Major Neuropsychiatric Manifestations Research Articles

Graves Disease Presenting Psychosis: a Case Report

Introductions: Graves’ disease is the most common cause of hyperthyroidism. Neuropsychiatric manifestations may occur in thyroid disease. As the premier clinical manifestation of Graves disease, psychosis is highly uncommon; it was reported in 1% of cases. The major neuropsychiatric manifestations of hyperthyroidism are acute psychosis, dementia, apathy, agitation, mania, delusional behavior, and hallucinations, especially in older people. Psychosis is highly rare as the first clinical symptom of a grave disease. Case: A 48-year-old female with grave disease symptoms had been taken to the emergency department with psychotic manifestations. She had a three-month history of increasing irritability, increasing irrational talking, staying awake most of the night, muttering, night-time wandering, and poor personal hygiene. She was admitted to the hospital, and the laboratory investigations showed an elevated FT4 and a decreased thyroid-stimulating hormone (TSH). The patient was started on propanolol 3 x 10 mg, propylthiouracil 3 x 50 mg tab, risperidone 2x2mg, trihexylphenidil 2x2mg, lorazepam 1x2mg, and Zyprexa injection once, which showed improvement in psychotic symptoms. Conclusion: Graves’ disease can present with neuropsychiatric manifestations such as psychosis, mania, or a combination of both. A detailed medical history and physical and psychiatric evaluation are necessary for diagnosing and giving adequate treatment. A detailed clinical evaluation, including thyroid function tests, could be recommended for all patients who showed psychotic symptoms. More research is needed to comprehend the pathophysiology underlying psychosis due to Graves’ disease, so that it is expected that the management can be carried out properly.

Spine morphogenesis and synapse formation in tubular sclerosis complex models.

Tuberous sclerosis complex (TSC) is caused by mutations in the Tsc1 or Tsc2 genes, whose products form a complex and inactivate the small G-protein Rheb1. The activation of Rheb1 may cause refractory epilepsy, intellectual disability, and autism, which are the major neuropsychiatric manifestations of TSC. Abnormalities in dendritic spines and altered synaptic structure are hallmarks of epilepsy, intellectual disability, and autism. In addition, spine dysmorphology and aberrant synapse formation are observed in TSC animal models. Therefore, it is important to investigate the molecular mechanism underlying the regulation of spine morphology and synapse formation in neurons to identify therapeutic targets for TSC. In this review, we focus on the representative proteins regulated by Rheb1 activity, mTORC1 and syntenin, which are pivotal downstream factors of Rheb1 in the alteration of spine formation and synapse function in TSC neurons.

Abnormal cortical thickness and structural covariance networks in systemic lupus erythematosus patients without major neuropsychiatric manifestations

BackgroundNon-neuropsychiatric systemic lupus erythematosus (non-NPSLE) has been confirmed to have subtle changes in brain structure before the appearance of obvious neuropsychiatric symptoms. Previous literature mainly focuses on brain structure loss in non-NPSLE; however, the results are heterogeneous, and the impact of structural changes on the topological structure of patients’ brain networks remains to be determined. In this study, we combined neuroimaging and network analysis methods to evaluate the changes in cortical thickness and its structural covariance networks (SCNs) in patients with non-NPSLE.MethodsWe compare the cortical thickness of non-NPSLE patients (N=108) and healthy controls (HCs, N=88) using both surface-based morphometry (SBM) and regions of interest (ROI) methods, respectively. After that, we analyzed the correlation between the abnormal cortical thickness results found in the ROI method and a series of clinical features. Finally, we constructed the SCNs of two groups using the regional cortical thickness and analyzed the abnormal SCNs of non-NPSLE.ResultsBy SBM method, we found that cortical thickness of 34 clusters in the non-NPSLE group was thinner than that in the HC group. ROI method based on Destrieux atlas showed that cortical thickness of 57 regions in the non-NPSLE group was thinner than that in the HC group and related to the course of disease, autoantibodies, the cumulative amount of immunosuppressive agents, and cognitive psychological scale. In the SCN analysis, the cortical thickness SCNs of the non-NPSLE group did not follow the small-world attribute at a few densities, and the global clustering coefficient appeared to increase. The area under the curve analysis showed that there were significant differences between the two groups in clustering coefficient, degree, betweenness, and local efficiency. There are a total of seven hubs for non-NPSLE, and five hubs in HCs, the two groups do not share a common hub distribution.ConclusionExtensive and obvious reduction in cortical thickness and abnormal topological organization of SCNs are observed in non-NPSLE patients. The observed abnormalities may not only be the realization of brain damage caused by the disease, but also the contribution of the compensatory changes within the nervous system.

