Drug-resistant Cluster Headache Research Articles

Gamma Knife radiosurgery for the treatment of cluster headache: a systematic review.

Cluster headache (CH) is a severe trigeminal autonomic cephalalgia that, when refractory to medical treatment, can be treated with Gamma Knife radiosurgery (GKRS). The outcomes of studies investigating GKRS for CH in the literature are inconsistent, and the ideal target and treatment parameters remain unclear. The aim of this systematic review is to evaluate the safety and the efficacy, both short and long term, of GKRS for the treatment of drug-resistant CH. A systematic review of the literature was performed to identify all clinical articles discussing GKRS for the treatment of CH. The literature review revealed 5 studies describing outcomes of GKRS for the treatment of CH for a total of 52 patients (48 included in the outcome analysis). The trigeminal nerve, the sphenopalatine ganglion, and a combination of both were treated in 34, 1, and 13 patients. The individual studies demonstrated initial meaningful pain reduction in 60-100% of patients, with an aggregate initial meaningful pain reduction in 37 patients (77%). This effect persisted in 20 patients (42%) at last follow-up. Trigeminal sensory disturbances were observed in 28 patients (58%) and deafferentation pain in 3 patients (6%). Information related to GKRS for CH are limited to few small open-label studies using heterogeneous operative techniques. In this setting, short-term pain reduction rates are high, whereas the long-term results are controversial. GKRS targeted on the trigeminal nerve or sphenopalatine ganglion is associated to a frequent risk of trigeminal disturbances and possibly deafferentation pain.

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.

Efficacy of transdermal rotigotine in chronic cluster headache: A case series

Cluster headache (CH) is one of the most severe forms of headache, but the number of effective treatments is still limited. Recently, we reported the case of a drug-resistant CH patient responsive to the rotigotine transdermal patch, which is used in the treatment of Parkinson’s disease. This report formed the basis for a case series where other drug-resistant CH patients were treated with rotigotine. Here are the results of this study. Twenty-two CH patients underwent the treatment. Eight were episodic cluster headache (ECH) patients and 14 were chronic cluster headache (CCH) patients. Of the eight ECH patients, four reported that their CH had been stopped by the treatment. Of the 14 CCH patients, 11 were considered responders to the treatment (5 experienced a full resolution of headache, and 6 had a headache reduction of at least 50% in terms of mean monthly number of attacks). Our case series confirms the previous observation that rotigotine could be helpful in the treatment of CH. It may even influence the monoaminergic system that has a key role in the pathogenesis of CH.

O060. Rotigotine improves drug-resistant cluster headache: a case series.

Cluster headache (CH) is a severe form of primary headache, characterized by trigeminal-autonomic system activation. Bouts, lasting 15-180 minutes, occur 1-8 times a day, for a period persisting for weeks or months, followed by a full remission. However, about 10-15% of patients have no remission periods and their CH is defined chronic (CCH). While symptomatic treatment is often effective, preventive treatments are limited. Our group has already reported the case of a patient affected by refractory CCH who underwent a complete and sustained response to rotigotine, a non-ergoline D3-like receptor agonist, also with a 5HT1A effect, administrated by transdermal patches. Here we report a case series of patients that have tried transdermal rotigotine for their drug-resistant CH.

O045. Cluster headache improvement during Ketogenic Diet.

Ketogenic diet (KD) is a valid treatment for drug-resistant epilepsy, recently proposed as effective also in migraine. Hitherto, no data are available about KD effects on cluster headache (CH), a severe form of primary headache, characterized (similarly to migraine) by a trigemino-vascular activation. Prophylaxis drug-resistant patients have a great need for care and could seek help in invasive treatments and/or alternative drugs, such as illegal substances. Here we performed a prospective observational study of the potential beneficial ketogenesis-induced effects on CH, studying a group of consecutive drug-resistant CH patients.

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.

