Complications related to the use of an intraventricular access device for the treatment of leptomeningeal metastases from solid tumor: a single centre experience in 112 patients.

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.

Increasing pro-survival factors within whole brain tissue of Sprague Dawley rats via intracerebral administration of modified valproic acid.

Neural tissue exposure to valproic acid (VPA) increases several pro-survival phospho-proteins that can be used as biomarkers for indicating a beneficial drug response (pAkt(Ser473), pGSK3ß(Ser9), pErk1/2(Thr202/Tyr204)). Unfortunately, targeting VPA to neural tissue is a problem due to severe asymmetrical distribution, wherein the drug tends to remain in peripheral blood rather than localizing within the brain. Intracerebral delivery of an amide-linked VPA-PEG conjugate could address these issues by enhancing retention and promoting cerebro-global increases in pro-survival phospho-proteins. It is necessary to assay for the retained bioactivity of a PEGylated valproic acid molecule, along with locating an intracranial cannula placement that optimizes the increase of a known downstream biomarker for chronic VPA exposure. Here we show an acute injection of VPA-PEG conjugate within brain tissue increased virtually all of the assayed phospho-proteins, including well-known pro-survival factors. In contrast, an acute injection of VPA expectedly decreased signaling throughout the hour. Needle penetration into whole brain tissue is the intentional cause of trauma in this procedure. The trauma to brain tissue was observed to overcome known phospho-protein increases for unmodified VPA in the injected solution, while VPA-PEG conjugate appeared to induce significant increases in pro-survival phospho-proteins, despite the procedural trauma.

Safety profile of long-term intraventricular access devices in pediatric patients receiving radioimmunotherapy for central nervous system malignancies.

BACKGROUND: The use of Ommaya catheters or ventriculoperitoneal shunts with programmable valves (pVP-shunts) for intraventricular drug administration is increasingly more common. PROCEDURE: We reviewed the safety and complication rate associated with ventricular access devices in patients receiving compartmental intraventricular radioimmunotherapy (cRIT). RESULTS: One hundred fifty one patients with recurrent primary or metastatic central nervous system (CNS) tumors (1-34 years) had a ventricular access device (143 Ommaya reservoirs, 8 VP shunts with programmable valves) placed for drug administration and cerebrospinal fluid acquisition. Patients received 2-5 serial injections (124) I- or (131) I- labeled monoclonal antibody 3F8 or 8H9. For each injection, catheters remained accessed for pharmacokinetic studies up to 48 hours or were individually accessed 3-6×/injection. Thereafter catheters were accessed for periodic routine cytology. Six patients (4%) had complications including three with catheter migration in the newly-placed setting requiring surgical revision. Two patients had pericatheter cyst formation (with cyst formation before radioimmunotherapy administration in one patient) resulting in elective removal and endoscopic cystoventriculostomy in both patients. There were no catheter-related infections, hemorrhages, seizures, focal deficits, or valve malfunctioning. Four patients later required Ommaya conversion to VP shunts because of hydrocephalus secondary to disease progression. CONCLUSIONS: We report a long-term safety profile of ventricular access devices in patients receiving cRIT. Minimal acute complications are observed despite the frequency of cerebrospinal fluid acquisition; long-term complications are rare. Programmable VP shunts appear to be a safe and effective alternative to Ommaya catheters.

Intrathecal/intraventricular colistin in external ventricular device-related infections by multi-drug resistant Gram negative bacteria: case reports and review.

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 antibiotics for bacterial meningitis in neonates.

