Richard Shek-kwan Chang

The default mode network is disrupted in parkinson's disease with visual hallucinations

Background: Visual hallucinations (VH) are one of the most striking nonmotor symptoms in Parkinsons disease (PD), and predict dementia and mortality. Aberrant default mode network (DMN) is associated with other psychoses. Here, we tested the hypothesis that DMN dysfunction contributes to VH in PD. Methods: Resting state functional data was acquired from individuals with PD with VH (PDVH) and without VH (PDnonVH), matched for levodopa drug equivalent dose, and a healthy control group (HC). Independent component analysis was used to investigate group differences in functional connectivity within the DMN. In addition, we investigated whether the functional changes associated with hallucinations were accompanied by differences in cortical thickness. Results: There were no group differences in cortical thickness but functional coactivation within components of the DMN was significantly lower in both PDVH and PDnonVH groups compared to HC. Functional coactivation within the DMN was found to be greater in PDVH group relative to PDnonVH group. Conclusion: Our study demonstrates, for the first time that, within a functionally abnormal DMN in PD, relatively higher “connectivity” is associated with VH. We postulate that aberrant connectivity in a large scale network affects sensory information processing and perception, and contributes to “positive” symptom generation in PD. Hum Brain Mapp 35:5658–5666, 2014.

Multimodal MRI of the hippocampus in Parkinson’s disease with visual hallucinations

Visual hallucinations carry poor prognosis in Parkinson’s disease. Here we tested the hypothesis that the hippocampus and visuospatial memory impairment play a central role in the pathology of PD with visual hallucinations. Multimodal magnetic resonance imaging of the brain was carried out in 12 people with PD and visual hallucinations; 15 PD individuals without hallucinations; and 14 healthy controls. Age, gender, cognitive ability, and education level were matched across the three groups. PD patients were taking dopaminergic medication. Hippocampal volume, shape, mean diffusivity (MD), and functional connectivity within the whole brain were examined. Visuospatial memory was compared between groups, and correlations with hippocampal MD, functional connectivity, and the severity of hallucinations were explored. There were no macrostructural differences across groups, but individuals with hallucinations had higher diffusivity in posterior hippocampus than the other two groups. Visuospatial memory was poorer in both PD groups compared to controls, and was correlated with hallucinations. Finally, hippocampal functional connectivity in the visual cortices was lower in those with hallucinations than other groups, and this correlated with visuospatial memory impairment. In contrast, functional connectivity between the hippocampus and default mode network regions and frontal regions was greater in the PD hallucinators compared to other groups. We suggest that hippocampal pathology, which disrupts visuospatial memory, makes a key contribution to visual hallucinations in PD. These findings may pave the way for future studies of imaging biomarkers to measure treatment response in those with PD who are most at risk of poor outcomes.

Long-term prognostic implications of visit-to-visit blood pressure variability in patients with ischemic stroke.

BACKGROUND Blood pressure (BP) variability (BPV) is a novel risk factor for the development of atherosclerotic diseases. High BPV has recently been shown to predict all-cause and cardiovascular mortality in patients with lacunar infarct. Whether BPV has prognostic implications in patients with ischemic stroke subtypes, other than those due to small-vessel occlusion, remains uncertain. METHODS We prospectively followed up the clinical outcome of 632 consecutive ischemic stroke patients without atrial fibrillation. The average BP and BPV, as determined by the coefficient of variation of the systolic and diastolic BP, were recorded during a mean 12 ± 6 outpatient clinic visits. RESULTS The average age of the population was 71 ± 11 years. After a mean of 76 ± 18 months of follow-up, 161 patients died (26%); 35% (n = 56 of 161) of these deaths were due to cardiovascular causes. Sixteen percent and 5% developed recurrent stroke and acute coronary syndrome (ACS), respectively. After adjusting for mean systolic BP and confounding variables, patients with high systolic BPV were at significantly greater risk of cardiovascular mortality (hazards ratio (HR) = 2.36; 95% confidence interval (CI) = 1.02-5.49; P < 0.05). High systolic BPV also predicted all-cause mortality after adjusting for mean systolic BP (HR = 1.79; 95% CI = 1.16-2.75; P < 0.05). There was no association between systolic BPV and nonfatal recurrent stroke or nonfatal ACS. Raised diastolic BPV did not predict recurrent nonfatal stroke, nonfatal ACS, or mortality. CONCLUSIONS Visit-to-visit systolic BPV predicts long-term all-cause and cardiovascular mortality in patients with ischemic stroke without atrial fibrillation, independent of other conventional risk factors, including average BP control.

