Transient side shift of cluster headache attacks after unilateral greater occipital nerve injection.

Attacks of cluster headache (CH) are usually side-locked in most, but not all, patients. In a few patients, the side may alternate between or, rarely, within cluster episodes. We observed seven cases in whom the side of CH attacks temporarily shifted immediately or shortly after unilateral injection of the greater occipital nerve (GON) with corticosteroids. In five patients with previously side-locked CH attacks and in two patients with previously side-alternating CH attacks, a side shift for several weeks occurred immediately (N = 6) or shortly (N = 1) after GON injection. We concluded that unilateral GON injections might cause a transient side shift of CH attacks through inhibition of the ipsilateral hypothalamic attack generator causing relative overactivity of the contralateral side. The potential benefit of bilateral GON injection in patients who experienced a side shift after unilateral injection should be formally investigated.

COVID-19 vaccination-triggered cluster headache episodes with frequent attacks.

BACKGROUND: The pathophysiology of cluster headache and how cluster episodes are triggered, are still poorly understood. Recurrent inflammation of the trigeminovascular system has been hypothesized. It was noted that some long-term attack-free cluster headache patients suddenly developed a new cluster episode shortly after COVID-19 vaccination. METHODS: Cases are described from patients with cluster headache who reported a new cluster episode within days after COVID-19 vaccination. All cases were seen in a tertiary university referral center and a general hospital in the Netherlands between March 2021 and December 2021, when the first COVID-19 vaccinations were carried out in The Netherlands. Clinical characteristics of the previous and new cluster episodes, and time between the onset of a new cluster episode and a previous COVID-19 vaccination were reported. RESULTS: We report seven patients with cluster headache, who had been attack-free for a long time, in whom a new cluster episode occurred within a few days after a COVID-19 vaccination. INTERPRETATION: COVID-19 vaccinations may trigger new cluster episodes in patients with cluster headache, possibly by activating a pro-inflammatory state of the trigeminocervical complex. COVID-19 vaccinations may also exacerbate other neuroinflammatory conditions. .

Increased use of illicit drugs in a Dutch cluster headache population.

INTRODUCTION: Many patients with cluster headache report use of illicit drugs. We systematically assessed the use of illicit drugs and their effects in a well-defined Dutch cluster headache population. METHODS: In this cross-sectional explorative study, 756 people with cluster headache received a questionnaire on lifetime use and perceived effects of illicit drugs. Results were compared with age and sex-matched official data from the Dutch general population. RESULTS: Compared to the data from the general population, there were more illicit drug users in the cluster headache group (31.7% vs. 23.8%; p < 0.01). Reduction in attack frequency was reported by 56% (n = 22) of psilocybin mushroom, 60% (n = 3) of lysergic acid diethylamide and 50% (n = 2) of heroin users, and a decreased attack duration was reported by 46% (n = 18) of PSI, 50% (n = 2) of heroin and 36% (n = 8) of amphetamine users. CONCLUSION: In the Netherlands, people with cluster headache use illicit drugs more often than the general population. The question remains whether this is due to an actual alleviatory effect, placebo response, conviction, or common pathophysiological background between cluster headache and addictive behaviours such as drug use.

The biological clock in cluster headache: A review and hypothesis.

OBJECTIVE: To review and discuss the putative role of light, sleep, and the biological clock in cluster headache. DISCUSSION: Cluster headache attacks are believed to be modulated in the hypothalamus; moreover, the severe pain and typical autonomic cranial features associated with cluster headache are caused by abnormal activity of the trigeminal-autonomic reflex. The temporal pattern of cluster headache attacks suggests involvement of the biological clock, and the seasonal pattern is influenced by the number of daylight hours. Although sleep is often reported as a trigger for cluster headache attacks, to date no clear correlation has been established between these attacks and sleep stage. CONCLUSIONS: We hypothesize that light, sleep, and the biological clock can change the brain's state, thereby lowering the threshold for activating the trigeminal-autonomic reflex, resulting in a cluster headache attack. Understanding the mechanisms that contribute to the daily and seasonal fluctuations in cluster headache attacks may provide new therapeutic targets.

Linking migraine frequency with family history of migraine.

