Neuropsychiatric Systemic Lupus Erythematosus: Molecules Involved in Its Imunopathogenesis, Clinical Features, and Treatment.

Systemic lupus erythematosus (SLE) is an idiopathic chronic autoimmune disease that can affect any organ in the body, including the neurological system. Multiple factors, such as environmental (infections), genetic (many HLA alleles including DR2 and DR3, and genes including C4), and immunological influences on self-antigens, such as nuclear antigens, lead to the formation of multiple autoantibodies that cause deleterious damage to bodily tissues and organs. The production of autoantibodies, such as anti-dsDNA, anti-SS(A), anti-SS(B), anti-Smith, and anti-neuronal DNA are characteristic features of this disease. This autoimmune disease results from a failure of the mechanisms responsible for maintaining self-tolerance in T cells, B cells, or both. Immune complexes, circulating antibodies, cytokines, and autoreactive T lymphocytes are responsible for tissue injury in this autoimmune disease. The diagnosis of SLE is a rheumatological challenge despite the availability of clinical criteria. NPSLE was previously referred to as lupus cerebritis or lupus sclerosis. However, these terms are no longer recommended because there is no definitive pathological cause for the neuropsychiatric manifestations of SLE. Currently, the treatment options are primarily based on symptomatic presentations. These include the use of antipsychotics, antidepressants, and anxiolytic medications for the treatment of psychiatric and mood disorders. Antiepileptic drugs to treat seizures, and immunosuppressants (e.g., corticosteroids, azathioprine, and mycophenolate mofetil), are directed against inflammatory responses along with non-pharmacological interventions.

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.

Case Report: Real NPSLE? A patient with systemic sclerosis overlapping systemic lupus erythematosus presenting as epilepsy.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is the diagnosis that rheumatologists most often need to consider when a patient with lupus presents with neurologic symptoms. However, neurological involvement is rare in systemic sclerosis (SSc), and high doses of steroids tend to trigger scleroderma renal crisis (SRC). When a patient with SSc overlapping SLE presents with epilepsy and renal crisis, the exact diagnosis and whether to initiate high-dose glucocorticoid therapy are questions to ponder. Here, we report a patient with overlap syndrome (SSc overlapping SLE), who developed CNS symptoms, and improved after treatment against SRC after excluding NPSLE. We report this case with the aim of arousing the attention of rheumatologists to SSc and SRC-related encephalopathy when SSc was overlapped with SLE.

Neuropsychiatric Systemic Lupus Erythematosus and Posterior Reversible Encephalopathy Syndrome in a Young Woman: A Case Report.

INTRODUCTION: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease with variable clinical presentation, including neuropsychiatric manifestations. It has a different diagnostic approach and several different therapeutic options. CASE REPORT: We describe a case of a young woman who first presented with arthritis, serositis, and pancreatitis, and was treated with mycophenolate mofetil initially. The patient presented with neurological symptoms suggestive of neuropsychiatric manifestations three weeks later, confirmed by Brain Magnetic Resonance Imaging (MRI). The treatment was changed to cyclophosphamide; however, the day after the infusion, she developed status epilepticus and was admitted to the intensive care unit. Repeated brain MRI revealed Posterior Reversible Encephalopathy Syndrome (PRES). Cyclophosphamide was discontinued and rituximab was initiated. The patient's neurological manifestations improved, and she was discharged after 25 days of use. CONCLUSION: Immunosuppressive agents, such as cyclophosphamide have been described as a potential risk factor for PRES; however, it is not clear from the available literature whether cyclophosphamide therapy is just a marker of more severe SLE or a true risk factor for PRES.

Cyclophosphamide-induced seizures in a patient with neuropsychiatric systemic lupus erythematosus (NPSLE): A case report.

Seizures are life-threatening complications of neuropsychiatric systemic lupus erythematosus (NPSLE) and are often associated with poor outcomes. Cyclophosphamide immunotherapy is the mainstay of NPSLE treatment. We report the unique case of a patient with NPSLE who developed seizures soon after her first and second doses of low-dose cyclophosphamide. The exact pathophysiological mechanism underlying cyclophosphamide-induced seizures is not well understood. However, this unusual drug-associated side effect of cyclophosphamide is thought to be due to the drug's unique pharmacology. Clinicians should be aware of this complication to make a correct diagnosis and adjust the immunosuppressive regimens very carefully.

