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Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. In general, polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

Background Impulsive and irritable behaviour have been reported in HD from the earliest clinical descriptions of the condition, and abnormalities on various measures of impulsive behaviour have been demonstrated. However these studies had small sample sizes, and did not account for potential confounding effects in the HD population such as IQ and medication. Furthermore, the links between impulsive and irritable behaviour in HD remain unclear. Aims Determine which cognitive mechanisms contribute to irritable behaviour in HD Determine which aspects of impulsive behaviour are seen in HD Methods/Techniques We recruited HD patients and familial controls from the South Wales HD Service and performed a battery of established and novel cognitive tasks, including questionnaire measures of impulsive behavour and irritability (UPPSP, Barrett Impulsivity Scale, PBAs and Snaith), motor inhibition (stop signal task), delay discounting (Kirby instrument) and cognitive impulsivity (Iowa Gambling task). We also performed tasks of provocation (a previously reported task, and a novel task) to determine the relative contributions of impaired inhibition and excessive response to provocation in mediating irritability in HD. Results We recruited 51 HD patients and 26 controls. We found differences in response to provocation and also impaired motor inhibition on the stop signal task in the HD population, even after correcting for relevant confounders such as IQ, medication, motor impairment and psychiatric comorbidity. However, only the response to provocation was associated with irritability in HD. The tasks of delay discounting, and cognitive impulsivity did not demonstrate any differences between HD patients and controls after controlling for relevant confounders. Conclusions Irritability in HD is mediated by excessive response to provocation rather than the known impairments in motor inhibition. Other aspects of impulsivity to contribute to impulsive behaviour in HD.

Background Apathy is a core symptom of Huntington’s Disease (HD), appearing up to 10 years before the onset of motor symptoms and worsening alongside disease progression. Research into the disease needs greater focus on this symptom, but to date, limited tools exist for measuring apathy in HD. Aims This study aimed to evaluate the longitudinal validity and sensitivity of two novel computer tasks that were designed to measure apathy in HD, to assess their potential for future use in clinical trials. Method A total of 83 individuals with HD and 54 controls underwent extensive testing on a battery of existing and novel tasks that measured a range of deficits in HD. Included in this battery were the two novel tasks, the Persistence task and the Maze task, as well as the current gold-standard measures: the Problem Behaviours Assessment Scale of apathy (PBA-apathy) and the Composite Unified Huntington’s Disease Rating scale (cUHDRS). Participants were tested on the entire battery at baseline and at 12-month follow up. Results Both the Maze and Persistence tasks were able to distinguish gene positive participants from controls, but only the Maze task was found to be sensitive to change between baseline and follow up. Moreover, it appeared to be more sensitive than the cUHDRS, which did not show significant change over 12 months in this population. However, the Maze task did not show association with PBA-apathy scores, suggesting it does not measure core elements of apathy as defined by the PBA. The Persistence task was associated with PBA-apathy at baseline, but this association did not persist to follow up, suggesting that the task lacks longitudinal validity. Conclusion This study highlights the potential utility of objective computer tasks in HD research, reducing the field’s reliance on subjective self-report measures. Excitingly the findings also suggest that the Maze task could become a new objective measure of disease progression, superior to existing tools.

