Severe symptomatic nickel allergy following stent graft implantation requiring excision and external iliac artery reconstruction.

Although nickel allergy is a common cause of contact dermatitis, systemic reactions to nitinol stents are rare. A 61-year-old woman had presented with a nonhealing toe wound. Angiography revealed an external iliac artery stenosis, which was treated with a nitinol stent graft. However, she developed severe truncal pruritus, and within 3 months, her external iliac stent graft had thrombosed. Allergy testing revealed nickel sensitivity. After medical therapy had failed, stent graft removal was performed, resulting in complete resolution of her symptoms. The present case demonstrates a rare allergic reaction to the nitinol in commercially available stent grafts. Pruritus and rash are rare reactions to stenting; however, a nitinol allergy should be considered for patients with no other identifiable primary source.

Contemporary management and outcomes of peripheral venous aneurysms: A multi-institutional study.

OBJECTIVE: Extremity venous aneurysms result in the risk of pulmonary embolism (PE) and chronic venous insufficiency. At present, owing to the rarity of these aneurysms, no consensus for their treatment has been established. The purpose of the present study was to review the presentation, natural history, and contemporary management of extremity venous aneurysms. METHODS: We performed a retrospective, multi-institutional review of all patients with extremity venous aneurysms treated from 2008 to 2018. A venous aneurysm was defined as saccular or fusiform with an aneurysm/vein ratio of >1.5. RESULTS: A total of 66 extremity aneurysms from 11 institutions were analyzed, 40 of which were in a popliteal location, 14 iliofemoral, and 12 in an upper extremity or a jugular location. The median follow-up was 27 months (range, 0-120 months). Of the 40 popliteal venous aneurysms, 8 (20%) had presented with deep vein thrombosis (DVT) or PE, 13 (33%) had presented with pain, and 19 had been discovered incidentally. The mean size of the popliteal venous aneurysms presenting with DVT or PE was larger than that of those presenting without thromboembolism (3.8 cm vs 2.5 cm; P = .003). Saccular aneurysm morphology in the lower extremity was associated with thromboembolism (30% vs 9%; P = .046) and fusiform aneurysm morphology with a thrombus burden >25% (45% vs 3%). Patients presenting with thromboembolism were more likely to have had a thrombus burden >25% in their lower extremity venous aneurysm compared with those who had presented without thromboembolism (70% vs 9%). Approximately half of all the patients underwent immediate intervention, and half were managed with observation or antithrombotic regimen. In the non-operative cohort, three patients subsequently developed a DVT. Eight patients in the medically managed cohort went on to require surgical intervention. Of the 12 upper extremity venous aneurysms, none had presented with DVT or PE, and only 2 (17%) had presented with pain. Of the 66 patients in the entire cohort, 41 underwent surgical intervention. The most common indication was the absolute aneurysm size. Nine patients had undergone surgery because of a DVT or PE, and 11 for pain or extremity swelling. The most common surgery was aneurysmorrhaphy in 21 patients (53%), followed by excision and ligation in 14 patients (35%). Five patients (12%) had undergone interposition bypass grafting. A postoperative hematoma requiring reintervention was the most common complication, occurring in three popliteal vein repairs and one iliofemoral vein repair. None of the patients, treated either surgically or medically, had reported post-thrombotic complications during the follow-up period. CONCLUSIONS: Large lower extremity venous aneurysms and saccular aneurysms with thrombus >25% of the lumen are more likely to present with thromboembolic complications. Surgical intervention for lower extremity venous aneurysms is indicated to reduce the risk of venous thromboembolism (VTE) and the need for continued anticoagulation. Popliteal aneurysms >2.5 cm and all iliofemoral aneurysms should be considered for repair. Upper extremity aneurysms do not have a significant risk of VTE and warrant treatment primarily for symptoms other than VTE.

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

OBJECTIVES: Congenital 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. METHODS: A 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). RESULTS: Among 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. CONCLUSIONS: Despite 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.

