Clinical characteristics of migraine: A prospective cross- sectional study over nine years [version 1; peer review: 2 approved with reservations, 1 not approved]

Background: Migraine is the most common primary headache. This study aimed to describe clinical observations about migraine in outpatients in Iraq, including migraine types and subtypes, duration and frequency of acute attacks, severity, disability, effects on the quality of life, and complications. Methods: This is an outpatient-based prospective cross-sectional study, conducted in the Misan province, Iraq over nine years, and included 1412 patients aged 12 to 50 years. The data was collected from clinical records of patients who attended outpatient clinics. Results: The study included 1100 women (77.9%) and 312 men (22.1%); the women/men ratio being 3.5:1. The median age and standard deviation (SD) was 21 ± 5.42 years. The mean age at first attack of migraine was 17 ± 4.91 years. Migraine without aura was the most common type, accounting for 68% of the cases. The mean frequency of the attacks was (2 ± 4.63) days/month. In general, acute attacks were moderate to severe. Conclusions: In our study, we observed that migraine causes a headache resulting in episodes of temporary functional disability and women suffered more than men (ratio of 3.5:1). The mean age at first attack was a young age, and a family history of migraine highly altered distribution. Migraine without aura was the most common type, and symptoms including nausea and vomiting and photophobia were experienced by patients, which were used to diagnose migraines. Experienced aura was the most common migraine with aura, but also aura without a headache and aura with migraine were prevalent; therefore, it is important to differentiate between migraine subtypes. Visual aura was the most common aura, while motor symptoms were very rare. Chronic persistent headaches were a common complication recorded. These features provide evidence for the creation of screening tools in migraine prevention migraine. Open Peer Review


Introduction
Migraine is the most common chronic inherited neurovascular disorder. The onset of migraine is typically between 15 and 24 years of age 1 , and the prevalence is highest in patients aged 35-45 years, 75% of whom have moderate to severe headaches 2,3 . Diagnosis is based on clinical features, together with radiology images 4 . The majority of migraine patients experience temporary disability that affects their work and daily activities and, thus, their productivity and quality of life 5-7 . Regarding pathophysiology, the constriction and then dilation of cerebral blood vessels was believed, until 25 years ago, to cause the neurologic symptoms associated with a migraine 8 . In approximately 60 -70% of patients with a migraine, the onset of the headache is preceded by a non-specific malaise and irritable feelings, such as euphoria, depression, food cravings, fatigue, hypomania, cognitive slowing, dizziness, or asthenia. These symptoms are called the migraine prodromes and may occur as early as 24 hours before the actual migraine 9-11 , followed by the "aura", which is a focal neurological sign, and then a severe, throbbing headache with photophobia and vomiting 12 . About 15 -20% of migraine patients experience aura within one hour of, or simultaneously with a headache 13 . The migraine aura consists of neurologic abnormalities, including visual loss, hallucinations, numbness, tingling, weakness, or confusion. The aura is due to the cortical spreading depression, a wave of abnormal electrical discharges that travels across the brain's surface and short-circuits the brain 14 . Furthermore, migraine is best conceptualized as a triad of a paroxysmal headache, nausea and/or vomiting, and an aura of focal neurological events (visual events) 15 . Patients with these three signs have migraine with aura (or "classical migraine"), while those with a paroxysmal headache (with or without vomiting) but do not have aura are classified as migraine without aura (or "common migraine") 16,17 .
The aim of this study was to observe migraines clinically, leading to infer causality behind this disease, risk factors and triggers. Evidence gathered from this study will enable diagnosis of migraine and its probability to occur in persons who have similarity to patients observed in this study. We believe that early detection of these manifestations correlates with time and money saving on unnecessary investigations and medications used in management and treatment.

Study design
Outpatient-based prospective cross-sectional study, which was conducted in the Al-Sadder Teaching Hospital, Misan Province, Iraq, over nine years from 23rd January 2010 to 14th July 2018.

Study size
The total number of patients included in this study was 1510 and included all those that attended to outpatient clinics.

Participants
The cases were aged 12-50 years, of both genders, suffering from migraine headaches according to the criteria of the International Classification of Headache Disorders (ICHD-III b version) 4,5 .
Inclusion criteria were: 1-8 attacks over four weeks, attacks fulfilling the International classification of Headache Disorders migraine diagnostic criteria, and absence of secondary causes of headaches.
Exclusion criteria: migraine onset at age >50, headaches attributable to underlying organic disorders, or no migraine attacks during the four weeks of assessment (this is made case by case for each patient from the point of diagnosis till the end of the study).

Data collection
All data were collected from participant records.
For all patients a full medical history and family history of migraine headaches was obtained, and a thorough clinical examination performed, including general examination, assessment of vital signs, Glasgow Coma Scale (GCS), neurological and physical examinations (as per the Seattle Children's Hospital Research Foundation migraine general assessment pathway).
All participants were assessed by a standard questionnaire from the Migraine Relief Center and a 4-week headache diagnostic diary procedure (as per the Migraine Trust guidelines) 4,18 . Disability due to acute migraine attacks was determined using the Migraine Disability Assessment Scale (MIDAS) questionnaire.

