Risk of Seizure Aggravation after COVID-19 Vaccinations in Patients with Epilepsy.

Although Coronavirus disease 2019 (COVID-19) vaccinations are generally recommended for persons with epilepsy (PwE), a significant vaccination gap remains due to patient concerns over the risk of post-vaccination seizure aggravation (PVSA). In this single-centre, retrospective cohort study, we aimed to determine the early (7-day) and delayed (30-day) risk of PVSA, and to identify clinical predictors of PVSA among PwE. Adult epilepsy patients aged ≥18 years without a history of COVID-19 infection were recruited from a specialty epilepsy clinic in early 2022. Demographic, epilepsy characteristics, and vaccination data were extracted from a centralized electronic patient record. Seizure frequency before and after vaccination, vaccination-related adverse effects, and reasons for or against vaccination were obtained by a structured questionnaire. A total of 786 PwEs were included, of which 27.0% were drug-resistant. At the time of recruitment, 74.6% had at least 1 dose of the COVID-19 vaccine. Subjects with higher seizure frequency (p < 0.0005), on more anti-seizure medications (p = 0.004), or had drug-resistant epilepsy (p = 0.001) were less likely to be vaccinated. No significant increase in seizure frequency was observed in the early (7 days) and delayed phases (30 days) after vaccination in our cohort. On the contrary, there was an overall significant reduction in seizure frequency 30 days after vaccination (1.31 vs. 1.89, t = 3.436; p = 0.001). This difference was seen in both types of vaccine (BNT162b2 and CoronaVac) and drug-resistant epilepsy, but just missed significance for the second dose (1.13 vs. 1.87, t = 1.921; p = 0.055). Only 5.3% had PVSA after either dose of vaccine. Higher pre-vaccination seizure frequency of ≥1 per week (OR 3.01, 95% CI 1.05-8.62; p = 0.04) and drug-resistant status (OR 3.32, 95% CI 1.45-249 7.61; p = 0.005) were predictive of PVSA. Meanwhile, seizure freedom for 3 months before vaccination was independently associated with a lower risk of PVSA (OR 0.11, 95% CI 0.04-0.28; p < 0.0005). This may guide epilepsy treatment strategies to achieve better seizure control for at least 3 months prior to vaccination. As COVID-19 shifts to an endemic phase, this study provides important data demonstrating the overall safety of COVID-19 vaccinations among PwE. Identification of high-risk patients with subsequent individualized approaches in treatment and monitoring strategies may alleviate vaccination hesitancy among PwE.

Impact of renal function variability on long-term prognosis in ischemic stroke patients with atrial fibrillation.

Background: Although renal dysfunction is associated with adverse clinical outcomes in patients with atrial fibrillation (AF) following stroke, the impact of renal function variability is unclear. Aim: This study aimed to assess the association between renal function variability and various adverse clinical outcomes in patients with transient ischemic attack (TIA)/ischemic stroke and atrial fibrillation (AF). Methods: We conducted a population-based study and retrospectively identified patients hospitalized with a diagnosis of TIA/ischemic stroke and AF during 2016-2020 using the Clinical Data Analysis and Reporting System of Hong Kong. Serial serum creatinine tested upon the onset of TIA/ischemic stroke and during their subsequent follow-up was collected. Renal function variability was calculated using the coefficient of variation of the estimated glomerular filtration rate (eGFR). Clinical endpoints that occurred during the study period were captured and included ischemic stroke/systemic embolism, intracerebral hemorrhage (ICH), total bleeding, major adverse cardiovascular events (MACE), cardiovascular, non-cardiovascular, and all-cause mortality. Competing risk regression and Cox proportional hazard regression models were used to assess the associations of renal function variability with the outcomes of interest. Results: A total of 3,809 patients (mean age 80 ± 10 years, 43% men) who satisfied the inclusion and exclusion criteria were followed up for a mean of 2.5 ± 1.5 years (9,523 patient-years). The mean eGFR was 66 ± 22 mL/min/1.73 m2 at baseline, and the median number of renal function tests per patient during the follow-up period was 20 (interquartile range 11-35). After accounting for potential confounders, a greater eGFR variability was associated with increased risks of recurrent ischemic stroke/systemic embolism [fully adjusted subdistribution hazard ratio 1.11, 95% confidence interval (CI) 1.03-1.20], ICH (1.17, 1.01-1.36), total bleeding (1.13, 1.06-1.21), MACE (1.22, 1.15-1.30), cardiovascular (1.49, 1.32-1.69), non-cardiovascular (1.43, 1.35-1.52), and all-cause mortality (fully adjusted hazard ratio 1.44, 1.39-1.50). Conclusion: Visit-to-visit renal function variability is independently associated with adverse clinical outcomes in TIA/ischemic stroke patients with AF. Further large-scale studies are needed to validate our results.

