You are here

  • Home
  • Archive
  • Volume 77, Issue 3
  • Neuropsychiatric lupus or not? Cerebral hypoperfusion by perfusion-weighted MRI in normal-appearing white matter in primary neuropsychiatric lupus erythematosus

Article Text

Article menu

Download PDFPDF

Basic and translational research
Extended report
Neuropsychiatric lupus or not? Cerebral hypoperfusion by perfusion-weighted MRI in normal-appearing white matter in primary neuropsychiatric lupus erythematosus
  1. Efrosini Papadaki1,2,
  2. Antonis Fanouriakis3,4,
  3. Eleftherios Kavroulakis1,
  4. Dimitra Karageorgou1,
  5. Prodromos Sidiropoulos3,
  6. George Bertsias3,5,
  7. Panagiotis Simos2,6,
  8. Dimitrios T Boumpas4,5,7,8,9
  1. 1 Department of Radiology, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion, Greece
  2. 2 Institute of Computer Science, Foundation of Research and Technology, Heraklion, Greece
  3. 3 Department of Rheumatology, Clinical Immunology and Allergy, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion, Greece
  4. 4 Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodestrian University of Athens, Athens, Greece
  5. 5 Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, Heraklion, Greece
  6. 6 Department of Psychiatry, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion, Greece
  7. 7 Laboratory of Autoimmunity and Inflammation, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
  8. 8 Joint Academic Rheumatology Program, Medical School, National and Kapodestrian University of Athens, Athens, Greece
  9. 9 Medical School, University of Cyprus, Nicosia, Cyprus
  1. Correspondence to Ass. Professor Efrosini Papadaki, Department of Radiology, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion 71306, Greece; fpapada{at}otenet.gr

Abstract

Objectives Cerebral perfusion abnormalities have been reported in systemic lupus erythematosus (SLE) but their value in distinguishing lupus from non-lupus-related neuropsychiatric events remains elusive. We examined whether dynamic susceptibility contrast-enhanced perfusion MRI (DSC-MRI), a minimally invasive and widely available method of cerebral perfusion assessment, may assist neuropsychiatric SLE (NPSLE) diagnosis.

Methods In total, 76patients with SLE (37 primary NPSLE, 16 secondary NPSLE, 23 non-NPSLE) and 31 healthy controls underwent conventional MRI (cMRI) and DSC-MRI. Attribution of NPSLE to lupus or not was based on multidisciplinary assessment including cMRI results and response to treatment. Cerebral blood volume and flow were estimated in 18 normal-appearing white and deep grey matter areas.

Results The most common manifestations were mood disorder, cognitive disorder and headache. Patients with primary NPSLE had lower cerebral blood flow and volume in several normal-appearing white matter areas compared with controls (P<0.0001) and lower cerebral blood flow in the semioval centre bilaterally, compared with non-NPSLE and patients with secondary NPSLE (P<0.001). A cut-off for cerebral blood flow of 0.77 in the left semioval centre discriminated primary NPSLE from non-NPSLE/secondary NPSLE with 80% sensitivity and 67%–69% specificity. Blood flow values in the left semioval centre showed substantially higher sensitivity than cMRI (81% vs 19%–24%) for diagnosing primary NPSLE with the combination of the two modalities yielding 94%–100% specificity in discriminating primary from secondary NPSLE.

Conclusion Primary NPSLE is characterised by significant hypoperfusion in cerebral white matter that appears normal on cMRI. The combination of DSC-MRI-measured blood flow in the brain semioval centre with conventional MRI may improve NPSLE diagnosis.

  • magnetic resonance imaging
  • systemic lupus erythematosus
  • disease activity

https://doi.org/10.1136/annrheumdis-2017-212285

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Systemic lupus erythematosus (SLE) affects the peripheral and central nervous system in up to 30% of cases (neuropsychiatric SLE (NPSLE)). NPSLE can present with focal neurological deficits, often related to antiphospholipid antibodies (aPL),1 or diffuse manifestations that vary from overt (eg, seizures, psychosis) to subtle presentations such as headache, mood disturbances, anxiety disorders and cognitive dysfunction.2–4 Only in 40% symptoms can be attributed to underlying SLE (primary NPSLE). In the remaining cases, they may be secondary to treatment, other systemic causes or concomitant psychiatric disorders (secondary NPSLE).2–6

    Despite advances, NPSLE still poses diagnostic and therapeutic challenges. To facilitate patient care, we have developed recommendations for the management of patients with SLE presenting with neuropsychiatric manifestations.5 Within the European League Against Rheumatism (EULAR) recommendations, brain MRI is the imaging technique of choice.2 3 5 6 On conventional imaging, the most frequent finding is focal, small, white matter hyperintensities, commonly related to small-vessel disease.7–12 However, these abnormalities are non-specific and may be absent in >50% of patients with NSPLE .7 9 12–15 To this end, advanced MRI techniques promise greater sensitivity in detecting microstructural and metabolic changes in normal-appearing white matter and deep grey matter structures.16–21

