The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination.

The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated demyelination, as occurs in multiple sclerosis. However, remyelination-the regeneration of myelin sheaths-also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that the inflammatory response during CNS remyelination in mice is modulated by antibiotic or probiotic treatment, as well as in germ-free mice. We also explore the effect of these changes on oligodendrocyte progenitor cell differentiation, which is inhibited by antibiotics but unaffected by our other interventions. These results reveal that high combined doses of oral antibiotics impair oligodendrocyte progenitor cell responses during remyelination and further our understanding of how mammalian regeneration relates to the microbiota.

Correction to: Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.

The article Niacin­mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system, written by Khalil S. Rawji, Adam M.H. Young, Tanay Ghosh, Nathan J. Michaels, Reza Mirzaei, Janson Kappen, Kathleen L. Kolehmainen, Nima Alaeiilkhchi, Brian Lozinski, Manoj K. Mishra, Annie Pu, Weiwen Tang, Salma Zein, Deepak K. Kaushik, Michael B. Keough, Jason R. Plemel, Fiona Calvert, Andrew J. Knights, Daniel J. Gaffney, Wolfram Tetzlaff, Robin J. M. Franklin and V. Wee Yong, was originally published electronically on the publisher's internet.

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.

Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.

Correction: Modelling outcomes after paediatric brain injury with admission laboratory values: a machine-learning approach.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Modelling outcomes after paediatric brain injury with admission laboratory values: a machine-learning approach.

BACKGROUND: Severe traumatic brain injury (TBI) is a leading cause of mortality in children, but the accurate prediction of outcomes at the point of admission remains very challenging. Admission laboratory results are a promising potential source of prognostic data, but have not been widely explored in paediatric cohorts. Herein, we use machine-learning methods to analyse 14 different serum parameters together and develop a prognostic model to predict 6-month outcomes in children with severe TBI. METHODS: A retrospective review of patients admitted to Cambridge University Hospital's Paediatric Intensive Care Unit between 2009 and 2013 with a TBI. The data for 14 admission serum parameters were recorded. Logistic regression and a support vector machine (SVM) were trained with these data against dichotimised outcomes from the recorded 6-month Glasgow Outcome Scale. RESULTS: Ninety-four patients were identified. Admission levels of lactate, H+, and glucose were identified as being the most informative of 6-month outcomes. Four different models were produced. The SVM using just the three most informative parameters was the best able to predict favourable outcomes at 6 months (sensitivity = 80%, specificity = 99%). CONCLUSIONS: Our results demonstrate the potential for highly accurate outcome prediction after severe paediatric TBI using admission laboratory data.

Multimodality neuromonitoring in severe pediatric traumatic brain injury.

Each year, the annual hospitalization rates of traumatic brain injury (TBI) in children in the United States are 57.7 per 100K in the <5 years of age and 23.1 per 100K in the 5-14 years age group. Despite this, little is known about the pathophysiology of TBI in children and how to manage it most effectively. Historically, TBI management has been guided by clinical examination. This has been assisted progressively by clinical imaging, intracranial pressure (ICP) monitoring, and finally a software that can calculate optimal brain physiology. Multimodality monitoring affords clinicians an early indication of secondary insults to the recovering brain including raised ICP and decreased cerebral perfusion pressure. From variables such as ICP and arterial blood pressure, correlations can be drawn to determine parameters of cerebral autoregulation (pressure reactivity index) and "optimal cerebral perfusion pressure" at which the vasculature is most reactive. More recently, significant advances using both direct and near-infrared spectroscopy-derived brain oxygenation plus cerebral microdialysis to drive management have been described. Here in, we provide a perspective on the state-of-the-art techniques recently implemented in clinical practice for pediatric TBI.

Pre-hospital Predictors of Impaired ICP Trends in Continuous Monitoring of Paediatric Traumatic Brain Injury Patients.

