Rating scales for behavioral symptoms in Huntington's disease: Critique and recommendations

Behavioral symptoms are an important feature of Huntington's disease and contribute to impairment in quality of life. The Movement Disorder Society commissioned the assessment of the clinimetric properties of rating scales in Huntington's disease to make recommendations regarding their use, following previously used standardized criteria. A systematic literature search was conducted to identify the scales used to assess behavioral symptoms in Huntington's disease. For the purpose of this review, 7 behavioral domains were deemed significant in Huntington's disease: irritability, anxiety, depression, apathy, obsessive‐compulsive behaviors, psychosis, and suicidal ideation. We included a total of 27 behavioral rating scales, 19 of which were of a single behavioral domain and the remaining 8 scales included multiple behavioral domains. Three rating scales were classified as “recommended” exclusively for screening purposes: the Irritability Scale for irritability, the Beck Depression Inventory‐II, and the Hospital Anxiety and Depression Scale for depression. There were no “recommended” scales for other purposes such as diagnosis, severity, or change in time or to treatment. The main challenges identified for assessment of behavioral symptoms in Huntington's disease are the co‐occurrence of multiple behavioral symptoms, the particular features of a behavioral symptom in Huntington's disease, and the need to address stage‐ and disease‐specific features, including cognitive impairment and lack of insight. The committee concluded that there is a need to further validate currently available behavioral rating scales in Huntington's disease to address gaps in scale validation for specific behavioral domains and purpose of use. © 2016 International Parkinson and Movement Disorder Society     

Rapid improvement of depression and psychotic symptoms in Huntington's disease: a retrospective chart review of seven patients treated with electroconvulsive therapy

Many patients with Huntington's disease (HD) develop psychiatric symptoms such as depression and psychosis. For severe symptoms, electroconvulsive therapy (ECT) can be a valuable treatment. In this case series, we identified seven patients with HD who received ECT at Massachusetts General Hospital in the past 20 years. In all cases, ECT was well tolerated and produced improvement in psychiatric and behavioral symptoms. Our case series supports the hypothesis of a positive risk–benefit ratio for ECT in patients with HD and severe depression or psychosis.     

Rating scales for cognition in Huntington's disease: Critique and recommendations

Cognitive impairment is one of the main features of Huntington's disease and is present across the disease spectrum. As part of the International Parkinson's Disease and Movement Disorder Society‐sponsored project to review all clinical rating scales used in Huntington's disease, a systematic review of the literature was performed to identify cognitive scales used in Huntington's disease and make recommendations for their use. A total of 17 cognitive scales were identified and evaluated. None of the scales met criteria for a “recommended” status. For assessing severity of cognitive dysfunction, the Montreal Cognitive Assessment was “recommended with caveats.” The UHDRS Cognitive Assessment, the UHDRS‐For Advanced Patients cognitive section, the Alzheimer's Disease Assessment Scale‐Cognitive Subscale, the Frontal Assessment Battery, the Mattis Dementia Rating Scale, the Mini‐Mental State Examination, and the Repeatable Battery for the Assessment of Neuropsychological Status were “suggested” for evaluating severity of cognitive impairment. The MoCA was “suggested” as a screening tool for cognitive impairment. The major challenge in the assessment of cognition in Huntington's disease is the lack of a formal definition of dementia and/or mild cognitive impairment in this disease. The committee concluded that there is a need to further validate currently available cognitive scales in Huntington's disease, but that it is premature to recommend the development of new scales. Recently developed Huntington's disease‐specific scales, such as the Huntington's Disease‐Cognitive Assessment Battery, hold promise but require the completion of more comprehensive clinimetric development. © 2017 International Parkinson and Movement Disorder Society     

Metyrosine in psychosis associated with 22q11.2 deletion syndrome: case report

This report describes the use of metyrosine (Demser) in an adolescent male with psychosis associated with the 22q11.2 deletion syndrome (velocardiofacial syndrome; VCFS), diagnosed by fluorescence in situ hybridization (FISH). He presented with multiple features of 22q11.2 deletion syndrome, including ventricular septal defect, palatal abnormalities, speech and motor delays, attention deficits, mood lability, and psychosis. After a failed trial of an atypical antipsychotic to address the psychosis, metyrosine was initiated, with significant reduction of psychotic symptoms and mood lability. Metyrosine treatment allowed this youth to live at home and to attend school, after months of recurrent psychiatric hospitalizations. The successful treatment of metyrosine for psychosis associated with VCFS represents a first in psychiatry, where a known biochemical abnormality in a psychiatric disorder was corrected by a treatment that targets the biochemical pathway, leading to reduction of psychiatric symptoms and improvement of functioning.     

