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Epilepsy treatment options
New, alternative, and experimental
Olgica Laban-Grant, MD
Northeast 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 treatment
• Medications
• Surgery
• 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.
New (FDA approved) treatment
• 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
New (FDA approved) treatment
• 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.
• Treatment is not part of established treatment
practice, or has not yet been subject to
extensive clinical studies
Experimental
• How to find open studies:
• http://www.clinicaltrials.gov
• http://epilepsygroup.com
– Clinical services
• open clinical studies
Antiepileptic Drugs
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1850: Bromides
1910: Phenobarbital
1940: Phenytoin
1950: Ethosuximide
1968: Carbamazepine
1974: Depakote
•1990s:
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newer AEDs were developed.
Good efficacy,
Fewer toxic effects,
Better tolerability
No blood level monitoring.
New Medications
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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
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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
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1-4% of childhood epilepsies
Different types of seizures
Mental retardation
Difficult to treat
Specific EEG pattern
Banzel (Rufinamide)
• reduction in total number of seizures
• 42.5% median percentage reduction in tonicatonic 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
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Onset typically 4-8 months
infantile spasms
developmental regression
specific pattern on EEG called hypsarrhythmia
(chaotic brain waves)
Sabril (Vigabatrin))
• Mechanism of action
• Preventing breaking down of GABA. GABA is
chemical that suppresses activity in neurons.
Sabril (Vigabatrin))
• 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)
FDA approved in 2011
• Approved for add on treatment for Lennox
Gastaut Syndrome.
• Variable efficacy in partial onset seizures.
• Mechanism of action: GABA
Clobazam (Onfi)
• Side effects
Common
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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.
Perampanel (Fycompa)
• Mechanism of action: selective, noncompetitive 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 partialonset 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
• Brivarecetam
analog of levetiracetam (Keppra)
Supposed to be more potent
Candidate Antiepileptic drugs
• Ganaxolone
Neurosteroid (metabolized from pogesterone),
modulation of GABA receptors
Good safety profile
Surgical Treatment Options
• Surgical resective
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Lobectomy
Hemispherectomy
Corpus callosotomy
Multiple subpial rescections
• Surgical Non-resective
– VNS (Vagal nerve stimulator)
– Brain stimulators
• DBS - Deep Brain Stimulators.
• RNS- Responsive neurostimulator ( Neuropace)
• r TMS ( repetitive transcranial magnetic stimulator)
• TNS – trigeminal nerve stimulator
Experimental
Surgical Treatment Options
• Surgical resection
– Focal radiation (gamma knife) vs. temporal
lobectomy
• Phase 3
– Visualase Thermal Therapy System - MR-guided
laser induced thermal therapy in patients
diagnosed with focal lesional epilepsy
• Phase 1
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
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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.
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treatment option for patients with bilateral independent seizure foci or with an
epileptogenic zone in eloquent cortex not suitable for surgical resection.
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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.
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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
• 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 treatment
The 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”
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)
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
1) delta-9-tetrahydrocannibinol (THC), the
primary psychoactive constituent, and
2) cannabidiol (CBD) the primary
nonpsychoactive constituent.
Cannabis sativa
(marijuana)
• 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
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 Dravet’s syndrome (rare
and catastrophic form of intractable epilepsy)
Cannabis sativa
(marijuana)
• 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.
Cannabis sativa
(marijuana)
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Small number of patients
Unclear randomization
Limited duration of use
No 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
admission
• conclusion: 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 efficacy
• virtually 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
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
Experimental
• How to find open studies:
• http://www.clinicaltrials.gov
• http://epilepsygroup.com
– Clinical services
• open clinical studies
Thank you