Premonitory Symptoms Of Migraine Research Articles

Premonitory symptoms in migraine: A REFORM Study.

Estimates of proportions of people with migraine who report premonitory symptoms vary greatly among previous studies. Our aims were to establish the proportion of patients reporting premonitory symptoms and its dependency on the enquiry method. Additionally, we investigated the impact of premonitory symptoms on disease burden using Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS) and World Health Organization Disability Assessment 2.0 (WHODAS 2.0), whilst investigating how various clinical factors influenced the likelihood of reporting premonitory symptoms. In a cross-sectional study, premonitory symptoms were assessed among 632 patients with migraine. Unprompted enquiry was used first, followed by a list of 17 items (prompted). Additionally, we obtained clinical characteristics through a semi-structured interview. Prompted enquiry resulted in a greater proportion reporting premonitory symptoms than unprompted (69.9% vs. 43.0%; p < 0.001) and with higher symptom counts (medians 2, interquartile range = 0-6 vs. 1, interquartile range = 0-1; p < 0.001). The number of symptoms correlated weakly with HIT-6 (ρ = 0.14; p < 0.001) and WHODAS scores (ρ = 0.09; p = 0.041). Reporting postdromal symptoms or triggers increased the probability of reporting premonitory symptoms, whereas monthly migraine days decreased it. The use of a standardized and optimized method for assessing premonitory symptoms is necessary to estimate their prevalence and to understand whether and how they contribute to disease burden.

Premonitory symptoms of migraine

Premonitory symptoms of migraine

Premonitory symptoms in migraine: a systematic review and meta-analysis of observational studies reporting prevalence or relative frequency

BackgroundObservational studies on the prevalence of premonitory symptoms in people with migraine, preceding the headache pain (or aura) phase, have shown conflicting results. We conducted a systematic review and meta-analysis to estimate the prevalence, and relative frequency among clinic populations, of premonitory symptoms in people with migraine, overall and of the multifarious individual symptoms, and to review the methodologies used to assess them.MethodsWe searched PubMed and Embase for studies published from database inception until 31st of May 2022. Two investigators independently screened titles, abstracts, and full texts. We retrieved observational studies that reported the prevalence/relative frequency of one or more premonitory symptoms in people with migraine. Two investigators independently extracted data and assessed risk of bias. Results were pooled using random-effects meta-analysis. Our main outcomes were the percentage of people with migraine who experienced at least one premonitory symptom and the percentages who experienced different individual premonitory symptoms. To describe our outcomes, we used the terms prevalence for data from population-based samples and relative frequency for data from clinic-based samples. We also descriptively and critically assessed the methodologies used to assess these symptoms.ResultsThe pooled estimated prevalence in population-based studies of at least one premonitory symptom was 29% (95% CI: 8–63; I2 99%) and the corresponding pooled estimated relative frequency in clinic-based studies was 66% (95% CI: 45–82; I2 99%). The data from clinic-based studies only supported meta-analysis of 11 of 96 individual symptoms, with relative frequency estimates ranging from 11 to 49%. Risk of bias was determined as high in 20 studies, moderate in seven, and low in two.ConclusionsThe substantial between-study heterogeneity demands cautious interpretation of our estimates. Studies showed wide methodological variations, and many lacked rigor. Overall, the evidence was insufficient to support reliable prevalence estimation or characterization of premonitory symptoms. More data are needed, of better quality, to confirm the existence of a distinctive premonitory phase of migraine, and its features. Methodological guidelines based on expert consensus are a prerequisite.

Exploring the neurobiology of the premonitory phase of migraine preclinically – a role for hypothalamic kappa opioid receptors?