Statistical analysis
We implemented standard descriptive statistics and data analysis using IBM SPSS Statistics Software (version 20.0, SPSS, Inc., Chicago, Illinois, USA). All p-values < 0.05 were considered statistically significant for on-sample t-test. Mean and standard deviation were used to present data.

Ethical considerations
Written informed consent was obtained from the patients or the parents/guardians of minors for those below age of 18 years, for participating in this study, and was conducted according to the ethical standards established by the 1964 Declaration of Helsinki. The Medical Ethical Committee of Misan University approved this study (code:270000425).

Results
A total of 1,412 patients with a migraine headache were included, including 1,100 women (77.9%) and 312 men (22.1%); women/men ratio of 3.5:1. Median age ±SD was 21 ± 5.42 years. The mean age at first attack was 17 ± 4.91 years. About 30 ± 15.79 mean±SD of the patients reported a family history of migraine (Table 1).
Migraine without aura was the most common (69.4%) subtype. The mean frequency of attacks was 2 ± 4.63 days per month. The mean duration of attack was 24 hours. Nausea and vomiting, photophobia and other nonspecific symptoms were experienced by 15%, 20%, and 12.5% of the patients respectively, while the remaining patients experienced non-specific prodromes 1-1.5 hours before the attacks (Table 1). About 27% of the patients in this study experienced aura during the period of Table 1. Clinical characteristic of a prospective cross-sectional migraine patients in Misan province, Iraq from 2010 to 2018.

Parameters
Type of a migraine *ICHD-3b Code study, the most common being migraine with aura, but also aura without a headache and aura with migraine (Table 1).
Migraine prevalence rates per year in this study are shown in Table 2; migraine without aura was the highest recorded in 2016 as 73%, which is common subtype with the mean 67.6 ± 2.934. Migraine with aura, in 2012 recorded 10.2%. Chronic migraine with continuous pain presented in 7.5% in 2013, whereas prevalence of chronic migraine (alternative criteria) in 2014 was 3.4%. In 2013, migraine with typical aura recorded a high rate as 4.3%, but in 2010, it was reported 1.2% had typical aura without headache. The medication-overuse headache reported a high rate in 2013 as 3.7%. Pure menstrual migraine without aura, and episodic syndromes-childhood periodic syndromes reported high rates in 2018 as 5.5% and 1.8%, respectively. Finally, others subtypes of migraine present in 2017 with a high prevalence rate 2.3%.
The duration (hours) and frequency (days per month) for migraine without aura, migraine with aura and chronic migraine with continuous pain exhibited are shown in Table 4. We also considered disabling symptoms, systemic blood pressure, changes in consciousness level (assessed by GCS in adult and pediatric groups, and trigger factors in relation to migraine without aura,  migraine with aura and chronic migraine with continuous pain ( Table 4).
Out of 1,412 patients with a migraine headache, enrolled in this study from 2010 to 2018, only a minority reported serious complications, such as chronic persistent headaches in 6.5% especially in migraine without aura and migraine with aura events (Table 5). The medication overuse headache 2.6% and thromboembolic stroke 0.7%, also recorded (Table 5).

Discussion
In this study, 1,412 patients diagnosed with migraine headaches, according to established criteria 4,19,20 were analyzed. Women were more affected (77.9%) than men (22.1%), and such a  3.5/1 female/male ratio is consistent with the results of largescale studies 6,10,12 . This skewed sex ratio is mostly due to hormonal variation during menstruation and pregnancy, and to genetic predisposition 1 . The median age of first onset in this study was 21 ± 5.42 years, with range 12-45 years. Migraine without aura was the most common subtype (69.4%) in the sample. Childhood migraine prevalence was 0.8%, including migraine with aura and episodic syndromes/childhood periodic syndromes. The pediatric Glasgow Coma Scale (GCS) score in this subgroup ranged between 3 and 14, but this result was not significant. Patients experienced non-specific prodromes 1-1.5 hours before the attacks, including nausea, vomiting, and photophobia. About 27% of the patients in this study experienced transient aura during the study period. Visual aura was the most common (50%), while unilateral sensory symptoms, tingling and numbness was the second most frequent type of aura and transient dysphasic speech disturbance was the third, while motor symptoms were very rare. Aura occurs because of the spreading of a wave of depolarization (cortical spreading depression) 20 , and is associated first with a reduction, and then an increase in blood flow, and affects the parieto-occipital cortex 10 . The mean frequency of acute migraine attacks was 2 ± 4.63 days per month; in very few patients (0.5%) the frequency of the attacks was 14-16 days per month, especially in patients suffering from migraine with aura and chronic migraine. The mean duration of acute attacks was 12-24 hours in 60% of the patients. The severity of acute attacks depends on their frequency, duration and disabling symptoms; in general, most of the acute attacks were moderate to severe 12 . In our study about 8% of migraine patients suffered from debilitating, disabling and incapacitating symptoms. Symptoms were considered disabling, if they reduced by half or more the patient's ability to work, or more generally to do what needs to be done, or at least 24 hours, thus impairing quality of life 2,11,18 . In this study about 10% of the patients had acute attacks associated with systemic hypotension (systolic blood pressure (BP) < 90 mmHg), especially in a migraine with aura, and women. Furthermore, systolic hypertension (≥ 150 mmHg) was found in 1.5% of the patients, especially in women. We found variation in the estimates of migraine prevalence and clinical characteristics symptoms, depending on the stage of the migraine (prodrome, aura, acute attack, and postdrome). One third of patients had a family history of migraine, showing that migraine is an inherited condition accompanied by episodic symptoms arising in the brain 10,19-21 . In our study chronic migraine with continuous pain and chronic migraine (according to alternative criteria) represented about 9% of the total sample, and had a detrimental influence on the patients' lives, impacting socioeconomic functioning and quality of life. It usually develops from an episode of migraine, with or without aura, which turns into a continuum, with an undetermined annual conversion rate 20,22 . Another important subtype of a migraine is medicationoveruse headache (MOH), which represented about 2.6% of the whole sample.
The limitation of this study were that it was a single center, local, regional, monophasic study and there was high financial cost involved. Therefore, for future studies we recommend a multicentric, national, and diphasic study to obtain more information and data to help advance management of migraine.

