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Objective: Management of patients experiencing massive pulmonary embolism-related cardiac arrest is controversial. Venoarterial extracorporeal membranous oxygenation has emerged as a potential therapeutic option for these patients. We performed a systematic review assessing survival and predictors of mortality in patients with massive PE-related cardiac arrest with venoarterial extracorporeal membranous oxygenation use., Data Sources: A literature search was started on February 16, 2020, and completed on March 16, 2020, using PubMed, Embase, Cochrane Central, Cinahl, and Web of Science., Study Selection: We included all available literature that reported survival to discharge in patients managed with venoarterial extracorporeal membranous oxygenation for massive PE-related cardiac arrest., Data Extraction: We extracted patient characteristics, treatment details, and outcomes., Data Synthesis: About 301 patients were included in our systemic review from 77 selected articles (total screened, n = 1,115). About 183 out of 301 patients (61%) survived to discharge. Patients (n = 51) who received systemic thrombolysis prior to cannulation had similar survival compared with patients who did not (67% vs 61%, respectively; p = 0.48). There was no significant difference in risk of death if PE was the primary reason for admission or not (odds ratio, 1.62; p = 0.35) and if extracorporeal membranous oxygenation cannulation occurred in the emergency department versus other hospital locations (odds ratio, 2.52; p = 0.16). About 53 of 60 patients (88%) were neurologically intact at discharge or follow-up. Multivariate analysis demonstrated three-fold increase in the risk of death for patients greater than 65 years old (adjusted odds ratio, 3.08; p = 0.03) and six-fold increase if cannulation occurred during cardiopulmonary resuscitation (adjusted odds ratio, 5.67; p = 0.03)., Conclusions: Venoarterial extracorporeal membranous oxygenation has an emerging role in the management of massive PE-related cardiac arrest with 61% survival. Systemic thrombolysis preceding venoarterial extracorporeal membranous oxygenation did not confer a statistically significant increase in risk of death, yet age greater than 65 and cannulation during cardiopulmonary resuscitation were associated with a three- and six-fold risks of death, respectively., Competing Interests: Dr. Bashir’s institution received funding from Thrombolex (equity interest). Dr. Zhao disclosed work for hire. Dr. Moores disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: The Bashir Endovascular Catheter (BEC) is a novel pharmaco-mechanical device designed to enhance thrombolysis by increasing the exposure of thrombus to endogenous and exogenous thrombolytics. The aim of this prospective, multicenter, single-arm study was to evaluate the feasibility and initial safety of the BEC in patients with acute intermediate-risk pulmonary embolism (PE)., Methods: Patients with symptomatic PE and right ventricular to left ventricular diameter ratio ≥0.9 as documented by computer tomography angiography were eligible for enrollment. The primary safety end points were device related death or adverse events, and major bleeding within 72 hours after BEC directed therapy., Results: Nine patients were enrolled across 4 US sites. The total dose of r-tPA (recombinant tissue-type plasminogen activator) was 14 mgs in bilateral PE and 12 mgs in unilateral PE over 8 hours delivered via the expanded BEC. At 30-day follow-up, there were no deaths or device-related adverse events. At 48 hours post-BEC therapy, the right ventricular to left ventricular diameter ratio decreased from 1.52±0.26 to 0.97±0.06 ( P =0.0009 [95% CI, 0.33-0.82]; 37.0% reduction). Thrombus burden as measured by the Modified Miller Index decreased from 25.4±5.3 to 16.0±4.0 ( P =0.0005; [95% CI, 5.5-13.4]; 37.1% reduction)., Conclusions: In this early feasibility study of the BEC for intermediate-risk PE, there were no deaths or device-related adverse events and a significant reduction in right ventricular to left ventricular diameter ratio and thrombus burden. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03927508.

