Non-aura visual disturbance with high visual aura rating scale scores has stronger association with migraine chronification than typical aura

Abstract

Objectives

To investigate the clinical correlates of visual symptoms in patients with migraine.

Method

Patients with migraine that attended our headache clinics were enrolled. Headache profiles, disability, and comorbidities were acquired with structured questionnaires. A semi-structured visual phenomenon questionnaire was also used to assess the characteristics of visual symptoms, including visual aura in patients with migraine with aura and transient visual disturbance in patients with migraine without aura. Headache specialists interviewed with the participants for the ascertainment of diagnosis and verification of the questionnaires.

Result

Migraine with aura patients with visual aura (n = 743, female/male = 2.3, mean age: 34.7 ± 12.2 years) and migraine without aura patients with non-aura transient visual disturbance (n = 1,808, female/male = 4.4, mean age: 39.4 ± 12.6 years) were enrolled. Patients with transient visual disturbance had higher headache-related disability and more psychiatric comorbidities. Chronic migraine was more common in migraine without aura than migraine with aura patients (41.9% vs. 11.8%, OR = 5.48 [95% CI: 4.33–7.02], p < 0.001). The associations remained after adjusting confounding factors.

Conclusion

Presence of non-aura transient visual disturbance may suggest a higher migraine-related disability and is linked to higher risk of chronic migraine than typical migraine aura in migraine patients. Further studies are needed to elucidate the potential mechanism.

Keywords

Aura chronic migraine transient visual disturbance medication-overuse headache

Introduction

Visual aura is the most commonly complained about aura symptom and occurs in 98% of patients with migraine with aura (MA) (1). It is believed that cortical spreading depression (CSD) is involved with the occipital cortical hyper-excitability and pathophysiology of migraine visual aura (2,3). While aura is generally a reversible and benign symptom, there were some adverse events related to migraine or migraine aura reported. Although these adverse events, such as persistent aura without infarction, ischemic stroke and epilepsy (4 –6), were extremely rare. However, these events may cause tremendous disability to patients with migraine and should not be ignored. Both genetic and environmental factors can contribute to these complications, but whether CSD is involved in the underlying pathophysiology of these complications is uncertain.

On the other hand, a substantial proportion of migraine without aura (MO) patients reported transient visual disturbance (TVD), although these TVDs did not fulfil the criteria of aura defined by International Classification of Headache Disorders (ICHD) (7). In our previous adolescents field study (341 boys and 322 girls; mean age 15.1 ± 0.3 years old), almost half of headache participants experienced headache-related TVD, with 14.6% with visual aura rating scale (VARS) ≥4 and 33.4% with VARS < 4 (8). These TVDs were described mainly as flickering lights or scotoma, movable, and monochromatic. Unlike typical visual aura, these TVD generally occurred over bilateral visual fields, with shorter onset and duration, and were mostly experienced during the headache phase. Cortical hyper-excitability among the patients with TVDs was postulated, but the underlying mechanisms remain unclear.

Evidence support the presence of cortical hyper-excitability in patients with MA (9), but it is not known whether the hyper-excitable state will lead to higher probability of migraine progression and evolution. On the other hand, evidence also suggest that cortical dysfunction is present in patients with MO (10 –13). However, whether these TVDs among MO patients are attributed to cortical hyper-excitable state or mechanistically similar to visual aura is not known. In this study, we aim to investigate the clinical significance of migraine visual symptoms, include typical aura and TVDs with comparable VARS scores. We hypothesized that these visual symptoms might cause increased disease burden in patients with migraine, which might be associated with higher risks of migraine chronification.

Material and methods

Study participants and data collection

We surveyed patients with headache that visited the headache specialists at Taipei Veterans General Hospital’s (TVGH) headache clinics during the period from May 2010 to July 2020. The headache specialists were board-certified neurologists who have engaged in studying headache disorders for at least ten years. A structured questionnaire to assess their headache profiles, comorbidities, medical history, mood, sleep, photophobic scale and presence of any pain over the body (see below) was completed by all participants at their first visit. A visual phenomenon questionnaire was included for assessment of the characteristics of visual symptoms. Later, a thorough clinical interview was arranged for all participants in order to ascertain the headache diagnosis as well as verify the responses to the questionnaires. Information collected from the questionnaires was anonymized and entered into the TVGH headache registry. The difference between the two groups cannot be estimated due to the lack of previous studies, therefore no a priori statistical power calculation was conducted, and the sample size was based on the available data. Retrospective power analysis was done based on the sample size and parameters derived from our dataset later. This is a post-hoc study implementing secondary analysis of previously collected data in the TVGH headache registry. Several studies adopting part of the dataset have been published previously (14,15).

