Skip to main content
Download PDF
Download ePub

Plasma calcitonin gene-related peptide levels in idiopathic intracranial hypertension: an exploratory study

The Journal of Headache and Pain volume 25, Article number: 92 (2024) Cite this article

Abstract

Background

Idiopathic intracranial hypertension (IIH) is a debilitating condition characterized by increased intracranial pressure often presenting with chronic migraine-like headache. Calcitonin gene-related peptide (CGRP) plays an important pathophysiological role in primary headaches such as migraine, whilst its role in IIH has not yet been established.

Methods

This longitudinal exploratory study included patients with IIH, episodic migraine (EM) in a headache-free interval and healthy controls (HC). Blood samples were collected from a cubital vein and plasma CGRP (pCGRP) levels were measured by standardized ELISA.

Results

A total of 26 patients with IIH (mean age 33.2 years [SD 9.2], 88.5% female, median BMI 34.8 kg/m2 [IQR 30.0–41.4]), 30 patients with EM (mean age 27.6 years [7.5], 66.7% female) and 57 HC (mean age 25.3 years [5.2], 56.1% female) were included. pCGRP levels displayed a wide variation in IIH as well as in EM and HC on a group-level. Within IIH, those with migraine-like headache had significantly higher pCGRP levels than those with non-migraine-like headache (F(2,524) = 84.79; p < 0.001) and headache absence (F(2,524) = 84.79; p < 0.001) throughout the observation period, explaining 14.7% of the variance in pCGRP levels. CGRP measurements showed strong intraindividual agreement in IIH (ICC 0.993, 95% CI 0.987–0.996, p < 0.001). No association was found between pCGRP levels and ophthalmological parameters.

Conclusions

Although interindividual heterogeneity of pCGRP levels is generally high, migraine-like headache seems to be associated with higher pCGRP levels. CGRP may play a role in the headache pathophysiology at least in a subgroup of IIH.

Peer Review reports

Introduction

Idiopathic intracranial hypertension (IIH) is a debilitating condition characterized by increased intracranial pressure, most commonly occurring in young obese women, causing chronic headaches and papilledema with a risk of permanent vision loss [1 [1]]. Its incidence is increasing with rising obesity rates worldwide [2], as even modest weight gain is associated with an increased risk of developing IIH [3]. While IIH can be a devastating condition leading to visual impairment or even blindness, these risks can often be avoided if diagnosis and treatment are made at an early stage of the disease and papilledema is carefully monitored. However, IIH is also associated with reduced quality of life due to severe headaches that interfere with patients’ daily activities. More than half of patients with IIH experience persistent headache even after resolution of the papilledema and normalization of intracranial pressure [4,5,6]. Why this is the case remains poorly understood.

Calcitonin gene-related peptide (CGRP) is a 37 amino acid regulatory neuropeptide and potent vasodilator [2], comprising two forms in humans, \(\alpha\)-CGRP and \(\beta\)-CGRP [3], both of which share structural similarity and 94% homology as well as identical binding affinity and intensity [4]. \(\alpha\)-CGRP is found in the central and peripheral nervous system, and is primarily produced and stored in A\(\delta\)- and C-fiber sensory neurons in the trigeminal ganglion and dorsal root ganglia [4, 5], playing a pivotal role in the pathophysiology of migraine [6]. Upon activation of nociceptors, CGRP is released into the innervated tissues, where it contributes to neurogenic inflammation, leading to arterial vasodilation [4]. It is then taken up by postcapillary vessels, appearing in the circulation [7], where it is considered to be a biomarker of various pain disorders, including primary headache disorders such as migraine [8]. In migraine patients, CGRP plasma levels are elevated during migraine attacks, and migraine-like attacks can be provoked by infusion of CGRP [9].

Monoclonal antibodies targeting CGRP or its receptor have not only dramatically changed the landscape of migraine, but also seem to be effective in reducing headache in IIH [10].

Given these circumstances, an exploratory study was undertaken to determine the role of CGRP in IIH.

Methods

Patients and definitions

For this exploratory study, we prospectively included patients with newly diagnosed IIH according to Friedman criteria from an ongoing prospectively followed observational cohort study (Vienna Idiopathic Intracranial Hypertension Biomarker study [VIIH-BIO]), jointly conducted by the Department of Neurology and Department of Ophthalmology at the Medical University of Vienna starting in January 2021.

