Cognitive impairment in systemic lupus erythematosus and neuropsychiatric systemic lupus erythematosus: a population-based neuropsychological study

We present a cross-sectional, population-based neuropsychological study of systemic lupus erythematosus (SLE) patients identified within Tampere University Hospital district, Finland with 440,000 inhabitants. Patients with definite SLE in the age range of 16-65 years (n = 46) and matched controls (n = 46) underwent neurological examination and comprehensive neuropsychological testing. On the basis of medical examination, the SLE patients were divided into neuropsychiatric (NP+; n = 15) and nonneuropsychiatric (NP-; n = 31) cases. The neuropsychological test results revealed more prevalent cognitive impairment in the NP+ patients, indicating that this subgroup mostly accounts for neuropsychological changes in SLE. Most characteristic changes in NP+ were observed in domains of memory, psychomotor speed, and complex attention. This suggests nonspecific CNS involvement, which is in line with neurological manifestations of the disease.     

Neuropsychological Functioning and Its Relationship to Antiphospholipid Antibodies in Patients With Systemic Lupus Erythematosus

While it is clear that central nervous system (CNS) lesions in systemic lupus erythematosus (SLE) adversely affect cognitive functioning, it is also evident that patients without visible lesions (non-CNS SLE) may also exhibit subtle cognitive impairment. The presence of antiphospholipid antibodies (aPLs) has been proposed as a marker of disease severity and hence should be correlated with neuropsychological dysfunction in this population. The current study compared groups of non-CNS lupus patients who were positive (LA+) or negative (LA-) for aPLs on selected measures of neuropsychological functioning. In addition, we attempted to characterize the pattern of cognitive impairment that is associated with LA status in these patients. No coherent neuropsychological pattern emerged, but LA+ patients performed worse than LA- patients on measures assessing attention, concentration, and visual search, as well as spatial learning and memory.     

Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus

This study aimed to characterise both neuronal autoantibodies and levels of interferon α, two proposed causative agents in neuropsychiatric systemic lupus erythematosus (NPSLE). Cerebrospinal fluid (CSF) and plasma from 35 patients with systemic lupus erythematosus (SLE; 15 with NPSLE) showed no antibodies against natively expressed N-methyl-D-aspartate receptors (NMDARs), or the surface of live hippocampal neurons. By comparison to controls (n = 104), patients with SLE had antibodies that bound to a peptide representing the extracellular domain of NMDARs (p < 0.0001), however, binding was retained against both rearranged peptides and no peptide (r = 0.85 and r = 0.79, respectively, p < 0.0001). In summary, neuronal-surface reactive antibodies were not detected in NPSLE. Further, while interferon α levels were higher in SLE (p < 0.0001), they lacked specificity for NPSLE. Our findings mandate a search for novel biomarkers in this condition. ANN NEUROL 2020;88:1244–1250     

The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus

OBJECTIVE: To describe the prevalence of neuropsychiatric (NP) syndromes in a Finnish population of patients with systemic lupus erythematosus (SLE) and to classify them according to the recently developed American College of Rheumatology (ACR) nomenclature and case definitions for NPSLE. METHODS: Cross-sectional, population-based study covering an area with 440,000 people. A total of 58 patients with a definite diagnosis of SLE and aged 16 to 65 years were found in the computerized database of the area hospitals. Of these, 46 (79%) agreed to participate. The diagnosis of various NP syndromes was based on clinical impression (H.A.) following history, examination, review of medical records, and neuropsychologic testing. RESULTS: At least one NP syndrome was identified in 42 patients (91%). The most frequent manifestation was cognitive dysfunction (n = 37; 81%), followed by headache (n = 25; 54%) and mood disorder (n = 20; 43%). When mild NP syndromes (mild cognitive deficit, headache, mild depression, anxiety, electroneuromyography-negative polyneuropathy) were excluded, the prevalence of NPSLE dropped to 46%. CONCLUSIONS: According to the ACR nomenclature, there is a high prevalence of NP manifestations in a population-based sample of patients with SLE. Most NP syndromes were classified as minor; if they were excluded, the 46% prevalence of NPSLE would be slightly less than estimated in previous studies.     

