This international open‐label study evaluated the tolerability and efficacy of zolmitriptan (Zomig®, 311C90), a selective 5‐HT1B/1D receptor agonist in the long‐term treatment of multiple migraine attacks. Patients who had previously participated in placebo‐controlled zolmitriptan studies were recruited. A total of 2058 patients treated 31 579 migraine attacks (average 15 per patient), for up to 1 year. Twenty‐six percent of attacks treated with a single zolmitriptan 5‐mg dose were associated with at least one adverse event (24% treated with two doses). The most frequent adverse events induded asthenia (14% of patients), nausea (12%), somnolence (10%), dizziness (11%), and paresthesia (11%). The rank order of the most common adverse events was not influenced by sex, age, or number of zolmitriptan doses taken and was similar between attacks 1 and 45. The majority of adverse events (59%) occurred within 2 hours of dosing, were of either mild (59%) or moderate (35%) intensity, of 4 hours' duration or less (67%), and required no further action (94%).Following an initial 5‐mg dose of zolmitriptan, the 2‐hour headache response rate (reduction in headache pain from moderate or severe before treatment to mild or no pain at 2 hours posttreatment) was 81% in patients treating moderate and severe attacks (19 639 of 24 161). Patients were pain‐free at 2 hours in 55% of all attacks (16 510 of 29 808). The efficacy of zolmitriptan was not influenced by age, sex, weight, use of prophylactic antimigraine medication, or association of attacks with menstruation. Analysis of the overall population and a subgroup who treated 30 or more migraine attacks showed that zolmitriptan was consistently effective across attacks. Overall, 67% of patients who treated five or more attacks reported zolmitriptan to be effective in 80% to 100% of attacks. Zolmitriptan produced meaningful migraine relief and improvement in normal activity impairment in 73% and 78% of moderate and severe attacks, respectively. Patients treated recurrence of moderate or severe headache with a second zolmitriptan dose in 32% of attacks which responded to the first dose within 2 hours. Where required, a second zolmitriptan 5‐mg dose for treatment of recurrence produced a headache response rate of 90% at 2 hours postdose. Thus, zolmitriptan 5 mg (plus an optional second 5‐mg dose for treatment of recurrence) is well tolerated and effective in the acute treatment of multiple migraine attacks over periods up to 1 year.

Amitriptyline is the medication of first choice in the treatment of chronic tension-type headache. In 197 patients with chronic tension-type headache (87M and 110F with a mean age of 38 ±13 (18–68)) efficacy and tolerability of 60–90 mg amitriptylinoxide (AO) were compared with 50–75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of a four weeks' baseline phase and 12 weeks of treatment. The primary study endpoint was a reduction of at least 50% of the product of headache duration and frequency and a reduction of at least 50% in headache intensity. Statistics used were Fisher's exact test and analysis of variance. No significant difference emerged between AO, AM and PL with respect to the primary study endpoint. Treatment response occurred in 30.3% of the AO, 22.4% of the AM and 21.9% of the PL group. A reduction in headache duration and frequency of at least 50% was found in 39.4% on AO, in 25.4% on AM and in 26.6% on PL (PAO-PL = .1384, PAM-PL = 1.000, PAO-AM = .0973). A reduction in headache intensity of at least 50% was found in 31.8% on AO, in 26.9% on AM and in 26.6% on PL (PAO-PL = .5657, PAM-PL = 1.000, PAO-AM = .5715). Trend analysis with respect to a significant reduction of headache intensity ( p < 0.05) and the product of headache duration and frequency revealed a superior effect of AO. Adverse events occurred in 75.8% on AO, 82.1% on AM and 76.6% on PL (PAO-PL = 1.000, PAM-PL =.5188, PAO-AM = .4017). Neither depressive symptoms, measured by the SCL-90-R, nor study drug-related adverse events had any influence on the results.