Background: Non‐motor symptoms are well established phenotypic components of adult‐onset idiopathic, isolated, focal cervical dystonia (AOIFCD). However, improved understanding of their clinical heterogeneity is needed to better target therapeutic intervention. Here, we examine non‐motor phenotypic features to identify possible AOIFCD subgroups. Methods: Participants diagnosed with AOIFCD were recruited via specialist neurology clinics (dystonia wales: n = 114, dystonia coalition: n = 183). Non‐motor assessment included psychiatric symptoms, pain, sleep disturbance, and quality of life, assessed using self‐completed questionnaires or face‐to‐face assessment. Both cohorts were analyzed independently using Cluster, and Bayesian multiple mixed model phenotype analyses to investigate the relationship between non‐motor symptoms and determine evidence of phenotypic subgroups. Results: Independent cluster analysis of the two cohorts suggests two predominant phenotypic subgroups, one consisting of approximately a third of participants in both cohorts, experiencing increased levels of depression, anxiety, sleep impairment, and pain catastrophizing, as well as, decreased quality of life. The Bayesian approach reinforced this with the primary axis, which explained the majority of the variance, in each cohort being associated with psychiatric symptomology, and also sleep impairment and pain catastrophizing in the Dystonia Wales cohort. Conclusions: Non‐motor symptoms accompanying AOIFCD parse into two predominant phenotypic sub‐groups, with differences in psychiatric symptoms, pain catastrophizing, sleep quality, and quality of life. Improved understanding of these symptom groups will enable better targeted pathophysiological investigation and future therapeutic intervention., We demonstrate that individuals with adult‐onset idiopathic, isolated, focal cervical dystonia parse into two subgroups dependent on their non‐motor symptoms. Approximately a third of participants showed increased levels of depression, anxiety, sleep impairment and pain catastrophising, as well as decreased quality of life, indicating that improved understanding of these symptom groups will lead to better targeted treatment plans.

Tau deposits is a core feature of neurodegenerative disorder following traumatic brain injury (TBI). Despite ample evidence from post-mortem studies demonstrating exposure to both mild-repetitive and severe TBIs are linked to tau depositions, associations of topology of tau lesions with late-onset psychiatric symptoms due to TBI have not been explored. To address this issue, we assessed tau deposits in long-term survivors of TBI by PET with 11C-PBB3, and evaluated those associations with late-life neuropsychiatric outcomes. PET data were acquired from 27 subjects in the chronic stage following mild-repetitive or severe TBI and 15 healthy control subjects. Among the TBI patients, 14 were diagnosed as having late-onset symptoms based on the criteria of traumatic encephalopathy syndrome. For quantification of tau burden in TBI brains, we calculated 11C-PBB3 binding capacity (cm3), which is a summed voxel value of binding potentials (BP*ND) multiplied by voxel volume. Main outcomes of the present study were differences in 11C-PBB3 binding capacity between groups, and the association of regional 11C-PBB3 binding capacity with neuropsychiatric symptoms. To confirm 11C-PBB3 binding to tau deposits in TBI brains, we conducted in vitro PBB3 fluorescence and phospho-tau antibody immunofluorescence labelling of brain sections of chronic traumatic encephalopathy obtained from the Brain Bank. Our results showed that patients with TBI had higher 11C-PBB3 binding capacities in the neocortical grey and white matter segments than healthy control subjects. Furthermore, TBI patients with traumatic encephalopathy syndrome showed higher 11C-PBB3 binding capacity in the white matter segment than those without traumatic encephalopathy syndrome, and regional assessments revealed that subgroup difference was also significant in the frontal white matter. 11C-PBB3 binding capacity in the white matter segment correlated with the severity of psychosis. In vitro assays demonstrated PBB3-positive tau inclusions at the depth of neocortical sulci, confirming 11C-PBB3 binding to tau lesions. In conclusion, increased 11C-PBB3 binding capacity is associated with late-onset neuropsychiatric symptoms following TBI, and a close correlation was found between psychosis and 11C-PBB3 binding capacity in the white matter.

