Christopher S. Coffey

Predicting Survival in Pulmonary Arterial Hypertension Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL)

Background— Factors that determine survival in pulmonary arterial hypertension (PAH) drive clinical management. A quantitative survival prediction tool has not been established for research or clinical use. Methods and Results— Data from 2716 patients with PAH enrolled consecutively in the US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) were analyzed to assess predictors of 1-year survival. We identified independent prognosticators of survival and derived a multivariable, weighted risk formula for clinical use. One-year survival from the date of enrollment was 91.0% (95% confidence interval [CI], 89.9 to 92.1). In a multivariable analysis with Cox proportional hazards, variables independently associated with increased mortality included pulmonary vascular resistance >32 Wood units (hazard ratio [HR], 4.1; 95% CI, 2.0 to 8.3), PAH associated with portal hypertension (HR, 3.6; 95% CI, 2.4 to 5.4), modified New York Heart Association/World Health Organization functional class IV (HR, 3.1; 95% CI, 2.2 to 4.4), men >60 years of age (HR, 2.2; 95% CI, 1.6 to 3.0), and family history of PAH (HR, 2.2; 95% CI, 1.2 to 4.0). Renal insufficiency, PAH associated with connective tissue disease, functional class III, mean right atrial pressure, resting systolic blood pressure and heart rate, 6-minute walk distance, brain natriuretic peptide, percent predicted carbon monoxide diffusing capacity, and pericardial effusion on echocardiogram all predicted mortality. Based on these multivariable analyses, a prognostic equation was derived and validated by bootstrapping technique. Conclusions— We identified key predictors of survival based on the patients most recent evaluation and formulated a contemporary prognostic equation. Use of this tool may allow the individualization and optimization of therapeutic strategies. Serial follow-up and reassessment are warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214.

2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

Purpose— The aim of this guideline is to provide a focused update of the current recommendations for the endovascular treatment of acute ischemic stroke. When there is overlap, the recommendations made here supersede those of previous guidelines. Methods— This focused update analyzes results from 8 randomized, clinical trials of endovascular treatment and other relevant data published since 2013. It is not intended to be a complete literature review from the date of the previous guideline publication but rather to include pivotal new evidence that justifies changes in current recommendations. Members of the writing committee were appointed by the American Heart Association/American Stroke Association Stroke Council’s Scientific Statement Oversight Committee and the American Heart Association/American Stroke Association Manuscript Oversight Committee. Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statement Oversight Committee and Stroke Council Leadership Committee. Results— Evidence-based guidelines are presented for the selection of patients with acute ischemic stroke for endovascular treatment, for the endovascular procedure, and for systems of care to facilitate endovascular treatment. Conclusions— Certain endovascular procedures have been demonstrated to provide clinical benefit in selected patients with acute ischemic stroke. Systems of care should be organized to facilitate the delivery of this care.Purpose— The aim of this guideline is to provide a focused update of the current recommendations for the endovascular treatment of acute ischemic stroke. Where there is overlap, the recommendations made here supersede those of previous guidelines. Methods— This focused update analyzes results from 8 randomized clinical trials of endovascular treatment and other relevant data published since 2013. It is not intended to be a complete literature review from the date of the previous guideline publication but rather to include pivotal new evidence that justifies changes in current recommendations. Members of the writing committee were appointed by the American Heart Association/American Stroke Association Stroke Council’s Scientific Statement Oversight Committee and the American Heart Association/American Stroke Association Manuscript Oversight Committee (MOC). Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statement Oversight Committee and Stroke Council Leadership Committee. Results— Evidence-based guidelines are presented for the selection of patients with acute ischemic stroke for endovascular treatment, the endovascular procedure and for systems of care to facilitate endovascular treatment. Conclusions— Certain endovascular procedures have been demonstrated to provide clinical benefit in selected patients with acute ischemic stroke. Systems of care should be organized to facilitate the delivery of this care.

