Osaama H. Khan

Brain damage in neonatal rats following kaolin induction of hydrocephalus

Neonatal and congenital hydrocephalus are common problems in humans. Hydrocephalus was induced in 1-day-old rats by injection of kaolin into the cisterna magna. At 7 and 21 days, magnetic resonance (MR) imaging was used to assess ventricle size, then brains were subjected to histopathological and biochemical analyses. Hydrocephalic pups did not exhibit delays in righting or negative geotaxis reflexes during the first week. At 7 days, there was variable ventricular enlargement with periventricular white matter edema, axon damage, reactive astrogliosis, and accumulation of macrophages in severe but not mild hydrocephalus. Cellular proliferation in the subependymal zone was significantly reduced. The cortical subplate neuron layer was disrupted. In rats allowed to survive to 21 days, weight was significantly lower in severely hydrocephalic rats. They also exhibited impaired memory in the Morris water maze test. Despite abnormal posture, there was minimal quantitative impairment of walking ability on a rotating cylinder. At 21 days, histological studies showed reduced corpus callosum thickness, fewer mature oligodendrocytes, damaged axons, and astroglial/microglial reaction. Reduced myelin basic protein, increased glial fibrillary acidic protein, and stable synaptophysin content were demonstrated by immunochemical methods. In conclusion, impairment in cognition and motor skills corresponds to ventricular enlargement and white matter destruction. Quantitative measures of weight, memory, ventricle size, and myelin, and glial proteins in this neonatal model of hydrocephalus will be useful tools for assessment of experimental therapeutic interventions.

Endoscopic endonasal resection of skull base meningiomas: the significance of a "cortical cuff" and brain edema compared with careful case selection and surgical experience in predicting morbidity and extent of resection.

OBJECT This paper describes a consecutive series of skull base meningiomas resected using an endoscopic endonasal approach through various corridors at a single institution over 7 years. The impact of case selection and experience, the presence of a cortical cuff between the tumor and surrounding vessels, and brain edema on morbidity and rates of gross-total resection (GTR) were examined. METHODS A retrospective review of a series of 46 skull base meningiomas from a prospective database was conducted. The series of cases were divided by location: olfactory groove (n = 15), tuberculum and planum (n = 20), sellar/cavernous (n = 9) and petroclival (n = 2). Gross-total resection was never intended in the sellar/cavernous tumors, which generally invaded the cavernous sinus. Clinical charts, volumetric imaging, and pathology were reviewed to assess the extent of resection and complications. Cases were divided based on a time point in which surgical technique and case selection improved into Group 1 (surgery prior to June 2008; n = 21) and Group 2 (surgery after June 2008; n = 25) and into those with and without a cortical cuff and with and without brain edema. RESULTS Improved case selection had the greatest impact on extent of resection. For the entire cohort, rates of GTR went from 38% to 76% (p = 0.02), and for cases in which GTR was the intent, the rates went from 63% to 84% (not significant), which was mostly driven by the planum and tuberculum meningiomas, which went from 75% to 91.7 % (nonsignificant difference). The presence of a cortical cuff and brain edema had no impact on outcomes. There were 3 CSF leaks (6.5%) but all were in Group 1. Hence, CSF leak improved from 14.2% to 0% with surgical experience. Lessons learned for optimal case selection are discussed. CONCLUSIONS Surgical outcome for endonasal endoscopic resection of skull base meningiomas depends mostly on careful case selection and surgical experience. Imaging criteria such as the presence of a cortical cuff or brain edema are less important.

Endoscopic Endonasal Resection of Suprasellar Meningiomas: The Importance of Case Selection and Experience in Determining Extent of Resection, Visual Improvement, and Complications

OBJECTIVE Suprasellar meningiomas have been resected via various open cranial approaches. During the past 2 decades, the endoscopic endonasal approach has been shown to be an option in selected patients. We wished to examine the learning curve for parameters such as extent of resection, visual outcome, and complications. METHODS We retrospectively reviewed a consecutive series of patients in whom suprasellar meningiomas were resected via an endonasal endoscopic approach between 2005 and 2013 at our institution. After June 2008, our surgical technique matured. Using this time point, we divided our case series into 2 chronological groups, group 1 (n=8) and group 2 (n=12). This cut-off also was used to examine rates of gross total resection (GTR) and visual improvement. Case selection criteria in successful and unsuccessful cases were examined to determine important principals for case selection. RESULTS Mean patient age at surgery was 57.05 years (range, 31-81 years). Mean tumor volume was 11.98 cm3 (range, 0.43-28.93 cm3). Overall, GTR was achieved in 80%, and vision improved or normalized in 14 patients (82.4%) with no occurrence of postoperative visual deterioration. Rates of GTR increased from 62.5% (group 1) to 91.7% (group 2). Visual improvement increased from 75% (group 1) to 88.9% (group 2). Rates of cerebrospinal fluid leak were 25% in group 1 and 0% in group 2. Average follow-up was 51.5 month (range, 3-96 months). CONCLUSION Once the learning curve is overcome, surgeons performing endonasal endoscopic resection of suprasellar meningiomas can achieve high rates of GTR with low complication rates in well-selected cases.

