Yen-Feng Wang

Oxidative stress and increased formation of vasoconstricting F2-isoprostanes in patients with reversible cerebral vasoconstriction syndrome.

The pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS) is unknown. Oxidative stress is detrimental to endothelial function and vascular reactivity. We hypothesized that the oxidative stress marker 8-iso-prostaglandin F2α, which is also a potent vasoconstrictor, might contribute to the pathogenesis of RCVS. Recruited participants included 103RCVS patients, 53 patients with primary headache with acute severe attacks, and 54 healthy controls. Subjects recruited prior to 2009 were discovery cohort, whereas those after 2009, replication cohort. Urine samples were obtained from all patients at registration and from 79 patients with RCVS again at remission stage. Urine 8-iso-prostaglandin F2α was analyzed by liquid chromatography-tandem mass spectrometry. Patients with RCVS received magnetic resonance angiography and transcranial color-coded sonography. In RCVS patients, the urine 8-iso-prostaglandin F2α level was higher than that in the other groups in discovery, replication, and combined cohorts (RCVS, 0.29±0.18; primary headache with acute severe attacks, 0.21±0.19; control, 0.18±0.09ng/mg creatinine; P<0.001), and it was positively correlated with the flow velocities of major intracranial arteries, especially within the first week of disease onset (middle cerebral artery, Spearmans correlation coefficient [rs]=0.580, P=0.002; anterior cerebral artery, rs=0.472, P=0.042; posterior cerebral artery, rs=0.457, P=0.022; basilar artery, rs= 0.530, P=0.002). The 8-iso-prostaglandin F2α level decreased from the ictalto remission stage in RCVS patients (0.31±0.21 vs 0.16±0.10ng/mg creatinine, P<0.001). 8-Iso-prostaglandin F2α was higher in patients with RCVS and correlated with the severity of vasoconstrictions. Further studies are required to explore its potential pathogenic role.

Clinical correlates and diagnostic utility of osmophobia in migraine

Background: Osmophobia is an under-investigated associated symptom in migraine. Objective: To evaluate the clinical correlates and diagnostic utility of osmophobia. Methods: Adult patients with migraine (with or without aura), probable migraine (PM), tension-type headache (TTH), and cluster headache (CH) were recruited retrospectively from our headache registration system. Migraine patients with and without osmophobia were compared. The newly proposed criteria for migraine requiring at least two of photo-, phono-, or osmophobia instead of both photo- and phonophobia were validated. Results: In total, 2883 patients were included: 1809 migraine, 792 PM, 138 TTH, and 144 CH. Osmophobia was more common in migraine (62.2%) than in PM (33.8%), TTH (14.5%), and CH (31.3%) (all p < 0.001). Migraine patients with osmophobia scored higher on the Hospital Anxiety and Depression Scale (HADS) than those without (15.6 ± 7.6 vs. 13.3 ± 7.8, p < 0.001). The concordance in headache diagnoses between ICHD-2 (International Classification of Headache Disorders, Second Edition) and the newly proposed criteria was “almost perfect” (κ = 0.886, p < 0.001). Additionally, 16.9% of ICHD-2 PM patients were reclassified as migraine using the newly proposed criteria. Conclusions: Osmophobia was prevalent in migraineurs, and was associated with higher HADS scores. The newly proposed criteria appear comparable to the ICHD-2 criteria, and may increase the diagnostic yield for Asian migraineurs, among whom photophobia was less common.

Recurrence of reversible cerebral vasoconstriction syndrome A long-term follow-up study