Stroke Patients with a Past History of Cancer Are at Increased Risk of Recurrent Stroke and Cardiovascular Mortality

Background and Purpose Cancer patients are at increased risk of cardiovascular and cerebrovascular events. It is unclear whether cancer confers any additional risk for recurrent stroke or cardiovascular mortality after stroke. Methods This was a single center, observational study of 1,105 consecutive Chinese ischemic stroke patients recruited from a large stroke rehabilitation unit based in Hong Kong. We sought to determine whether patients with cancer are at higher risk of recurrent stroke and cardiovascular mortality. Results Amongst 1,105 patients, 58 patients (5.2%) had cancer, of whom 74% were in remission. After a mean follow-up of 76±18 months, 241 patients developed a recurrent stroke: 22 in patients with cancer (38%, annual incidence 13.94%/year), substantially more than those without cancer (21%, 4.65%/year) (p<0.01). In a Cox regression model, cancer, age and atrial fibrillation were the 3 independent predictors of recurrent stroke with a hazard ratio (HR) of 2.42 (95% confidence interval (CI): 1.54–3.80), 1.01 (1.00–1.03) and 1.35 (1.01–1.82) respectively. Likewise, patients with cancer had a higher cardiovascular mortality compared with those without cancer (4.30%/year vs. 2.35%/year, p = 0.08). In Cox regression analysis, cancer (HR: 2.08, 95% CI: 1.08–4.02), age (HR: 1.04, 95% CI 1.02–1.06), heart failure (HR: 3.06, 95% CI 1.72–5.47) and significant carotid atherosclerosis (HR: 1.55, 95% CI 1.02–2.36) were independent predictors for cardiovascular mortality. Conclusions Stroke patients with a past history of cancer are at increased risk of recurrent stroke and cardiovascular mortality.

Classifications of seizures and epilepsies, where are we? – A brief historical review and update

In March 2017, the International League Against Epilepsy (ILAE) announced their new classifications of seizures and epilepsies. Development of these classification systems led by the ILAE is a long and complicated process. Outsiders may find it difficult to understand the arguments behind. We summarize the major developmental milestones of the ILAE classification schemata. An update of the latest classification is also included. It is hope that this review can serve as an outline in learning the taxonomy in epileptology.

Long‐Term Prognostic Implications of Cerebral Microbleeds in Chinese Patients With Ischemic Stroke

Background This study was performed to determine the clinical correlates and long‐term prognostic implications of microbleed burden and location in Chinese patients with ischemic stroke. Methods and Results We recruited 1003 predominantly Chinese patients with ischemic stroke who received magnetic resonance imaging at the University of Hong Kong. We determined the clinical correlates of microbleeds and the long‐term risks (3126 patient‐years of follow‐up) of recurrent ischemic stroke and intracerebral hemorrhage (ICH) by microbleed burden (0 versus 1, 2–4, and ≥5) and location, adjusting for age, sex, and vascular risk factors and stratified by antithrombotic use. Microbleeds were present in 450 of 1003 of the study population (119/450 had ≥5, 187/450 had mixed location). Having ≥5 microbleeds was independently associated with prior antiplatelet and anticoagulant use, whereas microbleeds of mixed location were independently associated with hypertension and prior anticoagulant use (all P<0.05). Microbleed burden was associated with an increased risk of ICH (microbleed burden versus no microbleeds: 1 microbleed: multivariate hazard ratio: 0.59 [95% confidence interval, 0.07–5.05]; 2–4 microbleeds: multivariate hazard ratio: 2.14 [95% confidence interval, 0.50–9.12]; ≥5 microbleeds: multivariate hazard ratio: 9.51 [95% confidence interval, 3.25–27.81]; P trend<0.0001), but the relationship of microbleed burden and risk of recurrent ischemic stroke was not significant (P trend=0.054). Similar findings were noted in the 862 of 1003 patients treated with antiplatelet agents only (ICH: P trend<0.0001; ischemic stroke P trend=0.096). Multivariate analysis revealed that, independent of vascular risk factors, antithrombotic use, and other neuroimaging markers of small vessel disease, having ≥5 microbleeds (multivariate hazard ratio: 6.08 [95% confidence interval, 1.11–33.21]; P=0.037) was identified as an independent predictor of subsequent ICH, but neither microbleed burden nor location was predictive of recurrent ischemic stroke risk. Conclusions In Chinese patients with ischemic stroke, a high burden of cerebral microbleeds was significantly associated with an increased risk of ICH; however, neither microbleed location nor burden was associated with recurrent ischemic stroke risk.