Deep Venous Stenting Improves Healing of Lower Extremity Venous Ulcers.

BACKGROUND: Long 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. METHODS: A 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. RESULTS: Between 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. CONCLUSIONS: In 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.

Contemporary Outcomes After Partial Resection of Infected Aortic Grafts.

INTRODUCTION: Aortic graft infection remains a considerable clinical challenge, and it is unclear which variables are associated with adverse outcomes among patients undergoing partial resection. METHODS: A retrospective, multi-institutional study of patients who underwent partial resection of infected aortic grafts from 2002 to 2014 was performed using a standard database. Baseline demographics, comorbidities, operative, and postoperative variables were recorded. The primary outcome was mortality. Descriptive statistics, Kaplan-Meier (KM) survival analysis, and Cox regression analysis were performed. RESULTS: One hundred fourteen patients at 22 medical centers in 6 countries underwent partial resection of an infected aortic graft. Seventy percent were men with median age 70 years. Ninety-seven percent had a history of open aortic bypass graft: 88 (77%) patients had infected aortobifemoral bypass, 18 (16%) had infected aortobiiliac bypass, and 1 (0.8%) had an infected thoracic graft. Infection was diagnosed at a median 4.3 years post-implant. All patients underwent partial resection followed by either extra-anatomic (47%) or in situ (53%) vascular reconstruction. Median follow-up period was 17 months (IQR 1, 50 months). Thirty-day mortality was 17.5%. The KM-estimated median survival from time of partial resection was 3.6 years. There was no significant survival difference between those undergoing in situ reconstruction or extra-anatomic bypass (P = 0.6). During follow up, 72% of repairs remained patent and 11% of patients underwent major amputation. On univariate Cox regression analysis, Candida infection was associated with increased risk of mortality (HR 2.4; P = 0.01) as well as aortoenteric fistula (HR 1.9, P = 0.03). Resection of a single graft limb only to resection of abdominal (graft main body) infection was associated with decreased risk of mortality (HR 0.57, P = 0.04), as well as those with American Society of Anesthesiologists classification less than 3 (HR 0.35, P = 0.04). Multivariate analysis did not reveal any factors significantly associated with mortality. Persistent early infection was noted in 26% of patients within 30 days postoperatively, and 39% of patients were found to have any post-repair infection during the follow-up period. Two patients (1.8%) were found to have a late reinfection without early persistent postoperative infection. Patients with any post-repair infection were older (67 vs. 60 years, P = 0.01) and less likely to have patent repairs during follow up (59% vs. 32%, P = 0.01). Patients with aortoenteric fistula had a higher rate of any post-repair infection (63% vs. 29%, P < 0.01) CONCLUSION: This large multi-center study suggests that patients who have undergone partial resection of infected aortic grafts may be at high risk of death or post-repair infection, especially older patients with abdominal infection not isolated to a single graft limb, or with Candida infection or aortoenteric fistula. Late reinfection correlated strongly with early persistent postoperative infection, raising concern for occult retained infected graft material.

Impact of Frailty on Clinical Outcomes after Carotid Artery Revascularization.

BACKGROUND: Frailty 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. METHODS: The 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). RESULTS: Of 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 (ß = +$5,980, 95% CI: $5,490-$6,470, P < 0.001) and LOS (ß = +2.6 days, 95% CI: 2.4-2.8, P < 0.001). CONCLUSIONS: Frailty 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.

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

OBJECTIVE: Spontaneous 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. METHODS: Patients 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. RESULTS: For 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). CONCLUSIONS: IVUS 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.

BACKGROUND: The 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. METHODS: A 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. RESULTS: Between 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%. CONCLUSIONS: After 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.

Contemporary management of lower extremity venous aneurysms.

