Dutch guidance for the treatment of chronic hepatitis C virus infection in a new therapeutic era.

BACKGROUND: A new era for the treatment of chronic hepatitis C is about to transpire. With the introduction of the first-generation protease inhibitors the efficacy of hepatitis C treatment improved significantly. Since then, the therapeutic agenda has moved further forward with the recent approval of sofosbuvir and the expected approval of agents such as simeprevir and daclatasvir. This paper, developed parallel to the approval of sofosbuvir, is to serve as a guidance for the therapeutic management of chronic hepatitis C. METHODS: We performed a formal search through PubMed, Web of Science and ClinicalTrials.gov to identify all clinical trials that have been conducted with EMA-approved new agents in hepatitis C; for this version (April 2014) we focused on sofosbuvir. For each disease category, the evidence was reviewed and recommendations are based on GRADE. RESULTS: We identified 11 clinical trials with sofosbuvir and for each disease category recommendations for treatment are made. Not all disease categories were studied extensively and therefore in some cases we were unable to provide recommendations. CONCLUSION: The recent approval of sofosbuvir will most likely change the therapeutic landscape of chronic hepatitis C. The use of sofosbuvir-containing regimens can shorten the duration of therapy, increase efficacy and result in less side effects, compared with standard of care. The efficacy relative to standard of care needs to be weighed against the increased costs of sofosbuvir. With future approval of the other direct-acting antivirals, the outcome of hepatitis C treatment will likely improve further and this guidance will be updated.

The 2012 revised Dutch national guidelines for the treatment of chronic hepatitis B virus infection.

In 2008, the Netherlands Association of Gastroenterologists and Hepatologists (Nederlands Vereniging van Maag-Darm-Leverartsen) published the Dutch national guidelines for the treatment of chronic hepatitis B virus infection. New insights into the treatment of chronic hepatitis B with relevance for clinical practice have been adopted in these concise, revised guidelines. The most important changes include the choice of initial antiviral therapy, licensing of tenofovir for the treatment of chronic hepatitis B and the management of antiviral resistance.

The accumulation of Zn, Se, Cd, and Pb and physiological condition of Anadara trapezia transplanted to a contamination gradient in Lake Macquarie, New South Wales, Australia.

The benthic bivalve, Anadara trapezia, was collected from a 'clean' reference site and transplanted along a suspected trace metal contamination gradient in Lake Macquarie, NSW. At monthly intervals, Zn, Se, Cd and Pb concentrations were measured in the surficial sediments and whole tissues of the cockle as well as their physiological condition (Scope for Growth). Zinc, Cd and Pb concentrations in sediments decreased together, southward, with the highest concentrations in the Cockle Bay area, suggesting that this is the main source of contamination. Zinc, Cd and Pb concentrations were near or above [ANZECC/ARMCANZ, 2000. National water quality management strategy paper 4. Australian and New Zealand Guidelines for Fresh and Marine Water Quality, Australian and New Zealand Conservation Council and Agriculture and Resource Management Council of Australia and New Zealand. pp. 3.5.-1-3.5-10] sediment quality guidelines at Cockle Creek, Warners Bay and Koorooa Bay. Significant differences in trace metal concentrations could not be attributed to grain size or Fe concentration differences. Se concentrations were highest in fine grain Fe rich sediments of Whiteheads Lagoon, and likely to be associated with power generation operations. Trace metal concentrations did not vary significantly over time. Zinc, Cd and Pb concentrations in the tissues of A. trapezia followed a similar pattern to that of sediments. Zinc and Pb concentrations in cockles and sediments were highly correlated, indicating significant exposure-dose relationships. Selenium concentrations in the tissues of A. trapezia were higher after transplantation to the lake, however, Se concentrations were similar in all transplanted cockles, indicating that Se in contaminated sediments is not the major source of Se to organisms. There was a decline in the physiological condition of A. trapezia transplanted to Lake Macquarie after a 90-day-period with marked differences in clearance rates and respiration rates at some locations and absorption efficiencies at all locations. The mean Scope for Growth value at the most contaminated location, Cockle Bay, was markedly lower than at other locations. A significant Zn exposure-dose response relationship indicates that Zn bioaccumulation is occurring in response to sediment contamination. A significant Cd exposure-response relationship indicates that Cd may be influencing the health of cockles. Significant Pb exposure-dose, exposure-response and dose-response relationships indicate that Pb probably is affecting the health of cockles in Lake Macquarie. Therefore, Zn, Cd and Pb concentrations in sediments are likely to be affecting the health of cockles in Lake Macquarie.