Matters arisingshift from ocular to generalised myasthenia gravis was a more common feature of anti-AChR antibodies-positive myasthenia gravis (14 of 28 patients, 50%) than that of seronegative myasthenia gravis (one of five patients, 20%).Subsequent to a follow-up period of more than one year, the group of anti-AChR antibodies-negative patients consisted of four (3%) ocular cases and 10 (7%) generalised cases.Consequently, I am unable to confirm Toyka's observation of only 45% anti- AChR antibodies-positive cases in long- standing ocular myasthenia gravis.Toyka also suggests that cases with questionable myasthenia gravis may have been included in the analysis of generalised myasthenia gravis' resulting in lower estimates of the sensitivity relating to such cases.This is a very unlikely explanation in view of the scrutiny of all cases including clinical assessment by an experienced examiner, all of which is thoroughly expounded in my article' and also in my epidemiological study.

Tricyclic antidepressants, especially amitriptyline, are the medication of first choice in the treatment of chronic tension headache. Few previous studies meet modern standards of study design and statistical analysis. Tolerability and efficacy of 60-90 mg amitriptyline oxide (AO) as a single dose in the evening were compared with 50-75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of a 4-week baseline phase and 12 weeks of treatment. The 3-armed study was conducted in 7 centers. The inclusion criterion was tension-type headache on at least 15 days monthly with a duration of at least 6 months. Exclusion criteria were a migraine history, previous participation in another clinical trial within the last 3 months, drug abuse, medication with other antidepressants or tranquilizers, current use of other acknowledged prophylactic headache medication, lack of compliance, major psychiatric disorder according to DSM-III and medical contra-indications against tricyclic antidepressants. The primary study endpoint was a reduction at least 50% of the product of headache duration and frequency and a reduction at least 50% in headache intensity. Statistics used were Fisher's Exact Test and an analysis of variance. A total of 211 patients were included in this trial. One hundred ninety-seven cases, 87 males and 110 females, with a mean age of 38+/-13 (18-68) years, could be analysed completely (66 AO, 67 AM, 64 PL). With regard to the strictly defined primary study endpoint, no significant difference emerged between AO, AM and PL: treatment responders were 30.3% with AO, 22.4% with AM and 21.9% with PL (p(AO-PL)=0.3210, p(AM-PL)=1.000, p(AO-AM)=0.3299 respectively). A reduction in headache duration and frequency of at least 50% was found in 39.4% under AO, in 25.4% under AM and in 26.6% under PL (p(AO-PL)=0.1384, p(AM-PL)=1.000, p(AO-AM)=0.0973). A reduction in headache intensity of at least 50% was found in 31.8% under AO, 26.9% under AM and in 26.6% under PL (p(AO-PL)=0.5657, p(AM-PL)=1.000, p(AO-AM)=0.5715). Trend analysis revealed a superior effect of AO with respect to a significant reduction (p<0.05) of headache intensity or the product of headache duration and frequency. Adverse events occurred in 75.8% under AO, 82.1 % under AM and 76.6% under PL (p(AO-PL)=1.000, p(AM-PL)=0.5188, p(AO-AM)=0.4017). Neither depression, measured by SCL-90-R, nor study drug-related adverse events had any influence on the results.

Tricyclic antidepressants, especially amitriptyline, are the medication of first choice in the treatment of chronic tension headache. Few previous studies meet modern standards of study design and statistical analysis. Tolerability and efficacy of 60-90 mg amitriptyline oxide (AO) as a single dose in the evening were compared with 50-75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of a 4-week baseline phase and 12 weeks of treatment. The 3-armed study was conducted in 7 centers. The inclusion criterion was tension-type headache on at least 15 days monthly with a duration of at least 6 months. Exclusion criteria were a migraine history, previous participation in another clinical trial within the last 3 months, drug abuse, medication with other antidepressants or tranquilizers, current use of other acknowledged prophylactic headache medication, lack of compliance, major psychiatric disorder according to DSM-III and medical contra-indications against tricyclic antidepressants. The primary study endpoint was a reduction at least 50% of the product of headache duration and frequency and a reduction at least 50% in headache intensity. Statistics used were Fisher's Exact Test and an analysis of variance. A total of 211 patients were included in this trial. One hundred ninety-seven cases, 87 males and 110 females, with a mean age of 38 +/- 13 (18-68) years, could be analysed completely (66 AO, 67 AM, 64 PL). With regard to the strictly defined primary study endpoint, no significant difference emerged between AO, AM and PL: treatment responders were 30.3% with AO, 22.4% with AM and 21.9% with PL (PAO-PL = 0.3210, PAM-PL = 1.000, PAO-AM = 0.3299 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

