Frequency of NMOSD misdiagnosis in a cohort from Latin America: Impact and evaluation of different contributors.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) misdiagnosis (i.e. the incorrect diagnosis of patients who truly have NMOSD) remains an issue in clinical practice. We determined the frequency and factors associated with NMOSD misdiagnosis in patients evaluated in a cohort from Latin America. METHODS: We retrospectively reviewed the medical records of patients with NMOSD, according to the 2015 diagnostic criteria, from referral clinics in six Latin American countries (Argentina, Chile, Paraguay, Colombia, Ecuador, and Venezuela). Diagnoses prior to NMOSD and ultimate diagnoses, demographic, clinical and paraclinical data, and treatment schemes were evaluated. RESULTS: A total of 469 patients presented with an established diagnosis of NMOSD (73.2% seropositive) and after evaluation, we determined that 56 (12%) patients had been initially misdiagnosed with a disease other than NMOSD. The most frequent alternative diagnoses were multiple sclerosis (MS; 66.1%), clinically isolated syndrome (17.9%), and cerebrovascular disease (3.6%). NMOSD misdiagnosis was determined by MS/NMOSD specialists in 33.9% of cases. An atypical MS syndrome was found in 86% of misdiagnosed patients, 50% had NMOSD red flags in brain and/or spinal magnetic resonance imaging (MRI), and 71.5% were prescribed disease-modifying drugs. CONCLUSIONS: NMOSD misdiagnosis is relatively frequent in Latin America (12%). Misapplication and misinterpretation of clinical and neuroradiological findings are relevant factors associated with misdiagnosis.

Chiasmatic lesions on conventional magnetic resonance imaging during the first event of optic neuritis in patients with neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-associated disease in a Latin American cohort.

BACKGROUND AND PURPOSE: Optic neuritis (ON) is often the initial symptom of neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-associated disease (MOGAD). We aimed to compare the frequency and pattern of chiasmatic lesions in MOGAD-related ON (MOGAD-ON) and NMOSD-related ON (NMOSD-ON) using conventional brain imaging (magnetic resonance imaging [MRI]) in Latin America (LATAM). METHODS: We reviewed the medical records and brain MRI (≤30 days from ON onset) of patients with a first event of MOGAD-ON and NMOSD-ON. Patients from Argentina (n = 72), Chile (n = 21), Ecuador (n = 31), Brazil (n = 30), Venezuela (n = 10) and Mexico (n = 82) were included. Antibody status was tested using a cell-based assay. Demographic, clinical, imaging and prognostic (as measured by the Visual Functional System Score [VFSS] of the Expanded Disability Status Scale) data were compared. RESULTS: A total of 246 patients (208 NMOSD and 38 MOGAD) were included. No differences were found in gender and ethnicity between the groups. We observed chiasmatic lesions in 66/208 (31.7%) NMOSD-ON and in 5/38 (13.1%) MOGAD-ON patients (p = 0.01). Of these patients with chiasmatic lesions, 54/66 (81.8%) and 4/5 had associated longitudinally extensive optic nerve lesions, 45/66 (68%) and 4/5 had bilateral lesions, and 31/66 (47%) and 4/5 showed gadolinium-enhancing chiasmatic lesions, respectively. A positive correlation was observed between VFSS and presence of bilateral (r = 0,28, p < 0.0001), chiasmatic (r = 0.27, p = 0.0001) and longitudinally extensive lesions (r = 0,25, p = 0.0009) in the NMOSD-ON group, but no correlations were observed in the MOGAD-ON group. CONCLUSIONS: Chiasmatic lesions were significantly more common in NMOSD than in MOGAD during an ON attack in this LATAM cohort. Further studies are needed to assess the generalizability of these results.

Occurrence of area postrema syndrome during follow-up: phenotype and influence over NMOSD activity in LATAM in real-world settings.

