Antioxidant Therapeutic Strategies in Neurodegenerative Diseases.

The distinguishing pathogenic features of neurodegenerative diseases include mitochondrial dysfunction and derived reactive oxygen species generation. The neural tissue is highly sensitive to oxidative stress and this is a prominent factor in both chronic and acute neurodegeneration. Based on this, therapeutic strategies using antioxidant molecules towards redox equilibrium have been widely used for the treatment of several brain pathologies. Globally, polyphenols, carotenes and vitamins are among the most typical exogenous antioxidant agents that have been tested in neurodegeneration as adjunctive therapies. However, other types of antioxidants, including hormones, such as the widely used melatonin, are also considered neuroprotective agents and have been used in different neurodegenerative contexts. This review highlights the most relevant mitochondrial antioxidant targets in the main neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and Huntington's disease and also in the less represented amyotrophic lateral sclerosis, as well as traumatic brain injury, while summarizing the latest randomized placebo-controlled trials.

Woven Endobridge (WEB) Device as a Retreatment Strategy After Unsuccessful Surgical Clipping.

BACKGROUND: Surgical clipping of intracranial aneurysms is typically robust and durable. However, residual aneurysmal components may be seen after clipping. Furthermore, there may be occasional aneurysmal recurrence. These factors are both clinically relevant because subarachnoid hemorrhage after clipping is a rare but important event. The rationale for any treatment is to substantially decrease the future risk of hemorrhage. Small series have shown coiling as a retreatment strategy after unsuccessful clipping, but none has explored the feasibility of Woven Endobridge (WEB) implantation. CASE DESCRIPTION: We examined the feasibility of WEB implantation as second-line treatment for wide-necked residual aneurysms after unsuccessful clipping. We also recorded the safety and efficacy in this small series of 6 patients. To determine safety, we measured the modified Rankin Scale score before and after the procedure, and at 2 later time points (mean follow-up, 5 months and 15 months). To determine efficacy, we obtained radiographic aneurysm occlusion outcomes (including WEB Occlusion Scale) at these 2 time points. Four middle cerebral artery and 2 anterior communicating artery complex aneurysms were treated with WEB implantation, showing feasibility in 6/6 cases (100%). Follow-up at 15 months showed no change from preprocedural modified Rankin Scale score and there were no other complications. There was adequate occlusion in 5/6 cases (83%). CONCLUSIONS: WEB implantation provided a feasible option in this challenging retreatment scenario. This is a small series and prospective data are required to make outcome inferences for this population. Nonetheless, we observed no complications and high adequate occlusion rates.

Patient-Reported Bladder, Bowel, and Sexual Function After Cauda Equina Syndrome Secondary to a Herniated Lumbar Intervertebral Disc.

BACKGROUND: Cauda equina syndrome (CES) is rare neurosurgical emergency requiring emergent surgical decompression to prevent bladder, bowel, and sexual dysfunction that can have significant impact on quality of life. There is a paucity of data relating to the prevalence of these long-term complications. OBJECTIVE: The aim of this observational study was to evaluate the long-term prevalence of CES-related bladder, bowel, and sexual dysfunction and impact on quality of life to inform service provision. METHODS: Participants were selected through coding of operative records of patients who underwent lumbar decompression for CES secondary to a herniated intervertebral disc at two large UK neurosurgical departments between 2011 and 2015 inclusive. A telephone-based survey including both validated and modified tools was used to collect data pertaining to bladder, bowel, and sexual function and impact on quality of life both before development of CES and at the time of the survey, at least 1 year postoperatively. RESULTS: Of 135 patients contacted, 71 (42 male, 29 female) responded. Post-CES compared to pre-CES, there was higher prevalence and significant intrarespondent deterioration of bowel dysfunction, bladder dysfunction, perception of bladder function, sexual function, effect of back pain on sex life, and activities of daily living/quality of life (p < .0001 for all). Significant differences in individual questions pre-CES versus post-CES were also found. CONCLUSION: We show high prevalence of long-term bowel, bladder, and sexual dysfunction post-CES, with functional and psychosocial consequences. Our results demonstrate the need for preoperative information and subsequent screening and long-term multidisciplinary support for these complications.

Subarachnoid haemorrhage with negative initial neurovascular imaging: a systematic review and meta-analysis.

