Serum Calcitonin Gene-Related Peptide Is Elevated in Patients With Migraine and Ophthalmoplegia

Background: There is ongoing debate about whether the oculomotor (III), trochlear (IV), or abducens (VI) nerve paresis in patients with migraine is directly attributable to migraine (ophthalmoplegic migraine [OM]) or is due to an inflammatory neuropathy (recurrent painful ophthalmoplegic neuropathy [RPON]). As migraine is associated with elevated serum calcitonin gene-related peptide (CGRP) levels, we studied serum CGRP levels among patients with OM/RPON to determine whether they are elevated during and between attacks. This is the first study assessing CGRP levels in the serum of patients with OM/RPON. Methods: The aim of this case-control study was to assess serum CGRP levels in patients with ophthalmoplegia and a headache consistent with migraine according to ICHD-3 criteria. Serum CGRP levels were measured during the ictal and interictal phases in 15 patients with OM/RPON and compared with age-matched and sex-matched controls without migraine (12 patients). Results: The median serum CGRP levels were significantly elevated ( P = 0.021) during the ictal phase (37.2 [36.4, 43.6] ng/L) compared with controls (32.5 [30.1, 37.3] ng/L). Serum CGRP levels during the attack correlated with the total duration of ophthalmoplegia. A CGRP level of 35.5 ng/L in the ictal phase of the attack had a sensitivity of 86.7% and specificity of 75.0% in diagnosing a patient with OM/RPON.Conclusions: Elevated serum CGRP levels during the ictal phase of OM/RPON favor migraine as the underlying cause of episodic headache with ophthalmoplegia.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Serum Calcitonin Gene-Related Peptide Is Elevated in Patients With Migraine and Ophthalmoplegia Aastha Takkar, DM, K. V. Anil Kumar, MD, Deeksha Katoch, MD, Paramjeet Singh, MD, Ranjana Minz, MD, Shashi Anand, MSc, Soundappan Kathirvel, MD, K. Ravishankar, DM, Vivek Lal, DM, Louis R. Caplan, MD Background: There is ongoing debate about whether the oculomotor (III), trochlear (IV), or abducens (VI) nerve paresis in patients with migraine is directly attributable to migraine (ophthalmoplegic migraine [OM]) or is due to an inflammatory neuropathy (recurrent painful ophthalmoplegic neuropathy [RPON]). As migraine is associated with elevated serum calcitonin gene-related peptide (CGRP) levels, we studied serum CGRP levels among patients with OM/ RPON to determine whether they are elevated during and between attacks. This is the first study assessing CGRP levels in the serum of patients with OM/RPON. Methods: The aim of this case–control study was to assess serum CGRP levels in patients with ophthalmoplegia and a headache consistent with migraine according to ICHD-3 criteria. Serum CGRP levels were measured during the ictal and interictal phases in 15 patients with OM/RPON and compared with age-matched and sex-matched controls without migraine (12 patients). Results: The median serum CGRP levels were significantly elevated (P = 0.021) during the ictal phase (37.2 [36.4, 43.6] ng/L) compared with controls (32.5 [30.1, 37.3] ng/L). Serum CGRP levels during the attack correlated with the total duration of ophthalmoplegia. A CGRP level of 35.5 ng/L in the ictal phase of the attack had a sensitivity of 86.7% and specificity of 75.0% in diagnosing a patient with OM/RPON. Departments of Neurology (AT, VL), Internal Medicine (KVAK), Ophthalmology (DK), Radiodiagnosis (PS), Immunopathology (RM, SA), and Community Medicine and School of Public Health (SK), Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India; The Headache and Migraine Clinics (KR), Jaslok and Lilavati Hospitals, Mumbai, India; and Beth Israel Deaconess Medical Center (LC) (LRC), and Department of Neurology (LC), Harvard University, Boston, Massachusetts. The authors report no conflicts of interest. Conclusions: Elevated serum CGRP levels during the ictal phase of OM/RPON favor migraine as the underlying cause of episodic headache with ophthalmoplegia. Journal of Neuro-Ophthalmology 2023;43:399–405 doi: 10.1097/WNO.0000000000001695 © 2022 by North American Neuro-Ophthalmology Society T here is ongoing debate about whether paresis of ocular motor nerves (III, IV, and VI) associated with a migraine attack is directly attributable to migraine (ophthalmoplegic migraine [OM]) or is due to an inflammatory neuropathy (recurrent painful ophthalmoplegic neuropathy [RPON]). OM is characterized by recurrent attacks of ocular motor nerve paresis, temporally associated with a severe migraine headache (1,2,3,4). The International Classification