Joshua P. Aronson

Lesion procedures in psychiatric neurosurgery.

OBJECTIVE Lesion procedures for psychiatric indications have a history that spans more than a century. This review provides a brief history of psychiatric surgery and addresses the most recent literature on lesion surgery for the treatment of anxiety and mood disorders. METHODS Relevant data described in publications from the early 1900 s through the modern era regarding lesion procedures for psychiatric indications, both historical and current use, are reported. RESULTS The early procedures of Burkhardt, Moniz, and Freeman are reviewed, followed by descriptions of the more refined techniques of Leksell, Knight, Foltz, White, and Kelly. The application of lesion procedures to obsessive-compulsive disorder, mood disorders, and addiction are discussed. CONCLUSIONS Lesioning procedures have informed modern deep brain stimulation targets. Recent lesioning studies demonstrate the efficacy and durability of these procedures in severely disabled patients. Judicious application of these techniques should continue for appropriately selected patients with severe, refractory psychiatric disorders.

A novel tissue engineering approach using an endothelial progenitor cell–seeded biopolymer to treat intracranial saccular aneurysms

OBJECT Recurrence after endovascular coiling of intracranial aneurysms is reported in up to 42% of cases and is attributed to the lack of endothelialization across the neck. In this study the authors used a novel tissue engineering approach to promote endothelialization by seeding endothelial progenitor cells (EPCs) within a fibrin polymer injected endovascularly into the aneurysm. METHODS Experimental aneurysms were created in New Zealand White rabbits and were left untreated, surgically clipped, or embolized with platinum coils, fibrin biopolymer alone, or fibrin combined with autologous cultured EPCs. RESULTS In aneurysms treated with EPCs, a confluent monolayer of endothelial cells with underlying neointima was demonstrated across the neck at 16 weeks posttreatment, which was not observed with aneurysms treated using the other methods. CONCLUSIONS This novel technique may address reasons for the limited durability of standard coil embolization and provides further avenues for the development of improved devices for the care of patients with aneurysms.

Treatment of moyamoya disease in the adult population with pial synangiosis

OBJECT Surgical treatment of moyamoya disease in the adult population commonly uses direct revascularization, the superficial temporal artery (STA) to middle cerebral artery (MCA) bypass (STA-MCA). Pial synangiosis, a method of indirect revascularization, has been used in adult patients with moyamoya when STA-MCA bypass was not technically feasible. Although the effectiveness of pial synangiosis has been well described in children, only limited reports have examined its role in adult patients with moyamoya disease. In this study the authors report on their experience with pial synangiosis revascularization for this population. METHODS The authors reviewed the clinical and radiographic records of all adult patients (≥ 18 years of age) with moyamoya disease who underwent cerebral revascularization surgery using pial synangiosis at a single institution. RESULTS From 1985 to 2010, 66 procedures (6 unilateral, 30 bilateral) were performed on 36 adult patients with moyamoya disease. The mean age at surgery was 28.3 years, and 30 patients were female. Twenty-eight patients (77.8%) presented with transient ischemic attacks (TIAs), 24 (66.7%) with stroke, and 3 (8.3%) with hemorrhage. Preoperative Suzuki stage was III or higher in 50 hemispheres (75.8%) and 3 patients had undergone prior treatments to the affected hemisphere before pial synangiosis surgery. Clinical follow-up was available for an average of 5.8 years (range 0.6-14.1 years), with 26 patients (72.2%) followed for longer than 2 years. Postoperative angiography was available for 24 patients and 46 revascularized hemispheres, and 39 (84.8%) of the 46 hemispheres demonstrated good collateral formation (Matsushima Grade A or B). Postoperative complications included 3 strokes, 5 TIAs, and 2 seizures, and there was no hemorrhage during the follow-up period. One patient required additional revascularization surgery 8 months after pial synangiosis. CONCLUSIONS Pial synangiosis is a safe and durable method of cerebral revascularization in adult patients with moyamoya and can be considered as a potential treatment option for moyamoya disease in adults.

Utility of foramen ovale electrodes in mesial temporal lobe epilepsy.

To determine the ability of foramen ovale electrodes (FOEs) to localize epileptogenic foci after inconclusive noninvasive investigations in patients with suspected mesial temporal lobe epilepsy (MTLE).

Neuromodulation for Obsessive-Compulsive Disorder

This article describes the basis for neuromodulation procedures for obsessive-compulsive disorder (OCD) and summarizes the literature on the efficacy of these interventions. Discussion includes neural circuitry underlying OCD pathology, the history and types of ablative procedures, the targets and modalities used for neuromodulation, and future therapeutic directions.

Three-dimensional brain surface visualization for epilepsy surgery of focal cortical dysplasia

Focal cortical dysplasia (FCD) causes medically intractable seizures in 5-10% of adult epilepsy patients, but patients can become seizure free through surgical resection. The authors present the utility of three-dimensional surface visualization (3DSV) that expands on existing imaging datasets to highlight surface vasculature as a tool for achieving more successful resections in patients with FCD. In this prospective series of six patients, preoperative 3DSV was performed for planning the surgical approach to the lesion and for intraoperative guidance. Reconstructions involved volume rendering of a contrast-enhanced dataset to visualize surface venous vasculature. Postoperatively, five of the six patients had complete resections, with one patient having a subtotal resection due to proximity to crucial vasculature. We report that 3DSV is a useful tool for surgical planning, since topographical relationships between lesion location and surface vasculature landmarks are less likely to change with surgical progress.

Rupture of a pseudoaneurysm of the posterior meningeal artery at its anomalous origin from the posteroinferior cerebellar artery: case report.