BackgroundThe migraine premonitory phase is characterized in part by increased thirst, urination and yawning. Imaging studies show that the hypothalamus is activated in the premonitory phase. Stress is a well know migraine initiation factor which was demonstrated to engage dynorphin/kappa opioid receptors (KOR) signaling in several brain regions, including the hypothalamus. This study proposes the exploration of the possible link between hypothalamic KOR and migraine premonitory symptoms in rodent models.MethodsRats were treated systemically with the KOR agonist U-69,593 followed by yawning and urination monitoring. Apomorphine, a dopamine D1/2 agonist, was used as a positive control for yawning behaviors. Urination and water consumption following systemic administration of U-69,593 was also assessed. To examine if KOR activation specifically in the hypothalamus can promote premonitory symptoms, AAV8-hSyn-DIO-hM4Di (Gi-DREADD)-mCherry viral vector was microinjected into the right arcuate nucleus (ARC) of female and male KORCRE or KORWT mice. Four weeks after the injection, clozapine N-oxide (CNO) was administered systemically followed by the assessment of urination, water consumption and tactile sensory response.ResultsSystemic administration of U-69,593 increased urination but did not produce yawning in rats. Systemic KOR agonist also increased urination in mice as well as water consumption. Cell specific Gi-DREADD activation (i.e., inhibition through Gi-coupled signaling) of KORCRE neurons in the ARC also increased water consumption and the total volume of urine in mice but did not affect tactile sensory responses.ConclusionOur studies in rodents identified the KOR in a hypothalamic region as a mechanism that promotes behaviors consistent with clinically-observed premonitory symptoms of migraine, including increased thirst and urination but not yawning. Importantly, these behaviors occurred in the absence of pain responses, consistent with the emergence of the premonitory phase before the headache phase. Early intervention for preventive treatment even before the headache phase may be achievable by targeting the hypothalamic KOR.

Premonitory symptoms in migraine from China: A multi-clinic study of 4821 patients.

To observe the prevalence and characteristics of premonitory symptoms in Chinese migraineurs and explore their associations with migraine-related factors. Migraineurs who visited a tertiary headache clinic and one of nine neurology clinics between May 2014 and November 2019 were studied. Among the 4821 patients meeting the migraine criteria (International Classification of Headache Disorders, 3rd edition), 1038 (21.5%) patients experienced at least one premonitory symptom. The most common premonitory symptoms were neck stiffness, dizziness, yawning and drowsiness. The logistic regression analysis demonstrated that aura, photophobia, aggravation by routine physical activity, triggers, family history, depression, coffee consumption and physical exercise were associated with an increased probability of experiencing premonitory symptoms (p ≤ 0.001). The premonitory symptoms of migraine with and without aura differ in prevalence and most common symptoms. The cluster analysis revealed pairwise clustering of the following premonitory symptoms: Photophobia/phonophobia, concentration change/dysesthesia, loquacity/overactivity, yawning/drowsiness, fatigue/dizziness, and mood change/irritability. The correlation analysis of triggers and premonitory symptoms revealed that temperature change, environment change, sleep disorder, activity and stress were related to multiple premonitory symptoms, and that food, light, menstruation, alcohol and odor were related to special premonitory symptoms (p ≤ 0.001). The prevalence of premonitory symptoms among migraineurs in China is 21.5%. Some factors influence the probability of experiencing premonitory symptoms. Paired premonitory symptoms in the clustering analysis may share similar origins. Certain triggers associated with multiple premonitory symptoms may induce brain dysfunction; however, other triggers that overlap with corresponding special premonitory symptoms may be premonitory symptoms or a form of premonitory symptom.

Premonitory Symptoms in Migraine from China: A Multiclinic Study of 4821 Patients

Objective: To observe the prevalence and characteristics of premonitory symptoms (PS) in Chinese migraineurs and explore their associations with migraine-related factors. Method: Migraineurs who visited a tertiary headache clinic and one of 9 neurology clinics between May 2014 and November 2019 were retrospectively studied. Result: Among the 4821 patients meeting migraine criteria (ICHD 3 edition), 1038 (21.5%) experienced at least one PS. The most common PS were neck stiffness, dizziness, yawning and drowsiness. Logistic regression demonstrated that aura, photophobia, aggravation by routine physical activity, trigger, family history, high educational level, depression, coffee consumption and physical exercise were associated with an increased probability of experiencing PS (P≤0.001). The PS of migraine with and without aura differ in prevalence and most common symptoms. Cluster analysis revealed pairwise clustering of the following PS: photophobia/phonophobia, concentration change/dysesthesia, loquacity/overactivity, yawning/drowsiness, fatigue/dizziness, and mood change/irritability. Analysis of correlation between triggers and PS revealed that temperature change, environment change, sleep disorder, activity and stress were related to multiple PS, and that food, light, menstruation, alcohol and odor were related to special PS (P≤0.001). Conclusion: The prevalence of PS among migraineurs of China is 21.5%. Some factors influence the probability of experiencing PS. PS clustered together in the clustering analysis may share similar origins. Among two subtypes of triggers, multiple PS related triggers may induce brain dysfunction, and some of special PS related triggers like light may be a form of PS or PS themselves. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (grant 81771200, 81671077), and Beijng Natural Science Foundation Essential Research Project (Z170002). Declaration of Interests: The authors report no disclosure relevant to this work. Ethics Approval Statement: The study was approved by the Ethics Committee at the Chinese PLA General Hospital (2020-263). The study protocol complied with China’s regulations and guidelines for Good Clinical Practice. Due to the retrospective nature of the study,oral informed consent was obtained from the patients before study inclusion according to the World Medical Association’s Declaration of Helsinki.

