Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study

Background Clinical observations and results from recent studies support the use of non-invasive vagus nerve stimulation (nVNS) for treating cluster headache (CH) attacks. This study compared nVNS with a sham device for acute treatment in patients with episodic or chronic CH (eCH, cCH). Methods After completing a 1-week run-in period, subjects were randomly assigned (1:1) to receive nVNS or sham therapy during a 2-week double-blind period. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 minutes after treatment initiation, without rescue treatment. Results The Full Analysis Set comprised 48 nVNS-treated (14 eCH, 34 cCH) and 44 sham-treated (13 eCH, 31 cCH) subjects. For the primary endpoint, nVNS (14%) and sham (12%) treatments were not significantly different for the total cohort. In the eCH subgroup, nVNS (48%) was superior to sham (6%;p<0.01). No significant differences between nVNS (5%) and sham (13%) were seen in the cCH subgroup. Conclusions Combing both eCH and cCH patients, nVNS was no different to sham. For the treatment of CH attacks, nVNS was superior to sham therapy in eCH but not in cCH. These results confirm and extend previous findings regarding the efficacy, safety, and tolerability of nVNS for the acute treatment of eCH

Cluster headache and arachnoid cyst.

BACKGROUND: Cluster headache is a primary headache by definition not caused by any known underlying structural pathology. However, symptomatic cases have been described, e.g. tumours, particularly pituitary adenomas, malformations, and infections/inflammations. The evaluation of cluster headache is an issue unresolved. CASE DESCRIPTION: We present a case of a 43-year-old patient who presented with a 2-month history of side-locked attacks of pain located in the left orbit. He satisfied the revised International Classification of Headache Disorders criteria for cluster headache. His medical and family histories were unremarkable. There was no history of headache. A diagnosis of cluster headache was made. The patient responded to symptomatic treatment. Computer tomography and enhanced magnetic resonance imaging after 1 month displayed a supra- and intrasellar arachnoid cyst with mass effect on adjacent structures. After operation, the headache attacks resolved completely. DISCUSSION AND EVALUATION: Although we cannot exclude an unintentional comorbidity, in our opinion, the co-occurrence of an arachnoid cyst with mass effect with unilateral headache, in a hitherto headache-free man, points toward the fact that in this case the CH was caused or triggered by the AC. The headache attacks resolved completely after the operation and the patient also remained headache free at the follow-up. The response of the headache to sumatriptan and other typical CH medications does not exclude a secondary form. Symptomatic CHs responsive to this therapy have been described. Associated cranial lesions such as tumours have been reported in CH patients and the attacks may be clinically indistinguishable from the primary form. CONCLUSIONS: Neuroimaging, preferably contrast-enhanced magnetic resonance imaging should always be considered in patients with cluster headache despite normal neurological examination. Late-onset cluster headache represents a condition that requires careful evaluation. Supra- and intrasellar arachnoid cyst can present as cluster headache