OBJECTIVEThe posterior meningeal artery (PMA) normally arises from the vertebral artery; however, its origin varies considerably as the result of its embryological development. This gains clinical significance when associated with vascular pathology. CLINICAL PRESENTATIONA 65-year-old man presented to his local hospital with a sudden-onset, severe headache. Computed tomography of the head revealed diffuse subarachnoid hemorrhage, mostly in the left posterior fossa. A computed tomographic angiogram demonstrated an anomalous origin of the PMA from the posteroinferior cerebellar artery (PICA). Cerebral angiography showed the PICA to be enlarged, with a reduced caliber at the takeoff of the PMA, which is consistent with possible dissection. INTERVENTIONThe patient was taken to the operating room for trapping of the dissecting segment of the PMA. A clip was placed across the PMA at its origin from the PICA, and the vessel was coagulated and transected. The PICA was wrapped in muslin gauze. CONCLUSIONThe variable origin of the PMA and PICA may be the result of the persistence of embryological anastomoses between the arteries, with regression of the normal channel. Physical stress at the junction of the anomalous PMA and the PICA may have contributed to the abnormality of the PMA, consistent with possible dissection. Because the PMA has multiple anastomoses with the arteries of the falx cerebri, the proximal PMA may be occluded with no compromise to its vascular territory.

Episodic ventriculomegaly due to hypernatremia mimicking shunt malfunction: case report.

Patients with shunted hydrocephalus presenting with altered mental status and ventriculomegaly are generally considered to be in shunt failure requiring surgical treatment. The authors describe a case of shunted hydrocephalus secondary to a disseminated neuroectodermal tumor in a pediatric patient in whom rapid fluctuations in sodium levels due to diabetes insipidus repeatedly led to significant changes in ventricle size, with invasively confirmed normal shunt function and low intracranial pressure. This clinical picture exactly mimics shunt malfunction, requires urgent nonsurgical therapy, and underscores the importance of considering serum osmolar abnormalities in the differential diagnosis for ventriculomegaly.

Sustained intrathecal therapeutic protein delivery using genetically transduced tissue implants in a freely moving rat model

Systemic delivery of therapeutic proteins to the central nervous system (CNS) is challenging because of the blood-brain barrier restrictions. Direct intrathecal delivery is possible but does not produce stable concentrations. We are proposing an alternative approach for localized delivery into the CNS based on the Transduced Autologous Restorative Gene Therapy (TARGT) system. This system was previously developed using a gene therapy approach with dermal tissue implants. Lewis rat dermal tissue was transduced to secrete human EPO (hEPO). TARGT viability and function were retained following cryopreservation. Upon implantation into the rat cisterna magna, a mild inflammatory response was observed at the TARGT-brain interface throughout 21-day implantation. hEPO expression was verified immunohistochemically and by secreted levels in cerebrospinal fluid (CSF), serum, and in vitro post explant. Detectable CSF hEPO levels were maintained during the study. Serum hEPO levels were similar to rat and human basal serum levels. In vitro, the highest hEPO concentration was observed on day 1 post-explant culture and then remained constant for over 21days. Prolonged incubation within the cisterna magna had no negative impact on TARGT hEPO secretion. These promising results suggest that TARGTs could be utilized for targeted delivery of therapeutic proteins to the CNS.

598. TARGTCNS for the Treatment of Central Nervous System Disorders

Diseases and disorders of the central nervous system (CNS) represent a large field of unmet need that significantly impacts the lifespan and quality of life of many patients. The ability to deliver therapeutic proteins from the systemic circulation to the CNS is hampered by the blood-brain barrier (BBB). A number of strategies have been developed to allow therapies to cross the BBB, but to date with limited success. We have developed a novel localized approach to deliver protein and peptide therapeutics to the CNS based on our proprietary Transduced Autologous Restorative Gene Therapy system (TARGT™) platform. TARGT is based on autologous dermal micro-organs (MO) harvested and transduced ex-vivo to produce a therapeutic protein and then re-implanted in the patient. In this study we assessed whether TARGT can survive and deliver sustained localized protein post implantation into the CNS. In rats, MOs, 2×1mm each, were harvested from Lewis rat skin, characterized in-vitro, and then implanted in the Lewis rats’ cisterna magna. The procedure was well-tolerated and without observed behavioral change in all implanted rats. Histopathology of MOs excised several weeks post implantation, demonstrated viable and integrated MOs without signs of implant rejection. In the second phase, rat MOs were processed ex-vivo into TARGT secreting erythropoietin (TARGTEPO) by transduction with Helper Dependent Adenoviral vector encoding human erythropoietin (HDAd-HuEPO). Rat TARGTs secreting human EPO were then implanted into Lewis rats’ cisterna magna. Post implantation, cerebrospinal fluid (CSF) and serum were collected and EPO levels were measured by HuEPO ELISA. Results obtained suggest that implantation was well tolerated with no observed signs of rejection. Measurable human EPO levels were detected in rat CSF for the duration of the experiment. Detectable but low levels of Hu-EPO were also measured in the rat serum, as expected, since CSF drains into the peripheral blood. In pigs we have tested the viability and monoclonal antibody secretion from TARGTs into the CNS. Humira, an established antibody drug, was selected as a proof of concept. Pig MOs were harvested and transduced with the HDAd vector carrying the Humira sequence. Two TARGTHumira were implanted in the pig subdural space at the parietal convexity region and the pig was followed for one week post implantation. Results obtained post implantation suggests no observed pigs behavioral change. Humira was measured in CSF samples taken from the implantation area and the lumbar space. One week post implantation, TARGTs were excised out of the pig brain when they are viable and no signs of inflammation or damage to the brain tissue were observed. These results demonstrate that TARGT is a promising novel therapeutic platform with the potential for treatment of CNS disorders. We are now actively studying TARGTCNS treatment of lysosomal storage diseases and brain malignancies.