Challenges in the Australasian neurosurgery training program: who should be trained and where should they train?

OBJECTIVE: Neurosurgical training poses particular challenges in Australia and New Zealand, given the large landmass, small population, and widely separated, often small, neurosurgical units. Such factors have necessitated a move away from autonomous, single-institution-based training to the selection of trainees by a centralized binational process. The success of this system is based on rigorous standardized evaluation of candidates' academic achievements, anatomical knowledge, references, and interview performance. Similarly, the accreditation of hospitals to train successful candidates has been standardized. The authors review the evolution of trainee selection and the accreditation of training posts in Australia and New Zealand. METHODS: The records of the Neurosurgical Society of Australasia Surgical Education and Training Board were reviewed for documents pertaining to the selection of neurosurgical trainees and the accreditation of training posts. Application records and referee scores from 2014 to the present were reviewed to encompass process changes, in particular the change from written referee reports to standardized interviews of referees. Surgical logbook case numbers for 23 trainees completing training in 2016, 2017, and 2018 were collated and presented in an aggregated, de-identified form as a measure of adherence to accreditation standards. Written evaluations of the training experience were also sought from two trainees reflecting on the selection process, the quality of training posts, and training limitations. RESULTS: While a time-consuming process, the method of obtaining referee reports by interview has resulted in a wider spread of scores, more able to separate high- and low-scoring applicants than other components of the selection process. Review of the training post accreditation records for the last 2 years showed that adherence to standards has resulted in loss of accreditation for one unit and shortened periods of review for units with more minor deficiencies. Two applications for accreditation have been denied. Examination of caseload data showed that trainees more than fulfill minimum requirements in accredited training posts, confirming the robust nature of this aspect of unit accreditation. CONCLUSIONS: A key factor determining the success of neurosurgical training in Australia and New Zealand has been a willingness to evolve selection and other processes to overcome challenges as they become apparent. According to available analyses, the revised referee process and strict accreditation standards appear effective. The benefits and challenges of the current training system are discussed in the context of a paucity of international literature.

Idiopathic granulomatous hypophysitis: a systematic review of 82 cases in the literature.

Idiopathic granulomatous hypophysitis (IGH) is a rare inflammatory disease of the pituitary. There is debate in the scientific literature as to whether IGH represents a continuum of disease with lymphocytic hypophysitis or has a distinct pathogenesis. Due to the rare nature of the disease, previous descriptions have been limited to single case reports or small series. In the present study, a systematic review of the literature was performed for cases of IGH. 82 cases met inclusion criteria. Data was gathered on IGH clinical aspects, in order to elucidate any associations useful in determining pathogenesis, appropriate clinical treatment, or prognosis. Univariate and multivariate analysis was performed on available data. Female sex was significantly associated with IGH (p < 0.0001). Fever (p = 0.002), nausea or vomiting at presentation (p = 0.031), and histological evidence of necrosis (p = 0.022) correlated with reduced time to presentation. Panhypopituitarism at presentation predicted need for long term hormone replacement (p = 0.014). Hyperprolactinaemia (p = 0.032), normal gonadal (p = 0.037) and thyroid axes (p = 0.001) were associated with reduced likelihood of long-term hormone replacement. Anorexia (p = 0.017), cold intolerance (p = 0.046), and fatigue (p = 0.0033) were associated with death from IGH. Patients who had excisional surgery alone trended towards increased rates of symptom resolution, compared with patients who received corticosteroids as an adjunct to excisional surgery (p = 0.11). This article details the first systematic review of IGH, and presents evidence for a female predilection of the disease. Implications for pathogenesis, and a suggested clinical approach are discussed. An online disease registry has been established to facilitate further IGH research.

A systematic review of cognitive interventions for adult patients with brain tumours.