Objective: We aimed to investigate whether reversible cerebral vasoconstriction syndrome (RCVS) could recur and to identify the potential predictors of recurrence in a large cohort of patients. Methods: This study followed a cohort of 210 patients with RCVS in a hospital-based headache center from 2000 to 2012. All patients were regularly followed up by telephone after remission for RCVS and were particularly asked to return to our hospital immediately if they developed new acute, severe (i.e., thunderclap-like) headaches. Sequential neuroimaging studies were used to determine whether the patients had recurrent RCVS. Results: One hundred sixty-eight patients were successfully followed. The response rate was 80.8%, and the mean follow-up period was 37.5 ± 24.4 (range 6–131) months. Eighteen patients (10.7%) returned to our hospital because of new thunderclap-like headaches, and 9 (5.4% of the total 168, and 50% of 18) were confirmed to have recurrent RCVS that occurred a mean 40.9 ± 27.2 (median 35, range 6–87) months after the initial bout. The incidence rate was 1.71 per 100 person-years (95% confidence interval 1.68–1.75). Having sexual activities as a trigger for thunderclap headaches (hazard ratio = 5.68, 95% confidence interval 1.11–29.15, p = 0.038) was an independent predictor of recurrent RCVS. None of the patients with recurrent RCVS developed cerebrovascular complications. Conclusions: Recurrent RCVS should be considered when patients with RCVS develop new thunderclap-like headaches. Having sexual activities as a trigger for RCVS is a potential predictor of recurrent RCVS.

Incidence and Risk Factors of Chronic Daily Headache in Young Adolescents: A School Cohort Study

OBJECTIVES: This study investigated the incidence and risk factors of chronic daily headache (CDH) and its major subtypes in young adolescents. METHODS: A field cohort of 3342 adolescents aged 13 to 14 was established in 3 middle schools in Taitung, Taiwan, from 2005 to 2007. Participants without CDH at baseline were annually followed up for 1 to 2 years using the same questionnaires, including the Adolescent Depression Inventory and Pediatric Migraine Disability Assessment. The neurologists made the headache diagnoses based on clinical interviews and headache diaries. The person-time incidence rates and risk factors of incident CDH and its subtypes (ie, chronic migraine [CM] and chronic tension-type headache [CTTH]) were calculated by using Cox proportional hazards models. RESULTS: The cohort completed 5586 person-years (PYs) of follow-up. Sixty-three subjects (21 boys/42 girls) developed incident CDH with an incidence rate of 1.13 per 100 PYs, including 37 with CM (0.66 per 100 PYs) and 22 with CTTH (0.39 per 100 PYs). Thirty-three subjects (52%) had a baseline diagnosis of migraine. The independent risk factors for incident CDH included female gender, acute family financial distress, obesity, higher headache frequency, and a baseline diagnosis of migraine. A higher headache frequency was the only identical risk factor for CDH, CM, and CTTH. A baseline diagnosis of migraine and obesity were significant predictors for both CM and CDH. Female gender was a significant predictor for both CTTH and CDH. CONCLUSIONS: Incident CDH was common in young adolescents. Some risk factors for incident CM and CTTH were different.

The visual aura rating scale as an outcome predictor for persistent visual aura without infarction

Persistent visual aura without infarction is rare. Its pathogenic mechanism is unknown, and the response to migraine prophylactic agents varies. A systematic analysis of 29 patients (23 from the literature and six in the present report; 6M/23F, mean age 37.6 years) was carried out in terms of demographics, headache and visual symptom profiles, treatment regimens and outcomes. Patterns of visual disturbances (VDs) were re-assessed with the Visual Aura Rating Scale (VARS, score 0-10). Even though the majority of patients had headache improvement, only eight (27.6±) had complete resolution of persistent VD, without definite relevance to any specific agent. Patients with complete resolution of VD tended to have scotoma (50.0± vs. 0±; P = 0.003), unilateral/homonymous involvement (62.5± vs. 9.5±; P = 0.008), higher VARS scores (1.88 ± 1.73 vs. 0.10 ± 0.30; P< 0.001) and shorter duration of illness (10.0 ± 12.9 vs. 60.2 ± 90.9 months, P = 0.008) compared with those without. These findings remained even when the six current patients were not included for analyses. In conclusion, the prognosis of persistent VD was poor, and higher VARS scores, i.e. more typical of migraine visual aura, predicted a better outcome. For those with a potential for complete resolution, improvement would occur early in the course.