BACKGROUND: Neonatal meningitis may be caused by bacteria, especially gram-negative bacteria, which are difficult to eradicate from the cerebrospinal fluid (CSF) using safe doses of antibiotics. In theory, intraventricular administration of antibiotics would produce higher antibiotic concentrations in the CSF than intravenous administration alone, and eliminate the bacteria more quickly. However, ventricular taps may cause harm. OBJECTIVES: To assess the effectiveness and safety of intraventricular antibiotics (with or without intravenous antibiotics) in neonates with meningitis (with or without ventriculitis) as compared to treatment with intravenous antibiotics alone. SEARCH METHODS: The Cochrane Library, Issue 2, 2007; MEDLINE; EMBASE; CINAHL and Science Citation Index were searched in June 2007. The Oxford Database of Perinatal Trials was searched in June 2004. Pediatric Research (abstracts of proceedings) were searched (1990 to April 2007) as were reference lists of identified trials and personal files. No language restrictions were applied.This search was updated in May 2011. SELECTION CRITERIA: Selection criteria for study inclusion were: randomised or quasi-randomised controlled trials in which intraventricular antibiotics with or without intravenous antibiotics were compared with intravenous antibiotics alone in neonates (< 28 days old) with meningitis. One of the following outcomes was required to be reported: mortality during initial hospitalisation; neonatal or infant mortality, or both; neurodevelopmental outcome; duration of hospitalisation; duration of culture positivity of CSF and side effects. DATA COLLECTION AND ANALYSIS: All review authors abstracted information for outcomes reported and one review author checked for discrepancies and entered data into RevMan 5.1. Risk ratio (RR), risk difference (RD), number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH), and mean difference (MD), using the fixed-effect model are reported with 95% confidence intervals (CI). MAIN RESULTS: The updated search in June 2011 did not identify any new trials. One study is included in the review. This study assessed the effect of intraventricular gentamicin in a mixed population of neonates (69%) and older infants (31%) with gram-negative meningitis and ventriculitis. Mortality was statistically significantly higher in the group that received intraventricular gentamicin in addition to intravenous antibiotics compared to the group receiving intravenous antibiotics alone (RR 3.43; 95% CI 1.09 to 10.74; RD 0.30; 95% CI 0.08 to 0.53); NNTH 3; 95% CI 2 to 13). Duration of CSF culture positivity did not differ significantly (MD -1.20 days; 95% CI -2.67 to 0.27). AUTHORS' CONCLUSIONS: In one trial that enrolled infants with gram-negative meningitis and ventriculitis, the use of intraventricular antibiotics in addition to intravenous antibiotics resulted in a three-fold increased RR for mortality compared to standard treatment with intravenous antibiotics alone. Based on this result, intraventricular antibiotics as tested in this trial should be avoided. Further trials comparing these interventions are not justified in this population.

Complications related to the placement of an intraventricular chemotherapy device.

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.

Neonatal ventriculitis: a case series and review of literature.

Ventriculitis after meningitis is a serious complication in the neonatal age group. The role of intraventricular antibiotics in treatment is controversial. We present five such cases which were refractory to conventional intravenous antibiotic therapy, had persistent features of ventriculitis and in whom raised intracranial pressure (ICP) necessitated insertion of an external ventricular drain (EVD). Three of the five infants required intraventricular antibiotics but also developed EVD-related complications. Early diagnosis of ventriculitis and treatment is necessary to avoid a fatal outcome. Intravenous antibiotics are the treatment of choice, but intraventricular therapy may be considered in refractory cases. As the incidence of EVD-associated ventriculitis is high, proper care of EVDs and their early removal is mandatory.

A Mesenchymal Stem Cell Line Transplantation Improves Neurological Function and Angiogenesis in Intraventricular Amyloid ß-Infused Rats.

BACKGROUND: Mesenchymal stem cell transplantation is demonstrated to improve neurological performance in neurodegenerative diseases including Alzheimer's disease. OBJECTIVE: The objective of this study is to understand the underlying mechanism of such improvement. METHODS: Amyloid ß (Aß) peptide was infused into the lateral ventricle of adult Wister rats using the osmotic pump. After 15 days of continuous infusion, a mesenchymal stem cell line (B10) was transplanted in the lateral ventricle. Learning-related behavior was evaluated by 2-way shuttle avoidance test. Fifteen days after B10 transplantation, pathological and expressional changes were evaluated. RESULTS: Compared to sham group, learning-related behavior was significantly decreased in Aß-infused non-transplanted group, but not in B10-transplanted group. Nissl staining results demonstrated that the number of hippocampal pyramidal neurons in CA1 area in B10-transplanted group was similar to the sham group, whereas that was decreased in Aß-infused non-transplanted group. Aß mainly deposited in the vessels of the brains of Aß-infused non-transplanted rats, which was decreased by B10 transplantation. Moreover, B10 transplantation increased vessel density as well as endoglin positive cells. The number of astrocyte and microglia was decreased in Aß-infused non-transplanted group, which was returned to the level of sham animals by B10 transplantation. Real-time PCR and immunostaining results showed that B10 transplantation significantly increased IL-1ß mRNA and protein expression. CONCLUSION: Thus, our result showed that MSC transplantation effectively decreased Aß deposition in the cerebral vessel and increased angiogenesis, which could be a possible cause of improved neurological performance in Aß-infused AD model rats.

Application of the Ommaya Reservoir in Managing Ventricular Hemorrhage.

