Epilepsy treatment options: new, alternative, experimental Olgica Laban-Grant, MD Northeast Regional Epilepsy Group.

Epilepsy treatment options: new, alternative, experimental

Olgica Laban-Grant, MDNortheast Regional Epilepsy Group

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

Epilepsy: In general two episodes of unprovoked seizures

Types of Epilepsies

• Generalized epilepsy

• Focal Epilepsy

Treatment of Epilepsy

• Medications• Surgery– Resection– Devices (stimulators)

• Diet

New (FDA approved) treatment

• preclinical testing in 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.


• Phase 1 – safety - usually conducted in healthy volunteers.

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

Clinical trials

• controlled 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


• Phase 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

Alternative

• Any 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)

Experimental

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

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

Anti epileptic Drugs

• 1850 : Bromides• 1910: Phenobarbital• 1940: Phenytoin• 1950: Ethosuximide• 1968: Carbamazepine• 1974: Depakote

•1990s: newer AEDs were developed.

• Good efficacy,• Fewer toxic effects, • Better tolerability• No blood level monitoring.

New Treatment

• Vimpat (lacosamide) 2008• Banzel (rufinamide) 2008• Sabril (vigabatrin) 2009• Onfi (clobazam) 2011• Fycompa (perampanel) 2012

Lacosamide (Vimpat)

• Approved in 2008• Epilepsy 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 action• Enhances the number of sodium channels

entering into the slow inactivated state • Does not affect activity mediated by fast

inactivation

• Dilantin• Tegretol• Trileptal• Zonegran

• Vimpat

Lacosamide (Vimpat)

• Side effects• Depression 1:500• Dizziness, double vision, sleepiness, problems

with coordination• Irregular heartbeat (may prolong PR interval

on EKG)• No effect on weight• No effect on memory

Banzel (Rufinamide)

• Approved in 2008• Indicated for adjunctive treatment of seizures

associated with Lennox-Gastaut syndrome in children 4 years and older and adults.

Lennox-Gastaut syndrome

• 1-4% of childhood epilepsies• Different types of seizures• Mental retardation• Difficult to treat• Specific EEG pattern

Banzel (Rufinamide)

• reduction in total seizure • 42.5% median percentage reduction in tonic-

atonic seizure(drop attack• significant 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 effects• Depression 1:500• Dizziness, double vision, sleepiness, problems

with coordination• May make the contraception less effective• It is contraindicated in familial short QT

syndrome-EKG prior to starting it

Sabril (Vigabatrin))

• Approved in 2009• Refractory complex partial seizures• Infantile spasms (IS) - babies between the

ages of 1 month and 2 years

Infantile spasms

• Onset typically 4-8 months• infantile spasms• developmental regression• specific pattern on EEG called hypsarrhythmia

(chaotic brain waves)


• Mechanism of action• Preventing breaking down of GABA. GABA is

chemical that suppresses activity in neurons.


• Side effects• It 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 effects• dizziness, fatigue, tremor, problems with

coordination, double vision• memory impairment• lack of strength.• urinary retention• confusion, hallucinations• depression

Ezogabine (Potiga)• New FDA warning in 2013

• can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retina

• It is unknown if this is reversible• Patients should have a baseline eye exam and

periodic eye exams that should include visual acuity testing

Clobazam (Onfi)

• Mechanism of action: GABA .

• Newer drug approved for add on treatment for Lennox Gastaut Syndrome.

• Variable efficacy in partial onset seizures.

Clobazam (Onfi)

• Side effectsCommon– sleepiness– unsteadiness– Aggression– Double vision– Nausea ,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.


• Mechanism of action: selective, non-competitive AMPA receptor antagonist (glutamate receptor)

• Glutamate is the main excitatory neurotransmitter in the brain

• novel mechanism of action


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

Perampanel (Fycompa)• Side effects• risk 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

Surgical Treatment Options

• Surgical resection• Surgical Non resection

– VNS (Vagal nerve stimulator)– Brain stimulators

• DBS - Deep Brain Stimulators.

• RNS- Responsive neurostimulator ( Neuropace)• r TMS ( repetitive transcranial magnetic stimulator)• TNS – trigeminal nerve stimulator

Other treatments: Devices

• DBS - Deep Brain Stimulator• RNS- Responsive neuro stimulator

( Neuropace)• r TMS - repetitive transcranial magnetic

stimulator.• TNS – trigeminal nerve stimulator

Deep brain stimulator: anterior thalamus

• Approved in Europe and in Canada.• FDA did not approve it in 2010• No safety issues – no sufficient time to

evaluate• Bilateral 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 method with mixed results.

• The 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 method• available in Europe• Pending phase 3 study in USA• External stimulation of the trigeminal nerve by

wearing a gel electrode on the forehead for 12 hours

Alternative treatment

Dietary Therapy

• Possible option in patients with drug resistant epilepsy and epilepsy surgery may not be an option.

Dietary Therapy

• Ketogenic Diet: • Modified Atkins diet• Low glycemic diet

Ketogenic diet• Very 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 β-oxidation defects.

Modified Atkins Diet

• It 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 diet

• The 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.

Neurofeedback

• The 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.

Neurofeedback

• A 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

Neurofeedback

• Results have not been encouraging although some studies showed improvement

• Patients 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 treatment

• No standardization• ingredients do not have to be listed• No scientific studies are required

• Natural is not always safe

Herbal treatment

• Most of them are relatively safe in recommended doses

• Overdose may be dangerous

Herbal “treatment”May 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 AED’s negatively (reduce effectiveness, increase toxicity)

• Gingko, St John’s 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).


• 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.


• main constituents

1) delta-9-tetrahydrocannibinol (THC), the primary psychoactive constituent, and

2) cannabidiol (CBD) the primary nonpsychoactive constituent.


• Effect on seizure threshold:

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

2) CBD- mostly anticonvulsant properties


• Effect on seizure threshold:

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


• Case reports

• Two families reported significant improvement in their children with Dravet’s syndrome (rare and catastrophic form of intractable epilepsy)


• 4 studies (by scientific standards of low quality)

– total 48 patients- 200 to 300 mg of cannabidiol (CBD) per day - Anti-epileptic drugs were continued in all- In two of the studies, marijuana had no effect

on seizure frequency; in one of the studies, 4/8 patients had significant improvement.


• Small number of patients• Unclear randomization• Limited duration of use• No information on safety/interactions with

other medications


• 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 admission• conclusion: marijuana is protective against the

first-time seizure in men but not women


• 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 efficacy

• virtually no data about the safety


• 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

Supplements

• Folic acid is recommended in women of child baring age

• Calcium and vitamin D are recommended in patients taking antiseizure medications.

• Vitamin B6 is sometimes prescribed with levetiracetam and in B6 sensitive seizures.

Supplements

• Sometimes mitochondrial disorder may be cause of seizures.

• Combination of supplements and vitamins may be recommended.

Supplements

• Vitamin E

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

Supplements

• Omega 3 fatty acids• A 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 therapy

• Hyperbaric 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.

Aromatherapy

• Uses aroma to produce relaxation• Jasmine has been proposed as helpful• Some aromas have been reported to worsen

seizures (camphor, eucalyptus, fennel, hyssop, rosemary, sage…)

Acupuncture

• There have been two trials of an 8 week 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

Yoga

• yoga’s 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

Thank you

Epilepsy treatment options: new, alternative, experimental Olgica Laban-Grant, MD Northeast Regional Epilepsy Group.

Documents

vimpat slide

blinded slide

epilepsy focal epilepsy

different treatment

fast inactivation slide

epilepsy treatment options

anti epileptic drugs

seizurefree days slide