Impact of Greater Occipital Nerve Block on Photophobia Levels in Migraine Patients

Background: To study the effect of greater occipital nerve (GON) block on migraine-associated photophobia levels. Photophobia is one of the most bothersome symptoms reported by migraine patients. Studies investigating the impact of migraine treatment on this symptom are scarce. Methods: This is an observational prospective case-control study. Patients with migraine and photophobia attending a Headache Clinic were recruited. Cases were defined as patients in whom GON block was performed, following usual clinical practice guidelines. All patients were evaluated with the Hospital Anxiety and Depression Scale, the Migraine Specific Quality of Life Questionnaire, the Utah Photophobia Symptom Impact Scale (UPSIS-12), and the Korean Photophobia Questionnaire (KUMC-8); both in the first visit (V1) and one week after (V2). Results: Forty-one patients were recruited, 28 (68.3%) cases and 13 (31.7%) controls. At V1, there were no significant differences in the median [p25-p75] score of UPSIS-12 in cases vs controls (32.0 [21.0-34.0] vs 30.5 [22.0-37.0], P = 0.497) or KUMC-8 (6.5 [5.5-7.0] vs 7.0 [6.0-8.0], P = 0.463). At V2, cases experimented a significant improvement in UPSIS-12 of -5.5 [-8.8 to -1.3] and in KUMC-8 of -0.5 [-2.0 to 0], whereas there were no significant changes in the control group. Migraine with aura patients presented higher UPSIS-12 score at V1 (33.5 [24.5-37.0] vs 26.0 [16.0-35.0]) and lesser improvement at V2 after GON block compared with migraine without aura patients (-4.0 [-6.0 to -1.0] vs -8.0 [-17.0 to -2.0]), although statistical significance was not achieved ( P = 0.643 and P = 0.122, respectively). There was no significant variation in the remaining scales. Conclusions: Greater occipital nerve block improves migraine-associated photophobia, measured with UPSIS-12 and KUMC-8. Patients without aura may exhibit a greater improvement. Physicians could consider GON block for management of photophobia in migraine patients.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Impact of Greater Occipital Nerve Block on Photophobia Levels in Migraine Patients Javier A. Membrilla, MD, Íñigo de Lorenzo, MD, Lucía Sánchez-Casado, MD, María Sastre, MD, Javier Díaz de Terán, MD Background: To study the effect of greater occipital nerve (GON) block on migraine-associated photophobia levels. Photophobia is one of the most bothersome symptoms reported by migraine patients. Studies investigating the impact of migraine treatment on this symptom are scarce. Methods: This is an observational prospective case–control study. Patients with migraine and photophobia attending a Headache Clinic were recruited. Cases were defined as patients in whom GON block was performed, following usual clinical practice guidelines. All patients were evaluated with the Hospital Anxiety and Depression Scale, the Migraine Specific Quality of Life Questionnaire, the Utah Photophobia Symptom Impact Scale (UPSIS-12), and the Korean Photophobia Questionnaire (KUMC-8); both in the first visit (V1) and one week after (V2). Results: Forty-one patients were recruited, 28 (68.3%) cases and 13 (31.7%) controls. At V1, there were no significant differences in the median [p25-p75] score of UPSIS-12 in cases vs controls (32.0 [21.0–34.0] vs 30.5 [22.0– 37.0], P = 0.497) or KUMC-8 (6.5 [5.5–7.0] vs 7.0 [6.0– 8.0], P = 0.463). At V2, cases experimented a significant improvement in UPSIS-12 of 25.5 [28.8 to 21.3] and in KUMC-8 of 20.5 [22.0 to 0], whereas there were no significant changes in the control group. Migraine with aura patients presented higher UPSIS-12 score at V1 (33.5 [24.5–37.0] vs 26.0 [16.0–35.0]) and lesser improvement at V2 after GON block compared with migraine without aura patients (24.0 [26.0 to 21.0] vs 28.0 [217.0 to 22.0]), although statistical significance was not achieved (P = 0.643 and P = 0.122, respectively). There was no significant variation in the remaining scales. Conclusions: Greater occipital nerve block improves migraine-associated photophobia, measured with UPSIS12 and KUMC-8. Patients without aura may exhibit a greater improvement. Physicians could consider GON block for management of