BackgroundChronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and... Show moreBackgroundChronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and prevention strategies. An important factor in the chronification of migraine is the overuse of acute headache medication. However, the mechanisms behind the transformation of episodic migraine to chronic migraine and vice versa have not yet been elucidated. We performed a longitudinal epigenome-wide association study to identify DNA methylation (DNAm) changes associated with treatment response in patients with chronic migraine and medication overuse as part of the Chronification and Reversibility of Migraine clinical trial. Blood was taken from patients with chronic migraine (n = 98) at baseline and after a 12-week medication withdrawal period. Treatment responders, patients with ≥ 50% reduction in monthly headache days (MHD), were compared with non-responders to identify DNAm changes associated with treatment response. Similarly, patients with ≥ 50% versus < 50% reduction in monthly migraine days (MMD) were compared.ResultsAt the epigenome-wide significant level (p < 9.42 × 10–8), a longitudinal reduction in DNAm at an intronic CpG site (cg14377273) within the HDAC4 gene was associated with MHD response following the withdrawal of acute medication. HDAC4 is highly expressed in the brain, plays a major role in synaptic plasticity, and modulates the expression and release of several neuroinflammation markers which have been implicated in migraine pathophysiology. Investigating whether baseline DNAm associated with treatment response, we identified lower baseline DNAm at a CpG site (cg15205829) within MARK3 that was significantly associated with MMD response at 12 weeks.ConclusionsOur findings of a longitudinal reduction in HDAC4 DNAm status associated with treatment response and baseline MARK3 DNAm status as an early biomarker for treatment response, provide support for a role of pathways related to chromatin structure and synaptic plasticity in headache chronification and introduce HDAC4 and MARK3 as novel therapeutic targets. Show less
BackgroundCentral sensitisation is an important mechanism in migraine chronification. It is presumed to occur in second and third order neurons sequentially, resulting in an analogous spatial... Show moreBackgroundCentral sensitisation is an important mechanism in migraine chronification. It is presumed to occur in second and third order neurons sequentially, resulting in an analogous spatial distribution of cutaneous allodynia with cephalic and extracephalic symptoms. We investigated whether allodynia, and its subtypes based on spatial distribution and type of stimulus, predict response to treatment in chronic migraine patients.MethodsThis study was conducted as part of the CHARM study (NTR3440), a randomized, double-blind, placebo-controlled trial in chronic migraine patients with medication overuse. We included 173 patients. The presence of cutaneous allodynia at baseline was established with the Allodynia Symptom Checklist. Primary endpoint was reversion from chronic to episodic migraine.ResultsOf all patients, 74.6% reported cutaneous allodynia. Absence of allodynia compared to presence of allodynia was predictive for reversion from chronic to episodic migraine, odds ratio (OR): 2.45 (95% CI: 1.03–5.84), p = 0.042. The predictive value was more pronounced when subdivided for spatial distribution, for participants without allodynia versus cephalic (OR: 4.16 (95% CI: 1.21–14.30), p = 0.024) and extracephalic (OR: 7.32 (95% CI: 1.98- 27.11), p = 0.003) allodynia. Mechanical, but not thermal, allodynia, was associated with outcome.ConclusionsCutaneous allodynia, an important marker for central sensitization, likely has predictive value for treatment response in chronic migraine. Show less
Chronic migraine is a highly disabling and difficult to treat form of migraine. In this thesis, various clinical aspects and the management of chronic migraine are investigated, in order to enhance... Show moreChronic migraine is a highly disabling and difficult to treat form of migraine. In this thesis, various clinical aspects and the management of chronic migraine are investigated, in order to enhance prevention and treatment of chronic migraine. Important risk factors for chronic migraine are depression, anxiety, cutaneous allodynia and especially overuse of acute anti-headache medication. The studies in this thesis conform that withdrawal of the overused medication results into a meaningful improvement in many patients. A double-blind randomised controlled trial did not show any additional benefit of treatment with Botulinum toxin A adjacent to acute withdrawal. Another double-blind randomised controlled trial did suggest effectiveness of a behavioural intervention during acute withdrawal on the reduction of medication intake during and shortly after withdrawal. Cutaneous allodynia (the perception of pain upon a non-painful stimuli) is a clinical marker of central sensitisation, an important mechanism in the pathophysiology of chronic migraine. The presence of cutaneous allodynia in general, and the extent of allodynia symptoms, appear to be a predictor for response to withdrawal therapy. Show less
Sacco, S.; Bendtsen, L.; Ashina, M.; Reuter, U.; Terwindt, G.; Mitsikostas, D.D.; Martelletti, P. 2019