Ethics

This retrospective study analyzed the data included in the TVGH headache registry. As this study involved secondary analysis of existing anonymized data, informed consent was been waived by the institutional review board of Taipei Veterans General Hospital, which approved the whole study protocol (TVGH IRB-2021-04-121-CC). The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit for publication.

Diagnoses of migraine

The diagnoses of MA, MO, chronic migraine (CM) and medication- overuse headache (MOH) were based on the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria (MO: code 1.1; MA: code 1.2; CM: code 1.3; MOH: 8.2) (7), made through face-to-face interviews by experienced headache specialists.

Visual Aura Rating Scale evaluation

In order to evaluate the visual symptoms, all of the participants received the five items of the Visual Aura Rating Scale (VARS) embedded in the questionnaires. The score is the weighted sum of the five-item scale: duration 5–60 minutes (three points), developing gradually ≥5 minutes (two points), scotoma (two points), zig-zag lines (two points) and unilateral visual field (one point). A VARS score of 5 or more diagnosed MA with a high sensitivity and specificity (16). Based on our previous study, a cut-off VARS score of 4 or more points is highly sensitive and specific to diagnose MA in our adolescent cohort (8). By using MA diagnoses made by neurologists based on ICHD as the gold standard and VARS > 4 as cut-off value, the sensitivity was 77.1% and the specificity of was 79.9% in our current cohort. The positive predictive value (PPV) was 0.29 and the negative predictive value (NPV) was 0.97. In this study, we aim to include only migraine patients with visual aura or transient visual symptoms comparable to typical visual aura. Therefore, we included only TVD with VARS ≥4 to exclude the potential inclusion of less significant visual symptoms. Finally, these migraine patients with visual symptoms and VARS ≥4 were divided into two subgroups based on the diagnosis of neurologists: MA with typical visual aura and MO with TVD (MA vs. MwTVD).

Questionnaires

Demographic data, including age, sex, height, weight, Body Mass Index (BMI), occupation, education level, marital status, and medical history were collected. A validated headache questionnaire was used to specifically inquire headache frequency (days/month), intensity (Numerical Rating Scale 0–10, NRS), duration, location, characteristics, accompanying symptoms, frequency of acute abortive medications usage (days/month), and disease duration of migraine (years), as well as the visual symptoms (15,17). A visual phenomenon questionnaire was used to assess all visual symptoms and composed of two parts, including patterns (zigzag flashes, flickering dots/lines, or blurred/foggy vision) in part A, and laterality of the visual fields, presence of movement, development time, duration and temporal relationship with headaches in part B. Any “yes” answer to part A questions (patterns including zigzag flashes, flickering dots/lines, or blurred/foggy vision) were considered as visual symptoms, and the characteristics of these symptoms in part B were evaluated afterward. The questions are listed in Table 1.

Table 1.

Questionnaires of the visual phenomenon among patients with migraine.

	Questions
Part A	A1. Have you ever seen zigzag flashes before or during the headache?
	A2. Have you ever seen flickering dots or lines before or during the headache?
	A3. Before or when the headache started, did you have blurred or foggy vision?
Part B	B1. Do these visual disturbances (zigzag flashes, flickering dots or lines, or blurred vision) occur every time you have a headache?
	B2. Are these visual disturbances that you have seen unilateral, bilateral or different every time?
	B3. Did your visual disturbance move?
	B4. How long did your visual disturbance develop?
	B5. How long did your visual disturbance last?
	B6. Did these visual disturbances develop before, after or during the onset of the headache?

