Consecutive PRES and diffuse alveolar hemorrhage in a patient with active lupus nephritis and antiphospholipid antibodies: a case report and systematic literature review

Abstract

Posterior reversible encephalopathy syndrome (PRES) is an uncommon but potentially life-threatening neurological complication of systemic lupus erythematosus (SLE). Its pathogenesis is multifactorial, especially in patients with active lupus nephritis receiving intensive immunosuppression. We report a 24-year-old woman with active class III/V lupus nephritis, persistent antiphospholipid antibody positivity, and profound hypoalbuminemia who developed severe atypical PRES with extensive multifocal vasogenic edema, despite only mildly elevated blood pressure, followed within 48 hours by fatal diffuse alveolar hemorrhage. A systematic PubMed search identified original case reports and case series of PRES in SLE. To avoid duplication, only studies with extractable individual patient data were included. Sixty-three studies comprising 103 patients were analyzed. PRES predominantly affected young women (93.3%), with a mean age of 27.3 years. Immunosuppressive therapy was a major precipitating factor, with corticosteroids implicated in 45.7% and cyclophosphamide in 14.3% of cases. Renal involvement, high disease activity, and endothelial dysfunction were frequent coexisting features. These findings suggest that cyclophosphamide usually acts as a final trigger on a critically primed endothelium rather than an isolated cause. Profound hypoalbuminemia and nephrotic syndrome may increase vulnerability by destabilizing the blood–brain barrier. Although often reversible, PRES may herald fatal multisystem endothelial failure in high-risk patients, underscoring the need for early recognition and multidisciplinary management.

Introduction

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by multi-organ involvement, heterogeneous clinical phenotypes, and a diverse immunopathological mechanisms [1]]. Neurological manifestations, collectively referred to as neuropsychiatric lupus (NPSLE), represent one of the most severe and challenging complications of the disease. Multiple mechanisms contribute to NPSLE, including vasculopathy, cytokine-mediated inflammation, autoantibody-induced neuronal injury, and ischemic processes [2]. When not promptly recognized and treated, these manifestations are associated with substantial morbidity and mortality [2].

Immunosuppressive therapy remains the cornerstone of management in such cases. Corticosteroids and cyclophosphamide have long formed the backbone of treatment, while biologic agents such as rituximab and belimumab have emerged as important options in selected patients [3]. Among the neurological complications of SLE, posterior reversible encephalopathy syndrome (PRES) has emerged as a distinct yet under-recognized entity [4]. PRES is a clinicoradiological syndrome characterized by acute neurological symptoms -most commonly seizures, visual disturbances, and altered mental status- accompanied by reversible vasogenic edema typically affecting the parieto-occipital regions on magnetic resonance imaging (MRI) [5]. Although PRES occurs in various clinical settings, including hypertensive crises, renal failure, and exposure to cytotoxic drugs, its association with active SLE is increasingly recognized. Although reported in fewer than 1% of SLE patients, PRES carries significant implications because it can closely mimic lupus cerebritis or infectious encephalopathy [6].

Recent multicentric case–control data by Merayo-Chalico et al. [7] identified hypertension, renal dysfunction, high SLE Disease Activity Index (SLEDAI ≥ 6), lymphopenia, and dyslipidemia as independent risk factors for the development of PRES. These findings underscore the central role of endothelial dysfunction and systemic inflammation in its pathogenesis. Immune complex deposition, complement activation, and cytokine-induced vascular permeability may further amplify endothelial injury, overlapping with mechanisms implicated in NPSLE [8]. These shared pathways support the concept that PRES may represent a severe, acute expression within the broader spectrum of lupus-related neurovascular involvement.

Although PRES is often reversible with timely recognition and appropriate management, delayed diagnosis or misclassification as lupus cerebritis may lead to unnecessary escalation of immunosuppressive therapy and increased morbidity. Therefore, a clear understanding of the clinical, radiological, and immunological features of PRES in SLE is crucial for accurate diagnosis and optimal treatment.

In this context, we present a case of lupus-associated PRES and review the current literature, focusing on its clinical characteristics, pathophysiology, risk factors, and therapeutic strategies. Our aim is to contribute to the growing recognition of PRES as a significant neurovascular manifestation of SLE and to highlight the importance of multidisciplinary management involving rheumatology, neurology, and radiology perspectives.

Case report

A 24-year-old woman with a known diagnosis of SLE initially presented at the age of 21 with profound fatigue and pallor. Initial laboratory evaluation revealed severe anemia with a hemoglobin level of 4.1 g/dL (reference range: 12–16 g/dL), marked hypoalbuminemia (1.2 g/dL, reference range: 3.8–5.1 g/dL), and nephrotic-range proteinuria, with a 24-hour urinary protein excretion of 4000 mg/day. Urinalysis demonstrated 3+ proteinuria and microscopic hematuria. Hemolysis parameters supported active intravascular hemolysis, including an elevated lactate dehydrogenase (LDH) level of 788 U/L (reference range: <250) and a markedly reduced haptoglobin level of <0.1 g/L, consistent with warm autoimmune hemolytic anemia.

Immunological evaluation showed elevated antiphospholipid antibodies, with anti-cardiolipin IgG of 19.67 PL-IgG-U/mL (reference range: <12) and markedly elevated anti-cardiolipin IgM levels (120 PL-IgM-U/mL; reference range: <12). Anti-β2 glycoprotein I IgM was strongly positive (>200 RU/mL; reference range: <20). Complement levels were markedly reduced, with C3 at 0.32 g/L (reference range: 0.9–1.8 g/L) and C4 at 0.03 g/L (reference range: 0.1–0.4 g/L). Anti-double-stranded DNA antibody levels were substantially elevated at 616.6 IU/mL (reference range: <100 IU/mL).

Renal biopsy demonstrated diffuse thickening of the glomerular basement membranes with segmental endocapillary hypercellularity in several glomeruli, accompanied by basement membrane spike formation and subepithelial immune complex deposits on light microscopy. No crescents, fibrinoid necrosis, or vasculitic lesions that were identified. Immunofluorescence microscopy revealed granular immune complex deposition along the glomerular basement membranes and in mesangial areas, showing a full-house staining pattern with IgG, IgA, IgM, C3, and C1q, as well as kappa and lambda light chains. These findings were consistent with International Society of Nephrology/Renal Pathology Society (ISN/RPS) class V and Class III (A) lupus nephritis (LN) [9].

At initial presentation at age 21, induction therapy consisted of intravenous pulse methylprednisolone (1 g/day for 3 days) followed by monthly intravenous cyclophosphamide per the NIH protocol (6 pulses of 1 g). Rituximab (1 g on days 0 and 15) was given concomitantly for severe warm autoimmune hemolytic anemia. Maintenance therapy was then initiated with mycophenolate mofetil 2 g/day, hydroxychloroquine 200 mg twice daily, and tapering oral prednisone (1 mg/kg/day). Adherence was suboptimal: the patient reported intermittent self-discontinuation of mycophenolate mofetil, and the duration of these interruptions could not be reliably reconstructed. At 23 years of age, she developed secondary hypogammaglobulinemia attributed to cumulative immunosuppressive therapy and was treated with IV immunoglobulin at a total dose of 0.4 g/kg/month. Later that year, she was hospitalized for worsening proteinuria. A repeat renal biopsy was performed. It was deemed insufficient for pathological assessment however, immunofluorescence microscopy demonstrated a full-house pattern with granular, diffuse global deposition of IgG, IgA, IgM, C3, and strong C1q along the glomerular basement membrane and mesangium, consistent with LN. She received another course of IV pulse methylprednisolone (1 g/day for three days), followed by low-dose Euro-Lupus cyclophosphamide (500 mg). She was discharged on oral prednisone 30 mg/day with a tapering schedule and rituximab maintenance therapy (1 g on days 0 and 15 every six months).

Several months later, the patient was readmitted with progressive generalized edema, persistent hypoalbuminemia, and marked complement consumption. Her SLEDAI index was 20, consistent with a severe disease flare. Abdominal ultrasonography demonstrated bilaterally enlarged kidneys (132 mm on the right and 136 mm on the left) with increased renal parenchymal echogenicity consistent with grade I–II renal parenchymal disease. In addition, modarete ascites was present, with free intraperitoneal fluid detected in multiple compartments and a maximum depth of 58 mm in the right lower quadrant.

At this admission, serum creatinine was 0.7 mg/dL (reference range: 0.6–1.2). Serum albumin was profoundly reduced at 0.93 g/dL (reference range: 3.8–5.1), hemoglobin was 9.3 g/dL (reference range: 12–16), LDH was elevated at 269 U/L (reference range: 125–220), and C-reactive protein was increased at 11.43 mg/L (reference range: <5), indicating ongoing systemic inflammation. Treatment included IV 20% albumin, IV furosemide at doses ranging from 40 to 80 mg/day, and IV methylprednisolone 250 mg administered every other day for three doses, followed by an additional 500 mg dose of IV cyclophosphamide according to Euro-Lupus protocol.

