[Posture-dependent headache caused by spontaneous intracranial hypotension]. / Houdingsafhankelijke hoofdpijn door spontane intracraniële hypotensie.

A 36-year-old woman presented with a 3-4 month history of severe, progressive headache. The headache was characterized by postural variation, with excruciating headache in the upright position and near-immediate relief upon recumbence. There was no history of trauma or lumbar puncture. Gadolineum-enhanced brain MRI revealed abnormalities characteristic intracranial hypotension. Spinal MRI showed a longitudinal extradural fluid collection; a localization of the dural defect was not found. The patient was treated with caffeine, bed rest and lumbar epidural blood patches; she recovered completely. Severe orthostatic headache which aggravates upon standing and is relieved by recumbence, can be caused by spontaneous intracranial hypotension. Recognition of its characteristic symptoms is needed for timely referral. Treatment is usually successful and can prevent life-threatening complications.

[Spinal metastases: early recognition and a multidisciplinary approach]. / Wervelmetastasen.

Early diagnosis of spinal metastases is essential. The neurological condition at the time of diagnosis determines functional outcome. Optimal treatment planning requires a multidisciplinary approach by the general practitioner, internist/oncologist/haematologist, radiotherapist, radiologist, neurologist and the spinal surgeon. Radiation therapy is the most common treatment for patients with spinal metastases. However, in specific cases, surgery or chemotherapy should be the primary treatment. We present three patients with spinal metastases: a 55-year-old woman with back pain and a history of breast cancer, a 71-year-old woman with instability of the spine requiring surgical stabilisation and a 68-year-old man with spinal localisation of multiple myeloma treated with systemic therapy. Their cases illustrate the early symptoms of spinal metastases, the role of spinal stability in treatment decisions and the role of systemic therapy in patients with spinal metastases or haematological tumours located in the spine. Recognising early symptoms and appropriate multidisciplinary treatment planning are essential in improving the functional outcome in patients with spinal metastases.

Current concepts of cerebral oxygen transport and energy metabolism after severe traumatic brain injury.

Before energy metabolism can take place, brain cells must be supplied with oxygen and glucose. Only then, in combination with normal mitochondrial function, sufficient energy (adenosine tri-phosphate (ATP)) can be produced. Glucose is virtually the sole fuel for the human brain. The brain lacks fuel stores and requires a continuous supply of glucose and oxygen. Therefore, continuous cerebral blood flow (CBF), cerebral oxygen tension and delivery, and normal mitochondrial function are of vital importance for the maintenance of brain function and tissue viability. This review focuses on three main issues: (1) Cerebral oxygen transport (CBF, and oxygen partial pressure (PO2) and delivery to the brain); (2) Energy metabolism (glycolysis, mitochondrial function: citric acid cycle and oxidative phosphorylation); and (3) The role of the above in the pathophysiology of severe head injury. Basic understanding of these issues in the normal as well as in the traumatized brain is essential in developing new treatment strategies. These issues also play a key role in interpreting data collected from monitoring techniques such as cerebral tissue PO2, jugular bulb oxygen saturation (SjvO2), near infra red spectroscopy (NIRS), microdialysis, intracranial pressure monitoring (ICP), laser Doppler flowmetry, and transcranial Doppler flowmetry--both in the experimental and in the clinical setting.

Appreciation of the informed consent procedure in a randomised trial of decompressive surgery for space occupying hemispheric infarction.

BACKGROUND AND AIM: As non-randomised studies have suggested that surgical decompression may reduce mortality in patients with space occupying hemispheric infarction, randomisation may be considered unethical in controlled trials testing this treatment strategy. We studied differences in recall of information and in appreciation of the informed consent procedure between representatives included in the Hemicraniectomy After Middle cerebral artery infarction with Life-threatening Edema Trial (HAMLET) and representatives of patients participating in the randomised trial of Paracetamol (Acetaminophen) In Stroke (PAIS). METHODS: 1 year after study inclusion, we contacted 30 consecutive representatives who had given informed consent for participation of their relative in HAMLET, and 30 for PAIS. Recall of trial details and appreciation of the informed consent procedure were investigated using standardised questionnaires and compared between the two groups. RESULTS: All 30 PAIS representatives and 28 HAMLET representatives were interviewed. Participation of their relative in a clinical trial was remembered by 86% of HAMLET and 40% of PAIS representatives (p<0.001). HAMLET representatives remembered more trial details (effect of the treatment under study (61% vs 3%, p<0.001); randomised treatment allocation (71% vs 0%, p<0.001)). With respect to appreciation of the informed consent procedure, we found no differences between the groups: in each trial, four representatives (14% vs 13%) had considered the question of randomisation unacceptable. CONCLUSIONS: Participation of patients in a randomised controlled trial of surgical decompression for space occupying infarction is generally considered acceptable by their representatives, and recall of trial details is better than in a trial in which less vital issues are at stake.

[Surgical decompression in space-occupying cerebral infarct; notification of a randomized trial]. / Chirurgische decompressie bij het ruimte-innemende herseninfarct; aanmelding voor een gerandomiseerde trial.