The structural involvement of the cingulate cortex in premanifest and early Huntington's disease

The impact of Huntington's disease neuropathology on the structure of the cingulate is uncertain, with evidence of both cortical enlargement and atrophy in this structure in early clinical disease. We sought to determine differences in cingulate volume between premanifest Huntington's disease and early Huntington's disease groups compared with controls using detailed manual measurements. Thirty controls, 30 subjects with premanifest Huntington's disease, and 30 subjects with early Huntington's disease were selected from the Vancouver site of the TRACK‐HD study. Subjects underwent 3 Tesla magnetic resonance imaging and motor, cognitive, and neuropsychiatric assessment. The cingulate was manually delineated and subdivided into rostral, caudal, and posterior segments. Group differences in volume and associations with performance on 4 tasks thought to utilize cingulate function were examined, with adjustment for appropriate covariates. Cingulate volumes were, on average, 1.7 mL smaller in early Huntington's disease (P = .001) and 0.9 mL smaller in premanifest Huntington's disease (P = .1) compared with controls. Smaller volumes in subsections of the cingulate were associated with impaired recognition of negative emotions (P = .04), heightened depression (P = .009), and worse visual working memory performance (P = .01). There was no evidence of associations between volume and ability on a performance‐monitoring task. This study disputes previous findings of enlargement of the cingulate cortex in Huntington's disease and instead suggests that the cingulate undergoes structural degeneration during early Huntington's disease with directionally consistent, nonsignificant differences seen in premanifest Huntington's disease. Cingulate atrophy may contribute to deficits in mood, emotional processing, and visual working memory in Huntington's disease. © 2011 Movement Disorder Society     

Cerebrospinal fluid flow dynamics in Huntington's disease evaluated by phase contrast MRI

Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross‐sectional study comparing people with early stage Huntington's disease with age‐ and gender‐matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub‐arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter‐group differences with Wilcoxon rank‐sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTTCAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics – that is, one that would justify dose‐adjustments of intrathecal drugs – is unlikely to exist in Huntington's disease.     

A randomized,double‐blind,placebo‐controlled trial evaluating cysteamine in Huntington's disease

Background : Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease. Methods : Ninety‐six patients with early‐stage Huntington's disease were randomized to 1200 mg delayed‐release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed‐effects model for repeated measures was used to assess treatment effect, expressed as the least‐squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo. Results : At 18 months, the treatment effect was not statistically significant — least‐squares mean difference, ‐1.5 ± 1.71 (P = 0.385) — although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated. Conclusions : Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society     

Patient‐reported outcomes in Huntington's disease: Quality of life in neurological disorders (Neuro‐QoL) and Huntington's disease health‐related quality of life (HDQLIFE) physical function measures

Background : There is a need for patient‐reported outcome measures that capture the impact that motor impairments have on health‐related quality of life in individuals with Huntington's disease. Objectives : The objectives of this study were to establish the reliability and validity of new physical functioning patient‐reported outcome measures in Huntington's disease. Methods : A total of 510 individuals with Huntington's disease completed 2 Quality of Life in Neurological Disorders (Lower Extremity Function and Upper Extremity Function) and 3 Huntington's Disease Health‐Related Quality of Life (Chorea, Speech Difficulties, and Swallowing Difficulties) measures. Clinician‐rated and generic self‐report measures were also administered. Results : Reliabilities for the new patient reported physical functioning measures were excellent (all Cronbach's α > .92). Convergent, discriminant validity and known group validity was supported. Conclusions : The results provide psychometric support for new patient‐reported physical functioning measures and the fact that these measures can be used as clinically meaningful endpoints in Huntington's disease research and clinical practice. © 2017 International Parkinson and Movement Disorder Society     

Clinical and molecular research of neuroacanthocytosis

Neuroacanthocytosis is an autosomal recessive or dominant inherited disease characterized by widespread, non-specific nervous system symptoms, or spiculated "acanthocytic" red blood cells. The clinical manifestations typically involve chorea and dystonia, or a range of other movement disorders. Psychiatric and cognitive symptoms may also be present. The two core neuroacanthocytosis syndromes, in which acanthocytosis is atypical, are autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome. Acanthocytes are found in a smaller proportion of patients with Huntington’s disease-like 2 and pantothenate kinase-associated neurodegeneration. Because the clinical manifestations are diverse and complicated, in this review we present features of inheritance, age of onset, neuroimaging and laboratory findings, as well as the spectrum of central and peripheral neurological abnormalities and extraneuronal involvement to help distinguish the four specific syndromes.     