In a cross-over design, six healthy volunteers received 50 mg amitriptylinoxide (AT-NO) IV and orally and 50 mg amitriptyline (AT) IV. Urine was collected completely for 8 h and occasionally up to 48 h. In addition, five patients each under treatment with AT-NO or AT for tension headache collected 24-h urine samples. The following compounds were analysed by HPLC: AT-NO, E- and Z-10-hydroxy-AT-NO (E- and Z-10-OH-AT-NO), free and conjugated AT, E- and Z-10-OH-AT and their mono- and didemethylated analogues, and 2-OH-nortriptyline (2-OH-NT). Unchanged AT-NO in urine accounted for an average of 34% and 22% of the single IV and oral doses, respectively, and for 28% in continuous therapy, with a further 8-9% being excreted as E- and Z-10-OH-AT-NO. The remaining part was converted to the same metabolites as was AT. In the steady state the measured compounds accounted for 74% and 77% of the daily AT-NO and AT doses, respectively. The renal plasma clearance of AT-NO varied between 75 and 265 ml/min in the six volunteers. Tubular secretion must play an important part in the renal excretion of AT-NO.

Compound muscle action potentials (CMAPs) were recorded from anterior tibial (TA) and soleus (SOL) muscles following transcranial magnetic stimulation of motor cortex in 10 healthy subjects: (1) while standing upright without support, (2) while sitting, and (3) while lying supine. The results of this study demonstrate a significant influence of posture upon the amplitudes of CMAPs. Postural facilitation presented itself, firstly, in terms of a higher incidence of bilateral activation of distal leg muscles during stance and, secondly, as significant enhancement of the amplitude of CMAPs while standing as compared to lying supine. The onset latency, however, did not disclose a significant shortening during stance. To assess the effects of preinnervation subjects voluntarily adjusted the level of TA activity to 5%, 10% and 20% of maximum isometric force respectively before cortex stimulation. Voluntary background contraction resulted in a significant increase of amplitude of CMAPs but, in contrast to postural facilitation, concomitant with a significant decrease in onset latency. These results point to a somewhat different mechanism of facilitation during stance as compared to voluntary preinnervation. But it cannot be decided whether cortical mechanisms, different descending systems, the spinal circuitry or a combination of these factors is responsible for the observed effects.

The aim of the present study was to ascertain, on the basis of single case statistics and time-series analysis, responder and non-responder rates for metoprolol, propranolol and nifedipine in migraine prophylaxis. In addition, an attempt was made to identify the dose relationship for the various drugs on headache parameters. In a double-blind dose-finding study, 58 patients were treated in five consecutive dosage steps each lasting 1-3 months. All patients kept a headache diary before, during and after treatment. Serum drug levels were also determined. The data were assessed by time-series analysis, as well as by multiple regression and analysis of variance. A significant improvement was noted in 54.4% of patients with migraine during treatment with metoprolol. The study did not confirm the high success rates in migraine prophylaxis of nifedipine and propranolol quoted in the literature. Administration of nifedipine led to an increase in migraine attacks in 71% of the patients. Nifedipine was of no value in the prophylaxis of migraine. Only 32% of patients showed a reduction in frequency of migraine attacks during administration of propranolol. The analysis of variance failed to show any significant difference between the responder rates for metoprolol and propranolol. Higher doses of propranolol and metoprolol were more effective. Multiple regression analysis explained a considerable part of variance for propranolol (but not for metoprolol) as a result of reduced intake of ergotamine preparations and analgesics. It can therefore be concluded that part of the prophylactic effect of propranolol is attributable to a reduction in the use of migraine medication.

