The neurocognitive and neuropsychiatric manifestations of Susac syndrome: a brief review of the literature and future directions.

Encephalopathy is part of the clinical triad of Susac syndrome, but a detailed understanding of the neurocognitive and neuropsychiatric profile of this condition is lacking. Existing literature indicates that cognitive deficits range in severity from subtle to profound. Executive function and short-term recall are affected frequently. Psychiatric manifestations may be absent or may include anxiety, mood disorders or psychosis. If psychiatric phenomena develop during the disease course, it can be hard to disentangle whether symptoms directly relate to the pathology of Susac syndrome or are secondary to treatment-related side effects. In this article, we review what is known about the cognitive and psychiatric morbidity of Susac syndrome and identify areas where knowledge is deficient. Importantly, we also provide a framework for future research, arguing that better phenotyping, understanding of pathophysiology, evaluation of treatments on cognitive and psychiatric outcomes, and longitudinal data capture are vital to improving patient outcomes.

Inter-rater variability in scoring of Addenbrooke's Cognitive Examination-Third Edition (ACE-III) protocols.

BACKGROUND: Despite its wide use in dementia diagnosis on the basis of cut-off points, the inter-rater variability of the Addenbrooke's Cognitive Examination-Third Edition (ACE-III) has been poorly studied. METHODS: Thirty-one healthcare professionals from an older adults' mental health team scored two ACE-III protocols based on mock patients in a computerised form. Scoring accuracy, as well as total and domain-specific scoring variability, were calculated; factors relevant to participants were obtained, including their level of experience and self-rated confidence administering the ACE-III. RESULTS: There was considerable inter-rater variability (up to 18 points for one of the cases), and one case's mean score was significantly higher (by nearly four points) than the true score. The Fluency, Visuospatial and Attention domains had greater levels of variability than Language and Memory. Higher scoring accuracy was not associated with either greater levels of experience or higher self-confidence in administering the ACE-III. CONCLUSIONS: The results suggest that the ACE-III is susceptible to scoring error and considerable inter-rater variability, which highlights the critical importance of initial, and continued, administration and scoring training.

Reliability and factor structure of the Short Problem Behaviors Assessment for Huntington's disease (PBA-s) in the TRACK-HD and REGISTRY studies.

The authors report the inter-rater reliability and factor structure of the Short Problem Behaviors Assessment (PBA-s), a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohen's kappa calculated to assess inter-rater reliability. The mean kappa was 0.74 for severity and 0.76 for frequency scores, whereas weighted kappa (allowing scores to differ by 1 point) was 0.94 for severity and 0.92 for frequency scores. The results of factor analysis were consistent with previous studies using other measures. The authors conclude that the PBA-s is a reliable measure.

Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy.

TRACK-HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3-Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross-sectional data from this large well-characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene-positive subjects (120 PreHD and 119 early HD) from the TRACK-HD study were included. Using voxel-based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti-saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD.

Emotional face recognition deficits and medication effects in pre-manifest through stage-II Huntington's disease.

Facial emotion recognition impairments have been reported in Huntington's disease (HD). However, the nature of the impairments across the spectrum of HD remains unclear. We report on emotion recognition data from 344 participants comprising premanifest HD (PreHD) and early HD patients, and controls. In a test of recognition of facial emotions, we examined responses to six basic emotional expressions and neutral expressions. In addition, and within the early HD sample, we tested for differences on emotion recognition performance between those 'on' vs. 'off' neuroleptic or selective serotonin reuptake inhibitor (SSRI) medications. The PreHD groups showed significant (p<0.05) impaired recognition, compared to controls, on fearful, angry and surprised faces; whereas the early HD groups were significantly impaired across all emotions including neutral expressions. In early HD, neuroleptic use was associated with worse facial emotion recognition, whereas SSRI use was associated with better facial emotion recognition. The findings suggest that emotion recognition impairments exist across the HD spectrum, but are relatively more widespread in manifest HD than in the premanifest period. Commonly prescribed medications to treat HD-related symptoms also appear to affect emotion recognition. These findings have important implications for interpersonal communication and medication usage in HD.

Improving memory in outpatients with neurological disorders using a group-based training program.

