Neurovista: Concept to first-in-man: The war story behind launching a venture to treat epilepsy.

Many medical (and nonmedical) technologies are the fruit of years and even decades of work by dedicated members of startup companies and commitment of capital by their investors. The launching of a medical device venture is fraught with many risks, but the personal, societal, and potential financial rewards of developing therapies that improve the lives of others makes the risk and sacrifice worthwhile. The litany of risks and challenges can be daunting, and persistence is the key ingredient to every incremental iota of success achieved. This is a personal war story behind the launching of a medical device venture that developed an implanted seizure prediction system (NCT01043406). The intent is to share the experience so that others with interest in the field may learn from the experience and also decide whether such an endeavor is something that they want to undertake.

Optimizations and Nuances in Neurosurgical Technique for the Minimization of Complications in Subdural Electrode Placement for Epilepsy Surgery.

BACKGROUND: Surgical intervention is an important therapeutic option for patients with intractable epilepsy and a well-characterized epileptogenic focus. Invasive monitoring with subdural electrodes is an effective technique for localizing epileptogenic foci. Previous studies reported varying complication rates, and these may deter more widespread adoption. We present potentially valuable technical nuances that may be associated with low complication rates. We assess the potential contribution of specific aspects of surgical technique to the reduction of complication rates. METHODS: We retrospectively reviewed patients from the Rush University Surgical Epilepsy database who underwent craniotomies for invasive electroencephalography monitoring for medically intractable epilepsy using our technique. We analyzed and compared complication rates and techniques with those reported elsewhere. RESULTS: The sample group comprised 127 consecutive patients who underwent electrode implantation. The average monitoring period was 6 days. There were 5 complications (3.9%), including 1 subdural hematoma requiring surgery (0.8%), 1 infection (0.8%), 2 pulmonary emboli (1.6%), and 1 deep vein thrombosis (0.8%). There were no symptomatic cerebrospinal fluid leaks or permanent neurologic complications. These results compare favorably with published results. Analysis and comparison of our technique anecdotally suggest the importance of use of a subgaleal drain throughout the monitoring period, postoperative antibiotic coverage for 1 week, meticulous hemostasis, and secure suturing of the electrodes to the dura mater to minimize trauma to superficial vessels as potential contributors to improved complication rates. CONCLUSIONS: A very low incidence of major morbidity can be achieved in invasive electroencephalography monitoring with this protocol.

Neurohistopathological findings at the electrode-tissue interface in long-term deep brain stimulation: systematic literature review, case report, and assessment of stimulation threshold safety.

OBJECTIVES: Despite the widespread use of deep brain stimulation (DBS) in the treatment of neurologic disorders for over a quarter of a century, there has not been a systematic review and analyses of cases in which long-term postmortem clinic-pathologic data have been collected demonstrating the effects of chronically implanted electrodes and electrical stimulation on human brain tissue. Our objective is to provide a comprehensive systematic review of the literature on clinicopathologic findings of DBS tissue-electrode interface (TEI) and to determine types and prevalences of neuropathological findings among electrode materials and stimulation parameters and to augment this with previously unpublished histopathological data, images, and analyses from a DBS case implanted for 12 years, providing the longest duration histopathological follow-up. MATERIALS AND METHODS: A Medline literature review identified DBS cases upon which postmortem clinicopathologic follow-up was performed with adequate characterization of TEI. Direct follow-up with authors augmented this with unpublished data and neuropathological details. RESULTS: We identified 40 cases, mean age 59.1 ± 13.0 (range: 21-88) years, involving 58 implanted DBS electrodes. The mean postmortem histopathological follow-up of the implanted DBS electrodes was 22.2 ± 29.2 (range: 0.067-146) months, including our case with a 12-year follow-up. The following histological changes were identified: fibrous sheaths (5-25 µm thickness) surrounding the electrode (94%), fibrillary gliosis (73%), reactive astrocytes (78%), multinucleated giant cells (75%), mononuclear leukocytes (92%), and macrophages (91%). Microglial activation (60%), axonal spheroids (64%), and neuronal loss (60%) were less common and absent at 12-year follow-up in the index case. This is seventh case reporting T cell presence at the TEI. CONCLUSIONS: Neuropathological findings from published cases and our 12-year follow-up index case confirm the long-term safety of neuromodulation and stimulation thresholds and demonstrate persistence of T cells and occasional subclinical focal tissue injury.