BACKGROUND: Migraine is a complex genetic disorder that is brought about by multiple genetic and environmental factors. We aimed to assess whether migraine frequency is associated with genetic susceptibility. METHODS: We investigated in 2829 migraine patients (14% males) whether 'migraine frequency' (measured as the number of migraine days per month) was related to 'genetic load' (measured as the number of parents affected with migraine) using a validated web-based questionnaire. In addition, we investigated associations with age-at-onset, migraine subtype, use of acute headache medication, and comorbid depression. RESULTS: We found an association between the number of migraine days per month and family history of migraine for males ( p = 0.03), but not for females ( p = 0.97). This association was confirmed in a linear regression analysis. Also, a lower age-at-onset ( p < 0.001), having migraine with aura ( p = 0.03), and a high number of medication days ( p = 0.006) were associated with a stronger family history of migraine, whereas lifetime depression ( p = 0.13) was not. DISCUSSION: Migraine frequency, as measured by the number of migraine days per month, seems associated with a genetic predisposition only in males. A stronger family history of migraine was also associated with a lower age-at-onset, a higher number of medication days, and migraine with aura. Our findings suggest that specific clinical features of migraine seem more determined by genetic factors.

Aura in Cluster Headache: A Cross-Sectional Study.

BACKGROUND: Aura symptoms have been reported in up to 23% of cluster headache patients, but it is not known whether clinical characteristics are different in participants with and without aura. METHODS: Using validated web-based questionnaires we assessed the presence and characteristics of attack-related aura and other clinical features in 629 subjects available for analysis from an initial cohort of 756 cluster headache subjects. Participants who screened positive for aura were contacted by telephone for confirmation of the ICHD-III criteria for aura. RESULTS: Typical aura symptoms before or during cluster headache attacks were found in 44/629 participants (7.0%) mainly involving visual symptoms (61.4%). Except for lower alcohol consumption and higher prevalence of frontal pain in participants with aura, no differences in clinical characteristics were found compared with participants without aura. CONCLUSION: At least 7.0% of the participants with cluster headache in our large cohort reported typical aura symptoms, which most often involved visual symptoms. No major clinical differences were found between participants with and without aura.

Oliver Sacks and migraine.

Background Oliver Sacks (1933-2015) published a large number of books on a variety of neurological topics. Of these, numerous copies have been sold and they probably serve as the only or main source of information on neurological diseases for many persons without a medical background. His first book was on migraine and in his subsequent books many descriptions of migraine can be found, mainly those of auras. Methods We explored the descriptions of migraine in Sacks' work in order to evaluate the image of migraine offered to the readers. Conclusion Oliver Sacks gave wonderful descriptions of migraine auras, but hardly any of migraine headache. Furthermore, he described rare auras such as 'amusia' and olfactory auras. Overall, this makes his descriptions of migraine not very useful to serve as medical information for laypersons. Oliver Sacks, however, wrote great literature.

The cavernous sinus in cluster headache - a quantitative structural magnetic resonance imaging study.

Background It has been hypothesized that a constitutionally narrow cavernous sinus might predispose individuals to cluster headache. Cavernous sinus dimensions, however, have never been assessed. Methods In this case-control study, we measured the dimensions of the cavernous sinus, skull base, internal carotid and pituitary gland with high-resolution T2-weighted magnetic resonance imaging in 25 episodic, 24 chronic and 13 probable cluster headache patients, 8 chronic paroxysmal hemicrania patients and 22 headache-free controls. Dimensions were compared between groups, correcting for age, sex and transcranial diameter. Results On qualitative inspection, no relevant pathology or anatomic variants that were previously associated with cluster headache or chronic paroxysmal hemicranias were observed in the cavernous sinus or paracavernous structures. The left-to-right transcranial diameter at the temporal fossa level (mean ± SD) was larger in the headache groups (episodic cluster headache: 147.5 ± 7.3 mm, p = 0.044; chronic cluster headache: 150.2 ± 7.3 mm, p < 0.001; probable cluster headache: 146.0 ± 5.3 mm, p = 0.012; and chronic paroxysmal hemicrania: 145.2 ± 9.4 mm, p = 0.044) compared with controls (140.2 ± 8.0 mm). After adjusting for transcranial diameter and correcting for multiple comparisons, there were no differences in the dimensions of the cavernous sinus and surrounding structures between headache patients and controls. Conclusion Patients with cluster headache or chronic paroxysmal hemicrania had wider skulls than headache-free controls, but the proportional dimensions of the cavernous sinus were similar.

The anterior hypothalamus in cluster headache.