Progressive improvement of impaired visual acuity during the first year after transsphenoidal surgery for non-functioning pituitary macroadenoma.

OBJECTIVE: Improvement of visual field defects continues even years after the initial surgical treatment. Because this process of continuing improvement has not been documented for visual acuity, we audited our data to explore the pattern of recovery of visual acuity until 1 year after transsphenoidal surgery for non-functioning pituitary macroadenoma. DESIGN: Retrospective follow-up study. PATIENTS: Forty-three patients (mean age 56 +/- 14 years), treated by transsphenoidal surgery for non-functioning pituitary macroadenoma, were included in this analysis. RESULTS: Visual acuity improved significantly within 3 months after transsphenoidal surgery. The mean visual acuity increased from 0.65 +/- 0.37 to 0.75 +/- 0.36 (P < 0.01) (right eye), and from 0.60 +/- 0.32 to 0.82 +/- 0.30 (P < 0.01) (left eye). Visual acuity was improved 1 year after transsphenoidal surgery compared to the 3 months postoperative values. The mean visual acuity increased from 0.75 +/- 0.36 to 0.82 +/- 0.34 (P < 0.05) (right eye), and from 0.82 +/- 0.30 to 0.88 +/- 0.27 (P < 0.05) (left eye). CONCLUSION: Visual acuity improves progressively after surgical treatment for non-functioning pituitary macroadenomas, at least within the first year after transsphenoidal surgery.

Quality of life is decreased after treatment for nonfunctioning pituitary macroadenoma.

OBJECTIVE: Although a reduced quality of life (QoL) has been reported after long-term cure of functioning pituitary adenomas, the effect of successful treatment of nonfunctioning pituitary macroadenoma (NFMA) on QoL has not been fully addressed. Therefore, we evaluated a broad spectrum of QoL parameters in patients successfully treated for NFMA in our center. DESIGN: We conducted a case-control study. PATIENTS AND METHODS: We assessed QoL in 99 adult patients (mean age, 61.9 yr; range, 24-86 yr) in remission during long-term follow-up after surgical (n = 99) and additional radiotherapeutic (n = 37) treatment for NFMA by four validated health-related questionnaires (Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index, Nottingham Health Profile, and Short Form-36). Patient outcomes were compared with 125 controls and with age-adjusted reference values derived from the literature. RESULTS: NFMA patients reported significantly impaired QoL in all questionnaires compared with the 125 controls and the age-adjusted reference values. All subscales of fatigue, assessed using the Multidimensional Fatigue Index (general fatigue, physical fatigue, reduction in activity, reduction in motivation, and mental fatigue) were impaired. The scores in the Nottingham Health Profile pointed toward reduced energy and affected emotional reaction. In several subscales of the Short Form-36 (social functioning, role limitations due to physical problems, role limitations due to emotional problems, and general health perception), NFMA patients reported a reduced QoL. CONCLUSION: QoL is considerably reduced in patients after successful treatment of NFMA.

A general solution for optimal egg size during external fertilization, extended scope for intermediate optimal egg size and the introduction of Don Ottavio 'tango'.

Egg sizes of marine invertebrates vary greatly, both within and between species. Among the proposed causes of this are a trade-off between egg size, egg number and survival probability of offspring, and a selection pressure exerted by sperm limitation during external fertilization. Although larger eggs are indeed a larger target for sperm, producing larger eggs also implies making fewer of them. There has been discussion about whether sperm limitation can (theoretically) and does (in nature) select for larger egg size than under ad libitum sperm. In one specific model, based on a particular fertilization kinetics model and an empirically derived mortality function, the theoretical possibility of a negative shift in optimal egg size with sperm concentration was demonstrated. Here we present a generalized analytical model to explore the effects of survival and fertilization probabilities on optimal egg size. It is demonstrated that incorporating fertilization kinetics greatly increases the scope for intermediate optimal egg size, as opposed to eggs of minimal or maximal size. Second, we present a general analytical qualitative solution to the question whether optimal egg size depends on sperm concentration. It is shown that, under the condition that an intermediate optimal egg size exists, this qualitative outcome of the model (positive, negative or no relation between optimal egg size and sperm limitation) depends on the structure of the fertilization kinetics part of the model. Finally, we evaluate fertilization kinetics models with respect to the general solution, using two previously published kinetics models ('Don Giovanni' and 'Don Ottavio') and a novel alteration of one of them in which sperm concentration covaries with egg concentration (Don Ottavio 'tango'). For all three models the relationship between optimal egg size and sperm concentration is shown to be always negative. This paper thus shows how biologically realistic relationships between egg size on the one hand and survival and fertilization probability on the other hand predict optimal egg size to be intermediate, and that this optimum is in general expected to increase when sperm become more limiting.