Current understanding of premonitory networks in migraine: A window to attack generation.

To describe neuronal networks underlying commonly reported migraine premonitory symptoms and to discuss how these might precipitate migraine pain. Migraine headache is frequently preceded by a distinct and well characterized premonitory phase including symptoms like yawning, sleep disturbances, alterations in appetite and food intake and hypersensitivity to certain external stimuli. Recent neuroimaging studies strongly suggest the hypothalamus as the key mediator of the premonitory phase and also suggested alterations in hypothalamic networks as a mechanism of migraine attack generation. When looking at the vast evidence from basic research within the last decades, hypothalamic and thalamic networks are most likely to integrate peripheral influences with central mechanisms, facilitating the precipitation of migraine headaches. These networks include sleep, feeding and stress modulating centers within the hypothalamus, thalamic pathways and brainstem centers closely involved in trigeminal pain processing such as the spinal trigeminal nucleus and the rostral ventromedial medulla, all of which are closely interconnected. Taken together, these networks represent the pathophysiological basis for migraine premonitory symptoms as well as a possible integration site of peripheral so-called "triggers" with central attack facilitating processes.

Premonitory Symptoms in Episodic and Chronic Migraine From a Pediatric Headache Clinic

ObjectiveWe evaluated the frequency of six commonly reported adult migraine premonitory symptoms in children and adolescents with episodic and chronic migraine and elicited psychological or behavioral comorbidities that may be associated with these symptoms. BackgroundPremonitory symptoms are commonly reported in the adult migraine population; however, little information is available for the pediatric population. MethodsData were collected on new patients being evaluated in our multidisciplinary pediatric headache clinic over a six-month time interval. The data collected from patients diagnosed with migraine were then reviewed for the following premonitory symptoms: yawning, neck stiffness, fatigue, increased urination, mood changes, and food cravings. History was obtained regarding the frequency of headaches and other associated behavioral or psychological problems. ResultsA total of 176 patients were enrolled over a six-month interval, ranging in age from four to 18 years (mean age 12 years); 64% were female, and 42% (74 of 176) of the subjects had at least one premonitory symptom. Patients with migraine with aura were noted to have a significantly higher association with premonitory symptoms (59%, 30 of 51) (P < 0.05). Anxiety disorder was also significantly associated with premonitory symptoms (55%, 11 of 20) (P < 0.05). Fatigue and mood changes were the most commonly reported premonitory symptoms. ConclusionsPremonitory symptoms occurred frequently in our population of pediatric patients with migraine. Fatigue and mood changes were the most frequent symptoms. There were no significant differences in premonitory symptoms by gender or age group (less than 12 years versus greater than 12 years). Anxiety and migraine with aura were correlated with an increased likelihood of premonitory symptoms.

Biological insights from the premonitory symptoms of migraine.

Migraine is a common neurological disorder with a diverse clinical phenotype that comprises more than just head pain. Premonitory (prodromal) symptoms can start hours to days before the onset of a migraine headache and can predict its onset in some individuals. Such symptomatology can include lethargy, yawning, light and sound sensitivity, thirst and cravings. This earliest phase of the migraine attack provides valuable insights into the neurobiology of the disorder, furthering our understanding of how and why these phenotypically heterogeneous symptoms are mediated. Improvements in our understanding of migraine could provide novel therapeutic opportunities, with the possibility of closing the therapeutic gap that remains owing to a lack of sufficiently effective and well-tolerated acute and preventive treatments. Improved understanding of disease mechanisms and potential therapeutic targets through bench-to-bedside research into the premonitory phase is an exciting and emerging means of achieving this aim going forward. In this Review, we discuss the current evidence in the literature in relation to the phenotype and mediation of premonitory symptoms in migraine, and discuss the neurobiological insights gained from these studies.

Migraine

Migraine

Premonitory symptoms in migraine: A cross-sectional study in 2714 persons.

