Axonal dysfunction is associated with interferon-γ levels in childhood-onset systemic lupus erythematosus: a multivoxel magnetic resonance spectroscopy study.

OBJECTIVE: Axonal/neuronal damage has been shown to be a pathological finding that precedes neuropsychiatric manifestations in SLE. The objective of this study was to determine the presence of axonal dysfunction in childhood-onset SLE patients (cSLE) and to determine clinical, immunological and treatment features associated with its occurrence. METHODS: We included 86 consecutive cSLE patients [median age 17 (range 5-28) years] and 71 controls [median age 18 (5-28) years]. We performed proton magnetic resonance spectroscopic imaging using point resolved spectroscopy sequence over the superior-posterior region of the corpus callosum and signals from N-acetylaspartate (NAA), choline-based (CHO), creatine-containing (Cr), myo-inositol (mI), glutamate, glutamine and lactate were measured and metabolites/Cr ratios were determined. Complete clinical, laboratory and neurological evaluations were performed in all subjects. Serum IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, TNF-α and INF-γ cytokine levels, antiribosomal P protein antibodies (anti-P) and S100ß were measured by ELISA using commercial kits. Data were compared by non-parametric tests. RESULTS: NAA/Cr ratios (P = 0.035) and lactate/Cr ratios (P = 0.019) were significantly decreased in cSLE patients when compared with controls. In multivariate analysis, IFN-γ levels [odds ratio (OR) = 4.1; 95% CI: 2.01, 7.9] and depressive symptoms (OR = 1.9; 95% CI: 1.1, 3.2) were associated with NAA/Cr ratio. Increased CHO/Cr was associated with the presence of cognitive impairment (OR = 3.4; 95% CI: 2.034, 5.078; P < 0.001). mI/Cr ratio correlated with cumulative glucocorticoids dosage (r = 0.361, P = 0.014). CONCLUSION: NAA and CHO ratios may be useful as biomarkers in neuropsychiatric cSLE. Longitudinal studies are necessary to determine whether they predict structural damage.

Depressive symptoms are associated with tumor necrosis factor alpha in systemic lupus erythematosus.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) is deeply related to pathogenesis of neurodevelopmental disorders, especially depression. The aim of this study was to explore potential relationships between sera TNF-α levels and mood and anxiety disorders in systemic lupus erythematosus (SLE) patients. METHODS: We included 153 consecutive SLE patients (women 148; median age 30; range 10-62) and 40 (women 37; mean age 28.5; range 12-59) age- and sex-matched healthy controls. Mood and anxiety disorders were determined through Beck Depression and Beck Anxiety Inventory. SLE patients were further assessed for clinical and laboratory SLE manifestations. TNF-α levels were measured by enzyme-linked immunosorbent assay using commercial kits. RESULTS: Depressive symptoms were identified in 70 (45.7 %) SLE patients and in 10 (25 %) healthy controls (p < 0.001). Anxiety symptoms were identified in 93 (60.7 %) SLE patients and in 16 controls (40 %) (p < 0.001). Sera TNF-α levels were increased in SLE patients with depressive symptoms (p < 0.001) and with anxiety symptoms (p = 0.014). A direct correlation between the severity of depressive symptoms and sera TNF-α levels (r = 0.22; p = 0.003) was observed. TNF-α levels were significantly increased in patients with active disease (p = 0.012). In addition, we observed a correlation between sera TNF-α levels and disease activity (r = 0.28; p = 0.008). In the multivariate analysis, sera TNF-α levels were independently associated with depressive symptoms (t = 3.28; 95 % CI 1.08-2.2; p = 0.002). CONCLUSIONS: Sera TNF-α levels are increased in SLE patients with mood and anxiety disorders. In SLE, sera TNF-α levels are independently associated with mood disorders. The etiology of mood disorders is still debated in SLE, but our findings suggest the presence of immunological basis for depression in SLE.

Schistosoma mansoni infection: an immune complex disease presenting with polyarthritis.

Schistosomiasis or bilharzia is a parasitic disease found in tropical countries. Most infections are subclinical but may progress to chronic form characterized most frequently by the presence of liver involvement and portal hypertension. We report a patient that presented chronic polyarthritis with positive rheumatoid factor. During investigation, increased liver enzymes, negative hepatitis serologies and signs of portal hypertension on an ultrasound examination raised suspicion of S. mansoni infection. We will discuss pathophysiology and clinical manifestations of S. mansoni infection with special attention to articular involvement.