Two days after cyclophosphamide administration, the patient developed acutely altered consciousness, with a Glasgow Coma Scale score of 8/15 (E2, V2, M4), prompting ICU admission. On bedside neurological examination, pupils were equal and reactive to light, with no gaze deviation or ocular asymmetry; motor responses to stimulation were present bilaterally without clear asymmetry or other lateralizing signs; deep tendon reflexes were preserved and symmetric; plantar responses were flexor bilaterally; and no meningeal signs were identified.

No seizure activity was witnessed; given the depth of impairment and the absence of seizure semiology, urgent neuroimaging was prioritized over EEG. Lumbar puncture was deferred in view of the rapidly evolving course, the imaging findings described below, and the rapid clinical reversibility. Blood pressure at deterioration was 130/90 mmHg—mildly elevated relative to baseline rather than overtly hypertensive.

Repeat antiphospholipid serology during this final admission showed anti-cardiolipin IgG 4.82 U/mL, anti-cardiolipin IgM 47.38 U/mL, anti-β2-glycoprotein I IgM 1.89 RU/mL, and negative lupus anticoagulant. Compared with the strongly triple-positive profile at initial presentation (anti-cardiolipin IgG 19.67 U/mL, anti-cardiolipin IgM 120 U/mL, anti-β2-glycoprotein I IgM > 200 RU/mL), anti-cardiolipin IgG and anti-β2-glycoprotein I IgM titers had declined substantially, plausibly reflecting cumulative B-cell-depleting and immunosuppressive therapy, while anti-cardiolipin IgM remained persistently positive at moderately elevated levels. Complement consumption persisted, with C3 and C4 well below reference range. Concurrent infectious work-up (blood cultures, procalcitonin, viral serologies) was negative, arguing against primary CNS infection or sepsis.

Urgent contrast-enhanced cranial MRI with diffusion-weighted sequences demonstrated multifocal lesions in the bilateral cerebellar hemispheres, bilateral occipital lobes, right thalamus, and the region anterior to the right lateral ventricle, with extensive bilateral T2/FLAIR vasogenic edema involving the cingulate gyri, corpus callosum, precuneus, cuneus, temporal lobes, and basal ganglia. Susceptibility-weighted imaging identified a right occipital microhemorrhage. Although the initial report raised acute/subacute infarction, neuroradiological review confirmed that the lesion distribution did not conform to any arterial vascular territory. After joint review with neuroradiology and interventional neuroradiology, the findings were interpreted as a severe atypical variant of PRES (Figs. 1A and 1B). Amlodipine 5 mg/day was initiated. CRRT was initiated for controlled ultrafiltration of refractory volume overload and to permit safe albumin repletion; relief of cerebral vasogenic edema and removal of circulating endothelial-injury mediators were considered possible additional benefits rather than the primary indication.

Fig. 1.

T2-FLAIR images (A–E) demonstrate widespread bilateral signal abnormalities. Diffusion-weighted imaging (DWI) and corresponding ADC maps (F–J) reveal multifocal areas of restricted diffusion. (A) predominant cortical and subcortical hyperintensity in the occipital lobes. (B) bilateral temporal lobe involvement with cortical–subcortical hyperintensity, more extensive on the right. (C) hyperintense signal changes in the bilateral basal ganglia and thalami (black arrows), accompanied by bilateral temporal and occipital lobe involvement, more pronounced on the right (white arrows). (D) sagittal T2-weighted image shows hyperintense signal abnormalities involving the genu and body of the corpus callosum. (E) increased signal intensity in the bilateral cingulate gyri on T2-FLAIR imaging. (F) millimetric diffusion-restricting lesions in the right thalamus and basal ganglia. (G) patchy diffusion restriction in the bilateral cerebellar hemispheres with a tendency to coalesce, not conforming to a specific vascular territory. (H) millimetric diffusion-restricting foci in the corpus callosum (red arrows) and bilateral precuneus regions (white arrows). (I) millimetric diffusion restriction in the right thalamus and basal ganglia. (J) a millimetric diffusion-restricting focus in the left cingulate gyrus

Within approximately six hours of combined blood pressure control and CRRT-mediated volume optimization, the patient regained full neurological function (Glasgow Coma Scale score of 15/15).

On the second day of intensive care unit admission, the patient developed hemoptysis and acute respiratory failure necessitating endotracheal intubation. Contrast-enhanced chest computed tomography demonstrated bilateral ground-glass opacities and consolidations compatible with diffuse alveolar hemorrhage (Fig. 2). She underwent three sessions of therapeutic plasma exchange, with 1–1.5 plasma volumes exchanged and replaced with fresh frozen plasma. Despite maximal supportive care and immunomodulatory therapy, respiratory failure progressed, and the patient ultimately died due to refractory hypoxemia.

Fig. 2.

Contrast-enhanced chest computed tomography findings. (A) diffuse bilateral ground-glass opacities are observed throughout both lungs (white arrows). (B) Complete loss of aeration due to dense consolidation is noted in both lower lobes (black arrows). (C) bilateral pleural effusions are present (yellow arrows)

Laboratory parameters obtained at referral, during hospitalization for the second renal biopsy, and at the final admission are summarized in Table 1.

Table 1.

Laboratory parameters through follow up

Parameter	1st Admission (0 month)	2nd Admission (18th month)	3rd Admission (31st month)	Reference Range
Age (years old)	21	23	24	-
Reason for Admission	Lupus nephritis treatment plan	Progression of proteinuria	Active disease	-
Hgb (g/dL)	4.1	11.4	9.3	12–16
Lymph (×109 /L)	0.4	1.28	0.55	1.3–3.5
Haptoglobin (mg/dL)	<0.1	0.92	N/A	0.3–2
LDH (U/L)	788	362	318	<250
ANA	Positive (1/1280, speckled)	Positive (1/640, homogeneous + speckled)	Positive (1/1280, homogeneous + speckled)	(IFA, 1/100, IgG)
C3 (mg/dL)	0.33	0.44	0.37	0.9–1.8 g/dl
C4 (mg/dL)	0.02	0.05	0.04	0.1–0.4 g/dL
Anti-dsDNA	247	N/A	164.28	<100 IU/mL
Proteinuria (mg/day)	4000	11.388	NA	<140
Serum Creatinine (mg/dL)	0.61	0.44	0.7	0.5–0.9
ESR (mm/h)	77	74	81	0–20
Serum Albumin	1.2	1.53	0.93	3.5–5.2
CRP (mg/L)	25.37	7.21	11.43	<5 mg/L
SLEDAI Score	16	16	20	LLDAS: SLEDAI ≤ 4
Treatment During Admission	IV methylprednisolone, IV cyclophosphamide	IV methylprednisolone, IV cyclophosphamide rituximab	IV methylprednisolone, IV cyclophosphamide	-

Hgb: Hemoglobin; Lymph: Lymphocyte; ANA: Antinuclear antibody; LDH: Lactate Dehydrogenase; C3: Complement component 3; C4: Complement component C4; Anti-dsDNA: Anti-double-stranded DNA; ESR: Erythrocyte Sedimentation Rate; CRP: C-reactive Protein; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; LLDAS: Lupus Low Disease Activity State

Method

We conducted a comprehensive systematic literature search in PubMed, in accordance with the PRISMA guideline, to identify published reports of PRES in patients with SLE. We used the following search terms: “lupus” AND “posterior reversible encephalopathy syndrome”; “lupus erythematosus” AND “posterior leukoencephalopathy syndrome”; and “systemic lupus erythematosus” AND “posterior reversible encephalopathy syndrome.”

The initial search yielded 125 records. We excluded seven non-English publications, 49 articles considered irrelevant based on title and abstract screening, and four articles for which full texts were unavailable. This process left 65 studies for full-text review. We included only original publications that reported extractable individual patient-level data. We excluded reviews, meta-analyses, and studies lacking individual patient data to avoid duplicate case inclusion (n:2).

All 63 included studies were primary reports (case reports or case series) and met the predefined inclusion criteria. The final pooled dataset comprised 103 individual patients derived exclusively from these primary studies. The selection process is summarized in the flow diagram (Fig. 3). Table 2 summarizes the characteristics of the included studies and the pooled patient data.

Fig. 3.

PRISMA 2020 flow diagram of study selection

Table 2.

