Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability globally. No drug treatments are available, so interest has turned to endogenous neural stem cells (NSCs) as alternative strategies for treatment. We hypothesized that regulation of cell proliferation through modulation of the sonic hedgehog pathway, a key NSC regulatory pathway, could lead to functional improvement. We assessed sonic hedgehog (Shh) protein levels in the cerebrospinal fluid (CSF) of patients with TBI. Using the cortical contusion injury (CCI) model in rodents, we used pharmacological modulators of Shh signaling to assess cell proliferation within the injured cortex using the marker 5-Ethynyl-2'-deoxyuridine (EdU); 50mg/mL. The phenotype of proliferating cells was determined and quantified. Motor function was assessed using the rotarod test. In patients with TBI there is a reduction of Shh protein in CSF compared with control patients. In rodents, following a severe CCI, quiescent cells become activated. Pharmacologically modulating the Shh signaling pathway leads to changes in the number of newly proliferating injury-induced cells. Upregulation of Shh signaling with Smoothened agonist (SAG) results in an increase of newly proliferating cells expressing glial fibrillary acidic protein (GFAP), whereas the Shh signaling inhibitor cyclopamine leads to a reduction. Some cells expressed doublecortin (DCX) but did not mature into neurons. The SAG-induced increase in proliferation is associated with improved recovery of motor function. Localized restoration of Shh in the injured rodent brain, via increased Shh signaling, has the potential to sustain endogenous cell proliferation and the mitigation of TBI-induced motor deficits albeit without the neuronal differentiation.

The efficacy of cystoperitoneal shunting for the surgical management of intracranial arachnoid cysts in the elderly: A systematic review of the literature.

BACKGROUND: Intracranial arachnoid cysts (AC) are benign, cerebrospinal fluid filled spaces within the arachnoid layer of the meninges. Neurosurgical intervention in children and young adults has been extensively studied, but the optimal strategy in the elderly remains unclear. Therefore, we performed a single center retrospective study combined with a systematic review of the literature to compare cystoperitoneal (CP) shunting with other surgical approaches in the elderly cohort. METHODS: Retrospective neurosurgical database search between January 2005 and December 2018, and systematic review of the literature using PRISMA guidelines were performed. Inclusion criteria: Age 60 years or older, radiological diagnosis of intracranial AC, neurosurgical intervention, and neuroradiological (NOG score)/clinical outcome (COG score). Data from both sources were pooled and statistically analyzed. RESULTS: Our literature search yielded 12 studies (34 patients), which were pooled with our institutional data (13 patients). CP shunts (7 patients; 15%), cyst fenestration (28 patients; 60%) and cyst marsupialisation/resection (10 patients; 21%) were the commonest approaches. Average duration of follow-up was 23.6, 26.9, and 9.5 months for each approach, respectively. There was no statistically significant association between choice of surgical intervention and NOG score (P = 0.417), COG score (P = 0.601), or complication rate (P = 0.955). However, CP shunting had the lowest complication rate, with only one patient developing chronic subdural haematoma. CONCLUSION: CP shunting is a safe and effective surgical treatment strategy for ACs in the elderly. It has similar clinical and radiological outcomes but superior risk profile when compared with other approaches. We advocate CP shunting as first line neurosurgical intervention for the management of intracranial ACs in the elderly.

Endoscopic biopsy and third ventriculostomy for the management of pineal region tumors.

OBJECTIVE: To assess the histologic accuracy of endoscopic biopsy samples of the pineal region. Pineal region tumors usually present with acute hydrocephalus. Histologic diagnosis is paramount, as it greatly influences treatment. Endoscopic techniques can combine histologic diagnosis with relief of the obstructive hydrocephalus in a single operation. Because pineal region tumors can be heterogeneous, initial biopsy samples may not represent the most aggressive portion of the tumor. METHODS: This retrospective study reviews our experience of endoscopic third ventriculostomy combined with biopsy of the lesion. The histologic diagnosis as a result of the initial biopsy was compared with the final histologic diagnosis to establish the accuracy of the endoscopic biopsy sample in aiding diagnosis. RESULTS: Forty-seven patients underwent an endoscopic third ventriculostomy. All but 1 patient underwent a concurrent biopsy of the space-occupying lesion and 39 of 46 patients (85%) had a histologic diagnoses. In the remaining 7 patients (15%), the histology was negative; in 6 cases, the second attempt to obtain a histologic diagnosis was successful (2 repeat endoscopic biopsy samples, 2 resections, 2 stereotactic biopsy samples). In 1 patient a presumed low-grade tectal tumor was followed up with sequential scanning. Twenty-eight patients underwent subsequent operations (24 resections, 4 stereotactic biopsies). In 6 of 28 patients (21%), the histologic report was amended after the second procedure. CONCLUSIONS: The endoscopic biopsy sample yields an accurate histologic diagnosis for most pineal region tumors, with a positive histologic sample in about 85% of patients. However, the results must be interpreted cautiously, as the heterogeneous nature of these tumors may lead to an approximately 21% error rate in the initial tumor diagnosis.

Endogenous GFAP-positive neural stem/progenitor cells in the postnatal mouse cortex are activated following traumatic brain injury.

Interest in promoting regeneration of the injured nervous system has recently turned toward the use of endogenous stem cells. Elucidating cues involved in driving these precursor cells out of quiescence following injury, and the signals that drive them toward neuronal and glial lineages, will help to harness these cells for repair. Using a biomechanically validated in vitro organotypic stretch injury model, cortico-hippocampal slices from postnatal mice were cultured and a stretch injury equivalent to a severe traumatic brain injury (TBI) applied. In uninjured cortex, proliferative potential under in vitro conditions is virtually absent in older slices (equivalent postnatal day 15 compared to 8). However, following a severe stretch injury, this potential is restored in injured outer cortex. Using slices from mice expressing a fluorescent reporter on the human glial fibrillary acidic protein (GFAP) promoter, we show that GFAP+ cells account for the majority of proliferating neurospheres formed, and that these cells are likely to arise from the cortical parenchyma and not from the subventricular zone. Moreover, we provide evidence for a correlation between upregulation of sonic hedgehog signaling, a pathway known to regulate stem cell proliferation, and this restoration of regenerative potential following TBI. Our results indicate that a source of quiescent endogenous stem cells residing in the cortex and subcortical tissue proliferate in vitro following TBI. Moreover, these proliferating cells are multipotent and are derived mostly from GFAP-expressing cells. This raises the possibility of using this endogenous source of stem cells for repair following TBI.

Giant prolactinoma causing cranio-cervical junction instability: a case report.

Prolactinomas are common secretory pituitary tumours, usually managed with dopamine agonists. There have previously been case reports of rarer giant prolactinomas causing invasion of surrounding structures. We describe a case report of an exceptionally aggressive giant prolactinoma that eroded the occipital condyles causing cranio-cervical joint instability mandating surgical fixation.