Treatment Of Cluster Headache Research Articles

Peripheral Neuromodulation for the Treatment of Migraine and Headache: Recent Advances

Noninvasive neuromodulation is a rapidly developing field that offers an attractive nonpharmacologic treatment option for headache patients. Devices that stimulate peripheral nerves (e.g., vagus nerve, trigeminal sensory nerve, somatic sensory nerve) or brain parenchyma (e.g., occipital cortex) have been developed for this purpose, with promising results in clinical trials. There are currently four US FDA-cleared devices for the treatment of migraine and/or cluster headache: Cefaly®, a trigeminal nerve stimulator; gammaCore™, a vagus nerve stimulator; sTMS mini™, a transcranial magnetic stimulator and Nerivio™, a remote electrical neurostimulator. This narrative review will provide an overview of FDA-cleared neuromodulatory devices, including their proposed mechanisms of action as well as device safety and efficacy as demonstrated in clinical trials.

Location and Volume of MRI Artifacts in Patients With Implanted Sphenopalatine Ganglion Neurostimulators for Treatment of Chronic Cluster Headache

Sphenopalatine ganglion stimulation (SPG-S) is an invasive form of neuromodulation by which a neurostimulator is implanted into the pterygopalatine fossa to treat refractory chronic cluster headache. The implant is MRI conditional, up to 3 T, however there is no clinical data on the shape, size, and location of the artifact produced by the implant. Records of patients with SPG-S were analyzed for postoperative cranial MRI scans. MRI and intraoperative CT scans for visualization of the implant were fused and volumetry was performed for both the implant and the MRI artifact in different MRI sequences. In total, n = 3 patients with postoperative MRI scans were identified. The mean CT artifact volume was 0.73 cm3 (±0.15 cm3 ). MRI artifact volume differed between sequences (range: 25.2-220.7 cm3 ). The intracranial space was largely unaffected besides the pole of the ipsilateral temporal lobe and the basal frontal gyrus. MRI artifacts affected the extracranial space (orbit, maxillary and ethmoid sinuses, and parts of the parotid gland). No adverse events occurred during or after MRI scans. Cranial MRI scans with SPG-S implants were safely performed in three patients following the manufacturer's MRI conditions. MRI artifacts were mostly located in the extracranial space. Brain MRI imaging is largely unaffected. The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

Effect of Ketamine Intranasal Spray in Treatment of Chronic Cluster Headache

Effect of Ketamine Intranasal Spray in Treatment of Chronic Cluster Headache

Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial

Chronic cluster headache is the most disabling form of cluster headache. The mainstay of treatment is attack prevention, but the available management options have little efficacy and are associated with substantial side-effects. In this study, we aimed to assess the safety and efficacy of sphenopalatine ganglion stimulation for treatment of chronic cluster headache. We did a randomised, sham-controlled, parallel group, double-blind, safety and efficacy study at 21 headache centres in the USA. We recruited patients aged 22 years or older with chronic cluster headache, who reported a minimum of four cluster headache attacks per week that were unsuccessfully controlled by preventive treatments. Participants were randomly assigned (1:1) via an online adaptive randomisation procedure to either stimulation of the sphenopalatine ganglion or a sham control that delivered a cutaneous electrical stimulation. Patients and the clinical evaluator and surgeon were masked to group assignment. The primary efficacy endpoint, which was analysed with weighted generalised estimated equation logistic regression models, was the difference between groups in the proportion of stimulation-treated ipsilateral cluster attacks for which relief from pain was achieved 15 min after the start of stimulation without the use of acute drugs before that timepoint. Efficacy analyses were done in all patients who were implanted with a device and provided data for at least one treated attack during the 4-week experimental phase. Safety was assessed in all patients undergoing an implantation procedure up to the end of the open-label phase of the study, which followed the experimental phase. This trial is registered with ClinicalTrials.gov, number NCT02168764. Between July 9, 2014, and Feb 14, 2017, 93 patients were enrolled and randomly assigned, 45 to the sphenopalatine ganglion stimulation group and 48 to the control group. 36 patients in the sphenopalatine ganglion stimulation group and 40 in the control group had at least one attack during the experimental phase and were included in efficacy analyses. The proportion of attacks for which pain relief was experienced at 15 min was 62·46% (95% CI 49·15-74·12) in the sphenopalatine ganglion stimulation group versus 38·87% (28·60-50·25) in the control group (odds ratio 2·62 [95% CI 1·28-5·34]; p=0·008). Nine serious adverse events were reported by the end of the open-label phase. Three of these serious adverse events were related to the implantation procedure (aspiration during intubation, nausea and vomiting, and venous injury or compromise). A fourth serious adverse event was an infection that was attributed to both the stimulation device and the implantation procedure. The other five serious adverse events were unrelated. There were no unanticipated serious adverse events. Sphenopalatine ganglion stimulation seems efficacious and is well tolerated, and potentially offers an alternative approach to the treatment of chronic cluster headache. Further research is need to clarify its place in clinical practice. Autonomic Technologies.