of Headache Disorders (ICHD-3) reclassified OM as RPON because some patients with this syndrome have enhancement of the oculomotor nerve on MRI (5). A recent article by Lal and Caplan, along with several previous publications, strongly supports a migraine pathogenesis of OM/RPON in view of a) history of migraine; b) increased severity of migraine attacks before developing ophthalmoplegia, which occurs during a severe attack of migraine; and c) close temporal association between attacks of migraine and ophthalmoplegia (2,6,9–11). Serum calcitonin gene-related peptide (CGRP) levels are elevated in migraine (7,8,12–15). We studied serum CGRP levels to further clarify the pathogenesis of OM/RPON. This is the first study assessing CGRP levels in the serum of patients with OM/RPON. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). METHODS Institute Ethics Committee Approval No. INT/IEC/2018/002121 (Institutional Ethics Committee-Postgraduate institute of Medical Education and Research, Chandigarh). Study Design Address correspondence to Vivek Lal, DM, Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India; E-mail: [e-mail] Takkar et al: J Neuro-Ophthalmol 2023; 43: 399-405 Case–Control Study: Study Setting and Period Patients with clinical signs and symptoms suggestive of OM/RPON who attended the Outpatient Department of 399 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Neurology of Postgraduate Institute of Medical Education and Research, Chandigarh, were recruited between June 2017 and December 2018. All consecutive patients 18 years and older presenting with migraine and ophthalmoplegia were screened. This study was approved by the institution review board and the institutional ethics committee (Postgraduate Institute of Medical Education and Research, Chandigarh), and all participants provided written informed consent. Participants fulfilled the ICHD-3 diagnostic criteria for RPON or recently proposed criteria for OM by Lal and Caplan (See Supplemental Digital Content 1, Supplement 1(A), http://links.lww.com/WNO/A623). Patients with ophthalmoplegia due to other causes; systemic conditions including cardiac, renal, or hepatic insufficiency; malignancies; recent trauma; and pregnant/ lactating women and patients with alcohol dependence or with active somatic and psychiatric diseases were excluded. Twelve individuals, matched for age and sex of the cases, served as controls after exclusion of the presence of chronic headache, migraine, any ophthalmic disease, recent trauma, systemic conditions, or malignancies. A detailed history and clinical examination were performed on all participants. All participants had 9-gaze external photography in the ictal and interictal phases. The intensity of headache among participants with OM/RPON was measured using a 10-point visual analogue scale (VAS). All patients underwent blood investigations, including complete hemogram; renal, liver, and thyroid function tests; erythrocyte sedimentation rate; C-reactive protein (CRP); fasting and postprandial blood sugar; and glycated hemoglobin. Cerebrospinal fluid (CSF) analysis was performed to rule out other secondary causes of ophthalmoplegia. Gadolinium-enhanced cranial MRI (Gd-MRI) as per a set protocol (See Supplemental Digital Content 1, Supplement 1(B), http://links.lww.com/WNO/A623) was performed on all participants during the ictal phase of OM/ RPON to rule out any other structural cause of ophthalmoplegia and to specifically look for cranial nerve enhancement. Laboratory analysis for serum CGRP was performed as per protocol. The serum sample for assessment of serum CGRP levels was collected from controls at the time of enrollment. Assessment of Serum CGRP Blood samples to estimate serum CGRP levels were collected in the following subgroups: 1. Acute/ictal phase: Blood samples were collected when the participant was first evaluated for an acute attack of migraine with ophthalmoparesis in all 15 participants meeting the inclusion criteria. None of these patients were on any prophylactic medications for migraine at the time of initial assessment. All participants were followed monthly on an outpatient basis until the resolution of symptoms (for at least 6 months duration). 