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

BACKGROUND: Despite 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. METHODS: We 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. RESULTS: Patients 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. CONCLUSIONS: We 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.

Different personality profiles in patients with cluster headache: a data-driven approach.

INTRODUCTION: Cluster headache (CH) is usually comorbid to mood spectrum disorders, but the psychopathological aspects are poorly explored. We aimed at identifying discrete profiles of personality traits and their association with clinical features. METHODS: Based on the personality scales of the Millon Clinical Multiaxial Inventory-III, principal component analysis (PCA) identified psychological patterns of functioning of 56 CH patients. PCA outcomes were used for hierarchical cluster analysis (HCA) for sub-groups classification. RESULTS: Eighty-seven percent of patients had personality dysfunctions. PCA found two bipolar patterns: (i) negativistic, sadic-aggressive, borderline, and compulsive traits were distinctive of the psychological dysregulation (PD) dimension, and (ii) narcissistic, histrionic, avoidant, and schizoid traits loaded under the social engagement (SE) component. PD was associated with disease duration and psychopathology. SE was related to educational level and young age. HCA found three groups of patients, and the one with high PD and low SE had the worst psychological profile. CONCLUSIONS: Personality disorders are common in CH. Our data-driven approach revealed distinct personality patterns which can appear differently among patients. The worst combination arguing against mental health is low SE and high PD. Linking this information with medical history may help clinicians to identify tailored-based therapeutic interventions for CH patients.

The neurobiology of cluster headache.

Cluster headache is a primary headache form occurring in paroxysmal excruciatingly severe unilateral head pain attacks usually grouped in periods lasting 1-2months, the cluster periods. A genetic component is suggested by the familial occurrence of the disease but a genetic linkage is yet to be identified. Contemporary activation of trigeminal and cranial parasympathetic systems-the so-called trigemino-parasympathetic reflex-during the headache attacks seem to cause the pain and accompanying oculo-facial autonomic phenomena respectively. At peripheral level, the increased calcitonin gene related peptide (CGRP) plasma levels suggests trigeminal system activation during cluster headache attacks. The temporal pattern of the disease both in terms of circadian rhythmicity and seasonal recurrence has suggested involvement of the hypothalamic biological clock in the pathophysiology of cluster headache. The posterior hypothalamus was investigate as the cluster generator leading to activation of the trigemino-parasympathetic reflex, but the accumulated experience after 20 years of hypothalamic electrical stimulation to treat the condition indicate that this brain region rather acts as pain modulator. Efficacy of monoclonal antibodies to treat episodic cluster headache points to a key role of CGRP in the pathophysiology of the condition.

Cluster headache and TACs: state of the art.

Cluster headache (CH), paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache attacks (including SUNCT and SUNA), and hemicrania continua (HC) compose the group of trigeminal autonomic cephalalgias (TACs). Here, we review the recent advances in the field and summarize the current knowledge about the origin of these headaches. Similar to the other primary headaches, the pathogenesis is still much obscure. However, advances are being made in both animal models and humans studies. Three structures clearly appear to be crucial in the pathophysiology of TACs: the trigeminal nerve, the facial parasympathetic system, and the hypothalamus. The physiologic and pathologic functioning of each of these elements and their interactions is being progressively clarified, but critical questions are still open.

Understanding Cluster Headache Using Magnetic Resonance Imaging.

Cluster headache is an excruciating pain syndrome characterized by unilateral head pain attacks, lasting between 15 and 180 min, accompanied by marked ipsilateral cranial autonomic symptoms, such as lacrimation and conjunctival injection. Despite important insights provided by neuroimaging studies and deep brain stimulation findings, the pathophysiology of cluster headache and its pathways of chronicization are still elusive. In this mini-review, we will provide an overview of the functional and structural neuroimaging studies in episodic and chronic cluster headache conditions conducted to clarify the underlying pathophysiology.

Galcanezumab for the prevention of cluster headache.

INTRODUCTION: Cluster headache (CH) is among the worst painful conditions. The available therapies are scarce and not specific, leaving many patients unsatisfied because of poor efficacy and/or tolerability. Patients not responding to common treatments are offered semi-invasive and invasive procedures with uncertain results. Based on the current understanding of CH pathophysiology, new possible therapeutic approaches come from drugs interfering with Calcitonin Gene Related Peptide (CGRP). AREAS COVERED: After summarizing the evidence for CGRP involvement in CH pathophysiology, we review the published literature (PubMed) and information (clinicaltrials.gov, EudraCT, EMA and FDA websites) regarding a novel anti-CGRP monoclonal antibody, Galcanezumab, its pharmacological properties, development, and evidence for the treatment of CH. Publications regarding other indications (migraine) are considered for completeness and safety/tolerability profile. EXPERT OPINION: In one randomized clinical trial, Galcanezumab has proven to be effective and safe as a preventive treatment in episodic CH, with a favorable tolerability profile offering a potential new option in the therapeutic arsenal. Inefficacy of galcanezumab in chronic CH as well as the inefficacy of another monoclonal antibody against CGRP (fremanezumab) in both episodic and chronic CH question the scalability of the drug in CH management. Further, studies comparing galcanezumab to the current standard treatments are highly desirable.