The Parkinson Progression Marker Initiative (PPMI)

The Parkinson Progression Marker Initiative (PPMI) is a comprehensive observational, international, multi-center study designed to identify PD progression biomarkers both to improve understanding of disease etiology and course and to provide crucial tools to enhance the likelihood of success of PD modifying therapeutic trials. The PPMI cohort will comprise 400 recently diagnosed PD and 200 healthy subjects followed longitudinally for clinical, imaging and biospecimen biomarker assessment using standardized data acquisition protocols at twenty-one clinical sites. All study data will be integrated in the PPMI study database and will be rapidly and publically available through the PPMI web site- www.ppmi-info.org. Biological samples including longitudinal collection of blood, cerebrospinal fluid (CSF) and urine will be available to scientists by application to an independent PPMI biospecimen review committee also through the PPMI web site. PPMI will rely on a partnership of government, PD foundations, industry and academics working cooperatively. This approach is crucial to enhance the potential for success of this ambitious strategy to develop PD progression biomarkers that will accelerate research in disease modifying therapeutics.

Effects of clopidogrel added to aspirin in patients with recent lacunar stroke.

BACKGROUND Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined. METHODS We conducted a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging. Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. RESULTS The participants had a mean age of 63 years, and 63% were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P=0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone). CONCLUSIONS Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death. (Funded by the National Institute of Neurological Disorders and Stroke and others; SPS3 ClinicalTrials.gov number, NCT00059306.).

Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial

BACKGROUND Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke. METHODS In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306. FINDINGS 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64-1·03, p=0·08), disabling or fatal stroke (0·81, 0·53-1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68-1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15-0·95, p=0·03). Treatment-related serious adverse events were infrequent. INTERPRETATION Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial. FUNDING National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS).

Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial

BACKGROUND The inconsistent effect of hypothermia treatment on severe brain injury in previous trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury. METHODS The National Acute Brain Injury Study: Hypothermia II (NABIS: H II) was a randomised, multicentre clinical trial of patients with severe brain injury who were enrolled within 2·5 h of injury at six sites in the USA and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomly assigned (1:1) by a random number generator to hypothermia or normothermia. Patients randomly assigned to hypothermia were cooled to 35°C until their trauma assessment was completed. Patients who had none of a second set of exclusion criteria were either cooled to 33°C for 48 h and then gradually rewarmed or treated at normothermia, depending upon their initial treatment assignment. Investigators who assessed the outcome measures were masked to treatment allocation. The primary outcome was the Glasgow outcome scale score at 6 months. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, NCT00178711. FINDINGS Enrolment occurred from December, 2005, to June, 2009, when the trial was terminated for futility. Follow-up was from June, 2006, to December, 2009. 232 patients were initially randomised a mean of 1·6 h (SD 0·5) after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia group and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35°C for the 52 patients in the hypothermia group was 2·6 h (SD 1·2) and to 33°C was 4·4 h (1·5). Outcome was poor (severe disability, vegetative state, or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (relative risk [RR] 1·08, 95% CI 0·76-1·53; p=0·67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1·30, 95% CI 0·58-2·52; p=0·52). INTERPRETATION This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury.

Clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy.

PURPOSE The role of radical cystectomy in patients with nonmuscle invasive urothelial carcinoma of the bladder remains controversial. The risk of overtreatment must be balanced against the potential benefit of aggressive therapy. We reviewed our results in these patients with a particular emphasis on clinical under staging. MATERIALS AND METHODS We reviewed the records of 214 consecutive patients who underwent radical cystectomy for urothelial carcinoma between April 1995 and August 1999, focusing on those with nonmuscle invasive, stages T1 or less disease. We assessed clinical and pathological data as well as outcomes based on pathological disease extent. RESULTS A total of 78 patients (36%) underwent radical cystectomy for clinical stages T1 or less disease. Indications included disease refractory to intravesical therapy in 29 cases (37%), pathological findings reflective of high grade stage T1 or multifocal disease in 26 (33%), radiographic suspicion of invasive disease in 15 (20%) and severe symptoms in 8 (10%). Cancer was clinically under staged with stages pT2 or greater disease in 31 patients (40%) according to final pathology results. Under staging was most pronounced in the 10 patients (67%) with suspicious radiography and in the 18 (64%) with absent muscle in the biopsy specimen. Of the 78 patients with pathological stages pT1 disease or less 98% had no evidence of disease compared to 65% with stages pT2 or greater disease (p <0.01). CONCLUSIONS Despite the intent to perform early cystectomy a significant percent of patients harbored occult muscle invasive and/or metastatic disease. In clinical and pathological, superficial stages T1 or less cases disease-free survival was excellent. Due to these results, the selection of high risk superficial transitional cell carcinoma cases for continued bladder sparing treatment should include uninvolved muscle on biopsy and absent radiographic suspicion of invasion.

