Neuropsychiatric Systemic Lupus Erythematosus in a Patient with Pancytopenia and Chronic Schizophrenia Requiring Hospitalisation

Abstract

We herein report a patient with systemic lupus erythematosus (SLE) and neuropsychiatric SLE (NPSLE), who had been misdiagnosed with schizophrenia for a long time and presented with pancytopenia. Brain magnetic resonance imaging revealed sporadic punctate hyperintense areas in the cerebral white matter. Single-photon emission computed tomography revealed a clear decrease in blood flow from the parietotemporal association area to the temporal lobe. NPSLE is a serious organ complication that significantly worsens the SLE prognosis. NPSLE symptoms are diverse and difficult to diagnose and differentiate from those of other neuropsychiatric disorders, especially in an early onset.

Introduction

Systemic lupus erythematosus (SLE) is a chronic, systemic, relapsing autoimmune inflammatory disease characterized by antibody production against antigens that affects multiple organs, including the nervous system. SLE is common, particularly in women (1,2). Nervous system involvement in SLE can manifest as neurological and psychiatric symptoms (1).

Approximately one-third of neuropsychiatric syndromes in patients with SLE are common primary manifestations of SLE-related autoimmunity, seizure disorders, cerebrovascular disease, acute confusional state, and neuropathy (2). Neuropsychiatric SLE (NPSLE) is a serious organ complication that significantly worsens the SLE prognosis (2). NPSLE symptoms are diverse and difficult to diagnose and differentiate from those of other neuropsychiatric disorders.

Case Report

A 67-year-old woman with pancytopenia was admitted to the authors' hospital. Thirty-five years prior, she had visited a local psychiatrist because of hallucinations and auditory hallucinations. She had been diagnosed with schizophrenia and had been going to a psychiatric hospital for 10 years. Just before her hospitalization, she exhibited abnormal behavior, including talking to herself incomprehensibly, mishandling fire, and wandering. No blood chemistry evaluations, serological tests, or urinalysis was performed, and only a complete blood count was examined.

She developed leukopenia (white blood cell count, 1,840 /μL) and thrombocytopenia (platelet, 9.5×10⁴/μL) 3 years ago, which gradually worsened. Two months ago, she had developed massive bleeding from internal hemorrhoids and was transferred to another hospital, where marked thrombocytopenia was noted. Subsequently, the platelet count did not improve, and she was referred to our hospital for a further examination.

On admission, a physical examination revealed decreased breath sounds in the lower right lung. Her vital signs were as follows: blood pressure, 129/85 mmHg; heart rate, 74 beats/min; respiratory rate, 16 counts/min; oxygen saturation, 99%; and temperature, 36.7°C. No skin, joint, or skeletal abnormalities were observed. As shown in Table, laboratory examinations showed reduced albumin levels [2.6 (normal: 4.1-5.1) g/dL] and slightly elevated C-reactive protein levels [0.59 (normal: ＜0.15) mg/dL]. Total complement (CH50), C3, and C4 levels decreased to 22.7 (normal: 31.6-57.6) U/mL, 69.7 (normal: 73-138) mg/dL, and 4.2 (normal: 11-31) mg/dL, respectively. Serology was positive for the anti-nuclear antibody (640×, normal: ＜40×), anti-ds-DNA antibody [111.9 (normal: ＜10.0) IU/mL], anti-ribonucleoprotein antibody [20.8 (normal: ＜3.5) U/mL], anti-SSA/Ro antibody [＞240 (normal: ＜7) U/mL], anti-SSB/La antibody [＞320 (normal: ＜7) U/mL], anti-cardiolipin IgG antibody [24 (normal: ＜10) U/mL], and anti-platelet-associated IgG antibody [＞800 (normal: ＜27.6) ng/10⁷ platelets]. Hepatitis C virus antibody, hepatitis B virus surface antigen, and hepatitis B surface antibody tests were negative, but hepatitis B core antibody test was positive. Serum hepatitis B virus deoxyribonucleic acid levels were not detected by a polymerase chain reaction assay. Her haemoglobin, platelet, and white blood cell counts were 7.5 g/dL (normal: 11.6-14.8), 2.2×10⁴/μL (normal: 15.8-34.8), and 400 /μL (normal: 3,300-8,600), respectively. The results of the direct Coombs test were positive. A urinalysis showed urinary protein excretion [0.4 (normal: ＜0.3) g/gCr] and occult blood positivity [20 (normal: 1-4) red blood cells/high-power field].

Table.

Laboratory Data at Admission.