Data are collected at the following time points: at diagnosis (D0) and after one day (D1), one (W1) and two weeks (W2), and one (M1), two (M2), three (M3) and six months (M6). Afterwards, patients are followed in a three-month interval. Briefly, standardized VIIH-BIO case reports include demographic data, disease specific parameters as well as documentation of diagnostic and therapeutic procedures. Specialized neurologists and neuro-ophthalmologists perform all examinations. Headache diagnosis is assessed by a headache specialist also using a specific headache diary. Headache phenotype is classified according to ICHD-3 [11]. All patients are treated according to best practice based on recommendation of weight loss, pharmacological treatment with acetazolamide, topiramate and/or furosemide, and invasive treatment options such as serial lumbar punctures and subsequent ventriculoperitoneal (VP) shunt or optic nerve sheath fenestration (ONSF) in case of visual-threatening treatment-refractory papilledema [12].

For the present study, the following data were obtained at each time point: body weight, monthly headache days (MHD) with headache phenotype recorded in a specific headache diary (including changes to those phenotypes during follow-up), and ophthalmological assessment including visual acuity, perimetry, fundoscopy, optical coherence tomography (OCT) and ocular ultrasonography. Patients with IIH with migraine history did not have a migraine attack for at least six months prior to the inclusion in the study or had < 1 migraine headache day on average in the last three months.

Patients with episodic migraine (EM) in a headache-free interval [17] and healthy controls (HC) from the Department of Neurology, Medical University of Innsbruck, Austria, served as control groups in the cross-sectional part of the study. In the EM group, only patients with ≥ 3 consecutive migraine- and headache-free days prior to blood sampling were included. Diagnosis of any primary headache syndrome except for infrequent episodic tension-type headache served as an exclusion criterion for HC. Importantly, none of the patients were on active preventatives or any CGRP targeting therapies.

Ophthalmological assessment

Best-corrected visual acuity was assessed using Sloan charts at distance after subjective refraction. Results were given in logarithm of the minimum angle of resolution (logMAR). Meaningful change was defined as ≥ 0.2 logMAR [13].

For perimetry, we performed automated visual field testing (Humphrey Field Analyzer, Carl Zeiss Meditec, Jena, Germany) using 30 − 2 Swedish Interactive Threshold Algorithm (SITA) standard protocols, quantifying the mean deviation in decibels (dB) of all test locations compared to age-matched controls and defining abnormal perimetry as a mean deviation lower than − 2 dB.

Fundoscopy included assessment of absence or presence of papilledema and secondary optic atrophy. We used the Frisén staging scale to rate papilledema severity, categorizing the swelling of optic discs from stage 0 (no papilledema) to stage 5 (severe papilledema) [14].

For OCT imaging, we used the same spectral-domain OCT (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany; software Heidelberg eye explorer software version 6.9a) adhering to the OSCAR-IB quality control criteria and describing findings in accordance with the APOSTEL criteria [15, 16]. For peripapillary retinal nerve fiber layer (pRNFL) measurement, a 12° (3.4 mm) ring scan centered on the optic nerve head was used (1536 A-scans, automatic real-time tracking [ART]: 100 averaged frames) [17]. Ganglion cell layer (GCL) volume was measured without pupil dilatation in both eyes of each patient by means of a 20°×20° macular volume scan (centered on the macula with 512 A-scans and 25 B-scans aligned vertically with 16 averaged frames). Volume values characterize the mean volume of the circular area centered around the foveola, corresponding to the 6 mm ring of the circular grid defined by the Early Treatment Diabetic Retinopathy Study [18]. Image processing was semiautomated using the built-in proprietary software for automated layer segmentation and manual correction of obvious errors. Measurements of worse eyes were used for statistical analysis, i.e., higher pRNFL thickness as a marker of oedema and lower GCL volume as a marker of neuroaxonal loss.

For assessment of the optic nerve sheath diameter (ONSD), we performed transbulbar sonography (ABSolu, Quantel Medical, Cournon d’Auvergne, France) after topical anesthesia with oxybuprocaine eye drops. We performed quantitative measurement of ONSD using standardized amplitude modulation (A-scan) echography with tissue sensitivity settings, placing the 8 MHz A-scan probe on the temporal eye equator in primary gaze position [19, 20]. At least two measurements were taken within 3 mm of the posterior bulb wall, and the highest was documented as the diameter.

Blood collection and separation of plasma

Blood was taken from a cubital vein using EDTA-K tubes (S-Monovetten, Sarstedt, Nümbrecht, Germany) and centrifuged at 4 °C for 5 min with 3,000 rpm/5,000 g. The plasma fraction was taken off with an Eppendorf pipette, transferred to cryovials (Nunc CryoTubes, Merck, Darmstadt, Germany), frozen in liquid nitrogen and stored at 80 °C within 10–12 min after blood sampling.

