Unilateral Cranial Autonomic Symptoms Research Articles

202 Placebo-controlled intravenous nitroglycerin phenotyping of acute attacks of cluster headache

IntroductionCluster headache (CH) is characterised by attacks of excruciating unilateral headache, ipsilateral cranial autonomic symptoms (CAS) and/or agitation. Nitroglycerin (NTG) is known to induce CH. This study is the first single-blind placebo-controlled study using intravenous NTG in CH to characterise comprehensively NTG induced CH attacks.MethodsCH patients attended three study visits in total, first visit CH patients were unblinded and received intravenous NTG 0.5mcg/kg/min over 20 minutes, if successful they were asked to return for blinded visits either receiving NTG or placebo. The clinical phenotype was recorded. The study was approved by the NHS Research Ethics Committee.ResultsThirty-three patients participated, 24 completed all study visits. Nineteen episodic cluster headache (58%) and 14 chronic cluster headache (42%). NTG brought on CH attacks (n= 26, 79%), agitation (n= 24, 73%) and CAS (n= 31, 94%) in the unblinded NTG visit. NTG brought on CH attacks (n= 19, 76%), agitation (n= 20, 80%) and CAS (n= 21, 84%) in the blinded NTG visit. Only one participant had a spontaneous CH attack (4%) in the placebo visits, four participants reported unilateral CAS symptoms, and none had agitation.ConclusionWe demonstrate that intravenous NTG effectively triggers CH attacks.diana.wei@kcl.ac.uk

Cranial autonomic symptoms: prevalence, phenotype and laterality in migraine and two potentially new symptoms

BackgroundWhilst cranial autonomic symptoms (CAS) are typically associated with trigeminal autonomic cephalalgias (TAC’s), they have also been reported in migraine. Identification and understanding of these symptoms in migraine is important to ensure timely diagnosis and effective management.MethodsMigraineurs seen in a tertiary headache service between 2014 and 2018 (n = 340): cohort one, and a separate cohort of headache patients seen between 2014-May 2021 reporting voice change, or throat swelling, or both, as CAS were selected (n = 64): cohort two. We performed a service evaluation of our records regarding age, sex, diagnosis, headache and CAS frequency and laterality as acquired from the first consultation, during which a detailed headache history is taken by a headache trained physician.ResultsCohort 1: Mean age 43 (range 14–94, SD 15). The most common diagnosis was chronic migraine (78%). Median monthly headache frequency was 26 days (IQR 15–75). At least one CAS was reported in 74%, with a median of two (IQR 0–3). The most common were nasal congestion (32%), lacrimation (31%) and aural fullness (25%). Most patients reported their most common headache as unilateral (80%) and with it strictly unilateral CAS (64%). There was a positive association between headache and CAS laterality (χ21 = 20.7, P < 0.001), with a positive correlation between baseline headache frequency and number of CAS reported (r = 0.11, P = 0.047). Cohort two: mean age 49 (range 23–83, SD 14). Diagnoses were chronic migraine (50%), chronic cluster headache (11%), undifferentiated continuous lateralised headache (9%), SUNCT/SUNA (8%), hemicrania continua (8%), episodic migraine (8%), episodic cluster headache (3%) and trigeminal neuropathies (3%). Most (89%) described trigeminal distribution pain; 25% involving all three divisions. Throat swelling was reported by 54, voice change by 17, and both by 7. The most common CAS reported were lacrimation (n = 47), facial swelling (n = 45) and rhinorrhoea (n = 37). There was significant agreement between the co-reporting of throat swelling (χ21 = 7.59, P = 0.013) and voice change (χ21 = 6.49, P = 0.02) with aural fullness.ConclusionsCAS are common in migraine, are associated with increasing headache frequency and tend to lateralise with headache. Voice change and throat swelling should be recognized as possible parasympathetically-mediated CAS. They may be co-associated and associated with aural fullness, suggesting a broadly somatotopic endophenotype.

Cranial Autonomic Symptoms in Migraine: An Observational Study.