Afterwards, the migraine patients without visual symptoms or visual symptoms with VARS < 4 were excluded. Additionally, the questionnaires also included the Migraine Disability Assessment (MIDAS), six-item Headache Impact Test (HIT-6), Migraine Photophobia Score (MPS), Hospital Anxiety and Depression Scale (HAS, HDS), Beck Depression Inventory (BDI), Perceived Stress Scale (PSS), and Pittsburgh Sleep Quality Index (PSQI), presence of CM, MOH and fibromyalgia. Unanswered questionnaires were interpreted as missing data. The responses to these questions were validated by experienced headache specialists with face-to-face interview.

The disability and impact caused by migraine were evaluated with MIDAS and HIT-6 (18,19). Headache intensity influences HIT-6 score more than the MIDAS, whereas the MIDAS is influenced more by headache frequency (20). MPS is a self-administered, eight-question questionnaires to evaluate the scale of photophobia in migraine patients. Adding the total number of “yes” responses generates the MPS (21). Anxiety was defined as a HAS score ≥11, and depression was defined as HDS score ≥11 (22). The BDI is a 21-item self-report measure that evaluates major depression symptoms according to diagnostic criteria listed in the Diagnostic and Statistical Manual for Mental Disorders (23). The PSS is a 14-item self-reported questionnaire that was designed to measure “the degree to which individuals appraise situations in their lives as stressful” (24). PSQI evaluates the quality and patterns of sleep in the past one month. Poor sleep quality was defined as a PSQI score of >5 (25). A validated fibromyalgia questionnaire based on the American College of Rheumatology (ACR) criteria for fibromyalgia was used to assess pain all over the body, including locations, number of regions, severity and duration of pain; associated symptoms and their severity, including cognitive dysfunction, fatigue, and unrefreshing sleep in the past week; and the presence of headache, abdominal pain, or depression in the past six months. The diagnosis of fibromyalgia was made by neurologists based on the ACR 2010 or the modified ACR 2016 criteria according to what was available at the time of patient recruitment (26,27). Unanswered questionnaires were interpreted as missing data.

Migrainous features

Migrainous features (including moderate to severe intensity; pulsating quality; unilaterality; aggravation by physical activity; nausea or vomiting; photophobia and photophobia) of each subject were evaluated. The “yes” responses to each feature were summed up to a total score of migrainous features, ranging from 0 to 6.

Statistical analysis

The descriptive data were presented as means ± SDs or percentages. The Chi square test was used to test the difference in categorical data. Multinomial logistic regressions were adjusted with age and gender to evaluate the of characteristics of visual symptoms. Normality was checked with histograms before conducting parametric tests. Continuous data between groups were analyzed using two-tailed independent sample t-test. Mann–Whitney U test was used to compare variables that were not distributed normally, including headache frequency, pain killer days/month, pain intensity, disease duration, BDI, HDS, MIDAS, and MPS. Bonferroni correction was done for the 19 variables (i.e., age, gender, BMI, disease duration of migraine (years), headache frequency (days/month), headache intensity (severe headache numerical rating scale (NRS) and average NRS), frequency of pain killer (days/month), MPS, MIDAS, HIT-6, HAS, HDS, BDI, PSS, PSQI, MOH, CM, fibromyalgia). For post-hoc subgroup analysis, logistic regression was performed to test the interaction effect. The factors associated with comorbid CM were analyzed separately by three layers of models: 1) no controlling for any covariates; 2) controlling for demographics; 3) controlling for demographics and clinical characteristics. These three layers of models were performed with “Enter” method. That is, the independent variables in each layer were fitted in the regression model simultaneously. Demographics included patients’ age, sex, BMI, and education level. Clinical characteristics included headache frequency (days/month), disease duration, HIT-6 score, depression (HDS score ≥11), anxiety (HAS score ≥11), poor sleep quality (PSQI >5), PSS, MOH, and fibromyalgia. The related factors were presented as odds ratio (OR) with 95% confidence interval. Results were considered significant for p value <0.05. Statistical analyses were performed with R for Mac OS (Version 3.6.3; R Core Team, Vienna, Austria.)