BACKGROUND: Intraventricular hemorrhage (IVH) is associated with high morbidity and mortality. This study evaluated the safety and efficacy of the combined treatment of an Ommaya reservoir and conventional external ventricular drainage (EVD) using urokinase in the management of IVH. METHODS: We performed a prospective controlled study. Sixty eligible patients with IVH received conventional EVD alone (group A) or combined EVD and Ommaya reservoir (group B) between January 2010 and January 2015. Clinical, cerebrospinal fluid, and radiographic data were used to assess clot clearance, clinical outcomes, and complications between the groups. RESULTS: There were no significant differences in gender, age, blood pressure, Glasgow Coma Scale, Graeb score, intracerebral hemorrhage volume on admission, and IVH volume before surgery between groups A and B (P > 0.05). The number of injections of urokinase (20,000 IU/dose) were significantly different in group B compared with group A (P < 0.05). Repeated computed tomography scans 3 days, 6 days, and 10 days after surgery revealed that clot clearance rates at each time point were significantly increased in group B compared with group A (P < 0.05). The conventional catheter-based EVD duration time was shortened to 5 (4-6) days in group B compared with 7 (5-9) days in group A (P < 0.05). The total drainage time was prolonged to 9 (8-11) days in group B compared with 7 (5-9) days in group A (P < 0.05). Ventriculitis was not significantly different between the 2 groups (P > 0.05). The hydrocephalus incidence and mortality revealed significant differences between the 2 groups (P < 0.05). The 30-day Glasgow Outcome Scale score was significantly increased in group B compared with group A (P < 0.05). CONCLUSIONS: The combined treatment approach of an Ommaya reservoir and EVD with intraventricular urokinase is safe and effective in patients with IVH. It increased clot clearance, shortened conventional catheter-based EVD duration, prolonged total drainage time, reduced the hydrocephalus incidence and mortality, and contributed to good clinical outcomes. The Ommaya reservoir provides a safe way to increase the injection times of urokinase, which accelerated clot resolution and did not increase the risk for ventriculitis infection.

Recurrent encephaloclastic cyst induced by intraventricular topotecan.

OBJECTIVE: To report two rare cases of encephaloclastic cyst induced by intraventricular topotecan. To share our experience in diagnosing and treating this rare disease. BACKGROUND: Ommaya reservoirs provide fast access and reliable drug delivery to cerebral spinal fluid. They are routinely utilized for the administration of intrathecal chemotherapy accounting for greater than 80% of cases for which they are used. Complications of Ommaya reservoir placement and its use consist of infectious and other late noninfectious causes. Encephaloclastic cysts provoked by intraventricular chemotherapy are very uncommon. The pathogenesis may result from alterations in CSF pulsations with retrograde flow of intraventricular chemotherapy into the brain parenchyma and subsequent development of a local chemical encephalopathy. It has been previously reported with methotrexate use but never with topotecan administration. METHODS: We report two rare cases of encephaloclastic cyst with intraventricular topotecan use. The patients were diagnosed and treated at The University of Texas MD Anderson Cancer Center. They consented to the publication of their laboratory results and imaging studies for educational purposes. RESULT: The patients presented with metastatic cancers (breast/lung) complicated by leptomeningeal disease. Ommaya reservoirs were placed in both cases and patients were initiated on intraventricular topotecan at 0.4 mg twice weekly. After approximately 12 intraventricular treatments, both patients developed confusion, seizures and headaches. MRI of the brain demonstrated cystic dilatation of the brain parenchyma around the catheter that connects to the reservoir dome and delivers the drug to the intraventricular space. The catheter was surrounded by vasogenic edema. Catheters were removed and analyzed and were found to be intact. CSF analyses showed no evidence of infection or malignancy. Intraventricular topotecan was discontinued and both patients demonstrated sustained clinical and radiological responses. CONCLUSION: These cases highlight an atypical complication of intraventricular use of topotecan with successful management.

Focal encephalopathy following methotrexate therapy. Administration via a misplaced intraventricular catheter.

Two patients with lymphoreticular malignant neoplasms and leptomeningeal tumor spread were treated with intraventricular administration of methotrexate via an Ommaya reservoir. The intraventricular instillation of methotrexate resulted in focal CNS damage in brain parenchyma inadvertently pierced by the shunt. Disorientation, aphasia, and right hemiparesis developed in both patients. Computed tomography disclosed a contrast-enhancing, low-density mass in the left cerebral cortex where the distal shunt tip was lodged. In one case the lesion was pathologically consistent with chronic inflammation. A lesion occurred in one patient despite repositioning of the shunt prior to methotrexate instillation. Shunt removal and administration of systemic corticosteroids resulted in resolution of symptoms in one patient.