BACKGROUND: Neurocognitive impairments are common in patients with current or previously treated brain tumours, and such impairments can negatively affect patient outcomes including quality of life and survival. This systematic review aimed to identify and describe interventions used to ameliorate (improve) or prevent cognitive impairments in adults with brain tumours. METHODS: We performed a literature search of the Ovid MEDLINE, PsychINFO and PsycTESTS databases from commencement until September 2021. RESULTS: In total, 9998 articles were identified by the search strategy; an additional 14 articles were identified through other sources. Of these, 35 randomised and nonrandomised studies were deemed to meet the inclusion/exclusion criteria of our review and were subsequently included for evaluation. A range of interventions were associated with positive effects on cognition, including pharmacological agents such as memantine, donepezil, methylphenidate, modafinil, ginkgo biloba and shenqi fuzheng, and nonpharmacological interventions such as general and cognitive rehabilitation, working memory training, Goal Management Training, aerobic exercise, virtual reality training combined with computer-assisted cognitive rehabilitation, hyperbaric oxygen therapy and semantic strategy training. However, most identified studies had a number of methodological limitations and were judged to be at moderate-to-high risk of bias. In addition, it remains unclear whether and to what extent the identified interventions lead to durable cognitive benefits after cessation of the intervention. CONCLUSION: The 35 studies identified in this systematic review have indicated potential cognitive benefits for a number of pharmacological and nonpharmacological interventions in patients with brain tumours. Study limitations were identified and further studies should focus on improved study reporting, methods to reduce bias and minimise participant drop-out and withdrawal where possible, and consider standardisation of methods and interventions across studies. Greater collaboration between centres could result in larger studies with standardised methods and outcome measures, and should be a focus of future research in the field.

Kala-azar: the world's guilty secret.

The clinic of the Sudan Medical Relief Project (www.sudanmedicalrelief.org) is in Old Fangak, in what is now the Republic of South Sudan. In 2010, I spent 7 weeks working there with an American medical team, before being evacuated owing to increasing violence in the area.

Influences on cognitive outcomes in adult patients with gliomas: A systematic review.

People with brain tumors, including those previously treated, are commonly affected by a range of neurocognitive impairments involving executive function, memory, attention, and social/emotional functioning. Several factors are postulated to underlie this relationship, but evidence relating to many of these factors is conflicting and does not fully explain the variation in cognitive outcomes seen in the literature and in clinical practice. To address this, we performed a systematic literature review to identify and describe the range of factors that can influence cognitive outcomes in adult patients with gliomas. A literature search was performed of Ovid MEDLINE, PsychINFO, and PsycTESTS from commencement until September 2021. Of 9,998 articles identified through the search strategy, and an additional 39 articles identified through other sources, 142 were included in our review. The results confirmed that multiple factors influence cognitive outcomes in patients with gliomas. The effects of tumor characteristics (including location) and treatments administered are some of the most studied variables but the evidence for these is conflicting, which may be the result of methodological and study population differences. Tumor location and laterality overall appear to influence cognitive outcomes, and detection of such an effect is contingent upon administration of appropriate cognitive tests. Surgery appears to have an overall initial deleterious effect on cognition with a recovery in most cases over several months. A large body of evidence supports the adverse effects of radiotherapy on cognition, but the role of chemotherapy is less clear. To contrast, baseline cognitive status appears to be a consistent factor that influences cognitive outcomes, with worse baseline cognition at diagnosis/pre-treatment correlated with worse long-term outcomes. Similarly, much evidence indicates that anti-epileptic drugs have a negative effect on cognition and genetics also appear to have a role. Evidence regarding the effect of age on cognitive outcomes in glioma patients is conflicting, and there is insufficient evidence for gender and fatigue. Cognitive reserve, brain reserve, socioeconomic status, and several other variables discussed in this review, and their influence on cognition and recovery, have not been well-studied in the context of gliomas and are areas for focus in future research. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42017072976.

Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice.

