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 drug-resistant 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 Definition of Drug Resistant Epilepsy (ILAE) failing two or more appropriately chosen drugs at adequate doses. Some patients are not eligible for surgery because their seizure onset zone is poorly localized, multiple, or overlaps with a region of the brain responsible for memory or language. 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 Epileptic seizures represent periods of increased excitation and neuronal network synchrony. 80-90% of the neurons of the brain are excitatry. Disruption of seizure activity can occur with excitation 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 In epilepsy, seizures are considered transient increases in abnormal synchronized electrical activity in part or both Sides of the brain. The idea behind neurostimulation is to 1) modulate the background brain activity to decrease the chances of having a seizure occurrence, and 2) possibly terminate seizure early before it spreads to become a disabling event.

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

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. -Very few patients are seizure free. Remember these trials are in patients with drug resistant partial epilepsy. -AEDs are required to demonstrate a 20-50% reduction in seizure frequency to be approved by the FDA. These numbers are similar to AEDs.

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) 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 40% decrease in seizure frequency after 3 months 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. *Highly refractory means that 54% of patients had previous epilepsy surgery or VNS therapy. Patients had to have focal or partial seizures, but could have multiple seizure foci. 40% decrease after the blinded phase compared to the controlled group 15% Effect seems to be especially great for patients with temporal lobe epilepsy Over 2 year follow up, the benefit seems to increase (41% at 13 months and 56% at 25 months. Major side effects were paresthesias, reported in 18.2 of participat

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 When a seizure is Detected, electrical Stimulation is delivered And stops the seizure from spreading Fridley Neurosurg Focus 2012

Responsive Nerve Stimulation (RNS) 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 A patient with temporal lobe epilepsy and RNS device. Bergey 2013 Fig.1 Skull film of a patient with a NeuroPace responsive neurostimulation device. The patient had temporal lobe neocortical onset seizures. Four subdural strips are shown, two of which (one lateral, one basal temporal) are connected to the RNS. *Patients with drug resistant partial epilepsy, 32% had previous epilepsy surgery, 34% had prior VNS placement (subsequently removed) and average number of AEDs was 2.8. Similar to SANTE trial, 1 months decrease in mean seizure frequency in both sham and treatment Groups, attributed to implantation effect (microlesioning effect, placebo effect, anaesthesia effect) 38% decreased seizure frequency, compared to 17% in sham group.

Summary: Invasive Neurostimulation PROS Could be an excellent therapy for patients with partial onset seizures who are not candidates for surgery. Good efficacy (25-40% seizure Reduction) with improved benefit over time Good safety profile May spare from side effects from epilepsy medications CONS Range from slightly invasive (VNS) to invasive (anterior thalamic and RNS) neurosurgical procedures 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

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) In TMS, a brief pulse of electrical current passes through the stimulation coil and produces a large magnetic flux. This magnetic field penetrates through the scalp and skull to induce a secondary electrical current in the underlying brain tissue. The induced currents can be strong enough to depolarize neurons to produce spiking; consequently, TMS can be either neuromodulatory or neurostimulatory. TMS directly stimulates a surface area of a few square centimeters of cortex (REFs – Wagner 2009; Deng 2012) and to a depth of 3-4 cm from the cortical surface (REF – Roth 2007; Deng 2012). While new coils for deeper stimulation have been developed (REFs – Roth 2007, Deng 2008, Cai 2012), the induced electric field remains maximal at the cortical surface (REF- Heller & van Hulsteyn 1992). When TMS is applied to motor cortex, a muscle response, called the motor-evoked potential (MEP), is generated. Stronger TMS stimuli produce larger MEPs (REF). The motor threshold, usually determined for a hand muscle, is defined as the minimum stimulus intensity needed to produce a MEP of 50 µV on 5 of 10 trials. In most research studies, the stimulation intensity at which TMS is applied is a percentage of the individual motor threshold. 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 Significant Decrease in Sz frequency Theodore (2002)* Fregni (2005) Joo (2007) Fregni (2006)* Cantello (2007) Santiago (2008) Sun (2012) Mix of findings due to mixed patients and protocols Meta-analysis of low-frequency rTMS (Hsu 2011) shows modest reduction in seizure frequency

Seizure Reduction after rTMS (Bae 2007) Review of studies published between 1990-2007 for rTMS and epilepsy which reported changes in seizure frequency (7 studies, 55 patients). These box and whisker plots show the median Percent change in seizure frequency, first and third quartiles, and max and mean reports. These data suggest a beneficial effect of rTMS between 2-8 weeks after stimulation. 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 (tDCS) • Application of a weak direct current (1-2 mA) to scalp • Modulation of brain activity, can enhance or suppress

tCS 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 tDCS is an older technique than TMS, and has some recognized advantages and disadvantages25. From a pragmatic perspective, some benefits of tDCS include its low cost, portability, and ease of use. Because it induces less scalp sensation than TMS, tDCS has a more reliable sham condition, which allows for improved double-blinding25 . Furthermore, tDCS can easily be combined with other interventions such as mental imagery, computerized cognitive interventions, or robot-assisted motor activity. However, a major limitation of tDCS is the delivery of a less focused stimulation than TMS. Direct current is delivered over relatively large electrodes (20-35 cm2), which makes precise stimulation and cortical mapping more difficult.  Some studies have reduced electrode size to produce a more spatially-restricted current, comparable to TMS26.  This is true ONLY when lower stim intensities are use (1 mA) – note and cite recent PLOS One paper regarding the issue – when 2 mA is use (as in most therapeutic aplications) the blinding is probably not very good !!  This is true, BUT, consider that (1) smaller electrodes can be used; (2) electrode montages with several ‘exit electrodes’ may offer greater focality; (3) current direction is CRUCIAL to consider and may lead to focal effects; (4) state-dependent effects of stimulation may be leveraged and may result in greater focality

Safety in tDCS Brunoni 2011

tDCS 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-tDCS for Ongoing Focal Seizures (Alex Rotenberg, MD PhD, 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 (tDCS) on: Working Memory Dysfunction? Depression? Seizure Frequency? Interictal Discharges/EEG?

Study Design A double-blinded, randomized, sham-controlled trial of tDCS 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 tDCS Repeat testing and EEG Followup at 2 and 4 weeks Compensated $50 a visit.

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

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.