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Abstract

Background

The socio-economic impact of migraine is mostly related to work loss either by absenteeism or decreased work performance. Migraine-associated cognitive dysfunction during an attack may contribute to these difficulties.

Objective

The objective of this article is to analyze the presence and relevance of cognitive symptoms during migraine attacks and to relate their intensity and symptom-related disability with other migraine-defining symptoms.

Methods

Consecutive migraine patients of a headache clinic completed diaries scoring each migraine symptom (including cognitive symptoms) intensity and symptom-related disability.

Results

Of 100 consecutive patients included in this study, 34 (all females, age average 31.8 ± 8.8 years) returned information on 229 attacks, on average 6.7 per participant. Every symptom’s intensity was always rated slightly higher than the disability it caused. Pain was the symptom scored with the highest intensity and disability, followed by cognitive symptoms (difficulty in thinking and worsening with mental effort) and photo- and phonophobia. Scoring was independent of any of the clinical variables. Attack intensity and disability scores correlated with intensity and disability from pain and from worsening with mental effort.

Conclusions

Attack-related cognitive symptoms are intense and disabling. Some attack-related cognitive symptoms correlate to intensity and disability subjectively attributed to the migraine attack. Cognitive performance should be addressed as a valuable secondary endpoint in trials of acute migraine treatment.

Keywords

Migraine cognitive symptoms disability headache

Introduction

Cognitive symptoms, although reported frequently by patients during migraine attacks (1 –7), are not considered as core symptoms of the migraine diagnosis (8). Patients self-report being only 46% effective when working during migraine (9), but which part of this disability is related to cognitive dysfunction is undetermined.

Cognitive symptoms often precede migraine attacks, being very frequent in the premonitory phase of migraine (10 –12) and being highly predictable of an attack (1). Disturbances of speech or thought are also described in the time gap between the end of the aura and the onset of pain (13). Cognitive difficulties can persist after the headache phase as postdromes (1,6,11,12,14) and may not be relieved by acute migraine medication (5,15). Cognitive symptoms are not a usual endpoint of acute treatment trials in migraine.

Cognitive dysfunction during migraine has been documented in some studies (16 –20), with involvement of the domains of processing speed (20), working memory, visual-spatial processing (16 –18), immediate and sustained attention and verbal learning (19,20). This is suggestive of preferential dysfunction of the pre-frontal and temporal cortices during migraine attacks.

These migraine-related clinical manifestations on cognition are important evidence of functional brain changes underling migraine pathophysiology and should be valued as therapeutic targets to be dealt with when evaluating acute treatment drugs.

Our objective was to analyze the presence and subjective relevance of cognitive symptoms during migraine attacks, by collecting data prospectively on paper diaries regarding the intensity and disability of cognitive and migraine-defining symptoms (8) in each attack of migraine patients.

Participants and methods

Population

Participants were recruited consecutively at a headache outpatient clinic, during either first or follow-up visits during the first semester of 2013 and invited to participate. Inclusion criteria were: a) age between 18 and 55 years; b) minimum education of nine years; c) minimum headache frequency of one monthly attack in the three months preceding inclusion; d) written informed consent; and e) diagnosis of definite episodic migraine with or without aura according to the International Classification of Headache Disorders, second edition (ICHD-II) (21).

Exclusion criteria were simultaneous presence of migraine (either with or without aura) and other headache types that could present with attack-related or non-attack-related cognitive symptoms, including tension-type headache, chronic migraine with or without medication overuse and migraine aura without headache. A history of past or current alcohol or drug dependence or abuse and the presence of a severe or uncontrolled medical or psychiatric disorder were also exclusion factors. The study protocol was approved by the institution’s review board and ethics committee.

