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Journal of Visualized Experiments : JoVE Jan 2021Leptomeningeal disease (LMD) is an uncommon type of central nervous system (CNS) metastasis to the cerebral spinal fluid (CSF). The most common cancers that cause LMD...
Leptomeningeal disease (LMD) is an uncommon type of central nervous system (CNS) metastasis to the cerebral spinal fluid (CSF). The most common cancers that cause LMD are breast and lung cancers and melanoma. Patients diagnosed with LMD have a very poor prognosis and generally survive for only a few weeks or months. One possible reason for the lack of efficacy of systemic therapy against LMD is the failure to achieve therapeutically effective concentrations of drug in the CSF because of an intact and relatively impermeable blood-brain barrier (BBB) or blood-CSF barrier across the choroid plexus. Therefore, directly administering drugs intrathecally or intraventricularly may overcome these barriers. This group has developed a model that allows for the effective delivery of therapeutics (i.e., drugs, antibodies, and cellular therapies) chronically and the repeated sampling of CSF to determine drug concentrations and target modulation in the CSF (when the tumor microenvironment is targeted in mice). The model is the murine equivalent of a magnetic resonance imaging-compatible Ommaya reservoir, which is used clinically. This model, which is affixed to the skull, has been designated as the "Murine Ommaya." As a therapeutic proof of concept, human epidermal growth factor receptor 2 antibodies (clone 7.16.4) were delivered into the CSF via the Murine Ommaya to treat mice with LMD from human epidermal growth factor receptor 2-positive breast cancer. The Murine Ommaya increases the efficiency of drug delivery using a miniature access port and prevents the wastage of excess drug; it does not interfere with CSF sampling for molecular and immunological studies. The Murine Ommaya is useful for testing novel therapeutics in experimental models of LMD.
Topics: Animals; Breast Neoplasms; Central Nervous System Diseases; Drug Delivery Systems; Female; Heterografts; Injections, Intraventricular; Meningeal Neoplasms; Mice; Models, Biological; Neoplasm Metastasis; Neoplastic Cells, Circulating; Prognosis
PubMed: 33586709
DOI: 10.3791/62033 -
Case Reports in Neurology 2021Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder, typically caused by survival motor neuron 1 (SMN1) gene deletion in chromosome 5q resulting in loss...
Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder, typically caused by survival motor neuron 1 (SMN1) gene deletion in chromosome 5q resulting in loss of SMN protein. SMA type 1 progresses rapidly leading to increased mortality usually before the age of 2 years. Nusinersen, the first approved disease-modifying treatment for all 5q-SMA types and ages, is an antisense oligonucleotide administered intrathecally via repeated lumbar punctures. However, adult SMA patients typically present with severe scoliosis and spinal deformity. We present a 28-year-old patient with SMA type 1 and severe spinal deformity, who received nusinersen via a subcutaneously implanted Ommaya reservoir connected with an intrathecal catheter at the thoracic level. The repetitive administrations were completed uneventfully, obviating the need for repeated laborious lumbar punctures and eliminating radiation exposure. In adult SMA patients, performing recurrent lumbar punctures can be technically challenging raising the need for an alternative route of administration. The use of Ommaya reservoirs is a viable, practical for repeated infusions, and safe option for the intrathecal delivery of nusinersen for select cases such as an adult SMA type 1 survivor with severe spinal deformity.
PubMed: 34950009
DOI: 10.1159/000519831 -
Neurology India 2020External ventricular drainage (EVD) is one of the commonest procedures in neurosurgical practice to manage acute hydrocephalus. We evaluated the infectious and...
BACKGROUND AND AIMS
External ventricular drainage (EVD) is one of the commonest procedures in neurosurgical practice to manage acute hydrocephalus. We evaluated the infectious and non-infectious complications associated with a modified technique for EVD using an Ommaya reservoir.
METHODS
Ommaya reservoir was placed in all patients who required EVD placement for CSF drainage. CSF drainage was achieved using a needle placed in a non-coring fashion percutaneously into the Ommaya reservoir to achieve CSF drainage externally. CSF was monitored for signs of infection regularly using CSF biochemistry and cultures. CSF infection was defined by a positive culture or a secondary infection in patients with already infected CSF.
RESULTS
59 patients required continuous CSF drainage during the study period from January 2014 to June 2017. 46 (77.96%) patients had non-infected CSF at time of starting drainage and 13 (22.03%) patients required external CSF drainage for primarily infected CSF. The study period had a total of 793 CSF drainage days (Range 3-64 days) with an average of 13.4 days per patient. The cumulative rate of new infection was 5.08%. No ventricular catheter blockage or dislodgement was seen in any of the patients.