To describe the frequency and number of premonitory symptoms (PS) in migraine, the co-occurrence of different PS, and their association with migraine-related factors. In this cross-sectional study, a validated questionnaire was sent to Finnish migraine families between 2002 and 2013 to obtain data on 14 predefined PS, migraine diagnoses, demographic factors, and migraine characteristics. The estimated response rate was 80%. Out of 2714 persons, 2223 were diagnosed with migraine. Among these, 77% reported PS, with a mean number of 3.0 symptoms compared to 30% (p < 0.001) and 0.5 symptoms (p < 0.001) among 491 persons with non-migraine headaches. Yawning was the most commonly reported symptom (34%) among migraineurs. Females reported PS more frequently than males (81 versus 64%, p < 0.001) and experienced a higher number of different symptoms (mean 3.3 versus 1.8, p < 0.001). All measures of migraine severity were associated with a higher burden of PS. Light and sound sensitivity showed the highest co-occurrence (kappa = 0.51, 95% CI 0.47-0.55). In a generalized linear model, age, gender, higher frequency, duration and intensity of headache, reduced working capacity, most aura symptoms, and associated symptoms of the headache phase were significantly associated with an increased in the number of PS. PS are experienced by a majority of migraineurs. More severe migraine is associated with a higher burden of PS. Since the material was not entirely representative of the general population of migraineurs, caution should be exercised in generalizing the results.

The Premonitory Phase of Migraine – What Can We Learn From It?

This review aims to understand the prevalence of premonitory symptoms in migraine, postulate their mechanisms, and compare these with functional imaging studies. A thorough literature review was conducted using PubMed for prevalence studies of premonitory symptoms in migraine and functional imaging studies in the premonitory phase. The majority of studies have been retrospective reporting a prevalence of 7-88% for premonitory symptoms in migraine. Only one study has investigated premonitory symptoms prospectively and used preselected patients with recognized premonitory symptoms. The majority of patients were able to predict correctly the onset of migraine headache. Only one functional imaging study has been conducted in the premonitory phase that showed activation of posterolateral hypothalamus, midbrain tegmental area and substantia nigra, periaqueductal gray, dorsal pons, and various cortical areas including occipital, temporal, and prefrontal cortex. Subgroup analysis of patients with photophobia more than without photophobia in the premonitory phase showed activation of the occipital cortex. Comparison of patients with nausea more than without nausea in the premonitory phase showed activation in upper dorsal medulla and periaqueductal gray. Premonitory symptoms are common in migraine, although the true prevalence cannot be stated with certainty in the absence of prospective studies in unselected patients. Hypothalamic involvement can explain many of the premonitory symptoms. Activation of the the brainstem structures and hypothalamus before pain suggests a pivotal role of these structures in the pathogenesis of migraine. Hypersensitivity to light and occurrence of nausea in migraine is associated with activation of central brain structures involved in these pathways, and this can occur in the absence of pain.

The premonitory phase of migraine and migraine management

The objective was to determine, through a literature review, whether treatment during the premonitory phase of migraine is a potentially useful migraine management strategy. A general literature review was done with regard to the nature of migraine premonitory symptoms, their frequency, their reliability in predicting migraine attacks, and the effectiveness of medication treatment when given during the premonitory phase. Many different symptoms have been reported as premonitory symptoms that occur before migraine attacks. Up to 87% of patients with migraine may experience premonitory symptoms, although some studies have provided estimates as low as 33%. In selected patients, premonitory symptoms may be relatively reliable predictors of a migraine attack to follow. Both naratriptan (open-label study) and domperidone (double-blind, randomized, placebo-controlled study) have been reported to be effective when given during the premonitory phase. More research is needed, but there is some evidence that medication treatment during the premonitory phase has the potential to be helpful in selected patients with migraine.

Atypical depression as a premonitory symptom of migraine managed by an oral contraceptive