Study design

Recruitment and inclusion were carried out at a regular clinic visit by a headache specialist who verified the patient eligibility criteria and carried out a standard clinical evaluation. After informed consent had been obtained, data were collected including verification of ICHD-II criteria for diagnosis, gender, age, literacy, disease duration, current attack frequency, duration and intensity, attack and aura characterization, use of prophylactic treatment and detailed medical and pharmacological history. At the end of the routine appointment, the patient was asked to complete the subjective cognitive impairment scale for migraine attacks (Mig-SCog) (7) and Headache Impact Test-6 (HIT-6) (22) scales. The Mig-SCog (7) is a nine-item questionnaire that quantifies self-reported subjective cognitive symptoms during migraine attacks and its score can run from 0 to 18, the higher scores representing higher frequency of cognitive symptoms; the HIT-6 (22) is a six-item standardized questionnaire that measures the impact of migraine on functional status and well-being. Patients were also given 10 headache diaries, one for each migraine attack, including information about timing of the attack (start and end of pain, timing of medication and of completion of the diary), medication use (acute and rescue medication) and about intensity and disability related to each attack. Attack treatments were grouped into four categories: triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics (including combination analgesics with codeine, caffeine or ergots) and antiemetic drugs in combination (either with triptan, NSAID or analgesic). On one side of the sheet, patients were asked to rate each migraine symptom’s intensity on a 0–10 visual analog scale (VAS) for that specific migraine attack (intensity of pain, nausea, photophobia, phonophobia, kinesiophobia (23), worsening with physical effort, worsening with mental effort, difficulty in thinking and global attack intensity). On the reverse side of the sheet, patients were asked to rate each migraine symptom-related disability on a 0–10 VAS scale for that specific migraine attack (disability attributed to pain, nausea, photophobia, phonophobia, kinesiophobia (23), worsening with physical effort, worsening with mental effort, difficulty in thinking and global attack disability).

Diaries were returned at follow-up appointments occurring before December 31, 2013.

Statistical analyses

Statistical analysis used Stata release 12 (Stata Corp., College Station, TX, USA). Generalized estimating equation (GEE) with gamma family and a log link, with an AR(1) correlation structure and robust standard errors based on the Huber-White-sandwich variance estimator was used to analyze the relationships between scores of the different migraine symptoms adjusted by all other symptoms. A correlation coefficient between scores of any two symptoms was obtained with Spearman’s rank correlation after averaging each patient’s symptom scores over all the episodes. GEE analyses using global attack intensity and global attack-related disability as the dependent variables were performed. Significance was set at the 5% level (p < 0.05). The Holm-Bonferroni procedure was used to correct p-values for multiple testing.

Results

Population

One hundred patients were included in this study, eight males, with an age average of 31.2 ± 7.5 years, of whom 13 had migraine with aura and 87 without aura. There were nine (14%) dropouts for several reasons (losing their diaries, forgetting to bring the diary to the scheduled follow-up, not having had time to fill out the diaries or returning very incomplete diaries that were not included; one patient emigrated); 57 patients failed to attend the scheduled follow-up.

Thirty-four patients returned 229 impact diaries, an average of 6.7 ± 3.0 (range 1 to 10) per participant. Patients not returning their diaries were similar in their demography and headache characteristics to participants (Table 1) but were excluded from further analysis.

Table 1.

Clinical characteristics of participants and non-participants.

	Non-participating	Participating
	patients	patients	p
Total number	66	34	–
Gender (female:male)	58:8	34:0	n.s.
Age (years, average ± SD)	30.9 ± 6.8	31.9 ± 8.8	n.s.
Literacy (years, average ± SD)	14.8 ± 1.5	15.4 ± 1.3	n.s.
Associated diseases (yes: no)	19:47	11:23	n.s.
Migraine (with:without aura)	8:58	7:27	n.s.
Disease duration (years, average ± SD)	15.1 ± 9.2	15.4 ± 9.7	n.s.
Attack frequency (monthly, average ± SD)	5.1 ± 4.8	5.8 ± 5.2	n.s.
Preventive medication (yes:no)	25:41	13:21	n.s.
HIT-6 (score, average ± SD)	62.9 ± 4.2	63.4 ± 4.4	n.s.
Mig-SCog (score, average ± SD)	7.6 ± 4.1	8.6 ± 4.1	n.s.

HIT-6: Headache Impact Test; Mig-SCog: subjective cognitive impairment scale for migraine attacks; SD: standard deviation; n.s.: non-significant. p > 0.010.

