Early Magnesium Treatment After Aneurysmal Subarachnoid Hemorrhage: Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Trials of magnesium treatment starting <4 days after symptom onset found no effect on poor outcome or DCI in SAH. Earlier installment of treatment might be more effective, but individual trials had not enough power for such a subanalysis. We performed an individual patient data meta-analysis to study whether magnesium is effective when given within different time frames within 24 hours after the SAH. METHODS: Patients were divided into categories according to the delay between symptom onset and start of the study medication: <6, 6 to 12, 12 to 24, and >24 hours. We calculated adjusted risk ratios with corresponding 95% confidence intervals for magnesium versus placebo treatment for poor outcome and DCI. RESULTS: We included 5 trials totaling 1981 patients; 83 patients started treatment<6 hours. For poor outcome, the adjusted risk ratios of magnesium treatment for start <6 hours were 1.44 (95% confidence interval, 0.83-2.51); for 6 to 12 hours 1.03 (0.65-1.63), for 12 to 24 hours 0.84 (0.65-1.09), and for >24 hours 1.06 (0.87-1.31), and for DCI, <6 hours 1.76 (0.68-4.58), for 6 to 12 hours 2.09 (0.99-4.39), for 12 to 24 hours 0.80 (0.56-1.16), and for >24 hours 1.08 (0.88-1.32). CONCLUSIONS: This meta-analysis suggests no beneficial effect of magnesium treatment on poor outcome or DCI when started early after SAH onset. Although the number of patients was small and a beneficial effect cannot be definitively excluded, we found no justification for a new trial with early magnesium treatment after SAH.

Effects of high-dose paracetamol on blood pressure in acute stroke.

BACKGROUND: Early administration of paracetamol may improve outcome of patients with acute stroke and a baseline body temperature of 37°C or above by lowering body temperature and preventing fever. Besides its antipyretic effects, paracetamol may affect blood pressure through cyclooxygenase-2 inhibition. We therefore aimed to assess the effect of high-dose paracetamol on blood pressure in patients with acute stroke. METHODS: We analyzed data of 540 patients admitted within 24 h of stroke onset who were randomized to treatment with either paracetamol (6 g daily) or placebo. Blood pressures were measured at 12, 24, and 48 h from the start of treatment. Changes in blood pressure from baseline in the two treatment groups and corresponding 95% confidence intervals (CI) were calculated with linear regression analysis. Adjustments for potential confounders were made with a multiple linear regression model. RESULTS: Treatment with high-dose paracetamol was associated with a significant reduction in systolic blood pressure of 4.5 mm Hg (95% CI 0.6-8.5) at 12 h from the start of treatment. This effect was no longer present after 24 and 48 h. CONCLUSION: High-dose paracetamol reduces not only body temperature but also systolic blood pressure in the first 12 h after start of treatment. Both effects may improve functional outcome after stroke, but this needs further study.

[Steno and his duct]. / Steno en zijn ductus.

Niels Stensen (Nicolaus Steno; 1638-1686) was son of a goldsmith in Copenhagen. He studied medicine in his native town. In 1660 he went to Amsterdam, where on dissecting the head of a sheep he discovered the parotid duct. An awkward dispute about priority with his teacher Blasius prompted a move to Leiden, where he worked on glands and muscles. In 1664 having failed to obtain an appointment in Copenhagen, he travelled to France and finally Florence, where the Medici dynasty paid him to teach and study not only anatomy but also geology. His interests gradually shifted to spiritual matters: in 1667 he converted to Catholicism, in 1675 (after an unsatisfactory interlude in Copenhagen) he was received into the priesthood. From 1677 until his death in 1686 he served as a travelling bishop in Northern Germany. He was beatified by the Pope in 1988.

Size of third and fourth ventricle in obstructive and communicating acute hydrocephalus after aneurysmal subarachnoid hemorrhage.

