Hsin-Hsi Tsai

Hepatitis C virus infection as a risk factor for Parkinson disease A nationwide cohort study

Objective: To determine whether hepatitis C virus (HCV) infection is a risk factor for developing Parkinson disease (PD). Methods: This nationwide population-based cohort study was based on data obtained from a dataset of the Taiwan National Health Insurance Research Database for the period 2000 to 2010. A total of 49,967 patients with viral hepatitis were included for analysis. Furthermore, 199,868 people without viral hepatitis were included for comparisons. Patients with viral hepatitis were further grouped into 3 cohorts: hepatitis B virus (HBV) infection, HCV infection, and HBV-HCV coinfection. In each cohort, we calculated the incidence of developing PD. A Cox proportional hazards model was applied to estimate the risk of developing PD in terms of hazard ratios (HRs) and 95% confidence intervals (CIs). Results: The crude HRs for developing PD was 0.66 (95% CI = 0.55–0.80) for HBV infection, 2.50 (95% CI = 2.07–3.02) for HCV infection, and 1.28 (95% CI = 0.88–1.85) for HBV-HCV coinfection. The association between HCV and PD remained statistically significant after adjustments for age, sex, and comorbidities (adjusted HR = 1.29, 95% CI = 1.06–1.56). Conclusions: We conducted a large nationwide population-based study and found that patients with HCV exhibit a significantly increased risk of developing PD.

Correlation of Cerebral Microbleed Distribution to Amyloid Burden in Patients with Primary Intracerebral Hemorrhage

The underlying pathology of cerebral microbleeds (CMBs) with mixed lobar and deep distribution remains contentious. The aim of this study was to correlate CMBs distribution to β-amyloid burden in patients with primary intracerebral hemorrhage (ICH). Fourty-seven ICH patients underwent magnetic resonance susceptibility-weighted imaging and 11C-Pittsburgh Compound B positron emission tomography. The amyloid burden was expressed as standardized uptake value ratio with reference to cerebellum, and presented as median (interquartile range). Patients were categorized into the lobar, mixed (both lobar and deep regions), and deep types of CMB. Comparing the lobar (17%), mixed (59.6%) and deep (23.4%) CMB types, the global amyloid burden was significantly higher in the mixed type than the deep type (1.10 [1.03–1.25] vs 1.00 [0.97–1.09], p = 0.011), but lower than in the lobar type (1.48 [1.18–1.50], p = 0.048). On multivariable analysis, the ratio of lobar to deep CMB number was positively correlated with global (p = 0.028) and occipital (p = 0.031) amyloid burden. In primary ICH, patients with lobar and mixed CMB types are associated with increased amyloid burden than patients with deep type. The ratio of lobar to deep CMB number is an independent indicator of cerebral β-amyloid deposition.

Increased risk of dementia in patients hospitalized with acute kidney injury: A nationwide population-based cohort study

Purpose To determine whether acute kidney injury (AKI) is a risk factor for dementia. Methods This nationwide population-based cohort study was based on data from the Taiwan National Health Insurance Research Database for 2000–2011. The incidence and relative risk of dementia were assessed in 207788 patients hospitalized for AKI. The comparison control was selected using the propensity score based on age, sex, index year and comorbidities. Results During the 12-year follow-up, patients with AKI had a significantly higher incidence for developing dementia than did the controls (8.84 vs 5.75 per 1000 person-y). A 1.88-fold increased risk of dementia (95% confidence interval, 1.76–2.01) was observed after adjustment for age, sex, and several comorbidities (diabetes, hypertension, hyperlipidemia, head injury, depression, stroke, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, atrial fibrillation, cancer, liver disease, chronic infection/inflammation, autoimmune disease, malnutrition). Conclusions We found that patients with AKI exhibited a significantly increased risk of developing dementia. This study provides evidence on the association between AKI and long-term adverse outcomes. Additional clinical studies investigating the related pathways are warranted.

