Mount Sinai Hospital

This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.

BACKGROUND: Studies in animals and an open-label trial have suggested a role for antibodies to tumor necrosis factor alpha, specifically chimeric monoclonal antibody cA2, in the treatment of Crohn's disease. METHODS: We conducted a 12-week multicenter, double-blind, placebo-controlled trial of cA2 in 108 patients with moderate-to-severe Crohn's disease that was resistant to treatment. All had scores on the Crohn's Disease Activity Index between 220 and 400 (scores can range from 0 to about 600, with higher scores indicating more severe illness). Patients were randomly assigned to receive a single two-hour intravenous infusion of either placebo or cA2 in a dose of 5 mg per kilogram of body weight, 10 mg per kilogram, or 20 mg per kilogram. Clinical response, the primary end point, was defined as a reduction of 70 or more points in the score on the Crohn's Disease Activity Index at four weeks that was not accompanied by a change in any concomitant medications. RESULTS: At four weeks, 81 percent of the patients given 5 mg of cA2 per kilogram (22 of 27 patients), 50 percent of those given 10 mg of cA2 per kilogram (14 of 28), and 64 percent of those given 20 mg of cA2 per kilogram (18 of 28) had had a clinical response, as compared with 17 percent of patients in the placebo group (4 of 24) (p<0.001 for the comparison of the cA2 group as a whole with placebo). Thirty-three percent of the patients given cA2 went into remission (defined as a score below 150 on the Crohn's Disease Activity Index), as compared with 4 percent of the patients given placebo (P=0.005). At 12 weeks, 41 percent of the cA2-treated patients (34 of 83) had had a clinical response, as compared with 12 percent of the patients in the placebo group (3 of 25) (P=0.008). The rates of adverse effects were similar in the groups. CONCLUSIONS: A single infusion of cA2 was an effective short-term treatment in many patients with moderate-to-severe, treatment-resistant Crohn's disease.

BACKGROUND: In the National Polyp Study (NPS), colorectal cancer was prevented by colonoscopic removal of adenomatous polyps. We evaluated the long-term effect of colonoscopic polypectomy in a study on mortality from colorectal cancer. METHODS: We included in this analysis all patients prospectively referred for initial colonoscopy (between 1980 and 1990) at NPS clinical centers who had polyps (adenomas and nonadenomas). The National Death Index was used to identify deaths and to determine the cause of death; follow-up time was as long as 23 years. Mortality from colorectal cancer among patients with adenomas removed was compared with the expected incidence-based mortality from colorectal cancer in the general population, as estimated from the Surveillance Epidemiology and End Results (SEER) Program, and with the observed mortality from colorectal cancer among patients with nonadenomatous polyps (internal control group). RESULTS: Among 2602 patients who had adenomas removed during participation in the study, after a median of 15.8 years, 1246 patients had died from any cause and 12 had died from colorectal cancer. Given an estimated 25.4 expected deaths from colorectal cancer in the general population, the standardized incidence-based mortality ratio was 0.47 (95% confidence interval [CI], 0.26 to 0.80) with colonoscopic polypectomy, suggesting a 53% reduction in mortality. Mortality from colorectal cancer was similar among patients with adenomas and those with nonadenomatous polyps during the first 10 years after polypectomy (relative risk, 1.2; 95% CI, 0.1 to 10.6). CONCLUSIONS: These findings support the hypothesis that colonoscopic removal of adenomatous polyps prevents death from colorectal cancer. (Funded by the National Cancer Institute and others.).

Charcoal premixed with dextran of average molecular weight 80,000 almost instantly adsorbs free insulin but rejects antibody-bound insulin. The use of such dextran-coated charcoal makes simpler and more rapid the immunoassay of insulin in biologic fluids, using radioisotope dilution with 131I-insulin and “biopsy” of the insulin pool by antibody to insulin. The procedure here described yields a straight line graph when insulin added is plotted against insulin recovered.