Background: The ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) previously reported that pharmacomechanical catheter-directed thrombolysis (PCDT) did not prevent postthrombotic syndrome (PTS) in patients with acute proximal deep vein thrombosis. In the current analysis, we examine the effect of PCDT in ATTRACT patients with iliofemoral deep vein thrombosis., Methods: Within a large multicenter randomized trial, 391 patients with acute deep vein thrombosis involving the iliac or common femoral veins were randomized to PCDT with anticoagulation versus anticoagulation alone (No-PCDT) and were followed for 24 months to compare short-term and long-term outcomes., Results: Between 6 and 24 months, there was no difference in the occurrence of PTS (Villalta scale ≥5 or ulcer: 49% PCDT versus 51% No-PCDT; risk ratio, 0.95; 95% CI, 0.78-1.15; P=0.59). PCDT led to reduced PTS severity as shown by lower mean Villalta and Venous Clinical Severity Scores ( P<0.01 for comparisons at 6, 12, 18, and 24 months), and fewer patients with moderate-or-severe PTS (Villalta scale ≥10 or ulcer: 18% versus 28%; risk ratio, 0.65; 95% CI, 0.45-0.94; P=0.021) or severe PTS (Villalta scale ≥15 or ulcer: 8.7% versus 15%; risk ratio, 0.57; 95% CI, 0.32-1.01; P=0.048; and Venous Clinical Severity Score ≥8: 6.6% versus 14%; risk ratio, 0.46; 95% CI, 0.24-0.87; P=0.013). From baseline, PCDT led to greater reduction in leg pain and swelling ( P<0.01 for comparisons at 10 and 30 days) and greater improvement in venous disease-specific quality of life (Venous Insufficiency Epidemiological and Economic Study Quality of Life unit difference 5.6 through 24 months, P=0.029), but no difference in generic quality of life ( P>0.2 for comparisons of SF-36 mental and physical component summary scores through 24 months). In patients having PCDT versus No-PCDT, major bleeding within 10 days occurred in 1.5% versus 0.5% ( P=0.32), and recurrent venous thromboembolism over 24 months was observed in 13% versus 9.2% ( P=0.21)., Conclusions: In patients with acute iliofemoral deep vein thrombosis, PCDT did not influence the occurrence of PTS or recurrent venous thromboembolism. However, PCDT significantly reduced early leg symptoms and, over 24 months, reduced PTS severity scores, reduced the proportion of patients who developed moderate-or-severe PTS, and resulted in greater improvement in venous disease-specific quality of life., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00790335.

Background: The introduction of transcatheter aortic valve replacement (TAVR) led to renewed interest in balloon aortic valvuloplasty (BAV). We sought to assess contemporary trends in BAV utilization and their outcomes., Methods and Results: The Nationwide Inpatient Sample was used to identify patients who underwent BAV between 2004 and 2013. In-hospital morbidity and mortality, and predictors of death after BAV were assessed. Outcomes of propensity-matched groups of patients undergoing elective BAV or TAVR were evaluated. BAV utilization increased from 707 cases in 2004 to 3715 cases in 2013 (national estimates). Procedural and in-hospital mortality were 1.4% and 8.5%, respectively. Vascular complications occurred in 7.0% of cases, blood transfusion in 17.5%, clinical stroke in 1.8%, and pacemaker implantation in 3.0%. The strongest predictors of in-hospital death were cardiogenic shock (odds ratio, 6.01; 95% confidence interval, 4.19-8.61; P <0.001), need for left ventricular assist device (odds ratio, 3.48; 95% confidence interval, 2.25-5.36; P <0.001), coagulopathy (odds ratio, 2.19; 95% confidence interval, 1.51-3.18; P <0.001), and low institutional volume of BAV (odds ratio, 1.58; 95% confidence interval, 1.06-2.37; P =0.03). In propensity-matched patients undergoing elective BAV or TAVR, rates of in-hospital mortality (2.9% versus 3.5%; P =0.60), clinical stroke (1.6% versus 3.1%; P =0.10), and vascular complications (8.2% versus 10.9%; P =0.14) were similar. However, BAV was associated with lower rates of pacemaker implantation (2.9% versus 8.0%; P <0.001) and blood transfusion (12.8% versus 22.9%; P <0.001)., Conclusions: In a contemporary national registry, BAV is associated with significant morbidity and mortality that are similar to TAVR. With the substantial increase in BAV utilization and the continuous improvement in TAVR outcomes, these data have important implications to aid clinicians in the selection of appropriate BAV candidates., (© 2017 American Heart Association, Inc.)