INTRODUCTION: We aimed to assess the frequency, duration, and severity of area postrema syndrome (APS) during follow-up in neuromyelitis optica spectrum disorder (NMOSD) patients, as well as its association with inflammatory activity and prognostic factors of APS severity in a real-world setting. METHODS: We conducted a retrospective study on a cohort of Latin American (LATAM) NMOSD patients who had experienced APS during their follow-up. Patients from Mexico, Peru, Brazil, Colombia, Panama, Chile and Argentina patients who met 2015 NMOSD criteria were included. We evaluated data on symptom type (nausea, vomiting and/or hiccups), frequency, duration, severity (measured by APS severity scale), association with other NMOSD core relapses, and acute treatments (symptomatic and immunotherapy or plasmapheresis). Logistic regression was conducted to evaluate factors associated with APS severity (vs. mild-moderate). RESULTS: Out of 631 NMOSD patients, 116 (18.3%) developed APS during their follow-up. The most common APS phenotype was severe. Inflammatory activity (i.e., relapses) significantly decreased after the onset of APS. Half of the patients experienced isolated APS with a median duration of 10 days, and the most frequently used acute treatment was IV steroids. All three symptoms were present in 44.6% of the patients. APS symptoms resolved following immunotherapy. Logistic regression did not identify independent factors associated with the severity of APS. CONCLUSIONS: Our findings indicate that 18.3% of NMOSD patients developed APS during the follow-up period, with most patients fulfilling criteria for severe APS. The inflammatory activity decreased after the onset of APS compared to the previous year.

Spatial and Ecological Factors Modulate the Incidence of Anti-NMDAR Encephalitis-A Systematic Review.

Anti-NMDAR encephalitis has been associated with multiple antigenic triggers (i.e., ovarian teratomas, prodromal viral infections) but whether geographic, climatic, and environmental factors might influence disease risk has not been explored yet. We performed a systematic review and a meta-analysis of all published papers reporting the incidence of anti-NMDAR encephalitis in a definite country or region. We performed several multivariate spatial autocorrelation analyses to analyze the spatial variations in the incidence of anti-NMDA encephalitis depending on its geographical localization and temperature. Finally, we performed seasonal analyses in two original datasets from France and Greece and assessed the impact of temperature using an exposure-lag-response model in the French dataset. The reported incidence of anti-NMDAR encephalitis varied considerably among studies and countries, being higher in Oceania and South America (0.2 and 0.16 per 100,000 persons-year, respectively) compared to Europe and North America (0.06 per 100,000 persons-year) (p < 0.01). Different regression models confirmed a strong negative correlation with latitude (Pearson's R = -0.88, p < 0.00001), with higher incidence in southern hemisphere countries far from the equator. Seasonal analyses showed a peak of cases during warm months. Exposure-lag-response models confirmed a positive correlation between extreme hot temperatures and the incidence of anti-NMDAR encephalitis in France (p = 0.03). Temperature analyses showed a significant association with higher mean temperatures and positive correlation with higher ultraviolet exposure worldwide. This study provides the first evidence that geographic and climatic factors including latitude, mean annual temperature, and ultraviolet exposure, might modify disease risk.

Therapeutic strategies in NMOSD and MOGAD patients: A multicenter cohort study in Latin America.

PURPOSE: This study describes the therapeutic strategies in NMOSD and MOGAD adopted by neurologists to treat both conditions in Latin America (LATAM) with main focus on rituximab (RTX) and the disease outcome. METHODS: retrospective study in a cohort of NMOSD and MOGAD patients followed in specialized MS/NMOSD centers from eight countries and 14 LATAM reference centers. Demographics and clinical characteristics were collected. RTX strategies on naïve (for rituximab) patients were summarized as follows: scheme A: two 1000 mg infusions 15 days apart and repeated every 6 months; scheme B: four 375 mg/m2 infusions every week for 4 weeks and repeated every 6 months; scheme C: one 1000 mg infusions and repeated every 6 months; scheme D: other scheme used. Relapse rate and adverse events during follow-up were analyzed considering the different RTX schemes. Poisson and logistic regression analysis were used to assess baseline aspects and disease activity during follow-up. RESULTS: A total of 217 patients were included. 197 were NMOSD patients (164, 83.2% AQP4-IgG seropositive and 16.7% seronegative) and 20 were MOGAD patients. The most frequent long-term treatment was RTX in both groups (48.2% and 65% for NMOSD and MOGAD patients, respectively). The most common RTX regimen used in 79 (83.1%) patients was two 1000 mg infusions 15 days apart and repeat every 6 months. Relapses under RTX treatment were observed in 21 (22.1%) patients. Relapses after RTX treatment were associated with higher EDSS (OR 1.75, 95%CI 1.44-2.34, p = 0.03) and higher ARR pre-RTX (OR = 2.17, 95% CI 1.72-3.12, p = 0.002) but not with RTX regimen (OR = 1.10, 95% CI 0.89-1.21, p = 0.60). CONCLUSION: the most strategy used in LATAM was RTX with two 1000 mg infusions 15 days apart. Relapses during follow up were not associated with RTX regimen used.

