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OBJECTIVES:. Hyper- and hypoinflammatory subphenotypes discovered in patients with acute respiratory distress syndrome predict clinical outcomes and therapeutic responses. These subphenotypes may be important in broader critically ill patient populations with acute respiratory failure regardless of clinical diagnosis. We investigated subphenotyping with latent class analysis in an inclusive population of acute respiratory failure, derived a parsimonious model for subphenotypic predictions based on a small set of variables, and examined associations with clinical outcomes. DESIGN:. Prospective, observational cohort study. SETTING:. Single-center, academic medical ICU. PATIENTS:. Mechanically ventilated patients with acute respiratory failure. MEASUREMENTS AND MAIN RESULTS:. We included 498 patients with acute respiratory failure (acute respiratory distress syndrome: 143, at-risk for acute respiratory distress syndrome: 198, congestive heart failure: 37, acute on chronic respiratory failure: 23, airway protection: 61, and multifactorial: 35) in our derivation cohort and measured 10 baseline plasma biomarkers. Latent class analysis considering clinical variables and biomarkers determined that a two-class model offered optimal fit (23% hyperinflammatory subphenotype). Distribution of hyperinflammatory subphenotype varied among acute respiratory failure etiologies (acute respiratory distress syndrome: 31%, at-risk for acute respiratory distress syndrome: 27%, congestive heart failure: 22%, acute on chronic respiratory failure 0%, airway protection: 5%, and multifactorial: 14%). Hyperinflammatory patients had higher Sequential Organ Failure Assessment scores, fewer ventilator-free days, and higher 30- and 90-day mortality (all p < 0.001). We derived a parsimonious model consisting of angiopoietin-2, soluble tumor necrosis factor receptor-1, procalcitonin, and bicarbonate and classified subphenotypes in a validation cohort (n = 139). Hyperinflammatory patients (19%) demonstrated higher levels of inflammatory biomarkers not included in the model (p < 0.01) and worse outcomes. CONCLUSIONS:. Host-response subphenotypes are observable in a heterogeneous population with acute respiratory failure and predict clinical outcomes. Simple, biomarker-based models can offer prognostic enrichment in patients with acute respiratory failure. The differential distribution of subphenotypes by specific etiologies of acute respiratory failure indicates that subphenotyping may be more relevant in patients with hypoxemic causes of acute respiratory failure and not in patients intubated for airway protection or acute on chronic decompensation.

Background:. Biofilm can impair wound healing by maintaining an elevated, but ineffective, inflammatory state. This article describes interim results from the prospective RESPOND postmarketing registry evaluating the use of a native type 1, porcine collagen matrix with the embedded antimicrobial polyhexamethylene biguanide (PCMP) in the management of chronic wounds. Methods:. Adults ≥18 years of age with ≥1 appropriate wound were eligible for inclusion. Data that were final on January 26, 2018 were included in this analysis. At week 0, wounds were cleaned, debrided, and prepared as necessary and PCMP was applied, with a dressing to fix it in place. Patients received standard wound care plus PCMP weekly, up to 24 weeks, at the investigator’s discretion. At each visit, wounds were assessed for area and quality of granulation tissue. Results:. Most common wound types (N = 63) were venous ulcers (28.6%), trauma and lacerations (22.2%), postsurgical open wounds (15.9%), pressure injuries (12.7%), and diabetic ulcers (9.5%). Median baseline wound area was 6.5 cm2; mean wound duration at baseline was 4 months. Of the 63 wounds, 43 (68.3%) achieved complete wound closure, 41 of 43 (95.3%) closed after PCMP treatment, and 2 of 43 (4.7%) after bridging to other modalities and surgical closure. Twelve out of 63 wounds were bridged to other modalities after PCMP treatment. Mean time to closure for PCMP wounds was 5.0 weeks. Conclusions:. PCMP appears to be a useful adjunct for treating various wound types. PCMP use should be considered when managing chronic or acute wounds.

Objective: Postoperative thrombotic complications represent a unique challenge in cranial neurosurgery as primary treatment involves therapeutic anticoagulation. The decision to initiate therapy and its timing is nuanced, as surgeons must balance the risk of catastrophic intracranial hemorrhage (ICH). With limited existing evidence to guide management, current practice patterns are subjective and inconsistent. The authors assessed their experience with early therapeutic anticoagulation (≤ 7 days postoperatively) initiation for thrombotic complications in neurosurgical patients undergoing cranial surgery to better understand the risks of catastrophic ICH., Methods: Adult patients treated with early therapeutic anticoagulation following cranial surgery were considered. Anticoagulation indications were restricted to thrombotic or thromboembolic complications. Records were retrospectively reviewed for demographics, surgical details, and anticoagulation therapy start. The primary outcome was the incidence of catastrophic ICH, defined as ICH resulting in reoperation or death within 30 days of anticoagulation initiation. As a secondary outcome, post-anticoagulation cranial imaging was reviewed for new or worsening acute blood products. Fisher's exact and Wilcoxon rank-sum tests were used to compare cohorts. Cumulative outcome analyses were performed for primary and secondary outcomes according to anticoagulation start time., Results: Seventy-one patients satisfied the inclusion criteria. Anticoagulation commenced on mean postoperative day (POD) 4.3 (SD 2.2). Catastrophic ICH was observed in 7 patients (9.9%) and was associated with earlier anticoagulation initiation (p = 0.02). Of patients with catastrophic ICH, 6 (85.7%) had intra-axial exploration during their index surgery. Patients with intra-axial exploration were more likely to experience a catastrophic ICH postoperatively compared to those with extra-axial exploration alone (OR 8.5, p = 0.04). Of the 58 patients with postoperative imaging, 15 (25.9%) experienced new or worsening blood products. Catastrophic ICH was 9 times more likely with anticoagulation initiation within 48 hours of surgery (OR 8.9, p = 0.01). The cumulative catastrophic ICH risk decreased with delay in initiation of anticoagulation, from 21.1% on POD 2 to 9.9% on POD 7. Concurrent antiplatelet medication was not associated with either outcome measure., Conclusions: The incidence of catastrophic ICH was significantly increased when anticoagulation was initiated within 48 hours of cranial surgery. Patients undergoing intra-axial exploration during their index surgery were at higher risk of a catastrophic ICH.