Background: Apathy is a deficit in goal‐directed behavior that significantly affects quality of life and function. It is common in Huntington's disease and other disorders affecting corticostriatal pathways. Deficits in processing of reward, altered effort, and executive dysfunction are associated with apathy in other disorders, but the cognitive processes leading to apathy in Huntington's disease remain largely unknown. A previously reported deficit in learning from losses in Huntington's disease raises the possibility of a hitherto unrecognized mechanism leading to apathy. This study's objective was to delineate the cognitive processes associated with apathy in HD. Methods: We tested 51 Huntington's disease participants and 26 controls on a battery of novel and established measures to assess the contribution to apathy in Huntington's disease of executive function, reward value, reward‐effort calculations, instrumental learning, and response to reward and loss. Results: Huntington's disase participants had deficits in instrumental learning with impaired response to loss, but no evidence to suggest altered reward‐related behavior or effort. We also saw an executive dysfunction contribution to apathy in Huntington's disease. Discussion: We report the novel finding that apathy in Huntington's disease is associated with blunted responses to losses and impaired instrumental learning. This association is consistent with the known early degeneration of the indirect pathway and amygdala involvement in apathy in Huntington's disease, but is previously unreported in any disorder. In keeping with the comparative preservation of the ventral striatum and orbitofrontal cortex in Huntington's disease, reward valuation and reward‐effort calculations did not contribute to apathy. © 2019 International Parkinson and Movement Disorder Society

Huntington’s disease is a neurodegenerative disorder, characterised by progressive cognitive, motor and psychiatric symptoms. Patients with advanced disease presenting to emergency medical services can pose a diagnostic and management challenge for physicians unfamiliar with the condition. We describe two patients with Huntington’s disease in whom the diagnosis of traumatic spinal cord injury was delayed, discuss the role that cognitive bias and other factors played in this delay, and the lessons we can learn.

Background and purposeHuntington's disease (HD) is an autosomal dominant, neurodegenerative movement disorder, typically characterized by chorea. Dystonia is also recognized as part of the HD motor phenotype, although little work detailing its prevalence, distribution, severity and impact on functional capacity has been published to date.MethodsPatients (>18 years of age) were recruited from the Cardiff (UK) HD clinic, each undergoing a standardized videotaped clinical examination and series of functional assessment questionnaires (Unified Huntington's Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale and modified version of the Toronto Western Spasmodic Torticollis Rating Scale). The presence and severity of dystonia were scored by four independent neurologists using the Burke-Fahn-Marsden Dystonia Rating Scale and Unified Huntington's Disease Rating Scale. Statistical analysis included Fisher's exact test, Wilcoxon test, anova and calculation of correlation coefficients where appropriate.ResultsForty-eight patients [91% (48/53)] demonstrated evidence of dystonia, with the highest prevalence in the left upper limb (n = 44, 83%), right upper limb most severely affected and eyes least affected. Statistically significant positive correlations (P ConclusionsWe report a high prevalence of dystonia in adult patients with HD, with worsening dystonia severity with increasing HD disease stage and motor disease duration. The recognition and management of dystonic symptoms in routine clinical practice will aid overall symptomatic treatment and functional improvement.

Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery.We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18-83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8-20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24-48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487.The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55-2·09], p=0·83).Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (36 h) are planned.Athersys Inc.

Background Depressed mood is common in Huntington’s disease (HD), with rates of between 33% and 69% in mutation carriers. Depressed mood is a major predictor of suicidal ideation, and is associated with significant impairments of quality of life and function. Despite this, little is understood regarding the neurobiology and cognitive processes underlying low mood and suicidal ideation in HD. Aims This study used a battery of neuropsychological tasks, that measure cognitive processes shown to be involved in major depressive disorder in the general population, and compared task performance with gold standard measures of mood and suicidal ideation in HD. Methods 53 gene positive HD patients and 26 healthy controls completed gold standard measures of mood in HD (Problem behaviours Assessment short form {PBAs}, Hospital Anxiety and Depression Scale{HADS}, Mini International Neuropsychiatric Interview{MINI}) in addition to a task battery encompassing a novel measure of depressive cognition (estimation of one’s own performance); measures of reward and effort (progressive ratio task, rewarded reaction time task); executive function measures (verbal fluency and extra-dimensional set shifting task); and a self report questionnaire of reward value. Results Patients had higher HADS scores and lower premorbid IQ than controls, no other demographic group differences were found. Group differences were seen on the executive function measures, reward value measure and depressive cognition task. Lower executive function and lower depressive cognition scores predicted suicidal ideation, but none of the other gold standard mood measures were associated with task performance. Discussion Suicidal ideation in Huntington’s disease is associated with impaired executive function and over-estimate of performance on a task of depressive cognition. Over-estimate of performance may relate to mania, which has been linked with suicidality in bipolar disorder.

