Comparative safety and tolerability of duloxetine vs. pregabalin vs. duloxetine plus gabapentin in patients with diabetic peripheral neuropathic pain.

OBJECTIVE: The safety and tolerability of three treatments for diabetic peripheral neuropathic pain (DPNP) were compared. METHODS: A 12-week, randomized, open-label study confirming the non-inferiority of duloxetine (N = 138) vs. pregabalin (N = 134) and the combination of duloxetine plus gabapentin (N = 135) as the primary outcome was previously published. Patients had an inadequate pain response to a stable dose of gabapentin (≥ 900 mg/day) for ≥ 5 weeks prior to study enrolment. Data from that study were assessed in this current analysis for a detailed report of safety and tolerability. RESULTS: Completion rates did not differ significantly between the groups. Discontinuation because of adverse events was significantly greater in the duloxetine (19.6%) vs. pregabalin group (10.4%; p = 0.04); no differences emerged between the duloxetine vs. duloxetine plus gabapentin (13.3%) groups (p = 0.19) or pregabalin vs. duloxetine plus gabapentin groups (p = 0.57). Adverse event rates varied: nausea, insomnia, hyperhidrosis and decreased appetite were reported significantly more often in patients treated with duloxetine vs. patients treated with pregabalin (each p ≤ 0.01); insomnia significantly more in patients treated with duloxetine vs. duloxetine plus gabapentin (p = 0.01); peripheral oedema significantly more in patients treated with pregabalin vs. duloxetine and duloxetine plus gabapentin (p ≤ 0.001 each) and nausea, hyperhidrosis, decreased appetite and vomiting significantly more in patients treated with duloxetine plus gabapentin vs. pregabalin (each p ≤ 0.05). At end-point, weight change differed significantly among treatment groups: patients in the pregabalin group on average gained weight (1.0 ± 0.04 kg); while, patients in the duloxetine and duloxetine plus gabapentin groups on average lost weight (-2.39 ± 0.04 and -1.06 ± 0.04 kg, respectively) (pregabalin vs. duloxetine, p ≤ 0.001; pregabalin vs. duloxetine plus gabapentin, p ≤ 0.001; duloxetine vs. duloxetine plus gabapentin, p = 0.01). CONCLUSION: Duloxetine, pregabalin and duloxetine plus gabapentin were generally safe and tolerable for the treatment of DPNP.

Responsiveness of the Intermittent and Constant Osteoarthritis Pain (ICOAP) scale in a trial of duloxetine for treatment of osteoarthritis knee pain.

OBJECTIVE: To assess the change in the Intermittent and Constant Osteoarthritis Pain (ICOAP)-scale scores in patients taking duloxetine or placebo and to characterize the responsiveness of the ICOAP by comparing the effect size associated with its scales to effect sizes seen with other pain scales used in this study. METHODS: This was a secondary analysis of data from a 10-week, double-blind, randomized, flexible-dose, placebo-controlled trial that enrolled patients who had persistent moderate pain due to osteoarthritis (OA) of the knee, despite having received nonsteroidal anti-inflammatory drug (NSAID) therapy. The pain measures used in this study (focusing on the drug-placebo difference at week 8) were patient-rated pain severity, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Brief Pain Inventory (BPI), and the ICOAP. RESULTS: The mean difference between duloxetine and placebo at week 8 for patient-rated pain severity, the BPI average pain, WOMAC pain, and each ICOAP scale was statistically significant (P < 0.001 for each). The ICOAP total showed a moderate effect size of 0.53, whereas the constant and intermittent scores showed effect sizes of 0.47 and 0.49, respectively. The patient-rated pain severity and the BPI average pain showed similar moderate effect sizes of 0.59 and 0.53, respectively. CONCLUSION: The study demonstrated efficacy of duloxetine compared with placebo when using the ICOAP scale in a placebo-controlled trial. The observed treatment effect size for the ICOAP scores was similar to that for other reliable, valid and responsive pain assessments. CLINICAL TRIALS REGISTRATION: ClinicalTrial.gov Identifier: NCT01018680.

