European Academy of Neurology guideline on the management of medication-overuse headache.

BACKGROUND: The frequent use of medication to treat migraine attacks can lead to an increase in migraine frequency and is called medication-overuse headache (MOH). METHODS: Based on the available literature in this guideline, the first step in patient management is education and counselling. RESULTS: Patients with MOH should be managed by a multidisciplinary team of neurologists or pain specialists and behavioral psychologists. Patients in whom education is not effective should be withdrawn from overused drugs and should receive preventive treatment with drugs of proven efficacy. Patients with MOH in whom preventive treatment is not effective should undergo drug withdrawal. Drug intake can be abruptly terminated or restricted in patients overusing simple analgesics, ergots or triptan medication. In patients with long-lasting abuse of opioids, barbiturates or tranquilizers, slow tapering of these drugs is recommended. Withdrawal can be performed on an outpatient basis or in a daycare or inpatient setting.

More precise phenotyping of cluster headache using prospective attack reports.

BACKGROUND AND PURPOSE: The clinical characteristics of cluster headache (CH) are based mainly on retrospective attack descriptions of 'usual' attacks, but whether these reports are reliable is uncertain. The aim was to compare retrospective and prospective attack descriptions and describe the within- and between-patient variability of attacks. METHOD: Fifty-seven CH patients underwent a semi-structured interview obtaining a retrospective account of usual CH attacks. Patients thereafter prospectively recorded the clinical characteristics of up to 10 attacks per patient in a headache diary. Four different attack characteristics were investigated: (i) severity, (ii) duration, (iii) number of autonomic symptoms and (iv) number of migrainous symptoms. Retrospective and prospective data were compared. Within- and between-patient variability of attacks was assessed. RESULTS: Retrospective attack descriptions (n = 57) were significantly longer (P = 0.046) and more severe (P < 0.0001) for untreated attacks compared with prospective reports (n = 500). The number of autonomic symptoms was significantly higher in the retrospective reports compared to the prospective reports (P < 0.0001). Within-patient variability for attack duration, pain severity and number of autonomic and migrainous symptoms was low. Compared to men, more women reported longer (P = 0.026) and more severe (P = 0.028) attacks with more migrainous symptoms (P = 0.033). CONCLUSIONS: Important differences were found between prospectively and retrospectively reported attacks with duration and severity of untreated attacks overestimated in retrospective attack descriptions. CH attacks display low within-patient variability, but the presentation of CH attacks varies between patients. The high prevalence of symptoms typically associated with migraine should raise more diagnostic awareness for CH, especially in women who are more often misdiagnosed as having migraine.

Medication-overuse headache detoxification reduces headache disability - the Akershus study of chronic headache.

BACKGROUND AND PURPOSE: Medication-overuse headache (MOH) is a chronic headache (≥15 days/month) associated with overuse of acute headache medication. The objective was to investigate headache-related disability before and after self-detoxification from MOH in the general population, as well as possible predictors for successful outcome. METHODS: This was a prospective cohort study. Participants were identified in a cross-sectional epidemiological sample of 30 000 persons aged 30-44 from the general Norwegian population. People with MOH received short information about the possible role of medication overuse in headache chronification. A total of 108 of the 128 participants (84%) were eligible for follow-up 1.5 years later. RESULTS: Using the Migraine Disability Assessment (MIDAS), people with MOH in the general population were heavily disabled (mean MIDAS score 42.1, 95% confidence interval 31.7-52.6) with a majority in the severe disability class. The MIDAS score was significantly reduced at follow-up (P < 0.001) for those with successful self-detoxification. In multivariate analyses, co-occurrence of migraine (P = 0.044) and lower headache frequency at baseline (P = 0.001) increased the odds for successful self-detoxification and reversion to episodic headache. CONCLUSION: Medication-overuse headache causes substantial disability in the general population. Self-detoxification leads to reduced headache frequency and disability, although 24% of the participants did not complete self-detoxification. Detoxification should be offered to MOH patients as early as possible with a focus on headache frequency, disability and psychological distress.

Increased infiltration and tolerised antigen-specific CD8+ TEM cells in tumor but not peripheral blood have no impact on survival of HCMV+ glioblastoma patients.