Depression and headaches are frequently associated comorbid disorders. In previous reports psychiatrists have tended to regard headaches as an accompanying symptom of depression while neurologists have tended to have the opposite opinion. The following case report characterizes migraine as a prime cause of major depression. A 27-year-old woman presented because of a self-poisoning attempt with 12 mg of alprazolam. She had been suffering from major depression and sporadic headaches from the age of 24. After onset of the symptoms she had often injured herself by cutting her arm and attempted to suicide by self-poisoning. A variety of antidepressants had failed to improve her symptoms and she had been diagnosed as having borderline personality disorder comorbid with major depression. A medical interview at her first visit revealed that her major depressive episode had been predominantly characterized by atypical features in DSM-IV such as overeating hypersomnia leaden paralysis interpersonal rejection sensitivity and mood reactivity. She had also suffered persistent aura and premonitory symptoms of migraine such as scintillating scotomas photopsia and phonophobia.1 Lomerizine a calcium channel antagonist was first administered at 10 mg/day for treatment of the migraine in combination with valproic acid at 600 mg/day. This medication led to prompt resolution of her self-injury and suicidal behaviors but depressive mood with a series of migraine attacks paralleling each menstrual period persisted. Therefore additionally the patient was prescribed Ortho-Novum®7/7/7 an oral contraceptive containing ethinyl estradiol and norethindrone to prevent ovulation. With this medication all the symptoms immediately disappeared. Lomerizine and valproic acid were gradually withdrawn and no recurrence has been noted for over 1 year. Depression is one of the common premonitory symptoms of migraine and a first-line treatment strategy for migraine showed some degree of clinical effectiveness on the depressive episode in the present case.12 Accordingly it was considered that the patients major depression was also a premonitory symptom of migraine. Ovarian hormones can alter neurotransmitter system theorized to play an important role in the pathogenesis of migraine.3 Although hormonal treatment of migraine is not a first-line strategy due to an increased risk of ischemic stroke oral contraceptives can have a broad effect on the character and frequency of migraine.45 We suggest that clinicians should check for the complication of migraine in depressive patients. Depressive patients with migraine might show a preferential response to management of migraine rather than medication with common antidepressants. In female patients it is also prudent to be aware of any symptomatic relevance to the menstrual cycle and that oral contraceptives have the potential to treat such problems. (full-text)

The premonitory symptoms (prodrome): a tertiary care study of 893 migraineurs.

This study of premonitory symptoms in migraine was performed to document the frequency, duration, and types of symptoms in a large group of migraine patients. Prodrome importance continues to be debated. Intervention early in the migraine attack is assuming more importance and necessitates better knowledge of the prodrome. A total of 893 migraine patients (IHS 1.1-1.7) were evaluated at first visit. Prodrome frequency, duration, and characteristics were analyzed in the total migraine population IHS 1.1-1.7 and IHS 1.1-1.6 migraine. A total of 32.9% of IHS migraine 1.1-1.6 patients reported prodrome symptoms with an average of 9.42 hours. IHS 1.1-1.7 migraine reported 29.7% and 6.8 hours, respectively. The most commonest symptoms were tiredness, mood change, and gastrointestinal symptoms; all three of these symptoms were present together in 17% of the patients with prodrome. The duration of prodrome was less than 1 hour in 45.1%, 1-2 hours in 13.6%, 2-4 hours in 15.0%, 4-12 hours in 13.1%, and greater than 12 hours in 13.2%. IHS 1.1-1.7 patients showed similar findings. IHS 1.1-1.6 patients with prodrome differed from patients without prodrome in having more triggers as a whole (P <.01), more individual triggers including alcohol (P <.01), hormones (P <.01), light (P <.001), not eating (P <.05), perfume (P <.01), stress (P <.01), and weather changes (P <.05), a longer duration of aura (P <.05), longer time between aura and headache (P <.05), more aura with no headache (P <.05), longer time to peak of headache (P <.05), longer time to respond to triptan (P <.05), longer maximum duration of headache (P <.05), and more headache associated nausea (P <.05), more headache associated running of the nose or tearing of the eyes (P <.05), more postdrome syndrome (P <.05), and longer duration of postdrome syndrome (P <.001). This study provides a portrait of prodrome in a large cohort of patients. It highlights differences between patients with prodrome and patients not having prodrome, and it draws attention to the potential of preventing the headache phase of the acute migraine attack.

Premonitory symptoms in migraine

Migraine is frequently associated with nonheadache symptoms before, during, and after the headache. Premonitory symptoms occurring before the attack have not been rigorously studied. Should these symptoms accurately predict headache, there are considerable implications for the pathophysiology and management of migraine. Electronic diaries were used in a 3-month multicenter study to record nonheadache symptoms before, during, and after migraine. The authors recruited subjects who reported nonheadache symptoms in at least two of three attacks that they believed predicted headache. Symptoms were entered in the diaries by patient initiation and through prompted entries at random times daily. Entries could not be altered retrospectively. Data recorded included nonheadache symptoms occurring during all three phases of the migraine, prediction of the attack from premonitory symptoms, general state of health, and action taken to prevent the headache. One hundred twenty patients were recruited: 97 provided usable data. Patients correctly predicted migraine headaches from 72% of diary entries with premonitory symptoms. A range of cognitive and physical symptoms was reported at a similar rate through all three phases of the migraine. The most common premonitory symptoms were feeling tired and weary (72% of attacks with warning features), having difficulty concentrating (51%), and a stiff neck (50%). Subjects who functioned poorly in the premonitory phase were the most likely to correctly predict headache. Using an electronic diary system, the authors show that migraineurs who report premonitory symptoms can accurately predict the full-blown headache.