencing 50% to 90% improvement. There was a correlation between efficacy and blood glucose at 1 month and 12 months of treatment.

NeurofeedbackThe theory behind this technique is that patients can be trained to increase certain frequencies on the EEG recordings that are known to inhibit seizures in animal studies.Patients are trained to do this by obtaining positive visual feedback with colored lights and images on a screen after producing the specific activity.

NeurofeedbackA therapy that trains patient with realtime feedback on brainwave activity (EEG)EEG is obtained to identify abnormal brain rhythms The patient is trained to change abnormal aspects of brain waves

NeurofeedbackResults have not been encouraging although some studies showed improvementPatients who have seizures triggered by anxiety or stressful situations may benefit from this therapy.

Herbal treatmentThe herbal medicines that are alleged, but not proven, to have a beneficial effect on seizures include:Ailanthus altissima (Tree of Heaven)Artemisia vulgaris (mugwort)Calotropis procera (calotropis)Cannabis sativa (marijuana)Centella asiatica (hydrocotyle)Convallaria majalis (lily of the valley)Dictamnus albus (burning bush)Paeonia officinalis (peony)Scutellaria lateriflora (scullcap)Senecio vulgaris (groundsel)Taxus baccata (yew)Valeriana officinalis (valerian)Viscum album (mistletoe)

Herbal treatmentNo standardizationingredients do not have to be listedNo scientific studies are required

Natural is not always safe

Herbal treatmentMay cause seizures:A study conducted with 70 herbal medicines found that 20 % of these products contain potentially harmful levels of neurotoxic materials such as lead, mercury or arsenic that may cause seizures

ephedra, gingko, ginseng, evening primrose, borage, and essential oils such as eucalyptus, fennel, hyssop, pennyroyal, rosemary, sage, savin, tansy, thuja, turpentine, and wormwood.

May interact with AEDs negatively (reduce effectiveness, increase toxicity)Gingko, St Johns Wort, hankhapusphi, sho-seiryu-to/sho saiko to and grapefruit

Cannabis sativa (marijuana)

naturally growing plant many chemical constituents are present in varying levels in the different varieties. approximately (60 cannabinoids and 260 noncannabinoid)

Cannabis sativa (marijuana)

cannabinoid receptors (receptors in the brain for marijuana) are localized in areas that are commonly known to cause seizures (such as the hippocampus and amygdala).

There is very little understanding as to what is the effect on seizures.

Cannabis sativa (marijuana)

main constituents

delta-9-tetrahydrocannibinol (THC), the primary psychoactive constituent, andcannabidiol (CBD) the primary nonpsychoactive constituent.

Cannabis sativa (marijuana)

Effect on seizure threshold:

THC-conflicting results depending on dose, seizure model, and factors of seizure initiation versus seizure spread

CBD- mostly anticonvulsant properties

Cannabis sativa (marijuana)

Effect on seizure threshold:

3) Cannabidivarin (CBDV) in rats and mice suppressed seizures

Cannabis sativa (marijuana)

Case reports

Two families reported significant improvement in their children with Dravets syndrome (rare and catastrophic form of intractable epilepsy)

Cannabis sativa (marijuana)

4 studies (by scientific standards of low quality) total 48 patients200 to 300 mg of cannabidiol (CBD) per day Anti-epileptic drugs were continued in allIn two of the studies, marijuana had no effect on seizure frequency; in one of the studies, 4/8 patients had significant improvement.

Cannabis sativa (marijuana)

Small number of patientsUnclear randomizationLimited duration of useNo information on safety/interactions with other medications

Cannabis sativa (marijuana)

Risk for the first time seizure one study (low quality by scientific standards)308 individuals who had been admitted to a hospital after their first seizure vs control group of 294 patients Marijuana within 90 days of hospital admissionconclusion: marijuana is protective against the first-time seizure in men but not women

Cannabis sativa (marijuana)

biological product containing multiple compounds with unclear, possible, anti- or pro-convulsant effects, delivered in varying amounts from dose to dose no reliable conclusions can be drawn at present regarding the efficacyvirtually no data about the safety

Cannabis sativa (marijuana)

Constituents of marijuana may be treatment option

GW Pharmaceuticals (UK) and Otsuka Pharmaceuticals (Japan) have funded CBD research since 2007 and will continue to until at least 2013

SupplementsFolic acid is recommended in women of child baring ageCalcium and vitamin D are recommended in patients taking antiseizure medications.Vitamin B6 is sometimes prescribed with levetiracetam and in B6 sensitive seizures.

SupplementsSometimes mitochondrial disorder may be cause of seizures.Combination of supplements and vitamins may be recommended.

SupplementsVitamin E

One small study (24 participants) found a significant decrease in seizure frequency in those treated with vitamin E compared to placebo.

SupplementsOmega 3 fatty acidsA 12-week double blind, placebo-controlled, parallel group trial 50% percent of reduction in complex partial seizures during the first 6 weeks of treatment in both the supplement group (weeks 1-6) but the results were not consistent during the following 6-week periods.

Oxygen therapyHyperbaric oxygen therapy is approved for treatment of skin ulcers and drowning.Studied in small study with epilepsy patients and revealed decrease in seizures.It is not approved, safety was not established and it might cause seizures even in patients who did not have history of epilepsy.

AromatherapyUses aroma to produce relaxationJasmine has been proposed as helpfulSome aromas have been reported to worsen seizures (camphor, eucalyptus, fennel, hyssop, rosemary, sage)

AcupunctureThere have been two trials of an 8week course of acupuncture versus sham acupuncture in adult patients with intractable epilepsy in addition to their usual AEDs. No significant differences were found between the two groups in either study.

Eleven randomized controlled trials. small sample sizes and without any sham or placebo control group. Could not prove whether acupuncture has any beneficiary effects to AEDs

Yogayogas effect on the autonomic functions of patients with refractory epilepsy improved parasympathetic parameters compared to no changes in the non-yoga exercise group

Results on control of seizures are inconclusive

ExperimentalHow to find open studies:

http://www.clinicaltrials.govhttp://epilepsygroup.comClinical servicesopen clinical studies

Thank you