The impact of analytic method on interpretation of outcomes in longitudinal clinical trials.

AIMS: Various analytical strategies for addressing missing data in clinical trials are utilised in reporting study results. The most commonly used analytical methods include the last observation carried forward (LOCF), observed case (OC) and the mixed model for repeated measures (MMRM). Each method requires certain assumptions regarding the characteristics of the missing data. If the assumptions for any particular method are not valid, results from that method can be biased. Results based on these different analytical methods can, therefore, be inconsistent, thereby making interpretation of clinical study results confusing. In this investigation, we compare results from MMRM, LOCF and OC in order to illustrate the potential biases and problems in interpretation. METHODS: Data from an 8-month, double-blind, randomised, placebo-controlled (placebo; n = 137), outpatient depression clinical trial comparing a serotonin-noradrenalin reuptake inhibitor (SNRI; n = 273) with a selective serotonin reuptake inhibitor (SSRI; n = 274) were used. The study visit schedule included efficacy and safety assessments weekly to week 4, bi-weekly to week 8, and then monthly. Visitwise mean changes for the 17-item Hamilton Depression Rating Scale (HAMD(17)) Maier subscale (primary efficacy outcome), blood pressure, and body weight were analysed using LOCF, MMRM and OC. RESULTS: Last observation carried forward consistently underestimated within-group mean changes in efficacy (benefit) and safety (risk) for both drugs compared with MMRM, whereas OC tended to overestimate within-group changes. CONCLUSIONS: Inferences are based on between-group comparisons. Therefore, whether or not underestimating (overestimating) within-group changes was conservative or anticonservative depended on the relative magnitude of the bias in each treatment and on whether within-group changes represented improvement or worsening. Preference should be given in analytic plans to methods whose assumptions are more likely to be valid rather than relying on a method based on the hope that its results, if biased, will be conservative.

Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade.

OBJECTIVES: We examined the time course of ventricular functional improvement in patients with dilated cardiomyopathy who received beta-blockade and the long-term effects of beta-blockade on ventricular mass and geometry in these patients. BACKGROUND: Previous studies have shown that beta-adrenergic blocking agents when administered long term improve ventricular function in patients with heart failure. However, the time course of improvement in ventricular function and the long-term effects of beta-blockade on ventricular mass and geometry are not known. METHODS: Twenty-six men with dilated cardiomyopathy underwent serial echocardiography on days 0 and 1 and months 1 and 3 of either metoprolol (n = 16) or standard therapy (n = 10). At 3 months all patients on standard therapy were crossed over to metoprolol, and late echocardiograms were obtained after 18 +/- 5 (mean +/- SD) months of metoprolol therapy. All echocardiograms were read in blinded manner. RESULTS: Patients treated with metoprolol had an initial decline (day 1 vs. day 0) in ventricular function (increase in end-systolic volume and decrease in ejection fraction). Ventricular function improved between months 1 and 3 (p = 0.013, metoprolol vs. standard therapy). Left ventricular mass regressed at 18 months (333 +/- 85 to 275 +/- 53 g, p = 0.011) but not at 3 months. Left ventricular shape became less spherical and assumed a more normal elliptical shape by 18 months (major/minor axis ratio 1.5 +/- 0.2 to 1.7 +/- 0.2, p = 0.0001). CONCLUSIONS: Patients with heart failure treated with metoprolol do not demonstrate an improvement in systolic performance until after 1 month of therapy and may have a mild reduction in function initially. Long-term therapy with metoprolol results in a reversal of maladaptive remodeling with reduction in left ventricular volumes, regression of left ventricular mass and improved ventricular geometry by 18 months.

Predictors of systolic and diastolic improvement in patients with dilated cardiomyopathy treated with metoprolol.

