Modified Frameless Stereotactic System for Intracerebral Delivery of Viral Vector in Young Children.

BACKGROUND: Stereotaxic surgery for viral vector delivery in young children is highly challenging because of their small cranial size, thin and fragile skull, and deformity of the skull or brain after prolonged bed ridden condition. OBJECTIVE: To develop a modified frameless stereotactic system especially suitable for intracerebral delivery of viral vector in young children for accurate localization of intracerebral targets during stereotactic surgery. METHODS: A modified frameless stereotactic system was developed for intracerebral delivery of viral vector in pediatric patients with congenital enzyme deficiency. Localization markers and a stereotactic stabilizer were designed specifically for surgery in pediatric patients, and this equipment is used along with a pre-existing frameless stereotactic and computer-assisted planning and navigation system. RESULTS: We applied this modified frameless stereotactic system to treat 10 children with aromatic L-amino acid decarboxylase deficiency. CONCLUSION: It is potentially suitable for stereotactic functional neurosurgery in pediatric patients as young as 1 yr and 8 mo of age.

Clinical characteristic of 15 cases of cryptococcal meningitis treated with Ommaya reservoir.

Cryptococcal meningitis is a severe subacute fungal meningoencephalitis. Intracerebroventricular (ICV) injection of antifungal medication and aspiration of cerebrospinal fluid (CSF) through Ommaya reservoir were reported to be useful cryptococcal meningitis treatment method. We want to evaluate the role of Ommaya reservoir in the treatment of refractory cryptococcal meningitis. We retrospectively analyzed clinical records and data of 15 refractory cryptococcal meningitis patients who were treated with Ommaya reservoir in Sir Run Run Shaw hospital from June 2013 to June 2017. Fifteen patients who underwent Ommaya reservoir implanted surgery include eight women and seven men. Headache and fever were the common clinical symptoms. Underlying diseases mainly include diabetes mellitus and hypertension. Three patients occurred renal dysfunction and four patients experienced liver damage. Thirteen patients recovered completely, whereas two patients died. Implant Ommaya reservoir which can serial extract CSF and ICV injection of Amphotericin B is a valuable approach in the treatment of Cryptococcal meningitis, especially for patients with refractory intracranial hypertension.

Best practices for the use of intracerebroventricular drug delivery devices.

For decades, intracerebroventricular (ICV), or intraventricular, devices have been used in the treatment of a broad range of pediatric and adult central nervous system (CNS) disorders. Due to the limited permeability of the blood brain barrier, diseases with CNS involvement may require direct administration of drugs into the brain to achieve full therapeutic effect. A recent comprehensive literature review on the clinical use and complications of ICV drug delivery revealed that device-associated complication rates are variable, and may be as high as 33% for non-infectious complications and 27% for infectious complications. The variability in reported safety outcomes may be driven by a lack of consensus on best practices of device use. Numerous studies have demonstrated that employing strict aseptic techniques and following stringent protocols can dramatically reduce complications. Key practices to be considered in facilitating the safe, long-term use of these devices are presented.

Cerebrospinal fluid injection into adult zebrafish for disease research.

A modified method of cerebrospinal fluid injection was developed for the efficient and reliable administration of substances to the zebrafish central nervous system. The accuracy of this modified method was evaluated using Alexa Fluor dye injection. A high survival ratio was achieved due to the simplicity of the procedure and ice-tricaine combined anaesthesia. To validate this new method, we injected ammonium chloride, which successfully blocked lysosome function resulting in elevated LC3-II and the accumulation of ubiquitinated proteins. Injection of human α-synuclein fibrils initiated a prion-like propagation of α-synuclein pathology in zebrafish. This method can be used to investigate the effects of various substances and the propagation of α-synuclein in the central nervous system.

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.

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.

Alternative treatment of stereotactic cyst aspiration and radiosurgery for cystic brain metastases.