Updates on Prevention of Hemorrhagic and Lacunar Strokes

Intracerebral hemorrhage (ICH) and lacunar infarction (LI) are the major acute clinical manifestations of cerebral small vessel diseases (cSVDs). Hypertensive small vessel disease, cerebral amyloid angiopathy, and hereditary causes, such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), constitute the three common cSVD categories. Diagnosing the underlying vascular pathology in these patients is important because the risk and types of recurrent strokes show significant differences. Recent advances in our understanding of the cSVD-related radiological markers have improved our ability to stratify ICH risk in individual patients, which helps guide antithrombotic decisions. There are general good-practice measures for stroke prevention in patients with cSVD, such as optimal blood pressure and glycemic control, while individualized measures tailored for particular patients are often needed. Antithrombotic combinations and anticoagulants should be avoided in cSVD treatment, as they increase the risk of potentially fatal ICH without necessarily lowering LI risk in these patients. Even when indicated for a concurrent pathology, such as nonvalvular atrial fibrillation, nonpharmacological approaches should be considered in the presence of cSVD. More data are emerging regarding the presentation, clinical course, and diagnostic markers of hereditary cSVD, allowing accurate diagnosis, and therefore, guiding management of symptomatic patients. When suspicion for asymptomatic hereditary cSVD exists, the pros and cons of prescribing genetic testing should be discussed in detail in the absence of any curative treatment. Recent data regarding diagnosis, risk stratification, and specific preventive approaches for both sporadic and hereditary cSVDs are discussed in this review article.

Re: Wangensteen et al. of a letter on 'Hepatitis C virus infection: a risk factor for Parkinson's disease.'.

To the Editor Thank you for your interesting postulate of a ‘double-hit’ theory in activating neuroinflammatory signalling and leading susceptible individuals to develop Parkinson’s disease (PD). You enquired whether our subjects infected with HCV in the recent study published in the Journal of Viral Hepatitis [1] were administered interferon and whether we have made allowance for this treatment in these patients. Unfortunately, most of the HCV-infected patients had not been exposed to interferon at the time while this community-based study was conducted between 2000 and 2004. Interferon has been reimbursed for anti-HCV therapy by the Bureau of National Health Insurance in Taiwan only since 2004. Moreover, HCV-infected Taiwanese patients have had a low treatment rate, 10.1% and 13.7% for antiHCV-seropositive and HVG-viremic population, respectively, according to a recent nationwide survey [2]. Therefore, interferon was very unlikely to confound the association between HCV and PD. Our study [1] has been recently confirmed by another large Taiwanese population-based study using a data set from the Taiwan National Health Insurance Research Database for the period 2000–2010 [3]. Our corresponding author Professor Liou, a senior neurologist, has also participated in this study. The crude hazard ratio for developing PD was 2.50 (95% CI = 2.07–3.02) for HCV infection; such an association between HCV and PD remained statistically significant after adjustments for age, sex and comorbidities (adjusted HR = 1.29; 95% CI = 1.06–1.56), which was slightly lower but still consistent with our figure of 1.39 (95% CI = 1.07–1.80). Although Tsai et al. included those who had been administered with interferon into the analysis, their results would not be substantially affected by interferon because the proportion of HCV-infected patients exposed to interferon is low. To prove this, Tsai analysed this data set (6943 HCV-infected patients) by stratifying the use of interferon as their data set has included information on interferon from 2004 onwards. Of the 6943 HCV-infected patients, only 1098 (15.81%) patients were administered with interferon. The incidence rates of PD were 248.75 (per 100 000 person-years) in those exposed to interferon and 30.21 (per 100 000 person-years) in those unexposed to interferon. Compared with a 79.75 (per 100 000 person-years) incidence rate in the average-risk Taiwanese population, the relative rate was 1.55 (1.17–2.06) for the interferon group and 0.5 (0.12–2.00) for the noninterferon group. Based on these findings, it seems that our Taiwanese data fail to support the proposed ‘double-hit’ theory. We still think that the main mechanism by which HCV might raise the risk for PD is mainly because HCV can induce dopaminergic neuron death in the midbrain neuron–glia coculture system (similar to that of MPP+) that is supported by the finding that HCV infection might release inflammatory cytokines, such as ICAM-1 and RANTES signalling.

Neurolymphomatosis as the primary presentation of non-Hodgkin's Lymphoma

A 57-year-old previous healthy woman was referred to our hospital due to progressive weakness, numbness and pain in the left leg for 3 months. She initially suffered from pain and numbness at left buttock and posteriolateral thigh without limitation in her daily activities. Two months later, the pain rapidly progressed to her left calf and dorsal foot, and weakness in left ankle followed by left proximal leg developed. She also felt numbness at right index finger, clumsiness in right hand and stress urinary incontinence. Neurological examinations showed normal functions of cranial nerves, weakness in flexion and extension of left hip, knee and ankle. Deep tendon reflexes at left knee and ankle were absent. Sensory evaluation showed hypoesthesia at left posteriolateral thigh and leg, and dorsal foot. Nerve conduction studies and electromyography showed (1) reduced amplitudes of compound muscle action potentials …

