Stimulating the Brain in Epilepsy Anli Liu MD

Stimulating the Brain in Epilepsy Anli Liu MD MA Assistant Professor of Neurology NYU FACES 2013 Epilepsy Conference May 5, 2013

Background: An Unmet Need • About 2/3 of patients with epilepsy will achieve seizure control with medications • Despite the introduction of 14 new anti-epileptic medications since 1993, there is still a huge need for patients with drugresistant epilepsy (DRE) • Seizure surgery is the best option for DRE patients and offers the best chance for seizure freedom. • However, some patients are not eligible for seizure surgery Bergey, 2013

Background: Neurostimulation Recent completion of well-designed large clinical Trials Advances in brain stimulation and hardware technology Neurostimulation options for patients with poorly controlled partial-onset epilepsy

Background: Neurostimulation While counterintuitive, delivering an excitatory stimulation during a seizure can Disrupt the seizure and prevent its spread. Mechanism not understood.

Background: Neurostimulation Potential benefits: • • Absent or minimal side effect profile No teratogenicity Distinct mechanism of action Can occur automatically and as a supplementary treatment

Background: Partial vs. Generalized Epilepsy Partial Epilepsy • Seizure starts from one side • Most adult-onset epilepsy • 50% have seizure control with medications Generalized Epilepsy • Seizure starts from both sides • Most childhood and adolescent onset • Primary generalized w 80% seizure control

Background: Neurostimulation While stimulating the brain in epilepsy seems counterintuitive, these therapies could potentially be an excellent treatment option for patients with partial onset seizures who are not candidates for surgery.

Neurostimulation Invasive • Vagal Nerve Stimulation (FDA 1997) • Deep Brain Stimulation (Thalamus) (Appr. Europe and Canada 2012) Non-invasive • Transcranial Magnetic Stimulation (TMS) • Transcranial Current Stimulation (TCS) • Responsive Neurostimulation (RNS) (FDA approval pending) Larger, multicenter controlled trials FDA approval granted or pending Smaller, pilot studies Applications in epilepsy, cognition, Psychiatry, and many other neuro Logic disorders.

Invasive Neurostimulation • Vagal Nerve Stimulation (VNS) • Deep Brain Stimulation (thalamus) • Responsive Neurostimulation (RNS) A vagal nerve stimulator

Vagal Nerve Stimulation • • • First FDA approved device for epilepsy and treatment refractory depression (1997) The most prevalent neurostimulation method (60, 000 patients in US) Programmed to have constant modulation, and a magnet rescue setting Trials demonstrate between 25 -50% of patients had a reduction of >50% of seizure frequency; few become seizure free. * Very safe. Side effects of hoarseness and cough.

Vagus Nerve Stimulation Leads are wrapped around the vagus nerve in the neck. Through an unknown Mechanism, can decrease the frequency of seizures in partial onset epilepsy. Fridley Neurosurg Focus 2012

Deep Brain Stimulation (DBS) has been FDA approved for Parkinson’s Disease and Esssential Tremor and is now investigated for epilepsy

Deep Brain Stimulation (DBS) of the Anterior Thalamus DBS delivers continuous low-level stimulation The anterior thalamus has widespread connections And is an attractive target. Patients can have multiple seizure onset zones

DBS Thalamus • A multicenter controlled trial (SANTE, Fisher 2010) of patients with poorly controlled partial epilepsy* 40% decrease in seizure frequency after 3 months 44% decrease for temporal lobe epilepsy 56% decrease by 2 years 13% were seizure free for at least 6 months • Safe: no significant bleeding or death. • Side effects: Sensory changes (18%), transient memory impairment and depression • Approved in Europe and Canada, but not in US.

Responsive Neuro Stimulation (RNS, Neuropace) • Depth electrodes Are placed into or near The seizure focus and Connected to a Neurostimulator Implanted into the Patient’s skull. • Continuous EEG Is recorded by implanted computer Fridley Neurosurg Focus 2012 • When a seizure is Detected, electrical Stimulation is delivered And stops the seizure from spreading

Responsive Nerve Stimulation (RNS) A patient with temporal lobe epilepsy and RNS device. Bergey 2013 • Large controlled trial (Morell, 2011) with drug resistant partial onset epilepsy showed a 38% seizure reduction • Progressive improvement over time: 50% reduction at 2 years. • Improvement in quality of life, Verbal ability, and memory • Retention 90% at 3 years, reflecting good side effect profile • Major risks: infection and bleeding • Waiting FDA approval

Summary: Invasive Neurostimulation PROS CONS • Could be an excellent therapy for patients with partial onset seizures who are not candidates for surgery. • Range from slightly invasive (VNS) to invasive (anterior thalamic and RNS) neurosurgical procedures • Good efficacy (25 -40% seizure Reduction) with improved benefit over time • Risks are bleeding and infection • Optimal stimulation parameters not proven • Number of seizure free patients is very low, partly because of patients enrolled in studies • Good safety profile • May spare from side effects from epilepsy medications

Non-invasive stimulation Transcranial Magnetic Stimulation (TMS) Transcranial Current Stimulation (TCS)

Why the excitement? We can stimulate a superficial area to activate Deeper and widespread networks To produce temporary and long-lasting effects

Many Treatment Applications in Neuropsychiatric Disorders • Depression (FDA cleared) • Parkinsons Disease • Stroke • Pain • Epilepsy • Schizophrenia • Autism • Tinnitus • Alzheimer’s Disease • Tourette’s syndrome • Ataxia

Research with noninvasive stimulation is rapidly growing (71)

Transcranial Magnetic Stimulation (TMS) TMS uses an alternating magnetic field to produce a secondary current in the underlying brain tissue

TMS-guidance with MRI Brain Co-registration of the TMS wand with the patient’s MRI Brain increases precision. Useful for presurgical planning.