400 2. Interictal phase: We obtained a second blood sample from 12 participants to measure serum CGRP levels at least 2 weeks after complete resolution of symptoms, that is, both headache and ophthalmoplegia. Serum samples of the remaining 3 patients were not obtained in the interictal phase due to the presence of residual headache or ophthalmoplegia at the time of assessment. Serum CGRP levels were measured using a commercially available ELISA kit (BIOCODON Technologies, BC-EH 100627) as per manufacturer guidelines (See Supplemental Digital Content 1, Supplement 1(C), http://links.lww.com/WNO/A623). Treatment Participants with OM/RPON were treated with analgesics for symptomatic relief (naproxen (up to 1 g/day), acetaminophen (up to 2 g/day), or ibuprofen (up to 2.4 g/day)). Participants requiring migraine prophylaxis were prescribed the following drugs alone or in combination: beta blocker (propranolol 40–160 mg/day), amitriptyline (10–100 mg/ day), topiramate (25–200 mg/day), or sodium valproate (200–1000 mg/day). Three patients received oral steroids (prednisone 0.75–1 mg/kg/day) in addition. Twelve of 15 participants had complete improvement of symptoms at the time of assessment of serum CGRP levels. Statistical Analysis Statistical Package for Social Sciences (SPSS) version 24 was used for data analysis. Receiver operating curve analysis was performed to estimate the sensitivity and specificity cut off level of serum CGRP to use as a candidate diagnostic marker for OM/RPON. A P value ,0.05 was considered statistically significant. RESULTS Nine of the 15 participants with OM/RPON (60.0%) were male. The median (interquartile range) age of the patients was 39.0 (24.0, 52.0) years. Table 1 summarizes the demographic and clinical characteristics of the enrollees. All participants had migraine without aura according to the ICHD3 diagnostic criteria (5). Supplemental Digital Content 1, Supplement 1(D), http://links.lww.com/WNO/A623 provides the clinical details of each participant’s characteristics of headache and ophthalmoplegia. The mean duration (SD) of migraine in these participants was 12.3 (10.7) years, and the median duration (interquartile range) was 9 years (4.0, 15.0). Six participants (40%) with OM/RPON had a family history of migraine. The median (interquartile range) intensity of pain was 7.0 (5.0, 8.0) on the VAS. The most common site of headache was in the temporal region (40%). No participant took long-term prophylaxis for migraine at presentation. All participants noted that their migraine attacks became more Takkar et al: J Neuro-Ophthalmol 2023; 43: 399-405 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographics, clinical characteristics, and serum CGRP values in participants with OM/RPON Frequency (%) or Median (Interquartile Range) Characteristics Age in years Sex Male Female Duration (in years) of migraine Duration (in days) of antecedent worsening of migraine Presence of nausea, vomiting, photophobia, or phonophobia Yes No Time (in hours) of occurrence of diplopia from the onset of headache in the presenting episode ,24 hrs 24–48 hrs .48 hrs Cranial nerve involvement Third Sixth Duration (in days) between the onset of ophthalmoplegia and visit to the neuro-ophthalmology clinic Severity (VAS 1–10) of headache at the onset of ophthalmoplegia (n=14) Resolution of worsened headache (in days) after the onset of ophthalmoplegia Total duration (in days) of ophthalmoplegia (n=12) Median (interquartile range) CGRP levels in the ictal phase (in ng/L) (n=15) Median (interquartile range) CGRP levels in the interictal phase (in ng/L) (n=15) severe before the presenting episode of OM/RPON. The median duration (interquartile range) of antecedent worsening of migraine attacks was 35 (28.0, 56.0) days. All participants except 1 had a severe migraine headache before the ophthalmoplegia developed. The migraine attacks with ophthalmoplegia were more severe in intensity than those without ophthalmoplegia. Other characteristics of the headache were similar. All patients had a history of headache meeting the ICHD-3 criteria of migraine (See Supplemental Digital Content 1, Supplement 1(D), http://links.lww.com/WNO/A623). A single ocular motor nerve was affected in all participants. In those with unilateral headache, the ophthalmoplegia was ipsilateral to the pain. The sixth nerve was the most common cranial nerve involved, seen in 12 patients (80%), followed by the third cranial nerve in 3 (20%). No participant had involvement of the fourth cranial nerve. Four patients had recurrent episodes of migraine with isolated cranial nerve palsy, involving the same ocular motor nerve in each episode. The median (interquartile range) duration of ophthalmoplegia (n = 12) was 35.0 days. Illustrative Case A 21-year-old woman experienced diplopia after an attack of severe migraine headache. She had a 1.5-year history of migraine without aura with recurrent episodes of throbbing left temporal and retro-orbital headache associated