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Background and Objectives: Deep brain stimulation (DBS) of the ventral tegmental area (VTA) is a surgical treatment option for selected patients with refractory chronic cluster headache (CCH). We aimed to identify clinical and structural neuroimaging factors associated with response to VTA DBS in CCH., Methods: This prospective observational cohort study examines consecutive patients with refractory CCH treated with VTA DBS by a multidisciplinary team in a single tertiary neuroscience center as part of usual care. Headache diaries and validated questionnaires were completed at baseline and regular follow-up intervals. All patients underwent T1-weighted structural MRI before surgery. We compared clinical features using multivariable logistic regression and neuroanatomic differences using voxel-based morphometry (VBM) between responders and nonresponders., Results: Over a 10-year period, 43 patients (mean age 53 years, SD 11.9), including 29 male patients, with a mean duration of CCH 12 years (SD 7.4), were treated and followed up for at least 1 year (mean follow-up duration 5.6 years). Overall, there was a statistically significant improvement in median attack frequency from 140 to 56 per month (Z = -4.95, p < 0.001), attack severity from 10/10 to 8/10 (Z = -4.83, p < 0.001), and duration from 110 to 60 minutes (Z = -3.48, p < 0.001). Twenty-nine (67.4%) patients experienced ≥50% improvement in attack frequency and were therefore classed as responders. There were no serious adverse events. The most common side effects were discomfort or pain around the battery site (7 patients) and transient diplopia and/or oscillopsia (6 patients). There were no differences in demographics, headache characteristics, or comorbidities between responders and nonresponders. VBM identified increased neural density in nonresponders in several brain regions, including the orbitofrontal cortex, anterior cingulate cortex, anterior insula, and amygdala, which were statistically significant ( p < 0.001)., Discussion: VTA DBS showed no serious adverse events, and, although there was no placebo control, was effective in approximately two-thirds of patients at long-term follow-up. This study did not reveal any reliable clinical predictors of response. However, nonresponders had increased neural density in brain regions linked to processing of pain and autonomic function, both of which are prominent in the pathophysiology of CCH., (© 2023 American Academy of Neurology.)

