OBJECTIVE: Chronic headaches are a significant source of disability worldwide. Despite the development of conventional strategies, a subset of patients remain refractory and/or experience side effects following these treatments. Hence, occipital nerve stimulation (ONS) should be considered as an alternative strategy for intractable chronic headaches. This review aims to provide a comprehensive overview of the effectiveness, safety, mechanisms and practical application of ONS for the treatment of headache disorders.
RESULTS: Overall response rate of ONS is 35.7-100%, 17-100%, and 63-100% in patients with cluster headache, chronic migraine and occipital neuralgia respectively. Regarding the long-term effectivity in all groups, 41.6-88.0% of patients remain responders after ≥ 18.3 months. The most frequently reported adverse events include lead migration/fracture (13%) and local pain (7.3%). Based on our results, ONS can be considered a safe and effective treatment for chronic intractable headache disorders. To support more widespread application of ONS, additional research with larger sample sizes should be conducted.

BACKGROUND: Cluster headache is a severe and debilitating neurological condition characterized by intense, excruciating pain with a significant impact on patients\' wellbeing. Although different treatment options are available, many patients continue to experience inadequate relief. Therefore, experimental strategies are increasingly studied. One of the more promising approaches is the use of ketamine. We present the currently available evidence and our own data.
METHODS: In this mixed-methods paper, we first summarize the available evidence of ketamine for treatment of cluster headache based on a systematic review of literature in MEDLINE, EMBASE and the Cochrane library of systematic reviews. As the level of evidence is quite limited, we report our own cohort study with ten patients treated with ketamine infusions for cluster headache. They were followed up to investigate the patients\' experience of treatment success and quality of life.
RESULTS: The search and review of literature identified four reports with a total of 68 patients. All were uncontrolled case series. The current literature suggests that ketamine might decrease cluster headache. However, as the applied regimes and reported outcomes are highly heterogeneous, further analysis was futile. Our own data show high patient satisfaction with ketamine treatment.
CONCLUSIONS: Despite the limited evidence, ketamine might be considered a potential therapeutic approach for cluster headache. Therefore, further research including randomized controlled trials should be encouraged.
This article discusses the potential use of ketamine for the treatment of cluster headache, a severe neurological condition that can have a significant impact on patients\' quality of life. The authors conducted a systematic review of the existing literature on ketamine for the treatment of cluster headache. Additionally, they also presented their own cohort study of ten patients receiving ketamine infusions. The review of the literature revealed four reports with a total of 68 patients, all of which were uncontrolled case series. While the current literature suggests that ketamine may be effective in relieving cluster headache symptoms, the heterogeneity of treatment regimens and reported outcomes makes it difficult to draw definitive conclusions. The authors\' own cohort study found that patients were very satisfied with ketamine treatment, indicating a potential benefit of this approach. However, due to the limited evidence available, further research, including randomized controlled trials, is needed to better understand the efficacy of ketamine in the treatment of cluster headaches.

Cluster headache (International Classification of Headache Disorders third edition, ICHD-3 3.1) is a primary headache disorder affecting around 0.12% of individuals. It is characterized by severe headache attacks causing significant negative impact on the lives of patients. While administration of 100% oxygen is considered to be the first-choice acute treatment, undertreatment also exists. Reasons for undertreatment may entail problems with the correct prescription of oxygen, reimbursement issues or the practical implementation of home oxygen therapy. The aim of this manuscript is to review the scientific evidence on oxygen therapy for cluster headache and provide a practical guidance for both physicians and patients to optimize its use in an acute setting. The current evidence of the administration of 100% oxygen as a safe and effective treatment for cluster headache is strong. Based on several clinical trials and surveys, the recommended flow rates range between 12 and 15 L/min via a non-rebreathing mask, for at least fifteen minutes. The frequency of cluster headache attacks and thus the need for acute treatment can be very high. Fortunately, the Belgian social security system provides a full and lifetime reimbursement of oxygen therapy for cluster headache if the diagnosis and the need for this therapy has been certified by a neurologist, neurosurgeon or neuropsychiatrist.

BACKGROUND: The burden and disability associated with headaches are conceptualized and measured differently at patients\' and populations\' levels. At the patients\' level, through patient-reported outcome measures (PROMs); at population level, through disability weights (DW) and years lived with a disability (YLDs) developed by the Global Burden of Disease Study (GBD). DW are 0-1 coefficients that address health loss and have been defined through lay descriptions. With this literature review, we aimed to provide a comprehensive analysis of disability in headache disorders, and to present a coefficient referring to patients\' disability which might inform future GBD definitions of DW for headache disorders.
METHODS: We searched SCOPUS and PubMed for papers published between 2015 and 2023 addressing disability in headache disorders. The selected manuscript included a reference to headache frequency and at least one PROM. A meta-analytic approach was carried out to address relevant differences for the most commonly used PROMs (by headache type, tertiles of medication intake, tertiles of females\' percentage in the sample, and age). We developed a 0-1 coefficient based on the MIDAS, on the HIT-6, and on MIDAS + HIT-6 which was intended to promote future DW iterations by the GBD consortium.
RESULTS: A total of 366 studies, 596 sub-samples, and more than 133,000 single patients were available, mostly referred to cases with migraine. Almost all PROMs showed the ability to differentiate disability severity across conditions and tertiles of medication intake. The indexes we developed can be used to inform future iterations of DW, in particular considering their ability to differentiate across age and tertiles of medication intake.
CONCLUSIONS: Our review provides reference values for the most commonly used PROMS and a data-driven coefficient whose main added value is its ability to differentiate across tertiles of age and medication intake which underlie on one side the increased burden due to aging (it is likely connected to the increased impact of common comorbidities), and by the other side the increased burden due to medication consumption, which can be considered as a proxy for headache severity. Both elements should be considered when describing disability of headache disorders at population levels.