Results

Prevalence of TVD

In total 12,255 patients who visited our headache clinic during the ten-year study period were enrolled. Migraine was diagnosed in 9946 patients, while the other 2309 patients were excluded due to non-migraine headache. Among the migraineurs, 7395 patients had no visual symptoms related to migraine (n = 4334) or some visual disturbance with VARS < 4 (n = 3061). After excluding those without significant visual symptoms (i.e., VARS < 4), the remaining 9946 patients were divided into subgroups based on the diagnosis of MA or MO. Finally, 743 MA patients and 1808 MO patients with VARS ≥4 (MwTVD) constituted our sample. A flow chart of the patient enrolment process is presented in Figure. 1.

Figure 1.

Flow chart depicting the patient selection. For all patients that visited our headache clinic, non-migraine headache was first excluded. Secondly, those without visual symptoms associated with migraine, and those with visual symptoms but Visual Aura Rating Scale (VARS) <4 were excluded. Patients were then divided into two subgroups based the diagnosis of neurologist: migraine with aura (MA), and MO patients with transient visual disturbance (MA v.s. MwTVD).

TVD characteristics and clinical features

Among the 2551 migraine patients, blurred vision is the most common visual symptom. Comparing with MA, patients with MwTVD had less zigzag flashes and flickering dots/line. In addition, the visual symptoms in the MwTVD group are more likely to be fixed, and less likely to be unilateral, before headache, or consistently occurred with headache. The detailed characteristics of the TVDs are shown in Table 2.

Table 2.

Characteristics of visual aura in MA patients and TVD in MwTVD patients, n (%)^a.

	MA patients,n = 743	MwTVD patients, n = 1808	p
Blurred/foggy vision	678 (91.3%)	1696 (93.8%)	0.0216
Flickering dots or lines	667 (89.8%)	1096 (60.6%)	<0.001
Zigzag flashes	594 (79.9%)	913 (50.5%)	<0.001
Co-occurrence of TVD and headache^b			<0.001
Not every time	435 (59.8%)	1478 (83.0%)
Every time	293 (40.2%)	303 (17.0%)
Laterality			<0.001
Non-specific	271 (36.5%)	808 (44.7%)
Bilateral	152 (20.5%)	545(30.1%)
Unilateral	320 (43.1%)	455 (25.2%)
Movable^c			<0.001
Yes	450 (60.9%)	822 (46.1%)
No	289 (39.1%)	960 (53.9%)
Time of development			0.016
≤30 seconds	129 (17.4%)	370 (20.5%)
0.5–1 minute	148 (19.9%)	291 (16.1%)
1–5 minutes	219 (29.5%)	266 (14.7%)
5–20 minutes	200 (26.9%)	436 (24.1%)
≥20 minutes	47 (6.3%)	445 (24.6%)
Duration			0.115
≤30 seconds	22 (3.0%)	332 (18.4%)
0.5–1 minute	23 (3.1%)	220 (12.2%)
1–5 minutes	63 (8.5%)	212 (11.7%)
5–30 minutes	408 (54.9%)	434 (24.0%)
0.5–1 hour	162 (21.8%)	257 (14.2%)
≥1 hour	65 (8.7%)	353 (19.5%)
Temporal relationship with headache^d			<0.001
Before headache	577 (82.9%)	283 (16.4%)
During headache	107 (15.4%)	1261 (73.2%)
After headache	12 (1.7%)	179 (10.4%)

Characteristics of visual aura in patients with migraine with aura (MA) and transient visual disturbance (TVD) in patients with migraine without aura (MO).

^aThe data represent the number of subjects who answered each questionnaire; unanswered questionnaires were interpreted as missing data and were excluded from analysis. All data was adjusted with age and genders.

^b15 of MA patients and 27 of MwTVD patients did not have data for co-occurrence of visual symptoms.

^c4 of MA patients and 26 of MwTVD patients did not have data for movability of visual symptoms.

^d47 of MA patients and 85 of MwTVD patients did not have data for temporal relationship with headache and visual symptoms.

The demographic data and clinical characteristics of MA and MwTVD are listed in Table 3. In general, patients with MwTVD had worse clinical features than MA. The MwTVD group, compared with the MA group, had higher headache frequency, more severe headache-related disability, higher proportions of MOH, fibromyalgia, CM, and psychiatric comorbidities.

