What is known about the effects of vitamin D in neuropsychiatric lupus?

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect several organs and systems. The central and/or peripheral nervous system can suffer from complications known as neuropsychiatric lupus (NPSLE). Studies have associated the manifestations of SLE or NPSLE with vitamin D deficiency. It has been shown that hypovitaminosis D can lead to cognition deficits and cerebral hypoperfusion in patients with NPSLE. In this review article, we will address the main features related to vitamin D supplementation or serum vitamin D levels with neuropsychiatric manifestations, either in patients or in animal models of NPSLE.

A case report: Catatonic symptoms secondary to systemic lupus erythematosus with multiple infections: neuropsychiatric or "mimickers?"

RATIONALE: Systemic lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric (NP) manifestations. However, typical symptoms of catatonia are uncommon. Neuropsychiatric SLE or its "mimickers" may cause NP symptoms, making differential diagnosis a significant challenge in clinical practice. PATIENT CONCERNS: A 68-year-old female with SLE was hospitalized for edema, lung infection, and recurrent fungal mouth ulcers after multiple courses of cortisol and immunosuppressive therapy. Five days after admission, stupor, immobility, mutism, and rigidity were observed. DIAGNOSIS: "Mimickers": catatonic disorder due to a general medical condition. INTERVENTION: Initially, relevant laboratory tests, imaging studies, and the disease activity index score were performed. A survey of the causes of the disease was conducted among the patient's relatives. Subsequently, we discontinued moxifloxacin, corticosteroids, fluconazole, and other medications and inserted a gastric tube for nutritional support. During this process, traditional Chinese medicine and acupuncture have been utilized. OUTCOMES: After 3 days, the patient recovered and only complained of fatigue. CONCLUSION: When SLE presents with NP symptoms, it is essential to make a correct diagnosis in order to guide appropriate treatment by actively searching for inducers and clinical, laboratory, and neuroradiological characteristics that can aid in the differential diagnosis. When treatment options are limited, it can be beneficial to try a variety of combination strategies, such as traditional Chinese medicine and acupuncture.

Higher IgG level correlated with vitamin D receptor in the hippocampus of a pristane-induced lupus model.

INTRODUCTION/OBJECTIVES: Patients with systemic lupus erythematosus (SLE) may have neurological complications, characterizing neuropsychiatric lupus (NPSLE). Studies have investigated alternative therapies such as vitamin D, which has an effect on the immune system and brain, to control manifestations of SLE. Experimental lupus models may be a good alternative to best study the immunological mechanisms underlying the development of NPSLE, and the animal model of pristane-induced lupus (PIL) may mimic SLE symptoms in humans. Our objective was to evaluate central nervous system involvement and vitamin D supplementation in a PIL model. METHOD: Female BALB/c mice were divided into controls (CO; n = 7), PIL (n = 9), and PIL supplemented with vitamin D (VD; n = 7). The hippocampus area was measured and immunoassays were performed for detecting vitamin D receptor (VDR) and IgG. RESULTS: The PIL group had a higher hippocampal IgG infiltrate when compared to the CO group. Vitamin D showed potential for reducing IgG infiltration. The hippocampus area was similar in all groups. No differences in VDR expression were observed between groups. A positive correlation was observed between the expression of VDR and IgG in the hippocampus. CONCLUSION: Our data suggest that increased IgG infiltration into the hippocampus indicated an inflammatory process that may have stimulated VDR expression. Key Points • IgG infiltrate is higher in PIL animals than controls • VDR increases along with IgG infiltrate • Hippocampal VDR expression does not increase with vitamin D supplementation.

Quantitative susceptibility mapping in the thalamus and basal ganglia of systemic lupus erythematosus patients with neuropsychiatric complaints.

Systemic lupus erythematosus (SLE) is an auto-immune disease characterized by multi-organ involvement. Although uncommon, central nervous system involvement in SLE, termed neuropsychiatric SLE (NPSLE), is not an exception. Current knowledge on underlying pathogenic mechanisms is incomplete, however, neuroinflammation is thought to play a critical role. Evidence from neurodegenerative diseases and multiple sclerosis suggests that neuroinflammation is correlated with brain iron accumulation, making quantitative susceptibility mapping (QSM) a potential hallmark for neuroinflammation in vivo. This study assessed susceptibility values of the thalamus and basal ganglia in (NP)SLE patients and further investigated the in vivo findings with histological analyses of postmortem brain tissue derived from SLE patients. We used a 3T MRI scanner to acquire single-echo T2*-weighted images of 44 SLE patients and 20 age-matched healthy controls. Of the 44 patients with SLE, all had neuropsychiatric complaints, of which 29 were classified as non-NPSLE and 15 as NPSLE (seven as inflammatory NPSLE and eight as ischemic NPSLE). Mean susceptibility values of the thalamus, caudate nucleus, putamen, and globus pallidus were calculated. Formalin-fixed paraffin-embedded post-mortem brain tissue including the putamen and globus pallidus of three additional SLE patients was obtained and stained for iron, microglia and astrocytes. Susceptibility values of SLE patients and age-matched controls showed that iron levels in the thalamus and basal ganglia were not changed due to the disease. No subgroup of SLE showed higher susceptibility values. No correlation was found with disease activity or damage due to SLE. Histological examination of the post-mortem brain showed no increased iron accumulation. Our results suggest that neuroinflammation in NPSLE does not necessarily go hand in hand with iron accumulation, and that the inflammatory pathomechanism in SLE may differ from the one observed in neurodegenerative diseases and in multiple sclerosis.

