Transient Visual Disturbance is Associated with Disability and Suicidal Risk in Patients with Migraine Without Aura

Background: Patients with migraine without aura frequently report transient visual disturbances (TVD) other than typical visual aura, but the clinical correlates are not determined. Method: Patients with migraine without aura (MO) that attended the headache clinic were enrolled. Structured questionnaires were self-administered by the patients including headache proles, comorbidities, lifetime suicidal ideation and attempts, six-item Headache Impact Test, Migraine Photophobia Score, Migraine Disability Assessment, Hospital Anxiety and Depression Scale, Beck Depression Inventory, and Pittsburgh Sleep Quality Index. A semi-structured visual phenomenon questionnaire was also used to assess the characteristics of TVDs. TVD is dened as any zigzag ashes, ickering dots/lines, or blurred/foggy vision associated with headache and with a Visual Aura Rating Scale < 4. Headache specialists interviewed with the participants for the ascertainment of diagnosis and veried of the questionnaires. Result: MO patients (n = 7,200, female/male = 3.56, mean age: 40.1 ± 13.4 years) were divided into 2 subgroups based on the presence (n=2,488) or absence of TVDs (n= 4,712). Patients with TVD had higher headache-related disability, more psychiatric comorbidities and were more likely to be photophobic. Suicidal ideation and attempts were more common in patients with TVD than in those without (ideation: 31.9% vs. 18.1%, OR = 1.92 [95% CI: 1.71−2.15], p < 0.001; attempt: 8.2% vs. 3.5%, OR = 2.23 [95% CI: 1.80−2.75], p < 0.001). The associations remained after adjustment of confounding factors. Conclusion: Presence of transient visual disturbance may suggest a higher migraine-related disability, higher level of photophobia and higher suicidal ideation/attempts in MO patients.


Introduction
Migraine aura is reversible visual, sensory, or language disturbances associated with headache, which develops gradually over more than 5 minutes and lasts between 5 and 60 minutes [1,2]. Among these neurological symptoms, visual aura is the most common and occurs in 98% of patients with migraine with aura (MA) [3]. Flashes of bright light, foggy/blurred vision, zigzag/jagged lines are the most frequent visual aura symptoms [4]. In clinical practice, however, many patients with migraine without aura (MO) also reported different and complex transient visual disturbances (TVD) other than typical visual aura. Our previous eld study in adolescents showed that almost half (48%) of migraine adolescents without characteristic migraine visual aura experienced TVD related to their headache attack [5]. Moreover, there are some migraine patients predominantly affected by the visual symptoms due to variable duration or complexity, such as photophobia and after-image [6,7]. Even though these TVDs do not ful ll the criteria of visual aura proposed by the International Classi cation of Headache Disorders (ICHD) [1,2], they are frequently reported by patients with MO. However, they are poorly characterized, often neglected, and related research is limited.
Previous studies have found connections between migraine aura and photophobia, which appear to be associated with cortical hypersensitivity [8]. Although the pathophysiology of TVD has not been fully investigated yet, we have found non-aura TVD is also associated with photophobia, implies the possibility of visual cortex hypersensitivity among patients with TVD [5]. On the other hand, studies have indicated that visual aura increased the odds of psychiatric comorbidities and suicide risk, possibly by alterations in the neuroendocrine system [9][10][11]. It is not known whether TVD could also be associated with psychiatric comorbidities and suicide risk among MO patients.
The aim of this study was to investigate the characteristics and clinical correlates of TVD among patients with migraine without visual aura, which may help understand the clinical signi cance of TVD and the complex neurobiology of migraine.

Study participants and data collection
The headache specialists at the headache clinic of the Taipei Veterans General Hospital (TVGH) surveyed patients presented with headache during the period from May 2010 to July 2020. All participants completed a structured questionnaire to assess their headache pro les, comorbidities, mood, sleep, photophobic scale and suicidal ideation or attempts (see below) at their rst visit. A semi-structured visual phenomenon questionnaire was used to assess the characteristics of TVDs. Later, they underwent a thorough clinical interview for the ascertainment of headache diagnosis as well as the questionnaires.
Information collected from the questionnaires was de-identi ed and entered into the TVGH headache registry.