Cognitive dysfunction and antiphospholipid antibodies.

Antiphospholipid syndrome (APS) is a multisystem prothrombotic condition, however, in recent years, its inflammatory nature has been studied extensively. Cerebral involvement is commonly observed in APS and results in different clinical manifestations. However, most of the studies include secondary APS. In this article, we review the prevalence, clinical characteristics, and physiopathology of cognitive impairment in patients with primary APS.

A framework for quality control of corpus callosum segmentation in large-scale studies.

BACKGROUND: The corpus callosum (CC) is the largest white matter structure in the brain, responsible for the interconnection of the brain hemispheres. Its segmentation is a required preliminary step for any posterior analysis, such as parcellation, registration, and feature extraction. In this context, the quality control (QC) of CC segmentation allows studies on large datasets with no human interaction, and the proper usage of available automated and semi-automated algorithms. NEW METHOD: We propose a framework for QC of CC segmentation based on the shape signature, computed at 49 distinct resolutions. At each resolution, a support vector machine (SVM) classifier was trained, generating 49 individual classifiers. Then, a disagreement metric was used to cluster these individual classifiers. The final ensemble was constructed by selecting one representation from each cluster. RESULTS: The proposed framework achieved an area under the curve (AUC) metric of 98.25% on the test set (207 subjects) employing an ensemble composed of 12 components. This ensemble outperformed all individual classifiers. COMPARISON WITH EXISTING METHODS: To the best of our knowledge, this is the first approach to assess quality of CC segmentations on large datasets without the need for a ground-truth. CONCLUSIONS: The shape descriptor is robust and versatile, describing the segmentation at different resolutions. The selection of classifiers and the disagreement measure lead to an ensemble composed of high-quality and heterogeneous classifiers, ensuring an optimal trade-off between the ensemble size and high AUC.

Brain diffusion tensor MRI in systematic lupus erythematosus: A systematic review.

Diffusion tensor imaging (DTI) maps the brain's microstructure by measuring fractional anisotropy (FA) and mean diffusivity (MD). This systematic review describes brain diffusion tensor Magnetic resonance imaging (MRI) studies in systemic lupus erythematosus (SLE).The literature was reviewed following the PRISMA guidelines and using the terms "lupus", "systemic lupus erythematosus", "SLE", "diffusion tensor imaging", "DTI", "white matter" (WM), "microstructural damage", "tractography", and "fractional anisotropy"; the search included articles published in English from January 2007 to April 2017. The subjects included in the study were selected according to the ACR criteria and included 195 SLE patients with neuropsychiatric manifestation (NPSLE), 299 without neuropsychiatric manifestation (non-NPSLE), and 423 healthy controls (HC). Most studies identified significantly reduced FA and increased MD values in several WM regions of both NPSLE and non-NPSLE patients compared to HC. Subclinical microstructural changes were observed in either regional areas or the entire brain in both the non-NPSLE and NPSLE groups.

Mimickers of neuropsychiatric manifestations in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE), presenting with new onset or worsening neuropsychiatric (NP) symptoms, is a challenge in clinical practice. Mimickers such as infections, drug-induced side effects, metabolic abnormalities, malignancies, and alcohol-related disorders have to be excluded, before attributing the manifestations to disease activity. Proper diagnosis is essential to guide adequate management and reduce morbidity and mortality. In this review article, we will highlight clinical, laboratorial, and neuroradiological features that are helpful to assist in the differential diagnosis.

Olfactory function in systemic lupus erythematosus and systemic sclerosis. A longitudinal study and review of the literature.

