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Abstract

Introduction

Cognitive symptoms have been described during migraine attacks since the Roman era; while being neglected throughout the centuries, they are relevant contributors to migraine-related disability.

Objective

To determine whether cognitive symptoms are included in clinical series describing migraine attack phenomenology, and which symptoms occur in each attack phase.

Method

Systematic review of existing data on clinical descriptions of migraine attacks, focusing on cognitive symptomatology. Data were organized and analyzed qualitatively, due to methodological differences between studies.

Results

Twenty-four articles were reviewed, with a total sample of 7007 patients, including 82.9% females with an average age of 39.2 years. Twenty one (75%) studies analyzed one phase of the attack (eight prodromes, five auras, one between aura and pain, three headaches and three postdromes), the remaining studied more than one phase. Cognitive complaints were the most frequent symptom of the prodromic (30%) and headache (38%) phases, while fatigue (70%) dominated the resolution phase. Not enough data is available to estimate the frequency of cognitive symptoms during the aura.

Discussion

Cognitive symptoms are described in all phases of the migraine attack phenomenology in published clinical series of migraine. Their characteristics appear to be different in each attack phase, although methodological limitations prevent generalization of this finding.

Keywords

Migraine cognition headache review

Introduction

Migraine is the third most frequent disease in the world, affecting 14.7% of the population (1) and impacting individuals during their most productive working years, between the third and fourth decades (24% of women, 7% of men) (2).

Migraine is a chronic disorder with episodic manifestations during which most patients become disabled to some degree (33% with severe, 47% moderate and 18% mild disability). Only 1% of patients are fully functional during attacks (2). The Burden of Migraine is estimated using the proportion of time spent in the symptomatic (ictal) state (5.3%) and the average disability (43.3%) assigned to attacks. Migraine is ranked in the top 10 of the highest specific causes of disability globally (1,3).

Migraine attacks are complex phenomena that start before pain onset. The elaboration of the International Headache Classification (4) has boosted the study of migraine by providing a simple migraine definition focused on its most expressive symptoms. The downside of this approach is that other ill-defined, less expressive, or less consistent symptoms tend to have been overlooked in the most recent years of migraine research. Some of these symptoms can be as frequent or as disturbing as pain, and may provide important clues to the pathology of the brain processes underlying attacks, thereby helping to define relevant therapeutic targets. One such example is the study of attack-related allodynia (5,6); another may be migraine attack-related cognitive dysfunction (7,8), with relevant impact on attack disability.

We performed a systematic literature review to identify migraine clinical series that included non-migraine defining symptoms occurring during migraine attacks and, in particular, cognitive symptomatology. The specific research questions were: Are cognitive symptoms included in clinical series describing the migraine attack phenomenology? If so, in which phase of the attack phase (prodromes, aura, pain, and postdromes) are they noticed? Are different symptoms described in different phases of the attack? Can published data be used to estimate a frequency of occurrence?

Methods

Search strategy

Potentially eligible studies were identified by searches of electronic databases: Medline (through PubMed) and the Cochrane Library, from inception to November 2014, without limitations or restrictions. Our search sequentially combined the free text term “migraine” with the terms “prodromes”, “premonitory”, “postdrome”, “resolution”, “cognition”, “cognitive”, “neuropsychological”, “executive”, “memory”, “language”, and “clinical characterization”. Each of these search combinations was analyzed separately; duplicate references were identified during abstract review.

Study selection and data collection

Titles and abstract screening identified studies that described cognitive symptoms in any attack phase, including reviews, clinical series, and research studies. Studies were excluded in title or abstract screening if they reported (a) cognitive testing of migraine patients; (b) cognitive symptoms associated with treatments used in migraine; (c) cognitive symptoms of chronic migraine, medication overuse headache or genetic migraine disorders (CADASIL, Familial Hemiplegic Migraine); (d) clinical characterization of migraine patients not including cognitive symptoms; (e) psychological or psychiatric symptoms; (f) cognitive behavioral therapy; (g) letters or comments; (h) small series (fewer than 10 patients) or case reports; (i) papers in which clinical characterization of attacks referred exclusively to ICHD defining symptoms and (j) data published in the form of abstracts. References to relevant papers and of reviews were also screened using the same criteria; selected papers were retrieved and evaluated using the same process.

Data extraction and analysis

Tables were constructed to summarize the included studies and their relevant results. Data was organized, classified, and analyzed qualitatively. The different symptoms listed in each series were grouped by characteristics into four categories: Migraine-related (including migraine defining symptoms and related GI, sensorial or aching sensations), autonomic (related to sleep, thirst, appetite, water balance or vascular tone) emotional/behavioral (related to humor changes, anxiety and associated behaviors) and cognitive/neuropsychological (related to changes of brain functions such as perception, reasoning, memory, language or learning and so on). Each attack phase (prodromes, aura, headache, and postdromes) (9,10) was evaluated independently. A study quality assessment was not performed given the diversity of designs, objectives, and outcome measurements. Only a narrative review of study data was performed, without statistical analysis. In this narrative review, we included a few basic quantitative analyses for the purpose of data organization. These include (a) average symptom frequency (requiring at least three different studies reporting frequency values for any given symptom); (b) total number of different symptoms reported within each group; (c) average number of symptoms reported per study, within each group; and (d) average symptom frequency within each group. Ethics committee authorization was not required as this study reviewed previously published data.