CGRP sample processing

For detailed information on the rigid (pre-)processing and analysis of the samples, please refer to our previous article [21]. In short, samples were processed with a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA; CGRP Enzyme Immunoassay #A05481, shortly named CGRP EIA, Bertin Bioreagent, Montigny-le-Bretonneux, France) for α- and β-CGRP, with a cross-reactivity with amylin, calcitonin and substance P of < 0.01%. For this purpose, a synthetic interstitial solution was prepared, and protease inhibitors were added to create a standard buffer, which was fitted with human CGRP and diluted to create serial dilutions of CGRP. Furthermore, human blood plasma was used as an alternative to the standard buffer. With these preparations a reference curve was fitted to later determine the individual CGRP concentrations of each sample. Detailed information on the processing and analysis of the sample is available elsewhere [21].

Standard protocol approvals, registrations, patient consents, and reporting

The study was approved by the ethics committee of the Medical University Vienna (ethical approval number: 2216/2020). Written informed consent was obtained from all patients. This study adheres to the reporting guidelines outlined within the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement.

Data availability statement

Data supporting the findings of this study are available from the corresponding author upon reasonable request by a qualified researcher and upon approval by the data-clearing committee of the Medical University Vienna.

Statistics

Statistical analysis was performed using SPSS 26.0 (SPSS Inc, Chicago, IL, USA). Categorical variables were expressed in absolute frequencies and percentages, continuous parametric variables as mean and standard deviation (SD) and continuous non-parametric variables as median with inter-quartile range (IQR) or absolute range (AR) as appropriate. Continuous variables were tested for normal distribution using Kolmogorov–Smirnov test with Lilliefors correction. Logarithmic transformation was used to reduce the skewness of the data. Univariate comparisons were performed by the chi-square test, one-way analysis of variance (ANOVA), and Kruskal-Wallis test with pairwise comparisons as appropriate. Univariate correlation analyses were performed using the Pearson or Spearman test as appropriate. Repeated measures ANOVA was used to determine the change in pCGRP levels over time, adjusted for age, sex, body mass index [BMI], headache duration and migraine history.

To test the intraindividual variability of CGRP levels, the intraclass correlation coefficient (ICC) was calculated based on a mean-rating, absolute-agreement, 2-way mixed-effects model.

Prespecified sensitivity analyses to determine the potential confounding influence were performed with the same statistical analysis setup excluding patients with IIH without papilledema (IIH-WOP).

Missing values were handled by multiple (20 times) imputation using the missing not at random (MNAR) approach with pooling of estimates according to Rubin’s rules [22].

The significance level was set at a two-sided p-value < 0.05.

Results

A total of 26 patients with IIH were enrolled in the VIIH-BIO study as of November 23rd, 2022 (mean age of 33.2 years [SD 9.2], 88.5% female, median BMI 34.8 kg/m2 [30.0–41.4]). The inclusion/exclusion process is depicted in Fig. 1. As controls, 30 patients with EM in a headache-free interval (mean age 27.6 years [7.5], 66.7% female), and 57 HC (mean age 25.3 years [5.2], 56.1% female) were recruited. Patients with EM and HC were significantly younger and more often male than patients with IIH (both p < 0.001). Detailed clinical characteristics of the IIH study cohort at baseline are given in Table 1.

Fig. 1
figure 1

Flow chart of inclusion/exclusion process. IIH: idiopathic intracranial hypertension, ONSF: optic nerve sheath fenestration

Full size image
Table 1 Clinical characteristics of the IIH study cohort at baseline
Full size table

Cross-sectional data

pCGRP levels showed wide variation within all three groups: IIH (median 15 pg/ml, 95% CI 10.8–237), EM (30.5 pg/ml, 95% CI 23.2–197.4), and HC (56.3 pg/ml, 95% CI 53.4–228.2) (Fig. 2). Notably, patients with IIH with a history of migraine had significantly higher median pCGRP levels than those without migraine (1,000 pg/ml [25–1,000] vs. 14 pg/ml [11,12,13,14,15,16,17], p < 0.001). CSF opening pressure did not correlate with pCGRP levels at baseline (rs= − 0.17, p = 0.423).

Fig. 2
figure 2

Baseline plasma CGRP (pCGRP) levels (pg/ml) (a) and log pCGRP levels (b) in patients with idiopathic intracranial hypertension (IIH), episodic migraine (EM) in a headache-free interval, and healthy controls (HC).

Full size image

Longitudinal data in IIH

In patients with IIH, no significant change in mean CGRP levels was observed during the observation period (F(1, 528) = 3.73; p = 0.231). Furthermore, the ICC for CGRP measurements showed excellent intraindividual agreement in patients with IIH (ICC 0.993, 95% CI 0.987–0.996, p < 0.001) and migraine (ICC 0.999, 95% CI 0.998–1.000, p < 0.001); no longitudinal data were available for HC. Individual CGRP levels for each patient are shown in Fig. 3.