BACKGROUND: In patients with spontaneous subarachnoid haemorrhage (SAH), a vascular cause for the bleed is not always found on initial investigations. This study aimed to systematically evaluate the delayed investigation strategies and clinical outcomes in these cases, often described as "non-aneurysmal" SAH (naSAH). METHODS: A systematic review was performed in concordance with the PRISMA checklist. Pooled proportions of primary outcome measures were estimated using a random-effects model. RESULTS: Fifty-eight studies were included (4473 patients). The cohort was split into perimesencephalic naSAH (PnaSAH) (49.9%), non-PnaSAH (44.7%) and radiologically negative SAH identified on lumbar puncture (5.4%). The commonest initial vascular imaging modality was digital subtraction angiography. A vascular abnormality was identified during delayed investigation in 3.9% [95% CI 1.9-6.6]. There was no uniform strategy for the timing or modality of delayed investigations. The pooled proportion of a favourable modified Rankin scale outcome (0-2) at 3-6 months following diagnosis was 92.0% [95% CI 86.0-96.5]. Complications included re-bleeding (3.1% [95% CI 1.5-5.2]), hydrocephalus (16.0% [95% CI 11.2-21.4]), vasospasm (9.6% [95% CI 6.5-13.3]) and seizure (3.5% [95% CI 1.7-5.8]). Stratified by bleeding pattern, we demonstrate a higher rate of delayed diagnoses (13.6% [95% CI 7.4-21.3]), lower proportion of favourable functional outcome (87.2% [95% CI 80.1-92.9]) and higher risk of complications for non-PnaSAH patients. CONCLUSION: This study highlights the heterogeneity in delayed investigations and outcomes for patients with naSAH, which may be influenced by the initial pattern of bleeding. Further multi-centre prospective studies are required to clarify optimal tailored management strategies for this heterogeneous group of patients.

Referrers' point of view on the referral process to neurosurgery and opinions on neurosurgeons: a large-scale regional survey in the UK.

OBJECTIVES: There is an increased reliance on online referral systems (ORS) within neurosurgical departments across the UK. Opinions of neurosurgeons on ORS are extensively reported but those of referrers have hardly been sought. Our study aims at ascertaining our referring colleagues' views on our ORS and its impact on patient care, their opinions on neurosurgeons and how to improve our referral process. SETTING: 14 district general hospitals and one teaching hospital. PARTICIPANTS: 641 healthcare professionals across a range of medical and surgical specialties including doctors of all grades, nurses and physiotherapists. Survey responses were obtained by medical students using a smartphone application. RESULTS: Although 92% of respondents were aware of the ORS, 74% would routinely phone the on-call registrar either before or after making referrals online. The majority (44%) believed their call to relate to a life-threatening emergency. 62% of referrers considered the ORS helpful in informing patients' care and 48% had a positive opinion of their interaction with neurosurgical registrars. On ways to improve the ORS, 50% selected email/text confirmation of response sent to referrers and 16% to referring consultants. CONCLUSION: Our results confirm that referrers feel that using our ORS positively impacts patient care but that it remains in need of improvement in order to better suit our colleagues' needs when it comes to managing neurosurgical patients. We feel that the promotion of neurosurgical education and mitigation of the effects of adverse workplace human factors are likely to achieve the common goal of neurosurgeons and referrers alike: a high standard in patient care.

Glucocerebrosidase Mutations in Parkinson Disease.

Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

Safinamide for the treatment of Parkinson's disease.

INTRODUCTION: The major unmet needs in the medical treatment of Parkinson disease (PD) are reduction of motor side effects from dopaminergic drugs, management of non-motor symptoms and disease modification. Areas covered: Motor fluctuations and OFF periods are a significant determinant of quality of life in PD and reducing their duration and severity can significantly improve motor function. This aim may be partly facilitated by the development of effective adjunctive drugs for dopamine replacement. Safinamide (Xadago), which is a first generation anticonvulsant, has pharmacological properties which are of interest in the context of neurodegenerative diseases, leading to research into its potential as an adjunct to levodopa in PD. Expert opinion: Although its mechanism has not been fully defined, safinamide provides enhanced symptom control of motor function in advanced PD and improves quality of life.

Subarachnoid haemorrhage secondary to traumatic intracranial aneurysm of the posterior cerebral circulation: case series and literature review.