Adenosine diphosphate ribosylation (ADP-ribosylation; ADPr), the addition of ADP-ribose moieties onto proteins and nucleic acids, is a highly conserved modification involved in a wide range of cellular functions, from viral defence, DNA damage response (DDR), metabolism, carcinogenesis and neurobiology. Here we study MACROD1 and MACROD2 (mono-ADP-ribosylhydrolases 1 and 2), two of the least well-understood ADPr-mono-hydrolases. MACROD1 has been reported to be largely localized to the mitochondria, while the MACROD2 genomic locus has been associated with various neurological conditions such as autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia; yet the potential significance of disrupting these proteins in the context of mammalian behaviour is unknown. Therefore, here we analysed both Macrod1 and Macrod2 gene knockout (KO) mouse models in a battery of well-defined, spontaneous behavioural testing paradigms. Loss of Macrod1 resulted in a female-specific motor-coordination defect, whereas Macrod2 disruption was associated with hyperactivity that became more pronounced with age, in combination with a bradykinesia-like gait. These data reveal new insights into the importance of ADPr-mono-hydrolases in aspects of behaviour associated with both mitochondrial and neuropsychiatric disorders.

Impairment of Macroautophagy in Dopamine Neurons Has Opposing Effects on Parkinsonian Pathology and Behavior.

Parkinson's disease (PD) is characterized by the death of dopamine neurons in the substantia nigra pars compacta (SNc) and accumulation of α-synuclein. Impaired autophagy has been implicated and activation of autophagy proposed as a treatment strategy. We generate a human α-synuclein-expressing mouse model of PD with macroautophagic failure in dopamine neurons to understand the interaction between impaired macroautophagy and α-synuclein. We find that impaired macroautophagy generates p62-positive inclusions and progressive neuron loss in the SNc. Despite this parkinsonian pathology, motor phenotypes accompanying human α-synuclein overexpression actually improve with impaired macroautophagy. Real-time fast-scan cyclic voltammetry reveals that macroautophagy impairment in dopamine neurons increases evoked extracellular concentrations of dopamine, reduces dopamine uptake, and relieves paired-stimulus depression. Our findings show that impaired macroautophagy paradoxically enhances dopamine neurotransmission, improving movement while worsening pathology, suggesting that changes to dopamine synapse function compensate for and conceal the underlying PD pathogenesis, with implications for therapies that target autophagy.

Preclinical development of a vaccine against oligomeric alpha-synuclein based on virus-like particles.

Parkinson's disease (PD) is a progressive and currently incurable neurological disorder characterised by the loss of midbrain dopaminergic neurons and the accumulation of aggregated alpha-synuclein (a-syn). Oligomeric a-syn is proposed to play a central role in spreading protein aggregation in the brain with associated cellular toxicity contributing to a progressive neurological decline. For this reason, a-syn oligomers have attracted interest as therapeutic targets for neurodegenerative conditions such as PD and other alpha-synucleinopathies. In addition to strategies using small molecules, neutralisation of the toxic oligomers by antibodies represents an attractive and highly specific strategy for reducing disease progression. Emerging active immunisation approaches using vaccines are already being trialled to induce such antibodies. Here we propose a novel vaccine based on the RNA bacteriophage (Qbeta) virus-like particle conjugated with short peptides of human a-syn. High titres of antibodies were successfully and safely generated in wild-type and human a-syn over-expressing (SNCA-OVX) transgenic mice following vaccination. Antibodies from vaccine candidates targeting the C-terminal regions of a-syn were able to recognise Lewy bodies, the hallmark aggregates in human PD brains. Furthermore, antibodies specifically targeted oligomeric and aggregated a-syn as they exhibited 100 times greater affinity for oligomeric species over monomer a-syn proteins in solution. In the SNCA-OVX transgenic mice used, vaccination was, however, unable to confer significant changes to oligomeric a-syn bioburden. Similarly, there was no discernible effect of vaccine treatment on behavioural phenotype as compared to control groups. Thus, antibodies specific for oligomeric a-syn induced by vaccination were unable to treat symptoms of PD in this particular mouse model.

Meta-Analysis of Anxiety as a Risk Factor for Cardiovascular Disease.