Autoantibodies against specific post-translationally modified proteins are present in patients with lupus and associate with major neuropsychiatric manifestations

BackgroundAlthough autoantibodies are an important hallmark of systemic lupus erythematosus (SLE), most are not specific for SLE or any of its clinical manifestations. Autoantibodies against post-translationally modified (PTM) proteins have...

Hippocampal Atrophy in Systemic Lupus Erythematosus Patients without Major Neuropsychiatric Manifestations.

This study was conducted to explore hippocampal structural changes and their possible associations with clinical characteristics, emotional status, and treatment regimens in patients with systemic lupus erythematosus (SLE) without major neuropsychiatric manifestations (non-NPSLE). Eighty-five non-NPSLE patients with normal conventional magnetic resonance imaging (MRI) and seventy-seven matched healthy control (HC) subjects were recruited. All participants underwent the standard high-resolution volumetric MRI. The bilateral hippocampal volume (HIPV) and hippocampal density (HIPD) were calculated, respectively, for each participant. We found that the bilateral HIPV and HIPD of the SLE patient group were significantly less than those of the HC group. The bilateral HIPV of female patients were significantly less than those of male patients. The SLE disease activity index (SLEDAI) was negatively correlated with the bilateral HIPV and the right HIPD. Urine protein quantity was negatively correlated with the bilateral HIPV and HIPD. Hydroxychloroquine (HCQ) showed a protective effect on right HIPV. In conclusion, we found that the early hippocampal atrophy could occur before obvious neuropsychiatric manifestations and might be associated with SLE disease activity and organ damages. Early detection and intervention of hippocampal damage might prevent the progression to NPSLE. More studies are needed to fully understand the underlying mechanisms of hippocampal atrophy in SLE.

A Conscious Resting State fMRI Study in SLE Patients Without Major Neuropsychiatric Manifestations.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the main causes of death in patients with systemic lupus erythematosus (SLE). Signs and symptoms of NPSLE are heterogeneous, and it is hard to diagnose, and treat NPSLE patients in the early stage. We conducted this study to explore the possible brain activity changes using resting state functional magnetic resonance imaging (rs-fMRI) in SLE patients without major neuropsychiatric manifestations (non-NPSLE patients). We also tried to investigate the possible associations among brain activity, disease activity, depression, and anxiety. In our study, 118 non-NPSLE patients and 81 healthy controls (HC) were recruited. Rs-fMRI data were used to calculate the regional homogeneity (ReHo) in all participants. We found decreased ReHo values in the fusiform gyrus and thalamus and increased ReHo values in the parahippocampal gyrus and uncus. The disease activity was positively correlated with ReHo values of the cerebellum and negatively correlated with values in the frontal gyrus. Several brain areas showed correlations with depressive and anxiety statuses. These results suggested that abnormal brain activities might occur before NPSLE and might be the foundation of anxiety and depression symptoms. Early detection and proper treatment of brain dysfunction might prevent the progression to NPSLE. More studies are needed to understand the complicated underlying mechanisms.

Clinical Factors Associated with Brain Volume Reduction in Systemic Lupus Erythematosus Patients without Major Neuropsychiatric Manifestations.