Intraparenchymal nerve growth factor improves behavioral deficits while minimizing the adverse effects of intracerebroventricular delivery.

Nerve growth factor (NGF) delivered via intracerebroventricular (ICV) infusion restores behavioral and biochemical deficits in animal models of cholinergic hypofunction. However, ICV infusion of NGF induces an array of adverse events including weight loss, thermal hyperalgesia, and Schwann cell hyperplasia. We compared ICV administration with three different doses of intraparenchymally delivered NGF with cytochrome C infusion serving as a control. The goal of the study was to determine whether direct infusion of NGF would result in a more restricted topographical distribution of NGF leading to a reduction or elimination of the adverse events while still augmenting cholinergic functioning sufficiently to restore spatial mnemonic processing. Subsequent to bilateral ibotenic acid lesions of the nucleus basalis magnocellularis (NBM), NGF was delivered into the lateral ventricle or adjacent to the NBM for 11 weeks. Ibotenic acid lesions resulted in reductions in choline acetyltransferase (ChAT) activity in the cortex. The highest and medium dose of NGF led to significant restoration in ChAT activity on par with ICV infusion. The lowest dose was ineffective in altering ChAT activity in any region assayed. Similarly, the two highest doses did not alter weight gain, but ICV-NGF led to a significant weight loss. Intraparenchymal infusion resulted in a dose-dependent attenuation of the development of thermal hyperalgesia. However, the highest dose of intraparenchymal NGF induced Schwann cell hyperplasia at the level of the medulla and upper cervical spinal cord. ICV-NGF was able to completely restore spatial learning and memory as predicted while only the highest intraparenchymal dose was able to able to restore the mnemonic deficits. These data suggest that intraparenchymal infusion of growth factors may provide a viable delivery method in clinical trials using this mode of drug delivery once an optimal dose has been established.

Infectious complications of intraventricular reservoirs in cancer patients.

Drug administration via an intraventricular reservoir is useful in the treatment of leukemic and carcinomatous meningitis that occurs in patients who have previously received lumbar intrathecal chemotherapy. The intraventricular route, however, is associated with a higher incidence of infectious complications compared with therapy given by the lumbar route. To characterize the infectious complications associated with such reservoirs, we reviewed the 10-year experience of the Pediatric Branch, National Cancer Institute, National Institutes of Health, and Children's Orthopedic Hospital, Seattle, WA, with 61 patients (49 with leukemia, 8 with lymphoma, 4 with solid tumors) who had intraventricular reservoirs placed for administration of chemotherapy. The reservoirs were in place for a median of 36 weeks and were punctured a median of 29.5 times, Infectious complications occurred in 14 of 61 patients (23%) and Propionibacterium acnes was the most common organism recovered from cultures. Twelve patients (19.7%) had 19 episodes of clinically suspected and microbiologically documented meningitis or of positive intraventricular reservoir cerebrospinal fluid cultures without symptoms which were treated successfully. Local cellulitis occurred at the site of intraventricular reservoir placement in 2 patients (3.3%) and removal of the intraventricular reservoir was necessary for successful management. Nine patients had their intraventricular reservoir removed (5 because of associated infection and 4 because of malfunction unassociated with infection).(ABSTRACT TRUNCATED AT 250 WORDS)

Imidazole therapy of coccidioidal meningitis in children.

The mortality related to coccidioidal meningitis (CM) has been reduced since the introduction of amphotericin B therapy, but children with CM continue to suffer significant morbidity. Some of this is related to the toxicity of the drug. We report nine children with CM treated with orally administered ketoconazole and intraventricularly administered miconazole. Four of them had been treated initially with amphotericin B with resultant failure in one and severe toxicity in all four. The other five children were treated only with imidazoles. All nine children had evidence of ventriculitis at the time of diagnosis and had ventriculoperitoneal shunts inserted for control of increased intracranial pressure. There was no relapse or recrudescence of CM in a follow-up period of 32 to 90 months on imidazole therapy. The coccidioidal complement-fixation antibody titers in the cerebrospinal fluid of the lateral ventricle became negative in all children 3 to 51 months after diagnosis (mean, 17 months). The serum antibody titers demonstrated a 16- to 256-fold decrease from their maximal levels. Four children are still receiving intraventricular miconazole whereas the others have not received miconazole for an average of 51 months. Therapy with the imidazoles was well-tolerated. The main morbidity was related to the shunts required for control of increased intracranial pressure. There was no evidence of hepatic toxicity and no clinical evidence of adrenal insufficiency although transient adrenal suppression was demonstrated at 4 but not at 24 hours after ketoconazole administration.