BACKGROUND: To identify the clinical features, rebleed risk, timing and method of diagnosis, complications and outcome for subarachnoid haemorrhage (SAH) from traumatic intracranial aneurysm (TICA) of the posterior circulation. Subjects included 26 patients aged 3-54 (mean 24.8). METHODS: Case series and literature search to identify all reported cases. RESULTS: In our series, two of three cases were fatal as a result of rebleed, and one case had a good outcome with no deficit, following prompt diagnosis and embolisation. Our key findings from the literature review were: 30.7 % of patients were age 16 and under; 88 % had an acute drop in consciousness, 46 % in a delayed manner; the mean time to diagnosis was 7.5 days; initial cerebrovascular imaging was normal in 23 %; the rebleed rate was 23 %; 61 % required emergency diversion of cerebrospinal fluid; 11 % developed vasospasm requiring treatment; 19.2 % had deficits that rendered them unable to live independently. The mortality rate was 27 %. CONCLUSIONS: SAH from ruptured posterior circulation TICA is associated with significant morbidity and mortality. A high index of suspicion as well as prompt diagnosis, repeat imaging in selected cases, and treatment of any associated TICA can be crucial to a favourable outcome.

EGFR and EGFRvIII analysis in glioblastoma as therapeutic biomarkers.

INTRODUCTION: EGFR and EGFRvIII analysis is of current interest because of new EGFRvIII vaccine trials opened in the UK. EGFR activation promotes cellular proliferation via activation of MAPK and PI3K-Akt pathways. EGFRvIII is the most common variant resulting from an in-frame deletion of 801bp, leading to constitutively active EGFR. METHOD: 51 glioblastoma samples from a cohort of 50 patients were tested for EGFR amplification by FISH and immunohistochemistry and EGFRvIII expression by reverse-transcriptase PCR (RT-PCR), and immunohistochemistry. EGFR and EGFRvIII expression was compared with Overall Survival in the cohort. RESULTS: Overall 22/51 samples (43%) were positive for EGFR, 16/51 (31%) were positive for EGFRvIII and 13/51 (25%) were positive for both. 9/51 cases (18%) were positive for EGFR alone, and 3/51 (6%) were positive for EGFRvIII alone. Of the EGFR positive cases, 22/51 (43%) were positive by FISH, 24/51 (47%) were positive by IHC and 2/51 (4%) were discrepant between methods (positive by IHC but non-amplified by FISH). Of the EGFRvIII positive cases, 16/51 (31%) were positive by RT-PCR, 17/51 (33%) were positive by IHC and 1/51 (2%) sample was discrepant (positive by IHC but not by RT-PCR). Neither EGFRvIII or EGFR are predictive of overall survival in this cohort. CONCLUSION: In our cohort, 25/51 (49%) of GBM showed EGFR alterations, including 16/51 (31%) with EGFRvIII. There was high concordance between IHC and FISH (96%) and IHC and RT-PCR (98%) as diagnostic methods. Neither EGFR or EGFRvIII is predictive of overall survival in this cohort. These results are key for selecting patients for novel individualised anti-EGFR therapies.

Medication overuse headache - An under-diagnosed problem in shunted idiopathic intracranial hypertension patients.

PURPOSE: Management of headache in a subgroup of shunted idiopathic intracranial hypertension (IIH) patients is a well- described and difficult task. We present our series of shunted IIH patients with medication overuse headache (MOH) and discuss the role of careful pain management in this group of patients. MATERIALS AND METHODS: A retrospective review of shunted IIH patients with headache, who had their shunt function assessed by monitoring their intracranial pressure and were subsequently diagnosed with MOH. RESULTS: A total of 15 patients were identified. The mean time between the diagnosis of IIH and the diagnosis of medication overuse headache was 6 years (standard deviation 4.9, range 2-18 years). The majority of patients in this group (12/15) had undergone multiple shunt revisions. CONCLUSIONS: Medication overuse headache in shunted IIH patients can lead to the requirement of hospital admission, investigations and procedures. We suggest that opiates and non-steroidal anti-inflammatory analgesics (NSAIDs) are used for a specified duration post-operatively and reviewed regularly. We suggest that patients are counselled regarding medication overuse headache in a multidisciplinary setting.

Pediatric medulloblastoma - update on molecular classification driving targeted therapies.

As advances in the molecular and genetic profiling of pediatric medulloblastoma evolve, associations with prognosis and treatment are found (prognostic and predictive biomarkers) and research is directed at molecular therapies. Medulloblastoma typically affects young patients, where the implications of any treatment on the developing brain must be carefully considered. The aim of this article is to provide a clear comprehensible update on the role molecular profiling and subgroups in pediatric medulloblastoma as it is likely to contribute significantly toward prognostication. Knowledge of this classification is of particular interest because there are new molecular therapies targeting the Shh subgroup of medulloblastomas.

