Treatment of Truncal Incompetence and Varicose Veins with a Single Administration of a New Polidocanol Endovenous Microfoam Preparation Improves Symptoms and Appearance.

OBJECTIVE: This multicenter, parallel group study was designed to determine if a single administration of ≤15 mL of pharmaceutical-grade polidocanol endovenous microfoam (PEM, now approved in the United States as Varithena [polidocanol injectable foam], BTG International Ltd.) could alleviate symptoms and improve appearance of varicose veins in a typical population of patients with moderate to very severe symptoms of superficial venous incompetence and visible varicosities of the great saphenous vein (GSV) system. METHODS: The primary endpoint was patient-reported venous symptom improvement measured by change from baseline to Week 8 in 7-day average VVSymQ score. Co-secondary endpoints measured improvement in appearance of visible varicose veins from baseline to Week 8, as measured by the Independent Photography Review-Visible Varicose Veins (IPR-V(3)) and Patient Self-assessment of Visible Varicose Veins (PA-V(3)) scores. Patients were randomized to five groups: PEM 0.125% (control), 0.5%, 1%, 2%, or placebo. Adverse events (AEs) were recorded at each study visit. Tertiary endpoints measured duplex ultrasound response, changes in venous clinical severity score, and the modified Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms. RESULTS: At Week 8, VVSymQ scores for the pooled PEM group (0.5% + 1% + 2%; p < .0001) and individual dose concentrations (p < .001) were significantly superior to placebo. Mean changes from baseline to Week 8 in IPR-V3 and PA-V(3) scores were significantly greater for pooled PEM than for placebo (p < .0001). Most AEs were mild and resolved without sequelae. No pulmonary emboli were reported. CONCLUSIONS: This study demonstrated that a single administration of up to 15 mL of PEM is a safe, effective, and convenient treatment for the symptoms of superficial venous incompetence and the appearance of visible varicosities of the GSV system. Doses of 0.5%, 1%, and 2% PEM appear to have an acceptable risk-benefit ratio.

Role of injection pressure, flow and sclerosant viscosity in causing cutaneous ulceration during sclerotherapy.

The objective of the study is to evaluate the viscosity of popular sclerosants and their flow hydrodynamics through a syringe/needle to further discuss Miyake's old, venous-capillary reflux theory, using additional objective data. The following sclerosing agents were tested in the study: 75% dextrose (D75%); 50% dextrose (D50%); 5% ethanolamine oleate (Etha5%); 0.5% laureth-9 (Aet0.5%) and 0.1% sodium tetradecyl sulphate (STS0.1%). Using 5 mL syringes and 27G needles, the resulting pressures and flows for each sclerosant agent were measured. To do this, a three-way stopcock was connected between the syringe and the needle so that an arm of the stopcock could be used to measure injection pressures with a digital monitor in 1 mmHg increments. Two trials were performed: in trial 1, the syringe was attached to a Samtronic 680 infusion pump and in trial 2, the solutions were injected manually. The observed sclerosant viscosities were as follows: D75%: 0.28 Poise; D50%: 0.12 Poise; Etha5%: 0.10 Poise; Aet0.5%: 0.07 Poise; and STS0.1%: 0.04 Poise. In trial 1 (constant flow), it was observed that D75%, which had the highest viscosity of the sclerosants tested, had the highest pressure readings. In trial 2 (constant pressure), the flow obtained with the D75% solution was lower than the flow of the other solutions. In conclusion, based on the rabbit study theory, vessel size and sclerosant viscosity and strength, not extravasation, play a role in causing ulceration from injection sclerotherapy. As a result, they all affect the potential of venous-capillary reflux being caused by sclerotherapy injection and, thus, the risk of postsclerotherapeutic cutaneous ulceration.

Social stress alters expression of large conductance calcium-activated potassium channel subunits in mouse adrenal medulla and pituitary glands.