Background Psychiatric symptoms are common in Huntington’s disease (HD) and contribute significantly to impairment of Functional Capacity. Low mood, anxiety and irritability are common in early HD, but affective symptoms are also common in the general population and previous studies have found that the mood disorder of HD correlates poorly with motor and cognitive measures of disease progression. Apathy tends to occur later, and correlates more closely with disease progression than the mood symptoms, probably because there is no effective symptomatic treatment. Measurement of psychiatric symptoms is also confounded by anosognosia and denial, limiting the usefulness of self-report measures. Methods One of the objectives of the Repair-HD study was to validate a new Core Assessment Protocol for Intra-cerebral Transplantation in HD (CAPIT-HD2), which includes several psychiatric measures. These include a semi-structured interview, the Problem Behaviours Assessment for HD (PBA-s), and several Patient-Reported Outcome (PRO) measures including the Frontal Systems Behaviour Scale (FrSBe), the Apathy Evaluation Scale (AES), the Hospital Anxiety and Depression Scale (HADS) and two PRO irritability scales. We examined correlations between the different measures of apathy, anxiety, depression, and irritability in the baseline psychiatric data. Results All four apathy measures were significantly correlated with each other (p Conclusions The interview and self-report measures used in this study were broadly consistent in this population of patients with stage 1 and stage 2 HD, with the possible exception of depression. A future analysis of changes between the baseline and 12-month assessments will examine the potential of each of these scales to measure disease progression in HD.

Background Psychiatric symptoms are common in Huntington’s disease (HD) and contribute significantly to functional impairment. Low mood, anxiety and irritability can all occur many years before motor onset, but are also common in the general population. Apathy and perseveration (repetitive thinking or behavior) can occur before motor onset, but usually appear after diagnosis and are worst from stage 3 onwards. Previous studies have found that apathy correlates with motor and cognitive measures of disease progression, while the mood disorder does not. Methods One of the objectives of the Repair-HD study was to develop and validate a new Core Assessment Protocol for Intra-cerebral Transplantation in HD (CAPIT-HD2), which includes a psychiatric interview, the Problem Behaviours Assessment for HD (PBA-s), and several Patient-Reported Outcome (PRO) measures. The 12-month follow-up is now complete and analysis underway. We report a preliminary analysis of data from the baseline psychiatric measures. Results Cases (N=73) and controls (N=50) differed significantly for PBA-s apathy (p Conclusions This preliminary analysis confirms that apathy and perseveration correlate with disease stage, while disorders of mood (depression and anxiety) and irritability are more variable over time, and from person to person. This may reflect the complex aetiology of affective symptoms, involving psychological variables and variation in genetic susceptibility as well as HD. Symptomatic treatment with antidepressants may also mask any relationship with disease progression.

This book, part biography part autobiography, relates the author’s encounters with death. He describes his father’s life, personality and ultimate end; his brother’s death; and innumerable violent deaths witnessed through his job as a reporter in conflict zones the world over. Nick Hornby once wondered whether his own obsessions with particular songs were an attempt to ‘solve’ them. The group felt that this book attempts to ‘solve’ the author’s misery over his brother’s early death. Toolis describes his own experiences in the ‘Chest ward’, where death was not mentioned by name, or even alluded to. Most patients died from malignancy but their beds were vacated and tidied with nary an explanation for other patients. The author finally gained an inkling into his own career choice; following colleagues’ deaths, and close encounters with his own mortality, he realised he wanted to allay his own ‘unrequited grief’(personal communication, TAT Hughes) over his brother’s death. …