In this paper, inspired by the plenary panel at the 2013 meeting of the International Society for Traumatic Stress Studies, Dr. Steven Southwick (chair) and multidisciplinary panelists Drs. George Bonanno, Ann Masten, Catherine Panter-Brick, and Rachel Yehuda tackle some of the most pressing current questions in the field of resilience research including: (1) how do we define resilience, (2) what are the most important determinants of resilience, (3) how are new technologies informing the science of resilience, and (4) what are the most effective ways to enhance resilience? These multidisciplinary experts provide insight into these difficult questions, and although each of the panelists had a slightly different definition of resilience, most of the proposed definitions included a concept of healthy, adaptive, or integrated positive functioning over the passage of time in the aftermath of adversity. The panelists agreed that resilience is a complex construct and it may be defined differently in the context of individuals, families, organizations, societies, and cultures. With regard to the determinants of resilience, there was a consensus that the empirical study of this construct needs to be approached from a multiple level of analysis perspective that includes genetic, epigenetic, developmental, demographic, cultural, economic, and social variables. The empirical study of determinates of resilience will inform efforts made at fostering resilience, with the recognition that resilience may be enhanced on numerous levels (e.g., individual, family, community, culture).

Background— Dual-chamber (DDDR) pacing preserves AV synchrony and may reduce heart failure (HF) and atrial fibrillation (AF) compared with ventricular (VVIR) pacing in sinus node dysfunction (SND). However, DDDR pacing often results in prolonged QRS durations (QRSd) as the result of right ventricular stimulation, and ventricular desynchronization may result. The effect of pacing-induced ventricular desynchronization in patients with normal baseline QRSd is unknown. Methods and Results— Baseline QRSd was obtained from 12-lead ECGs before pacemaker implantation in MOST, a 2010-patient, 6-year, randomized trial of DDDR versus VVIR pacing in SND. Cumulative percent ventricular paced (Cum%VP) was determined from stored pacemaker data. Baseline QRSd &lt;120 ms was observed in 1339 patients (707 DDDR, 632 VVIR). Cum%VP was greater in DDDR versus VVIR (90% versus 58%, P =0.001). Cox models demonstrated that the time-dependent covariate Cum%VP was a strong predictor of HF hospitalization in DDDR (hazard ratio [HR], 2.99 [95% CI, 1.15 to 7.75] for Cum%VP &gt;40%) and VVIR (HR 2.56 [95% CI, 1.48 to 4.43] for Cum%VP &gt;80%). The risk of AF increased linearly with Cum%VP from 0% to 85% in both groups (DDDR, HR 1.36 [95% CI, 1.09, 1.69]; VVIR, HR 1.21 [95% CI 1.02, 1.43], for each 25% increase in Cum%VP). Model results were unaffected by adjustment for known baseline predictors of HF hospitalization and AF. Conclusions— Ventricular desynchronization imposed by ventricular pacing even when AV synchrony is preserved increases the risk of HF hospitalization and AF in SND with normal baseline QRSd.

PURPOSE: To systematically review the methodologic rigor of the research on volume and outcomes and to summarize the magnitude and significance of the association between them. DATA SOURCES: The authors searched MEDLINE from January 1980 to December 2000 for English-language, population-based studies examining the independent relationship between hospital or physician volume and clinical outcomes. Bibliographies were reviewed to identify other articles of interest, and experts were contacted about missing or unpublished studies. STUDY SELECTION: Of 272 studies reviewed, 135 met inclusion criteria and covered 27 procedures and clinical conditions. DATA EXTRACTION: Two investigators independently reviewed each article, using a standard form to abstract information on key study characteristics and results. DATA SYNTHESIS: The methodologic rigor of the primary studies varied. Few studies used clinical data for risk adjustment or examined effects of hospital and physician volume simultaneously. Overall, 71% of all studies of hospital volume and 69% of studies of physician volume reported statistically significant associations between higher volume and better outcomes. The strongest associations were found for AIDS treatment and for surgery on pancreatic cancer, esophageal cancer, abdominal aortic aneurysms, and pediatric cardiac problems (a median of 3.3 to 13 excess deaths per 100 cases were attributed to low volume). Although statistically significant, the volume-outcome relationship for coronary artery bypass surgery, coronary angioplasty, carotid endarterectomy, other cancer surgery, and orthopedic procedures was of much smaller magnitude. Hospital volume-outcome studies that performed risk adjustment by using clinical data were less likely to report significant associations than were studies that adjusted for risk by using administrative data. CONCLUSIONS: High volume is associated with better outcomes across a wide range of procedures and conditions, but the magnitude of the association varies greatly. The clinical and policy significance of these findings is complicated by the methodologic shortcomings of many studies. Differences in case mix and processes of care between high- and low-volume providers may explain part of the observed relationship between volume and outcome.

