Assessing clinical progression measures in Alzheimer's disease trials: A systematic review and meta-analysis.

INTRODUCTION: Assessing treatments for Alzheimer's disease (AD) relies on reliable tools for measuring AD progression. In this analysis, we evaluate the sensitivity of clinical progression measures in AD within randomized controlled trials (RCTs) with confirmed positive amyloid (Aß+) status prior to trial enrollment. METHODS: Excluding trials targeting non-cognitive symptoms, we conducted meta-analyses on progression measures from 25 selected RCTs using R version 4.2.0, along with the metafor and emmeans libraries. RESULTS: The Functional Activities Questionnaire (FAQ) demonstrated the greatest sensitivity over 12 weeks. Other cognitive measures demonstrated lower sensitivity. The integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) seemed more effective than their individual cognitive components. Neuropsychiatric measures were the least sensitive in measuring progression. DISCUSSION: Functional measures generally outperformed other measure categories. Purely cognitive domain-based measures were suboptimal for tracking early AD progression. Ideally, future measures should incorporate both cognitive and functional components to enhance sensitivity. HIGHLIGHTS: Concerns remain regarding the limitations of current outcome measures used in AD clinical trials, particularly their sensitivity in the early and preclinical stages of the disease, which hampers their reliability as indicators of AD progression. The Functional Activities Questionnaire (FAQ) demonstrated the most substantial weighted mean change over 12 weeks, followed by the Mini-Mental State Examination (MMSE). Functional measures outperformed other measure categories. Composite scores of integrated Alzheimer's Disease Rating Scale and Clinical Dementia Rating-Sum of Boxes are more sensitive to change than their individual cognitive components, possibly driven by the functional components of the score. Neuropsychiatric measures analyzed in this study appeared to be the least sensitive in measuring progression.

Topiramate is more effective than acetazolamide at lowering intracranial pressure.

BACKGROUND: The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats. METHODS: We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate. RESULTS: At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% ( p = 0.0009) and 21% ( p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% ( p = 0.018), compared to 5% reduction with acetazolamide ( p = >0.999). CONCLUSION: Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest.

Segmentation error in spectral domain optical coherence tomography measures of the retinal nerve fibre layer thickness in idiopathic intracranial hypertension.

BACKGROUND: Optical Coherence Tomography (OCT) imaging is being increasingly used in clinical practice for the monitoring of papilloedema. The aim is to characterise the extent and location of the Retinal Nerve Fibre Layer (RNFL) Thickness automated segmentation error (SegE) by manual refinement, in a cohort of Idiopathic Intracranial Hypertension (IIH) patients with papilloedema and compare this to controls. METHODS: Baseline Spectral Domain OCT (SDOCT) scans from patients with IIH, and controls with no retinal or optic nerve pathology, were examined. The internal limiting membrane and RNFL thickness of the most severely affected eye was examined for SegE and re-segmented. Using ImageJ, the total area of the RNFL thickness was calculated pre and post re-segmentation and the percentage change was determined. The distribution of RNFL thickness error was qualitatively assessed. RESULTS: Significantly greater SegE (p = 0.009) was present in RNFL thickness total area, assessed using ImageJ, in IIH patients (n = 46, 5% ± 0-58%) compared to controls (n = 14, 1% ± 0-6%). This was particularly evident in moderate to severe optic disc swelling (n = 23, 10% ± 0-58%, p < 0.001). RNFL thickness was unable to be quantified using SDOCT in patients with severe papilloedema. CONCLUSIONS: SegE remain a concern for clinicians using SDOCT to monitor papilloedema in IIH, particularly in the assessment of eyes with moderate to severe oedema. Systematic assessment and manual refinement of SegE is therefore important to ensure the accuracy in longitudinal monitoring of patients.

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.

Time interval between primary radiotherapy and salvage laryngectomy: a predictor of pharyngocutaneous fistula formation.