Association of LDL-cholesterol <1.8 mmol/L and statin use with the recurrence of intracerebral hemorrhage.

BACKGROUND: Recent intensive low-density lipoprotein cholesterol (LDL-C) lowering trials, including FOURIER, ODYSSEY OUTCOMES, and Treat Stroke to Target (TST) trials, have mostly refuted the concern surrounding statin use, LDL-C lowering, and intracerebral hemorrhage (ICH) risk. However, the results from these trials may not be fully applied to ICH survivors, as the populations studied were mainly patients without prior ICH, in whom the inherent ICH risk is more than 10 times lower than that of ICH survivors. Although available literature on statin use after ICH has demonstrated no excess risk of recurrent ICH, other potential factors that may modify ICH risk, especially hypertension control and ICH etiology, have not generally been considered. Notably, data on LDL-C levels following ICH are lacking. AIMS: We aim to investigate the association between LDL-C levels and statin use with ICH risk among ICH survivors, and to determine whether the risk differed with patients' characteristics, especially ICH etiology. METHODS: Follow-up data of consecutive spontaneous ICH survivors enrolled in the University of Hong Kong prospective stroke registry from 2011 to 2019 were retrospectively analyzed. ICH etiology was classified as cerebral amyloid angiopathy (CAA) using the modified Boston criteria or hypertensive arteriopathy, while the mean follow-up LDL-C value was categorized as <1.8 or ⩾1.8 mmol/L. The primary endpoint was recurrent ICH. The association of LDL-C level and statin use with recurrent ICH was determined using multivariable Cox regression. Pre-specified subgroup analyses were performed, including based on ICH etiology and statin prescription. Follow-up blood pressure was included in all the regression models. RESULTS: In 502 ICH survivors (mean age = 64.2 ± 13.5 years, mean follow-up LDL-C = 2.2 ± 0.6 mmol/L, 28% with LDL-C <1.8 mmol/L), 44 had ICH recurrence during a mean follow-up of 5.9 ± 2.8 years. Statin use after ICH was not associated with recurrent ICH (adjusted hazard ratio (AHR) = 1.07, 95% confidence interval (CI) = 0.57-2.00). The risk of ICH recurrence was increased for follow-up LDL-C <1.8 mmol/L (AHR = 1.99, 95% CI = 1.06-3.73). This association was predominantly observed in ICH attributable to CAA (AHR = 2.52, 95% CI = 1.06-5.99) and non-statin users (AHR = 2.91, 95% CI = 1.08-7.86). CONCLUSION: The association between post-ICH LDL-C <1.8 mmol/L and recurrent ICH was predominantly observed in CAA patients and those with intrinsically low LDL-C (non-statin users). While statins can be safely prescribed in ICH survivors, LDL-C targets should be individualized and caution must be exercised in CAA patients.

High-sensitivity C-reactive protein level in stable-state bronchiectasis predicts exacerbation risk.

BACKGROUND: Elevation of systemic inflammatory markers were found to correlate with increased disease extent, reduced lung function and higher risk of future severe exacerbations in patients with bronchiectasis. Although a significant correlation of circulating hs-CRP levels with HRCT scores and resting oxygen saturation in patients with stable-state non-cystic fibrosis (CF) bronchiectasis was suggested, there is little data on the relationship between hs-CRP and the prognosis of bronchiectasis and a lack of data on the role of hs-CRP in predicting bronchiectasis exacerbation. METHODS: A prospective study was conducted on Chinese patients with non- CF bronchiectasis from 1st October to 31st December 2021. Baseline serum hs-CRP were obtained at stable-state. The follow-up period lasted for one year. Co-primary endpoints were the development of any bronchiectasis exacerbation and hospitalized bronchiectasis exacerbation. RESULTS: Totally 123 patients were included. Higher hs-CRP was associated with increased risk to develop any bronchiectasis exacerbation, adjusted odds ratio (aOR) of 2.254 (95% CI = 1.040-4.885, p = 0.039), and borderline significantly increased hospitalized bronchiectasis exacerbation with aOR of 1.985 (95% CI = 0.922-4.277, p = 0.080). CONCLUSION: Baseline serum hs-CRP level at stable-state can predict risk of bronchiectasis exacerbation, which is reflecting chronic low-grade inflammation in bronchiectasis.