OBJECTIVES: The aim of this study was to determine which patients will have systolic and diastolic improvement after beta-blockade with metoprolol. BACKGROUND: Beta-adrenergic blocking agents improve systolic and diastolic function in patients with heart failure. However, it is unclear which patients will respond best to therapy. METHODS: We retrospectively examined baseline characteristics of 24 patients who underwent double-blind then open-label treatment with metoprolol to determine which characteristic predicted improvement in systolic and diastolic function. Degree of improvement in systolic function (22 patients) was defined by the change in left ventricular ejection fraction after 3 months of therapy. Degree of improvement in diastolic function (15 patients) was defined as the change in left ventricular end-diastolic pressure and change in the slope of the isovolumetric relaxation rate-end-systolic pressure relation. RESULTS: Both systolic blood pressure at baseline (r = 0.54, p = 0.009) and the maximal positive value of the first derivative of left ventricular pressure with respect to time (peak +dP/dt) at baseline (r = 0.39, p = 0.07) correlated with improvement in ejection fraction after metoprolol treatment. Stepwise logistic regression demonstrated that only peak systolic pressure was an independent predictor of systolic improvement. Baseline heart rate, ventricular volumes, ejection fraction and adrenergic activation, as reflected by coronary sinus norepinephrine, did not predict response. Patients with the most diastolic impairment at baseline had the most favorable diastolic improvement. Those with the lowest myocardial respiratory quotient (most fatty acid utilization) at baseline also had the most marked reduction in left ventricular end-diastolic pressure. CONCLUSIONS: These data suggest that those patients with the highest peak systolic pressure, highest left ventricular end-diastolic pressure and most prolonged isovolumetric relaxation at baseline will respond best to therapy with metoprolol. However, other patients without these characteristics may also benefit.

Treatment of atypical depression with cognitive therapy or phenelzine: a double-blind, placebo-controlled trial.

BACKGROUND: Patients with atypical depression are more likely to respond to monoamine oxidase inhibitors than to tricyclic antidepressants. They are frequently offered psychotherapy in the absence of controlled tests. There are no prospective, randomized, controlled trials, to our knowledge, of psychotherapy for atypical depression or of cognitive therapy compared with a monoamine oxidase inhibitor. Since there is only 1 placebo-controlled trial of cognitive therapy, this trial fills a gap in the literature on psychotherapy for depression. METHODS: Outpatients with DSM-III-R major depressive disorder and atypical features (N = 108) were treated in a 10-week, double-blind, randomized, controlled trial comparing acute-phase cognitive therapy or clinical management plus either phenelzine sulfate or placebo. Atypical features were defined as reactive mood plus at least 2 additional symptoms: hypersomnia, hyperphagia, leaden paralysis, or lifetime sensitivity to rejection. RESULTS: With the use of an intention-to-treat strategy, the response rates (21-item Hamilton Rating Scale for Depression score, < or =9) were significantly greater after cognitive therapy (58%) and phenelzine (58%) than after pill placebo (28%). Phenelzine and cognitive therapy also reduced symptoms significantly more than placebo according to contrasts after a repeated-measures analysis of covariance and random regression with the use of the blind evaluator's final Hamilton Rating Scale for Depression score. The scores between cognitive therapy and phenelzine did not differ significantly. Supplemental analyses of other symptom severity measures confirm the finding. CONCLUSIONS: Cognitive therapy may offer an effective alternative to standard acute-phase treatment with a monoamine oxidase inhibitor for outpatients with major depressive disorder and atypical features.

Expression of telomerase RNA component correlates with the MIB-1 proliferation index in ependymomas.

