Machine prescription for chronic migraine

Responsive to treatment individually, chronic migraine remains strikingly resistant collectively, incurring the second-highest population burden of disability worldwide. A heterogeneity of responsiveness, requiring prolonged—currently heuristic—individual evaluation of available treatments, may reflect a diversity of causal mechanisms, or the failure to identify the most important, single causal factor. Distinguishing between these possibilities, now possible through the application of complex modelling to large-scale data, is critical to determining the optimal approach to identifying new interventions in migraine and making the best use of existing ones. Examining a richly phenotyped cohort of 1446 consecutive unselected patients with chronic migraine, here we use causal multitask Gaussian process models to estimate individual treatment effects across ten classes of preventatives. Such modelling enables us to quantify the accessibility of heterogeneous responsiveness to high-dimensional modelling, to infer the likely scale of the underlying causal diversity. We calculate the treatment effects in the overall population, and the conditional treatment effects among those modelled to respond and compare the true response rates between these two groups. Identifying a difference in response rates between the groups supports a diversity of causal mechanisms. Moreover, we propose a data-driven machine prescription policy, estimating the time-to-response when sequentially trialling preventatives by individualized treatment effects and compare it to expert guideline sequences. All model performances are quantified out-of-sample. We identify significantly higher true response rates among individuals modelled to respond, compared to the overall population (mean difference of 0.034; 95% confidence interval 0.003 to 0.065; p = 0.033), supporting significant heterogeneity of responsiveness and diverse causal mechanisms. The machine prescription policy yields an estimated 35% reduction in time-to-response (3.750 months; 95% confidence interval 3.507 to 3.993; p < 0.0001) compared with expert guidelines, with no substantive increase in expense per patient. We conclude that the highly distributed mode of causation in chronic migraine necessitates high-dimensional modelling for optimal management. Machine prescription should be considered an essential clinical decision-support tool in the future management of chronic migraine

An open-label observational study and meta-analysis of non-invasive vagus nerve stimulation in medically refractory chronic cluster headache

BackgroundMany patients with cluster headache (CH) are inadequately controlled by current treatment options. Non-invasive vagus nerve stimulation (nVNS) is reported to be effective in the management of CH though some studies suggest that it is ineffective.ObjectiveTo assess the safety and efficacy of nVNS in chronic cluster headache (CCH) patients.MethodWe prospectively analysed data from 40 patients with refractory CCH in this open-label, observational study. Patients were seen in tertiary headache clinics at the National Hospital for Neurology and Neurosurgery and trained to use nVNS as preventative therapy. Patients were reivewed at one month and then three-monthly from onset. The primary endpoint was number of patients achieving ≥50% reduction in attack frequency at 3  months. A meta-analysis of all published studies evaluating the efficacy of nVNS in CCH was also conducted. We searched MEDLINE and EMBASE for all studies investigating the use of nVNS as a preventive or adjunctive treatment for CCH with five or more participants. Combined mean difference and responder proportions with 95% confidence intervals (CI) were calculated from the included studies.Results17/40 patients (43%) achieved ≥50% reduction in attack frequency at 3  months. There was a significant reduction in monthly attack frequency from a baseline of 124 (±67) attacks to 79 (±63) attacks in month 3 (mean difference 44.7; 95% CI 25.1 to 64.3; p < 0.001). In month 3, there was also a 1.2-point reduction in average severity from a baseline Verbal Rating Scale of 8/10 (95% CI 0.5 to 1.9; p = 0.001). Four studies, along with the present study, were deemed eligible for meta-analysis, which showed a responder proportion of 0.35 (95% CI 0.07 to 0.69, n = 137) and a mean reduction in headache frequency of 35.3 attacks per month (95% CI 11.0 to 59.6, n = 108), from a baseline of 105 (±22.7) attacks per month.ConclusionThis study highlights the potential benefit of nVNS in CCH, with significant reductions in headache frequency and severity. To better characterise the effect, randomised sham-controlled trials are needed to confirm the beneficial response of VNS reported in some, but not all, open-label studies

Phenotype of new daily persistent headache: subtypes and comparison to transformed chronic daily headache

