Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial.

BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 µs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960. FINDINGS: Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group. INTERPRETATION: Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke. FUNDING: MicroTransponder.

Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial.

OBJECTIVE: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623). METHODS: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15). RESULTS: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25). CONCLUSIONS: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

Advances in Stroke: Therapies Targeting Stroke Recovery.

Stroke recovery therapies promote favorable neural plasticity, both during spontaneous recovery and the chronic phase. Activity-based therapies based on intense practice, some aided by integration of computers and telehealth, have shown promise. These studies emphasize key therapeutic variables such as dose, intensity, and timing. Preclinical drug studies have shown promise, but human translation has been challenged by identifying the target patient subgroup, requirements for concomitant training, and aligning biomarkers with preclinical evidence.

Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke.

Background and Purpose- Stroke is a leading cause of long-term disability. Limited treatment options exist for patients with chronic stroke and substantial functional deficits. The current study examined safety and preliminary efficacy estimates of intravenous allogeneic mesenchymal stem cells in this population. Methods- Entry criteria included ischemic stroke >6 months prior and substantial impairment (National Institutes of Health Stroke Scale score ≥6) and disability. Enrollees received a single intravenous dose of allogeneic ischemia-tolerant mesenchymal stem cells. Phase 1 used a dose-escalation design (3 tiers, n=5 each). Phase 2 was an expanded safety cohort. The primary end point was safety over 1-year. Secondary end points examined behavioral change. Results- In phase 1 (n=15), each dose (0.5, 1.0, and 1.5 million cells/kg body weight) was found safe, so phase 2 subjects (n=21) received 1.5 million cells/kg. At baseline, subjects (n=36) averaged 4.2±4.6 years poststroke, age 61.1±10.8 years, National Institutes of Health Stroke Scale score 8 (6.5-10), and Barthel Index 65±29. Two were lost to follow-up, one was withdrawn and 2 died (unrelated to study treatment). Of 15 serious adverse events, none was possibly or probably related to study treatment. Two mild adverse events were possibly related to study treatment, a urinary tract infection and intravenous site irritation. Treatment was safe based on serial exams, electrocardiograms, laboratory tests, and computed tomography scans of chest/abdomen/pelvis. All behavioral end points showed significant gains over the 12-months of follow-up. For example, Barthel Index scores increased by 6.8±11.4 points (mean±SD) at 6-months (P=0.002) and by 10.8±15.5 points at 12-months (P<0.001) post-infusion; the proportion of patients achieving excellent functional outcome (Barthel score ≥95) increased from 11.4% at baseline to 27.3% at 6-months and to 35.5% at 12-months. Conclusions- Intravenous transfusion of allogeneic ischemia-tolerant mesenchymal stem cell in patients with chronic stroke and substantial functional deficits was safe and suggested behavioral gains. These data support proceeding to a randomized, placebo-controlled study of this therapy in this population. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01297413.

Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke.

Background and Purpose- We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke. Methods- We performed a randomized, multisite, double-blinded, sham-controlled pilot study. All participants were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program. Randomization was to active VNS (n=8) or control VNS (n=9) paired with rehabilitation. Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy. Results- All participants completed the course of therapy. There were 3 serious adverse events related to surgery. Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 post-in-clinic therapy (difference, 2.3 points; CI, -1.8 to 6.4; P=0.20). At day 90, mean scores increased 9.5 points from baseline with active VNS, and the control scores improved by 3.8 (difference, 5.7 points; CI, -1.4 to 11.5; P=0.055). The clinically meaningful response rate of FMA-UE at day 90 was 88% with active VNS and 33% with control VNS ( P<0.05). Conclusions- VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke. A pivotal study of this therapy is justified. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02243020.

Human choriogonadotropin and epoetin alfa in acute ischemic stroke patients (REGENESIS-LED trial).

INTRODUCTION: Preclinical studies suggest that growth factors in the early days after stroke improve final outcome. A prior study found three doses of human choriogonadotropin alfa followed by three doses of erythropoietin to be safe after stroke in humans. A proof of concept trial (REGENESIS) was initiated but placed on regulatory hold during review of an erythropoietin neuroprotective trial. Due to financial constraints, the trial was largely moved to India, using lower erythropoietin doses, as the REGENESIS-LED trial. METHODS: Entry criteria included National Institutes of Health Stroke Scale 8-20, supratentorial ischemic stroke, and 24-48 h poststroke at start of therapy. Patients were randomized to three QOD doses of subcutaneous human choriogonadotropin alfa followed by three QD doses of intravenous erythropoietin (three escalating dose cohorts, 4000-20,000 IU/dose) vs. placebo. Primary outcomes were safety and neurological recovery. RESULTS: The study was halted early by the sponsor after 96 enrollees. There was no significant difference across treatment groups in the proportion of patients experiencing death, serious adverse events, or any adverse event. There was no significant difference in National Institutes of Health Stroke Scale score change from baseline to Day 90 between placebo and active treatment, whether active cohorts were analyzed together or separately, and no exploratory secondary measure of neurological recovery showed a significant difference between groups. DISCUSSION: Administration of human choriogonadotropin alfa followed by erythropoietin is safe after a new ischemic stroke. At the doses studied, placebo and active groups did not differ significantly in neurological recovery. Study limitations, such as the use of multiple assessors, differences in rehabilitation care, and being underpowered to show efficacy, are discussed.

Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke.

OBJECTIVES: To evaluate the quality of preclinical evidence for mesenchymal stromal cell (MSC) treatment of ischemic stroke, determine effect size of MSC therapy, and identify clinical measures that correlate with differences in MSC effects. METHODS: A literature search identified studies of MSCs in animal models of cerebral ischemia. For each, a Quality Score was derived, and effect size of MSCs was determined for the most common behavioral and histologic endpoints. RESULTS: Of 46 studies, 44 reported that MSCs significantly improved outcome. The median Quality Score was 5.5 (of 10). The median effect size was 1.78 for modified Neurological Severity Score, 1.73 for the adhesive removal test, 1.02 for the rotarod test, and 0.93 for infarct volume reduction. Quality Score correlated significantly and positively with effect size for the modified Neurological Severity Score. Effect sizes varied significantly with clinical measures such as administration route (intracerebral > intra-arterial > IV, although effect size for IV was nonetheless very large at 1.55) and species receiving MSCs (primate > rat > mouse). Because many MSC mechanisms are restorative, analyses were repeated examining only the 36 preclinical studies administering MSCs ≥ 24 hours poststroke; results were overall very similar. CONCLUSIONS: In preclinical studies, MSCs have consistently improved multiple outcome measures, with very large effect sizes. Results were robust across species studied, administration route, species of MSC origin, timing, degree of immunogenicity, and dose, and in the presence of comorbidities. In contrast to meta-analyses of preclinical data for other stroke therapies, higher-quality MSC preclinical studies were associated with larger behavioral gains. These findings support the utility of further studies to translate MSCs in the treatment of ischemic stroke in humans.

Evidence for high translational potential of mesenchymal stromal cell therapy to improve recovery from ischemic stroke.

Although ischemic stroke is a major cause of morbidity and mortality, current therapies benefit only a small proportion of patients. Transplantation of mesenchymal stromal cells (MSC, also known as mesenchymal stem cells or multipotent stromal cells) has attracted attention as a regenerative therapy for numerous diseases, including stroke. Mesenchymal stromal cells may aid in reducing the long-term impact of stroke via multiple mechanisms that include induction of angiogenesis, promotion of neurogenesis, prevention of apoptosis, and immunomodulation. In this review, we discuss the clinical rationale of MSC for stroke therapy in the context of their emerging utility in other diseases, and their recent clinical approval for treatment of graft-versus-host disease. An analysis of preclinical studies examining the effects of MSC therapy after ischemic stroke indicates near-universal agreement that MSC have significant favorable effect on stroke recovery, across a range of doses and treatment time windows. These results are interpreted in the context of completed and ongoing human clinical trials, which provide support for MSC as a safe and potentially efficacious therapy for stroke recovery in humans. Finally, we consider principles of brain repair and manufacturing considerations that will be useful for effective translation of MSC from the bench to the bedside for stroke recovery.

A system for addressing incidental findings in neuroimaging research.

When healthy subjects undergo brain imaging, incidental findings are not rare. The optimal response to such findings has been the focus of considerable discussion. The current report describes the operations and results of a system that provides a review of incidental findings by an appropriate medical professional. A web-based system was created whereby investigators performing brain MRI scans on healthy subjects could refer images with suspected concerns to a board certified radiologist who had a Certificate of Added Qualification in Neuroradiology. The specific details of this system are described. Among 27 scans suspected by an investigator of having a significant finding, all but one were referred by a researcher with a PhD. The most common concerns described by these investigators were for the possible presence of a cyst or of enlarged ventricles. The most common findings reported by the radiologist were Virchow-Robin spaces and cysts. Findings were generally of low clinical significance, with 1 major exception. Identifying the optimal response to incidental findings in neuroimaging research remains a challenge. The current report describes a system for providing expert assistance and so addresses these issues in the setting of suspected incidental findings. To our knowledge the current system is the first to provide a specific means for evaluation of incidental findings in neuroimaging research.

Stroke: working toward a prioritized world agenda.