Salvage laryngectomy (SL) is associated with high levels of morbidity. Rates of pharyngocutaneous fistulae (PCF) are as high as 35 % in some series. Patients at highest risk of such complications may be candidates for altered surgical management in terms of additional tissue transfer, or delayed tracheoesophageal puncture. This study investigates the relationship between the time from primary radiotherapy (RT) to salvage surgery and the development of PCF. 26 consecutive patients who underwent SL between 2000 and 2010 were identified from our institutional database. Demographic, staging, treatment and complication data were collected. Subgroup analysis was performed using the Student's t test or Mann-Whitney U test for continuous variables and either Chi-squared test or Fisher's Exact test for categorical variables. 26 patients underwent SL between October 2003 and July 2010. Of these, 15 (58 %) developed a PCF. On analysis of the time between pre-operative RT and surgery, a significant difference was seen, with a mean time of 19.5 months in those who developed a PCF versus 47.0 months in those who did not (p = 0.02). Patient characteristics, treatment, and pathology results were comparable between the two groups. There was no significant difference in distribution of the other covariates between the PCF and non-PCF groups. We reported a high rate of PCF and identified an association between PCF and a short time from primary treatment to salvage surgery. Identifying factors associated with higher rates of post-operative morbidity allows surgeons to adapt surgical planning in an attempt to minimize rates of PCF.

MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Glioblastomas with oligodendroglial component have the same clinical phenotype as classical glioblastomas.

INTRODUCTION: Glioblastomas are the commonest primary brain tumour and are considered one of the most heterogeneous tumour types. The introduction of a glioblastoma with oligodendroglial component (GBM + O) in the latest WHO Classification of Tumours of the Central Nervous System (1) was to help with this. There has been conflicting evidence as to whether this tumour conferred a better prognosis than classical glioblastoma (GBM). The aim of this study was to study the clinical phenotype of these GBM + O tumours and compare it to the classical GBM. MATERIALS AND METHODS: All patients with histological evidence of a glioblastoma between 1st January 2007 and 31st January 2011 were identified from the Neuropathology Database. Clinical and radiological details were obtained for all patients. The overall survival of patients who were treated with chemoradiotherapy was obtained and the GBM + O cohort compared to the classical GBM cohort. RESULTS: Three hundred and ninety-six patients with newly diagnosed glioblastomas were identified: 294 (74.2%) had classical GBM and 102 (25.6%) had GBM + O. The two cohorts presented at a similar age (61.1 years GBM + O vs. 63.2 years GBM; P = 0.09) and were matched for sex and side of the tumour. GBM + O were more likely to be located in the frontal lobes (38.2% for GBM + O vs. 27.2% for GBM: P = 0.04). In the group that was treated with chemoradiotherapy the overall survival was similar (median survival GBM + O 361 days vs. 379 days GBM; Log Rank 0.61, P = 0.43). CONCLUSION: The presence of an oligodendroglial component does not confer any improvement in survival and has a similar clinical phenotype to classical GBMs.

Community consultation in emergency neurosurgical research: lessons from a proposed trial for patients with chronic subdural haematomas.

INTRODUCTION: Chronic subdural haematoma (CSDH) is one of the most common neurosurgical disorders and is especially prevalent in old age. The subdural evacuating port system (SEPS) has emerged in the last few years as a minimally invasive alternative to the standard procedure of burr-hole evacuation. NHS practice is evidence-driven and evidence from high-quality clinical studies is required prior to implementation of any changes. In the UK, the National Research Ethics Service (NRES) advises community consultation prior to starting a clinical trial, where the patient is unlikely to have capacity to consent to enrolment in the trial. To prepare for a trial comparing minimally invasive (SEPS) versus burr-hole evacuation for evacuation of a CSDH, we have designed and undertaken a pre-protocol community consultation survey to examine potential patient participation. MATERIAL(S) AND METHODS: The study population consisted of patients, family members and carers/friends in neurosurgical clinic waiting rooms and wards at Addenbrooke's Hospital, Cambridge, who individually completed a questionnaire (n = 215). RESULTS: Most respondents were willing to participate in the proposed randomised clinical trial (77%; 165/215). Moreover, 80% (171/215) and 74% (159/215) were willing to allow their next of kin and an independent consultant neurosurgeon to give surrogate consent, respectively. CONCLUSION: The results of our pre-protocol community consultation showed that not only would most respondents be willing to participate in the proposed trial, but also would be happy for either next of kin or an independent consultant neurosurgeon to give surrogate consent if they lacked capacity to consent themselves. The advantages of this type of survey are twofold: they increase patient and public involvement in the research process and allow researchers to design study protocols that are acceptable to the community.

The temporal event-based model: Learning event timelines in progressive diseases.