Headache characteristics are described in 139 patients with chronic daily or almost daily headaches due to regular intake of analgesics and the short- and long-term results of drug withdrawal. Drug-induced headache was described as dull, diffuse, and band-like, and usually started in the early morning. The mean duration of the original headache (migraine or tension headache) was 25 years; regular intake of drugs and chronic daily headache had started 10 and 6 years prior to withdrawal therapy, respectively. Patients took an average of 34.6 tablets or analgesic suppositories or antimigraine drugs per week containing 5.8 different substances. The drugs most often used were caffeine (95%), ergotalkaloids (89%), barbiturates (64%), and spasmolytics, paracetamol, and pyrazolone derivates (45%–46%). A total of 103 patients (68 migraine, 35 tension or combination headache) were available for interviews at a mean time interval of 2.9 years after an inpatient drug withdrawal programme. Chronic headache had disappeared or was reduced by more than 50% in two-thirds of the patients. Positive predictors for successful treatment were migraine as primary headache, chronic headache lasting less than 10 years, and regular intake of ergotamine. Drug intake was significantly reduced and patients used single substances more often. Patients who originally suffered from migraine, superimposed on the daily headache, also experienced a significant improvement in the frequency of the migraines and their intensity. Migraine prophylaxis through beta-blocking agents and calcium channel antagonists was more efficient after drug-withdrawal therapy.

A new method is described that allows continuous quantification of parkinsonian and essential tremor over a period of up to 24 h on the basis of surface EMG recording from antagonistic forearm muscles. Tremor extraction from EMG data and all other calculations are performed on a digital computer. The occurrence, intensity and frequency of tremor are calculated. The data evaluation is fully automatic, including quality control and elimination of artifacts. Since tremor changes considerably over a 24 h period, long-term quantification gives more reliable data to study diurnal variations and to control the effects of medical treatment on tremor. As an additional advantage tremor recording is not restricted to a laboratory environment. Tremor can be monitored under everyday conditions and in the presence of moderate voluntary EMG activity.

Long-term recording is able to detect small amounts of low intensity tremor, which due to its intermittent manifestation may be missed during the routine clinical examination. Examples are given from patients with an established diagnosis of Parkinson’s disease in whom tremor could be observed only under special conditions, such as mental or emotional stress, or was just reported by the patient but could not be observed by the examiner. For reevaluation, data sample epochs classified by the automatic analysis as exhibiting tremor can be stored and visually inspected. Problems may arise with the diagnostic classification of tremor based on its frequency, since a considerable variation in frequency is observed in long-term recordings from parkinsonian patients. This may partially originate from the otherwise very advantageous fact that subjects are not restricted to a fixed position of the arms but are recorded under every day conditions.

The cerebellum is known to play a role in simple associative motor learning in animals. It has recently been suggested that the cerebellum might also contribute to cognitive abilities in humans. Therefore 5 patients with either cerebellar lesions or atrophy were compared with 10 controls on a range of intellectual and learning abilities

The present study used recordings of visual potentials evoked by pattern reversal (VEPs) to investigate the central effects of three drugs used in migraine prophylaxis: the calcium channel blocker nifedipine, the beta-1-selective blocker metoprolol, and the nonselective beta adrenoreceptor blocker propranolol. The study involved 58 patients with common or classical migraine who were treated in a double-blind randomized study over a period of 7 months, while the effectiveness of prophylactic treatment was recorded in headache diaries that were subjected to time series analysis. VEPs were recorded at the beginning of a 2-month baseline period without treatment, after 4 months of treatment, and at the end of a 3-month washout period. At baseline, migraine patients had significantly higher VEP amplitudes and longer latencies than did a group of 87 healthy control subjects. Patients were separated by statistical analysis into responders and nonresponders to each prophylactic treatment. Nifedipine had no effects on the frequency, intensity, and duration of migraine attacks, nor on amplitude and latency of the VEPs. In contrast, the use of beta blockers resulted in a significant decrease in VEP amplitude, both in responders and nonresponders, whereas VEP latency remained unchanged. VEP amplitudes returned to the initial values at follow-up in the nonresponders, but stayed at lower levels in responders. Beta blockers thus appear to have a significant effect on the increased excitability of the visual system in patients with migraine, although their action is not directly related to their reduction of migraine frequency.