CONCLUSIONS
External ventricular drainage through an Ommaya chamber is a safe and effective method and can be used to reduce the catheter related complications like infection, catheter blockage and dislodgement.
Topics: Acute Disease; Adolescent; Adult; Aged; Brain Neoplasms; Catheter-Related Infections; Catheters, Indwelling; Cerebral Intraventricular Hemorrhage; Cerebral Ventriculitis; Child; Child, Preschool; Drainage; Equipment and Supplies; Female; Humans; Hydrocephalus; Infant; Male; Middle Aged; Prosthesis Implantation; Scalp; Subarachnoid Hemorrhage; Ventriculostomy; Young Adult
PubMed: 32415024
DOI: 10.4103/0028-3886.284354 -
International Medical Case Reports... 2022, a common component of the skin and mucosal microbiota of both immunocompetent and immunocompromised individuals, has become an emerging pathogen, colonizing indwelling...
, a common component of the skin and mucosal microbiota of both immunocompetent and immunocompromised individuals, has become an emerging pathogen, colonizing indwelling medical devices and causing infections at multiple sites. A 3-year-old boy with an Ommaya reservoir in the right ventricle and a medical history of grade 3 intraventricular hemorrhage, Hirschsprung disease, catheter-related methicillin-resistant bacteremia, and congenital central hypoventilation syndrome was hospitalized for Ommaya reservoir infection with . He was treated with ampicillin, to which the initial isolate was susceptible. may have acquired multiple-drug resistance during the antibiotic treatment due to biofilm production. The Ommaya reservoir was replaced by external ventricular drainage. Cultures of the removed Ommaya reservoir, and cerebrospinal fluid samples grew , which was susceptible to meropenem and vancomycin and resistant to other antibiotics. The antibiotic was switched to vancomycin to treat this new multidrug-resistant strain. After 8 days of vancomycin treatment, the cerebrospinal fluid culture obtained by a lumbar puncture was negative for . In cases of device-associated infections caused by biofilm-producing bacteria, it is desirable to remove the device as soon as possible.
PubMed: 35535175
DOI: 10.2147/IMCRJ.S361505 -
Frontiers in Neurology 2022Glioma is the most common primary brain tumor in adults with poor prognosis. The glioma patients benefit from STUPP strategy, including maximum and safe resection and...
BACKGROUND
Glioma is the most common primary brain tumor in adults with poor prognosis. The glioma patients benefit from STUPP strategy, including maximum and safe resection and adjuvant radiotherapy and chemotherapy. Arsenic trioxide could inhibit various tumors. However, it is a challenge to evaluate the efficiency and safety of srsenic trioxide in glioma patients.
OBJECTIVE
The arsenic trioxide has the potent therapeutic effect on glioma. However, the safety and efficacy of local interstitial chemotherapy with arsenic trioxide in newly diagnosed glioma patients is unclear.
METHODS
All patients received partial or complete tumor resection and intraoperative implantation of Ommaya reservoirs followed by standard radiotherapy. Arsenic trioxide with the starting dose 0.3 mg was administered an Ommaya reservoir catheter inserted into the tumor cavity for 5 consecutive days every 3 months for a total of eight cycles unless tumor progression or excessive toxicity was observed.
RESULTS
No hematological or grade 4 non-hematological toxicity was observed in any patient during arsenic trioxide treatment. The maximum tolerated dose of 1.5 mg of arsenic trioxide was safe and well tolerated. The median overall survival for WHO grade 3 glioma was 33.6 months, and for glioblastoma was 13.9 months. The median progression-free survival for WHO grade 2 glioma was 40.3 months, for grade 3 glioma was 21.5 months, and for glioblastoma was 9.5 months.
CONCLUSION
These results suggest that arsenic trioxide is safe and well tolerated with local delivery into the tumor cavity of the brain, and the dose recommended for a phase II trial is 1.5 mg.
PubMed: 36212657
DOI: 10.3389/fneur.2022.1001829 -
Journal of Neuro-oncology Nov 2017This study aimed to assess the incidence and management of pseudoprogression after radiation therapy (RT) in patients with pediatric low-grade glioma (LGG). This...