Conclusions
In our study, we observed that migraine causes a headache resulting in episodes of temporary functional disability and women suffered more than men (ratio of 3.5:1). The mean age at first attack was a young age, and a family history of migraine highly altered distribution. Migraine without aura was the most common type, and symptoms including nausea and vomiting and photophobia were experienced by patients, which were used to diagnose migraines. Experienced aura was the most common migraine with aura, but also aura without a headache and aura with migraine were prevalent; therefore, it is important to differentiate between migraine subtypes. Visual aura was the most common aura, while motor symptoms were very rare. Chronic persistent headaches were a common complication recorded. These features provide evidence for the creation of screening tools in migraine prevention migraine.

Soodeh Razeghi Jahromi
Shahid Beheshti University of Medical Sciences, Tehran, Iran In methods you mentioned that 4-week headache diagnostic diary was used. As for assessing MIDS you need to record headache characteristics for 3 months, please explain how you assessed MIDAS based on one month headache dairy.
Please check the potential significant differences of confounding factors like age, sex, and prophylactic and abortive medication. For better comparison of headache characteristic, please adjust for the confounding factors which are significantly different between studied groups. If you have the data about abortive and prophylactic medication and the patients' comorbidities, it would be better to bring them in your article.
In table 4, by "migraine with/without aura" you meant episodic migraine with/without aura? If yes please revise it in the manuscript.

If applicable, is the statistical analysis and its interpretation appropriate? Partly
Are all the source data underlying the results available to ensure full reproducibility? Partly

Are the conclusions drawn adequately supported by the results?
Partly However, they did not assess the scores of standardized questionnaires such as the MIDAS or HIT-6, which constitutes a limitation.

Is the work clearly and accurately presented and does it cite the current literature? Partly
Is the study design appropriate and is the work technically sound? Partly

Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.

Suggested revisions:
The first sentence of the abstract background must be revised to: TTH is the most common primary headache disorder (ref: https://www.who.int/news-room/factsheets/detail/headache-disorders). Migraine might be the most common "disabling", but the word is missing.

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There's a point here to consider that if this is a longitudinal or cross sectional? Over 9 years have the patients been followed up? Or at one time point they have been seen in a period of 9 years? i.e. each patient has been only seen once or more during 9 years? ○ The age range of 12 to 50 years includes puberty and pediatric migraine, the authors need to separate data presentation of children and adolescence from adults. It seems here teat pooled data have been presented.

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Another point is the classification and diagnosis of migraine. The authors have mentioned that they have done this study with the aim of understanding migraine and to come in with better diagnose. This is a bit complicated, because we have the IHC (that authors have also followed the beta version) that is published and one must follow in diagnosis. Therefore, the suggestion is that perhaps authors wanted to know what are the specific characteristics of migraine patients in this geographical location, ethnic background, or racial effects on pattern and characteristics if we consider that most patients have been local with same ethnic and racial background? This must be clarified so that the purpose of the study can become clear. Besides, authors might have proposed that it might differences from rest of population or other parts of the world, or other racial or ethnic backgrounds, and that is why they wanted to characterize there for better clarification of some specific factors that might influence special populations around the word differently.

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What about the menstrual versus non-menstrual migraine. Did the authors follow that?
○ What about the drugs (any drug, including analgesics) and comorbidities? Hormone therapy is only for women or? ○ Conclusion needs revision, because the authors need to compare their data with general data available or some other studies around the word to identify the commonalities and differences that might help in understanding differences of racial and ethnic differences in clinical characteristics of migraine patients.

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Besides, management means prevention, treatment, or both strategies here, is that correct? Authors need to discuss how based on their findings they may consider different strategies because this study does not really concern management so that cannot be concluded here.

Is the work clearly and accurately presented and does it cite the current literature? Partly
Is the study design appropriate and is the work technically sound? Partly