Preventive treatment with CGRP monoclonal antibodies restores brain stem habituation deficits and excitability to painful stimuli in migraine: results from a prospective case-control study

Anne Thiele, Lara Klehr, Sebastian Strauß, Anselm Angermaier, Ulf Schminke, Martin Kronenbuerger, Steffen Naegel, Robert Fleischmann, Anne Thiele, Lara Klehr, Sebastian Strauß, Anselm Angermaier, Ulf Schminke, Martin Kronenbuerger, Steffen Naegel, Robert Fleischmann

Abstract

Background & objectives: Calcitonin gene-related peptide ligand/receptor (CGRP) antibodies effectively reduce headache frequency in migraine. It is understood that they act peripherally, which raises the question whether treatment merely interferes with the last stage of headache generation or, alternatively, causes secondary adaptations in the central nervous system and might thus possess disease modifying potential. This study addresses this question by investigating the nociceptive blink reflex (nBR), which is closely tied to central disease activity, before and after treatment with CGRP antibodies.

Methods: We enrolled 22 patients suffering episodic migraine (21 female, 46.2 ± 13.8 years of age) and 22 age-/gender-matched controls. Patients received assessments of the nBR (R2 component, 10 trials, 6 stimuli/trial) before (V0) and three months (V3) after treatment with CGRP antibodies started, controls were assessed once. The R2 area (R2a) and habituation (R2h; gradient of R2a against stimulus order) of the stimulated/non-stimulated side (_s/_ns) following repeated supraorbital stimulation provide a direct readout of brainstem excitability and habituation as key mechanisms in migraine.

Results: All patients showed a substantial reduction of headache days/month (V0: 12.4±3.3, V3: 6.6 ± 4.9). R2a_s (Fglobal=5.86, p<0.001; block 1: R2a_s: -28%, p<0.001) and R2a_ns (Fglobal=8.22, p<0.001, block 1: R2a_ns: -22%, p=0.003) were significantly decreased, and R2h_ns was significantly enhanced (Fglobal=3.07, p<0.001; block 6: R2h_ns: r=-1.36, p=0.007) from V0 to V3. The global test for changes of R2h_s was non-significant (Fglobal=1.46, p=0.095). Changes of R2h significantly correlated with improvement of headache frequency (R2h_s, r=0.56, p=0.010; R2h_ns: r=0.45, p=0.045). None of the nBR parameters assessed at baseline predicted treatment response.

Discussion: We provide evidence that three months of treatment with CGRP antibodies restores brain stem responses to painful stimuli and thus might be considered disease modifying. The nociceptive blink reflex may provide a biomarker to monitor central disease activity. Future studies should evaluate the blink reflex as a clinical biomarker to predict treatment response at baseline and to establish the risk of relapse after treatment discontinuation.

Trial registration: This trial was prospectively registered at clinicaltrials.gov (ID: NCT04019496, date of registration: July 15, 2019).

Keywords: Antibodies; Blink reflex; Calcitonin gene-related peptide; Disease modifying drug; Headache; Migraine; Prevention.

Conflict of interest statement

The author(s) declare(s) that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Superimposed 60 nBR traces of one participant. The R2 component is indicated by a box of red dashed lines between 30-80 ms. Note the stimulation artifact at the start and the immediately following R1 component. The R1 component has a low variability given its monosynaptic pathway through the principal trigeminal nucleus. The R2 component is more variable in amplitude and time given its polysynaptic pathway through the trigemino-cervical complex. The R3 follows the R2 component and starts at about 80-90 ms. Its underlying pathways and functions are still debated
Fig. 2
Fig. 2
blockwise comparison of nBR excitability in patients with migraine and controls. R2a is enhanced on the stimulated and non-stimulated side in migraineurs at V0, however only changes on the stimulated were significant given the high variance. These indicators of excessive brain stem excitability normalize after three months of treatment with CGRP mAbs and are then statistically indifferent from controls. * - indicates statistically significant difference between V0 and V3 in migraine. † - indicates statistically significant difference between V0 and controls
Fig. 3
Fig. 3
blockwise comparison of nBR habituation in patients with migraine and controls. R2h is attenuated in migraine and has even a trend towards facilitation in later blocks at V0. After three months of treatment with CGRP mAbs, R2h normalizes and consecutive stimuli are inhibited in all blocks. There remains a significant difference between V3 and controls on the non-stimulated side. * - indicates statistically significant difference between V0 and V3 in migraine. † - indicates statistically significant difference between V0 and controls. # - indicates statistically significant difference between V3 and controls
Fig. 4
Fig. 4
reduction in headache days as a function of R2h changes after initiation of CGRP mAbs. There is a statistically significant correlation of the change in R2h slope from V0 to V3 on the stimulated and non-stimulated side in blocks three and five. Block three results are adjusted for the time before the next headache attack. Note that the correlation coefficients reported in the results section are by definition standardized while lines plotted here are based on raw data