Results

Study flow and details

The study flow is depicted in Figure 1. A total of 24 papers met the eligibility criteria for review, and their characteristics are depicted in Table 1. The majority (83%) of the studies had prospective data collection that was mostly achieved by questionnaires (11 studies) and only one study was controlled (11) (see Table 1).

Figure 1.

Flow diagram.

Table 1.

Summary of included studies.

	Migraine phase				Method					Population
Study	Prodromes	Aura	Pain	Postdromes	Prospective	Retrospective	Data collection	Clinic sample	Population	Sample size	MO:MA	♀:♂	Age average
Lance 1966 (36)		+	+		+		Structured clinical interview	+		500	176:324	375:125	NI
Blau 1980 (9)	+				+		Clinical interview	+		50	31:19	28:22	34
Blau 1982 (10)				+	+		Clinical interview	+	+^†	50	34:16	35:15	42
Waelkens 1985 (20)	+	+	+		+		Clinical interview	+		49	30:19	38:11	38
Amery 1986 (19)	+		+		+		Self-fulfilled questionnaire		+	149	58:91	124:25	42
Bana 1986 (15)		+				+	Clinical interview	+		325	0:325	248:77	36.8
Ardila 1988 (12)		+			NI	NI	Clinical interview	+		20	0:20	14:6	35
Blau 1991 (38)				+	+		Self-fulfilled questionnaire	+		40	29:11	31:9	39
Blau 1992 (16)	+*	+*	+*		+		Clinical interview		+^†	25	0:25	17:8	42
Queiroz 1997 (17)		+			+		Self-fulfilled questionnaire	+		100	0:100	90:10	39.8
Giffin 2003 (29)	+		+	+	+		Electronic diary	+		82	61:21	78:4	42
Kelman 2004 (23)	+				+		Clinical interview + Questionnaire	+		893	NI	760:133	37.6
Quintela 2006 (25)	+			+	+		Clinical interview + Questionnaire	+		100	85:15	82:18	39.3
Kelman 2006 (22)				+	+		Structured clinical interview	+		827	473:354	705:122	38.2
Schoonman 2006 (24)	+				+		Self-fulfilled questionnaire	+		374	179:195	300:74	NI
Kelman 2006 (21)			+			+	Database review	+		1009	871:138	646:363	37.7
Vincent 2007 (28)		+			+		Email Questionnaire	+		143	107:36	118:25	36.9
Cuvellier 2009 (14)	+				+		Telephone interview	+		103	69:33	46:57	Child
Gil-Gouveia 2011 (26)			+		+		Self-fulfilled questionnaire	+		93	86:7	75:18	39.2
Schurks 2011 (13)			+		+		Questionnaire	+^∫	+^∫	1675	674:1001	1675:0	NI
Ng-Mak 2011 (37)			+	+	+		Concept elicitation focus group	+		34	NI	20:14	40.7
Petrusic 2013 (18)		+			+		Questionnaire	+		60	0:60	44:16	39.0
Houtveen 2013 (27)	+				+		Electronic diary	+	+	87	54:32	74:13	44.5
Jurgens 2014 (11)	+	+	+			+^‡	Questionnaire	+		219	149:70	189:30	39.8

Note: *This study focused on the time lapse between the end of the aura and pain onset. †: Convenience sample of medical practitioners; ‡: controlled study; ∫: sub-study of a clinical trial that recruited female health professionals; MA: Migraine with aura; MO: Migraine without aura.

Sample sizes varied from 20 (12) to 1675 patients (13); the total number of patients included was 7007, of which 5812 (82.9%) were females, with an average age of 39.2 years. One study included only children (14), one only females (13), five studies (530 patients) only patients with aura (12,15 –18); in total, more than one third (3110, 37.1%) of patients studied had aura. Nineteen (79%) studies recruited patients exclusively in headache clinics, yet only 12 (50%) contained information about headache impact (attack frequency, duration, disease duration, or impact scales) (13,14,18 –27) and two were about current prophylactic and/or acute medication for headache (9,20).

Twenty one (75%) studies analyzed only one attack phase (eight prodromes, five aura (12,15,17,18,28), one analyzed between the end of the aura and the beginning of pain, three headache and three postdromes (Table 1)). Further data analysis will be presented per attack phase.

Clinical description of the migraine attack

Prodromes

The prodrome includes symptoms attributed to migraine that start before headache or the aura’s onset (9), and can begin as early as three days before the attack, most often in the 24 h preceding pain (19,23 –25,29). We chose to use the term prodrome to distinguish this type of premonitory symptom from the aura symptoms, which also warn about impending headache (9). Self-reported impairment of cognitive function has been described within the 25 to 36 hours before pain onset, peaking in the last 12 preceding hours (27). The estimated prevalence of prodromes ranges from 7–88% (23,24,29) in adults and around two thirds of children, with an average of 12 (19) and two (14) different prodromal symptoms, respectively.

