Restoration of axon conduction and motor deficits by therapeutic treatment with glatiramer acetate.

Glatiramer acetate (GA; Copaxone) is an approved drug for the treatment of multiple sclerosis (MS). The underlying multifactorial anti-inflammatory, neuroprotective effect of GA is in the induction of reactive T cells that release immunomodulatory cytokines and neurotrophic factors at the injury site. These GA-induced cytokines and growth factors may have a direct effect on axon function. Building on previous findings that suggest a neuroprotective effect of GA, we assessed the therapeutic effects of GA on brain and spinal cord pathology and functional correlates using the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Therapeutic regimens were utilized based on promising prophylactic efficacy. More specifically, C57BL/6 mice were treated with 2 mg/mouse/day GA for 8 days beginning at various time points after EAE post-induction day 15, yielding a thorough, clinically relevant assessment of GA efficacy within the context of severe progressive disease. Therapeutic treatment with GA significantly decreased clinical scores and improved rotorod motor performance in EAE mice. These functional improvements were supported by an increase in myelinated axons and fewer amyloid precursor protein-positive axons in the spinal cords of GA-treated EAE mice. Furthermore, therapeutic GA decreased microglia/macrophage and T cell infiltrates and increased oligodendrocyte numbers in both the spinal cord and corpus callosum of EAE mice. Finally, GA improved callosal axon conduction and nodal protein organization in EAE. Our results demonstrate that therapeutic GA treatment has significant beneficial effects in a chronic mouse model of MS, in which its positive effects on both myelinated and non-myelinated axons results in improved axon function

Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis.

BackgroundTherapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future treatment of multiple sclerosis (MS), as well as other diseases. Laquinimod (LQ) is an orally administered, central nervous system (CNS)-active immunomodulator with demonstrated efficacy in MS clinical trials and a favorable safety and tolerability profile.AimsWe aimed to explore the pathological, functional, and behavioral consequences of prophylactic and therapeutic (after presentation of peak clinical disease) LQ treatment in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS.Materials and methodsActive EAE-induced 8-week-old C57BL/6 mice were treated with 5 or 25 mg/kg/day LQ via oral gavage beginning on EAE post-immunization day 0, 8, or 21. Clinical scores and rotorod motor performance were assessed throughout the disease course. Immune analysis of autoantigen-stimulated splenocytes, electrophysiological conduction of callosal axons, and immunohistochemistry of white matter-rich corpus callosum and spinal cord were performed.ResultsProphylactic and therapeutic treatment with LQ significantly decreased mean clinical disease scores, inhibited Th1 cytokine production, and decreased the CNS inflammatory response. LQ-induced improvement in axon myelination and integrity during EAE was functional, as evidenced by significant recovery of callosal axon conduction and axon refractoriness and pronounced improvement in rotorod motor performance. These improvements correlate with LQ-induced attenuation of EAE-induced demyelination and axon damage, and improved myelinated axon numbers.DiscussionEven when initiated at peak disease, LQ treatment has beneficial effects within the chronic EAE mouse model. In addition to its immunomodulatory effects, the positive effects of LQ treatment on oligodendrocyte numbers and myelin density are indicative of significant, functional neuroprotective and neurorestorative effects.ConclusionsOur results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression

Oestrogen receptor β ligand: a novel treatment to enhance endogenous functional remyelination