    Dynamic susceptibility contrast-enhanced T2*-weighted perfusion MRI (DSC-MRI) provides a minimally invasive assessment of brain haemodynamic status through quantitative estimates of regional cerebral blood volume (CBV, a marker of blood volume per cerebral tissue volume) and cerebral blood flow (CBF, a marker of instantaneous capillary flow). In contrast to radionuclide techniques, DSC-MRI does not expose patients to radiation (only to gadolinium administration), affords higher spatial resolution, inherent co-registration to anatomical images and simultaneous measurement of CBV and CBF.22 Although DSC-MRI has become available in clinical practice, very few studies have used it in SLE, with contradictory results.16 22–25

    Direct associations between brain perfusion findings and neuropsychiatric symptoms, disease activity and severity indices, and attribution to SLE have been scarce. We performed DSC-MRI studies to assess (a) haemodynamic changes in the normal-appearing white and grey matter of patients with NPSLE, (b) associations between brain perfusion and disease activity and (c) the utility of perfusion indices in the diagnosis of primary NSPLE and the discrimination between primary and secondary NPSLE.

    Methods

    Participants

    Patients from the Department of Rheumatology, Clinical Immunology and Allergy of the University Hospital of Heraklion, Greece, who met the revised American College of Rheumatology (ACR)26 or  Systemic Lupus International Collaborating Clinics (SLICC)27 classification criteria for SLE, were included. Patients with thromboembolic cardiovascular disease or other primary central nervous system (CNS) diseases (elicited through history or evident on MRI) were excluded. A healthy control (HC) group of 31 volunteers who had no history of neurological or other diseases and no evident MRI abnormalities were enrolled to generate perfusion MRI reference standards. All participants signed informed consent (see also online supplementary material).

    Case definitions and attribution of neuropsychiatric manifestations to SLE

    Neuropsychiatric manifestations were defined according to the 1999 ACR nomenclature and case definitions.28 Diagnostic work-up was according to the EULAR recommendations5; diagnosis of cognitive dysfunction was made either with a formal neuropsychological assessment (performed by an expert neuropsychologist (PS))29 and/or the Montreal Cognitive Assessment.30 Attribution of NP events was based on physician judgement, following multidisciplinary approach6 and considering patient age, risk factors for primary NPSLE (aPL), prior major neuropsychiatric manifestation, generalised disease activity, findings of conventional MRI imaging and other diagnostic procedures. Additionally, the ACR ‘exclusion’ and ‘association’ factors (ie, their absence favours attribution to SLE), as well as ‘SLE-favouring factors’ of the Italian Study Group on NPSLE attribution model,31 were also considered. Attribution was ascertained after prospective follow-up of patients and has been additionally retrospectively cross-checked with existing attribution models31 32 (online supplementary table 1). Physicians were blind to the DSC-MRI results.

    MRI

    All MRI scans were performed on a 1.5 T MR scanner (Vision/Sonata, Siemens, Erlangen). Lesion burden of small (<1 cm) white matter hyperintensities on T2/FLAIR sequences was classified according to their absolute number: grade 0=none, grade 1 (mild)=1–5, grade 2 (moderate)=6–10 or grade 4 (severe) >10.24 The T2* DSC-MRI was performed with 2D single-shot multislice Gradient Echo Planar Imaging sequence (time repetition (TR)/time echo (TE)/flip angle (FA): 1500 ms/40 ms/30o, band width (BW): 2442 Hz/pixel, echo spacing: 0.47 ms, echo planar imaging factor 64). Relative CBV, CBF and mean transit time values of normal-appearing white matter and grey matter areas were calculated in 18 regions of interest (ROI) of the brain, including representative areas in the periventricular region, semioval centre and subcortical white matter (frontal, parietal, temporal, occipital lobes) and grey matter in the thalami, putamen and caudate nuclei. The aforementioned values were normalised for each patient, divided by the respective average values of the middle cerebellar peduncles.

    Statistical analysis

    One-way analysis of variance (ANOVA) was used to assess differences in perfusion measurements between HC and patient subgroups, separately for each of the 18 ROI (Bonferroni-adjusted α=0.003). In separate analyses, disease duration, hypertension and smoking were used as covariates. Associations with clinical variables were assessed through Pearson correlation coefficients (zero-order and partial, controlling for age, disease duration and hypertension). Receiver operator characteristic (ROC) analysis was used to determine the sensitivity and specificity of each perfusion measure alone to differentiate HC and patient subgroups. We estimated the sensitivity of each measure and corresponding cut-off value in distinguishing between the clinical subgroups in order to maintain a minimum specificity of 80%. Likewise, we computed the specificity of each measure to obtain a minimum sensitivity of 80%. All analyses were performed with SPSS V.20.

    Results

    Clinical and demographic data

    From the 76 patients with SLE included in the study, 37 were diagnosed as primary NSPLE, 16 as secondary NPSLE and 23 as non-NPSLE (online supplementary table S1). Most common manifestations in the primary NPSLE group were mood disorder (32.40%), cognitive disorder (13.5%) and headache (10.8%); in secondary NPSLE, mood disorders and anxiety disorders (25.0% each) (table 1). The three patient groups were comparable in terms of age, gender, treatment regimens, smoking and disease duration. Patients with primary NPSLE had higher total Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (P<0.0001) and SLEDAI scores excluding any neurological component (non-neurological SLEDAI, P=0.02). The HC group was comparable in terms of age with each of the three patient subgroups, except for a higher percentage of men (29% vs 10.8% in primary NPSLE, 0% in non-NPSLE and 12.5% in secondary NPSLE, respectively) Smoking did not differ between HC (19.4%) and the patient subgroups.