Background and Objectives: Cluster headache is considered a male-dominated disorder, but we have previously suggested that female patients may display a more severe phenotype. Studies on sex differences in cluster headache have been conflicting; therefore, this study, with the largest validated cluster headache material at present, gives more insights into sex-specific characteristics of the disease. The objective of this study was to describe sex differences in patient demographics, clinical phenotype, chronobiology, triggers, treatment, and lifestyle in a Swedish cluster headache population., Methods: Study participants were identified by screening medical records from 2014 to 2020, requested from hospitals and neurology clinics in Sweden for the ICD-10 code G44.0 for cluster headache. Each study participant answered a detailed questionnaire on clinical information and lifestyle, and all variables were compared with regard to sex., Results: A total of 874 study participants with a verified cluster headache diagnosis were included. Of the participants, 575 (66%) were male and 299 (34%) were female, and biological sex matched self-reported sex for all. Female participants were to a greater extent diagnosed with the chronic cluster headache subtype compared with male participants (18% vs 9%, p = 0.0002). In line with this observation, female participants report longer bouts than male participants ( p = 0.003) and used prophylactic treatment more often (60% vs 48%, p = 0.0005). Regarding associated symptoms, female participants experienced ptosis (61% vs 47%, p = 0.0002) and restlessness (54% vs 46%, p = 0.02) more frequently compared with male participants. More female than male study participants had a positive family history of cluster headache (15% vs 7%, p = 0.0002). In addition, female participants reported diurnal rhythmicity of their attacks more often than male participants (74% vs 63%, p = 0.002). Alcohol as a trigger occurred more frequently in male participants (54% vs 48%, p = 0.01), whereas lack of sleep triggering an attack was more common in female participants (31% vs 20%, p = 0.001)., Discussion: With this in-depth analysis of a well-characterized cluster headache population, we could demonstrate that there are significant differences between male and female participants with cluster headache, which should be regarded at the time of diagnosis and when choosing treatment options. The data suggest that female patients generally may be more gravely affected by cluster headache than male patients., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To investigate the mechanism of action of deep brain stimulation for refractory chronic cluster headache and the optimal target within the ventral tegmental area., Methods: Seven patients with refractory chronic cluster headache underwent high spatial and angular resolution diffusion MRI preoperatively. MRI-guided and MRI-verified electrode implantation was performed unilaterally in 5 patients and bilaterally in 2. Volumes of tissue activation were generated around active lead contacts with a finite-element model. Twelve months after surgery, voxel-based morphometry was used to identify voxels associated with higher reduction in headache load. Probabilistic tractography was used to identify the brain connectivity of the activation volumes in responders, defined as patients with a reduction of ≥30% in headache load., Results: There was no surgical morbidity. Average follow-up was 34 ± 14 months. Patients showed reductions of 76 ± 33% in headache load, 46 ± 41% in attack severity, 58 ± 41% in headache frequency, and 51 ± 46% in attack duration at the last follow-up. Six patients responded to treatment. Greatest reduction in headache load was associated with activation in an area cantered at 6 mm lateral, 2 mm posterior, and 1 mm inferior to the midcommissural point of the third ventricle. Average responders' activation volume lay on the trigeminohypothalamic tract, connecting the trigeminal system and other brainstem nuclei associated with nociception and pain modulation with the hypothalamus, and the prefrontal and mesial temporal areas., Conclusions: We identify the optimal stimulation site and structural connectivity of the deep brain stimulation target for cluster headache, explicating possible mechanisms of action and disease pathophysiology., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To present outcomes in a cohort of medically intractable chronic cluster headache (CCH) patients treated with ventral tegmental area (VTA) deep brain stimulation (DBS)., Methods: In an uncontrolled open-label prospective study, 21 patients (17 male; mean age 52 years) with medically refractory CCH were selected for ipsilateral VTA-DBS by a specialist multidisciplinary team including a headache neurologist and functional neurosurgeon. Patients had also failed or were denied access to occipital nerve stimulation within the UK National Health Service. The primary endpoint was improvement in the headache frequency. Secondary outcomes included other headache scores (severity, duration, headache load), medication use, disability and affective scores, quality of life (QoL) measures, and adverse events., Results: Median follow-up was 18 months (range 4-60 months). At the final follow-up point, there was 60% improvement in headache frequency (p = 0.007) and 30% improvement in headache severity (p = 0.001). The headache load (a composite score encompassing frequency, severity, and duration of attacks) improved by 68% (p = 0.002). Total monthly triptan intake of the group dropped by 57% posttreatment. Significant improvement was observed in a number of QoL, disability, and mood scales. Side effects included diplopia, which resolved in 2 patients following stimulation adjustment, and persisted in 1 patient with a history of ipsilateral trochlear nerve palsy. There were no other serious adverse events., Conclusions: This study supports that VTA-DBS may be a safe and effective therapy for refractory CCH patients who failed conventional treatments., Classification of Evidence: This study provides Class IV evidence that VTA-DBS decreases headache frequency, severity, and headache load in patients with medically intractable chronic cluster headaches., (© 2016 American Academy of Neurology.)