Device review: Pulsante™ sphenopalatine ganglion microstimulator.

Cluster headache (CH) is a primary headache disorder. The use of neuromodulation in treatment of CH is well documented. The sphenopalatine ganglion (SPG) has long been a target for management of CH. Intervention at the level of the SPG can interrupt the trigemino-autonomic reflex, which mediates CH pain. The Pulsante system is the only device on the market created for SPG stimulation. The Pulsante device consists of the device body, a lead with six stimulating electrodes placed in the pterygopalatine fossa, and a fixation plate to allow anchoring of the device to the maxilla. Stimulation is administered via a patient-controlled handheld remote control held over the cheek. SPG stimulation is an important treatment option for CH patients.

Double-Blind Comparison of the Efficacy and Safety of C213 to Placebo for the Acute Treatment of Cluster Headaches

Double-Blind Comparison of the Efficacy and Safety of C213 to Placebo for the Acute Treatment of Cluster Headaches

Sphenopalatine Ganglion Stimulation Upregulates Transport of Intra-Arterial Temozolomide Across the Blood-Brain Barrier

Abstract INTRODUCTION Sphenopalatine ganglion (SPG) stimulation has been shown to reversibly alter blood–brain barrier (BBB) permeability. At the present time, it is widely used for the treatment of cluster headaches in Europe and is well tolerated for this use in humans. METHODS In a rat model, we assessed the permeability of intra-arterial temozolomide with and without sphenopalatine ganglion stimulation. We developed a high-performance liquid chromatography and mass spectrometry method to measure temozolomide in rat plasma and brain tissue, with caffeine as the internal standard. RESULTS Here we show a statistically significant (P = .0006), 5-fold upregulation of TMZ crossing the BBB and reaching brain parenchyma in rats receiving low-frequency (LF, 10 Hz) SPG stimulation. CONCLUSION Glioblastoma multiforme (GBM) remains an extremely difficult disease to treat. Since 2004, the gold standard of treatment for GBM in the United States includes surgery + TMZ and radiation. Our treatment paradigm shows a mechanism in which we could more effectively and safely deliver TMZ in a targeted manner, to minimize systemic toxicity and maximize action at the target tissue. The SPG Stimulation treatment paradigm could be used in a broad spectrum of central nervous system (CNS) pathologies.

Current understanding of pineal gland structure and function in headache.

The pineal gland plays an important role in biological rhythms, circadian and circannual variations, which are key aspects in several headache disorders. Melatonin, the main pineal secreting hormone, has been extensively studied in primary and secondary headache disorders. Altered melatonin secretion occurs in many headache syndromes. Experimental data show pineal gland and melatonin both interfere in headache animal models, decreasing trigeminal activation. Melatonin has been shown to regulate CGRP and control its release. Melatonin has been used successfully as a treatment for migraine, cluster headaches and other headaches. There is a rationale for including the pineal gland as a relevant brain structure in the mechanisms of headache pathophysiology, and melatonin as a treatment option in primary headache.

Verapamil and Cluster Headache: Still a Mystery. A Narrative Review of Efficacy, Mechanisms and Perspectives.