Objective:Our aim was to observe frequency of cranial autonomic symptoms (CAS) in migraineurs (primary) and its relation with laterality of headache or other factors, if any.Background:Migraine episodes have headaches with or without aura, and sometimes associated with systemic autonomic nervous system symptoms. Primarily presence of cranial autonomic symptoms suggests diagnosis of TACs. But many studies reported cranial autonomic symptoms (CAS) ranging from 26% to 80% in migraine patients.Material and Methods:Consecutive patients of migraine attending our headache clinic were included in our study. Presence of CAS was recorded with respect to ocular, nasal, facial and aural symptoms along with headache characteristics and laterality information. Detailed clinical examination was performed. We used ICHD 3 (beta version) criteria.Results:Our study cohort comprised of 200 patients having mean (± SD) age 31.12 (± 10.67) years. There were 157 (78.5%), females. Out of 200 patients, 148 (74%) were having at least one CAS, of which 70% were having 2 or more CAS. Frequency of CAS was lacrimation (45.5%), conjunctival injection (34.5%), eyelid edema (34%), aural fullness (27.5%), facial sweating (25%), facial flushing (17.5%), nasal congestion (9%), rhinorrhea (5%) and ptosis (4%). Bilateral CAS was present in 129 (87%) and unilateral CAS in 19 (13%) (OR 35.31; 95% CI 9.19 to 135.7), (P < 0.0001). Sunlight as a trigger was present in all 148 (100%) patients.Conclusion:Our study showed that CASs in migraine is common and bilateral. Sunlight triggers headache in almost all CAS positive patients.

Dopaminergic symptoms in migraine: A cross-sectional study on 1148 consecutive headache center-based patients.

Dopaminergic symptoms may be extremely pronounced in some migraine patients during the attack, representing a major source of disability. We aimed to carefully characterize the clinical picture of migraine patients with dopaminergic symptoms in a large patients' population as a putative migraine endophenotype, allowing more precise disease management, treatment and outcome prediction. We screened 1148 consecutive tertiary care episodic and chronic migraine patients with face-to-face interviews collecting thorough data on lifestyle, socio-demographic factors, and clinical migraine features. We identified 374 patients with migraine with dopaminergic symptoms (32.6%). The most frequent dopaminergic symptom was yawning followed by somnolence, nausea, vomiting, fatigue, mood changes and diuresis. Migraine patients with dopaminergic symptoms had longer attack duration (OR: 1.82; 95% CI: 1.41-2.36, p < 0.0001), more frequent osmophobia (OR: 2.01; 95% CI: 1.50-2.69, p < 0.0001), allodynia (OR: 1.43; 95% CI: 1.10-1.85, p = 0.0071) and unilateral cranial autonomic symptoms (OR: 1.31; 95% CI: 1.01-1.68, p = 0.045), but used less preventative treatments (OR: 0.74; 95% CI: 0.57-0.98, p = 0.033) than patients without dopaminergic symptoms. Migraine patients with dopaminergic symptoms are characterized by a full-blown, more disabling migraine. Dopaminergic system modulation should be carefully considered in individuals with migraine with dopaminergic symptoms for both acute and preventative treatments in future ad hoc designed studies.

Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis.

Cluster headache is a primary headache disorder affecting up to 0.1% of the population. Patients suffer from cluster headache attacks lasting from 15 to 180 min up to 8 times a day. The attacks are characterized by the severe unilateral pain mainly in the first division of the trigeminal nerve, with associated prominent unilateral cranial autonomic symptoms and a sense of agitation and restlessness during the attacks. The male-to-female ratio is approximately 2.5:1. Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. In addition, the circadian and circannual rhythmicity unique to this condition is postulated to involve the hypothalamus and suprachiasmatic nucleus. Although the clinical features are distinct, it may be misdiagnosed, with patients often presenting to the otolaryngologist or dentist with symptoms. The prognosis of cluster headache remains difficult to predict. Patients with episodic cluster headache can shift to chronic cluster headache and vice versa. Longitudinally, cluster headache tends to remit with age with less frequent bouts and more prolonged periods of remission in between bouts.

The phenotype of migraine with unilateral cranial autonomic symptoms documents increased peripheral and central trigeminal sensitization. A case series of 757 patients.

Migraine with unilateral cranial autonomic symptoms (UAS) is a putative migraine endophenotype with convincing response to trigeminal-targeted treatments that still needs a thorough characterization. The objective of this article is to carefully investigate the clinical phenotype of migraine with UAS in a large group of patients for more accurate migraine diagnoses, improved clinical management, and better outcome prediction. We studied 757 consecutive episodic and chronic migraineurs in a tertiary headache clinic with face-to-face interviews, detailing in depth their lifestyle, sociodemographic and headache characteristics. Migraineurs with UAS (37.4%) differed from the general migraine population with respect to longer attack duration (OR = 2.47, p < 0.02, having >72-hour long attacks), more strictly unilateral (OR = 3.18, p < 0.001) and severe headache (OR = 1.72, p = 0.011), more frequent allodynia (OR = 3.03, p < 0.001) and photophobia (OR = 1.87, p = 0.019). Migraine patients with UAS are characterized not only by symptoms due to intense peripheral trigeminal activation but also to central sensitization. Our study broadens the knowledge on the clinical and phenotypic characteristics of migraine with UAS, suggests pathophysiological implications, and supports the need for future prospective clinical studies.