with nausea, photophobia, and phonophobia occurring twice or thrice a month. The pain intensity during her usual attacks Takkar et al: J Neuro-Ophthalmol 2023; 43: 399-405 39.0 (24.0, 52.0) 9 (60.0) 6 (40.0) 09 (4.0, 15.0) 35.0 (28.0, 56.0) 5 (33.3) 10 (66.7) 3 (21.4) 2 (14.3) 9 (64.3) 3 (20.0) 12 (80.0) 14 (6, 24) 7.0 (5.0, 8.0) 7.0 (5.0, 15.0) 35.0 (25.8, 53.8) 37.2 (36.4, 43.6) 35.7 (31.2, 39.2) was rated 3–4 of 10 on the VAS, and each episode lasted 4– 5 hours. She missed 1 to 2 days of work per month because of these episodes. She only took over-the-counter analgesics and never consulted a specialist to consider prophylactic migraine therapy. Her migraine attacks increased in severity (4–5 on the VAS) and frequency for 4 weeks, with daily episodes, rated 5 of 10 in intensity, for 2 weeks before developing ophthalmoplegia. Ophthalmoplegia occurred at the peak of headache intensity (VAS 6), and the headache severity reduced (VAS 4–5) 12 hours after the onset of ophthalmoplegia. At presentation, 14 days after the ophthalmoplegia began, she had a persistent left-sided headache (VAS 3–4) and a left abducens palsy (Fig. 1A). Clinical examination, blood and CSF analysis, Gd-MRI brain, MR venography, and MR angiography of the intracranial and extracranial vessels were normal. (Figures 1C and D, See Supplemental Digital Content 1, Supplement 1(E), http://links.lww.com/WNO/A623). The serum CGRP level during the migraine ictus was 41.51 ng/L. She was initiated on preventive treatment with amitriptyline, naproxen (1–1.5 g per day in divided doses), and propranolol (80 mg daily). The headache resolved in 1 week, and the diplopia completely resolved (Fig. 1B) in 4 weeks. The repeat value of serum CGRP after resolution of symptoms was 35.8 ng/L (the patient was on prophylactic agents while this assessment was performed). General physical, systemic, and neurological examinations and routine investigations were normal in all participants (See Supplemental Digital Content 1, Supplement 1(F), http://links.lww.com/WNO/A623). CSF analysis in 401 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Nine-gaze photography of a participant with ophthalmoplegic migraine/RPON with a left sixth nerve palsy during the ictal phase (A) with complete resolution in the interictal phase (B). 14 patients showed normal opening pressure and composition (1 patient did not consent for CSF analysis). All participants had normal neuroimaging studies with no cranial nerve enhancement or thickening. As ophthalmoplegia/headache did not completely resolve in 3 patients at the time of analysis (at least 6-month followup), interictal samples of 12 patients were analyzed. Serum CGRP levels were significantly elevated (P = 0.021) during the ictal phase when compared with the age-matched and sex-matched controls (Table 2 and Fig. 2). Serum CGRP levels during the interictal phase were lower compared with those of the ictal phase (nonsignificant; P= 0.754) but higher when compared with controls (nonsignificant; P = 0.291) (Table 2). Correlation of Serum CGRP Levels in Ictal and Interictal Phases with Various Clinical Parameters We investigated whether serum CGRP levels in ictal and interictal phases correlated with various clinical, biochemical, or neuroimaging parameters (See Supplemental Digital Content 1, Supplement 1(G), http://links.lww.com/ WNO/A623). The ictal phase serum CGRP levels were positively correlated with the duration of ophthalmoplegia (P = 0.038). The area under curve after plotting the sensitivity and 1specificity for diagnosing OM/RPON in the receiver operator curve was 0.76 (95% confidence interval: 0.57, 402 0.95) and was statistically significant (P = 0.022) as a predictor of OM/RPON in the ictal phase compared with controls (See Supplemental Digital Content 1, Supplement 1(H), http://links.lww.com/WNO/A623). In participants meeting the clinical criteria of OM, the serum CGRP level of 35.46 ng/L had 86.7% of sensitivity and 75% of specificity for diagnosing OM/RPON. DISCUSSION Although abundant literature regarding the role of CGRP in migraine with and without aura is available (6,9,10), to the best of our knowledge, this is the first study to measure serum CGRP levels in patients with OM/RPON. This study of 15 participants evaluated during an episode of OM/RPON at a tertiary referral institute reflects the demographic, clinical, and laboratory profile in concordance with most previous studies of migraine (2,6,9,11,12,13). CGRP has a definite role in mediating vasodilatation of cerebral and dural vessels during an attack of migraine (14,15). CGRP-containing nerves