    View this table:
    Table 1

    Demographic, clinical and conventional MRI characteristics of SLE patients with and without neuropsychiatric involvement

    Higher lesion burden by conventional MRI in primary NPSLE

    MRI was normal in 15/37 (40.5%) primary NPSLE, 12/16 (75.0%) secondary SLE, 15/23 (65.2%) non-NPSLE patients and 28/31 (90.3%) HC. Within patients with abnormal MRI, the three subgroups did not differ significantly on the grade of white matter hyperintensities. Nevertheless, grade 3 lesions were slightly more prevalent in primary NPSLE (21.6%) compared with secondary NPSLE (12.5%) and non-NPSLE (13%) patients (table 1).

    Primary NPSLE displays widespread hypoperfusion in normal-appearing white matter

    Table 2 shows DSC-MRI results in several regions where significant between-group differences were found on perfusion measures. Analysis of covariance results remained essentially unchanged after inclusion of hypertension, disease duration and smoking as covariates (online supplementary result). Post hoc comparisons revealed significantly (P<0.003) reduced normalised CBF in patients with primary NPSLE compared with HC in the temporal, frontal, occipital, periventricular and semioval centre (the mass of white matter present in each hemisphere below the cerebral cortex) normal-appearing white matter bilaterally (figure 1). Reduced normalised CBV in primary NPSLE versus HC was found in frontal, periventricular and semioval centre normal-appearing white matter, bilaterally, as well as in all normal-appearing grey matter regions (online supplementary figure S1). Differences between HC and non-NPSLE or secondary NPSLE patients were not statistically significant in any ROI. Moreover, primary NPSLE displayed reduced CBF compared with non-NPSLE patients in left occipital and bilateral temporal and semioval centre normal-appearing white matter. The former group also displayed reduced CBV in the left semioval centre and thalamus. Together, these data suggest that primary NPSLE is characterised by widespread hypoperfusion across various cerebral regions.

    View this table:
    Table 2

    Main effects of group on normalised CBF and CBV in normal-appearing white matter and normal-appearing deep grey matter

    Figure 1
    Figure 1

    Average normalised cerebral blood flow (CBF) values in normal-appearing white matter regions of interest (ROIs) for healthy controls (HC), non-neuropsychiatric systemic lupus erythematosus (NPSLE), secondary NPSLE (S-NPSLE) and primary NPSLE patients (P-NPSLE). The locations of ROIs where perfusion measurements were made on scans from a representative HC participant are shown by white circles. Significant pairwise group differences (at Bonferroni-adjusted P<0.003) are indicated by brackets. Bars indicate SE. L, left hemisphere; PVL, periventricular white matter; R, right hemisphere; SOC, semioval centre.

    Normal-appearing white matter hypoperfusion is greater in primary compared with secondary NPSLE

    Attribution of neuropsychiatric, particularly non-focal, events to SLE is challenging in clinical practice. We examined the utility of perfusion MRI in discriminating primary from secondary NPSLE by performing pairwise comparisons in the ROIs where significant between-group effects were detected (table 2) and after controlling for MRI lesion load (grade 1–3). Patients with primary NPSLE demonstrated significantly reduced normalised CBF in the left and right semioval centres (P=0.001; figure 1) and CBV in the left thalamus (P=0.0001; online supplementary figure S1), compared with patients with secondary NPSLE. Similar, yet non-significant, trends were observed in several other normal-appearing white matter regions and grey matter structures. These findings suggest that patients with primary NPSLE may exhibit hypoperfusion at least in selected areas of the brain compared with patients with neuropsychiatric manifestations not attributable to SLE.

    Hypoperfusion in the brain semioval centre bilaterally correlates with SLE activity

    The clinical relevance of hypoperfusion in the left and right semioval centres was further examined through correlational analyses against disease characteristics in the entire SLE cohort. Weak negative correlations were found between disease duration and normalised CBF in the left (r=−0.282, P=0.04) and right semioval centres (r=−0.321, P=0.02). Reduced perfusion in these normal-appearing white matter ROIs correlated with increased disease activity (SLEDAI score: r=−0.409, P=0.003, and r=−0.399, P=0.003, respectively). These associations remained significant after controlling for age, disease duration and hypertension (left semioval centre: r=−0.386, P=0.007; right semioval centre: r=−0.355, P=0.009).

