Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder characterized by multiorgan involvement, the vast majority of whom are females of childbearing age (1). It presents clinically heterogeneous, usually involving in renal, dermatological, neuropsychiatric, musculo-skeletal and cardiovascular symptoms (1). Approximately 50 to 80% of patients have neuropsychiatric involvement in SLE (NPSLE) (2). NPSLE has been associated with an increase in the mortality rate and a lower quality of life (3, 4). Neuropsychiatric involvement occurs in the early stage of SLE and presents a variety of symptoms (4, 5). These include psychiatric manifestations (mood disorders, cognitive impairment, and psychosis), stroke, seizures, myelopathy, chorea, and headaches (5). While neuropsychiatric events as initial symptoms in SLE patients are rare (4). Moreover, neuropsychiatric manifestations were classified into focal and diffuse neuropsychological syndromes (6). In the diffuse neuropsychological syndromes, isolated diffuse leukoencephalopathy with acute confusional state or cognitive dysfunction in lupus has rarely been reported and presents benign or malignant outcomes (7). Given the heterogeneity of the clinical manifestations, it is extremely difficult to recognize and treat early.

Here, our case report illustrates neuropsychiatric symptoms as an initial and only manifestation of SLE, with bilateral, symmetric, and diffuse leukoencephalopathy with lasting hyperintense diffusion-weighted images (DWI). We reviewed the literature on the clinical characteristics of and treatment responses for this condition. These characteristics are rare and make diagnosis challenging. Such a presentation represents a severe variant of NPSLE requiring aggressive immunosuppressive therapies.

This case report describes a male patient with a diagnosis of SLE with the initial and only onset of diffuse leukoencephalopathy on imaging, characterized symptomatically only by the rapid progression of cognitive dysfunction. He had a gradual, but incomplete, recovery with a stronger immunosuppression treatment. To the best of our knowledge, no case reports have been made associating these entities.

SLE affects women more frequently than men, with the preponderance of occurrence around childbearing age (15–44) (19). Similarly, 12 patients with leukoencephalopathy and NPSLE have been reported, largely involving women around a mean age of 34 years (Table 2). NPSLE is more frequent in the juvenile-onset SLE than in adults with SLE (20, 21). Moreover, nearly half of children with SLE will exhibit CNS involvement in the first year after initial diagnosis (20, 21). As shown in Table 2, three cases that were children has been reported with leukoencephalopathy as the first manifestation of juvenile-onset NPSLE. Additionally, men with SLE often have a more rapid progression in the clinical course with severe organ damage, resulting in a poorer prognosis than women (19).

Many patients already had a diagnosis of SLE and/or other systemic symptoms related to their disease prior to CNS involvement (22). In contrast, our patient made a diagnosis of SLE charactered by isolated CNS involvement. Lab testing reveals ANA at a titer of ≥1:80 and then SLE classification requires at least one clinical criterion and ≥10 points according to the 2019 EULAR/ACR criteria for SLE (23). Thus, our case shown ANA at a titer of 1:320, rapid progression of cognitive dysfunction (2 points), positive Coomb's test (4 points), an increase in anti-cardiolipin antibody IgM level (2 points), and low complement (C3 and C4) (4 points). On the above findings, a diagnosis of SLE was highly suspected. However, NPSLE was not specific, and a careful process of exclusion of causes was necessary. In the literature review about leukoencephalopathy, etiologies were warranted to be excluded, involving in metabolism, leukodystrophies and infection. Evidence suggests that SLE is strongly associated with B cell lymphoma (24, 25). In our case, an extensive workup was performed and these results were normal, including autoantibodies and sequencing of CSF, tandem mass spectrometry of blood and urine, exercise testing on serum lactate, cerebral MR spectroscopy, plasma ammonium, thyroid studies, folate, vitamin B12 and leukodystrophy-associated gene panel testing. Ultimately, our case ruled out a CNS infection, metabolism, tumors and genetics etc.

Most SLE patients with cognitive dysfunction have subtle or subclinical disease with a stable, improving or fluctuating course and rarely have a rapid progression to dementia (2). In addition, most SLE-related cognitive dysfunction occurs in the absence of active systemic lupus or major NPSLE events (2). MRI has shown lower hippocampal volumes in SLE patients with cognitive dysfunction than in those without cognitive dysfunction (26). Interestingly, our patient presented dementia with a rapid course as the initial manifestation of active SLE with diffuse leukoencephalopathy, unlike two patients who had gradual cognitive decline and other organs involved, as shown in Table 2. This characteristic is extremely rare and makes early diagnosis difficult.