The study sample consisted of 34 females, one left-handed, of whom six had migraine with aura and 28 without aura, with an age average of 31.8 ± 8.8 years. Average HIT-6 score was 63.4 ± 4.4 (range 50 to 70), reflecting a moderate to severe impact of migraine although 68% of the sample had five or fewer headache days in the month preceding inclusion. Mig-SCog score average was 8.6 ± 4.1 (range 2 to 18), a medium score of subjective cognitive complaints.

Medical comorbidities were present in 11 (32%) patients, mostly vascular risk factors (high cholesterol and obesity, two patients each), followed by thyroid dysfunction (two), asthma or allergies (two), mild anxiety or depression (two) and others (congenital glaucoma and esophageal reflux or gastritis). Twenty (67%) of these patients were on birth control methods (19 oral contraception, one local hormonal device) and 13 (43%) on prophylactic headache treatment (amitriptyline two, topiramate six, propranolol three, valproic acid two). Five (15%) patients were on other medical treatments (lower-dose selective serotonin re-uptake inhibitor (SSRI) antidepressants two; asthma treatment, thyroid hormone, statin and topic glaucoma treatment, one patient each).

Headache diaries were completed on average 14.2 ± 7.5 hours (range 4.1 to 26.4) after the end of each attack. The average time interval from inclusion to handing back of the diaries was 96.1 ± 64.2 days (range 19 to 270 days, 8.8 months).

Migraine attack characteristics

Average duration of the studied attacks was 20.0 ± 14.3 hours (range 4.2 to 67.2 hours). Analyzing attack clinical features, 207 (90.4%) fulfilled the ICHD-II criteria for migraine, 19 (8.3%) for probable migraine and only two (0.9%) could be classified as probable tension-type headache. On average, patients waited 3.0 ± 4.5 hours (range 5 minutes to 20 hours and 45 minutes) before taking their acute medication.

All the patients took acute medication in at least one of their attacks; most of the patients (18, 52.9%) took it in all reported attacks and 12 (25%) took it in more than two-thirds of attacks.

Of the 229 attacks studied, 221 (96.5%) were treated. The first choice of abortive treatment in this sample were triptans (48.4% of treated attacks), either alone (38.5%) or in combination with an antiemetic drug (5.9%) or with an NSAID (4.1%). NSAIDs were the second choice in 40.7% of patients (alone 29.9% or with an antiemetic 6.8%). Analgesics, combination analgesics with codeine, caffeine or ergots were used in 9% of attacks, in 1.8% adding an antiemetic.

Rescue medication was used in 45.7% (101) of initially treated attacks and taken on average 4.5 ± 5.2 hours (range 15 minutes to 20.5 hours) after the initial therapy. The first choice of rescue treatment were NSAIDs (43.6%, with 5% adding an antiemetic and 5.9% a triptan). Triptans were chosen secondly as rescue therapy by 35.6%, adding an antiemetic in 3.0%. Thirteen percent of attacks required repeated rescue medication. Analgesics, combination analgesics with codeine, caffeine or ergots represented the choice in 10.9% of attacks, in 1% adding an antiemetic.

Symptom intensity and disability

Results of scoring symptom intensity and symptom-related disability on a 0–10 VAS scale are depicted in Table 2. Intensity was rated slightly higher than disability, in all symptoms. Pain was the symptom with higher intensity and disability, followed by cognitive symptoms (difficulty in thinking and worsening with mental effort) and photo- and phonophobia.

Table 2.

Average scores of symptom intensity and symptom-related disability. On a 0–10 VAS scale.

	Intensity (0–10 VAS)		Disability (0–10 VAS)
	Average ± SD	Range	Average ± SD	Range
Global—of the attack	5.5 ± 2.1	0.9–10	4.2 ± 2.0	0–9.3
Pain	6.0 ± 1.8	1.7–10	5.2 ± 2.2	0.7–9.9
Nausea	3.2 ± 2.1	0–8.6	2.5 ± 2.1	0–8.6
Photophobia	4.4 ± 2.3	0.4–9.6	3.5 ± 2.6	0–9.6
Phonophobia	4.3 ± 2.3	0.3–10	3.5 ± 2.6	0–9.4
Kinesiophobia	4.0 ± 2.0	0–8.6	3.2 ± 2.2	0–8.7
Worsening with physical effort	4.2 ± 2.1	0–9	3.6 ± 2.2	0–8.6
Worsening with mental effort	4.9 ± 2.0	0.4–9	4.1 ± 2.2	0–8.8
Difficulty in thinking	4.8 ± 2.1	0.3–9	4.1 ± 2.2	0–8.8

VAS: visual analog scale.