This study aimed to assess the incidence and management of pseudoprogression after radiation therapy (RT) in patients with pediatric low-grade glioma (LGG). This retrospective review included patients aged 21 years or younger with intracranial LGG treated with curative-intent RT. Pseudoprogression was defined as an increase in tumor size by ≥10% in at least two dimensions between two and three consecutive MR imaging studies. Overall survival (OS) and event-free survival (EFS) were measured from the first day of RT. EFS was defined as survival without true progression or secondary high-grade glioma. Sixty-two of 221 patients developed pseudoprogression, with a 10-year cumulative incidence of 29.0% (95% CI 23.0-35.2). Median time to pseudoprogression was 6.1 months after RT. Symptomatic pseudoprogression was managed with subtotal resection, shunt/Ommaya reservoir placement, or corticosteroids in 11 (18%), 7 (11%), and 2 patients (3%), respectively. The remaining tumors were observed (68%). Patients with pilocytic astrocytoma (PA) had 5.4-fold greater odds of developing pseudoprogression relative to tumors of other histology (odds ratio 95% CI 2.5-11.4, P < 0.0001). Among patients with PA (n = 127), the 10-year cumulative incidence of pseudoprogression was 42.9%. In this group, pseudoprogression was associated with improved 10-year EFS (84.5% vs. 58.5%, P = 0.008) and OS (98.0% vs. 91.2%, P = 0.03). Pseudoprogression after irradiation was common, especially in patients with pilocytic astrocytoma, and was associated with improved survival. Knowledge of the incidence and temporal course of pseudoprogression may help avoid unnecessary salvage therapy.
Topics: Adolescent; Brain; Brain Neoplasms; Child; Child, Preschool; Disease Management; Disease Progression; Female; Glioma; Humans; Incidence; Infant; Magnetic Resonance Imaging; Male; Neoplasm Grading; Retrospective Studies; Survival Analysis; Time Factors; Tumor Burden; Young Adult
PubMed: 28752498
DOI: 10.1007/s11060-017-2583-9 -
Therapeutic Advances in Neurological... 2020To investigate outcome and toxicity of high-dose systemic methotrexate (HDMTX)-based polychemotherapy and intracerebroventricular (ICV) chemotherapy an Ommaya reservoir...
BACKGROUND
To investigate outcome and toxicity of high-dose systemic methotrexate (HDMTX)-based polychemotherapy and intracerebroventricular (ICV) chemotherapy an Ommaya reservoir in elderly patients with primary central nervous system lymphoma (PCNSL).
METHODS
We performed a retrospective analysis on patients ⩾65 years with first diagnosis of PCNSL admitted to our center between January 2015 and December 2019. These patients were treated with a standardized chemotherapy protocol in case of absent contraindications for HDMTX-based chemotherapy. The protocol contained induction therapy with systemic rituximab, methotrexate and ifosfamide and consolidation treatment with systemic cytarabine (AraC) and ICV methotrexate, prednisolone and AraC.
RESULTS
Of a total of 46 patients seen in this period, 3 did not qualify for HDMTX. Thus, 43 patients were included in this analysis. Median age was 74 years (range 65-86), median Karnofsky performance score was 50 (range 20-90). Of the 43 patients, 32 (74.4%) completed treatment including ICV therapy. Complete remission/complete remission unconfirmed was achieved in 26 of 43 patients (60.5%), partial response (PR) in 3 (7%); 5 (11.6%) had progressive disease, and 3 (7.0%) died due to treatment-related complications; in the remaining 6 (14.0%) therapy could not be completed. Median progression free survival was 16 months (95% confidence interval 8-24 months) and median overall survival had not been reached after a median follow up of 23 months (range 1-52 months); the 75th percentile survival time was 12 months. No Ommaya reservoir infection was observed. Complications of ICV treatment were pericatheter leucencephalopathy in two patients and surgical scar dehiscence with cerebrospinal fluid leak in one patient.
CONCLUSION
Toxicity of HDMTX plus ICV chemotherapy for elderly patients with PCNSL was manageable and outcome was excellent for patients treated with this protocol.
PubMed: 33101460
DOI: 10.1177/1756286420951087 -
Acta Neuropathologica Communications Jun 2020Treatment with small-molecule inhibitors, guided by precision medicine has improved patient outcomes in multiple cancer types. However, these compounds are often not...