Clinical Associations and Prognostic Value of MRI-Visible Perivascular Spaces in Patients With Ischemic Stroke or TIA: A Pooled Analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Location-Specific Hematoma Volume Cutoff and Clinical Outcomes in Intracerebral Hemorrhage.

BACKGROUND: Major intracerebral hemorrhage (ICH) trials have largely been unable to demonstrate therapeutic benefit in improving functional outcomes. This may be partly due to the heterogeneity of ICH outcomes based on their location, where a small strategic ICH could be debilitating, thus confounding therapeutic effects. We aimed to determine the ideal hematoma volume cutoff for different ICH locations in predicting ICH outcomes. METHODS: We retrospectively analyzed consecutive ICH patients enrolled in the University of Hong Kong prospective stroke registry from January 2011 to December 2018. Patients with premorbid modified Rankin Scale score >2 or who underwent neurosurgical intervention were excluded. ICH volume cutoff, sensitivity, and specificity in predicting respective 6-month neurological outcomes (good [modified Rankin Scale score 0-2], poor [modified Rankin Scale score 4-6], and mortality) for specific ICH locations were determined using receiver operating characteristic curves. Separate multivariate logistic regression models were also conducted for each location-specific volume cutoff to determine whether these cutoffs were independently associated with respective outcomes. RESULTS: Among 533 ICHs, the volume cutoff for good outcome according to ICH location was 40.5 mL for lobar, 32.5 mL for putamen/external capsule, 5.5 mL for internal capsule/globus pallidus, 6.5 mL for thalamus, 17 mL for cerebellum, and 3 mL for brainstem. ICH smaller than the cutoff for all supratentorial sites had higher odds of good outcomes (all P<0.05). Volumes exceeding 48 mL for lobar, 41 mL for putamen/external capsule, 6 mL for internal capsule/globus pallidus, 9.5 mL for thalamus, 22 mL for cerebellum, and 7.5 mL for brainstem were at greater risk of poor outcomes (all P<0.05). Mortality risks were significantly higher for volumes that exceeded 89.5 mL for lobar, 42 mL for putamen/external capsule, and 21 mL for internal capsule/globus pallidus (all P<0.001). All receiver operating characteristic models for location-specific cutoffs had good discriminant values (area under the curve >0.8), except in predicting good outcome for cerebellum. CONCLUSIONS: ICH outcomes differed with location-specific hematoma size. Location-specific volume cutoff should be considered in patient selection for ICH trials.