Correlations and regression analysis

Age was found to correlate with disease duration (Spearman’s rho 0.659, p < 0.0001) and inversely with attack frequency (Spearman’s rho –0.475, p = 0.005). Reported attack duration correlated with time to take rescue medication (Spearman’s rho 0.645, p < 0.0001) after initial acute treatment, but not with time to take initial acute treatment. There were no other significant correlations between disease-related variables (age, literacy, disease duration, attack frequency, reported attack duration and number of attacks reported, HIT-6 and Mig-SCog scores).

Correlation coefficients between using each type of acute medication and intensity and disability of cognitive symptoms (worsening with mental effort and difficulty in thinking) are depicted in Table 3; intensity of cognitive symptoms was correlated with the use of triptans or analgesics as first choice in rescue treatment; disability of cognitive symptoms related to all drug groups except antiemetics in combination with any other drug. Intensity and disability of cognitive symptoms had no correlation to the need of rescue treatment.

Table 3.

Initial acute treatment correlations with attack-related cognitive symptoms.

		Spearman correlation coefficient	95% Confidence interval		p-value
Intensity of worsening with mental effort	Triptans	0.396	0.163	0.630	0.001^a
	NSAIDs	0.138	−0.018	0.294	0.083
	Analgesics	0.539	0.228	0.851	0.001^a
Antiemetic drugs plus	0.082	−0.157	0.320	0.502
Disability of worsening with mental effort	Triptans	0.653	0.293	1.012	<0.0001^a
	NSAIDs	0.427	0.201	0.652	<0.0001^a
	Analgesics	0.847	0.536	1.157	<0.0001^a
Antiemetic drugs plus	0.217	−0.161	0.594	0.261
Intensity of difficulty in thinking	Triptans	0.433	0.112	0.754	0.008^a
	NSAIDs	0.198	−0.024	0.420	0.081
	Analgesics	0.661	0.178	1.144	0.007^a
Antiemetic drugs plus	0.083	−0.210	0.376	0.578
Disability of difficulty in thinking	Triptans	0.627	0.261	0.992	0.001^a
	NSAIDs	0.359	0.116	0.602	0.004^a
	Analgesics	0.775	0.429	1.120	<0.0001^a
Antiemetic drugs plus	0.227	−0.117	0.570	0.196

NSAIDs: nonsteroidal anti-inflammatory drugs. ^aSignificant correlation, p < 0.010.

Correlations found between intensities of each migraine symptom were scarce—intensity of pain correlated only with intensity of worsening with mental effort (p = 0.02), intensity of nausea with intensity of kinesiophobia (p < 0.001), intensity of photophobia with that of phonophobia (p < 0.001), intensity of kinesiophobia with worsening with physical effort (p < 0.001), the degree of worsening with physical effort related to worsening with mental effort (p < 0.001) and with intensity of difficulties in thinking (p = 0.002); finally the degree of difficulty in thinking correlated with worsening with mental effort (p < 0.001). Global attack intensity was correlated with pain intensity and worsening with mental effort (Figure 1).

Figure 1.

Correlation of each symptom’s intensity with global attack intensity.

Correlations between disability scoring for each migraine symptom were also analyzed; disability of pain had no significant correlation with any other symptom. Disability due to nausea correlated with disability of kinesiophobia (p < 0.0001), disability of photophobia correlated with that of phonophobia (p = 0.002), phonophobia also correlated with the disability attributed to difficulty in thinking (p = 0.003), and disability of kinesiophobia with that of phonophobia (p < 0.001). Disability of worsening with physical effort correlated with disability due to kinesiophobia (p = 0.03) and disabilities of difficulty in thinking and worsening with mental effort were also correlated (p < 0.001). Attack disability correlated to pain and worsening with mental effort (Figure 2).

Figure 2.

Correlation of each symptom’s related disability with global attack disability.

