Pathophysiology Of Cluster Headache Research Articles

The relation of cluster headache to alexithymia, depression, and anxiety.

The pathophysiology of cluster headaches (CHs) involves the trigeminovascular system, the parasympathetic nervous system, and the hypothalamus. Because of the affected hypothalamus, there may be limbic system involvement in CH. To investigate the relationship between depression, anxiety, and alexithymia in CH, to demonstrate that the limbic system is affected. A total of 18 patients with CHs who were outside of cluster period and 18 healthy controls were included. Participants were administered the Beck depression inventory (BDI), Beck anxiety inventory (BAI), and Toronto alexithymia scale-20 (TAS-20). Patients with CHs had significantly higher rates of alexithymia (p = 0.003) and depression (p = 0.014) than controls. There was no significant difference in anxiety levels (p = 0.297) between groups. It was shown that, in addition to previously identified psychiatric disorders, alexithymia can accompany CHs in patients.

Circadian functional changes of pain-processing brainstem nuclei and implications for cluster headache: A 7 Tesla imaging study.

Pain thresholds and primary headaches, including cluster headache attacks, have circadian rhythmicity. Thus, they might share a common neuronal mechanism. This study aimed to elucidate how the modulation of nociceptive input in the brainstem changes from noon to midnight. Insights into the mechanism of these fluctuations could allow for new hypotheses about the pathophysiology of cluster headache. This repeated measure observational study was conducted at the University Hospital Zurich from December 2019 to November 2022. Healthy adults between 18 and 85 years of age were eligible. All participants were examined at noon and midnight. We tested the pain threshold on both sides of the foreheads with quantitative sensory testing, assessed tiredness levels, and obtained high-field (7 Tesla) and high-resolution functional magnetic resonance imaging (MRI) at each visit. Functional connectivity was assessed at the two visits by performing a region-of-interest analysis. We defined nuclei in the brainstem implicated in processing nociceptive input as well as the thalamus and suprachiasmatic nucleus as the region-of-interest. Ten people were enrolled, and seven participants were included. First, we did not find statistically significant differences between noon and midnight of A-delta-mediated pain thresholds (median mechanical pain threshold at noon: left 9.2, right 9.2; at night: left 6.5, right 6.1). Second, after correction for a false discovery rate, we found changes in the mechanical pain sensitivity to have a statistically significant effect on changes in the functional connectivity between the left parabrachial nucleus and the suprachiasmatic nucleus (T = -40.79). The MRI data analysis suggested that brain stem nuclei and the hypothalamus modulate A-delta-mediated pain perception; however, these changes in pain perception did not lead to statistically significantly differing pain thresholds between noon and midnight. Hence, our findings shed doubt on our hypothesis that the physiologic circadian rhythmicity of pain thresholds could drive the circadian rhythmicity of cluster headache attacks.

MERTK in the rat trigeminal system: a potential novel target for cluster headache?

The trigeminal system is key to the pathophysiology of migraine and cluster headache, two primary headache disorders that share many features. Recently, MER proto-oncogene tyrosine kinase (MERTK), a cell surface receptor, was strongly associated with cluster headache through genetic studies. Further, the MERTK ligand galectin-3 has been found to be elevated in serum of migraine patients. In this study, MERTK and MERTK ligands were investigated in key tissue to better understand their potential implication in the pathophysiology of primary headache disorders. Immunohistochemistry was used to map MERTK and galectin-3 expression in rat trigeminal ganglia. RT-qPCR was used to assess MERTK gene expression in blood, and ELISA immunoassays were used for MERTK ligand quantification in serum from study participants with and without cluster headache. MERTK gene expression was elevated in blood samples from study participants with cluster headache compared to controls. In addition, MERTK ligand galectin-3 was found at increased concentration in the serum of study participants with cluster headache, whereas the levels of MERTK ligands growth arrest specific 6 and protein S unaffected. MERTK and galectin-3 were both expressed in rat trigeminal ganglia. Galectin-3 was primarily localized in smaller neurons and to a lesser extent in C-fibres, while MERTK was found in satellite glia cells and in the outer membrane of Schwann cells. Interestingly, a strong MERTK signal was found specifically in the region proximal to the nodes of Ranvier. The overexpression of MERTK and galectin-3 in tissue from study participants with cluster headache, as well as the presence of MERTK in rat peripheral satellite glia cells and Schwann cells in the trigeminal ganglia, further highlights MERTK signalling as an interesting potential future therapeutic target in primary headache.Graphical