Clinical outcomes and prognostic factors in patients with optic neuritis related to NMOSD and MOGAD in distinct ethnic groups from Latin America.

BACKGROUND: Optic neuritis (ON) can be an initial manifestation of neuromyelitis optica spectrum disorder (NMOSD) associated with aquaporin 4-antibody (AQP4-Ab) or myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disease (MOGAD). Additionally, both diseases may have overlapping paraclinical and radiological features. These diseases may have different outcomes and prognoses. We aimed to compare clinical outcomes and prognostic features of patients with NMOSD and MOGAD presenting ON as first attack, from different ethnic groups in Latin America. METHODS: We conducted a retrospective observational multicenter study in patients from Argentina (n = 61), Chile (n = 18), Ecuador (n = 27), Brazil (n = 30), Venezuela (n = 10) and Mexico (n = 49) with MOGAD or NMOSD related ON. Predictors of disability outcomes at last follow-up, namely visual disability (Visual Functional System Score ≥4), motor disability (permanent inability to walk further than 100 m unaided) and wheelchair dependence based on EDSS score were evaluated. RESULTS: After a mean disease duration of 42.7 (±40.2) months in NMOSD and 19.7 (±23.6) in MOGAD, 55% and 22% (p>0.001) experienced permanent severe visual disability (visual acuity from 20/100 to 20/200), 22% and 6% (p = 0.01) permanent motor disability and 11% and 0% (p = 0.04) had become wheelchair dependent, respectively. Older age at disease onset was a predictor of severe visual disability (OR=1,03 CI95%1.01-1.05, p = 0.03); older age at disease onset (OR=1,04 CI95%1.01-1.07, p = 0.01), higher number of relapses (OR=1,32 CI95%1.02-1.71, p = 0.03) and rituximab treatment (OR=0,36 CI95%0.14-0.90, p = 0.02) were predictors of permanent motor disability, whereas ON associated with myelitis at disease onset was a predictor of wheelchair dependency (OR=4,16, CI95%1.23-14.08, p = 0,02) in NMOSD patients. No differences were found when evaluating distinct ethnic groups (Mixed vs. Caucasian vs. Afro-descendant) CONCLUSIONS: NMOSD was associated with poorer clinical outcomes than MOGAD. Ethnicity was not associated with prognostic factors. Distinct predictors of permanent visual and motor disability and wheelchair dependency in NMOSD patients were found.

Safety and humoral response rate of inactivated and mRNA vaccines against SARS-CoV-2 in patients with Multiple Sclerosis.

BACKGROUND: Safety and effectiveness outcomes in Multiple Sclerosis (MS) patients receiving different disease-modifying therapies (DMT) and different types of vaccines against SARS-CoV-2 are limited. Growing evidence coming mainly from Israel, Europe and North America using mRNA and adenoviral vector vaccines has been published. OBJECTIVES: To assess the safety and humoral response of inactivated virus and mRNA vaccines against SARS-CoV-2 in patients with MS. METHODS: Ongoing, multicentric, prospective, observational study performed between February and September 2021. Humoral response (antibodies against spike-1 protein) was determined at least 4 weeks after the complete schedule of anti-SARS-CoV-2 vaccines. Categorical outcome (positive/negative) and total antibody titres were recorded. Adverse events supposedly attributable to vaccination (AESAV) were collected. RESULTS: 178 patients, 68% women, mean age 39.7 ± 11.2 years, 123 received inactivated (Coronavac-Sinovac), 51 mRNA (Pfizer-BioNtech), and 4 adenoviral vector vaccines (CanSino n = 2, Jonhson&Johnson-Jannsen n = 1, Oxford-AstraZeneca n = 1). Six patients had a history of COVID-19 before vaccination. Overall humoral response was observed in 66.9% (62.6% inactivated vs. 78.4% mRNA, p = 0.04). Positive anti-S1-antibodies were observed in 100% of patients with no DMT (n = 3), 100% with interferon/glatiramer-acetate (n = 11), 100% with teriflunomide/dimethyl-fumarate (n = 16), 100% with natalizumab (n = 10), 100% with alemtuzumab (n = 8), 90% with cladribine (n = 10), and 88% with fingolimod (n = 17), while 43% of patients receiving antiCD20 (n = 99) were positive (38% inactivated vaccine vs. 59% mRNA vaccine, p = 0.05). In the multivariate analysis including antiCD20 patients, the predictors for a positive humoral response were receiving the mRNA vaccine (OR 8.11 (1.79-36.8), p = 0.007) and a lower number of total infusions (OR 0.44 (0.27-0.74) p = 0.002. The most frequent AESAV was local pain (14%), with 4 (2.2%) patients experiencing mild-moderate relapses within 8 weeks of first vaccination compared to 11 relapses (6.2%) within the 8 weeks before vaccination (Chi-squared 3.41, p = 0.06). DISCUSSION: A higher humoral response rate was observed using the mRNA compared to the inactivated vaccine, while patients using antiCD20 had a significantly lower response rate, and patients using antiCD20 and fingolimod had lower antibody titres. In this MS patient cohort, inactivated and mRNA vaccines against SARS-CoV-2 appear to be safe, with no increase in relapse rate. This information may help guidelines including booster shots and types of vaccines in selected populations.