Patients with a hemispheric infarct and massive space-occupying brain oedema have a poor prognosis. Despite intensive conservative treatment, the case fatality rate may be as high as 80%, and most survivors are left severely disabled. Non-randomised studies suggest that decompressive surgery substantially reduces mortality and improves the functional outcome of survivors. The 'Hemicraniectomy after middle cerebral artery infarction with life-threatening edema trial' (HAMLET) is a newly-conceived randomised multi-centre clinical trial that compares the efficacy of decompressive surgery to improve functional outcome with that of conservative treatment in patients with space-occupying supratentorial infarction.

Progesterone receptor isoform expression in human meningiomas.

The majority of meningiomas express the progesterone receptor (PR), and therefore meningiomas are considered to be progesterone-responsive. In addition, an association has been reported between PR and prognosis. At least two PR isoforms exist, PR-B (116--120 kDa) and PR-A (81 kDa), each of which are likely to have different biological functions. Knowledge of the differential expression of both isoforms is necessary to understand the effects of progesterone on meningioma growth. Therefore, in this study, PR-A and PR-B expression levels were determined in 61 human meningiomas by immunoblotting. Total PR expression levels were determined with a ligand binding assay (LBA) (total PR(LBA)). Both PR isoforms and an additional PR 78 kDa protein (PR-78) were expressed in the meningiomas. Meningiomas expressing more PR-A than PR-B had significantly higher total PR(LBA) levels (P<0.001). The PR-78 band intensity was negatively associated with that of PR-B (r(s)=-0.76, P<0.0001). PR-78 may represent an endogenous degradation product, but a similar regulation pathway in the biogenesis of both PR-B and PR-78 is not excluded. Meningiomas contain both PR isoforms, but in highly variable ratios and this variability may have some biological significance. Most meningiomas express more PR-A than PR-B. Therefore in meningioma, assuming that PR-B is more transcriptionally active than PR-A, progesterone responsiveness could be based on transrepression rather than on transactivation of target genes, and progesterone blockade may only be effective in certain subsets of meningiomas.

Exercise-induced muscle damage in the rat: the effect of vitamin E deficiency.

Rats, fed a vitamin-E-deficient diet for 6 weeks, performed treadmill exercise for 2 h. Muscle damage was assessed by measuring the creatine kinase (CK) activity in plasma before and after exercise, and by studying semi-thin longitudinal sections of the soleus muscle 48 h after running. Vitamin-E-deficient male and female rats showed an increased post-exercise CK activity when compared to matched controls, but male rats showed a larger CK response than females. This rise in plasma CK activity was caused mainly by an increased activity of the muscle-specific CK-isoenzyme, CK-MM (males + 1238%; females + 540%, P less than 0.05). In a parallel histological study we observed in vitamin-E-deficient male rats a dramatic and significant disturbance of the normal cyto-architecture of the muscle fibres after exercise (focal necrosis, phagocytosis and cellular infiltrates), whereas in females only minor, non-significant, changes were seen. We conclude that vitamin E deficiency enhances the susceptibility to exercise-induced muscle damage in male rats more than in female rats. This difference between the sexes is attributed to the protective effect of oestradiol that remains operative in female rats when the vitamin E status is disturbed: male rats lack such hormonal protection.

Tamoxifen and oestrogen both protect the rat muscle against physiological damage.

Tamoxifen (TX), an oestrogen antagonist, was used to characterize the protective effect of oestradiol (E2) on exercise-related creatine kinase (CK) release from skeletal muscle of the rat. Subcutaneous administration of TX for 3 weeks in female rats had a profound antioestrogen effect as evidenced by a reduced weight of the uterus. The CK release after electrical stimulation of the isolated soleus muscle, previously shown to be E2-dependent, was markedly reduced (30-50%) after treatment with TX; this observation points to an E2-like protective action of TX instead of E2-antagonism. This effect was dose-dependent (0.25-1.00 mg/kg) and was not seen when TX was given shortly (24 h) before the experiments. In ovariectomized females, that show more CK leakage due to the lack of circulating E2, both E2- and TX-treatment resulted in a 60% reduction of the CK leakage. Muscles from male rats, treated with TX, showed a similar response: after contractions the CK release was significantly lower. We conclude that TX, like E2, reduces contraction-induced muscle damage in the rat and, thus, has E2-agonistic properties on skeletal rat muscle.

Myoglobin is a sensitive marker of increased muscle membrane vulnerability.

Changes in muscle proteins in serum after exercise were studied to evaluate the use of such proteins as indicators of increased muscle membrane vulnerability. Seventy-one women were asked to perform bicycle exercise for 45 min at a moderate load; four proteins (creatine kinase - CK, myoglobin - Mb, aldolase - Ald and pyruvate kinase - PK) were measured in serum up to 24 h after exercise. Twenty-one women were carriers of Duchenne's muscular dystrophy (DMD); these are known to show an elevated serum CK activity at rest, as well as increased CK response after exercise. Fifty women without a family history of neuromuscular disease were tested to obtain normal values: they showed a small peak (18%) of CK activity 8 h after exercise, and an even smaller peak of Mb (9%) 1 h after exercise. The mean post-exercise increase for both CK and Mb in the 21 DMD carriers was significantly higher than in controls; the maximum of Mb, on average 70% of baseline levels, was reached 1 h after exercise and was higher than that for CK (48%), which was reached 8 h after exercise. It is concluded that myoglobin levels after exercise are a good index of increased vulnerability of the muscle membrane.