OBJECTIVE: Lower extremity venous aneurysms may lead to serious morbidity in patients, including pulmonary embolism (PE) and chronic venous insufficiency. Presently, because of the low incidence of these aneurysms, no consensus for their treatment exists. The purpose of this study was to review the presentation and management of lower extremity venous aneurysms at our institution. METHODS: A retrospective review of all patients with isolated lower extremity venous aneurysms treated at a single tertiary care medical center from 2005 to 2017 was conducted. RESULTS: Five male and six female patients with lower extremity venous aneurysms were identified, with a mean age of 50.4 years. Three patients presented with deep venous thrombosis or PE, three presented with pain, and five venous aneurysms were found incidentally. Nine of 11 patients had aneurysms involving the popliteal vein; one was in the iliac vein, and one was in the common femoral vein. Diagnosis was made by duplex ultrasound in five patients, magnetic resonance imaging in five patients, and computed tomography venography in one patient. Mean aneurysm to adjacent vein ratio was 2.62. No patients who had venous aneurysms discovered incidentally suffered thromboembolic complications. Three patients who were initially treated conservatively went on to eventual surgical intervention. Six patients underwent surgical intervention. The indication for operation was deep venous thrombosis or PE in three patients and lower extremity swelling in three patients; all were symptomatic at presentation. Three patients had simple venorrhaphy, two patients had aneurysmectomy and ligation of the vein, and one patient underwent aneurysmectomy with placement of an interposition vein graft. Mean follow-up was 26 months, with no recurrent thromboembolism. Perioperative complications included postoperative hematoma (one) and superficial thrombophlebitis (one). CONCLUSIONS: Lower extremity venous aneurysms continue to represent a rare yet potentially morbid vascular disease. Symptomatic patients demonstrated a clear benefit from surgery vs conservative management. Larger, multicenter studies are required to properly characterize the natural history and management of this disease.

Splenic artery pseudoaneurysm with hemosuccus pancreaticus requiring multimodal treatment.

Termed hemosuccus pancreaticus by Sandblom in 1970, hemorrhage from the pancreatic duct into the gastrointestinal tract represents a rare and challenging problem. Patients present with repeated upper gastrointestinal bleeding that is intermittent but often self-limited. In most cases, this pathophysiologic process is secondary to pancreatitis, chronic inflammation, and subsequent splenic artery pseudoaneurysm bleeding. Previously treated with open splenectomy and distal pancreatectomy, hemosuccus pancreaticus is now often managed with minimally invasive endovascular means. We describe an uncommon presentation of hemosuccus pancreaticus in the absence of prior pancreatitis, requiring open splenectomy, distal pancreatectomy, and celiac artery ligation after failed endovascular intervention.

Resection of Metastatic Hepatocellular Carcinoma in the Ventricular Septum Causing Left Ventricular Outflow Tract Obstruction.

Isolated cardiac involvement of recurrent metastatic hepatocellular carcinoma (HCC) is extremely rare. We report a patient with left ventricular outflow tract (LVOT) obstruction due to isolated recurrent HCC involving the interventricular septum (IVS). A ventriculotomy with resection of the tumor and patch repair of the IVS was performed with successful relief of LVOT obstruction. The patient was discharged home 6 days later symptom-free.

Yield of Graft Surveillance after Open Aortic Operations.