Are migraine endophenotypes needed?

Classification of migraine into different endophenotypes could aid diagnosis and treatment, but requires detailed characterization of different phenotypes. A new study provides insight into the clinical features of migraine with unilateral cranial autonomic symptoms, but raises questions about the value of such classifications.

Pharmacological Trials in Migraine: It's Time to Reappraise Where the Headache Is and What the Pain Is Like

Most pharmacological trials deal with migraine as if it were a clinically homogeneous disease, and when detailing its characteristics, they usually report only the presence, or absence, of aura and attack frequency but provide no information on pain location, a non-trivial clinical detail. The past decade has witnessed growing emerging evidence suggesting that individuals with unilateral pain, especially those with associated unilateral cranial autonomic symptoms, are more responsive than others to trigeminal-targeted symptomatic and preventive therapy with drugs such as triptans or botulinum toxin. A simple way for migraine research treatment to take a step forward might be to step back, reappraise, and critically evaluate easily obtainable patient-reported clinical findings along with current knowledge on pain features.

Is SOD2 Ala16Val polymorphism associated with migraine with aura phenotype?

Several studies suggest a role of oxidative stress in the physiopathology of migraine, particularly in the form with aura. In a case-control study, we investigated the association between migraine and superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) genes in a cohort of 490 consecutive unrelated Caucasian migraineurs (migraine with aura [MwA], n=107; migraine without aura [MwoA], n=246; chronic migraine [CM], n=137) and 246 healthy controls recruited at our Headache and Pain Unit and stored in the Interinstitutional Multidisciplinary BioBank (BioBIM). Migraine phenotype was carefully detailed using face-to-face interviews. We examined polymorphisms of SOD1 gene (A/C substitution-rs2234694) and SOD2 gene (C/T transition-rs4880-Ala16Val). The rs4880 TT (Val/Val) genotype was associated (p=0.042) with the presence of unilateral cranial autonomic symptoms (UAs) in MwA patients. We also found a mild correlation between SOD2 rs4880 genotype and the type of acute migraine treatment (p=0.048) in MwA patients. Our findings suggest that SOD2 is a disease-modifier gene influencing oxidative mechanisms in MwA. These observations lead to the hypothesis that SOD2 polymorphism may cause a defective control of the oxidative phenomena linked to cortical spreading depression, the neurophysiological hallmark of migraine aura, causing an overstimulation of trigeminal neurons and UAs triggering.

Unilateral cranial autonomic symptoms in patients with migraine

The aim of this study is to investigate the frequency of unilateral cranial autonomic symptoms during migraine attacks, and to compare the clinical characteristics of migraine patients with and without unilateral cranial autonomic symptoms. One hundred and eighty-six consecutive patients with episodic migraine attacks were prospectively included. Cranial autonomic symptoms of the patients occurred during headache, frequency, duration, severity and character of headache, disease duration, presence of aura, laterality of headache, accompanying symptoms, relation of migraine attacks with menstruation, lesions detected on magnetic resonance images, and family history of migraine were recorded. The patients with and without unilateral cranial autonomic symptoms during headache were compared in terms of above-mentioned parameters. Seventy-seven (41.4 %) patients were observed to develop unilateral cranial autonomic symptoms during migraine attack. Disease duration was longer in the patients with unilateral cranial autonomic symptoms than in those without (p = 0.045). Headache was unilateral in 83.1 % of the patients with unilateral cranial autonomic symptoms (p = 0.001). Pure menstrual or menstrually related migraine attacks were more common in the patients with unilateral cranial autonomic symptoms (p = 0.043) and is thought that menstruation-related hormonal factors might have a triggering role on the trigeminal-autonomic reflex pathway. The longer disease duration in patients with unilateral cranial autonomic symptoms might be associated with the activation of pathophysiological mechanisms that cause cranial autonomic symptoms in time. Frequent unilateral pain in migraine patients with unilateral cranial autonomic symptoms is likely to indicate that the development of autonomic symptoms may share common mechanisms with the pathogenesis of trigeminal autonomic cephalalgias.