The influence of intrathecal injection of methotrexate and dexamethasone on neuropsychiatric systemic lupus erythematosus (NPSLE): a retrospective cohort study of 386 patients with NPSLE.

BACKGROUND: Neuropsychiatric involvement is one of the major concerns in systemic lupus erythematosus (SLE). The therapeutic effect of intrathecal treatment of methotrexate and dexamethasone has been investigated in some exploratory studies, but its influence on the long-term prognosis of neuropsychiatric SLE (NPSLE) remains unknown. METHODS: This was a propensity score-matched retrospective study. Outcomes at discharge and time free from NPSLE relapse or death were evaluated by multivariate logistic regression, survival analysis, and Cox regression as appropriate. RESULTS: Among 386 hospitalized patients with NPSLE, the median [IQR] age was 30.0 [23.0-40.0] years, and 342 patients (88.4%) were female. Of those, 194 patients received intrathecal treatment. Patients in the intrathecal treatment group had higher Systemic Lupus Erythematosus Disease Activity Index 2000 scores (median 17 vs. 14 points, IQR 12-22 vs. 10-19 points, P <0 .001) and were more likely to receive methylprednisolone pulse therapy (71.6% vs. 49.5%, P < 0.001) than those who did not receive intrathecal therapy. Intrathecal treatment was associated with a higher probability of survival and being free from NPSLE relapse than control treatment among the 386 unmatched patients (P =0.042 by log-rank test) and within 147 propensity score-matched pairs (P =0.032 by log-rank test). In the subgroup of NPSLE patients with increased levels of protein in cerebrospinal fluid, intrathecal treatment had a positive influence on their prognosis (P < 0.001). CONCLUSIONS: Intrathecal treatment of methotrexate and dexamethasone was associated with a more favorable prognosis of NPSLE and may serve as a valuable additional therapy for NPSLE patients, especially for those with elevated levels of protein in cerebrospinal fluid.

Bortezomib is efficacious in the treatment of severe childhood-onset neuropsychiatric systemic lupus erythematosus with psychosis: a case series and mini-review of B-cell immunomodulation in antibody-mediated diseases.

Childhood-onset neuropsychiatric systemic lupus erythematosus (cNPSLE) with psychosis is a challenging manifestation of SLE. Pathogenic long-lived plasma cells (LLPCs) are not specifically targeted by standard immunosuppression and their persistence contributes to chronic autoimmunity. Bortezomib is approved for the treatment of multiple myeloma and has shown benefits in a variety of other antibody-mediated diseases. Bortezomib may be efficacious for severe or treatment-refractory cNPSLE through eradication of LLPCs, decreasing autoantibody production. We describe the first pediatric case series of five patients with unrelenting cNPSLE with psychosis who were treated safely and effectively with bortezomib between 2011 and 2017. Most patients had persistent cNPSLE with psychosis despite aggressive immunosuppression with methylprednisolone, cyclophosphamide, rituximab, and usually plasmapheresis. All patients demonstrated rapid clinical improvement in their psychotic manifestations with the ability to quickly taper immunosuppression after the introduction of bortezomib. No patient had a recurrence of overt psychosis during a follow-up period of 1-10 years. Secondary hypogammaglobulinemia developed in all five patients and required immunoglobulin replacement. No other severe side effects or adverse events were observed. Bortezomib-mediated LLPC depletion is a promising therapy for severe recalcitrant cNPSLE with psychosis when used as adjunctive therapy to conventional immunosuppression, B-cell, and antibody-depleting therapies. After initiation of bortezomib, patients had rapid, demonstrable improvement in psychosis as well as reduction in glucocorticoids and antipsychotics. Further investigation is needed to determine the therapeutic role of bortezomib in severe cNPSLE and cSLE. We present a mini-review of the rationale for bortezomib use and novel B-cell immunomodulation in rheumatic disease.

