Effect on sleep of posterior hypothalamus stimulation in cluster headache

OBJECTIVE: To evaluate the structure and quality of sleep and the circadian rhythm of body core temperature (BcT degrees ) in patients with drug-resistant chronic cluster headache (CH) before and during deep brain stimulation (DBS) of the posterior hypothalamus. BACKGROUND: Chronic CH is a severe primary headache and frequently associated with disturbances in sleep. Posterior hypothalamus DBS is performed as an effective treatment of drug-resistant chronic CH. The effects of posterior hypothalamus DBS on sleep and the circadian rhythm of BcT degrees are unknown. METHODS: Three male patients with chronic drug-resistant CH underwent 48-hour consecutive polysomnography (PSG) by means of the VITAPORT system with determination of BcT degrees by means of a rectal probe. Recordings were done before electrode implantation in the posterior hypothalamus and after optimized DBS of posterior hypothalamus. RESULTS: Before electrode implantation PSG showed nocturnal CH attacks, reduced sleep efficiency, fragmented sleep and increased periodic limb movements in sleep (PLMS). During DBS nocturnal CH attacks were abolished and sleep efficiency and PLMS improved. BcT degrees circadian rhythm was normal both before and during DBS. CONCLUSIONS: Our data show that DBS of posterior hypothalamus in drug-resistant chronic CH is effective in curtailing nocturnal CH attacks, and is associated with improved sleep structure and quality. Chronic CH displays a normal circadian rhythm of BcT degrees, unchanged during hypothalamic DBS.     

Lessons from 8 years' experience of hypothalamic stimulation in cluster headache

Neuroimaging studies in cluster headache (CH) patients have increased understanding of attack-associated events and provided clues to the pathophysiology of the condition. They have also suggested stimulation of the ipsilateral posterior inferior hypothalamus as a treatment for chronic intractable CH. After 8 years of experience, stimulation has proved successful in controlling the pain attacks in almost 60% of chronic CH patients implanted at various centres. Although hypothalamic implant is not without risks, it has generally been performed safely. Implantation affords an opportunity to perform microrecordings of individual posterior hypothalamic neurons. These studies are at an early stage, but suggest the possibility of identifying precisely the target site by its electrophysiological characteristics. Autonomic studies of patients undergoing posterior hypothalamic stimulation provide further evidence that long-term stimulation is safe, revealing that it can cause altered modulation of the mechanisms of orthostatic adaptation without affecting the baroreflex, cardiorespiratory interactions or efferent sympathetic and vagal functions. Chronically stimulated patients have an increased threshold for cold pain at the site of the first trigeminal branch ipsilateral to the stimulated side; when the stimulator is switched off, changes in sensory and pain thresholds do not occur immediately, suggesting that long-term stimulation is required to induce sensory and nociceptive changes. Posterior inferior hypothalamic stimulation is now established as a treatment for many chronic CH patients. The technique is shedding further light on the pathophysiology of the disease, and is also providing clues to functioning of the hypothalamus itself.     

Cluster headache, hypothalamus, and orexin

Cluster headache (CH) is a highly disabling condition resulting in severe, recurrent unilateral bouts of pain and accompanying autonomic symptoms. This review describes some current views regarding the underlying pathophysiology covering the pain and cranial autonomic (parasympathetic) activation, and highlights the potential importance of the hypothalamus in CH. The hypothalamus is known to modulate many functions and has been shown to be involved in the pathophysiology of a variety of primary headaches, including CH. Hypothalamic structures are likely to underlie the circadian and circannual periodicity of attacks and contribute to the pain and autonomic disturbances. We discuss the hypothalamic involvement in CH and modulation of trigeminovascular processing and examine the emerging involvement of the hypothalamic orexinergic system as a possible key pathway in CH pathophysiology.     

Deep brain stimulation for intractable chronic cluster headache: proposals for patient selection

Cluster headache is the most severe of the primary headaches. Positron emission tomography and functional MRI studies have shown that the ipsilateral posterior hypothalamus is activated during cluster headache attacks and is structurally asymmetric in these patients. These changes are highly specific for the condition and suggest that the cluster headache generator may be located in that brain area; they further suggest that electrical stimulation of that region might produce clinical improvement in chronic cluster headache sufferers refractory to medical therapy. In five patients with severe intractable chronic cluster headache, hypothalamic electrical stimulation produced complete and long-term pain relief with no relevant side-effects. We therefore consider it essential to propose criteria for selecting chronic cluster headache patients for hypothalamic deep brain stimulation before this procedure is undertaken at other academic medical centres.     

