Puneet Plaha

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

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

Bilateral stimulation of the caudal zona incerta nucleus for tremor control.

Introduction: The ventrolateral (VL) nucleus of the thalamus is the commonly chosen target for deep brain stimulation (DBS) to alleviate tremor. However, it has a poor efficacy in alleviating proximal tremor and patients may develop tolerance to the action component of tremor. We performed bilateral stimulation of the caudal or motor part of the zona incerta nucleus (cZI) to determine its safety and efficacy in alleviating tremor. Methods: 5 patients with parkinsonian tremor and 13 with a range of tremors (Holmes (HT), cerebellar (CT), essential (ET), multiple sclerosis (MS) and dystonic tremor (DT)) affecting both the proximal and distal body parts underwent MRI guided, bilateral cZI DBS. Tremor was assessed by the Fahn–Tolosa–Marin (FTM) tremor scale at baseline and at a mean follow-up of 12 months. Results: Resting PD tremor improved by 94.8% and postural tremor by 88.2%. The total tremor score improved by 75.9% in 6 patients with ET. HT improved by 70.2%, proximal CT by 60.4% and proximal MS tremor by 57.2% in the total tremor rating score. In the single patient with DT, there was improvement in both the dystonia and the tremor. Patients required low voltages of high-frequency stimulation and did not develop tolerance to it. Stimulation-related side effects were transient. Conclusion This prospective study shows that the cZI may be an alternative target for the treatment of tremor with DBS. In contrast to bilateral DBS of the VL nucleus, it improves all components of tremor affecting both the distal and proximal limbs as well as the axial musculature.

MRI directed bilateral stimulation of the subthalamic nucleus in patients with Parkinson’s disease

Objective: Bilateral chronic high frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) has emerged as an appropriate therapy for patients with advanced Parkinson’s disease refractory to medical therapy. Advances in neuroimaging and neurophysiology have led to the development of varied targeting methods for the delivery of this treatment. Intraoperative neurophysiological and clinical monitoring is regarded by many to be mandatory for accurate STN localisation. We have examined efficacy of bilateral STN stimulation using a predominantly magnetic resonance imaging (MRI)-directed technique. Methods: DBS leads were stereotactically implanted into the STN using an MRI directed method, with intraoperative macrostimulation used purely for adjustment. The effects of DBS were evaluated in 16 patients followed up to 12 months, and compared with baseline assessments. Assessments were performed in both off and on medication states, and were based on the Unified Parkinson’s Disease Rating Scale (UPDRS) and timed motor tests. Functional status outcomes were examined using the PDQ-39 quality of life questionnaire. A battery of psychometric tests was used to assess cognition. Results: After 12 months, stimulation in the off medication state resulted in significant improvements in Activities of Daily Living and Motor scores (UPDRS parts II and III) by 62% and 61% respectively. Timed motor tests were significantly improved in the off medication state. Motor scores (UPDRS part III) were significantly improved by 40% in the on medication state. Dyskinesias and off duration were significantly reduced and the mean dose of l-dopa equivalents was reduced by half. Psychometric test scores were mostly unchanged or improved. Adverse events were few. Conclusions: An MRI directed targeting method for implantation of DBS leads into the STN can be used safely and effectively, and results are comparable with studies using intraoperative microelectrode neurophysiological targeting. In addition, our method was associated with an efficient use of operating time, and without the necessary costs of microelectrode recording.

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.

Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations.

Mutations in the isocitrate dehydrogenase genes (IDH1/2) occur often in diffuse gliomas, where they are associated with abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Monitoring 2-HG levels could provide prognostic information in this disease, but detection strategies that are noninvasive and sufficiently quantitative have yet to be developed. In this study, we address this need by presenting a proton magnetic resonance spectroscopy ((1)H-MRS) acquisition scheme that uses an ultrahigh magnetic field (≥ 7T) capable of noninvasively detecting 2-HG with quantitative measurements sufficient to differentiate mutant cytosolic IDH1 and mitochondrial IDH2 in human brain tumors. Untargeted metabolomics analysis of in vivo (1)H-MRS spectra discriminated between IDH-mutant tumors and healthy tissue, and separated IDH1 from IDH2 mutations. High-quality spectra enabled the quantification of neurochemical profiles consisting of at least eight metabolites, including 2-HG, glutamate, lactate, and glutathione in both tumor and healthy tissue voxels. Notably, IDH2 mutation produced more 2-HG than IDH1 mutation, consistent with previous findings in cell culture. By offering enhanced sensitivity and specificity, this scheme can quantitatively detect 2-HG and associated metabolites that may accumulate during tumor progression, with implications to better monitor patient responses to therapy.

Outcomes from stimulation of the caudal zona incerta and pedunculopontine nucleus in patients with Parkinson's disease

Introduction. Axial symptoms including postural instability, falls and failure of gait initiation are some of the most disabling motor symptoms of Parkinsons disease (PD). We performed bilateral deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) in combination with the caudal zona incerta (cZi) in order to determine their efficacy in alleviating these symptoms. Methods. Seven patients with predominant axial symptoms in both the ‘on’ and ‘off’ medication states underwent bilateral cZi and PPN DBS. Motor outcomes were assessed using the motor component of the Unified Parkinsons Disease Rating Scale (UPDRS 3) and a composite axial subscore was derived from items 27, 28, 29 and 30 (arising from chair, posture, gait and postural stability). Quality of life was measured using the PDQ39. Comparisons were made between scores obtained at baseline and those at a mean follow-up of 12 months. Results. In both the off and on medication states, a statistically significant improvement in the UPDRS part 3 score was achieved by stimulation of the PPN, cZi and both in combination. In the off medication state, our composite axial subscore of the UPDRS part 3 improved with stimulation of the PPN, cZi and both in combination. The composite axial subscore, in the ‘on’ medication state, however, only showed a statistically significant improvement when a combination of cZi and PPN stimulation was used. Conclusions. This study provides evidence that a combination of PPN and cZi stimulation can achieve a significant improvement in the hitherto untreatable ‘on’ medication axial symptoms of PD.