[Liver transplantation in a HIV-positive patient receiving potent antiretroviral therapy; the first case in The Netherlands]. / Orthotope levertransplantatie bij HIV-positiviteit en krachtige antiretrovirale behandeling; de eerste patient in Nederland.

In a 49-year-old woman infected with HIV who was receiving highly-active antiretroviral treatment (HAART), terminal liver failure developed. She also had an acute exacerbation of hepatitis B. She was treated by means of liver transplantation and was in good condition two years later. At that time she was treated with tacrolimus, lamivudine, tenofovir, nelfinavir and hepatitis-B immunoglobulin. HIV-RNA and the DNA of hepatitis-B virus could not be detected, her CD4-count was not abnormal and the liver transplant functioned well. No opportunistic infections had developed. HIV infection has long been considered an absolute contraindication to solid organ transplantation, due to the increased risk of infection and rapid progression to AIDS. With HAART, restoration of immune function is possible. Currently, international experience with liver transplantation for HIV-positive patients that are not infected with hepatitis C has shown promising results. Specifically, the risks of transplant rejection, opportunistic infections and progression to AIDS are not increased. Therefore, criteria have been defined for solid organ transplantation in HIV-positive recipients.

Entecavir: a potent new antiviral drug for hepatitis B.

Entecavir, a new deoxyguanine nucleoside analogue, is a selective inhibitor of the replication of the hepatitis B virus. In vitro this compound has proven to be far more effective than other nucleoside analogues. In animal models, an impressive reduction of serum viral DNA has been observed with covalently closed circular DNA and hepatitis B viral core antigen negativity in liver biopsy specimens. In clinical studies, entecavir revealed excellent suppression of hepatitis B virus replication without significant side effects or evidence of mitochondrial toxicity. Until now, no entecavir-resistant viral mutants have been described. Prolonged therapy as well as prophylactic therapy, for example, in liver transplant recipients, is feasible and not limited by breakthrough infections. Data on entecavir therapy for treatment of nucleoside-naive, wild-type hepatitis B virus is being generated in Phase III clinical trials worldwide for both hepatitis B envelope antigen-positive and -negative subpopulations, as well as in lamivudine-resistant patients. Based on mechanism and potency of interferon and entecavir, clinical trials with combination therapy are eagerly awaited.

Physiological costs of reproduction in the Sydney rock oyster Saccostrea glomerata. How expensive is reproduction?

In this study, triploid Sydney rock oysters Saccostrea glomerata, which do not reproduce and have only limited gonadal development, were used to calculate the cost of producing and maintaining somatic tissues. The consumption of oxygen was measured and converted to units of energy expended. The consumption of oxygen of diploid oysters, in different stages of the reproductive cycle, was also measured. Knowing the costs of producing and maintaining somatic tissues (obtained from the triploid oysters), it was possible to calculate the energy demand of somatic and reproductive tissues of diploid oysters. The focus of this study was to test whether this method would work, to investigate if this method would give results in accordance with modern life-history theory and to test hypotheses about costs of reproduction in oysters. It was found that in diploid oysters, 27% of the consumed oxygen was needed for reproductive processes. It was also found that the costs of production and maintenance of reproductive tissues were on average 84% of those of somatic tissues. Costs for the production and maintenance of somatic tissues decreased over time. Costs for reproduction also decreased, but were dependent on the stage of gonadal development. If the relative mass of gametes in the gonads was large, the costs were relatively small; if the mass was relatively small, the costs were large. Differences between traits of males and females were never significant, suggesting that reproductive effort and costs were similar in males and females. It was estimated that if diploid oysters did not reproduce, they could gain 64% more somatic ash-free dry mass. Thus, in terms of growth, reproduction is an expensive activity.

[Collagenous colitis: macroscopically invisible, but with various treatment options]. / Collagene colitis: macroscopisch onzichtbaar, maar niet onbehandelbaar.