Tiefenhirnstimulation im posterioren Hypothalamus zur Behandlung des chronischen Clusterkopfschmerzes

Primary chronic cluster headache (CCH) is a rare but severe pain syndrome and pathophysiological explanations are still missing. PET studies revealed activation in the hypothalamus and therefore it became a target for therapeutic deep brain stimulation (DBS). A case of a 39-year-old woman and a literature review are presented. The patient suffered from left-sided primary CCH for 14 months. The headache was resistant to any pharmacological therapy or treatment was limited by major drug side effects. Using a stereotactic approach a quadripolar lead was inserted in the left posterior hypothalamus. A test trial was performed and attack frequency, intensity, and adverse events were noted. Intraoperative test stimulation evoked typical side effects like tachycardia, diplopia and panic attacks. During the trial test a marked reduction in frequency and intensity of CCH was recorded. After 7 days the stimulation device was implanted subcutaneously. DBS with implantation of a lead in the ipsilateral inferior posterior hypothalamus is an experimental treatment option and should be offered to selected patients in a prospective controlled clinical trial. Data concerning the long-term follow-up need to be collected.     

Local field potentials reveal a distinctive neural signature of cluster headache in the hypothalamus

Cluster headache (CH) is a debilitating neurovascular condition characterized by severe unilateral periorbital head pain. Deep brain stimulation of the posterior hypothalamus has shown potential in alleviating CH in its most severe, chronic form. During surgical implantation of stimulating macroelectrodes for cluster head pain, one of our patients suffered a CH attack. During the attack local field potentials displayed a significant increase in power of approximately 20 Hz. To the authors' knowledge, this is the first recorded account of neuronal activity observed during a cluster attack. Our results both support and extend the current literature, which has long implicated hypothalamic activation as key to CH generation, predominantly through indirect haemodynamic neuroimaging techniques. Our findings reveal a potential locus in CH neurogenesis and a potential rationale for efficacious stimulator titration.     

Hypothalamic deep-brain stimulation modulates thermal sensitivity and pain thresholds in cluster headache

Deep-brain stimulation (DBS) of the posterior hypothalamus has been shown to be clinically effective for drug-resistant chronic cluster headache, but the underlying mechanism is still not understood. The hypothalamus as an important centre of homeostasis is connected among others to the trigeminal system via the trigeminohypothalamic tract. We aimed to elucidate whether hypothalamic stimulation affects thermal sensation and pain perception only in the clinically affected region (the first trigeminal branch) or in other regions as well. Thus, we examined three groups: chronic cluster headache patients with unilateral DBS of the posterior hypothalamus (n = 11), chronic cluster headache patients without DBS (n = 15) and healthy controls (n = 29). Perception and pain thresholds for hot and cold stimuli were determined bilaterally in all subjects supraorbitally, at the forearm, and in the lower leg. In DBS patients, thresholds were determined with the stimulator activated and inactivated. Cold pain thresholds at the first trigeminal branch were increased on the stimulated side in the DBS group compared to healthy subjects (p = .015). The DBS group also had higher cold detection thresholds compared to non-implanted cluster headache patients (p < .05). Short-term interruption of stimulation did not induce any changes in DBS patients. Clinically relevant differences were found neither between non-stimulated cluster headache patients and healthy controls nor between the affected and the non-affected sides in the chronic cluster headache patients without DBS. These results support the notion that neurostimulation of the posterior hypothalamus is specific for cluster headache and only affects certain aspects of pain sensation.     

Deep Brain Stimulation in Cluster Headache: Hypothalamus or Midbrain Tegmentum?