The objectives were 1) to synthesize quantitative sensory testing results in cluster headache (CH) patients and to identify somatosensory differences from healthy subjects (HS), and 2) between symptomatic and asymptomatic sides in CH patients. Two independent reviewers conducted a literature search in MEDLINE, EMBASE, Web of Science, and CINAHL databases. Studies with observational designs were included. Methodological quality and risk of bias were assessed with the Newcastle Ottawa Scale. The selected studies underwent qualitative and quantitative analyses. The qualitative analysis showed inconsistent findings among multiple studies. Meta-analysis showed lower pressure pain thresholds (PPTs) on the symptomatic side of CH patients than HS in V2 (standardized mean difference [SMD] -1.01 [95% confidence interval (CI) -1.79, -.23], P = .01, I2 = 73%, n = 114), V3 (SMD -1 [95% CI -1.54, .45], P < .01, I2 = 82%, n = 354), and cervical region (SMD -1.25 [95% CI -2.07, -.44], P < .01, I2 = 84%, n = 194). Furthermore, lower PPTs than those detected in HS were found on the asymptomatic side in V3 (SMD -.77 [95% CI -1.27, -.27], P < .01, I2 = 79%, n = 354) and in the cervical region (SMD -1.13 [95% CI -1.97, -.3], P < .01, I2 = 85%, n = 194). However, no differences were found in V1 or the extratrigeminal points between these groups. No significant changes were found between symptomatic and asymptomatic sides in trigeminal and extratrigeminal regions. Mechanical hyperalgesia in the trigemino-cervical region of patients with CH could suggest the presence of central pain mechanisms. These results are of clinical relevance because their presence could be associated with a poorer prognosis, chronification, and treatment response. PERSPECTIVE: This study provides consistent findings on the somatosensory profile characterizing patients with CH. Clinicians should assess PPTs and other quantitative sensory testing variables in the trigeminal and extratrigeminal (cervical) regions.

Multiple sclerosis is a chronic and progressive neurological disease, with an important socio-economic burden. Over time, an increased incidence of headaches like migraines and tension headaches has been observed among these patients. Headaches have not been considered as multiple sclerosis-related symptoms, even representing a red flag for multiple sclerosis diagnosis. It is uncertain whether the headache-multiple sclerosis association could be explained by the presence of common triggers or a common physiopathological mechanism (involvement of tertiary B-cell follicles). An important differential diagnosis is between multiple sclerosis attacks and migraines with aura, which can also be associated with neurological deficits. Another important aspect is the occurrence or exacerbation of the cephalalgic syndrome after the initiation of therapy for multiple sclerosis (DMTs), or the improvement of headache after the initiation of certain DMT drugs. In addition to headaches, individuals diagnosed with multiple sclerosis often report experiencing diverse pain syndromes, contributing to an additional decline in their overall quality of life. These syndromes are frequently neglected, the focus being on slowing down the progression of neurological deficits. This review aims to evaluate the characteristics of multiple-sclerosis-related headaches (frequency, possible correlation with attacks, and disease-modifying therapies) and the key distinctions in imaging characteristics between demyelinating lesions in multiple sclerosis and those observed in cases of primary headaches.

To systematically investigate previously examined biomarkers in blood, urine, cerebrospinal fluid, tear fluid, and saliva of patients with cluster headache.
Cluster headache is a condition with extensive clinical challenges in terms of diagnosis and treatment. Identification of a biomarker with diagnostic implications or as a potential treatment target is highly warranted.
We conducted a systematic review including peer reviewed full text of studies that measured biochemical compounds in either blood, urine, cerebrospinal fluid, tear fluid, or saliva of patients with cluster headache diagnosed after the implementation of the International Classification of Headache Disorders (1988) written in English, Danish, Swedish, or Norwegian. Inclusion required a minimum of five participants. The search was conducted in PubMed and EMBASE, in September 2022, and extracted data were screened by two authors. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews were followed. The Newcastle-Ottawa Scale was used to assess the risk of bias in case-controlled studies.
We included 40 studies involving 832 patients with cluster headache and 872 controls, evaluating 80 potential biomarkers. The risk of bias for case-controlled studies was a median of 6 (range: 3-8) and 20 studies out of 40 (50%) were of fair or good quality. Most studies were identified within three groups: hypothalamic-regulated hormones, inflammatory markers, and neuropeptides. Among the hypothalamic hormones, cortisol was the most frequently investigated (N = 7) and was elevated in cluster headache in most of the studies. The most frequently examined inflammatory marker was interleukin 1 (N = 3), but findings were divergent. Calcitonin gene-related peptide was the most investigated neuropeptide (N = 9) and all studies found increased levels during attacks.
Biomarker findings have been inconsistent and widely non-specific for cluster headache, which explains why none of the previous studies succeeded in identifying a unique biomarker for cluster headache, but instead contributed to substantiating the underlying pathophysiologic mechanisms. Several of the examined biomarkers could hold promise as markers for disease activity but are unfit for a clear distinction from both controls and other headaches.