A evaluation of the effect of verapamil and other calcium channel blockers in cluster headache (CH) treatment and an investigation of possible effect mechanisms. Verapamil has been used in the prevention of CH for almost 3 decades, however, the mode of action and therapeutic target is still unknown. A Pubmed search was conducted: "Verapamil"[Mesh] and "Cluster Headache"[Mesh]. We identified 5 relevant studies for CH. Publications were included if they made a substantial contribution within 3 prespecified areas: Efficacy (randomized controlled-trials or open labels studies), safety, and mechanism of effect. Clinical effect: Clinical preventive treatment of CH with verapamil is based on 2 randomized controlled studies and 3 open-label studies. In total, 183 CH patients participated. Verapamil 360 mg/day was used in both controlled studies. Half of the chronic patients experienced benefit from verapamil treatment and the attack burden of episodic patients was, on average, reduced by 1 attack/day. Open-label studies support a dose-dependent level of efficacy. Mechanism of effect: Human and animal studies indicate that verapamil may exert its effect by modulating circadian rhythms, perhaps in central pacemakers, and/or by affecting release of calcitonin gene-related peptide. Verapamil appears to be an effective prophylactic drug in the treatment of CH and despite the scarcity of controlled trials, it is still the drug of choice. A chronotherapeutic approach might increase the effect. More basic and pharmacokinetic research is needed before the mechanism can be fully understood.

Availability of Effective Evidence-Based Symptomatic Treatments for Cluster Headache in the EU Countries-A Survey of the European Headache Alliance and European Headache Federation.

To assess the reimbursement options and accessibility of three effective medicines for cluster headache (CH) (subcutaneous sumatriptan, oxygen, and zolmitriptan spray) across the European Union (EU). A brief survey investigating the availability of symptomatic treatments for CH was sent by email in January 2017 to at least one headache specialist for every single country in the EU. The questionnaire was completed by 26 headache specialists (93% of the EU countries, representing 99.75% of the European population) and by 10 CH patients representative of patient organizations. Oxygen was reimbursable for 63% of the CH population. Oxygen device was reimbursable for 50% of the CH EU population. Subcutaneous sumatriptan was reimbursable for 66% and was accessible without restrictions for 45% of the CH EU population. Zolmitriptan spray was reimbursable for 23.7% and accessible without restrictions for 30.9% of the CH EU population. Only 47% of the EU population had unrestricted access to effective CH treatments, with unacceptable inequalities between eastern countries and the rest of Europe. Headache societies and patient associations should pressure European and national health authorities to improve the availability of effective symptomatic treatments for CH.

Suboccipital steroid injection alone as a preventive treatment for cluster headache

BackgroundSuboccipital steroid injection can be used as a preventive treatment for episodic and chronic cluster headache (CH). In recent studies, prophylactic treatment has been used in addition to suboccipital steroid injection. In this study, we aimed to investigate the effectivity of the sole use of rapid- and long-acting steroid injections without prophylactic treatment in patients with episodic and chronic CH. MethodsThe retrospective study included 51 patients with episodic and chronic CH that underwent greater occipital nerve (GON) blockade with a single dose of rapid- and long-acting steroid injection without additional prophylactic treatment. The frequency, severity, and duration of attacks after GON blockade as well as the side effects and long-term outcomes were reviewed. ResultsIn 28 (54.9%) patients, no attack occurred after GON blockade and cluster bouts were aborted. Mean duration of attacks was 86.67 ± 37.45 min before the treatment. However, in the 23 patients that had at least one attack after GON blockade, the mean duration of attacks was 31.73 ± 36.10 min between post-treatment days 0–3, 29.35 ± 40.49 min between post-treatment days 4–10, 28.48 ± 42.17 min between post-treatment days 11–28, and 35.65 ± 46.55 min after the post-treatment day 28 (p < 0.001). Moreover, 10 (37.04%) out of 27 patients with episodic CH who periodically had one or two cluster bouts in a year had no CH attack at the time of the expected subsequent cluster bout. ConclusionGON blockade is a practical, reliable, and cost-effective treatment option for patients with episodic and chronic CH. Moreover, GON blockade is highly effective in reducing headache attacks and even aborting cluster bouts in CH patients without requiring additional prophylactic treatment.

GON-injection for a Sooner and Better Treatment of Cluster Headache

GON-injection for a Sooner and Better Treatment of Cluster Headache

Collective self-experimentation in patient-led research: How online health communities foster innovation

Researchers across academia, government, and private industry increasingly value patient-led research for its ability to produce quick results from large samples of the population. This study examines the role played by self-experimentation in the production of health data collected in these projects. We ask: How does the collaborative context of online health communities, with their ability to facilitate far-reaching collaborations over time and space, transform the practice and epistemological foundations of engaging in n = 1 experimentation? We draw from a digital ethnography of an online patient-led research movement, in which participants engage in self-experiments to develop a protocol for using psilocybe-containing mushrooms as a treatment for cluster headache, an excruciating neurological disease for which there is little medical research and huge unmet treatment need. We find that the collectivizing features of the internet have collectivized self-experimentation. Group dynamics shape everything in “collective self-experimentation,” from individual choices of intervention, reporting of outcomes, data analysis, determinations of efficacy, to embodiment. This study raises important questions about the role that individuals play in the creation of medical knowledge and the data that informs crowdsourced research.

