Differential alterations of the inactivation properties of high voltage activated calcium currents in area CA1 and CA3 of the rat following photothrombotic lesion.

There are many indications that focal brain ischemia may alter the properties of remote brain tissue. We investigated whether changes of neuronal properties can be observed in the unlesioned ipsilateral hippocampus following cortical photothrombosis in the somatosensory cortex of rats. The whole-cell patch-clamp technique was used to investigate calcium current properties of hippocampal neurons (CA1 and CA3) 7 days after infarct induction. A significant alteration in the half-maximal potential of inactivation (V(h,i)) could be demonstrated, when comparing lesioned with sham operated animals, while other current parameters remained unchanged. The alterations of the V(h,i) in the CA1 and CA3 regions were of opposite directions: V(h,i) in CA1 neurons was shifted negatively by 5.6 mV, and positively by 5.0 mV in neurons from the CA3 region. It has been speculated that these differential alterations may be due to different subunit compositions of calcium channels in these two brain areas. The data indicate that small cortical lesions can lead to widespread alterations of the neuronal network's excitability in the hippocampal formation.

[Contraception and neurology]. / Contraception et Neurologie.

The purpose of this article is to clarify interactions between oral contraception (using low- and high-dose oral contraceptives) and the main neurological diseases occurring in genitally active women. Vascular disorders predominate, since contraception is in itself a well-recognized a risk factor, especially in case of other intercurrent risk factors (high blood pressure, smoking, diabetes, history of vascular event) contradicting contraception. Low-dose oral contraception can be proposed for women free of these risk factors. There is however a formal contraindication for oral contraception, even with mini-dose contraceptives, for women with a history of cerebral venous thrombosis. In case of migraine headache, which is also a risk factor of vascular disease (especially in case of aura), oral contraceptives should be discussed on an individual basis, depending on the presence of other risk factors. Contraception has no effect on epilepsy but oral contraceptives may be inhibited by inducing anti-seizure drugs. Non-inducing drugs are preferable. The course of certain brain tumors known to express estrogen or progesterone receptors (particularly meningiomas and hemangioblastomas) may worsen with oral contraception, which is formally contradicted except when search for hormone receptors is negative. Oral contraception has no influence in other disease such as multiple sclerosis

Cardiovascular events associated with different combined oral contraceptives: a review of current data.

Studies of combined oral contraceptive (COC) use and cardiovascular disease have been conducted against a background of low cardiovascular risk in young women, changing COC composition and changing user selection and monitoring. Studies of myocardial infarction have found inconsistent results, possibly because of differences in the prevalence of risk factors (particularly smoking and raised blood pressure) in the populations studied. In the absence of a history of smoking and other conventional risk factors, current users of modern COCs probably do not have an increased risk of myocardial infarction. Neither are former users at risk. Evidence for important differences in the risk of myocardial infarction between formulations is weak and contradictory. Current users of low estrogen dose COCs have a small increased risk of ischaemic stroke although most of the risk occurs in women with other risk factors (notably smoking, hypertension and probably a history of migraine). Former users of COCs do not have an increased risk of ischaemic stroke. There is insufficient information to determine whether major differences in the risk of ischaemic stroke exist between products. Current users appear to have a modestly elevated risk of haemorrhagic stroke, mainly in women older than 35 years; former users do not. Data examining the risk of haemorrhagic stroke in current COC users with other risk factors are very sparse, as are those relating to the haemorrhagic stroke risk associated with particular COCs. Numerous studies have found, with remarkable consistency, an elevated risk of venous thromboembolism among current users of low estrogen dose COCs. The risk is substantially elevated among women with various inherited clotting factor defects. The effects in COC users with other risk factors for venous thrombosis tend to be less pronounced and more inconsistent. A number of studies have found higher relative risks among current users of low estrogen dose COCs containing desogestrel or gestodene, than among users of similar products containing levonorgestrel. A number of explanations, in terms of bias or confounding, have been proposed for these clinically small differences. At best, empirical evidence for these explanations, is weak. The risk of cardiovascular disease of any description is low in COC users. Women can minimise, and possibly eliminate entirely, their arterial risks by not smoking and by having their blood pressure checked before using a COC (in order to avoid its use if raised blood pressure is discovered). Users may decrease their venous thromboembolic risk by their choice of COC preparation although the effects will be modest.

[Severe air embolism after surgical irrigation with hydrogen peroxide]. / Embolie gazeuse grave après une irrigation chirurgicale à l'eau oxygénée.