Summary of PRES cases reported in the literature among SLE patients

References	First author	Origin	Sex / Age at SLE Diagnosis / Age at PRES	Organ Involvement	Case Presentation	Antibody	MRI Findings	Blood Pressure (mmHg)	Treatment for PRES	Outcome
[40]	Yong PFK (2003)	United Kingdom	F / 31 / 39	Renal (Class IV LN with crescents); Diagnosis of systemic sclerosis (history of membranous glomerulonephritis, Raynaud’s phenomenon, pulmonary fibrosis, esophageal dysmotility)	Blindness followed by status epilepticus	N/A	Hyperintensities in left cerebellar white matter and both occipital pole	170/100 at first PRES episode; 150/90 at second episode	BP control	Recovery; alive
[48]	Shin KC (2005)	South Korea	F / N/A / 24	Hematologic (thrombocytopenia); skin (malar rash, photosensitivity); Musculoskeletal (joint pain, proximal muscle weakness); Raynaud’s phenomenon	Developed severe perspiration, headache, and generalized tonic-clonic seizures	ANA: Positive; Anti-dsDNA: Positive; LAC: Positive; Anticardiolipin IgG antibody: Positive	Hyperintensities and edema in frontal, parietal, and parietooccipital lobes	130/80	Antiepileptic Tx Withdrawal of immunosuppressants	Recovery; alive
[55]	Ozyurek H (2005)	Turkey	F / N/A / 13	N/A	Headache, vomiting, generalized seizure;	N/A	Bilateral occipital and posterior parietal lesions	215/100	BP control; Antiepileptic Tx Withdrawal of immunosuppressants	Recovery; alive
[56]	Renard D (2007)	France	F / N/A / 47	N/A	Subacute bilateral blindness and headache	Anti-dsDNA: Positive	Increased white matter signal	189/97	BP control	Recovery; alive
[10]	Zar T (2007)	USA	F / N/A / 20	Renal (Class IV LN); Musculoskeletal (arthralgia); Skin (Rash)	Seizure, blindness	Anti-dsDNA: Positive; C3: Low; C4: Low	New bilateral gray and white matter edematous lesions	190/110	BP control	Recovery; alive
[11]	Ishimori ML (2007)	USA	F / 47 / 47	Renal (LN); Skin (malar rash)	Headache, increase lower extremity edema	ANA: Positive; Anti-dsDNA: Positive	Hyperintensities in bilateral parieto-occipital lobes and cerebellum	200/110	BP control	Recovery; alive
[11]	Ishimori ML (2007)	USA	F / 18 / 20	Pulmonary (pneumonitis); Renal (proteinuria); Serositis (pleural effusion)	Tonic-clonic seizure	ANA: Positive; LAC Positive	Hyperintensities in parieto-occipital, posterior temporal, frontal lobes	132/104	BP control; Antiepileptic Tx	Recovery; alive
[11]	Ishimori ML (2007)	USA	M/N/A / 25	Renal (LN); Skin (Malar Rash)	Generalized weakness, nausea, fatigue, headache, new-onset blindness	ANA: Positive; Anti-dsDNA: Positive	Hyperintensities in bilateral occipital lobes	176/105	BP control	Recovery; alive
[11]	Ishimori ML (2007)	USA	F / 18 / 24	Renal (LN); Musculoskeletal (arthritis); Hematological (thrombocytopenia); Serositis (pleuritis)	Severe headache, visual changes, altered mental status	ANA: Positive; LAC: Positive; Anti-cardiolipin IgG antibody: Positive	Multiple bilateral foci of abnormal signal in frontal-parietal and parietal subcortical white matter	169/108	BP control	Recovery; alive
[12]	Sinha R (2007)	Canada	F / N/A / 16	Renal (LN)	Headache, disorientation, blurred vision, motor apraxia	N/A	Hyperintensities in left parietal and occipital region	160/90	BP control; Antiepileptic Tx	Recovery; alive
[13]	El Karoui K (2007)	France	F / 34 / 47	Renal (Class IV LN); Hematological (anemia, positive Coombs)	High BP, headache, vomiting, photophobia	ANA: Positive; Anti-dsDNA: Positive	Hyperintensities inn parietal and occipital lobes	199/90	BP control	Recovery; alive
[13]	El Karoui K (2007)	France	F / 13 / 17	Renal (First bx: Class IV-V LN; Second bx: Class IV LN); Serositis (pericarditis); Vasculitis (cutaneous)	Tonic-clonic seizure	N/A	Hyperintensities in cerebellar, parietal, occipital lobes and brainstem	172/110	BP control; Antiepileptic Tx	Recovery; alive
[13]	El Karoui K (2007)	France	F / 27 / 28	Renal (Class IV lupus nephritis); Hematological (anemia)	Headache, vomiting, blindness	ANA: Positive; Anti-dsDNA: Positive	Hyperintensities in bilateral occipital cortical and subcortical	190/120	BP control; Antiepileptic Tx	Recovery; alive
[14]	Zhang Y-X (2008)	China	F / 26 / 27	Renal (LN); Hematological (anemia)	Headache, vomiting, severe visual disturbance, high BP	ANA: Positive; Anti-dsDNA: Positive; C3: Low; C4: Positive; Anti-Ro/SS-A antibody: Positive: Anti-ENA: Positive	Hyperintensities in bilateral parietal and occipital cortical lesions	184/114	BP control	Recovery; alive
[15]	Leroux G (2008)	France	F / 19 / 46	Renal (LN), Skin (livedo); Musculoskeletal (polyarthritis); Vascular (vasculitis, face and digital ischemia complicated with cutaneous ulcers)	Hypertension, headaches, seizures, blindness, confusion, loss of consciousness	ANA: positive; Anti-dsDNA: Positive; Anti-SSA: Positive; Anti-SSB: Positive; Complement: Low; IgM kappa cryoglobulinemia: Positive	Hyperintensities in bilateral occipital, left frontal and parietal	190/100	BP control; Antiepileptic Tx Withdrawal of immunosuppressants	Recovery; alive
[15]	Leroux G (2008)	France	F / 14 / 22	Renal (Class IV LN); Skin; Musculoskeletal (polyarthritis)	Seizures, hypertension, visual blurring	ANA: Positive; Anti-dsDNA: Positive; Complement: Low; anti-beta 2-GPI: Positive	Hyperintensities in bilateral cortical, subcortical temporal, occipital, parietal, frontal lobes	180/120	BP control; Antiepileptic Tx	Recovery; alive
[15]	Leroux G (2008)	France	F / 21 / 23	Renal (nephrotic syndrome); Serositis (ascites, pleuritis); Musculoskeletal (polyarthritis); Hematological (hemolytic anemia, lymphopenia)	Hypertension, headaches, vomiting, seizures, blindness	ANA: Positive; Anti-SSA antibody: Positive	Hyperintensities in bilateral occipito-parietal region, hemorrhagic transformation	220/110	BP control; Antiepileptic Tx	Partial recovery (vision); alive
[15]	Leroux G (2008)	France	M / 14 / 40	Skin (cutaneous lupus); Musculoskeletal (polyarthritis); Hematological (thrombocytopenia); AFAS	Hypertension, headaches, blindness, abdominal pain	ANA: Positive; Anti-dsDNA: Positive; Anti-Sm Antibody: Positive	Hyperintensities in bilateral occipito-parieto-frontal	210/120	BP control	Recovery; alive
[49]	Lai TKK (2009)	Hong Kong	F / N/A / 35	Musculoskeletal (polymyositis)	Generalized tonic–clonic convulsions and sudden bilateral blindness	N/A	Bilateral hypodense lesions in occipital lobes (CT)	178/105	BP control; Withdrawal of immunosuppressants	Recovery; alive
[16]	Necioglu DO (2009)	Turkiye	F / 19 / 22	Renal (nephritis); Musculoskeletal (arthritis)	Generalized tonic-clonic seizure	ANA: Positive; Anti-dsDNA: Positive	Multiple focal hypodensities in basal ganglia, parietal and occipital lobes	155/115	BP control; Antiepileptic Tx	Recovery; alive
[17]	Bag AK (2010)	USA	F / 14 / 23	Skin (Rash)	Altered sensorium, diminished verbal response	N/A	Hyperintensities in bilateral thalamic and cerebral peduncle	141/91	Lupus treatment	Recovery; alive
[18]	Chen HA (2010)	Taiwan	F / N/A/N/A	Renal (Class IV LN); Musculoskeletal (polyarthritis); Skin (malar rash); Hematological (anemia)	Hypertension, headache, generalized seizure, confusion, vertigo, slurred speech	ANA: Positive, Anti-dsDNA: Positive; C3: Low; C4: Low	Hyperintensities in multiple areas, involving the bilateral cerebellum, dorsal pons, left midbrain, left thalamus and left high frontal subcortical regions	190/130	BP control	Death due to hemorrhagic complication
[57]	Efthimiou P (2010)	USA	F / N/A / 30	Renal (deterioration of renal function), CNS involvement (neuropsychiatric symptoms)	Generalized weakness, new-onset seizures, deterioration of renal function	N/A	Hypodense lesions in the occipital and parietal lobes bilaterally	NA	Lupus treatment	Recovery; alive
[19]	Ishikura K (2010)	Japan	F / 8 / 8	Renal (Class III lupus nephritis); Musculoskeletal (arthritis); Hematological (pancytopenia)	Headache, vomiting, seizures, and coma	ANA: positive; Hypocomplementemia	Hyperintensities in the right temporo-occipito-parietal regions	156/100	BP control; Supportive care	Recovery; alive
[50]	Golden J (2011)	USA	F / 12 / 13	Musculoskeletal (arthritis); Hematological (leukopenia); Skin (rash)	New-onset seizure	ANA: Positive; Anti-dsDNA: Positive	Curvilinear horseshoe-shaped signal abnormalities in posterior temporal, occipital, parietal lobes, and bilateral supraventricular frontal lobes	147/73	BP control; Antiepileptic Tx Supportive care	Recovery; alive
[20]	Barber EC (2011)	Canada	F / 20 / 22	Renal (Class IV LN);, Pulmonary (alveolar hemorrhage)	Tonic-clonic seizure	Anti-dsDNA: Positive; C3: Low; C4: Normal	Bilateral posterior and frontal lobe white matter hypoattenuation, extensive subcortical white matter involvement, microhemorrhages	175/120–200/120	BP control; Antiepileptic Tx	Recovery; alive
[20]	Barber EC (2011)	Canada	F / 44 / 44	Renal (LN); Skin (Malar Rash)	Nausea, vomiting, and diarrhea	ANA: Positive; C3: Low; C4:Low; Anti-Ro Antibody Positive; Anti-La Antibody: Positive	Hypoattenuation posterior parietal/occipital lobes	230/120	BP control	Recovery; alive
[20]	Barber EC (2011)	Canada	F / 26 / 26	Known history of AFAS; Renal (LN); Hematological (hemolytic anemia)	High BP, tonic-clonic seziure	ANA: Positive; Anti-dsDNA: Positive	Multiple cortical/subcortical lesions, cerebellum involvement	191/107	BP control; Antiepileptic Tx	Recovery; alive
[20]	Barber EC (2011)	Canada	F / 18 / 23	Musculoskeletal (arthritis); Skin (alopecia, malar rash); Hematological (cytopenia)	High BP, clonus, spasticity	ANA: Positive, Anti-dsDNA: Positive; Complements: Low	Bilateral parasagittal parietal/occipital hematomas with vasogenic edema	150–204/90–122	BP control	Recovery; lost to follow up
[20]	Barber EC (2011)	Canada	F / 22 / 34	Musculoskeletal (arthritis); Skin (rash); Neurological (Lupus cerebritis), Renal (LN)	Headache, blurred vision, edema, nausea, vomiting confusion, hypertension	Anti-dsDNA: Positive; C3: Low; C4: Low	hyperintensity in the right parietal lobe, petechial hemorrhage	216/130	BP control	Recovery; alive
[20]	Barber EC (2011)	Canada	F/ 37 / 37	Musculoskeletal (arthralgia); Skin (facial rash); Hematological (hemolytic anemia, cytopenia); GI PPancreatitis Renal (AKI)	Acute blindness	ANA: Weakly positive; Anti-dsDNA: Positive; C3: Low; C4: Low; Anticardiolipin IgM antibody: High	Hyperintensities in bilateral occipital hyperintensities	167/99	BP control	Partial recovery (vision)
[20]	Barber EC (2011)	Canada	F / 31 / 31	Musculoskeletal (arthralgia); Hematological (thrombocytopenia, lymphopenia); Renal (AKI)	High BP	ANA: Positive; Anti-dsDNA: Positive; C3: Low; C4: Low	Bilateral occipital vasogenic edema	179/120–244/151	Lupus treatment	Recovery; alive
[58]	Maeda H (2011)	Japan	F / 27 / 52	Renal (Proteinuria); Hematological (Pancytopenia, hemolytic anemia, TTP)	Consciousness disturbance and convulsion	Anti-dsDNA: Positive; LAK: Positive	Hyperintensities in right parietal and left occipital white matter	N/A	Lupus treatment	Recovery; alive
[59]	Sulaiman W (2011)	Malaysia	F / 33 / 33	Renal (Nephrotic syndrome)	Blurring of vision, associated with headache, nausea and vomiting for a week	N/A	Scattered areas of increased signal intensity seen in the white matter of the left posterior occipitoparietal regions (FLAIR and T2 weighted)	160/110	BP control	Recovery; alive