Rizatriptan in migraineurs with unilateral cranial autonomic symptoms: a double-blind trial

The objective and background is to confirm in a double-blind, placebo-controlled study the high triptan response rates we had previously reported in an open study in migraine patients with unilateral cranial autonomic symptoms. In this randomized, double-blind, placebo-controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to receive rizatriptan 10 mg wafer or placebo (ratio 1:1) and treated for a single moderate or severe migraine attack. The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h. Secondary endpoints included pain relief, no associated symptoms and sustained pain freedom or relief. Significantly more patients reported pain freedom at 2 h after taking rizatriptan (54 %) than after placebo (8 %) (therapeutic gain 46 % [28 %; 64 %]; P < 0.001). Similarly, significantly more patients reported total migraine freedom at 2 h after rizatriptan (51 %) than after placebo (8 %) (therapeutic gain 43 % [26 %; 61 %]; P < 0.001). Rizatriptan was also more effective than placebo on most secondary endpoints. We confirm in a placebo-controlled study our previous data suggesting that the presence of unilateral cranial autonomic symptoms in migraineurs predicts a positive response to triptans, probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular 5-HT1B/1D receptors. Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients.

A Report of Cranial Autonomic Symptoms in Migraineurs

The presence of cranial autonomic symptoms in migraine is well known and thought to represent activation of the trigeminal parasympathetic reflex pathway similar to trigeminal autonomic cephalalgias. However, studies regarding the prevalence of these symptoms are few. The characteristics of migraineurs with cranial autonomic symptoms and the association of cranial autonomic symptoms with laterality of headache have never been studied in a clinic population. Seventy-eight consecutive subjects with migraine were recruited from the Headache Clinic of the Department of Psychiatry after exclusion of subjects with secondary headache. Their demographic data and detailed history of headache were noted and leading questions were asked regarding cranial autonomic symptoms. chi(2) test and Fisher's exact test was used for categorical variables, whereas an independent sample t-test was applied on numerical data. Spearman's correlation was used for correlational analysis of categorical variables. Female subjects (78.2%) outnumbered males and the average duration of illness in the whole sample was 3.81 years. Migraine without aura (53.8%) was the commonest diagnosis, followed by migraine with aura (24.4%). Cranial autonomic symptoms were present in 73.1% of subjects and, commonly, they were ipsilateral to headache. Moreover, strictly unilateral cranial autonomic symptoms were reported by only 32% of patients. The anatomical side of headache did not affect the presence of autonomic symptoms. Those with or without autonomic symptoms did not differ with respect to gender, diagnosis, laterality of headache or associated symptoms except phonophobia, which was more common in subjects with autonomic symptoms (P = 0.05). Those with autonomic symptoms had longer duration of illness (P = 0.03) and longer headache episodes (P = 0.04). In addition, sleep was ineffective in relieving their headache (P = 0.02). Cranial autonomic symptoms are frequent in migraineurs and are common in subjects with long duration of illness and longer headache episodes. Clinical evidence in the present study suggests that subjects with cranial autonomic symptoms have a hyperactive efferent arm of trigeminal autonomic reflex. The connections of trigeminal nucleus with the locus coeruleus and dorsal raphe nucleus may account for the observed phenotypic differences between the two groups. Further research, however, is required to elucidate the underlying neural mechanisms of cranial autonomic symptoms in migraine.

Unilateral cranial autonomic symptoms in migraine.

Unilateral cranial autonomic symptoms (UAs) such as lacrimation, conjunctival injection, eyelid oedema and nasal congestion, which are the hallmark of trigeminal autonomic cephalgias, may also occur in an as yet undetermined proportion of migraine patients. We studied 177 consecutive migraineurs to assess the frequency of UAs and the clinical characteristics of such patients. UAs were reported by 81 patients (45.8%), ocular symptoms alone or in combination with nasal symptoms being the most frequent. The headache was more severe (P<0.0002) and more strictly unilateral (P<0.0004) in patients who reported UAs than in those without. Thus, the presence of UAs suggests an activation of the trigeminal-autonomic reflex, probably related to an over-activation of the trigeminal afferent arm. These findings could have therapeutic implications, given the potential large-scale recruitment of peripheral neurovascular 5-HT(1B/1D) receptors (the target of acute migraine treatment) in such patients.