Key points to keep in mind related to COVID-19 vaccines in people with multiple sclerosis.

Vaccinations are often the most effective tool against certain diseases known to mankind, and their interaction with multiple sclerosis (MS) has been discussed for decades. With rapidly accumulating numbers of cases and deaths due to COVID-19, there is a global effort to respond to this pandemic in terms of scale and speed. Different platforms are currently being used around the world for the development of best COVID-19 vaccine. While some COVID-19 vaccines have already been approved by different regulatory agencies, there is scarce data in large cohorts regarding the efficacy and security of COVID-19 vaccines in people with MS. In this short review we aimed the most important information to keep in mind regarding this topic.

Experience of South American MS and/or NMOSD experts in practice during the COVID-19 pandemic: Focus on Telemedicine.

BACKGROUND: COVID-19 pandemic has changed the way to manage MS and NMOSD, not only concerning treatment, but also regarding social distance and the increasing use of telemedicine (TM) to minimize the risk of infection. Currently, there is no data regarding TM among MS and NMOSD South American experts. OBJECTIVE: To investigate TM experiences from South American MS and/or NMOSD experts in the follow-up of their patients focusing on TM. METHODS: A cross-sectional study was performed. 141 MS and/or NMOSD experts from Argentina, Chile, Colombia and Brazil were invited to answer an web-based survey. RESULTS: A total of 129 (91.48 %) experts completed the survey. Only 19.4% had experience in TM previous COVID-19 pandemic, while 79.8% are currently using TM, most using video call (52.3%). Using TM, 44.1% of the experts were able to perform neurological examination, 85.6% believed to be able to identify a relapse, 48.6% use Patient Determined Disease Steps and 38.7% kept using the conventional Expanded Disability Status Scale. CONCLUSION: Our survey demonstrates preparedness and responsiveness among South American MS and/or NMOSD experts.  Despite scarce prior TM experience, most experts felt confident to use TM as a new tool for monitoring their patients.

Real-world experience of ocrelizumab in multiple sclerosis patients in Latin America.

BACKGROUND: Despite the abundance of information concerning ocrelizumab in phase III clinical trials, there is scarce evidence regarding real-world patient profiles. OBJECTIVE: The aim of this study was to investigate patient profiles, effectiveness and persistence with treatment among patients who used ocrelizumab for treatment of multiple sclerosis in Latin America. METHODS: This was a retrospective multicenter study in Argentina, Chile and Mexico. Medical record databases on patients who received ocrelizumab were analyzed. Demographic and clinical variables were described, along with effectiveness outcomes, which included the proportions of patients free from clinical relapses, from disability progression and from new or enlarging T2 or T1 gadolinium-enhancing lesions, on annual magnetic resonance imaging. RESULTS: A total of 81 patients were included. The most frequent phenotype was relapsing-remitting MS, in 64.2% of the patients. The mean age at study entry was 41.3 ± 12.0 years and 51.8% were women. A total of 38% had had relapse activity during the 12 months before starting on ocrelizumab, with a mean relapse rate of 1.3 ± 0.6 during that period. 75% were free from clinical relapses and 91% were free from gadolinium-enhancing lesions in the relapsing-remitting course. Ocrelizumab discontinuation during the first 12 months was observed in three patients (3.7%). The mean persistence observed during the first-year follow-up was 338 ± 24 days. CONCLUSIONS: Our study is in line with previous randomized clinical trials and recent real-world studies describing patient profiles, effectiveness and persistence regarding ocrelizumab treatment in multiple sclerosis patients in Latin America.