Although Huntington’s disease (HD) is rare, it deserves particular attention not only because of its devastating effects and inevitable progression as well as the familial ramifications, but also because of its potential utility as a model for other neurodegenerative diseases and psychiatric disorders. An autosomal dominant CAG trinucleotide repeat disorder, HD was first comprehensively phenotyped in an elegant study in 1872 by George Huntington, who clearly described the inheritance pattern and motor characteristics of the disease. The responsible gene locus was eventually found on chromosome 4 in a landmark paper in Cell in 1993. It is commonly accepted that 27–35 CAG repeats are ‘unstable’ and may produce disease in offspring, 36–39 repeats lead to later-onset disease and higher repeat lengths lead to inevitable disease with motor onset between the ages of 30–50 years. Several recent robust, large-scale prospective cohort studies have intensively studied the clinical and imaging biomarkers associated with disease progression in large cohorts over many years. As a result the genetics are well understood and the phenotype has been thoroughly investigated. However, the major challenge this field of research faces is in clarifying the intervening stages between genotype and phenotype, in the hope of developing disease-modifying drugs. This article reviews three papers that address significant gaps in our knowledge. Firstly, an article using a novel technique to identify biochemical pathways previously not known to be affected by mutant Huntingtin, secondly, a paper that robustly demonstrates respiratory chain enzyme dysfunction in vivo (and hence mitochondrial dysfunction in the disease), and finally, a paper that uses a large cohort to identify a putative novel phenotype associated with shorter CAG repeat lengths, challenging current assumptions about the repeat lengths necessary for disease development.

Spontaneous intracranial haemorrhage (ICH) is less common as a cause of stroke than ischaemia, but it has significantly worse morbidity and mortality. To some extent this reflects, the different demographics of the populations affected, but a lack of effective therapeutic options is also a contributory factor. Whilst ICH as a result of underlying vascular malformations or other structural lesions offers certain neuroradiological and/or neurosurgical possibilities to prevent recurrence, interventions to reverse damage caused by the index event remain limited regardless of aetiology. As a result, current management is mainly supportive and includes reversal of anticoagulation where appropriate, blood pressure control, prevention of hyperglycaemia and pyrexia, and the treatment of emergent complications, such as seizures. Anticoagulant and antiplatelet medications are often associated with ICH and adversely affect outcome. Patients are treated with these agents for a variety of reasons, including primary or secondary prevention of cardiac and cerebral ischaemic events. Historically, there has been a choice been between aspirin (or other antiplatelet agents) or a coumarin. However, recently a number of new agents have been developed (novel oral anticoagulants—NOACs), and have potential advantages over Warfarin, including a lower risk of haemorrhagic complications for an equivalent level of thrombo-embolic risk reduction and the lack of requirement for international normalised ratio (INR) monitoring. However, none of the NOACs has a specific agent to reverse their action in the event of haemorrhagic complications. This month, journal club focuses on reversal of drugs which contribute to or have the potential to worsen ICH. The first paper reports a randomised-controlled trial of platelet infusion versus the standard care in patients with ICH on antiplatelet agents. The second paper is a randomised-controlled trial of fresh frozen plasma versus prothrombin complex concentrate in the reversal of warfarin-associated ICH. Finally, we review an observational study of ICH associated with NOACs, focussing on prognostic factors and effectiveness of haemostatic treatments.

Vertebral artery dissection is an important cause of stroke in the young and diagnosis is often challenging as symptoms are varied and subtle.\ud Case presentation\ud \ud A 33-year-old, previously healthy, white male office worker was stretching his neck when he developed sudden left-sided visual loss lasting 5 minutes associated with headache. He had no other neurological symptoms or signs. He was investigated with a computed tomography angiogram, which revealed a left vertebral artery dissection with a right posterior cerebral artery vascular occlusion.\ud Conclusions\ud \ud We describe an atypical case of vertebral artery dissection presenting with sudden transient visual disturbance without neurological signs in an otherwise healthy man. This is a rare but potentially fatal condition that can result in thromboembolic infarction. A high index of suspicion is crucial to make an early diagnosis and avoid devastating neurological outcomes.