Ethics
This retrospective study analyzed these de-identi ed data included in the TVGH headache registry.
Because this study involved secondary analysis of existing de-identi ed data, informed consent has 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 authors had full access to all of the data in the study and had nal responsibility for the decision to submit for publication. De nition of TVD TVDs were de ned as transient visual phenomena related in time to the occurrence of a migraine headache attack, but not visual aura. All of the participants received the ve items of the Visual Aura Rating Scale (VARS) embedded in the questionnaires. The score is the weighted sum of the ve-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 eld (one point). A cutoff VARS score of ve or more points is reportedly highly sensitive and speci c to diagnose MA [12]. In order to exclude potential aura, we also explored the VARS cutoff value in our cohort. MA diagnoses made by neurologists based on ICHD [1,2] were used as the gold standard. Compared to physician diagnosis, a VARS score ≥ ve had a sensitivity of 68.4% and a speci city of 88.7%, while a VARS score ≥ 4 had a sensitivity of 77.1% and a speci city of 79.9% to identify typical migraine aura. By using the criteria, i.e. a VARS score of ≥ 4, the positive predictive value (PPV) was 0.29 and the negative predictive value (NPV) was 0.97 for MA. Hence, in this study, we included only MO patients (diagnosed by neurologists) with VARS < 4 to ensure that their TVDs are unlikely to be visual aura.

Questionnaires
Demographic data, including age, sex, occupation, education level, marital status, and medical history were collected. A validated headache questionnaire was used to speci cally inquire headache frequency (days/ month), intensity (Numerical Rating Scale 0-10), duration, location, characteristics, accompanying symptoms, frequency of acute abortive medications usage (days/month), and disease duration of migraine (years), as well as TVD symptoms [13,14]. To differentiate these visual symptoms from characteristic migraine aura de ned in the ICHD, a visual phenomenon questionnaire was used to assess the TVDs, including patterns (zigzag ashes, ickering dots/lines, or blurred/foggy vision), laterality of the visual elds, colors, presence of movement, development time, duration and temporal relationship with headaches. The questions were: 1. Have you ever seen zigzag ashes before or during the headache? 2. Have you ever seen ickering dots or lines before or during the headache?
3. Before or when the headache started, did you have blurred or foggy vision? 4. What colors are these zigzag ashes, ickering dots or lines? 5. Do these TVDs (zigzag ashes, ickering dots or lines, or blurred vision) occur every time you have a headache?
. Are these TVDs that you have seen unilateral, bilateral or different every time?
. How long did your TVDs develop?
9. How long did your TVDs last?
10. Did these TVDs develop before, after or during the onset of the headache?
Afterwards, the MO patients were divided in to 2 subgroups based on the presence (MwTVD) or absence (MwoTVD) of TVDs. Additionally, the questionnaires also include the Migraine Disability Assessment The Migraine Disability Assessment (MIDAS) questionnaire assesses headache-related disability in a 3month period and the six-item Headache Impact Test (HIT-6) measures the severity of headache pain and adverse impact of headache [15,16]. Both MIDAS and HIT-6 have been well accepted and widely utilized to evaluate the disability and impact caused by migraine. Headache intensity in uences HIT-6 score more than the MIDAS, whereas the MIDAS is in uenced more by headache frequency [17]. Migraine Photophobia Score (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 [18]. Hospital Anxiety and Depression Scale (HADS) is a self-administered instrument to detect psychiatric comorbidity in the setting of a hospital outpatient clinic [19]. Anxiety was de ned as a HADS score ≥ 13 based on our previous study [20]. The Beck Depression Inventory (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 [21], and moderate depression is de ned as a BDI ≥ 20 [22,23]. The Perceived Stress Scale (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" [24,25]. Pittsburgh Sleep Quality Index (PSQI) evaluates the quality and patterns of sleep in the past one month. Poor sleep quality was de ned as a PSQI score of > 5 [26]. Suicidal ideation and attempts were evaluated by 2 separate directly asked questions: (1) whether they, once in their lifetime, had ideational thoughts of engaging in suicidal behavior, and (2) whether they had engaged in any self-injury behavior with the intent to die. Unanswered questionnaires were interpreted as missing data.
Migrainous features, the prevalence of visual disturbance, and the severity of photophobia 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 features were summed up to a total score of migrainous features, ranging from 0 to 6. To evaluate the migrainous feature in patients with photophobia, we re-calculated numbers of migrainous features ranged from 0 to 5, including the same features mentioned above except photophobia and phonophobia.