Status of the neuromyelitis optica spectrum disorder in Latin America.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) is an increasing diagnostic and therapeutic challenge in Latin America (LATAM). Despite the heterogeneity of this population, ethnic and socioeconomic commonalities exist, and epidemiologic studies from the region have had a limited geographic and population outreach. Identification of some aspects from the entire region are lacking. OBJECTIVES: To determine ethnic, clinical characteristics, and utilization of diagnostic tools and types of therapy for patients with NMOSD in the entire Latin American region. METHODS: The Latin American Committee for Treatment and Research in MS (LACTRIMS) created an exploratory investigational survey addressed by Invitation to NMOSD Latin American experts identified through diverse sources. Data input closed after 30 days from the initial invitation. The questionnaire allowed use of absolute numbers or percentages. Multiple option responses covering 25 themes included definition of type of practice; number of NMOSD cases; ethnicity; utilization of the 2015 International Panel criteria for the diagnosis of Neuromyelitis optica (IPDN); clinical phenotypes; methodology utilized for determination of anti-Aquaporin-4 (anti- AQP4) antibodies serological testing, and if this was performed locally or processed abroad; treatment of relapses, and long-term management were surveyed. RESULTS: We identified 62 investigators from 21 countries reporting information from 2154 patients (utilizing the IPDN criteria in 93.9% of cases), which were categorized in two geographical regions: North-Central, including the Caribbean (NCC), and South America (SA). Ethnic identification disclosed Mestizos 61.4% as the main group. The most common presenting symptoms were concomitant presence of optic neuritis and transverse myelitis in 31.8% (p=0.95); only optic neuritis in 31.4% (more common in SA), p<0.001); involvement of the area postrema occurred in 21.5% and brain stem in 8.3%, both were more frequent in the South American cases (p<0.001). Anti-AQP4 antibodies were positive in 63.9% and anti-Myelin Oligodendrocyte Glycoprotein (MOG) antibodies in 4.8% of total cases. The specific laboratorial method employed was not known by 23.8% of the investigators. Acute relapses were identified in 81.6% of cases, and were treated in 93.9% of them with intravenous steroids (IVS); 62.1% with plasma exchange (PE), and 40.9% with intravenous immunoglobulin-G (IVIG). Therapy was escalated in some cases due to suboptimal initial response. Respondents favored Rituximab as long-term therapy (86.3%), whereas azathioprine was also utilized on 81.8% of the cases, either agent used indistinctly by the investigators according to treatment accessibility or clinical judgement. There were no differences among the geographic regions. CONCLUSIONS: This is the first study including all countries of LATAM and the largest cohort reported from a multinational specific world area. Ethnic distributions and phenotypic features of the disease in the region, challenges in access to diagnostic tools and therapy were identified. The Latin American neurological community should play a determinant role encouraging and advising local institutions and health officials in the availability of more sensitive and modern diagnostic methodology, in facilitating the the access to licensed medications for NMOSD, and addressing concerns on education, diagnosis and management of the disease in the community.

Real-world experience of ocrelizumab in multiple sclerosis patients in Latin America / Experiencia en la vida real con el uso de ocrelizumab en pacientes con esclerosis múltiple en Latinoamérica

