Drug-resistant Chronic Cluster Headache Research Articles

Occipital Nerve Stimulation for Pain Modulation in Drug-Resistant Chronic Cluster Headache.

Occipital nerve stimulation (ONS) is a surgical treatment proposed for drug-resistant chronic cluster headache (drCCH). Long-term series assessing its efficacy are scarce. We designed a retrospective observational study with consecutive sampling, evaluating the follow-up of 17 drCCH patients who underwent ONS. Our main endpoint was the reduction the rate of attacks per week. We also evaluated the pain intensity through the Visual Analogue Scale (VAS), patient overall perceived improvement and decrease in oral medication intake. After a median follow-up of 6.0 years (4.5–9.0), patients decreased from a median of 30 weekly attacks to 22.5 (5.6–37.5, p = 0.012), 7.5 at 1 year (p = 0.006) and 15.0 at the end of follow-up (p = 0.041). The VAS decreased from a median of 10.0 to 8.0 (p = 0.011) at three months, to 7.0 (p = 0.008) at twelve months and 7.0 (p = 0.003) at the end of the follow-up. A total of 23.5% had an overall perceived improvement of ≥70% at 3 months, 41.2% at 1 year and 27.8% at the end of follow-up. Reducing prophylactic oral medication was possible in 76.5% and it was stopped in 17.7%. Triptan use decreased in all the responder patients and 17.7% stopped its intake. A total of 41.2% presented mild adverse events. In conclusion, our long-term experience suggests that ONS could be an interesting option for drCCH-selected patients, as it is a beneficial and minimally invasive procedure with no serious adverse events.

Long-Term Results of Deep Brain Stimulation of the Mamillotegmental Fasciculus in Chronic Cluster Headache

Background: Deep brain stimulation (DBS) and the proper target for chronic cluster headache (CCH) are still subjects of controversy. Objectives: We present our long-term results of analysis of the target and its structural connectivity. Methods: Fifteen patients with drug-resistant CCH underwent DBS in coordinates 4 mm lateral to the III ventricular wall and 2 mm behind and 5 mm below the intercommissural point. The clinical parameters recorded were the number of weekly attacks, pain intensity, and duration of the headache. Structural connectivity was studied using 3-T MR diffusion tensor imaging (DTI). Results: All of our patients improved from a mean of 39 attacks/week to 2; pain intensity decreased from 9 to 3 out of 10, and the mean cephalalgia duration decreased from 53 to 8 min. The mean stereotactic coordinates of the effective contact location were 6.1 mm lateral to the midcommissural point and 1.2 mm behind and 4.0 mm below the intercommissural point. DTI analysis showed that this target was connected to tracts and nuclei of the posterior mesencephalic tegmentum, specifically the dorsal longitudinal and mamillotegmental fasciculi. Conclusions: Our data showed DBS to be a safe and useful procedure for the treatment of drug-resistant CCH; the rate of improvement was higher than those found in other series. Although these are promising results, larger series targeting those fasciculi with a longer follow-up are needed.

Efficacy of Modified Atkins Ketogenic Diet in Chronic Cluster Headache: An Open-Label, Single-Arm, Clinical Trial.

Drug-resistant cluster headache (CH) is still an open clinical challenge. Recently, our group observed the clinical efficacy of a ketogenic diet (KD), usually adopted to treat drug-resistant epilepsies, on migraine. Here, we aim to detect the effect of KD in a group of drug-resistant chronic CH (CCH) patients. Eighteen drug-resistant CCH patients underwent a 12-week KD (Modified Atkins Diet, MAD), and the clinical response was evaluated in terms of response (≥50% attack reduction). Of the 18 CCH patients, 15 were considered responders to the diet (11 experienced a full resolution of headache, and 4 had a headache reduction of at least 50% in terms of mean monthly number of attacks during the diet). The mean monthly number of attacks for each patient at the baseline was 108.71 (SD = 81.71); at the end of the third month of diet, it was reduced to 31.44 (SD = 84.61). We observed for the first time that a 3-month ketogenesis ameliorates clinical features of CCH. www.ClinicalTrials.gov, identifier NCT03244735.

Long-term use of daily sumatriptan injections in severe drug-resistant chronic cluster headache.