    Clinical validity of perfusion measures in the diagnosis of primary NPSLE

    To define the diagnostic utility of perfusion MRI, we performed ROC analyses to calculate sensitivity and specificity for discrimination between patient groups. Table 3 shows results of these analyses only if either specificity and/or sensitivity exceeded 50%. This criterion was met by three CBF indices, namely average normalised CBF across all normal-appearing white matter ROIs, and normalised CBF in the left and right semioval centres. Among single ROI indices, best results were obtained with CBF from the left semioval centre. Specifically, discrimination of primary NPSLE from HC was optimal using a normalised CBF cut-off of 0.77, to achieve 80% sensitivity and 78% specificity (figure 2, upper panel). Normalised CBF values from the left semioval centre (using the same cut-off of 0.77) showed 80% sensitivity and 67% specificity to discriminate primary NPSLE from non-NPSLE (figure 2, middle panel). Finally, normalised CBF values from the left semioval centre discriminated between primary and secondary NPSLE with 80% sensitivity and 69% specificity (figure 2, lower panel). Together, these findings indicate that perfusion measurements in the left semioval centre can differentiate patients with primary NPSLE from other groups of HC or patients with SLE (non-NPSLE or secondary NPSLE).

    Figure 2
    Figure 2

    Receiver  operator  characteristic  curve illustrating the relationship between sensitivity and 1-specificity in discriminating healthy participants from patients with primary neuropsychiatric systemic lupus erythematosus (NPSLE) (top panel), patients with SLE without neuropsychiatric manifestations from patients with primary NPSLE (middle panel) and patients with secondary neuropsychiatric manifestations from patients with primary NPSLE (lower panel), using normalised cerebral blood flow in left semioval centre normal-appearing white matter.

    View this table:
    Table 3

    Receiver operating characteristic analyses results, estimating sensitivity and specificity of perfusion measures in differentiating healthy participants (n=31), systemic lupus erythematosus (SLE) control (n=39), patients with primary neuropsychiatric SLE (NPSLE) (n=37) and secondary NPSLE (n=16)

    Combined perfusion and conventional MRI data allow for more accurate diagnosis of primary NPSLE with a sensitivity and specificity >80%

    Since conventional MRI is the recommended neuroimaging modality for NPSLE diagnosis, we sought to define the comparative and combined diagnostic utility of perfusion MRI and conventional MRI for identifying primary from secondary and non-NPSLE patients (table 4). CBF measures alone (especially in the left semioval centre) conferred substantial improvement in the ability to detect primary NPSLE cases over conventional MRI (81% vs 19%–24% for grade 1–3 brain lesions) with a modest reduction in specificity (68% vs 89%–100%). CBF in the right semioval centre provided similar specificity with left semioval centre CBF, although with moderately reduced sensitivity. Sensitivity estimates based on average normal-appearing white matter CBF were clearly inferior to those based on CBF in either semioval centre.

    View this table:
    Table 4

    Sensitivity and specificity of neuroimaging data in differentiating between systemic lupus erythematosus (SLE) controls (non-neuropsychiatric SLE (NPSLE)/secondary NPLSE) and patients with primary NPSLE

    Discussion

    This is the first DSC-MRI study in SLE to evaluate perfusion in normal-appearing white matter (ie, excluding white matter hyperintensities from the analyses) including also patients with secondary NPSLE as a separate clinical group. Our findings confirmed the presence of diffuse normal-appearing white matter hypoperfusion in primary NPSLE. Hypoperfusion, more pronounced in the semioval centre, could differentiate between patients with primary NPSLE and those with either no NP symptoms or with NP symptoms not attributed to the disease. Adopting a normalised left semioval centre CBF cut-off value of 0.77 increased the sensitivity for differentiating between primary and secondary NPSLE by a factor of 4 (81% vs 19%–24%) compared with conventional MRI findings alone, with only a small reduction in specificity (68% vs 75%).

    White matter hyperintensities are the most common MRI finding in diffuse NPSLE (40%–80%) but their specificity is low.10 In accordance with previous reports,7 9 10 12 MRI was normal in 55% of all SLE and 40% of primary NPSLE patients. Notably, histologically verified, small-vessel injury may be undetectable even with postmortem high-field MRI of 7T.8 In contrast, DSC-MRI detected brain hypoperfusion in 73% of patients with primary NPSLE, 27% of non-NPSLE patients and 33% of patients with secondary NPSLE who had normal conventional MRI (online supplementary table S2). Previous perfusion MRI studies have yielded conflicting results,16 22–25 possibly due to study variations in MR scanners and postprocessing techniques. Our finding of diffuse hypoperfusion in NPSLE concords with studies using PET and SPECT revealed moderate-to-severe perfusion defects in multiple brain regions.33–38

    Hypoperfusion in primary NPSLE was more pronounced in the semioval centre, a region associated with the lowest normalised CBF and CBV values, compared with other normal-appearing white matter areas. This may be due to increased susceptibility of this territory to haemodynamic impairment. Specifically, the distal region of semioval centre is perfused by the internal carotid artery and is located in the border zone between the territories of supply of the superficial perforators of the middle cerebral artery and the anterior cerebral artery (internal watershed area),39 thus being prone to cerebral small-vessel disease, which is prominent in SLE.40 41 Hypoperfusion was noted despite the fact that numerically more patients with primary NPSLE were using antiplatelet agents at the time of evaluation. Also, these patients had longer disease duration compared with patients with secondary NPSLE (mean 5.3 vs 2.8 years, respectively); although one could argue that this could have impacted brain perfusion, observational studies suggest that most SLE-attributed neuropsychiatric manifestations occur early in the disease course and do not arise as a result of long-standing disease. To this end, differences in perfusion estimates in our study were not affected by disease duration (online supplementary result).

