[Show abstract][Hide abstract] ABSTRACT: Cervicogenic headache (CEH) is a secondary headache which affects 1.0-4.6 % of the population. Although the costs are unknown, the health consequences are substantial for the individual; especially considering that they often suffers chronicity. Pharmacological management has no or only minor effect on CEH. Thus, we aim to assess the efficacy of chiropractic spinal manipulative therapy (CSMT) for CEH in a single-blinded placebo-controlled randomized clinical trial (RCT). According to the power calculations, we aim to recruit 120 participants to the RCT. Participants will be randomized into one of three groups; CSMT, placebo (sham manipulation) and control (usual non-manual management). The RCT consists of three stages: 1 month run-in, 3 months intervention and follow-up analyses at the end of intervention and 3, 6 and 12 months. Primary end-point is headache frequency, while headache duration, headache intensity, headache index (frequency × duration × intensity) and medicine consumption are secondary end-points. Primary analysis will assess a change in headache frequency from baseline to the end of intervention and to follow-up, where the groups CSMT and placebo and CSMT and control will be compared. Due to two group-comparisons, the results with p values below 0.025 will be considered statistically significant. For all secondary end-points and analyses, the significance level of 0.05 will be used. The results will be presented with the corresponding p values and 95 % confidence intervals. To our knowledge, this is the first prospective manual therapy three-armed single-blinded placebo-controlled RCT to be conducted for CEH. Current RCTs suggest efficacy in headache frequency, duration and intensity. However a firm conclusion requires clinical single-blinded placebo-controlled RCTs with few methodological shortcomings. The present study design adheres to the recommendations for pharmacological RCTs as far as possible and follows the recommended clinical trial guidelines by the International Headache Society. Trial registration ClinicalTrials.gov identifier: NCT01687881, 2 December 2012.
[Show abstract][Hide abstract] ABSTRACT: Medication-overuse headache (MOH) is a common health problem. Withdrawal of the overused medication is the treatment of choice. We investigated the long-term effectiveness of brief intervention (BI) for MOH patients in primary care. The BI for MOH in primary care study was a blinded, pragmatic, cluster-randomised controlled trial. 25,486 patients (age 18–50) from 50 general practitioners (GPs) were screened for MOH. GPs defined clusters and 23 GPs were randomised to receive BI training and 27 GPs to continue business as usual (BAU). The GPs assessed their MOH patients with the Severity of Dependence Scale, gave individual feedback about the risk of MOH and advice to reduce headache medication. Primary outcomes, assessed 6 months after the intervention, were reduction in headache and medication days/month. 42 % were screening responders. 2.4 % had self-reported MOH. A random selection of 104 patients with self-reported MOH were invited, 75 were randomised out of which 60 with a physician-defined MOH diagnosis were included. None were lost to follow-up. BI was significantly better than BAU regarding primary outcomes (p < 0.001–0.018). Headache and medication days were reduced by 5.9 (95 % CI 1.1–10.8) and 6.2 (1.1–11.3) more days/month in BI than BAU group. Chronic headache resolved in 63 and 11 % in the BI and the BAU group (p < 0.001). Headache-related disability was lower among those who detoxified. In conclusion, BI is an effective treatment in primary care with lasting effect 6 months after the intervention for MOH.
Trial Registration: ClinicalTrials.gov identifier: NCT01314768.
No preview · Article · Dec 2015 · Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Migraine affects 15% of the population, and has substantial health and socioeconomic costs. Pharmacological management is first-line treatment. However, acute and/or prophylactic medicine might not be tolerated due to side effects or contraindications. Thus, we aim to assess the efficacy of chiropractic spinal manipulative therapy (CSMT) for migraineurs in a single-blinded placebo-controlled randomised clinical trial (RCT).
Method and analysis:
According to the power calculations, 90 participants are needed in the RCT. Participants will be randomised into one of three groups: CSMT, placebo (sham manipulation) and control (usual non-manual management). The RCT consists of three stages: 1 month run-in, 3 months intervention and follow-up analyses at the end of the intervention and 3, 6 and 12 months. The primary end point is migraine frequency, while migraine duration, migraine intensity, headache index (frequency x duration x intensity) and medicine consumption are secondary end points. Primary analysis will assess a change in migraine frequency from baseline to the end of the intervention and follow-up, where the groups CSMT and placebo and CSMT and control will be compared. Owing to two group comparisons, p values below 0.025 will be considered statistically significant. For all secondary end points and analyses, a p value below 0.05 will be used. The results will be presented with the corresponding p values and 95% CIs.
