Objective assessment of the neuropsychiatric symptoms in Huntington's Disease

Huntington's disease (HD) is a progressive neurodegenerative disorder, caused by a repeat expansion in the HTT gene, carried on chromosome 4. HD causes motor symptoms (chorea, dystonia and an eye movement disorder), cognitive decline (impairments in social cognition, memory and executive function) and neuropsychiatric disorders. The commonest neuropsychiatric problems are apathy, depression and irritable behaviour, whilst disinhibited behaviour and perseveration are also frequently reported later in the disease course. The neuropsychiatric symptoms are common in HD and have signifcant, deleterious effects on quality of life and function, yet the underlying cognitive processes and neurobiology remain unclear. This study addresses the gap in knowledge: we have used a battery of established and novel tasks to delineate the specific cognitive processes leading to neuropsychiatric disorders in HD. 53 patients, with a confirmed genetic test for HD were recruited from the South Wales HD service, and 26 controls were recruited from both gene negative family members and local advertising. Subjects completed gold standard measures of europsychiatric symptoms in HD: Problem Behaviours Assessment- short form (PBA), Apathy Evaluation Scale (AES), Behavioural Inhibition Scale Behavioural Activation Scale (BISBAS), Urgency, Premeditation (lack of), Perseverance(lack of), Sensation Seeking, Positive Urgency, Impulsive Behaviour Scale (UPPSP), Barratt Impulsiveness Scale (BIS), Mini International Neuropsychiatric Interview (MINI); in addition to a battery of novel and established tasks measuring depressive cognition, planning, learning, reward value, reward-effort calculation, option generation, susceptibility to provocation, reactive aggression, delay discounting and response inhibition. We compared performance between groups and then used regression models, generalised linear models and generalised linear mixed models to study the cognitive processes underlying the neuropsychiatric symptoms in HD. We found that apathy in HD is predicted by a selective deficit in learning from aversive stimuli, in addition to impairments in executive dysfunction and option generation, whilst reward value and reward-effort calculations do not make major contributions to apathy in HD. Impulsivity in HD is associated with impairment on tasks measuring inhibition of pre-potent responses and cognitive impulsivity, with relative preservation of delay discounting and risk-taking. HD participants also had higher scores on some questionnaire measures of impulsive behaviour: the UPPS P Negative Urgency scale, Barratt Impulsiveness scale and the inhibitory subscale of the BISBAS. Irritability in HD is related to enhanced negative anticipatory emotional reactivity, but v not with measures of impulsive behaviour or reactive aggression. The data on mood disorders suggests that suicidal ideation is associated with executive dysfunction and over-estimate of performance. Reward and effort measures did not significantly contribute to mood symptoms in HD. This study has demonstrated an entirely novel cognitive mechanism leading to apathetic behaviour, and the finding of relatively preserved reward and effort in apathy and mood disorders is also novel. We have replicated previous findings of an executive function deficit leading to apathy. The data on impulsivity with regard to response inhibition and delay discounting is consistent with the known pattern of striatal degeneration in HD. Irritability in HD is not related to impulsive or reactive aggression, but to measures of negative mood induction. The data do not support anhedonia or negative cognitive bias as contributory mechanisms to mood disorders in HD, but executive dysfunction and over-estimate of performance are related to suicidal behaviour. This work demonstrates that the cognitive processes leading to neuropsychiatric symptoms in HD are consistent with the known degeneration in cortico-striatal circuits. The selective preferential degeneration in the indirect compared with the direct pathway is consistent with impaired learning from punishment, but not reward which we found in association with apathy in HD, whilst the dorso-ventral progression of striatal degeneration is consistent with the finding of preserved delay discounting, but impaired pre-potent response inhibition

Huntington's disease: A clinical primer for acute and general physicians

Huntington's disease (HD) usually manifests in adulthood and is characterised by progressive neurodegeneration in the brain that causes worsening involuntary movements, mental health and cognition over many years. Depression, anxiety and apathy are common. HD is autosomal dominant and affects about 1 in 8,000 people in the UK. There are currently no disease-modifying treatments and so patient care centres on multidisciplinary therapy support and medical treatments to relieve distressing symptoms. Progression of HD is usually slow, and so acute deteriorations often indicate another problem, such as intercurrent infections, constipation, urinary retention, gastro-oesophageal reflux disease or poor dentition. In this review we outline common presentations in HD patients, both acute and chronic, consider therapeutic options and discuss specific considerations in advanced HD

Headache and transient visual loss as the only presenting symptoms of vertebral artery dissection: a case report

Vertebral artery dissection is an important cause of stroke in the young and diagnosis is often challenging as symptoms are varied and subtle. Case presentation 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. Conclusions 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

Excessive response to provocation rather than disinhibition mediates irritable behaviour in Huntington’s disease

BackgroundIrritable and impulsive behaviour are common in Huntington’s disease (HD: an autosomal dominant disorder causing degeneration in cortico-striatal networks). However, the cognitive mechanisms underlying these symptoms remain unclear, and previous research has not determined if common mechanisms underpin both symptoms. Here we used established and novel tasks to probe different aspects of irritable and impulsive behaviour to determine the neural mechanisms involved.MethodsWe recruited a cohort of 53 gene positive HD participants and 26 controls from non-affected family members and local volunteers. We used established questionnaire measures of irritability in HD (Snaith Irritability Scale, Problem Behaviours Assessment) and impulsivity [Urgency, Premeditation Perseverance, Sensation-seeking, Positive urgency scale (UPPSP), Barratt Impulsivity Scale], in addition to cognitive tasks of provocation, motor inhibition, delay discounting and decision making under uncertainty. We used generalised linear models to determine differences between cases and controls, and associations with irritability in the HD group.ResultsWe found differences between cases and controls on the negative urgency subscale of the UPPSP, which was associated with irritability in HD. The frustrative non-reward provocation task also showed differences between cases and controls, in addition to predicting irritability in HD. The stop signal reaction time task showed case-control differences but was not associated with irritability in HD. None of the other measures showed group differences or predicted irritability in HD after correcting for confounding variables.DiscussionIrritability in HD is mediated by excessive response to provocation, rather than a failure of motor inhibition

Delayed diagnosis of spinal cord injuries in Huntington's disease

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

Cognitive processes of apathy in Huntington's Disease show high sensitivity to disease progression

Background Disease-modifying treatments for Huntington’s disease (HD) are entering clinical trials: there is a pressing need for objective outcome measures of disease progression. Our previous work showed an association between 2 novel, objective cognitive tasks and apathy - a core feature of disease progression in HD. Objective Evaluate the longitudinal validity and sensitivity of the novel Persistence and Maze tasks to assess their utility as clinical outcome measures in HD. Methods 83 participants positive for the HD gene and 54 controls performed a battery of established and novel tools, at baseline and 12 month follow up. Results The Maze task was found to be the most sensitive measure of change at 12 months, including the current gold-standard measure (the composite disease progression score). Conclusion The Maze task has potential as a novel outcome measure of disease progression in HD and may have utility in other major neurodegenerative diseases

Cement-in-cement stem revision for Vancouver type B periprosthetic femoral fractures after total hip arthroplasty: A 3-year follow-up of 23 cases

Background and purpose Revision surgery for periprosthetic femoral fractures around an unstable cemented femoral stem traditionally requires removal of existing cement. We propose a new technique whereby a well-fixed cement mantle can be retained in cases with simple fractures that can be reduced anatomically when a cemented revision is planned. This technique is well established in femoral stem revision, but not in association with a fracture