Nikunj K. Patel

Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease.

Glial cell line–derived neurotrophic factor (GDNF) is a potent neurotrophic factor with restorative effects in a wide variety of rodent and primate models of Parkinson disease, but penetration into brain tissue from either the blood or the cerebro-spinal fluid is limited. Here we delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the magnetic resonance images that disappeared after lowering the concentration of GDNF. After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinsons Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [18F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. This study warrants careful examination of GDNF as a treatment for Parkinson disease.

Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study.

We have shown previously that intraparenchymal infusion of glial cell line–derived neurotrophic factor (GDNF) continuously into the posterior putamen in five Parkinsons disease patients is safe and may represent a new treatment option. Here, we report a continuation of this phase I study. After 2 years of continual GDNF infusion, there were no serious clinical side effects and no significant detrimental effects on cognition. Patients showed a 57% and 63% improvement in their off‐medication motor and activities of daily living subscores of the Unified Parkinsons Disease Rating Scale, respectively, and health‐related quality‐of‐life measures (Parkinsons Disease Questionnaire–39 and Short Form–36) showed general improvement over time. Ann Neurol 2005;57:298–302

GDNF, NGF and BDNF as therapeutic options for neurodegeneration

Glial cell-derived neurotrophic factor (GDNF), and the neurotrophin nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the survival, maintenance and regeneration of specific neuronal populations in the adult brain. Depletion of these neurotrophic factors has been linked with disease pathology and symptoms, and replacement strategies are considered as potential therapeutics for neurodegenerative diseases such as Parkinsons, Alzheimers and Huntingtons diseases. GDNF administration has recently been shown to be an effective treatment for Parkinsons disease, with clinical trials currently in progress. Trials with NGF for Alzheimers disease are ongoing, with some degree of success. Preclinical results using BDNF also show much promise, although there are accompanying difficulties. Ultimately, the administration of a therapy involving proteins in the brain has inherent problems. Because of the blood-brain-barrier, the protein must be infused directly, produced by viral constructs, secreted from implanted protein-secreting cells or actively transported across the brain. An alternative to this is the use of a small molecule agonist, a modulator or enhancer targeting the associated receptors. We evaluate these neurotrophic factors as potential short or long-term treatments, weighing up preclinical and clinical results with the possible effects on the underlying neurodegenerative process.

Glial cell line–derived neurotrophic factor induces neuronal sprouting in human brain

To the editor: Intraputaminal delivery of glial cell line– derived neurotrophic factor (GDNF) causes sprouting of dopaminergic fibers and clinical improvement in experimental animal models of Parkinson disease. We provide the first neuropathological evidence that infusion of GDNF into the posterior putamen causes similar sprouting of dopaminergic fibers in association with clinical improvement in idiopathic Parkinson disease in humans. A 62-year-old man was one of five individuals in a phase 1 study of GDNF (Amgen) infusion into the posterodorsal putamen, for treatment of idiopathic Parkinson disease1,2. He had a 5-year history of poorly controlled tremor-predominant left hemiparkinsonism. An intraparenchymal catheter was stereotactically implanted in the right posterodorsal putamen and connected to a SynchroMed pump (Medtronic). GDNF was infused continuously, at 14.4–43.2 mg/putamen/d, for 43 months. Clinical assessments were based on the Core Assessment Program for Intracerebral Transplantations1–3. At 24 months, the Unified Parkinson’s Disease Rating Scale (UPDRS)-III motor score off-medication had improved by 38% (Fig. 1a). This was accompanied by an 18% increase in wholeputamen 18F-dopa uptake and increased uptake in the posterior putamen of 91%. In contrast, the noninfused side showed a 7.4% decrease in whole-putamen 18F-dopa uptake

Magnetic Resonance Imaging-Directed Method for Functional Neurosurgery Using Implantable Guide Tubes

OBJECTIVE We present a magnetic resonance imaging-directed stereotactic system using implantable guide tubes for targeting deep brain nuclei in functional neurosurgery. METHODS Our method relies on visualization of the deep brain nuclei on high-resolution magnetic resonance images that delineate the target boundaries and enable direct targeting of specific regions of the nucleus. The delivery system comprises a modified stereoguide capable of delivering an implantable guide tube to the vicinity of the desired target. The guide tube (in-house investigational device) has a hub at its proximal end that is fixed within a burr hole and accommodates a radioopaque stylette that is inserted such that its distal end is at the desired target. After perioperative radiological confirmation of the stylettes relationship to the desired brain target, it is withdrawn from the guide tube, which may then act as a port for the implantation of an electrode for deep brain stimulation (DBS) or radiofrequency lesioning. Alternatively, the guide tube can be used to insert a catheter for drug delivery, cell transplantation, or viral-vector delivery. Implantation and verification are guided by magnetic resonance imaging or computed tomography, which enable the entire procedure to be performed under general anesthesia. The technique of implantation helps ensure optimal accuracy, and we have successfully used this device for implanting electrodes for DBS in the treatment of Parkinsons disease, essential tremor, and dystonia, and for implanting catheters for continuous delivery of glial-derived neurotrophic factor in the treatment of Parkinsons disease. The device also aids in securely fixing the DBS electrode or catheter to the cranium with ease, limiting hardware problems. RESULTS A total of 205 guide tubes have been implanted in 101 patients. Major complications in these cases were limited to 4% of patients. At the initial implantations, 96.3% of the guide tubes were within 1.5 mm of the target. Ten guide tubes required reimplantation secondary to target errors. With corrections, the DBS electrode was delivered to within 1.5 mm from the planned target in all cases. CONCLUSION This system provides a safe and accurate magnetic resonance imaging-directed system for targeting deep brain nuclei in functional neurosurgery under general anesthesia and avoids the need for electrophysiological monitoring.