Diagnosis can prove challenging when a patient with a chronic neurological disease presents with acute deterioration. This is especially true in Huntington’s disease, where cognitive impairment is prominent. We present a case of hypercalcaemia causing an acute deterioration in physical and cognitive function in a patient with Huntington’s disease. Similarity in clinical phenotype between hypercalcaemia and Huntington’s disease, as well as failure to appreciate the acute nature of the deterioration resulted in diagnostic delay and prolonged admission. With treatment, the patient improved dramatically. The case highlights key learning points regarding assessment of patients with chronic neurological disease.

We present an unusual case of encephalopathy with profound MR white matter and cortical abnormalities secondary to, and responsive to treatment for, hepatic encephalopathy alone.A 52-year-old man with known alcohol related liver disease (now abstinent), previous intravenous drug abuse and treated Hepatitis C presented over 18 months with discrete episodes of fluctuating confusion, and altered consciousness progressing to coma.Neuroimaging demonstrated symmetrical confluent white matter T2/ FLAIR hyperintensities in the posterior frontal and parietal lobes with symmetrical dWI cortical ribboning in the precentral gyrus. Due to his clinical state and the unusual neuroimaging findings he was transferred for further neurological investigation and management.On admission a serum ammonia was 111 µmol/L (normal range 16 – 60 µmol/L). Further to this a detailed systemic blood, imaging and CSF analysis did not yield an alternative diagnosis. Electroencephalography revealed generalised slowing.Serial imaging showed persistent, fluctuating, confluent, and symmetrical white matter T2/ FLAIR hyperintensities. Fluctuations in his clinical state correlated with serum ammonia levels, bowel motions, neuroimaging and the EEG findings. He was treated for hepatic encephalopathy alone, on one occasion in intensive care, with lactulose, phosphate enemas and diuretics. He was discharged home independently after a period of sustained clinical improvement.

In the early twentieth century, knowledge of metabolic disorders was confined to a handful of ‘orphan’ diseases. Phenylketonuria was the first of these inborn errors of metabolism to be unravelled and identified as being caused by an enzyme deficit, which then could be managed with a low protein diet. Since that time many of these conditions have subsequently been recognised as having a single-gene origin. However, as is common for conditions initially defined on the basis of a rigid clinical phenotype, ‘forme frustes’ are identified when definitive genetic testing becomes more widely available. As a result there is often a later expansion of the initial phenotype, underlining the importance of careful clinical description and directed ancillary investigations in the diagnosis of these disorders. Unfortunately, the rarity of inborn errors of metabolism militates against large-scale studies of these conditions resulting in a paucity of evidence-based medicine to provide guidance in the diagnosis and management of these conditions. The three studies in this month’s journal club take different approaches to surmount the challenge posed by low disease frequency including careful and thorough clinical phenotyping and the development of a large recruitment base. Three uncertainties are addressed: clarification of the phenotype of a subset of Neuronal Ceroid Lipofuscinosis patients; a clinical description of Unverricht–Lundborg disease with an answer to the debate over correlation of repeat length expansions and disease severity; and finally, development of a radiological algorithm in diagnosing adult onset inherited white matter disease.

Background The course of Huntington’s disease (HD) is slowly progressive, typically over 20–30 years with little in the way of acute fluctuations, so any acute deterioration in either cognitive or motor symptoms justifies a search for an inter current illness. Here we describe three cases in which serious comorbidities were mistakenly ascribed to deterioration of HD. Case histories Case 1: A 64 year old lady with moderately advanced HD was still able to mobilise independently. Following a fall, she was admitted to hospital with increased chorea and some weakness, and a urinary tract infection was initially suspected. She went on to develop further weakness and urinary retention and eventually turned out to have a C2-7 spinal haematoma causing cord compression. She underwent decompression with some improvement. Case 2: A 58 year old man developed progressive weakness, reduced chorea and urinary retention following a fall. This was initially ascribed to progression of his HD and he was treated conservatively, but a subsequent MRI demonstrated complete dislocation of his cervical cord at C5. Surgery was not possible and he was treated palliatively. Case 3: A 42 year old woman presented with vomiting, reduced oral intake, severe constipation, confusion, restlessness and insomnia. Symptoms were attributed to her HD, but turned out to be secondary to primary hyperparathyroidism and improved with treatment. Conclusions All three cases demonstrate the diagnostic difficulties of clinical deterioration in a chronic progressive condition like HD. In all cases the initial symptoms did not trigger any suspicion of comorbidity amongst admitting physicians until further deterioration had taken place and concerns were raised by a specialist HD team. This led to delayed diagnosis which may have been associated with poor outcomes in two of the cases. Strategies for better recognising comorbidities in HD are discussed.

