Long-Term Follow-Up of a Phase I/II Study of ProSavin, a Lentiviral Vector Gene Therapy for Parkinson's Disease.

Parkinson's disease is typically treated with oral dopamine replacement therapies. However, long-term use is complicated by motor fluctuations from intermittent stimulation of dopamine receptors and off-target effects. ProSavin, a lentiviral vector based gene therapy that delivers local and continuous dopamine, was previously shown to be well tolerated in a Phase I/II first-in-human study, with significant improvements in motor behavior from baseline at 1 year. Here, patients with Parkinson's disease from the open-label trial were followed up in the long term to assess the safety and efficacy of ProSavin after bilateral injection into the putamen. Fifteen patients who were previously treated with ProSavin have been followed for up to 5 years, with some having been seen for 8 years. Eight patients received deep brain stimulation at different time points, and their subsequent assessments continued to assess safety. Ninety-six drug-related adverse events were reported (87 mild, 6 moderate, 3 severe) of which more than half occurred in the first year. The most common drug-related events were dyskinesias (33 events, 11 patients) and on-off phenomena (22 events, 11 patients). A significant improvement in the defined "off" Unified Parkinson's Disease Rating Scale part III motor scores, compared to baseline, was seen at 2 years (mean score 29 · 2 vs. 38 · 4, n = 14, p < 0.05) and at 4 years in 8/15 patients. ProSavin continued to be safe and well tolerated in patients with Parkinson's disease. Moderate improvements in motor behavior over baseline continued to be reported in the majority of patients who could still be evaluated up to 5 years of follow-up.

Three-dimensional SPACE fluid-attenuated inversion recovery at 3 T to improve subthalamic nucleus lead placement for deep brain stimulation in Parkinson's disease: from preclinical to clinical studies.

OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established therapy for motor symptoms in patients with pharmacoresistant Parkinson's disease (PD). However, the procedure, which requires multimodal perioperative exploration such as imaging, electrophysiology, or clinical examination during macrostimulation to secure lead positioning, remains challenging because the STN cannot be reliably visualized using the gold standard, T2-weighted imaging (T2WI) at 1.5 T. Thus, there is a need to improve imaging tools to better visualize the STN, optimize DBS lead implantation, and enlarge DBS diffusion. METHODS Gradient-echo sequences such as those used in T2WI suffer from higher distortions at higher magnetic fields than spin-echo sequences. First, a spin-echo 3D SPACE (sampling perfection with application-optimized contrasts using different flip angle evolutions) FLAIR sequence at 3 T was designed, validated histologically in 2 nonhuman primates, and applied to 10 patients with PD; their data were clinically compared in a double-blind manner with those of a control group of 10 other patients with PD in whom STN targeting was performed using T2WI. RESULTS Overlap between the nonhuman primate STNs segmented on 3D-histological and on 3D-SPACE-FLAIR volumes was high for the 3 most anterior quarters (mean [± SD] Dice scores 0.73 ± 0.11, 0.74 ± 0.06, and 0.60 ± 0.09). STN limits determined by the 3D-SPACE-FLAIR sequence were more consistent with electrophysiological edges than those determined by T2WI (0.9 vs 1.4 mm, respectively). The imaging contrast of the STN on the 3D-SPACE-FLAIR sequence was 4 times higher (p < 0.05). Improvement in the Unified Parkinson's Disease Rating Scale Part III score (off medication, on stimulation) 12 months after the operation was higher for patients who underwent 3D-SPACE-FLAIR-guided implantation than for those in whom T2WI was used (62.2% vs 43.6%, respectively; p < 0.05). The total electrical energy delivered decreased by 36.3% with the 3D-SPACE-FLAIR sequence (p < 0.05). CONCLUSIONS 3D-SPACE-FLAIR sequences at 3 T improved STN lead placement under stereotactic conditions, improved the clinical outcome of patients with PD, and increased the benefit/risk ratio of STN-DBS surgery.

Bilateral thalamic stimulation induces insomnia in patients treated for intractable tremor.

STUDY OBJECTIVES: To explore the influence of acute bilateral ventral intermediate thalamic nucleus (VIM) stimulation on sleep. DESIGN: Three consecutive full-night polysomnography recordings were made in the laboratory. After the habituation night, a random order for night ON-stim and OFF-stim was applied for the second and third nights. SETTING: Sleep disorders unit of a university hospital. PATIENTS: Eleven patients with bilateral stimulation of the ventral intermediate nucleus of the thalamus (VIM) for drug-resistant tremor. MEASUREMENTS: Sleep measures on polysomnography. RESULTS: Total sleep time was reduced during night ON-stim compared to OFF- stim, as well as rapid eye movement sleep percentage while the percentage of N2 increased. Wakefulness after sleep onset time was increased. CONCLUSION: Our results show that bilateral stimulation of the VIM nuclei reduces sleep and could be associated with insomnia.

Study of the long-term results of decompressive craniectomy after severe traumatic brain injury based on a series of 60 consecutive cases.

BACKGROUND: Decompressive craniectomy can be proposed in the management of severe traumatic brain injury. Current studies report mixed results, preventing any clear conclusions on the place of decompressive craniectomy in traumatology. METHODS: The objective of this retrospective study was to evaluate the results of all decompressive craniectomies performed between 2005 and 2011 for refractory intracranial hypertension after severe traumatic brain injury. Sixty patients were included. Clinical parameters (Glasgow scale, pupillary examination) and radiological findings (Marshall CT scale) were analysed. Complications, clinical outcome, and early and long-term Glasgow Outcome Scale (GOS) were evaluated after surgery. Finally, the predictive value of preoperative parameters to guide the clinician's decision to perform craniectomy was studied. RESULTS: Craniectomy was unilateral in 58 cases and the mean bone flap area was 100 cm(2). Surgical complications were observed in 6.7% of cases. Mean followup was 30 months and a favourable outcome was obtained in 50% of cases. The initial Glasgow Scale was the only statistically significant predictive factor for long-term outcome. CONCLUSION: Despite the discordant results in the literature, this study demonstrates that decompressive craniectomy is useful for the management of refractory intracranial hypertension after severe traumatic brain injury.