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Acute meningococcal meningitis in adults can be complicated by cranial neuropathies and more rarely by myelopathy. A 55-year-old woman presented with acute bacterial meningitis requiring intubation and was treated with intravenous antibiotics and dexamethasone. Cerebrospinal fluid 16S PCR was positive for Neisseria meningitidis and latex agglutination confirmed the W135 serotype. Ten days after presentation she developed mild upper limb and severe lower limb weakness with hyperreflexia, despite resolution of meningism and improvement of inflammatory markers. On the next day she developed complete bilateral hearing loss and bilateral facial palsy. Magnetic resonance imaging with contrast showed bilateral enhancement of VIIth and VIIIth cranial nerves, with focal signal change within the thoracic spinal cord. Audiometry confirmed complete sensorineural deafness. She was treated with five days of intravenous methylprednisolone and continued a further nine days of intravenous antibiotics. Four weeks after onset, she remained completely deaf with mild improvement of limb and facial weakness. We report a case of acute meningococcal meningitis complicated by presumed extensive vasculitis leading to myelopathy and delayed onset of multiple cranial neuropathies. There was an unusual biphasic presentation and the vasculitis was apparently ameliorated by glucocorticoids, suggesting conventional steroid recommendations may occasionally be inadequate.

Background With several clinical trials in progress and more expected to launch in the next few years exploring novel therapeutic approaches for treating Huntington’s disease, biomarkers are needed to evaluate target engagement, efficacy and disease progression. Cerebrospinal fluid (CSF) is ideal for assessing HD biomarkers, due to its proximity to the brain. There is currently no high-quality repository of CSF from well-characterised HD gene expansion carriers spanning the disease spectrum. Aims Now underway, HDClarity is a multisite, multinational initiative that aims to establish the largest, highest-quality repository of CSF from well-characterised HD mutation carriers and matched controls, to expedite research into biomarkers and evaluate pathways to enable development of novel treatments for HD. Methods/techniques CSF and blood samples will be collected at up to 30 sites using a standardised protocol. Careful collection of clinical and phenotypic data on each donor will enable us to appropriately select subsets of samples for each set of experimental assays. HDClarity uses a custom data capture system built upon the Enroll-HD Platform to identify participants and collect standardised data. HDClarity will recruit up to 600 participants from six cohorts: Healthy controls Early Pre-manifest HD Late Pre-manifest HD Early Manifest HD Moderate Manifest HD Advanced Manifest HD Participants attend two study visits: a Screening Visit and a Sampling Visit. Some participants are invited to return for an optional repeat sampling visit 4–8 weeks later. Custom biosample kits are supplied by BioRep to supply all equipment for standardised CSF and plasma collection and processing. BioRep is also the sample biorepository. In one usage, the sample collection will be assayed to determine whether the kynurenine pathway (KP) is dysregulated in HD. It will also enable the further development and validation of assays to measure huntingtin protein in CSF. The biorepository will enable the continued evaluation of potential novel biomarkers. A CSF Consortium will provide scientific oversight into the use of samples and data. HDClarity is sponsored by University College London and coordinated by UCL Huntington’s disease Centre. It is funded and supported by CHDI Foundation, Inc. For more information or to enquire about establishing an HDClarity clinical site, please email the Chief Investigator (e.wild@ucl.ac.uk)

Background Huntington’s disease (HD) is a complex neurodegenerative condition that calls for a multifaceted approach to patient care. Multidisciplinary team (MDT) meetings are one tool by which the expertise of multiple professionals can be focused into the care of a patient, combining the knowledge and expertise required to deliver the best management plan. Aims To estimate the time and monetary costs of a HD MDT meeting held after a specialist HD clinic, and its value to patient care. Methods This study was authorised by the department’s Audit Lead, as stipulated by the UCLH/UCL NHS Trust, London, UK. Data were prospectively retrieved from HD MDT meetings at the National Hospital for Neurology and Neurosurgery from February to June 2016. To ascertain cost, at each meeting, staff members registered their name, position and time spent to prepare the meeting. All patients attending the HD Multidisciplinary Specialist Clinic were included in this study; the time spent to discuss each patient was recorded, as was age, gender and diagnostic stage. To evaluate the value, the number and type of changes to management plans, performed as a result of the MDT discussion, were recorded. The cost per unit of time -- estimated based on midlevel salary for each of the healthcare professionals involved -- was multiplied by the time each staff member spent preparing and attending the meeting. The annual cost was computed by means of the average cost per patient, the frequency of the meetings (26 per year) and the average number of patients discussed per meeting. Results Six meetings, comprising 92 patients (mean age 52 years; 58% males; 15% pre-manifest, 52% early HD, 22% moderate HD, 11% advanced HD) were analysed. Each meeting had a median duration of 41.33 minutes, a median of 14.5 patients, and a mean total cost of 451 GBP. Each patient was discussed for an average of 2:34 minutes, costing 30 GBP, and no difference was found between gender, age or stage. The estimated annual cost of this MDT meeting was £11474 GBP. More than 40% of draft management plans experienced a change as a result of the MDT discussion, a cost of £12 per change of plan. Conclusions Our study demonstrates that HD MDT meetings bring significant value to the management plan of patients at a modest cost. Still, further multicentre outcome-focused studies are needed to ascertain cost-effectiveness.