Human cytomegalovirus (HCMV) antigens in glioblastoma (GBM) present opportunities for personalised immunotherapy. However, their presence in GBM tissue is still under debate, and evidence of their impact on functional immune responses and prognosis is sparse. Here, we investigated the presence of pp65 (UL83) and immediate early 1 (IE-1) HCMV antigens in a cohort of Norwegian GBM patients (n = 177), using qPCR, immunohistochemistry, and serology. HCMV status was then used to investigate whether viral antigens influenced immune cell phenotype, infiltration, activation and patient survival. Pp65 and IE-1 were detected by qPCR in 23% and 43% of GBM patients, respectively. Furthermore, there was increased seropositivity in GBM patients relative to donors (79% vs. 48%, respectively; Logistic regression, OR = 4.05, 95%CI [1.807-9.114], P = 0.001, also when adjusted for age (OR = 2.84, 95%CI [1.110-7.275], P = 0.029). Tissue IE-1-positivity correlated with increased CD3+CD8+ T-cell infiltration (P < 0.0001), where CD8+ effector memory T (TEM) cells accounted for the majority of CD8+T cells compared with peripheral blood of HCMV+ patients (P < 0.0001), and HCMV+ (P < 0.001) and HCMV- (P < 0.001) donors. HLA-A2/B8-restricted HCMV-specific CD8+ T cells were more frequent in blood and tumor of HCMV+ GBM patients compared with seronegative patients, and donors irrespective of their serostatus. In biopsies, the HCMV-specific CD8+ TEM cells highly expressed CTLA-4 and PD-1 immune checkpoint protein markers compared with populations in peripheral blood (P < 0.001 and P < 0.0001), which expressed 3-fold greater levels of CD28 (P < 0.001 and P < 0.0001). These peripheral blood T cells correspondingly secreted higher levels of IFNγ in response to pp65 and IE-1 peptide stimulation (P < 0.001). Thus, despite apparent increased immunogenicity of HCMV compared with tumor antigens, the T cells were tolerised, and HCMV status did not impact patient survival (Log Rank3.53 HR = 0.85 95%CI [0.564-1.290], P = 0.45). Enhancing immune functionality in the tumor microenvironment thus may improve patient outcome.

Lasting improvement of medication-overuse headache after brief intervention - a long-term follow-up in primary care.

BACKGROUND AND PURPOSE: Withdrawal therapy improves the headache situation for many patients with medication-overuse headache (MOH), but relapses are common. The objective was to assess the long-term effectiveness of a general practitioner conducted brief intervention (BI) for MOH. METHODS: Sixty MOH patients initially participating in a blinded cluster-randomized controlled trial evaluating BI versus business as usual (BAU) were followed up for 16 months. Follow-up was open after 6 months. Headache and medication days per month were evaluated in three groups: BI early (BI throughout the study, n = 24), BI late (initial BAU, then cross-over to BI, n = 22) and BAU throughout the study (n = 14). RESULTS: Fifty-five of 60 initially included patients completed the follow-up. The mean change over 16 months' observation in the BI early group was a reduction of 8.4 (5.4-11.4) headache and 13.5 (9.6-17.3) medication days per month. The relapse rate into medication overuse was 8.3%. Patients in the BI late group also improved significantly after a BI. BAU showed no significant improvement. CONCLUSIONS: Treatment for MOH in primary care through a BI is a simple intervention with lasting effects and low relapse rate. This approach may be a logical first step in MOH treatment, and referral should generally be reserved for primary care non-responders.

Predictors of successful primary care detoxification treatment for medication-overuse headache.

OBJECTIVES: To investigate predictors for successful treatment outcome after a brief intervention (BI) for medication-overuse headache (MOH). MATERIALS AND METHODS: This study evaluated predictors of successful withdrawal among patients initially participating in a pragmatic cluster-randomized controlled trial with single crossover in Norwegian general practice (the BIMOH study). BI (early or after crossover) was compared to business as usual (BAU) for the treatment of MOH. Patients were followed up 3 months after the BI. RESULTS: In total, 46 patients had the chance to receive the BI (24 early and 22 after crossover) and were included in the predictor analyses. The mean reduction in headache and medication days/month from baseline for the BI was 6.9 (95% CI: 4.8-9.1) and 10.9 (8.1-13.6). The mean percentage reduction in headache and medication days was 30.5% (21.4-39.7) and 50.4% (39.5-61.3). Only five patients started prophylactic medication. Neither age, gender, co-occurrence of migraine, main type of overused drug at baseline nor Severity of Dependence Scale score at baseline predicted successful withdrawal in the prespecified analyses. Headache days/month and medication use at baseline were significant predictors in exploratory analyses with more headache and medication days predicting worse outcome. CONCLUSIONS: Brief intervention for MOH is a simple and effective intervention in primary care. As the only identified predictors were frequency of headache and medication use, we conclude that treatment for all MOH patients should be attempted in primary care before referral. A raised awareness of MOH is important, as the condition is highly preventable and treatable. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01314768.