Table 3.

Demographic data, headache characteristics and comorbidity in patients with migraine with aura (MA) and migraine with transient visual disturbance (MwTVD).

	MA n = 743		MwTVDn = 1808		p value
	Mean (SD)	Median [25th, 75th]	Mean (SD)	Median [25th, 75th]
Age	34.7 (12.2)	32.2 [25.3, 42.8]	39.4 (12.6)	38.7 [29.6, 48.1]	<0.001*
Female/Male; n (%)	518 (69.7%)/225 (30.3%)		1,470 (81.3%)/338 (18.7%)		<0.001*
BMI	22.2 (3.9)	21.7 [19.5, 24.0]	22.8 (3.9)	22.1 [20.1, 24.9]	0.009
Education; n (%)
<High school	44 (5.9 %)		220 (12.3%)		<0.001*
High school	130 (17.5%)		479 (26.7%)
College	441 (59.4%)		918 (51.2%)
Graduated school	127 (17.1%)		176 (9.8%)
Disease duration of migraine (years)	16.2 (11.7)	13.6 [7.5, 22.6]	19.3 (11.7)	17.6 [10.0, 27.0]	<0.001*
Headache days/month	6.4 (6.6)	4 [2, 9]	13.6 (9.6)	10 [5, 20]	<0.001*
Pain killer days/month	3.5 (5.1)	2 [0, 4]	8.0 (8.5)	5 [2, 10]	<0.001*
Severe headache NRS	7.8 (2.0)	8 [7, 9]	8.2 (1.7)	8 [7, 10]	<0.001*
Average NRS	6.0 (2.1)	6 [5, 7]	6.5 (2.0)	6 [5, 8]	<0.001*
MPS	4.1 (2.2)	5 [3, 6]	3.7 (2.0)	4 [2, 5]	0.021
MIDAS	20.1 (29.3)	10 [4, 26]	41.1 (55.5)	22 [8, 50]	<0.001*
HIT-6	61.6 (7.7)	62 [57, 66]	63.9 (6.4)	64 [61, 68]	<0.001*
HAS	7.9 (4.2)	8 [5, 11]	9.1 (4.4)	9 [6, 12]	<0.001*
HDS	5.2 (3.9)	4 [2, 8]	7.0 (4.3)	7 [4, 10]	<0.001*
BDI	10.2 (8.0)	8 [4, 14]	13.9 (9.9)	12 [6, 19]	<0.001*
PSS	25.4 (8.7)	26 [19, 31]	27.1 (9.0)	28 [21, 33]	0.009
PSQI	8.4 (3.9)	8 [6, 11]	10.7 (4.4)	10 [7,14]	<0.001*
Fibromyalgia; n (%)	36 (4.8%)		256 (14.2%)		<0.001*
MOH; n (%)	48 (6.5%)		434 (24.0%)		<0.001*
CM; n (%)	88 (11.8%)		757 (41.9%)		<0.001*

BDI, Beck Depression Inventory; BMI, Body Mass Index; CM, chronic migraine; HAS, Hospital Anxiety Scale; HDS, Hospital depression scale; HIT-6, six-item Headache Impact Test; NRS, Numerical Rating scale; MIDAS, Migraine Disability Assessment; MOH, medication = overuse headache; MPS, Migraine Photophobia Score; PSS, Perceived Stress Scale; PSQI, Pittsburgh Sleep Quality Index. Data are presented as mean ± SD. *Significant after Bonferroni correction.

TVD, visual aura and migrainous features

There is an increasing TVD frequency with increasing migrainous features (Figure. 2). While the TVD was reported in only 23.4% of MO patients with least migrainous features, its prevalence increased to 68.4% in those with all six migrainous features. On the contrary, the prevalence of visual aura decreased from 61.5% in those with least migrainous features to 27.0% in those with all six migrainous features.

Figure 2.

Numbers of migrainous features are positively associated with prevalence of transient visual disturbance. The prevalence of visual symptoms in subjects with different numbers of migrainous features (including moderate to severe intensity, pulsating quality, unilateral, aggravation by physical activity, nausea or vomiting, photophobia and phonophobia; range of numbers: 0–6). The prevalence of TVD increased with increasing migrainous feature, but visual aura decreased while migrainous features increased.