Cognitive complaints are frequent amongst prodromal symptoms and are good attack predictors – difficulties with speech predicted 92% of attacks, difficulties with reading predicted 90%, increased emotionality 83% and yawning 84% (29). One study controlled the occurrence of prodromal symptoms with the occurrence of the same symptoms in the interictal period, concluding that impaired concentration, unhappiness, anxiety and yawning were the most common and consistent prodromal symptoms (25).

Ten (42%) of the 24 included studies analyzed the prodromal phase of the migraine attack, while eight studies included frequency data on non-migraine defining symptoms (Table 2). Forty nine different symptoms were described in the eight studies that detailed the prodromal phase (Table 2), mostly migraine-related (40%) or autonomic (30%). On average, 5.1 different symptoms were reported in each study (8.4 migraine-related and 5.8 autonomic).

Table 2.

Frequency of non-migraine defining symptoms in the prodromic phase of Migraine Attacks, as described in the literature.

	Average	Blau 1980 (9)	Waelkens 1985 (20)	Amery 1986 (19)	Giffin 2003 (29)	Kelman 2004 (23)	Quintela 2006 (25)	Schoonman 2006 (24)	Cuvellier 2009 (14)
Emotional/behavior
Fatigue/asthenia	33	12		10–49		25.6	38	46.5	41.7
Tiredness	32	12	6		72.5	25.6	31
Adynamic/inactive	–			>50
Emotional/ mood changes	24	24			24.3	23.4
Irritability	25	8	10	>50	38.5		42	28.1	24.3
Stress/anxiety	19	4					46	15.2	12.6
Claustrophobia	–		4
Depression	16	4		10–49			39	17.6	1.9
Hyperactivity/ excited/euphoric	8	10			5.2		9–13	15	2.9
Migraine-related
Nausea	18		8.2		23.5	24	28.6	5.8
Anorexia	–						20
Vomiting	–						6
Constipation	10	2			5.6		21
Diarrhea	–	2					4
Flatulence/abdominal distension	–		8.2	10–49			22
Abdominal pain/ GI disturbance	13		6.1			22	11
Phonophobia	23		6.1	>50	38.4	1.1	44	36.4	10.7
Photophobia	20		8.2	>50	48.8	1.3	37		7.8
Sensitive skin/ hyperesthesia	4		4.1	>50	5.7		1.6
Smell distortion/ osmophobia						0.7			3.9
Taste distortion	–	2				0.4
Paresthesia	–		6.1			0.9
Stiff neck	21		14.3	10–49	49.7	3		35	2.9
Muscle ache	–		2	10–49		0.2
Body weakness/ clumsiness	–		8.2	10.49		0.5
Blurred vision	24		36.7	10–49	28	3.3	26
Dizziness	15		20.4	10–49	22.9	1.1
Ear symptoms/ tinnitus	–					0.5
Strained/swollen head	–		25	10–49		5.6
Cognitive
Concentration problems	30			>50	51.1		36	28.1	4.8
Difficulty with thoughts	–				34.6
Difficult to read/write	–			>50	20.2
Difficulty with speech	–				9		17
Hazy mind/intellectual disturbance	–	4		>50		1.3
Autonomic
Pale face/ face changes	21		2	>50	17.6				43.7
Dark rings around eyes	–			10–49
Yawning	20	14	12.2	10–49	27.8	0.5	40	35.8	10.7
Somnolence	13	2	2				35
Insomnia	–						27
Sleep disturbances	–							13.9	1.9
Thirst/water craving	–				26		17
Hungry	12	6	12.2	10–49	18.2
Food craving	14	8			18.2	0.4	15	17.4	3.9
Frequent urination	10	2			16.2		12
Fluid retention	–	2					12
Feeling cold/shivering	2		4.1	>50		1.1	1.9
Sweating	–		2	10–49
Dry mouth/nose symptoms	–		2			0.9
Sighing/difficulty breathing	–		2			0.2

Note: Values represent percentages reported in each series. †: Average percentage was calculated for each symptom if the symptom was reported in at least three different studies.

Of all the consistently reported symptoms, the most frequent were fatigue/asthenia and tiredness (32–33% patients), concentration problems (30%) and irritability/mood changes (24–25%). Evaluating grouped symptom frequency, cognitive symptoms were the most frequent (30%), followed by mood/behavioral (22%), migraine related (16%), and autonomic (13%).

The aura

The most frequent aura manifestation is visual in 65 to 99% of patients. Other possible symptoms include sensory (31%), aphasic (18%) and motor (6%), occurring in various combinations (15,30). Visual phenomena are variable, yet photopsias, flickering lines and zig-zag lines are present in 40–87% of auras (17,30); typical fortification spectra are less frequent (20%) (17). Examples of other visuo-perceptive changes described during auras include macropsia, micropsia, cromatopia, acromatopsia, palianopsia, pelopsia, teleopsia, simultanagnosia or visual hallucinations in 1–13% of aura patients (12,17,18,28); less frequent and more complex visuo-perceptive changes include prosopoagnosia, visual agnosia (18,28) out-of-body experiences or parasomatic (“duplicated”) body phenomena (31). In a controlled study, only corona phenomenon and visual splitting were specific for migraine with aura, although many other visuo-perceptive symptoms seem to occur more frequently in aura patients (11). Other symptoms, such as double vision, inversion of 2D/3D vision and altered perception of body weight and size were related to migraine, but not aura. Micro and macropsia, teleopsia, pelopsia, inverted vision, out-of-body experience, visual hallucinations and altered perception of body position were not more frequent in migraineurs than in healthy controls (11).