Valproate-Induced Systemic Lupus Erythematosus in a Patient with Partial Trisomy of Chromosome 9 and Epilepsy

Summary: We report a mentally retarded 30–year-old woman with partial trisomy of chromosome 9 (46,XX6,+der(6)t(6,9)pat) who has had epilepsy since age 11 months. She had been treated with various combinations of drugs. After 1 year of treatment with valproate (VPA) and ethosuximide (ESM), the patient developed arthral-gias, muscle weakness, fatigue, and fever. Laboratory examination showed increased sedimentation rate, hyper-gammaglobulinemia, and high titers of antinuclear antibodies (ANA). The possibility of VPA-induced systemic lupus erythematosus (SLE) was considered. This diagnosis was supported by detection of antihistone antibodies and the HLA-DR4 antigen. VPA dosage was tapered and discontinued, with accompanying resolution of clinical, immunological and hematological signs of SLE 6 weeks after VPA discontinuation. This is the fourth reported case of VPA-induced SLE.     

Parkinsonian Syndrome Complicating Systemic Lupus Erythematosus

Two girls with florid extrapyramidal parkinsonism complicating systemic lupus erythematosus (SLE) are reported. One patient (15 years old) presented with extreme rigidity, irritability, and mutism initially diagnosed as acute psychosis. Examination revealed severe extrapyramidal akinetic mutism, along with marked restlessness. CT and MRI imaging of the brain were unremarkable. EEG revealed moderate generalized disturbance of background activity. ^99mTc-HmPAO SPECT cerebral scanning detected decreased regional cerebral blood flow at the basal ganglia. Dopamine-agonist drugs led to complete recovery after 3 months, along with normalization of EEG and SPECT alterations. The second patient (16 years old) was assessed for progressive bradykinesia and apathy impeding her active daily activities, and she was suspected to have developed depression. Neurologic assessment revealed a parkinsonian syndrome that was less severe than that of the first patient. The EEG showed mild disturbance of background activity, and ^99mTc-HmPAO SPECT demonstrated impaired regional cerebral blood flow over the basal ganglia. A parkinsonian extrapyramidal syndrome complicating SLE should therefore be taken into account in any patient with SLE presenting with marked behavioral alterations, rigidity, or akinetic mutism.     

Cerebral Venous Sinus Thrombosis as a Rare Complication of Systemic Lupus Erythematosus: Subgroup Analysis of the VENOST Study

AimSystemic lupus erythematosus (SLE) is an unusual risk factor for cerebral venous sinus thrombosis (CVST). As few CVST patients with SLE have been reported, little is known regarding its frequency as an underlying etiology, clinical characteristics, or long-term outcome. We evaluated a large cohort of CVST patients with SLE in a multicenter study of cerebral venous thrombosis, the VENOST study, and their clinical characteristics.Material and MethodAmong the 1144 CVST patients in the VENOST cohort, patients diagnosed with SLE were studied. Their demographic and clinical characteristics, etiological risk factors, venous involvement status, and outcomes were recorded.ResultsIn total, 15 (1.31%) of 1144 CVST patients had SLE. The mean age of these patients was 39.9 ± 12.1 years and 13 (86.7%) were female. Presenting symptoms included headache (73.3%), visual field defects (40.0%), and altered consciousness (26.7%). The main sinuses involved were the transverse (60.0%), sagittal (40.0%), and sigmoid (20.0%) sinuses. Parenchymal involvement was not seen in 73.3% of the patients. On the modified Rankin scale, 92.9% of the patients scored 0-1 at the 1-month follow-up and 90.9% scored 0-1 at the 1-year follow-up.ConclusionsSLE was found in 1.31% of the CVST patients, most frequently in young women. Headache was the most common symptom and the CVST onset was chronic in the majority of cases. The patient outcomes were favorable. CVST should be suspected in SLE patients, even in those with isolated chronic headache symptoms with or without other neurological findings.     