Demyelinating diseases, such as multiple sclerosis, are characterized by inflammatory demyelination and neurodegeneration of the central nervous system. Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future therapy of multiple sclerosis. Oestrogens and oestrogen receptor ligands are promising treatments to prevent multiple sclerosis-induced neurodegeneration. In the present study we investigated the capacity of oestrogen receptor β ligand treatment to affect callosal axon demyelination and stimulate endogenous myelination in chronic experimental autoimmune encephalomyelitis using electrophysiology, electron microscopy, immunohistochemistry and tract-tracing methods. Oestrogen receptor β ligand treatment of experimental autoimmune encephalomyelitis mice prevented both histopathological and functional abnormalities of callosal axons despite the presence of inflammation. Specifically, there were fewer demyelinated, damaged axons and more myelinated axons with intact nodes of Ranvier in oestrogen receptor β ligand-treated mice. In addition, oestrogen receptor β ligand treatment caused an increase in mature oligodendrocyte numbers, a significant increase in myelin sheath thickness and axon transport. Functional analysis of callosal axon conduction showed a significant improvement in compound action potential amplitudes, latency and in axon refractoriness. These findings show a direct neuroprotective effect of oestrogen receptor β ligand treatment on oligodendrocyte differentiation, myelination and axon conduction during experimental autoimmune encephalomyelitis

Deep Venous Stenting Improves Healing of Lower Extremity Venous Ulcers.

BackgroundLong standing, recalcitrant venous ulcers fail to heal despite standard compression therapy and wound care. Stenting of central veins has been reported to assist in venous ulcer healing. This study reports outcomes of deep venous stenting for central venous obstruction in patients with recalcitrant venous ulcers at a single comprehensive wound care center.MethodsA single center retrospective analysis was conducted of patients with CEAP (Clinical, Etiology, Anatomy, and Pathophysiology) 6 disease that had undergone deep venous stenting in addition to wound care and compression therapy. Intra-operative details, wound healing, and stent patency rates were recorded. Stent patency and intra-operative details were compared between the healed and unhealed groups.ResultsBetween 2010 and 2019, 15 patients met inclusion criteria (mean age: 63 years old, 12 males). Pre-operative mean wound area was 14.1 cm2 with mean wound duration of 30 months. 93% of patients healed the ulcers at mean healing time of 10.6 months. Wound recurrence rate was 57% with mean recurrence time of 14.8 months. Ten patients presented with an inferior vena cava (IVC) filter, 4 in the healed group and 6 in the unhealed group. The common iliac vein was stented in all patients. Extension into the IVC was required in 4, the common femoral vein in 11, and femoral vein in 2 patients. The average stent length was 190cm. During the follow-up period, primary patency rates in healed patients (mean follow-up time: 19.2 months) was 83% and 59% in the unhealed group (mean follow-up time: 36.6 months); secondary patency rates were 83% and 89%, respectively.ConclusionsIn patients with recalcitrant venous ulcers with central venous obstruction, deep venous stenting resulted in a high rate of healing. However, a prolonged 10 month healing time was observed and despite high stent patency, wound recurrence rate was high

Intravascular ultrasonography provides more sensitive detection of subclavian vein stenosis than venography in patients presenting with Paget-Schroetter syndrome.

ObjectiveSpontaneous subclavian vein (SCV) thrombosis (Paget-Schroetter syndrome [PSS]) has been attributed to venous compression at the thoracic outlet and traditionally diagnosed using venography. Intravascular ultrasonography (IVUS) allows for a multidimensional view of vascular structures and might be more accurate in revealing venous compression. The goal of the present study was to compare venography and IVUS in patients presenting with PSS to assess the relative accuracy of each modality.MethodsPatients presenting for evaluation of PSS from 2013 to 2019 were evaluated for SCV compression using venography and IVUS. Venography and IVUS measurements of stenosis were performed of the index and contralateral limbs in both neutral and stress (arm overhead) positions. The IVUS data included the SCV diameters in the anteroposterior (AP) plane, craniocaudal (CC) plane, and cross-sectional area (CSA). Stenosis was reported as the percentage of reduction from a reference point (lateral margin of the first rib) for the venography and IVUS data.ResultsFor the 35 subjects, the average age was 35 years, 57% were women, 20% had presented with a documented pulmonary embolus, and 70% had initially been treated with thrombolysis. Venography demonstrated SCV occlusion in 3 patients (16%) with the index limb in the neutral position and in 18 patients (54%) with the limb in the stress position. The average stenosis in the index limbs was 41.5% (venography), and the average IVUS stenosis was 41.9% (CC), 61.8% (AP), and 74.5% (CSA; P < .05). A subset analysis revealed that in 10 of 35 patients (28%) in whom venography had identified no significant stenosis (average, 10%), IVUS had identified significant stenosis (33.5% CC, 54.3% AP, 68.7% CSA; P < .05).ConclusionsIVUS proved more sensitive than venography in detecting significant stenosis leading to SCV thrombosis. A reduction in the CSA was the most sensitive measure of stenosis. IVUS identified significant stenosis in patients in whom venography failed to do so. The greatest utility of IVUS is in the evaluation of patients with PSS in whom venography shows no evident compression