Sensory symptoms are mostly unilateral (84%) and present as tingling or paresthesias, sometimes followed by numbness (30), while higher cortical sensory symptoms, such as hemiasomatognosia, are rare (0.5% of aura patients) (12). Aphasic symptoms may occur in up to 50% of auras (18,28), being most often expressive (paraphasias 76%, non-fluent aphasia 72%), although impaired comprehension (38%) (30) and/or alexia may ensue. Rarely, other higher cortical functions are involved, such as memory – anterograde or retrograde amnesia may occur in up to 18%, other phenomena being rarer (e.g. “dejá vu” and “jamais vu” phenomena, depersonalization). One study evaluated symptoms occurring outside and during migraine attacks and some (such as prosopagnosia, proper name agnosia, and transient amnesia) did not seem to be related to the attacks (28).

Calculus may also be disturbed (dyscalculia or acalculia) in up to 13% (18) of auras, as well as other “mental or personality” changes, with a frequency of around 3–7% (12,15,28). Hallucinations may occur as migraine auras, either gustatory (0.5%), olfactory (up to 1%) (12,32) or auditory (0.17%) (33).

Eight (33%) of the 24 included studies analyzed the aura phase, including 39 different symptoms (Table 3), mostly migraine-related (49%) or cognitive (28%). On average, 2.6 different symptoms were reported in each study (4.0 migraine-related and 3.8 cognitive). Five studies provided symptom frequency data, two of which contained details about sensorial migraine related symptoms (blurred vision 36.7%, dizziness 20.4%, stiff neck 14.3%, nausea 8.2%, photophobia 8.2%, and phonophobia 4.1%), autonomic symptoms (food craving 2.1 to 12.2%, yawning 1.4 to 12.2%, sleepiness 10.2%, pallor 2%, and temperature changes 4.1%) or mood changes (irritability 4.2–10.2% and fatigue 2.8–6.1%) (20,28). The remaining symptoms were mainly neuropsychological symptoms (other than ICDH-III aura defining symptoms) but only three symptoms were consistently described – speech and language difficulties (32.8% patients), visuo-perceptive changes (28.3%) and memory (19%).

Table 3.

Frequency of non-migraine defining symptoms occurring during the aura and headache phases of migraine attacks, as described in the literature.

	Aura						Headache
	Waelkens 1985 (23)	Ardila 1988 (15)	Queiroz 1997 (20)	Vincent 2007 (31)	Petrusic 2013 (21)	Blau 1992 (19)*	Lance 1966 (44)	Waelkens 1985 (23)	Amery 1986 (22)	Kelman 2006 (24)	Giffin 2003 (32)	Gil-Gouveia 2011 (29)	Ng-Mak 2011 (51)	Schurks 2011 (16)
Mood/behavior
Fatigue/asthenia	6.1			2.8						26.8	84.3	14.0	2.9
Eviction/isolation												10.7
Adynamia/lethargy						16.0		4.1	>50			26.9
Dysphoric/emotional						8.0			>50		29.9			63.0
Irritability/fear	10.2			4.2		24.0		8.2	>50		41.0	50.5
Depression						4.0		4.1	10–49
Hyperactivity/euphoria						12.0		4.1			2.7
Migraine-Related
Nausea	8.1					8.0	95.0	93.9	>50	54.5			67.6	89.1
Eructation	6.1							40.8
Abdominal distension	2.0							12.2	>50
Abdominal pain	6.1							2.0
Diarrhea							19.0			9.5
Constipation											6.6
Phonophobia	6.1							93.9	>50	68.8			64.7	86.1
Photophobia	8.2							100	>50	71.1			52.9	93.0
Sensitive skin/hyperesthesia	2.0							40.8	10–49		9.3
Smell distortion/osmophobia	4.1							53.1		13.6			8.8
Taste distortion										10.8
Paresthesia	6.1							22.4	10–49					39.7
Stiff neck	14.3							26.5			62.8		14.7
Muscle ache	2.0								10–49	12.3
Body weakness	8.2							6.1					2.9
Clumsy						16.0
Cranial autonomic										17.9
Feeling ill						12.0
Blurred vision	36.7		27.0					4.1	>50		34.7		17.6	50.9
Tinnitus	2.0							2.0
Dizziness	20.4							8.2	>50	36.3	31.1		23.5	61.0
Light/strained head	8.2					12.0
Swelling head	24.5					4.0
Tight head/pressure	6.1								>50				8.8
Throbbing blood vessels	12.2								10–49
Cognitive
Feels distant/ distracted/slow				7.7		28.0			>50		72.6	21.5
Disorientation/confusion					8.3	12.0	6.8
Impaired thinking						16.0			>50		50.5	90.3	14.7
Color naming					13.3
Difficulty with speech/language		40		4.9	53.3	20.0		10.2			39.2	25.8		24.7
Dyscalculia					13.3
Visuo-perceptive		27.5	45.0	34.1	6.7
Cognitive-dysmnesic		17.5		7.7	31.7							12.9
Hallucinations		7.5	1.0
Sensorial perception		2.5				4.0
Automatisms		5.0
Apraxia					11.4			4.1
Difficulty problem fixation/planning								6.1				31.2
Autonomic
Pale face	2.0								>50		32.2
Dark rings around eyes								2.0
Yawning	12.2			1.4							25.4
Thirst/water craving											32.2
Hungry/food craving	12.2			2.1							18.1			28.3
Fluid retention														55.9
Frequent urination							29.0				24.3
Lipothymia	2.0						12.2	2.0
Feels cold/shivers	4.1							2.0
Sweating	2.0
Dry mouth	2.0