    Autopsy findings have revealed widespread vascular lesions in NPSLE. Vasculopathy or hypercoagulopathy, resulting in diffuse chronic ischaemia and neuronal loss, are putative pathogenic processes.8 42 43 Our finding of widespread reduction of CBF and CBV in normal-appearing white matter of patients with NPSLE is consistent with these histopathological changes. True cerebral vasculitis is infrequent (6%–9%) and has been linked to inflammatory-like lesions on MRI, defined as medium or large, ill-defined, enhancing T2 hyperintensities.10 Such lesions were detected only in 5% of our patients with primary NPSLE. Inflammatory activity has been related to increased perfusion due to inflammation-mediated vasodilation.44 Our findings of diffuse hypoperfusion, along with the rarity of inflammatory-like lesions on conventional MRI, suggest that in most cases primary NPSLE is characterised by chronic widespread decreased perfusion and ischaemia due to microvasculopathy and subsequent neuronal loss in the absence of high-grade inflammation.

    In agreement with previous SPECT studies, we observed a trend for reduced perfusion in non-NPSLE patients compared with HC.33 35 37 38 Histopathological studies have showed non-specific focal vasculopathy in SLE without NP manifestations, while diffuse vasculopathy and microthrombi occurred more often in NPSLE. It has been proposed that ischaemic injury may occur in all patients with SLE, but primary NP manifestations emerge only after exceeding a certain threshold of ischaemic injury.8 By analogy, the normalised CBF cut-off value of 0.77 could correspond to the magnitude of hypoperfusion caused by ischaemic injury, which is necessary to induce NP manifestations in patients with SLE.

    Basal ganglia pathology in NPSLE is far less common (12%–30%) than in the white matter.37 45 In the present study, significant basal ganglia hypoperfusion in patients with NPSLE was evidenced only on CBV, although a potential bias in DSC-MR-based perfusion estimates due to increased iron deposition in the putamen, enhancing the susceptibility effect, cannot be ruled out.46

    Attribution of neuropsychiatric manifestations to SLE largely relies on expert physician judgement; neither clinical parameters nor conventional MRI have sufficient individual diagnostic accuracy. Moreover, recently proposed attribution models show suboptimal performance in non-focal manifestations. We employed multidisciplinary assessment tailored to each case and NP manifestation for attribution,6 47 and similar approaches have been used by others.48 We have also recently cross-checked our judgement with existing attribution models.6 49 In this process, tools that could aid the diagnostic process are eagerly awaited. While the cause of preferential hypoperfusion in the left semioval centre in primary NPSLE is not yet definitive, it provides proof of concept that attribution of neuropsychiatric manifestations to SLE can be assisted by parameters more objective than sole physician assessment. Notably, however, these results apply mainly to diffuse NPSLE as most of our patients had such manifestations and may not be directly extrapolated to all NPSLE syndromes.

    In addition to sample size, there are some limitations in our study. First, we had no data regarding internal carotid arteries atherosclerosis, which might affect cerebral perfusion. Although Doppler carotid artery examination was not performed in the context of our study, substantial left–right asymmetries in brain perfusion (suggestive of significant unilateral carotid stenosis) were not evident in our population (online supplementary material). Second, the HC group, which was recruited to obtain perfusion MRI reference standards, was not formally matched to patients with SLE and included more men. Nonetheless, auxiliary analyses showed (a) no significant gender bias on perfusion measurements and (b) between-groups differences in perfusion were unchanged when men were excluded (online supplementary results). Additional limitations include (a) the need for data normalisation using measurements from a brain structure assumed not to be affected by the disease (here, the middle cerebellar peduncle as the least frequently involved area in diffuse NPSLE50) and (b) the unreliability of cortical perfusion estimates, which were not obtained in the present study to avoid susceptibility effects from small vessels in the adjacent subarachnoid space.16 23–25

    In conclusion, DSC-MRI was able to detect brain haemodynamic abnormalities, even in the absence of macroscopic anatomic lesions, in patients with primary NPSLE. The present findings highlight the potential utility of perfusion indices in clinical practice for the diagnosis of NPSLE, in addition to conventional neuroimaging techniques recommended by the EULAR, with limited or no additional expense for the patient. Larger longitudinal studies, including comparisons before and after therapy, are needed to validate these data.

    Acknowledgments

    AF’s contribution to this work has been supported in part by a grant from the Hellenic Society of Rheumatology.