Large conductance calcium-activated potassium (BK) channels are very prominently expressed in adrenal chromaffin and many anterior pituitary cells, where they shape intrinsic excitability complexly. Stress- and sex-steroids regulate alternative splicing of Slo-alpha, the pore-forming subunit of BK channels, and chronic behavioural stress has been shown to alter Slo splicing in tree shrew adrenals. In the present study, we focus on mice, measuring the effects of chronic behavioural stress on total mRNA expression of the Slo-alpha gene, two key BK channel beta subunit genes (beta2 and beta4), and the 'STREX' splice variant of Slo-alpha. As a chronic stressor, males of the relatively aggressive SJL strain were housed with a different unfamiliar SJL male every 24 h for 19 days. This 'social-instability' paradigm stressed all individuals, as demonstrated by reduced weight gain and elevated corticosterone levels. Five quantitative reverse transcriptase-polymerase chain assays were performed in parallel, including beta-actin, each calibrated against a dilution series of its corresponding cDNA template. Stress-related changes in BK expression were larger in mice tested at 6 weeks than 9 weeks. In younger animals, Slo-alpha mRNA levels were elevated 44% and 116% in the adrenal medulla and pituitary, respectively, compared to individually-housed controls. beta2 and beta4 mRNAs were elevated 162% and 194% in the pituitary, but slightly reduced in the adrenals of stressed animals. In the pituitary, dominance scores of stressed animals correlated negatively with alpha and beta subunit expression, with more subordinate individuals exhibiting levels that were three- to four-fold higher than controls or dominant individuals. STREX variant representation was lower in the subordinate subset. Thus, the combination of subunits responding to stress differs markedly between adrenal and pituitary glands. These data suggest that early stress will differentially affect neuroendocrine cell excitability, and call for detailed analysis of functional consequences.

Beta2 and beta4 subunits of BK channels confer differential sensitivity to acute modulation by steroid hormones.

Membrane-associated receptors for rapid, steroidal neuromodulation remain elusive. Estradiol has been reported to facilitate activation of voltage- and Ca(2+)-dependent BK potassium channels encoded by Slo, if associated with beta1 subunits. We show here that 1) multiple members of the beta family confer sensitivity to multiple steroids on BK channels, 2) that beta subunits differentiate between steroids, and 3) that different betas have distinct relative preferences for particular steroids. Expressed in HEK 293 cells, inside-out patches with channels composed of Slo-alpha alone showed no steroid sensitivity. Cells expressing alphabeta4 exhibited potent, rapid, reversible, and dose-dependent potentiation by corticosterone (CORT; a glucocorticoid), and were potentiated to a lesser degree by other sex and stress steroids. In contrast, alphabeta2 channels were potentiated more strongly by dehydroepiandrosterone (DHEA; an enigmatic, stress-related adrenal androgen), and to a lesser extent by CORT, estradiol, testosterone, and DHEA-S. Cholesterol had no effect on any BK channel compositions tested. Conductance-voltage plots of channels composed of alpha plus beta2 or beta4 subunits were shifted in the negative direction by steroids, indicating greater activation at negative voltages. Thus our results argue that the variety of Slo-beta subunit coexpression patterns occurring in vivo expands the repertoire of Slo channel gating in yet another dimension not fully appreciated, rendering BK gating responsive to dynamic fluctuations in a multiple of steroid hormones.

A failure to communicate: patients with cerebral aneurysms and vascular neurosurgeons.