Fig. 3
figure 3

Heat map illustrating the longitudinal distribution of pCGRP levels (pg/ml) among patients with IIH (1–26). pCGRP levels are displayed as colors ranging from green to red as shown in the legend; absolute values of pCGRP levels (a) and relative change compared to baseline (b). The x-axis shows different time points with D0 as baseline (diagnosis), followed by day one (D1), week one (W1) and two (W2), and month one (M1), two (M2), three (M3) and six (M6). Missing data were imputed for 21/208 (10.1%) time points

Full size image

†Patients with migraine history

Headache outcomes in IIH

Patients with IIH with headache (n = 19) had significantly higher pCGRP levels compared to those without headache (n = 7; F(1, 528) = 105.38; p < 0.001). This association remained significant in the multivariate model after adjustment for migraine history (F(1, 527) = 25.60; p < 0.001), with headache explaining 4.6% of the variance in pCGRP levels. Furthermore, migraine-like headache was independently associated with higher pCGRP levels compared to both non-migraine-like headache and headache absence (F(2, 524) = 84.79; p < 0.001), explaining 14.7% of the variance in pCGRP levels in the multivariate model. However, pCGRP levels were not associated with headache frequency as per MHD (β= -0.06; 95% CI -0.02, 0.01; p = 0.477) (Fig. 4). pCGRP levels und log pCGRP levels in patients with IIH according to the headache phenotype are shown in Table 2. None of the patients changed their headache phenotype during the observation period. Prespecified sensitivity analyses excluding patients with IIH-WOP did not significantly alter the overall results or impact individual variables.

Ophthalmological outcomes

Papilledema degree was not associated with pCGRP levels (β= -0.03; 95% CI -0.16, 0.13; p = 0.798), neither did pCGRP levels significantly differ between patients with IIH and IIH-WOP (F(1, 528) = 1.86; p = 0.174) (Fig. 4). Also, neither visual acuity (β = 0.08; 95% CI -0.63, 1.72; p = 0.359) nor visual field (β = 0.15; 95% CI -0.01, 0.09; p = 0.142) of the worse eye were associated with pCGRP levels. In OCT, neither pRNFL thickness (β = 0.07; 95% CI -0.01, 0.01; p = 0.496) nor GCL volume (β = 0.04; 95% CI -1.05, 1.58; p = 0.690) were associated with pCGRP levels. Finally, pCGRP levels were also not associated with ONSD in transbulbar sonography (β= -0.05; 95% CI -0.21, 0.10; p = 0.487).

Prespecified sensitivity analyses excluding patients with IIH-WOP did not significantly alter the overall results or impact individual variables.

Fig. 4
figure 4

Longitudinal association between pCGRP levels (pg/ml) and monthly headache days (MHD) (a), headache presence (b), headache phenotype (c) and IIH without papilledema (IIH-WOP) (d)

Full size image
Table 2 Plasma CGRP (pCGRP) levels (a) and log pCGRP levels (b) in patients with idiopathic intracranial hypertension (IIH) according to the headache phenotype
Full size table

Discussion

Aiming to investigate the role of pCGRP levels in IIH, we observed a large interindividual variation in IIH comparable to that in EM and HC cross-sectionally, but a high intraindividual stability of CGRP levels longitudinally. Notably, patients with IIH with migraine history and/or displaying migraine-like headache had significantly higher pCGRP levels throughout the observation period.

The development of CGRP as a biomarker and treatment target in migraine has revolutionized the landscape of headache research [23, 24]. Migraine and IIH appear to be closely related: both share important risk factors such as female gender and obesity, the headache in IIH often resembles the migraine phenotype, and both respond to treatment with topiramate [25, 26]. Because of these similarities, it has been hypothesized that CGRP may also play a role in the pathophysiology of IIH-related headache [27]. CGRP is released upon stimulation of primary meningeal afferents, leading to vasodilation of intracranial arteries responsible for pain perception, as evidenced by elevated CGRP levels during and between migraine attacks [28, 29]. In support of this hypothesis, a series of seven patients with IIH with migraine-like headache who were successfully treated with anti-CGRP monoclonal antibodies has been recently published [30], implicating the CGRP pathway as a mechanistic driver of headache in IIH. A possible pathophysiological mechanism may be a nociceptive trigeminal firing at congested dural venous sinuses, leading to activation of the trigeminovascular system and subsequent pain sensitization [31, 32]. Trigeminovascular terminals appear to be widespread throughout the dural venous sinuses, particularly at the openings of the bridge veins, and contain large amounts of CGRP and other neuropeptides [33]. Distension of the intracranial vessels leads to the release of CGRP which, by binding to its receptors on neurons and glial cells, triggers neurogenic inflammation, a process similar to that seen during a migraine attack [34].

Our findings contribute to the increasing body of evidence linking CGRP and headache in IIH. We found evidence that patients with migraine-like headache features in IIH have higher pCGRP levels regardless of their migraine history. Although median pCGRP levels were significantly lower at baseline in the whole IIH cohort compared to controls, we observed a wide interindividual variation in IIH comparable to that in HC and EM, but a high intraindividual stability of CGRP levels longitudinally. Patients with IIH with migraine history and/or displaying migraine phenotype headache had significantly higher CGRP levels throughout the observation period.

