Search

Objective: The objective of this study was to develop and evaluate the feasibility and safety of a novel transaxial surgical approach for the delivery of human induced pluripotent stem cell-derived dopaminergic neuroprogenitor cells (DANPCs) into the putamen nucleus using nonhuman primates and surgical techniques and tools relevant to human clinical translation., Methods: Nine immunosuppressed, unlesioned adult cynomolgus macaques (4 females, 5 males) received intraputaminal injections of vehicle or DANPCs (0.9 × 105 to 1.1 × 105 cells/µL) under real-time intraoperative MRI guidance. The infusates were combined with 1-mM gadoteridol (for intraoperative MRI visualization) and delivered via two tracks per hemisphere (ventral and dorsal) using a transaxial approach. The total volumes of infusion were 25 µL and 50 µL for the right and left putamen, respectively (infusion rate 2.5 µL/min). Animals were evaluated with a battery of clinical and behavioral outcome measures and euthanized 7 or 30 days postsurgery; full necropsies were performed by a board-certified veterinary pathologist. Brain tissues were collected and processed for immunohistochemistry, including against the human-specific marker STEM121., Results: The optimized surgical technique and tools produced successful targeting of the putamen via the transaxial approach. Intraoperative MR images confirmed on-target intraputaminal injections in all animals. All animals survived to scheduled termination without clinical evidence of neurological deficits. The first 4 animals to undergo surgery had mild brain swelling noted at the end of surgery, of which 3 had transient reduced vision; administration of mannitol therapy and reduced intravenous fluid during the surgical procedure addressed these complications. Immunostaining against STEM121 confirmed the presence of grafted cells along the injection track within the targeted putamen area of DANPC-treated animals. All adverse histological findings were limited in scope and consistent with surgical manipulation, injection procedure, and postsurgical inflammatory response to the mechanical disruption caused by the cannula insertion., Conclusions: The delivery system, injection procedure, and DANPCs were well tolerated in all animals. Prevention of mild brain swelling by mannitol dosing and reduction of intravenous fluids during surgery allowed visual effects to be avoided. The results of the study established that this novel transaxial approach can be used to correctly and safely target cell injections to the postcommissural putamen and support clinical investigation.

Objective: Obsessive-compulsive disorder (OCD) is a severe psychiatric condition. The authors present their experience with Gamma Knife radiosurgery (GKRS) in the treatment of patients with OCD resistant to any medical therapy., Methods: Patients with severe OCD resistant to all pharmacological and psychiatric treatments who were treated with anterior GKRS capsulotomy were retrospectively reviewed. These patients were submitted to a physical, neurological, and neuropsychological examination together with structural and functional MRI before and after GKRS treatment. Strict study inclusion criteria were applied. Radiosurgical capsulotomy was performed using two 4-mm isocenters targeted at the midputaminal point of the anterior limb of the capsule. A maximal dose of 120 Gy was prescribed for each side. Clinical global changes were assessed using the Clinical Global Impression (CGI) scale, Global Assessment of Functioning (GAF) scale, EQ-5D, Beck Depression Inventory (BDI), and State-Trait Anxiety Inventory (STAI). OCD symptoms were determined by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS)., Results: Ten patients with medically refractory OCD (5 women and 5 men) treated between 2006 and 2015 were included in this study. Median age at diagnosis was 22 years, median duration of illness at the time of radiosurgery was 14.5 years, and median age at treatment was 38.8 years. Before GKRS, the median Y-BOCS score was 34.5 with a median obsession score of 18 and compulsion score of 17. Seven (70%) of 10 patients achieved a full response at their last follow-up, 2 patients were nonresponders, and 1 patient was a partial responder. Evaluation of the Y-BOCS, BDI, STAI-Trait, STAI-State, GAF, and EQ-5D showed statistically significant improvement at the last follow-up after GKRS. Neurological examinations were normal in all patients at each visit. At last follow-up, none of the patients had experienced any significant adverse neuropsychological effects or personality changes., Conclusions: GKRS anterior capsulotomy is effective and well tolerated with a maximal dose of 120 Gy. It reduces both obsessions and compulsions, improves quality of life, and diminishes depression and anxiety.

Object: For several decades, clinicians have predicted intraparenchymal brain pressure or brain tissue compression indirectly based on the degree of distortion of the midline structures (midline shift) and ventricle wall (ventriculomegaly) observed on conventional MRI. However, this method has several limitations. Diffusion tensor imaging (DTI) is a novel MRI technique that can provide information about the microstructural properties of compressed tissue. In this study, the authors evaluated whether DTI can precisely define the degree of tissue compression in patients with chronic subdural hematoma (CSDH)., Methods: The study sample consisted of 18 patients (mean age 71 years, 10 men and 8 women) with unilateral CSDH and 12 age-matched volunteers. Diffusion tensor imaging results were acquired before and after the surgical irrigation in the CSDH group. Subdural pressure during the operation was also measured. Fractional anisotropy (FA) values were evaluated at several locations, including the gray matter., Results: The FA values of the gray matter, especially in the caudate nucleus and putamen, were increased in the patients with CSDH compared with the control group. The change in FA data before and after surgery (ΔFA) correlated with the degree of tissue compression evaluated by measurement of the subdural pressure. Furthermore, the increased FA values in patients with CSDH decreased after surgery., Conclusions: These findings indicate that FA values of the gray matter, especially in the caudate nucleus and putamen, may be important markers of tissue compression. The assessment of FA values of the gray matter will result in a new, less-invasive diagnostic technique to evaluate the degree of brain compression.