ARISE (Aneurysm/AVM/cSDH Roundtable Discussion With Industry and Stroke Experts) organized a one-and-a-half day meeting and workshop and brought together representatives from academia, industry, and government to discuss the most promising approaches to improve outcomes for patients with chronic subdural hematoma (cSDH). The emerging role of middle meningeal artery embolization in clinical practice and the design of current and potential future trials were the primary focuses of discussion. Existing evidence for imaging, indications, agents, and techniques was reviewed, and areas of priority for study and key questions surrounding the development of new and existing treatments for cSDH were identified. Multiple randomized, controlled trials have met their primary efficacy end points, providing high-level evidence that middle meningeal artery embolization is a potent adjunctive therapy to the standard (surgical and nonsurgical) management of neurologically stable cSDH patients in terms of reducing rates of disease recurrence. Pooled data analyses following the formal conclusion and publication of these trials will form a robust foundation upon which guidelines can be strengthened for cSDH treatment modalities and optimal patient selection, as well as delineate future lines of investigation., Competing Interests: Disclosures Dr Kan reports compensation from Imperative Care, Inc, for consultant services; compensation from MicroVention, Inc, for consultant services; grants from Siemens Medical Solutions USA, Inc, the National Institutes of Health, and the Joe Niekro Foundation; and stock holdings in Vena Medical. Dr Fiorella reports compensation from Johnson & Johnson Health Care Systems, Inc, for consultant services. Dr Lanzino reports compensation from the American Heart Association for consultant services. Dr Siddiqui reports stock options in Createch Medical, Inc; securities holdings in VICIS, Inc; employment by the Jacobs Institute; stock holdings in NextGen Biologics, Inc; stock options in Three Rivers Medical, Inc; compensation from W. L. Gore & Associates, Inc, for consultant services; securities holdings in SongBird Therapy; compensation from Johnson & Johnson Medical Devices & Diagnostics Group-Latin America, LLC, for consultant services; stock holdings in Neurotechnology Investors; and stock holdings in Truvic Medical, Inc. Dr Khalessi reports compensation from Proximie for consultant services and stock options in Asayena. Dr Colby reports compensation from Cerenovus, Medtronic, Stryker, Balt USA, LLC, Rapid Medical Ltd, and MicroVention, Inc, for consultant services. Dr Wakhloo received grants from Philips and compensation from Acotec for consultant services; disclosures provided by Dr Wakhloo in compliance with the American Heart Association’s annual Journal Editor Disclosure Questionnaire are available at https://www.ahajournals.org/editor-coi-disclosures. Dr Arthur reports compensation from Perfuze for consultant services. The Aneurysm/AVM/Chronic Subdural Hematoma Roundtable Discussion With Industry and Stroke Experts I roundtable discussion event was collectively sponsored by Imperative Care, Stryker, InNeuroCo, the Brain Aneurysm Foundation, Philips, Bendit, Kaneka Neurovascular, Fluid Biomed, Johnson and Johnson Cerenovus, Penumbra, MicroVention, RapidAI, Viz.ai, Siemens Healthineers, and Medtronic. The content and writing of this article were not sponsored by industry. The other authors report no conflicts.

Background: Significant controversy exists about the management of unruptured cerebral arteriovenous malformations (AVMs). Results from A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) suggested that intervention increases the risk of stroke/death compared with medical management. However, numerous study limitations raised concerns about the trial's generalizability., Objective: To assess the rate of stroke/death and functional outcomes in ARUBA-eligible patients from a multicenter database, the Neurovascular Quality Initiative-Quality Outcomes Database (NVQI-QOD)., Methods: We performed a retrospective analysis of prospectively collected data of ARUBA-eligible patients who underwent intervention at 18 participating centers. The primary endpoint was stroke/death from any cause. Secondary endpoints included neurologic, systemic, radiographic, and functional outcomes., Results: 173 ARUBA-eligible patients underwent intervention with median follow-up of 269 (25-722.5) days. Seventy-five patients received microsurgery±embolization, 37 received radiosurgery, and 61 received embolization. Baseline demographics, risk factors, and general AVM characteristics were similar between groups. A total of 15 (8.7%) patients experienced stroke/death with no significant difference in primary outcome between treatment modalities. Microsurgery±embolization was more likely to achieve AVM obliteration (P<0.001). Kaplan-Meier survival curves demonstrated no difference in overall death/stroke outcomes between the different treatment modalities' 5-year period (P=0.087). Additionally, when compared with the ARUBA interventional arm, our patients were significantly less likely to experience death/stroke (8.7% vs 30.7%; P<0.001) and functional impairment (mRS score ≥2 25.4% vs 46.2%; P<0.01)., Conclusion: Our results suggest that intervention for unruptured brain AVMs at comprehensive stroke centers across the United States is safe., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Intracranial hemorrhage (ICH) secondary to hypertension (HTN) classically occurs in the basal ganglia, cerebellum, or pons. Vascular lesions such as aneurysms or arteriovenous malformations (AVMs) are more common in younger patients. We investigated the utility of diagnostic subtraction angiography (DSA) in young hypertensive patients with non-lobar ICH., Methods: A retrospective review (2013-2022) identified young (18-60 years) patients who underwent DSA for ICH. HTN history, ICH location, presence/absence of subarachnoid hemorrhage (SAH), and computed tomography angiography (CTA) findings were collected. The main outcome was DSA-positivity, defined as presence of an AVM, aneurysm, Moyamoya disease, reversible cerebral vasoconstriction syndrome, or dural arteriovenous fistula on DSA., Results: Two hundred sixty patients were included, and the DSA-positivity rate was 19%.DSA-positivity was lower in hypertensive patients with ICHs in the cerebellum, pons, or basal ganglia compared to the rest of the patient sample (9% vs 26%, p  = 0.0002, Fisher's exact test). We developed the ICH-Angio score (0-5 points) based on CTA findings, ICH location, HTN history, and presence of SAH to predict risk of underlying vascular lesions. DSA-positivity was lower in those with a score of 0 (0/62; 0%) compared to a score of 1 (5/52; 10%), 2 (17/48; 35%), 3 (10/20; 50%), 4 (5/6; 83%), or 5 (3/3; 100%)., Conclusion: The ICH-Angio score was able to non-invasively rule out an underlying vascular etiology for ICH in up to one-third of patients. HTN, ICH location, CTA findings, and associated SAH can identify patients at low risk for harboring underlying vascular lesions.