Editors' Note: Based on his experience, Dr. Verslegers disagrees with “Long-term use of daily sumatriptan injections in severe drug-resistant chronic cluster headache,” which presented arguments to use sumatriptan injections on a daily basis in refractory patients with cluster headache. Instead, he suggests that ergotamine should be employed when classical treatments fail. Drs. Leone and Proietti Cecchini, authors of the study, argue that ergots are less specific than triptans, have more side effects such as nausea and vomiting, increase the risk of cardiovascular events, and can lead to ergotism when taken frequently. The authors also suggest that neurostimulation procedures can be beneficial in treating intractable chronic cluster headache. Commenting on “Cognition and neuropsychiatry in …

Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage.

Editors' Note: Based on his experience, Dr. Verslegers disagrees with “Long-term use of daily sumatriptan injections in severe drug-resistant chronic cluster headache,” which presented arguments to use sumatriptan injections on a daily basis in refractory patients with cluster headache. Instead, he suggests that ergotamine should be employed when classical treatments fail. Drs. Leone and Proietti Cecchini, authors of the study, argue that ergots are less specific than triptans, have more side effects such as nausea and vomiting, increase the risk of cardiovascular events, and can lead to ergotism when taken frequently. The authors also suggest that neurostimulation procedures can be beneficial in treating intractable chronic cluster headache. Commenting on “Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage,” Bertoux et al. point to the issue …

Invasive pericranial nerve interventions.

Background In many patients suffering from primary headaches, the available pharmacological and behavioural treatments are not satisfactory. This is a review of (minimally) invasive interventions targeting pericranial nerves that could be effective in refractory patients. Methods The interventions we will cover have in common pericranial nerves as targets, but are distinct according to their rationale, modality and invasiveness. They range from nerve blocks/infiltrations to the percutaneous implantation of neurostimulators and surgical decompression procedures. We have critically analysed the published data (PubMed) on their effectiveness and tolerability. Results and conclusions There is clear evidence for a preventative effect of suboccipital injections of local anaesthetics and/or steroids in cluster headache, while evidence for such an effect is weak in migraine. Percutaneous occipital nerve stimulation (ONS) provides significant long-term relief in more than half of drug-resistant chronic cluster headache patients, but no sham-controlled trial has tested this. The evidence that ONS has lasting beneficial effects in chronic migraine is at best equivocal. Suboccipital infiltrations are quasi-devoid of side effects, while ONS is endowed with numerous, though reversible, adverse events. Claims that surgical decompression of multiple pericranial nerves is effective in migraine are not substantiated by large, rigorous, randomized and sham-controlled trials.

Long-term use of daily sumatriptan injections in severe drug-resistant chronic cluster headache.

Chronic cluster headache (CCH) is a rare but severely debilitating condition.1 Some patients have drug-resistant CCH and continue to have daily attacks using abortive agents for long periods many times per day, mainly subcutaneous sumatriptan (SS).2 According to pharmaceutical company indications, the maximum SS dosage is 2 injections (12 mg) per day but these patients often use more. This limitation appears reasonable because of single case reports of cardiac arrest attributable to SS vasoconstrictive properties.3,4 Usually these events occur at the initial administration, and an underlying occult coronary artery disease is disclosed.3,4 Very little is known about the risk of serious adverse events (AEs) (i.e., stroke, TIA, ischemic heart disease including myocardial infarction, arrhythmia, and any other vascular disorders) when the drug is used 2 or more times per day for long periods.

O065. Drug-resistant chronic cluster headache successfully treated with supraorbital plus occipital nerve stimulation. A rare case report.

Chronic cluster headache (CCH) is a rare and extremely disabling headache syndrome with a recent clinical systematization of its clinical frame from the European Headache Federation [1]. We present a case of a young man affected by drug-resistant chronic CH (rCCH) who showed improvement after a two-time combined supraorbital and occipital nerve stimulation (S-ONS). The clinical improvement was still present at 6-month follow-up. A 37-year-old man (LB), with an 18-year history of episodic CH ab initio, was referred to our Regional Referral Headache Centre first, and then to the Pain Unit, because the headache had become chronic (CCH), and the patient suffered from daily cluster attacks (4-6/day). The patient became progressively unresponsive to prophylactic/acute therapies, including O2-therapy, verapamil up to 600 mg/ day, external vagus nerve stimulation, etc. The headache was strictly left-sided. The pain emerged at the left occipital region and migrated towards the ipsilateral eye, becoming throbbing and increasing up to 10/10. It remained fixed within the orbital area between 45 and 80 minutes, accompanied by concurrent, ipsilateral conjunctival injection and tearing. Brain magnetic resonance imaging excluded any underlying lesions. Sumatriptan 6 mg i.m. maintained over time its efficacy, but during the last year the risk of serious cardiac side effects suggested to look for an alternative treatment to reduce its harmful overuse. After careful psychological assessment, the patient was considered eligible for occipital nerve stimulation (ONS) trial. Three weeks later he was implanted with a >50%/<85% reduction of attack number and intensity of pain. Unfortunately, three months after surgery, the patient complained of a reappearance of his usual severe CH attack (VAS 10), periorbitally located. We decided to implant an additional electrocatheter stimulating bilaterally the supraorbita ln erves (SON). At six-month follow-up the patient referred suffering of 1 attack a week, of mild/moderate intensity, not altering his overall improved quality of life. ONS was efficient in most of the rCCH patients reported in the literature with low complication rates [2]. In our patient, the ONS was partially effective in relieving symptoms, achieving excellent pain relief only when supraorbital stimulation (SON) was associated [Fig. 1]. Evidence from future RCTs should support this approach in order to give guidelines for a multimodal approach to similar rare/unusual case reports. Written informed consent to publication was obtained from the patient(s).