Proton-Pump Inhibitor Use and the Risk of First-Time Ischemic Stroke in the General Population: A Nationwide Population-Based Study

Objectives:An increased risk of adverse cardiovascular events was reported for concomitant use of proton-pump inhibitors (PPIs) in patients taking antiplatelet agents. The present study aimed at determining whether PPI use alone could be associated with first-time ischemic stroke.Methods:This was a retrospective nationwide study using database from Taiwan National Health Insurance and involved subjects aged ≥20 years. In propensity score-matched analysis, patients with current PPI use were compared with propensity score-matched PPI non-use controls at a 1:1 ratio. Patients with prior stroke or hospitalization before the index date were excluded. The primary outcome measure was hospitalization with a primary diagnosis of ischemic stroke during 120-day follow-up. A parallel analysis adopting a nested case–control design was carried out. Patients hospitalized for a first-time ischemic stroke were identified and were compared with matched controls using conditional logistic regression analyses focusing on PPI use before the index date.Results:The propensity score-matched analysis included 198,148 PPI treatment courses and control periods without PPI use. PPI use was associated with a higher risk of hospitalization due to ischemic stroke with a hazard ratio of 1.36 (95% confidence interval (CI) 1.14–1.620, P=0.001). Based on subgroup analysis, patients aged <60 years were more susceptible (P=0.043 for interaction), whereas gender, history myocardial infarction, diabetes mellitus, hypertension, use of antiplatelet agents of non-steroidal anti-inflammatory drugs, or type of PPIs had no effect on the risk. In the nested case–control analysis, 15,378 patients hospitalized owing to ischemic stroke were identified and were compared with 15,378 matched controls. An association between PPI use and increased cerebrovascular risks was identified, and the adjusted odds ratios for PPI use were 1.77 (95% CI 1.45–2.18, P<0.001) within 30 days, 1.65 (95% CI 1.31–2.08, P<0.001) between 31 and 90 days, and 1.28 (95% CI 1.03–1.59, P=0.025) between 91 and 180 days before the onset of first-time ischemic stroke.Conclusions:PPI use is associated with an increased risk of first-time ischemic stroke in the general population, and the risk is independent of antiplatelet agents. However, caution should be exercised when considering its clinical relevance as the magnitude of association was modest and a cause-and-effect relationship remained to be established.

ABCA7 gene and the risk of Alzheimer's disease in Han Chinese in Taiwan.

The ATP-binding cassette, subfamily A, member 7 gene (ABCA7) was recently identified as a susceptible gene of Alzheimers disease (AD) in the Caucasian population and African Americans. To test its genetic effect in the Han-Chinese population, 536 AD cases and 307 cognitive-intact, elder controls were genotyped for ABCA7 rs3764650 and apolipoprotein E (APOE) ε2/ε3/ε4 alleles. Global cognitive performance was assessed by the Mini-Mental State Examination in both AD patients and controls. For AD patients, comprehensive evaluation of each cognitive domain was further conducted as the following: (1) attention (forward and backward digit span); (2) memory (12-item word recall test); (3) executive function (category verbal fluency); (4) processing speed (Trail making test, part A); and (5) naming task (Boston naming test). ABCA7 rs3764650 was significantly associated with AD and the GG genotype carried a reduced risk for AD (odds ratio = 0.52, p = 0.0026). The association was further confirmed in 1802 population-based, healthy controls from Taiwan Biobank as a replicate (odds ratio = 0.70, p = 0.032). After adjustment of age, sex, and APOE ε4 allele, rs3764650 remained to be an independent predictor of AD (p = 0.001). The influence of ABCA7 was only evident in individuals without APOE ε4 alleles (p = 0.0004) but absent in ε4 carriers (p = 0.91). None of the cognitive tests was related to ABCA7 rs3764650 genotypes. The minor allele frequency and effect size of rs3764650 disclosed in the Han-Chinese population differed from those reported in the Caucasians and African Americans. Further studies were warranted to elucidate ABCA7s effect among different ethnic groups.

Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is originally featured with a strong clustering of mutations in NOTCH3 exons 3–6 and leukoencephalopathy with frequent anterior temporal pole involvement. The present study aims at characterizing the genotypic and phenotypic profiles of CADASIL in Taiwan. One hundred and twelve patients with CADASIL from 95 families of Chinese descents in Taiwan were identified by Sanger sequencing of exons 2 to 24 of NOTCH3. Twenty different mutations in NOTCH3 were uncovered, including 3 novel ones, and R544C in exon 11 was the most common mutation, accounting for 70.5% of the pedigrees. Haplotype analyses were conducted in 14 families harboring NOTCH3 R544C mutation and demonstrated a common haplotype linked to NOTCH3 R544C at loci D19S929 and D19S411. Comparing with CADASIL in most Caucasian populations, CADASIL in Taiwan has several distinct features, including less frequent anterior temporal involvement, older age at symptom onset, higher incidence of intracerebral hemorrhage, and rarer occurrence of migraine. Subgroup analyses revealed that the R544C mutation is associated with lower frequency of anterior temporal involvement, later age at onset and higher frequency of cognitive dysfunction. In conclusion, the present study broadens the spectrum of NOTCH3 mutations and provides additional insights for the clinical and molecular characteristics of CADASIL patients of Han-Chinese descents.

Connective tissue disorders in patients with spontaneous intracranial hypotension

Objective: Spontaneous intracranial hypotension (SIH) is caused by spinal cerebrospinal fluid (CSF) leakage. An underlying connective tissue disorder has been hypothesized to cause dural weakness and predisposition to CSF leak. We conducted a case-controlled study to investigate the role of connective tissue disorders in SIH patients. Methods: We recruited 55 consecutive SIH patients (38 F, 17 M; mean age, 40.8 ± 9.8 years) and 55 age- and sex-matched control individuals (mean age, 38.0 ± 8.9 years) for this study. The connective tissue disorders were evaluated by: (i) Beighton hypermobility scores and revised diagnostic criteria for benign joint hypermobility syndrome; (ii) skin and skeletal manifestations of Ehlers–Danlos syndrome (EDS); and (iii) skeletal features of Marfan syndrome. Results: The frequencies of joint hypermobility according to Beighton scores >4/9 (SIH 23.6% vs controls 16.4%, P = 0.48) and revised benign joint hypermobility syndrome criteria (SIH 23.6% vs controls 34.5%, P = 0.29) did not differ between SIH patients and controls. Sixteen patients and 16 controls had one or more skin features of EDS (P = 1.0). Nine SIH patients (16.4%) demonstrated the skeletal features of Marfan syndrome; this frequency did not differ from that of the control group (9.1%; P = 0.262). Only dolichostenomelia (disproportionately long limbs) was more prominent in SIH patients than in controls (34.5% vs 9.1%; P = 0.002). Conclusion: Compared with Western studies, the frequencies of connective tissue disorders were higher in our SIH patients. However, these frequencies did not differ between SIH patients and control individuals, except for dolichostenomelia.

Cerebrospinal fluid leakage and headache after lumbar puncture: a prospective non-invasive imaging study

The spatial distribution and clinical correlation of cerebrospinal fluid leakage after lumbar puncture have not been determined. Adult in-patients receiving diagnostic lumbar punctures were recruited prospectively. Whole-spine heavily T2-weighted magnetic resonance myelography was carried out to characterize post-lumbar puncture spinal cerebrospinal fluid leakages. Maximum rostral migration was defined as the distance between the most rostral spinal segment with cerebrospinal fluid leakage and the level of lumbar puncture. Eighty patients (51 female/29 male, mean age 49.4 ± 13.3 years) completed the study, including 23 (28.8%) with post-dural puncture headache. Overall, 63.6% of periradicular leaks and 46.9% of epidural collections were within three vertebral segments of the level of lumbar puncture (T12-S1). Post-dural puncture headache was associated with more extensive and more rostral distributions of periradicular leaks (length 3.0 ± 2.5 versus 0.9 ± 1.9 segments, P = 0.001; maximum rostral migration 4.3 ± 4.7 versus 0.8 ± 1.7 segments, P = 0.002) and epidural collections (length 5.3 ± 6.1 versus 1.0 ± 2.1 segments, P = 0.003; maximum rostral migration 4.7 ± 6.7 versus 0.9 ± 2.4 segments, P = 0.015). In conclusion, post-dural puncture headache was associated with more extensive and more rostral distributions of periradicular leaks and epidural collections. Further, visualization of periradicular leaks was not restricted to the level of dural defect, although two-thirds remained within the neighbouring segments.