Clinical outcome in patients with suspected inflammatory neuropsychiatric lupus treated with immunosuppression: an observational cohort study.

BACKGROUND: The short-term and long-term outcome of inflammatory neuropsychiatric SLE (NPSLE) with immunosuppressive treatment is largely unknown. We used clinical data from our tertiary referral centre for NPSLE to investigate the type of inflammatory NPSLE manifestations, type of immunosuppressive treatment prescribed for these manifestations and clinical outcomes. METHODS: All patients with SLE visiting the Leiden University Medical Centre NPSLE clinic between 2007 and 2021 receiving immunosuppressive therapy for neuropsychiatric symptoms were included. Clinical, immunological and radiological information was collected in as standardised way during a 1-day multidisciplinary assessment. In a multidisciplinary consensus meeting, the presence of NPSLE and the type of NPSLE manifestations and treatment were determined. For this study, short-term (0-6 months) and long-term outcomes (7-24 months) of the NP symptoms were assessed by two independent readers and scored on a 7-point Likert scale, ranging from death to resolved. RESULTS: In total, 95 out of 398 (24%) patients visiting the NPSLE clinic between 2007 and 2021 received any form of immunosuppressive treatment for 101 separate NPSLE events. The most common NP manifestation was cognitive dysfunction (50%) as identified by formal cognitive assessment, often present in combination with other NPSLE manifestations. Treatment modalities were induction (24%), induction and maintenance (73%) and other therapy (3%). The treatments mostly consisted of (combinations of) prednisone (97%), methylprednisolone (53%), azathioprine (generally 2 mg/kg daily) (49%) and cyclophosphamide (generally induction 750 mg/m2 every 4 weeks for 24 weeks or 500mg biweekly for 12 weeks) (42%). Short-term outcome showed improvement on the Likert scale in 73% (improved: 22%, much improved: 29%, resolved: 22%), no change in 21% and worsening in 6% of patients. Long-term outcome was available for 78 out of 101 events and showed improvement in 70% (improved: 14%, much improved: 28%, resolved: 28%), no change in 17%, worsening in 10% and death in 3% of patients (none directly NPSLE-related). CONCLUSION: The outcome of inflammatory NPSLE after immunosuppressive treatment is generally good, with improvement of neuropsychiatric symptoms occuring in approximately 70% of events.

Pristane induced lupus mice as a model for neuropsychiatric lupus (NPSLE).

BACKGROUND: The pristane-induced lupus (PIL) model is a useful tool for studying environmental-related systemic lupus erythematosus (SLE). However, neuropsychiatric manifestations in this model have not been investigated in detail. Because neuropsychiatric lupus (NPSLE) is an important complication of SLE, we investigated the neuropsychiatric symptoms in the PIL mouse model to evaluate its suitability for NPSLE studies. RESULTS: PIL mice showed olfactory dysfunction accompanied by an anxiety- and depression-like phenotype at month 2 or 4 after pristane injection. The levels of cytokines (IL-1ß, IFN-α, IFN-ß, IL-10, IFN-γ, IL-6, TNF-α and IL-17A) and chemokines (CCL2 and CXCL10) in the brain and blood-brain barrier (BBB) permeability increased significantly from week 2 or month 1, and persisted throughout the observed course of the disease. Notably, IgG deposition in the choroid plexus and lateral ventricle wall were observed at month 1 and both astrocytes and microglia were activated. Persistent activation of astrocytes was detected throughout the observed course of the disease, while microglial activation diminished dramatically at month 4. Lipofuscin deposition, a sign of neuronal damage, was detected in cortical and hippocampal neurons from month 4 to 8. CONCLUSION: PIL mice exhibit a series of characteristic behavioral deficits and pathological changes in the brain, and therefore might be suitable for investigating disease pathogenesis and for evaluating potential therapeutic targets for environmental-related NPSLE.

Acute cortical blindness caused by neuropsychiatric systemic lupus erythematosus.

