OBJECTIVE: Late-onset SLE is usually milder and associated with lower frequency of LN and neuropsychiatric manifestations. The diagnosis of NPSLE is especially challenging in older patients because of increased incidence of neurological comorbidities. We performed a systematic review and meta-analysis to evaluate the differences in NPSLE manifestations in early-onset (<50-year-old) vs late-onset (≥50-year-old) SLE patients.
METHODS: A literature search was performed using the PubMed, Web of Science and Cochrane Library databases. Studies available in English (1959-2022) including a late-onset SLE comparison group and evaluating the frequency of NPSLE were eligible. A forest plot was used to compare odds ratios (95% CI) of incidence and manifestations of NPSLE by age groups. Study heterogeneity was assessed using I2 statistics.
RESULTS: A total of 44 studies, including 17 865 early-onset and 2970 late-onset SLE patients, fulfilled our eligibility criteria. CNS involvement was reported in 3326 patients. Cumulative NPSLE frequency was higher in the early-onset group than in the late-onset group (OR: 1.41, 95% CI: 1.24, 1.59, P < 0.0001). In early-onset SLE patients, seizures (OR: 1.68, 95% CI: 1.27, 2.22) and psychosis (OR: 1.72, 95% CI: 1.23, 2.41) were more common than in late-onset SLE patients (P values, 0.0003 and 0.0014, respectively). Peripheral neuropathy was more commonly reported in the late-onset SLE group than in the early-onset SLE group (OR: 0.64, 95% CI: 0.47, 0.86, P = 0.004).
CONCLUSIONS: Our meta-analysis revealed that the frequencies of overall NPSLE, seizures, and psychosis were less common in late-onset SLE patients than in early-onset SLE patients. In contrast, peripheral neuropathy was more common in the late-onset SLE group.

BACKGROUND: Neuropsychiatric manifestations in systemic lupus erythematosus (SLE) occur in about half of the patients; however, movement disorders like Parkinsonism are rare. We describe a case of SLE who presented solely with features of Parkinsonism.
METHODS: 50-year-old female presented with global slowing of movements and slowing of speech since 2 months. On examination, she had mask-like facies with a faint malar rash sparing the nasolabial folds, hard palate ulcer, cog-wheel rigidity, and proximal muscle weakness. Lab evaluation revealed lymphopenia, high ESR, elevated lactate dehydrogenase, creatinine phosphokinase, AST, and ALT levels. She had high anti-dsDNA levels with low complements. Urinalysis showed proteinuria and hematuria. ANA was positive at a titer of 1:320, and she had positive anti-ribosomal-P antibody. She had severe flare with a SLEDAI of 33. She was treated with pulse IV methylprednisolone followed by cyclophosphamide (NIH protocol). At 4 weeks follow-up, she had dramatic improvement in her Parkinsonian symptoms and her proximal muscle weakness.
CONCLUSIONS: The prevalence of movement disorders in cases of neuropsychiatric SLE is very low at 0.7%, with chorea being most frequent and Parkinsonism rare. The pathogenesis is multifactorial including anti-dopaminergic antibodies or associated anti-phospholipids causing microvascular thrombosis or vasculitis of the thalamostriatal arteries or disease activity itself. As in our case, immunosuppression and optimal treatment of active lupus reverts symptoms in most cases.
CONCLUSIONS: A high index of suspicion needs to be exercised in cases of SLE presenting with Parkinsonism as adequate immunosuppression translates to near-complete recovery.

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.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that typically affects multiple organs and can lead to potentially fatal complications. Central nervous system (CNS) involvement in SLE is common, especially in children, and can present nonspecifically with various neuropsychiatric manifestations, described as neuropsychiatric SLE (NPSLE). Chronic headache is a common feature of NPSLE, secondary to increased intracranial pressure (also called pseudotumor cerebri (PTC)) due to inflammation or medication. Here, we highlight the importance of evaluating refractory headache (HA) in SLE patients to rule out PTC as a cause of severe morbidity.
METHODS: Single tertiary care pediatric center case series of 8 children who developed NPSLE in the form of intracranial hypertension at or after SLE diagnosis.
CONCLUSIONS: Neurologic and ophthalmologic evaluation of refractory HA in patients with SLE, especially children, is warranted to decrease the burden of the disease and rule out treatable causes like PTC.

