Showing papers by "Shuu Jiun Wang published in 2020"

Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine attacks in episodic migraine in adults.

Abstract: Clinical trials are a key component of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. Advances in drugs, devices, and biologicals, as well as novel trial designs, have prompted several updates over the nearly 30 years since, including most recently the Guidelines for controlled trials of preventive treatment of chronic migraine (2018), the Guidelines for controlled trials of acute treatment of migraine attacks in adults (2019), and Guidelines for controlled trials of preventive treatment of migraine in children and adolescents (2019). The present update incorporates findings from new research and is intended to optimize the design of controlled trials of preventive pharmacological treatment of episodic migraine in adults. A guideline for clinical trials with devices will be published separately.

Extraction of SSVEPs-Based Inherent Fuzzy Entropy Using a Wearable Headband EEG in Migraine Patients

Abstract: Inherent fuzzy entropy is an objective measurement of electroencephalography (EEG) complexity reflecting the robustness of brain systems In this study, we present a novel application of multiscale relative inherent fuzzy entropy using repetitive steady-state visual evoked potentials (SSVEPs) to investigate EEG complexity change between two migraine phases, ie, interictal (baseline) and preictal (before migraine attacks) phases We used a wearable headband EEG device with O1, Oz, O2, and Fpz electrodes to collect EEG signals from 80 participants [40 migraine patients and 40 healthy controls (HCs)] under the following two conditions: During resting state and SSVEPs with five 15-Hz photic stimuli We found a significant enhancement in occipital EEG entropy with increasing stimulus times in both HCs and patients in the interictal phase, but a reverse trend in patients in the preictal phase In the 1st SSVEP, occipital EEG entropy of the HCs was significantly lower than that of patents in the preictal phase (FDR-adjusted p p $ \pm $ 6% and area under the curve of 087 for classifying interictal and preictal phases In contrast, there were no differences in EEG entropy among groups or sessions by using other competing entropy models, including approximate entropy, sample entropy, and fuzzy entropy on the same dataset In conclusion, inherent fuzzy entropy offers novel applications in visual stimulus environments and may have the potential to provide a preictal alert to migraine patients

Vestibular migraine: An update on current understanding and future directions.

Abstract: BackgroundVestibular migraine is among the most common causes of recurrent vertigo in the general population. Despite its prevalence and high impact on healthcare cost and utilization, it has remai...

Vagus nerve stimulation inhibits cortical spreading depression exclusively through central mechanisms

Abstract: Experimental and clinical data strongly support vagus nerve stimulation (VNS) as a novel treatment in migraine. Vagus nerve stimulation acutely suppresses cortical spreading depression (CSD) susceptibility, an experimental model that has been used to screen for migraine therapies. However, mechanisms underlying VNS efficacy on CSD are unknown. Here, we interrogated the central and peripheral mechanisms using VNS delivered either invasively (iVNS) or noninvasively (nVNS) in male Sprague-Dawley rats. Cortical spreading depression susceptibility was evaluated 40 minutes after the stimulation. iVNS elevated the electrical CSD threshold more than 2-fold and decreased KCl-induced CSD frequency by 22% when delivered to intact vagus nerve. Distal vagotomy did not alter iVNS efficacy (2-fold higher threshold and 19% lower frequency in iVNS vs sham). By contrast, proximal vagotomy completely abolished iVNS effect on CSD. Pharmacological blockade of nucleus tractus solitarius, the main relay for vagal afferents, by lidocaine or glutamate receptor antagonist CNQX also prevented CSD suppression by nVNS. Supporting a role for both norepinephrine and serotonin, CSD suppression by nVNS was inhibited by more than 50% after abrogating norepinephrinergic or serotonergic neurotransmission alone using specific neurotoxins; abrogating both completely blocked the nVNS effect. Our results suggest that VNS inhibits CSD through central afferents relaying in nucleus tractus solitarius and projecting to subcortical neuromodulatory centers providing serotonergic and norepinephrinergic innervation to the cortex.

NOTCH3 cysteine-altering variant is an important risk factor for stroke in the Taiwanese population

Abstract: Objective To test the hypothesis that the prevalence and clinical effect of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been underestimated in Asian populations. Methods The Taiwan Biobank, containing 1,517 Taiwanese genome sequences, was queried for pathogenic NOTCH3 cysteine-altering mutations. NOTCH3 mutations identified in the reference population were genotyped in 7,038 stroke- and dementia-free individuals and 800 patients with ischemic stroke. NOTCH3 genotyping, clinical manifestations, and the severity of white matter lesions on MRI were compared between the 2 groups. Results Three cysteine-altering NOTCH3 variants (p.R544C, p.C853Y, and p.C884Y) were identified from the Taiwan Biobank. We confirmed that the NOTCH3 p.R544C mutation was present in a significant number of individuals in Taiwan, including 60 of the 7,038 healthy controls (0.9%), 17 of the 800 patients with ischemic stroke (2.1%), and 16 of the 245 patients with small vessel occlusion (SVO) stroke (6.5%). The other 2 cysteine-altering mutations were rarely detected. After adjusting for vascular risk factors, harboring the p.R544C variant resulted in a 3.40-fold increased risk for overall stroke and an 11.05-fold increased risk for SVO stroke (p = 0.0001 and 3.9 × 10−10, respectively). Three symptom-free individuals carrying the p.R544C mutation had extensive leukoencephalopathy typical of CADASIL at age 59, 66, and 67, suggesting that p.R544C-related CADASIL could remain subclinical at advanced age. Conclusion The NOTCH3 p.R544C variant is an important risk factor for SVO stroke in Taiwan. Phenotypic variation among individuals carrying a NOTCH3 mutation indicates the existence of disease-modifying factors in CADASIL.