Association of chronic migraine in patients with transient visual disturbance

Because the percentages of CM were much higher in the MwTVD group than those in the MA group (41.9% vs. 11.8%, p < 0.001), we further explored whether TVD could be an independent factor for CM. Univariate analysis showed that demographic risk factors for CM include female, older age, and lower education level. The unadjusted OR of BMI to CM was 1.03 without statistical significance (95% CI: 1.00–1.06, p = 0.055). MOH was significantly associated with CM, while TVD, fibromyalgia, depression, anxiety, poor sleep quality, headache frequency and headache-related disability, were also associated with CM in patients with migraine (Table 4). In multivariable analysis, the covariates associated with CM were fitted in the regression model first by controlling for demographics, and then by controlling for both demographics and clinical characteristics. TVD remained associated with CM even after controlling for demographics, HIT-6 score, headache frequency (days/month), disease duration of migraine, painkiller frequency (days/month), average headache intensity PSS, fibromyalgia, MOH and psychiatric comorbidities (Table 5).

Table 4.

Association of chronic migraine with potential risk factors.

	Chronic migraine
	OR (95%CI)	p value
Male	0.65 (0.52, 0.79)	<0.001*
Age	1.02 (1.02, 1.03)	<0.001*
MIDAS	1.02 (1.02, 1.02)	<0.001*
Disease duration (years)	1.02 (1.02, 1.03)	<0.001*
BMI	1.03 (1.00, 1.06)	0.055
PSS	1.03 (1.02, 1.05)	<0.001*
HIT-6	1.08 (1.06, 1.11)	<0.001*
MPS	1.13 (1.07, 1.20)	<0.001*
Pain killer days/month	1.20 (1.17, 1.21)	<0.001*
Average NRS	1.22 (1.17, 1.28)	<0.001*
Headache days/month	1.30 (1.27, 1.32)	<0.001*
Anxiety (HAS ≥11)	2.12 (1.79, 2.51)	<0.001*
Poor educated (<High School)	2.61 (2.02, 3.38)	<0.001*
Depression (HDS ≥11)	3.06 (2.49, 3.76)	<0.001*
Poor sleep quality (PSQI > 5)	3.30 (2.46, 4.50)	<0.001*
Fibromyalgia	3.97 (3.07, 5.14)	<0.001*
TVD	5.48 (4.33, 7.02)	<0.001*
MOH	232 (126, 489)	<0.001*

BMI, Body Mass Index; CI, confidence interval; HAS, Hospital Anxiety Scale; HDS, Hospital depression scale; HIT-6, six-item Headache Impact Test; NRS, Numerical Rating Scale; MIDAS, Migraine Disability Assessment; MOH, medication-overuse headache; MPS, Migraine Photophobia Score; OR, odds ratio; PSS, Perceived Stress Scale; PSQI, Pittsburgh Sleep Quality Index; TVD, transient visual disturbance.

Table 5.

Different models for the association of chronic migraine with TVD.

	Chronic migraine
	OR (95%CI)	p value
TVD + Demographics^a	8.01 (5.52, 11.96)	<0.001
TVD + Demographics +Confounders^b	4.75 (2.08, 12.21)	<0.001

CI, confidence interval; HIT-6, six-item Headache Impact Test; MPS, Migraine Photophobia Score; OR, odds ratio; TVD, transient visual disturbance.

^aage, gender, BMI, poor educated.

^bdepression, anxiety, poor sleep quality, HIT-6 score, headache frequency (days/month), disease duration of migraine, painkiller frequency (days/month), headache intensity (average NPRS), Perceived Stress Scale, medication over-used headache, fibromyalgia.