In patients with acute hydrocephalus after aneurysmal subarachnoid haemorrhage (SAH), lumbar drainage is possible if the obstruction is in the subarachnoid space (communicating hydrocephalus). In case of intraventricular obstruction (obstructive hydrocephalus), ventricular drainage is the only option. A small fourth ventricle is often considered a sign of obstructive hydrocephalus. We investigated whether the absolute or relative size of the fourth ventricle can indeed distinguish between these two types of hydrocephalus. On CT-scans of 76 consecutive patients with acute headache but normal CT and CSF, we measured the cross-sectional surface of the third and fourth ventricle to obtain normal planimetric values. Subsequently we performed the same measurements on 117 consecutive SAH patients with acute hydrocephalus. These patients were divided according to the distribution of blood on CT-scan into three groups: mainly intraventricular blood (n=15), mainly subarachnoid blood (n=54) and both intraventricular and subarachnoid blood (n=48). The size of the fourth ventricle exceeded the upper limit of normal in 2 of the 6 (33%) patients with intraventricular blood but without haematocephalus, and in 15 of the 54 (28%) patients with mainly subarachnoid blood. The mean ratio between the third and fourth ventricle was 1.45 (SD 0.66) in patients with intraventricular blood and 1.42 (SD 0.91) in those with mainly subarachnoid blood. Neither fourth ventricular size nor the ratio between the third and fourth ventricles discriminates between the two groups. A small fourth ventricle does not necessarily accompany obstructive hydrocephalus and is therefore not a contraindication for lumbar drainage.

Attentional modulation fails to attenuate the subjective pain experience in chronic, unexplained pain.

BACKGROUND: Chronic, unexplained pain is a common, ill-understood clinical problem. Increased sensitivity for pain and other stimuli is often implied as an underlying mechanism. Attentional processes influence central pain processing and might mediate hypersensitivity at a cerebral level. AIMS: To study patients with chronic, unexplained pain with respect to (a) subjective pain experience; (b) effects of attentional manipulation; (c) level at which alterations in pain processing occur: locally (symptomatic body region), or generalised. METHODS: We compared 16 patients with chronic, unexplained limb pain with 16 matched healthy controls. Pain thresholds to electrical stimuli were recorded. Subjects then received individually thresholded painful and non-painful stimuli, with manipulation of attention towards or away from pain. The intensity of pain perception was recorded by means of visual analogue scales (VAS). Pain thresholds and effects of Attention and Laterality on VAS scores were compared between groups by means of general linear modelling (restricted to 12 patients with unilateral pain and 12 controls). RESULTS: Distraction increased thresholds for pain in healthy volunteers, but this effect was significantly attenuated in patients. Significant interactions between attention-effects, stimulus laterality and stimulus intensity indicated that VAS scores for painful stimuli were attenuated during distraction in healthy controls, but not in pain patients. CONCLUSIONS: Results support the notion that pain processing is enhanced in chronic, unexplained pain, and that the influence of attentional modulation on pain processing is attenuated. Potential cerebral mechanisms are changes in either attentional allocation or attention-mediated descending pain modulation. The changes seem to occur at a generalised level.

Risk indicators for development of headache during dipyridamole treatment after cerebral ischaemia of arterial origin.

A considerable proportion of patients discontinue dipyridamole therapy because of headache. Risk indicators for the development of dipyridamole induced headache were identified by means of an exploratory analysis of data from the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) and the Second European Stroke Prevention Study (ESPS 2). In ESPRIT, dipyridamole induced headache was significantly associated with female sex, absence of hypertension and non-smoking (area under the receiver operator characteristic (ROC) curve 0.63 (95% CI 0.58 to 0.68)) and in ESPS 2 with female sex and absence of ischaemic lesions on imaging (area under the ROC curve 0.64 (95% CI 0.59 to 0.69)).

['Does reason drive out tenderness and love?'--debates about women and education in 1898]. / Verdrijft het intellect zachtaardigheid en liefde?--debatten over vrouw en studie in 1898.

In The Netherlands the first female medical student was admitted in 1871, despite formidable public resistance; the issue of higher education for women would remain controversial for several decades to come. In 1898, the coronation year of the 18-year-old Queen Wilhelmina, the subject was discussed in two separate lectures before a women's rights movement in Rotterdam. Speakers were the medical professors H. Treub (gynaecologist, proponent) and C. Winkler (psychiatrist and neurologist, opponent). In that same year the issue was also debated in journal articles. The main questions around which the arguments for and against women of academic standing revolved, were firstly the innate ability of women to reach the very top in any science or art and secondly the necessity to disown innate femininity in the process.