Functional and structural neuroimaging studies have provided pivotal insights into the pathophysiology of trigeminal autonomic cephalalgias (TACs), particularly cluster headache (CH). Functional imaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) in TACs have reported activation of the posterior hypothalamus. A structural neuroimaging study using voxel-based morphometry in CH reported increased volume of the hypothalamic gray, although another larger study failed to reproduce this finding. These studies in CH prompted the use of stereotactic stimulation of the target point identified by functional and structural neuroimaging. The precise anatomical localization of the deep brain stimulation (DBS) target places it at the midbrain tegmentum rather than the posterior hypothalamus. A comparison of the PET and fMRI studies in TACs reveals that the diencephalic/mesencephalic activation is more posteroinferior in the PET studies, straddling the hypothalamus and midbrain tegmentum, whereas the activation is centered on the hypothalamus in the higher spatial resolution fMRI studies. To optimize the outcomes from DBS, it is likely that patients will need to be studied individually using functional imaging techniques that have high spatial and temporal resolution to enable targeting of the appropriate locus with stereotactic stimulation.     

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.     

Neuromodulation bei Clusterkopfschmerz

Deep brain stimulation (DBS) of the posterior hypothalamic area is a new treatment option for patients with refractory chronic cluster headache (CCH). A review of the literature reveals that studies based on large numbers of patients, long-term observations and controlled randomised trials are still lacking. In 2006 a case report of the first patient in Germany to be operated on to allow DBS was published, and we now present a report of this patient’s course in the first 6 months after the operation; in addition, a current literature review is discussed.In July 2005 a DBS lead was placed in the left posterior hypothalamic area of this 39-year-old woman with CCH. Stimulation on demand achieved complete suppression of the cluster attacks, and the patient no longer needed medication. After about 8 months a decreasing effect of the stimulation, with only about 50% reduction of cluster attacks, and stimulation-induced side effects were observed.Neither reprogramming of the stimulation parameters nor pharmacological therapy with on-demand and long-term medication reduced the frequency or severity of CCH attacks to the level experienced in the early postoperative stage. Because of intolerable subjective side effects and tension-related pain at the site of the connection cable, in September 2006 the whole system was explanted at the patient’s request.DBS in the posterior hypothalamic area is an invasive treatment option for use in cases with CCH that is refractory to any pharmacological therapy. As demonstrated by this case report, it is not possible to give a prognosis concerning its long-term efficacy: despite the initial excellent benefit there can be a reduction and even a loss of the effect of stimulation. The clinical results and long-term follow-up observations of the few cases published so far need to be evaluated in a larger multicentre trial with a double-blind study design.     

Cluster headache: A review of neuroimaging findings

Classified as a trigeminal autonomic cephalalgia, cluster headache is characterized by recurrent short-lived excruciating pain attacks, which are concurrent with autonomic signs. These clinical features have led to the assumption that cluster headache’s pathophysiology involves central nervous system structures, including the hypothalamus. In the past decade, neuroimaging studies have confirmed such clinically derived theory by uncovering in vivo neuronal changes located in the inferior posterior hypothalamus. Using a variety of neuroimaging techniques (functional [eg, functional MRI], biochemical [eg, magnetic resonance spectroscopy], and structural [eg, morphometry]) in patients with cluster headache, we are making improvements in our understanding of the role of the brain in this disorder. This article summarizes neuroimaging findings in cluster headache patients, describing neuronal changes that occur during attacks and remission, as well as during hypothalamic stimulation.     

Neuromodulation in cluster headache. Clinical follow-up after deep brain stimulation in the posterior hypothalamus for chronic cluster headache, case report--Part II

Deep brain stimulation (DBS) of the posterior hypothalamic area is a new treatment option for patients with refractory chronic cluster headache (CCH). A review of the literature reveals that studies based on large numbers of patients, long-term observations and controlled randomised trials are still lacking. In 2006 a case report of the first patient in Germany to be operated on to allow DBS was published, and we now present a report of this patient's course in the first 6 months after the operation; in addition, a current literature review is discussed. In July 2005 a DBS lead was placed in the left posterior hypothalamic area of this 39-year-old woman with CCH. Stimulation on demand achieved complete suppression of the cluster attacks, and the patient no longer needed medication. After about 8 months a decreasing effect of the stimulation, with only about 50% reduction of cluster attacks, and stimulation-induced side effects were observed. Neither reprogramming of the stimulation parameters nor pharmacological therapy with on-demand and long-term medication reduced the frequency or severity of CCH attacks to the level experienced in the early postoperative stage. Because of intolerable subjective side effects and tension-related pain at the site of the connection cable, in September 2006 the whole system was explanted at the patient's request.DBS in the posterior hypothalamic area is an invasive treatment option for use in cases with CCH that is refractory to any pharmacological therapy. As demonstrated by this case report, it is not possible to give a prognosis concerning its long-term efficacy: despite the initial excellent benefit there can be a reduction and even a loss of the effect of stimulation. The clinical results and long-term follow-up observations of the few cases published so far need to be evaluated in a larger multicentre trial with a double-blind study design.     

