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.

Group schema therapy for cluster-C personality disorders: A multicentre open pilot study.

BACKGROUND: Group schema therapy (GST) is increasingly popular as a treatment for personality disorders (PDs), including Cluster-C PDs. Individual ST has proven to be effective for Cluster-C PD patients, while the evidence for GST is limited. This study aimed to investigate the effectiveness of GST for Cluster-C PD. Moreover, differences between the specific Cluster-C PDs (avoidant PD, dependent PD and obsessive-compulsive PD) were explored. METHODS: A multicentre open trial was conducted, including 137 patients with a Cluster-C PD (avoidant PD: n = 107, dependent PD: n = 11 and obsessive-compulsive PD: n = 19). Patients received 30 weekly GST sessions with a maximum of 180 min of individual ST and five optional monthly booster sessions. Outcome measures including Cluster-C PD severity, general psychopathological symptoms, quality of life, functional impairment, happiness, PD-related beliefs, self-esteem, self-ideal discrepancy, schemas and schema modes were assessed at baseline until 2-year follow-up with semi-structured interviews and self-report measures. Change over time and differences between the specific Cluster-C PDs were analysed with mixed regression analyses. RESULTS: The outcome measures showed significant improvements for all Cluster-C PDs, with medium to large effect sizes after 2 years. A treatment dropout rate of 11.7% was found. There were some indications for differences between the Cluster-C PDs in severity at baseline, change trajectories and effectiveness of GST. CONCLUSIONS: This study demonstrated that GST is a promising treatment for Cluster-C PDs. The following step is a randomized controlled trial to further document the (cost-)effectiveness of GST.

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.

Linking migraine frequency with family history of migraine.

BACKGROUND: Migraine is a complex genetic disorder that is brought about by multiple genetic and environmental factors. We aimed to assess whether migraine frequency is associated with genetic susceptibility. METHODS: We investigated in 2829 migraine patients (14% males) whether 'migraine frequency' (measured as the number of migraine days per month) was related to 'genetic load' (measured as the number of parents affected with migraine) using a validated web-based questionnaire. In addition, we investigated associations with age-at-onset, migraine subtype, use of acute headache medication, and comorbid depression. RESULTS: We found an association between the number of migraine days per month and family history of migraine for males ( p = 0.03), but not for females ( p = 0.97). This association was confirmed in a linear regression analysis. Also, a lower age-at-onset ( p < 0.001), having migraine with aura ( p = 0.03), and a high number of medication days ( p = 0.006) were associated with a stronger family history of migraine, whereas lifetime depression ( p = 0.13) was not. DISCUSSION: Migraine frequency, as measured by the number of migraine days per month, seems associated with a genetic predisposition only in males. A stronger family history of migraine was also associated with a lower age-at-onset, a higher number of medication days, and migraine with aura. Our findings suggest that specific clinical features of migraine seem more determined by genetic factors.

Allodynia in cluster headache.

Cutaneous allodynia is an established marker for central sensitization in migraine. There is debate whether cutaneous allodynia may also occur in cluster headache, another episodic headache disorder. Here, we examined the presence and severity of allodynia in a large well-defined nationwide population of people with cluster headache. Using validated questionnaires we assessed, cross-sectionally, ictal allodynia and comorbid depression and migraine in the nationwide "Leiden University Cluster headache neuro-Analysis" (LUCA) study. Participants with cluster headache were diagnosed according to the International Classification of Headache Disorders criteria. Multivariate regression models were used, with correction for demographic factors and cluster headache subtype (chronic vs episodic; recent attacks <1 month vs no recent attacks). In total, 606/798 (75.9%) participants with cluster headache responded; of whom, 218/606 (36%) had allodynia during attacks. Female gender (odds ratio [OR] 2.05, 95% confidence interval [95% CI] 1.28-3.29), low age at onset (OR 0.98, 95% CI 0.96-0.99), lifetime depression (OR 1.63, 95% CI 1.06-2.50), comorbid migraine (OR 1.96, 95% CI 1.02-3.79), and having recent attacks (OR 1.80, 95% CI 1.13-2.86), but not duration of attacks and chronic cluster headache, were independent risk factors for allodynia. The high prevalence of cutaneous allodynia with similar risk factors for allodynia as found for migraine suggests that central sensitization, like in migraine, also occurs in cluster headache. In clinical practice, awareness that people with cluster headache may suffer from allodynia can in the future be an important feature in treatment options.

Prevalence of lifetime depression in a large hemiplegic migraine cohort.

OBJECTIVE: To determine the prevalence of depression and determinants associated with depression in a large population of hemiplegic migraine (HM) patients. METHODS: We conducted a cross-sectional, validated questionnaire study among 89 well-defined HM patients and 235 headache-free controls. The prevalence of lifetime depression and its relation to migraine characteristics was assessed. RESULTS: HM patients had increased odds for lifetime depression (odds ratio 3.73, 95% confidence interval 2.18-6.38) compared with controls. Use of acute antimigraine medication was associated with lifetime depression. CONCLUSIONS: Depression is part of the monogenic hemiplegic migraine phenotype. Further studies are needed to elucidate the pathophysiologic role of HM genes in comorbid depression. For now, clinicians should take comorbid depression into consideration when starting prophylactic treatment of HM.

Cluster headache and depression.

