HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD).

PURPOSE: Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. METHODS: New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. RESULTS: Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. CONCLUSIONS: HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3.

OBJECTIVE: The objective of this double-blind, placebo-controlled, randomized study was to evaluate the efficacy of varenicline (Chantix), a partial agonist at α4ß2 neuronal nicotinic acetylcholine receptors used for smoking cessation, in patients with spinocerebellar ataxia (SCA) 3. METHODS: Patients with genetically confirmed SCA3 were randomly assigned to receive either varenicline (4 weeks for titration and 4 weeks at a dose of 1 mg twice daily) or placebo. Outcome measures included changes in the Scale for the Rating and Assessment of Ataxia (SARA) scores at endpoint (8 weeks) compared with baseline, a timed 25-foot walk and 9-hole peg test, measurements of mood and anxiety, and adverse events. RESULTS: Twenty patients with SCA3 (mean age = 51 ± 10.98 years; mean disease duration = 14 ± 9.82 years; mean SARA score = 16.13 ± 4.67) were enrolled in the study, and data on 18 patients were analyzed in period I. The most common side effect associated with varenicline was nausea. Improvements were noted in the SARA subsections for gait (p = 0.04), stance (p = 0.03), rapid alternating movements (p = 0.003), and timed 25-foot walk (p = 0.05) and Beck Depression Inventory scores (p = 0.03) in patients taking varenicline compared with those taking placebo at endpoint, with a trend toward improvement in the SARA total score (p = 0.06) in the varenicline group. CONCLUSIONS: In this controlled study, varenicline significantly improved axial symptoms and rapid alternating movements in patients with SCA3 as measured by SARA subscores and was fairly well tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that varenicline improved the axial functions of gait, stance, and timed 25-foot walk but did not improve appendicular function, except for rapid alternating movements, in adult patients with genetically confirmed SCA3.

Response to medication dosing alerts for pediatric inpatients using a computerized provider order entry system.

OBJECTIVE: Medication dosing errors are of particular concern in hospitalized children. Avoidance of such errors is essential to quality improvement and patient safety. Computerized provider order entry (CPOE) systems with clinical decision support (CDS) have the potential to reduce medication errors. The objective of this study was to evaluate provider response to the dosing alerts in a CPOE system with CDS for pediatric inpatients and to identify differences in provider response based on clinician specialty. PATIENTS AND METHODS: We conducted a retrospective analysis of all medication dosing alerts over a 1-year period (January 1 through December 31, 2008) for all pediatric inpatients at Hospital for Special Surgery. Alerts were analyzed with respect to medication dosing, prescriber, and action taken by the prescriber after the alert was triggered (i.e., accepted suggested change, ignored recommendation/overrode, or cancelled the order). RESULTS: During the study period, 18,163 medication orders were placed and 1,024 dosing alerts were fired. Overdosing of medications accounted for 91% of the alerts and underdosing 9%. The pediatric-trained providers ignored more alerts and cancelled fewer orders than the non-pediatric-trained providers (p<0.001). Both groups changed the order similarly based on CDS recommendations. CONCLUSIONS: Differences in response to CDS were found between pediatric-trained and non-pediatric-trained providers caring for pediatric patients; however, both groups changed orders based on CDS similarly. CPOE with built-in CDS may be of particular value when providers with different specialties and types of training are caring for pediatric patients.

Pontine and cerebellar atrophy correlate with clinical disability in SCA2.

Spinocerebellar ataxia type 2 (SCA2) has protean manifestations, and a clinical marker of progression is needed. Although MRI is a promising tool, it is unclear whether the degree of atrophy shown on MRI is correlated with clinical dysfunction. Here the authors used high-resolution volumetric MRI analysis to show that cerebellar and pontine volumes specifically and closely correlate with functional staging scores.

Relative atrophy of the flocculus and ocular motor dysfunction in SCA2 and SCA6.

Two hereditary ataxia syndromes show distinct profiles of region-specific atrophy and ocular motor deficits. Selective pontine atrophy is associated with slowed saccades in ataxin-2 mutations, and selective floccular atrophy is associated with impaired pursuit and gaze-holding abnormalities in Ca(V)2.1 mutations. Although the flocculus seems to be spared relative to the pons in ataxin-2 mutations, and pursuit and gaze-holding appear to be relatively normal, these can be difficult to assess at the bedside, as corrective saccades are also slow and hard to discern. Here, we show the presence of significant floccular atrophy compared with controls in both ataxin-2 and Ca(V)2.1 mutations, which raises the possibility that abnormalities of smooth pursuit or gaze-holding are present in both conditions.

Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia.

BACKGROUND: The small-conductance calcium-activated potassium channel gene (hSKCa3) contains 2 CAG repeats, 1 of which is highly polymorphic. Although this repeat is not pathologically expanded in patients with schizophrenia, some studies have suggested an allelic association with schizophrenia. CAG expansions in other genes such as the alpha1 subunit of a brain-specific P/Q-type calcium channel gene cause spinocerebellar ataxia type 6, whereas the length of the CAG repeat in the RAI1 gene modifies the age of onset of spinocerebellar ataxia type 2. OBJECTIVES: To evaluate expansions in the hSKCa3 polyglutamine domain as causative for ataxia, and to study the association between the length of the polyglutamine repeat and the presence of ataxia. METHODS: We analyzed this repeat in 122 patients with autosomal dominant cerebellar ataxia, or sporadic ataxia, and compared allele distribution with 750 alleles seen in 2 healthy control groups and 172 alleles in patients with Parkinson disease. RESULTS: The distribution of alleles in ataxia patients and controls was significantly different by Wilcoxon rank test (P <.001). Twenty-two or more polyglutamine tracts were more common in ataxia patients compared with controls by chi2 analysis (P<.001). CONCLUSION: Longer stretches of polyglutamines in a human potassium channel are not causative for ataxia, but they are associated with the presence of ataxia. There is no association with the presence of Parkinson disease.

Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset.

Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which encodes the alpha1 subunit of a P/Q-type voltage-gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo-ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.

Radiosensitivity of ataxia-telangiectasia, X-linked agammaglobulinemia, and related syndromes using a modified colony survival assay.

We used a modified colony survival assay to measure the sensitivity to ionizing radiation of more than 50 lymphoblastoid cell lines from normal individuals and from patients with ataxia-telangiectasia, Nijmegen breakage syndrome variants, and X-linked agammaglobulinemia. All of these disorders are associated with an increased frequency of cancer. Lymphoblastoid cell lines from patients with ataxia-telangiectasia complementation groups A, C, D, and E; ATFresno; Nijmegen breakage syndrome variants V1 and V2; and X-linked agammaglobulinemia showed marked radiosensitivity, whereas ataxia-telangiectasia heterozygotes were similar to controls. Friedreich's ataxia is not associated with increased cancer risk; lymphoblastoid cell lines from two such patients showed normal radiosensitivity. Taken together, these results suggest that some forms of X-ray sensitivity and cancer susceptibility share a common mechanism, such as an enzyme that is necessary both for the repair of radiation damage to DNA and for gene rearrangements during V(D)J recombination.

Modern techniques of pain management.

Even clinicians who keep up with the research literature on pain mechanisms may find themselves uncertain when trying to bring these new theories down to practical application for a patient with pain. The areas of dysfunction to be attacked should be systematically outlined, a complementary set of treatments be decided on, and follow-through be done in a reasonable number of visits. Physicians must also know when to refer a patient who goes beyond their own assessment and treatment skills.

The mental status of patients with Friedreich's ataxia.

In the clinical literature, the majority of patients with Friedreich's ataxia are described as having signs of intellectual decline and serious psychiatric symptomatology. Recent studies contradict this clinical picture, but indicate some discrete mental status changes, such as slowing of information processing speed not related to motor abnormality, in a more strictly defined Friedreich's population. This study describes the mental status changes in a sample of 38 patients seen at the University of California at Los Angeles Neuropsychiatric Hospital, Ataxia Clinic. The sample was defined using strict clinical and biochemical criteria. Only one of the 38 patients showed evidence of intellectual deterioration. Ninety-two percent of the patients experienced some affective difficulty, however, ranging from major depression to normal grief. Three patients have reached their mid-forties (one is 64 years of age) without any serious mental status changes. These findings point out the importance of nurses' expecting these patients to function normally in the cognitive domain. Implications related to specific nursing interventions are discussed.

Angulation of ringed grasping instruments.

A modification of conventional needleholders with grasping rings is presented. It consists of providing a 30 degree angulation of the rings to the body of the instrument, 1 cm. distal to the ratchet. The net effects are ease of grasping the instrument from the tray, increased comfort for both right- and left-handed surgeons, better visibility, and increased effectiveness in encompassing more tissue deeply for better wound edge eversion.

Evoked potential abnormalities in the various inherited ataxias.

Visual (VEP), brainstem auditory (BAEP), and somatosensory (SEP) evoked potential tests were performed in 45 patients representing ten types of inherited disorders in which ataxia was the most prominent symptom. Comparable VEP abnormalities were present among all types of patients. Normal BAEP tests were recorded in most patients except those with olivopontocerebellar atrophy. SEP results were often more severely abnormal in patients with Friedreich's ataxia. The observations emphasize the similarity in expression of different metabolic-degenerative disorders. When these tests are used clinically, certain features of evoked potentials (especially left-right symmetry) are typical of the inherited ataxias as a group. Few distinguishing features differentiate the individual disorders.

Optimal conditions for the assay of lipoamide dehydrogenase in homogenized human platelets.

Widely different method have been used to assay lipoamide dehydrogenase in tissues from patients with neurological diseases. We have re-examined conditions of assay in homogenized human platelets in the light of results of optimal and inhibitory conditions others have found for the purified pig and rat liver enzymes. Optimal conditions in homogenized platelets for the forward, physiological direction were pH 8.0, 2-4 mmol/l dihydrolipoamide and 1.6-2 mmol/l NAD+ and for the reverse reaction, pH 7.3, 1.2-2 mmol/l lipoamide and 0.125-0.2 mmol/l NADH. Km values by the Lineweaver-Burke method were approximately 420 mumol/l dihydrolipoamide, 180 mumol/l NAD+, 600 mumol/l lipoamide and 27 mumol/l NADH. The optimal conditions and Km values are similar to those reported for the purified pig and rat enzymes. Assays by the present methods should therefore reflect the activity of lipoamide dehydrogenase and not the effects of substrate or cofactor inhibition nor the effects of other, interfering enzyme activities.