Update on Cluster Headaches: From Genetic to Novel Therapeutic Approaches

Cluster headaches affect 0.1% of the population and are four times more common in males than in females. Patients with this condition present with severe unilateral head pain localized in the frontotemporal lobe, accompanied by ipsilateral lacrimation, conjunctival injection, nasal congestion, diaphoresis, miosis, and eyelid edema. Recently, the first genome-wide association study of cluster headaches was conducted with the goal of aggregating data for meta-analyses, identifying genetic risk variants, and gaining biological insights. Although little is known about the pathophysiology of cluster headaches, the trigeminovascular and trigeminal autonomic reflexes and hypothalamic pathways are involved. Among anti-calcitonin gene-related peptide monoclonal antibodies, galcanezumab has been reported to be effective in preventing episodic cluster headaches.

Compensated Hypogonadism Identified in Males with Cluster Headache: A Prospective Case-Controlled Study.

Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear. We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations. The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%-47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%-37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified. Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024;95:1149-1161.

Pathophysiology of cluster headache: From the trigeminovascular system to the cerebral networks.

Despite advances in neuroimaging and electrophysiology, cluster headache's pathogenesis remains unclear. This review will examine clinical neurophysiology studies, including electrophysiological and functional neuroimaging, to determine if they might help us construct a neurophysiological model of cluster headache. Clinical, biochemical, and electrophysiological research have implicated the trigeminal-parasympathetic system in cluster headache pain generation, although the order in which these two systems are activated, which may be somewhat independent, is unknown. Electrophysiology and neuroimaging have found one or more central factors that may cause seasonal and circadian attacks. The well-known posterior hypothalamus, with its primary circadian pacemaker suprachiasmatic nucleus, the brainstem monoaminergic systems, the midbrain, with an emphasis on the dopaminergic system, especially when cluster headache is chronic, and the descending pain control systems appear to be involved. Functional connection investigations have verified electrophysiological evidence of functional changes in distant brain regions connecting to wide cerebral networks other than pain. We propose that under the impact of external time, an inherited misalignment between the primary circadian pacemaker suprachiasmatic nucleus and other secondary extra- suprachiasmatic nucleus clocks may promote disturbance of the body's internal physiological clock, lowering the threshold for bout recurrence.

Involvement of the ipsilateral-to-the-pain anterior–superior hypothalamic subunit in chronic cluster headache

BackgroundDespite hypothalamus has long being considered to be involved in the pathophysiology of cluster headache, the inconsistencies of previous neuroimaging studies and a limited understanding of the hypothalamic areas involved, impede a comprehensive interpretation of its involvement in this condition.MethodsWe used an automated algorithm to extract hypothalamic subunit volumes from 105 cluster headache patients (57 chronic and 48 episodic) and 59 healthy individuals; after correcting the measures for the respective intracranial volumes, we performed the relevant comparisons employing logist regression models.Only for subunits that emerged as abnormal, we calculated their correlation with the years of illness and the number of headache attacks per day, and the effects of lithium treatment. As a post-hoc approach, using the 7 T resting-state fMRI dataset from the Human Connectome Project, we investigated whether the observed abnormal subunit, comprising the paraventricular nucleus and preoptic area, shows robust functional connectivity with the mesocorticolimbic system, which is known to be modulated by oxytocin neurons in the paraventricular nucleus and that is is abnormal in chronic cluster headache patients.ResultsPatients with chronic (but not episodic) cluster headache, compared to control participants, present an increased volume of the anterior–superior hypothalamic subunit ipsilateral to the pain, which, remarkably, also correlates significantly with the number of daily attacks. The post-hoc approach showed that this hypothalamic area presents robust functional connectivity with the mesocorticolimbic system under physiological conditions. No evidence of the effects of lithium treatment on this abnormal subunit was found.ConclusionsWe identified the ipsilateral-to-the-pain antero-superior subunit, where the paraventricular nucleus and preoptic area are located, as the key hypothalamic region of the pathophysiology of chronic cluster headache. The significant correlation between the volume of this area and the number of daily attacks crucially reinforces this interpretation. The well-known roles of the paraventricular nucleus in coordinating autonomic and neuroendocrine flow in stress adaptation and modulation of trigeminovascular mechanisms offer important insights into the understanding of the pathophysiology of cluster headache.