Objective: Intracranial aneurysms are present in up to 18% of arteriovenous malformations (AVMs) and increase the risk of intracranial hemorrhage. No consensus exists on the optimal treatment strategy for AVM-associated aneurysms. The goal of this study was to systematically review endovascular treatment methods of AVM-associated intracranial aneurysms, radiographic outcomes, and periprocedural complications., Methods: A systematic review was performed in accordance with PRISMA guidelines to identify studies that investigated the use of endovascular treatments for management of patients with AVM-associated aneurysms. Collected variables included aneurysm and AVM location, aneurysm size and characteristics, AVM and aneurysm treatment modality, periprocedural complications, and long-term clinical and radiographic outcomes., Results: Eight studies with 237 patients and 314 AVM-associated intracranial aneurysms were included. Two-hundred and twenty-four aneurysms were flow-related (71.3%), 80 were intranidal (25.5%), and 10 were unrelated (3.2%). Complete occlusion was 56.3% (18/32) for aneurysmal coil embolization and 99% (104/105) for parent vessel sacrifice. Of the 13 aneurysms treated with ethanol sclerotherapy, 8 were successfully obliterated (8/13; 61%) using ethanol sclerotherapy alone and the rest required adjunct endovascular embolization for obliteration of the artery and associated aneurysm. The periprocedural complication rate was approximately 12% and consisted of ischemic symptoms, intracranial hemorrhage, and coiling complications., Conclusions: Endovascular management options of AVM-associated intracranial aneurysms are limited and mostly comprised primary aneurysmal coil embolization or parent vessel sacrifice using coils or liquid embolics. Embolization strategy depends on factors such as AVM angioarchitecture, rupture status, and adjunct AVM treatments., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The vein of Galen aneurysm (VGAM) is the most common type of arteriovenous malformation in the neonate. These neonates commonly present with high output cardiac failure that may be associated with pulmonary hypertension. The medical management and stabilization of these neonates can be challenging before staged transarterial embolization of the aneurysm is undertaken., Case: A 2.34 kilogram neonate, antenatally diagnosed to have VGAM, was born at 36 weeks of gestation for fetal distress. The neonate failed to respond to medical management including inotropes, high frequency mechanical ventilation and inhaled nitric oxide. The patient's high-output heart failure and persistent pulmonary hypertension were stabilized with veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) using central cannulation. Further transarterial staged embolization of the VGAM was undertaken on VA-ECMO support., Conclusion: There may be a role of VA-ECMO using central cannulation to optimize management of high output cardiac failure and persistent pulmonary hypertension in neonatal VGAM patients who fail medical management to facilitate staged transarterial embolization of the VGAM.

Background: Clinical trials of extracranial-intracranial (EC-IC) bypass surgery studied patients in subacute and chronic stage after ischemic event., Objective: To investigate the short-term outcomes of EC-IC bypass in progressive acute ischemic stroke or recent transient ischemic attacks., Methods: The study was a retrospective review at a single tertiary referral center from 2008 to 2015. Inclusion criteria consisted of EC-IC bypass within 1 yr of last ischemic symptoms ipsilateral to atherosclerotic occlusion of internal carotid or middle cerebral artery. Early bypass group who underwent surgery within 7 d of last ischemic symptoms were compared to late bypass group who underwent surgery >7 d from last ischemic symptom. The primary endpoint was perioperative ischemic or hemorrhagic stroke or intracranial hemorrhage within 7 d of surgery., Results: Of 126 patients who underwent EC-IC bypass during the period, 81 patients met inclusion criteria, 69 (85%) persons had carotid artery occlusion, 7 (9%) had proximal MCA occlusion, and 5 (6%) had both. Early surgery had a 31% (9/29) perioperative stroke rate compared to 11.5% (6/52) of patients undergoing late bypass (P = .04). Of patients with acute stroke within 7 d of surgery, 41% (7/17) had perioperative stroke within 7 d (P = .07). Six of nine patients (67%) with blood pressure dependent fluctuation of neurologic symptoms had perioperative stroke (P = .049)., Conclusion: EC-IC bypass in setting of acute symptomatic stroke within 1 wk may confer higher risk of perioperative stroke. Patients undergoing expedited or urgent bypass for unstable or fluctuating stroke symptoms might be at highest risk for perioperative stroke., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Introduction: The low-profile Neuroform Atlas stent received FDA Humanitarian Device Exemption status (HDE) in January 2018 for stent-assisted coil embolization of wide-necked saccular aneurysms. We review and report our results with the Atlas stent in our institution within the first year after its HDE approval., Methods: Our retrospective chart review identified patients treated with the Atlas stent. We analyzed the patient demographics, aneurysm characteristics, stent parameters and configuration, complications, angiographic, and clinical outcomes at discharge., Results: From January to December 2018, 76 Atlas stents were deployed in 58 patients (average 1.3 stents/patient). Median patient age was 63.5 (IQR 56-71) years. Fifty-six (96.6%) patients had elective embolization of unruptured aneurysms, while two (3.4%) patients underwent embolization of a ruptured aneurysm within 2 weeks of subarachnoid hemorrhage. Forty (69.0%) patients were treated with a single stent, 15 (25.9%) with a Y-stent, and three (5.2%) with X-stent configuration. All stent deployments were technically successful. Most stents (82.9%) were the smallest 3 mm diameter devices. Procedural complications included transient stent-associated thrombosis in three (5.2%) patients and aneurysm rupture in one (1.7%). None had distal embolization, associated cerebral infarction, or permanent neurological deficits. Immediate Raymond-Roy 1 occlusion was achieved in 41 (70.7%) patients. Median hospital length of stay for elective aneurysm embolization was 1 day. Excellent outcomes with median National Institute of Health Stroke Scale score 0 (IQR 0-0) and modified Rankin Score 0 (IQR 0-1) were seen for elective patients at discharge., Conclusion: The Neuroform Atlas stent provided a reliable technical and safety profile for the treatment of intracranial wide-neck aneurysms. Further experience is needed to determine long-term durability and safety of this device., Competing Interests: Competing interests: MB is a consultant for Rebound Therapeutics and Stryker Neurovascular. MSH is a consultant for Cerenovus. PAR is on the Medical Advisory Board for Mehana Medical, Stryker Neurovascular, Medtronic Neurovascular, Perflow Medical, and has an Equity Position in Mehana Medical, Perflow Medical, and Bard Neurovascular. GT is a consultant for Dynamed EBSCO., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Robert J. White is probably best known as the first neurosurgeon to perform successful "cephalic exchange" on monkeys in 1971. However, he was also a pioneer in the field of neurosurgery and contributed tremendously to the field of neuroanesthesia and bioethics. White received medical training at the University of Minnesota, Harvard University, Peter Bent Brigham Hospital, and Mayo Clinic before becoming the first Chief of Neurosurgery at Metrohealth Hospital in Cleveland, Ohio. He made significant strides in the field of spinal cord cooling and hypothermia. White and his team was also the first to successfully isolate the monkey brain with retention of biological activity. In 2004 and 2006, White and colleagues were nominated for the Nobel Prize in Physiology and Medicine, with Harvey Cushing and Wilder Penfield being the only other 2 neurosurgeons ever to be nominated for the award. Aside from his career as a neurosurgeon, he was also an advisor to 2 popes and an advocate for animal research. By the end of his career, White performed over 10 000 brain operations and published over 1000 articles, which has pushed the frontiers of neurosurgical research., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments.

