French National Diagnostic and Care Protocol for antiphospholipid syndrome in adults and children.

Antiphospholipid syndrome (APS) is a chronic autoimmune disease involving vascular thrombosis and/or obstetric morbidity and persistent antibodies to phospholipids or certain phospholipid-associated proteins. It is a rare condition in adults and even rarer in children. The diagnosis of APS can be facilitated by the use of classification criteria based on a combination of clinical and biological features. APS may be rapidly progressive with multiple, often synchronous thromboses, resulting in life-threatening multiple organ failure. This form is known as "catastrophic antiphospholipid syndrome" (CAPS). It may be primary or associated with systemic lupus erythematosus (associated APS) and in very rare cases with other systemic autoimmune diseases. General practitioners and paediatricians may encounter APS in patients with one or more vascular thromboses. Because APS is so rare and difficult to diagnosis (risk of overdiagnosis) any suspected case should be confirmed rapidly and sometimes urgently by an APS specialist. First-line treatment of thrombotic events in APS includes heparin followed by long-term anticoagulation with a VKA, usually warfarin. Except in the specific case of stroke, anticoagulants should be started as early as possible. Any temporary discontinuation of anticoagulants is associated with a high risk of thrombosis in APS. A reference/competence centre specialised in autoimmune diseases must be urgently consulted for the therapeutic management of CAPS.

Radiation-Induced Imaging Changes and Cerebral Edema following Stereotactic Radiosurgery for Brain AVMs.

BACKGROUND AND PURPOSE: T2 signal and FLAIR changes in patients undergoing stereotactic radiosurgery for brain AVMs may occur posttreatment and could result in adverse radiation effects. We aimed to evaluate outcomes in patients with these imaging changes, the frequency and degree of this response, and factors associated with it. MATERIALS AND METHODS: Through this retrospective cohort study, consecutive patients treated with stereotactic radiosurgery for brain AVMs who had at least 1 year of follow-up MR imaging were identified. Logistic regression analysis was used to evaluate predictors of outcomes. RESULTS: One-hundred-sixty AVMs were treated in 148 patients (mean, 35.6 years of age), including 42 (26.2%) pediatric AVMs. The mean MR imaging follow-up was 56.5 months. The median Spetzler-Martin grade was III. The mean maximal AVM diameter was 2.8 cm, and the mean AVM target volume was 7.4 mL. The median radiation dose was 16.5 Gy. New T2 signal and FLAIR hyperintensity were noted in 40% of AVMs. T2 FLAIR volumes at 3, 6, 12, 18, and 24 months were, respectively, 4.04, 55.47, 56.42, 48.06, and 29.38 mL Radiation-induced neurologic symptoms were encountered in 34.4%. In patients with radiation-induced imaging changes, 69.2% had new neurologic symptoms versus 9.5% of patients with no imaging changes (P = .0001). Imaging changes were significantly associated with new neurologic findings (P < .001). Larger AVM maximal diameter (P = .04) and the presence of multiple feeding arteries (P = .01) were associated with radiation-induced imaging changes. CONCLUSIONS: Radiation-induced imaging changes are common following linear particle accelerator-based stereotactic radiosurgery for brain AVMs, appear to peak at 12 months, and are significantly associated with new neurologic findings.

Mechanically stimulated osteochondral organ culture for evaluation of biomaterials in cartilage repair studies.

Surgical procedures such as microfracture or autologous chondrocyte implantation have been used to treat articular cartilage lesions; however, repair often fails in terms of matrix organization and mechanical behaviour. Advanced biomaterials and tissue engineered constructs have been developed to improve cartilage repair; nevertheless, their clinical translation has been hampered by the lack of reliable in vitro models suitable for pre-clinical screening of new implants and compounds. In this study, an osteochondral defect model in a bioreactor that mimics the multi-axial motion of an articulating joint, was developed. Osteochondral explants were obtained from bovine stifle joints, and cartilage defects of 4 mm diameter were created. The explants were used as an interface against a ceramic ball applying dynamic compressive and shear loading. Osteochondral defects were filled with chondrocytes-seeded fibrin-polyurethane constructs and subjected to mechanical stimulation. Cartilage viability, proteoglycan accumulation and gene expression of seeded chondrocytes were compared to free swelling controls. Cells within both cartilage and bone remained viable throughout the 10-day culture period. Loading did not wear the cartilage, as indicated by histological evaluation and glycosaminoglycan release. The gene expression of seeded chondrocytes indicated a chondrogenic response to the mechanical stimulation. Proteoglycan 4 and cartilage oligomeric matrix protein were markedly increased, while mRNA ratios of collagen type II to type I and aggrecan to versican were also enhanced. This mechanically stimulated osteochondral defect culture model provides a viable microenvironment and will be a useful pre-clinical tool to screen new biomaterials and biological regenerative therapies under relevant complex mechanical stimuli. STATEMENT OF SIGNIFICANCE: Articular cartilage lesions have a poor healing capacity and reflect one of the most challenging problems in orthopedic clinical practice. The aim of current research is to develop a testing system to assess biomaterials for implants, that can permanently replace damaged cartilage with the original hyaline structure and can withstand the mechanical forces long term. Here, we present an osteochondral ex vivo culture model within a cartilage bioreactor, which mimics the complex motion of an articulating joint in vivo. The implementation of mechanical forces is essential for pre-clinical testing of novel technologies in the field of cartilage repair, biomaterial engineering and regenerative medicine. Our model provides a unique opportunity to investigate healing of articular cartilage defects in a physiological joint-like environment.