The correlation of each symptom-related disability with symptom intensity revealed that disability of nausea correlated with intensity of nausea (p < 0.001), intensity of worsening with mental effort (p = 0.01) and intensity of difficulty in thinking (p = 0.006). Disability of some symptoms correlated only with disability of the same symptom, such as with photophobia (p < 0.001), phonophobia (p < 0.001), kinesiophobia (p = 0.004) and worsening with physical effort (p = 0.004). Global attack disability also correlated with global attack intensity (p = 0.008). Disability due to pain, worsening with mental effort and difficulty in thinking had no correlations with any of the migraine symptoms’ intensity.

GEE analysis using global attack disability as the dependent variable failed to show an association with any of the studied variables (age, literacy, comorbidities, current medication, current migraine prophylactics, migraine diagnosis, disease duration, attack frequency and duration, HIT-6 and Mig-SCog scores) with the exception of global attack-related intensity. Gender was not included in the analysis because all the individuals were females.

Discussion

This prospective study of 229 migraine attacks revealed that patients are able to score intensity and disability of specific migraine attack-related symptoms independently. Patients’ scores of each symptom’s intensity were higher than the corresponding symptom-related disability scores, possibly reflecting self-perceived individual coping mechanisms during attacks although we cannot exclude a chance association. Among all migraine symptoms, pain was rated with the highest intensity, had the highest disability during attacks and was correlated with global attack intensity and attack-related disability, which supports the current view that pain control measures (pain freedom, pain relief and sustained pain freedom) are an appropriate primary endpoint of drug trials for the treatment of acute migraine attacks (24).

Cognitive symptoms sought (worsening with mental effort and difficulty in thinking during attacks) were scored in the second rank after pain both in intensity and attack-related disability, followed by photophobia, phonophobia, worsening with physical effort, and kinesiophobia. Unexpected findings were the low scores attributed to nausea intensity and associated disability that we speculate to be related to the early use of an antiemetic drug (in around 13% of treated attacks), associated with an analgesic, although our study design did not allow us to test this hypothesis.

Attack-related disability was highly correlated to both pain and worsening with mental effort, suggesting that some aspects of cognitive dysfunction have a role in migraine disability, independently of other symptoms. However, with our study design, we were unable to estimate the proportion of the variability of the attack-related disability that might be explained by cognitive symptoms.

Current guidelines include some other migraine-associated symptoms, such as nausea, photophobia and phonophobia and a measure of total migraine freedom (instead of simple pain freedom) as secondary endpoints in acute migraine treatment trials (24). These guidelines do not include cognitive endpoints nor other migraine-related symptoms. This fact reflects not only the lack of therapeutic agents that are able to treat all migraine symptoms but also influences the perceived lack of control of symptoms other than pain—if we are not measuring, we will never know. The inclusion of impact and quality of life measures, medication needs and other unconventional endpoints in prophylactic drug trials has allowed the evaluation of subtle benefits in difficult populations (25). The inclusion of measurements of cognitive impact or disability could help establish differences between acute medication profiles. To our knowledge, only two studies evaluated cognitive performance during an attack and after treatment (26,27) as outcome measures.

In our study, none of the clinical variables analyzed had an influence on symptom intensity or disability scoring. For most symptoms, their related disability correlated with its intensity, reflecting that intensity is related to the disability or symptom impact. Disability due to pain and to cognitive symptoms (worsening with mental effort and difficulty in thinking) failed to demonstrate a relationship to each symptom’s intensity, suggesting that the symptoms themselves are not the major factor determining their related disability.

Intensity of some symptoms was, however, related. Examples include kinesiophobia and worsening with physical effort, which is understandable if we acknowledge that kinesiophobia is a part of the avoidance behavior observed during migraine attacks, due to the aggravation of pain or enhancement of its throbbing character by head movement and/or psychical effort (23); nausea and kinesiophobia intensity were also correlated, which can be related to increased prevalence of motion sickness in migraine patients (28), as is supported by the fact that disability of kinesiophobia and disability of nausea and worsening with physical effort were also correlated. The degree of worsening with physical effort was associated with the degree of worsening with mental effort and of difficulty in thinking, probably reflecting the patients’ perception of the need to stop all activity.