Blood Pressure Control Targets and Risk of Cardiovascular and Cerebrovascular Events After Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) survivors are at high risk for recurrent stroke and cardiovascular events. Blood pressure (BP) control represents the most potent intervention to lower these risks, but optimal treatment targets in this patient population remain unknown. We sought to determine whether survivors of ICH achieving more intensive BP control than current guideline recommendations (systolic BP <130 mmHg and diastolic BP <80 mmHg) were at lower risk of major adverse cardiovascular and cerebrovascular events and mortality. METHODS: We analyzed data for 1828 survivors of spontaneous ICH from 2 cohort studies. Follow-up BP measurements were recorded 3 and 6 months after ICH, and every 6 months thereafter. Outcomes of interest were major adverse cardiovascular and cerebrovascular events (recurrent ICH, incident ischemic stroke, myocardial infarction), vascular mortality (defined as mortality attributed to recurrent ICH, ischemic stroke, or myocardial infarction), and all-cause mortality. RESULTS: During a median follow-up of 46.2 months, we observed 166 recurrent ICH, 68 ischemic strokes, 69 myocardial infarction, and 429 deaths. Compared with survivors of ICH with systolic BP 120 to 129 mmHg, participants who achieved systolic BP <120 mmHg displayed reduced risk of recurrent ICH (adjusted hazard ratio [AHR], 0.74 [95% CI, 0.59-0.94]) and major adverse cardiovascular and cerebrovascular events (AHR, 0.69 [95% CI, 0.53-0.92]). All-cause mortality (AHR, 0.76 [95% CI, 0.57-1.03]) and vascular mortality (AHR, 0.68 [95% CI, 0.45-1.01]) did not differ significantly. Among participants aged >75 years or with modified Rankin Scale score 4 to 5, systolic BP <120 mmHg was associated with increased all-cause mortality (AHR, 1.38 [95% CI, 1.02-1.85] and AHR, 1.36 [95% CI, 1.03-1.78], respectively), but not vascular mortality. We found no differences in outcome rates between survivors of ICH with diastolic BP <70 versus 70 to 79 mmHg. CONCLUSIONS: Targeting systolic BP <120 mmHg in select groups of survivors of ICH could result in decreased major adverse cardiovascular and cerebrovascular events risk without increasing mortality. Our findings warrant investigation in dedicated randomized controlled trials.

Lobar intracerebral hemorrhage and risk of subsequent uncontrolled blood pressure.

Background: Uncontrolled blood pressure (BP) in intracerebral hemorrhage (ICH) survivors is common and associated with adverse clinical outcomes. We investigated whether characteristics of the ICH itself were associated with uncontrolled BP at follow-up. Methods: Subjects were consecutive patients aged ⩾18 years with primary ICH enrolled in the prospective longitudinal ICH study at Massachusetts General Hospital between 1994 and 2015. We assessed the prevalence of uncontrolled BP (mean BP ⩾140/90 mmHg) 6 months after index event. We used multivariable logistic regression models to assess the effect of hematoma location, volume, and event year on uncontrolled BP. Results: Among 1492 survivors, ICH was lobar in 624 (42%), deep in 749 (50%), cerebellar in 119 (8%). Lobar ICH location was associated with increased risk for uncontrolled BP after 6 months (OR 1.35; 95% CI [1.08-1.69]). On average, lobar ICH survivors were treated with fewer antihypertensive drugs compared to the rest of the cohort: 2.1 ± 1.1 vs 2.5 ± 1.2 (p < 0.001) at baseline and 1.8 ± 1.2 vs. 2.4 ± 1.2 (p < 0.001) after 6 months follow-up. After adjustment for the number of antihypertensive drugs prescribed, the association of lobar ICH location with risk of uncontrolled BP was eliminated. Conclusions: ICH survivors with lobar hemorrhage were more likely to have uncontrolled BP after 6 months follow-up. This appears to be a result of being prescribed fewer antihypertensive medications. Future treatment strategies should focus on aggressive BP control after ICH independent of hemorrhage location.

Long-Term Blood Pressure Variability and Major Adverse Cardiovascular and Cerebrovascular Events After Intracerebral Hemorrhage.

Background Survivors of intracranial hemorrhage (ICH) are at increased risk for major adverse cardiovascular and cerebrovascular events (MACCE), in the form of recurrent stroke and myocardial Infarction. We investigated whether long-term blood pressure (BP) variability represents a risk factor for MACCE after ICH, independent of average BP. Methods and Results We analyzed data from prospective ICH cohort studies at Massachusetts General Hospital and the University of Hong Kong. We captured long-term (ie, visit-to-visit) BP variability, quantified as individual participants' variation coefficient. We explored determinants of systolic and diastolic BP variability and generated survival analyses models to explore their association with MACCE. Among 1828 survivors of ICH followed for a median of 46.2 months we identified 166 with recurrent ICH, 68 with ischemic strokes, and 69 with myocardial infarction. Black (coefficient +3.8, SE 1.3) and Asian (coefficient +2.2, SE 0.4) participants displayed higher BP variability. Long-term systolic BP variability was independently associated with recurrent ICH (subhazard ratio [SHR], 1.82; 95% CI, 1.19-2.79), ischemic stroke (SHR, 1.62; 95% CI, 1.06-2.47), and myocardial infarction (SHR, 1.54; 95% CI, 1.05-2.24). Average BP during follow-up did not modify the association between long-term systolic BP variability and MACCE. Conclusions Long-term BP variability is a potent risk factor for recurrent hemorrhage, ischemic stroke, and myocardial infarction after ICH, even among survivors with well-controlled hypertension. Our findings support the hypothesis that combined control of average BP and its variability after ICH is required to minimize incidence of MACCE.