photophobia in migraine patients. Journal of Neuro-Ophthalmology 2022;42:378–383 doi: 10.1097/WNO.0000000000001541 © 2022 by North American Neuro-Ophthalmology Society Neurology Department (JAM, IdL, LS-C, MS, JDdT), University Hospital “La Paz”, Madrid, Spain; and La Paz Institute for Health Research (IdiPAZ) (MS, JDdT), Madrid, Spain. The authors report no conflicts of interest. Address correspondence to Javier A. Membrilla, MD, Paseo de la Castellana 261, 28046 Madrid, Spain; E-mail: [e-mail] 378 P hotophobia is a sensory disturbance provoked by light commonly seen in several headache disorders. It is described as induction or worsening of headache and as uncomfortable vision without pain, inducing an avoidance of light behavior (1). Photophobia is one of the main nonhead pain symptoms defining migraine. Patients typically describe light as being too bright (abnormal sensitivity to light) or even painful, causing or worsening head or eye pain (phototic allodynia) (2). Photophobia affects as much as 80% of migraine patients, presenting even outside of migraine attacks (3). Migraine is a neurologic disorder that presents with headache, usually along with other symptoms such as nausea, vomiting, photophobia, and phonophobia. According to the third edition of the International Classification of Headache Disorders (ICHD-3), migraine diagnosis requires the occurrence of nausea/vomiting or photophobia/ phonophobia (4). Pathophysiology of pain in migraine attacks is complex. Both peripheral (direct or indirect activation of trigeminal primary afferents) and central (cortical spreading depression with subsequent activation of the trigeminal nerve fibers) sites of origin of migraine attacks have been proposed (5). 49.1% participants of the Migraine in America Symptoms and Treatment study reported photophobia as the most bothersome symptom (6). For a greater characterization of the photophobia impact in daily activities, several clinical scores have been validated. The 8-item Korean Photophobia Questionnaire (KUMC-8) consists of 8 yes–no questions, 7 of them relating light aversion with pain in the migraine phase, and the last one about photophobia in the out-of-pain phases of migraine (3). More recently, the 12-item Utah Photophobia Symptom Impact Scale (UPSIS-12) has been validated (7). Photophobia between the migraine attacks gains more relevancy in this questionnaire, representing 40 of a maximum score of 55. To date, most of the recommended treatments for photophobia are based on case reports or a few studies Membrilla et al: J Neuro-Ophthalmol 2022; 42: 378-383 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution with small sample sizes. Wearing sunglasses, magnesium, and OnabotulinumtoxinA were found to improve migraineassociated photophobia. However, new therapies are still needed to improve this bothersome symptom (1). The greater occipital nerve (GON) block with local anesthetics has become a widely used treatment for migraine pain management (8). The aim of our study is to assess whether anesthetic blockade of the GON can reduce photophobia in patients with migraine. METHODS Design According to International Recommendations for Observational Studies, items on the Strengthening the Reporting of Observational Studies in Epidemiology checklist were followed for this study (9). We conducted a prospective case–control observational study with successive recruitment at a specialized Headache Clinic in La Paz University Hospital, a public reference center in Madrid, Spain. Migraine patients were diagnosed by a headache specialist according to the ICHD-3 criteria (4). The inclusion period went from January 2020 to March 2020. Data were collected in 2 visits: the baseline visit (V1) and the follow-up visit (V2), which was scheduled 7 days after V1 and performed by telephone contact. The study was approved by the local Ethics Committee for Clinical Research of our center (PI-3954) and written informed consent was obtained for all participants. Study Population and Eligibility Patients attending the Headache Clinic during the recruiting period were included if they met all of the following requirements: (1) had a diagnosis of migraine without aura (code 1.1), migraine with aura (code 1.2), or chronic migraine (code 1.3) according to ICHD-3 criteria and (2) reported photophobia in the medical interview at V1. Patients were excluded if they had allergy to local anesthetics, other contraindications for GON block, cognitive disturbances that could interfere with the study procedures, or if they declared a lack of availability to complete the follow-up period. All patients received standard migraine treatment following the current guidelines of the Spanish Society of Neurology (10). As per usual clinical practice, GON block was offered to patients with an ongoing migraine attack at the time of the visit, frequent attacks in the previous week, a headache frequency that exceeded 15 days per month in the last 3 months despite adequate treatment and to patients that had reported a good previous response to GON block in pain. Greater occipital nerve block was performed by bilateral injection of 5 mL of 1% mepivacaine (2.5 mL per side) using a 25-gauge subcutaneous needle. The injection site was the medial onethird of the distance between the occipital process and the Membrilla et al: J Neuro-Ophthalmol 2022; 42: 378-383 mastoid process. When indicated, OnabotulinumtoxinA was administered following the PREEMPT paradigm (155–195 international units) (11). Data Collection KUMC-8 and UPSIS-12 were administered at V1 and V2 to assess changes in photophobia levels. In addition, we recorded depression and anxiety levels by the Hospital Anxiety and Depression Scale (HAD) and patient’s reported outcomes by the Migraine Specific Quality of Life Questionnaire v2.1 (MSQ) at both visits. Hospital Anxiety and Depression Scale is a short questionnaire with 14 items divided into 2 subsets: Anxiety (HAD-A) and Depression (HAD-D). A score of 11 or higher indicates probable presence of the mood disorder (12). Migraine Specific Quality of Life Questionnaire v2.1 explores the impact of migraine on health-related quality of life. It is a 14-item scale structured in 3 domains: role function restrictive (MSQ-RFR), role function preventive (MSQ-RFP), and emotional function (MSQ-EF). Each of its domains punctuate from 0 to 100, where higher scores indicate better health-related quality of life. The validated Spanish version was used for HAD and MSQ. A nonvalidated Spanish translated version of UPSIS-12 and KUMC-8 was used, because validated Spanish versions did not exist at the time of the conduction of this study. Figure 1 displays a chronogram of the study design and data collection. Statistical Analysis No statistical power calculation was performed before the study. The sample size was based on our previous experience with this design. Data analysis was performed using the Statistics Package for Social Science (SPSS 23.00; IBM Inc, Armonk, NY). Nominal variables were reported as percentages and compared using a two-tailed Chi-square or Fisher test, when applicable. A 2-tailed Shapiro-Wilk test was applied to examine whether the ratio variables followed a Gaussian distribution. Ratio variables were reported as mean ± SD if they followed a Gaussian distribution; otherwise, they were represented as median ± interquartile range [p25-p75]. Statistical significance was set at P , 0.05 and confidence interval was established at 95%. RESULTS We recruited 41 patients with a mean age of 43.9 (±12.9) years old. 39/41 (95.1%) were women. 26/41 patients (63.4%) had chronic migraine and 22/41 (53.7%) had migraine with aura. 28 patients (68.3%) received GON block. 21/41 patients (51.2%) were on oral preventive medication and 25/41 (61.0%) were receiving OnabotulinumtoxinA. 