Cortical morphological changes in chronic migraine in a Taiwanese cohort: Surface- and voxel-based analyses

Abstract: BackgroundPrevious voxel- or surface-based morphometric analysis studies have revealed alterations in cortical structure in patients with chronic migraine, yet with inconsistent results. The discre...

Temporal Profile of Blood-Brain Barrier Breakdown in Reversible Cerebral Vasoconstriction Syndrome

Abstract: Background and Purpose- Reversible cerebral vasoconstriction syndrome (RCVS) has a unique temporal course of vasoconstriction. Blood-brain barrier (BBB) breakdown is part of the pathophysiology of RCVS, but its temporal course is unknown. We aimed to investigate the temporal profile of BBB breakdown and relevant clinical profiles in a large sample size. Methods- In this prospective observatory bicenter study, patients who underwent contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging within 2 months from onset were included. The presence and extent of BBB breakdown were evaluated using contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging. Contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging data were analyzed using a semiautomated segmentation technique to quantitatively measure the area of Gadolinium leakage into cerebrospinal fluid space. The univariable and multivariable linear regressions were performed to investigate the independent effect of time from onset with adjustment for other covariates. Results- In the 186 patients with angiogram-proven RCVS included in this analysis, BBB breakdown was observed in 52.6%, 56.8%, 30.3%, 40.0%, and 23.8% in the first, second, third, fourth, and ≥fifth week after onset. The extent of BBB breakdown peaked at first and second week, whereas the peak of vasoconstriction was observed at the third week after onset. Multivariable analysis showed the second week from onset (β, 3.35 [95% CI, 0.07-6.64]; P=0.046) and blood pressure surge (β, 3.84 [95% CI, 1.75-5.92]; P<0.001) were independently associated with a greater extent of BBB breakdown. A synergistic effect of time from onset and blood pressure surge was found (P for interaction=0.006). Conclusions- Frequency and extent of BBB breakdown are more prominent during the early stage in patients with RCVS, with an earlier peak than that of vasoconstriction. The temporal course of BBB breakdown may provide a pathophysiologic background of the temporal course of neurological complications of RCVS.

The cerebellum is associated with 2-year prognosis in patients with high-frequency migraine

Abstract: The increase of headache frequency is associated with higher headache related disability and lower quality of life in patients with migraine. However, the pathophysiology of migraine progression, persistence, or remission is elusive. The purpose of this study is to identify the brain signatures that are predictive of the long-term outcomes among patients with high-frequency migraine (HFM: 10–30 headache days/month). We prospectively enrolled patients with HFM and healthy controls and collected their baseline clinical profiles and brain-MRI data at first visit. We longitudinally followed the patients and determined their outcomes at 2-year follow-up. Good outcome was defined as ≥50% reduction of baseline headache days and poor outcome was defined as reduction < 50% or frequency increase. Voxel-based morphometry was used to study gray matter volume (GMV), and structural covariance was used to investigate structural connectivity. Among 56 patients with HFM, 37 had good outcome and 19 poor outcome. Compared to the healthy controls (n = 37), patients with poor outcome had decreased GMV over the left posterior cingulate gyrus, and increased GMV over the bilateral cerebellum and the right precentral gyrus. Further, patients with poor outcome had greater GMV over the right and the left cerebella compared to patients with good outcome, and the GMVs of the cerebella were correlated to 2-year headache frequencies (right: r = 0.38, P = 0.005; left: r = 0.35, P = 0.009). Structural connectivity were increased between the cerebellum and the cuneus, the calcarine cortex, and the temporal lobe, respectively, in patients with poor outcome, and was decreased between the cerebellum and the prefrontal cortex in patients with poor outcome. The structural covariance integrities between the right cerebellum and the right cuneus were correlated to 2-year headache frequencies (r = 0.36, P = 0.008). Structural volume and connectivity changes of the cerebellum may underlie headache persistence in patients with HFM.