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. Continuous data between groups were analyzed using Student's t test with Bonferroni correction. For subgroup analysis, logistic regression was performed to test the interaction effect. The risks associated with comorbid suicidal ideation and attempts were predicted separately by 3 layers of models: (1) no controlling for any covariates; (2) controlling for demographics; (3) controlling for demographics and clinical characteristics. These models were performed stepwise.  Figure 1.

TVD characteristics and clinical features
Among the 2,488 MwTVD subjects, 865 (34.8%) patients reported more than one pattern of TVDs. The most common TVD was blurred or foggy vision (n = 1,766, 71.0%), followed by ickering dots/lines (n = 1,332, 53.5%) and zigzag ashes (n = 279, 11.2%). More than a quarter of the patients (n = 683, 27.5%) reported both positive TVDs ( ickering dots /lines, or zigzag ashes) and negative TVDs (blurred/foggy vision). Most of the TVDs happened during the headache (74.1%), while 18.4% happened before headache and 7.5% after the headache. The onset of TVD was commonly quick (59.2% of VD occurred in ≤ 30 seconds, 22.7% between 30 seconds to 1 minute, and 15.3% between 1-5 minutes), and the duration was also short (51.6% lasted ≤ 30 seconds, 23.0% lasted for 30 seconds to 1 minute, and 15.8% lasted for 1-5 minutes). The detailed characteristics of the TVDs are shown in Table 1. The onset time, duration, and temporal relationships with headache are the three major different characteristics of TVD comparing with typical visual aura. To validate phenotype-based diagnosis of TVD, we compared these three characteristics between our MwTVD and MA groups. For visual symptoms that did not ful ll typical visual aura but had at least two of these three characteristics: A. Develops or spreads in less than 5 minutes; B. Lasts last than 5 minutes; C. Occurs during headache phase, the sensitivity and speci city to identify TVD were 96.38% and 64.03%. Both the PPV and NPV were 0.87.
Details of demographic data and clinical characteristics of MwTVD and MwoTVD are listed in Table 2. In general, MwTVD had worse clinical features than MwoTVD. The MwTVD group, compared with the MwoTVD group, had higher headache frequency, more severe headache-related disability, higher proportions of CM, MOH and psychiatric comorbidities, and were more likely to be photophobic.

TVD, photophobia and migrainous features
There is a trend for increasing TVD frequency with increasing migrainous features ( Fig. 2A). While the TVD was reported in only 12.2% of MO patients with least migrainous features, its prevalence increased to 46.6% in those with all six migrainous features. To investigate whether patients with TVD were also more photophobic, we further compared the MPS between MwTVD and MwoTVD. Consistent with our speculation, MwTVD patients had higher MPS while comparing with MwoTVD (2.9 ± 2.0 vs. 1.6 ± 1.9, p < 0.001, Table 1). Moreover, we found MPS was a predictor of TVD (unadjusted OR = 1.37, 95% CI = 1.32-1.42, p < 0.001), and the result remained after gender and age were adjusted (adjusted OR = 1.36, 95% CI = 1.31-1.41, p < 0.001). Similar to TVD, there is also a trend for increasing photophobia frequency with increasing migrainous features, expanding from 15.6% to 38.4% (Fig. 2B).
Suicide risk in patients with migraine with visual disturbance and photophobia Because the percentages of suicidal ideation and attempts were much higher in the MwTVD group than those in the MwoTVD group (31.9% vs. 18.1%, p < 0.001 for suicidal ideation; 8.2% vs. 3.5%, p < 0.001 for suicide attempts, Table 2), we further explored whether TVD could be an independent risk factor for suicidal risk in patients with migraine without typical visual aura. Univariate analysis showed that TVD, photophobia, headache frequency and headache-related disability, CM, MOH, along with traditional risk factors including depression, anxiety, and poor sleep quality, were associated with higher risks of suicidal ideation and attempts in patients with migraine, while marriage had a protective effect in suicide ideation (Table 3). In multivariable analysis, TVD remained an independent risk factor for suicidal ideation and attempts even after controlling for demographics, headache frequency, headache-related disability, CM, MOH and psychiatric comorbidities (Table 4).