Disability, anxiety and depression in patients with medication-overuse headache in primary care - the BIMOH study.

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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Reduced Number of CD8+ Cells in Tonsillar Germinal Centres in Children with the Periodic Fever, Aphthous Stomatitis, Pharyngitis and Cervical Adenitis Syndrome.

The syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is an autoinflammatory disorder of unknown aetiology. Tonsillectomy may cause a prompt resolution of the syndrome. The aim was to study the histologic and immunological aspects of the palatine tonsils in PFAPA, to help understand the pathophysiology of the syndrome. Tonsils from children with PFAPA (n = 11) and children with tonsillar hypertrophy (n = 16) were evaluated histologically after haematoxylin and eosin staining. The number of different cell types was identified immunohistochemically by cluster of differentiation (CD) markers: CD3 (T cells), CD4 (T helper cells), CD8 (cytotoxic T cells), CD15 (neutrophils), CD20 (B cells), CD45 (all leucocytes), CD57 (NK cells) and CD163 (monocytes and macrophages). Tonsils from children with PFAPA showed reactive lymphoid hyperplasia dominated by well-developed germinal centres with many tingible body macrophages. The histologic findings were unspecific, and a similar morphologic appearance was also found in the tonsils from controls. The number of CD8+ cells in germinal centres differed between children with PFAPA [median 9 cells (quartiles: 5, 15)] and controls [18 cells (12, 33) (P = 0.001)] and between children with PFAPA with (median 14 cells; 9, 16) and without (4 cells; 3, 8) aphthous stomatitis (P = 0.015). For the other cell types, no differences in germinal centres were found between children with PFAPA and controls. In conclusion, a lower number of CD8+ cells were found in germinal centres of tonsils in children with PFAPA compared to controls, which may be a feature linked to the aetiology of the syndrome.

Severe human Babesia divergens infection in Norway.

Human babesiosis is a rare but potentially life-threatening parasitic disease transmitted by ixodid ticks, and has not previously been reported in Norway. We report a case of severe babesiosis that occurred in Norway in 2007. The patient had previously undergone a splenectomy. He was frequently exposed to tick bites in an area endemic for bovine babesiosis in the west of Norway. The patient presented with severe haemolysis and multiorgan failure. Giemsa-stained blood smears revealed 30% parasitaemia with Babesia spp. He was treated with quinine in combination with clindamycin, apheresis, and supportive treatment with ventilatory support and haemofiltration, and made a complete recovery. This is the first case reported in Norway; however Babesia divergens seroprevalence in cattle in Norway is high, as is the risk of Ixodes ricinus tick bite in the general population. Babesiosis should be considered in the differential diagnosis of unexplained febrile haemolytic disease.

Hyperleukocytosis and leukocytapheresis in acute leukaemias: experience from a single centre and review of the literature of leukocytapheresis in acute myeloid leukaemia.

BACKGROUND: Hyperleukocytosis is usually defined as leukocyte count >100 × 10(9) L(-1) and can be seen in newly diagnosed leukaemias. Hyperleukocytic leukaemia is associated with a risk of organ failure and early death secondary to leukostasis. Mechanical removal of leukocytes by the apheresis technique, leukocytapheresis, is a therapeutic option in these patients. METHODS: During a 16-year period, 16 patients were treated with leukocytapheresis (35 apheresis procedures) for hyperleukocytosis/leukostasis. We present our experience, and in addition we review previous studies of hyperleukocytosis/leukocytapheresis in patients with acute myeloid leukaemia (AML). RESULTS: We used a highly standardised approach for leukocytapheresis in leukaemia patients with hyperleukocytosis. The average leukocytapheresis number for each patient was 2·2 (range 1-6). Median leukocyte count before apheresis was 309 × 10(9) L(-1) (range 104-935); the mean leukocyte count reduction was 71%, corresponding to a mean absolute reduction of 219 × 10(9) L(-1). No serious side effects were seen during or immediately after apheresis. CONCLUSIONS: The data suggest that our standardised technique for leukocytapheresis effectively reduced the peripheral blood leukaemia cell counts. Previous studies in AML also support the conclusion that this is a safe and effective procedure for the treatment of a potentially life-threatening complication, but apheresis should always be combined with early chemotherapy.

Pandemic influenza vaccination elicits influenza-specific CD4+ Th1-cell responses in hypogammaglobulinaemic patients: four case reports.