MRI-directed subthalamic nucleus surgery for Parkinson's disease.

The subthalamic nucleus (STN) is now regarded as the optimal surgical target for the treatment of medically refractory idiopathic Parkinson’s disease. In our center, a predominantly MRI-directed method has been developed for targeting the STN. The STN is localized on T2-weighted images from a 1.5-T MRI scanner. Long acquisition, high-resolution images are acquired in both the axial and coronal planes under strict stereotactic conditions with the patient under general anesthesia. The boundary of STN is co-registered in both planes to give optimal 3-dimensional target definition. Stereotactic coordinates of the dorsolateral STN are recorded and the trajectory is planned down the axis of the nucleus in the coronal plane. Initially, per-operative macrostimulation was used for adjustment at the target prior to unilateral subthalamotomy in 26 patients. Five patients were lost to follow-up. Assessments of the lesions in post-operative images confirmed successful localisation of the lesions within the dorsolateral STN in all of the remaining 21 cases. In a subsequent series of 19 patients treated by deep brain stimulation (DBS), unilateral in 1 patient and bilateral in 18, the STN was targeted using the same MRI-directed method, guide tubes and radio-opaque stylettes were implanted, and target verification was entirely MRI-based. Following implantation of the guide tubes and stylettes, assessments of the per-operative MRI images for the 37 STN targetings confirmed a mean target error, between the stylette and the desired target in the axial plane, of 0.3 mm mediolaterally (SD = 0.4) and 0.4 mm anteroposteriorly (SD = 0.4), with median errors of 0.5 mm. This study demonstrates that MRI-directed targeting of the STN through guide tubes is accurate, and allows direct verification and corrections as necessary. Cumulative frequencies predict that the majority of DBS electrodes placed in this manner will be within 0.5 mm of the planned target. Because physiological methods are not required, the whole procedure can be performed under general anesthesia. We feel that planning with reference to a standard atlas is unreliable and not significantly helped by the addition of microelectrode recording, the accuracy of which in the axial plane is dependent upon the distance between the recording trajectories, which is typically 2 mm.

Comparison of atlas- and magnetic-resonance-imaging-based stereotactic targeting of the subthalamic nucleus in the surgical treatment of Parkinson's disease.

Aims: To assess the variability of the subthalamic nucleus (STN) size, orientation and target coordinates from direct visualization on high-resolution magnetic resonance (MR) images in patients undergoing surgical intervention for Parkinson’s disease. Methods: Sixty-six patients with Parkinson’s disease were included in this study. The STN was visualized directly on high-resolution MR images, the size and orientation in both coronal and axial planes were recorded, as were the coordinates of the dorsolateral STN target in relation to the anterior-posterior commissural (AC-PC) line. The same STN target was defined in the Schaltenbrand atlas and atlas-based coordinates in proportion to the patient’s AC-PC dimension were calculated. MR-imaging-based STN target coordinates were compared with the corresponding atlas-based coordinates. Results: Marked variation of STN size and orientation was observed. A significant difference was demonstrated on comparing left- and right-sided x and y coordinates. The comparison between MR-imaging-based and atlas-derived target coordinates demonstrated a significant difference in all directions except the left y coordinate. Conclusions: This study demonstrates the substantial individual variability of STN size, orientation and target coordinates and a significant difference between target coordinates obtained by direct visual targeting on MR images and those obtained by indirect targeting based on atlases.

Neuralgia of the glossopharyngeal and vagal nerves: long-term outcome following surgical treatment and literature review

This study describes our experience in the surgical treatment of neuralgia of the glossopharyngeal and vagal nerves. Over the last 19 years, 21 patients underwent surgery. Their case notes were reviewed to obtain demographic information, clinical presentation, surgical findings and early results. All patients were then contacted by telephone for long-term results and complications. Independent analysis of results was carried out by a Neurology team. Ten patients had microvascular decompression (MVD). Four patients had MVD and nerve section. In the remaining seven patients, the glossopharyngeal and first two rootlets of the vagal nerve were sectioned. Nineteen (90%) of 21 patients experienced complete relief of pain immediately after surgery. The remaining patients reported an improvement in their symptoms. There were no mortalities. Four patients experienced short-term complications, which resolved. Two patients were left with a persistent hoarse voice. At follow-up (mean duration of 4 years), there was no recurrence in symptoms. In our experience, surgery is safe and effective for the treatment of vago-glossopharyngeal neuralgia.

Unilateral Carotid Body Resection in Resistant Hypertension A Safety and Feasibility Trial

Summary Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension.

Benefits of putaminal GDNF infusion in Parkinson disease are maintained after GDNF cessation

We previously reported clinical improvement, increase in putamen [18F]-dopa uptake on PET imaging, and neuropathologic evidence of sprouting of dopaminergic fibers following chronic intraputaminal delivery of glial cell line–derived neurotrophic factor (GDNF) in idiopathic Parkinson disease (PD).1–3 We now provide clinical and PET evidence of persistent efficacy lasting for at least 3 years following cessation of GDNF infusion in a patient with PD. This is a single-case observational study, providing Class IV evidence.