The generation of cell-mediated immunity against many infectious pathogens involves the production of interleukin-12 (IL-12), a key signal of the innate immune system. Yet, for many pathogens, the molecules that induce IL-12 production by macrophages and the mechanisms by which they do so remain undefined. Here it is shown that microbial lipoproteins are potent stimulators of IL-12 production by human macrophages, and that induction is mediated by Toll-like receptors (TLRs). Several lipoproteins stimulated TLR-dependent transcription of inducible nitric oxide synthase and the production of nitric oxide, a powerful microbicidal pathway. Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens.

ENVIRONMENTAL and occupational diseases encompass a wide range of human illness and are important causes of disability and death in modern American society.1 , 2 They include lung cancer and mesothelioma in persons exposed to asbestos, leukemia in persons exposed to benzene, asthma and chronic bronchitis in persons exposed to organic dusts, lung cancer in persons exposed to radon, chronic disorders of the nervous system in workers exposed to solvents, kidney failure and hypertension in persons chronically exposed to lead, heart disease in persons exposed to carbon disulfide, impairment of reproductive function in persons exposed to certain solvents and pesticides, and chronic . . .

The efficacy and safety of donepezil as a treatment for patients with mild to moderate Alzheimer's disease (AD) was investigated in a multicenter, double-blind study. Patients were randomly assigned to treatment with placebo (n = 162), 5 mg/d donepezil (n = 154), or 10 mg/d donepezil (n = 157) for 24 weeks followed by a 6-week, single-blind placebo washout. The primary efficacy measures were the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Assessment of Change-Plus (CIBIC plus), with the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB), and patient rated Quality of Life (QoL) used as secondary measures. Cognitive function, as measured by the ADAS-cog, was significantly improved in the 5- and 10-mg/d donepezil groups as compared with the placebo group at weeks 12, 18, and 24. Clinician's global ratings on the CIBIC plus also improved in both the 5- and 10-mg/d donepezil groups relative to placebo. At the end of the 6-week placebo washout phase, ADAS-cog scores and CIBIC plus ratings were not significantly different for the three groups. Significant treatment benefits were also observed consistently in both the 5- and 10-mg/d groups on the MMSE and the CDR-SB, but there was no consistent effect on the patient-rated QoL. Cholinergic side effects (primarily diarrhea, nausea, and vomiting) were reported more often in the 10-mg/d group than either the 5-mg/d or placebo groups. Side effects were transient and generally mild in severity. These data indicate that donepezil is a well-tolerated drug that improves cognition and global function in patients with mild to moderate AD.

Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV-) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV - participants from the pre-CART era (1988-1995; N = 857) and CART era (2000-2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.

Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278-amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.