Identification of high thrombotic risk triple-positive antiphospholipid syndrome patients is dependent on anti-cardiolipin and anti-ß2glycoprotein I antibody detection assays.

Essentials Triple-positivity is associated with a high risk for a first thrombotic event and recurrence. Identification of triple-positives is dependent on the solid phase assay used. In triple-positivity, IgM only adds value in thrombotic risk stratification together with IgG. Thrombotic risk in triple-positive patients with IgM only, depends on the platform. ABSTRACT: Background The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPL). Triple-positivity (i.e. positivity for lupus anticoagulant [LAC], anti-cardiolipin [aCL] and anti-ß2glycoprotein I [aß2GPI] antibodies) is associated with a high thrombotic risk. Objectives We investigated the variability in triple-positivity detection by measuring the same samples with four commercially available solid phase assays. In addition, the added clinical value of aPL in LAC-positive patients was investigated, as well as the association of IgM triple-positivity and thrombosis. Patients/Methods We included 851 patients from seven European medical centers. Anti-CL and aß2GPI IgG/IgM antibodies were determined by four platforms: BioPlex® 2200, ImmunoCap® EliA, ACL AcuStar® and QUANTA Lite ELISA® . Results Triple-positivity detection by solid phase assays varied, ranging from 89 up to 118 in thrombotic APS patients (n = 258), of which 86 were detected independent of the platform. Lupus anticoagulant positivity resulted in an odds ratio (OR) for thrombosis of 3.4; triple-positivity (irrespective of the isotype) increased the OR from 4.3 up to 5.2, dependent on the platform. Triple-positivity solely for the IgM isotype did not increase the OR for thrombosis compared with LAC positivity. The highest OR for thrombosis was reached for positivity for IgG and IgM aß2GPI and aCL (8.6 up to 28.9). Conclusions Triple-positivity proved to be highly associated with thrombosis, but identification is assay dependent. Within triple-positivity, IgM antibodies only have an added clinical value in patients positive for IgG antibodies.

[A POEMS syndrome revealed by a blue toe syndrome]. / Un syndrome POEMS révélé par un syndrome des orteils bleus.

INTRODUCTION: Arterial and venous thromboses occur in almost one in five patients with POEMS syndrome and usually in macrocirculation. CASE REPORT: We report a 67-year-old male with a POEMS syndrome who presented initially with a blue toe syndrome. He complained of Raynaud's syndrome and left foot paresthesia. Physical examination showed gynecomastia, lymphadenopathies and skin lesions. Cardiovascular investigations excluded atrial fibrillation, unstable atherosclerotic lesions and vascular calcifications. Imaging studies showed diffuse osteosclerotic lesions. Monoclonal protein with lambda light chain was discovered and serum level of VEGF was increased at 2900pg/ml. CONCLUSION: This is to our knowledge the first case of thrombotic microangiopathy in POEMS syndrome without embolic cause or calciphylaxis.

Reversible drug-induced antiphospholipid syndrome.

We report an original case of reversible antiphospholipid syndrome (APS) due to minocycline in a young male patient who experienced recurrent strokes while taking minocycline. He started minocycline therapy (50 mg twice daily) at 15 years old for acne. After three years of treatment, the patient experienced a lateral medullary syndrome. He was treated with aspirin while minocycline was continued. Eighteen months later, the patient complained about horizontal binocular diplopia. MRI revealed an infarct of the oculomotor nerve nucleus. Laboratory investigations revealed high titers of anti-beta 2 glycoprotein 1 (antiß2GP1) antibodies of 470 U/ml (normal range <15 U/ml) and antiphosphatidylethanolamine antibodies of 137.4 U/ml (normal range <18 U/ml). Other laboratory tests were normal. Six weeks after discontinuation of minocycline, anti-ß2GP1 antibodies decreased to 335 U/ml and to 36 U/ml at six months and then remained negative for six years. Many drugs have been considered as possibly causing APS but only in a limited number of patients. To our knowledge this is the first case of drug-induced APS with complete disappearance of high titers of anti-ß2GP1 antibodies after minocycline withdrawal. This case also illustrates the need to monitor the levels of antiphospholipid antibodies, even though initial values are high and confirmed after 12 weeks.

Hydroxychloroquine in the primary thrombosis prophylaxis of antiphospholipid antibody positive patients without systemic autoimmune disease.