OBJECTIVE: To assess communication between vascular neurosurgeons and their patients with unruptured cerebral aneurysms about treatment options and expected outcomes. METHODS: Vascular neurosurgeons and their patients with cerebral aneurysms were surveyed immediately following outpatient appointments in a neurosurgery clinic. Data collected included how well the patient understood their aneurysm treatment options, the risks of a poor outcome from various treatments, and the consensus "best" treatment. Patient and neurosurgeon responses were measured using Likert scales, multiple choice questions, and visual analogue scales. Agreement between patient and neurosurgeon was assessed with kappa scores. The Wilcoxon sign rank test was used to compare visual analogue scale responses. RESULTS: Data for 44 patient-neurosurgeon pairs were collected. Only 61% of patient-neurosurgeon pairs agreed on the best treatment plan for the patient's aneurysm (kappa = 0.51, moderate agreement). Among the neurosurgeons, agreement with their patients ranged from 82% (kappa = 0.77, almost perfect agreement) to 52% (kappa = 0.37, fair agreement). Patients estimated much higher risks of stroke or death from surgical clipping, endovascular embolisation, or no intervention compared with the estimates offered by their neurosurgeons (surgical clipping: patient 36% v neurosurgeon 13%, p<0.001; endovascular embolisation: patient 35% v neurosurgeon 19%, p = 0.040; and no INTERVENTION: patient 63% v neurosurgeon 25%, p<0.001). CONCLUSIONS: Following consultation with a vascular neurosurgeon, many patients with cerebral aneurysms have an inaccurate understanding of their aneurysm treatment plan and an exaggerated sense of the risks of aneurysmal disease and treatment.

The value of diffusion-weighted imaging for prediction of lasting deficit in acute stroke: an analysis of 134 patients with acute neurologic deficits.

Acute stroke is one of the three major causes of death and disability in the United States. Now that new, and possibly effective therapy is becoming available, accurate, rapid diagnosis is important to provide timely treatment, while avoiding the risk of complications from unnecessary intervention. Our objective was to test the hypothesis that use of echo-planar (EPI) diffusion-weighted imaging (DWI) is more accurate than conventional T2 weighted MRI in predicting progression to stroke in patients with acute ischemic neurologic deficits. We studied 134 patients presenting with acute neurologic deficits to a community hospital emergency room with both conventional MRI and DWI within 72 h of the onset of the acute deficit. We found DWI significantly more sensitive to permanent neurologic deficit at discharge (sensitivity 0.81) than conventional MRI (sensitivity 0.41). When available, DWI should be considered for routine use in patients being imaged for acute stroke.

How many neurosurgeons does it take to write a research article? Authorship proliferation in neurosurgical research.

OBJECTIVE: Authorship proliferation in biomedical research has become rampant; the proportion of single-author articles is decreasing, the percentage of multiauthor articles is increasing, and the number of authors per publication is increasing. To determine whether authorship trends in the North American neurosurgical literature parallel trends observed in other areas of the biomedical literature, I studied original neurosurgical research articles published in the past 50 years. METHODS: I sampled clinical, anatomic, and laboratory investigations in Neurosurgery and the Journal of Neurosurgery at 10-year intervals from 1945 to 1995. For each research article, I determined the number of authors, the countries of origin, and the educational degrees of the authors. RESULTS: The mean number of authors per article has increased steadily in the past 50 years, from 1.8 (standard deviation, +/-0.8) authors per article in 1945 to 4.6 (standard deviation, +/-2.1) authors in 1995. The proportion of single-author articles is decreasing; these articles accounted for 43% of articles in 1945 and only 3% of articles in 1995. Increases in the proportions of non-M.D. authors and of articles originating outside the United States were also observed. CONCLUSION: The proliferation of multiauthor articles and the decrease in the proportion of single-author articles in the neurosurgical literature parallel trends observed in many other areas of biomedical research. Possible explanations include larger research teams, variable or absent journal criteria for defining authorship, and the increased awarding of "gift" authorships.

Cost and outcomes analysis.

Cerebral aneurysms and their treatment have numerous consequences for patients and society, including loss of life, permanent neurologic deficits, decreased functioning in daily life, vast expenditures of health care resources, and loss of economic productivity. By the use of administrative, clinical, functional, and economic data, outcomes research increases neuro-surgeons' understanding of aneurysmal disease, and consequently, our ability to provide more effective interventions.

Hypertension, small size, and deep venous drainage are associated with risk of hemorrhagic presentation of cerebral arteriovenous malformations.

