Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia: Secondary Analysis of a Randomized Clinical Trial.

Importance: Female gender is a major risk factor for dementia; however, gender has not yet been adequately addressed by clinical trials. A recent study demonstrated that sodium benzoate, a D-amino acid oxidase inhibitor, improved cognitive function in early-phase Alzheimer disease. Objective: To examine the potential gender difference in the effects of benzoate treatment on the behavioral and psychological symptoms of dementia (BPSD). Design, Setting, and Participants: This post hoc secondary analysis used data from a randomized, double-masked, placebo-controlled trial conducted in 3 major medical centers in Taiwan and enrolled 97 patients with BPSD. Data were analyzed between February 2014 and November 2017. Interventions: Six weeks of treatment of 250 to 1500 mg/d of sodium benzoate or placebo. Main Outcomes and Measures: The primary outcome measures were Alzheimer disease assessment scale-cognitive subscale (ADAS-cog) and Behavioral Pathology in Alzheimer Disease Rating Scale (BEHAVE-AD) scores. Results: Among 97 total participants (62 [64%] women; mean [SD] age, 75.4 [7.7] years), 49 patients (30 women and 19 men) were randomized to sodium benzoate, and 48 (32 women and 16 men) were randomized to placebo. Among 62 women, 6-week benzoate treatment significantly surpassed placebo in the effects on ADAS-cog performance (mean [SD] difference in score between baseline and end point, -3.1 [6.4] points vs 0 [4.5] points; Cohen d = 0.56; P = .04) but not BEHAVE-AD performance. In contrast, among 35 men, the 2 treatment groups did not differ significantly in both ADAS-cog and BEHAVE-AD scores. Compared with placebo, benzoate treatment also increased estradiol to follicle-stimulating hormone ratios among women (mean [SD] difference between baseline and end point, 0 [0.2] vs -0.1 [0.3]; P = .03). Conclusions and Relevance: These findings suggest that benzoate treatment may improve cognitive function in women with later-phase dementia. In the future, longer dose-finding trials are warranted to further clarify the efficacy of benzoate for later-phase dementia and investigate the role of sex hormones and other factors in the pathogenesis of dementia. Trial Registration: ClinicalTrials.gov Identifier: NCT02103673.

Precision Medicine of Sodium Benzoate for the Treatment of Behavioral and Psychological Symptoms of Dementia (BPSD).

OBJECTIVE: Behavioral and psychological symptoms of dementia (BPSD) are associated with poorer prognosis of dementia. A 24-week study demonstrated that sodium benzoate, a D-amino acid oxidase (DAAO) inhibitor, surpassed placebo in improving cognitive function in early-phase Alzheimer's disease; however, benzoate did not excel placebo in another 6-week study on BPSD. The current study examined whether the precision medicine approach was able to identify specific individuals with BPSD who could benefit from benzoate treatment. METHODS: In the randomized, double-blind, placebo-controlled, 6-week trial, 97 patients with BPSD were allocated to receive 250-1500 mg/day of sodium benzoate or placebo. Cognitive function was measured by the Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) and behavioral and psychological symptoms were mainly measured by Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). DAAO level, amino acids (L-serine, D-serine, L-alanine, and D-alanine, glycine), and two antioxidants (catalase, superoxide dismutase) were assayed in peripheral blood. RESULTS: After benzoate treatment, DAAO inhibition was correlated with ADAS-cog decrease (p = 0.034), while baseline DAAO level was correlated with baseline BEHAVE-AD score. Multiple linear regression analyses showed that cognitive improvement after benzoate treatment was correlated with DAAO decrease, female gender, younger age, BMI, baseline BPSD severity, and antipsychotic use. CONCLUSION: The finding suggests that sodium benzoate may have potential to benefit cognitive function in a fraction of BPSD patients after 6 weeks of treatment. Of note, the precision medicine approach may be helpful for identifying individuals who could respond to benzoate. More studies are warranted to confirm the preliminary findings. TRIAL REGISTRATION: The trial was registered online (https://clinicaltrials.gov/ct2/show/NCT02103673).

Medication Overuse and Medication Overuse Headache: Risk Factors, Comorbidities, Associated Burdens and Nonpharmacologic and Pharmacologic Treatment Approaches.