Background Irritability (reduced control of temper resulting in behavioural outbursts) often occurs before motor onset of Huntington’s disease (HD) and is responsible for significant impairments in quality of life and function, yet understanding of the pathophysiology is limited. Current assessments are based on diagnostic interview and self-report, but these are influenced by social context, and are unworkable in animal models. Objective tests of irritability would allow us to explore the underlying neuropsychological basis and neurobiology. Aims Established objective protocols measuring irritable, impulsive and aggressive behaviour were selected to compare with best, current assessments in order to delineate the neuropsychological basis of irritability in HD. Methods Participants carrying the gene expansion causing HD, from pre-symptomatic to moderately advanced stages were recruited. We compared scores on the Snaith Irritability scale and Problem Behaviours Assessment irritability sub-score with our battery. Subjects were tested on impulsivity measures (e.g. monetary temptation questionnaire) and provocation protocols (e.g. point subtraction aggression protocol). Results Fifty-three gene positive individuals were recruited. We recorded visual analogue scales (VAS) of irritability, anger and frustration in addition to repetitive and pre-emptive button presses (motor measures). Neither the VAS scores, motor measures or impulsivity scores correlated with standard irritability assessments. Conclusions The lack of correlation with self-report or clinician measures of irritability may reflect ineffective provocation or suggest that impulsive and irritable behaviour in HD are separate constructs, alternatively, correlation may be limited by lack of insight, drug treatment effects or impaired motor responses secondary to the motor impairments of HD.

Background Huntington’s disease (HD) is an autosomal dominant, neurodegenerative movement disorder, typically characterised by chorea. Dystonia is another frequently recognised movement disorder in HD, although little work detailing its prevalence, distribution, severity and correlation with HD characteristics has been published to date. Aims To determine the frequency and distribution of dystonia in a cohort of patients with HD. – To evaluate the severity of dystonia and its influence on the functional capacity of patients by use of standardised dystonia rating scales. Methods Patients (>18 yrs.) were consecutively recruited from the Cardiff (UK) HD-clinic, each undergoing a standardised videotaped clinical examination and functionality questionnaires (UHDRS functionality assessment and independence scale, Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) disability section and modified Toronto Western Spasmodic Torticollis Rating Scale). Dystonia severity was determined by four independent neurologists, each scoring the videotaped examinations using the BFMDRS and dystonia-section of the UHDRS. Statistical analysis included paired t-test, correlation coefficients, logistic regression analyses where appropriate. Results Eight patients have been recruited to date (5M:3F) and data collection is ongoing. We anticipate recruiting 50–60 further participants. Dystonia was deemed to be present in each body region if this was observed by the majority of the raters. Conclusions All patients recruited to date were observed to have dystonia with a varying distribution and mean severity scores. With a larger cohort we would anticipate performing further analysis to determine which, if any, clinical characteristics might be correlated with the presence and severity of dystonia. However, it is already apparent that cranio-cervical musculature is frequently involved and modification of the dystonia portion of the UHDRS might be helpful to allow for this distinction.