Analysis of brain metabolites by gas chromatography-mass spectrometry reveals the risk-benefit concerns of prednisone in MRL/lpr lupus mice.

OBJECTIVE: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a common cause of disability in systemic lupus erythematosus (SLE). This study aims to investigate the metabolic changes in the hypothalamus and frontal cortex in lupus-prone MRL/lpr mice. METHODS: Metabolic changes were analyzed using gas chromatography-mass spectrometry (GC-MS). RESULTS: According to the principal component analysis (PCA), the metabolic profiles were different between the frontal cortex and hypothalamus, but they were comparable between MRL/lpr and MRL/MpJ mice (16 weeks of age). By OPLS-DA, eight cortical and six hypothalamic differential metabolites were identified in MRL/lpr as compared to MRL/MpJ mice. Among these differential metabolites, we found a decrease of N-acetyl-L-aspartate (NAA, a potential marker of neuronal integrity), an increase of pyruvate and a decrease of glutamate in the frontal cortex but not in the hypothalamus. Prednisone treatment (3 mg/kg from 8 weeks of age) relieved the decrease of NAA but further increased the accumulation of pyruvate in the frontal cortex, additionally affected eight enriched pathways in the hypothalamus, and led to significant imbalances between the excitation and inhibition in both the frontal cortex and hypothalamus. CONCLUSION: These results suggest that the frontal cortex may be more preferentially affected than the hypothalamus in SLE. Prednisone disrupted rather than relieved metabolic abnormalities in the brain, especially in the hypothalamus, indicating that the risk-benefit balance of prednisone for SLE or NPSLE remains to be further evaluated.

The Neurochemical and Microstructural Changes in the Brain of Systemic Lupus Erythematosus Patients: A Multimodal MRI Study.

The diagnosis and pathology of neuropsychiatric systemic lupus erythematosus (NPSLE) remains challenging. Herein, we used multimodal imaging to assess anatomical and functional changes in brains of SLE patients instead of a single MRI approach generally used in previous studies. Twenty-two NPSLE patients, 21 non-NPSLE patients and 20 healthy controls (HCs) underwent 3.0 T MRI with multivoxel magnetic resonance spectroscopy, T1-weighted volumetric images for voxel based morphometry (VBM) and diffusional kurtosis imaging (DKI) scans. While there were findings in other basal ganglia regions, the most consistent findings were observed in the posterior cingulate gyrus (PCG). The reduction of multiple metabolite concentration was observed in the PCG in the two patient groups, and the NPSLE patients were more prominent. The two patient groups displayed lower diffusional kurtosis (MK) values in the bilateral PCG compared with HCs (p < 0.01) as assessed by DKI. Grey matter reduction in the PCG was observed in the NPSLE group using VBM. Positive correlations among cognitive function scores and imaging metrics in bilateral PCG were detected. Multimodal imaging is useful for evaluating SLE subjects and potentially determining disease pathology. Impairments of cognitive function in SLE patients may be interpreted by metabolic and microstructural changes in the PCG.

Uso de metotrexato en neurolupus pediátrico refractario: alternativa de tratamiento: revisión de la literatura / Use of methotrexate in pediatric refractory neurolupus: alternative treatment: literature review

The neuropsychiatric get involved in sistemic lupus erythematosus (SLE) is complex and is the major cause of morbidity and mortality. The incidence in children ranges from 20 percent to 95 percent. The recognition and treatment remain a major diagnostic and therapeutic challenge. The activity for the treatment remains empirical and based on clinical experience. The choice of treatment depends on an accurate diagnosis and identification of the underlying pathogenic mechanism. Symptomatic treatments, immunosuppressive and anti-coagulants are the main therapeutic strategies. You have searched other therapeutic measures in patients with severe disease refractory to standard therapy or the use of cyclophosphamide, immunoglobulin, rituximab, methotrexate + intrathecal dexamethasone, among others. We report one patient with neurolupus (NLES), refractory methylprednisolone and treatment with cyclophosphamide, continuing neurological activity is applied intrathecal MTX 10 mg + dexamethasone 10 mg intrathecal, in a total of 4 doses, finding satisfactory improvement, and controlling activity.