Differential efficacy of non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A meta-analysis.

BackgroundTwo randomized, double-blind, sham-controlled trials (ACT1, ACT2) evaluated non-invasive vagus nerve stimulation (nVNS) as acute treatment for cluster headache. We analyzed pooled ACT1/ACT2 data to increase statistical power and gain insight into the differential efficacy of nVNS in episodic and chronic cluster headache.MethodsData extracted from ACT1 and ACT2 were pooled using a fixed-effects model. Main outcome measures were the primary endpoints of each study. This was the proportion of participants whose first treated attack improved from moderate (2), severe (3), or very severe (4) pain intensity to mild (1) or nil (0) for ACT1 and the proportion of treated attacks whose pain intensity improved from 2–4 to 0 for ACT2.ResultsThe pooled population included 225 participants (episodic: n = 112; chronic: n = 113) from ACT1 (n = 133) and ACT2 (n = 92) in the nVNS (n = 108) and sham (n = 117) groups. Interaction was shown between treatment group and cluster headache subtype (p < 0.05). nVNS was superior to sham in episodic but not chronic cluster headache (both endpoints p < 0.01). Only four patients discontinued the studies due to adverse events.ConclusionsnVNS is a well-tolerated and effective acute treatment for episodic cluster headache.Trial registrationThe studies were registered at clinicaltrials.gov (ACT1: NCT01792817; ACT2: NCT01958125).

FDA approves first treatment for episodic cluster headache that reduces the frequency of attacks

FDA approves first treatment for episodic cluster headache that reduces the frequency of attacks

Emerging treatments for cluster headache: hopes and disappointments.

Cluster headache stands among the worst debilitating pain conditions. Available treatments for cluster headache have often disabling side effects, are not tolerated, or are ineffective. The management of drug-refractory chronic forms is challenging. New treatments are warranted and reported here. In cluster headache acute treatment, delivery systems like Demand Valve Oxygen or nonrebreather-type masks could enhance the effectiveness of inhaled oxygen therapy. Noninvasive vagus nerve stimulation relieves cluster headache pain at short-term in episodic patients. Sphenopalatine ganglion stimulation combines acute and preventive properties in subsets of patients and is of interest in selected refractory chronic forms. In cluster headache prevention, 'hypothalamic' deep brain stimulation is being refined using slightly different stereotactic coordinates or lower risk methods like endoventricular stimulation. Anti-CGRP monoclonal antibodies provide interesting results in episodic cluster headache, have a good safety profile, but do not appear effective in chronic cluster headache. These novel approaches provide additional alternatives to conventional cluster headache management, but results obtained in chronic forms are often disappointing. Research on cluster headache is often hampered by the lack of awareness in the medical world and by the relatively low prevalence of cluster headache compared with migraine. However, common features shared by these two primary headaches could help developing disease-specific therapies.

Primary headache disorders: Five new things.

Purpose of reviewTo review 5 new areas in primary headache disorders, especially migraine and cluster headache.Recent findingsCalcitonin gene-related peptide (CGRP) receptor antagonists (gepants—rimegepant and ubrogepant) and serotonin 5-HT1F receptor agonists (ditans—lasmiditan) have completed phase 3 clinical trials and will soon offer novel, effective, well-tolerated nonvasoconstrictor options to treat acute migraine. CGRP preventive treatment is being revolutionized after the licensing of 3 monoclonal antibodies (MABs), erenumab, fremanezumab, and galcanezumab, with eptinezumab to follow, especially designed for migraine; they are effective and well tolerated. For patients seeking a nondrug therapy, neuromodulation approaches, single-pulse transcranial magnetic stimulation, noninvasive vagus nerve stimulation (nVNS), and external trigeminal nerve stimulation, represent licensed, well-tolerated approaches to migraine treatment. For the acute treatment of episodic cluster headache, nVNS is effective, well tolerated, and licensed; nVNS is effective and well tolerated in preventive treatment of cluster headache. The CGRP MAB galcanezumab was effective and well tolerated in a placebo-controlled trial in the preventive treatment of episodic cluster headache. Sphenopalatine ganglion stimulation has been shown to be effective and well tolerated in 2 randomized sham-controlled studies on chronic cluster headache. Understanding the premonitory (prodromal) phase of migraine during which patients experience symptoms such as yawning, tiredness, cognitive dysfunction, and food cravings may help explain apparent migraine triggers in some patients, thus offering better self-management.SummaryHeadache medicine has made remarkable strides, particularly in understanding migraine and cluster headache in the past 5 years. For the most common reason to visit a neurologist, therapeutic advances offer patients reduced disability and neurologists a rewarding, key role in improving the lives of those with migraine and cluster headache.