Functional connectivity changes in core resting state networks are associated with cognitive performance in systemic lupus erythematosus

To investigate core resting state networks in SLE patients with and without neuropsychiatric symptoms by examining functional connectivity changes correlating with results of cognitive testing. Structural MRI and resting state-fMRI (rs-fMRI) were performed in 61 female SLE patients (mean age: 36.8 years, range 18.2–52.0 years) and 20 healthy controls (HC) (mean age 36.2 years, range 23.3–52.2 years) in conjunction with clinical examination and cognitive testing. Alterations in core resting state networks, not found in our healthy controls sample, correlated with cognitive performance gauged by neuropsychological tests in non-neuropsychiatric SLE (nNP) as well as in neuropsychiatric SLE patients (NP). The observed pattern of increased functional connectivity in core resting state networks correlated with reduced cognitive performance on all cognitive domains tested and with a heavy focus on DM, CE, and DM–CE in the NP subgroup. Furthermore, we found that the observed alterations in memory and psychomotor speed correlated with disease duration. In SLE patients both with and without clinically overt neuropsychiatric manifestations, we found changes in the functional connectivity of core resting state networks essential to cognitive functions. These findings may represent a rewiring of functional architecture in response to neuronal damage and could indicate suboptimal compensatory mechanisms at play.     

Neuropsykiatriske Manifestationer Ved Lupus Erythematosus Disseminatus

Neuropsychiatric Manifestations of Systemic Lupus Erythematosus (SLE).

The literature on psychiatric and neurological manifestations in SLE is discussed. Five cases are reported. The psychiatric picture is in accordance with the known classification of organic mental syndromes.

The differential diagnosis to non-organic psychosis depends on the demonstration of SLE. The symptomatology does not permit differenation to psychosis induced by steroids. If a patient suffering from SLE during treatment with steroids develops a psychotic episode, it is most likely caused by SLE-involvement of the central nervous system. Neuropsychiatric abnormality of SLE may be the initial or single manifestation of SLE.

Reservation with pharmacological treatment of the neuropsychiatric symptoms is warranted by possible aggravation of SLE by several medicaments.

In 3 of our 5 patients we noticed medicamental provocation during treatment with chlorprotixen, chlorpromazin and phenytoin.     

Possible Induction of Systemic Lupus Erythematosus by Valproate

Two patients developed clinical and laboratory evidence of systemic lupus erythematosus (SLE) during treatment with valproate (VPA) preparations. The first patient, a 47-year-old man, had fever, malaise, and thrombocytopenia 1 month after VPA was added to phenytoin (PHT) and primidone (PRM). He developed high titers of antinuclear antibodies (ANA) and anti-DNA antibodies, and hypocomplementemia. After discontinuation of PHT and VPA, steroid and immunoglobulin treatment was required for 4 weeks before his condition improved. The second patient, a 28-year-old woman, had been followed for idiopathic leukopenia for 3 years and had previously experienced fever and lymphadenopathy from PHT. After 4 months of divalproex therapy, she developed confusion, joint pain, and a dramatic increase in seizure frequency. She also developed high titers of ANA and anti-DNA antibodies and hypocomplementemia, along with a further decrease in white blood cell (WBC) count. These responded to steroid therapy and withdrawal of divalproex. Three months later, reintroduction of divalproex was followed by a return of ANA in low titer, which resolved after discontinuation. We believe that VPA may have caused true SLE in these patients, one of whom was probably predisposed.     

系统性红斑狼疮合并周围神经病的临床特点和肌电图改变

分析２２例临床有或疑有神经系统损害的系统性红斑狼疮（ＳＬＥ）患者，其中仅３例被临床诊断为ＳＬＥ合并周围神经病，然神经电生理检查证实１３例为周围神经损害。主要临床特点为对称性和非对称性四肢远端麻木、疼痛，深浅感觉障碍，肌力减退，肌萎缩等。神经电生理检查显示神经传导速度减慢，波幅降低，异常自发电位（纤颤电位和正锐波），运动单元多相电位增加。电生理检查与病理改变相符：ＳＬＥ合并周围神经病既有轴索损害，又有脱髓鞘改变。提示神经电生理检查可以为ＳＬＥ患者提供早期或亚临床周围神经损害的依据。     

Positron emission tomography and magnetic resonance imaging for cerebral involvement in patients with systemic lupus erythematosus

Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) remains difficult to diagnose, particularly since structural abnormalities may not be revealed by magnetic resonance imaging (MRI). Glucose utilisation was measured by positron emission tomography (PET) in 35 SLE patients to detect signs of CNS involvement. The patients were examined by a standardised neurological examination, a battery of tests to evaluate neuropsychological performance and MRI. Antineuronal antibodies were determined to investigate their putative role in CNS involvement in SLE. Twenty patients had distinct neurological (17) and/or psychiatric (3) symptoms. Ten patients had pronounced cognitive impairment. Neurological and cognitive deficits were thus found to be unrelated disorders in SLE. Global glucose utilisation of SLE patients did not differ significantly from that of normal controls, nor were differences found between SLE patients with or without neurological or cognitive abnormalities. On MRI of the brain, the number and size of white matter lesions correlated with the presence of neurological deficits but were unrelated to the severity of cognitive impairment. Within the normal range, lower global glucose utilisation tended towards lower values with increasing number and size of white matter lesions. Patients with lesions larger than 8 mm also showed distinctly increased IgG anticardiolipin antibody titres, whereas measuring antineuronal antibodies did not reveal any relation to the variables investigated. We conclude that the demonstration of CNS lesions by MRI can contribute confirmatory evidence for CNS involvement in SLE, but PET or the presence of antineuronal antibodies adds little if any information beyond that obtained by clinical examination, neuropsychological testing, and MRI. Received: 22 May 1996 Received in revised form: 15 October 1996 Accepted: 2 November 1996     

系统性红斑狼疮合并脊髓病变6例临床分析

目的初步探讨系统性红斑狼疮(systemic lupus erythematosus,SLE)合并脊髓病变的临床特征和诊治方法。方法收集SLE合并脊髓病变患者6例,分析其发病时间、临床表现、影像学和脑脊液(CSF)特征以及治疗和转归。结果临床均表现为受损平面以下截瘫,感觉障碍和括约肌功能异常。其中1例以脊髓损害(合并脑膜炎)为首发症状,余5例于狼疮活动期出现脊髓症状。脊髓MRI检查显示不同节段脊髓长T1长T2信号,病变主要位于胸段脊髓,累及节段较长。行CSF检查显示,CSF蛋白升高5例,寡克隆区带(oligoclonal band,OB)阳性3例,白细胞不同程度增加2例。5例给予甲基泼尼松龙冲击 环磷酰胺治疗,另1例仅予激素(地塞米松)治疗,结果显示,2例CSF恢复正常且临床症状好转,1例CSF恢复正常但症状无好转,1例临床症状好转但CSF蛋白进行性增高且有梗阻现象,2例死亡。结论SLE合并脊髓病变常出现在狼疮活动和/或减药过程中,也可作为SLE的首发症状;通过临床表现难以与其他原因引起的脊髓损害鉴别;预后不佳,系统而规范地治疗SLE值得重视。     

系统性红斑狼疮患者血清免疫抑制物的初步观察

目的　初步探讨系统性红斑狼疮 (SLE)患者血清中的免疫抑制物质。方法　选用 SLE患者、狼疮肾患者、慢性肾小球肾炎患者血清。以正常志愿者血清为对照。检测血清及其超滤后不同组分对由刀豆蛋白 (ConA)诱导的淋巴细胞转化的影响。结果　与正常对照组相比 ,狼疮性肾炎患者的血清可十分显著地抑制正常淋巴细胞转化 (抑制率在 90 %以上 ) ,超滤后大于相对分子质量为 3 0 0 0 0的组分具有抑制作用 ,而且其抑制强度与不作超滤处理的血清相同。相对分子质量 <3 0 0 0 0的组分未表现出任何抑制作用。临床诊断未明显累及肾脏的 SLE疮患者 ,其血清也具有明显抑制作用 (抑制率在 5 0 %左右 )。慢性肾小球肾炎患者的血清则对正常淋巴细胞转化几乎无抑制作用 (抑制率小于 2 0 % )。结论　 SLE患者血清中可能存在一种能抑制 T淋巴细胞转化的大分子物质 (相对分子质量 >3 0 0 0 0 ) ,它与由神经系统介导生成的应激免疫抑制蛋白的关系值得进一步探讨。     

Frontal cortex atrophy predicts cognitive impairment in multiple sclerosis

The association between regional measures of cortical atrophy and neuropsychological (NP) dysfunction was studied in 35 multiple sclerosis (MS) patients. Patients underwent neurological examination, MRI, and NP testing. Blind quantitative MRI analysis yielded total T(2) lesion area (TLA) and third ventricle width (3VW). Cortical atrophy, rated by blind visual inspection, was more extensive in superior frontal and parietal cortices than in other regions. No MRI measures were correlated with depression scores. TLA and 3VW were significantly correlated with each NP test. Cortical atrophy measures for bilateral superior frontal cortex were retained in regression models predicting impairments in verbal learning, spatial learning, attention, and conceptual reasoning. The authors conclude that cerebral atrophy predicts NP impairment while accounting for the influence of TLA or 3VW. Regions of cortex most susceptible to atrophic and cognitive changes in MS are the right and left superior frontal lobes.     

