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Neuropsychiatric manifestations in patients with systemic lupus erythematosus: epidemiology and radiology pointing to an immune-mediated cause
  1. Gerda M Steup-Beekman1,
  2. Elisabeth J M Zirkzee1,
  3. Danielle Cohen2,
  4. Bastiaan M A Gahrmann1,
  5. Bart J Emmer3,
  6. Stefan C A Steens3,
  7. Eduard L E M Bollen4,
  8. Mark A van Buchem3,
  9. Tom W J Huizinga1
  1. 1Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  3. 3Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
  4. 4Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Dr Gerda M Steup-Beekman, Department of Rheumatology, C1-R, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands; g.m.steup-beekman{at}lumc.nl

Abstract

Background Different pathogenetic pathways have been proposed for neuropsychiatric (NP) manifestations in systemic lupus erythematosus (SLE).

Objective To describe the patient characteristics of a large cohort of patients with SLE with NP manifestations (NPSLE) in a single centre and to review whether these and other data are compatible with immune-mediated mechanisms.

Methods A total of 212 patients were identified from MRI scans of the brain ordered for suspected NPSLE. Data were collected from the medical records. NP syndromes were classified according to the American College of Rheumatology (ACR) nomenclature and case definitions.

Results 155 patients fulfilled the criteria for SLE. In 102 patients NP manifestations were attributed to SLE itself (primary NPSLE) whereas, in the remaining patients, the NP symptoms were due to other causes. The median age at the time of SLE diagnosis in patients with primary NPSLE was 27.5 years and the median duration prior to NPSLE was 2.8 years. Forty patients (39%) had a NP manifestation in the first year of the disease. Cerebrovascular disease, cognitive dysfunction, seizures and headache were the most prevalent syndromes. In 47% of patients with primary NPSLE the MRI scan of the brain showed no abnormalities.

Conclusions Most NP manifestations in SLE occur early in the disease. This finding, as well as data from quantitative imaging studies and recent pathological studies, point to an immune-mediated pathogenesis.

  • Systemic Lupus Erythematosus
  • Autoantibodies
  • Magnetic Resonance Imaging

https://doi.org/10.1136/annrheumdis-2012-202369

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    Introduction

    The overall prognosis for survival in systemic lupus erythematosus (SLE) has improved dramatically in recent decades, but neuropsychiatric (NP) complications remain a major cause of morbidity.1 ,2

    The prevalence of NP syndromes in SLE varies from 15% to 91% depending on the diagnostic criteria and patient selection.3–5 The imaging modality of choice in patients with SLE with NP complications (NPSLE) is MRI. MRI abnormalities include small focal subcortical white matter lesions, cortical atrophy, periventricular white matter hyperintensities and infarctions, but are often non-specific.6 ,7 In 1999 the American College of Rheumatology (ACR) Ad Hoc Committee published a consensus document defining diagnostic and exclusion criteria for 12 CNS syndromes and seven peripheral nervous system (PNS) syndromes in SLE in order to facilitate research.8

    In about 60% of the cases NP disease can be attributed to SLE itself and is referred to as primary NPSLE.9 ,10 In the other 40%, NP symptoms are the consequence of secondary causes indirectly related to SLE such as infections, side effects of drugs or metabolic derangement. No specific test exists to discriminate primary from secondary NPSLE.

    In primary NPSLE the pathogenesis of diffuse NP syndromes such as cognitive dysfunction and psychosis remains unclear. True vasculitis is observed only in a minority of histopathological cases.11 The integrity of the blood–brain barrier seems to play an important role in autoantibody-mediated CNS manifestations.12 Diamond et al demonstrated that a subset of the antibodies to double-stranded DNA in patients with SLE cross-reacts with subunits of the N-methyl-D-aspartate receptor on neuronal cells and can cause neuronal death by excito-toxicity and apoptosis.13 In normal circumstances the blood–brain barrier prevents these antibodies from causing neuronal damage. In a subsequent study in which these antibodies were induced in mice, neuronal damage occurred only when a breach in the integrity of the blood–brain barrier was present.14 ,15 A recent study suggested that this model might indeed be operative in patients with NPSLE, although the presence of these antibodies in serum alone seems to have no direct correlation with NP manifestations in SLE in other studies.16 ,17 If such a mechanism was operative in clinical practice, it would be expected that NP symptoms would occur early in the disease course in a substantial proportion of patients.