After consuming comparable amounts of ethanol, women have higher blood ethanol concentrations than men, even with allowance for differences in size, and are more susceptible to alcoholic liver disease. Recently, we documented significant "first-pass metabolism" of ethanol due to its oxidation by gastric tissue. We report a study of the possible contribution of this metabolism to the sex-related difference in blood alcohol concentrations in 20 men and 23 women. Six in each group were alcoholics. The first-pass metabolism was determined on the basis of the difference in areas under the curves of blood alcohol concentrations after intravenous and oral administration of ethanol (0.3 g per kilogram of body weight). Alcohol dehydrogenase activity was also measured in endoscopic gastric biopsies. In nonalcoholic subjects, the first-pass metabolism and gastric alcohol dehydrogenase activity of the women were 23 and 59 percent, respectively, of those in the men, and there was a significant correlation (rs = 0.659) between first-pass metabolism and gastric mucosal alcohol dehydrogenase activity. In the alcoholic men, the first-pass metabolism and gastric alcohol dehydrogenase activity were about half those in the nonalcoholic men; in the alcoholic women, the gastric mucosal alcohol dehydrogenase activity was even lower than in the alcoholic men, and first-pass metabolism was virtually abolished. We conclude that the increased bioavailability of ethanol resulting from decreased gastric oxidation of ethanol may contribute to the enhanced vulnerability of women to acute and chronic complications of alcoholism.

This article describes research criteria and probability methodology for the diagnosis of prodromal PD. Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Given the lack of clear neuroprotective/disease-modifying therapy for prodromal PD, these criteria were developed for research purposes only. The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty. Certainty estimates rely upon calculation of an individual's risk of having prodromal PD, using a Bayesian naïve classifier. In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios. This diagnostic information combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing. In order to be included, diagnostic markers had to have prospective evidence documenting ability to predict clinical PD. They include motor and nonmotor clinical symptoms, clinical signs, and ancillary diagnostic tests. These criteria represent a first step in the formal delineation of early stages of PD and will require constant updating as more information becomes available.

Abstract A new type of research, termed meta-analysis, attempts to analyze and combine the results of previous reports. We found 86 meta-analyses of reports of randomized controlled trials in the English-language literature. We evaluated the quality of these meta-analyses, using a scoring method that considered 23 items in six major areas — study design, combinability, control of bias, statistical analysis, sensitivity analysis, and application of results. Only 24 meta-analyses (28 percent) addressed all six areas, 31 (36 percent) addressed five, 25 (29 percent) addressed four, 5 (6 percent) addressed three, and 1 (1 percent) addressed two. Of the 23 individual items, between 1 and 14 were addressed satisfactorily (mean ±SD, 7.7±2.7). We conclude that an urgent need exists for improved methods in literature searching, quality evaluation of trials, and synthesizing of the results. (N Engl J Med 1987; 316:450–5.)

PURPOSE: Traumatic brain injury (TBI) not only has considerable morbidity and mortality, but it is a major cause of epilepsy. We wish to determine the frequency of TBI, special groups at risk for TBI, and mortality from TBI. METHODS: We reviewed studies of TBI that are either population based or derived from definable catchment areas that allow determination of incidence, identification of risk groups, and mortality. We review methodology used in epidemiologic studies of TBI and try to distinguish this data from that of head injury not necessarily affecting the brain. We report epidemiologic characteristics of TBI, including incidence, differences by age, gender, race and ethnic group, and geographic variation, and mortality. RESULTS: Population-based studies in the United States suggest that the incidence of TBI is between 180 and 250 per 100,000 population per year. Incidence may be higher in Europe and South Africa. There are groups at high risk for TBI. This includes males and individuals living in regions characterized by socioeconomic deprivation. There are selective age groups at risk for TBI. This includes the very young, adolescents and young adults, and the elderly. Mortality varies by severity but is high in those with severe injury and in the elderly. CONCLUSIONS: TBI is a major public health problem as well as a major cause of epilepsy. If primary prevention is to be undertaken, we must understand the epidemiology of the condition. The primary causes of TBI vary by age, socioeconomic factors, and geographic region, so any planned interventions must be tailored accordingly.

