November 2008 • www.clinicalneurologynews.com Epilepsy 9 Brain Stimulation Evolves for Refractory Epilepsy

BY MICHELE G. SULLIVAN be presented at the American Epilepsy Society meeting in synchronizing synchronized high-voltage cortical dis- Mid-Atlantic Bureau Seattle in December. By way of detailing his financial con- charges. During chronic DBS, the stimulation is applied flicts of interest, Dr. Boon said in an interview that constantly to the epileptogenic focus, regardless of the M ADRID — Deep brain stimulation shows considerable Medtronic Inc., the company that makes DBS hardware, area’s own discharge. promise for reducing intractable seizures in patients who has been and is providing devices and electrodes in support However, there is some evidence that stimulation only are not candidates for epilepsy surgery, even though of the pilot trial, and has provided an educational grant. in response to epileptiform activity might be more ef- there have been few large-scale controlled trials to back The medial temporal lobe and the hippocampus are oth- fective. This “closed-loop” stimulation would require a de- up the practice. er potential targets. Last year, Dr. Boon and his colleagues vice that could read and analyze brain waves and then “We have no idea what the best stimulation parameters published a study of 12 patients with refractory temporal “decide” what type of stimulation to deliver—a process are, we don’t know whether to stimulate in response to lobe epilepsy, who were also candidates for surgery. Instead that clearly presents a technological challenge. epileptiform activity or continuously, and, of course, the of implanting recording electrodes during the presurgical Early external devices were tested in small numbers of search for the optimal target is ongoing,” Dr. Paul Boon period, they implanted DBS electrodes in the medial tem- patients in the late 1990s and early 2000s. More recently, a said at the annual congress of the Eu- poral lobe. California-based company, NeuroPace Inc., has developed ropean Federation of Neurological ‘We got a 70% response “We aimed to adjust the simula- the RNS System, which includes fully implantable in- Societies. “Most of our information tion parameters to get a 50% re- tracranial components as well as external products, he said. has come from uncontrolled studies rate, with no significant duction in spikes for 7 consecutive The device consists of an implanted neurostimulator and case reports, which included adverse events or changes days,” he said. “If the patient with one or two strip leads that can be placed in differ- about 115 people worldwide.” achieved that, then we went to ent areas of the brain to allow activity to be monitored Now, data from three new or up- in memory,’ suggesting that chronic stimulation, and if they did and controlled. An external programming device allows coming studies might help shed light DBS of the medial temporal not achieve that, then we adjusted the stimulator to detect predetermined electrographic on some of these questions, said Dr. the parameters until we met those patterns; the physician can also program the type of re- Boon of University Hospital Ghent lobe is safe and effective. criteria. If the patient still didn’t sponse that the device delivers. (Belgium), where he and his col- achieve the reduction, then we re- A treatment can consist of up to five different stimu- leagues are leaders in researching an epilepsy application moved the electrodes and proceeded to surgery.” lation parameters delivered sequentially. After each stim- for DBS. Of the 12 patients, 10 underwent long-term DBS, and ulation, the device tries to detect further epileptiform ac- Some of the earliest studies, in the 1980s and early 2 had the resection. After a mean follow-up of 31 months, tivity; it will deliver the next stimulation if such activity 1990s, used the electrodes in the brain’s cerebellar regions, both of the surgical patients were seizure free. One of the is present, or cease stimulation if there is no epileptiform but with very little effect, so the cerebellum is no longer DBS patients had a seizure reduction of more than 90%; discharge. considered a target. The caudate nucleus and centrome- five had a reduction of at least 50%, and two had a re- In a feasibility study of 65 patients, the system was dial nucleus of the thalamus have also been examined as duction of 30%-40% (Epilepsia 2007;48:1551-60). deemed safe. In a preliminary analysis of 24 patients, the possible targets, but in very small numbers of patients and “We got a 70% response rate, with no significant ad- response rate (defined as a seizure reduction of at least with varying results, said Dr. Boon. verse events or changes in memory,” he said. “This shows 50%) was 43% for complex partial seizures and 35% for The most promising approach to date is bilateral stim- that DBS of the medial temporal lobe is safe, feasible, and total disabling seizures, which included simple partial mo- ulation of the anterior thalamic nucleus, he said. Early un- effective.” tor, complex partial, and secondarily generalized tonic- controlled studies of this application had small patient Dr. Boon and his group are also seeking to recruit 45 clonic seizures (Neurotherapeutics 2008;5:68-74). numbers, but their success led to the Stimulation of the patients for an upcoming study in which they will com- NeuroPace is recruiting up to 240 patients with re- Anterior Nucleus of the Thalamus for Epilepsy trial of 110 pare DBS of the hippocampus with medial temporal lobe fractory partial-onset seizures for a randomized, sham- patients with medically refractory partial-onset seizures. resection or with hippocampal DBS delayed for 6 months controlled trial of the system, with 2-3 years of follow- All of the patients received the implants; for the first 3 after implantation. The 1-year CoRaStiR (Controlled up. During the initial 4-month double-blinded phase, half months, only half of the patient had their stimulators Randomized Stimulation Versus Resection) trial will also of the patients will have the system turned on and half turned on. After this blinded treatment phase, all of the be sponsored by Medtronic. of them will have it remain off, after which all of the pa- patients received neurostimulation. The results are due to Researchers believe that DBS controls seizures by de- tients will receive stimulation. ■ Cortical Malformation Type Determines Deficits in Epilepsy