Neurostimulators For the Treatment of Primary Headaches

Neurostimulation techniques have increased our therapeutic armamentarium, providing additional options for the treatment of patients with drug-resistant headache. Occipital nerve stimulation can be considered in drug-resistant chronic cluster headache and, with more caution, in drug-resistant chronic migraine. Approximately 12 years after its introduction, hypothalamic stimulation is a valid option for drug-resistant chronic cluster headache to be considered when occipital nerve stimulation fails. Several other peripheral stimulation approaches (in addition to occipital nerve stimulation) have been introduced in recent years; however, for the most part, appropriate studies supporting their efficacy are lacking. Transcranial magnetic stimulation, transcutaneous supraorbital nerve stimulation, sphenopalatine ganglion stimulation and vagal nerve stimulation have all been tried, but results are not wholly convincing, and more extensive evaluations are required.

A case of cluster headache treated with rotigotine: Clinical and neurophysiological correlates

Chronic cluster headache (CCH) is characterized by recurrent bouts of facial pain lasting up to 180 minutes in the absence of a long remission period. We report the case of a 43-year-old male patient with treatment-resistant CCH, who improved with administration of transdermal rotigotine. We also evaluated the nociceptive blink reflex habituation that was reduced before the treatment (as is usual in CH patients) and normalized by transdermal rotigotine. We suggest that rotigotine could represent a further therapeutic option in the treatment of drug-resistant CCH.

Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster headache

Drug-resistant chronic cluster headache (CH) is an unremitting illness with excruciatingly severe headaches that occur several times daily. Starting in 2000, a total of 19 patients with long-lasting chronic CH, with multiple daily attacks unresponsive to all known prophylactics, received stimulation of the posterior inferior hypothalamic area ipsilateral to the pain as treatment. We report long-term follow-up (median 8.7years, range 6–12years) in 17 patients. Long-lasting improvement occurred in 70% (12 of 17): 6 are persistently almost pain-free; another 6 no longer experience daily attacks but rather episodic CH interspersed with long-lasting remissions. In 5 of 6 almost pain-free patients, the stimulators have been off for a median of 3years (range 3–4years). Five patients did not improve: 4 had bilateral CH, and 3 developed tolerance after experiencing relief for 1–2years. Adverse events are electrode displacement (n=2), infection (electrode n=3; generator n=1), electrode malpositioning (n=1), transient nonsymptomatic third ventricle hemorrhage (n=1), persistent slight muscle weakness on one side (n=1), and seizure (n=1). This exceptionally long follow-up shows that hypothalamic stimulation for intractable chronic CH produces long-lasting improvement in many patients. Previous experience was limited to a median of 16months. Important new findings are as follows: stimulation is well tolerated for many years after implantation; after several years during which stimulation was necessary for relief, a persistent almost pain-free condition can be maintained when stimulation is off, suggesting that hypothalamic stimulation can change disease course; tolerance can occur after marked long-lasting improvement; and bilateral chronic CH seems to predict poor response to hypothalamic stimulation.

