Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study.

BACKGROUND: Chronic 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. RESULTS: At 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. CONCLUSIONS: Our 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.

Functional connectivity of the visual cortex in chronic migraine before and after medication withdrawal therapy.

Acute withdrawal of headache medication in chronic migraine patients with medication overuse may lead to a dramatic reduction in headache frequency and severity. However, the brain networks underlying chronic migraine and a favorable response to acute withdrawal are still poorly understood. The goal of the present study was to characterize the pattern of intrinsic magnetic resonance imaging (MRI) functional connectivity (FC) specific to chronic migraine and to identify changes in FC that characterize subjects with CM reverting to less frequent headaches. Subjects with chronic migraine (N = 99) underwent a resting-state functional MRI scan before and after three months of medication withdrawal therapy. In addition, we included four control groups who were scanned once: healthy participants (N = 27), patients with episodic migraine (N = 25), patients with chronic back pain (N = 22), and patients with clinical depression (N = 17). Using dual regression analysis, we compared whole-brain voxel-level functional connectivity with ten well-known resting-state networks between chronic migraine and control groups, and between responders to treatment (≥50 % reduction in monthly headache days) and non-responders (<50 % reduction), before and after treatment. Subjects with chronic migraine showed differences in FC with a number of RS-networks, most of which involved the visual cortex, compared with healthy controls. A comparison with patients with episodic migraine, chronic pain and depression showed differences in the same direction, suggesting that altered patterns of functional connectivity in chronic migraine patients could to some extent be explained by shared symptomatology with other pain, depression, or migraine conditions. A comparison between responders and non-responders indicated that effective withdrawal reduced FC with the visual cortex for responders. Interestingly, responders already differed in functional connectivity of the visual cortex at baseline compared with non-responders. Altogether, we show that chronic migraine and successful medication withdrawal therapy are linked to changes in the functional connectivity of the visual cortex. These neuroimaging findings provide new insights into the pathways underlying migraine chronification and its reversibility.

Cutaneous allodynia as predictor for treatment response in chronic migraine: a cohort study.

BACKGROUND: Central 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. METHODS: This 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. RESULTS: Of 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. CONCLUSIONS: Cutaneous allodynia, an important marker for central sensitization, likely has predictive value for treatment response in chronic migraine.

Early recognition of characteristic conventional and amplitude-integrated EEG patterns of seizures in SCN2A and KCNQ3-related epilepsy in neonates.

PURPOSE: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pattern was described in neonates with KCNQ2-related epilepsy. We report a similar aEEG pattern in seizures caused by SCN2A- and KCNQ3-pathogenic variants, as well as conventional EEG (cEEG) descriptions. METHODS: International multicentre descriptive study, reporting clinical characteristics, aEEG and cEEG findings of 13 neonates with seizures due to pathogenic SCN2A- and KCNQ3-variants. As a comparison group, aEEGs and cEEGs of neonates with seizures due to hypoxic-ischemic encephalopathy (n = 117) and other confirmed genetic causes affecting channel function (n = 55) were reviewed. RESULTS: In 12 out of 13 patients, the aEEG showed a characteristic sequence of brief onset with a decrease, followed by a quick rise, and then postictal amplitude attenuation. This pattern correlated with bilateral EEG onset attenuation, followed by rhythmic discharges ending in several seconds of post-ictal amplitude suppression. Apart from patients with KCNQ2-related epilepsy, none of the patients in the comparison groups had a similar aEEG or cEEG pattern. DISCUSSION: Seizures in SCN2A- and KCNQ3-related epilepsy in neonates can usually be recognized by a characteristic ictal aEEG pattern, previously reported only in KCNQ2-related epilepsy, extending this unique feature to other channelopathies. Awareness of this pattern facilitates the prompt initiation of precision treatment with sodium channel blockers even before genetic results are available.

Behavioural intervention in medication overuse headache: A concealed double-blind randomized controlled trial.