    References

    1. ↵
      2. Kitagawa Y ,
      3. Gotoh F ,
      4. Koto A , et al
      . Stroke in systemic lupus erythematosus. Stroke 1990;21:1533–9.
      OpenUrlAbstract/FREE Full Text
    2. ↵
      2. Bertsias GK ,
      3. Boumpas DT
      . Pathogenesis, diagnosis and management of neuropsychiatric SLE manifestations. Nat Rev Rheumatol 2010;6:358–67.doi:10.1038/nrrheum.2010.62
      OpenUrlCrossRefPubMed
    3. ↵
      2. Futrell N ,
      3. Schultz LR ,
      4. Millikan C
      . Central nervous system disease in patients with systemic lupus erythematosus. Neurology 1992;42:1649–57.doi:10.1212/WNL.42.9.1649
      OpenUrlCrossRefPubMed
    4. ↵
      2. Stojanovich L ,
      3. Zandman-Goddard G ,
      4. Pavlovich S , et al
      . Psychiatric manifestations in systemic lupus erythematosus. Autoimmun Rev 2007;6:421–6.doi:10.1016/j.autrev.2007.02.007
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      2. Bertsias GK ,
      3. Ioannidis JP ,
      4. Aringer M , et al
      . EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 2010;69:2074–82.doi:10.1136/ard.2010.130476
      OpenUrlAbstract/FREE Full Text
    6. ↵
      2. Fanouriakis A ,
      3. Pamfil C ,
      4. Rednic S , et al
      . Is it primary neuropsychiatric systemic lupus erythematosus? Performance of existing attribution models using physician judgment as the gold standard. Clin Exp Rheumatol 2016;34:910–7.
      OpenUrl
    7. ↵
      2. Appenzeller S ,
      3. Pike GB ,
      4. Clarke AE
      . Magnetic resonance imaging in the evaluation of central nervous system manifestations in systemic lupus erythematosus. Clin Rev Allergy Immunol 2008;34:361–6.doi:10.1007/s12016-007-8060-z
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      2. Cohen D ,
      3. Rijnink EC ,
      4. Nabuurs RJ , et al
      . Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement. Rheumatology 2017;56:77–86.doi:10.1093/rheumatology/kew341
      OpenUrlCrossRefPubMed
    9. ↵
      2. Jennings JE ,
      3. Sundgren PC ,
      4. Attwood J , et al
      . Value of MRI of the brain in patients with systemic lupus erythematosus and neurologic disturbance. Neuroradiology 2004;46:15–21.doi:10.1007/s00234-003-1049-2
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      2. Sarbu N ,
      3. Alobeidi F ,
      4. Toledano P , et al
      . Brain abnormalities in newly diagnosed neuropsychiatric lupus: systematic MRI approach and correlation with clinical and laboratory data in a large multicenter cohort. Autoimmun Rev 2015;14:153–9.doi:10.1016/j.autrev.2014.11.001
      OpenUrlCrossRefPubMed
    11. ↵
      2. Sibbitt WL ,
      3. Brooks WM ,
      4. Kornfeld M , et al
      . Magnetic resonance imaging and brain histopathology in neuropsychiatric systemic lupus erythematosus. Semin Arthritis Rheum 2010;40:32–52.doi:10.1016/j.semarthrit.2009.08.005
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      2. Toledano P ,
      3. Sarbu N ,
      4. Espinosa G , et al
      . Neuropsychiatric systemic lupus erythematosus: magnetic resonance imaging findings and correlation with clinical and immunological features. Autoimmun Rev 2013;12:1166–70.doi:10.1016/j.autrev.2013.07.004
      OpenUrlCrossRefPubMed
    13. ↵
      2. Bortoluzzi A ,
      3. Padovan M ,
      4. Azzini C , et al
      . Brain unidentified bright objects (“UBO”) in systemic lupus erythematosus: sometimes they come back. A study of microembolism by cMRI and Transcranial Doppler ultrasound. Lupus 2016;25:193–8.doi:10.1177/0961203315608256
      OpenUrlCrossRefPubMed
    14. ↵
      2. Luyendijk J ,
      3. Steens SC ,
      4. Ouwendijk WJ , et al
      . Neuropsychiatric systemic lupus erythematosus: lessons learned from magnetic resonance imaging. Arthritis Rheum 2011;63:722–32.doi:10.1002/art.30157
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      2. Zardi EM ,
      3. Taccone A ,
      4. Marigliano B , et al
      . Neuropsychiatric systemic lupus erythematosus: tools for the diagnosis. Autoimmun Rev 2014;13:831–9.doi:10.1016/j.autrev.2014.04.002
      OpenUrlCrossRefPubMed
    16. ↵
      2. Emmer BJ ,
      3. van Osch MJ ,
      4. Wu O , et al
      . Perfusion MRI in neuro-psychiatric systemic lupus erthemathosus. J Magn Reson Imaging 2010;32:283–8.doi:10.1002/jmri.22251
      OpenUrlCrossRefPubMed
    17. ↵
      2. Emmer BJ ,
      3. Veer IM ,
      4. Steup-Beekman GM , et al
      . Tract-based spatial statistics on diffusion tensor imaging in systemic lupus erythematosus reveals localized involvement of white matter tracts. Arthritis Rheum 2010;62:3716–21.doi:10.1002/art.27717
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      2. Filley CM ,
      3. Kozora E ,
      4. Brown MS , et al
      . White matter microstructure and cognition in non-neuropsychiatric systemic lupus erythematosus. Cogn Behav Neurol 2009;22:38–44.doi:10.1097/WNN.0b013e318190d174
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      2. Sundgren PC ,