Anti-CGRP in cluster headache therapy.

Cluster headache is a primary headache characterized by recurring excruciating pain and autonomic signs, leading to significant suffering and derangement of patients' life. Efficacious new preventive treatments are needed. The pathophysiology of cluster headache comprises mechanisms both in the peripheral and central nervous system, involving the trigeminovascular system, the trigemino-parasympathetic reflex, and central modulating systems. Calcitonin gene-related peptide (CGRP) has an active role throughout these systems. It is increased during spontaneous and provoked attacks, and itself can induce attacks. Recently, drugs against this neuropeptide have been developed for the treatment of different headache disorders. In particular, monoclonal antibodies vs CGRP as galcanezumab and fremanezumab have been tested in cluster headache, with promising results for the episodic form. Considering the relevance of central mechanisms in CH, drugs interfering with the CGRP pathway in the central nervous system can enlarge the therapeutic armamentarium against this highly disabling condition.

Defective functional connectivity between posterior hypothalamus and regions of the diencephalic-mesencephalic junction in chronic cluster headache.

OBJECTIVE: We tested the hypothesis of a defective functional connectivity between the posterior hypothalamus and diencephalic-mesencephalic regions in chronic cluster headache based on: a) clinical and neuro-endocrinological findings in cluster headache patients; b) neuroimaging findings during cluster headache attacks; c) neuroimaging findings in drug-refractory chronic cluster headache patients improved after successful deep brain stimulation. METHODS: Resting state functional magnetic resonance imaging, associated with a seed-based approach, was employed to investigate the functional connectivity of the posterior hypothalamus in chronic cluster headache patients (n = 17) compared to age and sex-matched healthy subjects (n = 16). Random-effect analyses were performed to study differences between patients and controls in ipsilateral and contralateral-to-the-pain posterior hypothalamus functional connectivity. RESULTS: Cluster headache patients showed an increased functional connectivity between the ipsilateral posterior hypothalamus and a number of diencephalic-mesencephalic structures, comprising ventral tegmental area, dorsal nuclei of raphe, and bilateral substantia nigra, sub-thalamic nucleus, and red nucleus ( p < 0.005 FDR-corrected vs . control group). No difference between patients and controls was found comparing the contralateral hypothalami. CONCLUSIONS: The observed deranged functional connectivity between the posterior ipsilateral hypothalamus and diencephalic-mesencephalic regions in chronic cluster headache patients mainly involves structures that are part of (i.e. ventral tegmental area, substantia nigra) or modulate (dorsal nuclei of raphe, sub-thalamic nucleus) the midbrain dopaminergic systems. The midbrain dopaminergic systems could play a role in cluster headache pathophysiology and in particular in the chronicization process. Future studies are needed to better clarify if this finding is specific to cluster headache or if it represents an unspecific response to chronic pain.

Long-term occipital nerve stimulation for drug-resistant chronic cluster headache.

Introduction Chronic cluster headache is rare and some of these patients become drug-resistant. Occipital nerve stimulation has been successfully employed in open studies to treat chronic drug-resistant cluster headache. Data from large group of occipital nerve stimulation-treated chronic cluster headache patients with long duration follow-up are advantageous. Patients and methods Efficacy of occipital nerve stimulation has been evaluated in an experimental monocentric open-label study including 35 chronic drug-resistant cluster headache patients (mean age 42 years; 30 men; mean illness duration: 6.7 years). The primary end-point was a reduction in number of daily attacks. Results After a median follow-up of 6.1 years (range 1.6-10.7), 20 (66.7%) patients were responders (≥50% reduction in headache number per day): 12 (40%) responders showed a stable condition characterized by sporadic attacks, five responders had a 60-80% reduction in headache number per day and in the remaining three responders chronic cluster headache was transformed in episodic cluster headache. Ten (33.3%) patients were non-responders; half of these have been responders for a long period (mean 14.6 months; range 2-48 months). Battery depletion (21 patients 70%) and electrode migration (six patients - 20%) were the most frequent adverse events. Conclusions Occipital nerve stimulation efficacy is confirmed in chronic drug-resistant cluster headaches even after an exceptional long-term follow-up. Tolerance can occur years after improvement.

Advances in the understanding of cluster headache.

INTRODUCTION: Cluster headache is the worst primary headache form; it occurs in paroxysmal excruciatingly severe unilateral head pain attacks usually grouped in cluster periods. The familial occurrence of the disease indicates a genetic component but a gene abnormality is yet to be disclosed. Activation of trigeminal afferents and cranial parasympathetic efferents, the so-called trigemino-parasympathetic reflex, can explain pain and accompanying oculo-facial autonomic phenomena. In particular, pain in cluster headache is attributed, at least in part, to the increased CGRP plasma levels released by activated trigeminal system. Posterior hypothalamus was hypothesized to be the cluster generator activating the trigemino-parasympathetic reflex. Efficacy of monoclonal antibodies against CRGP is under investigation in randomized clinical trials. Areas covered: This paper will focus on main findings contributing to consider cluster headache as a neurovascular disorder with an origin from within the brain. Expert commentary: Accumulated evidence with hypothalamic stimulation in cluster headache patients indicate that posterior hypothalamus terminates rather than triggers the attacks. More extensive studies on the genetics of cluster headache are necessary to disclose anomalies behind the increased familial risk of the disease. Results from ongoing clinical trials in cluster headache sufferers using monoclonal antibodies against CGRP will open soon a new era.