Association between tooth loss and gray matter volume in cognitive impairment

Abstract: Previous studies have reported an association between tooth loss and gray matter volume (GMV) in healthy adults. The study aims to elucidate the link between tooth loss, brain volume differences, and cognitive impairment by investigating the total and regional differences in GMV associated with tooth loss in older people with and without cognitive impairment. Forty older participants with mild cognitive impairment or Alzheimer's disease [the cognitive impairment (CI) group] and 30 age- and sex-matched healthy participants [the control (CON) group] received T1-weighted magnetic resonance imaging scans and assessments of oral functions, including masticatory performance (MP) and the number of missing teeth (NMT). Voxel-based morphometry was used to assess the total and regional GMV, including that of the medial temporal lobe and motor-related areas. (A) When the total intracranial volume and age were controlled for, an increased MP was associated with a larger GMV in the premotor cortex in the CON group. (B) In the CI group, an increased NMT was significantly correlated with smaller regional GMV of the bilateral primary motor cortex and the premotor cortex. (C) In the CI group, but not the CON group, an increased NMT was associated with both smaller total GMV and regional GMV of the left medial temporal lobe, including the left hippocampus and parahippocampus. Tooth loss may be preferentially related to the structural differences in the medial temporal lobe in cognitively impaired older people. Further research is required to understand the mechanisms of the relationships.

Summative Effects of Vascular Risk Factors on the Progression of Alzheimer Disease

Abstract: Objectives To investigate the summative effects of vascular risk factors (VRFs) on the progression of Alzheimer disease (AD). Design Longitudinal follow-up cohort study. Setting AD patients from two teaching hospitals in Taiwan with 3-year follow-ups. Participants A total of 330 AD patients with a mean age of 80.7 years, a mean Mini-Mental State Examination (MMSE) score 18.7, and a mean Clinical Dementia Rating Sum of Boxes (CDRSB) score of 6.9. Measurements All patients completed a clinically functional assessment and a neuropsychological test battery at baseline and yearly follow-ups. The VRF burden was combined into a summative VRF index at baseline (ie, having one, two, or more VRFs); VRFs included coronary heart disease, cardiac arrhythmia, hypertension, cerebrovascular disease, diabetes mellitus, obesity, smoking, and physical inactivity. The generalized estimating equation (GEE) method was used to analyze the correlations between the VRFs and longitudinal MMSE and CDRSB changes. Results The results of the GEE adjusted for age, years of education, sex, disease duration, baseline MMSE score, time, apolipoprotein E (APOE) e4 carrier status, use of medications (acetylcholinesterase inhibitors or N-methyl-D-aspartate receptor antagonists), and hospitalization rates and showed that patients with more than three VRFs had more rapid cognitive decline than patients without VRFs (MMSE, P = .02; CDRSB, P = .001) as well as patients with three or fewer VRFs (MMSE, P = .009; CDRSB, P = .02). Subsequent analyses of APOE e4 carriers with more than three VRFs also showed their more rapid cognitive decline compared with patients without VRFs (MMSE, P = .02; CDRSB, P = .001) and patients with three or fewer VRFs (MMSE, P = .009; CDRSB, P = .02), but no significant difference was found in APOE e4 noncarriers. Conclusion Multiple VRFs have summative effects on the progression of AD, especially in APOE e4 carriers. J Am Geriatr Soc 68:129-136, 2019.

Effect of vitamin D on cognitive function and white matter hyperintensity in patients with mild Alzheimer's disease.

Abstract: Aim To examine the effect of vitamin D level on cognitive function and white matter hyperintensity (WMH) in patients with mild Alzheimer's disease (AD). Methods We recruited patients with mild AD, and carried out clinical interviews, neuropsychological assessments, laboratory tests and brain magnetic resonance imaging. Results In total, 146 patients with mild AD (68 men, 78 women; mean age 79.1 ± 7.0 years; mean education 10.2 ± 4.3 years) were enlisted. The mean Mini-Mental State Examination (MMSE) score was 21.0 ± 3.8. The 25-hydroxy vitamin D (25[OH]D) level was correlated negatively with the WMH volume (β = -0.219, P = 0.004) after adjusting for age, sex, years of education, apolipoprotein e4 allele status, seasons of blood sampling, hypertension, diabetes mellitus, hyperlipidemia, coronary heart disease and total brain volume. The 25(OH)D level was correlated positively with the MMSE score (β = 0.309, P Conclusions Reduced plasma 25(OH)D levels were associated with low MMSE scores in patients with mild AD, but the underlying mechanism is not attributable to WMH. Thus, it suggested that the presence of another pathomechanism exists. Geriatr Gerontol Int 2020; 20: 52-58.

Mechanical punctate pain threshold is associated with headache frequency and phase in patients with migraine.

Abstract: ObjectivePrevious studies regarding the quantitative sensory testing are inconsistent in migraine. We hypothesized that the quantitative sensory testing results were influenced by headache frequenc...

Better endovascular mechanical thrombectomy outcome in atrial fibrillation patients with acute ischemic stroke: A single-center experience.