The genetics and chronobiology of cluster headache.

Cluster headache displays uniquely rhythmic patterns in its attack manifestation. This strong chronobiological influence suggests that part of the pathophysiology of cluster headache is distinctly different from migraine and has prompted genetic investigations probing these systems. This is a narrative overview of the cluster headache chronobiological phenotype from the point of view of genetics covering existing knowledge, highlighting the specific challenges in cluster headache and suggesting novel research approaches to overcome these. The chronobiological features of cluster headache are a hallmark of the disorder and while discrepancies between study results do exist, the main findings are highly reproducible across populations and time. Particular findings in subgroups indicate that the heritability of the disorder is linked to chronobiological systems. Meanwhile, genetic markers of circadian rhythm genes have been implicated in cluster headache, but with conflicting results. However, in two recently published genome wide association studies two of the identified four loci include genes with an involvement in circadian rhythm, MER proto-oncogene, tyrosine kinase and four and a half LIM domains 5. These findings strengthen the involvement of circadian rhythm in cluster headache pathophysiology. Studying chronobiology and genetics in cluster headache presents challenges unique to the disorder. Researchers are overcoming these challenges by pooling various data from different cohorts and performing meta-analyses providing novel insights into a classically enigmatic disorder. Further progress can likely be made by combining deep pheno- and genotyping.

Altered functional connectivity of the thalamus and salience network in patients with cluster headache: a pilot study.

Previous studies have shown that the salience network (SN) and the thalamus are involved in cluster headache (CH) attacks. However, very little is known regarding the altered thalamus-SN functional connectivity in CH. The aim of this study was to explore alterations of functional connectivity between the thalamus and the SN in patients with CH to further gain insight into the pathophysiology of CH. The resting-state functional MRI (rs-fMRI) data of 21 patients with CH in the headache attack remission state during in-bout periods and 21 age- and sex-matched normal controls were obtained. The rs-fMRI data were analyzed by the independent component analysis (ICA) method, and the thalamus-SN functional connectivity in patients with right-sided and left-sided CH was compared with that in normal controls. Decreased functional connectivity was found between the thalamus, both ipsilateral and contralateral to the headache side, and the SN during headache remission state in both right-sided CH patients and left-sided CH patients. The findings suggest that the decreased functional connectivity between the thalamus and SN might be one of the pathologies underpinning the CH. This helps us to understand better the nature of the brain dysfunction in CH and the basic pathologies of CH, which implies that this deserves further investigation.

Sleep and Chronobiology as a Key to Understand Cluster Headache

The cluster headache is a primary headache characterized by attacks of unilateral pain associated with ipsilateral cranial autonomic features. These attacks recur in clusters during the years alternating with periods of complete remission, and their onset is often during the night. This annual and nocturnal periodicity hides a strong and mysterious link among CH, sleep, chronobiology and circadian rhythm. Behind this relationship, there may be the influence of genetic components or of anatomical structures such as the hypothalamus, which are both involved in regulating the biological clock and contributing even to the periodicity of cluster headaches. The bidirectional relationship manifests itself also with the presence of sleep disturbances in patients affected by cluster headaches. What if the key to studying the physiopathology of such disease could rely on the mechanisms of chronobiology? The purpose of this review is to analyze this link in order to interpret the pathophysiology of cluster headaches and the possible therapeutic implications.

Alterations of limbic structure volumes and limbic covariance network in patients with cluster headache

The aim of this study was to compare the limbic structures and covariance network in patients with cluster headache to those of healthy controls. We enrolled 23 patients with newly diagnosed cluster headache and 31 healthy controls. They underwent three-dimensional T1-weighted imaging utilizing a 3.0 Tesla MRI scanner. Volumetric analysis of the subcortical limbic structures, including the hippocampus, amygdala, thalamus, mammillary body, hypothalamus, basal forebrain, septal nuclei, fornix, and nucleus accumbens, was performed. We examined the limbic covariance network using a graph theory. The volumes of the limbic structures between patients with cluster headache and healthy controls were significantly different. The volume of the left hippocampus in patients with cluster headache was significantly lower than that in healthy controls (0.256 vs 0.291 %, p = 0.002). Patients with cluster headache showed significant alterations of the limbic covariance network. The average strength, global efficiency, local efficiency, mean clustering coefficient, and transitivity were lower (5.238 vs 10.322, p = 0.030; 0.355 vs 0.608, p = 0.020; 0.547 vs 1.553, p = 0.020; 0.424 vs 0.895, p = 0.016; respectively), whereas the characteristic path length was higher (3.314 vs 1.752, p = 0.040) in patients with cluster headache than in healthy controls. We detected alterations of limbic structure volumes in patients with cluster headache compared to healthy controls, especially in the hippocampus. We also found significant alterations in the limbic covariance network in patients with cluster headache who showed decreased segregation and integration. These abnormalities could be related to the pathophysiology of cluster headache.

COVID-19 vaccination-triggered cluster headache episodes with frequent attacks.

The pathophysiology of cluster headache and how cluster episodes are triggered, are still poorly understood. Recurrent inflammation of the trigeminovascular system has been hypothesized. It was noted that some long-term attack-free cluster headache patients suddenly developed a new cluster episode shortly after COVID-19 vaccination. Cases are described from patients with cluster headache who reported a new cluster episode within days after COVID-19 vaccination. All cases were seen in a tertiary university referral center and a general hospital in the Netherlands between March 2021 and December 2021, when the first COVID-19 vaccinations were carried out in The Netherlands. Clinical characteristics of the previous and new cluster episodes, and time between the onset of a new cluster episode and a previous COVID-19 vaccination were reported. We report seven patients with cluster headache, who had been attack-free for a long time, in whom a new cluster episode occurred within a few days after a COVID-19 vaccination. COVID-19 vaccinations may trigger new cluster episodes in patients with cluster headache, possibly by activating a pro-inflammatory state of the trigeminocervical complex. COVID-19 vaccinations may also exacerbate other neuroinflammatory conditions. .

Reduced expression of inflammasome complex components in cluster headache.

The involvement of inflammation in the pathophysiology of cluster headache (CH) has been suggested, with a role implied for interleukin (IL)-1β. We aimed to measure peripheral blood expression levels of IL-1β-inducing systems, the inflammasome complex, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, and investigate their values as putative biomarkers in CH. In this cross-sectional study conducted in the Headache Unit of Istanbul University, Turkey, blood mononuclear cells (PBMCs) and sera were collected from 30 patients with episodic migraine, 4 with chronic CH, and 47 healthy individuals. Levels of inflammasome complex components (NLRP1, NLRP3, caspase 1, and ASC), end products of inflammasome complex activity (IL-1β, IL-18, and nitric oxide synthase isoforms), neuron-specific enolase, other inflammatory factors (NF-κB, HMGB1, and s100b), and anti-inflammatory IL-4 were measured by real-time quantitative polymerase chain reaction and/or enzyme-linked immunosorbent assay. NLRP3 expression levels were significantly reduced in PBMC samples of patients with CH, obtained during CH attacks (n=24) or headache-free (out of cycle) episodes (n=10). CH-attack patients showed greater expression levels of IL-1β (2-ΔΔCT median [25th-75th percentile], 0.96 [0.66-1.29 vs. 0.52 [0.43-0.73]) and NF-κB (1.06 [0.66-3.00] vs. 0.62 [0.43-1.19]) in PBMCs but not in sera compared with headache-free CH patients. However, these differences did not attain statistical significance (p=0.058 and p=0.072, respectively). Moreover, NLRP1 (52.52 [35.48-67.91] vs. 78.66 [54.92-213.25]; p=0.017), HMGB1 (11.51 [5.20-15.50] vs. 13.33 [8.08-18.13]; p=0.038), S100b (569.90 [524.10-783.80] vs. 763.40 [590.15-2713.00]; p=0.013), NSE (11.15 [6.26-14.91] vs. 13.93 [10.82-19.04]; p=0.021), nNOS (4.24 [3.34-12.85] vs. 12.82 [4.52-15.44]; p=0.028), and eNOS (64.83 [54.59-91.14] vs. 89.42 [61.19-228.40]; p=0.034) levels were lower in patients with three or more autonomic manifestations (n=9). No correlation was found between inflammation factors and clinical parameters of CH. Our results support the involvement of the IL-1β system in attacks of CH. However, the components of the inflammasome complex are suppressed in the peripheral blood and do not appear to play a role in the pathophysiology of CH. These findings argue against a potential biomarker value of the inflammasome complex in CH.

