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Ventricular access devices (VAD) offer several advantages compared to intralumbar injections for the administration of intra-CSF agents in the treatment of leptomeningeal metastases (LM). However, there are few prospective studies reporting on complications with the use of VADs. All complications were prospectively collected that pertained to the implantation and use of a VAD in consecutive patients with solid tumor-related LM from June 2006 to December 2013. Clinical follow-up was every 2 weeks during the initial 2 months of treatment and then once monthly. Complete neuraxis MRI was performed at baseline and then every 2–3 months. A total of 112 patients (88 women) with a mean age of 51.1 years (range 26–73) were included. Primary cancers included breast (79 patients), lung (12) and melanoma (6). All patients were treated with intra-CSF liposomal cytarabine. 72 % of the patients received concomitant systemic and intra-CSF chemotherapy. The placement of the VAD was performed under local anesthesia in all cases. The mean operative time was 15 min and no perioperative complications were reported. The mean number of intraventricular injections per patient was 9.34 (range 1–47). A total of 11 complications in 11 patients were seen including 7 infections, 1 intracranial hemorrhage, 2 instances of symptomatic leukoencephalopathy and 1 catheter malpositioning. 8 complications required an operation and 1 complication was fatal. The use of a VAD is safe and may improve patients’ comfort and compliance with LM-directed therapy.

We report three cases of external ventricular derivation infections caused by multidrug-resistant Gram-negative rods and treated successfully with intraventricular colistin. The intrathecal or intraventricular use of colistin have been reported in more than 100 cases without any consensus on dosage, duration and type (monotherapy or combination therapy) of treatment. Based on our comprehensive review of the relevant literature relating to both clinical and pharmacokinetic data, we conclude that the intrathecal/intraventricular administration of colistin is a safe and effective option to treat central nervous system infections caused by multidrug-resistant Gram-negative bacteria.

Intraventricular hemorrhage (IVH) is associated with a poor outcome. External ventricular drainage together with clot lysis through intrathecal tissue plasminogen activator (IT-tPA) has been proposed as a promising therapy. However, recent experimental work has implicated tissue plasminogen activator (tPA) in the pathogenesis of cerebral edema. We reviewed the records of all patients with IVH caused by primary supratentorial intracerebral hemorrhage who underwent external ventricular drainage without surgical evacuation between January 2001 and June 2008. Of these 30 patients, we identified 13 who received IT-tPA. The remaining 17 patients served as controls. Hemorrhage, edema volume, and IVH score were determined on admission and by follow-up computed tomographic scans for 96 hours after admission. Discharge outcome was evaluated using the modified Rankin Scale. There were no significant differences between the treatment and controls in terms of age, Glasgow Coma Scale score, Graeb and LeRoux IVH scores, or intracerebral hemorrhage volume on admission. IT-tPA resulted in more rapid clearance of IVH as determined by the 96-hour decrease in both the Graeb IVH score (tPA, 3.00 +/- .55; control, 1.00 +/- 0.57; P = .05) and the LeRoux IVH score (tPA, 6.2 +/- 0.80; control, 2.25 +/- 1.32; P = .05). Patients treated with IT-tPA demonstrated significantly larger peak ratios of edema to intracerebral hemorrhage volume (1.24 +/- 0.14 vs 0.70 +/- 0.08 in controls; P = .002). Additionally, increased rates of sterile meningitis (46% vs 12%; P = .049) and a trend toward shunt dependence (38% vs 6%; P = .06) were observed in the tPA cohort. Nevertheless, no significant differences in outcome at discharge or length of hospital stay were observed between cohorts. Although IT-tPA hastens the resolution of IVH, it may worsen perihematomal edema formation. Larger prospective studies are required to confirm these findings and to determine whether outcome is adversely affected by IT-tPA administration.

Leptomeningeal meningitis occurs in 4–15% of patients with solid tumors. It is a severe disease which seriously affects patients’ neurological status and quality of life. Intrathecal chemotherapy increases survival and improves quality of life. Administration of drugs by lumbar puncture causes pain and discomfort, reducing therapeutic compliance. Implantation of an intraventricular catheter fixed to a subcutaneous reservoir overcomes these drawbacks. To evaluate complications compared with implantation of an intraventricular chemotherapy device, between June 2006 and December 2009, 50 patients with a solid tumor underwent implantation of a catheter to treat leptomeningeal metastases. Clinical evaluation of all patients was performed every two weeks and magnetic resonance imaging at one month then every three months. Surgical data (operative time, blood loss) and all clinical and radiological complications were prospectively monitored. All patients underwent surgery with local anesthesia. The mean operative time was 15 min, with no complication during surgery. We report five complications (10%) during the follow-up; three required the removal of the device and another was lethal. There was no case of misplacement or obstruction of the catheter. Intraventricular chemotherapy is an effective treatment procedure which improves therapeutic compliance with acceptable morbidity.