A man in his 30s, who presented with fevers and a diffuse purpuric rash, developed sudden-onset visual loss on day 2. He was unable to perceive light in either eye. Examination by a neurologist confirmed cortical blindness, and the MRI showed subtle juxtacortical infarcts and leptomeningeal enhancement in the occipital region. Further history taken in the patient's native language revealed a history of untreated systemic lupus erythematosus. A diagnosis of central nervous system lupus was made and he was treated promptly with pulse methylprednisolone and cyclophosphamide. His vision gradually improved to 80% on day 10 and eventually returned to baseline. He continued with high-dose prednisolone and monthly cyclophosphamide for 6 months and remained on hydroxychloroquine and mycophenolate mofetil with no relapses. This case shows the importance of approaching the uncommon but potentially dangerous issue of acute visual loss with a broad differential.

Treatment with lysophosphatidic acid prevents microglial activation and depression-like behaviours in a murine model of neuropsychiatric systemic lupus erythematosus.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is an incurable disease characterised by neuropsychiatric symptoms, particularly depression. Novel therapeutic options for NPSLE are urgently needed. Several previous reports have suggested that both microglial activation and impaired neurogenesis may be involved in the progression of depression. In contrast, the administration of lysophosphatidic acid (LPA) ameliorates depression and anxiety. Therefore, in the present study, we determined whether treatment with LPA affects microglial activation, impaired neurogenesis, and abnormal behaviour in MRL/lpr mice. In both tail suspension test and forced swim test, the MRL/lpr mice exhibited a significant increase in total immobility time compared with MRL/+ mice. Treatment with LPA significantly suppressed the prolonged immobility time in MRL/lpr mice. In contrast, pretreatment with ki16425 (a specific antagonist of LPA receptor 1 and 3) significantly reversed the effects of LPA. Furthermore, MRL/lpr mice exhibited impairments in spatial working memory and visual cognitive memory, which were suppressed by LPA treatment. The expression levels of TMEM119, CD68, GFAP, and caspase-3 in the hippocampus and prefrontal cortex of MRL/lpr mice were significantly higher than those in MRL/+ mice. Treatment with LPA inhibited these increases in MRL/lpr mice. Pretreatment with ki16425 reversed LPA-mediated inhibition of microglial activation. The quantity of sodium fluorescein that leaked into the brain tissues in MRL/lpr mice were significantly higher than that in MRL/+ mice. Treatment with LPA tended to decrease the sodium fluorescein leakage. These findings suggest that treatment with LPA may regulate microglial activation, which is important in the pathogenesis of NPSLE, as well as blood-brain-barrier weakening and abnormal behaviour.

Neuropsychiatric Systemic Lupus Erythematosus: A Remaining Challenge.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease, which affects a wide range of organs with variable clinical features. Involvement of the nervous system is a challenging and multifaceted manifestation of the disease, presenting with a broad range of symptoms. Neuropsychiatric lupus (NPSLE) encompasses seven syndromes of the peripheral and 12 of the central nervous system, associated with a high disease burden. Despite advances in the management of SLE, NP manifestations still pose a challenge to clinicians. First, diagnosis and attribution of SLE are difficult due to the lack of specific biomarkers or imaging modalities. Second, therapeutic options are limited, and evidence is mainly based on case reports and expert consensus, as clinical trials are sparse. Moreover, no validated outcome measure on disease activity exists. Current recommendations for treatment include supportive as well as immunosuppressive medication, depending on the type and severity of manifestations. As NPSLE manifestations are increasingly recognized, a broader spectrum of therapeutic options can be expected.

Neuropsychiatric Systemic Lupus Erythematosus with Cerebral Vasculitis and Lupus Nephritis Successfully Treated with High-dose Glucocorticoids and Mycophenolate Mofetil.

Neuropsychiatric systemic lupus erythematosus (NPSLE) with cerebral vasculitis is rare, and its prognosis is unfavorable. High-dose glucocorticoids and cyclophosphamide are widely used for the treatment of NPSLE, but cyclophosphamide has a risk of cervical intraepithelial neoplasia and ovarian insufficiency, which may discourage its use in young women. We experienced a case of NPSLE with cerebral vasculitis and lupus nephritis that responded successfully to glucocorticoids and mycophenolate mofetil (MMF). MMF might be a treatment option for NPSLE without concern for reproductive toxicity. However, there are only a few reports on the efficacy of MMF in NPSLE, and further investigations are needed.