In these case reports, we investigated pandemic influenza 2009 vaccination of primary hypogammaglobulinaemic patients. Three combined variable immunodeficiency (CVID) patients and one X-linked agammaglobulinaemia (XLA) patient were vaccinated with the pandemic vaccine A/California/7/2009 (H1N1)-like split virus (X179a) adjuvanted with the oil-in-water emulsion AS03. Subsequently, serum and peripheral blood mononuclear cells were sampled and used to measure the haemagglutination inhibition (HI) and antibody-secreting cell (ASC) responses. In addition, the IFN-γ, IL-2 and TNF-α producing CD4(+) Th1-cell response was determined as these cytokines are important indicators of cell-mediated immunity. Two of the CVID patients responded to vaccination as determined by a >4-fold rise in HI antibodies. These subjects also had influenza-specific ASC numbers, which, albeit low, were higher than prevaccination levels. In addition, vaccination induced CD4(+) Th1-cell responses in both the XLA patient and the CVID patients, although the frequency of influenza-responsive cells varied amongst the patients. These results suggest that hypogammaglobulinaemia patients can mount a CD4(+) Th1 cell-mediated response to influenza vaccination and, additionally, that influenza vaccination of some hypogammaglobulinaemia patients can produce an influenza-specific humoral immune response. The findings should be confirmed in larger clinical studies.

Quantification of S100A12 (EN-RAGE) in blood varies with sampling method, calcium and heparin.

S100A12 is a calcium-binding protein predominantly found in neutrophil granulocytes and monocytes. Its usefulness in monitoring inflammatory disease states depends on documentation that assay results are reliable. This study aimed at defining guidelines for blood sampling, selection of optimal material handling and reference intervals in healthy controls while taking into account the basic features of S100A12. An enzyme linked immunosorbent assay was developed based upon antibodies induced in rabbits by injection of recombinant S100A12. Our studies confirm that oligomers of S100A12 are generated in the presence of calcium. Structural changes in S100A12 mediated by calcium influence the interaction with antibody. This is proposed as the background for our very low readings of S100A12 in Ethylene Diamine Tetraacetic Acid (EDTA) plasma. Individual S100A12 levels did not change substantially over a 5-week sampling period. Based upon testing of 150 blood donors we suggest reference intervals of S100A12 in serum to be 49-1340 microg/l for women and 27-1750 microg/l for men. The estimated mean concentrations were 234 microg/l in serum samples (range 12-15791), 114 microg/l (range 3-17282) in re-calcified EDTA plasma and 48 microg/l (range 2-14843) in heparin plasma. Without adding calcium to EDTA plasma before running the assay, concentrations were around 2 microg/l (16 persons). S100A12 quantification is assumed to become relevant for diagnostic use in many disease states. The importance of the handling and analysing conditions for a reliable result was examined. We recommend serum collected in gel-containing tubes as the preferred sample material and have suggested reference intervals for healthy individuals.

Placental expression of glycophosphatidylinositol (GPI)-anchored proteins in paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal stem cell disorder in which a defect of glycophosphatidylinositol (GPI)-anchored proteins leads to higher morbidity and mortality because of intravascular haemolysis, haemoglobinuria, pancytopenia and an increased frequency of thrombotic events. We report here the clinical features of a pregnant woman with PNH and present an immunhistochemical analysis of complement regulators, leukocyte activation markers and placental alkaline phosphatase (PALP) on syncytiotrophoblasts and inflammatory cells in her placenta. Placental tissue from normal deliveries served as controls. The patient had severe PNH with haemolysis, thrombosis episodes and signs of bone marrow failure. Placental syncytiotrophoblasts and villous cells of fetal origin in both normal placentas and the placenta from the PNH patient expressed PALP and the complement regulators CD46, CD55 and CD59. Additionally, CD11b-positive leukocytes of presumed maternal origin were negative for CD15 in the PNH placenta, while they stained positive within the villous space and in normal placentas. These findings show that fetally derived cells in the PNH placenta expressed GPI-linked molecules that are known to be of importance for a successful pregnancy outcome.

Tetanus immunity among pregnant women attending antenatal care in Dar es Salaam, Tanzania.