BACKGROUND: Surgical removal is the first choice of treatment for large cystic brain metastases. However, some patients cannot undergo surgical resection due to their general condition and/or the tumor location. AIMS: In this study, we investigated the feasibility and safety of stereotactic cyst aspiration and gamma knife radiosurgery (GKR) as an alternative treatment for these lesions and followed the volumetric changes in cystic and solid portions. METHODS: Between February 2005 and March 2012, a total of 24 patients underwent GKR after cyst aspiration for 29 cystic metastatic brain tumors. The median age was 60 years (range, 18-81). The number of male patients was 18 and that of female patients 6. Most of the patients were in class II (87.5%) based on the data of the Radiation Therapy Oncology Group using recursive partitioning analysis. We analyzed the changes in tumor volume, the local control rate, intracranial progression-free survival (PFS) and overall survival (OS). RESULTS: Before aspiration, the mean total tumor volume was 32.7 cm(3) (range, 12.1-103.3) and cystic volume was 18.6 cm(3) (range, 8-72.3). The mean duration of cyst drainage was 1 day (range, 1-2). The mean amount of aspiration was 16.8 cm(3) (range, 6-67.4). After aspiration, the total mean volume was 12.4 cm(3) (range, 3.7-38.1) and cystic volume was 2.0 cm(3) (range, 0.1-9.5). The nature of the cyst was serous in 18, serous and hemorrhagic in 3, and serous and necrotic in 8. The median prescription dose was 16 Gy (range, 14-20). There was no treatment-related complication. The local control rate was 58.6% (17/29). The median survival to local recurrence was 6.0 (±1.42) months. During the follow-up period, an Ommaya reservoir was placed in 3 patients. Insertion of an Ommaya reservoir and whole-brain radiotherapy (WBRT) or GKR were done in 2 patients, WBRT in 2, GKR in 1 and operation in 1. The median intracranial PFS and OS after intracranial metastasis was 5.2 (±0.42) and 6.8 (±0.38) months. CONCLUSIONS: Cyst aspiration and GKR were feasible and safe but not very efficient, which could be an alternative option for large cystic metastases in patients who could not expect longer survival time.

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.

Selective injection system into hippocampus CA1 via monitored theta oscillation.

Methods of cell biology and electrophysiology using dissociated primary cultured neurons allow in vitro study of molecular functions; however, analysis of intact neuronal circuitry is often preferable. To investigate exogenous genes, viral vectors are most commonly injected using a pipette that is inserted from the top of the cortex. Although there are few reports that describe the success rate of injection in detail, it is sometimes difficult to locate the pipette tip accurately within the CA1 pyramidal cell layer because the pyramidal layer is only 0.1 mm thick. In the present study, we have developed a system to inject viral vectors accurately into the mouse hippocampal CA1 pyramidal cell layer using a stereotaxic injection system with simultaneous electrophysiological monitoring of theta oscillation. The pipette tip was positioned reliably based on integrated values of the theta oscillation in the hippocampal CA1 pyramidal cell layer. This approach allows accurate injection of solutions and provides an efficient method of gene transfer using viral vectors into the hippocampus, which can be a useful tool for studies involving the molecular mechanisms of neuronal functions.

Delivery of therapeutic agents through intracerebroventricular (ICV) and intravenous (IV) injection in mice.

Despite the protective role that blood brain barrier plays in shielding the brain, it limits the access to the central nervous system (CNS) which most often results in failure of potential therapeutics designed for neurodegenerative disorders. Neurodegenerative diseases such as Spinal Muscular Atrophy (SMA), in which the lower motor neurons are affected, can benefit greatly from introducing the therapeutic agents into the CNS. The purpose of this video is to demonstrate two different injection paradigms to deliver therapeutic materials into neonatal mice soon after birth. One of these methods is injecting directly into cerebral lateral ventricles (Intracerebroventricular) which results in delivery of materials into the CNS through the cerebrospinal fluid. The second method is a temporal vein injection (intravenous) that can introduce different therapeutics into the circulatory system, leading to systemic delivery including the CNS. Widespread transduction of the CNS is achievable if an appropriate viral vector and viral serotype is utilized. Visualization and utilization of the temporal vein for injection is feasible up to postnatal day 6. However, if the delivered material is intended to reach the CNS, these injections should take place while the blood brain barrier is more permeable due to its immature status, preferably prior to postnatal day 2. The fully developed blood brain barrier greatly limits the effectiveness of intravenous delivery. Both delivery systems are simple and effective once the surgical aptitude is achieved. They do not require any extensive surgical devices and can be performed by a single person. However, these techniques are not without challenges. The small size of postnatal day 2 pups and the subsequent small target areas can make the injections difficult to perform and initially challenging to replicate.

A simple and inexpensive method to fabricate a cannula system for intracranial injections in rats and mice.