BACKGROUND: It is unknown whether new daily persistent headache (NDPH) is a single disorder or heterogenous group of disorders, and whether it is a unique disorder from chronic migraine and chronic tension-type headache. We describe a large group of patients with primary NDPH, compare its phenotype to transformed chronic daily headache (T-CDH), and use cluster analysis to reveal potential sub-phenotypes in the NDPH group. METHODS: We performed a case-control study using prospectively collected clinical data in patients with primary NDPH and T-CDH (encompassing chronic migraine and chronic tension-type headache). We used logistic regression with propensity score matching to compare demographics, phenotype, comorbidities, and treatment responses between NDPH and T-CDH. We used K-means cluster analysis with Gower distance to identify sub-clusters in the NDPH group based on a combination of demographics, phenotype, and comorbidities. RESULTS: We identified 366 patients with NDPH and 696 with T-CDH who met inclusion criteria. Patients with NDPH were less likely to be female (62.6% vs. 73.3%, p < 0.001). Nausea, vomiting, photophobia, phonophobia, motion sensitivity, vertigo, and cranial autonomic symptoms were all significantly less frequent in NDPH than T-CDH (p value for all < 0.001). Acute treatments appeared less effective in NDPH than T-CDH, and medication overuse was less common (16% vs. 42%, p < 0.001). Response to most classes of oral preventive treatments was poor in both groups. The most effective treatment in NDPH was doselupin in 45.7% patients (95% CI 34.8-56.5%). Cluster analysis identified three subgroups of NDPH. Cluster 1 was older, had a high proportion of male patients, and less severe headaches. Cluster 2 was predominantly female, had severe headaches, and few associated symptoms. Cluster 3 was predominantly female with a high prevalence of migrainous symptoms and headache triggers. CONCLUSIONS: Whilst there is overlap in the phenotype of NDPH and T-CDH, the differences in migrainous, cranial autonomic symptoms, and vulnerability to medication overuse suggest that they are not the same disorder. NDPH may be fractionated into three sub-phenotypes, which require further investigation

An open-label observational study and meta-analysis of non-invasive vagus nerve stimulation in medically refractory chronic cluster headache

BACKGROUND: Many patients with cluster headache (CH) are inadequately controlled by current treatment options. Non-invasive vagus nerve stimulation (nVNS) is reported to be effective in the management of CH though some studies suggest that it is ineffective. OBJECTIVE: To assess the safety and efficacy of nVNS in chronic cluster headache (CCH) patients. METHOD: We prospectively analysed data from 40 patients with refractory CCH in this open-label, observational study. Patients were seen in tertiary headache clinics at the National Hospital for Neurology and Neurosurgery and trained to use nVNS as preventative therapy. Patients were reivewed at one month and then three-monthly from onset. The primary endpoint was number of patients achieving ≥50% reduction in attack frequency at 3  months. A meta-analysis of all published studies evaluating the efficacy of nVNS in CCH was also conducted. We searched MEDLINE and EMBASE for all studies investigating the use of nVNS as a preventive or adjunctive treatment for CCH with five or more participants. Combined mean difference and responder proportions with 95% confidence intervals (CI) were calculated from the included studies. RESULTS: 17/40 patients (43%) achieved ≥50% reduction in attack frequency at 3  months. There was a significant reduction in monthly attack frequency from a baseline of 124 (±67) attacks to 79 (±63) attacks in month 3 (mean difference 44.7; 95% CI 25.1 to 64.3; p < 0.001). In month 3, there was also a 1.2-point reduction in average severity from a baseline Verbal Rating Scale of 8/10 (95% CI 0.5 to 1.9; p = 0.001). Four studies, along with the present study, were deemed eligible for meta-analysis, which showed a responder proportion of 0.35 (95% CI 0.07 to 0.69, n = 137) and a mean reduction in headache frequency of 35.3 attacks per month (95% CI 11.0 to 59.6, n = 108), from a baseline of 105 (±22.7) attacks per month. CONCLUSION: This study highlights the potential benefit of nVNS in CCH, with significant reductions in headache frequency and severity. To better characterise the effect, randomised sham-controlled trials are needed to confirm the beneficial response of VNS reported in some, but not all, open-label studies