Accuracy and inter-observer variation in the classification of dysarthria from speech recordings.

BACKGROUND: Dysarthria may be classified as flaccid, spastic, ataxic, hypokinetic, choreatic, dystonic, or mixed. We hypothesized that in routine neurological practice the reliability and accuracy of perceptual analysis alone in the classification of dysarthria is low and that this classification is mainly based on the clinical context rather than on the perception of speech. We therefore studied the accuracy and the inter- observer agreement in the classification of dysarthrias on the basis of perceptual analysis alone. METHODS: Seventy two neurologists and neurological trainees classified recorded speech samples of 100 patients as flaccid, spastic, ataxic, extrapyramidal, or mixed dysarthria, or as not dysarthric. All observers were blinded to the patients' final diagnosis, which was based on all clinical features and investigations. In the analysis the observers were arranged in eight groups of nine observers, or four paired groups with similar levels of clinical experience. Together, the observers in a given group rated all 100 recordings. RESULTS: The accuracy of the classification was poor (35 % were classified correctly) and the inter-observer agreement between paired groups low (kappa 0.16 to 0.32). The level of experience in neurology did not have a significant influence. CONCLUSION: Neurological trainees as well as experienced neurologists have great difficulty in identifying specific types of dysarthria on the basis of perceptual analysis alone. In clinical practice this probably means that most neurologists will classify dysarthria in the context of other features from neurological examination or ancillary investigations.

Long-term occurrence of death and cardiovascular events in patients with transient ischaemic attack or minor ischaemic stroke: comparison between arterial and cardiac source of the index event.

BACKGROUND AND AIMS: Published data suggest that patients with cerebral ischaemia and atrial fibrillation (CIAF) have higher inhospital mortality than patients with cerebral ischaemia of arterial origin (CIAO). Data on long term risks are scarce. We compared the long term risks of death and vascular events (VE) between these groups. METHODS: We extended the follow-up of 2473 patients from the Dutch TIA Trial (recruitment March 1986 to March 1989, all treated with aspirin; CIAO) and 186 Dutch participants of the European Atrial Fibrillation Trial (recruitment June 1988 to May 1992, 26% on anticoagulants during the trial; CIAF). Hazard ratios (HRs) for death and VE of CIAF versus CIAO were analysed by means of Cox regression analysis and adjusted for age, sex and several cardiovascular risk factors. RESULTS: After a mean follow-up of 10.1 years, 1484 patients with CIAO had died and 1336 had suffered at least one VE (377 cardiac, 455 stroke). Mean follow-up of the CIAF patients was 6.8 years; 150 patients had died and 136 had suffered at least one VE (41 cardiac, 63 stroke). Adjusted HRs (CIAF vs CIAO) were 1.46 (95% CI 1.22 to 1.74) for death, 1.49 (1.24 to 1.79) for first VE, 1.94 (1.47 to 2.55) for first stroke and 1.41 (1.01 to 1.96) for first cardiac event. These HRs were essentially the same as those for the duration of the trials. CONCLUSION: Our study shows that the long term risk of death or vascular events is 1.5 times higher in patients with CIAF than in those with CIAO, after adjustment for differences between the groups.

[Chronic low back pain: the failure of organic medicine]. / Chronische lage rugpijn: het falen van de orgaangeneeskunde.

In this issue of the journal, a series of 67 patients is presented with persistent or recurrent chronic low back pain and leg pain after insertion of a lumbar-disc prosthesis in a private hospital in Germany. A relationship between degenerative changes in the vertebral column and chronic low back pain is often assumed but lacks a scientific basis. Psychosocial factors are much more important than biomechanical factors in determining the outcome, but the interaction between these determinants is far more complicated than just 'having problems'. Accordingly, a multidisciplinary approach is the most successful mode of treatment, while local measures aimed at the vertebral column are generally ineffective or of unproven value. Patients will continue to seek magic cures from 'quacks with a knife' as long as medical specialists are insufficiently trained to deal with unexplained somatic symptoms.

Calcium antagonists for aneurysmal subarachnoid haemorrhage.