BACKGROUND AND PURPOSE: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. METHODS: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. RESULTS: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (e.g., social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures. CONCLUSIONS: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.

The beta-hCG+erythropoietin in acute stroke (BETAS) study: a 3-center, single-dose, open-label, noncontrolled, phase IIa safety trial.

BACKGROUND AND PURPOSE: Animal data suggest the use of beta-human chorionic gonadotropin followed by erythropoietin to promote brain repair after stroke. The current study directly translated these results by evaluating safety of this sequential growth factor therapy through a 3-center, single-dose, open-label, noncontrolled, Phase IIa trial. METHODS: Patients with ischemic stroke 24 to 48 hours old and National Institutes of Health Stroke Scale score of 6 to 24 started a 9-day course of beta-human chorionic gonadotropin (once daily on Days 1, 3, and 5 of study participation) followed by erythropoietin (once daily on Days 7, 8, and 9 of study participation). This study also evaluated performance of serially measured domain-specific end points. RESULTS: A total of 15 patients were enrolled. Two deaths occurred, neither related to study medications. No safety concerns were noted among clinical or laboratory measures, including screening for deep vein thrombosis and serial measures of serum hemoglobin. In several instances, domain-specific end points provided greater insight into impairments as compared with global outcome measures. CONCLUSIONS: Results support the safety of this sequential, 2-growth factor therapy initiated 24 to 48 hours after stroke onset.

Liquid storage of marrow stromal cells.

BACKGROUND: Marrow stromal cells (MSCs) for clinical trials are inevitably stored before administration, but little is known about the effects of storage on MSCs. The effects of short-term liquid storage on the in vitro function of MSCs intended for a clinical trial were studied. STUDY DESIGN AND METHODS: Early-passage human MSCs were suspended in 0.9% saline or culture medium and stored at 4 degrees C or room temperature for up to 72 hours followed by assessment of cell loss, viability, and growth in culture. RESULTS: When stored in saline at 4 degrees C, MSC counts decreased by 5% to 20%, MSC viability decreased 17% to 37%, and MSC growth decreased 65% to 100% after 24-hour storage. Similar results were obtained by MSC storage at room temperature or in Dulbecco's modified Eagle's medium or by addition of 1% human serum albumin (HSA) from two manufacturers. Storage of MSCs in saline with HSA from a third manufacturer maintained MSC viability at prestorage levels and improved poststorage MSC growth versus saline (32 +/- 9% vs. 9 +/- 9%; p < 0.05) or saline with two other HSA preparations (4 +/- 4 and 8 +/- 11%; p < 0.05). CONCLUSION: MSCs stored at 4 degrees C or room temperature, in saline or culture medium, rapidly become nonviable. HSA preparations vary significantly in their ability to maintain poststorage MSC viability and growth. These results provide insight regarding the effects of storage on MSCs and indicate the need to screen HSA preparations before their use as additives to preserve MSCs during short-term liquid storage.

Motor cortex stimulation for the enhancement of recovery from stroke: a prospective, multicenter safety study.

OBJECTIVE: Functional magnetic resonance imaging and transcranial magnetic stimulation studies suggest that human cortex shows evidence of neuroplasticity. Preclinical studies in rats and monkeys suggest that motor cortical stimulation can enhance plasticity and improve recovery after stroke. This study assesses the safety and preliminary efficacy of targeted subthreshold epidural cortical stimulation delivered concurrently with intensive rehabilitation therapy while using an investigational device in patients with chronic hemiparetic stroke. METHODS: This is a prospective, multicenter, and nonblinded trial randomizing patients to rehabilitation with or without cortical stimulation. Patients aged 20 to 75 years who had had an ischemic stroke at least 4 months previously causing persistent moderate weakness of the arm were included. Functional magnetic resonance imaging localized hand motor function before surgery to place an epidural cortical electrode. Both groups then underwent rehabilitation for 3 weeks after which the electrode was removed. Outcome measures were obtained at baseline, during therapy, and at 1, 4, 8, and 12 weeks postprocedure. RESULTS: Ten patients were randomized; six patients to surgery, four to the control group. No patient deaths, neurological deterioration, or seizures occurred. There were two infections from nonprotocol-related causes. Of the eight patients completing the treatment, the stimulation plus rehabilitation group improved significantly better than controls in the Upper Extremity Fugl-Meyer (P = 0.003 overall) and the hand function score of the Stroke Impact Scale (P =0.001 overall). CONCLUSION: The technique of cortical stimulation to enhance stroke recovery is well tolerated and safe.

Orthopaedic management of the upper extremity of stroke patients.