Background Inflammation and neuronal cell death are involved in HD pathogenesis and biomarkers for these processes could better characterise disease progression and the response to specific interventions. Aims This exploratory work intended to study general inflammatory cytokines, microglial activation markers, and neuronal cell death markers in the cerebrospinal fluid (CSF) of HD patients. Methods We assayed CSF TNF-α, IL-1β, IL-6, IL-8, YKL-40, chitotriosidase, tau and NFL from 23 mutation carriers and 14 healthy controls. TNF-α, IL-1β, IL-6, IL-8 and YKL-40 were measured using a MSD antibody-based tetra-plex array with electrochemiluminiscence detection. Chitotriosidase was measured using an in-house enzyme activity assay. Tau and NFL were quantified using commercial ELISAs. Results TNF-α and IL-1β were below the limit of detection. Mutation carriers had higher YKL-40 (p = 0.003), chitotriasidase (p = 0.015), IL-6 (p = 0.041) and NFL (p = 4.61*10−7) than healthy controls. NFL was different between pre-manifest and manifest mutation carriers (p = 0.006). YKL-40 and NFL showed significant association with age, and YKL-40, IL-8, Tau and NFL displayed significant association with disease burden score. Age-adjusted YKL-40 significantly correlated with disease stage (p = 0.001), TFC score (r = −0.46, p = 0.003), and TMS (r = 0.59, p = 4.32*10−4). TMS remained significant after adjusting for disease burden (r = 0.49, p = 0.028). Age-adjusted NFL significantly correlated with disease stage (p = 6.07*10−5), TFC (r = −0.38, p = 0.005) and TMS (r = 0.47, p = 6.89*10−5). Conclusions CSF biomarkers of inflammation and neuronal cell death may be useful biomarkers for HD. In particular, YKL-40, IL-8, Tau and NFL may independently predict clinical phenotype and could be useful as biomarkers of disease activity and treatment response. Further investigation is needed to support our exploratory findings. Funding CHDI Foundation Inc, GSK, Medical Research Council UK, Swedish Research Council and the Wolfson Foundation.

Background and aims Huntington’s disease (HD) is an autosomal-dominant condition and defined by a triad of movement, cognitive, and psychiatric symptoms. However, some patients in whom HD is suspected do not carry the CAG expansion in the Huntingtin gene (HTT). These cases, with symptoms on the HD spectrum, but without the HTT expansion, are called HD phenocopy syndromes. Their most frequent known cause has recently been identified as C9orf72, but recessive conditions can also mimic HD. Next generation sequencing technologies (NGS) facilitate the simultaneously screening of genes linked to other neurodegenerative conditions. Methods We applied a validated 17-gene NGS dementia panel (PRNP, PSEN1, PSEN2, APP, GRN, MAPT, TREM2, CHMP2B, CSF1R, FUS, ITM2B, NOTCH3, SERPINI1, SQSTM1, TARDBP, TYROBP and VCP) combined with PCR-based assessments of the C9orf72 and PRNP expansions to the UCL HD phenocopy cohort (n = 444). We classified mutations by likelihood of pathogenicity and compared with clinical data, including HD-likeness and family history. Results In the cohort, 7.2% of all patients displayed the complete triad of symptoms, and for 46.9% of these a relevant family history was reported. A further 32.7% presented with 2/3 of the triad, 20.3% of these had a relevant family history. Overall, a relevant family history was reported for 24% of patients. In the 409 cases processed so far, yet to be tested for the C9orf72 and PRNP expansions, 4.5% of patients were found to carry a (likely) deleterious variant, a further 4.1% carried a potentially deleterious variant and 7.9% carried a higher-risk allele. Conclusions A custom panel provides affordable high quality sequencing. These panels can now help identify mutations in genes not previously linked to HD phenocopies, and reduce the number of cases where even with a strong family history no genetic mutation is found. This ongoing work will help to provide answers to patients and families, who present with an HD syndrome without the diagnostic certainty of the HTT expansion.