BACKGROUND: Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage (SAH). Its pathogenesis has been incompletely elucidated, but vasospasm probably is a contributing factor. Experimental studies have suggested that calcium antagonists can prevent or reverse vasospasm and have neuroprotective properties. OBJECTIVES: To determine whether calcium antagonists improve outcome in patients with aneurysmal SAH. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched April 2006), MEDLINE (1966 to March 2006) and EMBASE (1980 to March 2006). We handsearched two Russian journals (1990 to 2003), and contacted trialists and pharmaceutical companies in 1995 and 1996. SELECTION CRITERIA: Randomised controlled trials comparing calcium antagonists with control, or a second calcium antagonist (magnesium sulphate) versus control in addition to another calcium antagonist (nimodipine) in both the intervention and control groups. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data and assessed trial quality. Trialists were contacted to obtain missing information. MAIN RESULTS: Sixteen trials, involving 3361 patients, were included in the review; three of the studies were of magnesium sulphate in addition to nimodipine. Overall, calcium antagonists reduced the risk of poor outcome: the relative risk (RR) was 0.81 (95% confidence interval (CI) 0.72 to 0.92); the corresponding number of patients needed to treat was 19 (95% CI 1 to 51). For oral nimodipine alone the RR was 0.67 (95% CI 0.55 to 0.81), for other calcium antagonists or intravenous administration of nimodipine the results were not statistically significant. Calcium antagonists reduced the occurrence of secondary ischaemia and showed a favourable trend for case fatality. For magnesium in addition to standard treatment with nimodipine, the RR was 0.75 (95% CI 0.57 to 1.00) for a poor outcome and 0.66 (95% CI 0.45 to 0.96) for clinical signs of secondary ischaemia. AUTHORS' CONCLUSIONS: Calcium antagonists reduce the risk of poor outcome and secondary ischaemia after aneurysmal SAH. The results for 'poor outcome' depend largely on a single large trial of oral nimodipine; the evidence for other calcium antagonists is inconclusive. The evidence for nimodipine is not beyond all doubt, but given the potential benefits and modest risks of this treatment, oral nimodipine is currently indicated in patients with aneurysmal SAH. Intravenous administration of calcium antagonists cannot be recommended for routine practice on the basis of the present evidence. Magnesium sulphate is a promising agent but more evidence is needed before definite conclusions can be drawn.

Dipyridamole for preventing stroke and other vascular events in patients with vascular disease.

BACKGROUND: Patients with limited cerebral ischaemia of arterial origin are at risk of serious vascular events (4% to 11% annually). Aspirin reduces that risk by 13%. In one trial, adding dipyridamole to aspirin was associated with a 22% risk reduction compared with aspirin alone. However, a systematic review of all trials of antiplatelet agents by the Antithrombotic Trialists' Collaboration showed that, in high-risk patients, there was virtually no difference between the aspirin-dipyridamole combination and aspirin alone. OBJECTIVES: To assess the efficacy and safety of dipyridamole versus control in the secondary prevention of vascular events in patients with vascular disease. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (searched June 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to May 2006) and EMBASE (1980 to May 2006). We contacted authors and pharmaceutical companies in the search for further data on published and unpublished studies. SELECTION CRITERIA: We selected randomised long-term secondary prevention trials with concealed treatment allocation, treatment for more than one month, starting within six months after presentation of an arterial vascular disease. Treatment consisted of dipyridamole with or without other antiplatelet drugs compared with no drug or an antiplatelet drug other than dipyridamole. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trial quality and extracted data. Data were analysed according to the intention-to-treat principle. MAIN RESULTS: Twenty-nine trials were included, with 23019 participants, among whom 1503 vascular deaths and 3438 fatal and non-fatal vascular events occurred during follow up. Compared with control, dipyridamole had no clear effect on vascular death (relative risk (RR) 0.99, 95% confidence interval (CI) 0.87 to 1.12). This result was not influenced by the dose of dipyridamole or type of presenting vascular disease. Compared with control, dipyridamole appeared to reduce the risk of vascular events (RR 0.88, 95% CI 0.81 to 0.95). This effect was only statistically significant in patients presenting with cerebral ischaemia. AUTHORS' CONCLUSIONS: For patients who presented with arterial vascular disease, there was no evidence that dipyridamole, in the presence or absence of another antiplatelet drug reduced the risk of vascular death, though it reduces the risk of further vascular events. This benefit was found only in patients presenting after cerebral ischaemia. There was no evidence that dipyridamole alone was more efficacious than aspirin.