Management of Cluster Headache

The prevalence of cluster headache is 0.1% and cluster headache is often not diagnosed or misdiagnosed as migraine or sinusitis. In cluster headache there is often a considerable diagnostic delay - an average of 7 years in a population-based survey. Cluster headache is characterized by very severe or severe orbital or periorbital pain with a duration of 15-180 minutes. The cluster headache attacks are accompanied by characteristic associated unilateral symptoms such as tearing, nasal congestion and/or rhinorrhoea, eyelid oedema, miosis and/or ptosis. In addition, there is a sense of restlessness and agitation. Patients may have up to eight attacks per day. Episodic cluster headache (ECH) occurs in clusters of weeks to months duration, whereas chronic cluster headache (CCH) attacks occur for more than 1 year without remissions. Management of cluster headache is divided into acute attack treatment and prophylactic treatment. In ECH and CCH the attacks can be treated with oxygen (12 L/min) or subcutaneous sumatriptan 6 mg. For both oxygen and sumatriptan there are two randomized, placebo-controlled trials demonstrating efficacy. In both ECH and CCH, verapamil is the prophylactic drug of choice. Verapamil 360 mg/day was found to be superior to placebo in one clinical trial. In clinical practice, daily doses of 480-720 mg are mostly used. Thus, the dose of verapamil used in cluster headache treatment may be double the dose used in cardiology, and with the higher doses the PR interval should be checked with an ECG. At the start of a cluster, transitional preventive treatment such as corticosteroids or greater occipital nerve blockade can be given. In CCH and in long-standing clusters of ECH, lithium, methysergide, topiramate, valproic acid and ergotamine tartrate can be used as add-on prophylactic treatment. In drug-resistant CCH, neuromodulation with either occipital nerve stimulation or deep brain stimulation of the hypothalamus is an alternative treatment strategy. For most cluster headache patients there are fairly good treatment options both for acute attacks and for prophylaxis. The big problem is the diagnosis of cluster headache as demonstrated by the diagnostic delay of 7 years. However, the relatively short-lasting attack of pain in one eye with typical associated symptoms should lead the family doctor to suspect cluster headache resulting in a referral to a neurologist or a headache centre with experience in the treatment of cluster headache.

Neurostimulation therapies for primary headache disorders

Most pharmacological treatments of primary headache disorders are partially effective and have cumbersome side effects. Therapies with better efficacy and tolerance are needed. Neurostimulation techniques may have this potential. This is an attempt to summarize the latest clinical trial results published in the field. Hypothalamic deep brain stimulation is effective in drug-resistant chronic cluster headache (drCCH) but not riskless. Recent anatomical MRI studies indicate that the effective stimulation sites are rather widespread. Occipital nerve stimulation (ONS) seems to be effective in up to 76% of drCCH patients and its benefit long-lasting. A minority of patients are able to abandon preventive drugs. Its mechanism of action appears nonspecific. In chronic migraine, randomized controlled trials of ONS showed recently encouraging results, but long-term studies are missing. An ongoing sham-controlled trial suggests sphenopalatine ganglion neurostimulation (SPGS) efficacy in drCCH acute treatment, but possibly also in preventive therapy. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) modulate cortical excitability and connectivity. TMS could prevent headache when applied over the occipital cortex during the migraine aura. Repetitive TMS and tDCS have provided mixed results in a few small studies and warrant further trials. Neurostimulation therapies inaugurate a new era in headache management and offer a promising alternative to medications. Future studies are necessary to provide evidence-based efficacy data, knowledge on their mode of action and information about their pharmaco-economic advantages.

Efficacy of hypothalamic stimulation for chronic drug-resistant cluster headache

The study of Seijo et al. recently published in this journal (1) provides further convincing evidence that posterior hypothalamic stimulation can be an effective treatment for carefully selected patients with drug-resistant chronic cluster headache. All five patients had a severe condition that had not responded to either drugs or previous surgical treatments. A number of aspects of the study deserve closer examination.

Sustained Effectiveness of Occipital Nerve Stimulation in Drug-Resistant Chronic Cluster Headache