Common MRI changes in NPSLE patients include small punctate focal lesions in periventricular and subcortical white matter hyperintensity, brain atrophy, and infarcts (27). Indeed, there have been case reports of patients with T2/FLAIR abnormalities with associated leukoencephalopathy, as shown in Table 2. However, we were unable to find an instance of a patient with a lasting DWI abnormality in leukoencephalopathy as the presenting sign of lupus upon initial diagnosis. Furthermore, patients have shown near-complete resolution of FLAIR abnormalities after immunosuppressive treatment. In contrast to these cases, our patient had a unique feature of hyperintense DWI and no reversible lesions at 3 months following a series of immunosuppressive therapies. There was a disappearance of hyperintensity on DWI after 1 year, while the FLAIR abnormalities remained. Hyperintensity on DWI MRI indicates that cytotoxic oedema has occurred and the damage is irreversible. This may be an indicator of severe NPSLE. What is more, inconsistent with most common findings, such as microinfarction and vasculitis in NPSLE (28), the pathology showed hydropic degeneration, gliocyte proliferation in our patient. Based on the relatively severe pathologic injury in brain, we might make an explanation on severe cognitive dysfunction in our patient.

Diagnosis of NPSLE is the lack of specific and sensitive CSF testing (6). As previous studies have shown, some autoantibodies have been suggested as a potential biomarker for diagnosis and therapeutic decision, such as antineuronal, anti-ribosomal P, and ant-NR2 antibodies (6). Autoantibodies may be detected in the CSF as a result of the transfer of peripherally produced autoantibodies across a breached blood brain barrier or increased intrathecal production (2). In addition, these autoantibodies could be synthesized intrathecally, supported by studies reporting that CSF lgG index/oligoclonal bands (OB) are frequently elevated in patients with NPSLE (29). Nevertheless, three NPSLE patients with leukoencephalopathy (Table 2), besides our case, presented negative, and these mechanisms will be warranted to further explore. Idiopathic intracranial hypertension (IIH), defined by an increased intracranial pressure without hydrocephalus or lesions on the MRI and with normal CSF composition, has been reported in a few patients with NPSLE (30). IIH usually indicates a favorable outcome (30). According to Table 2 findings, the increased intracranial pressure was a common manifestation in NPSLE patients with diffuse leukoencephalopathy. Therefore, difference from IIH, this subtype could be considered as vasogenic oedema and requires treatment aggressively to avoid death, especially combined immunotherapy with dehydrant usage, including acetazolamide, mannitol and furosemide.

High dose steroids have been a unifying treatment choice for neuropsychiatric lupus (31). In addition, due to patients' significant autoantibody loads and severe symptoms, rituximab and cyclophosphamide have been used to treat the severity of CNS involvement (32, 33). As Table 2 shows, most patients with acute SLE leukoencephalopathy had a full clinical recovery after alone high-dose steroid therapy. Of course, others had experienced incomplete or no clinical response and combined immunotherapy was warranted, including rituximab and cyclophosphamide. Overall, there have been reports that a large of patients experienced a gradual or marked improvement of clinical symptoms after treatment at period of acute course. In the follow-up visit, oral prednisone was used to maintain therapy and, whether examination or symptom, some patients were under a stable state. But, in the patients with lupus relapse, the aggressive immunosuppressants, such as rituximab, immunoglobulin G, plasmapheresis and even autologous stem cell transplantation, is warranted to avoid death as soon as possible (34). In our patient, given the low response to steroids, various methods were used for treatment, including immunoglobulin G, rituximab, and plasma exchange. Meanwhile, his SLE disease activity index recovered to baseline, and his orientation was improved (Table 1), confirming the response to treatment. At his one-year follow-up visit, his symptoms had improved further without recurrence following low-dose oral prednisone.

NPSLE diagnosis is a challenge for clinicians, both at the diagnostic and therapeutic levels. Isolated leukoencephalopathy with hyperintense DWI on MRI in SLE, an indicator of severe NPSLE, has rarely been reported in the literature. Taken together, as a subtype of NPSLE, it is necessary to recognize severe NPSLE and provide aggressive immunosuppression therapy as soon as possible.

The datasets presented in this article are not readily available because of ethical and privacy restrictions. Requests to access the datasets should be directed to the corresponding author/s.

The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

YF, QX, and XY wrote the paper. TY implemented tissue staining. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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