Pure endoscopic expanded endonasal approach for olfactory groove and tuberculum sellae meningiomas

The expanded endoscopic endonasal (EEE) approach for the removal of olfactory groove (OGM) and tuberculum sellae (TSM) meningiomas is currently becoming an acceptable surgical approach in neurosurgical practice, although it is still controversial with respect to its outcomes, indications and limitations. Here we provide a review of the available literature reporting results with use of the EEE approach for these lesions together with our experience with the use of the endoscope as the sole means of visualization in a series of patients with no prior surgical biopsy or resection. Surgical cases between May 2006 and January 2013 were retrospectively reviewed. Twenty-three patients (OGM n=6; TSM n=17) were identified. In our series gross total resection (GTR) was achieved in 4/6 OGM (66.7%) and 11/17 (64.7%) TSM patients. Vision improved in the OGM group (2/2) and 8/11 improved in the TSM group with no change in visual status in the remaining three patients. Post-operative cerebrospinal fluid (CSF) leak occurred in 2/6 (33%) OGM and 2/17 (11.8%) TSM patients. The literature review revealed a total of 19 OGM and 174 TSM cases which were reviewed. GTR rate was 73% for OGM and 56.3% for TSM. Post-operative CSF leak was 30% for OGM and 14% for TSM. With careful patient selection and a clear understanding of its limitations, the EEE technique is both feasible and safe. However, longer follow-ups are necessary to better define the appropriate indications and ideal patient population that will benefit from the use of these newer techniques.

Cerebral White Matter Oxidation and Nitrosylation in Young Rodents With Kaolin-Induced Hydrocephalus

Abstract Hydrocephalus is associated with reduced blood flow in periventricular white matter. To investigate hypoxic and oxidative damage in the brains of rats with hydrocephalus, kaolin was injected into the cisterna magna of newborn 7- and 21-day-old Sprague-Dawley rats, and ventricle size was assessed by magnetic resonance imaging at 7, 21, and 42 days of age. In-situ evidence of hypoxia in periventricular capillaries and glial cells was shown by pimonidazole hydrochloride binding. Biochemical assay of thiobarbituric acid reaction and immunohistochemical detection of malondialdehyde and 4-hydroxy-2-nonenal indicated the presence of lipid peroxidation in white matter. Biochemical assay of nitrite indicated increased nitric oxide production. Nitrotyrosine immunohistochemistry showed nitrosylated proteins in white matter reactive microglia and astrocytes. Activities ofthe antioxidant enzymes catalase and glutathione peroxidase were notincreased, and altered hypoxia-inducible factor 1&agr; was not detectedby quantitative reverse transcription–polymerase chain reaction. Cerebral vascular endothelial growth factor expression determined byquantitative reverse transcription–polymerase chain reaction and enzyme-linked immunosorbent assay was not changed, but vascular endothelial growth factor immunoreactivity was increased in reactive astrocytes of hydrocephalic white matter. To determine if nitric oxide synthase is involved in the pathogenesis, we induced hydrocephalus in 7-day-old wild-type and neuronal nitric oxide synthase–deficient mice. At 7 days, the wild-type and mutant mice exhibited equally severe ventriculomegaly and no behavioral differences, although increased glial fibrillary acidic protein was less in the mutant mice. We conclude that hypoxia, via peroxidation and nitrosylation, contributes to brain changes in young rodents with hydrocephalus and that compensatory mechanisms are negligible.