BACKGROUND: Hydrogen peroxide is widely used for its antiseptic properties. In certain circumstances, however the risk of air embolism can create a life-threatening situation. CASE REPORT: A 16-year-old adolescent required surgical treatment for femorotibial trauma. During the surgical procedure, cardiac arrest suddenly occurred when hydrogen peroxide was being used to irrigate the wound. A central catheter was inserted and aspiration of air bubbles in the line led to the diagnosis of air embolism. Outcome was unfavorable despite successful resuscitation. A chronic neurovegatative state ensued and the patient died 8 months later. DISCUSSION: Several cases of air embolism have been described due to hydrogen peroxide in surgical, medical and accidental circumstances. Our case emphasizes the potential danger of using hydrogen peroxide in certain situations, including orthopedic surgery. Clinicians should be aware that hydrogen peroxide is not a perfectly safe product.

Bihemispheric reduction of GABAA receptor binding following focal cortical photothrombotic lesions in the rat brain.

Focal brain lesions may lead to neuronal dysfunctions in remote (exofocal) brain regions. In the present study, focal lesions were induced in the hindlimb representation area of the parietal cerebral cortex in rats using the technique of photothrombosis. Photothrombosis occurs after illumination of the brain through the intact skull following intravenous injection of the photosensitive dye Rose Bengal. This resulted in cortical lesions with a diameter of about 2 mm. Quantitative receptor autoradiography was used to study alterations in the density of [3H]muscimol binding sites to GABAA receptors seven days after lesion induction. A reduced GABAA receptor binding (-13 to -27% of the control value) was found in layers II and III of remote exofocal regions in the ipsi- and contralateral cortex. The reduction was consistently more intense in the ipsilateral cortical areas than in those of the contralateral hemisphere. Using extracellular recordings, significant correlations between GABAA receptor binding and paired pulse inhibition could be demonstrated. The present investigation demonstrates that focal brain lesions cause a widespread, functionally effective down-regulation of GABAA receptors. These postlesional changes may result from lesion-induced alterations in cortical connectivity.

Acute cerebral gas embolism from hydrogen peroxide ingestion successfully treated with hyperbaric oxygen.

CASE REPORT: We present a case of an adult who suffered an apparent stroke shortly after an accidental ingestion of concentrated hydrogen peroxide. Complete neurologic recovery occurred quickly with hyperbaric therapy. Hydrogen peroxide can produce acute gas embolism. Hyperbaric therapy is the definitive treatment for gas embolism from hydrogen peroxide ingestion as it is for all other causes of acute gas embolism. This is the first case reported in the literature of hyperbaric therapy used successfully to treat cerebral gas embolism caused by hydrogen peroxide.

[P-pills and thrombosis]. / P-piller og trombose.

This review provides an account of the present situation as reflected by findings in recent studies, which illustrate epidemiological, clinical and metabolic aspects of thrombosis associated with oral contraceptive (OC) usage. With the reduction of the oestrogen content of OCs, the relative risk for acute myocardial or cerebral thrombosis is now 1.5-3. Low-dose OCs containing third generation gestagens seem to be associated with less risk of infarction, and possibly of cerebral thrombosis, than are OCs containing second generation gestagens. The risk of venous thrombosis is increased 2-4-fold in conjunction with the usage of low-dose OCs with second generation gestagens, and possibly slightly more (3-5-fold) in conjunction with OCs containing third generation gestagens, though this is of small clinical significance. When prescribing OCs for women at an increased risk of venous thrombosis, a low-dose pill with a second generation progestagen seems to be preferable. If OCs are prescribed to women at an increased risk of arterial thrombosis, OCs with third generation progestagens seem to be a reasonable first choice. Women with no thrombotic predisposion can safely use any type of low-dose OCs [corrected].

Cerebral thrombosis and oral contraceptives. A case-control study.

To assess the influence of oral contraceptives (OC) on the risk of cerebral thrombosis and transient cerebral ischemic attacks, a 5-year case-control study including all Danish hospitals was conducted. All women 15-44 years old who suffered a cerebral thromboembolic attack (CTA) during the period 1994-95 and 1200 age matched control subjects were included. Of 309 patients and 1200 control subjects questionnaires sent out, 271 patients (87.7%) and 1074 control subjects (89.5%) responded and agreed to participate. After exclusion of women with nonvalid diagnoses, previous thromboembolic diseases, or current pregnancy, 219 patients and 1041 control subjects were available for analysis. After confounder control and with nonusers as reference, current users of first generation OC (50 micrograms of ethinyl estradiol [EE] or estrans) had an odds ratio (OR) of CTA of 1.86 (95% confidence interval [CI] 0.88-3.92); users of second generation OC (levonorgestrel or norgestimate) had an OR of 2.37 (1.35-4.16); and users of third generation OC (desogestrel or gestodene) had an OR of 1.32 (0.78-2.22). Users of OC with 50, 30-40, or 20 micrograms EE had OR of 2.65 (1.11-6.34), 1.60 (1.05-2.43), and 1.59 (0.57-4.58), respectively. Odds ratios for specific progestin types were as follows: estrans 1.37 (0.60-3.13), levonorgestrel 2.43 (1.40-4.21), norgestimate 7.09 (1.87-26.8), desogestrel 1.62 (0.72-3.63), and gestodene 1.24 (0.67-2.30). Duration of use was without significant influence on the risk and the OR were constant across the age bands. Compared with women who had never used OC, former users had an OR of CTA of 0.95 (0.66-1.51). In conclusion, use of OC with 50 micrograms of EE and OC with second generation progestins increased the risk of CTA significantly. OC with third generation progestins did not have any significant influence on the risk of CTA. The risk of CTA among former users of OC was not increased.