Deep Brain Stimulation in Trigeminal Autonomic Cephalalgias

Cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT syndrome) are primary headaches grouped together as trigeminal autonomic cephalalgias (TACs). All are characterized by short-lived unilateral head pain attacks associated with oculofacial autonomic phenomena. Neuroimaging studies have demonstrated that the posterior hypothalamus is activated during attacks, implicating hypothalamic hyperactivity in TAC pathophysiology and suggesting stimulation of the ipsilateral posterior hypothalamus as a means of preventing intractable CH. After almost 10 years of experience, hypothalamic stimulation has proved successful in preventing pain attacks in approximately 60% of the 58 documented chronic drug-resistant CH patients implanted at various centers. Positive results have also been reported in drug-resistant SUNCT and PH. Microrecording studies on hypothalamic neurons are increasingly being performed and promise to make it possible to more precisely identify the target site. The implantation procedure has generally proved safe, although it carries a small risk of brain hemorrhage. Long-term stimulation is proving to be safe: studies on patients under continuous hypothalamic stimulation have identified nonsymptomatic impairment of orthostatic adaptation as the only noteworthy change. Studies on pain threshold in chronically stimulated patients show increased threshold for cold pain in the distribution of the first trigeminal branch ipsilateral to stimulation. When the stimulator is switched off, changes in sensory and pain thresholds do not occur immediately, indicating that long-term hypothalamic stimulation is necessary to produce sensory and nociceptive changes, as also indicated by clinical experience that CH attacks are brought under control only after weeks of stimulation. Infection, transient loss of consciousness, and micturition syncope have been reported, but treatment interruption usually is not required.

Cluster headache and TACs: rationale for central and peripheral neuromodulation

Cluster headache, the most severe of primary headache conditions for functional and social impairment it provokes, has been recently the object of a great amount of clinical, physiopathological, surgical and functional neuroradiological studies aimed to uncover the real mechanisms which underlie its disabling manifestations. Refinement of methodological and systematic features of multidisciplinary researches in this field has been allowing for more and more precise delineations of the role of both peripheral and central nervous system's contribution in pathophysiology of the disease. Aim of this manuscript is the report of the present knowledge in the role of the different surgical options in the treatment of drug-resistant cluster headache and Short-lasting Unilateral neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT), which take into account their different hypothesized pathological mechanisms and which comprise central nervous system's approach (Deep Brain Stimulation [DBS] and peripheral approach, namely Occipital Nerve Stimulation (ONS) and Vagal Nerve Stimulation (VNS).

Costs of hypothalamic stimulation in chronic drug-resistant cluster headache: preliminary data

In about 20% of chronic cluster headache (CH) cases, drugs may become ineffective. Under these circumstances, steroids and triptans are frequently employed leading to fearful side effects in one and high costs in the other. The direct costs of drug-resistant chronic CH are mainly due to frequent medical consultations and frequent use of expensive drugs. In recent years, hypothalamic stimulation has been employed to treat drug-resistant chronic CH patients suffering multiple daily attacks and long-term results from different centres show a 60% overall benefit. Nine years since the introduction of this technique, we attempt a preliminary analysis of the direct costs of hypothalamic stimulation based on patients treated at our centre. We estimated the following direct costs as follows: cost of neurosurgery plus cost of equipment (electrode, connection and impulse generator = 25,000 euro), cost of hospital admissions in long-term follow-up (2,000 euro per admission), cost of single sumatriptan injection (25 euro). Number of daily sumatriptan injections in the year before and for each year after hypothalamic implantation was obtained from headache diaries. To estimate the saving due to the reduction in sumatriptan consumption following hypothalamic stimulation, we calculated the following for each year of follow-up after surgery: number of sumatriptan injections in the year before surgery minus number of sumatriptan injections in each year, updated to December 2008. In our 19 implanted patients, the costs of neurosurgery plus cost of equipment were 475,000 euro; the costs of hospital admissions during follow up were 250,000 euro. Reduction in sumatriptan consumption resulted in a total saving of 3,573,125 euro. Hence, in our 19 patients, the sumatriptan saving (3,573,125 euro) minus the direct costs due to operation and follow up hospitalisations (475,000 + 250,000) euro is equal to 2,848,125 euro. These preliminary results indicate that hypothalamic stimulation is associated with marked reduction of direct costs in the management of complete drug-resistant chronic CH.