Objective To evaluate the presence, localization, and specificity of structural hypothalamic and whole brain changes in cluster headache and chronic paroxysmal hemicrania (CPH). Methods We compared T1-weighted magnetic resonance images of subjects with cluster headache (episodic n = 24; chronic n = 23; probable n = 14), CPH ( n = 9), migraine (with aura n = 14; without aura n = 19), and no headache ( n = 48). We applied whole brain voxel-based morphometry (VBM) using two complementary methods to analyze structural changes in the hypothalamus: region-of-interest analyses in whole brain VBM, and manual segmentation of the hypothalamus to calculate volumes. We used both conservative VBM thresholds, correcting for multiple comparisons, and less conservative thresholds for exploratory purposes. Results Using region-of-interest VBM analyses mirrored to the headache side, we found enlargement ( p < 0.05, small volume correction) in the anterior hypothalamic gray matter in subjects with chronic cluster headache compared to controls, and in all participants with episodic or chronic cluster headache taken together compared to migraineurs. After manual segmentation, hypothalamic volume (mean±SD) was larger ( p < 0.05) both in subjects with episodic (1.89 ± 0.18 ml) and chronic (1.87 ± 0.21 ml) cluster headache compared to controls (1.72 ± 0.15 ml) and migraineurs (1.68 ± 0.19 ml). Similar but non-significant trends were observed for participants with probable cluster headache (1.82 ± 0.19 ml; p = 0.07) and CPH (1.79 ± 0.20 ml; p = 0.15). Increased hypothalamic volume was primarily explained by bilateral enlargement of the anterior hypothalamus. Exploratory whole brain VBM analyses showed widespread changes in pain-modulating areas in all subjects with headache. Interpretation The anterior hypothalamus is enlarged in episodic and chronic cluster headache and possibly also in probable cluster headache or CPH, but not in migraine.

A Case Report About Cluster-Tic Syndrome Due to Venous Compression of the Trigeminal Nerve.

BACKGROUND: The term "cluster-tic syndrome" is used for the rare ipsilateral co-occurrence of attacks of cluster headache and trigeminal neuralgia. Medical treatment should combine treatment for cluster headache and trigeminal neuralgia, but is very often unsatisfactory. CASE: Here, we describe a 41-year-old woman diagnosed with cluster-tic syndrome who underwent microvascular decompression of the trigeminal nerve, primarily aimed at the "trigeminal neuralgia" part of her pain syndrome. After venous decompression of the trigeminal nerve both a decrease in trigeminal neuralgia and cluster headache attacks was seen. However, the headache did not disappear completely. Furthermore, she reported a decrease in pain intensity of the remaining cluster headache attacks. DISCUSSION: This case description suggests that venous vascular decompression in cluster-tic syndrome can be remarkably effective, both for trigeminal neuralgia and cluster headache.

Long Lasting Impairment of Taste and Smell as Side Effect of Lithium Carbonate in a Cluster Headache Patient.

BACKGROUND: Preventive treatment with lithium carbonate is a therapeutic option for chronic cluster headache. Lithium can lead to a broad spectrum of severe side effects, many of which are generally unknown. CASE DESCRIPTION: One week after starting treatment with lithium, a 55-year-old man with chronic cluster headache noticed a strange and unpleasant taste of various foods and a diminished smell. After 4 weeks, he decided to stop the therapy because of these complaints, but 9 months later both taste and smell still had not returned to normal. DISCUSSION: We present the first description of long-lasting dysgeusia and hyposmia as a side effect of lithium therapy in cluster headache. Dysgeusia has only rarely been reported as a side effect of lithium in other conditions and hyposmia has not previously been reported. Physicians should be aware of this rare, but severe, side effect when prescribing lithium.

C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.

Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis.