Note: Values represent percentages reported in each series; migraine-defining symptoms are plotted in grey. *This study focused on the time lapse between the end of the aura and pain onset.

The headache

The painful phase of migraine often starts within the aura phase, with as many as 54% of attacks already having a migraine defining pain within 15 minute of aura onset (34); the remaining patients have a free interval between the end of the visual aura and headache onset, during which some patients feel completely well while others describe mood changes (60%, including feeling fearful, euphoric, dysphoric or depressed), perception difficulties (40%, including feeling distant, disoriented or below others), cognitive changes (36%, including slowness of thinking, difficulty in concentrating, difficulties in speaking, reading and communicating) and somatic symptoms (72%, including lack of energy, clumsiness, feeling ill or light headache, nausea, facial edema) (16). It is unclear whether these symptoms represent the onset of prodromes after the aura, although some prodromes persist through all attack phases (20,23,25,29).

Cognitive symptoms often accompany the headache phase of migraine, such as being unable to think or concentrate (up to 71% of patients), unable to carry out activities such as shopping (up to 83%), work or taking care of children (60%). These symptoms are recorded more often in high intensity attacks and contribute to migraine associated disability (35). Cognitive and non-cognitive prodromal symptoms persist thought the headache phase (29) or may appear only during headache (13,20,21,26,36,37).

Of the 28 included studies, one study analyzed the time elapsed between the aura and the pain and nine (32%) analyzed the headache phase of the attack, detailing 41 different symptoms (Table 3), mostly migraine-related (44%) or autonomic (22%). On average, 2.7 different symptoms were reported in each study (4.6 migraine-related and 2.4 mood/behavior). The most frequently occurring consistent symptoms were impaired thinking (51.8% of patients), blurred vision (36%), and stiff neck (34.7%). Other very frequent symptoms included irritability (33.2%), fatigue/asthenia and dizziness (32%). Evaluating symptom frequency within each group, the most frequent symptoms were cognitive (38%), followed by mood/behavioral (32%) and migraine related (32%). Some of the changes occurring during attacks are even noticed by family or friends, and described as facial changes (pallor, rings around eyes, altered facial expression, lusterless eyes, swollen frontal veins) as well as irritability and mood swings (19).

Postdromes or resolution symptoms

The headache of the migraine attack will at some point decrease progressively, either imperceptibly or faster, until it disappears, even without any intervention to shorten the attack (10). Attacks can be shortened or interrupted with several strategies, the most common being medication, sleep or vomiting (10). However, 60–94% of patients have persisting migraine symptoms after headache resolution, lasting on average 25.2 hours (<12 h in 54% of patients). On average, each migraineur reports up to seven postdromal symptoms (10,22,25,38). The definition of postdromes varies in different studies, with some authors even allowing the existence of mild headache in this phase (22,37,38).

Six (25%) of the included studies analyzed 42 different resolution symptoms (Table 4), the most frequent being migraine-related (43%) or autonomic (24%), with an average of 4.8 different symptoms being reported in each study (8.7 migraine-related and 4.3 autonomic).

Table 4.

Frequency of non-migraine defining symptoms in the postdromic phase of migraine attacks, as described in the literature.