Prevalence of cognitive impairment in systemic lupus erythematosus

We administered a battery of neuropsychological tests to 62 female patients with systemic lupus erythematosus (SLE), 12 female patients with rheumatoid arthritis (RA), and 35 normal control subjects. By applying objective decision rules to individual test protocols, an overall prevalence of cognitive impairment of 66% was obtained in the SLE patient sample. Independent clinical, radiological, and laboratory data were used to determine neuropsychiatric (NP) symptomatology and to group SLE patients as 1) "active" (N = 21), 2) "inactive" (N = 15), and 3) "never" (N = 26) NP-SLE. More than 80% of the patients in groups 1 and 2 and 42% in group 3 showed significant cognitive impairment as compared with 17% of the RA patients and 14% of the normal control subjects. Neither steroid medication nor psychological distress could account for these findings. The unexpectedly high prevalence of cognitive impairment in SLE patients with either inactive or absent neuropsychiatric symptomatology provides evidence for subclinical nervous system involvement in SLE.     

Systemic Lupus Erythematosus Associated with Use of Valproate

Summary: A 30-year-old man with long-standing localization-related epilepsy and mental retardation had seizures that were partially controlled with valproate (VPA) 500 mg four times daily. Routine examination showed severe thrombocytopenia with mild leukopenia and chronic lowgrade hemolytic anemia. Pertinent laboratory results included positive ANA, rheumatoid factor, anti-NIA, circulating immune complexes, and antihistone antibody. The patient was treated with high dosage prednisone with partial improvement, but continued to have exacerbations at lower dosages. Fourteen months later, VPA was discontinued, and rapid improvement ensued. Prednisone was subsequently discontinued, and the patient has now maintained normal platelet counts for 18 months.     

Long-term effects of high-dose zidovudine treatment on neuropsychological performance in mildly symptomatic HIV-positive patients: results of a randomized, double-blind, placebo-controlled investigation.

This study examined the treatment outcome of high-dose (1500 mg/day) zidovudine (AZT) on neuropsychological (NP) functioning (Trailmaking Test A & B, WAIS-R Digit Symbol, and Rey Auditory Verbal Learning Test) across a 12-month period in mildly symptomatic HIV-1 seropositive men (n = 46 at entry) enrolled in a randomized, double-blind, placebo-controlled trial (VA Cooperative Studies Program #298). Neither short-term (0-6 months) nor long-term (0-12 months) AZT administration revealed enhancement in NP performance. The results suggest that, although AZT may afford patients prophylactic benefits, protracted high-dose AZT treatment does not improve NP functioning in mildly symptomatic HIV-positive individuals.     

Neuropsychological test profile differences between young and old human immunodeficiency virus-positive individuals

Human immunodeficiency virus (HIV) dementia remains as an important cause of neurological morbidity among HIV-seropositive (HIV+) individuals. Differences in the neuropsychological profiles between older and younger HIV+ individuals have not been examined extensively. The objective of this study was to examine the neuropsychological test performance between old and young HIV+ individuals (a) with and without cognitive impairment (total cohort) and (b) with dementia. One hundred thirty-three older (age >or= 50 years) HIV+ individuals and 121 younger (age 20 to 39 years) HIV+ individuals were evaluated with a standardized neuropsychological test battery. Differences between age groups in the mean z score for each neuropsychological test were determined. The older HIV+ (total) cohort had greater impairment in tests of verbal memory (P = .006), visual memory (P < .002), verbal fluency (P = .001), and psychomotor speed (P < .001) compared to the young HIV+ (total) cohort. After adjusting for differences in education, older HIV+ patients with dementia (n = 31) had a greater deficit in the Trail Making test Part B (P = 0.02) compared to younger HIV+ patients with dementia (n = 15). Age was associated with lower performance in tests of memory, executive functioning, and motor performance in older HIV+ individuals with and without cognitive impairment (total cohort), compared to younger HIV+ individuals. Among HIV+ patients with dementia, age may be associated with greater impairment in a test of executive functioning. These differences could be a result of advanced age itself or age-associated comorbidities such as coexisting cerebrovascular or neurodegenerative disease.