[21]	Monteiro C (2012)	Portugal	F / 43 / 45	Skin (discoid rash, chilblain lupus); Serositis (pericardial effusion); Hematological (thrombocytopenia, lymphopenia)	Acute aphasia, right homonymous hemianopsia, intense headache	ANA: Positive	Multiple hyperintense lesions in temporal and frontal cortex, head of caudate nucleus, left thalamus, brain stem (T2)	Normal	Lupus treatment	Recovery; alive
[60]	Bhavsar SV (2012)	Canada	F / 23 / 23	Renal involvement (necrotizing vasculitis and focal proliferative glomerulonephritis)	Left hand weakness and numbness, drowsiness	ANA: Positive; Anti-dsDNA: Positive; C4: Low; Anticardiolipin antibodies: Positive; LACPositive; Anti-b2-glycoprotein type 1 antibodies: Positive	Hyperintensities in bilateral parieto-occipital, frontal, and basal ganglia lesions (T2/FLAIR)	200/130	BP control,; Withdrawal of immunosuppressants	Recovery; alive
[61]	Martínez-Martínez MU (2012)	Mexico	F / 23 / 27	Renal (Class IV LN); Pulmonary (DAH / four episodes); GI (Intestinal vasculitis); Hematological (lymphopenia); Musculoskeletal (arthritis)	Seizures	ANA: Positive; Anti-dsDNA: Positive	CT: Diffuse bilateral alveolar infiltrates (lungs)	180/100	BP control; Antiepileptic Tx Supportive care	Recovery; alive
							MRI: Bilateral occipital lobe involvement (PRES)
							Abdominal CT: Target sign (intestinal vasculitis)
[22]	Dhillon A (2012)	USA	F/ NA / 25	Renal (LN)	Sudden loss of vision in both eyes, headaches with high BP	N/A	Bilateral hyperintensity in frontal, parietal-occipital, and left cerebellar regions (T2 FLAIR)	170/103	BP control	Recovery; alive
[22]	Dhillon A (2012)	USA	F / 8 / 27	Renal (LN)	Altered mental status during hospitalization for sepsis	N/A	MRI showing PRES	Elevated diastolic pressure	BP control	Recovery; alive
[62]	Grewal HK (2012)	USA	F / 25 / 25	Renal (non-biopsy proven); Serositis (pericardial effusion, pleural effusion); Hematological (pancytopenia)	Nauseas, vomiting, seizures, AMS, loss of vision	ANA: Positive; Anti-dsDNA; Anti-Sm: Positive; Anti-SSA: Positive	Diffuse abnormal signal in posterior parietal and occipital lobes (T2/FLAIR)	N/A	BP control	Recovery; alive
[23]	Shaharir SS (2013)	Malaysia	F / 14 / 17	Renal (Class III, V LN)	Headache, Status epilepticus (intubated)	N/A	Bilateral occipital lesions	233/120	Lupus treatment	Recovery; alive
[23]	Shaharir SS (2013)	Malaysia	M / 28 / 30	Renal (Class IV, V LN, %20 crescents);	Headache, Status epilepticus	N/A	Bilateral frontal, basal ganglia, thalamus, midbrain, cerebellum lesions, SAH	230/134	Lupus treatment	Recovery; alive
[23]	Shaharir SS (2013)	Malaysia	F / 19 / 25	Renal (Class IV, V LN, %20 crescents); APLS	Headache, generalized tonic-clonic seizure	N/A	Bilateral occipital, parietal lesions	140/100	Lupus treatment	Recovery; alive
[23]	Shaharir SS (2013)	Malaysia	F / 15 / 22	Lupus nephritis (Class III/V or IV/V, 20% crescents)	Headache, generalized tonic-clonic seizure	N/A	Bilateral occipital, frontal lesions	140/50	Lupus treatment	Recovery; alive
[23]	Shaharir SS (2013)	Malaysia	F / 23 / 23	Renal (Class III, V LN)	Headache, Status epilepticus	N/A	Bilateral occipital, temporal, parietal lesions	210/120	Lupus treatment	Recovery; alive
[23]	Shaharir SS (2013)	Malaysia	F / 41 / 46	Renal (Class IV LN)	Headache, cortical blindness, right hemiparesis, status epilepticus	N/A	Bilateral occipital, temporal, parietal, frontal lesions	196/111	Lupus treatment	Recovery; alive
[63]	Li Q (2013)	China	M / 28 / 36	Lupus nephritis; Skin (malar rash); Musculoskeletal (arthritis); Hematological (pancytopenia)	Headache and blurred vision	ANA: Positive; C3: Low; C4: Normal; Anti-dsDNA: Positive	Bilateral hyperintensities in the frontal, parietal, temporal, occipital lobes, and cerebellum are consistent with vasogenic edema (FLAIR)	N/A	Lupus treatment	Recovery; alive
[24]	Gatla N (2013)	USA	F / 19 / 19	Kidneys (class IV lupus nephritis); Hematological (anemia); Serosal (pericardial and pleural effusion); Skin (malar rash)	New-onset generalized tonic–clonic seizures, severe headache	ANA: Positive; Anti-dsDNA: Positive; Anti-Sm Antibody: Positive; C3: Low; C4: Low	Vasogenic edema in frontal and parietal-occipital regions	150/100	BP control; Antiepileptic Tx Withdrawal of immunosuppressants	Recovery; alive
[24]	Gatla N (2013)	USA	F / 20 / 26	Renal (Class IV LN); Skin (malar rash); Musculoskeletal (arthritis); Raynaud syndrome	Blurry vision, headache	ANA: Positive; Anti-dsDNA: Positive; C3: Low; C4: Low	Patchy increased T2/FLAIR signal in bilateral occipital lobes, petechial hemorrhages, subtle basal ganglia involvement	170/120	BP control	Recovery; alive
[24]	Gatla N (2013)	USA	F / 13 / 21	Renal (LN); AFAS	Headache	ANA: Positive; Anti-SM antibody: Positive; Anti-dsDNA: Positive	High T2/FLAIR signal in frontal, parietal, occipital, left temporal white matter	156/107	BP control; Antiepileptic Tx Dialysis/CRRT	Recovery; alive
[24]	Gatla N (2013)	USA	F / 19 / 19	Renal (Class IV LN); Pulmonary (DAH); Hematological (anemia)	Headache, fecal incontinence, seizure-like activity	ANA: Positive; Anti-dsDNA: Positive; C3: Low; C4: Low	Hemorrhage in left superior frontoparietal region, cortical/subcortical hyperintensities in frontal, parietal, temporal, occipital lobes, cerebellum, microhemorrhages	200/100	BP control; Antiepileptic Tx Withdrawal of immunosuppressants	Recovery; alive
[24]	Gatla N (2013)	USA	F / 37 / 37	SLE–RA overlap; Serosal (pericardial tamponade); Hematological (hemolytic anemia); Musculoskeletal (joint stiffness in the morning)	Syncopal episode	ANA: Positive; Anti-dsDNA: Positive; Anti-Sm Antibody: Positive	Diffuse vasogenic edema in white matter (supratentorial and infratentorial), new T2/FLAIR hyperintense signals	>220 systolic	BP control; Supportive care	Recovery; alive
[64]	Chan DYS (2013)	Hong Kong	F / NA / 54	Renal (proteinuria); Hematological (hemolytic anemia, thrombocytopenia, leucopenia); Raynaud’s syndrome	Sudden bilateral visual loss, seizures, headache, confusion	Complements Low	Bilateral hypodense lesions in parieto-occipital white matter and right frontal region (CT)	173/100	BP control; Antiepileptic Tx	Recovery; alive
[25]	Chennareddy S (2013)	India	F / 17 / 17	Hematologic (severe pancytopenia, autoimmune hemolytic anemia); skin (malar rash); Mucosal (oral ulcers)	Sudden onset headache, blurred vision, one episode of generalized tonic–clonic seizure	ANA: Positive, Anti-dsDNA: Positive; C3: Low; C4: Low	Hyperintense signal in the left occipital lobe (FLAIR)	110/70	Antiepileptic Tx Supportive care	Recovery; alive
[25]	Chennareddy S (2013)	India	F / 16 / 16	Hematologic (Autoimmune hemolytic anemia); Skin (malar rash); Lymphatic (generalized lymphadenopathy)	Sudden onset headache, blurred vision	ANA: Positive, Anti-dsDNA: Positive; C3: Low; C4: Low	Hyperintense signal in the bilateral occipital areas (FLAIR)	120/70	Supportive care	Recovery; alive
[65]	Sato S (2014)	Japan	F / 10 / 11	Skin (malar rash); Musculoskeletal (arthralgia); Renal (minimal mesangial nephritis)	Fever, headache, arthralgia, tremors, mood disorder	ANA: Positive, Anti-dsDNA: Positive; C3: Low; C4: Low	Increased signal intensity in anterior basal ganglia bilaterally (T2, FLAIR, DWI, ADC)	102/74	Lupus treatment	Recovery; alive
[65]	Sato S (2014)	Japan	F / 13 / 14	Musculoskeletal (polyarthritis); Skin (purpura); Hematologic (MAS); Mucosal (oral ulcers)	Fever, headache, tremors, memory dysfunction	ANA: Positive; Anti-SSA-Ro: Positive	Increased signal intensity in right caudate nuclei and paralateral ventricle	103/70	Lupus treatment	Recovery; alive
[65]	Sato S (2014)	Japan	F / 14 / 15	Renal (Minimal mesangial nephritis); Skin (malar rash); Mucosal (oral ulcers)	Fever, headache, rash	ANA: Positive; Anti-dsDNA: Positive; Anti-Sm Antibody: Positive; Anti-RNP: Positive; Lupus anticoagulant: Positive	Increased signal intensity in the anterior lentiform nuclei on the left side	100/53	Lupus treatment	Recovery; alive
[66]	Ungprasert P (2014)	Thailand	F / 48 / 51	Skin (malar rash, photosensivity); Musculoskeletal (polyarthritis); Renal (Class IV LN- diagnosed after PRES episode)	AMS	ANA: Positive; Anti-Sm antibody: Positive	Ill-defined hypodensity in subcortical white matter of posterior parietal and occipital lobes (CT)	180/90	BP control	Recovery; alive
[26]	Jacquot C (2014)	USA	F / 22 / 57*/ 62**	Renal (LN); Hematological (hemolytic anemia), Musculoskeletal (arthritis, myositis); APLS	*Generalized tonic-clonic seizure **AMS, seizures, respiratory distress	N/A	*First episode Extensive symmetric subcortical white matter T2 hyperintensity in posterior cerebral regions, basal ganglia, thalami, cerebellum, brainstem	*164/97; **NA	Antiepileptic Tx	Recovery; Death 4.5 years later due sepsis
[27]	Jabrane M (2014)	Morocco	F/ 16 / 16	Renal (Class VI lupus nephritis); Hematological (Anemia); Mucocutaneous (Photosensivity)	Sudden onset of headache and blurred vision	ANA: positive; C3: Low C4: Low	Abnormal signal intensity in parietal and occipital regions (T1, T2, FLAIR),	120/70	Supportive care	Recovery; alive
[41]	Jayaweera JL (2014)	Sri Lanka	F / 33 / 33	Renal (Class IV LN); Musculoskeletal (Arthritis)	Generalized tonic-clonic seizure	C3: Low; C4: Low	Symmetrical occipital white matter lesions (FLAIR)	115/70	Antiepileptic Tx Supportive care	Recovery; alive
[28]	Arslan ZI (2015)	Turkiye	F / 32 / 35	Renal (class IV and later class V lupus nephritis)	Hypertensive crisis, seizures, encephalopathy	ANA: positive; C3: Low C4: Low	Bilateral brain T2 hyperintensities, volume growth, widespread white matter involvement (Diffusion)	240/120	BP control; Antiepileptic Tx Supportive care	Recovery; alive
[45]	Mondal S (2015)	India	F/ 14 / 17	Renal (Class IV LN)	Convulsion, visual disturbance, stupor	N/A	Bilateral occipital hyperintensities	130/98	Withdrawal of immunosuppressants; Supportive care	Recovery; alive
[29]	Khajuria B (2016)	Canada	F / 29 / 29	Renal (Class IV LN); Hematological (pancytopenia, hemolytic anemia)	Seizure, bowel incontinence, altered mental status, and tongue biting	ANA: Negative; Anti-dsDNA: Positive	Bilateral posterior hemispheric subcortical edema	below 140/90 mmHg with treatment	BP control; Antiepileptic Tx Withdrawal of immunosuppressants	Recovery; alive
[30]	Ferreira TS (2016)	Brazil	M/N/A / 8	Serosal (serositis); Hematological (leucopenia, thrombocytopenia)	Headache, vomiting, seizures, and coma	AFAS antibodies: Positive	Hyperintensities in the cortex and subcortical regions in parieto-occipital lobes (T2/FLAIR)	110/75	Antiepileptic Tx	Recovery; alive
[30]	Ferreira TS (2016)	Brazil	F / 8 / 21	Hematological (Thrombocytopenia, leucopenia); Musculoskeletal (polyarthritis)	Severe headache, visual disturbances, tonic-clonic seizures	AFAS antibodies: Positive	Hypodensities in cortico-subcortical parieto-occipital regions (CT)	200/130	BP control	Recovery; alive
[30]	Ferreira TS (2016)	Brazil	NA / 35	Renal (Class IV LN); Hematological (anemia)	Headache	ANA: Positive; Anti-ds DNA positive; C3: Low; LAC Positive	Hypodensities in parieto-occipital regions (CT)	160/120	BP control	Recovery; alive