Aspects of inflammation and nitric oxide in cluster headache

Cluster Headache (CH) is an uncommon headache disorder, with severe implications for the individual patient. The headache is excruciating, unilateral and appearing in attacks. It is common that CH patients show ipsilateral associated symptoms, like for example conjunctival injection, lacrimation and nasal congestion. The pathophysiology of CH is still not completely understood. The overall objective of this thesis was to explore if inflammation and nitric oxide participate in the pathophysiology of CH. Study I The aim of study I was to identify differentially expressed genes during clinical phases of CH, assuming that changes of pathophysiological importance would also be observed in peripheral venous blood. Blood samples were drawn at 3 consecutive occasions from 3 episodic CH patients: during attacks, between attacks and in remission, and at 1 occasion from 3 matched controls. Global gene expression was analyzed with microarray tehnology using the Affymetrix Human Genome U133 2.0 Plus GeneChip® Set. In addition, quantitative RT-PCR on S100P gene expression was analyzed in 6 patients and 14 controls. Small differences were seen intraindividually and large differences interindividually. Intraindividual comparisons showed upregulation of severaS100 calcium binding proteins; S100A8 (calgranulin A), S100A12 (calgranulin C), and S100P during active phase of the disease compared to remission. The S100A8 and S100A12 proteins are considered markers of noninfectious inflammatory disease, while increased levels of S100P have been associated to different forms of cancer. RT-PCR analysis of S100P confirmed the Affymetrix´ results. Study II We investigated the cytokine interleukin-2 (IL-2) as a possible marker of immune system involvement in the pathophysiology of CH. Eight episodic CH patients and 16 healthy headache-free control subjects matched for age and gender were studied. Venous blood samples were drawn from the CH patients at three occasions; during active period between headache attacks, during attack and in remission. Venous blood samples were drawn once from each control subject. We analyzed IL-2 gene expression, using quantitative real-time polymerase chain reaction (RT-PCR). Patients with CH had significantly increased relative IL-2 gene expression levels during active period between headache attacks compared to during attacks, remission and controls. Study III In this study we have investigated white blood cell accumulation into potential inflammatory areas intracranially in 14 CH patients, both in active period and in remission, and 5 control subjects, with single photon emission computer tomography (WBC-SPECT). To enable precise definition of regions of interest (ROI:s) in the brain, all CH patients and control subjects also underwent magnetic resonance imaging (MRI) of the brain. We found no statistically significant difference in 99m Tc-labeled WBC uptake between CH patients in active period and controls. Furthermore CH patients in active period were not significantly different in uptake compared to CH patients in remission. Study IV We investigated the role of nitric oxide (NO) in CH, by measuring its oxidation products, nitrite and nitrate, in the cerebrospinal fluid (CSF). We collected CSF from 14 episodic CH patients. Lumbar puncture was performed at two occasions: in active period between headache attacks, and in remission, not earlier than three weeks after their last headache attack. Eleven healthy volunteers served as controls. To estimate NO production, we determined the levels of NO-oxidation end products (NOx), that is, the sum of nitrite and nitrate, by using capillary electrophoresis (CE). CH patients in active period had significantly increased NOx levels compared with those in remission and control subjects. CH patients had also significantly enhanced NOx levels in remission compared to control subject