Chronic unlimited recording electrocorticography-guided resective epilepsy surgery: technology-enabled enhanced fidelity in seizure focus localization with improved surgical efficacy.

OBJECT: Epilepsy surgery is at the cusp of a transformation due to the convergence of advancements in multiple technologies. Emerging neuromodulatory therapies offer the promise of functionally correcting neural instability and obviating the need for resective or ablative surgery in select cases. Chronic implanted neurological monitoring technology, delivered as part of a neuromodulatory therapeutic device or as a stand-alone monitoring system, offers the potential to monitor patients chronically in their normal ambulatory setting with outpatient medication regimens. This overcomes significant temporal limitations, pharmacological perturbations, and infection risks inherent in the present technology comprising subacute percutaneous inpatient monitoring of presurgical candidates in an epilepsy monitoring unit. METHODS: As part of the pivotal study for the NeuroPace Responsive Neurostimulation (RNS) System, the authors assessed the efficacy of the RNS System to control seizures in a group of patients with medically refractory epilepsy. Prior to RNS System implantation, these patients were not candidates for further resective surgery because they had temporal lobe epilepsy with bilateral temporal sources, frontal lobe reflex epilepsy with involvement of primary motor cortex, and occipital lobe epilepsy with substantial involvement of eloquent visual cortex. Without interfering with and beyond the scope of the therapeutic aspect of the RNS System study, the authors were able to monitor seizure and epileptiform activity from chronically implanted subdural and depth electrodes in these patients, and, in doing so, they were able to more accurately localize the seizure source. In 5 of these study patients, in whom the RNS System was not effective, the notion of resective surgery was revisited and considered in light of the additional information gleaned from the chronic intracranial recordings obtained from various permutations of electrodes monitoring sources in the frontal, temporal, parietal, and occipital lobes. RESULTS: Through long-term analysis of chronic unlimited recording electrocorticography (CURE) from chronically implanted electrodes, the authors were able to further refine seizure source localization and sufficiently increase the expected likelihood of seizure control to the extent that 4 patients who had previously been considered not to be candidates for surgery did undergo resective surgery, and all have achieved seizure freedom. A fifth patient, who had a double-band heterotopia, underwent surgery but did not achieve significant seizure reduction. CONCLUSIONS: Chronic unlimited recording electrocorticography-guided resective epilepsy surgery employs new monitoring technology in a novel way, which in this small series was felt to improve seizure localization and consequently the potential efficacy of resective surgery. This suggests that the CURE modality could improve outcomes in patients who undergo resective surgery, and it may expand the set of patients in whom resective surgery may be expected to be efficacious and therefore the potential number of patients who may achieve seizure freedom. The authors report 4 cases of patients in which this technique and technology had a direct role in guiding surgery that provided seizure freedom and that suggest this new approach warrants further study to characterize its value in presurgical evaluation. Clinical trial no.: NCT00572195 (ClinicalTrials.gov).

C4-C5 post-traumatic spondyloptosis with in situ fusion: systematic literature review and case report.