Discussion

In our migraine cohort, the number of patients reporting non-aura TVD with high VARS was more than double the number of MA patients (n = 1808 vs. n = 743), indicating that the prevalence of clinically disturbing TVD is much higher than typical aura. Compared with MA patients, patients with TVD had worse headache-related disability, more psychiatric comorbidities, and higher prevalence of fibromyalgia and CM. Patients who exhibited more migrainous features were more likely to have a higher prevalence of TVD while the numbers of migrainous features seem to have an inversed trend in MA, suggesting that TVDs may be distinct from MA and mechanistically more akin to core migrainous features. Moreover, the presence of TVD is highly related to CM in our model, even after the other risk factors were adjusted, which further supported the importance of differentiating TVD from typical visual aura. Therefore, we speculated that the presence of TVD might serve as a marker of disease severity and even a potential indicator of CM.

Blurred vision was the most common TVD, which was noted in 93.8% of our MwTVD patients. Unlike typical visual aura, most of the TVDs occurred during the headache phase, being non-specific or at bilateral visual fields, and with various onset time and duration. While there are many studies investigating the pathophysiology of migraine aura, research about TVD is scarce and the mechanism remains unclear. In a previous study, we reasoned that non-aura TVD is possibly associated with visual cortex hypersensitivity in patients with migraine (8). Following the same notion, we postulate that our patients with high VARS TVDs may have a hyper-excitable visual cortex with mechanisms distinct from aura, which not only contributes to non-aura TVD but also worse migraine-related disability. Interestingly, research also showed that patients with visual snow (VS) had hyper-excitable visual and prefrontal cortex, and comorbid migraine may aggravate the clinical phenotype of the VS (28 –30). However, patients with VS mostly complained of continuous perception of innumerable flickering dots (29,30), while the visual phenomena investigated in this study are transient. Another potential mechanism is that the blurred vision during headache phase among the TVD patients could be a trigeminal autonomic symptom of the impaired modulation, e.g., a problem of accommodation or a corneal edema (31). It can also explain why the prevalence of TVD increased with other migrainous autonomic symptoms, such as nausea and vomiting. We propose that TVDs might be associated abnormal trigeminal autonomic reflexes, that may reflect a worse disease severity.

The headache frequency varies between individuals. With increasing frequency of headaches, episodic migraine (EM) could evolve to CM. According to the ICHD, CM is defined as headache occurring on 15 or more days/month for more than three months, which, on at least eight days/month, has the features of migraine headache or is responsive to migraine-specific treatment (7). Around 3% of patients with EM progress to CM annually, and their headaches become more disabling and less responsive to treatment (32). The proportion of CM patients having reduced household productivity are two to three fold higher than those with EM, which causes profound effects on patients’ family, workplace and society (33). The risk factors of CM include age, female sex, low educational status, obesity, overuse of acute migraine medication, depression and stressful life events (34,35). Cortical hyper-excitability and dysfunction of descending pain-modulating network are believed to be associated with this chronic, progressive migraine headache (34,36 –38). Accumulating evidence indicates that there are structural, functional, and pharmacologic changes in the brains of patients with CM (38). In this study, we found patients with non-aura TVDs, as compared to typical visual aura, are more likely to have CM. Furthermore, the odds ratios of TVD on CM are higher than the traditionally-known risk factors of migraine chronification, including headache frequency, acute migraine medication frequency, and severity of headache impact evaluated by neurophysiological instrument such as HIT-6 and MIDAS. Our results imply that non-aura TVDs may be a clinical marker of migraine chronification or reflecting its underlying pathophysiology.

Although the pathophysiological mechanism of migraine chronification remains under debate, it is believed that dysfunction of the descending pain-modulating network, altered trigeminal and autonomic system function, and central sensitization were involved (34). Studies had shown that neurons near or within the periaqueductal grey (PAG) had increased activity during migraine attacks (39 –41). Higher frequency of migraine attack might lead to more frequent activations within the PAG, and further cause dysfunction of the descending pain-modulating network (42). Such dysfunction might lower the threshold for migraine attack generation, further cause migraine evolution and other widespread chronic pain disorder such as fibromyalgia. On the other hand, PAG also receive input from the olivary pretectal nucleus (OPN), which influence the pupillary light reflex under the control of retinal ganglion cells projection (43). Based on these findings, we postulated that TVDs in patients with migraine may be related to various mechanisms, including cortical hyper-excitability or impaired pain-modulation involving PAG that leads to impaired autonomic function and accommodation to light. These non-classical transient visual symptoms might have been interpreted as atypical aura anecdotally, however, we consider that they need be identified separately since the prognosis varied. We suggest non-aura TVD has crucial clinical implications and should be identified in clinical practice.