It has often been argued that migraine patients suffer from predispositional orthostatic dysregulation in the circulation (Raskin & Appenzeller 1980). Some authors assumed that constitutional hypotonia could be one etiological factor in migraine (Heyck 1975). According to these assumptions and clinicalobservations it has been supposed that pharmacological interventions which are directed to a stabilization of the othostatic dysregulation counteract the lack of perfusion of cerebral vessels (Berde & Stuermer, 1978). Some authors reported significant improvements of prophylatic antihypotonic treatment with dihydroergotamine in migraine patients (Martucci et al., 1983). Etilefrinepivalate is an antihypotensive drug which in moderate doses exerts little effect on the arterial resistance (Jansen et al., 1985). It has been reported that etilifrinepivalate significantly reduced migraine attacks in accordance with an increase of blood pressure (Cruz et al., 1985). Flunarizine has shown to be one of the effectivenessly substance in migraine prophylaxis (e.g. Diamond & Schenbaum 1983). The aim of the present study was to compare these both drugs in the prophylatic treatment of migraine. based on antihypotonic 30 migraine patients with and without aura symptoms were treated in a double-blind "placebo-randomized" study. After a 6 weeks baseline period all patients obtained placebo medication for 4 weeks. Subsequently to this period the patients were subdivided into "high placebo responder" and "low placebo responder" groups and randomly assigned by their placebo effects to the treatment groups flunarizine and etilefrinepivalate. Thus both groups contained the same placebo source of variance. During the randomization period (2 weeks) no prophylactic medication was allowed. Flunarizine (10 mg/die) and etilefrinpivalate (20mg/die) were given for 3 months. A follow up period of 6 weeks finished the study. All patients kept headache diaries which contained ratings in regard to migraine attacks, headache duration and intensity, daily mood and the consumption of acute medications. The diaries were analyzed by convential, statistics and time series analysis. During baseline, placebo period and twice during treatment period schellong tests were carried out (diastolic and systolic blood pressure, heart rates) and analyzed by ANOVA.

Ergotamine preparations were used in the treatment of migraine attacks for the first time at the turn of this century. Between 1934 and 1946, Horton and coworkers performed several studies on the action of ergotamine, dihydroergotamine, and combinations with caffeine and barbiturates in the treatment of acute migraine attacks (Logan and Allen 1934; Horton et al. 1945, 1948; Peters 1953; Horton 1961). But already in 1951 (Peters and Horton 1951) and in a more extended study in 1963 (Horton and Peters 1963), the authors realized that patients with periodic headache (migraine and tension headache) who had used excessive amounts of ergotamine preparations for prolonged periods not only developed signs of ergotamine intoxication (vasospastic disturbances in the extremities, peripheral neuropathy), but in addition they also developed chronic headache.

Although the clinical problem of chronic daily headache induced by chronic intake of ergotamine tartrate and/or analgesics is known to clinicians (Lippman 1955; Horton et al. 1963; Rowsell et al. 1973; Wainscott et al. 1974; Andersson 1975; Ala-Hurula et al. 1982; Kudrow 1982; Saper 1983; Dichgans et al. 1984), no information is as yet available about the dosages of different drugs necessary to provoke this response. The patients’ histories show a gradual increase in frequency and dose of drug intake, eventually ending in daily administration of high dosages. It is unknown whether the daily intake itself or the drug dosage plays the crucial role.

A new method of prolonged recording of EMG provides a good estimate of spontaneous and induced diurnal variations in resting tremor in Parkinson's disease. It provides a record and a measure of the effects of treatment. Tremor intensity shows considerable variations even over short periods of time. Therefore short-term measurements of tremor are unhelpful. Long-term recordings agree better with the patient's assessment than with the clinical rating score. Repeated recordings over a similar 10-h period on 3 consecutive days in one patient showed fairly constant measures of occurrence and intensity of tremor. In contrast to accelerometer measurements of tremor, artefacts caused by movements and general activity of the patient do not materially interfere with tremor evaluation using surface EMG.