El involucro neuropsiquiátrico en el lupus eritematoso sistémico (LES) es complejo y es causa importante de morbimortalidad. La incidencia en la edad pediátrica va de 20 por ciento al 95 por ciento. Su reconocimiento y tratamiento siguen representando un importante reto diagnóstico y terapéutico. La actividad para el tratamiento sigue siendo empírica y basada en la experiencia clínica; la elección terapéutica depende de un diagnóstico preciso y la identificación del mecanismo patogénico subyacente. Los tratamientos asintomáticos, inmunosupresores y anticoagulantes representan las principales estrategias terapéuticas. Se han buscado otras medidas terapéuticas en pacientes con afección severa o refractarios al tratamiento habitual, como el uso de ciclofosfamida, inmunoglobulina, rituximab, metotrexato + dexametasona intratecal, entre otros. Presentamos el caso de un paciente con neurolupus (NLES), refractario al tratamiento con metilprednisolona y ciclofosfamida, continuando con actividad neurológica; se aplica MTX 10 mg intratecal + dexametasona 10 mg IT, en un total de 4 dosis, encontrando mejoría satisfactoria y control de la actividad.

Commentary on neuropsychiatric symptoms associated with lupus.

Treatments for neuropsychiatric complications of systemic lupus erythematosus are reviewed, including psychiatric medications, corticosteroids (which may also cause psychiatric complications), and emerging non-steroidal immune modulators.

Saikosaponins: a potential treatment option for systemic lupus erythematosus.

While the exact cause of systemic lupus erythematosus (SLE) is still unknown, modern medicine has a number of effective treatments for this complex disorder. Corticosteroid hormones help reduce inflammation, antimalarial treatments address flare-ups and immunosuppressive medications work to keep the immune system in check. All these therapies are well tolerated, but accompany an increased risk of infection and nephrotoxicity. Recently, several studies showed that a number of natural and herbal products may also help some SLE patients deal with the debilitating symptoms. In this brief report, we proposed a traditional Chinese medicinal herb--Saikosaponins, and discussed its potential as a treatment option for SLE.

Autoantibody-mediated neuroinflammation: pathogenesis of neuropsychiatric systemic lupus erythematosus in the NZM88 murine model.

Autoantibodies play an important role in central nervous system manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE). Previous studies have shown that the lupus-prone NZM88 strain has major neural deficits and high titers of serum IgG to brain antigens. ELISA was performed to detect the presence of IgG in different brain regions of NZM88 mice and to compare the levels with NZM2758 mice and control strains (NZW and BALB/c). There was a substantial increase of IgG in the substantia nigra (SN) and hypothalamus (HT) of brains from NZM88 mice compared to control NZW and BALB/c mice, whereas NZM2758 mice had more IgG in the cortex. The increased presence of IgG in the NPSLE-prone NZM88 mouse brain was paralleled by increased TNF-alpha and IL-12 in the SN and HT regions; significantly elevated expression of MHC Class-II was also observed in the SN of NZM88 mice and cortex of NZM2758 mice. A co-culture system of dopaminergic neurons and microglia was used to demonstrate that NZM88 sera modifies dopaminergic cell activity only in the presence of microglia and that TNF-alpha is synthesized and released in this co-culture. This study demonstrates a functional link between the autoantibodies, the activation of microglia, and neuronal function associated dopamine production, which is suggested to be causally related to the predominant NPSLE syndromes.

Clinical validation of the watershed sign as a marker for neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: To study the relationship between single-photon-emission computed tomography (SPECT) brain imaging and neuropsychiatric signs/symptoms in a cohort of patients with systemic lupus erythematosus (SLE), analyzed using a stereotactic surface projection (SSP) technique. METHODS: Thirty-seven SLE patients were referred for 99mTc-ethyl cysteinate dimer SPECT brain imaging because of neuropsychiatric signs/symptoms. Nineteen normal controls were studied with the identical protocol. Reconstructed images were computed and Z scores were calculated using the SSP technique with the 2-sample t-tests comparing normal controls with SLE patients, and patients with mild cognitive dysfunction with those with severe cognitive dysfunction. The clinical characteristics of SLE patients were collected by retrospective chart review and categorized according to American College of Rheumatology case definitions for neuropsychiatric SLE. Cognitive dysfunction was rated by the treating physician on a scale of 0-3. RESULTS: Thirty of 37 SLE patients had abnormal SPECT results. SLE patients had reduced perfusion in the watershed areas of the frontal lobes bilaterally compared with controls. Additionally, SLE patients with severe cognitive dysfunction had more severe perfusion deficits than those with mild cognitive dysfunction. In some patients with severe cognitive dysfunction, the watershed areas had Z scores > or =4 SDs below controls. CONCLUSION: A convenience sample of patients with SLE and neuropsychiatric signs/symptoms demonstrated reduced perfusion in the watershed areas of the frontal lobes on SPECT scanning analyzed by the SSP technique. The severity of findings correlated with severity of cognitive dysfunction. The area of the brain affected is one that is susceptible to ischemia.