Background Quantification of mutant and wild-type Huntingtin (HTT) and their cleaved or truncated species in living Huntington’s disease (HD) patients is challenging but desirable, with the potential to assist in measuring disease progression objectively and illuminating the pathobiology of HD. Aims Explore the nature of the soluble HTT proteins detected in HD patient samples with a series of novel, immunoassays developed for the Meso Scale electrochemiluminescence platform (PLoS One. 2014 9(5):e96854). Investigate the relationship between HTT protein and disease stage, burden and brain imaging measures. Methods In 104 subjects (32 controls, 30 premanifest HTT-expansion carriers, 26 early and 16 moderate HD patients) we collected blood and quantified HTT protein species in mixed peripheral blood mononuclear cell pellets. Antibody combinations designed to detect total, mutant, N-terminal, mid-region and C-terminal HTT proteins were used. Between stage differences in HTT levels were analysed using linear regression, adjusted for age and gender. Associations with disease burden were analysed with and without adjusting for CAG repeats. A linear mixed model was used to estimate assay reliability. Results Analysis of HTT protein levels across groups indicates that soluble mHTT in leukocytes is robustly detected in mutation carriers but not controls, with a signal that tends to increase with advancing disease. mHTT level was significantly associated with disease burden score. Longitudinal analysis, and associations with imaging measures are underway and will be presented at the meeting. Conclusions This assay provides a reproducible read out of mutant HTT protein in easily accessible tissue which correlates with disease trajectory.

Huntington9s disease (HD) is a fatal, autosomal dominant neurodegenerative disease. No disease-modifying treatments exist, but oligonucleotide-based ‘gene silencing’ approaches that aim to reduce expression of the causative mutant huntingtin (mHTT) protein are in advanced development. Low-abundance mHTT has never been quantified in the patient CNS, limiting our understanding of its role in the neuropathobiology of HD in vivo, and precluding the demonstration of target engagement by HTT-lowering drugs. We developed a novel ultra-sensitive mHTT immunoassay using single-molecule counting technology. Using cerebrospinal fluid (CSF) collected from 9 HD mutation carriers and 3 controls, under strictly standardised conditions, mHTT was successfully quantified and its levels completely distinguished controls, premanifest mutation carriers and manifest HD patients. mHTT level was significantly associated with disease burden score, a measure of lifetime exposure to mHTT, suggesting that soluble mHTT species increase in concentration with disease progression. An independent association with CSF neurofilament light chain level suggests the mHTT detected is neuronal in origin. Quantifying mHTT in CSF may provide a means of monitoring disease progression in HD. Our novel assay will be refined using larger CSF collections, and used to better understand the neuropathobiology of HD and to support clinical trials of disease-modifying HD therapeutics.

Background In many cases where Huntington’s disease (HD) is suspected, the genetic test for HD is negative: these are known as HD phenocopies. Most of these individuals remain without a genetic diagnosis. A repeat expansion in the C9orf72 gene has been identified as the major cause of familial and sporadic frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Aim To determine whether the C9orf72 expansion mutation causes HD phenocopies. Methods A cohort of 514 HD phenocopy patients were analysed for the C9orf72 expansion using repeat-primed PCR. In cases where the expansion was found, Southern hybridisation was performed to determine expansion size. Clinical case notes were reviewed to determine the phenotype of expansion-positive cases. Results 10 subjects (1.95%) had the expansion, making it the commonest identified genetic cause of HD-phenocopy presentations. The size of expansion was not significantly different from that associated with other clinical presentations of C9orf72 expanded cases. The C9orf72 expansion-positive subjects were characterised by the presence of movement disorders including dystonia, chorea, myoclonus, tremor and rigidity. Furthermore the age of onset in this cohort was lower than previously reported for subjects with the C9orf72 expansion, and included one case with paediatric onset. Conclusions This study extends the known phenotype of the C9orf72 expansion, both in age of onset and movement disorder symptoms. We propose a revised clinico-genetic algorithm for the investigation of HD-phenocopy patients based on these data.

Background Huntington9s Disease (HD) is a progressive neurodegenerative genetic disorder characterised by motor dysfunction, cognitive decline and psychiatric disturbance. Although HD is not traditionally thought of as an inflammatory disorder, it has been shown that there is a parallel immune activation in CNS and the periphery that can be seen throughout the course of the disease (Bjorkqvist et al , J Exp Med 2008). The cytokines that are increased earliest in the disease course are IL-6 and IL-8, both of which are involved in the innate immune response. Aims The aim of this study is to investigate whether components of innate immunity may serve as biomarkers of disease progression in HD. Methods/Techniques We investigated the potential of several components of innate immunity, such as S100 proteins and complement factors, as biomarkers in HD by measuring their levels in plasma from healthy controls, premanifest HD and early HD subjects. The plasma samples were obtained from the TRACK-HD study. Results/Outcome S100A12 and calprotectin were increased in moderate HD compared with healthy controls. Levels of clusterin, complement factors H, 3, 3a, 4, 4a, 5, 5a and 9, α-2 macroglobulin, and α1-antitrypsin did not differ between healthy controls and HD subjects. Conclusion Of the analytes tested in this study, none showed potential as a biomarker in early stages of HD.