Cluster headache: from treatment to pathophysiology

This key note lecture illustrates the role of clinical developments in stimulating research and discovery in the area of the pathophysiology of cluster headache (CH) and other trigeminal autonomic cephalalgias (TACs), reviewing the physiological, biochemical and neuroimaging data that have suggested involvement of the hypothalamus in CH pathogenesis. These findings suggested the use of deep brain stimulation as a treatment for chronic drug-resistant CH. The typical circadian and circannual periodicity of CH attacks were the fundamental clinical characteristics that shifted focus from peripheral hypotheses to the idea of central origin for this headache form. Functional neuroimaging demonstrated that TACs are associated with activation of the posterior hypothalamus and there is clinical evidence that patients who suffer from CH have altered biological rhythms. Furthermore, the principal seat of biorhythm regulation - the hypothalamus - is known to have a modulatory role on nociceptive and autonomic pathways, specifically trigemino-vascular nociceptive pathways. Future research will elucidate why neuromodulatory approaches are effective in CH and other TACs, determine whether the hypothalamus is itself the generator of CH attacks, or whether it is activated in response to a generator situated elsewhere, and identify pharmacological treatments that directly target the hypothalamus.

Investigation of the T3111C CLOCK gene polymorphism in cluster headache

Sirs: Cluster headache (CH) is a primary headache characterized by severe unilateral pain, ipsilateral autonomic symptoms and, in many cases, restlessness. The etiology of CH is still unclear, although clinical, endocrine and neuroimaging studies implicate the hypothalamus. Hypothalamic involvement is also supported by the efficacy of stereotactic deep brain stimulation of the posterior hypothalamic area in chronic drug resistant CH [1]. The increased familial risk of CH suggests a genetic liability with inheritance likely to be autosomal dominant with low penetrance, although autosomal recessive or multifactorial inheritance have also been suggested in some families [2]. A polymorphism of the hypocretin receptor 2 gene has recently been associated with CH [3], a remarkable association since hypocretin-containing cells are located exclusively in the posterolateral hypothalamus. A striking feature of CH is its diurnal and seasonal periodicity, suggesting that circadian and infradian rhythms regulate CH attacks. Polymorphisms in the CLOCK gene, a highly conserved circadian gene, influence the circadian phase in humans [4] and circadian mood fluctuations in bipolar patients [5]. We performed a genetic association study to evaluate whether the T3111C CLOCK polymorphism (also known as T3092C) might be related to CH susceptibility under the assumption of autosomal dominant inheritance. A total of 101 consecutive, unrelated Italian patients (79 men and 22 women) with CH (85 episodic and 16 chronic CH) gave informed consent to the study. All patients were diagnosed after direct interview by a neurologist expert in headache disorders and according to ICHD-II criteria [6]. Of the 101 patients, 87 described a clear circadian rhythmicity of the attacks. 100 healthy individuals, in whom CH and migraine were excluded by direct interview, served as controls. The control sample came from the same geographical region as the CH patients. We analyzed a single nucleotide polymorphism, T3111C, in the 3’ flanking region of the CLOCK gene [4]. DNA was extracted from whole blood by standard methods [7]. PCR primers and methods were those reported by Katzenberg et al. [4]. The T3111C polymorphism was detected by enzymatic digestion with Sdu I (Fermentas) and electrophoresed on MetaPhor agarose 2 % gel. The allelic and genotypic frequencies were compared by means of the Fisher’s exact test. The Hardy-Weinberg equilibrium was verified for all tested populations, and alleles were in Hardy-Weinberg equilibrium in both controls and patients. We found no significant difference in allelic and genotypic frequencies between the total CH patient group and the control subjects (χ2 = 1.261, p = 0.261; χ2 = 5.791, p = 0.055) (Table 1). Nor was a significant difference found when considering the 87 CH patients with circadian rhythmicity of the attacks alone. Our study does not support the hypothesis that the T3111C CLOCK polymorphism is associated with CH. It therefore strengthens the similar negative results reported previously by Rianero et al. [8]. Our analysis moreover resulted in nonsignificant differences when the 87 CH patients reporting a clear periodicity of the attacks were considered separately. It thus appears that CLOCK gene T3111C polymorphism does not influence CH, but our result of course cannot exclude that polymorphic variations at other biological rhythm genes LETTER TO THE EDITORS