Abstract: BACKGROUND Endovascular thrombectomy (EVT) has become the standard treatment for acute ischemic stroke with large vessel occlusion. Atrial fibrillation (AF) is one of the major causes. However, the impact of AF on the treatment has not yet been clearly discussed. This study is to evaluate the influence of AF on the outcomes of EVT in patients with acute ischemic stroke. METHODS Data from our Stroke Registry Database from April 2015 to July 2018 were reviewed. Technical efficacy, functional, and safety outcomes were reported and compared between patients with and without AF. A multivariate logistic regression model was performed to identify the predictors of the good functional outcome. RESULTS We reviewed 83 eligible patients receiving EVT. Patients (51.8%) were eventually found to have AF. The substantial reperfusion rate (modified thrombolysis in cerebral infarction 2b-3) was 72.1% and 55.0% in patients with and without AF, respectively, inclusive of a learning curve (p = 0.12). The good functional outcome (90-day modified Rankin scale: 0 to 2) rate was 55.8% and 17.5% in patients with and without AF, respectively (p < 0.01). A multivariable logistic regression analysis showed that age <70 years, the substantial reperfusion, and the presence of AF were three significant predictors for a good functional outcome. CONCLUSION Our study showed that patients with AF responded significantly better to EVT than those without AF did. Intracranial atherosclerotic diseases in patients without AF which were especially refractory to EVT may contribute to the difference of the functional outcomes between the two groups.

Brain metabolites in chronic migraine patients with medication overuse headache

Abstract: BackgroundMedication overuse headache may be associated with widespread alterations along the thalamocortical pathway, a pathway involved in pain perception and disease progression. This study addr...

Urine metabolomics signatures in reversible cerebral vasoconstriction syndrome.

Abstract: BackgroundThe pathophysiology of reversible cerebral vasoconstriction syndrome is unclear. An unbiased systems-based approach might help to illustrate the metabolite profiling and underlying pathop...

HLA class I alleles are associated with clinic-based migraine and increased risks of chronic migraine and medication overuse:

Abstract: ObjectiveWe aimed to evaluate associations of human leukocyte antigen variants with migraine or headache in hospital and population-based settings.MethodsThe case-control study population, aged 30–...

Individual pain sensitivity is associated with resting-state cortical activities in healthy individuals but not in patients with migraine: a magnetoencephalography study

Abstract: Pain sensitivity may determine the risk, severity, prognosis, and efficacy of treatment of clinical pain. Magnetic resonance imaging studies have linked thermal pain sensitivity to changes in brain structure. However, the neural correlates of mechanical pain sensitivity remain to be clarified through investigation of direct neural activities on the resting-state cortical oscillation and synchrony. We recorded the resting-state magnetoencephalographic (MEG) activities of 27 healthy individuals and 30 patients with episodic migraine (EM) and analyzed the source-based oscillatory powers and functional connectivity at 2 to 59 Hz in pain-related cortical regions, which are the bilateral anterior cingulate cortex (ACC), medial orbitofrontal (MOF) cortex, lateral orbitofrontal (LOF) cortex, insula cortex, primary somatosensory cortex (SI), primary motor cortex (MI), and posterior cingulate cortex (PCC). The mechanical punctate pain threshold (MPPT) was obtained at the supraorbital area (the first branch of the trigeminal nerve dermatome, V1) and the forearm (the first thoracic nerve dermatome, T1) and further correlated with MEG measures. The MPPT is inversely correlated with the resting-state relative powers of gamma oscillation in healthy individuals (all corrected P < 0.05). Specifically, inverse correlation was noted between the MPPT at V1 and gamma powers in the bilateral insula (r = − 0.592 [left] and − 0.529 [right]), PCC (r = − 0.619 and − 0.541) and MI (r = − 0.497 and − 0.549) and between the MPPT at T1 and powers in the left PCC (r = − 0.561) and bilateral MI (r = − 0.509 and − 0.520). Furthermore, resting-state functional connectivity at the delta to beta bands, especially between frontal (MOF, ACC, LOF, and MI), parietal (PCC), and sensorimotor (bilateral SI and MI) regions, showed a positive correlation with the MPPT at V1 and T1 (all corrected P < 0.05). By contrast, in patients with EM, the MPPT was not associated with resting-state cortical activities. Pain sensitivity in healthy individuals is associated with the resting-state gamma oscillation and functional connectivity in pain-related cortical regions. Further studies must be conducted in a large population to confirm whether resting-state cortical activities can be an objective measurement of pain sensitivity in individuals without clinical pain.