Ethics and dissemination:
The RCT will follow the clinical trial guidelines from the International Headache Society. The Norwegian Regional Committee for Medical Research Ethics and the Norwegian Social Science Data Services have approved the project. Procedure will be conducted according to the declaration of Helsinki. The results will be published at scientific meetings and in peer-reviewed journals.
Trial registration number:
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Medication-overuse headache (MOH) is common in the general population. Detoxification is the general treatment principle for MOH. The present paper is based on a study of a brief intervention (BI) for MOH in primary care. New data on headache disability and the Hospital Anxiety and Depression Scale (HADS) for MOH patients compared to population controls with and without chronic headache are presented and compared to previously published main outcome data.
This was a double-blind pragmatic cluster randomized controlled trial carried out amongst 50 general practitioners in Norway. The BI was compared to business as usual (BAU) and population controls, and patients were followed up after 3 months. Primary outcomes were headache and medication days per month after 3 months. Headache disability and HADS were also measured as secondary outcomes.
Sixty MOH patients and 40 population controls were included. BI was significantly better than BAU after 3 months regarding primary outcomes. Non-intervention population controls did not change. The MOH patients had significantly higher headache disability and anxiety scores than the population controls.
Patients with MOH are a highly disabled group where anxiety and depression are important comorbidities. Detoxification of MOH by a BI in primary care is effective and has potential for saving resources for more treatment-resistant cases in neurologist care.
Full-text · Article · Nov 2015 · European Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND Next-generation sequencing (NGS) is a genetic technique used to determine the order of nucleotides in DNA. The technique has proved to be more efficient than the traditional method, Sanger sequencing, for sequencing multiple genes. NGS is now being used to diagnose disorders in which multiple genes are involved. This study has examined whether next-generation sequencing produces a greater number of positive diagnoses than its traditional counterpart in patients with suspected hereditary peripheral neuropathy. MATERIAL AND METHOD This study is a retrospective review of samples from 103 patients investigated for hereditary peripheral neuropathy, received by Telemark Hospital in the period 2012 - 14. After exclusion of duplication/deletion of PMP22, 96 samples were analysed by NGS with physical enrichment of 52 hereditary peripheral neuropathy genes. RESULTS A genetic cause was identified in 35 patients (34 %) with peripheral neuropathy, of which 28 (27 %) were point mutations identified by NGS. INTERPRETATION Of the pathogenic point mutations identified in this study, 12 were in genes that would previously have been analysed by Sanger sequencing in our department, whereas 16 were in genes that would not previously have been tested.
Full-text · Article · Nov 2015 · Tidsskrift for den Norske laegeforening
[Show abstract][Hide abstract] ABSTRACT: IntroductionCharcot–Marie–Tooth disease (CMT) is a heterogeneous inherited neuropathy. The number of known CMT genes is rapidly increasing mainly due to next-generation sequencing technology, at present more than 70 CMT-associated genes are known. We investigated whether variants in the DCTN2 could cause CMT.Material and methodsFifty-nine Norwegian CMT families from the general population with unknown genotype were tested by targeted next-generation sequencing (NGS) for variants in DCTN2 along with 32 CMT genes and 19 other genes causing other inherited neuropathies or neuronopathies, due to phenotypic overlap. In the family with the DCTN2 variant, exome sequencing was then carried out on all available eight family members to rule out the presence of more potential variants.ResultsTargeted NGS identified in one family a variant of DCTN2, c.337C>T, segregating with the phenotype in five affected members, while it was not present in the three unaffected members. The DCTN2 variant c.337C>T; p.(His113Tyr) was neither found in in-house controls nor in SNP databases. Exome sequencing revealed a singular heterozygous shared haplotype containing four genes, DCTN2, DNAH10, LRIG3, and MYO1A, with novel sequence variants. The haplotype was shared by all the affected members, while the unaffected members did not have it.Conclusions
This is the first time a haplotype on chromosome 12 containing sequence variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A has been linked to an inherited neuropathy in humans.