innervate the cerebral arteries, and several studies showed that migraine ictus triggers the release of CGRP from these nerve fibers. Serum CGRP levels increase during the migraine ictus, and a modest increase (as compared to controls) can occur during the interictal/chronic phase. Takkar et al: J Neuro-Ophthalmol 2023; 43: 399-405 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Comparison of serum CGRP between patients with ophthalmoplegic migraine/recurrent painful ophthalmoplegic neuropathy and controls Characteristics Cases (n = 15) Controls (n = 12) P* Median (interquartile range) CGRP levels in the ictal phase (in ng/L) 37.2 (36.4, 43.6) 32.5 (30.1, 37.3) 0.021 Median (interquartile range) CGRP levels in the interictal phase (in ng/L)† 35.7 (31.2, 39.2) 0.291 P value‡ 0.754 Not applicable *Mann–Whitney U test. † n = 12. ‡ Wilcoxon signed rank test. Goadsby PJ et al (16) first demonstrated an increase in CGRP from the external jugular vein in 1990 (16). They subsequently showed a decrease in CGRP levels after treatment with the antimigraine drug sumatriptan. Ashina M et al compared the interictal plasma levels of CGRP in adult subjects with migraine and healthy controls and concluded that long-lasting abnormal neurogenic vascular control in people with migraine may be the cause of increased CGRP outside the migraine attack (17). Since then, many studies have tried to reproduce the validity of this observation. Although there were some initial concerns of focal increase of CGRP only in external jugular vessels, many studies subsequently demonstrated that there is a definite increase in the CGRP levels during migraine in the peripheral circulation as well (17,18). Table 3 shows the important observations in this regard from the available studies, which have focused on the role of serum CGRP in migraine. Our study showed a statistically significant elevation in serum CGRP during the ictal phase of OM/RPON compared with controls. The levels in the interictal period were lower than the ictal phase, which is expected because of the usual decay in CGRP levels as the symptoms resolve. Although no direct comparison is possible because no previous study assessed serum CGRP levels in ictal and interictal phases of OM, indirect comparisons can be drawn from available studies assessing levels of serum CGRP in migraine with and without aura. The significantly raised value of CGRP during acute presentation supports the role of CGRP signaling in patients with migraine with ophthalmoplegia, necessitating studies to assess the role of CGRP inhibitors in patients with OM/RPON. We extrapolate that the significant increase in serum CGRP levels FIG. 2. Median serum CGRP levels in ictal and interictal phases of participants with OM/RPON and controls. Takkar et al: J Neuro-Ophthalmol 2023; 43: 399-405 during the ictal phase in our cohort favors a migrainous pathology. Furthermore, the duration of ophthalmoplegia correlated with the increase in CGRP levels, suggesting that neuroinflammation is potentiated during the ophthalmoplegic event in OM. The fact that CGRP has been considered as a sensitive marker to differentiate between migraine and nonmigraine headaches further supports our hypothesis. The enhancement of the involved cranial nerves may be due to the neuroinflammatory cascade triggered due to the activation of the trigeminovascular system. The stimulation of the proinflammatory neuropeptides such as calcitonin gene-related peptide leads to a breach in the blood–nerve barrier (BNB) (16). We hypothesize that in patients with OM, the inflammation is significant enough to cause functional nerve deficits but may not always cause structural changes visible on imaging. Enhancement of the nerve is common in pediatric patients, which may be due to relative immaturity of blood–nerve barrier (BNB) as compared to their adult counterparts (2,9,19,20). We propose that serum CGRP levels may be a biomarker for OM. In our study, the levels of serum CGRP were significantly higher in the ictal phase compared with the age-matched and sex-matched controls. The interictal serum CGRP levels, although raised, were not significantly different than levels in controls. One possible explanation is that CGRP levels gradually decline as the migraine attack wanes, hence causing the highest level of CGRP early during the attack of OM. Limitations of the Study A major limitation in our study was our inability to collect the blood sample from all participants at the same interval after the onset of an attack. Previous studies show that CGRP levels peak in a few hours of the onset of the attack and tend to decrease subsequently. In our cohort, there was a mean delay of presentation (from the onset of symptoms) of 14 days. The sample size in our study was small, being conducted from a single center in India over a period of 1.5 years. This reflects the low prevalence of OM, with fewer than 300 cases reported worldwide since around the first description of OM. Another limitation was the inability to assess interictal CGRP levels in 3 patients because their symptoms and signs had not yet resolved at their last visit. 