Neuromagnetic Amygdala Response to Pain-Related Fear as a Brain Signature of Fibromyalgia

Abstract: Fibromyalgia (FM) is a chronic pain condition characterized by impaired emotional regulation. This study explored the brain response to pain-related fear as a potential brain signature of FM. We used a conditioned fear task and magnetoencephalography to record pain-related fear responses in patients with FM. Two blocks of 30 fear responses were collected to compute the response strength in the first block and the strength difference between the first and second blocks (fear habituation). These measurements were investigated for their clinical relevance and compared with measurements obtained from healthy controls and patients with chronic migraine (CM), a different chronic pain condition often comorbid with FM. Pain-related fear clearly activated the bilateral amygdala and anterior insula in patients with FM (n = 52), patients with CM (n = 50), and the controls (n = 30); the response strength in the first block was consistent across groups. However, fear habituation in the right amygdala decreased in the FM group (vs. CM and control groups, both p ≤ 0.001, no difference between CM and control groups). At the 3-month follow-up, the patients with FM reporting 0.7). Amygdala activation to pain-related fear is maladaptive and linked to treatment outcomes in patients with FM. Because the aberrant amygdala response was not observed in the CM group, this response is a potential brain signature of FM. ClinicalTrials.gov Identifier, NCT02747940.

Persistence of pregabalin treatment in Taiwan: a nation-wide population-based study

Abstract: Pregabalin is approved for the treatment of neuropathic pain, fibromyalgia, and seizure disorders, although the pivotal trials were mostly carried out in Europe or North America. The prescribing patterns among different indications in Asia have rarely been explored. This was a population-based retrospective cohort study based on the National Health Insurance Research Database in Taiwan. Prescriptions of pregabalin were identified, and data regarding demographics, indications, co-existing diagnoses, and concomitant medications were extracted. Pregabalin users were followed for at least one year, and factors associated with persistence at one year were determined by using multivariate logistic regression analysis. Between June 2012 and December 2016, 114,437 pregabalin users (mean age 60.7 ± 15.4 years, 57.8% female) were identified. The indications included post-herpetic neuralgia (PHN) (30.5%), musculoskeletal diseases other than fibromyalgia (21.2%), fibromyalgia (18.4%), diabetic peripheral neuropathic pain (DPNP) (11.7%) and epilepsy (2.9%). Overall, 62.5% and 6.4% of patients achieved a maximum dose of ≥150 and ≥ 300 mg/day, respectively. The median duration of persistent pregabalin use was 28 days (interquartile range 14–118 days). The one-year persistence rate was 12.1%, and the indications associated with the highest and lowest persistence rates were epilepsy (42.4%) and PHN (6.1%), respectively. Male gender (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.09–1.18), older age (OR 1.01 per year, 95% CI 1.01–1.01), indications other than PHN, especially epilepsy (OR 8.04, 95% CI 7.33–8.81, PHN as reference), and a higher initial dose (OR 1.12 per 75 mg, 95% CI = 1.10–1.15) were associated with persistence at one year, whereas the initial concomitant use of antiviral agents decreased the likelihood (OR 0.41, 95% CI 0.35–0.47). Pregabalin prescriptions for pain disorders were limited to short-term use, which is consistent around the world. However, the average prescribed dose in Taiwan was lower than those in Western countries, and was frequently below the recommended ranges. Potential causes included the duration of natural history of PHN, and off-label prescriptions for pain in acute herpes zoster, rather than PHN, as well as intolerance to the side effects.

Genetics of neuropsychiatric symptoms in patients with Alzheimer's disease: A 1-year follow-up study.

Abstract: AIM The aim of this study was to investigate the associations between candidate gene variants and domains of neuropsychiatric symptoms (NPS) and the changes in these associations over a 1-year period. METHODS Seven hundred and ninety-three Taiwanese participants (47.8% female) with Alzheimer's disease (AD) were enrolled. Genes associated with a risk of developing AD were selected as candidate genes. NPS were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q), and the NPI-Q total score and sub-scores for the Psychosis, Mood, and Frontal Syndrome domains were calculated. RESULTS Patients with AD and the APOE e4 allele exhibited more obvious symptoms of psychosis. Mood symptoms were associated with CD33 rs3865444 and EPHA1 rs11767557, and frontal symptoms were associated with SORL1 rs3824968. A 1-year Time × Alleles interaction effect of CD33 rs3865444 on mood symptoms was discerned. CONCLUSION Risk genes of AD, which are also associated with NPS, are APOE e4 for psychosis, CD33 and EPHA1 for mood symptoms, and SORL1 for frontal symptoms. The association between CD33 and mood symptoms is dynamic and could change over 1 year; however, the results should be interpreted with caution because corrections for multiple comparisons were not performed.

Posttraumatic epilepsy after traumatic brain injury and prophylactic administration of antiepileptic drugs.