OBJECTIVE: Although secondary insults such as raised intracranial pressure (ICP) or cardiovascular compromise strongly contribute to morbidity, a growing interest can be noticed in how the pre-hospital management can affect outcomes after traumatic brain injury (TBI). The objective of this study was to determine whether pre-hospital co-morbidity has influence on patterns of continuously measured waveforms of intracranial physiology after paediatric TBI. MATERIALS AND METHODS: Thirty-nine patients (mean age, 10 years; range, 0.5-15) admitted between 2002 and 2015 were used for the current analysis. Pre-hospital motor score, pupil reactivity, pre-hospital hypoxia (SpO2 < 90%) and hypotension (mean arterial pressure < 70 mmHg) were documented. ICP and arterial blood pressure (ABP) were monitored continuously with an intraparenchymal microtransducer and an indwelling arterial line. Pressure monitors were connected to bedside computers running ICM+ software. Pressure reactivity was determined as the moving correlation between 30 10-s averages of ABP and ICP (PRx). The mean ICP and PRx were calculated for the whole monitoring period for each patient. RESULTS: Those with pre-hospital hypotension were susceptible to higher ICP [20 (IQR 8) vs 13 (IQR 6) mmHg; p = 0.01] and more frequent ICP plateau waves [median = 0 (IQR 1), median = 4 (IQR 9); p = 0.001], despite having similar MAP, CPP and PRx during monitoring. Those with unreactive pupils tended to have higher ICP than those with reactive pupils (18 vs 14 mmHg, p = 0.08). Pre-hospital hypoxia, motor score and pupillary reactivity were not related to subsequent monitored intracranial or systemic physiology. CONCLUSION: In paediatric TBI, pre-hospital hypotension is associated with increased ICP in the intensive care unit.

Computed Tomography Indicators of Deranged Intracranial Physiology in Paediatric Traumatic Brain Injury.

OBJECTIVE: Computed tomography (CT) of the brain can allow rapid assessment of intracranial pathology after traumatic brain injury (TBI). Frequently in paediatric TBI, CT imaging can fail to display the classical features of severe brain injury with raised intracranial pressure. The objective of this study was to determine early CT brain features that influence intracranial or systemic physiological trends following paediatric TBI. MATERIALS AND METHODS: Thirty-three patients (mean age, 10 years; range, 0.5-16) admitted between 2002 and 2015 were used for the current analysis. Presence of petechial haemorrhages, basal cistern compression, subarachnoid blood, midline shift and extra-axial masses on the initial trauma CT head were assessed. ICP and arterial blood pressure (ABP) were then monitored continuously with an intraparenchymal microtransducer and an indwelling arterial line. Pressure monitors were connected to bedside computers running ICM+ software. Pressure reactivity was determined as the moving correlation between 30, 10-s averages of ABP and ICP (PRx). The mean ICP, ABP, cerebral perfusion pressure (CPP; ABP minus ICP) and PRx were calculated for the whole monitoring period for each patient. RESULTS: The presence of subarachnoid blood was related to higher ICP, higher ABP and a trend toward higher PRx. Smaller basal cisterns were related to increased ICP (R = -0.42, p = 0.02), impaired PRx (R = -0.5, p = 0.003). The presence of an extra-axial mass was associated with deranged PRx (-0.02 vs. 0.41, p = 0.003) and a trend toward higher ICP (14 vs. 40, p = 0.07). Interestingly the degree of midline shift was not related to ICP or PRx. CONCLUSIONS: The size of the basal cisterns, the presence of subarachnoid blood or an extra-axial mass are all related to disturbed ICP and pressure reactivity in this paediatric TBI cohort. Patients with these features are ideal candidates for invasive multimodal monitoring.

Predictors of early progression of surgically treated atypical meningiomas.