STUDY DESIGN: A case report with systematic review of the literature. OBJECTIVE: To report a case of post-traumatic C4-C5 spondyloptosis without neurological deficit not associated with posterior element fractures and presenting in a delayed fashion with fusion in situ of C4 and C5 vertebral bodies influencing the management strategy. SUMMARY OF BACKGROUND DATA: Traumatic spondyloptosis of the subaxial cervical spine is typically associated with neurological injury. To the best of the author's knowledge, this is the first case of spondyloptosis not associated with fractures of the posterior elements but with locked facets at C4-C5 and fusion in situ, presenting in a delayed fashion with remarkable paucity of symptoms that was managed surgically. METHODS: A 45-year-old male presented 8 months after a motor vehicle collision with radicular arm pain and mild spasticity involving the legs. Cervical radiograph, computed tomographic scan, and magnetic resonance image revealed bilateral locked facets at C4-C5 with spondyloptosis. Fusion had occurred in situ. RESULTS: Traction did not correct alignment and the patient underwent circumferential reduction and fusion and postoperative halo-vest placement. At 6-month follow-up, the patient remained neurologically intact with regression of preoperative symptoms. CONCLUSION: Longstanding post-traumatic spondyloptosis may lead to fusion in situ complicating the surgical management. Insufficient suspicion during workup can lead to the omission of this important diagnosis, further complicating operative intervention. Traction is not useful when in situ fusion has occurred in delayed presentation cases. LEVEL OF EVIDENCE: N/A.

Long-term deep brain stimulation for essential tremor: 12-year clinicopathologic follow-up.

We describe the clinical course and postmortem pathological findings in a patient with essential tremor (ET) treated with deep brain stimulation (DBS) for 12 years. This 75 year old woman had a 13-year history of progressive ET prior to implantation of bilateral quadripolar DBS electrodes in the region of her ventral intermediate thalamic nuclei in 1996, producing immediate relief of arm tremor. Histopathological examination of the brain, performed 12 years after the initial implantation, demonstrated electrode catheter tracts rimmed by 20-25 micron fibrous sheaths, with multinucleated giant cells and reactive gliosis. Lymphocytic infiltration was seen by L26 immunoreactivity with CD3 (T cells) staining predominating over CD20 (B cells). Cerebellar axonal spheroids and Purkinje cell loss were found. The minimal foreign body reaction and gliosis around the electrodes 12 years after implantation supports the long-term safety of DBS. The case represents the longest reported follow-up with autopsy examination after DBS and confirmed histological changes associated with ET.

Stimulation of sympathetic innervation in the upper gastrointestinal tract as a treatment for obesity.

Sympathetic activity and obesity have a reciprocal relationship. Firstly, hypothalamic obesity is associated with decreased sympathetic activity. Caffeine and ephedrine increase sympathetic activity and induce weight loss, of which 25% is due to increased metabolic rate and 75% is due to a reciprocally decreased food intake. Secondly, hormones and drugs that affect body weight have an inverse relationship between food intake and metabolic rate. Neuropeptide Y decreases sympathetic activity and increases food intake and body weight. Thirdly, a gastric pacemaker Transcend and vagotomy increase the ratio of sympathetic to parasympathetic activation, decrease food intake, and block gut satiety hormones. Weight loss with the pacemaker or vagotomy is variable. Significant weight reduction is seen only in a small group of those treated. This suggests that activation of the sympathetic arm of the autonomic nervous system may be most important for weight loss. Systemic sympathetic activation causes weight loss in obese patients, but side effects limited its use. We hypothesize that selective local electrical sympathetic stimulation of the upper gastrointestinal tract may induce weight loss and offer a safer, yet effective, obesity treatment. Celiac ganglia delivers sympathetic innervation to the upper gastrointestinal tract. Voltage regulated electrical simulation of the rat celiac ganglia increased metabolic rate in a dose-dependent manner. Stimulation of 6, 3, or 1.5 V increased metabolic rate 15.6%, 6.2%, and 5%, respectively in a single rat. These responses support our hypothesis that selective sympathetic stimulation of the upper GI tract may treat obesity while avoiding side effects of systemic sympathetic activation.

Severe coagulopathy following intraoperative use of topical thrombin.

This report describes a case of severe coagulopathy and bleeding related to the intraoperative use of topically applied thrombin. Commercial thrombin preparations contaminated with bovine factor V have been shown to stimulate the production of antibodies directed against factor V. These antibodies can cause coagulopathy. Our patient developed antibodies against factor V after intraoperative exposure to topical thrombin. The resulting antibody-mediated depletion of factor V caused a severe and refractory coagulopathy. Vascular surgeons should be aware that the use of topical bovine thrombin can cause severe coagulopathy.