The first strength of our study is the large sample size that increased the precision of our estimations. Second, we have detailed questionnaires to obtain the visual symptoms characteristics, which are also embedded with validated neuropsychological instruments enabling multidimensional assessments (14,15). Third, experienced headache specialists made face-to-face interview of each subject, which makes the final diagnoses of MA, MO, MOH and CM reliable. However, there are also several limitations in our study. First, our patients were recruited from a tertiary medical center, which means the patients we saw were at the worse end of disease spectrum. Nevertheless, patients with TVDs still had much worse clinical features than those with typical visual aura. Second, this is a retrospective study analyzing a pre-existing dataset. Our questionnaires were not specifically designed to establish the reliability of visual symptoms, and the validity of questionnaires assessing visual symptoms and VARS need further examination. The high frequency of visual aura and TVD accompanying headache occurrence should be interpreted cautiously and investigated in future studies. Also, a variety of visual aura symptoms and the symptoms of VS syndrome, such as palinopsia, entopic phenomena arising from the optic apparatus itself, nyctalopia, as well as the non-visual symptom tinnitus, were not included in our questionnaires (29,44). However, while we included MO with significant TVD and comparable VARS, the diagnosis of MA with visual aura and MO were made with face-to-face interviews by our headache specialists. Meanwhile, patients with MA were relatively younger in our study. It is possible that these patients might seek for medical help earlier in life, which may further prevent the chronification of the disease. Last, there were some other psychiatric or personality conditions that were related to CM but not controlled in the multivariable analysis, such as the presence of craniomandibular disorders, metabolic syndrome, post-traumatic symptoms and certain personality profiles (34,35). Further study to investigate these risk factors should be conducted in the future.

Conclusions

We found non-aura TVD was associated with worse headache, higher migraine-related disability, and higher rate of fibromyalgia and CM among migraine patients. The odds ratio of TVD on CM is higher than traditional risk factors such of overuse of acute medication and headache frequency, implying that the impact of non-aura TVD on migraine might be underestimated. We suggested that TVD should be considered as one of the indicators to evaluate the prognosis of migraine. Nevertheless, the exact pathophysiology is unknown and requires further exploration.

Clinical implications

Non-aura TVD is associated with worse headache and higher migraine-related disability, and is highly associated with CM among migraine patients.

The odds ratio of TVD on CM is higher than traditional risk factors, suggesting the impact of non-aura TVD on migraine might be underestimated.

TVD should be considered as one of the indicators to evaluate the prognosis of migraine.

Footnotes

Acknowledgment

The authors would like to thank the study participants for their contributions.

Author contributions

Conception and design: SJW, SPC. Acquisition of data: YFW, JLF, WTC, KLL, HYL, SJW, SPC. Analysis and interpretation of data: YCT, SPC. Drafting the manuscript: YCT, SPC. Revising manuscript for intellectual content: SPC, SJW. Final approval of the completed manuscript: SPC, SJW.

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 disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Brain Research Center, National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (SJW & SPC); the Ministry of Science and Technology, Taiwan [MOST-107-2314-B-010-021, 108-2314-B-010 -022 -MY3 & 110-2326-B-A49A-501 -MY3 (SPC) and MOST 108-2321-B-010-014-MY2, 108-2321-B-010-001-, 108-2314-B-010-023-MY3, 110-2321-B-010-005- & 111-2321-B-A49 -004 - (SJW)] , Ministry of Health and Welfare, Taiwan [MOHW107-TDU-B-211-123001 and MOHW 108-TDU-B-211-133001] (SJW), and Taipei Veterans General Hospital, Taiwan [VGH-106-D9-001-MY2-2 (to SJW) & V111C-158, V109D52-001-MY3-3, VGHUST110-G1-3-1 (SPC)]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

ORCID iDs

Yen-Feng Wang

Kuan-Lin Lai

Shuu-Jiun Wang

Shih-Pin Chen

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