Abstract: More than 50 million people endure traumatic brain injuries (TBI) each year in the world.1 TBI impacts lead to many negative outcomes including various disabilities, neurologic deficits, and even deaths for all ages in all countries,2 which make TBI a chronic health condition and a global healthcare burden.3 In the United States, approximately 1.5 million people suffer from TBI, 280 000 hospitalizations and 50 000 deaths annually during 1997–2007.4,5 Approximately one-third of adults hospitalized with TBI still need assistance with daily activities one year after their discharge. Estimated lifetime costs of TBI in America totaled approximately $56.3 billion in 1995.4 During 2007–2008 in Taiwan, a total of 99 391 patients were admitted with TBI, 48 792 (49.1%) of which had moderate-to-severe head injury.5 The most common group of people (30.1%, 29930/99391) with TBI are motorcycle riders or passengers. The in-hospital mortality rate for patients with severe TBI (Abbreviated Injury Score head of 4, 5, 6) was up to 12.3% during 2007–2008 despite the enforcement of motorcycle helmet use law in 1997 in Taiwan.5 Furthermore, Taiwan also institute the new trauma care hospital classification system in 2009.5 Posttraumatic epilepsy (PTE) after head injuries is a recognized complication of TBI.1,6 The risk factors based on initial clinical radiological findings of patients with TBI developing PTE included men, a history of alcohol abuse, posttraumatic amnesia, focal neurologic signs, and loss of consciousness at initial TBI, skull fracture, midline shift, brain contusion, subdural hemorrhage, epidural hemorrhage, and intracranial hemorrhage.7 Prior studies with various research designs showed the severity of TBI as the greatest predictor of PTE.8 The Glasgow Coma Scale (GCS) is often used as an assessment tool for severity of TBI.9 The cumulative incidence rates of PTE over the past 30 years encompass 2% patients with mild TBI, 4% patients with moderate TBI, and over 15% with severe.10 PTE has three subtypes: immediate epilepsy (occurring within 24 h), early PTE (occurring between 24 h and 7 d after TBI), and late PTE (occurring after 7 d).6 Increasing computed tomography findings identify PTE outcomes 3–5 years following TBI: specially, 75% of patients with hemorrhagic contusions and related extracerebral hematoma had late PTE; only 16.7% of patients presenting intracerebral hemorrhage alone without extracerebral hematoma developed late seizures.11 A recent pilot study further reported that lesions in the temporal lobe rather than overall injury severity were associated with the highest risk of PTE.11 Brain blood barrier abnormalities predicting delayed, long-lasting seizures near the injured tissue are detectable on dynamic contrast-enhanced magnetic resonance imaging, gadolinium‐enhanced T1, and T2‐weighted fluid attenuated inversion recovery.11 Because PTE following TBI has a significant negative impact on patients regarding physical safety and life quality,8 the prophylactic use of antiepileptic drugs (AED) in patients with TBI seems an option for clinicians. A previous randomized study reported that prophylactic AED administration (Phenytoin) decreased the early PTE rate of TBI patients from 14.2% to 3.6% (p < 0.001) but has no effect on late PTE.12 Liou’s study with a propensity score analysis published in the current issue of the Journal of the Chinese Medical Association reported that AED prophylaxis was ineffective in preventing PTE (p = 0.566),13 which is compatible with a previous Cochrane systemic review.14 Controlling the potential confounders made Liou’s results more reliable than prior studies. This finding has clinical implications, and the authors conclude that clinicians should reevaluate the benefit of routine prophylactic AED in caring patients with TBI. Increasing studies support that there is a causal relationship between PTE induction propagation and TBI-associated neuroinflammation, characterized by the activation of microglia and astrocytes, and the massive release of proinflammatory cytokines and chemokines.15 It has potential in the future to develop immune-based biomakers for PTE prediction and immune-targeted therapies for PTE prevention.15

Cost-effectiveness of mirogabalin for the treatment of post-herpetic neuralgia in Taiwan.

Abstract: Objectives: To assess the cost-effectiveness of mirogabalin versus no treatment or pregabalin in patients with post-herpetic neuralgia (PHN) from a third-party perspective in Taiwan.Methods: A Mark...

Nomenclature for flunarizine, cinnarizine, and lomerizine

Abstract: To the Editor, Flunarizine, cinnarizine, and lomerizine have been used for the prophylactic treatment of migraine in certain countries and have been classified as calcium channel blockers (CCBs). These drugs, however, have other pharmacological characteristics in addition to those of CCBs. In addition to the T-type calcium channel blocking effect, flunarizine, cinnarizine, and lomerizine have antihistamine and anti-serotonin effects. Moreover, flunarizine and cinnarizine, but not lomerizine, have antidopaminergic effects (Table 1) (1). Other agents with antihistamine effects, such as cyproheptadine and pizotifen, are also effective in migraine prevention. In contrast, other T-type CCBs, including verapamil, diltiazem, and nimodipine, do not show a definitive migraine prevention effect. Similarly, L-type CCBs, including nimodipine, nifedipine, and nicardipine, do not demonstrate a migraine prevention effect. Appropriate nomenclature can lead to the enhanced understanding of a disease as well as the proper identification of drug mechanisms. Although the pharmacological characteristics of a drug may not explain the exact mechanisms of a particular drug function, the pharmacological characteristics of drugs with and without migraine prevention effects propose that the T-type or L-type calcium channel blocking alone cannot account for the prevention effects of migraine. It remains unclear whether histamine receptor blocking has a definitive migraine prevention effect; however, many histamine H1 and H2 receptor blocking agents show a significant effect in migraine prevention (2). Flunarizine, cinnarizine, and lomerizine were given

The influence of friendship on migraine in young adolescents: A social network analysis.