Low-Density Lipoprotein Cholesterol and Risk of Recurrent Vascular Events in Chinese Patients With Ischemic Stroke With and Without Significant Atherosclerosis.

Background Recent trials have shown that low-density lipoprotein cholesterol (LDL-C) <1.80 mmol/L (<70 mg/dL) is associated with a reduced risk of major adverse cardiovascular events in White patients with ischemic stroke with atherosclerosis. However, it remains uncertain whether the findings can be generalized to Asian patients, or that similar LDL-C targets should be adopted in patients with stroke without significant atherosclerosis. Methods and Results We performed a prospective cohort study and recruited consecutive Chinese patients with ischemic stroke with magnetic resonance angiography of the intra- and cervicocranial arteries performed at the University of Hong Kong between 2008 and 2014. Serial postevent LDL-C measurements were obtained. Risk of major adverse cardiovascular events in patients with mean postevent LDL-C <1.80 versus ≥1.80 mmol/L, stratified by presence or absence of significant (≥50%) large-artery disease (LAD) and by ischemic stroke subtypes, were compared. Nine hundred four patients (mean age, 69±12 years; 60% men) were followed up for a mean 6.5±2.4 years (mean, 9±5 LDL-C readings per patient). Regardless of LAD status, patients with a mean postevent LDL-C <1.80 mmol/L were associated with a lower risk of major adverse cardiovascular events (with significant LAD: multivariable-adjusted subdistribution hazard ratio, 0.65; 95% CI, 0.42-0.99; without significant LAD: subdistribution hazard ratio, 0.53; 95% CI, 0.32-0.88) (both P<0.05). Similar findings were noted in patients with ischemic stroke attributable to large-artery atherosclerosis (subdistribution hazard ratio, 0.48; 95% CI, 0.28-0.84) and in patients with other ischemic stroke subtypes (subdistribution hazard ratio, 0.64; 95% CI, 0.43-0.95) (both P<0.05). Conclusions A mean LDL-C <1.80 mmol/L was associated with a lower risk of major adverse cardiovascular events in Chinese patients with ischemic stroke with and without significant LAD. Further randomized trials to determine the optimal LDL-C cutoff in stroke patients without significant atherosclerosis are warranted.

Impact of Uncontrolled Hypertension at 3 Months After Intracerebral Hemorrhage.

Background Survivors of intracerebral hemorrhage (ICH) are at high risk for recurrent stroke, which is associated with blood pressure control. Because most recurrent stroke events occur within 12 to 18 months of the index ICH, rapid blood pressure control is likely to be crucial. We investigated the frequency and prognostic impact of uncontrolled short-term hypertension after ICH. Methods and Results We analyzed data from Massachusetts General Hospital (n=1305) and the University of Hong Kong (n=523). We classified hypertension as controlled, undertreated, or treatment resistant at 3 months after ICH and determined the following: (1) the risk factors for uncontrolled hypertension and (2) whether hypertension control at 3 months is associated with stroke recurrence and mortality. We followed 1828 survivors of ICH for a median of 46.2 months. Only 9 of 234 (4%) recurrent strokes occurred before 3 months after ICH. At 3 months, 713 participants (39%) had controlled hypertension, 755 (41%) had undertreated hypertension, and 360 (20%) had treatment-resistant hypertension. Black, Hispanic, and Asian race/ethnicity and higher blood pressure at time of ICH increased the risk of uncontrolled hypertension at 3 months (all P<0.05). Uncontrolled hypertension at 3 months was associated with recurrent stroke and mortality during long-term follow-up (all P<0.05). Conclusions Among survivors of ICH, >60% had uncontrolled hypertension at 3 months, with undertreatment accounting for the majority of cases. The 3-month blood pressure measurements were associated with higher recurrent stroke risk and mortality. Black, Hispanic, and Asian survivors of ICH and those presenting with severe acute hypertensive response were at highest risk for uncontrolled hypertension.