Deciphering the role of genetics and circadian rhythm in cluster headache

Cluster headache (CH) is a complex neurovascular disorder with a distinct circadian attack pattern. Although many aspects of the disease’s pathophysiology remain to be elucidated, it is likely caused by a combination of different genetic and environmental risk factors. Making use of an extensive CH biobank established by our lab, genetic material from patients and controls were screened for several single nucleotide polymorphisms (SNPs) in different candidate genes. In addition, gene expression was analyzed in fibroblast cell lines from patients and healthy controls. Using a hypothesis-free approach, a genome-wide association study (GWAS) was performed on the Swedish material as well as in a combined analysis with a CH cohort from the UK. To characterize the Swedish CH population in terms of clinical patterns and sex differences, two observational studies were conducted based on questionnaire data from CH patients. In study I, we could demonstrate a clear diurnal attack pattern for a majority of patients and that tobacco consumption delays the onset of CH. Pronounced gender differences were detected in study II, where we showed that a significantly higher proportion of female patients suffered from the chronic form of CH, had a positive family history for the disorder, and reported diurnal rhythmicity of their attacks to a larger extent than male patients. Because of evident circadian attack patterns in CH, study III-V focused on circadian rhythm genes. We found a link between one SNP in the hypocretin receptor 2 (HCRTR2) gene and the disorder, but could not confirm previously reported associations of other HCRTR2 SNPs with CH. However, a SNP in the core clock gene circadian locomotor output cycles kaput (CLOCK) was associated with CH and led to increased CLOCK gene expression. Another core clock gene, cryptochrome circadian regulator 1 (CRY1), included a variant that was less common in patients, and was more highly expressed in patients compared to controls. Alcohol, nitric oxide (NO), and calcitonin gene-related peptide (CGRP) are all vasodilators which may induce CH attacks, therefore genes connected to these molecules have been of interest in genetic studies of CH. The alcohol dehydrogenase 4 (ADH4) gene was previously linked to CH in smaller case-control studies, however in our much larger study VI, we could not confirm this association with ADH4. In study VII, we investigated SNPs in the different NO synthase (NOS) genes but could not identify a clear role for these variants in the disorder. In study VIII, we demonstrated a link between CH and a SNP in the receptor activity modifying protein 1 (RAMP1) gene, encoding a CGRP receptor component, as well as increased RAMP1 gene expression in CH patients compared to controls. The first-line prophylactic treatment for CH is verapamil, a calcium-channel blocker and vasodilator. The anoctamin 3 (ANO3) gene encodes for a calcium-activated ion channel, and in study IX we found an association between an ANO3 gene variant and CH. Previous GWAS on migraine have yielded two interesting SNPs in the Swedish migraine population. In study X, we reported that the variant in the metadherin (MTDH) gene was also associated with CH, while the variant in the PR/SET domain 16 (PRDM16) gene was migraine-specific. The first GWAS on CH was performed on a very small Italian cohort, andin study XI, we could not confirm the findings for PACAP receptor 1 (ADCYAP1R1), membrane metalloendopeptidase (MME), and a 14q21 variant. When performing a GWAS on our Swedish CH material in study XII, we detected two significant loci near the genes MER proto-oncogene, tyrosine kinase (MERTK) and special AT-rich sequence-binding protein 2 (SATB2), which could be consolidated in a UK CH cohort. These studies demonstrate an involvement of the circadian rhythm in the pathophysiology of CH, and revealed some possibly dysregulated pathways in relation to treatment of CH. The GWAS findings underline that there is a genetic component to CH which needs to be investigated further

The genetics and pathophysiology of cluster headache and associated disorders

Cluster headache (CH) is described as one of the most painful conditions known to humans. It effects approximately 60,000 individuals in the UK and carries significant morbidity. It exhibits hereditability evident by reports of familial aggregation and is categorised as a trigeminal autonomic cephalalgia (TAC). Despite this, the exact pathophysiological and genetic drivers of this condition remain elusive. The purpose of this thesis is to examine the clinical and genetic determinants of CH, and thus gain insights into the underlying neurobiological mechanisms. This work consists of two components. In the first section, I conduct clinical observational studies to further delineate the CH phenotype. I address the postulated association between pituitary adenomas and CH and question the utility of dedicated pituitary imagining in this patient group. I also describe the largest series of Post-Traumatic Headache of Cluster Headache (PTH-CH) and demonstrate its distinct features and increased intractability to treatment. Finally, through meta-analysis, I estimate the prevalence of familial CH to be 6.27% and demonstrate an overlap with concurrent short-Lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) in familial cases. The second section explores the genetics architecture underlying CH. I perform a Genome-Wide Association Study (GWAS) to identify replicable susceptibility loci and conduct a downstream analysis. Subsequent genetic correlation analysis showed an overlap with migraine, depression, bipolar and sleep disturbance implying the possibility of a common genetic driver for these conditions, which frequently present concurrently. I then carry out linkage analysis in CH families and replicate a linked region suggestive of significance on chromosome 2 that also overlaps a genome wide significant locus. Finally, I execute whole exome sequencing and utilise rare variant association tests and segregation analysis to identify causal variants for familial CH

Impact of continuing or quitting smoking on episodic cluster headache: a pilot survey

