Neuromodulation in Epilepsy Frederick Langendorf,, MD Department of Neurology Univ of MN and Hennepin Co Medical Center June 4, 2007
disclosures No financial conflicts-of of-interest
Epilepsy the problem of refractoriness to medication
What is medically intractable? A thought experiment 15 relatively commonly used AEDs,, so 15 monotherapies (15)(14)=210 double therapies (15)(14)(13)=2730 triple therapies Or one therapeutic regimen for each 9 days of life (based on lifespan of 75 yrs.)
Medically refractory epilepsy 525 patients with epilepsy #AEDs 0 1 2 3 #subjects 44 423 53 5 % sz-free* 77 68 23 0 *Seizure-free >1 year, o/w medically refractory Kwan P, Brodie MJ. NEJM 2000;342:314-9.
Medically refractory epilepsy Total szfree: 64% 2 nd AED: 13% 3 rd AED: 4% 1 st AED: 47%
Impact of medically-intractable intractable epilepsy Driving Employment Associated memory loss, depression Stigma Side effects of AEDs Sudden death (SUDEP)
Directions in treatment of medically refractory epilepsy Non-pharmacologic treatment of epilepsy Resective brain surgery Ketogenic diet Stimulators Vagus nerve stimulator Deep brain stimulation Transcranial magnetic stimulation Future directions Genetics-based treatment of epilepsy
Epilepsy is a promising disease for Epidemiology stimulators 3 3 Es Many young, otherwise healthy patients Electricity Fight fire with fire Episodic Stimulator as abortive/use when needed and only when needed
Rationale for stimulators Desynchronize Inhibit seizure propogation Decrease excitability
Rationale for stimulators: 1. desynchronize cerebral electrical activity
Stimulators are hard to study Parameter for drug study Dose Parameters for stimulator study Site of stimulation: fixed vs tied to site of seizures Continuous vs cyclic (on time, off time) Cyclic: Spontaneous (scheduled; open-loop) vs. responsive (closed-loop) loop) Current (current, pulse width, frequency)
Vagus nerve stim: : beneficial outcomes 1/3 experience >50% seizure decrement; 5% seizure-free off AEDs Decreased AEDs/polyRx Improved mood, energy, QOL Reverse honeymoon effect
Vagus Nerve Stimulation: common side effects Hoarseness/voice alteration Cough Paresthesias Pain Dyspnea Note what isn t t here: drowsiness, dizziness, unsteadiness, blurred vision, tremor, cognitive problems, etc
VNS: How does it work? Excites myelinated fibers afferents afferents to nucleus of solitary tract, then multiple areas of brain: locus ceruleus,, cerebellum, thalamus, hypothalamus, amygdala/hippocampus, cortex
But what is principal effect or at least principal marker: neurotransmitter changes? Neurotransmitter receptor changes? Activation of inhibitory centers? Changes in cerebral blood flow? Changes in cerebrospinal fluid composition? Desynchronization of EEG? Reduction in EEG spikes? Change in cortical excitability? All occur, but correlate poorly with seizure control
Brain stimulation sites sites with human experience cerebellum (superiomedial( superiomedial) Thalamus (centromedian( nucleus, anterior thalamus) Subthalamic nucleus Hippocampus cortex
Brain stimulation-- --methods Transcranial magnetic stimulation Open-loop Closed loop
Clinical trials: brain stim for epilepsy* *www.clinicaltrials.gov Recruiting Sponsor: NINDS Modality: transcranial direct current stimulation Design: randomized stim vs sham stim Outcomes: sz frequency; neuropsych Sponsor: Univ Hosp Grenoble; ; Ministry of Health, France Modality: subthalamic nucleus stim Design: crossover; on or off Outcomes: sz frequency; QOL; neuropsych
(2) Sponsor: Univ of Strasbourg Modality: rtms; ; frontal lobe epilepsy Design: crossover; Outcomes: electrophys; sz frequency Sponsor: Univ Hosp Ghent; Medtronic Modality: med TL resection vs hippocampal stim Design: randomized; control arm: stim off 6 mos Outcomes: sz freq; safety; QOL; neuropsych Sponsor: Neuropace Modality: responsive stimulator (RNS) Design: randomized, stim vs sham stim Outcomes: sz freq; health
no longer recruiting Sponsor: Medtronic Modality: stim of anterior n. of thalamus Design: randomized; stim off/on Outcomes: sz frequency complete Sponsor: NINDS Modality: rtms for neocortical epilepsy Design: randomized, stim vs sham stim Outcomes: sz freq
Questions re neuromodulation Are stimulators antiepileptogenic? Some evidence for VNS effect in kindled cat?use in high risk patients eg head injury Do stimulators alter the course of disease? Reverse honeymoon:?accelerate;?avoid plateau Are stimulators curative? A few reported cases of continued freedom from seizures after VNS turned off