Dantrolene sodium diminishes exercise-induced muscle damage in the rat.

We tested the hypothesis that calcium from the sarcoplasmic reticulum contributes to exercise-induced muscle damage. Dantrolene sodium (Dantrium) is a muscle relaxant that affects the flux of calcium over the sarcoplasmic membrane. Rats were treated with dantrolene sodium for a week before a 2 h run on a treadmill. We measured the total creatine kinase activity and isoenzyme composition in plasma before and after exercise. We also prepared muscle sections to correlate the biochemical data with morphological evidence of muscle damage. The treated rats showed a marked decrease (34%) in exercise-induced enzyme efflux, caused by a decrease in the muscle specific isoenzyme: instead of a 13-fold increase found in control rats we observed only a 6.5-fold increase in treated animals. The latter showed significantly less muscle damage 48 h later. It is concluded that dantrolene sodium protects the muscle against exercise-induced damage. The possible mechanism of this protection, and its applications in neuromuscular disease are discussed.

Sex-linked variation in creatine kinase release, and its dependence on oestradiol, can be demonstrated in an in-vitro rat skeletal muscle preparation.

Creatine kinase (CK) release from male and female rat soleus muscles was studied for 4.5 h in vitro, under basal conditions and after electrical stimulation. Basal CK release was greater from male than from female muscles, and CK release from male muscles increased significantly when the muscle tension in the in-vitro set-up was increased. CK release after electrical stimulation was also more marked in male soleus muscles. Pretreatment of male rats and ovariectomized female rats with oestradiol for 3 weeks attenuated the enzyme efflux, but ovariectomy 24 h before in females, or oestradiol administration 24 h before in males, did not affect the release of CK in vitro. The data show that sex-linked differences in CK efflux are still present, under both basal and stimulated conditions, when muscles are isolated from the intact animal, and that hormone treatment of the intact animal affects these properties in the isolated muscle in vitro.

Creatine kinase isoenzyme profiles after exercise in the rat: sex-linked differences in leakage of CK-MM.

Changes in creatine kinase (CK) activity and CK isoenzyme profiles in plasma after exercise were studied in rats in order to establish the source of the exercise-induced rise in CK activity. Male and female rats ran on a treadmill for 2 h and blood samples, taken before and after exercise, were assayed for total CK, CK isoenzymes and aminoaspartate transaminase (AST) activity. These enzymes were also assayed in homogenates of liver and several muscles. We found that the isoenzyme composition of liver, plasma and muscle did not differ between the sexes. However, the exercise-induced CK and AST responses did differ: CK and AST increased after exercise in males (101% and 15% resp.), but much less in females (47% and 1%). Although the isoenzyme profiles in rest did not differ, significant differences were observed after running: in males CK-MM increased with 678%, but females only showed a 114% increase. In contrast, CK-BB showed a small increase that was about the same for both sexes (males 41%, females 35%). We conclude that both males and females show a small and similar increase in CK-BB activity after exercise, and that a large release of CK-MM from skeletal muscle, observed only in males, accounts for sex-linked differences reported earlier.

Prevention of exercise-induced muscle membrane damage by oestradiol.

Exercise can damage the muscle membrane, followed by leakage of certain muscle proteins into the bloodstream. This postexercise response differs for males and females; as an explanation for this difference it has been suggested that oestrogens have a protective effect on the female muscle membrane. We recently developed an animal exercise model in which postexercise damage can be studied in laboratory animals in vivo. A postexercise dimorphism, similar to that in humans, exists in rats and indirect evidence for the involvement of oestradiol (E2) was found. We report here 1) that ovariectomized females show postexercise damage like males, 2) that this response can be prevented by E2-replacement before exercise, and 3) that males, after E2-treatment, no longer show postexercise muscle damage. We therefore conclude that oestradiol indeed plays an important role in protecting skeletal muscle, both in females and in males.

Exercise-induced muscle protein leakage in the rat. Effects of hormonal manipulation.

Differences in exercise-induced muscle damage between males and females were studied in an animal model by measuring the serum activities of specific muscle enzymes (creatine kinase and aspartate aminotransferase). It was found that rats showed muscle damage, comparable to that observed in humans after long-term exercise: males were much more affected than females. For example, the CK activity in male rats immediately after exercise was 335% of the resting value, but remained unchanged in females. To test the hypothesis that oestrogens may protect the female muscle membrane, female rats were ovariectomized at different stages of sexual maturity and exercised. A clear effect of this hormonal manipulation was observed: operated animals showed post-exercise CK elevations, depending of the age at the time of ovariectomy. Rats, ovariectomized before reaching sexual maturity, showed more damage than those ovariectomized after reaching sexual maturity.