From basic mechanisms to therapeutic perspectives in cluster headache.

The pathophysiological understanding of cluster headache has evolved significantly over the past years. Although it is now well known that the trigeminovascular system, the parasympathetic system and the hypothalamus play important roles in its pathomechanism, we increasingly understand the functional role several neurotransmitters and hormones play in the communication between these structures. This work will give an overview of the current understanding of the role of calcitonin gene-related peptide, vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, melatonin and orexins in cluster headache. On the basis of recent evidence, this study will also review the relevance of the monoclonal calcitonin gene-related peptide antibody galcanezumab as well as the sleep-regulating hormone melatonin in the treatment of cluster headache. Herein, we aim to review the basic mechanisms implicated in the pathophysiology of cluster headache and how the increased mechanistic understanding may lead to the discovery of novel therapeutic targets.

Glymphatic system dysfunction in patients with cluster headache

IntroductionThe aim of this study was to investigate alterations of the glymphatic system function in patients with cluster headache.MethodsWe enrolled patients with cluster headache and healthy controls, and they underwent brain magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI). We used the MRIcron and DSI studio programs for DTI preprocessing and DTI analysis with perivascular space (DTI‐ALPS) index calculation.ResultsFourteen patients with cluster headache and 23 healthy controls were enrolled. The DTI‐ALPS indexes of the groups were significantly different. The DTI‐ALPS index for the patients with cluster headache was lower than that for the healthy controls (1.586 vs. 1.786, p = 0.044). There was a significant negative correlation between the DTI‐ALPS index and age in the patients with cluster headache (r = −0.549, p = 0.042). However, the DTI‐ALPS index was not associated with other clinical characteristics, including disease duration and headache intensity (r = −0.405, p = 0.150; r = −0.048, p = 0.869, respectively).ConclusionPatients with cluster headache had a lower DTI‐ALPS index than the healthy controls; this might indicate glymphatic system dysfunction in the patients with cluster headache. Further research is required to determine whether glymphatic system dysfunction is related to the pathophysiology of cluster headache.

Galcanezumab for episodic and chronic cluster headache

Cluster headache (CH) is ahighly debilitating headache disorder characterized by frequent attacks of excruciating unilateral pain accompanied by cranial autonomic symptoms. Calcitonin gene-related peptide (CGRP) is implicated in the pathophysiology of CH. Preventive efficacy and tolerability of the anti-CGRP antibody galcanezumab in patients with episodic (eCH) and chronic CH (cCH). Review of the study results and the challenges in developing drugs for the preventive treatment of CH. In two international multicenter phaseIII trials galcanezumab 300 mg given subcutaneously every 4weeks was compared with placebo. The double-blind study period (8weeks in eCH, 12weeks in cCK) was preceded by abaseline period in both trials. The primary endpoint was the reduction in weekly attack frequency. In the eCH trial, 106patients were randomized to either galcanezumab (n = 49) or placebo (n = 57). The mean weekly attack frequency during the first 3weeks decreased by 52% in the galcanezumab group compared with 27% in the placebo group (p = 0.036). In the cCH trial, 237patients were randomized to galcanezumab (n = 117) or placebo (n = 120). The primary endpoint was not met in this study. The reduction in mean weekly attack rate was 5.4 with galcanezumab versus 4.6 with placebo (p = 0.334). Galcanezumab was well tolerated in both studies. Galcanezumab had asignificant effect in the prevention of eCH attacks but not in cCH. Possible reasons for this discrepancy are discussed.

Alterations of thalamic nuclei volumes in patients with cluster headache.