BACKGROUND: Clinical behaviour of atypical meningiomas is not uniform. While, as a group, they exhibit a high recurrence rate, some pursue a more benign course, whereas others progress early. We aim to investigate the imaging and pathological factors that predict risk of early tumour progression and to determine whether early progression is related to outcome. METHODS: Adult patients with WHO grade II meningioma treated in three regional referral centres between 2007 and 2014 were included. MRI and pathology characteristics were assessed. Gross total resection (GTR) was defined as Simpson 1-3. Recurrence was classified into early and late (≤ 24 vs. > 24 months). RESULTS: Among the 220 cases, 37 (16.8%) patients progressed within 24 months of operation. Independent predictors of early progression were subtotal resection (STR) (p = 0.005), parafalcine/parasagittal location (p = 0.015), peritumoural oedema (p = 0.027) and mitotic index (MI) > 7 (p = 0.007). Adjuvant radiotherapy was negatively associated with early recurrence (p = 0.046). Thirty-two per cent of patients with residual tumour and 26% after GTR received adjuvant radiotherapy. There was a significantly lower proportion of favourable outcomes at last follow-up (mRS 0-1) in patients with early recurrence (p = 0.001). CONCLUSIONS: Atypical meningiomas are a heterogeneous group of tumours with 16.8% patients having recurrence within 24 months of surgery. Residual tumour, parafalcine/parasagittal location, peritumoural oedema and a MI > 7 were all independently associated with early recurrence. As administration of adjuvant radiotherapy was not protocolised in this cohort, any conclusions about benefits of irradiation of WHO grade II meningiomas should be viewed with caution. Patients with early recurrence had worse neurological outcome. While histological and imaging characteristics provide some prognostic value, further molecular characterisation of atypical meningiomas is warranted to aid clinical decision making.

Probable Catastrophic Antiphospholipid Syndrome with Intracerebral Hemorrhage Secondary to Epstein-Barr Viral Infection.

BACKGROUND: Catastrophic antiphospholipid syndrome (CAPS) is a rare, severe variant of antiphospholipid syndrome with a high mortality rate. We report a unique case of CAPS secondary to Epstein-Barr viral (EBV) infection complicated by pulmonary and intracerebral hemorrhage. A review of the CAPS literature relevant to intensive care practice is used to outline a rational approach to diagnosis and management. METHODS: All data are from a single patient admitted to the Neurosciences Critical Care Unit in Addenbrooke's Hospital, Cambridge, in March 2016. Medline, Web of Science, PubMed, and the Cochrane Library were searched through September 2016 without restrictions for cases of CAPS, management of CAPS in the intensive care unit, and hemorrhage complicating CAPS. The patient gave express written consent to access and publish these data. RESULTS: This is only the second reported case of probable CAPS secondary to EBV infection. Furthermore, pulmonary and intracerebral hemorrhage is rare manifestations of this multisystem prothrombotic state which provided unique challenges to the management. CONCLUSIONS: While rare, CAPS should be considered in any patient presenting with rapidly progressive multiorgan failure, evidence of thrombotic microangiopathy, and antiphospholipid antibodies. A high index of suspicion is required as early, aggressive, multimodal treatment with anticoagulation, and immunosuppression improves outcomes.

On the brain structure heterogeneity of autism: Parsing out acquisition site effects with significance-weighted principal component analysis.

Neuroimaging studies have reported structural and physiological differences that could help understand the causes and development of Autism Spectrum Disorder (ASD). Many of them rely on multisite designs, with the recruitment of larger samples increasing statistical power. However, recent large-scale studies have put some findings into question, considering the results to be strongly dependent on the database used, and demonstrating the substantial heterogeneity within this clinically defined category. One major source of variance may be the acquisition of the data in multiple centres. In this work we analysed the differences found in the multisite, multi-modal neuroimaging database from the UK Medical Research Council Autism Imaging Multicentre Study (MRC AIMS) in terms of both diagnosis and acquisition sites. Since the dissimilarities between sites were higher than between diagnostic groups, we developed a technique called Significance Weighted Principal Component Analysis (SWPCA) to reduce the undesired intensity variance due to acquisition site and to increase the statistical power in detecting group differences. After eliminating site-related variance, statistically significant group differences were found, including Broca's area and the temporo-parietal junction. However, discriminative power was not sufficient to classify diagnostic groups, yielding accuracies results close to random. Our work supports recent claims that ASD is a highly heterogeneous condition that is difficult to globally characterize by neuroimaging, and therefore different (and more homogenous) subgroups should be defined to obtain a deeper understanding of ASD. Hum Brain Mapp 38:1208-1223, 2017. © 2016 Wiley Periodicals, Inc.