The latter were significantly younger and more often male, which may have likely influenced our results due to the known association between age, sex and pCGRP levels [35]. Furthermore, pCGRP levels may be negatively influenced by BMI in the same way as serum neurofilament light chains (sNfL) [36], which may have also contributed to lower pCGRP levels in some patients with IIH. Thus, it seems unlikely that patients with IIH generally have lower pCGRP levels than patients with EM and/or HC, but rather this could be due to confounding factors not taken into account in the cross-sectional data analysis. On the contrary, we found that there are some patients with IIH that displayed high pCGRP levels. Despite the lack of association between pCGRP levels and MHD, this is consistent with recent studies [35, 37]. Additionally, it may be speculated that CGRP is produced, released and/or degraded at different rates in different individuals possibly explaining the huge variance on an individual level.

Most interestingly, CGRP levels were not associated with the degree of papilledema or other parameters of the degree of intracranial pressure in our cohort. This strengthens the hypothesis that pathophysiological pathways involving CGRP may partially explain the well-known puzzle of poor correlation between intracranial pressure and headache in IIH [27, 38, 39].

As we have recently shown, migraine-like headache is an independent predictor of adverse headache outcome in IIH even after resolution of papilledema, i.e., when intracranial pressure is significantly reduced if not normalized [39]. This may be explained by higher CGRP levels observed in a recent study [40]. Our findings support these results and additionally show that pCGRP levels are not associated with ophthalmological outcomes and only seem elevated in patients with migraine-like headache, confirming a potential common pathophysiological pathway in a subgroup of IIH and migraine.

We hypothesize that a subset of individuals with IIH may have an increased sensitivity or susceptibility to CGRP pathways, leading to a migraine-like pain experience and possibly clinical response to CGRP targeting therapies. Measurement of pCGRP may provide a practical and clinically feasible approach to identify this subgroup and provide insight into both prognosis and treatment strategy.

Several limitations of this study need to be acknowledged: the exploratory study design with a rather small sample size (due to the rarity of IIH) prevented more complex statistical models, and some missing values during the follow-up due to the observational study design, which were mitigated by the imputation of missing values. Due to the limited dataset, we were unable to fully match patients with EM and HC. Importantly, it is not possible to objectively distinguish between IIH and migraine as independent comorbidities as opposed to IIH with a migraine-like headache phenotype. Thus, it could be that patients with IIH with elevated pCGRP levels in our cohort have migraine as an independent coexisting comorbidity, explaining the elevated pCGRP levels in IIH. However, even after adjusting the model for covariates including migraine history, headache remained associated with higher pCGRP levels. Also, no data about headache intensity or headache presence during the blood sampling were systematically collected. As some authors argue that patients with IIH-WOP should be excluded or investigated separately when studying IIH, we performed prespecified sensitivity analyses excluding patients with IIH-WOP, which did not significantly change the results giving strength to our data. Finally, there was a ceiling effect of extreme pCGRP levels as samples were not further diluted, which seemed sufficient for the exploratory nature of the study.

Conclusion

This study is a pioneering investigation into the development of pCGRP levels in IIH and sheds light on its potential role in the pathophysiology of headache in this disorder. First, interindividual heterogeneity of pCGRP levels is high in IIH as well as in EM and HC, while intraindividually, pCGRP levels seem to be quite stable. Second, migraine-like headache seems to be associated with higher pCGRP levels. Thus, CGRP may play a role in the headache pathophysiology at least in a subgroup of IIH. Third, it is noteworthy that pCGRP levels do not seem to be associated with ophthalmological parameters, which again challenges the conventional explanation linking intracranial pressure and headache in IIH.

Further studies should focus on measuring pCGRP levels in IIH, which may be a promising and clinically feasible way to identify relevant subgroups and inform both prognosis and treatment strategy.

Data availability

Data supporting the findings of this study are available from the corresponding author upon reasonable request by a qualified researcher and upon approval by the data-clearing committee of the Medical University Vienna.