Drug-resistant chronic cluster headache (drCCH) is a devastating condition for which various invasive therapeutic procedures have been tempted without any satisfactory effect. Recent studies suggest that occipital nerve stimulation (ONS) could be an efficient preventive treatment of drCCH. We conducted a prospective pilot trial of ONS in 8 subjects suffering from drCCH with encouraging results at 15 months. However, studies on a larger population with a longest follow-up were warranted. We recruited 15 patients with drCCH according to the previously published criteria of intractability. They were implanted with suboccipital stimulators on the side of their headache. Long-term follow-up was achieved by questionnaires administered during a headache consultation and/or by phone interviews. Mean follow-up time post surgery is 36.82 months (range 11-64 months). One patient had an immediate post-operative infection of the material. Among the 14 remaining patients, 11 (i.e., ∼80%) have at least a 90% improvement with 60% becoming pain-free for prolonged periods. Two patients did not respond or described mild improvement. Intensity of residual attacks is not modified by ONS. Four patients (29%) were able to reduce their prophylaxis. The major technical problems were battery depletion due to the use of high current intensities (N = 9/14, 64%) and immediate or delayed material infection (N = 3/15, 20%). Significant electrode migration was only seen in 1 patient. Clinical peculiarities during the ONS follow-up period were side shift with infrequent contralateral attacks (N = 5/14, 36%), and/or isolated ipsilateral autonomic attacks without pain (N = 5/14, 36%). Two patients found ONS-related paresthesias unbearable: one had his stimulator removed, and the other switched it off although he was objectively ameliorated. Subjectively, 9 patients are very satisfied by ONS and 3 patients moderately satisfied. Effective stimulation parameters varied between patients. Our long-term follow-up confirms the efficacy of ONS in drCCH, which remains a safe and well-tolerated technique. The occurrence of contralateral attacks and isolated autonomic attacks in nearly 50% of ONS responders may have therapeutic and pathophysiological implications.

Neuromodulation in drug-resistant primary headaches: what have we learned?

In the last years neurostimulation procedures have been introduced to treat primary neurovascular headaches, namely cluster headache and migraine. Hypothalamic stimulation is now accepted as therapeutic procedure to treat drug-resistant chronic cluster headache when patients suffer from daily multiple attacks. The inadequacy of the definition of the term "chronic" according to the International Headache Society criteria for both cluster headache and migraine when it is used to select patients for neurostimulation procedures is now evident. On the same side, there is no agreement about the use of the term "drug-resistant" again when it is used to select patients for neurostimulation procedures. We have proposed that only patients suffering from daily neurovascular headaches in the last 1-2years, with complete drug-resistance should be proposed for invasive procedures.

Central modulation in cluster headache patients treated with occipital nerve stimulation: an FDG-PET study

BackgroundOccipital nerve stimulation (ONS) has raised new hope for drug-resistant chronic cluster headache (drCCH), a devastating condition. However its mode of action remains elusive. Since the long delay to meaningful effect suggests that ONS induces slow neuromodulation, we have searched for changes in central pain-control areas using metabolic neuroimaging.MethodsTen drCCH patients underwent an 18FDG-PET scan after ONS, at delays varying between 0 and 30 months. All were scanned with ongoing ONS (ON) and with the stimulator switched OFF.ResultsAfter 6-30 months of ONS, 3 patients were pain free and 4 had a ≥ 90% reduction of attack frequency (responders). In all patients compared to controls, several areas of the pain matrix showed hypermetabolism: ipsilateral hypothalamus, midbrain and ipsilateral lower pons. All normalized after ONS, except for the hypothalamus. Switching the stimulator ON or OFF had little influence on brain glucose metabolism. The perigenual anterior cingulate cortex (PACC) was hyperactive in ONS responders compared to non-responders.ConclusionsMetabolic normalization in the pain neuromatrix and lack of short-term changes induced by the stimulation might support the hypothesis that ONS acts in drCCH through slow neuromodulatory processes. Selective activation in responders of PACC, a pivotal structure in the endogenous opioid system, suggests that ONS could restore balance within dysfunctioning pain control centres. That ONS is nothing but a symptomatic treatment might be illustrated by the persistent hypothalamic hypermetabolism, which could explain why autonomic attacks may persist despite pain relief and why cluster attacks recur shortly after stimulator arrest. PET studies on larger samples are warranted to confirm these first results.

Sphenopalatine endoscopic ganglion block in cluster headache: a reevaluation of the procedure after 5 years

Cluster headache (CH) is considered the most painful form of primary headaches. It is characterized by severe unilateral pain, typically associated with autonomic manifestations and may be divided into an episodic and a chronic form. The latter is often resistant to a multitude of medication and is, therefore, very hard to treat. In 2002, our group developed a technique for the endoscopic sphenopalatine ganglion block that was able to ameliorate the symptoms in 55% of drug-resistant chronic CH patients. This paper is intended as an update on the technique as well as a comparison in effectiveness to our prior approach.