Primary central nervous system lymphoma in a patient with neuropsychiatric systemic lupus erythematosus receiving mycophenolate mofetil: A case report and literature review.

A 41-year-old woman with a 14-month history of systemic lupus erythematosus (SLE) presented with headache, aphasia, and agraphia. A laboratory examination revealed mild proteinuria, hypocomplementemia, and elevated anti-double-stranded DNA antibody levels. A cerebrospinal fluid analysis demonstrated elevated protein and interleukin-6 levels. Magnetic resonance imaging (MRI) of the brain identified multiple lesions suggestive of brain edemas and small haemorrhages. She was diagnosed as having neuropsychiatric lupus and lupus nephritis and received remission induction therapy with high-dose corticosteroid and intravenous cyclophosphamide. She achieved a complete remission, and treatment with mycophenolate mofetil (MMF) was initiated 3 months thereafter for remission maintenance. At 13 months after the exacerbation of SLE, she complained of headache and nausea. A gadolinium-enhanced MRI of the brain revealed a low-signal-intensity tumour with marginal ring enhancement of 50 mm in the left frontal lobe. The tumour was excised, and the histological diagnosis was diffuse large B-cell lymphoma with positive Epstein-Barr virus (EBV). MMF was discontinued. Remission induction therapy with rituximab, high-dose methotrexate, procarbazine, and vincristine was administered, and she achieved remission. Previous reports suggest that use of MMF is associated with primary central nervous system (CNS) lymphoma (PCNSL) in patients with lupus nephritis or other autoimmune diseases or in post-transplant patients. Our observation that PCNSL occurred after CNS involvement of SLE suggests that EBV and CNS inflammation arising from SLE might have contributed to the development of PCNSL.

Neuropsychiatric Systemic Lupus Erythematosus in Older Adults: Diagnosis and Management.

Systemic lupus erythematosus (SLE) is a multisystem chronic autoimmune disease with variable clinical manifestations. Neuropsychiatric systemic lupus erythematosus (NPSLE) includes the neurologic syndromes of the central, peripheral and autonomic nervous system and the psychiatric syndromes observed in patients with SLE. Neuropsychiatric systemic lupus erythematosus events may present as an initial manifestation of SLE or may be diagnosed later in the course of the disease. Older adults with NPLSE include those who are ageing with known SLE and those with late-onset SLE. The diagnosis of NPSLE across the lifespan continues to be hampered by the lack of sensitive and specific laboratory and imaging biomarkers. In this review, we discuss the particular complexity of NPSLE diagnosis and management in older adults. We first discuss the epidemiology of late-onset NPSLE, then review principles of diagnosis of NPSLE, highlighting issues that are pertinent to older adults and that make diagnosis and attribution more challenging, such as atypical disease presentation, higher medical comorbidity, and differences in neuroimaging and autoantibody investigations. We also discuss clinical issues that are of particular relevance to older adults that have a high degree of overlap with SLE, including drug-induced lupus, cerebrovascular disease and neurocognitive disorders. Finally, we review the management of NPSLE, mainly moderate to high- dose glucocorticoids and immunosuppressants, again highlighting considerations for older adults, such as increased medication (especially glucocorticoids) adverse effects, ageing-related pharmacokinetic changes that can affect SLE medication management, medication dosing and attention to medical comorbidities affecting brain health.

Spastic paraplegia as the only manifestation in neuropsychiatric lupus: a case report.

Demyelination syndrome is one manifestation of neuropsychiatric lupus erythematosus (NPLE) and is rare in systemic lupus erythematosus (SLE). When SLE presents only neuropsychiatric symptoms without damage to other systems, its diagnosis becomes difficult. Herein, we report a 29-year-old male who suffered from lower limb stiffness with recessive onset and progressive aggravation in one year. He had paraplegia, spastic hypertonia, abnormal gait, and bilateral positive Babinski signs. His symptoms indicated spastic paraplegia. Brain MRI showed multiple small demyelinating lesions in the lateral ventricle, brainstem, and cerebellum. Anti-ds DNA, anti-Sm and anti-RNP antibodies were positive. He was diagnosed with NPLE and had a good treatment response to steroids. To the best of our knowledge, this is the first case of spastic paraplegia as the only manifestation in SLE.

