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.     

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.     

Hypothalamic deep-brain stimulation: target and potential mechanism for the treatment of cluster headache

Recently, functional imaging data have underscored the crucial role of the hypothalamus in trigemino-autonomic headaches, a group of severe primary headaches. This prompted the application of hypothalamic deep-brain stimulation (DBS), with the intention to preventing cluster headache (CH) attacks in selected severe therapy-refractory cases. To date, a total of 50 operated intractable CH patients, one patient with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and three with atypical facial pain, have been reported. However, it is not apparent why the spontaneous bursts of activation in the inferior posterior hypothalamus result in excruciating head pain, whereas continuous electrical stimulation of the identical area is able to prevent these attacks. Recently, this issue has been addressed by examining 10 operated chronic CH patients, using H₂¹⁵O-positron emission tomography and alternately switching the hypothalamic stimulator on and off. The stimulation-induced activation in the ipsilateral posterior inferior hypothalamic grey (the site of the stimulator tip) as well as activation and de-activation in several cerebral structures belonging to neuronal circuits usually activated in pain transmission. These data argue against an unspecific antinociceptive effect or pure inhibition of hypothalamic activity as the mode of action of hypothalamic DBS and suggest functional modulation of the pain-processing network.     

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.     

CLUSTER

The authors observed a high rate of suicide (6/140 patients, 4.3%) in a large cohort of patients with movement disorders treated with deep brain stimulation (DBS). Apparent risk factors included a previous history of severe depression and multiple successive DBS surgeries, whereas there was no relationship with the underlying condition, DBS target, electrical parameters, or modifications of treatment. Paradoxically, all patients experienced an excellent motor outcome following the procedure. The authors propose that patients at high risk for suicide should be excluded from DBS surgery.
Comment: I included this abstract because of the patients treated with DBS for cluster in Italy and Belgium. The Italian experience has been "five patients operated on … for chronic intractable cluster with the stimulator in the cluster hypothalamic generator with good results and "no relevant side effects" (Leone M, May A, Franzini A, Broggi G, Dodick D, Rapoport A, Goadsby PJ, Schoenen J, Bonavita V, and Bussone G. Deep brain stimulation for intractable chronic cluster headache: proposals for patient selection. Cephalalgia. 2004;24: 934-937) . The Belgian experience " was uneventful in 4 of 5 patients … Unfortunately, one patient developed massive brainstem and basal ganglia hemorrhage 4 hours after surgery and died after 2 days … " (Vendenheede M, Maertens de Noordhout AS, Remacle JM, Mouchamps M, Schoenen J. Deep Brain Stimulation of Posterior Hypothalamus in Chronic Cluster Headache. Neurology. 2004; 62(Suppl5):A356). Add to that death the above concern on suicide, and it is clear that patient selection will be crucial in deciding whether to do this surgery, should it become available in North America, and even then, the hemorrhage and death risk must be confronted.—Stewart J. Tepper, MD     

Chronic cluster headache: New and emerging treatment options

Cluster headache (CH) is a primary headache syndrome characterized by short-lasting unilateral head pain attacks accompanied by ipsilateral oculofacial autonomic phenomena. Approximately 20% of CH patients have the chronic form and need continuous medical care. In the chronic form, attacks continue unabated for years, often on a daily basis, resulting in severe debilitation. It is a common experience that drug treatments are able to control or prevent the attacks in approximately 80% of chronic CH patients. In the remaining 20% of chronic cases, drugs are ineffective. Until recently, the etiology of CH was poorly understood and this hampered the development of new therapies. However, we have now gained a much improved understanding of the peripheral and central mechanisms giving rise to the pain in CH and this has inspired the development of new treatment approaches, which, although still in the initial phases of validation, appear to be very promising. Among these, the novel approach based on hypothalamic deep brain stimulation is one of the most promising.     

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.     

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.     

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.     

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.     