Background: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are well-established treatments that have been shown to decrease stroke recurrence in patients with underlying carotid artery disease. We assessed clinical outcome, safety, and restenosis rates for patients who underwent standardized CEA or CAS at our tertiary care center using patient selection criteria based on available scientific evidence., Methods: Retrospective chart review of patients who underwent CEA or CAS between 2009 and 2016., Results: In total, 314 cases (204 with CEA and 110 with CAS) were analyzed. Patients were predominantly white (84.4%), men (61.1%) with hypertension (86.9%) and hyperlipidemia (81.8%). Most patients (84.5%) had symptomatic carotid disease. No significant differences were observed in median postoperative National Institutes of Health Stroke Scale and modified Rankin scale (mRS) scores based on pretreatment symptomatic status or treatment modality (CEA vs. CAS). Most patients (85.9%) had favorable outcomes (mRS score 0-2) at a median follow-up of 11.7 months (interquartile range, 1.8-28.8). The perioperative complication rate was low (3.2%), and permanent neurologic deficit was seen in only 3 patients (1%). Restenosis was found in 7.3%, without significant difference between CEA and CAS at last follow-up. Restenosis was asymptomatic in most patients., Conclusions: Our findings in a real-world predominantly symptomatic cohort demonstrate that favorable patient outcomes and low restenosis and complication rates can be achieved with both CEA and CAS by the utilization of a consistent institutional patient selection and treatment process., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that is caused by mutations in the nuclear thymidine phosphorylase gene ( TYMP ) gene, encoding for the enzyme thymidine phosphorylase. There are currently no approved treatments for MNGIE. The aim of this study was to investigate the safety, tolerability, and efficacy of an enzyme replacement therapy for the treatment of MNGIE. In this single centre study, three adult patients with MNGIE received intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase (EE-TP; dose range: 4 to 108 U/kg/4 weeks). EE-TP was well tolerated and reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. Clinical improvements, including weight gain and improved disease scores, were observed in two patients, suggesting that EE-TP is able to reverse some aspects of the disease pathology. Transient, non-serious adverse events were observed in two of the three patients; these did not lead to therapy discontinuation and they were managed with pre-medication prior to infusion of EE-TP. To conclude, enzyme replacement therapy with EE-TP demonstrated biochemical and clinical therapeutic efficacy with an acceptable clinical safety profile.

Background: Anterior inferior cerebellar artery (AICA) aneurysms are rare lesions whose treatment can involve microsurgical and/or endovascular techniques. Such treatment can be challenging and may carry a significant risk of neurological morbidity., Objective: To demonstrate a case involving a complex AICA aneurysm that was treated with a unique microsurgical approach involving trapping the aneurysm and performing in Situ bypass from the posterior inferior cerebellar artery (PICA) to the distal AICA. The nuances of AICA aneurysms and revascularization strategies are discussed., Methods: The aneurysm and the distal segments of AICA and PICA were exposed with a retrosigmoid and far lateral approach. A side-to-side anastomosis was performed between the adjacent caudal loops of PICA and AICA. The AICA aneurysm was then treated by trapping the aneurysm-bearing segment of the parent vessel between 2 clips., Results: A postoperative angiogram demonstrated a patent PICA-AICA bypass and complete occlusion of the AICA aneurysm. There were no complications, and the patient made an excellent recovery., Conclusion: The combination of parent vessel sacrifice and bypass remains an excellent option for certain difficult-to-treat aneurysms. This case involving PICA-AICA bypass to treat an AICA aneurysm serves as an example of the neurosurgeon's ability to develop unique solutions that take advantage of individual anatomy.

Background: The guideline for treating unruptured brain arteriovenous malformations (ubAVMs) remains controversial. A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) reported lower risk of stroke or death with conservative management compared to interventional treatment. There were numerous limitations to the study, including short follow-up period and disproportionate number of patients treated with surgery and embolization., Objective: To evaluate whether treatment of ARUBA-eligible patients have acceptable outcomes at our institution., Methods: Retrospective analysis was performed on 673 patients with brain AVMs treated at our institution between 2001 and 2014. One hundred five patients were ARUBA eligible and included in the study. Patients were divided into the microsurgery or Gamma Knife Radiosurgery (GKS; Elekta, Stockholm, Sweden) arm depending on their final treatment. Mean follow-up period was 43 mo (range 4-136 mo). Primary outcome was stroke or death., Results: A total of 8 (7.6%) patients had a stroke or died. The overall risk of stroke or death was 11.4% (5 of 44 patients) for the microsurgery arm and 4.9% (3 of 61 patients) for the GKS arm. The annual rates of stroke or death were 2.1%, 4.0%, and 1.2% for the entire patient cohort, microsurgery arm, and GKS arm, respectively. AVM obliteration rates at the end of the follow-up period were 95.5% and 47.5% for the microsurgery and GKS arms, respectively., Conclusion: We report a lower overall risk of stroke or death in our ARUBA-eligible patients following treatment than ARUBA. Our results suggest that microsurgery and GKS may be appropriate treatments for patients with ubAVM.