Two female patients, aged 54 and 67 years, respectively, had suffered from watery diarrhoea for several weeks or months without cramps or blood in the stools. The findings upon physical examination, blood and faecal examination and endoscopy were normal, and subsequent histological examination of intestinal biopsies revealed collagenous colitis. After treatment with a high-fibre diet, sulphasalazine and either prednisone or budesonide, the symptoms subsided. Collagenous colitis is a chronic watery diarrhoea disorder with unknown aetiology and pathogenesis. It is characterised by macroscopically normal mucosa, while histopathologically an abnormal thickening of the subepithelial collagenous layer and an increase in the number of intra-epithelial lymphocytes is found. There are various treatment options such as dietary fibre, mesalazine or bismuthsubsalicylate. Recently budesonide has been found to have a favourable effect both clinically and histologically. Complications of the disease are rare.

Precipitating and aggravating factors of migraine versus tension-type headache.

OBJECTIVE: We conducted the present study to determine whether there are headache precipitating and aggravating factors that differentiate migraine from tension-type headache and headache precipitating and aggravating factors that differentiate tension-type headache from migraine. METHODS: We interviewed 38 patients with migraine and 17 patients with tension-type headache (diagnosed using International Headache Society criteria) by telephone, using a questionnaire. The questionnaire inquired about the following precipitating and aggravating headache factors: (1) physical activity, (2) straining, (3) bending over, (4) stress/tension, (5) coughing/sneezing, (6) fatigue, (7) reading, (8) driving, (9) lack of sleep, (10) specific foods/drinks, (11) alcohol, (12) not eating on time, (13) smoke, (14) smell, (15) light, (16) noise, (17) menstruation, and (18) weather. RESULTS: The most common precipitating factors acknowledged by both groups of patients were stress/tension, not eating on time, fatigue, and lack of sleep. Weather, smell, smoke, and light were the precipitating factors that differentiated migraine from tension-type headache. Excluding those factors that are part of the International Headache Society migraine diagnosis, the aggravating factors were straining, bending over, and smell. We found no precipitating or aggravating factors differentiating tension-type headache from migraine. CONCLUSION: Apparently there are precipitating and aggravating factors differentiating migraine from tension-type headache but not vice versa. It is interesting that three of the migraine-specific precipitating factors (ie, weather, smell, and smoke) involve the nose/sinus system, suggesting a greater significance of this system in headache than is generally considered.

Lamivudine-high dose interferon combination therapy for chronic hepatitis B patients co-infected with the hepatitis D virus.

Currently, the best option for patients with hepatitis delta is interferon alpha therapy for at least one year. To evaluate the effect of the combination lamivudine-high-dose interferon alpha therapy, we first treated eight patients with chronic hepatitis delta infection with lamivudine for at least 24 weeks; then lamivudine was combined with a high dose of interferon alpha followed by a regular dose (9 MU tiw). Follow-up was 12 weeks. Virological, biochemical and histological features were evaluated for response to therapy. At baseline, all patients were HBsAg positive in serum and HDV RNA-(PCR)positive in plasma; HBV DNA was undetectable with the Digene Hybrid Capture assay (limit of detection 1.5 x 10(6) geq ml-(1)) in all cases. Transaminases were elevated in all patients; median ALT 68 (range 48-143) IU l(1). Seven of eight patients completed the course; one patient with a pre-existing sickle cell trait was withdrawn from the trial due to the development of a nephrotic syndrome. The HBsAg-concentration in serum decreased in two out of seven patients (29%). However, there was no significant decrease in the HBsAg-concentration in serum during treatment (median 3654 PEU l(-1) (range 548-7,684) to 5300 PEU l(-1) (range 168-19,639)). The drop of HDV RNA in plasma from baseline during treatment was not significant. Decrease of HDV RNA was observed in three out of seven patients (43%) (median 10(5) geq ml(-1); range 10(3)-10(6) to median 10(3) geq ml(-1); range 10(2)-10(7)). Serum ALT did not change as reflected by a median of 68 IU l(-1) (range 48-143) at start of therapy to 63 IU l(-1) (range 20-171) at the end of therapy. At the end of treatment transaminases had normalised in one patient and decreased in three other patients (improvement in 57%). However, three of these four patients showed a rebound after withdrawal of therapy. The Histology Activity Index (HAI) indicated a drop from a median score of 7 (range 5-9) at baseline to 5 (range 3-8) at the end of treatment, but an increase in fibrosis from a median grade of 2 (range 1-3) at baseline to 3 (range 1-4) at the end of treatment was observed. In conclusion, this study does not yield support for the combination of an HBV suppressor and 16 weeks of high-dose interferon for therapy aimed at eradicating the hepatitis delta virus.

Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy.

Acute exacerbations of chronic hepatitis B virus (HBV) infection occur after withdrawal of lamivudine therapy in approximately 16% of patients and are considered of little clinical significance. We observed "lamivudine withdrawal hepatitis" accompanied by jaundice and incipient liver failure, but also followed by complete recovery and viral clearance. To investigate the incidence, severity, timing, and virologic characteristics of "lamivudine withdrawal hepatitis" we monitored 41 patients for at least 6 months after discontinuation of nucleoside analogue therapy. The incidence of hepatitis flares was estimated to be 7 of 41 (17%); in 2 of 41 cases (5%), hepatitis flares were associated with jaundice and incipient liver failure. A noticeable feature of the "lamivudine withdrawal hepatitis" flares were the high HBV-DNA levels at the time of the alanine transaminase (ALT) peak. All were wild-type HBV, even the one that emerged from a lamivudine-resistant strain during therapy. To minimize the risk of liver failure and to enhance the elimination of HBV following flares, lamivudine therapy was reinstituted in an icteric patient. Clinical and biochemical remission ensued, followed by loss of HBV DNA and hepatitis B e antigen (HBeAg) seroconversion. Such a virologic response did not occur in 5 other patients with a nonicteric "lamivudine withdrawal hepatitis," who were not retreated with lamivudine. Hepatitis after withdrawal of lamivudine resembles acute hepatitis B with a predominance of anicteric flares within a time frame of 6 months. Active management of hepatitis flares following withdrawal of nucleoside analogue therapy should be investigated further.

A survey of liver pathology in needle biopsies from HBsAg and anti-HBe positive individuals.

AIMS: To use laboratory data and liver biopsies, prospectively obtained from hepatitis B surface antigen (HBsAg) and anti hepatitis B e antigen (anti-HBe) positive patients, for the assessment of: (1) the relation between biopsy length/number of portal tracts and sampling error; (2) the relation between the severity of piecemeal necrosis and the new grading terminology (minimal, mild, moderate, and severe chronic hepatitis); and (3) liver pathology, which has not been studied in patients with this specific serological profile. METHODS: The study group (n = 174) included 104 patients with normal aminotransferase concentrations and no cases with clinically apparent cirrhosis. The specimen length and number of portal tracts were measured at light microscopy examination. Sampling error analysis was related to the discrepancies between aminotransferase concentrations versus histological grade. Detailed histological scorings were undertaken by the reference pathologist and compared with laboratory and hepatitis B virus (HBV) DNA precore sequence data. RESULTS: Sampling error seemed to be a constant feature, even for biopsies > or = 20 mm, but increased dramatically in biopsies < 5 mm long and/or containing less than four portal tracts. Between 25% and 30% of biopsies, graded as "mild" or "moderate" activity showed features of moderate and severe piecemeal necrosis, respectively. Ten per cent of the patients with normal aminotransferase values had stage III-IV hepatic fibrosis, and 20% had piecemeal necrosis. Only cytoplasmic, not nuclear, core antigen expression was a strong predictor of high hepatitis B viraemia. There was no association between precore stop codon mutations, grade/stage of liver disease, and hepatitis B core antigen (HBcAg) expression. CONCLUSIONS: The specimen available for light microscopical examination should be > 5 mm long and should contain more than four portal tracts. In addition, the new grading terminology might give the clinician an inappropriately mild impression of the severity of piecemeal necrosis. Furthermore, even in the presence of normal aminotransferase concentrations, considerable liver pathology can be found in 10-20% of HBsAg and anti-HBe positive individuals; such pathology is not associated with the occurrence of precore stop codon mutations.

Chronic daily headache: a time perspective.

OBJECTIVE: To determine the development and outcome of chronic daily headache in 258 headache practice patients, consisting of 50 men and 208 women. Chronic daily headache was defined as headaches occurring on at least 5 days per week for at least 1 year. METHODS: Two hundred fifty-eight patients with headache were interviewed and evaluated. Ninety-one patients were contacted by telephone for follow-up. RESULTS: Twenty-two percent of the patients had daily headaches from the onset, and 78% initially experienced intermittent headaches. Of the patients with initially intermittent headaches, 19% experienced an abrupt transition into daily headaches and 81%, a gradual one. In the patients with gradual transition, the transition of the initial, intermittent headaches into daily headaches took an average of 10.7 years. The initial headaches were mild in 33% of the patients and severe in 67%. The severe headaches were associated with nausea and vomiting significantly more often than the mild ones. However, the daily headaches that these patients ultimately developed were the same, regardless of whether the initial headaches were mild or severe. The patients who gradually developed daily headaches from initially intermittent headaches were contacted to determine the outcome of their headaches. Of these patients, 33% continued to have daily headaches and 67% again experienced intermittent headaches. Of the latter group, 88% of the patients who now had migraine also had migraine initially.