Cluster headache as a manifestation of intracranial inflammatory myofibroblastic tumour: a case report with pathophysiological considerations

We report a patient with a secondary form of chronic cluster headache, caused by an intracranial presentation of inflammatory myofibroblastic pseudotumour located in the posterior fossa, with total remission of the pain after resection. The headaches were resistant to many of the usual treatments for cluster headache. The patient had two normal computed tomography scans and one normal magnetic resonance imaging of the head before the additional diagnosis of brain tumour was made. This is an unusual cause of cluster headache with intracranial mass, with an unexpected clinical presentation, a rare triggering manoeuvre, unusual pathology and successful treatment. This patient probably had the hypothalamic biological predisposition to cluster headache and, when a small mass disturbed pain-sensitive structures in the posterior fossa, it excited the trigeminovascular system via posterior fossa trigeminal and upper cervical afferents, and triggered the pathophysiological processes that resulted in a secondary form of chronic cluster headache.     

Cluster headache syndrome. Ways to abort or ward off attacks.

Cluster headache is a syndrome of severe head and facial pain accompanied by autonomic abnormalities. Men are affected more frequently than women. Headaches occur daily during periods of susceptibility, which may be followed by periods of remission. The etiology of cluster headache is uncertain. Recent work suggests that hypothalamic dysfunction and/or oxyhemoglobin desaturation may be involved in its pathogenesis. Effective medical regimens are available for aborting acute attacks and for preventing attacks. Surgical ablation of the trigeminal ganglion has been effective in some patients when conventional medical therapy has failed.     

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.     

Testosterone replacement therapy for treatment refractory cluster headache

OBJECTIVES: To describe the clinical characteristics and laboratory findings of cluster headache patients whose headaches responded to testosterone replacement therapy. BACKGROUND: Current evidence points to hypothalamic dysfunction, with increased metabolic hyperactivity in the region of the suprachiasmatic nucleus, as being important in the genesis of cluster headaches. This is clinically borne out in the circadian and diurnal behavior of these headaches. For years it has been recognized that male cluster headache patients appear overmasculinized. Recent neuroendocrine and sleep studies now point to an association between gonadotropin and corticotropin levels and hypothalamically entrained pineal secretion of melatonin. RESULTS: Seven male and 2 female patients, seen between July 2004 and February 2005, and between the ages of 32 and 56, are reported with histories of treatment resistant cluster headaches accompanied by borderline low or low serum testosterone levels. The patients failed to respond to individually tailored medical regimens, including melatonin doses of 12 mg a day or higher, high flow oxygen, maximally tolerated verapamil, antiepileptic agents, and parenteral serotonin agonists. Seven of the 9 patients met 2004 International Classification for the Diagnosis of Headache criteria for chronic cluster headaches; the other 2 patients had episodic cluster headaches of several months duration. After neurological and physical examination all patients had laboratory investigations including fasting lipid panel, PSA (where indicated), LH, FSH, and testosterone levels (both free and total). All 9 patients demonstrated either abnormally low or low, normal testosterone levels. After supplementation with either pure testosterone in 5 of 7 male patients or combination testosterone/estrogen therapy in both female patients, the patients achieved cluster headache freedom for the first 24 hours. Four male chronic cluster patients, all with abnormally low testosterone levels, achieved remission. CONCLUSIONS: Abnormal testosterone levels in patients with episodic or chronic cluster headaches refractory to maximal medical management may predict a therapeutic response to testosterone replacement therapy. In the described cases, diurnal variation of attacks, a seasonal cluster pattern, and previous, transient responsiveness to melatonin therapy pointed to the hypothalamus as the site of neurological dysfunction. Prospective studies pairing hormone levels and polysomnographic data are needed.     

Treatment of the Patient with Refractory Headache

Purpose of Review

To review recent studies outlining the management of refractory primary headache patients, including emerging therapies such as neuromodulation. This includes both noninvasive and invasive neuromodulation techniques. Recent studies on the management of medication overuse headache were also reviewed.