      3. Jennings J ,
      4. Attwood JT , et al
      . MRI and 2D-CSI MR spectroscopy of the brain in the evaluation of patients with acute onset of neuropsychiatric systemic lupus erythematosus. Neuroradiology 2005;47:576–85.doi:10.1007/s00234-005-1371-y
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      2. Welsh RC ,
      3. Rahbar H ,
      4. Foerster B , et al
      . Brain diffusivity in patients with neuropsychiatric systemic lupus erythematosus with new acute neurological symptoms. J Magn Reson Imaging 2007;26:541–51.doi:10.1002/jmri.21036
      OpenUrlCrossRefPubMed
    21. ↵
      2. Zhang L ,
      3. Harrison M ,
      4. Heier LA , et al
      . Diffusion changes in patients with systemic lupus erythematosus. Magn Reson Imaging 2007;25:399–405.doi:10.1016/j.mri.2006.09.037
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      2. Borrelli M ,
      3. Tamarozzi R ,
      4. Colamussi P , et al
      . Evaluation with MR, perfusion MR and cerebral flowSPECT in NPSLE patients. Radiol Med 2003;105:482–9.
      OpenUrlPubMed
    23. ↵
      2. Gasparovic CM ,
      3. Roldan CA ,
      4. Sibbitt WL , et al
      . Elevated cerebral blood flow and volume in systemic lupus measured by dynamic susceptibility contrast magnetic resonance imaging. J Rheumatol 2010;37:1834–43.doi:10.3899/jrheum.091276
      OpenUrlAbstract/FREE Full Text
    24. ↵
      2. Wang PI ,
      3. Cagnoli PC ,
      4. McCune WJ , et al
      . Perfusion-weighted MR imaging in cerebral lupus erythematosus. Acad Radiol 2012;19:965–70.doi:10.1016/j.acra.2012.03.023
      OpenUrlCrossRefPubMed
    25. ↵
      2. Zimny A ,
      3. Szmyrka-Kaczmarek M ,
      4. Szewczyk P , et al
      . In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy, perfusion-weighted and diffusion-tensor imaging. Lupus 2014;23:10–19.doi:10.1177/0961203313511556
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      2. Hochberg MC
      . Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.doi:10.1002/art.1780400928
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      2. Petri M ,
      3. Orbai AM ,
      4. Alarcón GS , et al
      . Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677–86.doi:10.1002/art.34473
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599–608.doi:10.1002/1529-0131(199904)42:4<599::AID-ANR2>3.0.CO;2-F
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      2. Karademas EC ,
      3. Ktistaki G ,
      4. Dimitraki G , et al
      . Adaptation to an autoimmune disorder: Does mental flexibility impact illness-related self-regulation? Psychol Health 2016;31:276–91.doi:10.1080/08870446.2015.1083568
      OpenUrl
    30. ↵
      2. Nasreddine ZS ,
      3. Phillips NA ,
      4. Bédirian V , et al
      . The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695–9.doi:10.1111/j.1532-5415.2005.53221.x
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      2. Bortoluzzi A ,
      3. Scirè CA ,
      4. Bombardieri S , et al
      . Development and validation of a new algorithm for attribution of neuropsychiatric events in systemic lupus erythematosus. Rheumatology 2015;54:891–8.doi:10.1093/rheumatology/keu384
      OpenUrlCrossRefPubMed
    32. ↵
      2. Hanly JG ,
      3. Urowitz MB ,
      4. Sanchez-Guerrero J , et al
      . Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: an international inception cohort study. Arthritis Rheum 2007;56:265–73.doi:10.1002/art.22305
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      2. Chen JJ ,
      3. Yen RF ,
      4. Kao A , et al
      . Abnormal regional cerebral blood flow found by technetium-99m ethyl cysteinate dimer brain single photon emission computed tomography in systemic lupus erythematosus patients with normal brain MRI findings. Clin Rheumatol 2002;21:516–9.doi:10.1007/s100670200126
      OpenUrlCrossRefPubMedWeb of Science
    34. ↵
      2. Handa R ,
      3. Sahota P ,
      4. Kumar M , et al
      . In vivo proton magnetic resonance spectroscopy (MRS) and single photon emission computerized tomography (SPECT) in systemic lupus erythematosus (SLE). Magn Reson Imaging 2003;21:1033–7.doi:10.1016/S0730-725X(03)00200-5
      OpenUrlCrossRefPubMedWeb of Science
    35. ↵
      2. Kao CH ,
      3. Lan JL ,
      4. ChangLai SP , et al
      . The role of FDG-PET, HMPAO-SPET and MRI in the detection of brain involvement in patients with systemic lupus erythematosus. Eur J Nucl Med 1999;26:129–34.doi:10.1007/s002590050368
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      2. Lee SW ,
      3. Park MC ,
      4. Lee SK , et al
      . The efficacy of brain (18)F-fluorodeoxyglucose positron emission tomography in neuropsychiatric lupus patients with normal brain magnetic resonance imaging findings. Lupus 2012;21:1531–7.doi:10.1177/0961203312459104
      OpenUrlCrossRefPubMed
    37. ↵
      2. Lin WY ,
      3. Wang SJ ,
      4. Yen TC , et al