Hypothalamic deep brain stimulation in the treatment of chronic cluster headache

Cluster headache (CH) is a short-lasting unilateral headache associated with ipsilateral craniofacial autonomic manifestations. A positron emission tomography (PET) study has shown that the posterior hypothalamus is activated during CH attacks, suggesting that hypothalamic hyperactivity plays a key role in CH pathophysiology. On this basis, stimulation of the ipsilateral posterior hypothalamus was hypothesized to counteract such hyperactivity to prevent intractable CH. Ten years after its introduction, hypothalamic stimulation has been proved to successfully prevent attacks in more than 60% of 58 hypothalamic implanted drug-resistant chronic CH patients. The implantation procedure has generally been proved to be safe, although it carries a small risk of brain haemorrhage. Long-term stimulation is safe, and nonsymptomatic impairment of orthostatic adaptation is the only noteworthy change. Microrecording studies will make it possible to better identify the target site. Neuroimaging investigations have shown that hypothalamic stimulation activates ipsilateral trigeminal complex, but with no immediate perceived sensation within the trigeminal distribution. Other studies on the pain threshold in chronically stimulated patients showed increased threshold for cold pain in the distribution of the first trigeminal branch ipsilateral to stimulation. These studies suggest that activation of the hypothalamus and of the trigeminal system are both necessary, but not sufficient to generate CH attacks. In addition to the hypothalamus, other unknown brain areas are likely to play a role in the pathophysiology of this illness. Hypothalamus implantation is associated with a small risk of intracerebral haemorrhage and must be performed by an expert neurosurgical team, in selected patients.

Commentary on Fontaine et al.: 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

Among primary headaches, cluster headache is certainly the most painful and unbearable, particularly for the patients suffering from its chronic form. It is characterized by attacks of unilateral periorbital, frontal and/or temporal pain associated with ipsilateral autonomic signs (ptosis, miosis, conjunctival injection, tearing, rhinorrhoea, nasal congestion). Its episodic form is characterized by bouts (clusters) of weeks or months, separated by headache-free intervals of variable length (months or years), but in chronic cluster headache (CCH), which affects almost 10% of patients, the attacks persist for at least 1 year without remission, or with remissions lasting less than 1 month [1]. These patients often require one or more preventive drugs for relief, such as steroids, verapamil, lithium carbonate and methysergide. Unfortunately, about 1% of CCH patients become refractory to all existing pharmacological treatments. In fact, suffering from intractable CCH is an atrocious condition, which affects every aspect of the patients’ lives, and may even push some of them to commit suicide as the ultimate desperate solution to avoid pain. Thus, it is imperative for headache clinicians and researchers, to test any possible remedy to this condition by invasive and non-invasive surgical procedures when pharmacological remedies have failed. Over the years, many such procedures have been used, such as radiofrequency lesions, glycerol injections or balloon compressions of the gasserian ganglion, gamma knife surgery or root section of the trigeminal nerve, trigeminal tractotomy, lesions of the nervus intermedius or greater superficial petrosal nerve, blockade or radiofrequency lesions of the pterygopalatine ganglion, and microvascular decompression of the trigeminal nerve combined with nervus intermedius section [2]; none of these have displayed satisfactory long-term results. In addition, when neuromodulation methods were first applied with success in some cases of intractable CCH [3], they immediately had a great resonance in the scientific community and aroused great hope in affected patients. The neuromodulation techniques used up to now are deep brain stimulation (DBS) of the ventro-posterior hypothalamus [3–6] and occipital nerve stimulation [7, 8]. Observational studies of hypothalamic DBS (hBDS) seemed to report slightly better results, but also more serious side effects, culminating in fatal cerebral haemorrhage in one patient. Because of this potential risk of hDBS procedures, it is of uttermost importance to carefully select CCH patients to whom hDBS will be proposed and to provide evidence-based proof of its clinical efficacy. Criteria defining drug-resistant chronic cluster headache (iCCH) patients are based on experts’ opinion and widely accepted [9, 10]. The consensus is that patients cannot be considered drug-resistant unless drugs known to be effective in cluster headache and belonging to at least three different pharmacological classes have been administered at a sufficient dose and for a sufficient time. In two studies [5, 6], attack recurrence at varying delays was described when the stimulator was switched off or when the battery ran flat, suggesting that the clinical effect was probably not due to the natural history of the disorder. Since the stimulation is not perceived by the patient, these observations also do not favour a placebo effect, although they cannot rule it out [11]. A placebo-controlled study was A. Ambrosini (&) Headache Clinic, INM Neuromed, IRCCS, Pozzilli (Isernia), Italy e-mail: anna.ambrosini@neuromed.it