Objective: To report our initial experience with a novel device, designed to provide portable, noninvasive, transcutaneous stimulation of the vagus nerve, both acutely and preventively, as a treatment for cluster headache., Methods: Patients with cluster headache (11 chronic, 8 episodic), from 2 centers, including 7 who were refractory to drug treatment, had sufficient data available for analysis in this open-label observational cohort study. The device, known as the gammaCore, was used acutely to treat individual attacks as well as to provide prevention. Patient-estimated efficacy data were collected by systematic inquiry during follow-up appointments up to a period of 52 weeks of continuous use., Results: Fifteen patients reported an overall improvement in their condition, with 4 reporting no change, providing a mean overall estimated improvement of 48%. Of all attacks treated, 47% were aborted within an average of 11 ± 1 minutes of commencing stimulation. Ten patients reduced their acute use of high-flow oxygen by 55% with 9 reducing triptan use by 48%. Prophylactic use of the device resulted in a substantial reduction in estimated mean attack frequency from 4.5/24 hours to 2.6/24 hours (p < 0.0005) posttreatment., Conclusion: These data suggest that noninvasive vagus nerve stimulation may be practical and effective as an acute and preventive treatment in chronic cluster headache. Further evaluation of this treatment using randomized sham-controlled trials is thus warranted., Classification of Evidence: This study provides Class IV evidence that for patients with cluster headache, transcutaneous stimulation of the vagus nerve aborts acute attacks and reduces the frequency of attacks., (© 2015 American Academy of Neurology.)

Background: Cluster headache is a primary headache involving repeated attacks of excruciatingly severe headache usually occurring several times a day. Most patients with chronic cluster headache (CCH) have an unremitting illness requiring daily preventive therapy for years., Objective: To describe the clinical outcome of occipital nerve stimulation (ONS) for 14 patients with intractable CCH., Methods: Fourteen patients with medically intractable CCH were implanted with bilateral electrodes in the suboccipital region for ONS and a retrospective assessment of their clinical outcome obtained., Results: At a median follow-up of 17.5 months (range 4-35 months), 10 of 14 patients reported improvement and 9 of these recommend ONS. Three patients noticed a marked improvement of 90% or better (90%, 90%, and 95%), 3 a moderate improvement of 40% or better (40%, 50%, and 60%), and 4 a mild improvement of 20-30% (20%, 20%, 25%, and 30%). Improvement occurred within days to weeks for those who responded most and patients consistently reported their attacks returned within hours to days when the device was off. One patient found that ONS helped abort acute attacks. Adverse events of concern were lead migrations and battery depletion., Conclusion: Intractable chronic cluster headache (CCH) is a devastating, disabling condition that has traditionally been treated with cranially invasive or neurally destructive procedures. ONS offers a safe, effective option for some patients with CCH. More work is required to evaluate and understand this novel therapy.

Long-term hypothalamic stimulation is effective in improving drug-resistant chronic cluster headache (CH). We assessed acute hypothalamic stimulation to resolve ongoing CH attacks in 16 patients implanted to prevent chronic CH, investigating 136 attacks. A pain intensity reduction of > or =50% occurred in 25 of 108 evaluable attacks (23.1%). Acute hypothalamic stimulation is not effective in resolving ongoing CH attacks, suggesting that hypothalamic stimulation acts by complex mechanisms in CH prevention.

In this article we describe the clinical features, natural history, and clinical variants of cluster headaches, following the modern International Headache Society classification of cluster headaches in its two types: episodic and chronic. The basic pathophysiology is considered to be the trigeminal vascular system, the common final pain pathway, with pain initiated in a cyclical fashion by disordered central hypothalamic pacemaker. Oxygen, rapidly acting ergotamine, or dihydroergotamine preparations serve as abortive treatment of acute attacks; various pharmacotherapeutic options and combination therapies aid in the prophylaxis of cluster headache; and trigeminal radio frequency gangliorhizolysis is a very useful surgical approach in patients with chronic cluster headache who are resistant to medical treatment.

Eleven patients were examined thermographically during spontaneous cluster headaches and 22 during attacks induced by nitroglycerin or alcohol. In cluster headache, heat loss increased from the affected orbital region, and in some patients, this spread above and below the eye, down the nose, and to the affected temple. Inhalation of 100% oxygen reduced or abolished cluster pain in 22 of 25 instances, and asymmetry of heat loss then disappeared. Since the unilateral increase in blood flow usually followed the onset of pain in affected areas, the vascular changes of cluster headache are probably secondary phenomena, initiated by a vasodilator pathway, with the trigeminal nerve as the afferent and the greater superficial petrosal nerve as the efferent limb.