Correlating optic nerve sheath diameter with opening intracranial pressure in pediatric traumatic brain injury.

INTRODUCTION: The use of clinical markers to predict intracranial pressure (ICP) is desirable as a first-line measure to assist in decision making as to whether invasive monitoring is required. Correlations between ICP and optic nerve sheath diameter (ONSD) using CT and MRI have been observed in adult populations. However, data on this modality in children is less well documented. METHODS: ONSD was measured by independent observers and correlated with opening ICP at insertion of invasive monitoring probes in pediatric traumatic brain injury patients admitted to Addenbrookes Hospital between January 2009 and December 2013. RESULTS: Thirty-six patients with a mean age of 8.2 y were admitted to the Pediatric Intensive Care Unit (PICU) with a traumatic head injury and required invasive neurosurgical monitoring. The median ICP was 18 ± 10 mmHg (median ± IQR), the median right ONSD was 5.6 ± 2.5 mm and the left was 5.9 ± 3.2 mm. The Intraclass correlation between observers was 0.91 (P < 0.0001). The correlation of mean ONSD and max ONSD with ICP was 0.712 (P < 0.0001) and 0.713 (P < 0.0001), respectively. Area under ROC curve for both mean and max ONSD is 0.85 (95% CI: 0.73-0.98). CONCLUSION: Where pediatric patients present with an ONSD of over 6.1 mm following a traumatic brain injury (TBI), ICP monitoring should be implemented.

Advanced monitoring in traumatic brain injury: microdialysis.

PURPOSE OF REVIEW: Here, we review the present state-of-the-art of microdialysis for monitoring patients with severe traumatic brain injury, highlighting the newest developments. Microdialysis has evolved in neurocritical care to become an established bedside monitoring modality that can reveal unique information on brain chemistry. RECENT FINDINGS: A major advance is recent consensus guidelines for microdialysis use and interpretation. Other advances include insight obtained from microdialysis into the complex, interlinked traumatic brain injury disorders of electrophysiological changes, white matter injury, inflammation and metabolism. SUMMARY: Microdialysis has matured into being a standard clinical monitoring modality that takes its place alongside intracranial pressure and brain tissue oxygen tension measurement in specialist neurocritical care centres, as well as being a research tool able to shed light on brain metabolism, inflammation, therapeutic approaches, blood-brain barrier transit and drug effects on downstream targets. Recent consensus on microdialysis monitoring is paving the way for improved neurocritical care protocols. Furthermore, there is scope for future improvements both in terms of the catheters and microdialysate analyser technology, which may further enhance its applicability.

Autoregulation in paediatric TBI-current evidence and implications for treatment.

BACKGROUND: Children who survive acute traumatic brain injury are at risk of death from subsequent brain swelling and secondary injury. Strict physiologic management in the ICU after traumatic brain injury is believed to be key to survival, and cerebral perfusion pressure is a prominent aspect of post brain injury care. However, optimal cerebral perfusion pressure targets for children are not known. Autoregulation monitoring has been used to delineate individualized optimal perfusion pressures for patients with traumatic brain injury. The methods to do so are diverse, confusing, and not universally validated. METHODS: In this manuscript, we discuss the history of autoregulation monitoring, outline and categorize the methods used to measure autoregulation, and review the available validation data for methods used to monitor autoregulation. CONCLUSIONS: Impaired autoregulation after traumatic brain injury is associated with a poor prognosis. Observational data suggests that optimal neurologic outcome and survival are associated with optimal perfusion pressure defined by autoregulation monitoring. No randomized, controlled, interventional data is available to assess autoregulation monitoring after pediatric traumatic brain injury.

Decompressive craniectomy for traumatic intracranial hypertension: application in children.