OBJECTIVE: To identify clinical and angiographic factors of cerebral arteriovenous malformations (AVMs) associated with hemorrhage to improve the estimation of the risks and help guide management in clinical decision making. METHODS: We conducted a retrospective analysis of 100 consecutive adults who have presented during the past 3 years to our institution with cerebral AVMs. Angiographic and clinical parameters were evaluated using multivariate logistic regression analysis to analyze factors associated with hemorrhagic presentation. RESULTS: The group had a mean age of 37.8 years; 53% were men, 48% presented with intracranial hemorrhage, and 40% presented with seizures. All 10 patients with cerebellar AVMs presented with hemorrhage. The following factors were independently associated with AVM hemorrhage: history of hypertension (P = 0.019; odds ratio [OR] = 5.36), nidal diameter <3 cm (P = 0.023: OR = 4.60), and deep venous drainage (P = 0.009: OR = 5.77). Dural arterial supply (P = 0.008; OR = 0.15) was independently associated with decreased risk of bleed. Location, nidal aneurysms, patient age, and smoking were not associated with increased or decreased bleeding risk. CONCLUSION: In this study, we found small AVM size and deep venous drainage to be positively associated with AVM hemorrhage. Dural supply was associated with a decreased likelihood of hemorrhagic presentation. Hypertension was found to be the only clinical factor positively associated with hemorrhage, a finding not previously reported. Smoking, although associated with increased risk of aneurysmal subarachnoid hemorrhage, was not associated with a higher risk of AVM hemorrhage.

Management of incidental pituitary microadenomas: a cost-effectiveness analysis.

The objective of this study was to compare the cost-effectiveness of four management strategies for a patient with an incidentally discovered asymptomatic pituitary microadenoma. A decision analytic Markov model was used to determine the incremental cost-effectiveness of four clinical management strategies: 1) expectant management, 2) PRL screening, 3) an endocrine screening panel (PRL, insulin-like growth factor I, and 1-mg dexamethasone suppression test), and 4) magnetic resonance imaging (MRI) follow-up. The model incorporated the natural history of incidental microadenomas, test characteristics, pharmacological and surgical treatment outcomes, patient's quality of life, discounting, and the costs of hormone testing, bromocriptine, MRIs, hospitalization for surgery, and physician services. PRL screening, endocrine screening panel, and MRI follow-up all provided slightly greater quality-adjusted survival than expectant management, but the costs increased disproportionately more than the benefits. The incremental cost per quality-adjusted life year for PRL screening is $1,428, and that for the endocrine screening panel is $69,495. These results are most sensitive to patient anxiety about the microadenoma; increased anxiety shifts the recommended strategy to the endocrine screening panel. We conclude that in patients with an incidental asymptomatic pituitary microadenoma, a single PRL test may be the most cost-effective management strategy.

Epidemiology of aneurysmal subarachnoid hemorrhage.

An estimated 1% to 5% of adults have a cerebral aneurysm. Each year, approximately 1 in 10,000 North Americans suffer an aneurysmal subarachnoid hemorrhage, with greater than 50% combined morbidity and mortality. Cerebral aneurysm formation and rupture is associated with a variety of factors, including increasing age, female gender, hypertension, alcohol, smoking, and genetic factors.

Cigarette smoking-induced increase in the risk of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage.

Vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is correlated with the thickness of blood within the basal cisterns on the initial computerized tomography (CT) scan. To identify additional risk factors for symptomatic vasospasm, the authors performed a prospective analysis of 75 consecutively admitted patients who were treated for aneurysmal SAH. Five patients who died before treatment or were comatose postoperatively were excluded from the study. Of the remaining 70 patients, demographic (age, gender, and race) and clinical (hypertension, diabetes, coronary artery disease, smoking, alcohol abuse, illicit drug use, sentinel headache, Fisher grade, Hunt and Hess grade, World Federation of Neurological Surgeons grade, and ruptured aneurysm location) parameters were evaluated using multivariate logistic regression to determine factors independently associated with cerebral vasospasm. All patients were treated with hypervolemic therapy and administration of nimodipine as prophylaxis for vasospasm. Cerebral vasospasm was suspected in cases that exhibited (by elevation of transcranial Doppler velocities) neurological deterioration 3 to 14 days after SAH with no other explanation and was confirmed either by clinical improvement in response to induced hypertension or by cerebral angiography. The mean age of the patients was 50 years. Sixty-three percent of the patients were women, 74% were white, 64% were cigarette smokers, and 46% were hypertensive. Ten percent of the patients suffered from alcohol abuse, 19% from sentinel bleed, and 49% had a Fisher Grade 3 SAH. Twenty-nine percent of the patients developed symptomatic vasospasm. Multivariate analysis demonstrated that cigarette smoking (p = 0.033; odds ratio 4.7, 95% confidence interval [CI] 2.4-8.9) and Fisher Grade 3, that is, thick subarachnoid clot (p = 0.008; odds ratio 5.1, 95% CI 2-13.1), were independent predictors of symptomatic vasospasm. The authors make the novel observation that cigarette smoking increases the risk of symptomatic vasospasm after aneurysmal SAH, independent of Fisher grade.

A cost-effectiveness analysis of anterior temporal lobectomy for intractable temporal lobe epilepsy.

Patients with medically intractable temporal lobe epilepsy are potential candidates for anterior temporal lobectomy (ATL), in which epileptogenic temporal lobe tissue is localized and surgically removed. This surgical approach can eliminate or drastically reduce seizures in the majority of patients. The authors used a decision-analysis model to examine the cost-effectiveness of a surgical evaluation and treatment protocol for medically intractable temporal lobe epilepsy. This model compared a cohort treated with the new protocol with a continuation of their immediate preoperative medical management and projected these differences over the patient's lifetime. The Markov model incorporated postoperative seizure status, patient quality of life, death from surgical and natural causes, discounting, and the direct medical costs associated with outpatient evaluation, hospitalization, surgery, antiepileptic drugs, and lifetime outpatient treatment. The intent-to-treat analysis included patients who underwent evaluation but were not eligible for ATL. Sensitivity analyses were also performed on the variables in the model. Data from the baseline model indicated that evaluation for ATL provided an average of 1.1 additional quality-adjusted life years (QALYs) compared with continued medical management, at an additional cost of $29,800. Combining the clinical and economic outcomes yielded a cost-effectiveness ratio of $27,200 per QALY. This value is comparable to other accepted medical or surgical interventions, such as total knee arthroplasty ($16,700/QALY) or coronary artery balloon angioplasty ($40,800/QALY). Sensitivity analyses demonstrate that the results are critically dependent on postoperative seizure status and improvement in quality of life. Although further work is necessary to quantify the improvement in quality of life after epilepsy surgery better, the present data indicate that ATL for treatment of intractable temporal lobe epilepsy is a cost-effective use of medical resources.

Do acute care for elders units increase hospital costs? A cost analysis using the hospital perspective.

OBJECTIVE: To compare the hospital costs of caring for medical patients on a special unit designed to help older people maintain or achieve independence in self-care activities with the costs of usual care. DESIGN: A randomized controlled study. PARTICIPANTS: A total of 650 medical patients (mean age 80 years, 67% women, 41% nonwhite) assigned randomly to either the intervention unit (n = 326) or usual care (n = 324). MEASURES: The hospital's resource-based cost of caring for patients was determined from the hospital's cost-accounting system. The cost of the intervention program was estimated and included in the intervention patients' total hospital cost. RESULTS: The development and maintenance costs of the intervention added $38.43 per bed day to the intervention patients' hospital costs. As a result, the cost per day to the hospital was slightly higher in the intervention patients than in the control patients ($876 vs $847, P = .076). However, the average length of stay was shorter for intervention patients (7.5 vs 8.4 days, P = .449). As a result, the hospital's total cost to care for intervention patients was not greater than caring for usual-care patients ($6608 in intervention patients vs $7240 in control patients, P = .926). Sensitivity analysis demonstrated that the cost of the intervention program would need to be 220% greater than estimated before intervention patients would be more expensive then control patients. There were no examined subgroups of patients in whom care on the intervention unit was significantly more expensive than care on the usual-care unit. Ninety-day nursing home use was lower in intervention than control patients (24.1% vs 32.3%, P = .034). Ninety-day readmission rates (36.7% vs 41.1%, P = .283) and caregiver strain scores (3.3 vs. 2.7, P = .280) were similar. CONCLUSION: Caring for patients on an intervention ward designed to improve functional outcomes in older patients was not more expensive to the hospital than caring for patients on a usual-care ward even though the intervention ward required a commitment of hospital resources.