This study was conducted to investigate immunity to tetanus among pregnant women with verbal histories or documentation of having been vaccinated under the current five-dose tetanus toxoid (TT) schedule. It examined sera from 176 pregnant women attending antenatal care at Muhimbili Medical Centre in Dar es Salaam, Tanzania. Tetanus antitoxin level of 0.1 IU/ml was considered protective. Our findings show that 94.9% of women had tetanus antitoxin > or = 0.1 IU/ml. Multivariate analysis revealed that time after last vaccination, TT doses received and TT vaccination status explained 7.5%, 5.7% and 2.3% of variations in tetanus antitoxin levels respectively. Pregnant women with non-protective levels of tetanus antitoxin (5.1%) pose great risks of neonatal tetanus to their newborns and are also susceptible to maternal tetanus. Proper keeping of TT vaccination records is vitally important to avoid hyper-immunisation.

Immunity to tetanus in male adults in Dar es Salaam, Tanzania.

OBJECTIVE: To determine immunity to tetanus in male blood donors with previous diphtheria-pertussis-tetanus (DPT)/tetanus toxoid (TT) vaccination. DESIGN: A cross sectional study, conducted in September 1999. SETTING: Blood bank, Muhimbili Medical Centre, Dar es Salaam, Tanzania. METHODS: Using an antigen competition ELISA technique, serum tetanus anti-toxin levels in two hundred male blood donors were determined. RESULTS: Vaccination history was absent in 43 (21.5%) blood donors, whereas 60 (30%) and 97 (48.5%) reported childhood DPT and TT vaccination, respectively. Tetanus anti-toxin was undetectable in 47 (23.5%) blood donors and the levels were below that considered protective (> or = 0.1 IU/ml) in 25 (12.5%). Among those with undetectable level, 43 (91.5%) had no vaccination history. Time after last DPT/TT vaccination correlated significantly with tetanus anti-toxin levels (r2=-0.331, p=0.001). In multivariate analysis, TT doses received and time after last vaccination explained 4.8% and 29.4%, respectively, of the variations in tetanus anti-toxin levels. CONCLUSION: Seventy two (36%) male blood donors were susceptible to tetanus and the susceptibility was highest from 48 years. A regular TT booster dose at 10 yearly intervals is recommended to provide adequate and long lasting immunity in male adults. Proper keeping of vaccination records is emphasised.

Diagnostic and biological significance of anti-p41 IgM antibodies against Borrelia burgdorferi.

We performed a prospective study to investigate the biological significance and diagnostic specificity of anti-p41 immunoglobulin (Ig)M antibodies against Borrelia burgdorferi. During a 1-year interval 2403 patients were referred to our department for B. burgdorferi serology. Sixty-three patients had repetitive positive tests for IgM anti-p41 antibodies and negative tests for anti-p41 IgG antibodies. Ten of the 63 patients recently had symptoms of erythema migrans. A confirmatory IgM Western blot gave a positive reaction in 5 patients out of 53 patients with little or no clinical evidence of B. burgdorferi infection. The remaining 48 patients were negative in this test and were considered as false-positives. Two whole cell enzyme-linked immunosorbent assay (ELISAs), two immunofluorescence assays and Western blotting were not useful as confirmatory tests. Sera from 330 blood donors and 72 cord sera were also screened for anti-p41 IgM. Five blood donor sera and five cord sera showed an IgM reactivity against p41. Based on our data we hypothesize that up to 1.5% of the population may have natural IgM antibodies against p41 in their sera. We observed that six out of nine sera with such antibodies could immobilize a B. afzelii reference strain in vitro. Whether anti-p41 IgM antibodies are capable of inactivating infective spirochetes and thereby prevent infection in vivo is, however, not yet clarified. The paradoxical conclusion that anti-p41 IgM antibodies may be a sign of resistance to infection rather than a sign of infection should be given consideration.

Antibodies to tetanus toxoid in women of childbearing age in Dar es Salaam and Bagamoyo, Tanzania.

Our aim was to determine tetanus immunity in women of childbearing age (15-44 years) with histories and/or documentation of having been vaccinated with Tetanus Toxoid (TT) under the Expanded Programme on Immunization in Dar es Salaam and Bagamoyo, Tanzania. Using an ELISA technique, serum levels of TT antibody, antibody avidity and distribution of TT IgG subclass antibodies were determined in 207 apparently healthy women. A TT antibody level of 0.1 IU/ml was considered protective. 99% and 100% of women in Dar es Salaam and Bagamoyo, respectively, had a TT antibody level > or = 0.1 IU/ml. Anti-toxin binding avidity was found to be high in most of the women. In addition to TT IgG3 subclass antibody, TT IgG1 subclass antibody was the most dominant subclass type. A substantial number of women also had TT IgG2 and TT IgG4 subclass antibody responses. A better recording system on TT immunization is recommended to avoid hyper-immunization of women and to optimize the cost-effectiveness of the immunization programme.