ABSTRACT Background: Despite the abundance of information concerning ocrelizumab in phase III clinical trials, there is scarce evidence regarding real-world patient profiles. Objective: The aim of this study was to investigate patient profiles, effectiveness and persistence with treatment among patients who used ocrelizumab for treatment of multiple sclerosis in Latin America. Methods: This was a retrospective multicenter study in Argentina, Chile and Mexico. Medical record databases on patients who received ocrelizumab were analyzed. Demographic and clinical variables were described, along with effectiveness outcomes, which included the proportions of patients free from clinical relapses, from disability progression and from new or enlarging T2 or T1 gadolinium-enhancing lesions, on annual magnetic resonance imaging. Results: A total of 81 patients were included. The most frequent phenotype was relapsing-remitting MS, in 64.2% of the patients. The mean age at study entry was 41.3 ± 12.0 years and 51.8% were women. A total of 38% had had relapse activity during the 12 months before starting on ocrelizumab, with a mean relapse rate of 1.3 ± 0.6 during that period. 75% were free from clinical relapses and 91% were free from gadolinium-enhancing lesions in the relapsing-remitting course. Ocrelizumab discontinuation during the first 12 months was observed in three patients (3.7%). The mean persistence observed during the first-year follow-up was 338 ± 24 days. Conclusions: Our study is in line with previous randomized clinical trials and recent real-world studies describing patient profiles, effectiveness and persistence regarding ocrelizumab treatment in multiple sclerosis patients in Latin America.

RESUMEN Introducción: A pesar de la abundante información sobre ocrelizumab proveniente de los ensayos clínicos de fase III, todavía se tiene poca evidencia sobre la efectividad y el perfil de pacientes provenientes de la vida real. Objetivo: Evaluar el perfil clínico y demográfico, la efectividad y la persistencia al tratamiento en pacientes que usaron el ocrelizumab para el tratamiento de esclerosis múltiple (EM) en Latinoamérica. Métodos: Estudio retrospectivo multicéntrico en Argentina, Chile y México. Se analizaron los datos de los pacientes que recibieron ocrelizumab. Se describieron las variables demográficas y clínicas, así como los resultados de efectividad que incluyeron la proporción de pacientes libres de recaídas clínicas, libres de progresión de la discapacidad, libres de nuevas lesiones en la secuencia T2 o T1 con gadolinio durante el seguimiento. Resultados: Se incluyeron 81 pacientes. El fenotipo más frecuente fue EM remitente recurrente (EMRR) en el 64,2% de los pacientes. La edad media fue de 41.3±12 años, y el 51,8% eran mujeres. Un total de 38% tuvo recaídas durante los 12 meses previos al inicio de ocrelizumab, con una tasa anualizada de recaídas media de 1.3±0.6 durante ese período. En el seguimiento a 12 meses, el 75% estuvo libre de recaídas clínicas y el 91%, libre de nuevas lesiones en RM. Tres pacientes interrumpieron el tratamiento durante el seguimiento (3,7%). La persistencia al tratamiento observada durante el primer año de seguimiento fue de 338±24 días. Conclusión: Nuestro estudio está en línea con los datos provenientes de ensayos clínicos aleatorizados previos y estudios recientes del mundo real que describen la efectividad de los perfiles de pacientes y la persistencia al tratamiento con ocrelizumab en pacientes con EM en Latinoamérica.

Basis for fluctuations in lymphocyte counts in fingolimod-treated patients with multiple sclerosis.

OBJECTIVE: To determine the range of fluctuation in total lymphocyte counts (TLCs) in peripheral blood over a 4- to 7-year period in patients with MS receiving fingolimod (FTY720) and the relation between TLCs and T-cell subsets (CD4+, CD8+, CCR7+/-) that are differentially regulated in the lymph nodes by fingolimod. METHODS: TLCs were measured every 3 months in patients (n = 23) receiving fingolimod for 4 to 7 years. T-cell subset (CD4+, CD8+, and CCR7+/-) analyses were performed on whole-blood samples and/or freshly isolated or cryopreserved mononuclear cells. RESULTS: All serially studied patients had mean TLCs <0.6 × 10(9) lymphocytes/L. In 30% of patients, 20% to 40% of TLCs were >0.6 × 10(9) lymphocytes/L vs mean 4.0% for "nonfluctuator" patients. Cross-sectional analysis indicated that TLCs of 0.2-0.6 × 10(9) lymphocytes/L correlated with numbers of CD8+ effector (CCR7-) cells. For patients discontinuing therapy, TLCs between 0.6 and 1.0 × 10(9) lymphocytes/L were associated with a relative increase of CD4 T cells and reappearance of CCR7+ (CD4+ and CD8+) T cells. Analysis of cryopreserved mononuclear cell samples from patients receiving therapy with TLCs >0.6 × 10(9) lymphocytes/L indicated no differences in total CD4 or CD8+ T cells but increased proportion of CD4+CCR7+ T cells compared to samples with TLCs <0.6 × 10(9) lymphocytes/L. CONCLUSION: Fluctuations of TLCs within 0.2-0.6 × 10(9) lymphocytes/L in patients receiving fingolimod reflect changes in total CCR7-CD8+ effector cells, a population less regulated by this agent. Although less apparent than for patients discontinuing therapy, cells expected to be sequestered by this therapy may begin to re-emerge when TLC values are >0.6 × 10(9) lymphocytes/L.