BACKGROUND/PURPOSE: To evaluate olfactory function in systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and healthy controls over a 2-year period, and to determine the association of olfactory dysfunction with age, disease activity, disease damage, treatment, anxiety and depression symptoms and limbic structures volumes. METHODS: Consecutive SLE and SSc patients were enrolled in this study. Clinical, laboratory disease activity and damage were assessed according to diseases specific guidelines. Olfactory functions were evaluated using the Sniffin' Sticks test (TDI). Volumetric magnetic resonance imaging (MRI) was obtained in a 3T Phillips scanner. Amygdalae and hippocampi volumes were analyzed using FreeSurfer® software. RESULTS: We included 143 SLE, 57 SSc and 166 healthy volunteers. Olfactory dysfunction was observed in 78 (54.5%) SLE, 35 (59.3%) SSc patients and in 24 (14.45%) controls (p<0.001) at study entry. SLE and SSc patients had significantly lower mean in all three phases (TDI) of the olfactory assessment when compared with healthy volunteers. In SLE, the presence of olfactory dysfunction was associated with older age, disease activity, higher anxiety and depression symptoms score, smaller left hippocampus volume, smaller left and right amygdalae volume and the presence of anti-ribosomal P (anti-P) antibodies. In SSc the presence of olfactory impairment was associated with older age, disease activity, smaller left and right hippocampi volumes and smaller right amygdala volume. Olfactory function was repeated after a 2-year period in 90 SLE, 35 SSc and 62 controls and was stable in all three groups. CONCLUSION: Both SLE and SSc patients with longstanding disease had significant reduction in all stages of TDI that maintained stable over a 2-year period. Olfactory dysfunction was associated with age, inflammation and hippocampi and amygdalae volumes. In SLE, additional association with anti-P, anxiety and depression symptoms was observed.

Neurologic involvement in scleroderma: a systematic review.

OBJECTIVES: To perform a systematic review of neurologic involvement in Systemic sclerosis (SSc) and Localized Scleroderma (LS), describing clinical features, neuroimaging, and treatment. METHODS: We performed a literature search in PubMed using the following MeSH terms, scleroderma, systemic sclerosis, localized scleroderma, localized scleroderma "en coup de sabre", Parry-Romberg syndrome, cognitive impairment, memory, seizures, epilepsy, headache, depression, anxiety, mood disorders, Center for Epidemiologic Studies Depression (CES-D), SF-36, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Patient Health Questionnaire-9 (PHQ-9), neuropsychiatric, psychosis, neurologic involvement, neuropathy, peripheral nerves, cranial nerves, carpal tunnel syndrome, ulnar entrapment, tarsal tunnel syndrome, mononeuropathy, polyneuropathy, radiculopathy, myelopathy, autonomic nervous system, nervous system, electroencephalography (EEG), electromyography (EMG), magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA). Patients with other connective tissue disease knowingly responsible for nervous system involvement were excluded from the analyses. RESULTS: A total of 182 case reports/studies addressing SSc and 50 referring to LS were identified. SSc patients totalized 9506, while data on 224 LS patients were available. In LS, seizures (41.58%) and headache (18.81%) predominated. Nonetheless, descriptions of varied cranial nerve involvement and hemiparesis were made. Central nervous system involvement in SSc was characterized by headache (23.73%), seizures (13.56%) and cognitive impairment (8.47%). Depression and anxiety were frequently observed (73.15% and 23.95%, respectively). Myopathy (51.8%), trigeminal neuropathy (16.52%), peripheral sensorimotor polyneuropathy (14.25%), and carpal tunnel syndrome (6.56%) were the most frequent peripheral nervous system involvement in SSc. Autonomic neuropathy involving cardiovascular and gastrointestinal systems was regularly described. Treatment of nervous system involvement, on the other hand, varied in a case-to-case basis. However, corticosteroids and cyclophosphamide were usually prescribed in severe cases. CONCLUSIONS: Previously considered a rare event, nervous system involvement in scleroderma has been increasingly recognized. Seizures and headache are the most reported features in LS en coup de sabre, while peripheral and autonomic nervous systems involvement predominate in SSc. Moreover, recently, reports have frequently documented white matter lesions in asymptomatic SSc patients, suggesting smaller branches and perforating arteries involvement.

Cognitive impairment in antiphospholipid syndrome: evidence from animal models.

Although antiphospholipid syndrome (APS) is a multisystem prothrombotic condition, its inflammatory nature has been increasingly recognized in recent years. Stroke and transitory ischemic attacks are the neurological manifestations included in APS criteria, however many other neurological involvements have been attributed to antiphospholipid antibodies (aPL), such as seizures, transverse myelitis, and cognitive impairment. In this article we will review evidence from animal model that explain the role of aPL in cognition.

Neurologic involvement in scleroderma en coup de sabre.