Discussion
Our study demonstrated that the prevalence of the non-aura TVD was as high as 34.6% among MO patients. Patients with TVD are predominately female, had worse headache-related disability, more psychiatric comorbidities, and were more likely to be photophobic compared with patients without TVD. Patients who exhibited more migrainous features were more likely to have a higher prevalence of TVD and photophobia, implying the clinical signi cance of non-aura visual symptoms in migraine. Moreover, the presence of TVD was positively correlated with increased suicidal ideation and attempts, even after the other suicide risk factors were adjusted. Based on these ndings, we speculated that the presence of TVD might serve as a marker of disease severity and even a potential indicator of higher suicidal risk.
Blurred/foggy vision is the most common type of TVD, and more than a quarter of these patients (27.5%) also have seen ickers or zigzag ashes. This is similar to a previous study, stating that "blurred/foggy vision" was the most common visual symptom other than aura among MA patients [27]. The TVDs reported in our patients are mostly xed, colorless, over non-speci c elds, developing within 5 minutes, lasting less than 5 minutes, and occurring during the headache phase. This nding is consistent with our previous study indicating the transient TVDs are short in onset to development as well as the duration and is common among adolescent patients with migraine [5]. The major differences between typical visual aura and TVD are the onset and duration of the symptoms, and the temporal relation with headache. Also, among our 9,946 migraine patients, one-fourth of them reported to have non-aura TVD (n=2,488) but only less than one-tenth of then have MA (n=962), showing that the prevalence of TVD is much higher than that of typical aura. We proposed that these non-classic visual symptoms should not be classi ed as atypical aura, and might be identi ed separately. We suggest non-aura TVD has crucial clinical implications and should be identi ed in clinical practice. Herein we proposed an operational criteria to characterize these migraine-associated TVD, the clinical utility of which needs be validated in future studies (Table 5).
To our best knowledge, this is the rst study that found TVD is related to higher migraine-related disability, higher level of photophobia, and higher suicidal ideation/attempts risk. Furthermore, the odds ratios of TVD and MPS on suicide are higher than HIT-6 and headache frequency, which were previously thought to be highly related to suicide risk [28]. This implies the impact of non-aura TVD on migraine might be underestimated. Also, both TVD and photophobia have a higher prevalence among those with more migrainous features than those without (Fig. 2). Although photophobia is known as one of the most disabling symptoms of migraine [29], the disabilities caused by TVD are seldom addressed. Therefore, we propose that TVD should be considered as one of the indicators to evaluate the prognosis of migraine.
The pathophysiology of TVD in patients with migraine is unknown. Typical aura is associated with abnormal cortical hyper-excitability, and visual percept of aura could change depends on the region of the occipital cortex involved [30]. Previous studies also found cortical hypersensitivity might be the link between migraine aura and photophobia [8]. Since patients with TVD were more photophobic than those without and that increased interictal visual sensitivity is present in both MA and MO [31], the TVD in some patients might also be linked to mechanisms similar to cortical hyper-excitability but involving a less eloquent visual cortex [32]. We speculate that our patients with TVD may have a hyperexcitable visual cortex, which contributes to non-aura TVD and more severe photophobia and may thus lead to worse migraine-related disability. Furthermore, we found non-aura TVD as an independent risk factor of increased suicidal ideation or attempts even after adjusting other potential confounders. Studies have reported that suicide survivors had lower oxytocin concentration both in serum and CSF [33,34], and oxytocin is a potential biomarker of attempted suicide [35]. On the other hand, oxytocin released from paraventricular neurons (PVN) can suppress nociception of in ammatory pain [36]. Since PVN also channels the photic input from the retina [37], it is possible that oxytocin may be also related to migrainetype photophobia and worse headache-related disability. However, it is hypothetical and systematic studies should be conducted in the future.
There are several strengths in our study. First, our sample size is large, with more than 7,000 patients with MO enrolled consecutively in the ten-year study period. The large sample size increased the validity of this clinic-based study. Second, we have detailed and validated questionnaires to speci cally inquire headache characteristics and TVD symptoms. The data from the questionnaires was highly quali ed, and these questionnaires have been widely accepted as reliable neuropsychological instruments in many studies [13,14,20]. Furthermore, the nal diagnoses of MO and TVD were ascertained by experienced headache specialists made through face-to-face interview, which help to con rm the accuracy of our data. We also used VARS to exclude the potential inclusion of aura. Additionally, we provided our proposed TVD diagnostic criteria based the phenotype of the visual symptoms. Therefore, we believe our ndings could have a practical implication for neurologists.
However, there are also some limitations in our study. First, all the patients were recruited from a tertiary medical center; thus, the patients we seen were at the worse end of the disease spectrum. Nevertheless, even in these patients, those with TVD still had much worse clinical features than those without. Second, the suicide risk was evaluated based on single-item direct questions, questioning of the suicidal ideation and attempts. Although the patients received face-to-face interview, detailed information regarding the potential etiologies of suicidal ideation or attempts was not systematically collected. However, the overall lifetime suicidal attempts in our MwoTVD was very close to previous cross-national, multicultural study (3.5% and 2.7%, respectively), indicating the reliability of our study [38]. As previous studies have shown that more than half of suicidal ideations transform into plan and attempt in one year, and suicide attempt is the best predictor of a completed suicide [39]. Last, we focused on psychiatric diseases and some other demographics factors since these are the strongest predictors of suicide while some other risk factors for suicide such as chronic pain disorders, bromyalgia, major life events, and nancial status were not controlled in the multivariable analysis [40,41]. Further study to investigate these risk factors should be conducted in the future.