BY MICHELE G. SULLIVAN with these malformations can become Generalized seizures—either West’s or and focal cortical dysplasia. Medically re- Mid-Atlantic Bureau seizure-free after antiepileptic surgery.” Lennox-Gastaut syndrome—were signifi- fractory epilepsy was present in 150 pa- The most commonly observed malfor- cantly associated with , tients (63%). Forty-three patients under- M ADRID — Patients with microcephaly, mations in the cohort were focal cortical tuberous sclerosis, and diffuse focal le- went epilepsy surgery, and 26 of them hemimegalencephaly, tuberous sclerosis, dysplasia (62; 26%) and sions. Temporal lobe epilepsy was signif- (60%) have been seizure-free for at least 1 and polymicrogyria have an earlier onset (49; 21%). There were also 30 patients icantly associated with single focal lesions year after the procedure. ■ of epilepsy and are more likely to experi- with periventricular nodular heterotopia, ence comorbid neurologic and cognitive 27 with ganglioglioma, 26 with tuberous D A T A W A T C H deficits than are patients with other mal- sclerosis, 14 with microcephaly, 13 with formations, according to an observation- hemimegalencephaly, 8 with dysembryo- al study performed in Austria. plastic neuroepithelial tumor, 6 with sub- Top 10 Reasons for Hospital Admissions for Children “In comparison, patients with focal cor- cortical laminar heterotopia, and 2 with Number of discharges tical dysplasia very rarely had cognitive im- /. Pneumonia 162,000 pairment or neurologic deficits,” Dr. Gior- The mean age of seizure onset was 12 gi Kuchukhidze said at the annual years, but this varied with the type of mal- Acute bronchitis 140,000 congress of the European Federation of formation. “The majority of patients with Asthma 137,700 Neurological Societies. microcephaly, hemimegalencephaly, and Fluid and electrolyte disorders 90,100 Dr. Kuchukhidze, a neurologist at the tuberous sclerosis had seizure onset during Medical University of Innsbruck, Austria, the first year of life, whereas in most of the Appendicitis 82,500 discussed the results of his prospective patients with focal cortical dysplasia, gan- Affective disorders 73,600 study of 237 epilepsy patients, all of whom glioglioma, and periventricular heterotopia, were seen at the university’s tertiary the seizures manifested during the second Epilepsy, convulsions 69,500 EWS epilepsy referral center. All of the patients decade of life,” Dr. Kuchukhidze said. Skin and subcutaneous tissue infections 67,200 N had a cortical malformation as the root Delayed developmental milestones were Intestinal infections 53,200 cause of their seizure disorder. seen in 39% of the patients, and various EDICAL M “Certain EEG patterns and clinical pic- levels of cognitive impairment were pre- Urinary tract infections 49,400

tures create a strong suspicion of malfor- sent in 43%. “These were apparent in the LOBAL mations of cortical development,” he said. majority of patients with microcephaly, Note: Based on 2006 data; excludes newbornrn conditionsconditions. G However, the prognosis for such patients tuberous sclerosis, hemimegalencephaly, Source: Agency for Healthcare Research and Quality LSEVIER is not always grim. “Up to 70% of patients and polymicrogyria,” he said. E