Factors contributing to institutionalization in patients with Huntington's disease

The objective of this study was to determine which factors are predictive of institutionalization in Huntington's disease. Seven hundred and ninety‐nine subjects with 4313 examinations from the Baltimore Huntington's Disease Center were included in the data set; 88 of these patients with an average follow‐up time of 9.2 years went from living at home to being institutionalized while being observed in our clinic. We examined demographic, genetic, and clinical variables for a relationship with institutionalization using linear regressions, a Cox proportional hazards model, and χ² or t tests in certain cases. In our linear models, scores on the Quantified Neurologic Examination (R² = 0.203, P < .001), Huntington's disease Activities of Daily Living Scale (R² = 0.259, P < .001), and Motor Impairment Score (R² = 0.173, P < .001) were found to have the strongest correlation with time until institutionalization. In addition, CAG repeat length (R² = 0.248, P < .001) was significantly associated with disease duration at institutionalization, when controlling for age at onset. In the Cox proportional hazards model, scores on the Activities of Daily Living Scale, Mini–Mental State Examination, Quantified Neurologic Examination, and Motor Impairment Score all significantly predicted placement in long‐term care. Finally, institutionalized patients were shown to have a higher CAG number and a lower level of educational attainment than patients who avoided institutionalization for at least 15 years after disease onset. Neurologic findings, functional capacity, cognitive impairment, and CAG repeat length are all likely determinants of institutionalization. In contrast with other dementing conditions like Parkinson's and Alzheimer's, psychiatric symptoms were not shown to predict institutionalization in Huntington's disease. This may illustrate the especially debilitating nature of the movement disorder of Huntington's disease in comparison with the other dementias. © 2011 Movement Disorder Society     

Mutant huntingtin and glycogen synthase kinase 3‐β accumulate in neuronal lipid rafts of a presymptomatic knock‐in mouse model of Huntington's disease

Patients with Huntington's disease have an expanded polyglutamine tract in huntingtin and suffer severe brain atrophy and neurodegeneration. Because membrane dysfunction can occur in Huntington's disease, we addressed whether mutant huntingtin in brain and primary neurons is present in lipid rafts, which are cholesterol‐enriched membrane domains that mediate growth and survival signals. Biochemical analysis of detergent‐resistant membranes from brains and primary neurons of wild‐type and presymptomatic Huntington's disease knock‐in mice showed that wild‐type and mutant huntingtin were recovered in lipid raft‐enriched detergent‐resistant membranes. The association with lipid rafts was stronger for mutant huntingtin than wild‐type huntingtin. Lipid rafts extracted from Huntington's disease mice had normal levels of lipid raft markers (G_αq, Ras, and flotillin) but significantly more glycogen synthase kinase 3‐β. Increases in glycogen synthase kinase 3‐β have been associated with apoptotic cell death. Treating Huntington's disease primary neurons with inhibitors of glycogen synthase kinase 3‐β reduced neuronal death. We speculate that accumulation of mutant huntingtin and glycogen synthase kinase 3‐β in lipid rafts of presymptomatic Huntington's disease mouse neurons contributes to neurodegeneration in Huntington's disease. © 2009 Wiley‐Liss, Inc.     

Plasma melatonin is reduced in Huntington's disease

This study was undertaken to determine whether the production of melatonin, a hormone regulating sleep in relation to the light/dark cycle, is altered in Huntington's disease. We analyzed the circadian rhythm of melatonin in a 24‐hour study of cohorts of control, premanifest, and stage II/III Huntington's disease subjects. The mean and acrophase melatonin concentrations were significantly reduced in stage II/III Huntington's disease subjects compared with controls. We also observed a nonsignificant trend toward reduced mean and acrophase melatonin in premanifest Huntington's disease subjects. Onset of melatonin rise was significantly more temporally spread in both premanifest and stage II/III Huntington's disease subjects compared with controls. A nonsignificant trend also was seen for reduced pulsatile secretion of melatonin. Melatonin concentrations are reduced in Huntington's disease. Altered melatonin patterns may provide an explanation for disrupted sleep and circadian behavior in Huntington's disease, and represent a biomarker for disease state. Melatonin therapy may help the sleep disorders seen in Huntington's disease. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Quality of Life in Huntington's Disease: Critique and Recommendations for Measures Assessing Patient Health‐Related Quality of Life and Caregiver Quality of Life