Oral contraceptives and thrombosis.

PIP: Recent studies have identified an increased risk of venous thromboembolism associated with use of third-generation oral contraceptives (OCs). Use of these newer formulations has been estimated to cause an excess of 10 deaths/year in the UK. The possibility has been raised, however, that prescribing bias and confounding by duration of OC use and other personal risk factors accounts for the difference in the risk of venous thromboembolism between second- and third-generation OCs. Other studies have identified an increased risk of myocardial infarction and stroke in OC users, including users of low-dose formulations, but this risk is almost exclusively limited to older women who smoke or have other cardiovascular risk factors. The interpretation of all such studies on OC side effects should take into account that the absolute risk of an adverse thrombotic event while taking OCs is small. This risk appears to be affected far more by factors such as smoking, age, hypertension, and familial disorders than the type of progestagen contained in the OC.^ieng

High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.

BACKGROUND: Idiopathic cerebral-vein thrombosis can cause serious neurologic disability. We evaluated risk factors for this disorder, including genetic risk factors (mutations in the genes encoding factor V and prothrombin) and nongenetic risk factors (such as the use of oral contraceptive agents). We compared the prevalence of these risk factors in 40 patients with cerebral-vein thrombosis, 80 patients with deep-vein thrombosis of the lower extremities, and 120 healthy controls. The G1691A mutation in the factor V gene and the G20210A prothrombin-gene mutation, which are established genetic risk factors for venous thrombosis, were studied. We also assessed the use of oral contraceptives and other risk factors for thrombosis. RESULTS: The prevalence of the prothrombin-gene mutation was higher in patients with cerebral-vein thrombosis (20 percent) than in healthy controls (3 percent; odds ratio, 10.2; 95 percent confidence interval, 2.3 to 31.0) and was similar to that in patients with deep-vein thrombosis (18 percent). Similar results were obtained for the mutation in the factor V gene. The use of oral contraceptives was more frequent among women with cerebral-vein thrombosis (96 percent) than among controls (32 percent; odds ratio, 22.1; 95 percent confidence interval, 5.9 to 84.2) and among those with deep-vein thrombosis (61 percent; odds ratio, 4.4; 95 percent confidence interval, 1.1 to 17.8). For women who were taking oral contraceptives and who also had the prothrombin-gene mutation (seven patients with cerebral-vein thrombosis but only one control), the odds ratio for cerebral-vein thrombosis rose to 149.3 (95 percent confidence interval, 31.0 to 711.0). CONCLUSIONS: Mutations in the prothrombin gene and the factor V gene are associated with cerebral-vein thrombosis. The use of oral contraceptives is also strongly and independently associated with the disorder. The presence of both the prothrombin-gene mutation and oral-contraceptive use raises the risk of cerebral-vein thrombosis further.

PIP: The role of the prothrombin-gene mutation in idiopathic cerebral-vein thrombosis and its interaction with other risk factors was investigated in a study of 40 patients (9 men and 31 women) 15-64 years of age who presented to a thrombosis center in Milan, Italy, in 1991-97 after a first episode of this thrombosis. Also enrolled were 80 men and women randomly selected from patients screened at the same center during the study period after a first documented episode of proximal deep-vein thrombosis of the lower extremities. 120 healthy controls were matched to cerebral-vein thrombosis patients by sex, age, geographic origin, and education. 20% of patients with cerebral-vein thrombosis (odds ratio (OR), 10.2; 95% confidence interval (CI), 2.3-31.0), 18% of those with deep-vein thrombosis, and 3% of controls were carriers of the prothrombin-gene mutation. Factor V mutation was more prevalent in patients with cerebral-vein thrombosis (15%) than controls (3%) (OR, 7.8; 95% CI, 1.8-34.1), but the thrombotic risks associated with these two mutations were independent of each other. Oral contraceptive (OC) ever-use was more frequent among women with cerebral-vein thrombosis (96%) (OR, 22.1; 95% CI, 5.9-84.2) and deep-vein thrombosis (61%) (OR, 4.4; 95% CI, 1.1-17.8) compared with controls (32%). For the 7 women with cerebral-vein thrombosis who were both OC ever-users and had the prothrombin-gene mutation, the thrombotic risk rose to 149.3 (95% CI, 31.0-711.0). These findings show that there is a hypercoagulable state in 35% of patients with idiopathic cerebral-vein thrombosis. Although screening for the prothrombin-gene mutation in young women before they are prescribed OCs is unlikely to be cost-effective, carriers of the mutation who have had a thrombosis episode should discontinue OC use.