BACKGROUND: A recombinant, soluble fusion protein that is a dimer of an extracellular portion of the human tumor necrosis factor (TNF) receptor and the Fc portion of IgG1 (TNFR:Fc) binds and neutralizes TNF-alpha and prevents death in animal models of bacteremia and endotoxemia. METHODS: To evaluate the safety and efficacy of TNFR:Fc in the treatment of septic shock, we conducted a randomized, double-blind, placebo-controlled, multicenter trial. A total of 141 patients were randomly assigned to receive either placebo or a single intravenous infusion of one of three doses of TNFR:Fc (0.15, 0.45, or 1.5 mg per kilogram of body weight). The primary end point was mortality from all causes at 28 days. RESULTS: There were 10 deaths among the 33 patients in the placebo group (30 percent mortality), 9 deaths among the 30 patients receiving the low dose of TNFR:Fc (30 percent mortality), 14 deaths among the 29 receiving the middle dose (48 percent mortality), and 26 deaths among the 49 receiving the high dose (53 percent mortality) (P = 0.02 for the dose-response relation). Baseline differences in the severity of illness did not account for the increased mortality in the groups receiving the higher doses of TNFR:Fc. CONCLUSIONS: In patients with septic shock, treatment with the TNFR:Fc fusion protein does not reduce mortality, and higher doses appear to be associated with increased mortality.

BackgroundMerkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1.MethodsIn this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing.ResultsA total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients.ConclusionsIn this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.).

Guidelines for clinical practice are aimed to indicate preferred approaches to medical problems as established by scientifically valid research. Double-blind placebo controlled studies are preferable, but compassionate-use reports and expert review articles are used in a thorough review of the literature conducted through Medline with the National Library of Medicine. When only data that will not withstand objective scrutiny are available, a recommendation is identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject regardless of specialty training or interests and are aimed to indicate the preferable but not necessarily the only acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standards of care, which are inflexible and rarely violated. Given the wide range of specifics in any health-care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision. Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the board of trustees. Each has been intensely reviewed and revised by the Committee, other experts in the field, physicians who will use them, and specialists in the science of decision analysis. The recommendations of each guideline are therefore considered valid at the time of composition based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at a time established and indicated at publication to assure continued validity. The recommendations made are based on the level of evidence found. Grade A recommendations imply that there is consistent level 1 evidence (randomized controlled trials), grade B indicates that the evidence would be level 2 or 3, which are cohort studies or case-control studies. Grade C recommendations are based on level 4 studies, meaning case series or poor-quality cohort studies, and grade D recommendations are based on level 5 evidence, meaning expert opinion.

CONTEXT: The optimal pharmacologic treatment for early convulsive status epilepticus is unclear. OBJECTIVE: To analyze efficacy, tolerability and safety data for anticonvulsant treatment of children and adults with convulsive status epilepticus and use this analysis to develop an evidence-based treatment algorithm. DATA SOURCES: Structured literature review using MEDLINE, Embase, Current Contents, and Cochrane library supplemented with article reference lists. STUDY SELECTION: Randomized controlled trials of anticonvulsant treatment for seizures lasting longer than 5 minutes. DATA EXTRACTION: Individual studies were rated using predefined criteria and these results were used to form recommendations, conclusions, and an evidence-based treatment algorithm. RESULTS: A total of 38 randomized controlled trials were identified, rated and contributed to the assessment. Only four trials were considered to have class I evidence of efficacy. Two studies were rated as class II and the remaining 32 were judged to have class III evidence. In adults with convulsive status epilepticus, intramuscular midazolam, intravenous lorazepam, intravenous diazepam and intravenous phenobarbital are established as efficacious as initial therapy (Level A). Intramuscular midazolam has superior effectiveness compared to intravenous lorazepam in adults with convulsive status epilepticus without established intravenous access (Level A). In children, intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (Level A) while rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam are probably effective (Level B). No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in adults or children with convulsive status epilepticus (Level A). Respiratory and cardiac symptoms are the most commonly encountered treatment-emergent adverse events associated with intravenous anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). The evidence was synthesized into a treatment algorithm. CONCLUSIONS: Despite the paucity of well-designed randomized controlled trials, practical conclusions and an integrated treatment algorithm for the treatment of convulsive status epilepticus across the age spectrum (infants through adults) can be constructed. Multicenter, multinational efforts are needed to design, conduct and analyze additional randomized controlled trials that can answer the many outstanding clinically relevant questions identified in this guideline.