The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review

The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms. It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder. The advent of next generation sequencing (NGS) has allowed for a system-wide, unbiased approach to identify all gene variants in the genome simultaneously. With the plethora of new genes being identified, genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia (SCA), hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth disease (CMT) has become widely accepted. It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). The observation of pleiotropy has emerged, with mutations in the same gene giving rise to diverse phenotypes, which further increases the complexity of phenotype-genotype correlation. Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene, presence of modifier genes, and oligogenic inheritance. Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms, translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies, and ultimately finding disease-modifying therapies for neurodegenerative disorders.

Visuomotor control in patients with Parkinson's disease

Previous studies have suggested that the deteriorated visuomotor control in patients with PD (Parkinsons disease) is due to deficits in various aspects of the sensory-motor processing rather than motor control itself. In the current study, by taking a control-theoretic approach, we systematically examined how PD and antiparkinsonian medication affect visuomotor control and the underlying sensory-motor system. We tested 20 PD patients in both ON and OFF medication states and 20 demographically matched healthy controls with a commonly used manual control task. Specifically, in each 95-s trial, participants were instructed to use a joystick to control a randomly moving target to keep it centered on a computer display. We found that although antiparkinsonian medication improved visuomotor control in PD patients, they still showed significantly decreased control precision (measured by RMS error) and response amplitude (gain) as well as increased response delay (phase lag) compared with healthy controls. Our model-driven analysis revealed that PD impairs the responsiveness and the predicting ability of the sensory-motor system as well as the stability of the neuromuscular system. Taking antiparkinsonian medication improves the responsiveness of the sensory-motor system. More importantly, it improves the ability of the sensory-motor system to make sensory predictions of the current control actions (see Wolpert et al., 1995) to anticipate the input error signals and generate control responses ahead of time up to the level of healthy controls. However, taking antiparkinsonian medication does not improve the stability of the neuromuscular system. These results support the claim that the effect of antiparkinsonian medication on visuomotor control is mainly through improving visual-stimulus-dependent sensory-motor processing. The present study provides the first quantitative examination of the effects of PD and antiparkinsonian medication on the visual-stimulus-dependent sensory-motor and visual-stimulus-independent neuromuscular systems underlying visuomotor control. The findings have practical implications for developing sensitive assessment tools to evaluate the efficacy of different therapies for PD and preliminary screening and training tools for fitness-to-drive in PD patients.

Gabapentin-induced myoclonus in an elderly with end-stage renal failure

A 79-year-old woman, with end stage renal failure (ESRF) due to diabetic nephropathy, presented with generalized involuntary movements for 3 days. She had a history of hypertension, hyperlipidemia, and gouty arthritis. Gabapentin (GBP) 300 mg nocte was prescribed for her postherpetic neuralgia involving her right V1 dermatome. Ten hours later, she developed generalized involuntary jerky movements, and was also drowsy and unable to walk. She did not take further doses of GBP. On the following 2 days, her involuntary movements persisted but were decreasing in severity. She presented to us on the third day. She had a Glasgow coma scale of 15 and had high frequency multifocal myoclonus involving her neck, bilateral upper extremities, and trunk. Blood tests showed random glucose 8.1 mmol/L, urea 27.4 mmol/L, creatinine 531 mmol/L, adjusted calcium 2.15 mmol/L, phosphate 1.87 mmol/L, and normal liver function test. Computed tomography of the brain reviewed cerebral atrophy. Her medications include calcium supplements, frusemide, amlodipine, isosorbide mononitrate, sodium bicarbonate, and paracetamol. GBP level measured 67 hours later was 23 mmol/L (reference range 70e120 mmol/L). Clonazepam was prescribed but she was unable to tolerate it due to

Cavum septum pellucidum and vergae in an elderly man

An 88-year-old man, who was a chronic smoker with history of chronic obstructive pulmonary disease, cervical myelopathy, hypertension, pulmonary tuberculosis, myocardial infarction, and peripheral vascular disease, was admitted because of an episode of chronic obstructive pulmonary disease exacerbation and non-syncopal fall with head injury. Upon admission, the Glasgow Coma Scale was full, there was no focal neurological deficit, and respiratory examination revealed diffuse wheezing. Because of the