The compromise of quality of life in Huntington's disease is a major issue, both for individuals with the disease as well as for their caregivers. The International Parkinson and Movement Disorder Society commissioned a review of the use and clinimetric validation status of measures used in Huntington's disease to assess aspects related with quality of life and to make recommendations on their use following standardized criteria. We included both patient‐centered measures (patient health‐related quality‐of‐life measures) and caregiver‐centered measures (caregiver quality‐of‐life measures). After conducting a systematic literature search, we included 12 measures of patient health‐related quality of life and 2 measures of caregiver quality of life. Regarding patient‐centered measures, the Medical Outcomes Study 36‐Item Short‐Form Health Survey is “recommended” as a generic assessment of health‐related quality of life in patients with Huntington's disease. The 12‐Item Short Form Health Survey, the Sickness Impact Profile, the 12‐item World Health Organization Disability Assessment Schedule, and the Huntington's Disease Health‐Related Quality of Life questionnaire are “suggested.” No caregiver‐centered quality‐of‐life measure obtained a “recommended” status. The Alzheimer's Carer's Quality of Life Inventory and the Huntington's Disease Quality of Life Battery for Carers are “suggested.” Recognizing that the assessment of patient health‐related quality of life can be challenging in Huntington's disease, as patients may lack insight and there is insufficient clinimetric testing of these scales, the committee concluded that further validation of currently available health‐related quality‐of‐life measures should be undertaken, namely, those Huntington's disease–specific health‐related quality‐of‐life measures that have recently been reported and used. © 2018 International Parkinson and Movement Disorder Society     

Huntington's disease as caused by 34 CAG repeats

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by an abnormal expansion of a polymorphic stretch of CAG repeats in the coding 5′ part of the HD gene on chromosome 4p. Expansions of CAG blocks beyond 35 repeats are associated with the clinical presentation of HD. There is an intermediate range of rare alleles between 27 and 35 CAG repeats with a higher risk for further expansion in subsequent generations. Here, we report a 75‐year‐old male with clinical features of HD and 34 CAG repeat units. © 2008 Movement Disorder Society     

Trinucleotide repeat length and rate of progression of Huntington's disease

The Huntington's disease gene contains an expanded unstable (CAG)_n repeat, and the repeat lengths have been shown to correlate with the age of onset. Using detailed clinical scales, we evaluated the rate of progression of Huntington's disease and its relationship to the number of triplet repeats. We found significant positive correlation between the rate of progression of clinical symptoms (both neurological and psychiatric) and CAG repeat length. These data suggest an important role of expanded trinucleotide repeat length in affecting the pathological process during the enitre course of Huntington's disease.     

Falls and gait disturbances in Huntington's disease

Falls are common in patients with Huntington's disease, but the incidence, falling circumstances and contributing factors have never been examined. We recorded falls in 45 early to midstage Huntington's disease patients, both retrospectively (12 months) and prospectively (3 months). Fall rates were related to relevant baseline measures, including the Unified Huntington's Disease Rating Scale (UHDRS) and quantitative measures of balance (using angular velocity sensors) and gait (using a pressure‐sensitive walkway). Balance and gait measures were compared between patients and 27 healthy age‐matched controls. Twenty‐seven patients (60%) reported two or more falls in the previous year and were classified as fallers. During prospective follow‐up 40% reported at least one fall. A high proportion of falls (72.5%) caused minor injuries. Compared to nonfallers, fallers showed significantly higher scores for chorea, bradykinesia and aggression, as well as lower cognitive scores. Compared to controls, Huntington patients had a decreased gait velocity (1.15 m/s versus 1.45 m/s, P < 0.001) and a decreased stride length (1.29 m versus 1.52 m, P < 0.001). These abnormalities were all significantly greater in fallers compared to nonfallers. In addition, fallers had an increased stride length variability and a significantly greater trunk sway in medio‐lateral direction compared to nonfallers. We conclude that falls are common in Huntington's disease. Contributing factors include a combination of “motor” deficits (mainly gait bradykinesia, stride variability and chorea, leading to excessive trunk sway), as well as cognitive decline and perhaps behavioral changes. These factors should be considered as future targets for therapies that aim to reduce falls in Huntington's disease. © 2008 Movement Disorder Society     

