Neuromodulation in Epilepsy Gregory C. Mathews, M.D., Ph.D.
Disclosure There are no disclosures to share with regards to this presentation.
Epilepsy Basics What is epilepsy? Partial versus generalized Treatment of epilepsy Refractory epilepsy
Epilepsy What is epilepsy? A chronic disorder characterized by recurrent (at least two) unprovoked seizures What is a seizure? The manifestations (symptoms and signs) of excessive and hypersynchronous, usually self limited, activity of networks of neurons in the brain
Not Only a Pediatric Disease
Prevalence and Causes Prevalence in most developed countries is 4 to 10 per 1000 people ( = 1% of the population)
Physiology of a Seizure
Electroencephalography
Epilepsy Classification: Partial epilepsy
Epilepsy Classification: Primary generalized epilepsy
Seizure Focus and Spread thalamus
Treatment of Epilepsy Complete seizure remission is the main determinant of quality of life Medication is the mainstay of treatment In newly diagnosed patients: 1/2 are seizure free on first medication 2/3 eventually become seizure free More than 20 medications are available Most modulate excitability by decreasing neuronal excitation or enhancing neuronal inhibition
Limitations of Antiepileptic Medications Control seizures, do not cure or change long term prognosis Many patients have adverse effects Drowsiness, dizziness Cognitive Long term eg. bone metabolism Teratogenicity Adherence is difficult, non-adherence is dangerous
Refractory Epilepsy 30-40% of people with epilepsy do not have good control with medications In some people, drug resistance develops In some people, the underlying disease is different or changes over time Seizure free for the past year Generalized 82% Post-stroke 54% Dysgenetic 24% Hippocampal atrophy 10% Dual pathology 3%
Treatment options when patients are medically refractory Resective surgery Ketogenic diet Vagus nerve stimulator Newer stimulation technologies
Resective Surgery: The Only Cure Identify the seizure focus and resect it
Surgical treatment of temporal lobe epilepsy
Resective Surgery: Not for everyone! Easy decision Lesion (eg. tumor, developmental anomaly, vascular malformation) Hippocampal sclerosis More difficult decision Partial epilepsy with no structural abnormality Not an option Generalized epilepsy Seizure focus involves eloquent cortex Multiple seizure foci
Electrical stimulation for seizure cessation
Vagus nerve stimulation
Anatomy of Vagus Nerve From: GI Motility online (2006)
Central nervous system influence of vagus nerve From Journal of Cerebral Blood Flow & Metabolism
Vagus nerve stimulation: a long history 1950 s, vagus nerve stimulation shown to produce desynchronization of the EEG in animal models 1980 s: VNS shown to prevent seizures in animal models 1990 s: VNS tested in humans with epilepsy 1997: VNS approved for use in patients with refractory partial-onset seizures
What is the VNS? The VNS Therapy System consists of an implanted pacemaker-like generator and nerve stimulation electrodes, which deliver intermittent stimulation to the patient s left vagus nerve that sends signals to the brain
Therapeutic stimulation parameters Parameters Units Range Typical Output current Milliamps (ma) 0 3.5 1-2 Signal frequency Hertz (Hz) 1 30 20-30 Pulse width Microseconds (µsec) 130 1000 250-500 Signal ON time Seconds (sec) 7 60 30 Signal OFF time Minutes (min) 0.2 180 5
Results of VNS Therapy 60% % of Patients with 50 seizure frequency reduction 50% 40% 30% 20% 10% 0% 3 months 1 year 2 years 3 years Morris GL, et al. Neurology 1999;53:1731-5.
VNS Side Effects Hoarseness Cough Paresthesia Shortness of breath Notably ABSENT side effects: Medication adverse effects Eg. sedation or dizziness, cognitive effects, drug interactions, bone loss, teratogenicity
Who should try VNS? Patients who: Are refractory to medications Experience severe medication side effects Are not candidates for resective surgery
Responsive Stimulation
A closed loop system monitors EEG and detects seizure onset delivers electrical impulse to site of seizure origination requires identification of the focus and programming to set parameters for detection and impulse delivery What is RNS?
Results with RNS Approximately 30% reduction in seizure frequency 191 patients 1 or 2 seizure foci Morrell MJ: Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 77:1295 1304, 2011
Deep Brain Stimulation
DBS for epilepsy 1960 s 1970 s: recognized that lesions of the anterior thalamus could reduce seizure frequency in animal models and in humans
SANTE Trial
Results with DBS
Summary of Stimulation for Epilepsy Table 1. Large randomized controlled trials of brain stimulation Authors & Year No. of Patients Target Seizure Frequency Reduction Group Treatment Sham Ben-Menachem et al., 1994 114 VNS 25% 6% Handforth et al., 1998 196 VNS 28% 15% Fisher et al., 2010 110 ANT 40.4% 14.5% (median) Morrell et al., 2011 191 direct-seizure foci 37.9% 17.3%