Intensity of photo- and phonophobia being related reflects the fact that sensitivity to light and sound are believed to be the clinical expression of impairment of sensory processing during attacks (29), which is supported by the fact that their associated disabilities are also correlated; using the same line of thought difficulty in thinking and worsening with mental effort intensities and disabilities are also related as both can be interpreted as cognitive dysfunction-related phenomena (7,20).

Interesting enough, pain intensity was associated with the degree of worsening with mental effort, which may reflect higher impact of the attack, as pain intensity has been shown to have some influence in attack-related cognitive changes (20). The fact that we analyzed treated attacks is an obvious limitation of this study, as treatment influences symptom intensity and symptom-related perceived disability. Treatments can also act as confounders, for cognitive symptoms and nausea can be side effects of migraine acute medications (15,30), although in some reports enhancement of cognitive function was reported after treatment (31,32). We were able to identify some associations between some of the initial acute treatments used and cognitive symptoms, although the interpretation of these data is conflicting. The association of the use of triptans and combination analgesics with a higher intensity of cognitive symptoms might be either a consequence of drug effects or of the choice of such more effective drugs in face of a higher intensity attack. Taking antiemetics doesn’t seem to correlate with cognitive symptom impact yet this group was heterogeneous (including patients taking triptans, NSAIDs and analgesics). Our study design does not allow an accurate determination of the effect of each treatment in cognitive functioning, although this is an important topic for future research.

Our patient sample was clinic-based, reflecting episodic migraine patients with some comorbidities and a moderate to high impact disease (high HIT-6 score), some (38%) requiring migraine prophylactic medication. Migraine prophylactics and other chronic medications can influence cognitive performance and subjective symptom reporting (33). The comorbidities and concomitant treatments of our study population were scarce and mild and we assumed they had little influence on cognitive or other migraine-related symptoms, as reflected in the GEE analysis. Although the sample was clinic-based, it does not represent the usual population of tertiary headache centers (high-frequency attacks, high need for prophylactics, medication overuse and frequent comorbidities) nor does it apply to the population-based low-impact migraineur, which are limitations to the generalization of our findings. On the other hand, it was useful to select the migraine patients in whom disability is almost exclusively related to the attacks (i.e. having low interictal impact) and who have a high probability of being active and employed, strengthening the view that episodic attack-related cognitive dysfunction contributes to disability. The possibility of a recall bias is also a limitation that we attempted to minimize by having the patients report as soon as possible (on average 14 hours) after each migraine attack.

The most important limitation of this study is the high attrition, as only 35% of the patients returned their diaries. However, participating patients were similar to non-participating patients in all clinical variables, including disease impact and Mig-SCog scores. There were 14% dropouts, and other potential reasons for the high attrition include the lack of financial compensation for the participants and the demography of the sample that consisted of young working adults with a moderate impact long standing disease who failed to return to the follow-up appointment within the estimated time frame.

The benefits of treating the attacks early (first two hours, when the pain is mild (34)) are common knowledge for sufferers and have been documented in clinical trials and cost-effectiveness studies (35), leading to better medical counseling especially in headache clinics such as ours. An interesting observation of this study was that our population, despite having a high-impact migraine and being treated and coached in a headache clinic, still waited on average three hours before taking their acute medication after the onset of the attack. There may be many reasons explaining this delay such as fear of side effects, availability of medication or cost (34), yet another speculative contributing factor could relate to cognitive dysfunction, such as lack of initiative or mental slowing, to explain this delay.

There is some evidence that reversible cognitive dysfunction occurs during migraine attacks (36,37), corroborating patients’ spontaneous and subjective complaints (1,7). Migraine subtypes and disease severity may influence the expression of such symptoms (37). The mechanisms explaining these symptoms are still elusive yet functional imaging has contributed to document changes in the human cingulated and pre-frontal cortex (38) during migraine attacks, as well as in the insula and temporal lobe (39). Interictal functional connectivity changes on executive resting state and salience networks have been documented (40,41), as well as cortical gray matter differences of migrainous brains (42 –44).

One aspect of cognitive dysfunction during attacks (worsening with mental effort) was found to correlate with attack-related disability, supplanting disability caused by nausea, photo- and phonophobia, which is a reflex of its importance to migraine sufferers.