BACKGROUND: Cluster headache (CH) is a type of headache that has a global prevalence of 0.5-3/1000 people, provokes severe, strictly unilateral pain through the first branch of the trigeminal nerve, and is associated with observable autonomous responses. CH provokes intense pain and decreases quality of life.
OBJECTIVE: In this study, we aimed to carry out a systematic review of the effectiveness of non-invasive neuromodulation of the vagus nerve in patients with cluster headaches, which was registered on PROSPERO No. CRD42021265126.
METHODS: Six databases were used from their date of inception to February 2023 to obtain studies with the group intervention of non-invasive neuromodulation of the vagus nerve for cluster headache, with outcomes based on pain attacks, duration, and disabilities. Data on the subjects, group intervention, main outcomes, and results were collected by two authors.
RESULTS: The search provided 1003 articles, with three clinical trials being eligible for inclusion in the review. The methodological quality scores ranged from 6 to 8 points (mean: 7.3, SD: 0.8) out of a maximum of 10 points. The post-treatment results showed some positive effects using n-VNS as a treatment for cluster headache, more specifically regarding cervical neuromodulation of the vagus nerve.
CONCLUSIONS: The systematic review found moderate-to-high-quality evidence supporting that n-VNS and cervical n-VNS may have some positive effects at the end of the treatment being effective to relieve the frequency and intensity of cluster headaches. The poor quantity of studies available and the lack of homogeneity in the study protocols did not allow the pooling of data for a meta-analysis.

BACKGROUND: Headache is one of the most common neurological symptoms. Many previous studies have indicated a relationship between primary headaches and alcohol. Drinking has been associated with increased risk of tension-type headache (TTH) and migraine. However, recently published studies have not confirmed this relationship. The existing literature is inconclusive; however, migraine patients avoid alcohol. Therefore, the primary objective was to provide a reliable assessment of alcohol intake in people with primary headaches; the secondary objective was to identify any potential relationship between alcohol consumption and headache risk.
METHODS: This study was based on PubMed, Embase and Web of Science database searches performed on 11 July 2023. This systematic review was registered in PROSPERO (CRD42023412926). Risk of bias for the included studies was assessed using the Joanna Briggs Institute critical appraisal tools. Meta-analyses were performed using Statistica software. The Risk Ratio (RR) was adopted as the measure of the final effect. Analyses were based on a dichotomous division of the respondents into \"non-drinkers\" and \"drinkers\" for headache patients and matched non-headache groups.
RESULTS: From a total of 1892 articles, 22 were included in the meta-analysis. The majority demonstrated a moderate or high risk of bias. The first part of the meta-analysis was performed on data obtained from 19 migraine studies with 126 173 participants. The risk of migraine in alcohol drinkers is approximately 1.5 times lower than in the group of non-drinkers (RR = 0.71; 95% CI: 0.57-0.89). The second part involved 9 TTH studies with 28 715 participants. No relationship was found between TTH diagnosis and alcohol consumption (RR = 1.09; 95% CI: 0.93-1.27). Two of the included cluster-headache articles had inconclusive results.
CONCLUSIONS: Alcohol consumption and migraine are inversely correlated. The exact mechanism behind this observation may indicate that migraine leads to alcohol-avoidance, rather than alcohol having any protective role against migraine. There was no relationship between TTH and drinking. However, further studies related to primary headaches and alcohol consumption with low risk of bias are required. Additionally, patients and physicians should consider the latest medical data, in order to avoid the myths about alcohol consumption and primary headaches.

OBJECTIVE: To provide an integrated overview of the current state of knowledge of neuromodulation for the sphenopalatine ganglion (SPG) by reviewing relevant and significant literature.
RESULTS: There are several case reports and clinical trials evaluating neuromodulation for the SPG. We identified two blinded, randomized clinical trials for patients with chronic cluster headache. The randomized trials and additional studies demonstrated the long-term safety, efficacy, and cost-effectiveness of neuromodulation for the SPG. Recent studies in Europe and the USA suggest that SPG neuromodulation is a novel modality with clinical importance for treating acute cluster headaches and reducing the frequency of attacks.