Traumatic brain injury remains prevalent in children, particularly within the adolescent age group. In severe injury, the priority of treatment is to stabilise the patient initially and prevent the evolution of brain swelling and secondary ischaemia using tiers of medical therapy. The final stage of intervention for such patients is a decompressive craniectomy. Here in, we identify the current evidence for performing decompressive crainectomy in children including the results from the RESCUEicp study.

Increased trends in the use of treatment-limiting decisions in a regional neurosurgical unit.

INTRODUCTION: Treatment-limiting decisions (TLDs) are employed to actively withhold treatment from patients whom clinicians feel would derive no benefit or suffer detrimental effects from further intervention. The use of such decisions has been heavily discussed in the media and clinicians in the past have been reluctant to institute them, even though it is in the best interests of the patients. Their use is influenced by several ethical, religious and social factors all of which have changed significantly over time. This study reports the trends in use of TLDs in a regional neurosurgical unit over 23 years. METHODS: Patient archives were reviewed to identify the number of admissions and procedures performed at the Institute of Neurological Sciences, Glasgow, in the years 1988, 1997 and 2011. Death certificate records were used to identify mortality in the unit in the year 2011. Patient records were used to obtain details of diagnosis, time from admission to death, and the presence and timing of a TLD. RESULTS: The results show an increase in the use of TLDs, with decisions made for 89% of those who died in 2011, compared to 68% in 1997 and 51% in 1988. The number of admissions has increased substantially since 1988 as has the percentage of patients undergoing surgery (46, 67 and 72% in 1988, 1997 and 2011, respectively). CONCLUSION: There is a trending increase in the number of patients who have a TLD in our regional neurosurgical unit. This demonstrates an increased willingness of clinicians to recognise poor prognosis and to withdraw or withhold treatment in these cases. Continued appropriate use of the TLD is recommended but it is to only ever reflect the best interests of the patient.

Multimodal MRI can identify perfusion and metabolic changes in the invasive margin of glioblastomas.

PURPOSE: To use perfusion and magnetic resonance (MR) spectroscopy to compare the diffusion tensor imaging (DTI)-defined invasive and noninvasive regions. Invasion of normal brain is a cardinal feature of glioblastomas (GBM) and a major cause of treatment failure. DTI can identify invasive regions. MATERIALS AND METHODS: In all, 50 GBM patients were imaged preoperatively at 3T with anatomic sequences, DTI, dynamic susceptibility perfusion MR (DSCI), and multivoxel spectroscopy. The DTI and DSCI data were coregistered to the spectroscopy data and regions of interest (ROIs) were made in the invasive (determined by DTI), noninvasive regions, and normal brain. Values of relative cerebral blood volume (rCBV), N-acetyl aspartate (NAA), myoinositol (mI), total choline (Cho), and glutamate + glutamine (Glx) normalized to creatine (Cr) and Cho/NAA were measured at each ROI. RESULTS: Invasive regions showed significant increases in rCBV, suggesting angiogenesis (invasive rCBV 1.64 [95% confidence interval, CI: 1.5-1.76] vs. noninvasive 1.14 [1.09-1.18]; P < 0.001), Cho/Cr (invasive 0.42 [0.38-0.46] vs. noninvasive 0.35 [0.31-0.38]; P = 0.02) and Cho/NAA (invasive 0.54 [0.41-0.68] vs. noninvasive 0.37 [0.29-0.45]; P = < 0.03), suggesting proliferation, and Glx/Cr (invasive 1.54 [1.27-1.82] vs. noninvasive 1.3 [1.13-1.47]; P = 0.028), suggesting glutamate release; and a significantly reduced NAA/Cr (invasive 0.95 [0.85-1.05] vs. noninvasive 1.19 [1.06-1.31]; P = 0.008). The mI/Cr was not different between the three ROIs (invasive 1.2 [0.99-1.41] vs. noninvasive 1.3 [1.14-1.46]; P = 0.68). In the noninvasive regions, the values were not different from normal brain. CONCLUSION: Combining DTI to identify the invasive region with perfusion and spectroscopy, we can identify changes in invasive regions not seen in noninvasive regions.