Memory problems are common in patients with a range of neurological conditions, but there have been few attempts to provide and evaluate the usefulness of memory training for groups of neurological outpatients. We used a waitlist-controlled trial design to assess the effectiveness of a newly created, 6-session intervention, which involved training in the use of compensatory strategies as well as education regarding memory function, neurological damage, sleep and lifestyle factors that have an impact on memory. Fifty-six patients with neurological conditions (e.g., stroke, epilepsy) and memory complaints completed the training and assessments. Outcomes were evaluated in terms of reported strategy use as well as objective and subjective measures of anterograde and prospective memory. Training resulted in significant improvements on number of strategies used, scores on the Rey Auditory Verbal Learning Test (total learning and delayed recall) and self-report on the Comprehensive Assessment of Prospective Memory. Improvements were stable at 3-month follow-up. Better individual outcomes were related to lower baseline memory scores, fewer symptoms of depression and greater self-awareness of memory function. Overall the study provides encouraging results to indicate that patients with neurological conditions such as stroke and epilepsy can show improvements in memory after a relatively short group-based intervention.

Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington's disease.

BACKGROUND: Deterioration of cognitive functioning is a debilitating symptom in many neurodegenerative diseases, such as Huntington's disease (HD). To date, there are no effective treatments for the cognitive problems associated with HD. Cognitive assessment outcomes will have a central role in the efforts to develop treatments to delay onset or slow the progression of the disease. The TRACK-HD study was designed to build a rational basis for the selection of cognitive outcomes for HD clinical trials. METHODS: There were a total of 349 participants, including controls (n=116), premanifest HD (n=117) and early HD (n=116). A standardised cognitive assessment battery (including nine cognitive tests comprising 12 outcome measures) was administered at baseline, and at 12 and 24 months, and consisted of a combination of paper and pencil and computerised tasks selected to be sensitive to cortical-striatal damage or HD. Each cognitive outcome was analysed separately using a generalised least squares regression model. Results are expressed as effect sizes to permit comparisons between tasks. RESULTS: 10 of the 12 cognitive outcomes showed evidence of deterioration in the early HD group, relative to controls, over 24 months, with greatest sensitivity in Symbol Digit, Circle Tracing direct and indirect, and Stroop word reading. In contrast, there was very little evidence of deterioration in the premanifest HD group relative to controls. CONCLUSIONS: The findings describe tests that are sensitive to longitudinal cognitive change in HD and elucidate important considerations for selecting cognitive outcomes for clinical trials of compounds aimed at ameliorating cognitive decline in HD.

Visual Working Memory Impairment in Premanifest Gene-Carriers and Early Huntington's Disease.

Working memory deficits have been found in Huntington's disease (HD) and in a small group of premanifest (PreHD) gene-carriers. However, the nature and extent of these deficits are unknown. In a large cross-sectional study, we aimed to determine the degree of visuospatial working memory dysfunction across multiple stages of HD. Specifically, visuospatial working memory capacity and response times across various degrees of difficulty were examined, as well as the relationship between visuospatial working memory and motor dysfunction. We examined 62 PreHD-A gene-carriers (>10.8 years from estimated disease onset), 58 PreHD-B gene-carriers (<10.8 years from estimated disease onset), 77 stage-1 HD patients (HD1), 44 stage-2 HD patients (HD2), and 122 healthy controls. Participants viewed coloured squares (in sets of 3, 5 and 7) on a screen and were to decide whether on a subsequent screen the encircled square has changed colour. Accuracy and response times were recorded. Compared to controls, significant group differences in visuospatial working memory capacity (accuracy) were seen in PreHD-B, HD1 and HD2 groups across the difficulty levels. Significant group differences on response times were found for all groups (PreHD-A to HD2) compared to controls; the most difficult level producing the only group difference in speed between PreHD-A and controls. Accuracy and speed were positively correlated only in the HD groups. These findings suggest that visuospatial working memory impairments are detectable in both premanifest and manifest HD; the manifest HD showed evidence for a "worse-worse phenomenon" whereby reductions were present in both motor speed and accuracy.

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.

Validation of a new measure of prospective memory: the Royal Prince Alfred Prospective Memory Test.