Although there is general agreement that certain morphologic subtypes of ependymoma are benign, the biologic behavior of other ependymal neoplasms is poorly understood and not clearly related to conventional histopathologic criteria. The absence of universally accepted standards has prompted the search for more objective biologic markers. Telomerase is an RNA-containing enzyme associated with immortality in proliferating stem cells and many tumors. We investigated the proliferative activity of 26 ependymomas as determined by MIB-1 immunolabeling and compared the results with the in situ expression of human telomerase RNA (hTR) and WHO tumor grade. The study included 9 WHO grade I ependymomas (6 subependymomas and 3 myxopapillary ependymomas), 13 WHO grade II ependymomas, and 4 anaplastic (WHO grade III) ependymomas. The proliferation index (PI) and telomerase RNA expression were significantly increased in grade III ependymomas (p < 0.0001 for PI and p = 0.0015 for hTR). In these tumors, the PI and hTR expression were highly correlated (p = 0.0001). Of note, a single case designated grade II showed both increased proliferative activity and the highest hTR expression detected in this series of ependymal neoplasms. Our results suggest that the PI and hTR expression may be important biologic markers, independent of other histopathologic criteria of tumor grade. Future studies examining the correlation of MIB-1 cell kinetics and hTR expression with clinical parameters in selected ependymoma subtypes are needed to determine the prognostic relevance of these markers.

Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson disease.

We undertook this study to investigate the neuropathologic relationships among Alzheimer disease (AD), idiopathic Parkinson disease (PD), and the Lewy body variant of AD (AD/LBV). We retrieved 30 autopsy cases in which Lewy bodies (LB) had been identified in the substantia nigra (SN) in routine hematoxylin-eosin-stained sections. Twenty-two of the cases had a primary clinical diagnosis of dementia and neuropathologic changes of AD; 12 of these demented patients also had clinical parkinsonism. Eight cases had clinical and neuropathologic evidence of PD with minimal or no AD neuropathology, though 6 had clinical dementia. Controls consisted of 6 cases of AD without SN LB by hematoxylin-eosin, and 5 neurologically normal aged controls. Paraffin sections of SN, superior temporal gyrus, and cingulate gyrus from each case were immunostained with rabbit anti-ubiquitin antiserum, randomized, and analyzed individually by light microscopy, and the density of LB-like profiles in each section were graded. None of 5 nondemented aged controls showed any neocortical LB, even though 2 had significant numbers of incidental SN LB by ubiquitin immunostaining. Of 6 AD cases without SN LB by hematoxylin-eosin, 3 had rare SN LB on ubiquitin stain, 1 of which showed rare neocortical Lewy-like profiles. Seven of 8 PD cases showed neocortical LB, including the 6 with dementia. Twenty-one of 22 AD cases with SN LB showed ubiquitin-immunoreactive Lewy-like bodies in the neocortex that were statistically significantly greater in number than in either pure PD or pure AD cases. The frequent occurrence of LB in the neocortex in PD alone suggests that AD/LBV likely represents mixed AD/PD. However, AD neuropathology may favor or promote the formation of neocortical LB in patients who go on to develop mixed AD/PD pathology.

Neocortical synapse density and Braak stage in the Lewy body variant of Alzheimer disease: a comparison with classic Alzheimer disease and normal aging.

Substantial numbers of cortical and subcortical Lewy bodies are seen in approximately one quarter of patients whose brains show sufficient histopathologic changes for a neuropathologic diagnosis of definite Alzheimer disease (AD). This subset of cases has been named the Lewy body variant of AD (LBV). Despite comparable dementia and the presence of neocortical senile plaques in LBV patients, the overall burden of neuropathologic changes, in particular neurofibrillary tangles (NFT), is less than in classic AD. While NFT frequency correlates with dementia severity in classic AD, the cognitive impairment in patients with LBV cannot be completely explained by such changes. Since several studies have suggested a role for synapse loss in relation to dementia severity in classic AD, we decided to investigate the role of synapse loss as a candidate for the cognitive impairment of LBV. The Braak staging method is based upon the distribution and severity of neurofibrillary changes, and one therefore would expect LBV cases to be assigned to lower Braak stages. In the present study we assigned a Braak stage to 14 LBV cases, 31 classic AD cases, and a group of 10 non-demented aged controls. We compared the severity of synapse loss as determined by ELISA immunoassay for synaptophysin and Braak stage among the three diagnostic groups. When compared to normal controls, synaptophysin concentrations were statistically significantly lower in both demented groups. There was comparable synapse loss in LBV and AD despite significantly lower Braak stages in the LBV cases. These results suggest a major role for loss of synapses as the substrate of cognitive impairment in LBV.