References

    1. Buse DC, Fanning KM, Reed ML, Murray S, Dumas PK, Adams AM, et al. Life With Migraine: Effects on Relationships, Career, and Finances From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. Headache. 2019;59(8):1286–1299.
    1. Dodick D, Edvinsson L, Makino T, Grisold W, Sakai F, Jensen R, et al. Vancouver Declaration on Global Headache Patient Advocacy 2018. Cephalalgia. 2018;38(13):1899–1909.
    1. Diener HC, Förderreuther S, Gaul C, Giese F, Hamann T, Holle-Lee D, et al. Prevention of migraine with monoclonal antibodies against CGRP or the CGRP receptor: Addition to the S1 guideline: Therapy of migraine attacks and prevention of migraine. Recommendations of the Germany Society of Neurology and the German Migraine and Headache Society. Neurological research and practice. 2020;2:11.
    1. Blumenfeld AM, Bloudek LM, Becker WJ, Buse DC, Varon SF, Maglinte GA, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II) Headache. 2013;53(4):644–655.
    1. Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nature reviews Neurology. 2018;14(6):338–350.
    1. Reuter U, Ehrlich M, Gendolla A, Heinze A, Klatt J, Wen S et al Erenumab Versus Topiramate for the Prevention of Migraine–A Randomised, Double-Blind, Active-Controlled Phase 4 Trial. Available at SSRN: https://ssrncom/abstract=3791424 or http://dxdoiorg/102139/ssrn3791424 2021(01.09.2021).
    1. Schoenen J, Manise M, Nonis R, Gerard P, Timmermans G. Monoclonal antibodies blocking CGRP transmission: An update on their added value in migraine prevention. Rev Neurol (Paris) 2020;176(10):788–803.
    1. Sacco S, Bendtsen L, Ashina M, Reuter U, Terwindt G, Mitsikostas DD, et al. European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention. J Headache Pain. 2019;20(1):6.
    1. Ailani J, Burch RC, Robbins MS, Board of Directors of the American Headache S The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. 2021;61(7):1021–1039.
    1. Sandor PS, Afra J, Ambrosini A, Schoenen J. Prophylactic treatment of migraine with beta-blockers and riboflavin: differential effects on the intensity dependence of auditory evoked cortical potentials. Headache. 2000;40(1):30–35.
    1. Diener HC, Agosti R, Allais G, Bergmans P, Bussone G, Davies B, et al. Cessation versus continuation of 6-month migraine preventive therapy with topiramate (PROMPT): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2007;6(12):1054–1062.
    1. Martelletti P, Edvinsson L, Ashina M. Shaping the future of migraine targeting Calcitonin-Gene-Related-Peptide with the Disease-Modifying Migraine Drugs (DMMDs) J Headache Pain. 2019;20(1):60.
    1. Committee for Medicinal Products for Human Use . European Medicines Agency. editor. London: European Medicines Agency; 2018. Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease; pp. 17–18.
    1. Martelletti P. The Application of CGRP(r) Monoclonal Antibodies in Migraine Spectrum: Needs and Priorities. BioDrugs. 2017;31(6):483–485.
    1. de Tommaso M, Ambrosini A, Brighina F, Coppola G, Perrotta A, Pierelli F, et al. Altered processing of sensory stimuli in patients with migraine. Nature reviews Neurology. 2014;10(3):144–155.
    1. Lundblad C, Haanes KA, Grande G, Edvinsson L. Experimental inflammation following dural application of complete Freund’s adjuvant or inflammatory soup does not alter brain and trigeminal microvascular passage. J Headache Pain. 2015;16:91.
    1. Gantenbein AR, Agosti R, Gobbi C, Flugel D, Schankin CJ, Viceic D et al (2021) Impact on monthly migraine days of discontinuing anti-CGRP antibodies after one year of treatment - a real-life cohort study.Cephalalgia. :3331024211014616
    1. Raffaelli B, Mussetto V, Israel H, Neeb L, Reuter U. Erenumab and galcanezumab in chronic migraine prevention: effects after treatment termination. J Headache Pain. 2019;20(1):66.
    1. Ziegeler C, Mehnert J, Asmussen K, May A. Central effects of erenumab in migraine patients: An event-related functional imaging study. Neurology. 2020;95(20):e2794–ee802.
    1. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017;97(2):553–622.
    1. Kaube H, Katsarava Z, Przywara S, Drepper J, Ellrich J, Diener HC. Acute migraine headache: possible sensitization of neurons in the spinal trigeminal nucleus? Neurology. 2002;58(8):1234–1238.
    1. Galletti F, Cupini LM, Corbelli I, Calabresi P, Sarchielli P. Pathophysiological basis of migraine prophylaxis. Prog Neurobiol. 2009;89(2):176–192.
    1. De Marinis M, Pujia A, Natale L, D’Arcangelo E, Accornero N. Decreased habituation of the R2 component of the blink reflex in migraine patients. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology. 2003;114(5):889–893.