Health Related Quality of Life Assessment After Radical Cystectomy: Comparison of Ileal Conduit with Continent Orthotopic Neobladder

PURPOSE Health related quality of life after urinary diversion has been increasingly recognized as an important outcome measure. However, few studies have directly compared patients with an ileal conduit with those with a continent orthotopic neobladder and even fewer have used validated quality of life instruments. Therefore, we compared health related quality of life in patients who underwent neobladder versus ileal conduit creation using validated questionnaires. MATERIALS AND METHODS We mailed 2 validated questionnaires that are measures of health related quality of life, namely the RAND 36-Item Health Survey (SF-36) and Functional Assessment of Cancer Therapy-General (FACT-G), to patients who underwent radical cystectomy for urothelial carcinoma between January 1995 and December 1999. Statistical analysis was performed, including univariate and multivariate analysis. RESULTS A total of 112 patients were available for assessment. A total of 72 (64%) questionnaires were returned, including 23 (32%) and 49 (68%) from patients with an ileal conduit and neobladder, respectively. On the SF-36 questionnaire there were significant univariable relationships between treatment and age (p <0.001 and 0.01, respectively). Younger patients and those with a neobladder had higher health related quality of life scores, including significant differences in 5 of the 9 SF-36 domains (general health, physical functioning, physical health, social functioning and energy/fatigue). There was no relationship between health related quality of life and the final pathological stage (p = 0.25). On multivariate analysis adjusting for age led to a suggestive but nonsignificant difference in health related quality of life scores favoring neobladders (p = 0.09). On the FACT-G there were no significant differences in health related quality of life due to treatment (p = 0.28), pathological stage (p = 0.5), age (p = 0.72) or current disease status (p = 0.27). On the FACT-G 2 of the 4 domains (emotional and functional well-being) were significantly in favor of neobladders. Overall satisfaction was high in the 2 groups with 96% and 85% of patients with a neobladder and ileal conduit, respectively, reporting that they would make the same choice of diversion. CONCLUSIONS Based on validated health related quality of life instruments these findings suggest that patients with an orthotopic neobladder have marginal quality of life advantages over those with an ileal conduit. However, differences in health related quality of life in the 2 types of urinary diversion are confounded by age since patients who underwent orthotopic diversion were younger and as a result of age would be expected to have a higher health related quality of life score. A prospective longitudinal study of health related quality of life after adjusting for differences in age among patients undergoing urinary diversion is currently underway to extend further these observations.

Detection of Gene × Gene Interactions in Genome-Wide Association Studies of Human Population Data

Empirical evidence supporting the commonality of gene × gene interactions, coupled with frequent failure to replicate results from previous association studies, has prompted statisticians to develop methods to handle this important subject. Nonparametric methods have generated intense interest because of their capacity to handle high-dimensional data. Genome-wide association analysis of large-scale SNP data is challenging mathematically and computationally. In this paper, we describe major issues and questions arising from this challenge, along with methodological implications. Data reduction and pattern recognition methods seem to be the new frontiers in efforts to detect gene × gene interactions comprehensively. Currently, there is no single method that is recognized as the ‘best’ for detecting, characterizing, and interpreting gene × gene interactions. Instead, a combination of approaches with the aim of balancing their specific strengths may be the optimal approach to investigate gene × gene interactions in human data.

