Intraputamenal cerebral dopamine neurotrophic factor in Parkinson's disease: a randomized, double‐blind, multicenter phase 1 trial

Background: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). Objective: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. Methods: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone‐anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo‐controlled, double‐blind, 6‐month main study followed by an active‐treatment 6‐month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18F]FE‐PE2I. Results: Drug‐related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. Conclusions: Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Intracerebral Infections as a Complication of Deep Brain Stimulation

Background: Intracerebral infections after deep brain stimulation (DBS) are rare. The published material is limited to 2 case reports. A review of 20 publications of 3,818 patients focusing on complications of DBS did not reveal one single case. For that reason, we decided to present our own experience of 4 patients with this complication. Objectives: To analyze and present our material regarding intracerebral infections after DBS. Methods: Four patients with intracerebral infection after DBS were retrospectively analyzed. Results: The 4 patients exhibited signs of intracerebral infection 2-14 days after DBS for Parkinson's disease. CT and MRI verified signs of possible cerebral involvement. In 3 patients, positive cultures were obtained from the extracted electrodes. All patients recovered completely following treatment with antibiotics and removal of the implanted hardware. Two of the patients were later re-implanted. Conclusions: Intracerebral infection is a rare complication of DBS. It does, however, occur occasionally and should be taken into consideration when evaluating the risks of DBS. Copyright (c) 2012 S. Karger AG, Base

Comparison of accuracy and precision between frame-based and frameless stereotactic navigation for deep brain stimulation electrode implantation

The accuracy and precision of frameless neuronavigation as compared to conventional frame-based stereotaxy for implantation of deep brain stimulation (DBS) electrodes were studied in 14 patients with essential tremor. DBS electrodes were implanted bilaterally in the ventrolateral thalamus [ventrointermediate nucleus ( VIM)] in one procedure. Frameless neuronavigation was used on one side and the conventional frame-based technique on the other. Targeting was guided by MRI and CT imaging. Intraoperative stereotactic plain X-ray verified final electrode positions and electrode deviations from the planned target were measured. Clinical outcome was evaluated with the Essential Tremor Rating Scale. Thirteen of the patients were eligible for measuring electrode deviations and 10 of them were available for a clinical follow-up. Electrode deviations from target were larger using the frameless technique in the mediallateral (x: 1.9 +/- 1.3 mm) and anterior- posterior (y: 0.9 +/- 0.8 mm) directions as compared to the frame-based technique (x: 0.5 +/- 0.5 and y: 0.4 +/- 0.4 mm) but similar in the superior- inferior direction (z). The vector of deviation was 2.5 +/- 1.4 mm with the frameless technique and 1.2 +/- 0.6 with the frame-based technique. The differences were statistically significant (p < 0.05-0.001). The dispersion was larger with the frameless technique as represented by the larger standard deviations in all three planes. At clinical follow-ups, tremor reduction was similar irrespective of the implantation technique. It is concluded that conventional frame-based stereotaxy has higher accuracy/precision for hitting a small brain target than the frameless technique. However, the difference is relatively small and does not influence the clinical result of DBS electrode implantations in the VIM when treating tremor. Copyright (c) 2007 S. Karger AG, Base

A Subgaleal Hematoma That Turned Out to Be a B-Cell Lymphoma

Background Subgaleal masses are relatively common in the clinical praxis, and after a trauma to the head, a subgaleal hematoma is usually suspected. However, other differential diagnoses, such as malignant tumors, should be kept in mind despite a history of a previous trauma. Case description and Conclusions We report a case of a subgaleal mass that was clinically and radiologically diagnosed as a subgaleal hematoma in a patient on antiplatelet therapy. The patient had a history of trauma to her head, but pathologic examination after surgery unexpectedly showed a malignant B-cell lymphoma. A review of the literature is also presented

Segmental cerebral vasoconstriction: successful treatment of secondary cerebral ischaemia with intravenous prostacyclin.