No preview · Article · Oct 2015 · Acta Neurologica Scandinavica
[Show abstract][Hide abstract] ABSTRACT: At present, no consensus exists among clinical and academic experts regarding an appropriate placebo for randomized controlled trials (RCTs) of spinal manipulative therapy (SMT). Therefore, we investigated whether it was possible to conduct a chiropractic manual-therapy RCT with placebo. Seventy migraineurs were randomized to a single-blinded placebo-controlled clinical trial that consisted of 12 treatment sessions over 3 months. The participants were randomized to chiropractic SMT or placebo (sham manipulation). After each session, the participants were surveyed on whether they thought they had undergone active treatment (“yes” or “no”) and how strongly they believed that active treatment was received (numeric rating scale 0–10). The outcome measures included the rate of successful blinding and the certitude of the participants’ beliefs in both treatment groups. At each treatment session, more than 80% of the participants believed that they had undergone active treatment, regardless of group allocation. The odds ratio for believing that active treatment was received was >10 for all treatment sessions in both groups (all p < 0.001). The blinding was maintained throughout the RCT. Our results strongly demonstrate that it is possible to conduct a single-blinded manual-therapy RCT with placebo and to maintain the blinding throughout 12 treatment sessions given over 3 months.
[Show abstract][Hide abstract] ABSTRACT: Copy number variations (CNVs) are important in relation to diversity and evolution but can sometimes cause disease. The most common genetic cause of the inherited peripheral neuropathy Charcot-Marie-Tooth disease is the PMP22 duplication; otherwise, CNVs have been considered rare. We investigated CNVs in a population-based sample of Charcot-Marie-Tooth (CMT) families. The 81 CMT families had previously been screened for the PMP22 duplication and point mutations in 51 peripheral neuropathy genes, and a genetic cause was identified in 37 CMT families (46%). Index patients from the 44 CMT families with an unknown genetic diagnosis were analysed by whole-genome array comparative genomic hybridization to investigate the entire genome for larger CNVs and multiplex ligation-dependent probe amplification to detect smaller intragenomic CNVs in MFN2 and MPZ. One patient had the pathogenic PMP22 duplication not detected by previous methods. Three patients had potentially pathogenic CNVs in the CNTNAP2, LAMA2, or SEMA5A, that is, genes related to neuromuscular or neurodevelopmental disease. Genotype and phenotype correlation indicated likely pathogenicity for the LAMA2 CNV, whereas the CNTNAP2 and SEMA5A CNVs remained potentially pathogenic. Except the PMP22 duplication, disease causing CNVs are rare but may cause CMT in about 1% (95% CI 0–7%) of the Norwegian CMT families.
Full-text · Article · Jan 2015 · BioMed Research International
[Show abstract][Hide abstract] ABSTRACT: The debate on the clinical definition of refractory Chronic Migraine (rCM) is still far to be concluded. The importance to create a clinical framing of these rCM patients resides in the complete disability they show, in the high risk of serious adverse events from acute and preventative drugs and in the uncontrolled application of therapeutic techniques not yet validated.
The European Headache Federation Expert Group on rCM presents hereby the updated definition criteria for this harmful subset of headache disorders. This attempt wants to be the first impulse towards the correct identification of these patients, the correct application of innovative therapeutic techniques and lastly aim to be acknowledged as clinical entity in the next definitive version of the International Classification of Headache Disorders 3 (ICHD-3 beta).
Full-text · Article · Nov 2014 · The Journal of Headache and Pain
[Show abstract][Hide abstract] ABSTRACT: This is to our knowledge the first systematic review regarding the efficacy of manual therapy randomized clinical trials (RCT) for primary chronic headaches. A comprehensive English literature search on CINHAL, Cochrane, Medline, Ovid and PubMed identified 6 RCTs all investigating chronic tension-type headache (CTTH). One study applied massage therapy and five studies applied physiotherapy. Four studies were considered to be of good methodological quality by the PEDro scale. All studies were pragmatic or used no treatment as a control group, and only two studies avoided co-intervention, which may lead to possible bias and makes interpretation of the results more difficult. The RCTs suggest that massage and physiotherapy are effective treatment options in the management of CTTH. One of the RCTs showed that physiotherapy reduced headache frequency and intensity statistical significant better than usual care by the general practitioner. The efficacy of physiotherapy at post-treatment and at 6 months follow-up equals the efficacy of tricyclic antidepressants. Effect size of physiotherapy was up to 0.62. Future manual therapy RCTs are requested addressing the efficacy in chronic migraine with and without medication overuse. Future RCTs on headache should adhere to the International Headache Society's guidelines for clinical trials, i.e. frequency as primary end-point, while duration and intensity should be secondary end-point, avoid co-intervention, includes sufficient sample size and follow-up period for at least 6 months.