Abstract: ObjectiveThe current study explored whether the chances of having migraine are influenced by a youth’s friendship with a migraineur.MethodsThe study was centered on a community-based non-referral c...

We still have no data to change the diagnostic criteria for chronic migraine

Abstract: To the Editor: We read with great interest the article by Chalmer and colleagues on the proposed new diagnostic criteria of chronic migraine (CM) (1). The authors found no differences between patients with CM and patients with high frequency episodic migraine (HFEM), 8–14 migraine days per month, in the demographic profile, disability, or disease chronicity. Therefore, they concluded both groups are comparable and proposed new diagnostic criteria for CM to include those currently diagnosed as HFEM. We have concerns about the authors’ interpretation of the data and believe they do not support their conclusion (2,3). First, the comparison of the demographic profile was limited to the following variables: Sex, age, age of onset, and self-reported provocation by triggers. Several variables previously shown to be different between patients with CM and episodic migraine (EM), including body-mass index, education, ethnicity, household income, or marital status, all have not been included in the current study for comparison (4,5). Second, the authors did not show the data on the disease frequency using the headache/migraine days per month. Instead, they used lifetime/previous year attacks. The information of lifetime attacks is hard to interpret when the disease duration is unknown. The attack frequency over the previous year is an oxymoron: In the CM group, only 31% of patients had >36 migraine attacks in the previous year. That means, 69% of the CM patients had on average 3 migraine attacks monthly over the previous year? Third, the authors claimed that HFEM is comparable to CM in disability. The four disability measures in the current study are defined by the receipt of social security benefits, including early retirement pension, receipt of sickness benefit, cash assistance, and rehabilitation benefit. For the following reasons, this claim requires further evidence:

Is Lower Glucose Level a Risk Factor for Post-Dural Puncture Headache?

Abstract: Lumbar puncture is a widely used procedure for the diagnosis of neurological disorders. However, postdural puncture headache (PDPH) caused by persistent cerebrospinal fluid (CSF) leakage is a common complication of lumbar puncture, with the incidence of PDPH as 17.5-32% for diagnostic lumbar puncture and 0-18% for spinal anesthesia. According to the International Classification of Headache Disorders, 3rd edition, the diagnosis of PDPH requires headache developed within 5 days after dural puncture, and the headache should fulfill the criteria of “7.2. low CSF pressure headache.” Currently, several studies analyzed the risk factors for PDPH, which can be further divided into non-modifiable and modifiable ones. Non-modifiable risk factors include younger age, female gender, lower body mass index, previous PDPH, and a history of chronic headache. Moreover, the modifiable risk factors include the size of the spinal needle, needle shape, operator experience, and the number of attempts. To date, the only reported susceptibility biomarker is the lower CSF level of substance P (see below). Hwang et al. analyzed a sizable number of patients (n = 969), who received diagnostic lumbar puncture and they found lower serum and CSF glucose level as a new risk factor for the PDPH. They also showed that younger age, but not female gender, was associated with a higher risk for PDPH. The subsequent analysis showed that older PDPH patients (>60 years old) had a lower serum glucose level in comparison with the non-PDPH group, but this difference did not reach significance in patients ≤60 years old. This research finding may provide insights into the pathophysiology for PDPH. The lower serum glucose level may attribute to decreased CSF production or impaired dura healing. A previous study showed that the lower substance P level linked to 3-fold risk for PDPH and substance P might inhibit insulin-mediated glucose uptake, resulting in relatively high serum glucose levels. Therefore, the lower serum glucose level may be an epiphenomenon of lower substance P level, which was associated with impaired wound healing. One issue that should be noted for this article is that the difference in serum glucose levels might be derived from heterogeneous study samples, such as meningitis, encephalitis, or neurodegenerative diseases. However, in real-world practice, it is difficult to minimize the procedural variables of diagnostic lumbar punctures for different neurological disorders. Another issue is the diagnosis of PDPH in this paper. The determination of PDPH solely depended on symptoms and the temporal relationship with a lumbar puncture. The evidence for low CSF pressure from direct measurement or neuroimaging was not required. It is difficult to ensure patients with possible central nervous system infection or neurodegenerative disorders can precisely report the core symptoms of PDPH, which may account for the relatively lower incidence of PDPH (5%). Nonetheless, this study provides a possible new risk factor for PDPH, and further studies are warranted to confirm their interesting finding and to disclose the underlying pathophysiology of the PDPH. Headache doi: 10.1111/head.13881 © 2020 American Headache Society Published by Wiley Periodicals, LLC. ISSN 0017-8748

Reply to Letter to the Editor, "Creatine loading for chronic migraine?"