Complete blood count				Blood chemistry				Serological tests
WBC	400	/μL		TP	7.4	g/dL		CRP	0.59	mg/dL
Neu	34.9	%		Alb	2.6	g/dL		CH50	22.7	U/mL
Lym	48.8	%		T-Bil	0.8	mg/dL		C3	69.7	mg/dL
Mon	16.3	%		I-Bil	0.4	mg/dL		C4	4.2	mg/dL
Eos	0.0	%		Alp	121	U/L		IC	11.0	μg/mL
Bas	1.0	%		γGTP	14	U/L		ANA	640	×
RBC	309	×104/μL		ChE	131	U/L		speckled	640	×
Hb	7.5	g/dL		ALT	49	U/L		diffuse	80	×
Ht	24.8	%		AST	75	U/L		CL IgG-Ab	24	U/mL
Plt	2.2	×104/μL		LDH	152	U/L		CLβ2GPI	3.5	U/mL
Retic	0.2	×104/μL		CPK	32	U/L		LAC	0.98
IPF	3.2	%		SCr	0.61	mg/dL		RNP-Ab	20.8	U/mL
Electrolytes				BUN	8.3	mg/dL		Sm-Ab	5.1	U/mL
Na	139	mmol/L		UA	4.1	mg/dL		dsDNA-Ab	111.9	IU/mL
K	4.2	mmol/L		Amy	97	U/L		ssDNA-Ab	357.1	U/mL
Cl	110	mmol/L		T-Chol	101	mg/dL		SSA/Ro-Ab	>240	U/mL
Ca	7.9	mg/dL		NH3	40	μg/dL		SSB/La-Ab	>320	U/mL
Infection				COL4-7S	11.9	ng/mL		D-Coombs	(+)
HCV-Ab	(-)			M2BPGi	(2+)			I-Coombs	(-)
HBs-Ag	(-)			P-FDP	12.7	μg/mL		PA-IgG	>800	ng/107Plt
HBs-Ab	(-)			FDP-DD	4.6	μg/mL		AQP4-Ab	3.1	U/mL
HBc-Ab	(+)			Hp	81	mg/dL		Ribo P-Ab	1.6
HBV-DNA	(-)							Mit M2-Ab	<20	×

WBC: white blood cell count, Neu: neutrophil, Lym: lymphocyte, Mon: monocyte, Eos: eosinophil, Bas: basophil, RBC: red blood cell count, Ht: hematocrit, Hb: hemoglobin, Plt: platelet, Retic: reticulocyte count, IPF: immature platelet fraction, Na: sodium, K: potassium, Cl: chlorine, Ca: calcium, HCV-Ab: hepatitis C virus antibody, HBs-Ag: hepatitis B virus surface antigen, HBs-Ab: hepatitis B surface antibody, HBc-Ab: hepatitis B core antibody, HBV-DNA: hepatitis B virus deoxyribonucleic acid, TP: total protein, Alb: albumin, T-Bil: total bilirubin, I-Bil: indirect bilirubin, Alp: alkaline phospartase, γGTP: γ-glutamyltransferase, ChE: cholinesterase, ALT: alanine aminotransferase, AST: aspartate aminotransferase, LDH: lactate dehydrogenase , CPK: creatine phosphokinase, SCr: serum creatinine, BUN: blood urea nitrogen, UA: uric acid, Amy: amylase, T-Chol: total cholesterol, NH3: ammonia, COL4-7S: type IV collagen 7S, M2BPGi: Mac 2-binding protein gylcan isomer, P-FDP: products of fibrinogen digestion by plasmin, FDP-DD: fibrin degradation product D-dimer, Hp: haptoglobin, CRP: C-reactive protein, IC: immune complex, ANA: antinuclear antibody, CL IgG-Ab: anti-cardiolipin IgG antibody, CLβ2GPI: anti-cardiolipin-beta2-GPI complex antibody, LAC: lupus anticoagulant, RNP-Ab: anti-ribonucleoprotein antibody, Sm-Ab: anti-Smith antibody, dsDNA-Ab: anti-double-stranded deoxyribonucleic acid antibody, ssDNA-Ab: anti-single-stranded deoxyribonucleic acid antibody, SSA/Ro-Ab: anti-SSA/Ro antibody, SSB/La-Ab: anti-SSB/La antibody, D-Coombs: direct Coombs test, I-Coombs: indirect Coombs test, PA-IgG: platelet-associated IgG, AQP4-Ab: anti-aquaporin 4 antibody, Ribo P-Ab: anti-ribosomal P antibody, Mit M2-Ab: anti-mitochondrial M2 antibody

Magnetic resonance imaging of the brain revealed sporadic punctate hyperintense areas in the cerebral white matter (Fig. 1). Single-photon emission computed tomography revealed a clear decrease in blood flow from the parietotemporal association area to the temporal lobe, predominantly on the left side (Fig. 2). Computed tomography of the chest and abdomen revealed right bronchitis, massive right pleural effusion, splenomegaly, and ascites (Fig. 3). Accordingly, she was diagnosed with hepatitis B cirrhosis, long-term NPSLE, and pancytopenia due to an SLE flare-up.