INTRODUCTION: Stereotaxic administration of neuroactive agents, either in ventricles, or targeted at specific intracranial sites, is a widely employed strategy for neurological studies in rodents. Surgical implantation of cannula on the skull is particularly useful in chronic treatments. We describe a simple, inexpensive and reliable method to fabricate a cannula system for delivery of drugs at the targeted sites in the brain of rat or mouse. METHODS: The system consists of a guide cannula made from a hypodermic needle (24 gauge), a stainless steel wire (30 gauge) that serves as a dummy cannula, and an internal cannula made of stainless steel needle (30 gauge) taken from a hypodermic syringe. The cannula can be implanted by routine stereotaxic procedure and used for acute or chronic drug administration to conscious, free moving animals. RESULTS: With a view to test the system for accuracy, the guide cannula was stereotaxically implanted, and neuropeptide Y was directly delivered into the lateral ventricle. These rats showed a significant increase in food intake. Another set of rats were cannulated for chronic protocol, wherein ethanol was delivered directly into the ventral tegmental area. In operant chamber, these rats showed increased ethanol self-administration. The proposed cannula takes around 5 min to fabricate and costs less than a dollar. CONCLUSION: We feel that it may serve as an economical and reliable tool in neuropharmacological and neurobehavioral studies.

Intraventricular baclofen for dystonia: techniques and outcomes. Clinical article.

OBJECT: The aim of this study was to evaluate the use of intraventricular baclofen (IVB) for the treatment of severe generalized secondary and heredodegenerative dystonia. METHODS: Nine children and 1 adult with severe dystonia unresponsive to multiple oral medications were treated with IVB. Intraventricular catheters were positioned endoscopically in the third ventricle. RESULTS: Eight of the 10 patients responded to IVB; their mean dystonia scores on the Barry-Albright dystonia scale decreased from 23 to 8. The 2 patients who did not respond had not responded to previous high doses of intrathecal baclofen. No adverse side effects related to IVB occurred. One child developed a pump infection that required pump removal, 1 developed a CSF infection that cleared after antibiotic administration, and 1 developed ventriculomegaly that required a shunt placement. CONCLUSIONS: Intraventricular baclofen is an effective method of infusing baclofen to treat severe, generalized secondary dystonia, and, at times, heredodegenerative dystonia. The site of baclofen's activity when treating dystonia may be at the cortical level, and intraventricular infusion may result in higher baclofen concentrations over the cortex than intrathecal infusion. Additional studies are necessary to determine whether IVB is effective at lower doses than those used with intrathecal baclofen administration.

Navigation-guided Ommaya reservoir placement: implications for the treatment of leptomeningeal metastases.

Ommaya reservoirs are commonly used in the diagnosis and management of leptomeningeal metastases (LM) from malignant tumors. The present study investigates the utility of an intraoperative navigation-guided technique for Ommaya reservoir placement. Between March 2004 and December 2005, 85 navigation-guided Ommaya reservoir placements were performed in 77 patients with intracranial malignancies at the Komagome Metropolitan Hospital. Anterior horn puncture and posterior horn puncture were used for 59 and 26 procedures, respectively. A slit ventricle was present in 6 cases. All procedures were performed under assistance from the Medtronic STEALTH STATION TRIA navigation system. Computed tomographic (CT) scans were routinely obtained just after completion of the procedure. Patients diagnosed with LM received subsequent treatment. An Ommaya catheter was applied to the ventricular puncture needle registered in the navigation system and was inserted into the lateral ventricle. Using the real-time "Guidance View", the surgeon was able to verify the catheter position continuously during the procedure. Postoperative CT scan revealed an appropriate catheter position in all except for one case. Complications (catheter malposition) occurred in only one case (complication rate, 1.2%). None of the patients experienced hemorrhage or infection. In conclusion, navigation-guided Ommaya reservoir placement was associated with a very low incidence of complications. This method appears to be safe and effective when employed in patients with intracranial malignancy.

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.

Microdialysis in freely moving mice: determination of acetylcholine, serotonin and noradrenaline release in galanin transgenic mice.