Background: Although tubular retractor systems have gained popularity for other indications, there have been few reports of their use for arteriovenous malformation (AVM) surgery. A patient was diagnosed with a ruptured 1.2-cm subcortical AVM after presenting with intracerebral hemorrhage in the right frontal lobe and anterior basal ganglia. The characteristics of this AVM made it amenable to resection using a tubular retractor., Objective: To demonstrate the feasibility and safety of AVM resection using a tubular retractor system., Methods: Resection of the ruptured 1.2-cm subcortical AVM was performed utilizing the BrainPathTM (NICO corp, Indianapolis, Indiana) tubular retractor system., Results: The BrainPathTM approach provided sufficient visualization and surgical freedom to permit successful AVM resection and hematoma evacuation. Postoperative imaging demonstrated near total hematoma removal and angiographic obliteration of the AVM. There were no complications, and the patient made an excellent recovery., Conclusion: Tubular retractors warrant consideration for accessing small, deep, ruptured AVMs. The nuances of such systems and their role in AVM surgery are discussed.

Background: Patients with Moyamoya or other intracranial steno-occlusive disease are at risk for developing aneurysms associated with flow through collateral vessels. Because these lesions are rare, the optimal management remains unclear. Here, we describe 2 cases of microsurgical repair of ruptured collateral vessel aneurysms associated with middle cerebral artery (MCA) occlusion., Case Description: The first patient was a 61-year-old man who presented with right frontal and intraventricular hemorrhage. Angiography revealed chronic right M1 occlusion and a 3-mm spherical lenticulostriate aneurysm. The frontal lobe hematoma was evacuated to reveal the aneurysm, which was safely cauterized and resected by coagulating and dividing the lenticulostriate parent vessel. The procedure was carried out with neuronavigation guidance and intraoperative neuromonitoring. The patient was discharged with no neurologic deficits. The second patient was a 53-year-old woman who presented with subarachnoid and intracerebral hemorrhage. Computed tomography angiogram showed a 2-mm saccular MCA aneurysm. Emergency left decompressive hemicraniectomy and hematoma evacuation were performed. The aneurysm, arising from a small collateral type vessel, was safely clipped without complications. Postoperative angiography revealed absence of the superior MCA trunk with a dense network of collateral vessels at the site of the clipped aneurysm. The patient recovered well and was ambulating independently 6 months postoperatively. No rebleeding occurred in the 2 patients., Conclusions: Our experience suggests that patients with MCA occlusion can harbor associated aneurysms related to flow through collateral vessels and can present with hemorrhage. Microsurgical repair of these aneurysms can be performed safely to prevent rebleeding., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Surgical intervention has been proposed as a means of reducing the high morbidity and mortality associated with acute intracerebral hemorrhage (ICH), but many previously reported studies have failed to show a clinically significant benefit. Newer, minimally invasive approaches have shown some promise., Objective: We report our early single-center technical experience with minimally invasive clot evacuation using the BrainPath system., Methods: Prospective data were collected on patients who underwent ICH evacuation with BrainPath at the Cleveland Clinic from August 2013 to May 2015., Results: Eighteen patients underwent BrainPath evacuation of ICH at our center. Mean ICH volume was 52.7 mL ± 22.9 mL, which decreased to 2.2 mL ± 3.6 mL postevacuation, resulting in a mean volume reduction of 95.7% ± 5.8% (range 0-14 mL, P < .001). In 65% of patients, a bleeding source was identified and treated. There were no hemorrhagic recurrences during the hospital stay. In this cohort, only 1 patient (5.6%) died in the first 30 days of follow-up. Median Glasgow Coma Score improved from 10 (interquartile range 5.75-12) preoperation to 14 (interquartile range 9-14.25) postoperation. Clinical follow-up in this cohort is ongoing., Conclusion: Evacuation of ICH using the BrainPath system is safe and technically effective. The volume of clot removed compares favorably with other published studies. Early improved clinical outcomes are suggested by improvement in Glasgow Coma Score and reduced 30-day mortality. Ongoing analysis is necessary to elucidate long-term clinical outcomes and the subsets of patients who are most likely to benefit from surgery., (Copyright © 2016 by the Congress of Neurological Surgeons)

Excoriation disorder (ED), also known as dermatotillomania, is a condition characterized by repeated "skin picking" that leads to the formation of skin lesions. Because of the similarity of its symptoms to obsessive compulsive disorder, ED is classified as a subcategory of obsessive compulsive disorder by Diagnostic and Statistical Manual of Mental Disorders Fifth Edition. Although the majority of the self-inflicted wounds are not clinically significant, many wounds lead to social and occupational dysfunction by becoming infected, chronic, and life threatening. This report describes the successful use of a viable intact cryopreserved human amniotic membrane in conjunction with selective serotonin re-uptake inhibitors in treating an ED patient who presented with a large calvarial wound of 3-year duration that had failed previous extensive medical and surgical interventions.