The aim of the study was to find structural brain changes in systemic lupus erythematosus patients without major neuropsychiatric manifestations [non-neuropsychiatric systemic lupus erythematosus (non-NPSLE)] using quantitative magnetic resonance imaging (MRI) and possible associations with clinical characteristics. 89 non-NPSLE patients with normal conventional MRI and 84 healthy controls (HCs) were recruited. The whole brain gray matter volume (GMV) and white matter volume (WMV) were calculated for each individual. We found obvious GMV and WMV reduction in the systemic lupus erythematosus (SLE) group compared with HCs. Female patients showed significant reduction of GMV and WMV compared with male patients. Patients treated with immunosuppressive agents (ISA) showed less WMV reduction than those without. Cognitive impairment was the most common subclinical neuropsychiatric manifestation and had a prevalence of 46.1%. Association between WMV reduction with cognitive impairment was found. Thus, we concluded that structural brain atrophy could happen even before occurrence of obvious neuropsychiatric signs and symptoms and was associated with subclinical symptoms such as cognitive impairment. ISA treatment might have a protective effect on the brain atrophy. Early treatment might prevent the progressive damage to the brain. More studies are needed to fully understand the complicated underlying mechanisms of brain atrophy in SLE.

Neuropsychiatric Lupus in clinical practice.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs, characterized by the production of autoantibodies and the development of tissue injury. The etiology of SLE is partially known, involving multiple genetic and environmental factors. As many as 50% of patients with SLE have neurological involvement during the course of their disease. Neurological manifestations are associated with impaired quality of life, and high morbidity and mortality rates. Nineteen neuropsychiatric syndromes have been identified associated with SLE, and can be divided into central and peripheral manifestations. This article reviews major neuropsychiatric manifestations in patients with SLE and discusses their clinical features, radiological findings and treatment options.

Depressive and Anxiety Disorders in Systemic Lupus Erythematosus Patients without Major Neuropsychiatric Manifestations.

Depressive and anxiety disorders are frequently observed in patients with Systemic Lupus Erythematosus (SLE). However, the underlying mechanisms are still unknown. We conducted this survey to understand the prevalence of depression and anxiety in SLE patients without major neuropsychiatric manifestations (non-NPSLE) and to explore the relationship between emotional disorders, symptoms, autoantibodies, disease activity, and treatments in SLE. 176 SLE patients were included, and SLE disease activity index (SLEDAI), Hamilton Depression Rating Scale (HAMD), and Hamilton Anxiety Rating Scale (HAMA) were recorded to evaluate their disease activity and emotional status. We found that depressive and anxiety disorders were common among SLE patients: 121 (68.8%) patients were in depression status while 14 (8.0%) patients could be diagnosed with depression. Accordingly, 101 (57.4%) were in anxiety status and 21 (11.9%) could be diagnosed with anxiety. Depression was associated with disease activity, and anxiety was associated with anti-P0 antibody, while both of them were associated with proteinuria. HAMA and HAMD scores were in strong positive correlation and they were independent risk factors of each other. We concluded that the high prevalence of depression and anxiety and the association between depression and SLE disease activity might reveal the covert damage of central nervous system in SLE. The role of anti-P0 antibody in SLE patients with emotional disorders warrants more researches.

A133: Initial Benchmarking of the Quality of Medical Care of Children and Adolescents with Lupus

