NEUROPSYCHIATRIC MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS (NPSLE) AND SLE-RELATED PSYCHOSIS: EPIDEMIOLOGY, PATHOGENESIS, TREATMENTS
Authors: Cheng *Kuoheng , Hsu Wenyu 
Published: February 2025

Abstract

Background
A 38 year-old female diagnosed with SLE at 16 years old. After 3 weeks of flaring up, she had seizures,intracranial hemorrhage (ICH) and partial amnesia afterwards. Ten Years later, she had recurrent seizure episodes and persecutory delusion. Brain MRI showed middle cerebral artery occlusion and brain atrophy, which suggests old insult. Since then she started to be socially withdrawn and sometimes was admitted due to SLE nephritis with leg edema, persecutory and grandiose delusions and auditory hallucinations despite SLE under control for years.

Aims & Objectives
NPSLE occurs in early stages of SLE and 39%-50% of SLE patients have cognitive deficit (6.6-80%), mood disorders (7.4%-65%), psychosis (0.6-11%), seizures (7-20 %), and cerebrovascular events (8-15%). We want to investigate relationships among seizure, ICH, brain atrophy, and psychosis.

Method
We searched PubMed for SLE-related psychosis from January, 2018 to October, 2023 with the following keywords: NPSLE, SLE AND psychosis, psychiatric symptoms in SLE, brain atrophy AND psychosis, including systematic reviews and meta-analysis. We found 266, 66, 181, and 62 results respectively. We selected a literature review: Neuropsychiatric Systemic Lupus Erythematosus: A 2021 Update on Diagnosis, Management, and Current Challenges, and searched common neuropsychiatric symptoms and their pathogenesis or medication-related causes that were mentioned and from reviews in results above.

Results
Two mechanisms have been proposed contributing to NPSLE: (1) Inflammatory mediators or autoantibodies causing brain edema, or diffuse endothelial injury, and ultimately disrupted blood-brain barrier (BBB). (2) ischemic pathway such as atherosclerosis, immune complex deposition-caused vascular injury leading to cerebral microangiopathy, vascular occlusion, and hemorrhage. Anti-NR2 antibodies induce neuronal cell death and pass through disrupted BBB, which result in motor dysfunction in visuospatial processing. Anti-GAPDH antibodies block synaptic molecules and cause cognitive dysfunction. Brain structural changes could be associated with seizures, such as scarring associated with chronic damage from thrombosis. Significantly lower volume in hippocampus, corpus callosum, and gray or white matter was seen in patients with SLE and maybe psychosis-related. As treatments, antidepressants and anxiolytics can improve cognitive functions and treat psychosis. Antimalarials can prevent seizure and thrombosis, which statins, antiplatelets, and anticoagulants also prevent from. Corticosteroid, Cyclophosphamide, and Azathioprine are effective for SLE-related psychosis. Rituximab may be used in treatment-resistant schizophrenia.

Discussion & Conclusion
We found seizures and antiepileptics, corticosteroid, and antimalarials may cause psychosis. Psychosis due to antimalarials are dose-independent. Psychosis due to corticosteroid can be resolved after 2 weeks of dosage reduction. Antidepressants and antipsychotics are associated with bleeding, therefore, should be used with caution with antiplatelet therapy. Diuretics, such as Thiazide, for lupus nephritis may cause psychosis due to hyponatremia and hypercalcemia. Furosemides may cause Thiamine deficiency. However, Spironolactone can be adjunctive therapy of risperidone to improve symptoms of schizophrenia. To sum up, SLE-related psychosis might be due to disease itself or medications that require precautions.

References
1.Sobia Sarwar, Alaa S. Mohamed, Sylvette Rogers, et.al. (2021). Neuropsychiatric Systemic Lupus Erythematosus:A 2021 Update on Diagnosis, Management, and Current Challenges,Cureus 13(9): p.e17969. DOI 10.7759/cureus.17969
2.Seoyoung Yoon, Dae Hun Kang, Tae Young Choi. (2019). Psychiatric Symptoms in Systemic Lupus Erythematosus: Diagnosis and Treatment. Journal of Rheumatic Diseases 26(2), DOI 10.4078/jrd.2019.26.2.93
3.M. B. Humble, D. Eklund, D. Fresnais, et al. ( 2023). Rituximab for treatment-resistant schizophrenia and/or obsessive-compulsive disorder (OCD): functional connectivity and cytokines associated with symptomatic improvements. European Psychiatry, 66 (S1): Abstracts of the 31st European Congress of Psychiatry,pp.S629, DOI:10.1192/j.eurpsy.2023.1309
4.Fernanda Talarico, Sucheta Chakravarty, Yang S. Liu, Andrew Greenshaw, Ives Cavalcante Passos & Bo Cao. (2023). Psychiatric side effects induced by chloroquine and hydroxychloroquine: a systematic review of case reports and population studies. Annals of Pharmacotherapy, 57(4):463- 479.DOI:10.1177/10600280221113572.
5.Yuhong Liu, Zhihua Tu, Xi Zhang, Keqian Du, Zhengquan Xie, Zhiming Lin.(2022). Pathogenesis and treatment of neuropsychiatric systemic lupus erythematosus: A review. Frontiers in Cell and Developmental Biology, 10:998328.DOI:10.3389/fcell.2022.998328
6.Nozomi Akanuma, Naoto Adachi, Peter Fenwick, et al. (2020). Individual vulnerabilities to psychosis after antiepileptic drug administration. BMJ Neurology Open, 2:e000036. DOI:10.1136/bmjno-2019- 000036
7.Jennifer G. Cox, Marius de Groot, James H. Cole, Steven C.R. Williams, Matthew J. Kempton. (2023). A meta-analysis of structural MRI studies of the brain in systemic lupus erythematosus (SLE). Clinical Rheumatology, 42:319–326. DOI: 10.1007/s10067-022-06482-8
8.Di Kang, Chi Chiu Mok. (2019). Management of Psychosis in Neuropsychiatric Lupus. Journal of Clinical Rheumatology and Immunology, 19(1):9–17, DOI: 10.1142/S2661341719300015
9.Adrian Rodriguez-Hernandez, Javier Ortiz-Orendain, Lucia E. Alvarez-Palazuelos, Laura Gonzalez- Lopez, Jorge Ivan Gamez-Nava, Maria G. Zavala-Cerna.(2021). Seizures in systemic lupus erythematosus: A scoping review. Seizure: European Journal of Epilepsy, 86:161–167, DOI:10.1016/j.seizure.2021.02.02.1 10.10.B.M.Verdel, P.C. Souverein, S.D. Meenks, E.R. Heerdink, H.G.M. Leufkens, T.C.G Egberts. (2011). Use of Serotonergic Drugs and the Risk of Bleeding. Clinical Pharmacology & Therapeutics, 89(1):89–96. DOI: 10.1038/clpt.2010.240
11.Jeff C. Huffman, MD; Theodore A. Stern, MD. (2007). Neuropsychiatric consequences of cardiovascular medications. Dialogues in Clinical Neuroscience, 9(1):29-45. DOI: 10.31887/DCNS.2007.9.1/jchuffman
12.Atefeh Zandifar, Rahim Badrfam, Hossein Sanjari Moghaddam, Shahin Akhondzadeh. (2022).Efficacy of Spironolactone as an Adjunctive Therapy to Risperidone to Improve Symptoms of Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled, Clinical Trial,Iranian Journal of psychiatry,17(1):14-23.DOI: 10.18502/ijps.v17i1.8045