Localized scleroderma is a rare disease, characterized by sclerotic lesions. A variety of presentations have been described, with different clinical characteristics and specific prognosis. In scleroderma en coup de sabre (LScs) the atrophic lesion in frontoparietal area is the disease hallmark. Skin and subcutaneous are the mainly affected tissues, but case reports of muscle, cartilage, and bone involvement are frequent. These cases pose a difficult differential diagnosis with Parry-Romberg syndrome. Once considered an exclusive cutaneous disorder, the neurologic involvement present in LScs has been described in several case reports. Seizures are most frequently observed, but focal neurologic deficits, movement disorders, trigeminal neuralgia, and mimics of hemiplegic migraines have been reported. Computed tomography and magnetic resonance imaging have aided the characterization of central nervous system lesions, and cerebral angiograms have pointed to vasculitis as a part of disease pathogenesis. In this paper we describe the clinical and radiologic aspects of neurologic involvement in LScs.

Análise das alterações nas estruturas de substância branca e cinzenta através da ressonância magnética no lúpus eritematoso sistêmico juvenil / Analysis of structural changes in gray and white matter by magnetic resonance in juvenile systemic lupus erythematosus

O Lúpus Eritematoso Sistêmico (LES) é uma doença autoimune e multissistêmica. Cerca de 15-20% dos pacientes com LES desenvolve a doença ainda na infância e adolescência. O comprometimento do sistema nervoso central (SNC) é freqüente. No entanto, muitas vezes, se observa uma dissociação entre a clínica e os achados em neuroimagem. Alguns biomarcadores associados à lesão neuronal têm sido relacionados ao LES neuropsiquiátrico, mas seus papéis na patogênese e sua validade e aplicabilidade clínica não tem sido muito estudado em pacientes LESj. Objetivo: Determinar a prevalência de manifestações neuropsiquiátricas (NP) no LESj, analisarem a prevalência de alterações estruturais e lesões de substância branca em imagens de ressonância magnética (RM); além de determinar se S100B e NF-H podem estar associados a alterações estruturais e lesão de substância branca, em pacientes com LESj e controles. Método: Foram incluídos pacientes com LESj e controloes pareados. Manifestações clínicas, laboratoriais e medicação em uso foram avaliadas. A atividade da doença foi analisada através do SLEDAI (SLE Disease Activity Index) e o dano cumulativo foi analisado através do SDI (Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). Os transtornos de humor foram determinados através dos inventários de Depressão (BDI) e Ansiedade (BAI) de Beck e os distúrbios cognitivos foram avaliados pelo teste de inteligência Wechsler de acordo com a idade. As manifestações NP foram analisadas através da revisão de prontuários médicos. Foram consideradas manifestações neuropsiquiátricas presentes no inicio da doença quando ocorreram nos primeiros seis meses de doença e na evolução, quando ocorreram após este período. Pacientes e controles foram submetidos ao exame de 9 RM. A dosagem dos marcadores foi realizada por ELISA (Enzyme Linked Immuno Sorbent Assay...

Systemic lupus erythematosus (SLE) is an autoimmune disease and multisystem. About 15-20% of SLE patients develop the disease in childhood and adolescence. The involvement of the central nervous system (CNS) is frequent. However, often it is observed a dissociation between clinical and neuroimaging findings. Some biomarkers associated with neuronal injury have been associated with neuropsychiatric SLE, but their roles in the pathogenesis and its validity and clinical applicability has not been studied in patients cSLE. Objective: To determine the prevalence of neuropsychiatric (NP) manifestations in SLE analyze the prevalence of structural changes and white matter lesions on magnetic resonance imaging (MRI), in addition to determining whether S100B and NF- H may be associated with structural changes and white matter lesion in JSLE patients and controls. Methods: Clinical, laboratory and medication use were assessed. Disease activity was assessed by SLEDAI (SLE Disease Activity Index) and the cumulative damage was analyzed by SDI (Lupus International Collaborating Clinics / American College of Rheumatology Damage Index). Mood disorders were determined through the Depression inventory (BDI) and anxiety (BAI) and Beck's cognitive disturbances were assessed by the Wechsler intelligence test according to age. The NP manifestations were analyzed by reviewing medical records. Neuropsychiatric symptoms were considered present early in the illness when they occurred in the first six months of disease and evolution, as occurred after this period. Patients and controls underwent MRI. The dosage of the markers was performed by ELISA (Enzyme Linked Immuno Sorbent Assay. Results: 71 patients were included in the retrospective study and 51 patients were included in cross-sectional study...