[67]	Nasri A (2016)	Tunisia	F / 12 / 12	Renal (LN), Hematological (anemia)	Headache, generalized hypotonic and tonic seizures; loss of consciousness	ANA: Positive; C3: Low; C4: Normal	Asymmetrical bilateral cortico-subcortical fronto-parieto-occipital abnormalities	180/100	Antiepileptic Tx	Recovery; alive
[68]	Song X (2017)	China	F/ 65 / 65	Renal (proteinuria); Sjogren’ syndrome; PBS	Upper extremity shaking, lower extremity weakness, fatigue, anorexia, dry mouth, dry eyes	ANA: Positive; Anti-dsDNA: Positive; Anti-Sm Antibody: Positive; Complement: Low; Anti-SSA: Positive; AMA: Positive	Symmetrically patchy lesions involving predominantly the subcortical white matter of bilateral temporal and occipital lobes	NA	Lupus treatment	Recovery; alive
[31]	Zekić T (2017)	Croatia	F / 17 /18	Renal (Class IV lupus nephritis); Hematologic (Anemia, leukopenia, positive Coombs)	Grand mal status epilepticus	C3: Low; C4: Low; Anti-dsDNA: High	Cortical and subcortical hyperintensities in the right frontal and bilateral parietal lobes	160/100	BP control; Antiepileptic Tx	Recovery; alive
[32]	Szamosi S (2017)	Hungary	F / 20 / 20	Musculoskeletal (polyarthritis); Serositis (pleuritis, pericarditis); Hematological (anemia, leukopenia, thrombocytopenia); TTP	confuse	ANA: Positive; Anti-dsDNA: Positive; C3: Normal; C4: Low	Subcortical edema in temporal, occipital, and basal ganglia regions	N/A	BP control	Death due to progressive cerebral edema and hemorrhage
					early in the course of the disease–only 1
					Confusion, unconsciousness, and a new onset of seizure
[44]	Zhang L (2018)	China	F / 16 / 22	Renal (Class IV LN); Musculoskeletal (polyarthritis); Skin (malar rash, photosensivity); Serositis (pleural effusion, pericardial effusion); Hematological (hemolytic anemia, thrombocytopenia)	Headache, nausea, vomiting, and seizure	ANA: Positive; Anti-dsDNA: Positive; C3: Low; C4: Low; Anti-Sm antibody: Positive	High signal intensity in cortical and subcortical parieto-occipital regions (T2, DWI, ADC, FLAIR)	190/110	BP control; Antiepileptic Tx Withdrawal of immunosuppressants	Complete resolution; seizure-free
[33]	Mustafa KN (2018)	Jordan	F / 36 / 36	Renal (Class IV LN); Musculoskeletal (weakness, arthralgia); Skin (Rash)	Severe headache, loss of vision, tonic-clonic seizures, AMS	ANA: positive; C3: Low C4: Low	Abnormal cortical and subcortical white matter involvement in parietal, occipital and frontal lobes as well as watershed areas and between cerebellar hemispheres	152/88	Antiepileptic Tx	Complete recovery (2d)
[34]	Maier S (2018)	Romania	F / 12 / 22	Mucocutaneous (facial rash, cutaneous abnormalities); Hematological (pancytopenia)	Tonic-clonic seizure	Anti-dsDNA: Positive	CT: Symmetrical hypodense lesions in basal ganglia and mild hypodense lesion in pons, no contrast enhancement, normal CT angiography	Normal	Antiepileptic Tx; Supportive care	Death due to pulmonary sepsis, hemorrhagic alveolitis (DIC), bilateral bronchopneumonia, polyserositis
							MRI: Bilateral symmetric hyperintense signal in basal ganglia and pons on T2/FLAIR
[35]	Vaysman T (2019)	USA	F / 20 / 22	Renal (Class IV LN)	Severe headache, right eye blurry vision	ANA: positive; Anti-dsDNA: Positive; C3: Low; C4: Low	Hyperintensity in the midbrain and thalami, sparing the red nucleiMRI FLAIR)	197/121	BP control	Recovery; alive
[46]	Ho CM (2019)	Hong Kong	F / 12 / 24	Renal (Class IV LN); Hematological (hemolytic anemia, thrombocytopenia); Serositis	Tonic-clonic seizure	ANA: Positive, Anti-dsDNA: Positive; Anti-Ro: Positive; Anti-cardiolipin: Positive	CT: New hypoattenuating lesions in bilateral occipital lobes	150/100	BP control; Antiepileptic Tx Supportive care	Recovery; alive
[69]	García-Grimshaw M (2020)	Mexico	F / 15 / 18	Renal (LN); Hematological (Hemolytic anemia), Serositis (pleural effusion); Musculoskeletal (arthritis)	Generalized seizures	Complements: Low	Hyperintensities in the bilateral subcortical of the occipital, parietal, and frontal lobes	Normal	Supportive care	Recovery; alive
[36]	Abraham P (2020)	USA	F / 25 / 25	Renal (Class IV LN)	Generalized tonic-clonic seizure	N/A	Symmetric bilateral paramedian thalamic and pontine hyperintensity	Systolic 140–190	Supportive care; Dialysis/CRRT	Recovery; alive
[70]	Hartman EN (2020)	USA	F / 21 / 21	Renal (Class V LN); Skin (rash); Musculoskeletal (polyarthralgia)	Altered mental status, visual disturbances, and new-onset seizures	ANA: positive; Anti-dsDNA: Positive; C3: Low; C4: Low	Patchy cortical and subcortical edema in posterior lobes	200/108	BP control; Antiepileptic Tx Withdrawal of immunosuppressants	Recovery; alive
[37]	Ulutas F (2020)	Turkiye	M / 39 / 39	Musculoskeletal (symmetrical arthralgia)	Tonic-clonic seizures, headache	ANA: Positive; Anti-dsDNA: Positive; Anti-Sm Antibody: Positive; Anti-SSA: Positive; Complements: Low	Hyperintense white matter vasogenic edema predominantly on the right posterior brain (T2-weighted MRI)	160/110	BP control; Antiepileptic Tx	Death due to neurological insult
[71]	de Medeiros FC (2021)	Brasil	F / 21 / 21	Renal (Class V LN); Hematological (anemia)	Headache, nausea, high blood pressure, altered mental status	ANA: Positive; Anti-dsDNA: Positive	Bilateral parieto-occipital hypodensities on CT	240/110	BP control; Antiepileptic Tx Dialysis/CRRT	Recovery; alive
[72]	Jesrani G (2021)	India	F / 29 / 39	Skin (Oral ulcers and rash)	Sudden onset shortness of breath, loss of consciousness, two generalized tonic-clonic seizures	ANA: Positive; Anti-dsDNA: Positive	Abnormal signals in right caudate nucleus, bilateral thalami, and left globus pallidus without involvement of frontal, parietal, or occipital lobes (MRI FLAIR, and diffusion)	118/74	Antiepileptic Tx	Death
[38]	Hao D-L (2021)	Mexico	F / 28 / 28	Hematological (pancytopenia); Mucosal (oral sores); Skin (rash); Musculoskeletal (arthritis)	Convulsions, loss of consciousness, cyanosis, upturned eyes, trismus, foaming at the mouth, and urinary incontinence	ANA: Positive, Anti-dsDNA: Positive; C3: Low; C4: Low; Anti-histone: Positive; p-ANCA: Positive; Anti-Sm antibody: Positive; Anti-nucleosome antibody: Positive; Anti-SSA/Ro60: Positive	Multiple patchy low (T1), high (T2/FLAIR/DWI)	Increase	BP control; Antiepileptic Tx Supportive care	Recovery; alive
[73]	Rafat WK (2021)	Pakistan	F / 31 / 31	Mucocutaneous (oral ulcers, rash, hair loss); Musculoskeletal (polyarthralgia); Hematological (anemia, thrombocytopenia)	Sudden generalized seizure with urinary incontinence, tongue bite, AMS, headache, blurry vision	Anti-dsDNA: Positive; C3: Low; C4: Low	Brain MRI showed patchy hyperintense signals in cortical and subcortical areas of temporal, parietal, and occipital lobes	170/110	BP control;Antiepileptic Tx	Recovery; alive
[74]	Gros C (2022)	France	F / 34 / 42	Renal (arteriolar TMA with minimal sign of LN); Skin (telangiectasia, limited cutaneous sclerosis); Musculoskeletal (synovitis, inflammatory arthralgia); GI (Esophagitis); Raynaud’s phenomenon complicated with digital ulcers	Behavioral disorders, confusion, high BP	ANA: postive; Anti-DNA: Positive; Anti-RNP: Positive; Anti-Sm antibody: Positive; C3: low; C4: Low	Cortico-subcortical FLAIR hypersignals in posterior junctional territories, asymmetrical occipital hypersignals consistent with PRES	191/128	BP control; Dialysis/CRRT	Recovery; alive
[42]	Tabot-Tabot MK (2023)	USA	F / 14 / 23	Renal (Class III LN)	Agitation, restlessness, confusion, waxing and waning consciousness, headaches and hallucinations	C3: Low; C4: Low; Anti-dsDNA: High	MRI: Extensive bilateral cerebral and cerebellar deep white matter hyperintensities	Systolic 140s–170s, Diastolic 90s–100s, worsened to 160/100 mmHg during critical illness	BP control; Supportive care; Dialysis/CRRT	Recovery; alive
				Possible CNS (initial suspicion of lupus cerebritis)
				TMA; Repeat kidney biopsy showed Class IV LN
[75]	Ozturk Y (2023)	Turkiye	F/ 18 / 25	Kidney (Class IV Lupus Nephritis); Skin (rash); Musculoskeletal (arthritis) Mucosal (oral sores)	Generalized tonic-clonic seizure	C3: Low	Hyperintense signal changes in the left posterior frontal lobe, bilateral occipital, posterior parietal lobes, basal ganglia, and cerebellar hemispheres, with faint diffusion restriction (T2/FLAIR)	170/80	BP control; Antiepileptic Tx	Recovery; alive
[39]	Dai Y (2023)	China	F / 16 / 16	Kidney involvement (Class IV+V LN, acute tubulointerstial injury); Hematological (pancytopenia)	Generalized tetanic convulsion, accompanied by foaming at the mouth, trismus, eyes turned up, unconsciousness	ANA: Positive; Anti-dsDNA: Positive; C3: Low; C4: Low; Anti nRNP/Sm: Positive	Multiple abnormal signals in bilateral frontal, parietal, temporal, and occipital cortices, subcortical white matter, and right pons	135/84	Withdrawal of immunosuppressants; Supportive care; Dialysis/CRRT	Recovery; alive
[47]	Sharma PK (2025)	India	F/ 15 / 23	Renal (LN)	Seizures, severe headache, visual disturbances, and AMS	N/A	Multifocal/multi-centric asymmetrical hypointensities (T1-weighted), hyperintensities/areas in the deep gray matter, deep white matter, sub-cortical white matter U-fibers and cortical white matter of bilateral cerebral hemispheres bilateral cerebellar hemispheres with perifocal sub-cortical mild edema with effacement of adjacent sulci (FLAIR, T2-weighted)	Normal	BP control; Antiepileptic Tx Withdrawal of immunosuppressants	Recovery; alive
[43]	Chen B (2025)	China	F / 17 / 17	Renal (LN); Hematologic (Hemolytic anemia, thrombocytopenia); Serosal (Pericardial effusion, seroperitoneum); Pulmonary (Pneumonia (later H1N1-associated interstitial pneumonia))	Tonic-clonic seizure	ANA: Positive; Anti-Sm antibody: Positive; Anti-SS-A antibody: Positive; Anti-dsDNA: Positive; C3:Low; C4: Low	First episode: Hyperintense lesions in bilateral frontal and parieto-occipital regions (T2/FLAIR)	At lupus diagnosis: 150/100 mmHg	BP control; Antiepileptic Tx; Supportive care; Dialysis/CRRT	Recovery; alive
							Second episode: Recurrence with worsening hyperintensities	At first PRES episode: 200/110 mmHg
								At recurrence: 230/130 mmHg
								Target BP after treatment: maintained < 140/90 mmHg
[76]	Kadoh Y (2025)	Japan	F / 37 / 37	Renal (Class IV LN); Hematological (hemolytic anemia); Skin (malar rash)	Sudden onset of visual impairment, headache, and severe hypertension	ANA: Positive; Anti-dsDNA: Positive; C3: Low; C4: Low; Anti-SSA antibody: Positive; Anti-SSB: Positive; Anti-cardiolipin IgG: Positive	FLAIR MRI – high-intensity zones in bilateral occipital lobes and cerebellum	236/122	BP control	Recovery; alive
	Ersoy Y, Ozcan SG (2026)	Turkiye	F / 21 / 24	Renal (Class V+III LN); Skin (rash); Hematological (hemolytic anemia, lymphopenia)	Altered mental status	ANA: positive; Anti-dsDNA: Positive; C3: Low; C4: Low; Anti-Beta 2-Glycoprotein IgM: Positive; Anti-Sm/RNP: Positive; Anti-Sm: Positive; Nucleosome Positive; Anti-ribosomal P protein: Positive	Extensive bilateral hyperintense edema involving the cingulate gyri, corpus callosum (genu and body), precuneus, cuneus, temporal and occipital lobes, basal ganglia, thalami, and cerebellar hemispheres (T2/FLAIR)	130/90	Supportive care; CRRT	Death due to alveolar hemorrhage