Figure 1.

Magnetic resonance imaging of the brain shows sporadic punctate hyperintense areas (arrows) in the cerebral white matter (A-C: T1 weighted image, D-F: T2 weighted image).

Figure 2.

Single photon emission computed tomography shows a clear decrease in blood flow from the parietotemporal association area to the temporal lobe (arrows), predominantly on the left side.

Figure 3.

Computed tomography shows right bronchitis and massive right pleural effusion (arrow) (A) as well as splenomegaly and ascites (arrow) (B).

Oral prednisolone (PSL) (40 mg/day) was started, and laboratory findings, including pancytopenia (haemoglobin, 14.4 g/dL; platelet, 8.0×10⁴/μL; white blood cell count, 6,100 /μL, respectively), pleural effusion, and ascites, improved. During the 2-year follow-up, the PSL dose was reduced to 5 mg/day, with no recurrence reported, and her abnormal behavior almost disappeared.

Discussion

Psychiatric symptoms are rarely reported as the first isolated feature of SLE, although many patients experience psychiatric symptoms before being diagnosed with SLE (3). Furthermore, NPSLE is not always considered a complication of SLE and may occur due to the absence of systemic autoimmunity (4), suggesting that central inflammation is always consistent with systemic symptoms. The diagnosis is difficult for several reasons. In many NPSLE cases, there is a considerable delay between the first psychiatric and physical symptoms (5). Therefore, accompanying systemic signs may be misunderstood or remain undiagnosed. The clinical symptoms of NPSLE are diverse and can be broadly divided into psychiatric and organic symptoms. In particular, psychiatric symptoms, such as schizophrenia, are self-reported by patients, making it difficult to differentiate them from other psychiatric disorders. Patients who develop NPSLE while young often do not undergo an extensive evaluation of their underlying illnesses. The treatment of acute psychiatric symptoms takes precedence, with no extensive evaluation of organic diseases.

In addition, because it is difficult for people with schizophrenia to accurately recognize and report physical symptoms, it is unlikely that all chief complaints will be examined in detail by healthcare professionals. Primary NPSLE events result from microangiopathy, thrombosis, autoantibodies, or inflammatory mediators (2). An NPSLE diagnosis requires the exclusion of other causes, and a clinical evaluation guides the selection of appropriate investigations (2). These investigations include autoantibody measurements, cerebrospinal fluid analyses, electrophysiological studies, neuropsychological assessments, and neuroimaging to assess the brain structure and function (2). Autoimmune diseases and severe infections are associated with an increased risk of late schizophrenia and other psychiatric disorders (6). NPSLE accounts for 6.2% of chronically hospitalized schizophrenia patients, and complement depletion is an indicator of NPSLE activity (7).

NPSLE treatment includes managing comorbidities leading to neuropsychiatric events, symptomatic therapy, and the use of anticoagulants or immunosuppressants, depending on the primary immunopathogenic mechanism (2). SLE is known to involve the central nervous system and requires early and intensive immunosuppressive treatment (8). Studies suggest a better prognosis for early NPSLE symptoms than for neuropsychiatric events of non-SLE causes (2). Therefore, the early detection and treatment of NPSLE are critical for improving the long-term prognosis of SLE.

The increased risk of neuropsychiatric symptoms in SLE emphasizes an early NPSLE diagnosis in neuropsychiatric patients and differentiation from other central nervous system diseases (9). It is difficult to track the exact start of SLE in patients diagnosed with SLE because of significant organ damage during prolonged hospitalization. Furthermore, the mortality rate of cerebrovascular events, which are severe in patients with NPSLE, has been reported to be approximately 15% (10,11), suggesting that patients with NPSLE do not necessarily die and may remain undiagnosed and survive without treatment. It was thought that, in our case, SLE was not examined as a differential diagnosis, and she received only psychiatric treatment for a long period, so her cranial nerve damage became organic, and her psychiatric symptoms became fixed. Although there was little improvement in cognitive abilities that had become chronic and fixed, there was a tendency for improvement in mental symptoms, which are suspected to be caused by immunological mechanisms, as well as physical symptoms.

In conclusion, NPSLE is a serious organ complication that significantly worsens the life prognosis of SLE and is an important causative disease in patients with neuropsychiatric disorders. Although NPSLE is difficult to diagnose and distinguish from other neuropsychiatric disorders, it is extremely important to suspect this disease and conduct blood tests and immunological tests for screening to avoid delaying the start of treatment. Clinicians should remember that young women should be examined for potential organic disorders at the onset of mental illness. Furthermore, clinicians must not forget that when a patient diagnosed with schizophrenia exhibits an abnormality, it is important to include SLE as an underlying disease in the differential diagnosis.

The authors state that they have no Conflict of Interest (COI).