Pediatric awake craniotomy and intra-operative stimulation mapping

The indications for operating on lesions in or near areas of cortical eloquence balance the benefit of resection with the risk of permanent neurological deficit. In adults, awake craniotomy has become a versatile tool in tumor, epilepsy and functional neurosurgery, permitting intra-operative stimulation mapping particularly for language, sensory and motor cortical pathways. This allows for maximal tumor resection with considerable reduction in the risk of post-operative speech and motor deficits. We report our experience of awake craniotomy and cortical stimulation for epilepsy and supratentorial tumors located in and around eloquent areas in a pediatric population (n=10, five females). The presenting symptom was mainly seizures and all children had normal neurological examinations. Neuroimaging showed lesions in the left opercular (n=4) and precentral or peri-sylvian regions (n=6). Three right-sided and seven left-sided awake craniotomies were performed. Two patients had a history of prior craniotomy. All patients had intra-operative mapping for either speech or motor or both using cortical stimulation. The surgical goal for tumor patients was gross total resection, while for all epilepsy procedures, focal cortical resections were completed without any difficulty. None of the patients had permanent post-operative neurologic deficits. The patient with an epileptic focus over the speech area in the left frontal lobe had a mild word finding difficulty post-operatively but this improved progressively. Follow-up ranged from 6 to 27 months. Pediatric awake craniotomy with intra-operative mapping is a precise, safe and reliable method allowing for resection of lesions in eloquent areas. Further validations on larger number of patients will be needed to verify the utility of this technique in the pediatric population.

The Role of Left Inferior Fronto-Occipital Fascicle in Verbal Perseveration: A Brain Electrostimulation Mapping Study

The subcortical connectivity underlying verbal perseveration (VP) remains poorly understood. We have previously reported that intraoperative electrical stimulation of the caudate nucleus during awake surgery resulted in VP. Here, our purpose is to study the white matter pathway underlying VP using subcortical stimulation mapping in a series of patients who underwent glioma resection. Eleven patients with a left hemispheric low grade glioma were operated on while awake. Intraoperative direct electrical stimulation was used both at cortical and subcortical levels while the patients carried out motor and naming tasks during the resection. All patients experienced VP during electrical stimulation performed at the level of different subcortical locations, which corresponded in the 11 cases to different parts of the left inferior fronto-occipital fascicle. Perseveration persisted into the postoperative days, but resolved completely by three months.Our original findings provide further insight into the neuroanatomical basis of VP, by supporting the role of left inferior fronto-occipital fascicle. Such data may have both fundamental and clinical implications.

The genomic landscape of schwannoma

Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.

Calcium antagonism in neonatal rats with kaolin-induced hydrocephalus

Juvenile rats with kaolin-induced hydrocephalus have reduced brain injury if treated with nimodipine or magnesium sulfate. Experiments were conducted to determine if the neuroprotective effects could be replicated in neonatal rats with experimental hydrocephalus at an age comparable to prematurely born humans. In a blinded and randomized manner, drugs were administered for 14 days beginning 7 days after induction of hydrocephalus. Nimodipine was given twice daily by subcutaneous injections. Daily doses greater than 38 mg/kg of body weight were fatal. Daily doses of 3.8 to 30 mg/kg were not associated with behavioral, structural, or biochemical improvements. Magnesium chloride was administered via daily subcutaneous minipump infusion (0.87 or 1.74 mM/kg) along with twice daily injections of 0.74 or 1.48 mM/kg. Magnesium sulfate was administered by twice daily subcutaneous doses of 1.54 or 7.72 mM/kg. Sedation occurred, but there was no statistically significant protection in regard to behavior, brain structure, or brain composition in any of the magnesium experiments. Developmental alterations in calcium channels of the neonatal rat brain could account for differences from prior experiments in young hydrocephalic rats.

Magnesium sulfate therapy is of mild benefit to young rats with kaolin-induced hydrocephalus.

Hydrocephalus causes damage to periventricular white matter at least in part through chronic ischemia. Magnesium sulfate (MgSO4) has been shown to be protective in various models of neurologic injury. We hypothesized that this agent would ameliorate the effects of experimental childhood-onset hydrocephalus. Hydrocephalus was induced in 3- and 4-wk-old rats by injection of kaolin into the cisterna magna. Tests of cognitive and motor function were performed on a weekly basis. In a blinded and randomized manner, MgSO4 was administered in two separate experiments (s.c. injection 0.85, 4.1, or 8.2 mM/kg/d), supplemented by osmotic minipump infusion (0.03 mM/d) to prevent low trough levels for 2 wk, beginning 2 wk after induction of hydrocephalus. The brains were then subjected to histopathological and biochemical analyses. With the 4.1 mM/kg/d dose, serum Mg++ levels were elevated transiently from 1.3 to ∼7 mM/L. We observed statistically significant improvement in gait performance and reduced astroglial reaction. There was also a trend to improved memory performance, but no evidence of increased myelin or synaptic protein content. The 8.2 mM/kg/d dose was associated with sedation and there was no evidence of improvement in any parameter. We conclude that MgSO4 might be mildly protective in experimental hydrocephalus.