Previous studies suggested that patients with Systematic Lupus Erythematosus (SLE) have a higher risk of suicidal behavior, including suicidal ideation, attempt and complete suicide. Systematic data describing the SLE patients\' clinical characteristics and risk factors of suicidal behavior are lacking.
To determine the magnitude of suicidal behavior among SLE patients and to examine predictors associated with suicidal behavior. An additional aim was to identify common genes or coinherited single nucleotide polymorphisms (SNP) implicated in suicidal behavior and SLE.
We conducted a systematic literature review based on PRISMA guidelines using the online databases PubMed/Medline, EMBASE and Web of Science, from inception to August 2021. Full-text original articles that examined the relationship between SLE patients with suicidal behavior were eligible for our review. Two reviewers independently reviewed articles to assess eligibility using the Newcastle-Ottawa Scale and the Joanna Briggs Institute criteria. Systematic reviews, metanalysis, narrative review, case reports, case series, including less than 10 patients, and conference abstracts, were excluded. All registered genome-wide association study (GWAS) data in the GWAS catalog database for SLE and psychiatric traits (suicidal behavior, depression, anxiety, psychosis) were downloaded for further analysis. Special in silico tools were used to examine if any genetic polymorphisms (SNPs) that predispose for SLE or psychiatric traits can be inherited together as a single haplotype. This could be posing a risk factor for a coexisting psychiatric condition in SLE patients.
Of the 64 articles identified, 22 were relevant to the study question; cross-sectional (n = 8) and prospective cohorts (n = 6) were the most frequently retrieved studies. Among the 27,106 SLE patients with SLE, 802 had suicidal behavior (2.9%), and of those, 87.9% were female. Suicide attempt occurred in 573/802 (71.4%) and complete suicide in 18/802 (3%). Major depressive disorder was the most frequently reported coexisting psychiatric condition associated with suicidal behavior, followed by psychosis and social phobia. In addition, several clinical manifestations were linked to suicidal behavior, particularly neuropsychiatric lupus, serositis, mucocutaneous, and renal involvement. Further, high scores in disease activity and damage indices were associated with suicidal behavior. A haplotype in chromosomal region 6p21.33 was found to contain a combination of risk alleles predisposing for SLE and depression, the most common psychiatric disorder associated with suicidal behavior.
Suicide behavior in SLE patients was associated with depression, neuropsychiatric lupus, active disease and damage. Further evidence supports a genetic origin of psychiatric symptoms in SLE patients. Awareness of these findings can guide clinicians to recognize suicide behavior promptly and prevent suicide attempts.

The neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) is a challenge for clinicians, both at a diagnostic and therapeutic level. Although in 1999 the American College of Rheumatology (ACR) proposed a set of definitions for 19 NPSLE syndromes, with the intention of homogenizing the terminology for research purposes and clinical practice, the prevalence of NPSLE varies widely according to different series and is estimated to be between 37 and 95%. This is due to multiple factors such as the unalike definitions used, the diverse design of the studies, type of population, race, type and severity of symptoms, and follow-up of the different cohorts of patients with SLE. In recent years, some authors have tried excluding minor neuropsychiatric manifestations in order to try to reduce this wide variation in the prevalence of NPSLE since they are very prevalent in the general population; others authors have developed various models for the attribution of neuropsychiatric events to SLE that can assist clinicians in this diagnostic process, and finally, some authors developed and validated in 2014 a new algorithm based on the definitions of the ACR that includes the evaluation of the patient\'s lupus activity together with imaging techniques and the analysis of cerebrospinal fluid (CSF), with the aim of trying to differentiate the true neuropsychiatric manifestations attributable to SLE. In 2010, the European League Against Rheumatism (EULAR) developed recommendations for the management of NPSLE. We found abundant literature published later where, in addition to the recommendations for the management of the 19 NPSLE syndromes defined by the ACR, additional recommendations are given for other neurological and/or psychiatric syndromes, conditions, and complications that have been associated to SLE in recent years. We review below the diagnostic and therapeutic management of the different entities.