Background: The long-term effect of flow diversion (FD) on aneurysms has not been well studied., Objective: We aimed to assess the effect of the Pipeline embolization device (Covidien, Irvine, California, USA) on large and giant intracranial aneurysms with magnetic resonance imaging (MRI) and digital subtraction angiography (DSA) and then correlate with clinical follow-up., Methods: We conducted a retrospective analysis of aneurysms treated solely with Pipeline without adjunctive therapy. The largest aneurysm diameters were compared with pretreatment and post treatment MRI and correlated with DSA and clinical symptoms., Results: Twelve patients harboring large and giant saccular unruptured aneurysms, treated with Pipeline, were included. Mean follow-up times were as follows: MRI 22.8 months (range 1-57), DSA 18.2 months (range 1-33), and clinical 29 months (range 1-48). Ten (83%) of 12 treated aneurysms decreased in size on MRI, which was first seen at an average of 17 months (range 4-57). In 70% of patients the change was noted on MRI ≤1 year after treatment, at an average of 9.1 months (range 4-12). MRI reduction was more likely in angiographically occluded aneurysms. Five aneurysms with complete occlusion on early angiogram showed size reduction on MRI only at ≥12 months. Mean aneurysm size reduction was 57% (range 19.6-94.2), which correlated well with improvement of cranial neuropathies in 75% and headaches in 100% of patients., Conclusion: Most aneurysms treated with Pipeline decreased in size, correlating with clinical improvement. Some aneurysms remained unchanged on MRI until a later time point despite early DSA occlusion. It may be reasonable to eliminate early postprocedural imaging and start follow-up only as late as 1 year after FD treatment in clinically stable, asymptomatic patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Cerebrospinal fluid diversion through lumbar drainage catheters is a routine procedure that is used in a variety of clinical applications. Fracture of catheters during insertion or removal may result in retained foreign bodies that may lead to patient morbidity with potential legal ramifications. Fracture resistance is an important component of drain selection., Objective: To analyze catheter integrity to determine which commercially available catheters are most robust and resistant to fracture., Methods: Physical properties of the commercially available drainage catheters that can be advanced through a Touhy needle were assessed using laboratory equipment and reported. Five types of catheter were analyzed for break load, tensile strength, extension at break, and shear strength., Results and Conclusions: Of the five types of catheter, the Arrow catheter showed the greatest resistance to fracture. Of the drainage catheters, the Codman catheter showed the greatest resistance to fracture., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: There is scant information on in-stent stenosis after flow diversion treatment of intracranial aneurysms with the Pipeline Embolization Device (PED)., Objective: To assess the incidence, severity, nature, and clinical consequences of in-stent stenosis on angiographic follow-up after treatment with the PED., Methods: A retrospective study of patients who underwent aneurysm treatment with the PED was conducted. In-stent stenosis was assessed on subsequent follow-up angiography. Intimal hyperplasia was defined as a uniform growth process beyond the limits of the metallic mesh at <25%. In-stent stenosis represented an area of parent vessel narrowing, most often focal, graded as mild (25%-50%), moderate (50%-75%), or severe (>75%)., Results: Between June 2011 and April 2015, 80 patients were treated with the PED. Angiographic follow-up was available for 51 patients (representing 76% of available or 64% of all patients). Mean follow-up was 12.5 months. In-stent stenosis was detected in 5 patients (9.8%) at a median of 6 months. Stenosis was mild in 4 of 5 (80%) and moderate in 1 of 5 (20%) patients. There were no cases of severe stenosis. No stenosis caused flow limitation, clinical symptoms, or required re-treatment. Additional follow-up angiography was available in 2 of 5 stenosis patients showing marked improvement. Sixteen patients (31%) had intimal hyperplasia, and 28 patients (55%) had no stenosis. Asymptomatic stent occlusion occurred in 2 patients (4%) related to medication noncompliance., Conclusion: Treatment with the PED was associated with a 9.8% rate of in-stent stenosis, detected on first angiographic follow-up, at a median of 6 months. None were symptomatic or required re-treatment, and they showed significant improvement on follow-up., Abbreviation: FD, flow diverter.

Background and Importance: The publication of the COSS (Carotid Occlusion Surgery Study) trial in 2011 concluded that the addition of external carotid to internal carotid (EC-IC) bypass to a medical regimen "did not reduce the risk of ipsilateral ischemic stroke at 2 years" for patients with symptomatic internal carotid artery occlusion. This has resulted in decreasing referrals for surgical management under the guise of "evidence-based" medicine. The conclusions drawn from a study can only be as good as the selected end points. COSS did not consider important end points such as the effects of long-term cerebral ischemia or recurrent debilitating transient ischemic attacks (TIAs). However, the study is often quoted as "proof" that EC-IC bypass has no role in the treatment of these patients., Clinical Presentation: A middle-aged patient presented to a primary neurologist with left-sided weakness and 2 months of personality changes. Magnetic resonance imaging (MRI) showed small watershed infarcts in the right hemisphere. An angiogram showed right carotid occlusion. Perfusion scans confirmed hypoperfusion. The patient was managed medically. Without any further clinical stroke events, the patient progressed to complete hemispheric infarction on MRI over the next 5 months., Conclusion: The public perception of the results of large randomized clinical trials is significantly altered by their ubiquitous dissemination and broad generalization without adequate understanding of the details. Careful assessment of the methodology and end points of a trial are essential when applying the results for evidence-based medicine to individual patients. This patient would have been considered a medical "success" in COSS, but her outcome with surgical intervention will never be known., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Carotid artery sacrifice remains an important procedure for cerebral vascular disorders despite the development of new endovascular devices. Conventional carotid artery sacrifice with detachable coils alone often requires numerous coils to complete occlusion., Objective: To describe the initial human experience with balloon-augmented Onyx and coil vessel sacrifice based on our previous experience with animals., Methods: We performed a retrospective review of patients who underwent carotid artery sacrifice between 2008 and 2012 in accordance with local investigational review board approval. Two methods were used to occlude carotid arteries-namely, combined Onyx and coil embolization and traditional coil embolization. We compared the two methods for the cost of embolizate, time to occlude the vessels, and the number of coils., Results: Eight consecutive patients (combined group n=3, traditional group n=5) were assessed. The median cost of embolic material was $6321 in the combined Onyx and coil embolization group and $29 996 in the traditional coil embolization group. The median time from first coil placement to achievement of vessel occlusion was 52 min in the Onyx group and 113 min in the coil embolization group. The median number of coils used was 4 in the Onyx group and 35 in the coil embolization group (p<0.05). No symptomatic complications or recurrences were seen in the combined group., Conclusions: Balloon-augmented Onyx endovascular ligation may reduce costs and fluoroscopy times during vessel sacrifice. Further studies in a larger number of patients are needed to confirm these findings., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Brain arteriovenous malformations (BAVM) are some of the most complex lesions treated by clinical neuroscientists. The recent publication of the ARUBA trial, showing higher complication rates with treatment compared with the natural history over a short period of follow-up, puts even more pressure on the physician to achieve complete BAVM eradication without complication. These lesions are often treated by multimodality therapy with some combination of endovascular embolization, radiosurgery, and microsurgical resection; however, multimodality therapy involves the additive risk of procedural complication with each procedure. While surgical resection has long been accepted as monotherapy with good cure rates, staged pre-operative endovascular embolization has facilitated microsurgical resection with lower blood loss. Endovascular embolization is more often utilized in conjunction with surgical resection, and often the portions of the AVM and feeders that are completely embolized with Onyx or glue may not be surgically resected since they have been "internally obliterated." We present a case where the AVM was preoperatively embolized with Onyx and subsequently partially surgically resected. Post-operative angiography showed complete obliteration or "cure" of the AVM with no filling of the nidus or early venous drainage. The patient presented 12 months later with seizures and imaging showed volume loss in the residual Onyx cast and recanalization of the AVM nidus. The patient subsequently underwent repeat resection with complete removal of the residual AVM and Onyx cast. To our knowledge this is the first published report of volume loss within the Onyx cast leading to recanalization of the AVM nidus. This suggests that extreme care should be taken with partial resection of the AVM nidus or with embolization for cure, as late recanalization may occur., (© The Author(s) 2015.)