PURPOSE OF REVIEW: With a worldwide high disease burden, medication overuse headache (MOH) is an endemic and disabling neurological disorder. Because of the limitations of previous study designs, there are still debates and questions regarding the disease's nature and treatment strategy. This review will discuss the following concepts; (1) recent progress in association between medication overuse (MO) and MOH; (2) the burden, risk factors and comorbidities of MOH; (3) evidence of treatment in patients with MOH. RECENT FINDINGS: The causal relationship between MO and MOH has not been identified. Currently, the treatment policy is still mainly based on small clinical observations, some with highly specified patients. In addition to withdrawal and preventive treatment, some studies have provided evidence for nonpharmacological treatments. Well-designed studies for specific treatment strategies with enough statistical power are warranted to make more relevant, better clinical decisions.

Non-headache symptoms in migraine patients.

Migraine is one of the most common neurological disorders. In addition to severe headaches, non-headache symptoms associated with migraine attacks as well as co-morbid disorders frequently aggravate the disabling of migraine patients. Some of these symptoms are related to poor outcomes. In this review, we update the advances of studies on certain non-headache symptoms, including visual disturbance, gastrointestinal symptoms, allodynia, vestibular symptoms, and symptoms of co-morbid restless legs syndrome and psychiatric disorders.

Change in 1-year hospitalization of overall and older patients with major depressive disorder after second-generation antipsychotics augmentation treatment.

BACKGROUND: Studies on second-generation antipsychotics (SGA) augmentation treatment for older adults with major depressive disorder (MDD) remain limited. We aimed to investigate the effectiveness of SGA augmentation for overall and older patients with MDD inpatient history by assessing the change in 1-year hospitalization before and after SGA augmentation using the latest National Health Insurance Research Database (NHIRD) in Taiwan. METHODS: The samples were MDD patients (ICD-9 CM code: 296.2 and 296.3) who had psychiatric inpatient history. A total of 2602 MDD patients including 430 elderly subjects (age ≥ 60 years) who received SGA augmentation for 8 weeks between January 1998 and December 2012 were included in this 1-year mirror-image study. Outcome measures included number and length of psychiatric and all-cause hospitalizations. RESULTS: After 8-week continuous SGA augmentation in the study subjects, the total number and days of psychiatric hospitalizations among overall patients reduced by 33.57% (p < .0001) and 18.24% (p < .0001), respectively; the total number and days of psychiatric hospitalizations among older patients (age ≥ 60) reduced by 44.52% (p < .0001) and 27.95% (p < .0001), respectively. Similarly, the total number and days of all-cause hospitalizations were significantly reduced. LIMITATIONS: MDD patients without inpatient history were not included due to data limitation; hence, the results may not be generalized to all patients. CONCLUSIONS: The results support that SGA may be effective in reducing psychiatric and all-cause hospitalization among overall and elderly MDD patients. More studies focusing on the safety of SGA among older MDD patients is warranted.

Genome-wide association study identifies novel susceptibility loci for migraine in Han Chinese resided in Taiwan.

Background Susceptibility genes for migraine, despite it being a highly prevalent and disabling neurological disorder, have not been analyzed in Asians by genome-wide association study (GWAS). Methods We conducted a two-stage case-control GWAS to identify susceptibility genes for migraine without aura in Han Chinese residing in Taiwan. In the discovery stage, we genotyped 1005 clinic-based Taiwanese migraine patients and 1053 population-based sex-matched controls using Axiom Genome-Wide CHB Array. In the replication stage, we genotyped 27 single-nucleotide polymorphisms with p < 10-4 in 1120 clinic-based migraine patients and 604 sex-matched normal controls by using Sequenom. Variants at LRP1, TRPM8, and PRDM, which have been replicated in Caucasians, were also genotyped. Results We identified a novel susceptibility locus (rs655484 in DLG2) that reached GWAS significance level for migraine risk in Han Chinese ( p = 1.45 × 10-12, odds ratio [OR] = 2.42), and also another locus (rs3781545in GFRA1) with suggestive significance ( p = 1.27 × 10-7, OR = 1.38). In addition, we observed positive association signals with a similar trend to the associations identified in Caucasian GWASs for rs10166942 in TRPM8 (OR = 1.33, 95% confidence interval [CI] = 1.14-1.54, Ppermutation = 9.99 × 10-5; risk allele: T) and rs1172113 in LRP1 (OR = 1.23, 95% CI = 1.04-1.45, Ppermutation = 2.9 × 10-2; risk allele: T). Conclusion The present study is the first migraine GWAS conducted in Han-Chinese and Asians. The newly identified susceptibility genes have potential implications in migraine pathogenesis. DLG2 is involved in glutamatergic neurotransmission, and GFRA1 encodes GDNF receptors that are abundant in CGRP-containing trigeminal neurons. Furthermore, positive association signals for TRPM8 and LRP1 suggest the possibility for common genetic contributions across ethnicities.