Memory formation in birds: 2. Effects of stress due to experimental procedures on the conditioning of the budgerigar (Melopsittacus undulatus) to sound stimuli.

Conditioning studies involving administration of biochemical or pharmacological agents are often stressful to experimental animals. Some of these stressful manipulations were examined for their effect on the avoidance conditioning of the budgerigar to sound stimuli. There were individual variations in the capacity of the birds to accommodate to these stresses, but generally the stress factors had negative effects on their subsequent conditioning, the degree of this effect depending upon the type and severity of stress. Simple anesthesia with ether had the least effect, intravenous injection being next in severity, while intracerebral injection was most inhibitory. The effects due to anesthesia and intravenous injection could be decreased by delaying the conditioning procedure for 1 to 2 hours following the treatment, but the effect of intracerebral injection was more prolonged. The retrieval of temporarily lost conditioned response through brief reconditioning was not affected by intracerebral injection, indicating that, once a memory trace was formed, subsequent emotional and physical stresses did not obliterate it irreversibly.

Nociceptin/orphanin FQ and related peptides reduce the increase in plasma corticosterone elicited in mice by an intracerebroventricular injection.

Nociceptin/orphanin FQ (=N/OFQ), the endogenous ligand of ORL1 receptor (=NOP), has been reported to induce, in rodents, after intracerebroventricular (i.c.v.) administration, anti-stress and anxiolytic effects. We have observed that the handling of mice followed by an i.c.v. injection of saline, induced a marked increase in the plasma corticosterone level (+250%) measured 30 minutes later. When N/OFQ was injected intracerebroventricularly, using a 1 microg dose, the increase in plasma corticosterone was significantly lower than in saline injected mice. N/OFQ(1-13)NH(2), known as a NOP receptor agonist, at the same 1 microg dose, also induced a lesser increase in plasma corticosterone level than a saline i.c.v. injection. The pseudopeptide [Phe(1)-psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)NH(2), defined either as an agonist or an antagonist of NOP receptor, at the 0.1 microg dose, behaved in a similar manner as N/OFQ, by decreasing the plasma corticosterone level. Finally, [Nphe(1)]N/OFQ(1-13)NH(2), although presumed to be a selective NOP receptor antagonist, also decreased the corticosterone level at the 0.1 microg dose. These observations suggest the implication of N/OFQ in the regulation of response to stress, through an action on the hypothalamo-pituitary-adrenocortical axis. Moreover, they evidence a similar effect of N/OFQ and N/OFQ(1-13)NH(2), but also of two other related peptides displaying antagonist properties on NOP receptors. These data suggest that several subtypes of N/OFQ receptors could exist.

Arterial, peritoneal, and intraventricular access devices.

OBJECTIVE: To provide an overview of access devices used to treat cancers through the arterial, peritoneal, and intraventricular body systems. CONCLUSIONS: Short-term and long-term devices have been developed over the last 35 years for cancer treatment. Although less amenable to standard methods of therapy, the various access devices available to access the arterial, peritoneal, and intraventricular systems have provided a safe and reliable means for drug therapy. Access devices assist in delivering high concentrations of drugs directly to the center of the tumor. Complications and toxicities are inherent with these devices from the drug therapy as well as the device. Nursing assessment can provide early identification of potential problems and implementation of appropriate interventions. IMPLICATIONS FOR NURSING PRACTICE: As the availability of these devices increases, so must the nurse's knowledge base to provide optimal safe care. Oncology nurses are challenged to know the differences between the devices, the device of choice for the individual patient, insertion procedures, and maintenance protocols.

Accidental intraventricular vincristine administration: an avoidable iatrogenic death.

A patient with acute lymphoblastic leukaemia was mistakenly given vincristine intraventricularly, as part of an intensified course of chemotherapy. Despite a CNS washout and supportive treatment, the patient developed progressive ascending paralysis, gradually lapsed into coma and died some 10 days later. Autopsy and post-mortem histological examination showed evidence of brain death caused by florid encephalomyelitis, apparently induced by the intraventricular administration of vincristine.