Cortisol secretion and Alzheimer's disease progression: a preliminary report.

We report preliminary findings in a study of the relationship of plasma cortisol concentration (CORT) to the clinical progression of Alzheimer's disease (AD), testing the hypotheses that CORT predicts AD progression and that CORT increases as the disease advances. In 12 subjects with NINCDS/ADRDA probable AD, we performed cognitive testing and plasma cortisol determinations at baseline and again in 12 months. A modified Alzheimer's Disease Assessment Scale-Cognitive (ADAS-COG) measured disease progression. Plasma cortisol concentration CORT was determined at 12 AM and 1 PM, and an Afternoon Cortisol Test (ACT) was used to estimate average 24-hr CORT. Baseline 12 AM CORT correlated with the change in ADAS-COG from start of study to 12 months. No cortisol measure increased over the study period; estimated average 24-hr CORT and 12 AM CORT remained constant, whereas while 1 PM CORT declined. There was no relationship between age or duration of illness and any of the cortisol measures at baseline.

Cortisol secretion and Alzheimer's disease progression.

BACKGROUND: Mild hypercortisolemia is a frequent concomitant of Alzheimer's disease (AD). In an effort to ascertain the relationship between serum cortisol concentration (CORT) and disease progression, aging, and survival, we followed 9 persons with AD, ages from 56 to 84 years, from an original cohort of 19 enrollees with serial cognitive testing and CORT determinations. METHODS: The cognitive instrument was a modification of the Alzheimer's Disease Assessment Scale-Cognitive (mADAS-COG). Serum cortisol determinations were performed at noon, and an Afternoon Cortisol Test (ACT) was used to obtain an estimate of average CORT. RESULTS: Baseline 12:00 hours CORT but not ACT correlated significantly with the change in mADAS-COG (r = .90, p < .01). ACT levels increased as the mADAS-COG increased over time (p = .037), by 0.156 +/- 0.06 microgram/dL for each one-point increase (indicating greater impairment) in cognitive test score. ACT levels did not increase significantly simply with aging. For the entire cohort of 19 subjects, neither baseline ACT nor 12:00 hours CORT was significantly related to survival. CONCLUSIONS: Hypercortisolemia in AD appears related to the clinical progression of the disease, but not to aging or length of survival.

Apolipoprotein E epsilon 4, other risk factors, and course of Alzheimer's disease.

BACKGROUND: The epsilon 4 allele of apolipoprotein E (apoE epsilon 4) is associated with late-onset Alzheimer's disease (AD), but its relationship to various aspects of AD has become increasingly unclear. We studied the relationship of apoE genotype in AD to educational attainment, history of heart disease or head injury, age of onset, gender, severity of illness, depression, psychotic symptoms, rate of dementia progression, and time from initial evaluation to nursing home placement. METHODS: ApoE epsilon 4 genotype was determined for 97 clinically diagnosed AD patients and 61 neuropathologically confirmed cases of AD. RESULTS: Presence of one or more epsilon 4 alleles occurred in 66% of AD cases as compared with 27% in control subjects (allele frequency was .40 for AD, .15 for control subjects). Among AD subjects there was no significant relationship between epsilon 4 alleles and educational attainment, history of heart disease, head injury, age of onset, severity of illness, depression, history of depression, rate of dementia progression, or time to nursing home placement. Marginal correlations emerged between number of epsilon 4 alleles, and delusions (p = .05) and hallucinations (p = .05). There was a trend toward increased epsilon 4 homozygosity in patients with onset between ages 65 and 70 years. CONCLUSIONS: We did not find that individuals with one or two apoE epsilon 4 alleles differed significantly in clinical course of AD from those without epsilon 4 except for a trend toward increased psychotic symptoms in the group as a whole and an increase in epsilon 4 homozygosity in patients with reported symptom onset in the late 60s.