Prospective memory problems are common in patients with brain injury, but appropriate measures are limited. The reliability and validity of the newly designed Royal Prince Alfred Prospective Memory Test (RPA-ProMem), which has three alternate versions, was investigated in 20 healthy volunteers and 20 neurological patients with everyday prospective memory problems. The RPA-ProMem was found to be easy to score reliably (inter-rater reliability = .90) and its three versions were well matched (delayed alternate-form reliability = .71). Test validity and sensitivity to patient deficits were also supported. This new measure of prospective memory should be particularly useful in situations that require repeated assessments, such as evaluation of rehabilitation efforts.

Visuomotor integration deficits precede clinical onset in Huntington's disease.

OBJECTIVES: Visuomotor integration deficits have been documented in Huntington disease (HD), with disproportionately more impairment when direct visual feedback is unavailable. Visuomotor integration under direct and indirect visual feedback conditions has not been investigated in the stage before clinical onset ('premanifest'). However, given evidence of posterior cortical atrophy in premanifest HD, we predicted visuomotor integration would be adversely affected, with greater impairment under conditions of indirect visual feedback. METHODS: 239 subjects with the HD CAG expansion, ranging from more than a decade before predicted clinical onset until early stage disease, and 122 controls, completed a circle-tracing task, which included both direct and indirect visual feedback conditions. Measures included accuracy, speed, and speed of error detection and correction. Using brain images acquired with 3T magnetic resonance imaging (MRI), we generated grey and white matter volumes with voxel-based morphometry, and analyzed correlations with circle-tracing performance. RESULTS: Compared with controls, early HD was associated with lower accuracy and slower performance in both circle-tracing conditions. Premanifest HD was associated with lower accuracy in both conditions and fewer rotations in the direct condition. Comparing performance in the indirect condition with the direct condition, HD gene expansion-carriers exhibited a disproportionate increase in errors relative to controls. Premanifest and early HD groups required longer to detect and correct errors, especially in the indirect condition. Slower performance in the indirect condition was associated with lower grey matter volumes in the left somatosensory cortex in VBM analyses. CONCLUSIONS: Visuomotor integration deficits are evident many years before the clinical onset of HD, with deficits in speed, accuracy, and speed of error detection and correction. The visuomotor transformation demands of the indirect condition result in a disproportionate decrease in accuracy in the HD groups. Slower performance under indirect visual feedback was associated with atrophy of the left-hemisphere somatosensory cortex, which may reflect the proprioceptive demands of the task.

Scheimpflug keratometry versus conventional automated keratometry in routine cataract surgery.

PURPOSE: To evaluate keratometry (K) readings obtained with an automated keratometer (IOLMaster) and Scheimpflug imaging (Pentacam) in eyes having routine cataract surgery and to compare the predicted and actual refractive outcomes. SETTING: Epsom/St. Helier University Hospitals, London, United Kingdom. METHODS: In this retrospective study, the mean absolute prediction errors (MAEs) were obtained for automated keratometry and Scheimpflug keratometry: true net power, anterior K, and equivalent K [corrected] values for 1.0 to 7.0 mm corneal diameters. Eyes were divided into lower delta K (mean 1.15 diopters [D]) and higher delta K (mean 2.13 D) groups and lower preoperative astigmatism (mean 0.83 D) and higher preoperative astigmatism (mean 2.55 D) groups to determine notable trends. RESULTS: The study evaluated 29 eyes. The lowest MAE was 0.424 D +/- 0.421 (SD) for Scheimpflug equivalent [corrected] K at 3.0 mm; the second lowest was 0.452 +/- 0.359 D for automated keratometry, which had the smallest SD overall. The difference was not statistically significant. In the lower delta K and astigmatism groups, the automated keratometer had the lowest MAE and smallest standard deviation. In the higher groups, there was a trend toward increased accuracy for the Scheimpflug equivalent [corrected] K values at 3.0 mm. CONCLUSION: In this small study, Scheimpflug imaging was not superior to automated keratometry overall, but the data suggest a trend toward increased accuracy of Scheimpflug equivalent [corrected] K values in eyes with more irregular corneas. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.