Timelines of events, such as symptom appearance or a change in biomarker value, provide powerful signatures that characterise progressive diseases. Understanding and predicting the timing of events is important for clinical trials targeting individuals early in the disease course when putative treatments are likely to have the strongest effect. However, previous models of disease progression cannot estimate the time between events and provide only an ordering in which they change. Here, we introduce the temporal event-based model (TEBM), a new probabilistic model for inferring timelines of biomarker events from sparse and irregularly sampled datasets. We demonstrate the power of the TEBM in two neurodegenerative conditions: Alzheimer's disease (AD) and Huntington's disease (HD). In both diseases, the TEBM not only recapitulates current understanding of event orderings but also provides unique new ranges of timescales between consecutive events. We reproduce and validate these findings using external datasets in both diseases. We also demonstrate that the TEBM improves over current models; provides unique stratification capabilities; and enriches simulated clinical trials to achieve a power of 80% with less than half the cohort size compared with random selection. The application of the TEBM naturally extends to a wide range of progressive conditions.

Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning.

To better understand the pathological and phenotypic heterogeneity of progressive supranuclear palsy and the links between the two, we applied a novel unsupervised machine learning algorithm (Subtype and Stage Inference) to the largest MRI data set to date of people with clinically diagnosed progressive supranuclear palsy (including progressive supranuclear palsy-Richardson and variant progressive supranuclear palsy syndromes). Our cohort is comprised of 426 progressive supranuclear palsy cases, of which 367 had at least one follow-up scan, and 290 controls. Of the progressive supranuclear palsy cases, 357 were clinically diagnosed with progressive supranuclear palsy-Richardson, 52 with a progressive supranuclear palsy-cortical variant (progressive supranuclear palsy-frontal, progressive supranuclear palsy-speech/language, or progressive supranuclear palsy-corticobasal), and 17 with a progressive supranuclear palsy-subcortical variant (progressive supranuclear palsy-parkinsonism or progressive supranuclear palsy-progressive gait freezing). Subtype and Stage Inference was applied to volumetric MRI features extracted from baseline structural (T1-weighted) MRI scans and then used to subtype and stage follow-up scans. The subtypes and stages at follow-up were used to validate the longitudinal consistency of subtype and stage assignments. We further compared the clinical phenotypes of each subtype to gain insight into the relationship between progressive supranuclear palsy pathology, atrophy patterns, and clinical presentation. The data supported two subtypes, each with a distinct progression of atrophy: a 'subcortical' subtype, in which early atrophy was most prominent in the brainstem, ventral diencephalon, superior cerebellar peduncles, and the dentate nucleus, and a 'cortical' subtype, in which there was early atrophy in the frontal lobes and the insula alongside brainstem atrophy. There was a strong association between clinical diagnosis and the Subtype and Stage Inference subtype with 82% of progressive supranuclear palsy-subcortical cases and 81% of progressive supranuclear palsy-Richardson cases assigned to the subcortical subtype and 82% of progressive supranuclear palsy-cortical cases assigned to the cortical subtype. The increasing stage was associated with worsening clinical scores, whilst the 'subcortical' subtype was associated with worse clinical severity scores compared to the 'cortical subtype' (progressive supranuclear palsy rating scale and Unified Parkinson's Disease Rating Scale). Validation experiments showed that subtype assignment was longitudinally stable (95% of scans were assigned to the same subtype at follow-up) and individual staging was longitudinally consistent with 90% remaining at the same stage or progressing to a later stage at follow-up. In summary, we applied Subtype and Stage Inference to structural MRI data and empirically identified two distinct subtypes of spatiotemporal atrophy in progressive supranuclear palsy. These image-based subtypes were differentially enriched for progressive supranuclear palsy clinical syndromes and showed different clinical characteristics. Being able to accurately subtype and stage progressive supranuclear palsy patients at baseline has important implications for screening patients on entry to clinical trials, as well as tracking disease progression.

The IPDGC/GP2 Hackathon - an open science event for training in data science, genomics, and collaboration using Parkinson's disease data.

Open science and collaboration are necessary to facilitate the advancement of Parkinson's disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD.

Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease.

Background: Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD. Methods: We established the Pick's disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521). Findings: Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65). Interpretation: The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.

Prognostic categories for amyotrophic lateral sclerosis.