The neurological and psychiatric manifestations of systemic lupus erythematosus (NPSLE) are a heterogeneous group of conditions with variable clinical presentation and significant morbidity and mortality.
Our aim was to comprehensively assess and present the evidence for treatments used in the management of inflammatory NPSLE.
Medline, Embase, CINHAL and Cochrane CENTRAL were searched from 1990 to end of March 2019 using key words that related to NPSLE and treatment. Included studies comprised clinical trials, observational studies or case series with ≥5 patients and sufficient data related to treatment and outcome in NPSLE patients.
There were 7222 studies identified in the search, of which 90 were included in the review. There was a notable paucity of clinical trials, with only two randomised controlled trials and one pilot study. Treatment categories included corticosteroids (14 studies), cyclophosphamide (18 studies), synthetic DMARDs (7 studies), biologic therapies (14 studies), therapeutic plasma exchange (6 studies), intravenous immunoglobulin (2 studies), autologous stem cell transplant (3 studies), other therapies (8 studies), combination therapies (6 studies), studies with grouped outcome data (5 studies) and observational studies with therapy-specific associations (7 studies). Corticosteroids are accepted as first line treatment in NPSLE and there is low-moderate evidence supporting their benefit. Moderate evidence, based on consistent data in numerous studies and some trial data, supports the use of cyclophosphamide in the treatment of NPSLE. Limited data support some synthetic DMARDs such as mycophenolate, azathioprine and intrathecal methotrexate. In refractory disease, low-moderate evidence supports rituximab therapy and limited evidence supports benefit following autologous stem cell transplant. Regarding adjuvant treatments, limited evidence favours addition of plasma exchange, intravenous immunoglobulin and hydroxychloroquine. There exists very limited data for other therapies.
There are multiple therapeutic options for the management of inflammatory NPSLE including systemic, biologic and interventional therapies; however, currently there is a paucity of high-quality trial data to guide firm recommendations. In order to better understand the optimal treatment of NPSLE and its different subtypes, further well-designed clinical trials are needed.

A 62-year-old female patient with systemic lupus erythematosus (SLE) was admitted for cerebral infarction. The magnetic resonance angiography showed focal narrowing of the cerebral arteries that was initially considered as atherosclerosis due to her cardiovascular risk factors. Ten weeks later, she was again admitted for multiple cerebral infarctions. Vessel wall magnetic resonance imaging revealed gadolinium enhancement of the arterial walls of the narrowing lesions, leading to a diagnosis of cerebral arteritis. Based on a literature review, cerebral medium-sized arteritis in SLE likely progresses insidiously during the active phase of SLE, which may later result in occlusion irrespective of disease activity.

This study aimed to systematically review neuropsychiatric lupus erythematosus (NPSLE) and establish a simplified diagnostic criterion for NPSLE. Publications from 1994 to 2018 in the database (Wanfang data (http://www.wanfangdata.com.cn/index.html) and China National Knowledge Internet (http://www.cnki.net)) were included. In total, 284 original case reports and 24 unpublished cases were collected, and clinical parameters were analyzed. An attempt was made to develop a set of simplified diagnostic criteria for NPSLE based on cases described in the survey and literature; moreover, and pathophysiology and management guidelines were studied. The incidence rate of NPSLE was estimated to be 12.4% of SLE patients in China. A total of 408 NPSLE patients had 652 NP events, of which 91.2% affected the central nervous system and 8.8% affected the peripheral nervous system. Five signs (manifestations, disease activity, antibodies, thrombosis, and skin lesions) showed that negative and positive predictive values were more than 70%, included in the diagnostic criteria. The specificity, accuracy, and positive predictive value (PPV) of the revised diagnostic criteria were significantly higher than those of the American College of Rheumatology (ACR) criteria (χ2=13.642, 15.591, 65.010, p<0.001). The area under the curve (AUC) for revised diagnostic criteria was 0.962 (standard error=0.015, 95% confidence intervals [CI] =0.933-0.990), while the AUC for the ACR criteria was 0.900 (standard error=0.024, 95% CI=0.853-0.946). The AUC for the revised diagnostic criteria was different from that for the ACR criteria (Z=2.19, p<0.05). Understanding the pathophysiologic mechanisms leading to NPSLE is essential for the evaluation and design of effective interventions. The set of diagnostic criteria proposed here represents a simplified, reliable, and cost-effective approach used to diagnose NPSLE. The revised diagnostic criteria may improve the accuracy rate for diagnosing NPSLE compared to the ACR criteria.

Primary central nervous system lymphoma (PCNSL) sometimes occurs in immune-compromised hosts or patients with autoimmune diseases. Some cohort studies have previously reported an increased risk of non-Hodgkin\'s lymphoma in systemic lupus erythematosus (SLE), while some cases of PCNSL in patients with SLE were reported. We present the case of PCNSL which developed in a patient with the active phase of neuropsychiatric SLE (NPSLE). Furthermore, we reviewed published English articles to confirm the characteristics of PCNSL related to SLE. To our knowledge, this is the first report of PCNSL occurring in NPSLE. Histology demonstrated B-cell lymphoma with a positive Epstein-Barr virus-encoded RNA. This patient recovered following surgical resection of the lymphoma, whole brain radiation therapy, intravenous infusion of rituximab (RTX), and administration of belimumab after RTX. Given the series of reviews, our report suggests that the persistence of damage in the central nervous system (CNS) and long-term exposure to immunosuppressants may impact oncogenic immune responses within the CNS, leading to PCNSL development.