Recent Findings

There is no consensus as yet on the definitions of refractory chronic migraine and chronic cluster headache although there is broad agreement on some aspects of these terms. The importance of identifying medication overuse headache and dealing effectively with it has been highlighted in several studies although there is still not consensus on how best to achieve the cessation of medication overuse. Some recommend the use of preventative medication together with medication cessation, while others do not. Recent studies on neuromodulation have used both noninvasive vagal nerve stimulation as well invasive techniques. Recent studies using noninvasive vagal nerve stimulation for chronic migraine have been disappointing although the data in chronic cluster headache are more encouraging. Similarly, recent studies on occipital nerve stimulation have again been more positive in chronic cluster headache and generally negative in chronic migraine.

Summary

In recent years, new forms of neuromodulation have emerged and long-term follow-up data from previous invasive neuromodulation techniques have become available. The sphenopalatine ganglion has been increasingly targeted by various interventions in several different headache types. Sphenopalatine ganglion stimulation is yielding encouraging data for the treatment of chronic cluster headache. New studies and long-term follow-up data from previous studies have provided further evidence for the benefit of deep brain stimulation for refractory chronic cluster headache although the exact target location is still debated. Data from phase 3 trials using CGRP monoclonal antibodies in chronic migraine and chronic cluster headache, if positive, may herald a long overdue, new and effective treatment for our refractory headache patients.

     

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.     

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).     

Chronischer Clusterkopfschmerz

Chronic cluster headache is a devastating pain condition where invasive methods such as occipital or deep brain stimulation are discussed when the condition is medically intractable. These methods are expensive but may well be economically reasonable if medications such as triptans can be reduced. However, little is known about how much a cluster headache costs, even if only primary parameters such as costs of medication, doctors and diagnostics are considered. We describe a patient with a secondary chronic cluster headache who over the course of 10 years prospectively recorded every single attack as well as all expenses for his condition. In these 10 years he suffered a total of 5,447 attacks and the overall medical expenses amounted to 60,667 EUR, the predominant part of which was caused by costs due to the cluster headache itself (47,030 EUR, 77.5%). The inhalation of oxygen accounted for the lion’s share     

Childhood Onset Cluster Headaches

Cluster headaches are rare in childhood. We identified 35 patients with cluster headaches starting at or before 18 years of age, including 7 patients with onset prior to age 10. All patients met the criteria of the International Headache Society for episodic or chronic cluster headaches. Patients experienced cluster headaches for as long as 20 years before seeking medical attention and required many medical contacts to establish the correct diagnosis. The clinical features of cluster headaches during childhood were similar to those which typically occur in adult life. Cluster headache patterns changed over 18 years of follow up. The frequency and duration of cluster periods increased in 14 subjects. The frequency of single headache attacks during cluster periods also increased in a similar number of subjects. We conclude that cluster headaches starting in childhood or adolescence closely resemble the adult form of the disease. In many patients, the frequency and duration of cluster periods and the frequency of the individual headache episodes increased over time. Cluster headache represent a treatable under-recognized cause of severe headaches in childhood and adolescence.     

Non-invasive Neuromodulation in Primary Headaches

Purpose of Review

There is growing interest in neuromodulation for primary headache conditions. Invasive modalities such as occipital nerve stimulation, deep brain stimulation and sphenopalatine ganglion stimulation are reserved for the most severe and intractable patients. Non-invasive options such as vagal nerve stimulation (nVNS), supraorbital nerve stimulation (nSONS) and transcranial magnetic nerve stimulation (TMS) have all emerged as potentially useful headache treatments. This review examines the evidence base for non-invasive neuromodulation in trigeminal autonomic cephalalgias and migraine.

Recent Findings

Although a number of open-label series of non-invasive neuromodulation devices have been published, there is very little controlled evidence for their use in any headache condition. Open-label evidence suggests that nVNS may have a role in the prophylactic treatment of cluster headache and there is limited evidence to suggest it may be useful in the acute treatment of cluster and potentially migraine attacks. There is limited controlled evidence to suggest a role for nSONS in the prophylactic treatment of episodic migraine but there is no evidence to support its use in cluster headache. TMS may be efficacious in the acute treatment of episodic migraine has no controlled evidence to support its use as a preventative in any headache condition.

Summary

Non-invasive neuromodulation techniques are an attractive treatment option with excellent safety profiles but their use is not yet supported by high-quality randomised controlled trials.