    The Leiden University Medical Center has been a tertiary referral centre for patients with NPSLE for over 20 years. This has allowed us retrospectively to study features and time of occurrence of NP disease in a large cohort of patients with suspected NPSLE.

    Methods

    The case records were evaluated of 212 patients who were referred for an MRI scan of the brain because of possible NPSLE between January 1989 and January 2006. Patients were admitted to the Leiden University Medical Center (LUMC), a tertiary referral centre for the south-western part of the Netherlands, a region with a population of about three million inhabitants. This centre also serves as a national referral centre for NPSLE in the Netherlands (16 million inhabitants).

    A diagnosis of SLE was established based on the presence of at least four of the ACR 1982 revised criteria for the classification of SLE.18 ,19 Fifteen records showed insufficient clinical information and in 42 patients the SLE criteria were not met or a different diagnosis was made. These 57 patients were not evaluated in this study.

    The medical records of the 155 patients with SLE were reviewed with particular attention to documented NP manifestations present at any time from the date of SLE diagnosis. The NP manifestations were classified retrospectively by a team of rheumatologists according to the ACR nomenclature and case definitions for NPSLE syndromes.8

    Patients were categorised as primary NPSLE when symptoms were most likely attributed to SLE activity itself after extensive clinical evaluation and exclusion of other possible causes of NP symptoms. Secondary NPSLE was established when NP symptoms were the consequence of causes indirectly related to SLE, specifically infections, side effects of drugs or metabolic derangement due to damage to other organs. A single patient could have more than one NP syndrome and primary as well as secondary NPSLE could be established in the same patient. In cases where NP symptoms could not be related to SLE the patients were classified as ‘non-NPSLE’. If patients did not fulfil the classification criteria for SLE or if a different diagnosis was made, they were classified as ‘other disease’. Early onset NPSLE was defined as a diagnosis of NPSLE within 1 year after the diagnosis of SLE was recorded. Focal CNS, diffuse CNS and PNS manifestations were defined according to the 1999 ACR definitions.8

    All MRI scans were carried out on a Philips Gyroscan Intera ACS-NT 1.5T MR scanner (Philips Medical Systems, Best, The Netherlands). The first MRI scan of the brain made after the onset of NP symptoms was evaluated. White matter hyperintensities, infarctions, atrophy and all visible abnormalities were recorded.

    In cases of suspected cognitive dysfunction, the neuropsychological status was determined by means of an extensive neuropsychological battery including the domains suggested by the 1999 ACR NPSLE nomenclature and case definition system, appendix C.8

    The presence of the antiphospholipid syndrome was based on the preliminary classification criteria for definite antiphospholipid syndrome.20

    To determine whether the patients with NPSLE studied had a phenotype similar to the average SLE patient, the prevalence of the 1982 ACR criteria for SLE was listed and compared with the cohort used by the ACR as classic SLE patients.19 Descriptive statistics were used for the characteristics of patients.

    Results

    A total of 155 patients (90% women) fulfilled the criteria for SLE. The median age at SLE diagnosis in all patients was 29.7 years (IQR 20.5–40.3). In 102 patients (66%), primary NPSLE was diagnosed (91% women) and NP manifestations secondary to SLE-related problems were established in 15 patients (87% women). Four patients with primary NPSLE also developed secondary NPSLE during the course of their disease. In 42 patients with SLE, NP symptoms were not attributable to SLE (non-NPSLE). The median age of SLE diagnosis in this group was 34.9 years (IQR 26.1–42.7).

    The median age of SLE diagnosis in patients with primary NPSLE was 27.5 years (IQR 19.64–39.3). NP symptoms developed after a median of 2.8 years (IQR 0.4–9.0). Early onset NPSLE was observed in 40 patients (39%). In 21 of these 40 patients, NP symptoms were the first manifestation of SLE. The median age of SLE diagnosis in patients with secondary NPSLE was 23.3 years (IQR 15.4–40.1). In these patients, NP symptoms developed after a median of 1.3 years (IQR 0.2–10.7).