Background: The use of catheter-directed thrombolysis (CDT) in the treatment of acute proximal lower-extremity deep vein thrombosis is increasing in the United States and has been linked to higher bleeding rates. Whether this relationship is interrelated with institution volume of CDT is unknown., Methods and Results: The Nationwide Inpatient Sample database was used to identify all patients admitted with a principal diagnosis of proximal or inferior vena caval deep vein thrombosis and treated with CDT from 2005 to 2010. Institutions were divided into high-volume (≥6 procedures a year) and low-volume (<6 procedures a year) centers. Propensity score matching was used to create 2 matched groups for comparative analysis. A total of 90 618 patients were hospitalized for proximal lower-extremity deep vein thrombosis, and 3649 patients (4.1%) underwent CDT. In-hospital mortality was significantly lower at high-volume centers (0.6% versus 1.5%; P=0.04) with a trend toward lower intracranial hemorrhage rates compared with low-volume centers (0.4% versus 1%; P=0.07). No significant difference was seen with blood transfusion (10.4% versus 10.8%; P=0.70), gastrointestinal bleeding (1.4% versus 1.8%; P=0.35), or pulmonary embolism rates (18.4% versus 17.9%; P=0.72). Median length of stay was similar (6 days) and hospital charges were higher ($65 500 versus $75 870) at high-volume centers., Conclusions: In this observational study, we found that an increase in institutional volume of CDT was associated with lower in-hospital mortality and lower intracranial hemorrhage rates. Further studies are needed to assess whether standardization of CDT protocols across all institutions in the United States improves outcomes., (© 2015 American Heart Association, Inc.)

Background: The contemporary practice patterns and role of catheter-directed thrombolysis (CDT) in the treatment of inferior vena cava thrombosis is unknown., Methods and Results: The Nationwide Inpatient Sample database was used to identify patients with a principal discharge diagnosis of inferior vena cava thrombosis (International Classification of Diseases-Ninth Revision-Clinical Modification, 453.2) from 2005 to 2011. We compared patients treated with CDT plus anticoagulation with patients treated with anticoagulation alone. We used propensity scores to construct 2 matched groups of 563 patients for comparative outcomes analysis. Among 2674 patients admitted with inferior vena cava thrombosis, 718 (26.9%) underwent CDT. The national CDT utilization rates increased from 16.0% in 2005 to 34.7% in 2011 (P<0.001). Based on the propensity-matched comparison, the inhospital mortality was not significantly different between the CDT and the anticoagulation groups (2.0% versus 1.4%; P=0.49). The rates of pulmonary embolism (12.1% versus 7.8%; P=0.02), intracranial hemorrhage (1.6% versus 0.2%; P=0.03), and acute renal failure (13.9% versus 9.4%; P=0.02) were significantly higher in the CDT group. The CDT group had longer length of stay and higher hospital charges compared with the anticoagulation group., Conclusions: There has been a steady increase in the use of CDT in the treatment of patients with inferior vena cava thrombosis in the United States. This observational study showed no significant difference in mortality between CDT versus anticoagulation alone; however, the bleeding events and resource utilization were higher in the CDT group. Adequately powered randomized controlled trials are needed in this area., (© 2015 American Heart Association, Inc.)

Multiple sclerosis (MS) is an immune-mediated neurologic disease in which acute inflammatory events early in the disease course contribute to subsequent neurologic disability. The early relapsing inflammatory phase is followed by a progressive degenerative phase in which the frequency of acute inflammatory attacks diminishes but progressive loss of neurologic function continues. Current immune therapies are most effective in suppressing the acute inflammatory events that characterize the earlier stages of disease. Optimal suppression of these inflammatory events is likely to have the best potential for delaying or preventing loss of axons and decline in neurologic function. In view of these considerations, and because MS is a heterogeneous disease and response to disease-modifying agents (DMA) varies across individuals, it is important to identify suboptimal responders as early as possible to allow therapeutic modification while the opportunity to avert future loss of function remains. At present, no criteria for identifying suboptimal responders have been validated. In January 2004, a group of neurologists from 16 MS centers in the United States met to develop a consensus on criteria for defining suboptimal response for use in compelling clinical situations and to prompt clinical studies to validate the efficacy of these criteria. Consensus criteria included relapse rates of either 1/year or unchanged from pretreatment rates, incomplete recovery from multiple attacks, evolution of polyregional neurologic involvement, recurrent brainstem or spinal cord lesions, and cumulative loss of neurologic function sufficient to disrupt daily activities. The panel then considered the use of mitoxantrone for patients with worsening MS and a suboptimal response to DMA therapy.