Abbreviations

ANOVA:

Analysis of Variance

AR:

Absolute Range

ART:

Automatic Real-Time Tracking

BMI:

Body Mass Index

CGRP:

Calcitonin Gene-Rlated Peptide

CSF:

Cerebrospinal Fluid

dB:

Decibels

ELISA:

Enzyme-Linked Imunosorbent Assa

EM:

Episodic Migraine

GCL:

Ganglion Cell Layer

HC:

Healthy Controls

ICC:

Intraclass Correlation Coefficient

ICHD:

International Classification of Headache Disorders

IIH:

Idiopathic Intracranial Hypertension

IIH-WOP:

Idiopathic Intracranial Hypertension Without Papilledema

IQR:

Interquartile Range

logMAR:

Logarithm of the Minimum Angle of Resolution

MHD:

Monthly Headache Days

MNAR:

Missing Not At Random

OCT:

Optical Coherence Tomography

ONSD:

Optic Nerve Sheath Diameter

ONSF:

Optic Nerve Sheath Fenestration

pCGRP:

Plasma Calcitonin Gene-Related Peptide

pRNFL:

Peripapillary Retinal Nerve Fiber Layer

SD:

Standard Deviation

SITA:

Swedish Interactive Threshold Algorithm

STROBE:

Strengthening the Reporting of Observational Studies in Epidemiology

VIIH-BIO:

Vienna Idiopathic Intracranial Hypertension Biomarker

VP:

Ventriculoperitoneal

References

  1. Peng MG, Gokoffski KK (2021) Updates on recent developments in idiopathic intracranial hypertension. SN Compr Clin Med 3(4):1031–1041

    Article  Google Scholar 

  2. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298(5871):240–244

    Article  CAS  PubMed  Google Scholar 

  3. Brain SD, MacIntyre I, Williams TJ (1986) A second form of human calcitonin gene-related peptide which is a potent vasodilator. Eur J Pharmacol 124(3):349–352

    Article  CAS  PubMed  Google Scholar 

  4. Russell FA, King R, Smillie SJ, Kodji X, Brain SD (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 94(4):1099–1142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Iyengar S, Ossipov MH, Johnson KW (2017) The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain 158(4):543–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen ST, Wu JW (2020) A new era for migraine: the role of calcitonin gene-related peptide in the trigeminovascular system. Prog Brain Res 255:123–142

    Article  PubMed  Google Scholar 

  7. Messlinger K (2018) The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular system. J Headache Pain 19(1):22

    Article  PubMed  PubMed Central  Google Scholar 

  8. Schou WS, Ashina S, Amin FM, Goadsby PJ, Ashina M (2017) Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain 18(1):34

    Article  PubMed  PubMed Central  Google Scholar 

  9. Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28(2):183–187

    Article  CAS  PubMed  Google Scholar 

  10. Yiangou A, Mitchell JL, Fisher C, Edwards J, Vijay V, Alimajstorovic Z et al (2021) Erenumab for headaches in idiopathic intracranial hypertension: a prospective open-label evaluation. Headache 61(1):157–169

    Article  PubMed  Google Scholar 

  11. Headache Classification Committee of the International Headache Society (IHS) (2018) The International classification of Headache disorders, 3rd edition. Cephalalgia 38(1):1–211

    Article  Google Scholar 

  12. Pruckner P, Mitsch C, Macher S, Krajnc N, Marik W, Novak K et al (2022) The Vienna Idiopathic Intracranial Hypertension (VIIH) database – an Austrian registry

  13. Rosser DA, Cousens SN, Murdoch IE, Fitzke FW, Laidlaw DA (2003) How sensitive to clinical change are ETDRS logMAR visual acuity measurements? Invest Ophthalmol Vis Sci 44(8):3278–3281

    Article  PubMed  Google Scholar 

  14. Frisen L (1982) Swelling of the optic nerve head: a staging scheme. J Neurol Neurosurg Psychiatry 45(1):13–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tewarie P, Balk L, Costello F, Green A, Martin R, Schippling S et al (2012) The OSCAR-IB consensus criteria for retinal OCT quality assessment. PLoS ONE 7(4):e34823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Aytulun A, Cruz-Herranz A, Aktas O, Balcer LJ, Balk L, Barboni P et al (2021) APOSTEL 2.0 recommendations for reporting quantitative Optical Coherence Tomography studies. Neurology 97(2):68–79

    Article  PubMed  PubMed Central  Google Scholar 

  17. Pemp B, Kardon RH, Kircher K, Pernicka E, Schmidt-Erfurth U, Reitner A (2013) Effectiveness of averaging strategies to reduce variance in retinal nerve fibre layer thickness measurements using spectral-domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 251(7):1841–1848

    Article  PubMed  Google Scholar 

  18. Classification of diabetic retinopathy from fluorescein angiograms (1991) ETDRS report number 11. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98(5 Suppl):807–822

    Google Scholar 

  19. Ossoinig KC (1975) A-scan echography and orbital disease. Mod Probl Ophthalmol 14:203–235

    CAS  PubMed  Google Scholar 

  20. Atta HR (1988) Imaging of the optic nerve with standardised echography. Eye (Lond) 2(Pt 4):358–366

    Article  PubMed  Google Scholar 

  21. Messlinger K, Vogler B, Kuhn A, Sertel-Nakajima J, Frank F, Broessner G (2021) CGRP measurements in human plasma - a methodological study. Cephalalgia 41(13):1359–1373