Bow hunter's syndrome is a condition in which vertebrobasilar insufficiency is resultant from head rotation, clinically manifested by presyncopal sensation, syncope, dizziness, and nausea. It is usually diagnosed clinically, with supporting vascular imaging demonstrating an occluded or at the very least compromised unilateral vertebral artery, while the dominant vertebral artery remains patent in the neutral position. Dynamic imaging is utilized to confirm the rotational compression of the dominant vertebral artery. We present the rare case of a patient with typical Bow hunter's symptoms, bilaterally patent vertebral arteries on neutral imaging, and bilateral compromise with head rotation. Our patient underwent posterior decompression of the culprit atlanto-axial transverse foramen and subaxial cervical fusion, with resolution of his symptoms. Our patient exemplifies the possibility of bilateral dynamic vertebral artery occlusion. We show that Bow hunter's syndrome cannot be ruled out in the setting of bilaterally patent vertebral arteries on neutral imaging and that severe cervical spondylosis should impart further clinical suspicion of this unusual phenomenon., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Defects in mitochondrial function are increasingly recognised as central to the pathogenesis of many diseases, both inherited and acquired. Many of these mitochondrial defects arise from abnormalities in mitochondrial DNA and can result in multisystem disease, with gastrointestinal involvement common. Moreover, mitochondrial disease may present with a range of non-specific symptoms, and thus can be easily misdiagnosed, or even considered to be non-organic. We describe the clinical, histopathological and genetic findings of six patients from three families with gastrointestinal manifestations of mitochondrial disease. In two of the patients, anorexia nervosa was considered as an initial diagnosis. These cases illustrate the challenges of both diagnosing and managing mitochondrial disease and highlight two important but poorly understood aspects, the clinical and the genetic. The pathophysiology of gastrointestinal involvement in mitochondrial disease is discussed and emerging treatments are described. Finally, we provide a checklist of investigations for the gastroenterologist when mitochondrial disease is suspected., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Cardiac emboli are a feared complication for patients with left ventricular assist devices (LVAD). Septic emboli are rare but carry a poor prognosis in the setting of large artery occlusion. We report the case of a 24-year-old woman who presents with a left internal carotid artery terminus occlusion secondary to a septic emboli from a LVAD. The patient was not a candidate for intravenous thrombolytics due to an elevated international normalized ratio, and thus was taken for intra-arterial treatment. Initial treatment with mechanical thrombectomy and balloon angioplasty was not successful; thus, a balloon-mounted coronary stent was placed to achieve successful recanalization. Fragments of thrombus on the mechanical thrombectomy device revealed gram-positive bacilli on gram stain. Patients with large artery occlusion due to a septic embolus can be successfully treated with endovascular therapies in select patients., (Copyright © 2009 by the American Society of Neuroimaging.)

Background and Importance: Early origin of the middle cerebral artery M2 segment is a normal variant. When such a vessel is occluded proximally, the parenchyma distal to the vessel may become ischemic. Targeted extracranial to intracranial bypass to such a specific branch may preserve perfusion to the end organ. We describe the use of intra-aneurysmal injection of indocyanine green to identify a target middle cerebral artery branch (MCA) for bypass, immediately followed by proximal parent vessel sacrifice via endovascular embolization., Clinical Presentation: A 45-year-old woman presented to an outside hospital with headaches. Magnetic resonance imaging revealed a giant aneurysm of the right MCA. The aneurysm gave rise to an M2 branch that supplied the right anterior frontal operculum, as well as the anterolateral portion of the superior temporal gyri. Balloon test occlusion was nondiagnostic because of the territory involved, and the risk of sizable infarction after vessel sacrifice was thought to be high. Craniotomy and targeted extracranial to intracranial bypass to an M4 opercular branch was performed with intra-aneurysmal injection of indocyanine green. In our combined endovascular/open cerebrovascular suite, an opercular MCA branch that fluoresced during the first-pass arterial circulation of indocyanine green was identified, and a superficial temporal artery to MCA bypass was performed. Angiographic verification of bypass patency was confirmed, followed by embolic occlusion of the giant aneurysm with preservation of flow to the parenchyma at risk through the bypass., Conclusion: Targeted bypass to distal branches is feasible with intra-arterial and intra-aneurysmal injection of indocyanine green, allowing confident preservation of blood supply to areas distal to the sacrificed vessel.

The department of Neurological Surgery at the Cleveland Clinic is one of the largest and most specialized in the country. This report recounts the Clinic's early history, beginning with the ties between its principal founder, George W. Crile, and Harvey Cushing, through the tragic "Clinic disaster," the death of its first dedicated neurosurgeon, and the arrival of W. James Gardner. The evolution of the department and the present state of the residency training program are discussed.