Background/Purpose:Recently, 26 quality indicators (QI) categorized into 9 domains for childhood‐onset systemic lupus erythematous (cSLE) have been developed based on international consensus and scientific evidence. QI are defined as minimum standards of medical care in support of optimal disease outcomes. The current level at which these QI are followed has not been well documented. Hence, the objective of this study is to assess the current quality of medical care received by patients with cSLE at tertiary pediatric rheumatology centers.Methods:Cross‐sectional data pertaining to the QI were acquired via chart review and analyzed collectively in 290 cSLE patients followed at four tertiary pediatric rheumatology centers—two in the United States and two in Brazil.Results:Adherence to the QI differed by QI domain, ranging from 41 to 100%. The QI domain with the highest adherence 100% was Laboratory Testing at the time of diagnosis, and the lowest domain 41% was Medication Management. The recommended kidney biopsies for newly diagnosed lupus nephritis were done in only 67% of the patients and 85% of the patients received at least one of the recommended vaccinations (Table ). Cardiovascular risks factors were discussed in 86% of cases when patient was 13 years or older. Adherence to the QI differences between countries and insurance status will be presented, supporting that the set of current QI are suitable for international use. Adherence to QI by Domain Quality Indicators by Domain Results Lab testing at diagnosis & screening Obtained diagnostic/confirmatory labs within first two visits 100% Obtained lab surveillance of CBC, renal, LFT every 12 months 85% General prevention Prescribed influenza and/or encapsulated organisms vaccination, unless contraindicated 85% Discussed and documented education on sun avoidance at least once in the medical record (e.g., wearing protective clothing, applying sunscreens whenever outdoors, and avoiding sunbathing) 89% Discussed transition plan to appropriate adult healthcare providers with patient age ≥14 years. 78% Lupus nephritis (LN) and hypertension management Kidney biopsy discussed/ordered/performed if developed proteinuria >500 mg/day, or worsening GFR, or urinary sediment 60% Evaluated by a nephrologist in the last year of care for lupus nephritis (LN) and of hypertension 65% Evaluated by rheumatologist every 3 months in last year if a patient has known LN regardless of disease activity. 96% Received kidney biopsy when diagnosed with LN 67% Class III/IV, treated with immunosuppressive + glucocorticoids within 1 month 92% Angiotensin receptor blocker (ARB) or, Angiotensin–converting enzyme (ACE) inhibitor were prescribed if ongoing proteinuria >500 mg/day or worsening GFR in last year of care. 96% Check assessments (Kidney function, urine sediment, and proteinuria) every three months. 99% Medication Management If started new meds, discussed risk vs. benefit of therapy 97% Currently prescribed any antimalarial therapy 92% Attempted to taper a dose of steroids not acceptable for chronic use. 89% Attempted to taper and unable to decrease steroid; added/increased steroid sparing agent. 41% Surveillance for medication safety done at regular intervals. 99% Bone Health Received at least one bone mineral density testing DEXA scan 72% Repeat bone mineral density testing if baseline testing outside normal limits (Z score ≤2) 62% Prescribed calcium/vitamin D if a patient is on any steroid therapy. 78% Ophthalmological surveillance Receives eye exams annually while on anti‐malarial therapy 82% Receives eye exams annually while on glucocorticoids 85% Education on cardiovascular risk factors Education on cardiovascular risk factors (smoking, hypertension, high BMI) every 1 year with patient and parent if patient is 13 years or older. 86% Discussed lifestyle modifications (smoking cessation, weight control, exercise) every 2 years with parent and patient 13 years or older. 87% Pregnancy Anti‐SSA, anti‐SB and anti‐phospholipid antibodies have been assessed during pregnancy 100% CNS health Prescribed Immunosuppressive therapy if patient has major neuropsychiatric manifestations in last year of care (Optic neuritis, coma, psychosis … etc.) 94%Conclusion:Based on this initial benchmarking effort, the medical care of patients with cSLE at tertiary pediatric rheumatology centers is very good. Systematic planning and documentation of patient education on lifestyle modifications seems warranted and is expected to improve the self‐management skills of cSLE patients. Furthermore, increased focus on bone health, eye exams annually, and adequate vaccination of cSLE patients are areas to continue to monitor.

Apathy-like syndrome associated with early lesion in the triple-transgenic 3xTgAD mouse