      . Technetium-99m-HMPAO brain SPECT in systemic lupus erythematosus with CNS involvement. J Nucl Med 1997;38:1112–5.
      OpenUrlAbstract/FREE Full Text
    38. ↵
      2. Zhang X ,
      3. Zhu Z ,
      4. Zhang F , et al
      . Diagnostic value of single-photon-emission computed tomography in severe central nervous system involvement of systemic lupus erythematosus: a case-control study. Arthritis Rheum 2005;53:845–9.doi:10.1002/art.21591
      OpenUrlCrossRefPubMedWeb of Science
    39. ↵
      2. Momjian-Mayor I ,
      3. Baron JC
      . The pathophysiology of watershed infarction in internal carotid artery disease: review of cerebral perfusion studies. Stroke 2005;36:567–77.doi:10.1161/01.STR.0000155727.82242.e1
      OpenUrlAbstract/FREE Full Text
    40. ↵
      2. Wardlaw JM ,
      3. Smith C ,
      4. Dichgans M
      . Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013;12:483–97.doi:10.1016/S1474-4422(13)70060-7
      OpenUrlCrossRefPubMedWeb of Science
    41. ↵
      2. Wiseman SJ ,
      3. Bastin ME ,
      4. Jardine CL , et al
      . Cerebral small vessel disease burden is increased in systemic lupus erythematosus. Stroke 2016;47:2722–8.doi:10.1161/STROKEAHA.116.014330
      OpenUrlAbstract/FREE Full Text
    42. ↵
      2. Devinsky O ,
      3. Petito CK ,
      4. Alonso DR
      . Clinical and neuropathological findings in systemic lupus erythematosus: the role of vasculitis, heart emboli, and thrombotic thrombocytopenic purpura. Ann Neurol 1988;23:380–4.doi:10.1002/ana.410230411
      OpenUrlCrossRefPubMedWeb of Science
    43. ↵
      2. Hanly JG ,
      3. Walsh NM ,
      4. Sangalang V
      . Brain pathology in systemic lupus erythematosus. J Rheumatol 1992;19:732–41.
      OpenUrlPubMedWeb of Science
    44. ↵
      2. Papadaki EZ ,
      3. Mastorodemos VC ,
      4. Amanakis EZ , et al
      . White matter and deep gray matter hemodynamic changes in multiple sclerosis patients with clinically isolated syndrome. Magn Reson Med 2012;68:1932–42.doi:10.1002/mrm.24194
      OpenUrlCrossRefPubMed
    45. ↵
      2. Colamussi P ,
      3. Giganti M ,
      4. Cittanti C , et al
      . Brain single-photon emission tomography with 99mTc-HMPAO in neuropsychiatric systemic lupus erythematosus: relations with EEG and MRI findings and clinical manifestations. Eur J Nucl Med 1995;22:17–24.doi:10.1007/BF00997243
      OpenUrlCrossRefPubMedWeb of Science
    46. ↵
      2. Ogasawara A ,
      3. Kakeda S ,
      4. Watanabe K , et al
      . Quantitative susceptibility mapping in patients with systemic lupus erythematosus: detection of abnormalities in normal-appearing basal ganglia. Eur Radiol 2016;26:1056–63.doi:10.1007/s00330-015-3929-3
      OpenUrl
    47. ↵
      2. Pamfil C ,
      3. Fanouriakis A ,
      4. Damian L , et al
      . EULAR recommendations for neuropsychiatric systemic lupus erythematosus vs usual care: results from two European centres. Rheumatology 2015;54:1270–8.doi:10.1093/rheumatology/keu482
      OpenUrlCrossRefPubMed
    48. ↵
      2. Zirkzee EJ ,
      3. Steup-Beekman GM ,
      4. van der Mast RC , et al
      . Prospective study of clinical phenotypes in neuropsychiatric systemic lupus erythematosus; multidisciplinary approach to diagnosis and therapy. J Rheumatol 2012;39:2118–26.doi:10.3899/jrheum.120545
      OpenUrlAbstract/FREE Full Text
    49. ↵
      2. Bortoluzzi A ,
      3. Fanouriakis A ,
      4. Appenzeller S , et al
      . Validity of the Italian algorithm for the attribution of neuropsychiatric events in systemic lupus erythematosus: a retrospective multicentre international diagnostic cohort study. BMJ Open 2017;7:e015546.doi:10.1136/bmjopen-2016-015546
    50. ↵
      2. Mauro D ,
      3. Barbagallo G ,
      4. D’Angelo S , et al
      . Role of positron emission tomography for central nervous system involvement in systemic autoimmune diseases: status and perspectives. Curr Med Chem 2017.doi:10.2174/0929867324666170523144402

    Footnotes

    • AF and EK contributed equally.

    • Handling editor Tore K Kvien

    • Contributors EP designed the study, performed and interpreted the MRI exams, analysed the MR perfusion data, wrote, edited and critically reviewed the manuscript. AF performed clinical examination of patients, edited the manuscript. EK collected image data and performed image analysis. DK performed image analysis. PS performed clinical examination of patients. GB performed clinical examination of patients, edited and critically reviewed the manuscript. PS performed neuropsychological assessment and statistical analysis, edited and critically reviewed the manuscript. DTB designed the study, performed clinical examination of patients, edited and critically reviewed the manuscript. All authors contributed substantially to discussion of content.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval University Hospital of Heraklion Ethical Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.