OBJECTIVE: As cluster headache (CH) is often referred to as "suicide headache," we wanted to assess the prevalence of depression in CH patients, and to investigate determinants of depression such as sleep disturbances. METHODS: In a cross-sectional, web-based, validated questionnaire study among 462 well-defined CH patients and 177 controls, we diagnosed CH according to the ICHD-III. We assessed depression using the Hospital Anxiety and Depression Scale (HADS-D) and the Center for Epidemiologic Studies Depression scale (CES-D) with supplementary questions to assess lifetime depression. Data were analyzed with logistic and linear regression models. RESULTS: Lifetime depression showed almost 3 times higher odds in CH patients (n = 462) than controls (n = 177) (odds ratio 2.77; 95% confidence interval 1.70-4.51). Chronic (n = 67) vs episodic (n = 394) patients had a higher prevalence of lifetime depression and more sleeping problems. Current depression was associated with having active attacks (last attack <1 month) (adjusted p = 0.02), but no effect remained after correction for sleep disturbances. CONCLUSIONS: CH is associated with an almost 3 times increased odds of lifetime depression. Current depression is highly prevalent in patients with active disease, in part related to sleep disturbances due to current nocturnal attacks.

What do patients consider to be the most important outcomes for effectiveness studies on migraine treatment? Results of a Delphi study.

BACKGROUND: The outcome measures most frequently used in studies on the effectiveness of migraine treatment are whether the patient is free of pain, nausea, and free of photophobia/phonophobia within two hours. However, no patient-centred outcome measures are available. Therefore, we performed an online Delphi procedure to compile a list of outcome measures deemed most important to migraine patients. METHODS: From a large database of migraine patients, we randomly selected 150 males and 150 females patients. We asked the open-ended question: 'If a new medicine was developed for migraine attacks, what would you wish the effect of this medication to be?' In the second and third rounds, we presented the answers of the first round and asked the patients to rate the importance of each item. RESULTS: The initial response rate was 56% (n = 169). In the subsequent rounds the response rates were 90% (n = 152), and 97% (n = 147), respectively. Patients wanted their attack medication to treat the headache within 30 min, to prevent the attack from getting worse, to ensure they could function properly within 1 h, and prevent the recurrence of symptoms during the same day. CONCLUSIONS: The currently used outcome measures in migraine research do not sufficiently reflect the wishes of patients. Patients want the medication to work faster, to take away pain at an earlier stage, to make them able to function properly quickly, and to prevent recurrence. These aspects should be considered in future evaluation of new attack medication for migraine.

Cutaneous allodynia as a predictor of migraine chronification.

Cutaneous allodynia is a common feature accompanying migraine attacks and considered a clinical marker for central sensitization. In a longitudinal study, we wanted to investigate if allodynia in migraine patients is a predictor of increasing frequency of migraine days. We included 3029 well-defined, web-based migraine patients (86% female, mean age 42.8 ± 11.4 years, 61% migraine without aura). Questionnaires on migraine characteristics (including allodynia), depression and demographic factors were applied. The number of migraine days was measured twice. Multivariate regression models were used, with correction for other factors that are involved in the relation between allodynia and the number of migraine attacks or migraine days, with specific focus on depression. Of all 2331 eligible migraine patients, 1624 (70%) had allodynia. Lifetime depression was an independent risk factor for allodynia (odds ratio 1.52, 95% confidence interval 1.26-1.84), as well as female gender, low age at onset, and high migraine attack frequency. Analysis of the longitudinal data (in migraineurs with a follow-up period of >6 months) showed that, apart from the known risk factors (low age at onset, high baseline number of migraine days, and depression), allodynia was an independent predictor for increase in number of migraine days over a mean follow-up period of 93 ± 30 weeks (median 103 weeks, range 26-160 weeks). Cutaneous allodynia is a risk factor for migraine chronification and may warrant preventive treatment strategies.

Genome-wide association analysis identifies susceptibility loci for migraine without aura.

Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.

A long-term follow-up study of 18 patients with sporadic hemiplegic migraine.

OBJECTIVE: Our objective was to study the long-term prognosis of sporadic hemiplegic migraine (SHM). METHODS: We performed a longitudinal follow-up study in 18 patients who were diagnosed with SHM between 1993 and 1996. Follow-up time between the first and second survey ranged from nine to 14 years. These patients were included as part of a genetic study in which we systematically analysed the role of the three known familial hemiplegic migraine (FHM) genes. RESULTS: In 12 out of 18 patients the clinical diagnosis was unchanged. In two of the six remaining patients the attacks were no longer associated with hemiplegia; one of them had an ATP1A2 gene mutation (E120A). In the four other patients, the diagnosis changed into FHM, because a family member had developed hemiplegic migraine since the initial diagnosis was made. In two of the four patients a mutation was demonstrated (CACNA1A [R583Q] and ATP1A2 [R834X]). CONCLUSION: This study shows that the diagnosis of SHM changes into FHM in a considerable percentage of patients (22% [4 of 18]), almost a decade after the initial diagnosis. This indicates that a careful follow-up of SHM patients and their families is advisable for optimal care and counseling. Diagnostic screening of FHM genes in SHM patients can be of value. Our genetic and clinical follow-up studies reinforce the evidence that FHM and SHM are part of the same spectrum of migraine.

[Migraine and depression should be treated concurrently]. / Migraine en depressie verdienen gezamenlijke zorg.

Migraine and depression are highly prevalent disorders with a strong bidirectional comorbidity: migraine patients have an increased risk for depression and patients suffering from depression have an increased risk for migraine. This comorbidity could be due to an underlying common pathophysiological mechanism. Chronification of migraine further increases the chance of developing depression, and vice versa. Misuse of migraine attack medication plays an important role in the development of chronic migraine. It is important for general practitioners, psychiatrists and neurologists to be alert to the comorbidity of migraine and depression. It is recommended that different hospital specialists should be involved in both the diagnosis and treatment of patients with comorbidity of migraine and depression.