[Chronic hepatitis-b-virus infections: new options for antiviral therapy]. / Chronische hepatitis-B-virusinfecties: nieuwe mogelijkheden voor antivirale therapie.

The possibilities for antiviral treatment of patients with chronic hepatitis B virus (HBV) infections have been in flux for the last few years. Apart from interferon alpha, oral nucleoside analogues are given a place. The treatment focuses on the group of patients with active virus multiplication (hepatitis B e antigen (HBeAg) and HBV DNA are demonstrable), abnormal liver enzyme values and histologically demonstrated inflammatory activity in the liver. For the individual patient the pros and cons of protracted virus inhibition should be weighted by means of an orally administered nucleoside analogue such as lamivudine, immunostimulation with injections of interferon alpha or a combination of these two.

Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP).

Interferon alfa (IFN-alpha) is the primary treatment for chronic hepatitis B. The standard duration of IFN-alpha therapy is considered 16 weeks; however, the optimal treatment length is still poorly defined. We evaluated the efficacy and acceptability of prolonged IFN-alpha treatment in patients with chronic hepatitis B. To investigate whether treatment prolongation could enhance the rate of hepatitis B e antigen (HBeAg) seroconversion, we conducted a prospective, controlled, multicenter trial in which all patients were treated with a standard regimen of 10 million units IFN-alpha 3 times per week over 16 weeks. Patients who were still HBeAg-positive after 16 weeks of therapy were randomized to prolongation of the identical regimen up to 32 weeks (prolonged therapy) or discontinuation of treatment (standard therapy). Among the 162 patients who entered the study, 27 (17%) were HBeAg-negative after the first 16 weeks of treatment, and 118 were randomized to standard or prolonged therapy. After randomization, a response (HBeAg seroconversion and sustained hepatitis B virus [HBV]-DNA negativity) was observed in 7 of the 57 (12%) patients assigned to standard therapy versus 17 of the 61 (28%) patients assigned to prolonged therapy (P =.04). A low level of viral replication after 16 weeks of treatment, as indicated by serum HBV-DNA values under 10 pg/mL, was found to be the only independent predictor of response (52% vs. 0%; P <.001) during prolonged therapy. The prolonged IFN-alpha schedule was well tolerated in the large majority of patients. In chronic hepatitis B, prolongation of IFN-alpha therapy up to 32 weeks is superior to a standard course of 16 weeks. Those patients who exhibit a low level of viral replication at the end of the standard regimen benefit most from prolonged treatment.

High-density assessment of the IHS classification criteria for migraine without aura: a prospective study.

Fifty-six adult female patients with the clinical diagnosis of MwoA kept a diary 6 times per day for 10 consecutive weeks to record the occurrence, pain characteristics, and accompanying symptoms of headache. In order to avoid bias due to retrospection or expectancy the diary was programmed into palmtop computers which signaled the patients with a beep to enter the diary with a random-fixed time schedule: two signals occurred in, respectively, the morning, the afternoon, and the evening, but at different times for each day. The palmtop computers also warranted flawless data storage and automatic computations of response delay and missing values. Of the 339 attacks, 75% had a duration of 4-72 h and 94% confirmed the International Headache Society classification criteria for MwoA concerning pain characteristics and accompanying symptoms. Our results obtained for attacks in treated patients are highly comparable with the results of Rasmussen, Jensen, and Olesen (1991) obtained in the general population with unknown treatment of headache. Together, both studies support the IHS classification criteria for MwoA. The electronic Experience Sampling Method also allowed for an unbiased description of the course of treated MwoA attacks: 67% subsided in the first day. In the 16 attacks the characteristics and accompanying symptoms were present in 60-80% of the attacks at the first assessment (9.30 a.m.) with the exception of moderate to severe pain intensity (37%) and nausea or vomiting (31%). A waxing and waning of characteristics and symptoms over the day remained in about 30-40% of the attacks with a tendency towards increases in the evening (7.30 p.m. and 10 p.m.). The method is there for a replication of this study in untreated MwoA patients.