    NP syndromes in all patients with NPSLE are listed in table 1. In 102 patients with primary NPSLE, 172 syndromes were established. Fifty-six patients (55%) had one NP syndrome. Two or more NP syndromes were diagnosed in 45% of the patients; 28 patients (28%) had two NP syndromes, 13 (13%) had three NP syndromes, four patients (4%) had four NP syndromes and one patient had five different NP syndromes during the course of the disease. CNS manifestations accounted for 92% of the syndromes and PNS manifestations for 8%. Sixteen of the 19 established NP syndromes occurred at least once. The highest prevalence was found for cerebrovascular disease (CVD) (43%); a high prevalence was also found for seizures (28%), cognitive dysfunction (27%) and headache (23%). In secondary NPSLE the highest prevalence was for seizures (33%), headache (33%) and cognitive dysfunction (20%). The majority of secondary NPSLE manifestations were related to hypertension. Other causes were prednisone-induced psychosis, acute confusional state following septicaemia, mood disorders and cognitive dysfunction associated with seizures.

    View this table:
    Table 1

    Neuropsychiatric syndromes according to the American College of Rheumatology definitions in patients with primary and secondary neuropsychiatric systemic lupus erythematosus (NPSLE)8

    The prevalence of the 11 different ACR 1982 criteria for SLE is shown in table 2. The mean (SD) number of SLE criteria per patient was 6.3 (1.6) (median 6) exclusive of the NP symptoms. Antiphospholipid antibodies (aPL) were present in 69% of patients with primary NPSLE (table 3); 66% were positive for anticardiolipin antibodies (aCL) and 23% for lupus anticoagulant (LAC). The antiphospholipid syndrome was established in 25% of patients with primary NPSLE. aPL antibodies were found in 67% of patients with CVD, and 49% of these patients were diagnosed with the antiphospholipid syndrome.

    View this table:
    Table 2

    Revised ACR1982 SLE criteria (cumulative) present in 102 patients with primary NPSLE compared with the ACR 1982 cohort19

    View this table:
    Table 3

    Prevalence of antiphospholipid antibodies

    For the treatment of NP syndromes in this cohort, physicians prescribed methylprednisolone intravenously or high-dose oral prednisone in 69% of the patients, cyclophosphamide pulse therapy intravenously in 28%, azathioprine in 24%, aspirin in 22% and oral anticoagulants in 29% of patients.

    The MRI findings in 102 patients with primary NPSLE are listed in table 4. In 48 patients (47%) the MRI scan of the brain showed no abnormalities, including 14 patients with clinical stroke syndrome. In 22 patients with an abnormal MRI scan only non-specific abnormalities (white matter hyperintensities and atrophy) were found. This implies that, in 70 patients with primary NPSLE (69%), the MRI scan showed no or non-specific abnormalities.

    View this table:
    Table 4

    Imaging findings in 102 patients with primary NPSLE studied by MRI of the brain

    Discussion

    This study demonstrates that NP symptoms occur early in the disease course of SLE and that a large proportion of patients had no abnormalities on the MRI scan of the brain.

    The age of onset of SLE, the occurrence of NP symptoms after a mean of 2.8 years and the finding of 39% of patients having NP symptoms as the presenting symptoms are in line with previous studies.21 ,22 In a recent prospective analysis of a large inception cohort of patients with SLE, NP symptoms also frequently presented early in the disease course and 40% of the patients experienced at least one NP symptom within the first 3 years.23

    Only in the last decade has more evidence emerged for an autoimmune pathogenesis of NP symptoms in patients with SLE. Previously, the pathogenesis was largely unclear and a diagnosis of NPSLE was often disputed. Besides an autoimmune pathogenesis, thrombosis and atherosclerosis are other possible aetiological factors involved in NPSLE.