BACKGROUND: Cluster headache is a severe neurological disorder with a complex genetic background. A missense single nucleotide polymorphism (rs2653349; p.Ile308Val) in the HCRTR2 gene that encodes the hypocretin receptor 2 is the only genetic factor that is reported to be associated with cluster headache in different studies. However, as there are conflicting results between studies, we re-evaluated its role in cluster headache. METHODS: We performed a genetic association analysis for rs2653349 in our large Leiden University Cluster headache Analysis (LUCA) program study population. Systematic selection of the literature yielded three additional studies comprising five study populations, which were included in our meta-analysis. Data were extracted according to predefined criteria. RESULTS: A total of 575 cluster headache patients from our LUCA study and 874 controls were genotyped for HCRTR2 SNP rs2653349 but no significant association with cluster headache was found (odds ratio 0.91 (95% confidence intervals 0.75-1.10), p = 0.319). In contrast, the meta-analysis that included in total 1167 cluster headache cases and 1618 controls from the six study populations, which were part of four different studies, showed association of the single nucleotide polymorphism with cluster headache (random effect odds ratio 0.69 (95% confidence intervals 0.53-0.90), p = 0.006). The association became weaker, as the odds ratio increased to 0.80, when the meta-analysis was repeated without the initial single South European study with the largest effect size. CONCLUSIONS: Although we did not find evidence for association of rs2653349 in our LUCA study, which is the largest investigated study population thus far, our meta-analysis provides genetic evidence for a role of HCRTR2 in cluster headache. Regardless, we feel that the association should be interpreted with caution as meta-analyses with individual populations that have limited power have diminished validity.

A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood.

BACKGROUND: Hemiplegic migraine (HM) and alternating hemiplegia of childhood (AHC) are rare episodic neurological brain disorders with partial clinical and genetic overlap. Recently, ATP1A3 mutations were shown to account for the majority of AHC patients. In addition, a mutation in the SLC2A1 gene was reported in a patient with atypical AHC. We therefore investigated whether mutations in these genes may also be involved in HM. Furthermore, we studied the role of SLC2A1 mutations in a small set of AHC patients without ATP1A3 mutations. METHODS: We screened 42 HM patients (21 familial and 21 sporadic patients) for ATP1A3 and SLC2A1 mutations. In addition, four typical AHC patients and one atypical patient with overlapping symptoms of both disorders were screened for SLC2A1 mutations. RESULTS: A pathogenic de novo SLC2A1 mutation (p.Gly18Arg) was found in the atypical patient with overlapping symptoms of AHC and hemiplegic migraine. No mutations were found in the HM and the other AHC patients. CONCLUSION: Screening for a mutation in the SLC2A1 gene should be considered in patients with a complex phenotype with overlapping symptoms of hemiplegic migraine and AHC.

Symptomatic Trigeminal Autonomic Cephalalgias.

Trigeminal autonomic cephalalgias (TACs) are primary headache syndromes that share some clinical features such as a trigeminal distribution of the pain and accompanying ipsilateral autonomic symptoms. By definition, no underlying structural lesion for the phenotype is found. There are, however, many descriptions in the literature of patients with structural lesions causing symptoms that are indistinguishable from those of idiopathic TACs. In this article, we review the recent insights in symptomatic TACs by comparing and categorizing newly published cases. We confirm that symptomatic TACs can have typical phenotypes. It is of crucial importance to identify symptomatic TACs, as the underlying cause will influence treatment and outcome. Our update focuses on when a structural lesion should be sought.

Amyloid ß in hereditary cerebral hemorrhage with amyloidosis-Dutch type.

Hereditary cerebral hemorrhage with amyloidosis - Dutch type is an autosomal dominant hereditary disease caused by a point mutation in the amyloid precursor protein gene on chromosome 21. The mutation causes an amino acid substitution at codon 693 (E22Q), the 'Dutch mutation'. Amyloid ß, the product after cleavage of the amyloid precursor protein, is secreted into the extracellular space. The Dutch mutation leads to altered amyloid ß cleavage and secretion, enhanced aggregation properties, higher proteolysis resistance, lowered brain efflux transporter affinity, and enhanced cell surfaces binding. All these result in amyloid ß accumulation in cerebral vessel walls, causing cell death and vessel wall integrity loss, making cerebral vessel walls in hereditary cerebral hemorrhage with amyloidosis-Dutch type more prone to rupture and obstruction, leading to hemorrhages and infarcts. Studying the effects of altered amyloid ß metabolism due to mutations like the 'Dutch' provides us with a better understanding of amyloid ß toxicity, also in other amyloid ß diseases like sporadic cerebral amyloid angiopathy and Alzheimer's disease.

Familial hemiplegic migraine treated by sodium valproate and lamotrigine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura that includes motor auras. Prophylactic treatment of FHM often has marginal effects and involves a trial-and-error strategy based on therapeutic guidelines for non-hemiplegic migraine and on case reports in FHM. METHODS: We assessed the response to prophylactic medication in an FHM family and sequenced the FHM2 ATP1A2 gene in all available relatives. RESULTS: A novel p.Met731Val ATP1A2 mutation was identified. Attack frequency was reduced significantly with sodium valproate monotherapy (n = 1) and attacks ceased completely with a combination of sodium valproate and lamotrigine (n = 2). CONCLUSIONS: We report dramatic prophylactic effects of sodium valproate and lamotrigine in an FHM2 family, making these drugs worth considering in the treatment of other FHM patients.