Abstract BACKGROUND: The majority of patients suffering from cluster headache (CH) are smokers and it has been suggested that smoking may trigger the development of CH. The aim of this pilot survey was to describe: 1. the differences between current, former, and never smokers CH patients; 2. if smoking changed during an active cluster period; 3. if CH changed after quitting. METHODS: All outpatients with episodic CH according to the criteria of ICHD-II who were consecutively seen for the first time from October 2010 to April 2012 at a headache centre were interviewed by phone using a specifically prepared questionnaire. Statistical differences between continuous variables were analysed by the Student's t-test or the one-way analysis of variance (ANOVA), followed by Newman-Keuls post-hoc testing. Comparisons between percentages were made using the Chi-square test or Fisher's exact test. All data were expressed as the mean ± standard deviation (SD). RESULTS: Among a total of 200 patients surveyed (172 males, 28 females; mean age ± SD: 48.41 ± 12 years) there were 60%, 21%, and 19% of current, former, and never smokers, respectively. Current smokers reported longer active periods (12.38 ± 10 weeks) and a higher maximum number of attacks per day (3.38 ± 1) compared to never smoker CH patients (5.68 ± 4 weeks, P <0.05 and 2.47 ± 1, P <0.05, respectively). During the active period most of the patients stated to decrease (45.7%) or not to change (45.7%) the number of cigarettes smoked. Among those who decreased smoking, most (83.8%) reported that they had less desire to smoke. After quitting, the majority of former smokers stated that their headache had not changed. CONCLUSIONS: Patients with episodic CH who are also smokers appear to have a more severe form of the disorder. However, it is unlikely that between CH and smoking there is a causal relationship, as CH patients rarely improve quitting smoking

The Pauline traditions in the acts of apostles

Part I. The theme of Pauline tradition is mentioned by Barrett and Schenke, and further, Roloff and Plamacher indicate traditional material behind the image of Paul in Acts, part of which is analyzed by burchard and Loning (ch.l). The date of Acts is placed at the end of the first century and the author confronted Jewish Christianity crossed with Gnosticism (ch.2), Historical criticism, form criticism and redaction criticism are methodological principles for our investigation. Any source theories are problematical. However, the author utilized traditional material in depiction of Paul in Acts, namely, the Pauline traditions, which are parallel to the Pauline Epistles, the Pauline legends, which are parallel to the miracle stories in the synoptic tradition, and the local community traditions (ch.5).Part II. Paul's background in Acts (Jewish, Hellenistic and Roman) is based on the Pauline traditions. Judaizing and anti-Jewish tendencies are seen in it (ch.4), Paul's pre-conversion period is also based on the Pauline traditions, but coloured with Judaizing tendencies (ch.3). Paul's conversion and call are due to traditional material, out modified with literary devices. Anti-gnostic tendencies can be traced behind it (ch.6). The earliest years after conversion and call are based on tradition; however, it is dominated by anti-Jewish tendencies (ch.7). The first missionary journey is not totally a "model” journey, but two parts of it are based on the Pauline traditions respectively together with the Pauline legends. But the author arranged them in order to make a circular journey. Judaizing tendencies and ambivalent anti-Jewish tendencies are seen in it (ch.8). In the second missionary journey, in contrast to the first one, the local community traditions are employed together with the Pauline traditions and the Pauline legends. Judaizing tendencies are seen in it (ch.9). The Pauline traditions, the Pauline legends and the local community traditions are utilized in the depiction of the third missionary journey. Apologetic tendencies against syncretism and paganism are seen in it (ch.lO). The image of Paul in Acts is not only based on traditional material but also transformed by the author in order to defend the legitimacy of the Gentile mission under anti-Pauline attacks. Acts is governed by rhetorical Peripatetic historiography (ch.11)