Meta-Analysis: Cysticidal Drugs for Neurocysticercosis: Albendazole and Praziquantel

Context Neurocysticercosis (tapeworm [Taenia solium] infection of the brain and meninges) is a common cause of acquired epilepsy worldwide. The efficacy of treatment with praziquantel and albendazole is controversial. Contribution The authors identified 11 randomized, controlled trials. All trials used neuroimaging end points to compare albendazole and nonspecific therapy, and 4 compared seizure outcomes. The effects on neuroimaging end points were relatively small (odds ratios <2.2). Treatment reduced the frequency of seizures (odds ratio, 0.36 [95% CI, 0.21 to 0.62]). Safety information was limited and inconclusive. Cautions The studies were small and heterogeneous, and only 5 of 11 were good quality. Implications These studies provide limited evidence of a modest effect of drug treatment in patients with neurocysticercosis. The Editors Neurocysticercosis, defined as infection of the brain and its coverings by the larval stage of the tapeworm Taenia solium, is the most common helminthic infection of the central nervous system and a leading cause of acquired epilepsy worldwide (1). Praziquantel was introduced in 1979 as the first specific cysticidal drug (2), followed by albendazole in 1987 (3). During the past 25 years, contrasting opinions on the efficacy of these drugs in hastening the resolution of intracranial cysticerci and improving the natural course of the disease have caused controversy (4, 5). We performed a meta-analysis of randomized trials comparing the effect of albendazole and praziquantel with no specific therapy to evaluate the effect of cysticidal drug therapy on complete destruction of active lesions and on the risk for seizure recurrence. Cysticerci appearing as cystic lesions on neuroimaging tests are viable parasites, unlike degenerating cysticerci, which appear as enhancing lesions on neuroimaging tests. The outcomes were analyzed separately according to whether the trial included patients with enhancing lesions (colloidal cysticerci) or those with cystic lesions (vesicular cysticerci). We assessed the number of cystic lesions before and after the trial when available to look for differences in the percentage of cyst destruction among study groups. We also performed a subgroup analysis of trials in which corticosteroids were routinely given to 1 or more study groups to assess the effect of corticosteroids on the efficacy of cysticidal drugs. Methods Data Sources We searched MEDLINE, the Cochrane Database of Systematic Reviews, and Literatura Latino-Americana y del Caribe en Ciencias de la Salud (LILACS) for controlled trials of cysticidal drug therapy for human neurocysticercosis published between January 1979 and August 2005. The keywords cysticidal, anticysticercal, albendazole, and praziquantel were combined with the keywords cysticercosis and neurocysticercosis. Limits, such as controlled or trial, were not applied; instead, we read the abstracts of all selected articles to identify those that were potentially eligible. We also looked at reference lists from cysticercosis books and position papers and requested relevant articles written by cysticercosis experts. There were no language restrictions for the search. Study Selection We selected randomized, controlled trials in which 1) at least 1 study group received a cysticidal drug and the other group did not receive specific therapy; 2) the viability and location of parasites were described and were homogeneous among study groups; 3) intervention, including cysticidal drugs and regimen used, was consistent throughout each study group; 4) patients included in the final analysis were evaluated with neuroimaging studies before and after therapy; 5) an imaging evaluation was performed at predefined times after the intervention and the timing of such evaluations was provided; and 6) the number of patients who had complete resolution of lesions after therapy or the total number of intracranial lesions before and after therapy was provided. Trials were not excluded because of lack of a specific clinical end point if the data allowed objective evaluation of the intervention on the basis of neuroimaging findings. Data Abstraction and Quality Assessment Three of the authors independently reviewed the articles and resolved disagreements in inclusion criteria or data abstraction through discussions and consensus. Abstracted data included study design, number of randomly assigned patients, percentage of patients lost to follow-up, intervention, adverse events, timing of control neuroimaging studies, main outcomes, and duration of follow-up. Because we restricted the analysis to randomized, controlled trials, we were theoretically dealing only with class I evidence. Therefore, assessment of the methodologic quality of each trial was mandatory. We used operational variables proposed by the U.S. Preventive Services Task Force for internal validation of randomized, controlled trials and classified each