Low cholesterol level associated with severity and outcome of spontaneous intracerebral hemorrhage: Results from Taiwan Stroke Registry.

The relationship between cholesterol level and hemorrhagic stroke is inconclusive. We hypothesized that low cholesterol levels may have association with intracerebral hemorrhage (ICH) severity at admission and 3-month outcomes. This study used data obtained from a multi-center stroke registry program in Taiwan. We categorized acute spontaneous ICH patients, based on their baseline levels of total cholesterol (TC) measured at admission, into 3 groups with <160, 160-200 and >200 mg/dL of TC. We evaluated risk of having initial stroke severity, with National Institutes of Health Stroke Scale (NIHSS) >15 and unfavorable outcomes (modified Rankin Scale [mRS] score >2, 3-month mortality) after ICH by the TC group. A total of 2444 ICH patients (mean age 62.5±14.2 years; 64.2% men) were included in this study and 854 (34.9%) of them had baseline TC <160 mg/dL. Patients with TC <160 mg/dL presented more often severe neurological deficit (NIHSS >15), with an adjusted odds ratio [aOR] of 1.80; 95% confidence interval [CI], 1.41-2.30), and 3-month mRS >2 (aOR, 1.41; 95% CI, 1.11-1.78) using patients with TC >200 mg/dL as reference. Those with TC >160 mg/dL and body mass index (BMI) <22 kg/m2 had higher risk of 3-month mortality (aOR 3.94, 95% CI 1.76-8.80). Prior use of lipid-lowering drugs (2.8% of the ICH population) was not associated with initial severity and 3-month outcomes. A total cholesterol level lower than 160 mg/dL was common in patients with acute ICH and was associated with greater neurological severity on presentation and poor 3-month outcomes, especially with lower BMI.

Neuropsychiatric Symptoms in Parkinson's Disease Dementia Are More Similar to Alzheimer's Disease than Dementia with Lewy Bodies: A Case-Control Study.

BACKGROUND AND PURPOSE: Previous studies on the clinical and pathological manifestations of Parkinson's disease dementia (PDD) have reported findings more similar to dementia with Lewy bodies (DLB) than to Alzheimer's disease (AD). The aim of this study was to investigate the neuropsychiatric symptoms of PDD compared to DLB and AD. METHODS: We conducted a retrospective case-control study on 125 newly diagnosed consecutive PDD patients and age- and dementia stage-matched controls with either DLB (N = 250) or AD (N = 500) who visited the same hospital over the same period. For each case and control, neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI). RESULTS: Overall, 513 (58.6%) patients were female and 362 (41.4%) were male. Comparisons of clinical data revealed that the PDD group, similar to the AD group, had a lower NPI total score, NPI caregiver burden score, and rate of antipsychotic use (all p < 0.001) than the DLB group. One or more psychiatric symptoms were reported in 95.2% of the PDD, 99.2% of the DLB, and 96.8% of the AD patients. The PDD group had lower subscores in the items of delusions, hallucinations, agitation, anxiety, irritation, aberrant motor behavior compared to the DLB group. Severe neuropsychiatric symptoms among all dementia patients were associated with younger age, more advanced stage, and a diagnosis of DLB. CONCLUSION: Neuropsychiatric symptoms in PDD were more like those in AD than in DLB. Severe neuropsychiatric symptoms in degenerative dementia were associated with younger age, more advanced stage of dementia, and a diagnosis of DLB.