Induction of parkinsonian resting tremor by stimulation of the caudal zona incerta nucleus: a clinical study

Introduction: We hypothesise that parkinsonian tremor arises when the caudal zona incerta (cZI) and subthalamic nucleus (STN) are deprived of dopamine and become increasingly responsive to motor cortical α and β frequency oscillations. These oscillations are synchronised and amplified through the basal ganglia thalamocortical loop and entrained into the cerebello-thalamocortical loop via the cZI. On receiving potent γ-aminobutyric acid (GABA)-ergic α and β frequency oscillations in cZI afferents, ventrolateral (VL) thalamocortical neurons become hyperpolarised and rebound burst fire, generating 4–6 Hz tremor oscillations. We test this hypothesis by stimulating the cZI at α and β frequencies using deep brain stimulation (DBS) in non-tremulous parkinsonian patients to see whether a 4–6 Hz tremor can be induced. Method: This study included 11 patients with non-tremulous Parkinson’s disease (PD), who had DBS leads implanted in a range of targets, including the cZI, STN, VL nucleus, globus pallidus internus (GPi), centromedian and parafascicular nucleus (CM/Pf), and the pedunculopontine nucleus (PPN). All patients underwent stimulation of active contacts within their respective targets at a standard pulse width, with frequencies ranging from 5 to 80 Hz up to a maximum tolerated voltage. The frequency of the tremor induced in the hands was recorded by accelerometry. Result: Resting tremor in the 4–6 Hz range could be readily induced following stimulation of the cZI and the VL nucleus between 5 and 40 Hz. Tremor was also seen following STN stimulation; however, this was only at high stimulation voltages (>5 volts). No tremor could be induced following CM/Pf, PPN or GPi stimulation. Conclusion: We discuss the implications of these findings and argue that resting tremor in PD is generated in the cortico-ZI-VL-thalamocortical loop rather than in the cortico-basal-ganglia-thalamocortical loop.

Clinical outcomes from bilateral versus unilateral stimulation of the pedunculopontine nucleus with and without concomitant caudal zona incerta region stimulation in Parkinson's disease

Abstract Introduction. The Pedunculopontine nucleus is a novel target for deep brain stimulation and this may improve postural instability and gait dysfunction in Parkinsons disease. If unilateral Pedunculopontine nucleus stimulation is as efficacious as bilateral stimulation this would lead to less surgical risk. Methods. 5 Parkinsons disease patients with bilateral caudal Zona Incerta region and Pedunculopontine nucleus electrodes were assessed using the motor component of the Unified Parkinsons Disease Rating Scale. Patients were assessed in the on-medication state to determine the optimal combination of stimulation setting for axial symptom control. Results. The on-medication composite axial-subscore only showed a statistically significant improvement when bilateral Pedunculopontine nucleus and caudal Zona Incerta region stimulation was used. Conclusions. In the on-medication state bilateral Pedunculopontine nucleus and caudal Zona Incerta region stimulation is required in order to produce a significant change in the motor Unified Parkinsons Disease Rating Scale axial-subscore from baseline.

Outcome in surgically treated Rathke’s cleft cysts: long-term monitoring needed

OBJECTIVE To clarify the outcome of all cases of Rathkes cleft cysts (RCC) treated surgically and followed up in Oxford during a long-term period. SUBJECTS AND METHODS The records of all patients with RCC seen in the Department of Endocrinology between January 1978 and June 2009 were reviewed. RESULTS A total of 33 patients (20 females, median age 43 years) were identified. At presentation, major visual field defects were detected in 58% of patients and gonadotrophin, ACTH and TSH deficiency in 60, 36 and 36% of patients respectively. Desmopressin treatment was required in 18% of patients. Treatment consisted of cyst evacuation combined with or without biopsy/removal of the wall. Post-operatively, visual fields improved in 83% of patients with impairment, whereas there was no reversal of ACTH or TSH deficiency or of diabetes insipidus. All but one subject had imaging follow-up during a mean period of 48 months (range 2-267). Cyst relapse was detected in 22% of patients at a mean interval of 29 months (range 3-48 months); in 57% of them, the recurrence was symptomatic. Relapse-free rates were 88% at 24-months and 52% at 48-months follow-up. At last assessment, at least quadrantanopia was reported in 19% of patients, gonadotrophin, ACTH and TSH deficiency in 50, 42 and 47% of patients respectively. Desmopressin treatment was required in 39% of patients. CONCLUSIONS In this study of patients with RCC and long-term follow-up, we showed a considerable relapse rate necessitating long-term monitoring. Surgical intervention is of major importance for the restoration of visual field defects, but it does not improve endocrine morbidity, which in the long-term affects a substantial number of patients.