Epidemiology of diagnosed cluster headache in Norway

Background: Cluster headache (CH) is one of the most painful conditions in humans and there is limited epidemiological data on this debilitating condition. Objectives: To describe the epidemiology of CH in Norway Methods: We conducted a nationwide study to investigate the prevalence, incidence, and comorbidity of CH in Norway between January 1 2008 and December 31 2016. Treatment and outcome data from the Norwegian patient registry and the Norwegian prescription database were linked on an individual basis. Results: Among 3,892,260 individuals ≥18 years old of age, we identified a total of 1891 patients with CH. The prevalence of CH was 48.6 per 100,000, and the male-to-female ratio was 1.47. The estimated incidence of CH was 3.0 per 100,000/year. Among patients with CH, increased age and sex adjusted odds ratios ([OR], all with p-values &lt;0.0001, were observed for medication-induced headache (OR 50.7, 95% CI 36.7–69.9), migraine (OR 25.2, 95% CI 22.5–28.3), chronic posttraumatic headache (OR 22.2, 95% CI 12.8–38.45), history of cranial trauma (OR 1.9, 95% CI 1.5–2.4), somatoform disorders (OR 4.2, 95% CI 3.0–5.8), suicide attempt (OR 3.9, 95% CI 2.6–5.8), personality disorder (OR 3.6, 95% CI 2.6–4.9), bipolar disorder (OR 3.6, 95% CI 2.8–4.8), peptic ulcer (OR 2.8, 95% CI 2.3–3.3), depression (OR 2.8, 95% CI 2.4–3.1), substance abuse (OR 2.6, 95% CI 2.0–3.3), and cerebrovascular disease (OR 2.4, 95% CI 1.8–3.1). Use of opioid analgesics during the study period was more common among patients with CH compared to others (81% vs. 22%, sex and age adjusted OR 23.4, 95% CI 20.8–26.2, p &lt; 0.0001)

Continuous positive airway pressure in cluster headache: A randomized, placebo-controlled, triple-blind, crossover study

Background - Oxygen inhalation aborts cluster headache attacks, and case reports show the effect of continuous positive airway pressure. The aim of this study was to investigate the prophylactic effect of continuous positive airway pressure in chronic cluster headache. Methods - This was a randomized placebo-controlled triple-blind crossover study using active and sham continuous positive airway pressure treatment for chronic cluster headache. Patients entered a one month’s baseline period before randomly being assigned to two months’ active continuous positive airway pressure treatment followed by a four weeks’ washout period and two months’ sham continuous positive airway pressure or vice versa. Primary outcome measure was number of cluster headache attacks/week. Results - Of the 30 included participants (12 males, median age 49.5 years, min-max 20–66 years), 25 completed both treatment/sham cycles (two discontinued, three lost to follow-up). The median number of cluster headache attacks per week was reduced from 8.25 (0.75–89.75) attacks to 6.25 (0–56.00) attacks for active continuous positive airway pressure and to 7.50 (0.50–43.75) attacks for sham continuous positive airway pressure, but there was no difference in active versus sham (p = 0.904). One patient had a serious adverse event during active treatment, none occurred during sham treatment. Conclusions - Continuous positive airway pressure treatment did not reduce the number of cluster headache attacks compared to sham treatment in chronic cluster headache patients

Forecasting migraine with machine learning based on mobile phone diary and wearable data

INTRODUCTION: Triggers, premonitory symptoms and physiological changes occur in the preictal migraine phase and may be used in models for forecasting attacks. Machine learning is a promising option for such predictive analytics. The objective of this study was to explore the utility of machine learning to forecast migraine attacks based on preictal headache diary entries and simple physiological measurements. METHODS: In a prospective development and usability study 18 patients with migraine completed 388 headache diary entries and self-administered app-based biofeedback sessions wirelessly measuring heart rate, peripheral skin temperature and muscle tension. Several standard machine learning architectures were constructed to forecast headache the subsequent day. Models were scored with area under the receiver operating characteristics curve. RESULTS: Two-hundred-and-ninety-five days were included in the predictive modelling. The top performing model, based on random forest classification, achieved an area under the receiver operating characteristics curve of 0.62 in a hold-out partition of the dataset. DISCUSSION: In this study we demonstrate the utility of using mobile health apps and wearables combined with machine learning to forecast headache. We argue that high-dimensional modelling may greatly improve forecasting and discuss important considerations for future design of forecasting models using machine learning and mobile health data