	Average^†	Blau 1982 (10)	Blau 1991 (38)	Giffin 2003 (29)	Quintela 2006 (25)	Kelman 2006 (22)	Ng-Mak 2011 (37)
Emotional/behavioral
Fatigue/tiredness	70	52.0	67.5	88.2	55.0	71.8	88.2
Emotional/mood changes	–			23.5		6.8
Stress/anxiety	–				15.0
Irritability	22		12.5	28.5	20.0		26.5
Depression/lower mood	42	56.0	42.5		26.0
Happy/euphoric	18	16.0	15.0		10.0		29.4
Introverted/isolation	–		7.5				14.7
Hyperactivity	–			2.4	9.0
Migraine-Related
Nausea/anorexia	21			14.8	10.0		38.2
Constipation/diarrhea	12		22.5	6.8	13.0	8.4
Abdominal pain	–				6.0
Photophobia	16		12.5	36.0	26.0	2.1	5.9
Phonophobia	15		0.5	31.8	27.0	0.4	14.7
Osmophobia	–		2.5				2.9
Taste distortion	–		7.5
Sensitive skin/hypersensitivity	–			5.2	10.0
Paresthesia	–					1.8
Cranial autonomic	–		2.5			0.5
Stiff/aching neck	26		35.0	41.9		3.2	23.5
Reduced physical energy	34		72.5			5.2	23.5
Muscular weakness	25	54.0	5.0			6.2	35.3
Clumsy/hungover	15		15.0			11.7	17.6
Blurred vision	13		17.5	17.4	16.0	2.0	11.8
Dizziness	20			19.3		5.7	35.3
Head tenderness	–		57.5
Mild head pain	37		35.0			33.1	44.1
Cognitive
Concentration problems	40		65.0	55.5	28.0	11.7	38.2
Difficulty with thoughts	–			33.4			8.8
Lower intellect/“fog”	–	56.0					14.7
Reduced attention span	–		55.0
Difficulty reading/writing	–			16.8
Difficulty with speech	19		42.5	8.5	6.0
Autonomic
Yawning	20	8.0	32.5	13.9	24.0
Thirst/drinking more	18	8.0	35.0	32.2	15.0	0.5
Frequent/lower urination	17	14.0	22.5	21.2	10.0
Fluid retention	–				5.0
Feeling cold	–				17.0
Less appetite	–	32.0					23.5
Food craving	10	16.0		15.1	9.0	0.2
Pale face	–			21.4		0.2
Somnolence	–				29.0
Insomnia	–		0.5		12.0

Note: Values represent percentages reported in each series. †: Average percentage was calculated for each symptom if the symptom was reported in at least three different studies.

Among the consistently reported symptoms, the most frequently occurring were fatigue/tiredness (70% patients), mood disturbances (42%) and concentration problems (40%). Evaluating frequency by symptom group, the most frequent symptoms were of mood/behavioral (38%), cognitive (30%), migraine related (21%) and autonomic (13%). One study controlled the occurrence of postdromal symptoms with the occurrence of the same symptoms in the interictal period, concluding that tiredness, asthenia and somnolence were the most common and consistent resolution symptoms (25). The most common postdromal symptoms reported in a study using focus groups to detail this phase of attacks were tiredness, nausea, head pain, difficulty concentrating, and physical weakness (37). These patients reported that postdromal symptoms were clinically relevant, as they felt decreased physical activity, difficulty at work, difficulty performing general cognitive tasks and true impact on family and social life (37).

A summary of each symptom frequency through the headache phases is presented in Table 5.

Table 5.

Average frequency of non-migraine defining symptoms in each phase of migraine attacks.

	Prodromes	Aura	Aura-headache	Headache	Postdromes
Emotional/behavioral
Fatigue/asthenia	33	4.4		32	70
Tiredness	32
Adynamic/inactive	50		16	27
Emotional/mood changes	24		8	47.6	15
Irritability	25		24	37.4	22
Stress/anxiety	19				15
Eviction/isolation	–			10.7	11.1
Depression	16	4	4	16.8	42
Hyperactivity/excited/euphoric	8	10	12	3.4	11.8
Migraine-related
Nausea	18	8.1	8	75	21
Eructation		6.1		40.8
Taste distortion	1.2			10.8	7.5
Flatulence/abdominal distension	5.2	2		31.1
Abdominal pain/GI disturbance	13	6.1		2	6
Constipation/diarrhea	13			10.4	12
Cranial autonomic				17.9	1.5
Phonophobia	23	6.1		72.7	15
Photophobia	20	8.2		73.4	16
Sensitive skin/hyperesthesia	4	2		26.5	7.6
Smell distortion/osmophobia	2.3	4.1		25.2	2.7
Paresthesia	3.5	6.1		30.5	1.8
Stiff neck	21	14.3		34.7	26
Muscle ache/weakness	10.6	2.0		20.9	25
Body weakness/clumsiness	6.4	8.2	16	4.5	15
Blurred vision	24	31.8		31.5	13
Dizziness	15	20.4		35	20
Ear symptoms/tinnitus	1.2	2.0		2.0
Strained/swollen head	20	8.2	8
Tight head/pressure/mild pain		6.1		29.4	37
Throbbing blood vessels		12.2		29.5
Reduced physical energy/feeling ill			12		34
Cognitive
Concentration problems	30	7.7	28	48	40
Difficulty with thoughts	34.6		16	51.4	21.1
Visuo-perceptive	–	28.3
Difficulty with speech	13	2.7	20	25	19
Hazy mind/intellectual disturbance/“fog”	18.4	8.3	12	6.8	35.3
Cognitive-dysmnesic		19		12.9
Sensorial perception changes		2.5	4
Apraxia		11.4		4.1
Difficulty problem fixations/planning				4.5	55
Autonomic
Pale face/face changes	21	2		41.1	10.8
Dark rings around eyes	29.5			2
Yawning	20	6.8		25.4	20
Somnolence	13				29
Insomnia	27				6.2
Sleep disturbances	7.9
Thirst/water craving	21.5			32.2	18
Hungry/food craving	13	2.1		23.2	10
Frequent urination	10			26.6	17
Fluid retention	7			55.9	5
Feeling cold/shivering	2	4.1		2	17
Sweating	15.6	2
Dry mouth/nose symptoms	1.5	2	2
Sighing/difficulty breathing	1.1		2

Note: Values represent percentages reported in each series.