Cerebral infarction in young adults: the Baltimore-Washington Cooperative Young Stroke Study.

BACKGROUND: Few reports on stroke in young adults have included cases from all community and referral hospitals in a defined geographic region. METHODS: At 46 hospitals in Baltimore City, 5 central Maryland counties, and Washington, DC, the chart of every patient 15 to 44 years of age with a primary or secondary diagnosis of possible cerebral arterial infarction during 1988 and 1991 was abstracted. Probable and possible etiologies were assigned following written guidelines. RESULTS: Of 428 first strokes, 212 (49.5%) were assigned at least one probable cause, 80 (18.7%) had no probable cause but at least one possible cause, and 136 (31.8%) had no identified probable or possible cause. Of the 212 with at least one probable cause, the distribution of etiologies was cardiac embolism (31.1%), hematologic and other (19.8%), small vessel (lacunar) disease (19.8%), nonatherosclerotic vasculopathy (11.3%), illicit drug use (9.4%), oral contraceptive use (5.2%), large artery atherosclerotic disease (3.8%), and migraine (1.4%). There were an additional 69 recurrent stroke patients. CONCLUSIONS: In this hospital-based registry within a region characterized by racial/ethnic diversity, cardiac embolism, hematologic and other causes, and lacunar stroke were the most common etiologies of cerebral infarction in young adults. Nearly a third of both first and recurrent strokes had no identified cause.

Thromboembolic stroke in young women. A European case-control study on oral contraceptives. Transnational Research Group on Oral Contraceptives and the Health of Young Women.

A matched case-control study was performed between 1993 and 1996 in 16 centers in the United Kingdom, Germany, France, Switzerland, and Austria. The objective was to determine the influence of oral contraceptives (OC), particularly those containing modern progestins, on the risk for ischemic stroke in women aged 16-44 years. A total of 220 women who had had an incident ischemic stroke and were compared with 775 control subjects who were unaffected by stroke. At least one hospital and one community control subject per patient was matched and interviewed with the corresponding patient for 5-year age band and for area of residence. Crude odds ratios (95% confidence intervals [CI]) for ischemic stroke were as follows. For current use of any OC versus no use 2.3 (1.7-3.2), the adjusted odds ratio (OR) 3.6 (2.4-5.4). The OC associated risk was higher for first generation than for second or third generation OC. The risk estimates for patients versus community control subjects were always lower than for hospital control subjects. No major regional difference of the risk estimates was found. Compared with nonusers of OC without hypertension, women with hypertension who used OC had an almost 10-fold increased risk. However, OC users who had had a blood pressure check before OC prescription had a lower risk than did those without such a check. Smoking > 10 cigarettes/day is associated with higher risk of stroke, particularly for OC users. No significant effect was found for duration of OC use. We conclude that although there is a small relative risk of occlusive stroke for healthy women currently using OC, the attributable risk is very small because the incidence in this age group is very low. The small increase in risk of OC use may be further reduced by preventive efforts for cardiovascular risk factors, particularly hypertension and smoking.

Pharmacotherapy of cerebral ischemia in cocaine dependence.

This paper will examine how cerebral perfusion deficits in cocaine abusers may be a target for pharmacotherapy. The review covers five areas: (1) cerebral ischemia and neuropsychological impairment in cocaine abusers, (2) neuroimaging evidence for cerebral perfusion defects in cocaine abusers, (3) mechanisms for cocaine induced cerebral thrombosis, (4) neurotoxicity from cerebral ischemia and excitatory amino acids, (5) glutamate antagonists as potential treatment agents for cocaine induced neurotoxicity. Several pharmacotherapies are suggested including antiplatelet agents and excitatory amino acid (EAA) antagonists such as lamotrigine. Clinical trials in cocaine abusers with cerebral perfusion defects are indicated and EAA antagonists hold promise as they are developed for stroke treatment.