403 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Studies of serum CGRP in migraine Author (Year of Publication) Serum CGRP in the Ictal and Interictal Phases; Other Relevant Findings Diagnosis Number Goadsby PJ et al (1990) MO, MA 22 Goadsby PJ and Edvinsson L (1993) Friberg L et al (1994) MO, MA 8 Migraine provoked with intracranial Xenon-133 injection technique MA MO 8 No increase in CGRP from carotid artery and internal jugular vein. 30 Increased CGRP levels in peripheral blood during the attack of MO and MA. No significant elevation during the interictal period. Increased CGRP in peripheral blood in the interictal period. Gallai V et al (1995) Ashina M et al (2000) Juhasz G et al (2003) MO, MA 20 Migraine attack provoked by nitroglycerine 15; migraine attack not precipitated in 11 subjects 17 Tvedskov JF et al (2005) MO Juhasz G et al (2005) (20) Sarchielli P et al (2006) Fusayasu E et al (2007) Cady RK et al (2009) Nitroglycerin-induced migraine MO 19 MO, MA MA- 41 MO 54 22 Zhu X et al (2011) Rat models migraine triggered by nitroglycerin EM with and without aura 19- ictal 47- interictal Cernuda-Morollon E et al (2013) MO, MA 103 CM Dominguez C et al (2018) CM 62 Kamm K et al (2019) EM CM 48 EM 45 CM Rodriguez-Osorio X et al (2012) 404 Migraine 20 48 Increased CGRP in the external jugular vein. No change in the cubital vein. No comparison between ictal and interictal phases. Decrease in the CGRP level and resolution of headache seen after treatment with sumatriptan. CGRP levels from peripheral vein increased significantly during the migraine attack and returned to baseline after the cessation. CGRP concentration correlated with the timing and severity of a migraine headache. No statistically significant difference noted in the external jugular vein/cubital vein between ictal and interictal samples. CGRP concentration decreases parallel to headache intensity during sumatriptan treatment. CGRP levels from external jugular vein elevated during acute attacks. CGRP levels in peripheral blood were significantly high in the interictal period as compared to controls CGRP levels were statistically increased in saliva during premonitory and ictal phase as compared to the interictal period. CGRP elevation correlated with response to rizatriptan. Marked increase in plasma CGRP during induced migraine. Heat coagulation of middle meningeal artery decreased the plasma CGRP level. CGRP in peripheral blood elevated in patients with acute migraine as compared to controls. CGRP level was higher in ictal as compared to the interictal period. CGRP levels in peripheral blood significantly increased in CM as compared with healthy controls, women with EM, and patients with episodic cluster headache. CGRP levels significantly increased in women with a history of MA vs MO. Interictal CGRP in peripheral blood increased in CM who responded to onabotulinumtoxin-A treatment as compared to nonresponders. CGRP tear fluid levels increased in patients with migraine compared with healthy subjects. Level of CGRP was higher in ictal as compared to the interictal period. Takkar et al: J Neuro-Ophthalmol 2023; 43: 399-405 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (Continued ) Author (Year of Publication) Fan PC et al (2019) Diagnosis Number Serum CGRP in the Ictal and Interictal Phases; Other Relevant Findings Migraine Nonmigraine headache (NM) 68 migraine 30 nonmigraine headache Plasma CGRP level in people with migraine either during or between attacks is higher than in controls (both NM and healthy controls). MO: migraine without aura; MA: migraine with aura; EM: episodic migraine; CM: chronic migraine; NM: nonmigraine; CGRP: calcitonin gene-related peptide. CONCLUSIONS Serum CGRP levels are significantly raised during acute attacks in participants with OM. CGRP levels during the ictal phase correlate with the duration of ophthalmoplegia. The CGRP level of 35.46 ng/L in the ictal phase had a sensitivity of 86.7% and specificity of 75% for diagnosing a participant with OM/RPON. 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