Ethical dilemmas are commonplace in clinical cardiology. There has been a recent focus on ethical behaviour of cardiologists and debate about resource allocation and cost-effectiveness of new technologies. The case of an intravenous drug addict, with native aortic valve endocarditis complicated by a cerebral abscess and severe aortic regurgitation, is presented to illustrate some common ethical and moral dilemmas. The predominant theories in medical ethics, including the "Four-Principles Approach," is discussed, and a model to translate these ethical theories into a clinical decision-making tool is presented.

Patients undergoing treatment for haematological malignancies can present to neurological services with complications from the disease or the treatment. We present a case displaying a complication that is rarely diagnosed by adult neurologists. A 20 year old student undergoing treatment with vincristine, daunorubicin, asparaginase and intra-thecal methotrexate for Acute Lymphoblastic Leukaemia (ALL) originally presented with featureless headaches and visual disturbance. She was extensively investigated for inflammatory, metabolic, nutritional and vascular causes of pathology with MRI, LP, serological and autoimmune investigations all proving normal or negative. The symptoms resolved over several weeks. She deteriorated again 4 weeks following her initial recovery with a rapid onset of an encephalopathy: displaying roving eye movements, trismus and rapidly deteriorating conscious level. She required admission to intensive care for monitoring. Ultimately the clinical picture, negative ancillary investigations and repeat imaging enabled a diagnosis of methotrexate induced encephalopathy to be made. Methotrexate induced encephalopathy is seen in a significant minority of patients in clinical trials for ALL, and predominantly occurs in older children and young adults. Various approaches to treatment based on hypothesised pathophysiology of the condition, and small case series have been used.

A number of therapeutic strategies have been tried for SUNCT with limited success, including medical management, nerve blockade and neurosurgical procedures. A 74-year-old man was admitted with unilateral intense, short lived retro-orbital pain in association with conjunctival injection, rhinorrhea and prominent lacrimation. These brief attacks would last for seconds, but recurred with no refractory period. Neurological examination was unremarkable. Imaging was limited by the presence of a permanent pacemaker, however CT Brain did not demonstrate any abnormalities. His condition was felt to warrant urgent intervention owing to a very poor oral intake (related to his triggered attacks). Cardiological problems made intravenous lidocaine a high risk strategy. A trial of supra and infra-orbital nerve blockade produced immediate relief of pain, symptoms returned after the effects of the local anaesthetic had worn off. Radiofrequency ablation led to complete relief of the pain and the patient was able to resume oral nutrition. Various therapeutic strategies have been advocated for SUNCT. The larger case series recommend lamotrigine, gabapentin and topiramate, with intravenous lidocaine for short-term relief. Some benefit from greater occipital nerve blockade is reported, but results have been equivocal and surgical approaches have not shown consistent benefit. This is the first effective use of supra and infra-orbital nerve blockade that has been reported to our knowledge.

Acute symptomatic seizures (ASS) occur at the time or in close temporal association with a documented systemic or brain insult and are a common cause for seeking an emergency neurological opinion. The major issues involved in their management are the diagnosis and treatment of the underlying cause, whether seizures should be treated or not, the choice of anti-epileptic drug (AED) and the duration of AED treatment. These decisions are not straightforward and currently no clear guidelines exist to guide management in this area. We outline our current practice which is based on the evidence available on risks of seizure recurrence, and on our own experience. Most ASS only need short term therapy (up to 3 months) if there is complete recovery from the acute insult. Patients with residual structural brain abnormalities with focal neurological deficit and/or MRI changes need long term prophylactic treatment. We make suggestions for minimum duration of treatment for ASS associated with some common conditions, including—subarachnoid and intracerebral haemorrhage—1 year; ischaemic stroke and venous sinus thrombosis—1 year; mild to moderate head injury—acute seizure control only; severe head injury—2 years; metabolic and toxic disorders (including alcohol withdrawal)—correction of underlying cause only; meningoencephalitis with complete recovery and normal MRI—3 months, residual focal deficit and/or MRI changes—2 years; cerebral abscess, tuberculoma—2 years; parasitic granuloma—if completely resolved with normal MRI—3 months, if persistent/calcified—2 years.