    Article  PubMed  PubMed Central  Google Scholar 

  22. in The Prevention and Treatment of Missing Data in clinical trials. (2010) : Washington (DC)

  23. Bigal ME, Walter S, Rapoport AM (2013) Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development. Headache 53(8):1230–1244

    Article  PubMed  Google Scholar 

  24. Edvinsson L, Haanes KA, Warfvinge K, Krause DN (2018) CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol 14(6):338–350

    Article  CAS  PubMed  Google Scholar 

  25. Buse DC, Greisman JD, Baigi K, Lipton RB (2019) Migraine Progression: A Systematic Review. Headache ; 59 (3): 306–338

  26. Celebisoy N, Gokcay F, Sirin H, Akyurekli O (2007) Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study. Acta Neurol Scand 116(5):322–327

    Article  CAS  PubMed  Google Scholar 

  27. De Simone R, Sansone M, Russo C, Miele A, Stornaiuolo A, Braca S (2022) The putative role of trigemino-vascular system in brain perfusion homeostasis and the significance of the migraine attack. Neurol Sci 43(9):5665–5672

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ramon C, Cernuda-Morollon E, Pascual J (2017) Calcitonin gene-related peptide in peripheral blood as a biomarker for migraine. Curr Opin Neurol 30(3):281–286

    Article  CAS  PubMed  Google Scholar 

  29. Cernuda-Morollon E, Larrosa D, Ramon C, Vega J, Martinez-Camblor P, Pascual J (2013) Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 81(14):1191–1196

    Article  CAS  PubMed  Google Scholar 

  30. Yiangou A, Mitchell JL, Vijay V, Grech O, Bilton E, Lavery GG et al (2020) Calcitonin gene related peptide monoclonal antibody treats headache in patients with active idiopathic intracranial hypertension. J Headache Pain 21(1):116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. De Simone R, Ranieri A, Fiorillo C, Bilo L, Bonavita V (2010) Is idiopathic intracranial hypertension without papilledema a risk factor for migraine progression? Neurol Sci 31(4):411–415

    Article  PubMed  Google Scholar 

  32. Bono F, Curcio M, Rapisarda L, Vescio B, Bombardieri C, Mangialavori D et al (2018) Cerebrospinal fluid pressure-related features in chronic headache: a prospective study and potential diagnostic implications. Front Neurol 9:1090

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sampaolo S, Liguori G, Vittoria A, Napolitano F, Lombardi L, Figols J et al (2017) First study on the peptidergic innervation of the brain superior sagittal sinus in humans. Neuropeptides 65:45–55

    Article  CAS  PubMed  Google Scholar 

  34. Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland PR (2009) Neurobiol Migraine Neurosci 161(2):327–341

    CAS  Google Scholar 

  35. Frank F, Kaltseis K, Messlinger K, Broessner G (2022) Short report of longitudinal CGRP-Measurements in migraineurs during a hypoxic challenge. Front Neurol 13:925748

    Article  PubMed  PubMed Central  Google Scholar 

  36. Manouchehrinia A, Piehl F, Hillert J, Kuhle J, Alfredsson L, Olsson T et al (2020) Confounding effect of blood volume and body mass index on blood neurofilament light chain levels. Ann Clin Transl Neurol 7(1):139–143

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lee MJ, Lee SY, Cho S, Kang ES, Chung CS (2018) Feasibility of serum CGRP measurement as a biomarker of chronic migraine: a critical reappraisal. J Headache Pain 19(1):53

    Article  PubMed  PubMed Central  Google Scholar 

  38. Friedman DI (2019) Headaches in idiopathic intracranial hypertension. J Neuroophthalmol 39(1):82–93

    Article  PubMed  Google Scholar 

  39. Bsteh G, Macher S, Krajnc N, Pruckner P, Marik W, Mitsch C et al (2023) Idiopathic intracranial hypertension presenting with migraine phenotype is associated with unfavorable headache outcome. J Headache Pain

  40. Ak AK, Gemici YI, Batum M, Karakas B, Ozmen EY, Gokcay F et al (2024) Calcitonin gene-related peptide (CGRP) levels in peripheral blood in patients with idiopathic intracranial hypertension and migraine. Clin Neurol Neurosurg 237:108136

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the VIIH investigators, clinical research staff, and especially the patients for helping to collect these data. The named individuals were not compensated for their help.VIIH investigators in alphabetical order: Bsteh, Gabriel (Department of Neurology, Medical University of Vienna); Kircher, Karl (Department of Ophthalmology, Medical University of Vienna); Krajnc, Nik (Department of Neurology, Medical University of Vienna); Macher, Stefan (Department of Neurology, Medical University of Vienna); Michl, Martin (Department of Ophthalmology, Medical University of Vienna), Mitsch, Christoph (Department of Ophthalmology, Medical University of Vienna); Pemp, Berthold (Department of Ophthalmology, Medical University of Vienna); Reitner, Andreas (Department of Ophthalmology, Medical University of Vienna); Rudzki, Dagmar (Department of Neurology, Medical University of Innsbruck), Wöber, Christian (Department of Neurology, Medical University of Vienna); Zebenholzer, Karin (Department of Neurology, Medical University of Vienna).