RISK OF NEW ONSET TYPE II DM IN MDD PATIENTS RECEIVING SECOND-GENERATION ANTIPSYCHOTICS TREATMENT: A NATIONWIDE COHORT STUDY.

BACKGROUND: Second-generation antipsychotics (SGA) augmentation treatment has showed better efficacy in patients with major depressive disorder (MDD). However, the association between SGA and diabetes mellitus (DM) in MDD patients deserves further investigation. The study aimed to examine the risk of new onset type II DM in MDD patients receiving SGA treatment. METHODS: From the Psychiatric Inpatient Medical Claim Dataset, MDD patients treated with SGA continuously for more than 8 weeks were analyzed in a 1:1 propensity score matched pair sample to 1,049 patients that had never been treated with SGA. Patients were followed up to 5 years based on ICD-9 CM codes indicating incident type II DM. Cumulative incidences of type II DM were calculated and the Cox proportional hazards model with competing risk was applied to determine the risk factors for type II DM onset. RESULTS: Cumulative incidences of new-onset type II DM between the two groups were similar. Use of SGA showed no significant increase in risk for new-onset type II DM (hazard ratio [HR] = 0.898; 95% confidence interval [CI], 0.605-1.334; P-value = 0.596). Increased risk for type II DM was shown to be associated with aging (per year) (HR = 1.039; 95% CI, 1.026-1.053; P-value < 0.001) and history of hyperlipidemia (HR = 2.323; 95% CI, 1.469-3.675; P-value < 0.001). CONCLUSIONS: This study indicated that there is no significant difference in the risk of developing type II DM between MDD patients with and without SGA exposure. More studies focused on the benefit-risk assessment of SGA treatment in patients with MDD are warranted.

Bidirectional triggering association between migraine and restless legs syndrome: A diary study.

OBJECTIVE: Migraine is comorbid with restless legs syndrome (RLS). However, the temporal association between these two episodic disorders remains elusive. The current study investigated the temporal relationship between migraine and RLS attacks. METHODS: Migraine patients with RLS were recruited from a headache clinic. Patients with symptomatic RLS, RLS mimics, daily headaches, or daily RLS attacks were excluded. The patients recorded their headaches and RLS attacks for two weeks in a diary. The severity of each headache or RLS attack was rated on a four-point (0-3) Likert scale. Logit-normal, random-effects models were employed to estimate the odds ratios (ORs) for the temporal association between migraine and RLS attacks. RESULTS: Thirty migraine patients with RLS (28 F/2 M, mean age 35.5 ± 9.0 years) completed the study. On the basis of 420 daily diary records, migraine attacks were associated with subsequent RLS attacks occurring on the same and next nights (OR = 6.94, 95% confidence interval (CI) = 4.39-11.0 and OR = 3.00, CI = 1.92-4.68; both ITALIC! p < 0.001). RLS attacks were associated with subsequent migraine attacks only on Day 1 (OR = 1.97 (CI = 1.3-2.98; ITALIC! p = 0.01). Overall, the frequencies of migraine and RLS attacks in two weeks were correlated (Spearman's correlation = 0.56, ITALIC! p = 0.001). CONCLUSIONS: Our study results showed a bidirectional triggering association between migraine and RLS attacks. The association was stronger and lasted longer for migraine triggering subsequent RLS than that for vice versa.

Susceptible genes of restless legs syndrome in migraine.

Objective Several genetic variants have been found to increase the risk of restless legs syndrome (RLS). The aim of the present study was to determine if these genetic variants were also associated with the comorbidity of RLS and migraine in patients. Methods Thirteen single-nucleotide polymorphisms (SNPs) at six RLS risk loci ( MEIS1, BTBD9, MAP2K5, PTPRD, TOX3, and an intergenic region on chromosome 2p14) were genotyped in 211 migraine patients with RLS and 781 migraine patients without RLS. Association analyses were performed for the overall cohort, as well as for the subgroups of patients who experienced migraines with and without aura and episodic migraines (EMs) vs. chronic migraines (CMs). In order to verify which genetic markers were potentially related to the incidence of RLS in migraine patients, multivariate regression analyses were also performed. Results Among the six tested loci, only MEIS1 was significantly associated with RLS. The most significant SNP of MEIS1, rs2300478, increased the risk of RLS by 1.42-fold in the overall cohort ( p = 0.0047). In the subgroup analyses, MEIS1 augmented the risk of RLS only in the patients who experienced EMs (odds ratio (OR) = 1.99, p = 0.0004) and not those experiencing CMs. Multivariate regression analyses further showed that rs2300478 in MEIS1 (OR = 1.39, p = 0.018), a CM diagnosis (OR = 1.52, p = 0.022), and depression (OR = 1.86, p = 0.005) were independent predictors of RLS in migraine. Conclusions MEIS1 variants were associated with an increased risk of RLS in migraine patients. It is possible that an imbalance in iron homeostasis and the dopaminergic system may represent a link between RLS incidence and migraines.

Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint. RESULTS: Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects. CONCLUSIONS: Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes.

Onset headache predicts good outcome in patients with first-ever ischemic stroke.

BACKGROUND AND PURPOSE: The study aimed to assess whether onset headache is an ominous sign in patients with first-ever ischemic stroke. METHODS: A large population of ischemic stroke patients was obtained from the Taiwan Stroke Registry. Stroke subtypes were classified by the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. On the basis of the International Classification of Headache Disorders, second version, onset headache was defined as a new headache that developed at the onset of ischemic stroke. Clinical features and impact on stroke outcomes, including in-hospital stroke in evolution, changes in National Institutes of Health Stroke Scale on discharge, and Barthel index and modified Rankin scale ≤6 months after stroke were compared between those with and without onset headache. RESULTS: Among 11 523 patients with first-ever ischemic stroke, 848 had onset headache (7.4%). Patients with specific cause, large-artery atherosclerosis, or cardioembolism were more likely to have onset headache. Patients with onset headache were younger, predominantly female, and more likely to have posterior circulation ischemic lesions. Compared with patients without onset headache, those with onset headache had a lower frequency of stroke in evolution (4.5% versus 6.7%; adjusted relative risk, 0.64; 95% confidence interval, 0.52-0.79), greater improvement in National Institutes of Health Stroke Scale score on discharge (0.08 versus -0.20; P=0.02), higher mean Barthel index scores (86.5±20.0 versus 83.9±23.3; adjusted difference, 1.43; 95% confidence interval, 0.28-2.89), and a lower frequency of modified Rankin scale higher than 2 (27.6% versus 31.5%; adjusted relative risk, 0.85; 95% confidence interval, 0.72-0.95) at 1-month follow-up. There was also a trend for better functional outcome in 3- and 6-month follow-ups. CONCLUSIONS: By adopting standard classification criteria, this large-scale study demonstrated that onset headache was associated with modest but significantly better outcomes after ischemic stroke.

Depression in Taiwanese patients with Alzheimer's disease determined by the National Institutes of Mental Health Provisional Criteria.

BACKGROUND: Depression is a common behavioral and psychological symptom of Alzheimer's disease (AD). The aims of the present study were to determine the rate of depression in Taiwanese patients with AD using the National Institutes of Mental Health Provisional Criteria for Depression in AD (NIMH-dAD criteria) and to investigate the association of depression with other behavioral and psychological symptoms. METHODS: A consecutive series of 302 AD patients registered in a dementia clinic were investigated in this study. All patients met the criteria of the National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association for probable AD. The rates of depression were determined according to the criteria of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders for major depression (DSM-IV), the International Classification of Diseases-9-Clinical Modification (ICD-9-CM) for neurotic depression, the depression subscale of the Neuropsychiatric Inventory (NPI), and the NIMH-dAD criteria. Depression severity was assessed using the 17-item Hamilton Depression Rating Scale. The rates of depression determined by the NIMH-dAD criteria were compared with the rates derived from each of the other instruments. Other behavioral and psychological symptoms were assessed using NPI. A behavioral neurologist or a geriatric psychiatrist interviewed all the patients. RESULTS: Using the NIMH-dAD criteria, it was found that 90 (29.8%) of the AD patients had depression, and all depressive symptoms in NIMH-dAD were significantly higher among depressed patients. Among other depression instruments, the frequency of depression was lowest using the DSM-IV major depression criteria (9.3%) and highest with the NPI depression subscale (54%). Behavioral and psychological symptoms determined with NPI were significantly higher among depressed patients in all domains except euphoria. CONCLUSIONS: This is the first study of depression in Taiwanese patients with AD using the NIMH-dAD criteria. Our findings suggest that comorbid depression is high in Taiwanese patients with AD. It is clinically important to note the high frequency of most behavioral and psychological symptoms among depressed AD patients.