Discussion

This review aimed to identify clinical information about non-migraine defining symptomatology occurring during migraine attacks, retrieved from clinical series of migraine patients, with a special focus on cognitive and neuropsychological symptoms. Addressing our first research question, 24 studies including 7007 patients were identified in which cognitive symptoms were described, either spontaneously in clinical interviews or actively sought by questionnaires, electronic diaries or even specifically in a concept elicitation focus group. The frequency of reporting cognitive symptoms in these studies varied from 4% (9) to 90.3% (26) in different studies and different phases of the attack. These observations support that cognitive symptoms are a part of the subjective experience of the migraine attack, in agreement with early historical descriptions of migraine.

The oldest consistent description of the migraine syndrome (39) was made by the Greek Aretaeus of Cappadocia (30–90 A.D.) (40) and already included details about attack related humor changes “…torpor, heaviness of the head, anxiety, and ennui…”. The Treatise de Medicina, written by the Roman Aulus Cornelius Celsus (25–50 A.D.) includes the first allusion to attack-related cognitive symptoms: “In the head, then, there is at times an acute and dangerous disease, which the Greeks call cephalaia; the signs of which are hot shivering, paralysis of sinews, blurred vision, alienation of the mind, vomiting….” (41). The English Thomas Willis (1621–1675 A.D.) described migraine prodromal symptoms including fatigue, bursts of energy and hunger (42) and Edward living (43) (1832–1919 A.D.) published the first medical book about headache, where cognitive symptoms are included as disturbance of “ideational consciousness” as described in “Chapter III -Phenomena of the Paroxysm” (43). He divided these phenomena into “intellectual” and “emotional”, describing the former as “…impairment of memory and in confusion and incoordination of ideas…”, “… confusion of thought…”, “…unable to collect his thoughts…”, “…feeling silly…”, “…losing their senses…”; whereas “emotional” phenomena were part of the attack premonition, including “…irritability of temper…”, “ill-humor” and a “vague and unaccountable sense of fear…”, which could precede the attack by one or two days, while “great mental depression” could linger through the entire paroxysm (43).

Even by then, it was clear that the migraine attack represented a complex phenomenon with different phases. In this review, cognitive symptoms were described in all phases of the attack, although the pattern described in each phase differed. The prodromal phase has the highest amount of available information available, with 46% of the studies (involving 2106 patients) containing information about prodromes. Forty-nine different prodromal symptoms were described that were mostly migraine-related or autonomic, supporting the view that the hypothalamus may play a role in the development of migraine attacks (44). Despite the high number of different autonomic and migraine-related symptoms reported in this phase, the pooled data revealed that those were not the most frequent, but rather the cognitive symptoms were most frequent (driven by the high frequency of “concentration problems” or attention complaints), and mood/behavioral (“fatigue, asthenia and mood changes”). The attentional networks depend on the thalamus, parietal cortex and anterior cingulum (45), all structures which have been found to be activated in the prodromal phase of migraine attacks (44). Other relevant brain activations in this phase include the cerebellar, temporal, frontal and (again) the cingulum areas, which may be implicated in the neural mechanism of mental fatigue (46).

Studies about the aura were scarcer, with only five (involving1416 patients) describing 39 different symptoms, mostly migraine related or cognitive. These observations may be biased, as it is difficult to disentangle certain complex neuropsychological phenomena from vaguer cognitive symptoms – an example being “speech difficulties”, which may reflect true aphasia or mild word-finding hesitations. Additionally, since pain does not always start only after the aura (34), so some aura-related symptoms could actually belong to the pain phase by itself. The most frequent symptoms could not be determined, as very scarce frequency information was available about other symptoms (described in only two studies) yet most reflect probable cortical involvement – speech and language problems, visuoperceptive difficulties, apraxia or cognitive- dysmnesic complaints. The aura phenomena are related to cortical dysfunction, usually starting in the striate cortex and propagating across different cortical areas, producing different clinical manifestations according to the involved areas (47). An fMRI study has concluded that several extrastriate visual areas are involved in visual manifestations, while somasthetic symptoms probably relate to cortical changes in somatosensory cortices (48).

Seven (25%) of studies including 3810 patients described 41 different non-migraine defining symptoms occurring in the headache phase of migraine attacks, most migraine-related such as blurred vision, dizziness, stiff neck, or osmophobia. However, the most frequent occurring symptoms were cognitive, such as “impaired thinking”, “feeling distracted or slow”, and “speech difficulties”, in line with previous studies suggesting the existence of attack-related cognitive dysfunction (7,8) in the domains of attention, processing speed, working memory and language. Brain activations documented in the headache phase of migraine without aura attacks include many structures relevant to these functions, such as the cingulum, parietal cortex and thalamus (attention), additional subcortical structures such as raphe nuclei (processing speed), pre-frontal cortex (working memory) and fontal and temporal lobes (language) (44,49,50).