Objective The objective of this study was to determine the efficacy of hydroxychloroquine (HCQ) in the primary thrombosis prevention of antiphospholipid antibody (aPL)-positive patients with no other systemic autoimmune diseases. Methods Under the auspices of Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking, a multicenter, international, randomized controlled trial (RCT) was initiated, in which persistently aPL-positive but thrombosis-free patients without systemic autoimmune diseases were randomized to receive HCQ or no treatment in addition to their standard regimen. The primary objective was the efficacy of HCQ in preventing the first thrombosis. The secondary objectives were the thrombosis incidence rate, and the effects of HCQ on aPL profile and mortality rate. Patients were risk-stratified based on antiplatelet agent use. The goal was to follow patients every 6 months for 5 years. Results We recruited 20 persistently aPL-positive patients (female: 19, mean age: 46.6 ± 9.9 years, and baseline antiplatelet medication: 14); 9/20 were randomized to HCQ. During the mean follow-up of 1.7 years, no patients developed thrombosis or a serious adverse event. The study was terminated early due to the low recruitment rate, exacerbated by the prolonged manufacturing shortage and significant price increase of HCQ in the United States. Conclusion Given that a small number of patients with a relatively short follow-up were enrolled in our RCT, and no patients developed thrombosis, we cannot accurately assess the effectiveness of HCQ for primary thrombosis prevention in persistently aPL-positive patients with no other systemic autoimmune diseases. Our experience suggests that conducting an international RCT, especially without pharmaceutical support, is an extremely challenging undertaking.

[Development of an objective structured clinical examination (OSCE) for evaluating clinical competence in vascular medicine]. / Développement d'un examen clinique objectif structuré (ECOS) pour évaluer les compétences des étudiants en médecine vasculaire.

OBJECTIVES: Vascular medicine is now a clinical specialty in France. During their studies, students will acquire clinical reasoning in addition to technical skills. An Objective Structured Clinical Examination (OSCE) is considered as the gold standard for evaluating clinical competence. Our main objective was to evaluate the feasibility and acceptability of OSCE for the evaluation of students, secondarily their performance. METHODS: Three representative clinical cases of the specialty were developed. The OSCE consisted of a sequence of clinical situations presented in three stations of 7minutes each. The role of the simulated patient was played by medical students. At the end of the OSCE, observers and students completed the evaluation form. We compared the performances between junior and senior vascular medicine students. Written questionnaires were used to measure OSCE satisfaction. RESULTS: We were able to develop and organize this examination without difficulties. Fifteen students were evaluated. All participants agreed that the clinical situations were representative of vascular medicine practice, the cases were realistic and standardized patients were convincing. The performance of senior students was statistically higher than junior students in one case. DISCUSSION: Our study demonstrates the feasibility and acceptability of the OSCE in students in vascular medicine. The small number of stations and candidates requires further studies on a larger scale to evaluate their performance.

A foot tumour as late cutaneous Lyme borreliosis: a new entity?

Acrodermatitis chronica atrophicans (ACA) is the late cutaneous form of Lyme borreliosis. The early inflammatory phase manifests with a bluish-red discoloration and doughy swelling of the skin. The atrophic phase represents a late-phase process with red discoloration, and a thin and wrinkled appearance of the skin. We present a patient who exhibited a previously undescribed form of late cutaneous Lyme borreliosis (LCLB) with a foot tumour. A 64-year-old woman had a large tumorous lesion on the right sole. The tumour size and deformation of the feet made wearing shoes difficult. On skin histology, a granulomatous lymphohistiocytic infiltrate with plasma cells was noticed. In fact, the patient recalled tick bites 2 or 3 years before. Borrelia burgdorferi (Bb) serology was highly positive and a polymerase chain reaction analysis on the skin biopsy detected Bb sensu lato, genospecies B. afzelii. We diagnosed LCLB and antibiotics were prescribed. On the more recent examination, the tumour had totally disappeared; the skin was atrophic and dry with only few scales. We report an atypical case of European LCLB, suggesting that ACA is not the only possible presentation of LCLB. The diagnosis of ACA is often clinically missed for months or years, and may be mistaken at the inflammation phase for vascular disorders, erysipelas or bursitis/arthritis, and at the atrophic phase for lichen sclerosus atrophicus, morphoea or anetoderma. To our knowledge, no such tumorous LCLB has previously been described.

[Management of deep-vein thrombosis: A 2015 update]. / Prise en charge de la thrombose veineuse profonde en 2015.

Deep vein thrombosis (DVT) is a frequent and multifactor disease, with two major complications, post thrombotic syndrome and pulmonary embolism. Both transient (surgery, plaster immobilization, bed rest/hospitalization) and chronic/persistent (age, cancer, clinical or biological thrombophilia…) risk factors modulate treatment duration. Diagnostic management relies on clinical evaluations, probability followed by laboratory tests or imaging. So far, compression ultrasound is the diagnostic test of choice to make a positive diagnosis of DVT. Anticoagulants at therapeutic dose for at least 3 months constitute the cornerstones of proximal (i.e. involving popliteal or more proximal veins) DVT therapeutic management. The arrival of new oral anticoagulants should optimize ambulatory management of DVT.