In conclusion, cognitive symptoms are important contributors to migraine attack-related disability. The cutting edge of new acute migraine drugs should evaluate the return to normal function as a primary endpoint, including cognitive-related measures to evaluate the efficacy of such drugs in the return to normal cognitive performance, instead of simple freedom of pain.

Clinical implications

Pain and cognitive dysfunction during the migraine attack are correlated with total attack disability.

According to the perception of migraineurs, pain is the symptom that most contributes to attack-related disability, followed by cognitive symptoms that produce higher disability than nausea, photo-, phonophobia and kinesiophobia.

Cognitive performance should be valued as a secondary endpoint in clinical trials of acute migraine drugs.

Footnotes

Acknowledgements

Author contributions: Raquel Gil-Gouveia, Isabel Martins and António Oliveira were responsible for conception and study design, Raquel Gil-Gouveia for data acquisition, Raquel Gil-Gouveia and António Oliveira for data analysis, and Raquel Gil-Gouveia and Isabel Martins for data interpretation. Raquel Gil-Gouveia drafted the manuscript, António Oliveira and Isabel Martins revised it critically and all the authors agreed to the final version submitted. All authors agree to all aspects of the work and revised it for integrity and accuracy.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Giffin

Ruggiero

Lipton

. Premonitory symptoms in migraine: An electronic diary study. Neurology 2003; 60: 935–940.

El Hasnaoui

Vray

Richard

. Assessing the severity of migraine: Development of the MIGSEV scale. Headache 2003; 43: 628–635.

Stewart

Lipton

Simon

. Reliability of an illness severity measure for headache in a population sample of migraine sufferers. Cephalalgia 1998; 18: 44–51.

Lipton

Kolodner

Bigal

. Validity and reliability of the Migraine-Treatment Optimization Questionnaire. Cephalalgia 2009; 29: 751–759.

Caro

O’Brien

. Migraine therapy: Development and testing of a patient preference questionnaire. Headache 1998; 38: 602–607.

Ng-Mak

Fitzgerald

Norquist

. Key concepts of migraine postdrome: A qualitative study to develop a post-migraine questionnaire. Headache 2011; 51: 105–117.

Gil-Gouveia

Oliveira

Martins

. A subjective cognitive impairment scale for migraine attacks. The MIG-SCOG: Development and validation. Cephalalgia 2011; 31: 984–991.

Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders. 3rd ed. (beta version). Cephalalgia 2013; 33: 629–808.

Gerth

Carides

Dasbach

. The multinational impact of migraine symptoms on healthcare utilisation and work loss. Pharmacoeconomics 2001; 19: 197–206.

10.

Kelman

. The premonitory symptoms (prodrome): A tertiary care study of 893 migraineurs. Headache 2004; 44: 865–872.

11.

Rossi

Ambrosini

Buzzi

. Prodromes and predictors of migraine attack. Funct Neurol 2005; 20: 185–191.

12.

Quintela

Castillo

Muñoz

. Premonitory and resolution symptoms in migraine: A prospective study in 100 unselected patients. Cephalalgia 2006; 26: 1051–1060.

13.

Blau

. Classical migraine: Symptoms between visual aura and headache onset. Lancet 1992; 340: 355–356.

14.

Blau

. Migraine postdromes: Symptoms after attacks. Cephalalgia 1991; 11: 229–231.

15.

Goadsby

Dodick

Almas

. Treatment-emergent CNS symptoms following triptan therapy are part of the attack. Cephalalgia 2007; 27: 254–262.

16.

Mulder

Linssen

Passchier

. Interictal and postictal cognitive changes in migraine. Cephalalgia 1999; 19: 557–565. discussion 541.

17.

Farmer

Cady

Springfield

. Cognitive efficiency during migraine. Neurology 1999; 52(Suppl 2): A469–A470.

18.

Meyer

Thornby

Crawford

. Reversible cognitive decline accompanies migraine and cluster headaches. Headache 2000; 40: 638–646.

19.

Black

Horn

Miller

. Migraine headache disorder and cognitive abilities. Headache 1997; 37: A301–A302.

20.

Gil-Gouveia

Oliveira

Martins

. Cognitive dysfunction during migraine attacks: A study on migraine without aura. Cephalalgia 2015; 35: 662–674.