Thoracic radicular vessels by simultaneous intra-arterial and intravenous injection of araldite.

Spinal dural arteriovenous fistulas (SDAVF) consist of a shunt between a radicular artery and a radicular vein, resulting in a progressive paraparesis. They are most prevalent in middle-aged men (male to female ratio 5 to 1). It is unknown why the shunt develops. It is possible that there are anatomical differences between men and women, which may account for the sex difference in prevalence. We performed a study with simultaneous arterial and venous araldite injection in 5 male and 5 female human cadavers using different colors. The mean age of the human cadavers was 78 years (range 70-91). The human cadavers were not known to have suffered from spinal disease. We did not find significant differences in thoracic vasculature between men and women. Two different types of radicular arteries could be identified: The first was the arterial feeder of the root ganglion or the dura mater, which is also called the distal radicular artery. The second was the tributary of the anterior spinal artery, which is also called the medullary artery. We found three arteriovenous anastomoses between the radicular artery and the corresponding vein, and three between the radicular artery and venous plexus. We found a total of six thoracic arteriovenous shunts in four cadavers but their role in the pathogenesis of SDAVF remains uncertain. No vascular anatomic differences between men and women were found.

Mental status and health-related quality of life in an elderly population 15 years after limited cerebral ischaemia.

BACKGROUND: Stroke has a major impact on survivors. Our study was designed to describe the mental status and health-related quality of life (HRQoL) in long-term survivors of TIA or minor ischaemic stroke (MIS) and evaluate associations of mental and physical factors with HR-QoL. METHODS: A random sample of the 10-year survivors of the Dutch TIA Trial (DTT) and the dutch participants of the European Atrial Fibrillation Trial (EAFT) were interviewed by postal questionnaire (n = 468) and at home (n = 198). Demographic data, mental health status (depression (CES-D), cognition (CAMCOG)), and health perception (SF-36 and Euroqol) were measured. RESULTS: 198 long-term survivors were included; mean age was 72.5 (SD 8.7 years), 22% was depressed (CES-D > or = 16) and 15% had cognitive dysfunction (CAMCOG < 80). The overall HR-QoL did not differ much from the norm population. Physical disability, occurrence of a major stroke and comorbidity of locomotion or the heart were independently associated with a low health perception. CONCLUSIONS: Despite varying amounts of disability, the majority of long-term survivors of a TIA or MIS rated their quality of life as rather good. Physical factors, rather than mental status were independently related to a decrease in perceived health.

[Functional imaging of the brain in the investigation of chronic unexplained pain]. / Functionele beeldvorming van de hersenen in het onderzoek naar chronische, onverklaarde pijn.

Chronic unexplained pain poses a major problem in both clinical practice and society. The traditional psychological explanations have recently been supplemented by neurobiological data from functional neuroimaging studies, particularly functional MRI. Sensitization, hypersensitivity of the nervous system for sensory stimuli, is an important element in several theories about the pathophysiology of chronic pain. Functional MRI has yielded evidence for central sensitization in several chronic pain syndromes; such sensitization seems to occur mainly in regions of secondary pain processing, i.e. outside the primary pathways for sensory stimuli. More accurate insight into the underlying cerebral processes opens up possibilities for the diagnosis and treatment of chronic unexplained pain.

[On the way to our 200th anniversary]. / Op naar de 200 jaargangen.

The Dutch Journal of Medicine celebrates 150 years of continuous publication and looks forward to the next 50 years, notwithstanding the hazards offorecasting. In the coming years, the practice of medicine will see more teamwork and more specialisation, but the core process will remain personal counselling by a physician who manages to address somatic and psychological factors. Medical research will continue to include patients as well as molecules, but clinical trials will be threatened by overregulation through bureaucracy and legalism. Despite easy access to search facilities in the digital era, the future of general medical journals in local languages seems assured, because physicians need to keep abreast of developments in other specialties; the only uncertainty is whether these journals will continue to be read on paper.