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.

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.

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.

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.

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.

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.

Complex imaging features of accidental cerebral intraventricular gadolinium administration.

Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) is a contrast agent commonly used for enhancing MRI. In this paper, the authors report on 2 cases of postoperative inadvertent administration of Gd-DTPA directly into a ventriculostomy tubing side port that was mistaken for intravenous tubing. Both cases demonstrated a low signal on MRI throughout the ventricular system and dependent portions of the subarachnoid spaces, which was originally believed to be CSF with areas of T1 shortening in the nondependent portions of the subarachnoid spaces, and misinterpreted as basal leptomeningeal enhancement and meningitis. The authors propose that the appearance of profound T1 hypointensity within the ventricles and diffuse susceptibility artifact along the ependyma is pathognomonic of intraventricular Gd-DTPA and should be recognized.

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.

Variable behavior and complications of autologous bone marrow mesenchymal stem cells transplanted in experimental autoimmune encephalomyelitis.

Autologous bone marrow stromal cells (BMSCs) offer significant practical advantages for potential clinical applications in multiple sclerosis (MS). Based on recent experimental data, a number of clinical trials have been designed for the intravenous (IV) and/or intrathecal (ITH) administration of BMSCs in MS patients. Delivery of BMSCs in the cerebrospinal fluid via intracerebroventricular (ICV) transplantation is a useful tool to identify mechanisms underlying the migration and function of these cells. In the current study, BMSCs were ICV administered in severe and mild EAE, as well as naive animals; neural precursor cells (NPCs) served as cellular controls. Our data indicated that ICV-transplanted BMSCs significantly ameliorated mild though not severe EAE. Moreover, BMSCs exerted significant anti-inflammatory effect on spinal cord with concomitant reduced axonopathy only in the mild EAE model. BMSCs migrated into the brain parenchyma and, depending on their cellular density, within brain parenchyma formed cellular masses characterized by focal inflammation, demyelination, axonal loss and increased collagen-fibronectin deposition. These masses were present in 64% of ICV BMASC-transplanted severe EAE animals whereas neither BMSCs transplanted in mild EAE cases nor the NPCs exhibited similar behavior. BMSCs possibly exerted their fibrogenic effect via both paracrine and autocrine manner, at least partly due to up-regulation of connective tissue growth factor (CTGF) under the trigger of TGFb1. Our findings are of substantial relevance for clinical trials in MS, particularly regarding the possibility that ICV transplanted BMSCs entering the inflamed central nervous system may exhibit - under conditions - a local pathology of yet unknown consequences.

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.

Exacerbation of perihematomal edema and sterile meningitis with intraventricular administration of tissue plasminogen activator in patients with intracerebral hemorrhage.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Where errors occur in the preparation and administration of intravenous medicines: a systematic review and Bayesian analysis.

OBJECTIVE: To 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. DESIGN: Systematic review and random-effects Bayesian conditional independence modelling. METHODS: Medline 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. RESULTS: Nine 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). CONCLUSIONS: Intravenous 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.

Initial clinical experience of vasodilatory effect of intra-cisternal infusion of magnesium sulfate for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

The vasodilatory effect of intra-cisternal infusion of magnesium sulfate solution was evaluated in 10 patients with symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH) who underwent early clipping surgery. Cisternal drainage was installed in the prepontine and/or sylvian fissures. Carotid angiography was performed immediately after the onset of symptomatic vasospasm, then intra-cisternal infusion of 15 mmol/l magnesium sulfate in Ringer solution was started at 20 ml/hr and continued until day 14. Irrigation was performed from the cisternal tube (inlet) to the spinal drainage (outlet). The cerebrospinal fluid magnesium ion concentration (1.2 +/- 0.2 mEq/l) significantly increased after the infusion therapy (6.0 +/- 1.7 mEq/l, p < 0.001). Repeat angiography showed vasodilatory effect on the spastic cerebral arteries at 3 hours after the infusion, especially in the arteries near to the site of cisternal drainage placement. The magnesium infusion also caused decreased mean arterial blood velocity in the spastic arteries in 6 of the 7 measured patients (162 +/- 38 cm/sec to 114 +/- 42 cm/sec, p < 0.001). Finally, 5 of the 10 patients achieved good recovery, 1 patient had moderate disability, 1 patient became severely disabled due to meningitis, and 3 patients were vegetative or dead, due to failure of magnesium irrigation in 1 patient and advanced age in the other 2 (more than 80 years old). This preliminary study indicates that intra-cisternal infusion of magnesium sulfate solution has vasodilatory effect on the spastic cerebral arteries after aneurysmal SAH.

Development of a cavum septi pellucidi after Ommaya reservoir placement: report of an unusual complication.

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.

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.