21.

Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004; 24(Suppl 1): 9–160.

22.

Kosinski

Bayliss

Bjorner

. A six-item short-form survey for measuring headache impact: The HIT-6. Qual Life Res 2003; 12: 963–974.

23.

Martins

Gouveia

Parreira

. Kinesiophobia in migraine. J Pain 2006; 7: 445–451.

24.

Tfelt-Hansen

Pascual

Ramadan

. Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators. Cephalalgia 2012; 32: 6–38.

25.

Lipton

Varon

Grosberg

. OnabotulinumtoxinA improves quality of life and reduces impact of chronic migraine. Neurology 2011; 77: 1465–1472.

26.

Cady

Ryan

Jhingran

. Sumatriptan injection reduces productivity loss during a migraine attack: Results of a double-blind, placebo-controlled trial. Arch Intern Med 1998; 158: 1013–1018.

27.

Edwards

Rosenthal

Farmer

. Evaluation of sumatriptan-naproxen in the treatment of acute migraine: A placebo-controlled, double-blind, cross-over study assessing cognitive function. Headache 2013; 53: 656–664.

28.

Kayan

Hood

. Neuro-otological manifestations of migraine. Brain 1984; 107(Pt 4): 1123–1142.

29.

Goadsby

. Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med 2007; 13: 39–44.

30.

Feleppa

Apice

D’Alessio

. Tolerability of acute migraine medications: Influence of methods of assessment and relationship with headache attributes. Cephalalgia 2008; 28: 1012–1016.

31.

Mulder

Passchier

Linssen

. Effects of medication use on health state in postictal migraineurs. Headache 2001; 41: 782–791.

32.

Farmer

Cady

Bleiberg

. A pilot study to measure cognitive efficiency during migraine. Headache 2000; 40: 657–661.

33.

Kececi

Atakay

. Effects of topiramate on neurophysiological and neuropsychological tests in migraine patients. J Clin Neurosci 2009; 16: 1588–1591.

34.

Dodick

. Applying the benefits of the AwM study in the clinic. Cephalalgia 2008; 28(Suppl 2): 42–49.

35.

Slof

. Cost-effectiveness analysis of early versus non-early intervention in acute migraine based on evidence from the ‘Act when Mild’ study. Appl Health Econ Health Policy 2012; 10: 201–215.

36.

Gil-Gouveia

Oliveira

Martins

. Assessment of cognitive dysfunction during migraine attacks: A systematic review. J Neurol 2015; 262: 654–665.

37.

O’Bryant

Marcus

Rains

. Neuropsychology of migraine: Present status and future directions. Expert Rev Neurother 2005; 5: 363–370.

38.

Afridi

Giffin

Kaube

. A positron emission tomographic study in spontaneous migraine. Arch Neurol 2005; 62: 1270–1275.

39.

Moulton

Becerra

Maleki

. Painful heat reveals hyperexcitability of the temporal pole in interictal and ictal migraine states. Cereb Cortex 2011; 21: 435–448.

40.

Russo

Tessitore

Giordano

. Executive resting-state network connectivity in migraine without aura. Cephalalgia 2012; 32: 1041–1048.

41.

Xue

Yuan

Zhao

. Intrinsic brain network abnormalities in migraines without aura revealed in resting-state fMRI. PLoS One 2012; 7: e52927–e52927.

42.

Valfrè

Rainero

Bergui

. Voxel-based morphometry reveals gray matter abnormalities in migraine. Headache 2008; 48: 109–117.

43.

Kim

Suh

Seol

. Regional grey matter changes in patients with migraine: A voxel-based morphometry study. Cephalalgia 2008; 28: 598–604.

44.

DaSilva

Granziera

Snyder

. Thickening in the somatosensory cortex of patients with migraine. Neurology 2007; 69: 1990–1995.

The impact of cognitive symptoms on migraine attack-related disability

Abstract

Background

Objective

Methods

Results

Conclusions

Keywords

Introduction

Participants and methods

Population

Study design

Statistical analyses

Results

Population

Migraine attack characteristics

Symptom intensity and disability

Correlations and regression analysis

Discussion

Clinical implications

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

References