Distribution of Lacunar Infarcts in Asians With Intracerebral Hemorrhage: A Magnetic Resonance Imaging and Amyloid Positron Emission Tomography Study

Background and Purpose— We evaluated whether lacunes in centrum semiovale (lobar lacunes) were associated with cerebral amyloid angiopathy (CAA) markers in an Asian intracerebral hemorrhage (ICH) population. Methods— One hundred ten patients with primary ICH were classified as CAA-ICH (n=24; mean age, 70.9±13.9) or hypertensive ICH (n=86; mean age, 59.3±13.0) according to the presence of strictly lobar (per modified Boston criteria) or strictly deep bleeds (both ICH and cerebral microbleeds), respectively. Lacunes were evaluated in the supratentorial area and classified as lobar or classical deep based on the location. A subgroup of 36 patients also underwent Pittsburgh Compound B positron emission tomography to measure cerebral amyloid deposition and global standardized uptake value ratio were calculated. Results— Lobar lacunes were more frequent in CAA-ICH than hypertensive ICH (29.2 versus 11.6%; P=0.036). In multivariable models, lobar lacunes were associated with lobar cerebral microbleed (odds ratio, 6.8; 95% confidence interval, 1.6–29.9; P=0.011) after adjustment for age, sex, hypertension, and white matter hyperintensity. In 15 CAA-ICH and 21 hypertensive ICH patients with Pittsburgh Compound B positron emission tomography, correlation analyses between lobar lacune counts and global standardized uptake value ratio showed positive association (&rgr;=0.40; P=0.02) and remained significant after adjustment for age (r=0.34; P=0.04). Conclusions— Our findings expand on recent work showing that lobar lacunes are more frequent in CAA-ICH than hypertensive ICH. Their independent association with lobar cerebral microbleeds and brain amyloid deposition suggests a relationship with CAA even in an Asian cohort with overall higher hypertensive load.

Amyloid-PET burden and regional distribution in cerebral amyloid angiopathy: a systematic review and meta-analysis of biomarker performance

Introduction We performed a meta-analysis to synthesise current evidence on amyloid-positron emission tomography (PET) burden and presumed preferential occipital distribution in sporadic cerebral amyloid angiopathy (CAA). Methods In a PubMed systematic search, we identified case–control studies with extractable data on global and occipital-to-global amyloid-PET uptake in symptomatic patients with CAA (per Boston criteria) versus control groups (healthy participants or patients with non-CAA deep intracerebral haemorrhage) and patients with Alzheimer’s disease. To circumvent PET studies’ methodological variation, we generated and used ‘fold change’, that is, ratio of mean amyloid uptake (global and occipital-to-global) of CAA relative to comparison groups. Amyloid-PET uptake biomarker performance was then quantified by random-effects meta-analysis on the ratios of the means. A ratio >1 indicates that amyloid-PET uptake (global or occipital/global) is higher in CAA than comparison groups, and a ratio <1 indicates the reverse. Results Seven studies, including 106 patients with CAA (>90% with probable CAA) and 138 controls (96 healthy elderly, 42 deep intracerebral haemorrhage controls) and 72 patients with Alzheimer’s disease, were included. Global amyloid-PET ratio between patients with CAA and controls was above 1, with an average effect size of 1.18 (95% CI 1.08 to 1.28; p<0.0001). Occipital-to-global amyloid-PET uptake ratio did not differ between patients with CAA versus patients with deep intracerebral haemorrhage or healthy controls. By contrast, occipital-to-global amyloid-PET uptake ratio was above 1 in patients with CAA versus those with Alzheimer’s disease, with an average ratio of 1.10 (95% CI 1.03 to 1.19; p=0.009) and high statistical heterogeneity. Conclusions Our analysis provides exploratory actionable data on the overall effect sizes and strength of amyloid-PET burden and distribution in patients with CAA, useful for future larger studies.

Ictal Phase Perfusion SPECT of Nonketotic Hyperglycemia-Induced Parieto-occipital Seizure.

A 68-year-old man with diabetes mellitus type 2 presented himself with visual distortion and apraxia. Nonketotic hyperglycemic seizure with both motor and sensory components was suspected. Tc-ECD perfusion SPECT demonstrated hyperperfusion at right parieto-occipital lobe during ictal phase. Normalization of hyperperfused area was noted on follow-up perfusion SPECT after intense glucose control. In nonketotic hyperglycemic state, the depletion of GABA in cerebral neurons lowers the seizure threshold. We demonstrated that ictal phase perfusion SPECT contributed to not only diagnosis but also served as a follow-up tool.