Funding

There was no funding to this research.

Author information

Authors and Affiliations

  1. Department of Neurology, Medical University of Vienna, Vienna, Austria

    Nik Krajnc, Stefan Macher, Nina Müller, Sina Zaic, Christian Wöber & Gabriel Bsteh

  2. Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria

    Nik Krajnc, Stefan Macher, Nina Müller, Sina Zaic, Christian Wöber & Gabriel Bsteh

  3. Department of Neurology, Headache Outpatient Clinic, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, 6020, Austria

    Florian Frank & Gregor Broessner

  4. Department of Ophthalmology, Medical University of Vienna, Vienna, Austria

    Martin Michl & Berthold Pemp

  5. Institute of Medical Statistics and Informatics, Medical University of Innsbruck, Innsbruck, Austria

    Sarah Maier

Authors
  1. Nik Krajnc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Florian Frank
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefan Macher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Michl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nina Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sarah Maier
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sina Zaic
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christian Wöber
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Berthold Pemp
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gregor Broessner
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gabriel Bsteh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NK: study concept and design, acquisition of data, data management, statistical analysis and interpretation of data, drafting of manuscript. FF: acquisition of data, data management, interpretation of data, critical revision of manuscript for intellectual content. StM: acquisition of data, interpretation of data, critical revision of manuscript for intellectual content. MM: acquisition of data, interpretation of data, critical revision of manuscript for intellectual content. NM: acquisition of data, interpretation of data, critical revision of manuscript for intellectual content. SaM: acquisition of data, interpretation of data, critical revision of manuscript for intellectual content. SZ: acquisition of data, interpretation of data, critical revision of manuscript for intellectual content. BP: acquisition of data, interpretation of data, critical revision of manuscript for intellectual content. CW: acquisition of data, interpretation of data, critical revision of manuscript for intellectual content. GrB: acquisition of data, interpretation of data, critical revision of manuscript for intellectual content. GaB: study concept and design, acquisition of data, interpretation of data, study supervision, critical revision of manuscript for intellectual content.

Corresponding author

Correspondence to Gregor Broessner.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the ethics committee of the Medical University Vienna (ethical approval number: 2216/2020). Written informed consent was obtained from all patients.

Consent for publication

Not applicable.

Competing interests

Nik Krajnc: has participated in meetings sponsored by, received speaker honoraria or travel funding from Alexion, BMS/Celgene, Janssen-Cilag, Merck, Novartis, Roche and Sanofi-Genzyme and held a grant for a Multiple Sclerosis Clinical Training Fellowship Programme from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).Florian Frank: nothing to disclose.Stefan Macher: declares no conflict of interest relevant to this study.Martin Michl: declares no conflict of interest relevant to this study.Nina Müller: declares no conflict of interest relevant to this study.Sarah Maier: declares no conflict of interest relevant to this study.Sina Zaic: declares no conflict of interest relevant to this study.Berthold Pemp: has received honoraria for speaking from Novartis.Christian Wöber: has received honoraria consultancy/speaking from Apomedica, Curelator, Eli Lilly, Grünenthal, Hermes, Lundbeck, Novartis, Pfizer, Ratiopharm/Teva, and Stada.Gregor Broessner: has received unrestricted grants, honoraria, personal fees, travel grants from Allergan, AMGEN, Menarini, Pfizer, Linde AG, Astra Zeneca, St. Jude Medical, Reckitt Benkiser, Novartis, TEVA, Fresenius, Janssen Cilag, Lilly, Österreichische Gesellschaft für Neurologie (ÖGN), European Headache Foundation (EHF), Österreichische Kopfschmerzgesellschaft (ÖKSG), Österreichische Akademie der Wissenschaften (ÖAW) and European FP7 Framework Programme.Gabriel Bsteh: has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene/BMS, Lilly, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Novartis, Roche, Sanofi-Genzyme and Teva. He has received unrestricted research grants from Celgene/BMS and Novartis.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Krajnc, N., Frank, F., Macher, S. et al. Plasma calcitonin gene-related peptide levels in idiopathic intracranial hypertension: an exploratory study. J Headache Pain 25, 92 (2024). https://doi.org/10.1186/s10194-024-01799-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s10194-024-01799-y

Keywords

The Journal of Headache and Pain

ISSN: 1129-2377

Contact us