Objective: Mutations in the skeletal muscle gene dysferlin cause two autosomal recessive forms of muscular dystrophy: Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). The purpose of this study was to define the genomic organization of the dysferlin gene and conduct mutational screening and a survey of clinical features in 21 patients with defined molecular defects in the dysferlin gene., Methods: Genomic organization of the gene was determined by comparing the dysferlin cDNA and genomic sequence in P1-derived artificial chromosomes (PACs) containing the gene. Mutational screening entailed conformational analysis and sequencing of genomic DNA and cDNA. Clinical records of patients with defined dysferlin gene defects were reviewed retrospectively., Results: The dysferlin gene encompasses 55 exons spanning over 150 kb of genomic DNA. Mutational screening revealed nine novel mutations associated with MM. The range of onset in this patient group was narrow with a mean of 19.0 +/- 3.9 years., Conclusion: This study confirms that the dysferlin gene is mutated in MM and LGMD2B and extends understanding of the timing of onset of the disease. Knowledge of the genomic organization of the gene will facilitate mutation detection and investigations of the molecular biologic properties of the dysferlin gene.

The SJL mouse strain has been widely used as an animal model for experimental autoimmune encephalitis (EAE), inflammatory muscle disease and lymphomas and has also been used as a background strain for the generation of animal models for a variety of diseases including motor neurone disease, multiple sclerosis and atherosclerosis. Recently the SJL mouse was shown to have myopathy due to dysferlin deficiency, so that it can now be considered a natural animal model for limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). We have cloned the mouse dysferlin cDNA and analysis of the sequence shows that the mouse dysferlin gene is characterized by six C2 domain sequences and a C-terminal anchoring domain, with the human and the mouse dysferlin genes sharing > 90% sequence homology overall. Genomic analysis of the SJL mutation confirms that the 171 bp RNA deletion has arisen by exon skipping resulting from a splice site mutation. The identification of this mutation has implications for the various groups using this widely available mouse stock.

Objective: To describe a family with chromosome 2p-linked hereditary spastic paraparesis (HSP) associated with dementia and illustrate the cerebral pathology associated with this disorder., Background: HSP comprises a heterogeneous group of inherited disorders in which the main clinical feature is severe, progressive lower limb spasticity. Nongenetic classification relies on characteristics such as mode of inheritance, age at onset, and the presence or absence of additional neurologic features. Several loci have been identified for autosomal dominant pure HSP. The most common form, which links to chromosome 2p (SPG4), has recently been shown to be due to mutations in spastin, the gene encoding a novel AAA-containing protein., Results: The authors report four generations of a British family with autosomal dominant HSP in whom haplotype analysis indicates linkage to chromosome 2p. In addition, a missense mutation has been identified in exon 10 of the spastin gene (A1395G). Dementia was documented clinically in one member of the family, two other affected family members were reported to have had late onset memory loss, and a younger affected individual showed evidence of memory disturbance and learning difficulties. Autopsy of the demented patient confirmed changes in the spinal cord typical of HSP and also demonstrated specific cortical pathology. There was neuronal depletion and tau-immunoreactive neurofibrillary tangles in the hippocampus and tau-immunoreactive balloon cells were seen in the limbic and neocortex. The substantia nigra showed Lewy body formation. The pathologic findings are not typical of known tauopathies., Conclusions: The authors confirm that chromosome 2p-linked HSP can be associated with dementia and that this phenotype may be associated with a specific and unusual cortical pathology.