Full-text · Article · Oct 2014 · The Journal of Headache and Pain
[Show abstract][Hide abstract] ABSTRACT: Most knowledge on chronic tension-type headache (CTTH) is based on data from selected clinic populations, while data from the general population is sparse. Since pericranial tenderness is found to be the most prominent finding in CTTH, we wanted to explore the relationship between CTTH and pericranial muscle tenderness in a population-based sample.
An age- and gender-stratified random sample of 30,000 persons aged 30-44 years from the general population received a mailed questionnaire. Those with a self-reported chronic headache were interviewed and examined by neurological residents. The questionnaire response rate was 71% and the interview participation rate was 74%. The International Classification of Headache Disorders II was used. Pericranial muscle tenderness was assessed by a total tenderness score (TTS) involving 8 pairs of muscles and tendon insertions. Cross-sectional data from the Danish general population using the same scoring system were used for comparison.
The tenderness scores were significantly higher in women than men in all muscle groups. The TTS was significantly higher in those with co-occurrence of migraine compared with those without; 19.3 vs. 16.8, p = 0.02. Those with bilateral CTTH had a significantly higher TTS than those with unilateral CTTH. The TTS decreased significantly with age. People with CTTH had a significantly higher TTS compared to the general population.
People with CTTH have increased pericranial tenderness. Elevated tenderness scores are associated with co-occurrence of migraine, bilateral headache and low age.
Whether the increased muscle tenderness is primary or secondary to the headache should be addressed by future studies.
Full-text · Article · Sep 2014 · The Journal of Headache and Pain
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The objective of this article is to compare the diagnosis of menstrual migraine without aura (MM) from a clinical interview with prospective headache diaries in a population-based study.
Material and methods:
A total of 237 women with self-reported migraine in at least half of menstruations were interviewed by a neurologist about headache and diagnosed according to the International Classification of Headache Disorders II (ICHD II). Additionally, the MM criteria were expanded to include other types of migraine related to menstruation. Subsequently, all women were asked to complete three month prospective headache diaries.
A total of 123 (52%) women completed both clinical interview and diaries. Thirty-eight women were excluded from the analyses: Two had incomplete diaries and 36 women recorded ≤1 menstruation, leaving 85 diaries eligible for analysis. Sensitivity, specificity, positive and negative predictive value and Kappa for the diagnosis of MM in clinical interview vs. headache diary were 82%, 83%, 90%, 71% and 0.62 (95% CI 0.45-0.79). Using a broader definition of MM, Kappa was 0.64 (95% CI 0.47-0.83).
A thorough clinical interview is valid for the diagnosis of MM. When this is undertaken, prospective headache diaries should not be mandatory to diagnose MM but may be necessary to exclude a chance association.
Full-text · Article · Aug 2014 · The Journal of Headache and Pain
[Show abstract][Hide abstract] ABSTRACT: Background Medication-overuse headache (MOH) is common in the general population. We investigated effectiveness of brief intervention (BI) for achieving drug withdrawal in primary care patients with MOH.
Methods The study was double-blind, pragmatic and cluster-randomised controlled. A total of 25 486 patients (age 18–50) from 50 general practitioners (GPs) were screened for MOH. GPs defined clusters and were randomised to receive BI training (23 GPs) or to continue business as usual (BAU; 27 GPs). The Severity of Dependence Scale was applied as a part of the BI. BI involved feedback about individual risk of MOH and how to reduce overuse. Primary outcome measures were reduction in medication and headache days/month 3 months after the intervention and were assessed by a blinded clinical investigator.
Results 42% responded to the postal screening questionnaire, and 2.4% screened positive for MOH. A random selection of up to three patients with MOH from each GP were invited (104 patients), 75 patients were randomised and 60 patients included into the study. BI was significantly better than BAU for the primary outcomes (p<0.001). Headache and medication days were reduced by 7.3 and 7.9 (95% CI 3.2 to 11.3 and 3.2 to 12.5) days/month in the BI compared with the BAU group. Chronic headache resolved in 50% of the BI and 6% of the BAU group.
Conclusions The BI method provides GPs with a simple and effective instrument that reduces medication-overuse and headache frequency in patients with MOH.
Trial registration number NCT01314768.
Full-text · Article · Aug 2014 · Journal of Neurology Neurosurgery & Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency.
Full-text · Article · Jun 2014 · BioMed Research International