We describe a 23-year-old male patient who presented with spontaneous intermittent and increasing attacks of severe, left-sided thunderclap headache combined with rapidly progressive muscle weakness and dysphasia, including gradual loss of consciousness. Subsequent CT, MRI and DSA showed progressive brain ischaemia and oedema within the left cerebral hemisphere with strict ipsilateral segmental arterial vasoconstriction. Despite extensive medical care, including steroids, the patient deteriorated rapidly. However, the clinical course changed dramatically within 15 h after the start of an intravenous infusion of prostacyclin at a dose of 0.9 ng/kg/min, with an almost complete recovery of consciousness and speech. In addition the pathophysiological alterations seen on magnetic resonance (imaging and digital) subtraction angiography including diffusion-weighted imaging and apparent diffusion coefficient maps shortly before prostacyclin treatment were clearly reduced when the patient was examined 3-4 days later and he continued to recover thereafter. Although not fully compatible, our case had several clinical characteristics and radiological findings reminiscent of those of the 'segmental reversible vasoconstriction syndrome', sometimes called the Call-Fleming syndrome

Microelectrode clusters enable therapeutic deep brain stimulation without noticeable side-effects in a rodent model of Parkinson's disease

Background: Deep Brain Stimulation (DBS) is an established treatment for motor symptoms in Parkinson's disease (PD). However, side effects often limit the usefulness of the treatment. New method: To mitigate this problem, we developed a novel cluster of ultrathin platinum-iridium microelectrodes (n = 16) embedded in a needle shaped gelatin vehicle. In an established rodent PD-model (6-OHDA unilateral lesion), the clusters were implanted in the subthalamic area for up to 8 weeks. In an open field setting, combinations of microelectrodes yielding therapeutic effects were identified using statistical methods. Immunofluorescence techniques were used for histological assessments of biocompatibility. Results: In all rats tested (n = 5), we found subsets of 3–4 microelectrodes which, upon stimulation (160 Hz, 60 μs pulse width, 25–40 μA/microelectrode), prompted normal movements without noticeable side effects. Other microelectrode subsets often caused side effects such as rotation, dyskinesia and tremor. The threshold (per microelectrode) to elicit normal movements strongly depended on the number of activated microelectrodes in the selected subset. The histological analysis revealed viable neurons close to the electrode contacts, minor microglial and astrocytic reactions and no major changes in the vasculature, indicating high biocompatibility. Comparison to existing methods and conclusion: By contrast to the continuous and relatively large stimulation fields produced by existing DBS electrodes, the developed microelectrode cluster enables a fine-tuned granular and individualized microstimulation. This granular type of stimulation pattern provided powerful and specific therapeutic effects, free of noticeable side effects, in a PD animal model

Quality of life of people with Parkinson’s disease and their caregivers

We previously reported the occurrence of Lewy bodies in grafted human fetal mesencephalic neurons in two patients with Parkinson's disease. Here, we have used immunohistochemistry and electron microscopy to characterize the development of Lewy bodies in one of these cases. This patient was operated in putamen on both sides at 12 or 16 years before death, respectively. We demonstrate that 2% of the 12-year-old and 5% of the 16-year-old grafted, presumed dopaminergic neurons contained Lewy bodies immunoreactive for alpha-synuclein. Based on morphological analysis, two forms of alpha-synuclein-positive aggregates were distinguished in the grafts, the first a classical and compact Lewy body, the other a loose meshwork aggregate. Lewy bodies in the grafts stained positively for ubiquitin and thioflavin-S, and contained characteristic alpha-synuclein immunoreactive electron dense fibrillar structures on electron microscopy. Our data indicate that Lewy bodies develop gradually in transplanted dopaminergic neurons in a fashion similar to that in dopaminergic neurons in the host substantia nigra. (c) 2010 Movement Disorder Society

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 mu g rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD

Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease

Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials