A prospective open label 2-8 year extension of the randomised controlled ICON trial on the long-term efficacy and safety of occipital nerve stimulation in medically intractable chronic cluster headache.

BACKGROUND: We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety. METHODS: ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals. FINDINGS: Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8-6.3), two (5.1; 3.5-7.6) and five years (4.1; 3.0-5.5) compared to baseline (16.2; 14.4-18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68-0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70-0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year-1 [0.28-0.41]). We didn't find predictive factors for effectiveness. INTERPRETATION: ONS is a safe, well-tolerated and long-term effective treatment for MICCH. FUNDING: The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.

The role of neurotransmitters and neuromodulators in the pathogenesis of cluster headache: a review.

The pathogenesis underlying cluster headache remains an unresolved issue. Although both the autonomic system and the hypothalamus play a central role, the modality of their involvement remains largely unknown. It is, also, unknown why the duration of the pain attacks is so brief and why their onset and termination are abrupt and extremely painful. This review summarizes the evidence to date accumulated in favor of a possible role of anomalies in the metabolism of tyrosine, tryptophan, and arginine in these unresolved issues.

Invasive occipital nerve stimulation for refractory chronic cluster headache: what evolution at long-term? Strengths and weaknesses of the method.

BACKGROUND: Invasive Occipital Nerve Stimulation (iONS) is a costly technique which appears effective in drug-refractory chronic cluster headache (drCCH) management. Available data on long-term effectiveness and safety of iONS in this indication are scarce, though they could be useful to neurologists and patients in daily practice. The purpose of this short report is to discuss the very long-term outcome of a drCCH cohort, including adverse events. FINDINGS: Previously, favourable results were obtained with iONS in 15 drCCH patients: 80 % were significantly improved and 60 % were pain free. We report here the very long-term follow-up (up to nine years) of 10 patients belonging to this cohort. Meanwhile 5 patients had to be definitively explanted because of device infection (3) or paresthesia intolerance (2). Four patients (40 %) evolved to an episodic form of CH. Six remained chronic but their attack frequency was decreased by 70 % on average. Intake of preventive drugs is still necessary in 80 % of patients. All patients needed at least one battery replacement. CONCLUSIONS: Up to nine years after implantation, iONS is still effective in most patients with drCCH. Concomitant preventive drugs remain often necessary. Forty percent of patients reverse to episodic CH, possibly by natural history. iONS is not a benign procedure but device-related complications appear similar to those reported with other invasive neurostimulators.

[Pathophysiology of cluster headache]. / Physiopathologie de l'algie vasculaire de la face (AVF).

The aetiology of cluster headache is partially unknown. Three areas are involved in the pathogenesis of cluster headache: the trigeminal nociceptive pathways, the autonomic system and the hypothalamus. The cluster headache attack involves activation of the trigeminal autonomic reflex. A dysfunction located in posterior hypothalamic gray matter is probably pivotal in the process. There is a probable association between smoke exposure, a possible genetic predisposition and the development of cluster headache.

Experimental activation of the sphenopalatine ganglion provokes cluster-like attacks in humans.

BACKGROUND: High frequency (HF) stimulation of the sphenopalatine ganglion (SPG) is an emerging abortive treatment for cluster headache (CH) attacks. HF SPG stimulation is thought to exert its effect by physiologically blocking parasympathetic outflow. We hypothesized that low frequency (LF) SPG stimulation may activate the SPG, causing increased parasympathetic outflow and thereby provoking cluster attacks in CH patients. METHODS: In a double-blind randomized cross-over study, seven CH patients implanted with an SPG neurostimulator were randomly allocated to receive HF or LF stimulation for 3 min on 2 separate days. We recorded headache characteristics and autonomic symptoms during and after stimulation. RESULTS: Six patients completed the study. Three out of six patients (50%) reported ipsilateral cluster-like attacks during or within 30 min of LF SPG stimulation. These cluster-like attacks were all successfully treated with the therapeutic HF SPG stimulation. One out of six reported a cluster-like attack with 3 min HF SPG stimulation, which was also successfully treated with continued HF therapeutic SPG stimulation. DISCUSSION: LF SPG stimulation may induce cluster-like attacks with autonomic features, which can subsequently be treated by HF SPG stimulation. Efferent parasympathetic outflow from the SPG may initiate autonomic symptoms and activate trigeminovascular sensory afferents, which may initiate the onset of pain associated with CH.

Cluster-like headache and a cystic hypothalamic tumour as first presentation of sarcoidosis.

INTRODUCTION: Sarcoidosis is a granulomatous, multisystem inflammatory disease of unknown cause, which presents with a wide variety of symptoms. We describe a rare case of a newly diagnosed sarcoidosis, with cluster-like headache as a presenting symptom. CASE: A 31-year-old man presented with cluster headache with a cystic lesion in the hypothalamus. A non-caseating granuloma consistent with the diagnosis sarcoidosis was found at biopsy. Pulmonary involvement was confirmed on positron electron tomography-computed tomography (PET-CT). Treatment with prednisone led to regression of the hypothalamic lesion. Headache attacks did not recur. DISCUSSION: Cluster-like headache with a cystic hypothalamic lesion as first presentation of sarcoidosis has never been reported. Their possible relationship seems to underline the role of the hypothalamus in the central pain-regulatory areas in the brain, but is not undisputed. This case clearly demonstrates once again the relevance of neuroimaging in new-onset cluster-like headache.

Cluster headache and the hypothalamus: causal relationship or epiphenomenon?

Typical clinical features of cluster headache (CH) include circadian/circannual rhythmicity and ipisilateral cranial autonomic features. This presentation has led to the assumption that the hypothalamus plays a pivotal role in this primary headache disorder. Several studies using neuroimaging techniques or measuring hormone levels supported the hypothesis of a hypothalamic involvement in the underlying pathophysiology of CH. Animal studies added further evidence to this hypothesis. Based on previous data, even invasive treatment methods, such as hypothalamic deep brain stimulation, are used for therapy. However, the principal question of whether these alterations are pathognomonic for CH or whether they might be detected in trigeminal pain disorders in general, in terms of an epiphenomenon, is still unsolved. This article summarizes studies on hypothalamic involvement in CH pathophysiology, demonstrates the involvement of the hypothalamus in other diseases and tries to illuminate the role of the hypothalamus based on this synopsis.

Cluster headache following dental treatment: a case report.

Cluster headache is a neurovascular disorder characterized by attacks of severe and strictly unilateral pain presenting in and around the orbit and temporal area. Attacks occur in series lasting for weeks or months separated by remission periods. An individual attack lasts 15-180 min with a frequency of once every other day to as often as 8 times per day. Ipsilateral radiation of the headache to orofacial regions, including the teeth, is not unusual. The area of involvement may obscure the diagnosis and lead to irreversible and unnecessary dental treatment. A case in which cluster attacks occurred immediately after a dental procedure is described.

Electrical stimulation of sphenopalatine ganglion for acute treatment of cluster headaches.

INTRODUCTION: Cluster headaches (CH) are primary headaches marked by repeated short-lasting attacks of severe, unilateral head pain and associated autonomic symptoms. Despite aggressive management with medications, oxygen therapy, nerve blocks, as well as various lesioning and neurostimulation therapies, a number of patients are incapacitated and suffering. The sphenopalatine ganglion (SPG) has been implicated in the pathophysiology of CH and has been a target for blocks, lesioning, and other surgical approaches. For this reason, it was selected as a target for an acute neurostimulation study. METHODS: Six patients with refractory chronic CH were treated with short-term (up to 1 hour) electrical stimulation of the SPG during an acute CH. Headaches were spontaneously present at the time of stimulation or were triggered with agents known to trigger clusters headache in each patient. A standard percutaneous infrazygomatic approach was used to place a needle at the ipsilateral SPG in the pterygopalatine fossa under fluoroscopic guidance. Electrical stimulation was performed using a temporary stimulating electrode. Stimulation was performed at various settings during maximal headache intensity. RESULTS: Five patients had CH during the initial evaluation. Three returned 3 months later for a second evaluation. There were 18 acute and distinct CH attacks with clinically maximal visual analog scale (VAS) intensity of 8 (out of 10) and above. SPG stimulation resulted in complete resolution of the headache in 11 attacks, partial resolution (>50% VAS reduction) in 3, and minimal to no relief in 4 attacks. Associated autonomic features of CH were resolved in each responder. Pain relief was noted within several minutes of stimulation. CONCLUSION: Sphenopalatine ganglion stimulation can be effective in relieving acute severe CH pain and associated autonomic features. Chronic long-term outcome studies are needed to determine the utility of SPG stimulation for management and prevention of CH.

Cluster headache and lifestyle habits.

Cluster headache (CH) has traditionally been associated with certain anthropometric features, personality traits, and lifestyle features. This article focuses on lifestyle features in patients with CH. Especially excessive smoking and alcohol consumption have been ascribed to patients with CH. Despite country-specific habits and a time trend, smoking is much more prevalent among CH patients compared with the general population. Although excessive alcohol consumption was reported in early studies, this was not corroborated more recently. On the contrary, patients with CH seem to avoid alcohol, particularly during active phases, likely due to its ability to trigger attacks. Present studies are purely descriptive. Thus, the associations sketched give no information about the long-term effects of smoking or alcohol consumption on the course of CH.