Object: The aim of this study was to estimate the impact of stereotactic pallidal surgery on the binding potential of dopamine D2 receptors in patients with advanced Parkinson disease (PD)., Methods: Six patients with advanced PD (three men and three women; mean age 56.7 +/- 9.8 years, Hoehn and Yahr stage 3.3 +/- 1.1/3.9 +/- 1.2 [on/off scores], mean +/- standard deviation) underwent stereotactic pallidal surgery. One underwent right posteroventral pallidotomy (PVP), one received left PVP, three were treated with deep brain stimulation (DBS) of the left globus pallidus internus (GPi), and one with bilateral DBS of the GPi. The binding potential of the dopamine D2 receptors of these patients was determined before and after surgery by using positron emission tomography scanning with 11C-nemonapride and it was compared with the value in eight healthy volunteers. The authors also examined whether changes in the D2 receptor binding potential were correlated with the clinical outcome. The clinical symptoms, especially those in the off state, were significantly improved after surgery. Preoperatively, the D2 receptor binding potential in the putamen was elevated by 27% (p < 0.01) and that in the thalamus was 29% lower than that in controls (p < 0.01). The D2 receptor binding potential in the putamen and thalamus returned to control levels after surgery. The preoperative level of the D2 receptor binding potential in the anterior cingulate cortex was comparable to that of controls, but it declined significantly after surgery, whereas the D2 receptor binding potential in other regions of both hemispheres showed no significant changes after surgery. Although the D2 receptor binding potential did not correlate with the Hoehn and Yahr stage, the Schwab and England score, or the Unified PD Rating Scale (UPDRS) score, a positive correlation was seen between the percent improvement rate of the total UPDRS score in the off state and the percentage change of the D2 receptor binding potential in the putamen (r = 0.773, p = 0.0417 according to the Pearson linear correlation)., Conclusions: The altered dopamine D2 receptor binding potential in the putamen might play a crucial role in clinical improvement after PVP or DBS of the GPi in advanced PD.

The main neural transplantation strategy in Parkinson disease (PD) has been focused on reinnervating the striatum. The clinical results reported in patients who receive transplants have been limited and do not justify the use of neural transplantation as a routine therapeutic procedure for PD. Identifying the optimal target for transplantation may be one of the critical factors for optimizing clinical outcomes. Evidence from preclinical studies indicates that simultaneous intrastriatal and intranigral grafts (double grafts) may produce a more complete functional recovery. The authors report the clinical and positron emission tomography (PET) scanning results in three patients enrolled in a safety and feasibility pilot study who received double grafts and who have been followed for up to 13 months posttransplantation. Patients included in the study had idiopathic PD. All patients underwent detailed assessments before and after surgery, in accordance with the Core Assessment Program for Intracerebral Transplantation. The patients received implants of fetal mesencephalic cell suspensions in the putamen and substantia nigra (SN) bilaterally. There were no intraoperative or perioperative complications. Follow-up PET scans demonstrated an increase in the mean fluorodopa uptake constant values in the putamen and SN 12 months postsurgery. Improvements were also noted in the total Unified Parkinson's Disease Rating Scale, Hoehn and Yahr, Schwab and England, and pronation/supination scores after transplantation. The authors demonstrate the feasibility of reinnervating the SN and striatum by using a double transplant strategy in humans.

Object: There is growing evidence to indicate that tissue transplantation can potentially be a restorative neurosurgical treatment for patients with Parkinson disease (PD). In this study the authors investigated the clinical effect of unilateral intrastriatal grafting of autologous sympathetic neurons in patients with PD., Methods: Four patients with PD who had been observed for 1 year after graft placement of autologous sympathetic neurons were selected for an analysis of the effect of that procedure. Sympathetic ganglion tissue was endoscopically excised from the thoracic sympathetic trunk and grafted into the unilateral caudate head and putamen of the PD patients. No changes were made in the patients' preoperative regimens of antiparkinsonian medications, and clinical evaluations were made principally according to those established by the Core Assessment Program for Intracerebral Transplantation Committee. Whereas the sympathetic neuron grafts failed to affect clinical scores reflecting the patients' motor performance, which was evaluated during either the "on" or "off' phases, the grafts significantly increased the duration of the levodopa-induced on period with consequent reduction in the percentage of time spent in the off phase. This beneficial effect may be explained by the results of the present in vitro experiment, which show that human sympathetic neurons have the ability to convert exogenous levodopa to dopamine and to store this synthesized dopamine., Conclusions: Sympathetic neuron autografts were found to improve performance status in patients with PD by reducing the time spent in the off phase. This clearly indicates that sympathetic ganglion tissue, the use of which involves few ethical issues, can be an efficacious donor source in cell transplantation therapy for PD. Further studies are needed to determine whether the grafts may provide long-lasting clinical benefits.