Alzheimer's disease and its Lewy body variant: a clinical analysis of postmortem verified cases.

OBJECTIVE: The authors compared clinical findings of Alzheimer's disease and the so-called Lewy body variant of Alzheimer's disease. METHOD: Available data were analyzed on the clinical features of 58 patients with Alzheimer's disease and 24 patients with the Lewy body variant of Alzheimer's disease who underwent postmortem examination. RESULTS: The proportion of men was significantly larger in the Lewy body variant group than in the Alzheimer's disease group (66.7% versus 34.5%), and, concordantly, the Lewy body variant group was slightly taller. The prevalence of hallucinations and delusions was significantly higher in Lewy body variant subjects than the Alzheimer's disease subjects, but there were no significant differences between the two groups in educational attainment, family history of dementia, age at onset, duration of illness, cognitive impairment, overall severity of illness, or neuropsychological findings. Patients with the Lewy body variant of Alzheimer's disease tended to experience more frequent extrapyramidal side effects of neuroleptics than did the patients with Alzheimer's disease, but for patients in the two groups who were not exposed to neuroleptics, there was little difference in frequency of extrapyramidal side effects. CSF concentration of homovanillic acid (HVA) was significantly lower in the Lewy body variant patients, even when correction was made for height. CONCLUSIONS: The Lewy body variant of Alzheimer's disease may be suspected in elderly male dementia patients who otherwise meet criteria for Alzheimer's disease but who manifest significant psychiatric symptoms and neuroleptic-induced extrapy-ramidal side effects and have low levels of CSF HVA.

Genetic factors for the development of Alzheimer disease in the Cherokee Indian.

OBJECTIVE: To study the relationship between the genetic degree of Cherokee ancestry, the apolipoprotein E *E4 (APOE*E4) allele type, and the development of Alzheimer disease (AD) in individuals from the Cherokee Nation who reside in northeastern Oklahoma. SETTING: Alzheimer disease center satellite clinic and university departments of neurology, psychiatry, and academic computing. DESIGN: Standardized dementia evaluations based on criteria from the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association were performed on 26 patients aged 65 years or older to establish a diagnosis of AD. Twenty-six control subjects were recruited and similarly assessed. The APOE allele type determinations were obtained on all patients and control subjects. Appropriate statistical analyses were used to compare the genetic degree of Cherokee ancestry, the APOE allele type, and the development of AD. RESULTS: The data indicated that as the genetic degree of Cherokee Indian ancestry increased, the representation of AD decreased. The 9 patients with AD with a greater than 50% genetic degree of Cherokee ancestry constituted 35% of the group with AD. The 17 remaining patients with AD who were less than 50% Cherokee constituted 65% of the group with AD. In contrast, 17 (65%) of the control subjects were more than 50% Cherokee; only 9 (35%) were less than 50% Cherokee. These percentages of AD were not changed by the *E4 allele. This inverse relationship between the genetic degree of Cherokee ancestry and AD, independent of the APOE*E4 allele status, diminished with increasing age, suggesting an age-related protective effect of being Cherokee. For a decrease of 10% in Cherokee ancestry, the odds of developing AD are estimated to be 9.00 times greater at age 65 years but only 1.34 times greater at age 80 years. CONCLUSIONS: A greater genetic degree of Cherokee ancestry reduces the risk of developing AD and, thus, seems protective. This protective genetic factor is independent of APOE allele type and diminishes with age.

Cerebrospinal fluid interleukin 1-beta and tumor necrosis factor concentrations and outcome from neonatal gram-negative enteric bacillary meningitis.