TMS for Epilepsy • As seizures arise from areas of hyperexcitability, we apply low-frequency TMS to suppress this activity • Since 2002, a few controlled trials published showing mixed results: No significant effect Theodore (2002)* Joo (2007) Cantello (2007) Significant Decrease in Sz frequency Fregni (2005) Fregni (2006)* Santiago (2008) Sun (2012) • Mix of findings due to mixed patients and protocols • Meta-analysis of low-frequency r. TMS (Hsu 2011) shows modest reduction in seizure frequency

Seizure Reduction after r. TMS (Bae 2007) Suggestion of TMS benefit persisting between 2 to 8 weeks after stimulation.

TMS Batwing (H) Coil: Stimulating Deep Targets • Batwing Coil increases Depth of Penetration, up to 6 cm • Currently a Pilot Study of Deep TMS in Patients with Temporal Lobe Epilepsy (Rotenberg)

TMS Safety • • Rare reports of seizure (1. 4%) Bae 2007 Most seizures typical in character and duration No reported instances of status epilepticus Safety guidelines are now published

Transcranial Direct Current Stimulation (t. DCS) • Application of a weak direct current (1 -2 m. A) to scalp • Modulation of brain activity, can enhance or suppress

t. CS advantages • Easy to use • Low cost • Non-invasive • Painless • Long lasting effects • Few mild side effects (itching, tingling, headache, burning sensation and discomfort limited to the scalp site) • Safe: no reports of seizures

Safety in t. DCS Brunoni 2011

t. DCS for Epilepsy Fregni (2006): RCT of single 20 minute session of over cortical malformation showed trend toward reduction in seizure frequency Potentially good for patients with partial onset epilepsy with a seizure focus that is near the surface

HD-t. DCS for Ongoing Focal Seizures (Alex Rotenberg, MD Ph. D, CHB/Harvard) • Targeted direct current stimulation may produce a more potent effect.

Summary: Non-Invasive Neurostimulation PROS • Could be an excellent therapy for patients with partial onset seizures where seizure focus is superficial. • Noninvasive • Safe • May spare from side effects from epilepsy medications • May eventually be a portable, inexpensive office or home treatment CONS • Current research is early with mixed results • Treatments will likely need to be repeated • Optimal stimulation parameters not proven

Research at NYU Comprehensive Epilepsy Center • Efficacy of TDCS for Working Memory Dysfunction and Depression in Patients with Temporal Lobe Epilepsy (now recruiting) • TCS during Sleep to Improve Cognition in Epilepsy

Research Question In patients with temporal lobe epilepsy (TLE), what is the efficacy of transcranial direct current stimulation (t. DCS) on: • Working Memory Dysfunction? • Depression? • Seizure Frequency? • Interictal Discharges/EEG?

Study Design A double-blinded, randomized, sham-controlled trial of t. DCS on patients diagnosed with temporal lobe epilepsy Outcomes: • Verbal and visuospatial working memory tests • Mood questionnaires • Seizure frequency • Interictal discharge frequency

Study Design • Participation involves 8 visits (1 -3 hrs) • Subjects undergo memory and mood testing, 20 minutes of EEG at baseline • Five (5) sessions of real of sham t. DCS • Repeat testing and EEG • Followup at 2 and 4 weeks Compensated $50 a visit.

Summary: Neurostimulation Invasive • Vagal Nerve Stimulation (FDA 1997) • Anterior Thalamic Stimulation (Appr. Europe and Canada 2012) Non-invasive • Transcranial Magnetic Stimulation (TMS) • Transcranial Current Stimulation (TCS) • Responsive Neurostimulation (RNS) (FDA approval pending) Larger, multicenter controlled trials FDA approval granted or pending Smaller, pilot studies Applications in epilepsy, cognition, Psychiatry, and many other neuro Logic disorders.

Summary: Neurostimulation While stimulating the brain in epilepsy seems counterintuitive, these therapies could potentially be an excellent treatment option for patients with partial onset seizures who are not candidates for surgery.

Summary: Neurostimulation Discuss your eligibility for neurostimulation with your epilepsy doctor. Supporting research is important: Find out how you can get involved!

References Bergey G. , Neurostimulation in the Treatment of Epilepsy, Experimental Neurology, epub 2013 Fridley et al. Brain Stimulation for the Treatment of Epilepsy, Neurosurg Focus 32 (3) E 13, 2012. Morrell MJ. Responsive Cortical Stimulation for the Treatment of Medically Intractable Partial Epilepsy, Neurology 2011.