Caval Reconstruction with Undersized Ringed Graft after Resection of Inferior Vena Cava Leiomyosarcoma

BackgroundThe en bloc resection of inferior vena cava (IVC) leiomyosarcoma often necessitates IVC reconstruction. The objective of this study is to examine outcomes after IVC reconstruction and determine optimal graft sizing.MethodsA retrospective review was conducted of all IVC reconstructions after IVC leiomyosarcoma resection at a single institution. Cross-sectional dimensions at the IVC resection margins were measured on preoperative imaging. The tumor location was based on the most superiorly involved region of the IVC and was classified as infrarenal, between hepatic and renal veins, or superior to the hepatic veins. Perioperative details and long-term outcomes including graft sizing, graft patency, morbidity, and mortality were recorded.ResultsBetween 2007 and 2017, 12 patients (6 females, mean age: 64.5 years, age range: 46-80 years) underwent IVC leiomyosarcoma resection and reconstruction. All reconstructions were performed with ringed polytetrafluoroethylene (PTFE); graft sizes ranged from 12 mm to 16 mm. The tumor location was exclusively infrarenal in seven patients, between the renal and hepatic veins in two patients, and involved multiple segments in three patients. Larger graft sizes were utilized in reconstructing more superior segments of the IVC. Grafts were typically undersized and based on the diameter of the superior resection margin with 12 mm grafts approximately correlating to a 20 mm diameter, 14 mm to 25 mm, and 16 mm to 30 mm. The average undersizing ratio was 0.6. At a mean follow-up time of 43 ± 27 months, radiographic graft patency was 92%, overall survival was 83%, and disease-free survival was 25%.ConclusionsAfter en bloc resection of IVC leiomyosarcoma, caval reconstruction with an undersized ringed PTFE has acceptable patency. Grafts sizes should be based on the IVC diameter superior to the tumor and undersizing by approximately 40% appears to be associated with acceptable patency rates. Further multiinstitutional studies should be performed to best determine the optimal treatment of this rarely encountered tumor

Impact of Frailty on Clinical Outcomes after Carotid Artery Revascularization.

BackgroundFrailty has been increasingly recognized as an important risk factor for vascular procedures. To assess the impact of frailty on clinical outcomes and resource utilization in patients undergoing carotid revascularization using a national cohort.MethodsThe 2005-2017 National Inpatient Sample was used to identify patients who underwent carotid endarterectomy (CEA) or carotid stenting (CAS). Patients were classified as frail using diagnosis codes defined by the Johns Hopkins Adjusted Clinical Groups frailty indicator. Multivariable regression was used to evaluate associations between frailty and in-hospital mortality, postoperative stroke, myocardial infarction (MI), hospitalization costs, and length of stay (LOS).ResultsOf 1,426,343 patients undergoing carotid revascularization, 59,158 (4.2%) were identified as frail. Among frail patients, 79.4% underwent CEA and 20.6% underwent CAS. Compared to CEA, a greater proportion of patients undergoing CAS were frail (6.0% vs. 3.8%, P < 0.001). Compared to the nonfrail cohort, frail patients had higher rates of mortality (2.2% vs. 0.5%, P < 0.001), postoperative stroke (2.6% vs. 1.0%, P < 0.001), MI (2.2% vs. 0.8%, P < 0.001), and stroke/death (4.4% vs. 1.4%, P < 0.001). After adjustment, frailty was associated with increased odds of mortality (AOR = 1.59, 95% CI: 1.30-1.80, P < 0.001), stroke (AOR = 1.66, 95% CI: 1.38-1.83 P < 0.001), MI (AOR = 1.51, 95% CI: 1.29-1.72, P < 0.001), and stroke/death (AOR = 1.62, 95% CI: 1.45-1.81, P < 0.001). Furthermore, frailty was associated with increased hospitalization costs (β = +$5,980, 95$5,490-$6,470, P < 0.001) and LOS (β = +2.6 days, 95% CI: 2.4-2.8, P < 0.001).ConclusionsFrailty is associated with adverse outcomes and greater resource use for those undergoing carotid revascularization. Risk models should include an assessment of frailty to guide management and improve outcomes for these high-risk patients