Subkutane periphere Stimulation des N. occipitalis major zur Behandlung chronischer Kopfschmerzsyndrome

Medical treatment for certain chronic headache syndromes such as hemicrania continua (HC), chronic migraine (CM) or chronic cluster headache (CCH) is challenging and in many cases does not lead to sufficient pain relief or is limited by severe side effects. In the last few years neuromodulatory treatments such as subcutaneous stimulation of the greater occipital nerve or deep brain stimulation (DBS) in the hypothalamus have evolved. This report focuses on current knowledge and the results of peripheral subcutaneous nerve stimulation (SPNS) in the literature of the described headache syndromes and presents our own long-term results in ten patients. Technical details of implantation and possible complications are reported. The results between the two different stimulation types are compared. In summary, peripheral nerve stimulation of the greater occipital nerve is less invasive but also less effective in comparison to hypothalamic stimulation. However, the severity and frequency of pain attacks is significantly reduced. For other intractable headache syndromes SPNS of the greater occipital nerve offers a reasonable addition to medical treatment.     

Posterior hypothalamic and brainstem activation in hemicrania continua

OBJECTIVE: To determine the brain structures involved in mediating the pain of hemicrania continua using positron emission tomography. BACKGROUND: Hemicrania continua is a strictly unilateral, continuous headache of moderate intensity, with superimposed exacerbations of severe intensity that are accompanied by trigeminal autonomic features and migrainous symptoms. The syndrome is exquisitely responsive to indomethacin. Its clinical phenotype overlaps with that of the trigeminal autonomic headaches and migraine in which the hypothalamus and the brainstem, respectively, have been postulated to play central pathophysiologic roles. We hypothesized, based on the clinical phenotype, that hemicrania continua may involve activations in the hypothalamus, or dorsal rostral pons, or both. METHODS: Seven patients with hemicrania continua were studied in two sessions each. In one session, the patients were scanned during baseline pain and when rendered completely pain free after being administered indomethacin 100 mg intramuscularly. In the other session, the patients were scanned during baseline pain and when still in pain after being administered placebo intramuscularly. Seven age- and sex-matched nonheadache subjects acted as the control group. The scan images were processed and analyzed using SPM99. RESULTS: There was a significant activation of the contralateral posterior hypothalamus and ipsilateral dorsal rostral pons in association with the headache of hemicrania continua. In addition, there was activation of the ipsilateral ventrolateral midbrain, which extended over the red nucleus and the substantia nigra, and bilateral pontomedullary junction. No intracranial vessel dilatation was obvious. CONCLUSIONS: This study demonstrated activations of various subcortical structures, in particular the posterior hypothalamus and the dorsal rostral pons. If posterior hypothalamic and brainstem activation are considered as markers of trigeminal autonomic headaches and migrainous syndromes, respectively, then the activation pattern demonstrated in hemicrania continua mirrors the clinical phenotype, with its overlap with trigeminal autonomic headaches and migraine.     

Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series

Deep brain stimulation (DBS) of the posterior hypothalamus was found to be effective in the treatment of drug-resistant chronic cluster headache. We report the results of a multicentre case series of six patients with chronic cluster headache in whom a DBS in the posterior hypothalamus was performed. Electrodes were implanted stereotactically in the ipsilateral posterior hypothalamus according to published coordinates 2 mm lateral, 3 mm posterior and 5 mm inferior referenced to the mid-AC-PC line. Microelectrode recordings at the target revealed single unit activity with a mean discharge rate of 17 Hz (range 13–35 Hz, n  = 4). Out of six patients, four showed a profound decrease of their attack frequency and pain intensity on the visual analogue scale during the first 6 months. Of these, one patient was attack free for 6 months under neurostimulation before returning to the baseline which led to abortion of the DBS. Two patients had experienced only a marginal, non-significant decrease within the first weeks under neurostimulation before returning to their former attack frequency. After a mean follow-up of 17 months, three patients are almost completely attack free, whereas three patients can be considered as treatment failures. The stimulation was well tolerated and stimulation-related side-effects were not observed on long term. DBS of the posterior inferior hypothalamus is an effective therapeutic option in a subset of patients. Future controlled multicentre trials will need to confirm this open-label experience and should help to better define predictive factors for non-responders.     

The electrophysiology of cluster headache

Cluster headache (CH) is a neurovascular headache disease characterized by recurrent, strictly unilateral, severe pain attacks. Despite its typical clinical features, including circadian rhythm of the attacks and ipsilateral autonomic dysfunction, the underlying pathophysiology of CH is still unclear. Electrophysiological data point to central disinhibition of the trigeminal nociceptive system as one of the key mechanisms of CH pain. Therefore, altered habituation pattern and changes within trigeminal-facial neuronal circuits due to central sensitization seem to be involved. One biochemical correlate is probably represented in dysfunctions of serotonergic raphe nuclei-hypothalamic pathways. Structural and functional imaging data show an alteration of hypothalamic structures in CH patients, supporting the hypothesis that the hypothalamus, according to its function as a circadian pacemaker, plays a pivotal role in CH pathology. Cortical and brainstem reflexes are reviewed to illuminate the pathophysiology of CH.     

Hypothalamische Tiefenhirnstimulation bei Patienten mit chronischen Cluster-Kopfschmerzen

Cluster headaches involve a stereotypic symptomatic and belong to the most severe primary pain syndromes. Imaging studies have demonstrated functional and structural changes in the inferior-posterior hypothalamus ipsilateral to the pain. These changes are highly specific to the syndrome, strongly suggesting that this anatomical region is the trigger or generator of the acute attacks and/or determine the duration of the acute pain. These findings have led to the successful therapy of 19 not or difficult to treat patients with hypothalamic deep brain stimulation, resulting in long-term periods without pain and without significant side effects. Recently, however, a patient was reported who died after the operation due to increased blood pressure leading to the rupture of a previously non-diagnosed aneurysm. This article offers a translated summary of the recently published criteria of an international consensus group, which, in addition to a positive ethics vote, should be fulfilled before such deep brain stimulation of the hypothalamus is carried out in such patients.     

Mere surgery will not cure cluster headache--implications for neurostimulation

This case study concerns a patient with primary chronic cluster headache, who was unresponsive to all treatments and consecutively underwent hypothalamic deep brain stimulation (DBS). DBS had no effect on the cluster attacks, but cured an existing polydipsia as well as restlessness. However, hypothalamic DBS produced a constant, dull headache without concomitant symptoms and a high-frequent tremor. All of these effects were repeated when the stimulation was stopped and than started again. DBS had no effect on a pathological weight gain from 70?kg to 150?kg due to bulimia at night, usually during headache attacks. This case illustrates that cluster headache is, in some patients, only one symptom of a complex hypothalamic syndrome. This case also underlines that the stimulation parameters and anatomical target area for hypothalamic DBS may be too unspecific to do justice to the clinical variety of patients and concomitant symptoms. Hypothalamic DBS is an exquisite and potentially life-saving treatment method in otherwise intractable patients, but needs to be better characterised and should only be considered when other stimulation methods, such as stimulation of the greater occipital nerve, are unsuccessful.     

Electrical Stimulation of Sphenopalatine Ganglion for Acute Treatment of Cluster Headaches

(Headache 2010;50:1164‐1174) 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.     

Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension

Chronic cluster headache (CCH) is a disabling primary headache, considering the severity and frequency of pain attacks. Deep brain stimulation (DBS) has been used to treat severe refractory CCH, but assessment of its efficacy has been limited to open studies. We performed a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic DBS in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity, sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions. During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation (weekly frequency of attacks decrease >50%), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies (clinicaltrials.gov number NCT00662935).