Behavioral and psychological aspects of cluster headache: an overview.

This paper overviews available literature addressing behavioral and psychological aspects of cluster headache. Behavioral correlates of sleep and drug use are explored, as are the psychological correlates pertaining to psychopathology and cognitive functioning. We conclude with a review of the few investigations addressing adjunctive behavioral treatments for cluster headache, and provide suggestions for possible ways to enhance effects of behavioral interventions for this painful and difficult to treat headache disorder.

The Development of Evidence-Based Guideline for Diagnosis and Management of Headache in Korea.

ObjectiveWe aimed to develop the clinical guideline for headache by the systematic review and synthesis of existing evidence-based guidelines. The purpose of developing the guideline was to improve the appropriateness of diagnosis and treatment of headache disorder, and consequently, to improve patients’ pain control and quality of life. The guideline broadly covers the differential diagnosis and treatment of tension-type headache, migraine, cluster headache, and medication-overuse headache. MethodsThis is a methodological study based on the ADAPTE methodology, including a systematic review of the literature, quality assessment of the guidelines using the Appraisal of Clinical Guidelines for REsearch & Evaluation II (AGREE II) Instrument, as well as an external review using a Delphi technique. The inclusion criteria for systematic search were as follows: topic-relevant, up-to-date guidelines including evidence from within 5 years, evidence-based guidelines, guidelines written in English or Korean, and guidelines issued by academic institutions or government agencies. ResultsWe selected five guidelines and conducted their quality assessment using the AGREE II Instrument. As a result, one guideline was found to be eligible for adaptation. For 13 key questions, a total of 39 recommendations were proposed with the grading system and revised using the nominal group technique. ConclusionRecommendations should be applied to actual clinical sites to achieve the ultimate goal of this guideline; therefore, follow-up activities, such as monitoring of guideline usage and assessment of applicability of the recommendations, should be performed in the future. Further assessment of the effectiveness of the guideline in Korea is needed.

Cluster headache: crosspoint between otologists and neurologists-treatment of the sphenopalatine ganglion and systematic review.

Among cephalgias, cluster headache (CH) is the rarest and the most disabling, explaining the appellation of "suicide headache." Up to 20% of chronic CH reveals to be resistant to pharmacological treatments, in which case interventional procedures should be considered. Many reports evaluated invasive approaches and a wide strand of research is dedicated to the sphenopalatine ganglion. Our paper will now be focused on providing an overview on modern applications on the sphenopalatine ganglion (SPG), their outcomes, and their feasibility in terms of risks and benefits. The group reviewed the international literature systematically for procedures targeting the sphenopalatine ganglion and its branches for episodic and chronic CH, including block, stimulation, radiofrequency, stereotactic radiosurgery, and vidian neurectomy. Seventeen articles fixed our inclusion criteria. Comparing the outcomes that have been analyzed, it is possible to notice how the most successful procedure for the treatment of refractory chronic and episodic CH is the SPG block, which reaches respectively 76.5% and 87% of efficacy. Radiofrequency has a wide range of outcomes, from 33 to 70.3% in CCH. Stimulation of SPG only achieved up to 55% of outcomes in significant reduction in attack frequency in CCH and 71% in ECH. Radiosurgery and vidian neurectomy on SPG have also been analyzed. Generally, ECH patients show better response to standard medical therapies; nevertheless, even this more manageable condition may sometimes benefit from interventional therapies mostly reserved for CCH. First results seem promising and considering the low frequency of side effects or complications, we should think of expanding the indications of the procedures also to those conditions. Outcomes certainly suggest that further studies are necessary in order to understand which method is the most effective and with less side effects. Placebo-controlled studies would be pivotal, and tight collaboration between neurologists and otorhinolaryngologists should also be central in order to give correct indications, which allow us to expect procedures on the SPG to be an effective and mostly safe method to control either refractory ECH or CCH.