This study aimed to compare the alterations of thalamic nuclei volumes and the intrinsic thalamic network in patients with cluster headache and healthy controls. We retrospectively enrolled 24 patients with episodic cluster headache and 24 healthy controls. We calculated the thalamic nuclei volumes in the patients with cluster headache and healthy controls based on three-dimensional T1-weighted imaging with automated segmentation using the FreeSurfer program. We also investigated the intrinsic thalamic network using structural co-variance analysis based on the thalamic nuclei volumes and graph theory under the BRAPH program. We compared the thalamic nuclei volumes and intrinsic thalamic networks in patients with cluster headaches and healthy controls. The right and left whole thalamic volumes did not differ in the patients with cluster headaches and healthy controls (0.4199 vs. 0.4069%, p = 0.2008; 0.4386 vs. 0.4273%, p = 0.3437; respectively). However, there were significant alterations of right and left medial geniculate nuclei volumes in the patients with cluster headaches and the healthy controls. The right and left medial geniculate nuclei volumes of the patients with cluster headaches were greater than those of the healthy controls (0.0088 vs. 0.0075%, p < 0.0001; 0.0086 vs. 0.0072%, p < 0.0001; respectively). The intrinsic thalamic networks of the groups were not different. This study demonstrates significant alterations in the bilateral medial geniculate nuclei volumes in patients with cluster headache compared to healthy controls. These alterations may be related to the pathophysiology of cluster headache. However, there are no changes in the intrinsic thalamic network in patients with cluster headache.

Cluster headache pathophysiology: What we have learned from advanced neuroimaging

BackgroundAlthough remarkable progress has been achieved in understanding cluster headache (CH) pathophysiology, there are still several gaps about the mechanisms through which independent subcortical and cortical brain structures interact with each other. These gaps could be partially elucidated by structural and functional advanced neuroimaging investigations.ObjectiveAlthough we are aware that substantial achievements have come from preclinical, neurophysiological, and biochemical experiments, the present narrative review aims to summarize the most significant findings from structural, microstructural, and functional neuroimaging investigations, as well as the consequent progresses in understanding CH pathophysiological mechanisms, to achieve a comprehensive and unifying model.ResultsAdvanced neuroimaging techniques have contributed to overcoming the peripheral hypothesis that CH is of cavernous sinus pathology, in transitioning from the pure vascular hypothesis to a more comprehensive trigeminovascular model, and, above all, in clarifying the role of the hypothalamus and its connections in the genesis of CH.ConclusionAltogether, neuroimaging findings strongly suggest that, beyond the theoretical model of the “pain matrix,” the model of the “neurolimbic pain network” that is accepted in migraine research could also be extended to CH. Indeed, although the hypothalamus’ role is undeniable, the genesis of CH attacks is complex and seems to not be just the result of a single “generator.” Cortical‐hypothalamic‐brainstem functional interconnections that can switch between out‐of‐bout and in‐bout periods, igniting the trigeminovascular system (probably by means of top‐down mechanisms) and the consensual trigeminal autonomic reflexes, may represent the “neuronal background” of CH.

Clínica y fisiopatología de la cefalea en racimos. Acercamiento a la indicación de neuroestimulación combinada occipital y supraorbitaria

Cluster headache (CH) is included under section 3 - Trigeminal autonomic cephalalgias (TAC) of the International Headache Society (IHS) classification. It is one of the most frequent, painful and disabling primary headaches. Acute and preventive pharmacological treatments are often poorly tolerated and of limited effectiveness. Due to improved understanding of the pathophysiology of CH, neuromodulation devices are now considered safe and effective options for preventive and acute treatment of CH. In this paper, we review the information available to date, and present the case of a patient with disabling cluster headache highly resistant to medical treatment who underwent implantation of a peripheral nerve neurostimulation system to stimulate the supraorbital nerves (SON) and greater occipital nerve (GON) in our Pain Unit. We also review the diagnostic criteria for CH, the state of the knowledge on the pathophysiology of CH, and the role played by neuromodulation in treating this condition

Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

Cluster headache is a primary headache disorder and is the most prevalent of the trigeminal autonomic cephalalgias. Cluster headache significantly impacts those affected, necessitating early diagnosis and management. Despite unique clinical features, such as patients experiencing attacks in a circannual pattern and often with a circadian rhythm within bouts, cluster headache patients often are misdiagnosed, mismanaged and have a delay in diagnosis. Preclinical, neuroimaging and clinical studies have advanced our understanding of cluster headache pathophysiology. The trigeminovascular system, the trigeminal autonomic reflex, and the hypothalamus are all involved in the pathophysiology of cluster headache. As our understanding of the pathophysiology of cluster headaches has evolved, new therapeutic options, such as calcitonin gene-related peptide monoclonal antibodies, non-invasive vagal nerve stimulation and sphenopalatine ganglion stimulation, have proved to have efficacy in the treatment of cluster headache. Herein, we aim to review developments to aid readers in their understanding of this debilitating disorder.