Medical student perceptions of research and research-orientated careers: An international questionnaire study.

BACKGROUND: Engaging and inspiring the next generation of physician-scientists at an early stage is recognised as key to ensure the future of medical research. However, little is known about medical student perceptions of research. OBJECTIVES: We attempted to ascertain perceptions of research and research-orientated careers from medical students studying in different countries. METHODS: An online questionnaire was developed, piloted, and promoted to medical students in various countries. RESULTS: 1625 responses were collected from 38 countries. Analysis was restricted to data collected from countries with >100 responses (n = 890). Less than half the respondents felt their medical school provided adequate research training. Key perceived barriers to research participation as a student included lack of time and difficulty finding mentors or projects. A significant gender disparity existed in research ambitions of students with females desiring less research involvement. The importance of barriers and satisfaction with research training differed significantly between countries. CONCLUSIONS: Students perceive a number of key barriers to research involvement and pursuit of research-orientated careers. Programmes designed to engage students with research should focus on overcoming identified barriers. Greater effort is needed to engage female students who report more significant barriers and less desire to follow research-orientated careers.

Comparative surgical outcome associated with the management of brain arteriovenous malformation in a regional neurosurgical centre.

OBJECTIVES: Microsurgical resection of brain arteriovenous malformation (AVMs) is challenging, however, expert surgical series from large volume centres, have reported over 95% occlusion rates with 2 to 8% risk of morbidity & mortality. Data from a regional neurosurgical unit was analysed and compared with published series for the purposes of quality control. We also compared our surgical result with other treatment modalities from the whole AVM cohort managed over the same study period. DESIGN: Retrospective analysis of a locally held AVM database. SUBJECTS: Of the 141 AVM patients, 54 (35M, 19F, age range 9-68 years) underwent microsurgical removal of AVM by the senior author, from 2006 to 2012. 27 (19%), 18 (13%), 20 (14%), 22 (16%) had endovascular therapy only, radiosurgery only, combination therapy (endovascular and radiosurgery) and conservative management, respectively. METHODS: Case notes were reviewed to determine clinical and radiological outcomes. Statistical analysis performed using SPSS with p < 0.05 defined as statistical significance. RESULTS: In the surgical series, the Spetzler-Martin (SM) grade distribution was as follows: 17 grade I (32%), 31 grade II (57%), and 6 grade III (11%). 31 patients (57%) presented with intracranial haemorrhage, 12 patients (22%) with seizures. Of the 54 patients, 51 (94%) had angiographically confirmed obliteration of their AVM. Median follow-up for the entire cohort was 7 years. 83% of surgical patients have mRS 0-1, compared to 78%, 67%, 45%, 18% of patients managed by endovascular therapy, radiosurgery, combination therapy, conservative surveillance, respectively (p < 0.0001). However, the groups were not comparable in terms of SM grade or clinical presentation and the numbers in each group were relatively small. Seizure presentations were encountered in 23% (32/141) of the overall patients, and all the surviving patients were on anticonvulsants, except in the surgical arm, 7/12 (58%) patients were off their antiepileptic medications at last follow-up. CONCLUSIONS: The results demonstrate a 94% surgical obliteration rate and 11% long-term neurological deficits for brain AVM patients managed surgically and were comparable to expert series. Achieving acceptable results is possible in lower volume settings, however, patient selection is important and the role of an experienced neurovascular team cannot be overstated.