Deep brain stimulation in headache.

BACKGROUND: Deep brain stimulation of the posterior hypothalamic area was first introduced in 2000 to treat drug-refractory chronic cluster headache (CH). FINDINGS: So far, hypothalamic stimulation has been employed in 79 patients suffering from various forms of intractable short-lasting unilateral headache forms, mainly trigeminal autonomic cephalalgias. The majority were (88.6%) chronic CH, including one patient who suffered from symptomatic chronic CH-like attacks; the remaining were short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), one had paroxysmal hemicranias and one symptomatic trigeminal neuralgia. Overall, after a mean follow up of 2.2 years, 69.6% (55) hypothalamic-stimulated patients showed a ≥50% improvement. CONCLUSIONS: These observations need confirmation in randomised, controlled trials. A key role of the posterior hypothalamic area in the pathophysiology of unilateral short-lasting headaches, possibly by regulating the duration rather than triggering the attacks, can be hypothesised. Because of its invasiveness, hypothalamic stimulation can be proposed only after other, less-invasive, neurostimulation procedures have been tried.

Emerging therapies for chronic migraine.

Not all chronic migraines are medication-overuse headaches and so the challenge is how to treat them. Currently available pharmacological therapies may be ineffective or they are abandoned because of intolerable side effects. There is still much room for novel therapeutic approaches in those with drug refractory migraine (RM). Occipital nerve stimulation (ONS) and botulinum toxin type A have finally gained a level of evidence based on the results of RCTs and pooled analysis, which by and large have shown at least a modest but valuable therapeutic effect. For a long time, these two approaches were only supported by clinical experience and open-label studies. Considering the disabling nature of migraine disorder, the large prevalence and serious impact on health-related quality of life and health care costs, any degree of response to treatment is acceptable and welcomed by the patient. An important issues for future studies would be better patient selection when finding candidates for each procedure.

From neuroimaging to patients' bench: what we have learnt from trigemino-autonomic pain syndromes.

Trigeminal autonomic cephalalgias (TACs) are primary headaches including cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). A number of neuroimaging studies have been conducted in last decade showing involvement of brain areas included in the pain matrix. Apart from pain matrix involvement, other neuroimaging findings data deserve special attention. The hypothalamic activation reported in the course of TAC attacks coupled with the efficacy of hypothalamic neurostimulation to treat drug-resistant TAC forms clearly indicate the posterior hypothalamus as a crucial area in TAC pathophysiology. In animal models this brain area has been shown to modulate craniofacial pain; moreover, hypothalamic activation occurs in other pain conditions, suggesting that posterior hypothalamus has a more complex role in TAC pathophysiology rather than simply being considered as a trigger. In contrast, hypothalamic activation may serve as a crucial area in terminating rather than triggering attacks. It also could lead to a central condition facilitating initiation of TAC attacks.

Surgical treatment of primary headaches.

Neuromodulation for the treatment of drug-refractory cranial neuralgias constitutes an exciting field of research for physicians; in the last decade, several methodologies have been described which could help many patients to exit such desperate conditions; although the exact mechanisms of action of these techniques are still matter of debate, several experimental and neuroradiological modalities can help us to get near the concept of understanding them. In this paper, the authors summarize the most recent surgical procedures used to treat severe and pharmaco-resistant cranial painful conditions, along with brief descriptions of the results obtained in the several published so far.

Management of chronic cluster headache.

OPINION STATEMENT: Primary cluster headache (CH) is an excruciatingly severe pain condition. Several pharmacologic agents are available to treat chronic CH, but few double-blind, randomized clinical trials have been conducted on these agents in recent years, and the quality of the evidence supporting their use is often low, particularly for preventive agents. We recommend sumatriptan or oxygen to abort ongoing headaches; the evidence available to support their use is good (Class I). Ergotamine also appears to be an effective abortive agent, on the basis of experience rather than trials. We consider verapamil and lithium to be first-line preventives for chronic CH, although the trial evidence is at best Class II. Steroids are clearly the most effective and quick-acting preventive agents for chronic CH, but long-term steroid use carries a risk of several severe adverse effects. We therefore recommend steroids only if verapamil, lithium, and other preventive agents are ineffective. In rare cases, patients experience multiple daily cluster headaches for years and are also refractory to all medications. These patients almost always develop severe adverse effects from chronic steroid use. Such patients should be considered for neurostimulation. Occipital nerve stimulation is the newest and least invasive neurostimulation technique and should be tried first; the evidence supporting its use is encouraging. Hypothalamic stimulation is more invasive and can be performed only in specialist neurosurgical centers. Published experience suggests that about 60% of patients with chronic CH obtain long-term benefit with hypothalamic stimulation.