27/41 patients (65.9%) received more than one treatment. None of these patients were under calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies. 379 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Chronogram of the study design. V1, baseline visit; V2, follow-up visit; HAD, hospital anxiety depression scale; MSQ, migraine-specific quality of life questionnaire. UPSIS-12, 12-item Utah photophobia symptom impact scale; KUMC-8, 8-item Korean photophobia questionnaire. At V1, the median scores in clinical questionnaires were as follows: 31.0 [22–35.5] in UPSIS-12, 7.0 [6.0–8.0] in KUMC-8, 10.0 [7.5–13.0] in HAD-A, 7.0 [3.0–11.0] in HAD-D, 43.0 [29.0–52.5] in MSQ-RFR, 60.0 [29.0–52.5] in MSQ-RFP, and 40.0 [23.5–73.0] in MSQ-EF. There were no statistically significant differences in the questionnaires at V1 between GON block group and controls (see Table 1). At V2, GON block group exhibited a statistically significant improvement in photophobia levels, scoring a median of 23.5 [16.3–32.5] in UPSIS-12 and 6.0 [5.0–7.0] in KUMC-8, compared with control group (33.0 [22.5–35.0] and 6.0 [5.5–7.5], respectively). Thus, patients who received a GON blockade showed a change in UPSIS-12 of 25.5 [28.8 to 21.3] and in KUMC-8 of 20.5 [22.0 to 0], whereas there were no significant changes in the control group (see Fig. 2). The reduction in photophobia levels showed statistical significance between GON block group and control group (P , 0.001 for UPSIS-12 and P = 0.010 for KUMC-8). The changes of the remaining questionnaires did not present statistically significant differences between groups (see Table 2). There were no differences in the photophobia level improvement between patients treated with both GON block and OnabotulinumtoxinA and those treated with GON block alone. 17 patients treated with OnabotulinumtoxinA and GON block reported an improvement of 26.0 points [28.0 to 21.0] in UPSIS-12 at V2, whereas the remaining 11 patients treated with GON block scored 25.0 points [213.0 to 23.0]. This difference did not achieve statistical significance (P = 0,517), neither did the differences in changes in KUMC-8: ±0.0 [21.0 to 0.0] vs 22.0 [22.0 to 0.0], respectively (P = 0.134). Patients with migraine with aura showed higher photophobia scores in UPSIS-12 at baseline (33.5 [24.5–37.0] vs 26.0 [19.0–35.0], P = 0.643), but not in KUMC-8 (6.5 [6.0–8.0] vs 7.0 [5.0–7.0], P = 0.926). In the GON block group, the patients without aura (11/28%, 39.3%) experimented a greater decrease in both UPSIS-12 (28.0 [217.0 to 22.0] vs 24.0 [26.0 to 21.0], P = 0.122) and KUMC8 (22.0 [23.0 to 0.0] vs ± 0.0 [21.5 to 0.0], P = 0.264). None of these differences achieve statistical significance. DISCUSSION Several placebo-controlled clinical trials have shown the efficacy of GON block in chronic migraine management, leading to a decrease in the number of headache days and pain intensity (13–16). In addition, 3 clinical trials have demonstrated that GON block is effective for an acute migraine attack compared with placebo (17–19). However, this is, to the best of our knowledge, the first study that evaluates the effect of GON block in photophobia levels. TABLE 1. Participants’ score in clinical questionnaires at baseline Controls N = 13 GON block group N = 28 P HAD-A HAD-D MSQ-RFR MSQ-RFP MSQ-EF UPSIS-12 KUMC-8 9.0 [5.5–12.5] 11.0 [8.0–13.8] 0.159 7.0 [4.0–10.5] 6.5 [2.0–11.0] 0.945 43.0 [34.0–50.0] 40.0 [26.8–55.5] 0.772 55.0 [40.0–62.5 60.0 [41.3–75.0] 0.570 40.0 [20.0–60.0] 43.5 [28.5–78.3] 0.367 32.0 [21.0–34.0] 30.5 [22.0–37.0] 0.497 6.5 [5.5–7.0] 7.0 [6.0–8.0] 0.463 GON, greater occipital nerve; HAD-A, hospital anxiety depression scale—anxiety; HAD-D, hospital anxiety depression—depression; KUMC8, 8-item Korean photophobia questionnaire; MSQ-RFR, migraine-specific quality of life questionnaire—role function restrictive; MSQ-RFP, migraine-specific quality of life questionnaire—role function preventive; MSQ-EF, migraine-specific quality of life questionnaire—emotional function; UPSIS-12, 12-item Utah photophobia symptom impact scale. 380 Membrilla et al: J Neuro-Ophthalmol 2022; 42: 378-383 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Graphical representation of photophobia scores at baseline (V1) and 7 days after (V2). A. UPSIS-12 scores in the control group (N = 13), B. UPSIS-12 scores in the GON-block group (N = 28), C. KUMC-8 scores in the control group (N = 13), D. KUMC-8 scores in the GON block group (N = 28). GON, greater occipital nerve; UPSIS-12, 12-item Utah photophobia symptom impact scale; KUMC-8, 8-item Korean Photophobia Questionnaire. Our results suggest that GON block could reduce photophobia in migraine patients. In our study, GON block lead to an improvement in photophobia impact one week after treatment compared with control group. The greater reduction was registered in UPSIS-12 score, indicating