Objective: The use of deep brain stimulation (DBS) to treat a variety of disorders has expanded and will result in an increasingly larger number of patients and implanted electrodes. Hardware failure can result from malfunction, lead migration, fracture, and infection. Scalp erosion with exposure of underlying hardware can lead to potential infectious complications and is, in itself, a strong indication for explantation of the neurostimulation system. The patient's relief of symptoms after DBS will be limited by hardware-related complications and thus, strategies to revise scalp overlying hardware are important in the widespread application of DBS., Clinical Presentation: We describe strategies to address complications related to implanted DBS neurostimulator hardware specifically designed to address breach of the integrity of the scalp over the burr hole site. The aim of these approaches is to treat scalp erosion to allow for the reimplantation of previously explanted, infected hardware, or to treat thinned scalp with threatened erosion and prevent the need to remove exposed hardware that is otherwise functioning., Intervention: Two different approaches are presented: 1) a temporoparieto-occipital flap based on the superficial temporal artery with or without scalp expansion, and 2) a scalp fasciocutaneous flap with or without cranioplasty., Conclusion: Stimulation of various deep brain targets helps patients with a wide range of diseases. In the future, with continued refinement, hardware complications can be minimized. Until then, novel approaches need to be developed to save DBS systems and provide symptomatic relief to patients.

Adenosine deaminase (ADA) deficiency is an inherited disorder which leads to elevated cellular levels of deoxyadenosine triphosphate (dATP) and systemic accumulation of its precursor, 2-deoxyadenosine. These metabolites impair lymphocyte function, and inactivate S-adenosylhomocysteine hydrolase (SAHH) respectively, leading to severe immunodeficiency. Enzyme replacement therapy with polyethylene glycol-conjugated ADA is available, but its efficacy is reduced by anti-ADA neutralising antibody formation. We report here carrier erythrocyte encapsulated native ADA therapy in an adult-type ADA deficient patient. Encapsulated enzyme is protected from antigenic responses and therapeutic activities are sustained. ADA-loaded autologous carrier erythrocytes were prepared using a hypo-osmotic dialysis procedure. Over a 9-yr period 225 treatment cycles were administered at 2-3 weekly intervals. Therapeutic efficacy was determined by monitoring immunological and metabolic parameters. After 9 yr of therapy, erythrocyte dATP concentration ranged between 24 and 44 micromol/L (diagnosis, 234) and SAHH activity between 1.69 and 2.29 nmol/h/mg haemoglobin (diagnosis, 0.34). Erythrocyte ADA activities were above the reference range of 40-100 nmol/h/mg haemoglobin (0 at diagnosis). Initial increases in absolute lymphocyte counts were not sustained; however, despite subnormal circulating CD20(+) cell numbers, serum immunoglobulin levels were normal. The patient tolerated the treatment well. The frequency of respiratory problems was reduced and the decline in the forced expiratory volume in 1 s and vital capacity reduced compared with the 4 yr preceding carrier erythrocyte therapy. Carrier erythrocyte-ADA therapy in an adult patient with ADA deficiency was shown to be metabolically and clinically effective.

Fever is associated with improved survival during infection in endothermic and ectothermic species although the protective mechanisms are largely undefined. Previous studies indicate that fever-range thermal stress increases the binding activity of the L-selectin homing receptor in human or mouse leukocytes, thereby promoting trafficking to lymphoid tissues across high endothelial venules (HEV). Here, we examined the evolutionary conservation of thermal regulation of L-selectin-like adhesion. Leukocytes from animals representing four taxa of vertebrates (mammals, avians, amphibians, teleosts) were shown to mediate L-selectin-like adhesion under shear to MECA-79-reactive ligands on mouse HEV in cross-species in vitro adherence assays. L-selectin-like binding activity was markedly increased by fever-range thermal stress in leukocytes of all species examined. Comparable increases in L-selectin-like adhesion were induced by thermal stress, IL-6, or the IL-6/soluble IL-6 receptor fusion protein, hyper-IL-6. Analysis of the molecular basis of thermal regulation of L-selectin-like adhesion identified a common IL-6 trans-signaling mechanism in endotherms and ectotherms that resulted in activation of JAK/STAT signaling and was inhibited by IL-6 neutralizing antibodies or recombinant soluble gp130. Conservation of IL-6-dependent mechanisms controlling L-selectin adhesion over hundreds of millions of years of vertebrate evolution strongly suggests that this is a beneficial focal point regulating immune surveillance during febrile inflammatory responses.

This study investigated the potential of a single administration of carrier erythrocyte entrapped antigen to elicit humoral responses in the Balb/c mouse. Humoral responses to primary immunizations of erythrocyte encapsulated antigens were compared with those obtained with adjuvanted antigen administered via the subcutaneous route. Ig isotype responses to primary immunizations of erythrocyte entrapped antigen and subcutaneous antigen were compared to responses observed in mice that subsequently received booster immunizations with un-entrapped antigen. This study demonstrates that a single administration of antigen-loaded carrier erythrocytes is able to elicit humoral immune responses comparable or superior to those obtained via the adjuvanted subcutaneous vaccination route. The IgG isotype profiles demonstrate that the erythrocyte entrapment of antigens is another mechanism by which the Th responses to antigens maybe modulated.

We report here riboflavin responsiveness in a patient with glutaryl CoA dehydrogenase (GCDH) deficiency, compound heterozygous for the S139L and P248L mutations and with 20% residual GCDH enzyme activity in vitro. Our results suggest the mitochondrial GCDH homotetramer remains intact with one of these mutations associated with the binding site of the single FAD cofactor and that pharmacological doses of the cofactor precursor may be sufficient to induce an increase in activity in the mutant GCDH enzyme, although not sufficient to normalise urinary organic acid excretion. Serine139 is one of nine conserved amino acid residues that line the binding site of the protein and is in close proximity to both substrate and FAD cofactor. It is possible that steric alterations caused by substitution of serine with leucine at this position may be overcome with high cofactor concentrations. P248L is also associated with some residual GCDH activity in other patients and the unique combination of S139L with P248L may also explain the results in our patient. Responsiveness to riboflavin in our patient has been compared with two other patients with glutaric aciduria type 1 and minimal residual GCDH activity, one with homozygosity for the R257Q mutation and one with heterozygosity for the G354S mutation and a novel G156V mutation. A low lysine diet reduced glutaric acid excretion in our riboflavin-responsive GCDH-deficient patient almost to control values. She is now 21 years of age and clinically and neurologically normal.