A Single Institution 30-Year Review of Abnormal First Rib Resection for Thoracic Outlet Syndrome.

ObjectivesCongenital abnormalities of the first rib (ABNFR) are a rare cause of thoracic outlet syndrome (TOS). The range of abnormalities have not been clearly documented in the literature. Surgical decompression in these patients presents with increased complexity secondary to anomalous anatomy. Our goal is to review an institutional experience of first rib resection (FRR) performed for ABNFRs, to present a novel classification system, and to analyze outcomes according to clinical presentation.MethodsA prospectively collected database was used to identify individuals with ABNFRs who underwent FRR for TOS between 1990-2021. These individuals were identified both by preoperative imaging and intraoperative descriptions of the first rib after resection. Demographic, clinical, perioperative and pathological data were reviewed. ABNFRs were classified into 3 categories according to anatomical criteria: (I) Hypoplastic, (II) Fused, and (III) Hyperplastic. Outcomes were rated using the standardized Quick Disability of Arm Shoulder and Hand Scores (QDS), Somatic Pain Scores (SPS) and Derkash Scores (DkS).ResultsAmong the 2200 cases of TOS, there were 19 patients (0.8%) with ABNFR who underwent FRR. Average age at surgery was 30.5 (range 11-74), including 13 men and 6 women. Presentations included 9 arterial (ATOS), 6 neurogenic (NTOS), and 4 venous (VTOS) cases. There were 6 class I, 6 class II, and 7 class III ABNFRs. Among 6 NTOS patients there were 4 abnormal nerve conduction tests and 5 positive anterior scalene muscle blocks. Among the 9 patients with ATOS, thrombolysis was attempted in 5 patients, and of these, 3 ultimately required surgical thrombectomy. Of 4 VTOS cases, 2 were managed with thrombolysis, and 2 with anticoagulation alone. The approach for FRR was transaxillary in all patients. Secondary procedures included 1 pectoralis minor tenotomy, 1 scalenectomy, and 1 contralateral rib resection. No major neurological or vascular complications occurred. There was 1 patient who required surgical evacuation of a hematoma. Intraoperative chest tube placement was required in 5 patients secondary to pleural entry during dissection. There was an overall improvement in symptoms over an average follow-up of 7.4 months. QDS reduced from 49.7 pre-op to 22.1 (P < 0.05). SPS improved from 3.4 pre-op to 1.8. DkS scores were good to excellent in 79% of patients. Residual symptoms were noted in 7, and ATOS accounted for 5 (70%) of these. All patients were able to return to work.ConclusionsDespite increased complexity, ABNFRs may be safely resected via transaxillary approach with low incidence of complications, very good symptom relief, and excellent outcomes. Congenital ABNFRs may by classified into 3 categories (hypoplastic, fused, and hyperplastic) with a variety of presentations, including ATOS, NTOS, and VTOS. Classification of ABNFRs allows concise description of abnormal anatomy which facilitates comparison between series and provides direction for surgical management to ultimately optimize patient outcomes