Abstract: We read the comments to our paper published in Cephalalgia (1) with great interest. In his comments, Dr. Ostojic (2) suggests that the reduced thalamic total creatine levels we observed in chronic migraine (CM) patients could potentially be remediated with oral creatine supplementation. It was further suggested that this could lead to a reduction in migraine symptoms. Dr. Ostojic nicely lists several potential hurdles that may have to be overcome for the therapy to be successful in CM patients. Here, we wish to further elaborate on the proposition put forward by Dr. Ostojic. Oral creatine supplementation for 2–4 weeks may increase brain creatine levels by about 8–15% in healthy adults (3,4), with the highest increase observed in the thalamus after 4 weeks of continuous administration (3). These results, however, should be interpreted with caution as they need to be confirmed in a larger study cohort. In our study, total creatine levels were reduced by about 10% (6.34 mM vs. 7.04 mM) in CM patients. Hence, the magnitude of the required change is within the range obtainable with oral supplementation. Furthermore, it has been suggested that the effects of creatine supplementation on brain function could be larger in conditions with chronic depletion of brain creatine (5). Modulation of thalamic creatine levels by supplementation furthermore has the potential to answer whether the observed total creatine reduction is a consequence of the headaches or if it contributes directly to generation or maintenance of the headaches. It would also be possible to examine whether the reduced total creatine levels are coupled to the concomitant reductions in thalamic total N-acetylaspartate observed in our study; that is, whether altered energy homeostasis leads to compromised neuronal health. It is noteworthy that a study on creatine supplementation in CM would have to control for the diet (vegetarian vs. non-vegetarian) and exercise patterns, as both can influence the available creatine levels (5). Finally, the long-term effects of creatine supplementation on endogenous creatine synthesis in the brain remains largely unknown and require further studies. Declaration of conflicting interests

Brain Excitability in Tension-Type Headache: a Separate Entity from Migraine?

Abstract: Tension-type headache is often regarded as the “normal” headache due to its high prevalence and mild disability in contrast with migraine. Clinically, both headaches are common comorbidities to each other. To date there has been many studies linked migraine to a brain excitability disorder. This review summarized earlier studies on brain excitability of TTH and discuss if TTH is a separate clinical entity from migraine as suggested by the diagnostic criteria. A recent magnetoencephalographic study from our group enrolled patients with “strict-criteria” TTH (i.e., absence of any migraine characteristics and associated symptoms) to compare the somatosensory excitability with patients with migraine and controls. This study provided evidence that TTH and migraine differ in excitability profiles and the measurement of preactivation excitability was able to discriminate TTH from migraine. Earlier studies on brain excitability of TTH yielded negative findings or a common change shared with migraine. Future studies using strict diagnostic criteria to avoid the unwanted interference from migraine comorbidity may help decipher the “true” pathophysiology of TTH, which may pave the way to a TTH-specific brain signature and treatment.

Reply to letter to the editor: Insights into chronic migraine pathophysiology – what measures of gray matter reveal:

Abstract: We appreciate DeSouza et al.’s interest in and comments (1) on our study (2) and find the results from their recent study of great interest (3). In their study, in addition to conventional volume and thickness-based measures, a graph-theoretical approach was used to delineate differences in structural covariance networks between patients with chronic migraine (CM) and healthy controls (HC). While DeSouza et al. did not find any between-group differences using the conventional volume or thickness-based measures, we showed that cortical thickness was decreased in several painrelated cortical regions in CM patients (2). Their finding of significant differences in structural network measures leads DeSouza et al. to suggest that such measures may provide a more sensitive means to detect structural differences in CM (3). While we agree with DeSouza et al. on the importance of using structural covariance network analysis, as it provides complementary information, we want to emphasize with our study (2) that homogeneity of the patient population is of utmost importance in order to reveal subtle differences, even if those differences appear to be shared with other chronic pain conditions. Hence, if medication overuse, psychiatric comorbidities, and ongoing preventive medication are not controlled for then, irrespective of the structural measure used, it is difficult to ascribe the presence or absence of findings to CM pathophysiology alone. For example, it has previously been demonstrated by our group that medication overuse is associated with specific structural and neurochemical differences (4,5). Additionally, depression itself is known to affect brain morphology and connectivity, as revealed by graph theory-based brain network analysis (6). As for the discrepancy between DeSouza et al.’s study (3) and ours (2), differences in the abovementioned factors possibly account for this. Furthermore, DeSouza et al. measured the averaged cortical thickness in 68 cortical regions of interest (ROIs) (34 in each hemisphere) parcellated according to the Desikan-Killiany atlas, rather than using a vertex-based approach. The subtle differences within a sub-ROI area between groups could theoretically be averaged out by such an ROI analysis. Further studies applying all of the above-mentioned structural measures in a more homogenous patient population are warranted and may provide additional novel insights into CM-specific pathophysiology.