Expression of S100B protein levels in serum and cerebrospinal fluid with different forms of neuropsychiatric systemic lupus erythematosus.

The aim of this study is to determine S100B protein levels in serum and cerebrospinal fluid (CSF) in patients with different forms of neruopsychiatric systemic lupus erythematosus (NPSLE). There were 157 SLE patients (65 with and 92 without NPSLE, and 20 patients without rheumatic diseases served as controls) recruited in the present study. Serum and CSF S100B protein levels were measured by ELISA assay. Serum S100B protein levels in patients with NPSLE (0.179 +/- 0.095 microg/l) were significantly higher than the levels in patients without NPSLE (0.110 +/- 0.091 microg/l; p < 0.001) and in controls (0.103 +/- 0.065 microg/l; p = 0.005). Thus, the differences in serum levels between non-NPSLE patients and controls had no statistical significance. The serum and CSF S100B protein contents in patients with organic brain syndrome, seizures, cerebral vascular accident, and psychosis were significantly higher than those in controls (all p < 0.001). However, there was no significant difference in serum and CSF S100B protein levels among patients with headache, patients with neuropathy, and controls. In conclusion, serum and CSF S100B levels were raised in NPSLE, especially concerning patients with organic brain syndrome, seizures, cerebral vascular accident, and psychosis. The results obtained imply that S100B protein is possibly an available and complementary biochemical marker within evaluation of NPSLE and deserves further study.

Deep brain reversible encephalopathy: association with secondary antiphospholipid antibody syndrome.

We present a case of a patient with systemic lupus erythematosus and secondary antiphospholipid syndrome. The patient presented with acute right cerebellar infarction and clinical and imaging evidence of brain stem and bilateral thalamic encephalopathy that resolved completely.

Hypothalamic-mediated model for systemic lupus erythematosis: relation to hemispheric chemical dominance.

The isoprenoid pathway including endogenous digoxin was assessed in systemic lupus erythematosis (SLE). All the patients with SLE were right-handed/left hemispheric dominant by the dichotic listening test. This was also studied for comparison in patients with right hemispheric and left hemispheric dominance. The isoprenoid pathway was upregulated with increased digoxin synthesis in patients with SLE and in those with right hemispheric dominance. In this group of patients (i) the tryptophan catabolites were increased and the tyrosine catabolites reduced, (ii) the dolichol and glycoconjugate levels were elevated, (iii) lysosomal stability was reduced, (iv) ubiquinone levels were low and free radical levels increased, and (v) the membrane cholesterol:phospholipid ratios were increased and membrane glycoconjugates reduced. On the other hand, in patients with left hemispheric dominance the reverse patterns were obtained. The biochemical patterns obtained in SLE is similar to those obtained in left-handed/right hemispheric chemically dominant individuals. But all the patients with SLE were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. SLE occurs in right hemispheric chemically dominant individuals, and is a reflection of altered brain function. The role of the isoprenoid pathway in the pathogenesis of SLE and its relation to hemispheric dominance is discussed.

Early and delayed Tc-99m ECD brain SPECT in SLE patients with CNS involvement.

We compared early and delayed Tc-99m ECD SPECT scans in 32 SLE patients (Group 1, definite neuropsychiatric disorders; Group 2, minor neurologic symptoms or normal) with those of normal controls by visual inspection and semi-quantitative evaluation. With visual interpretation, 13 out of 14 patients in Group 1 (93%) and 7 out of 18 patients in Group 2 (39%) had diffuse uneven decrease in early scans. Seven patients in Group 2 (39%) who had normal early scans demonstrated focal decrease in the medial frontal lobe in delayed scans. With cerebral region to cerebellar ratios, in early scans, the medial frontal lobe in Group 1 and Group 2 was significantly lower than in normal controls, and lateral frontal lobe and occipital lobes in Group 1 were significantly lower than in normal controls. Nevertheless, in delayed scans, every cortical region except for the parietal lobe in Groups 1 and 2 was significantly lower than in normal controls. The retention rates in all regions in SLE patients were significantly lower than in normal controls. No case showed SPECT improvement on follow-up studies in either group in spite of clinical improvement. Delayed Tc-99m ECD brain SPECT of high sensitivity might be useful in detecting CNS involvement. Although the SPECT findings did not correlate with the neuropsychiatric symptoms, early and delayed Tc-99m ECD SPECT seems to provide useful objective diagnostic information in SLE patients.