BACKGROUND: To examine the value of routine postoperative surveillance duplex in identifying late graft-related complications after open aortic operations for occlusive and aneurysmal disease. METHODS: All open aortic operations performed at a single institution between 1998 and 2012 were retrospectively reviewed. All patients were scheduled for yearly postoperative surveillance duplex. Patients who had at least 30-day follow-up and at least 1 surveillance duplex were analyzed. RESULTS: Two hundred thirty-eight open aortic operations were performed during the study period, 140 of which met the inclusion criteria. Mean follow-up was 3.9 years. A tube graft was performed in 65 (46%), and the proximal anastomosis was in the infrarenal or juxtarenal position in 126 (90%). Overall survival at was 100% and 85.3% at 1 and 5 years, respectively. A mean of three surveillance duplexes was performed per patient. Surveillance duplex scanning identified 31 significant findings in 31 patients, including 13 significant velocity increases (>3:1) and 18 aneurysms/pseudoaneurysms. Thirteen (9%) patients required a graft-related operation at a mean of 3.5 years. Indications included anastomotic aneurysm/pseudoaneurysm (n = 7), limb occlusion (n = 3), graft stenosis (n = 2), and graft infection (n = 1). The indication for operation was identified by surveillance duplex in 5 of the 13 cases. The remainder were identified by physical examination and/or clinical presentation. Reintervention-free survival (RIFS) was 98.5% at 1 year and 80.4% at 5 years. On multivariable analysis, RIFS was improved only by the use of a tube graft during the index operation (hazard ratio, 0.73; 95% confidence interval, 0.54-0.96). CONCLUSIONS: Routine surveillance duplex identifies few findings that lead to reintervention. Patients with a non-tube-graft reconstruction are at greater risk for reintervention and may benefit from surveillance duplex after open aortic operations.

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.

BACKGROUND: Therapeutic 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. AIMS: We 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 METHODS: Active 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. RESULTS: Prophylactic 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. DISCUSSION: Even 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. CONCLUSIONS: Our results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression.

Estrogen receptor ß ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis.

The identification of a drug that stimulates endogenous myelination and spares axon degeneration during multiple sclerosis (MS) could potentially reduce the rate of disease progression. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we have previously shown that prophylactic administration of the estrogen receptor (ER) ß ligand 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) decreases clinical disease, is neuroprotective, stimulates endogenous myelination, and improves axon conduction without altering peripheral cytokine production or reducing central nervous system (CNS) inflammation. Here, we assessed the effects of therapeutic DPN treatment during peak EAE disease, which represents a more clinically relevant treatment paradigm. In addition, we investigated the mechanism of action of DPN treatment-induced recovery during EAE. Given that prophylactic and therapeutic treatments with DPN during EAE improved remyelination-induced axon conduction, and that ER (α and ß) and membrane (m)ERs are present on oligodendrocyte lineage cells, a direct effect of treatment on oligodendrocytes is likely. DPN treatment of EAE animals resulted in phosphorylated ERß and activated the phosphatidylinositol 3-kinase (PI3K)/serine-threonine-specific protein kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, a pathway required for oligodendrocyte survival and axon myelination. These results, along with our previous studies of prophylactic DPN treatment, make DPN and similar ERß ligands immediate and favorable therapeutic candidates for demyelinating disease.

Attenuation of corpus callosum axon myelination and remyelination in the absence of circulating sex hormones.

Sex differences in the structure and organization of the corpus callosum (CC) can be attributed to genetic, hormonal or environmental effects, or a combination of these factors. To address the role of gonadal hormones on axon myelination, functional axon conduction and immunohistochemistry analysis of the CC in intact, gonadectomized and hormone-replaced gonadectomized animals were used. These groups were subjected to cuprizone diet-induced demyelination followed by remyelination. The myelinated component of callosal compound action potential was significantly decreased in ovariectomized and castrated animals under normal myelinating condition. Compared to gonadally intact cohorts, both gonadectomized groups displayed more severe demyelination and inhibited remyelination. Castration in males was more deleterious than ovariectomy in females. Callosal conduction in estradiol-supplemented ovariectomized females was significantly increased during normal myelination, less attenuated during demyelination, and increased beyond placebo-treated ovariectomized or intact female levels during remyelination. In castrated males, the non-aromatizing steroid dihydrotestosterone was less efficient than testosterone and estradiol in restoring normal myelination/axon conduction and remyelination to levels of intact males. Furthermore, in both sexes, estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes. These studies suggest an essential role of estradiol to promote efficient CC myelination and axon conduction in both sexes.

Oestrogen receptor beta 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 ß 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 ß 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 ß ligand-treated mice. In addition, oestrogen receptor ß 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 ß ligand treatment on oligodendrocyte differentiation, myelination and axon conduction during experimental autoimmune encephalomyelitis.