Steven S. Gill

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.

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

Glial cell line–derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open‐label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin).

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.

Aβ-Degrading Enzymes: Potential for Treatment of Alzheimer Disease

There is increasing evidence that deficient clearance of &bgr;-amyloid (A&bgr;) contributes to its accumulation in late-onset Alzheimer disease (AD). Several A&bgr;-degrading enzymes, including neprilysin (NEP), insulin-degrading enzyme, and endothelin-converting enzyme reduce A&bgr; levels and protect against cognitive impairment in mouse models of AD. The activity of several A&bgr;-degrading enzymes rises with age and increases still further in AD, perhaps as a physiological response to minimize the buildup of A&bgr;. The age- and disease-related changes in expression of more recently recognized A&bgr;-degrading enzymes (e.g. NEP-2 and cathepsin B) remain to be investigated, and there is strong evidence that reduced NEP activity contributes to the development of cerebral amyloid angiopathy. Regardless of the role of A&bgr;-degrading enzymes in the development of AD, experimental data indicate that increasing the activity of these enzymes (NEP in particular) has therapeutic potential in AD, although targeting their delivery to the brain remains a major challenge. The most promising current approaches include the peripheral administration of agents that enhance the activity of A&bgr;-degrading enzymes and the direct intracerebral delivery of NEP by convection-enhanced delivery. In the longer term, genetic approaches to increasing the intracerebral expression of NEP or other A&bgr;-degrading enzymes may offer advantages.

Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation.

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale—Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale—Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2–6 and 9–15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2–6 months and 25.7% at 9–15 months. At 9–15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9–15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2–6 months; this failed to reach significance at 9–15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

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.

GDNF delivery for Parkinson’s disease

The mainstays of Parkinsons disease (PD) treatment remain symptomatic, including initial dopamine replacement and subsequent deep brain stimulation, however, neither of these approaches is neuroprotective. Neurotrophic factors - proteins that activate cell signalling pathways regulating neuronal survival, differentiation, growth and regeneration - represent an alternative for treating dopaminergic neurons in PD but are difficult to administer clinically because they do not pass through the blood-brain barrier. Glial cell line-derived neurotrophic factor (GDNF) has potent neurotrophic effects particularly but not exclusively on dopaminergic neurons; in animal models of PD, it has consistently demonstrated both neuroprotective and neuroregenerative effects when provided continuously, either by means of a viral vector or through continuous infusion either into the cerebral ventricles (ICV) or directly into the denervated putamen. This led to a human PD study in which GDNF was administered by monthly bolus intracerebroventricular injections, however, no clinical benefit resulted, probably because of the limited penetration to the target brain areas, and instead significant side effects occurred. In an open-label study of continuous intraputamenal GDNF infusion in five patients (one unilaterally and four bilaterally), we reported excellent tolerance, few side effects and clinical benefit evident within three months of the commencement of treatment. The clinical improvement was sustained and progressive, and by 24-months patients demonstrated a 57 and 63% improvement in their off-medication motor and activities of daily living UPDRS subscores, respectively, with clear benefit in dyskinesias. The benefit was associated with a significant increase in putamenal 18F-dopa uptake on positron emission tomography (PET), and in one patient coming to autopsy after 43 months of unilateral infusion there was evident increased tyrosine hydroxylase immunopositive nerve fibres in the infused putamen. A second open trial in 10 patients using unilateral intraputamenal GDNF infusions has also demonstrated a greater than 30% bilateral benefit in both on- and off-medication scores at 24 weeks. Based on our 6-month results, a randomized controlled clinical trial was conducted to confirm the open-label results, however, GDNF infusion over 6-months did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F-dopa uptake surrounding the catheter tip. It is possible that technical differences between this trial and the positive open label studies contributed to this negative outcome.

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.