Cerebrovascular accidents often produce significant pathology, including upper extremity muscle contractures and deformities that may be painful and aesthetically unappealing and that interfere with activities of daily living and hygiene. Orthopaedic intervention may be required to manage these disabilities. Nonsurgical management includes brachial plexus and phenol nerve blocks, which provide temporary relief of painful contractures and allow for a period of spontaneous neurologic recovery of up to 6 months. Definitive surgical procedures should be avoided during this time. After this period, surgical management can be valuable in releasing muscle spasticity, managing painful contractures, and positioning the deformed extremity in a more functional and aesthetically appealing position. Current surgical management is directed at reducing or eliminating muscle spasticity and joint contractures, with the goal of correcting deformities in shoulder adduction, elbow flexion, forearm pronation, wrist and finger flexion, intrinsic muscle spasticity, thumb-in-palm deformity, wrist extension, and finger extension.

Repairing the human brain after stroke. II. Restorative therapies.

Spontaneous behavioral recovery is usually limited after stroke, making stroke a leading source of disability. A number of therapies in development aim to improve patient outcomes not by acutely salvaging threatened tissue, but instead by promoting repair and restoration of function in the subacute or chronic phase after stroke. Examples include small molecules, growth factors, cell-based therapies, electromagnetic stimulation, device-based strategies, and task-oriented and repetitive training-based interventions. Stage of development across therapies varies widely, from preclinical to late-phase clinical trials. The optimal methods to prescribe such therapies require further studies, for example, to best identify appropriate patients or to guide features of dosing. Likely, anatomic, functional, and behavioral measures of brain state, as well as measures of injury, will each be useful in this regard. Considerations for clinical trials of restorative therapies are provided, emphasizing both similarities and points of divergence with acute stroke clinical trial design.

Motor cortex stimulation for the enhancement of recovery from stroke: a prospective, multicenter safety study.

OBJECTIVE: Functional magnetic resonance imaging and transcranial magnetic stimulation studies suggest that human cortex shows evidence of neuroplasticity. Preclinical studies in rats and monkeys suggest that motor cortical stimulation can enhance plasticity and improve recovery after stroke. This study assesses the safety and preliminary efficacy of targeted subthreshold epidural cortical stimulation delivered concurrently with intensive rehabilitation therapy while using an investigational device in patients with chronic hemiparetic stroke. METHODS: This is a prospective, multicenter, and nonblinded trial randomizing patients to rehabilitation with or without cortical stimulation. Patients aged 20 to 75 years who had had an ischemic stroke at least 4 months previously causing persistent moderate weakness of the arm were included. Functional magnetic resonance imaging localized hand motor function before surgery to place an epidural cortical electrode. Both groups then underwent rehabilitation for 3 weeks after which the electrode was removed. Outcome measures were obtained at baseline, during therapy, and at 1, 4, 8, and 12 weeks postprocedure. RESULTS: Ten patients were randomized; six patients to surgery, four to the control group. No patient deaths, neurological deterioration, or seizures occurred. There were two infections from nonprotocol-related causes. Of the eight patients completing the treatment, the stimulation plus rehabilitation group improved significantly better than controls in the Upper Extremity Fugl-Meyer (P = 0.003 overall) and the hand function score of the Stroke Impact Scale (P = 0.001 overall). CONCLUSION: The technique of cortical stimulation to enhance stroke recovery is well tolerated and safe.

Paradoxical emboli from calf and pelvic veins in cryptogenic stroke.

PURPOSE: The increased prevalence of patent foramen ovale in patients with cryptogenic strokes suggests the occurrence of paradoxical embolism. The identification of deep venous thromboses (DVTs) in this population would strengthen this hypothesis. The purpose of this study was to image the subdiaphragmatic venous system in a cohort of patients with cryptogenic strokes. MATERIALS AND METHODS: In 37 patients with cryptogenic brain ischemia and interatrial communication, duplex studies of calf, popliteal, and femoral veins, and magnetic resonance imaging venograms of the pelvis veins were performed. RESULTS: In 10 patients, DVTs were diagnosed that were considered to be the cause of cryptogenic brain ischemia on probable (n = 6) or possible (n = 4) bases. In these patients, the median time from stroke to DVT was 3.25 days. In 5 of these 10 patients, DVTs did not involve popliteal and femoral veins, areas thought most important to pulmonary embolism, but instead were isolated to calf or pelvic veins. Although none of these 10 patients had abnormal blood hypercoagulation tests, 8 of the 10 did have clinical conditions suggesting predisposition to developing DVTs, such as concomitant neoplasms or pulmonary embolism. CONCLUSIONS: Increased evidence for paradoxical embolism may emerge when diagnostic strategies use multiple imaging methods and evaluate a broad extent of the subdiaphragmatic veins.