Abstract
Background & ObjectivesCalcitonin 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.MethodsWe 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.ResultsAll 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.DiscussionWe 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 registrationThis trial was prospectively registered at clinicaltrials.gov (ID: NCT04019496, date of registration: July 15, 2019).
Highlights
Background & ObjectivesCalcitonin gene-related peptide ligand/receptor (CGRP) antibodies effectively reduce headache frequency in migraine
This discrepancy of guidelines reveals uncertainty about long-term effects of calcitonin gene-related peptide (CGRP) mAbs on the natural course of migraine, but it is generally acknowledged that the preventive treatment should potentially lead to a sustained amelioration of headache frequency as it is shown for oral preventives, which may be considered disease modifying [10,11,12]
This study aims to address this ambiguity of findings by investigating patients with migraine treated with CGRP mAbs for longitudinal changes of brain stem excitability and habituation to nociceptive stimuli, which were shown to be deficient in migraine and closely tied to central disease activity [15, 20]
Summary
Background & ObjectivesCalcitonin gene-related peptide ligand/receptor (CGRP) antibodies effectively reduce headache frequency in migraine. European guidelines are less absolute about the treatment duration and advise to continue for about 6-12 months while the American Headache Society Consensus Statement considers reauthorization duration indefinite and should be guided by patient response and medical professional attestation [8, 9]. This discrepancy of guidelines reveals uncertainty about long-term effects of CGRP mAbs on the natural course of migraine, but it is generally acknowledged that the preventive treatment should potentially lead to a sustained amelioration of headache frequency as it is shown for oral preventives, which may be considered disease modifying [10,11,12]. It is unclear if a course of CGRP mAbs possesses disease modifying potential
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