Conclusions
In this study, we found that non-aura TVD was associated with higher level of photophobia, higher migraine-related disability, and higher suicidal ideation/attempts. The odds ratio of TVD and MPS on suicide are higher than HIT-6 and headache frequency, implies the impact of non-aura TVD and photophobia on migraine might be underestimated. We suggested that TVD should be considered as one of the indicators to evaluate the prognosis of migraine, and proposed an operational criteria for TVD. Nevertheless, the exact pathophysiology is unknown and required further exploration.

Declarations
Ethics approval and consent to participate This retrospective study analyzed these de-identi ed data included in the TVGH headache registry.
Because this study involved secondary analysis of existing de-identi ed data, informed consent has 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 authors had full access to all of the data in the study and had nal responsibility for the decision to submit for publication.

Consent for publication
Not applicable.
Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors have declared no relevant con ict of interests.      There is a trend for increasing TVD frequency with increasing migrainous features ( Fig. 2A). While the TVD was reported in only 12.2% of MO patients with least migrainous features, its prevalence increased to 46.6% in those with all six migrainous features. To investigate whether patients with TVD were also more photophobic, we further compared the MPS between MwTVD and MwoTVD. Consistent with our speculation, MwTVD patients had higher MPS while comparing with MwoTVD (2.9 ± 2.0 vs. 1.6 ± 1.9, p < 0.001, Table 1). Moreover, we found MPS was a predictor of TVD (unadjusted OR = 1.37, 95% CI = 1.32-1.42, p < 0.001), and the result remained after gender and age were adjusted (adjusted OR = 1.36, 95% CI = 1.31-1.41, p < 0.001). Similar to TVD, there is also a trend for increasing photophobia frequency with increasing migrainous features, expanding from 15.6% to 38.4% (Fig. 2B).