BACKGROUND AND PURPOSE: Medication overuse headache is a prevalent disorder, with a strong biobehavioural component. Hence, behavioural interventions might effectuate reduction of the overused medication. We assessed in a double-blind manner the efficacy of a behavioural intervention during medication withdrawal therapy. METHODS: In this concealed, double-blind, randomized controlled trial in medication overuse headache, conducted at the Leiden University Medical Centre, we compared the effect of maximal versus minimal behavioural intervention by a headache nurse during withdrawal therapy. Maximal intervention consisted of an intensive contact schedule, comprising education, motivational interviewing, and value-based activity planning during 12 weeks of withdrawal therapy. Minimal intervention consisted of a short contact only. Patients were unaware of the existence of these treatment arms, as the trial was concealed in another trial investigating botulinum toxin A. Endpoints were successful withdrawal and monthly days of acute medication use after the withdrawal period. RESULTS: We enrolled 179 patients (90 maximal, 89 minimal intervention). At Week 12, most patients achieved withdrawal in both groups (82/90 [93%] maximal intervention vs. 75/89 [86%] minimal intervention, odds ratio = 2.44, 95% confidence interval [CI] = 0.83-7.23, p = 0.107). At Week 24, patients in the maximal intervention group had fewer medication days (mean difference = -2.23, 95% CI = -3.76 to -0.70, p = 0.005). This difference receded over time. Change in monthly migraine days did not differ between groups (-6.75 vs. -6.22). CONCLUSIONS: This trial suggests modest benefit of behavioural intervention by a headache nurse during withdrawal therapy for medication overuse headache, to reduce acute medication use during and shortly after intervention, but extension seems warranted for a prolonged effect.

Acute withdrawal and botulinum toxin A in chronic migraine with medication overuse: a double-blind randomized controlled trial.

Botulinum toxin A (BTA) is widely used as treatment of chronic migraine. Efficacy in studies, however, was only modest and likely influenced by unblinding due to BTA-induced removal of forehead wrinkles. Moreover, most study participants were overusing acute headache medications and might have benefitted from withdrawal. We assessed in a double blind, placebo-controlled, randomized clinical trial whether add-on therapy with BTA enhances efficacy of acute withdrawal. Participants were enrolled between December 2012 and February 2015, with follow-up to January 2016, in a single academic hospital in the Netherlands. A total of 179 participants, male and female, aged 18-65, diagnosed with chronic migraine and overuse of acute headache medication were included. All participants were instructed to withdraw acutely from all medication for a 12-week period, in an outpatient setting. In addition, they were randomly assigned (1:1) to 31 injections with BTA (155 units) or placebo (saline); to prevent unblinding, placebo-treated participants received low doses of BTA (17.5 units in total) in the forehead, along with saline injections outside the forehead region. Primary endpoint was percentage change in monthly headache days from baseline to the last 4 weeks of double-blind treatment (Weeks 9-12). Among 179 randomized patients, 90 received BTA and 89 received placebo, and 175 (98%) completed the double-blind phase. All 179 patients were included in the intention-to-treat analyses. BTA did not reduce monthly headache days versus placebo (-26.9% versus -20.5%; difference -6.4%; 95% confidence interval: -15.2 to 2.4; P = 0.15). Absolute changes in migraine days at 12 weeks for BTA versus placebo were -6.2 versus -7.0 (difference: 0.8; 95% confidence interval: -1.0 to 2.7; P = 0.38). Other secondary endpoints, including measures for disability and quality of life, did also not differ. Withdrawal was well tolerated and blinding was successful. Thus, in patients with chronic migraine and medication overuse, BTA does not afford any additional benefit over acute withdrawal alone. Acute withdrawal should be tried first before initiating more expensive treatment with BTA.

Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine.

OBJECTIVE: To identify a plasma metabolomic biomarker signature for migraine. METHODS: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses. RESULTS: Decreases in the level of apolipoprotein A1 (ß -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (ß -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (ß -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status. CONCLUSIONS: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.