Two novel SCN1A mutations identified in families with familial hemiplegic migraine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura, characterized by motor auras. The majority of FHM families have mutations in the CACNA1A and ATP1A2 genes; less than 5% of FHM families are explained by mutations in the SCN1A gene. Here we screened two Spanish FHM families for mutations in the FHM genes. METHODS: We assessed the clinical features of both FHM families and performed direct sequencing of all coding exons (and adjacent sequences) of the CACNA1A, ATP1A2, PRRT2 and SCN1A genes. RESULTS: FHM patients in both families had pure hemiplegic migraine with highly variable severity and frequency of attacks. We identified a novel SCN1A missense mutation p.Ile1498Met in all three tested hemiplegic migraine patients of one family. In the other family, novel SCN1A missense mutation p.Phe1661Leu was identified in six out of eight tested hemiplegic migraine patients. Both mutations affect amino acid residues that either reside in an important functional domain (in the case of Ile(1498)) or are known to be important for kinetic properties of the NaV1.1 channel (in the case of Phe(1661)). CONCLUSIONS: We identified two mutations in families with FHM. SCN1A mutations are an infrequent but important cause of FHM. Genetic testing is indicated in families when no mutations are found in other FHM genes.

Special considerations in management of migraine in the elderly.

Migraine in elderly patients requires an individualized approach, with unique considerations and challenges in both diagnosing and managing the disorder. Aging brains differ from younger ones in many ways, with distinct trajectories impacting brain volume, neurotransmitter systems, and functional systems, such as the descending pain inhibitory system. In this chapter, we will deconstruct migraine in the elderly by discussing the definitions of the elderly and migraine, the prevalence of migraine, and the management of migraine including the challenges posed by its comorbidities, limitations of treatments, and its effects on cognition. Studying, quantifying, characterizing, diagnosing, or managing migraine in the elderly is a challenge. However, it is clear that migraine in the elderly is not an uncommon occurrence, and providers should be aware that many elderly patients will not present with the complete phenotypic profile. Fortunately, the weight of evidence has not established migraine as a risk factor for dementia in the elderly, although migraine and its pharmacologic treatments may adversely impact cognition. Successful management requires understanding the interactions of migraine with comorbidities in the elderly and the adverse impacts of polypharmacy.

Coral reefs in transition: Temporal photoquadrat analyses and validation of underwater hyperspectral imaging for resource-efficient monitoring in Guam.

The island of Guam in the west Pacific has seen a significant decrease in coral cover since 2013. Lafac Bay, a marine protected area in northeast Guam, served as a reference site for benthic communities typical of forereefs on the windward side of the island. The staghorn coral Acropora abrotanoides is a dominant and characteristic ecosystem engineer of forereef communities on exposed shorelines. Photoquadrat surveys were conducted in 2015, 2017, and 2019, and a diver-operated hyperspectral imager (i.e., DiveRay) was used to survey the same transects in 2019. Machine learning algorithms were used to develop an automated pipeline to assess the benthic cover of 10 biotic and abiotic categories in 2019 based on hyperspectral imagery. The cover of scleractinian corals did not differ between 2015 and 2017 despite being subjected to a series of environmental disturbances in these years. Surveys in 2019 documented the almost complete decline of the habitat-defining staghorn coral Acropora abrotanoides (a practically complete disappearance from about 10% cover), a significant decrease (~75%) in the cover of other scleractinian corals, and a significant increase (~55%) in the combined cover of bare substrate, turf algae, and cyanobacteria. The drastic change in community composition suggests that the reef at Lafac Bay is transitioning to a turf algae-dominated community. However, the capacity of this reef to recover from previous disturbances suggests that this transition could be reversed, making Lafac Bay an excellent candidate for long-term monitoring. Community analyses showed no significant difference between automatically classified benthic cover estimates derived from the hyperspectral scans in 2019 and those derived from photoquadrats. These findings suggest that underwater hyperspectral imagers can be efficient and effective tools for fast, frequent, and accurate monitoring of dynamic reef communities.