Ischemic stroke as the first manifestation of severe ventricular hypertrabeculation/non-compaction.

A rare congenital myocardial defect, known as left ventricular hypertrabeculation/non-compaction (LVHT), has been occasionally described associated with thrombus formation with a potential systemic embolic risk, but its association with ischemic strokes remains controversial. We report a case of ischemic stroke in a patient with severe LVHT and ventricular dysfunction as a possible etiologic synergistic association. In absence of other embolic sources, a severe LVTH associated with ventricular dysfunction could constitute a potential source of brain embolism, especially in patients with high suspicion of an embolic mechanism of ischemic stroke.

High-salt diet inhibits expression of angiotensin type 2 receptor in resistance arteries.

Recent studies suggested that type 2 angiotensin receptor (AT2R) could contribute to regulation of blood pressure and/or vascular remodeling. A key question relates to the effects of potential modulators of vascular AT2R expression. In the present work, we evaluated if high salt intake (70 mmol/L NaCl in drinking water) could modulate rat mesenteric artery AT2R function and expression. Angiotensin II dose-response curves were studied in rat perfused pressurized small-diameter arteries in the presence of losartan (AT1R antagonist). Arteries were precontracted with phenylephrine, yielding approximately 30% decrease in resting diameter. AT2R activation by angiotensin-induced dose-dependent relaxation of precontracted arteries (60.1+/-9.1% of phenylephrine-induced contraction, P<0.05). In contrast, AT2R-dependent relaxation was not observed in arteries obtained from rats on high-salt diet. Semi-quantitative reverse-transcription polymerase chain reaction experiments demonstrated reduced amount of AT2R mRNA in arteries of rats on high-salt diet (65.5+/-7.5% of control levels, P<0.05). Western blot studies demonstrated decreased AT2R in mesenteric artery protein fractions of high-salt diet rats (60.0+/-18.0 of control levels, P<0.05). In a second set of experiments, adrenalectomy (4 days) blunted AT2R-mediated vasorelaxation and decreased AT2R mRNA (72.0+/-11.0% of control levels, P<0.05). AT2R abundance in protein fractions of mesenteric arteries of ADX rats was also diminished (64.0+/-13% of control levels, P<0.05). Both, AT2R mRNA and protein downregulation were prevented by mineralocorticoid replacement therapy. Finally, physiological concentrations of aldosterone caused a dose-dependent increase in AT2R mRNA of small diameter mesenteric artery explants. The results are consistent with aldosterone-mediated upregulation AT2R.

Derrame isquêmico como a primeira manifestação de hipertrabeculação/não-compactação ventricular grave / Ischemic stroke as the first manifestation of severe ventricular hypertrabeculation/non-compaction

Um raro defeito congênito do miocárdio, conhecido como hipertrabeculação/não-compactação do ventrículo esquerdo (HTVE/NCVE) tem sido ocasionalmente descrito em associação com a formação de trombos com um potencial risco embólico sistêmico, mas sua associação com derrames isquêmicos permanece controversa. Reportamos o caso de um derrame isquêmico em paciente com grave (HTVE/NCVE) e disfunção ventricular como uma possível associação sinérgica etiológica. Na ausência de outras fontes embólicas, uma grave HTVE/NCVE associada com disfunção ventricular poderia constituir uma fonte potencial de embolismo cerebral, especialmente em pacientes com alta suspeita de um mecanismo embólico de derrame sistêmico.

A rare congenital myocardial defect, known as left ventricular hypertrabeculation/non-compaction (LVHT), has been occasionally described associated with thrombus formation with a potential systemic embolic risk, but its association with ischemic strokes remains controversial. We report a case of ischemic stroke in a patient with severe LVHT and ventricular dysfunction as a possible etiologic synergistic association. In absence of other embolic sources, a severe LVTH associated with ventricular dysfunction could constitute a potential source of brain embolism, especially in patients with high suspicion of an embolic mechanism of ischemic stroke.