    Some features in our study suggest the involvement of immune-mediated pathogenetic mechanisms of NP manifestations. First, the early onset of NP symptoms indicates that SLE-specific mechanisms such as autoantibodies might be involved. In SLE, the specificity of autoreactive antibodies increases early in the development and disease course of SLE and it is also conceivable that antibodies that are cross-reactive with brain tissue develop during this process.24 Atherosclerosis is less likely as a possible pathogenetic mechanism since, owing to its progressive nature, a relation with young age is not expected.

    Second, the possible immune-mediated pathogenesis is supported by the absence of abnormalities on a conventional MRI scan of the brain in almost half of the patients, a phenomenon referred to as the ‘clinicoradiological paradox’. In a recent systematic analysis of MRI findings in the setting of NPSLE, the absence of MRI abnormalities despite signs and symptoms of active disease was found in 42% of all patients.25

    Previous studies have shown that normal appearing brain tissue is abnormal using quantitative imaging techniques such as volumetric magnetisation transfer imaging (MTI). The histograms produced by MTI reflect diffuse tissue abnormalities not visible on normal MR analysis which reflects contrast between structures. MTI histogram peak height values in NPSLE were lower than in controls or patients with SLE without NP symptoms but were the same as in patients with inactive multiple sclerosis. Moreover, MTI parameters in the active phase of NPSLE differed from those in the chronic phase.26 These quantitative volumetric estimates of global brain involvement correlated significantly with the neuropsychological test results as well as with proton magnetic resonance spectroscopy (1H-MRS) data (the N-acetylaspartate to creatine ratio), all suggesting neuronal dysfunction.27 ,28 We recently correlated postmortem histopathology with ex vivo 7-Tesla MRI scans in the brains of three patients with SLE. In the three patients high resolution MRI could not detect disturbances while histological examination of the normal appearing brain tissue showed complement deposition which was not observed in controls. Microthrombi were exclusively found in patients with NPSLE and were associated with C4d deposition (p=0.029).29

    This might indicate subtle and more diffuse involvement of brain tissue in some patients with NPSLE. Although the presence of aPL antibodies is correlated with focal syndromes such as stroke and seizures, these antibodies are also more frequently observed in SLE patients with diffuse NP manifestations such as cognitive dysfunction.30–32 MTI studies showed evidence for the fact that, apart from giving rise to macroscopic cerebral infarctions, aCL antibodies may play a role in the pathogenesis of diffuse microscopic brain damage in NPSLE.33 These data are in line with the observed correlation in this study between the antiphospholipid syndrome and CVD. However, in the group of NPSLE patients with CVD, MRI scans showed no abnormalities in a substantial proportion of patients. CVD was diagnosed by neurological dysfunction which could be attributed to ischaemia in brain tissue vascularised by a specific cerebral artery but was apparently not always caused by visible vascular occlusion or thrombosis.

    Compared with the literature, we found fewer patients with secondary NPSLE, especially infections. This could be caused by referral bias as many patients were referred to our clinic after careful evaluation in other departments or institutions.

    The selection of patients based on referral for an MRI scan of the brain might also cause other bias. First, not all patients with NP symptoms are referred for MRI scan and probably more severe cases will be selected. This is also indicated by the observation that a high number of patients were treated with immunosuppressive agents and anticoagulants. Second, more CNS disease and less PNS disease will be observed. This could explain the higher number of patients with CVD and lower number of patients with PNS disorders than reported in literature. On the other hand, clear cases with cerebral infarctions, aPL antibodies and compatible MRI abnormalities may have been referred less frequently and can therefore be underrepresented.

    We conclude that the epidemiology, imaging, quantitative imaging and studies that observed complement disposition in the tissue of patients with NPSLE taken from areas that were normal on 7-Tesla MRI all suggest a role for an immune-mediated pathogenesis, specifically in patients with SLE with diffuse NP symptoms.

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    Footnotes

    • Contributors All authors contributed sufficiently in the intellectual content, the analysis of data and the writing of the manuscript. Each has reviewed the final version of the manuscript and approves it for publication.

    • Funding None.

    • Competing interests None.

    • Provenance and peer review Commissioned; externally peer reviewed.