Role of barbiturate coma in the management of focally induced, severe cerebral edema in children.

Barbiturates are widely used in the management of high intracranial pressure (ICP) caused by diffuse brain swelling. The cardiovascular, renal, and immunological side effects of these drugs limit them to last-line therapy. There are few published data regarding the role of barbiturates in focal brain lesions causing refractory elevated ICP and intraoperative brain swelling in the pediatric population. The authors here present 3 cases of nontraumatic, focally induced, refractory intracranial hypertension due to 2 tumors and 1 arteriovenous malformation, in which barbiturate therapy was used successfully to control elevated ICP. They focus on cardiovascular, renal, and immune function during the course of pentobarbital therapy. They also discuss the role of pentobarbital-induced hypothermia. From this short case series, they demonstrate that barbiturates in conjunction with standard medical therapy can be used to safely reduce postoperative refractory intracranial hypertension and intraoperative brain swelling in children with focal brain lesions.

Timing of deep brain stimulation in Parkinson disease: a need for reappraisal?

We review the current application of deep brain stimulation (DBS) in Parkinson disease (PD) and consider the evidence that earlier use of DBS confers long-term symptomatic benefit for patients compared to best medical therapy. Electronic searches were performed of PubMed, Web of Knowledge, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials to identify all article types relating to the timing of DBS in PD. Current evidence suggests that DBS is typically performed in late stage PD, a mean of 14 to 15 years after diagnosis. Current guidelines recommend that PD patients who are resistant to medical therapies, have significant medication side effects and lengthening off periods, but are otherwise cognitively intact and medically fit for surgery be considered for DBS. If these criteria are rigidly interpreted, it may be that, by the time medical treatment options have been exhausted, the disease has progressed to the point that the patient may no longer be fit for neurosurgical intervention. From the evidence available, we conclude that surgical management of PD alone or in combination with medical therapy results in greater improvement of motor symptoms and quality of life than medical treatment alone. There is evidence to support the use of DBS in less advanced PD and that it may be appropriate for earlier stages of the disease than for which it is currently used. The improving short and long-term safety profile of DBS makes early application a realistic possibility.

Transplacental passage of metal ions in women with hip resurfacing: no teratogenic effects observed.

Over recent years, hip resurfacing has been performed in young, active patients, including women in their child bearing years. Current work investigating the transplacental passage of metal ions (cobalt and chromium) suggests significant passage of ions across the placenta in mothers with metal on metal hip resurfacing. In vitro studies show that cobalt and chromium can create DNA and chromosome damage in human cells. The consequences of this ion transfer on the child during fetal development and thereafter have not been fully quantified. We report on 3 patients with metal on metal hip resurfacings who had the prosthesis in situ during pregnancy. Our data show that umbilical cord blood chromium levels are under a quarter of the maternal serum levels. Cord blood cobalt levels are approximately half that of maternal blood. All 3 children are healthy. Although there was transplacental passage of ions, there was no significant effect on the child in these cases. We did not show any teratogenic effect of metal ions on the child, and this is consistent with the reported literature.

Chiari malformation type I: related conditions.

Chiari malformation type I (CMI) is a morphological diagnosis defined as the inferior displacement of the cerebellum through the foramen magnum. In parallel to this basic definition of CMI, there are diagnoses that co-exist with CMI in selected patients. In addition, there are specific constellations of clinical symptoms and signs reported in the literature that occur non-randomly in patients affected by CMI. There is no established system that categorizes these CMI-related conditions or even defines them as causes or consequences of CMI. Identifying the relationship between CMI and these associated disorders may allow greater understanding of CMI etiology and potentially inform CMI management.

Chordoid glioma: ten years of a low-grade tumor with high morbidity.

We report two new cases of chordoid glioma of the third ventricle and review all previously published cases of this rare tumor with regard to presentation, optimum management, and outcome. Two new cases are reported with the radiological and histopathologic findings. We searched and cross-referenced PubMed and published reports of this tumor to retrieve an additional 51 cases of this tumor, which were then analyzed according to a proforma. Chordoid glioma has consistent radiological features, although some atypical elements including a cystic component are well described. The insidious presentation and morbidity of attempted surgical resection combine to give high overall morbidity. There is a high incidence of postoperative thromboembolic disturbance. Adjuvant radiosurgery has a promising role. The morbidity of this condition is likely to remain high but may be minimized by a less aggressive surgical approach together with surveillance and early use of radiosurgery.