Epilepsy treatment options: new, alternative, experimental Olgica Laban-Grant, MD Northeast 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.
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. • it is not part of established treatment practice, or has not yet been subject to extensive clinical studies
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
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)
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) • Mechanism of action: GABA . • Newer drug approved for add on treatment for Lennox Gastaut Syndrome. • Variable efficacy in partial onset seizures.
Clobazam (Onfi) • Side effects Common • 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, 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 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
Surgical Treatment Options • Surgical resection • Surgical Non resection • VNS (Vagal nerve stimulator) • Brain stimulators • DBS - Deep Brain Stimulators. • RNS- Responsive neurostimulator ( Neuropace) • rTMS (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
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 .