Concentrations of interleukin 1-beta and tumor necrosis factor in cerebrospinal fluid (CSF) of 42 neonates with Gram-negative enteric bacillary meningitis were determined and correlated with outcome and other CSF indices. At the time of diagnosis interleukin 1-beta was detected in CSF of 40 infants and peak concentrations correlated significantly with outcome from disease. Days of interleukin 1-beta concentrations of greater than 200 pg/ml or greater than or equal to 20 pg/ml were significantly correlated with days that CSF cultures were positive and that K1 antigen and endotoxin were detected in CSF. Tumor necrosis factor activity was detected in CSF of 25 of 27 infants; there was no correlation between outcome and CSF tumor necrosis factor concentrations. The results provide a possible rationale for therapeutic intervention to improve outcome.

Preoperative embolization of cerebral arteriovenous malformations with polyvinyl alcohol particles: experience in 51 adults.

In order to determine possible risk factors and to assess the value of platinum microcoils added to polyvinyl alcohol particles in preoperative embolization of cerebral arteriovenous malformations in adults, we reviewed our experience with this procedure. Between September 1985 and June 1989, we performed embolizations in 54 patients with cerebral arteriovenous malformations. Of these, procedures in 51 adults involved the use of polyvinyl alcohol particles, either alone (n = 29) or in combination with platinum microcoils (n = 21). A complication during catheterization precluded embolization in another patient. Beginning as flow-directed embolizations via carotid artery catheterizations (n = 12), newer catheters allowed progression to superselective intracerebral catheterizations (n = 38). Embolization has led to shorter surgical procedures, more clearly defined operative margins, and less bloody operative fields. We have not found recanalization to significantly hinder embolization results with polyvinyl alcohol when resection is undertaken within 1-4 weeks of embolization. Its relative safety and ease of manipulation at surgery argue for its use. We found no significant increase in complications based on patient age, venous drainage of the arteriovenous malformation, or the circulation embolized. Embolization results in cerebral arteriovenous malformations were improved with superselective catheterization and most improved with the combined use of polyvinyl alcohol for nidus embolization followed by occlusion of the feeding vessel with microcoils.

Arteriovenous malformations of the brain: choosing embolic materials to enhance safety and ease of excision.

The authors report their experience with surgical resection of 108 previously embolized arteriovenous malformations (AVM's). Embolization was performed via only transfemoral catheterization in 70 lesions and via the surgical exposure of feeding vessels in 32. The remaining six patients were referred for resection following silicone sphere embolization elsewhere. Materials used included polyvinyl alcohol (PVA) foam, platinum microcoils, detachable silicone balloons, surgical silk, a mixture of 33% ethanol and microfibrillar collagen, and isobutyl cyanoacrylate (IBCA). It is believed that proximal arterial occlusion with balloons is an inferior choice for preresection embolization, because the technical difficulty of placement is high and the nidus of the AVM is unaffected. Vascular coagulation and section and AVM retraction are more difficult with IBCA; therefore, this is also considered an inferior choice. Among the materials studied, the combination of PVA for distal occlusion and microcoils for proximal occlusion appears to be the superior choice. Fewer complications (stroke or hemorrhage) are seen when intraarterial Amytal (amobarbital) testing is used to guide the embolization. Data regarding toxicity, oncogenicity, and vascular metabolism or recanalization associated with PVA, IBCA, and n-butyl cyanoacrylate are reviewed.

Olanzapine versus haloperidol in schizoaffective disorder, bipolar type.