    1. Olesen J. International Classification of Headache Disorders. Lancet Neurol. 2018;17(5):396–397.
    1. Schoenen J. Is chronic migraine a never-ending migraine attack? Pain. 2011;152(2):239–240.
    1. Magis D, Ambrosini A, Bendtsen L, Ertas M, Kaube H, Schoenen J, et al. Evaluation and proposal for optimalization of neurophysiological tests in migraine: part 1--electrophysiological tests. Cephalalgia. 2007;27(12):1323–1338.
    1. Ambrosini A, Magis D, Schoenen J. Migraine--clinical neurophysiology. Handb Clin Neurol. 2010;97:275–293.
    1. Katsarava Z, Giffin N, Diener HC, Kaube H. Abnormal habituation of ‘nociceptive’ blink reflex in migraine--evidence for increased excitability of trigeminal nociception. Cephalalgia. 2003;23(8):814–819.
    1. Giffin NJ, Kowacs F, Libri V, Williams P, Goadsby PJ, Kaube H. Effect of the adenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects. Cephalalgia. 2003;23(4):287–292.
    1. Marx JJ. Die elektrophysiologische Untersuchung des Blinkreflexes. Klinische Neurophysiologie. 2003;34(01):8–14.
    1. Oostenveld R, Fries P, Maris E, Schoffelen JM, FieldTrip Open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data. Comput Intell Neurosci. 2011;2011:156869.
    1. Grinnon ST, Miller K, Marler JR, Lu Y, Stout A, Odenkirchen J, et al. National Institute of Neurological Disorders and Stroke Common Data Element Project - approach and methods. Clin Trails. 2012;9(3):322–329.
    1. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39(2):175–191.
    1. Khan KS, Ball E, Fox CE, Meads C. Systematic reviews to evaluate causation: an overview of methods and application. Evid Based Med. 2012;17(5):137–141.
    1. de Tommaso M, Delussi M. Nociceptive blink reflex habituation biofeedback in migraine. Funct Neurol. 2017;32(3):123–130.
    1. Artemenko AR, Kurenkov AL, Nikitin SS, Filatova EG. [Duloxetine in the treatment of chronic migraine] Zh Nevrol Psikhiatr Im S S Korsakova. 2010;110(1):49–54.
    1. Ayzenberg I, Obermann M, Nyhuis P, Gastpar M, Limmroth V, Diener HC, et al. Central sensitization of the trigeminal and somatic nociceptive systems in medication overuse headache mainly involves cerebral supraspinal structures. Cephalalgia. 2006;26(9):1106–1114.
    1. Schulte LH, May A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain. 2016;139(Pt 7):1987–1993.
    1. de Tommaso M, Guido M, Libro G, Sciruicchio V, Puca F. Zolmitriptan reverses blink reflex changes induced during the migraine attack in humans. Neurosci Lett. 2000;289(1):57–60.
    1. Katsarava Z, Limmroth V, Baykal O, Akguen D, Diener HC, Kaube H. Differences of anti-nociceptive mechanisms of migraine drugs on the trigeminal pain processing during and outside acute migraine attacks. Cephalalgia. 2004;24(8):657–662.
    1. FDA-NIH Biomarker Working Group (2016) BEST (Biomarkers, EndpointS, and other Tools) Resource. Food and Drug Administration (US).
    1. Stauffer VL, Wang S, Voulgaropoulos M, Skljarevski V, Kovacik A, Aurora SK. Effect of Galcanezumab Following Treatment Cessation in Patients With Migraine: Results From 2 Randomized Phase 3 Trials. Headache. 2019;59(6):834–847.
    1. De Matteis E, Affaitati G, Frattale I, Caponnetto V, Pistoia F, Giamberardino MA, et al. Early outcomes of migraine after erenumab discontinuation: data from a real-life setting. Neurol Sci. 2021;42(8):3297–3303.
    1. Raffaelli B, Terhart M, Overeem LH, Mecklenburg J, Neeb L, Steinicke M et al (2021) Migraine evolution after the cessation of CGRP(-receptor) antibody prophylaxis: a prospective, longitudinal cohort study.Cephalalgia. :3331024211046617
    1. Lipton RB, Tepper SJ, Silberstein SD, Kudrow D, Ashina M, Reuter U, et al. Reversion from chronic migraine to episodic migraine following treatment with erenumab: Results of a post-hoc analysis of a randomized, 12-week, double-blind study and a 52-week, open-label extension. Cephalalgia. 2021;41(1):6–16.
    1. Lipton RB, Manack Adams A, Buse DC, Fanning KM, Reed ML. A Comparison of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study and American Migraine Prevalence and Prevention (AMPP) Study: Demographics and Headache-Related Disability. Headache. 2016;56(8):1280–1289.
    1. Dresler T, Caratozzolo S, Guldolf K, Huhn JI, Loiacono C, Niiberg-Pikksoot T, et al. Understanding the nature of psychiatric comorbidity in migraine: a systematic review focused on interactions and treatment implications. J Headache Pain. 2019;20(1):51.

Source: PubMed

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