SLE: Systemic Lupus Erythematosus; PRES: Posterior Reversible Encephalopathy Syndrome; MRI: Magnetic Resonance Imaging; mmHg: Millimeters of Mercury; LN: Lupus Nephritis; N/A: Not Available; BP: Blood Pressure; ANA: Antinuclear Antibody; Anti-dsDNA: Anti–Double-Stranded DNA Antibody;LAC: Lupus Anticoagulant; Tx: Treatment; C3: Complement Component 3; C4: Complement Component 4; Anti-Ro / SSA: Anti-Ro (Sjogren’s Syndrome–Related Antigen A) Antibody; Anti-ENA: Anti–Extractable Nuclear Antigen Antibodies; Anti-SSA: Anti-Sjogrens Syndrome–Related Antigen A Antibody; Anti-Sm: Anti-Smith Antibody; Anti-La / SSB: Anti-La (Sjogrens Syndrome–Related Antigen B) Antibody; aPL: Antiphospholipid Antibodies; DAH: Diffuse alveolar hemorrhage; AMS: Altered Mental Status; RA: Rheumatoid arthritis; APS: Antiphospholipid Syndrome; p-ANCA: Perinuclear Antineutrophil Cytoplasmic Antibody; TMA: Thrombotic Microangiopathy; Anti-RNP: Anti-Ribonucleoprotein Antibody; CRRT: Continues Renal Replacement Therapy; DWI: Diffusion-weighted imaging; ADC: Apparent diffusion coefficient