In the present study, we describe micro-surgical methods for simultaneous implantation of a microdialysis probe and an intraventricular injection cannula via their respective guide cannulas into the mouse brain. Basal and stimulated release of acetylcholine (ACh), serotonin (5-HT) and noradrenaline (NA) was determined in the ventral hippocampus of freely moving mice. NA and 5-HT were determined in one run by a newly developed HPLC method based on precolumn derivatization with benzylamine and fluorescence detection. The mice with a loss-of-function mutation of the galanin gene (KO) and the mice that over-expressed galanin (OE) were studied. No significant differences in basal, potassium-stimulated or scopolamine-induced extracellular ACh levels were observed in 4-month-old wild-type (WT) and KO mice. In the aged, 10-month-old animals, the basal extracellular ACh levels were significantly reduced in both WT and KO groups. Galanin (1 nmol i.c.v.) caused a significant reduction of basal extracellular NA by about 40% in both WT and galanin OE mice, however, in the latter group the effect was delayed by almost 2 h. A 10-min forced swimming stress caused a higher increase in release of NA and 5-HT in the OE group than in the corresponding WT mice. Finally, venlafaxin (10 mg/kg i.p.) increased extracellular NA to 400% of the control values in the CBA mice, but only to 250% in the C57BL mice. It is concluded that galanin may play an important role in the cholinergic mechanisms underlying cognitive disorders. Furthermore, modulation by galanin and by behavioral activation, of NA and 5-HT neurotransmission in galanin over-expressing mice indicates its possible role in the aetiology of mood disorders.

A novel stereotaxic-like method for injecting into the lateral ventricles of small passerine birds.

Recently, there has been an increase in the interest in various aspects of the biology of small passerine birds. In order to apply many modern neurobiological techniques, it would be useful to be able to surgically inject hormones and drugs directly into passerine brains. We describe a novel and cost-effective stereotaxic-like technique for injecting substances into the lateral ventricles of small passerine birds. The technique is rapid, reducing the period of anesthesia, and reliable. In addition, using this technique, we injected [3H]cysteine (to label newly synthesized proteins) with small doses of colchicine. Colchicine decreased the content of newly synthesized protein in the median eminence, thus suggesting that colchicine inhibited protein transport. The technique should prove useful in a number of neurobiologial applications.

Magnetic resonance ventriculography with gadolinium DTPA: report of two cases.

We report intrathecal use of gadolinium DTPA for MRI of the cerebrospinal fluid (CSF). In two patients with leptomeningeal carcinomatosis, we injected 0.01 mmol gadolinium DTPA into the lateral ventricle via an Ommaya device. Coronal T1-weighted images of the head were obtained at 0.2 T prior to and after injection. There was pronounced enhancement of CSF close to the injection site, allowing good delineation of CSF and surrounding brain tissue. No side effects occurred. MRI with intrathecal administration of highly diluted gadolinium DTPA may be a promising alternative to conventional investigation of CSF-filled cavities using iodinated X-ray contrast media or radionuclides.

An approach to study molecular mechanisms involved in cytokine-induced anorexia.

Cytokines are released during pathophysiological processes. Cytokines (e.g., interleukin-1 beta or IL-1 beta) induce neurological manifestations including anorexia. Here, we show an integrative approach to investigate the cellular and molecular basis of cytokine-induced anorexia. In this approach: (1) the chronic intracerebroventricular (icv) microinfusion (via osmotic minipumps) of cytokines, at doses that will yield estimated pathophysiological concentrations reported in the cerebrospinal fluid, is used. (2) General and computerized behavioral monitoring characterizes the microstructure of behavioral modifications induced by a cytokine, and the time course for cytokine action. (3) Brain regions and subregions (nuclei/areas) from animals exhibiting significant anorexia in response to cytokine(s) are dissected, and RNA and protein are isolated. (4) The profile of cytokine subsystems (ligands, receptors, endogenous inhibitors; for example, IL-1 alpha and beta, IL-1 receptor types I and II, and IL-1 receptor antagonist) is characterized in the same brain samples with polymerase chain reaction, sensitive RNase protection assays and immunoblots. (5) The relationship between changes in cytokine subsystems at the molecular level and cytokine-induced anorexia within an animal is determined, and the general profile is analyzed with statistical methods. This approach is also pertinent to study neurotransmitter and neuropeptide profiles, and cytokine-cytokine, cytokine-neuropeptide and cytokine-neurotransmitter interactions in vivo. The results show that this integrative and novel strategy can be used to study the molecular basis of anorexia and other neurological manifestations (e.g., fever, sleep changes) induced by cytokines.