Our objective was to generate a prognostic classification method for amyotrophic lateral sclerosis (ALS) from a prognostic model built using clinical variables from a population register. We carried out a retrospective multivariate analysis of 713 patients with ALS over a 20-year period from the South-East England Amyotrophic Lateral Sclerosis (SEALS) population register. Patients were randomly allocated to 'discovery' or 'test' cohorts. A prognostic score was calculated using the discovery cohort and then used to predict survival in the test cohort. The score was used as a predictor variable to split the test cohort in four prognostic categories (good, moderate, average, poor). The accuracy of the score in predicting survival was tested by checking whether the predicted survival fell within the actual survival tertile which that patient was in. A prognostic score generated from one cohort of patients predicted survival for a second cohort of patients (r(2) = 0.72). Six variables were included in the survival model: age at onset, diagnostic delay, El Escorial category, use of riluzole, gender and site of onset. Cox regression demonstrated a strong relationship between these variables and survival (χ(2) 80.8, df 1, p < 0.0001, n = 343) in the test cohort. Kaplan-Meier analysis demonstrated a significant difference in survival between clinical categories (log rank 161.932, df 3, p < 0.001), and the prognostic score generated for the test cohort accurately predicted survival in 64% of the patients. In conclusion, it is possible to correctly classify patients into prognostic categories using clinical data easily available at time of diagnosis.

Glutamate Receptor Antibodies in Autoimmune Central Nervous System Disease: Basic Mechanisms, Clinical Features, and Antibody Detection.

Immune-mediated inflammation of the brain has been recognized for more than 50 years, although the initial descriptions were mainly thought to be secondary to an underlying neoplasm. Some of these paraneoplastic encephalitides express serum antibodies, but these were not thought to be pathogenic but instead have a T-cell-mediated pathophysiology. Over the last two decades, several pathogenic antibodies against neuronal surface antigens have been described in autoimmune encephalitis, which are amenable to immunotherapy. Several of these antibodies are directed against glutamate receptors (GluRs). NMDAR encephalitis (NMDARE) is the most common of these antibodies, and patients often present with psychosis, hallucinations, and reduced consciousness. Patients often progress on to develop confusion, seizures, movement disorders, autonomic instability, and respiratory depression. Although initially described as exclusively occurring secondary to ovarian teratoma (and later other tumors), non-paraneoplastic forms are increasingly common, and other triggers like viral infections are now well recognized. AMPAR encephalitis is relatively less common than NMDARE but is more likely to paraneoplastic. AMPAR antibodies typically cause limbic encephalitis, with patients presenting with confusion, disorientation, memory loss, and often seizures. The syndromes associated with the metabotropic receptor antibodies are much rarer and often can be paraneoplastic-mGluR1 (cerebellar degeneration) and mGluR5 (Ophelia syndrome) being the ones described in literature.With the advance in molecular biology techniques, it is now possible to detect these antibodies using cell-based assays with high sensitivity and specificity, especially when coupled with brain tissue immunohistochemistry and binding to live cell-based neurons. The rapid and reliable identification of these antibodies aids in the timely treatment (either in the form of identifying/removing the underlying tumor or instituting immunomodulatory therapy) and has significantly improved clinical outcome in this otherwise devastating group of conditions.

Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions.

Serotonin syndrome (SS) (also referred to as serotonin toxicity) is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in both the peripheral (PNS) and central nervous systems (CNS). It is characterised by a dose-relevant spectrum of clinical findings related to the level of free serotonin (5-hydroxytryptamine [5-HT]), or 5-HT receptor activation (predominantly the 5-HT1A and 5-HT2A subtypes), which include neuromuscular abnormalities, autonomic hyperactivity, and mental state changes. Severe SS is only usually precipitated by the simultaneous initiation of 2 or more serotonergic drugs, but the syndrome can also occur after the initiation of a single serotonergic drug in a susceptible individual, the addition of a second or third agent to long-standing doses of a maintenance serotonergic drug, or after an overdose. The combination of a monoamine oxidase inhibitor (MAOI), in particular MAO-A inhibitors that preferentially inhibit the metabolism of 5-HT, with serotonergic drugs is especially dangerous, and may lead to the most severe form of the syndrome, and occasionally death. This review describes our current understanding of the pathophysiology, clinical presentation and management of SS, and summarises some of the drugs and interactions that may precipitate the condition. We also discuss the newer novel psychoactive substances (NPSs), a growing public health concern due to their increased availability and use, and their potential risk to evoke the syndrome. Finally, we discuss whether the inhibition of tryptophan hydroxylase (TPH), in particular the neuronal isoform (TPH2), may provide an opportunity to pharmacologically target central 5-HT synthesis, and so develop new treatments for severe, life-threatening SS.