Whether anxiety is a risk factor for a range of cardiovascular diseases is unclear. We aimed to determine the association between anxiety and a range of cardiovascular diseases. MEDLINE and EMBASE were searched for cohort studies that included participants with and without anxiety, including subjects with anxiety, worry, posttraumatic stress disorder, phobic anxiety, and panic disorder. We examined the association of anxiety with cardiovascular mortality, major cardiovascular events (defined as the composite of cardiovascular death, stroke, coronary heart disease, and heart failure), stroke, coronary heart disease, heart failure, and atrial fibrillation. We identified 46 cohort studies containing 2,017,276 participants and 222,253 subjects with anxiety. Anxiety was associated with a significantly elevated risk of cardiovascular mortality (relative risk [RR] 1.41, CI 1.13 to 1.76), coronary heart disease (RR 1.41, CI 1.23 to 1.61), stroke (RR 1.71, CI 1.18 to 2.50), and heart failure (RR 1.35, CI 1.11 to 1.64). Anxiety was not significantly associated with major cardiovascular events or atrial fibrillation although CIs were wide. Phobic anxiety was associated with a higher risk of coronary heart disease than other anxiety disorders, and posttraumatic stress disorder was associated with a higher risk of stroke. Results were broadly consistent in sensitivity analyses. Anxiety disorders are associated with an elevated risk of a range of different cardiovascular events, including stroke, coronary heart disease, heart failure, and cardiovascular death. Whether these associations are causal is unclear.

Impaired intracellular trafficking defines early Parkinson's disease.

Parkinson's disease (PD) is an insidious and incurable neurodegenerative disease, and represents a significant cost to individuals, carers, and ageing societies. It is defined at post-mortem by the loss of dopamine neurons in the substantia nigra together with the presence of Lewy bodies and Lewy neurites. We examine here the role of α-synuclein and other cellular transport proteins implicated in PD and how their aberrant activity may be compounded by the unique anatomy of the dopaminergic neuron. This review uses multiple lines of evidence from genetic studies, human tissue, induced pluripotent stem cells, and refined animal models to argue that prodromal PD can be defined as a disease of impaired intracellular trafficking. Dysfunction of the dopaminergic synapse heralds trafficking impairment.

Successful treatment of negative pressure hydrocephalus using timely titrated external ventricular drainage: a case series.

OBJECTIVE: Negative-pressure hydrocephalus (NegPH) is a rare clinical entity characterised by enlarged ventricles and symptoms consistent with increased intracranial pressure (ICP) in the setting of negative ICP. Little has been published regarding appropriate treatment and outcomes of negative-pressure hydrocephalus patients, and no data have been published demonstrating successful therapy producing acceptable long-term outcomes. Here we present 8 cases successfully treated by titrated external ventricular drainage (TEVD), including drainage at negative (subatmospheric) pressure, and subsequent low-pressure ventriculoperitoneal shunting. METHODS: A retrospective audit of all cases of negative-pressure hydrocephalus occurring at a university teaching hospital between 2006 and 2012 was undertaken. The clinical features of these cases, results of radiological investigations, treatment, and outcome were drawn from the patients' records. RESULTS: Eight cases of NegPH were identified. All patients had at least one preceding intracranial procedure (mean number of procedures 3.0). All cases were treated using TEVD, titrated to produce between 5 and 15 mL per hour of CSF drainage, including drainage under subatmospheric pressure if this was required to maintain CSF flow. Mean delay from first negative ICP to TEVD was 1.8 days. All 8 patients demonstrated clinical improvement. TEVD resulted in improvement in Glasgow Coma Scale (mean increase 4.6, p=0.003), and increases in ICP (mean increase 8.5, p<0.001). Mean length of follow-up was 471.8 days. At follow-up, four patients had returned to pre-morbid functioning, three had a reduction in functioning attributable to their initial presentation (not NegPH), and one had died of unknown cause. Illustrative case descriptions are included. CONCLUSIONS: Negative-pressure hydrocephalus is a rare but underrecognised syndrome that can be successfully treated by timely external ventricular drainage titrated to maintain CSF flow, and subsequent low-pressure ventriculoperitoneal shunting.