Chronic cluster headache: a review.

Cluster headache (CH) is a rare but severe headache disorder characterised by repeated unilateral head pain attacks accompanied by ipsilateral autonomic features. In episodic CH, there are periods of headache attacks with pain-free intervals of weeks, months or years in between. A minority of patients have the chronic form, without pain-free intervals between the headache attacks. Chronic CH can occur as primary or secondary chronic CH; the rarest form is episodic CH arising from chronic CH. In this article, we give a review of the chronic forms of CH and focus on demographics, clinical manifestations, social habits, predictive factors, head injury, genetics, neuroimaging and therapy. It is remarkable that little is known about risk factors that make CH chronic.

Tearing without pain after trigeminal root section for cluster headache.

The cranial autonomic symptoms (CAS) in patients with cluster headache (CH) are considered to occur as a result of intense ophthalmic division pain. Five CH patients underwent transection of the trigeminal nerve root but continued to experience periodic CAS without pain, whereas another five patients continued to experience typical cluster headaches. These findings confirm that CH is generated by a central pacemaker and the pain may be expressed without activation of the peripheral trigeminovascular network.

[Pathophysiology of cluster headache]. / Physiopathologie de l'algie vasculaire de la face.

The aetiology of cluster headache (CH) is unknown and an unifying pathophysiologic explanation is not available. Based on the clinical features of the disorder, three areas appear to be involved in the pathogenesis and the expression of cluster headache: the trigeminal nociceptive pathways, the autonomic system and the hypothalamus. A brain stem connection may exist between the trigeminal nerve and the cranial parasympathetics. This would explain the reflex trigeminal-autonomic activation but a central nervous system dysfunction located in posterior hypothalamic gray matter is probably pivotal in the process. Such a dysfunction is supported by both posterior hypothalamic activation shown during CH attacks by positron emission tomography and increase of posterior hypothalamic volume shown in magnetic resonance imaging using voxel morphometry. Moreover, such a neurovascular model could be more precise considering some recent experimental and clinical research data as serotoninergic neuromediation involvement, nitric oxide one and a possible genetic predisposition.

Hypothalamic involvement and activation in cluster headache.

Cluster headache is an episodic form of primary neurovascular headache that is both severe and relatively rare. It is characterized by episodes of headache with cranial parasympathetic activation and sympathetic impairment that come in bouts, or clusters. Its pathophysiology can be divided into understanding the attack phenotype and the biotype of the periodicity. Acute attacks of cluster headache are marked by trigeminal nerve-mediated pain and with cranial autonomic activation, trigeminal-autonomic cephalalgia; an activation that characterizes the phenotype of a group of headaches. The signature feature of cluster headache is its periodicity, the daily cycle of attacks when the patient is in an active bout, or the circumannual, or other period, cycling that distinguishes the on period from the off period. Functional brain imaging with positron emission tomography and structural imaging with voxel-based morphometry have identified an area in the posterior hypothalamic gray as key in understanding cluster headache. This area is subtly enlarged in its gray matter volume, active during an acute cluster headache but inactive when patients are challenged between bouts. Cluster headache is likely to be a form of primary neurovascular pain whose phenotypic expression relies on the trigeminal-autonomic reflex, with a biotype determined by the brain area, the posterior hypothalamus, in which the lesion seems to be located. Understanding both the phenotypic expression and the biotype will, respectively, enable better acute attack treatments and better preventative management of this horrible form of headache.

Hypothalamic activation in cluster headache attacks.

BACKGROUND: Cluster headache, one of the most severe pain syndromes in human beings, is usually described as a vascular headache. However, the striking circadian rhythmicity of this strictly half-sided pain syndrome cannot be readily explained by the vascular hypothesis. We aimed to assess changes in regional cerebral blood flow (rCBF) in patients with cluster headache. METHODS: We used positron emission tomography (PET) to assess the changes in rCBF, as an index of synaptic activity, during nitroglycerin-induced cluster headache attacks in nine patients who had chronic cluster headache. Eight patients who had cluster headache but were not in the bout acted as a control group. FINDINGS: In the acute pain state, activation was seen in the ipsilateral inferior hypothalamic grey matter, the contralateral ventroposterior thalamus, the anterior cingulate cortex, and bilaterally in the insulae. Activation in the hypothalamus was seen solely in the pain state and was not seen in patients who have cluster headache but were out of the bout. INTERPRETATION: Our findings establish central nervous system dysfunction in the region of the hypothalamus as the primum movens in the pathophysiology of cluster headache. We suggest that a radical reappraisal of this type of headache is needed and that it should in general terms, be regarded as a neurovascular headache, to give equal weight to the pathological and physiological mechanisms that are at work.