Cochrane systematic review and meta-analysis of botulinum toxin for the prevention of migraine.

OBJECTIVES: To assess the effects of botulinum toxin for prevention of migraine in adults. DESIGN: Systematic review and meta-analysis. DATA SOURCES: CENTRAL, MEDLINE, Embase and trial registries. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) of botulinum toxin compared with placebo, active treatment or clinically relevant different dose for adults with chronic or episodic migraine, with or without the additional diagnosis of medication overuse headache. DATA EXTRACTION AND SYNTHESIS: Cochrane methods were used to review double-blind RCTs. Twelve week post-treatment time-point data was analysed. RESULTS: Twenty-eight trials (n=4190) were included. Trial quality was mixed. Botulinum toxin treatment resulted in reduced frequency of -2.0 migraine days/month (95% CI -2.8 to -1.1, n=1384) in chronic migraineurs compared with placebo. An improvement was seen in migraine severity, measured on a numerical rating scale 0 to 10 with 10 being maximal pain, of -2.70 cm (95% CI -3.31 to -2.09, n=75) and -4.9 cm (95% CI -6.56 to -3.24, n=32) for chronic and episodic migraine respectively. Botulinum toxin had a relative risk of treatment related adverse events twice that of placebo, but a reduced risk compared with active comparators (relative risk 0.76, 95% CI 0.59 to 0.98) and a low withdrawal rate (3%). Although individual trials reported non-inferiority to oral treatments, insufficient data were available for meta-analysis of effectiveness outcomes. CONCLUSIONS: In chronic migraine, botulinum toxin reduces migraine frequency by 2 days/month and has a favourable safety profile. Inclusion of medication overuse headache does not preclude its effectiveness. Evidence to support or refute efficacy in episodic migraine was not identified.

A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics.

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison with sex-, BMI-, and age-matched control groups with either simple obesity or PCOS (i.e., obesity and androgen excess). Women with IIH showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line, testosterone significantly enhanced the activity of Na+/K+-ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH.

Characterising the patient experience of diagnostic lumbar puncture in idiopathic intracranial hypertension: a cross-sectional online survey.

OBJECTIVES: Patients with idiopathic intracranial hypertension (IIH) usually require multiple lumbar punctures (LPs) during the course of their disease, and often report significant morbidity associated with the procedure. The aim of this study was to assess the patient's experience of diagnostic LP in IIH. DESIGN, METHODS AND PARTICIPANTS: A cross-sectional study of patients with IIH was conducted using an anonymous online survey, with the questions designed in collaboration with IIH UK (the UK IIH charity). Responses were collated over a 2-month period from April to May 2015. Patients were asked to quantify responses using a Verbal Rating Score (VRS) 0-10 with 0 being the minimum and 10 the maximum score. RESULTS: 502 patients responded to the survey, of which 463 were analysed for this study. 40% of patients described severe pain during the LP (VRS ≥8), and the median pain score during the LP was 7 (VRS, IQR 5-7). The majority of patients felt they received insufficient pain relief (85%). Levels of anxiety about future LPs were high (median VRS 7, IQR 4-10), with 47% being extremely anxious (VRS ≥8). LPs performed as an emergency were associated with significantly greater pain scores compared with elective procedures (median 7, IQR 5-7 vs 6, IQR 4-8, p=0.012). 10.7% went on to have an X-ray-guided procedure due to failure of the initial LP, and the body mass index was significantly higher in this group (mean kg/m240.3 vs 35.5, p=0.001). Higher LP pain scores (VRS) were significantly associated with poorly informed patients (Spearman's correlation, r=-0.32, p<0.001). Patients felt more informed when the LP was performed by a specialist registrar compared with a junior doctor (median 7 vs 5, p=0.001) or a consultant compared with a junior doctor (median 8 vs 5, p<0.001). CONCLUSIONS: This study was commissioned by the IIH patient group and is the first to document the patient experience of diagnostic LPs in IIH. It shows that the majority of these patients are experiencing significant morbidity from pain and anxiety. Patient experience of LP may be improved through changing clinical practice to include universal detailed preprocedural information, and where possible, avoiding emergency LPs in favour of LPs booked on an elective day-case unit.