Treatment with small-molecule inhibitors, guided by precision medicine has improved patient outcomes in multiple cancer types. However, these compounds are often not effective against central nervous system (CNS) tumors. The failure of precision medicine approaches for CNS tumors is frequently attributed to the inability of these compounds to cross the blood-brain barrier (BBB), which impedes intratumoral target engagement. This is complicated by the fact that information on CNS penetration in CNS-tumor patients is still very limited. Herein, we evaluated cerebrospinal fluid (CSF) drug penetration, a well-established surrogate for CNS-penetration, in pediatric brain tumor patients. We analyzed 7 different oral anti-cancer drugs and their metabolites by high performance liquid chromatography mass spectrometry (HPLC-MS) in 42 CSF samples obtained via Ommaya reservoirs of 9 different patients. Moreover, we related the resulting data to commonly applied predictors of BBB-penetration including ABCB1 substrate-character, physicochemical properties and in silico algorithms. First, the measured CSF drug concentrations depicted good intra- and interpatient precision. Interestingly, ribociclib, vorinostat and imatinib showed high (> 10 nM), regorafenib and dasatinib moderate (1-10 nM) penetrance. In contrast, panobinostat und nintedanib were not detected. In addition, we identified active metabolites of imatinib and ribociclib. Comparison to well-established BBB-penetrance predictors confirmed low molecular weight, high proportion of free-drug and low ABCB1-mediated efflux as central factors. However, evaluation of diverse in silico algorithms showed poor correlation within our dataset. In summary, our study proves the feasibility of measuring CSF concentration via Ommaya reservoirs thus setting the ground for utilization of this method in future clinical trials. Moreover, we demonstrate CNS presence of certain small-molecule inhibitors and even active metabolites in CSF of CNS-tumor patients and provide a potential guidance for physicochemical and biological factors favoring CNS-penetration.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adolescent; Adult; Antineoplastic Agents; Biological Transport; Blood-Brain Barrier; Brain Neoplasms; Child; Drug Delivery Systems; Female; Humans; Male; Young Adult
PubMed: 32493453
DOI: 10.1186/s40478-020-00953-2 -
The New Microbiologica Feb 2023The genus Nocardia consists of a group of gram-positive environmental bacteria. They typically cause lung and brain infections in immunocompromised patients, even though... (Review)
Review
The genus Nocardia consists of a group of gram-positive environmental bacteria. They typically cause lung and brain infections in immunocompromised patients, even though one out of three infected patients have a normally functioning immune system. Being a ubiquitous microorganism, in some cases Nocardia has been associated with nosocomial acquired infections and surgical procedures. A review of the literature in this field follows the case report. A 47-year-old woman underwent an endoscopic third ventriculostomy and a left retro-sigmoid craniotomy for a schwannoma removal. Meningeal symptoms began a week later, in association with C reactive protein rise and leukocytosis. Cerebrospinal fluid (CSF) examination was clear with hypoglycorrhachia, hyperprotidorrachia and polymorphonuclear cells. Cultural exam was negative. At the brain magnetic resonance imaging (MRI) purulent material was described in the occipital ventricular horns. Empirical broad spectrum antibiotic therapy was given for 31 days until the brain MRI showed a resolution of the infection. Ten days later, the patient was admitted to the hospital because of new meningeal symptoms. Cerebrospinal fluid culture and Polymerase-chain reaction (PCR) Multiplex for the most important meningitis viruses and bacteria tested negative. A broad-spectrum antibiotic therapy was started with no benefit; thus, a broad-spectrum antifungal therapy was added with little success on clinical status. Meanwhile, a 16s and 18s rRNA PCR was executed on a previous Cerebrospinal fluid with negative results, excluding bacterial and fungal infections. For this reason, all the therapies were stopped. After a few days, high fever and meningeal signs reappeared. The brain MRI showed a meningoventriculitis. An Ommaya catheter with reservoir was inserted and the drawn CSF resulted in the growth of Nocardia farcinica. Antibiogram-based antibiotic therapy was started with intravenous imipenem and trimethoprim-sulfamethoxazole, showing clinical benefit. The patient was sent home with oral linezolid and amoxicillin/clavulanate for a total of 12 months of therapy. Nocardia rarely causes post-neurosurgical complication in a nosocomial setting. This case shows the difficulty in detecting Nocardia and the importance of the correct microbiological sample and antibiogram-based antibiotic therapy to achieve successful treatment.
Topics: Animals; Female; Humans; Middle Aged; Amoxicillin-Potassium Clavulanate Combination; Cross Infection; Anti-Bacterial Agents
PubMed: 36853823
DOI: No ID Found -
Molecular Genetics and Metabolism Jul 2018For decades, intracerebroventricular (ICV), or intraventricular, devices have been used in the treatment of a broad range of pediatric and adult central nervous system...
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.
Topics: Central Nervous System Agents; Central Nervous System Diseases; Drug Delivery Systems; Humans; Injections, Intraventricular; Practice Guidelines as Topic
PubMed: 29793829
DOI: 10.1016/j.ymgme.2018.05.003