We stained 13 primary CNS lymphomas (PCNSLs) (six from patients with AIDS, seven from immunocompetent patients) with a panel of antibodies to T cells (pan T cell [CD3], T helper cell [CD4], T suppressor cell [CD8], delta/delta cell [CD4-8-]), B cells (CD20), hematopoietic cells (T200), and NK cell (CD56). We estimated the percentage of tumor cells staining with each antibody. All tumors were B-cell lymphomas. The non-AIDS tumors showed a significant infiltration with CD3+ cells (mean of 10.82% of total cells). The AIDS patients' tumors showed a smaller percentage of CD3+ infiltrating cells (mean, 4.88% of total cells) (p<0.01). CD4+ cells were 9.11% of the total hematopoietic cells in the non-AIDS patients and 3.13% in AIDS patients (p<0.01). AIDS patients showed some CD8+ cells (0.3%), which was significantly higher than in immunocompetent patients (0%) (p<0.05). Very few tumor cells stained with the NK cell and delta/delta cell markers. Both immunocompetent and AIDS patients with PCNSL exhibit significant CD3+ and CD4+ cell infiltration of their tumors; this infiltration is significantly lower in AIDS patients. AIDS patients show a minor CD8+ cell infiltration of their tumors. These results on PCNSL are different from systemic lymphomas, which show a higher CD4 and CD8 cell infiltration, and may offer insights into the more aggressive nature of AIDS-related PCNSL.

We analyzed 168 consecutive patients with Hodgkin's disease who were treated at the University of Nebraska Medical Center between 1985 and 1990 with high-dose chemotherapy followed by autologous bone marrow transplantation (BMT) or peripheral stem-cell transplantation (PSCT), and describe their neurologic complications. All these patients had relapsed or had failed to achieve a remission with initial chemotherapy. Early complications, defined as those occurring during the first 6 weeks following the transplantation, occurred in 65 patients (39%) and included encephalopathy, seizures, psychiatric symptoms, and cerebral hemorrhage; these were mild and reversible in 47 and fatal in 18 patients. The major cause of these early neurologic complications was pulmonary failure. Late neurologic complications, defined as those occurring 6 weeks after the BMT or PSCT was performed, occurred in 21% of patients and included encephalopathy, peripheral neuropathy, cerebral hemorrhage, and spinal cord compression. Serious nervous system complications following autologous BMT or PSCT for Hodgkin's disease are less frequent than those following allogeneic BMT and are usually a result of injury to other organ systems.

We examined the expression of the Epstein-Barr virus (EBV)-induced proteins (LMP [latent membrane protein], EBNA-2, and CD23) and a lytic protein, viral capsid antigen (VCA), in five acquired immune deficiency syndrome (AIDS)-related primary CNS lymphomas (PCNSLs). We compared that expression with the expression of the same proteins in PCNSL from six immunocompetent patients and severe combined immune deficiency (SCID) mouse brains injected with EBV-infected lymphoblastoid cell lines (LCLs). Brain biopsy tissue from an AIDS patient with progressive multifocal leukoencephalopathy (PML) and a normal brain was also studied. Three of the AIDS PCNSLs expressed both human immunoglobulin kappa and lambda light chains and two expressed lambda light chain only. All non-AIDS-related PCNSLs expressed a single light-chain isotype. All five AIDS-related PCNSLs expressed LMP-1 (> 40%), EBNA-2 (> 60%), and VCA (1 to 5%) of tumor cells. These proteins were similarly expressed in the SCID/human chimeras. None of the PCNSLs from immunocompetent subjects, the normal brain, or the brain of the patient with PML expressed these proteins. PCNSL in AIDS patients bears greater similarity to EBV-infected LCLs than to PCNSL from immunocompetent patients.

We present a normal 13-year old female who developed left cerebral infarction following envenomation by the carpet viper (Echis carinatus). We have read of only one other case of cerebral infarction following viper envenomation (Viperi russelli). Possible mechanisms for cerebral infarction in these circumstances are discussed. It is believed that this complication may be more common than is reported in the literature.

We treated six patients with nervous system brucellosis causing polyradiculitis (2 patients), myelopathy (2), encephalitis (1), or meningitis (1). Diagnosis was based on Brucella species cultured from one patient, and a twofold or greater rise in antibody titer after therapy was started in the others. Treatment with trimethoprim-sulfamethoxazole with rifampin (5 patients) or tetracycline (1 patient) produced excellent clinical and laboratory response.