From the Skin to the Brain: Pathophysiology of Colonization and Infection of External Ventricular Drain, a Prospective Observational Study.

Ventriculostomy-related infection (VRI) is a serious complication of external ventricular drain (EVD) but its natural history is poorly studied. We prospectively tracked the bacteria pathways from skin towards ventricles to identify the infectious process resulting in ventriculostomy-related colonization (VRC), and VRI. We systematically sampled cerebrospinal fluid (CSF) on a daily basis and collected swabs from both the skin and stopcock every 3.0 days for microbiological analysis including in 101 neurosurgical patient. Risk factors for positive event defined as either VRC or VRI were recorded and related to our microbiological findings. A total of 1261 CSF samples, 473 skin swabs, and 450 stopcock swabs were collected. Skin site was more frequently colonized than stopcock (70 (60%) vs 34 (29%), p = 0.023), and earlier (14 ±1.4 vs 24 ±1.5 days, p<0.0001). Sixty-one (52%) and 32 (27%) skin and stopcock sites were colonized with commensal bacteria, 1 (1%) and 1 (1%) with pathogens, 8 (7%) and 1 (1%) with combined pathogens and commensal bacteria, respectively. Sixteen positive events were diagnosed; a cutaneous origin was identified in 69% of cases. The presence of a pathogen at skin site (6/16 vs 4/85, OR: 11.8, [2.5-56.8], p = 0.002) and CSF leakage (7/16 vs 6/85, OR 10 [2.4-41.2], p = 0.001)) were the two independent significant risk factors statistically linked to positive events occurrence. Our results suggest that VRC and VRI mainly results from an extra-luminal progression of pathogens initially colonizing the skin site where CSF leaks.

Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial.

BACKGROUND: Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease. METHODS: We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose (1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439. FINDINGS: 15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on-off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline. INTERPRETATION: ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients. FUNDING: Oxford BioMedica.

Screening patients with prolonged neuromuscular blockade after succinylcholine and mivacurium.

UNLABELLED: Patients with pseudocholinesterase (BChE) variants may exhibit markedly prolonged paralysis after the administration of succinylcholine or mivacurium. We sought to evaluate to what extent molecular biology may contribute to the biological assessment of such patients. We conducted a prospective cohort study in patients referred to our center between 1995 and 1999 for prolonged neuromuscular blockade after mivacurium or succinylcholine. For each patient, phenotyping was performed with a conventional biochemical technique and molecular biology for the detection of the atypical mutation (A variant). Among the 36 patients referred, 31 had low BChE activity, 26 had received mivacurium (BChE activity, 2.1 U/mL; 0.3-4.3 U/mL), and 5 had received succinylcholine (BChE activity, 1.9 U/mL; 1.1-3.2 U/mL) (mean; extreme values). The mean clinical duration of paralysis was 90 min (40-140 min) after succinylcholine and 301 min (120-720 min) after mivacurium. Thirty-two patients had a BChE deficiency of genetic origin: 20 were homozygous (AA), 10 were heterozygous (UA) for the A variant, and 2 did not have the A mutation (UU). One heterozygous UA patient had normal BChE activity. Nine among the heterozygous UA and the two homozygous UU patients probably carried a not-screened variant. In most cases, biochemical diagnosis was sufficient to confirm the existence of constitutional deficiency; molecular biology improved the accuracy of diagnosis in 11 patients (30%) but had few or no clinical implications for the patient him- or herself. IMPLICATIONS: Systematic screening for the pseudocholinesterase atypical variant by biochemical and DNA analysis after a prolonged neuromuscular blocking effect of succinylcholine or mivacurium shows that molecular biology could improve the diagnosis in approximately one third of patients, but with few clinical implications, compared with biochemical testing.