Discussion

Posterior reversible encephalopathy syndrome (PRES) is an increasingly recognized neurological complication in patients with SLE. Through a comprehensive review of 103 individually reported cases, we identified key demographic and clinical patterns that contextualize this potentially life-threatening condition.

We report a 24-year-old woman who developed PRES two days after receiving cyclophosphamide for severe LN with nephrotic-range proteinuria and marked hypoalbuminemia. This case closely mirrors patterns observed in the literature. The patient’s age falls within the typical range observed in our analysis, which showed a mean age at PRES onset of 27.3 years (median 24.5 years, range 8–65 years), indicating that PRES predominantly affects young adults with SLE. A marked female predominance was evident, with 84 of 90 cases with available sex data (93.3%) occurring in women, reflecting both the epidemiology of SLE and potential sex-specific susceptibility to PRES. Renal involvement emerged as a near-universal feature, with LN documented in the majority of cases, underscoring the intimate relationship between nephropathy and neurovascular complications (Table 1).

Our analysis supports a multifactorial pathogenesis. Immunosuppressive therapy emerged as a major contributor to PRES development. Corticosteroids were the most frequently reported agents at the time of PRES onset, identified in 48 cases (45.7%), consistent with their known effects on fluid retention, hypertension, and endothelial function [10]–[39]. Cyclophosphamide was the second most commonly associated drug, reported in 15 cases (14.3%), making it the second most common pharmacological association [11]–[13], [15], [16], [23], [24], [27], [28], [30], [31], [33], [37], [40]–[43]. Other immunosuppressive agents were temporally associated with PRES less frequently, including mycophenolate mofetil in nine cases (8.7%), rituximab in six cases (5.8%) [26], [32], [33], [44]–[46], cyclosporine in four cases (3.8%) [23], [47], [48], and hydroxychloroquine in two cases (1.8%) [28], [49] although for most of these reports the temporal link does not establish a direct causal relationship, and multiple concurrent risk factors were typically present.