trial as good, fair, or poor (6). Because 2 of the authors have performed trials on cysticidal drug therapy, quality grading was done by a coauthor who was not previously involved in such trials. Statistical Analysis Data analysis was performed by using Comprehensive Meta-Analysis software (Biostat, Englewood, New Jersey) and SAS software, version 9.0 (SAS Institute, Inc., Cary, North Carolina). Data were grouped as stratified 2 2 tables, and initial analyses were performed by using the fixed-effects method (7). The combined odds ratio estimate was obtained by using the MantelHaenszel method, which is the preferable method when some studies have small or zero cell frequencies (8). For studies that involved outcomes with zero cell frequencies in 1 of the 2 groups, we used a treatment arm continuity correction, which adds a factor of the reciprocal of the size of the opposite treatment arm to the cells (9). With imbalanced data as observed in our study, this approach has been shown to yield less biased results than the standard approach of adding 0.5 to all cells. Approximate 95% CIs were based on the asymptotic normality of the combined estimates and were obtained by exponentiating the upper and lower confidence limits for the log odds ratio. Heterogeneity was calculated by using the chi-square test of homogeneity, where a p(Q) greater than 0.1 was considered as a reflection of combinable studies. Because the chi-square test of homogeneity is known to have low power for comparisons involving a small number of studies (10), we also report the I2 statistic as an index of study heterogeneity (11). This statistic, defined as max(0, [Q df]/Q), represents the proportion of the total variance in the pooled estimate that is attributable to between-study variance. Although there is no standard definition, an I2 statistic greater than 20% suggests heterogeneity and an I2 statistic greater than 50% generally indicates substantial heterogeneity. For comparisons for which the assumption of homogeneity was rejected or the I2 statistic suggested heterogeneity, we applied a random-effects model to estimate the variance component associated with between-study variation (12). Hence, for these instances, the variance for each individual study is represented by the sum of the fixed and random study components of variance. Statistical significance of combined data was defined by a P value less than 0.05. Role of the Funding Source This work was not supported by external funding sources. Results Figure 1 summarizes the trial selection process. Our search identified 764 papers, of which 28 were controlled trials. Only 11 met the inclusion criteria (13-23). The main reasons for excluding controlled trials were lack of a placebo or control group (24-29), use of historical controls only (30), no randomized allocation of patients to study groups (31-36), and inadequate description of imaging and clinical follow-up (37, 38). Two papers that examined secondary information from included trials were also excluded from the analysis (39, 40). Figure 1. Study flow diagram. Table 1 summarizes the design and main results of included trials. Five studies had a double-blind design comparing albendazole versus placebo (13-17). The other 6 studies were nonblinded randomized trials allocating patients to albendazole and control groups (18-21) or to albendazole, praziquantel, and control groups (22, 23). Patients included in 1 or more study groups in all trials were given albendazole, 15 mg/kg of body weight per day; lengths of therapy ranged from 3 days to 4 weeks (13-23). Praziquantel was used in only 2 trials, at a dosage of 50 mg/kg of body weight per day for 2 weeks (22, 23). Corticosteroids were routinely added to 1 or more study groups in 6 studies (15-19, 22). Table 1. Design and Main Results of Trials Included in the Meta-Analysis All studies included patients with cysticerci located in the brain parenchyma or in the subarachnoid space at the convexity of cerebral hemispheres. Five papers provided information on the management of enhancing lesions(13, 15, 16, 18, 19), and the other 6 papers provided information on cystic lesions (14, 17, 20-23). Three of the studies on the management of enhancing lesions only included patients with a single lesion (13, 15, 19). In the other 2 studies, 71% and 82% of patients, respectively, had a single enhancing lesion at the time of randomization, and most of the remaining patients had 2 or 3 lesions (16, 18). However, trials on cystic lesions included patients with infections of varying severity, ranging from 1 to more than 100 intracranial cysts (17, 20-23). There were no controlled trials on the management of patients with racemose subarachnoid, intraventricular, or spinal cysts. In all studies, outcome was considered positive when control neuroimaging studies performed from 3 to 6 months after the trial showed improvement, defined as the resolution or transformation of lesions into small calcified nodules (13-23). Six studies also evaluated cli