a greater improvement in interictal photophobia. The shortterm effectivity of GON block in migraine has been proved in a clinical trial that showed improvement of pain after 7 days (15). Given that GON block has short-term effectivity in pain management, it makes sense that we can also see improvement in other migraine-related symptoms such as photophobia as soon as 7 days after this intervention. Given the fact that we can block nociceptive inputs into the trigeminal cervical complex using GON block, we may TABLE 2. Variation of scores 7 days after baseline Controls N = 13 GON block group N = 28 P HAD-A HAD-D MSQ-RFR MSQ-RFP MSQ-EF +2.0 [22.0 to +4.5] +2.0 [21.8 to +5.5] 0.901 ±0.0 [21.0 to 0] ±0.0 [21.0 to +1.0] 0.688 ±0.0 [21.5 to +14.5] +11.0 [0.5 to 20.0] 0.121 ±0.0 [22.5 to +20.0] 2.5 [25.0 to +20.0] 0.730 ±0.0 [23.5 to +9.5] +7.0 [0.0 to 18.3] 0.128 GON, greater occipital nerve; HAD-A, hospital anxiety depression scale—anxiety; HAD-D, hospital anxiety depression—depression; MSQRFR, migraine-specific quality of life questionnaire—role function restrictive; MSQ-RFP, migraine-specific quality of life questionnaire—role function preventive; MSQ-EF, migraine-specific quality of life questionnaire—emotional function. Membrilla et al: J Neuro-Ophthalmol 2022; 42: 378-383 381 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution modulate photophobia with this intervention, because its mechanisms seem to involve the trigeminal nucleus caudalis and its projections to the posterior thalamus. This thalamic region has been proposed as a core element for photophobia in migraine, because it contains both dura-sensitive neurons and retinal projections (20). A decrease in photophobia could be achieved by a therapy with peripherical site of action. This was demonstrated in an experimental study in which migraine-like photophobic behavior was induced in mice by both peripherical (intraperitoneal) and central (intracerebroventricular) CGRP injections. The peripherical CGRP-induced light aversion behavior was attenuated after treatment with an anti-CGRP monoclonal antibody (21). Our results showed that the improvement in photophobia scores in patients treated with GON block did not differ significantly if the patients were receiving OnabotulinumtoxinA, making the co-intervention bias unlikely. Some observational studies have proposed an improvement of light aversion in migraine patients treated with OnabotulinumtoxinA. A retrospective study showed that treatment with OnabotulinumtoxinA for an average period of 3 years resulted in an improvement in photophobia frequently reported by patients (22). A similar retrospective investigation showed a benefit in interictal photophobia measured with a specific score (the Visual Light Sensitivity Questionnaire) in chronic migraine patients treated with OnabotulinumtoxinA for a mean period of 2.7 years (23). We observed that patients with migraine with aura reported higher UPSIS-12 scores, in accordance with previous investigations showing higher photophobia impact in migraine with aura individuals (24). In a cross-sectional study, migraine with aura patients reported greater photophobia scores (using the Photosensitivity Assessment Questionnaire) (25). Investigations using blood oxygen level-dependent functional MRI have suggested cortical hyperexcitability of the visual system in the interictal state of migraine with aura (26,27), which could have a role in patients with aura experimenting higher photophobia impact. In our study, these patients experimented a lesser improvement with GON block than patients of migraine without aura. This lesser improvement could be because of a basal higher cortical excitability state in migraine with aura patients. Along with the small sample size, our study has several limitations, such as the lack of randomization, unicentric design, and biases derived from the successive recruitment. More than 95% of the sample were women, which prevents the comparison between genders. Finally, as mentioned before, UPSIS-12 and KUMC-8 have not been validated in the Spanish language yet, so we had to use a nonvalidated Spanish version of these questionnaires. 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