Interventions for idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) has an estimated incidence of one to three people per 100,000 people per year, and occurs most commonly in obese, young women. IIH is associated with severe morbidity, notably due to a significant threat to sight and severe headache. Several different management options have been proposed. Conservative measures centre on weight loss. Pharmacological therapy includes use of diuretics. Refractory and sight-threatening cases demand surgical intervention, most often in the form of cerebrospinal fluid (CSF) diversion or optic nerve sheath fenestration. Other treatments include venous sinus stenting and bariatric surgery. OBJECTIVES: To assess the effects of any intervention for IIH in any patient group. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015 Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2015), EMBASE (January 1980 to July 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 22 July 2015. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) in which any intervention was compared to placebo, or to another form of treatment, for people with a clinical diagnosis of IIH. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results for trials to be included in the review. We resolved any discrepancies by third party decision. MAIN RESULTS: We identified two completed RCTs (enrolling a total of 211 participants and conducted in the UK and US) and two ongoing trials that met the inclusion criteria. Both completed trials compared acetazolamide to placebo, in conjunction with a weight loss intervention in both groups. Attrition bias was a problem in both trials with high loss to follow-up, in one study this loss to follow-up occurred particularly in the acetazolamide arm. One trial was unmasked and we judged it to be at risk of performance and detection bias.In these studies, change in visual acuity was similar in the treatment and control groups as measured by logMAR acuity. In one study people in the acetalomazide group had a similar change in logMAR acuity compared to the placebo group between baseline and 12 months in the right eye (MD 0.04 logMAR, 95% CI -0.08 to 0.16) and left eye (MD 0.03 logMAR, 95% CI -0.09 to 0.15). In the other study people in the acetalomazide group had a similar change in vision over six months compared with people in the placebo group (mean difference in change in letters read was 0.01 (95% CI -1.45 to 1.46). One study reported no cases of visual loss in 21 people treated with acetalomazide compared to 2/20 cases in the placebo group (odds ratio 0.17, 95% CI 0.01, 3.82).The prespecified outcome for this review was reduction in CSF pressure to normal levels which was not reported by the two trials. One trial reported that, in a subsample of 85 participants who agreed to lumbar puncture at 6 months, people in the acetalomazide group on average had a greater reduction in CSF pressure (MD -59.9 mmH(2)O, 95% CI -96.4, -23.4).In one study, people in the acetalozamide group on average experienced a greater reduction in papilloedema as assessed by fundus photographs MD -0.70 (95% CI -1.00 to -0.40) and by clinical grading MD -0.91 (95% CI -1.27 to -0.54) between baseline and six months in the study eye.Headache was recorded as present/absent in one study at 12 months (OR 0.42, 95% CI 0.12,1.41, 41 participants). Both studies reported headache on visual analogue scales (different ones) but results were inconclusive (MD for change in headache score measured on 10-point visual analogue scale at 12 months was 1.0 (-1.80, 3.70, 41 participants) and MD for change in headache score on a 6 point scale measured at 6 months was -0.45 (-3.5,2.6, number of participants unclear).In one study, a similar proportion of people in the acetalomazide group were in remission (however, the trial authors did not state their definition of this term) at 12 months compared to the placebo group. However, the 95% CIs were wide and there is considerable uncertainty as to the effect (OR 1.13 (95% CI 0.32 to 3.90, 41 participants).In one study of 185 participants, people in the acetalomazide group had an increased risk of decreased CO2, diarrhoea, dysgeusia, fatigue, nausea, paresthesia, tinnitus and vomiting compared to people in the placebo group. In general, the estimates of effect were uncertain with wide 95% CIs. Adverse effects were not reported in the other study.One study reported that quality of life was better in acetazolamide-treated patients based on the visual quality of life (VFQ-25) (MD 6.35, 95% CI 2.22 to 10.47) and the physical (MD 3.02, 95% CI 0.34 to 5.70) and mental (MD 3.45, 95% CI 0.35 to 6.55) components of the 36-Item Short Form Health Survey tool at six months. Costs were not reported in either study.We judged the evidence to be low certainty (GRADE) downgrading for imprecision and risk of bias. AUTHORS' CONCLUSIONS: Although the two included RCTs showed modest benefits for acetazolamide for some outcomes, there is insufficient evidence to recommend or reject the efficacy of this intervention, or any other treatments currently available, for treating people with IIH. Further high-quality RCTs are required in order to adequately assess the effect of acetazolamide therapy in people with IIH.