Alzheimer's disease (AD) is characterized by progressive impairment of memory accompanied by several psychiatric disturbances. Apathy is one of the major neuropsychiatric manifestations in AD and is considered as the most severe symptom. Apathy is an early hallmark of the disease and consistently persists as the disease progresses. In humans, apathy can be assessed by measuring locomotor activity by ambulatory actigraphy. One of the best animal models of AD is the triple-transgenic 3xTgAD mouse harbouring PS1M146V, APPswe and tauP301L (LaFerla). These mice progressively accumulate intraneuronal Abeta, mainly in the hippocampus, amygdala and entorhinal cortex, and develop extracellular Abeta deposits and neurofibrillary tangle-like pathology in a progressive and age-dependent manner. We measured mice circadian amplitude of locomotor rhythms using a fully automatized photocell activity meter system. All animals were further examined for motor function using an accelerating rotarod task. Abeta immunohistochemistry was performed using FCA18 and 2H3 that recognizes the N-terminal free Asp residue and amino acids 1-12 of Abeta, respectively. Profound decreased locomotor activity was observed in 3xTgAD mice as early as 3 month of age as compared to non-transgenic mice. Both horizontal activity and rearing were decreased in an age-dependent manner in both males and females. After the assessment of spontaneous activity, we examined motor function with an accelerating rotarod task. The 3xTgAD mice did not show any disturbed sensorimotor function. Using FCA18 or 2H3 antibodies, we detected intracellular labeling in a specific subset of pyramidal neurons in the subiculum and CA1 of the hippocampus in mice as early as 3 month. The number of immunostained neurons was progressively increased until about 13-14 month, where after the staining became mainly extracellular. These studies show a decreased locomotor activity in the 3xTgAD mice without impairment in sensorimotor function. Therefore, altered locomotor activity most likely reflects an apathy-like phenotype of the 3xTgAD mouse, which occurs early in the pathology and progressively worsens during life-time, as observed in AD patients. Moreover our data show a perfect correlation between the kinetics of intracellular FCA18-related labeling and loss of locomotor activity and suggest a direct or indirect link of intracellular Abeta-like immunoreactivity and apathy.

Cognitive Dysfunction in Systemic Lupus Erythematosus: Prevalence and Correlates

Little is known about the mechanisms and relevance of cognitive dysfunction in systemic lupus erythematosus (SLE) patients who never displayed major neuropsychiatric manifestations (nSLE). Thirty-one nSLE female patients and 31 cognitively healthy control women were recruited. Sociodemographic, clinical, neuropsychological and SLE-related markers were collected including cerebral perfusion by single-photon emission computed tomography. Prevalences of cognitive complaints were 22.6% in nSLE versus 6.5% in the control group (p = 0.147); respective prevalences of cognitive dysfunction were 32.3 versus 6.5% (p = 0.01). Within the nSLE group, all cognitive domains appeared similarly affected, and correlations were found between cognitive dysfunction and less skilled occupation (r = –0.41, p = 0.02) and between cognitive complaints and depressive symptoms (r = 0.35, p = 0.05). Cognitive dysfunction is rather frequent in nSLE and seems to negatively impinge on social functioning.

A longitudinal study of autoantibodies against central nervous system tissue and gangliosides in connective tissue diseases.

Our objective was to investigate longitudinally, antibodies against central nervous tissue (anti-CNS) derived from bovine brain and gangliosides GM 1, GD1a, GD1b, and GT1b in 91 patients with connective tissue diseases (systemic lupus erythematosus, n = 38; mixed connective tissue disease, n = 16; primary Sjogren's syndrome, n = 7; progressive systemic sclerosis, n= 13; polymyositis/dermatomyositis, n=4; overlap syndrome, n = 5; undifferentiated connective tissue disease, n = 8). Anti-CNS and anti-ganglioside antibodies, measured by enzyme-linked immunosorbent assay, were found in 73% and 63% of patients, respectively. Anti-CNS positive sera were also reactive in Western blotting in 74% of cases and recognized up to 14 different polypeptides from 29 to 130 kDa. Anti-CNS and anti-ganglioside antibodies reflected only in a limited extent the disease activity. In 27 of 58 patients, anti-CNS antibodies remained positive independently of disease activity and antibody levels did not correlate with the phases of exacerbations. A total of 36 of 60 anti-CNS-positive patients, in contrast to two of 22 anti-CNS-negative patients, had major neuropsychiatric manifestations (P < 0.001). Anti-ganglioside antibodies were not significantly associated with neuropsychiatric manifestations. In conclusion, our longitudinal data suggest that anti-CNS antibodies may be an important marker for the diagnosis of cerebral involvement in connective tissue diseases, but the pathogenic role of these autoantibodies remains to be determined.

NEUROPSYCHIATRIC MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Forty-six episodes of major neuropsychiatric manifestations of systemic lupus erythematosus occurring in 35 patients over a ten-year period were reviewed. The frequency of central nervous system SLF was lower than that reported from overseas referral centres. Glucocorticosteroid treatment did not precipitate psychiatric problems in this group. Whilst neuropsychiatric recovery was the rule, such features indicated a subgroup of SLE with high short-term mortality.