Cranial autonomic ganglia in headache disorders

Headache disorders are amongst the most prevalent causes of disability worldwide. Most of the effort to develop new therapeutics has focused on migraine. Patients suffering from less common headache disorders such as trigeminal neuralgia (TN) or cluster headache (CH) are also in need of new and better treatments. Our group has developed a new navigation based surgical tool that allows accurate targeting of small anatomical structures that might be involved in cranial and facial pain. Two previous pilot trials have used this technique to inject botulinum toxin type A (BTA) towards the sphenopalatine ganglion (SPG) in 10 patients with intractable chronic CH (1) and in 10 patients with intractable chronic migraine (2). In this Thesis, we further explore the possibilities of this new device. Most of the studies targeting the SPG do not localize the ganglion directly and use anatomical landmarks which have not been validated (3). Our group has depicted the SPG in living humans using MRI for the first time (4). Nonetheless, MRI might not always be available or some patients might have medical contraindications to undergo this examination. For this reason, we developed an algorithm to predict the location of the SPG using bony landmarks identified in CT-scans (paper 1). Classical TN is not classified under trigeminal autonomic cephalalgias but recent studies have shown that one third of the patients might present autonomic symptoms and the SPG has been involved in its pathophysiology. In paper 2, we conducted a pilot study with 10 patients with classical TN (ICHD-3 beta criteria). Patients were injected with 25 units (U) BTA towards the ipsilateral SPG. The primary outcome was the occurrence of adverse events (AEs). The main efficacy outcome was the number of TN attacks at weeks 5-8 after injection compared to baseline. CH is the most common trigeminal autonomic cephalalgia and it inflicts great suffering among patients. The SPG has been involved in its pathophysiology but no other cranial autonomic ganglia have been targeted in this condition. In paper 3 we describe the rational for the role of the otic ganglion (OG) in autonomic cephalalgias. The OG is a smaller and less studied cranial autonomic ganglion. It cannot be seen in CT-scans or in conventional MR imaging. Its relation to the mandibular nerve has been described to be constant in the literature, with the OG being in direct contact to the medial surface of the third division of the trigeminal nerve (5). The mandibular nerve can be easily localized in MRI. In order to target one structure, which cannot be directly depicted, at least one other anatomical landmark is necessary in addition to the mandibular nerve. The foramen ovale (FO) can be seen clearly in CT-images. One anatomicalcadaveric study describes that the OG “lies immediately below the FO”, however the distance between the FO and the OG was not reported in this study (5). In order to target the OG we measured the average distance between the FO and the OG in 21 high definition photographs of 21 infratemporal fossae from 18 cadavers (paper 3). In a pilot study with 10 patients with intractable chronic CH (paper 4), 5 patients were injected with 12.5 U of BTA and 5 patients with 25 U of BTA towards the ipsilateral OG. The primary endpoint was the occurrence of AEs. The main efficacy outcome was the number of attacks in month 2 after injection compared to baseline. Main findings of this Thesis: • The SPG localization can be predicted on CT-images using 2 bony landmarks. Localizing the SPG on CT-images will be important for patients with contraindications to undergo an MRI (e.g. claustrophobia, MR-incompatible metallic foreign bodies or stimulators, etc.), when access to MRI is limited, and in those patients where repeated injections are needed. • Injection of BTA towards the SPG in classical TN (ICHD-3 beta) appears to be safe. We did not find any indication for effect in reducing the number of TN attacks after injection of 25 U of BTA towards the SPG. A better understanding of the role of the SPG in TN is necessary. • The OG appears to have a constant location, being situated 4.5 mm inferior of the FO and medial to the mandibular nerve. The FO is easily localized on CT-scans and may be an interesting anatomical landmark when trying to develop navigation-based therapies towards the OG • Injection of BTA towards the OG in CH appears to be feasible and safe. We did not find a clear indication for effect in reducing the number of CH attacks after injection of 25 U of BTA towards the OG. A better description of the topography of the OG in living humans should precede further clinical studies targeting this structure

Efficacy of modified atkins ketogenic diet in chronic cluster headache. An open-label, single-arm, clinical trial

Introduction: 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. Aim: Here, we aim to detect the effect of KD in a group of drug-resistant chronic CH (CCH) patients. Materials and methods: 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). Results: 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). Conclusion: We observed for the first time that a 3-month ketogenesis ameliorates clinical features of CCH