Premonitory symptoms in migraine : A cross-sectional study in 2714 persons

Aim To describe the frequency and number of premonitory symptoms (PS) in migraine, the co-occurrence of different PS, and their association with migraine-related factors. Methods In this cross-sectional study, a validated questionnaire was sent to Finnish migraine families between 2002 and 2013 to obtain data on 14 predefined PS, migraine diagnoses, demographic factors, and migraine characteristics. The estimated response rate was 80%. Results Out of 2714 persons, 2223 were diagnosed with migraine. Among these, 77% reported PS, with a mean number of 3.0 symptoms compared to 30% (p Conclusion PS are experienced by a majority of migraineurs. More severe migraine is associated with a higher burden of PS. Since the material was not entirely representative of the general population of migraineurs, caution should be exercised in generalizing the results.Peer reviewe

Surgery for degenerative cervical myelopathy in patients with rheumatoid arthritis and ankylosing spondylitis: a nationwide registry-based study with patient-reported outcomes

Purpose To compare patient-reported outcomes (PROMs) following surgery for degenerative cervical myelopathy (DCM) among patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) versus those without rheumatic diseases. Methods Data were obtained from the Norwegian Registry for Spine Surgery. The primary outcome was change in the Neck Disability Index (NDI) at 1 year. Secondary endpoints included the European Myelopathy Score (EMS), quality of life (EuroQoL-5D [EQ-5D]), numeric rating scales (NRS) for headache, neck pain, and arm pain, and complications. Results Among 905 participants operated between 2012 and 2018, 35 had RA or AS. There were signifcant improvements in all PROMs at 1 year and no statistically signifcant diference between the cohorts in mean change in NDI (−0.64, 95% CI−8.1 to 6.8, P=.372), EQ-5D (0.10, 95% CI−0.04 to 0.24, P=.168), NRS neck pain (−0.8, 95% CI−2.0 to 0.4, P=.210), NRS arm pain (−0.6, 95% CI−1.9 to 0.7, P=.351), and NRS headache (−0.5, 95% CI−1.7 to 0.8, P=.460). Discussion and conclusion Our study adds to the limited available evidence that surgical treatment cannot only arrest further progression of myelopathy but also improve functional status, neurological outcomes, and quality of life in patients with rheumatic disease

Angiotensin-converting enzyme gene insertion/deletion polymorphism in migraine patients

<p>Abstract</p> <p>Background</p> <p>The main objective of this study was to investigate the angiotensin converting enzyme (<it>ACE</it>) genotype as a possible risk factor for migraine (both with and without aura) compared to controls. We also wanted to examine whether a clinical response to an ACE inhibitor, lisinopril, or an angiotensin II receptor blocker, candesartan, in migraine prophylaxis was related to <it>ACE </it>genotype.</p> <p>Methods</p> <p>347 migraine patients aged 18–68 (155 migraine without aura (MoA), 187 migraine with aura (MwA) and 5 missing aura subgroup data) and 403 healthy non-migrainous controls > 40 years of age were included in the study. A polymerase chain reaction (PCR) was performed on the genomic DNA samples to obtain the <it>ACE </it>insertion (I)/deletion(D) polymorphisms.</p> <p>Results</p> <p>No significant differences between migraine patients and controls were found with regard to <it>ACE </it>genotype and allele distributions. Furthermore, there was no significant difference between the controls and the MwA or MoA subgroups.</p> <p>Conclusion</p> <p>In our sample there is no association between <it>ACE </it>genotype or allele frequency and migraine. In addition, <it>ACE </it>genotype in our experience did not predict the clinical response to lisinopril or candesartan used as migraine prophylactics.</p