CXCL13 Neutralization Attenuates Neuropsychiatric Manifestations in Lupus-Prone Mice.

Neuropsychiatric lupus (NPSLE), the nervous system presentation of systemic lupus erythematosus (SLE), remains challenging to treat due to its unclear pathogenesis and lack of available targeted therapies. A potential contributor to disease progression is brain tertiary lymphoid structures (TLS); these ectopic lymphoid follicles that can develop tissue-targeted antibodies have recently been described in the MRL/lpr lupus mouse strain, a classic model for studying NPSLE. The brains of MRL/lpr mice show a significant increase of CXCL13, an important chemokine in lymphoid follicle formation and retention that may also play a role in the disease progression of NPSLE. The aim of the present study was to inhibit CXCL13 and examine the effect of this intervention on lymphoid formation and the development of neurobehavioral manifestations in lupus mice. Female MRL/lpr mice were injected with an anti-CXCL13 antibody, an IgG1 isotype-matched antibody, or PBS either three times a week for 12 weeks intraperitoneally (IP) starting at 6-8 weeks of age, or continuously intracerebroventricularly (ICV) with an osmotic pump over a two-week period starting at 15 weeks of age. Cognitive dysfunction and depression-like behavior were assessed at the end of treatment. When treatment was delivered IP, anti-CXCL13 treated mice showed significant improvement in cognitive function when compared to control treated mice. Depression-like behavior was attenuated as well. Furthermore, mice that received anti-CXCL13 by the ICV route showed similar beneficial effects. However, the extent of lymphocyte infiltration into the brain and the general composition of the aggregates were not substantively changed by anti-CXCL13 irrespective of the mode of administration. Nevertheless, analysis of brain gene expression in anti-CXCL13 treated mice showed significant differences in key immunological and neuro-inflammatory pathways that most likely explained the improvement in the behavioral phenotype. Our results indicate that CXCL13 affects the behavioral manifestations in the MRL/lpr strain and is important to the pathogenesis of murine NPSLE, suggesting it as a potential therapeutic target.

Neuropsychiatric lupus with posterior reversible encephalopathy syndrome: a rare presentation.

Systemic lupus erythematosus presenting with neuropsychiatric symptoms (NPSLE) along with posterior reversible encephalopathy syndrome (PRES) is rare. A young woman of 29 years presented with various neuropsychiatric symptoms along with low-grade fever, occasional headache, skin rash, arthralgias and gradually became non-ambulatory over last 6 months. After admission, she had an episode of generalised tonic-clonic seizure, followed by drowsiness. She was normotensive. Investigations revealed no evidence of any underlying infection, normal renal functions and electrolytes; but other parameters were supportive to a diagnosis of NPSLE. MRI brain showed vasogenic oedema characterised by symmetrical hyperintensities over posterior brain regions in T2 and fluid attenuated inversion recovery images with no restricted diffusion in diffusion weighted image suggestive of PRES. A diagnosis of NPSLE presenting with PRES, particularly in the absence of hypertension and abnormal renal functions was made, which is a rare presentation. She responded well to immunomodulatory therapy with methylprednisolone and monthly cyclophosphamide.

Cerebellar ataxia as a primary manifestation of neuropsychiatric systemic lupus erythematosus.

Acute cerebellar ataxia is a rare primary manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE). We report a case of a 22-year-old woman who presented with gait instability, behavioural changes and new-onset seizures. The tempo of disease progression was explained by an autoimmune cause, eventually fulfilling the criteria for systemic lupus erythematosus. The patient's neurological symptoms improved markedly following administration of steroids and immunomodulators. A review of literature on cerebellar ataxia in NPSLE and a summary of all reported cases to date are also presented.