The authors have studied the ability of glial cell line-derived neurotrophic factor (GDNF) to promote survival of human fetal dopaminergic tissue after a storage period of 6 days and subsequent implantation into the human putamen. The results indicate that GDNF promotes survival of stored dopaminergic cells. Cells stored without GDNF had a 30.1% decrease in survival time compared with those exposed to GDNF. Two patients with Parkinson's disease received bilateral putaminal implants of fetal dopaminergic cells exposed to GDNF for 6 days and showed enhancement of graft survival as assessed by positron emission tomography scanning. A mean increase of 107% in putaminal fluorodopa uptake from baseline values was observed 12 months postgrafting.

The authors present a simple, reliable, and safe system for performing neural transplantation in the human brain. The device consists of a transplantation cannula and microinjector system that has been specifically designed to reduce implantation-related trauma and to maximize the number of graft deposits per injection. The system was evaluated first in an experimental rat model of Parkinson's disease (PD). Animals in which transplantation with this system had been performed showed excellent graft survival with minimal trauma to the brain. Following this experimental stage, the cannula and microinjector system were used in eight patients with PD enrolled in the Halifax Neural Transplantation Program who received bilateral putaminal transplants of fetal ventral mesencephalic tissue. A total of 16 transplantation operations and 64 trajectories were performed in the eight patients, and there were no intraoperative or perioperative complications. Magnetic resonance imaging studies obtained 24 hours after surgery revealed no evidence of tissue damage or hemorrhage. Transplant survival was confirmed by fluorodopa positron emission tomography scans obtained 6 and 12 months after surgery. As neural transplantation procedures for the treatment of neurological conditions evolve, the ability to deliver viable grafts safely will become critically important. The device presented here has proved to be of value in maximizing the number of graft deposits while minimizing implantation-related trauma to the host brain.

Object: In recent years, fetal mesencephalic tissue transplant for the treatment of Parkinson's disease (PD) has been demonstrated to hold promise, but potential complications related to growth of allograft tissue have not been well described. This report explores the development and possible causation of a fatal cyst arising from a fetal transplant in the brain., Methods: The authors report the case of a 52-year-old woman who underwent bilateral putamenal fetal mesencephalic allograft transplant for PD at another hospital. Twenty-three months later she presented to the authors' institution in a coma. Admission computerized tomography and magnetic resonance (MR) studies revealed a contrast-enhancing mural nodule and associated large cyst arising from the left putamen and causing brainstem compression. Despite surgical decompression of the cyst, the patient did not regain consciousness. Biopsy and autopsy specimens were obtained, along with an analysis of the cyst fluid. Genotyping of the nodule and the patient's peripheral lymphocytes by using polymerase chain reaction-based microsatellite analysis was also performed. Biopsy samples and autopsy histopathological studies showed inflammatory cells, hemosiderin-laden macrophages, and astrocytosis. Scattered neurons and multiple rests of choroid plexus were also noted. The cyst had a thin wall and contained liquid that was identical in composition to cerebrospinal fluid (CSF). Genotyping demonstrated the presence of alleles in the nodule DNA that were not present in lymphocytic DNA, indicating that the nodule contained allograft tissue., Conclusions: The authors hypothesize that the choroid plexus tissue contained in the allograft resulted in CSF production and cyst formation at the transplant site, ultimately leading to the patient's herniation syndrome. The clinical history and large size of the mural nodule indicate slow growth of this allograft site and cyst over time. This case demonstrates that unusual patterns of tissue growth can occur in the brain after fetal tissue transplant and emphasizes the need for long-term monitoring of posttransplant patients by means of MR imaging. Cell sorting should be considered to ensure transplant of pure neuronal and astroglial populations.

Serial computerized tomography (CT) scans were correlated with a precise time-course analysis of the neurological condition of 180 patients with hypertensive putaminal hemorrhage. All patients entered the study within 3 hours of the ictus. In this series, 111 patients were treated conservatively and 69 surgically. The neurological condition of each patient was measured by means of a newly proposed grading system for intracerebral hemorrhage-intracranial hemorrhage (ICH grade) which is a modification of the Glasgow Coma Scale. Serial CT scans revealed that most hemorrhages were completed within 6 hours after ictus. Based on the ICH grade at 6 hours postictus, a clinical classification of the severity of putaminal hemorrhage was defined: fulminant, rapidly progressive, slowly progressive, and nonprogressive. According to this classification, precise time courses of the ICH grade were compared between the conservative and surgical treatment groups in a 7-day postictal period. Activities of daily living at 6 months after ictus were also compared. Surgical treatment for a rapidly progressive hemorrhage appears to be beneficial if undertaken in patients under 65 years of age. Surgery in a slowly progressive hemorrhage should be considered only in a small number of patients who deteriorate neurologically with conservative treatment. In this series of patients, surgical treatment of fulminant and nonprogressive hemorrhage was not likely to improve the quality of life or functional recovery. Regardless of treatment modality, CT provided evidence that patients with anterior capsular hemorrhage (16% in this series) showed good recovery of motor and speech function.