Genetically confirmed Huntington's disease masquerading as motor neuron disease

We describe a patient with Huntington's disease (HD) who showed asymmetrical upper limb amyotrophy as a main manifestation. Chorea and psychiatric symptoms were not prominent. Electromyography revealed generalized active and chronic denervation and fasciculations. A genetic test showed 46 CAG repeats in the huntingtin gene. Asymmetrical amyotrophy restricted to the upper limb has been reported in some patients with progressive chorea and amyotrophy without acanthocytosis, but genetically proven cases of HD have rarely been reported. It is not known why only a few HD patients show the motor neuronal loss; however, certain as‐yet‐unidentified genetic factors combined with some environment factors and the underlying cellular dysfunctions by polyglutamine aggregation could be responsible for the motor neuronal loss similar to that in amyotrophic lateral sclerosis. © 2008 Movement Disorder Society     

Altered behavioral responses to gamma‐aminobutyric acid pharmacological agents in a mouse model of Huntington's disease

Background : Disruptions in gamma‐aminobutyric (GABA) acid signaling are believed to be involved in Huntington's disease pathogenesis, but the regulation of GABAergic signaling remains elusive. Here we evaluated GABAergic signaling by examining the function of GABAergic drugs in Huntington's disease and the expression of GABAergic molecules using mouse models and human brain tissues from Huntington's disease. Methods : We treated wild‐type and R6/2 mice (a transgenic Huntington's disease mouse model) acutely with vehicle, diazepam, or gaboxadol (drugs that selectively target synaptic or extrasynaptic GABA_A receptors) and monitored their locomotor activity. The expression levels of GABA_A receptors and a major neuron‐specific chloride extruder (potassium‐chloride cotransporter‐2) were analyzed by real‐time quantitative polymerase chain reaction, Western blot, and immunocytochemistry. Results : The R6/2 mice were less sensitive to the sedative effects of both drugs, suggesting reduced function of GABA_A receptors. Consistently, the expression levels of α1/α2 and δ subunits were lower in the cortex and striatum of R6/2 mice. Similar results were also found in 2 other mouse models of Huntington's disease and in Huntington's disease patients. Moreover, the interaction and expression levels of potassium‐chloride cotransporter‐2 and its activator (brain‐type creatine kinase) were decreased in Huntington's disease neurons. These findings collectively suggest impaired chloride homeostasis, which further dampens GABA_A receptor‐mediated inhibitory signaling in Huntington's disease brains. Conclusions : The dysregulated GABAergic responses and altered expression levels of GABA_A receptors and potassium‐chloride cotransporter‐2 in Huntington's disease mice appear to be authentic and may contribute to the clinical manifestations of Huntington's disease patients. © 2017 International Parkinson and Movement Disorder Society     

Inhibitory control during smooth pursuit in Parkinson's disease and Huntington's disease

The basal ganglia are involved in the preferential selection and suppression of competing responses. Parkinson's disease and Huntington's disease are 2 prototypical basal ganglia disorders that feature impaired inhibitory control, a function of poor conflict resolution. Previous saccadic studies showed that individuals with Parkinson's disease experience difficulty suppressing unwanted ocular motor responses, whereas evidence for a similar difficulty in Huntington's disease is more equivocal. Relative to saccades, few research studies have examined inhibitory control processes in the context of an ongoing smooth pursuit task. In this study, we examined the ability of 16 patients with Parkinson's disease and 12 patients with Huntington's disease to suppress automatic responses to irrelevant distracters that transiently appeared during the tracking of a moving visual stimulus. Compared with an equivalent number of age‐matched controls, patients with Parkinson's disease generated proportionately more saccades to distracter stimuli. This was particularly evident for distracters appearing far away from the target. Conversely, whereas individuals with early‐stage Huntington's disease and healthy controls made a comparable number of errors toward distracter stimuli, those in a more advanced clinical stage demonstrated significantly poorer inhibitory control. The current findings in parkinsonian patients replicate those previously reported in the saccadic and manual response literature, demonstrating difficulty inhibiting a competing motor response. However, in Huntington's disease we demonstrate for the first time that inhibitory control declines in more advanced‐disease stages. This suggests that ocular motility may provide a sensitive marker of clinical disease progression in Huntington's disease. © 2011 Movement Disorder Society