Objective and importance. We present a complication of Ommaya reservoir placement that has not been previously reported. Following injection of a seemingly appropriately placed catheter, the patient developed seizures. Imaging studies showed the development and resolution of a cavum septi pellucidi. This case illustrates that the septum pellucidum is made of two layers and that a potential space exists between these layers. Caution is recommended when injecting a single-hole ventricular catheter if the tip is against the septum pellucidum.

ObjectiveTo investigate the overall probability of error in preparing and administering intravenous medicines; to identify at which stage of the process an error is most likely to occur; and to determine the impact of error correction on the error probability.DesignSystematic review and random-effects Bayesian conditional independence modelling.MethodsMedline and EMBASE were searched for studies on intravenous medicines. The error rates of each stage were extracted. These, expert estimates, and error rates from generic tasks, were used in a Bayesian conditional independence model to find error ‘hot-spots.’ The main outcome measure was the probability of at least one error occurring during intravenous therapy.ResultsNine published studies were identified for inclusion in the systematic review and meta-analysis. The overall probability of making at least one error in intravenous therapy was 0.73 (95% credible interval (CrI) 0.54 to 0.90). If error-checking was introduced at each stage of the process, the overall rate fell to 0.22 (95% CrI 0.14 to 0.31). Errors were most likely in the reconstitution step. Removing the reconstitution step by providing preprepared injections would reduce the overall error rate to 0.17 (95% CrI 0.09 to 0.27).ConclusionsIntravenous therapy is complex and error-prone. Error-checking at each stage could reduce the error probability. The use of preprepared injections may help by eliminating errors in the reconstitution of drug and diluent. However, it will be important to ensure that benefits are not outweighed by practical disadvantages such as an increase in selection errors.

ABSTRACT BACKGROUND A sustained release microparticle formulation of nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. METHODS Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. RESULTS The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral nimodipine patient. Four EG-1962 and the oral nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of nimodipine in both groups. CONCLUSION Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.

Hepatic steatosis develops when lipid influx and production exceed the liver’s ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin’s anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis. Obesity is associated with leptin resistance and rising blood leptin levels while central leptin exposure may be limited. Here, the authors show that brain leptin infusion reduces hepatic lipid content in rats by increasing hepatic VLDL secretion and lowering liver de novo lipogenesis via a vagal mechanism.

The neurodegenerative disease spinal muscular atrophy (SMA) is caused by deficiency in the survival motor neuron (SMN) protein. Currently approved SMA treatments aim to restore SMN, but the potential for SMN expression beyond physiological levels is a unique feature of adeno-associated virus serotype 9 (AAV9)-SMN gene therapy. Here, we show that long-term AAV9-mediated SMN overexpression in mouse models induces dose-dependent, late-onset motor dysfunction associated with loss of proprioceptive synapses and neurodegeneration. Mechanistically, aggregation of overexpressed SMN in the cytoplasm of motor circuit neurons sequesters components of small nuclear ribonucleoproteins, leading to splicing dysregulation and widespread transcriptome abnormalities with prominent signatures of neuroinflammation and the innate immune response. Thus, long-term SMN overexpression interferes with RNA regulation and triggers SMA-like pathogenic events through toxic gain-of-function mechanisms. These unanticipated, SMN-dependent and neuron-specific liabilities warrant caution on the long-term safety of treating individuals with SMA with AAV9-SMN and the risks of uncontrolled protein expression by gene therapy. AAV9-SMN is used to treat SMA. This study shows that AAV9-mediated SMN overexpression in mice causes late-onset motor dysfunction and synaptic and neuronal loss through protein aggregation, suggesting caution on the long-term safety of SMN gene therapy.

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lep ob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling. In rodent models of type 2 diabetes, sustained remission of hyperglycemia can be induced by FGF1 action in the mediobasal hypothalamus. Here, the authors show that FGF1-injection is followed by marked changes in glial cell populations and that the sustained glycemic response is dependent on intact melanocortin signaling.