Chinese medicine patterns in patients with post-stroke dementia.

UNLABELLED: A stroke often results in post-stroke dementia, a rapid decline in memory and intelligence causing dysfunctions in daily life. The Chinese medicine doctor uses 4 examinations of inspection, listening, smelling, and feeling to determine the Chinese medicine pattern (CMP). Therefore, the purpose of the present study was to investigate the CMP in patients with post-stroke dementia. A total of 101 stroke patients were examined, consistent with the DSM IV diagnostic criteria of the American Psychiatric Association, as well as the National Institute of Neurological Disorders and Stroke-Association International pour Ia Recherche et I'Enseignement en Neurosciences vascular dementia diagnostic criteria of post-stroke dementia. RESULTS: 100 patients (99.0%) were KEDP (kidney essence deficiency pattern, shèn jing kui xu zhèng, ), 83 patients were AHLYP (ascendant hyperactivity of liver yang pattern, gan yáng shàng kàng zhèng, ), 83 patients were QBDP (qi-blood deficiency pattern, qì xuè kui xu zhèng, ), 81 patients were SBOCP (static blood obstructing the collaterals pattern, yu xuè zǔ luò zhèng, ), 72 patients were BSTRP (bowels stagnation turbidity retention pattern, fǔ zhì zhuó liú zhèng, ), 50 patients were FHIEP (fire heat interior excess pattern, huǒ rè nèi sheng zhèng, ), and 39 participants (38.6%) were PTOOP (phlegm turbidity obstructing the orifices pattern, tán zhuó zǔ qiào zhèng, ); one to 31 patients have at least 2 CMPs simultaneously. In conclusion, the most CMP is KEDP CMP in the post-stroke dementia patients, and one patient may have one or at least 2 CMPs simultaneously.

[Treatment guidelines for acute and preventive treatment of cluster headache].

The Treatment Guideline Subcommittee of the Taiwan Headache Society evaluated both the acute and the preventive treatments for cluster headache now being used in Taiwan, based on the principles of evidence- based medicine. We assessed the quality of clinical trials and levels of evidence, and referred to other treatment guidelines proposed by other countries. Throughout several panel discussions, we merged opinions from the subcommittee members and proposed a consensus on the major roles, recommended levels, clinical efficacy, adverse events and cautions of clinical practice regarding acute and preventive treatments of cluster headache. The majority of Taiwanese patients have episodic cluster headaches, because chronic clusters are very rare. Cluster headache is characterized by severe and excruciating pain which develops within a short time and is associated with ipsilateral autonomic symptoms. Therefore, emergency treatment for a cluster headache attack is extremely important. Within the group of acute medications currently available in Taiwan, the subcommittee determined that high-flow oxygen inhalation has the best evidence of effectiveness, followed by intranasal triptans. Both are recommended as first-line medical treatments for acute attacks. Oral triptans were determined to be second-line medications. For transitional prophylaxis, oral corticosteroids are recommended as the first-line medication, and ergotamine as the second-line choice. As for maintenance prophylaxis, verapamil has the best evidence and is recommended as the first-line medication. Lithium, melatonin, valproic acid, topiramate and gabapentin are suggested as the second-line preventive medications. Surgical interventions, including occipital nerve stimulation, deep brain stimulation, radiofrequency block of the sphenopalatine ganglion, percutaneous radiofrequency rhizotomy and trigeminal nerve section, are invasive and their long-term efficacy and adverse events are still not clear in Taiwanese patients; therefore, they are not recommended currently by the subcommittee. The transitional and maintenance prophylactic medications can be used together to attain treatment efficacy. Once the maintenance prophylaxis achieves efficacy, the transitional prophylactic medications can be tapered gradually. We suggest the corticosteroids be used within two weeks, if possible. The duration of maintenance treatment depends on the individual patient's clinical condition, and the medications can be tapered off when the cluster period is over.