BACKGROUND: The present analysis was performed on data from a subsample of patients with schizoaffective disorder, bipolar type, who participated in a multicenter, double-blind study comparing olanzapine to haloperidol. METHODS: Patients with schizoaffective disorder bipolar type, characterized as currently manic, mixed, depressed, or euthymic, were assessed weekly for 6 weeks during treatment with either olanzapine or haloperidol. Manic symptoms were measured using the sum of six items of the BPRS, and depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale. In addition, cognitive functioning was measured using the sum of seven items from the PANSS. Repeated measures analyses were performed using random coefficients regression of the serial measurement of manic, cognitive, and depressive symptoms. RESULTS: A significant treatment difference was detected overall, indicating that olanzapine was significantly more effective than haloperidol in reducing symptoms of depression and improving patients' cognitive symptoms. The superiority of olanzapine over haloperidol in the reduction of manic symptoms did not reach statistical significance (P=.052). The greatest improvement in both manic and cognitive symptoms was seen in the olanzapine-treated 'currently manic' subgroup, and least improvement in the haloperidol-treated 'euthymic' subgroup. Depressive symptoms were most improved in the olanzapine-treated 'depressed' subgroup, and least improved in the corresponding haloperidol subgroup. CONCLUSIONS: Overall, olanzapine was superior to haloperidol with respect to thymoleptic effects in patients with schizoaffective disorder, bipolar type.

Susceptibility of corneal and conjunctival pathogens to ciprofloxacin.

Ciprofloxacin 0.3% ophthalmic solution has been shown to be effective in the treatment of bacterial keratitis and conjunctivitis, and many physicians use ciprofloxacin as sole therapy in these conditions. In this retrospective study, we found seven of 84 isolates from corneal and conjunctival cultures that were resistant to ciprofloxacin. All of the resistant organisms were gram positive. Six of the isolates (Staphylococcus aureus, Staphylococcus hominis, and four isolates of the Streptococcus viridans group) were from corneal cultures, and one (Staphylococcus aureus) was from a conjunctival culture. Yearly records of systemic isolates from 1988 to 1993 (n = 35,308) demonstrated a statistically significant decrease in susceptibility for several organisms that are common pathogens in the conjunctiva and cornea: Pseudomonas aeruginosa (95-90%, p = 0.001); Staphylococcus aureus (96-87%, p < 0.0001); Staphylococcus spp., coagulase negative (97-81%, p < 0.0001); Enterococcus spp. (92-79%, p < 0.0001); Acinetobacter anitratus (97-77%, p = 0.0006); and Enterobacter cloacae (100-96%, p = 0.03). Although the susceptibility of corneal and conjunctival isolates in this series remained relatively high (91.7%), a much larger series of systemic isolates that are common ocular pathogens revealed a statistically significant increase in resistance to ciprofloxacin over the preceding 5 years.

A prospective open-label treatment trial of olanzapine monotherapy in children and adolescents with bipolar disorder.

OBJECTIVE: The goal of this study was to assess the effectiveness and tolerability of olanzapine in the treatment of acute mania in children and adolescents. METHODS: This was an 8-week, open-label, prospective study of olanzapine monotherapy (dose range 2.5-20 mg/day) involving 23 bipolar youths (manic, mixed, or hypomanic; 5-14 years old). Weekly assessments were made using the Young Mania Rating Scale (YMRS), Clinical Global Impressions Severity Scale (CGI-S), Brief Psychiatric Rating Scale, and Children's Depression Rating Scale. Adverse events were assessed through self-reports, vital sign and weight monitoring, laboratory analytes, and extrapyramidal symptom rating scales (Barnes Akathisia Scale, Simpson-Angus Scale, and Abnormal Involuntary Movement Scale). RESULTS: Twenty-two of the 23 youths (96%) completed the study. Olanzapine treatment was associated with significant improvement in mean YMRS score (-19.0 +/- 9.2, p < 0.001). Using predefined criteria for improvement of > or = 30% decline in the YMRS and a CGI-S Mania score of < or = 3 at endpoint, the overall response rate was 61%. Overall, olanzapine was well tolerated, and extrapyramidal symptom measures were not significantly different from baseline. Body weight increased significantly over the study (5.0 +/- 2.3 kg, p < 0.001). CONCLUSIONS: Open-label olanzapine treatment was efficacious and well tolerated in the treatment of acute mania in youths with bipolar disorder. Future placebo-controlled, double-blind studies are warranted.