Elective surgery for asymptomatic, unruptured, intracranial aneurysms: a cost-effectiveness analysis.

Cost-effectiveness analysis uses both economic and clinical outcomes data to evaluate treatment options. In this era of economic constraints on health care, treatments that are not cost-effective will increasingly be denied public and private insurance reimbursement. The authors used mathematical modeling techniques to assess the cost-effectiveness of elective surgery for the treatment of asymptomatic, unruptured, intracranial aneurysms. Input values for the Markov model used in this study were determined from both the literature and clinical judgment. Direct medical costs for hospitalization and physician fees were derived from Medicare cost reports and resource-based relative-value units, expressed in 1992 U.S. dollars. Costs and benefits were discounted at an annual rate of 5%. Using baseline model assumptions for a 50-year-old patient, elective aneurysm surgery provides an average of 0.88 additional quality-adjusted life years (QALYs) compared with nonsurgical treatment. However, prompt elective surgery ($23,300) costs more than expectant management ($2100), in which only patients whose aneurysms rupture incur treatment costs. Combining the outcomes and cost data, the incremental cost-effectiveness of elective aneurysm surgery is $24,200 per QALY, which is comparable to other accepted medical or surgical interventions, such as total knee arthroplasty ($15,200/QALY) or antihypertensive therapy in a 50-year-old patient ($29,800/QALY). Prompt elective surgery for asymptomatic, unruptured, intracranial aneurysms is recommended as a cost-effective use of medical resources provided: 1) surgical morbidity and mortality remain at reported levels; 2) the patient has a life expectancy of at least 13 additional years; and 3) the patient experiences a decrease in quality of life from knowingly living with an unruptured aneurysm.

Morbidity and mortality from elective surgery for asymptomatic, unruptured, intracranial aneurysms: a meta-analysis.

A meta-analysis of the literature on morbidity and mortality from elective surgery for asymptomatic unruptured intracranial aneurysms was performed to obtain a more precise, accurate, and generalizable estimate of operative risk than is currently available. The authors used a MEDLINE search from 1966 to 1992, supplemented with manual searches, to locate studies containing four or more patients who had undergone elective surgery for these aneurysms. Only patients with asymptomatic, unruptured aneurysms were eligible for inclusion. Demographic and clinical data were collected from each series; aneurysms were categorized as incidental, multiple, or unclassifiable. Data were analyzed using Fisher's exact test and logistical regression. There were twenty-eight articles containing data on 733 patients who met eligibility criteria. The mean patient age was 48.6 +/- 5.5 years, and 55% +/- 17% of the patients were women. There was a total of 30 deficits for a morbidity rate of 4.1% (95% confidence interval 2.8, 5.8%) and a total of seven deaths for a mortality rate of 1.0% (95% confidence interval 0.4, 2.0%). There was insufficient statistical power to detect a difference in morbidity or mortality rates related to study size, year of publication, or potential risk factors such as patient sex or age, or aneurysm size, location, or category (incidental, multiple, or unclassifiable) (for all analyses, p > or = 0.16). Elective surgery for asymptomatic unruptured intracranial aneurysms, as reported in the literature, has low rates of morbidity (4.1%) and mortality (1.0%). At present there is insufficient detail in the literature to understand the impact of patient and aneurysm characteristics on elective surgical outcomes.