There were six available studies detailing the postdromes, involving 1133 patients and describing 42 different symptoms, the majority migraine-related – including persistent mild pain in 37% of patients. Again, the most frequently reported symptoms were mood or behavioral changes, specially fatigue and/or tiredness, reported in all studies with frequencies varying from 52 to 88% (average 70%), depressive feelings (42%) and reduced physical energy (34%), although concentration problems were present in 40% of patients. Persistent activation of the brain stem (51) has been documented by PET in sumatriptan treated attacks, which correlate to the decrease in the serotonin synthesis burst observed during the attack (52). Serotonin depletion in serotonergic projections to corticolimbic circuitry can influence the occurrence of mood related symptoms. A different PET study has shown persistent activation of all headache activated areas after sumatriptan treatment – hypothalamus, midbrain, dorso-medial pons, cerebellum, fronto-inferior and cingulate cortex (53).

With the present data, it is possible to assume that cognitive symptoms occur frequently in all phases of the migraine attack, mostly affecting executive function (concentration difficulties, impaired thinking, and slow processing) and language, a pattern consistent with evidence of attack-related neuropsychological dysfunction (7,8). We cannot assume, with data from this revision, that these symptoms are present in most or all patients, nor if they occur consistently in all attacks nor through all phases of the attack. Having migraine predicts limitations in cognitively demanding work (54), with specifically the migraine-attack associated concentration problems contributing to a perceived difficulty in handling the mental aspect of work during attacks, such as making decisions or performing out-of-the ordinary or complex work tasks. Patients also report more errors in tasks involving reading, writing, communication and arithmetic, and the need to work in a slower pace. Mood changes, such as irritability, additionally limit patients’ working abilities and interfere with interpersonal issues at work (55). Patients spontaneously discussing their experiences of migraine attacks on Twitter report impact on productivity at work (3.5%) and school (2.8%), but also in social life (3.5%) and particularly in mood (43.9%) (56), which are possibly a reflection of persisting mood changes in the resolution phase.

There are a number of limitations to our study, the most important being the heterogeneity of the included studies, which precludes any attempt to determine the quality of the studies and the performance of quantitative analyses. None of the included studies shared the same objectives, almost all were uncontrolled, and data collection was different in each study – most studies used clinical interviews and several different questionnaires, inducing an insurmountable bias on item selection and valorization. The quantitative analysis performed in this review merely aims to be indicative of the relative proportion of each symptom, and should not be assumed at face value. The samples were mostly clinic-based, yet little information was provided in each study about attack frequency and disease impact. Recruiting was heterogeneous, with some studies including only aura patients, only children or only females. Another methodological limitation includes the definition of migraine attack phases, which was not uniform across studies – as there is no consensus about their definition, an overlap between phases is likely. Additionally, the majority of studies did not include information about the use of preventives or acute attack treatments, which can produce concurrent symptoms as side-effects. Adding to the potential reporting bias in this review is the fact that not all the patients experienced all attack phases. Furthermore, the symptoms described for each attack phase were reported by different patients, across different studies. It can even be argued if patients noticing versus not noticing prodromes and postdromes may be different – in the Kelman series (23) patients seem to be more sensitive to triggers, having longer duration of every phase of the migraine attack and have higher frequency of accompanying symptoms (nausea and Cranial Autonomic Symptoms).

Conclusions

Due to the large number of patients implicated in this review, it is possible to conclude that cognitive symptoms are consistently included in the description of the migraine attack phenomenology in published clinical series of migraine patients. Existing data also seem to support that cognitive symptoms are described for all attack phases, while being the most frequent non-migraine defining symptoms reported in the prodromal phase and during headache. The cognitive symptoms most frequently described by patients are “concentration problems” in the prodromal phase and “impaired thinking” during headache. Concentration is also the most relevant cognitive complaint during the resolution phase of headache, but the most frequent non-migraine defining symptom of this phase is fatigue. However, interpretation of this data is limited due to important methodological discrepancies and limitations of the evaluated studies.

Footnotes

Article highlights

Migraine attack-related cognitive dysfunction is consistently described by patients in published clinical series of migraine.

Cognitive symptoms occur in all attack phases, being most relevant in the prodromal phase and during headache.

Authors contributions

Raquel Gil-Gouveia and Isabel Pavão Martins have participated in study design, analysis and interpretation of data, draft revision, and both have approved the final version submitted; Raquel Gil-Gouveia collected the data from the literature and drafted the manuscript.

Acknowledgment

The authors would like to thank Miguel Vaz Afonso MD, PhD for editorial support.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Gil-Gouveia reports non-financial support from Allergan, and non-financial support from Sanofi, outside the submitted work.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr. Gil-Gouveia reports grants from Sociedade Portuguesa de Cefaleias – Tecnifar, outside the submitted work.

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Clinical description of attack-related cognitive symptoms in migraine: A systematic review

Abstract

Introduction

Objective

Method

Results

Discussion

Keywords

Introduction

Methods

Search strategy

Study selection and data collection

Data extraction and analysis

Results

Study flow and details

Clinical description of the migraine attack

Prodromes

The aura

The headache

Postdromes or resolution symptoms

Discussion

Conclusions

Footnotes

Article highlights

Authors contributions

Acknowledgment

Declaration of conflicting interests

Funding

References