Delays in Stroke Onset to Hospital Arrival Time During COVID-19.

BACKGROUND AND PURPOSE: The current coronavirus disease 2019 (COVID-19) pandemic represents a global public health crisis, disrupting emergency healthcare services. We determined whether COVID-19 has resulted in delays in stroke presentation and affected the delivery of acute stroke services in a comprehensive stroke center in Hong Kong. METHODS: We retrospectively reviewed all patients with transient ischemic attack and stroke admitted via the acute stroke pathway of Queen Mary Hospital, Hong Kong, during the first 60 days since the first diagnosed COVID-19 case in Hong Kong (COVID-19: January 23, 2020-March 24, 2020). We compared the stroke onset to hospital arrival (onset-to-door) time and timings of inpatient stroke pathways with patients admitted during the same period in 2019 (pre-COVID-19: January 23, 2019-March 24, 2019). RESULTS: Seventy-three patients in COVID-19 were compared with 89 patients in pre-COVID-19. There were no significant differences in age, sex, vascular risk factors, nor stroke severity between the 2 groups (P>0.05). The median stroke onset-to-door time was ≈1-hour longer in COVID-19 compared with pre-COVID-19 (154 versus 95 minutes, P=0.12), and the proportion of individuals with onset-to-door time within 4.5 hours was significantly lower (55% versus 72%, P=0.024). Significantly fewer cases of transient ischemic attack presented to the hospital during COVID-19 (4% versus 16%, P=0.016), despite no increase in referrals to the transient ischemic attack clinic. Inpatient stroke pathways and treatment time metrics nevertheless did not differ between the 2 groups (P>0.05 for all comparisons). CONCLUSIONS: During the early containment phase of COVID-19, we noted a prolongation in stroke onset to hospital arrival time and a significant reduction in individuals arriving at the hospital within 4.5 hours and presenting with transient ischemic attack. Public education about stroke should continue to be reinforced during the COVID-19 pandemic.

Age-Specific Associations of Renal Impairment and Cerebral Small Vessel Disease Burden in Chinese with Ischaemic Stroke.

BACKGROUND: Recent studies in Caucasians with transient ischaemic attack or ischaemic stroke have demonstrated significant age-specific associations between cerebral small vessel disease (SVD) burden on magnetic resonance imaging and renal impairment. We aimed to validate these findings in a large cohort of Chinese with ischaemic stroke. METHODS: In 959 Chinese with ischaemic stroke who received a brain magnetic resonance imaging at the University of Hong Kong, we determined the age-specific associations of renal impairment (glomerular filtration rate < 60 mL/min/1.73 m2) with neuroimaging markers of SVD as well as with the SVD score. RESULTS: Although renal impairment was associated with the SVD score in univariate analysis in all patients (odds ratio 1.61, 95% confidence interval 1.24-2.09, P < .0001), these associations were attenuated after adjusting for age and sex (P = .38). Similar findings were noted in patients with ischaemic stroke due to SVD and non-SVD subtypes. However, in 222 of 959 patients aged <60, renal impairment was independently associated with an increasing microbleed (adjusted odds ratio 6.82, 2.26-20.59), subcortical (4.97, 1.62-15.24) periventricular white matter hyperintensity (3.96, 1.08-14.51) and global SVD burden (3.41, 1.16-10.04; all P < .05) even after adjusting for age, sex, and vascular risk factors. Nevertheless, there were no associations between renal impairment and individual neuroimaging markers of SVD nor with the SVD score in patients aged ≥60 after adjusting for age and sex (all P > .05). CONCLUSIONS: In Chinese with ischaemic stroke, renal impairment was independently associated with microbleed, white matter hyperintensity and global SVD burden in individuals aged <60, but not in those aged ≥60, suggesting that there may be shared susceptibilities to premature systemic disease.

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]; Ptrend<0.0001), but the relationship of microbleed burden and risk of recurrent ischemic stroke was not significant (Ptrend=0.054). Similar findings were noted in the 862 of 1003 patients treated with antiplatelet agents only (ICH: Ptrend<0.0001; ischemic stroke Ptrend=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.

Burden of rare variants in ALS genes influences survival in familial and sporadic ALS.

Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more. Patients with 2 or more rare variants had lower probability of survival than patients with 0 or 1 variant (p = 0.001). After adjusting for other factors, each additional rare variant increased the risk of respiratory failure or death by 60% (p = 0.0098). The presence of the rare variant was associated with the risk of ALS (Odds ratio 1.91, 95% confidence interval 1.03-3.61, p = 0.03), and ALS patients had higher rare variant burden than controls (MB, p = 0.004). Our findings support an oligogenic basis with the burden of rare variants affecting the development and survival of ALS.

Antiplatelet Resumption after Antiplatelet-Related Intracerebral Hemorrhage: A Retrospective Hospital-Based Study.

BACKGROUND: Antiplatelet resumption in patients who developed intracerebral hemorrhage (ICH) while on antiplatelet therapy (antiplatelet-related ICH) represents an important medical dilemma. We aimed to study the long-term cardiovascular outcomes of antiplatelet-related ICH survivors, and the risk of recurrent ICH with antiplatelet resumption. METHODS: This was an observational study of 109 antiplatelet-related ICH survivors. The clinical end points were recurrent ICH, ischemic vascular events, and vascular death (fatal ICH or ischemic vascular events). Predictors of recurrent ICH and vascular death were derived using a multivariable Cox regression model. RESULTS: The median duration of follow-up was 3.5 years (interquartile range, 1.6-5.8 years). Ischemic vascular events were more common than recurrent ICHs (6.8 per 100 patient-years vs. 2.6 per 100 patient-years; P = 0.028). Antiplatelet use was not associated with an elevated risk of recurrent ICH (hazard ratio [HR], 1.11, 95% confidence interval [CI], 0.27-4.62). A mean follow-up systolic blood pressure of >140 mmHg increased the risk of both recurrent ICH (HR, 4.28; 95% CI, 1.01-18.11) and vascular death (HR, 11.14; 95% CI, 2.72-45.62). Cerebral amyloid angiopathy (CAA) was an independent predictor for recurrent ICH (HR, 24.34; 95% CI, 2.80-211.47). CONCLUSIONS: Antiplatelet resumption after antiplatelet-related ICH did not appear to carry a clinically significant risk of recurrent ICH, whereas inadequate blood pressure control and CAA contributed to a more robust risk. Antiplatelet resumption should be considered, especially in survivors with adequate blood pressure control and without CAA.

Visit-to-visit blood pressure variability as a prognostic marker in patients with cardiovascular and cerebrovascular diseases--relationships and comparisons with vascular markers of atherosclerosis.

BACKGROUND: Visit-to-visit blood pressure variability (BPV) is a simple surrogate marker for the development of atherosclerotic diseases, cardiovascular and all-cause mortality. Nevertheless, the relative prognostic value of BPV in comparison with other established vascular assessments remain uncertain. METHODS: We prospectively followed-up 656 high-risk patients with diabetes or established cardiovascular or cerebrovascular diseases for the occurrence of major adverse cardiovascular events (MACEs). Baseline brachial endothelial function, carotid intima-media thickness (IMT) and plaque burden, ankle-brachial index and arterial stiffness were determined. Visit-to-visit BPV were recorded during a mean 18 ± 9 outpatient clinic visits. RESULTS: After a mean 81 ± 12 month's follow-up, 123 patients (19%) developed MACEs. Patients who developed a MACE had significantly higher systolic BPV, more severe endothelial function, arterial stiffness and systemic atherosclerotic burden compared to patients who did not develop a MACE (all P<0.01). BPV significantly correlated with all of the vascular assessments (P<0.01). A high carotid IMT had the greatest prognostic value in predicting development of a MACE (area under receiver operating characteristic curve (AUC) 0.69 ± 0.03, P<0.01). A high BPV also had moderate prognostic value in prediction of MACE (AUC 0.65 ± 0.03, P<0.01). After adjustment of confounding factors, a high BPV remained a significant independent predictor of MACE (hazards ratio 1.67, 95% confidence interval 1.14-2.43, P<0.01). CONCLUSIONS: Compared with established surrogate markers of atherosclerosis, visit-to-visit BPV provides similar prognostic information and may represent a new and simple marker for adverse outcomes in patients with vascular diseases.

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.