Several alternative diagnoses were considered before PRES was established as the leading interpretation. Neuropsychiatric SLE / lupus cerebritis was felt unlikely given the acute monophasic onset, the predominantly posterior imaging distribution, and rapid reversibility within six hours, a time course atypical for lupus cerebritis. Antiphospholipid-related cerebrovascular disease was a major consideration given persistent aPL positivity; however, the lesion distribution did not conform to any single arterial vascular territory, an observation that argues strongly against thromboembolic infarction. Primary CNS vasculitis was considered but unsupported by the rapid reversibility, bilateral symmetric posterior predominance, and absence of corroborating imaging features. Metabolic/toxic encephalopathy was considered less likely as a primary cause, given the normal arterial blood gas, lactate, and electrolytes at the time of deterioration. CNS infection was not supported by the available clinical and laboratory data, including negative cultures, procalcitonin, and viral serologies, and the absence of meningeal signs or a relevant fever pattern.

The combination of acute encephalopathy, multifocal non-territorial bilateral imaging abnormalities with posterior predominance, mildly elevated blood pressure responsive to antihypertensive therapy, and rapid reversibility was therefore most consistent with severe atypical PRES driven by multifactorial endothelial injury.

Our patient exemplifies the convergence of multiple pathological processes that characterize lupus-associated PRES. She developed acute PRES two days after receiving cyclophosphamide for severe LN in the setting of uncontrolled disease activity, high-dose corticosteroid therapy, and profound hypoalbuminemia. At symptom onset, blood pressure was only mildly elevated (130/90 mmHg). Although antihypertensive treatment was initiated and longitudinal blood pressure data are limited, this degree of elevation alone seems unlikely to account for the severity of the imaging findings. Reports of PRES occurring without significant hypertension at symptom onset further support a non-purely-hemodynamic mechanism [41], [42]. This presentation aligns with the emerging concept that cyclophosphamide acts not as an isolated trigger but as a final precipitating factor in patients with critically vulnerable cerebral endothelium already compromised by active SLE, systemic inflammation, and renal dysfunction. Several lines of evidence support direct cyclophosphamide-mediated endothelial toxicity [50].

Severe hypoalbuminemia represents a critical yet underrecognized cofactor in this process. Markedly reduced oncotic pressure facilitates interstitial fluid extravasation and vasogenic edema and exacerbating blood-brain barrier permeability in the setting of endothelial injury. In patients with nephrotic-range proteinuria due to LN, this mechanism likely lowers the threshold for cerebral edema formation. In our patient, an albumin level of 0.93 g/dL likely played a key role in destabilizing the blood–brain barrier and accelerating edema development following cyclophosphamide exposure.

The neuroimaging pattern in our patient deserves specific comment. The non-territorial multifocal distribution, with cerebellar, occipital, thalamic, periventricular, cingulate, callosal, basal ganglia, and temporal involvement, is best understood within the recognized spectrum of atypical PRES, in which cerebellar, brainstem, basal ganglia, thalamic, and frontal involvement occurs in up to one-third of cases and reflects severe systemic endothelial injury rather than a regionally restricted hemodynamic phenomenon (Bartynski’s anatomical variants) [51]–[53]. The right occipital microhemorrhage on susceptibility-weighted imaging additionally places this case within the subset of hemorrhagic PRES, which has been associated with greater severity and less favorable outcomes [54], [55]. Taken together, extensive bilateral vasogenic edema, central involvement, multifocality without territorial distribution, and microhemorrhage argue for a severe atypical PRES variant—fully compatible with aPL-mediated microvascular injury distinct from large-vessel thrombotic APS [56], [57], providing a unifying mechanistic thread linking the neurological event to the subsequent diffuse alveolar hemorrhage [58], [59].

Intriguingly, the relationship between hypoalbuminemia and cyclophosphamide pharmacokinetics adds another dimension to this vulnerability. While the parent compound exhibits only approximately 20% plasma protein binding, its active metabolites demonstrate greater than 60% protein binding [60]. Pharmacokinetic studies in LN patients have suggested that decreased serum albumin correlates with altered exposure to 4-hydroxycyclophosphamide, the primary active metabolite [61]. However, albumin also serves a critical detoxification function by covalently binding acrolein, a highly reactive and toxic cyclophosphamide metabolite that mediates direct endothelial injury [8]. In profound hypoalbuminemia, reduced acrolein-scavenging capacity may permit greater endothelial damage despite potentially lower overall metabolite exposure. This paradoxical relationship warrants further investigation and may explain why standard dosing guidelines do not currently incorporate albumin-based adjustments.

The contribution of CRRT to neurological recovery merits explicit and cautious comment. CRRT is best regarded as part of the systemic and volume optimization that was temporally associated with neurological improvement, rather than as a proven neurological therapy. Since our patient was not significantly metabolically deranged at the time of deterioration, correction of metabolic encephalopathy is unlikely to have been the operative mechanism. Mechanisms that may have contributed, in concert with blood pressure control, to the rapid six-hour recovery include reduction of cerebral vasogenic edema via controlled ultrafiltration for refractory anasarca and safe albumin repletion without precipitating further fluid shifts; direct removal of circulating mediators of endothelial injury remains biologically plausible but unproven in this individual patient. The relative contribution of each cannot be quantified from a single case.

Antiphospholipid antibodies represent a further pathogenic dimension worth explicit discussion. Our patient was persistently aPL-positive from presentation, with the serological course detailed above. Although she did not fulfill formal classification criteria for definite antiphospholipid syndrome, the literature increasingly recognizes a continuum of aPL-mediated endothelial injury extending from clinically silent seropositivity to overt thrombotic and microangiopathic complications [56]. Within this spectrum, high-titer aPL positivity has been linked to PRES, pulmonary capillaritis [58], [59], and diffuse alveolar hemorrhage, with aPL-driven complement activation, NETosis, and endothelial dysfunction as plausible mechanistic links [62]. The rapid multisystem deterioration in our patient is phenotypically compatible with a CAPS-like microvascular catastrophe superimposed on active lupus nephritis, even though strict criteria for definite CAPS were not met. In this context, aPL likely acted in concert with active SLE, severe hypoalbuminemia, nephrotic-range proteinuria, and recent immunosuppressive exposure to produce a converging endothelial injury manifesting first as PRES and culminating in fatal DAH [63].

Despite the traditionally favorable prognosis of PRES, our case underscores that reversibility is not universal in patients with advanced multisystem SLE. The coexistence of multiple high-risk features, including active LN, profound hypoalbuminemia, and recent exposure to cytotoxic therapy appears to synergistically increase risk to fatal outcomes.

There are some limitations of our study. First, heterogeneity in reporting precluded standardized assessment of disease activity, treatment protocols, and outcome measures across studies. Third, missing data on key variables such as blood pressure at PRES onset and immunological profiles limited our ability to perform quantitative analyses. Finally, the retrospective nature of most reports prevented assessment of temporal relationships and potential confounders. Despite these limitations, the consistency of findings across diverse populations and clinical settings strengthens the validity of our observations.

In conclusion, PRES in SLE predominantly affects young women and arises from the interaction between disease activity, immunosuppressive therapy, and systemic vascular vulnerability [64–86]. Cyclophosphamide should be viewed not as an isolated cause, but as a potent precipitating factor acting on a critically primed endothelium. Patients with active LN, particularly those with severe nephrotic syndrome and profound hypoalbuminemia, appear to be at especially high risk. Although neurological manifestations of PRES may be reversible with prompt recognition and management, its occurrence may signal severe, potentially fatal multisystem endothelial injury. Early risk stratification, close monitoring, and timely neuroimaging are therefore essential in high-risk patients receiving immunosuppressive treatment.

Author contributions

SGO and YE conceptualized the study. YE, SGO, CT and OK were involved in data collection. SGO and YE drafted the manuscript. MTD, AM, ES, ST, and NS involved in patient evaluation and reviewed the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

Funding

This research received no specific grant from any funding agency.

Data availability

The data analyzed during the current study are not publicly available due to privacy concerns and protection of patient confidentiality but are available from the corresponding author on reasonable request with appropriate anonymization.

Declarations

Ethical approval

The present work was conducted in accordance with the Declaration of Helsinki. This study is a case report with a literature review; therefore, approval by an ethics committee was not required.

Consent for publication

As the patient is deceased, written informed consent for publication of this case report was obtained from the next of kin.

Competing interests

The authors declare no competing interests.