Cerebral imaging by magnetic resonance imaging and single photon emission computed tomography in systemic lupus erythematosus with central nervous system involvement

K. Oku, T. Atsumi, S. Furukawa, T. Horita, Y. Sakai, S. Jodo, Y. Amasaki, K. Ichikawa, O. Amengual and T. Koike

Department of Medicine II, Hokkaido University School of Medicine, N15 W7, Kita-ku, Sapporo 060-8638, Japan


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To assess the significance of magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) abnormalities in patients with systemic lupus erythematosus (SLE).

Methods. Forty-four patients with SLE were retrospectively analysed. Patients were classified into three groups [1 and 2: patients with central nervous system (CNS) manifestations before and after starting high-dose steroid therapy, respectively; 3: patients without CNS manifestations. MRI was performed in all 44 patients and SPECT in 31.

Results. Abnormal findings in MRI were found in 19 patients. MRI abnormalities were significantly more frequent in patients with CNS manifestations than in those without [71 vs 17%, odds ratio (OR) 11.9, confidence interval (CI) 2.8–49.9, P=0.0003]. After the initiation of steroid therapy, patients with CNS manifestations also had an increased frequency of abnormal MRI. No correlation was found between SPECT findings and CNS manifestations. However, patients with CNS manifestations after starting steroids showed a markedly increased frequency of abnormal MRI and SPECT compared with those without CNS manifestations (80 vs 7%; OR 56, CI 4.4–719, P=0.0003). The positive predictive value of abnormality in both techniques in developing CNS manifestations after starting steroids was 89%.

Conclusion. MRI findings correlated with CNS manifestations in SLE. Where there is a high suspicion of CNS involvement, the combination of MRI and SPECT may be useful in predicting CNS manifestations after starting steroid therapy.

KEY WORDS: MRI, SPECT, SLE, CNS involvement.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Involvement of the central nervous system (CNS) is one of the most important complications of systemic lupus erythematosus (SLE), partly accounting for significant morbidity [13]. Neuropsychiatric events are seen in 14–75% of patients with SLE with a wide range of clinical syndromes [4, 5]. Those clinical features are classified as neuropsychiatric lupus (NPSLE) [6].

Although the pathophysiology of CNS manifestations remains obscure, many mechanisms have been implicated in the pathogenesis of these disorders including vascular and perivascular immune complex-mediated damage [7], local production of cytokines and induction of cell-mediated autoreactivity [8], direct interactions of autoantibodies with antigens on neuronal cell membrane [9] and antiphospholipid antibody (aPL)-mediated thrombosis [10, 11].

Our understanding of NPSLE is still far from clear. First, it is difficult to distinguish between events resulting from the direct effect of active SLE on the CNS and events attributed to SLE-induced dysfunction of other organs or to the side-effects of drug therapy [12]. Second, the specific diagnostic methods have not been established.

Neuroimaging has greatly advanced our knowledge of brain lesions, but has severe limitations for diagnosis of active NPSLE. X-ray computed tomography can detect structural abnormalities, but has low sensitivity in evaluating NPSLE [13]. Magnetic resonance imaging (MRI) appears to provide a superior means of documenting the presence and course of cerebral damage in SLE [1417] and represents a valid way to assess disease progression or reversal in NPSLE [18]. Single photon emission computed tomography (SPECT) has been used to evaluate regional cerebral blood flow and proves accurate in detecting many neurological and psychiatric diseases [19, 20]. In addition, SPECT was shown to be very sensitive in detecting brain functional involvement in patients with rheumatic disorders [21]. However, SPECT findings in NPSLE show great variation and its utility for evaluation of CNS damage in SLE patients is not clearly established [22]. In this study, we investigated the significance of MRI and SPECT abnormalities in SLE patients and the correlation between the image findings and CNS manifestations, in particular, after starting steroid therapy.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Forty-four patients with SLE admitted to the Department of Internal Medicine II, Hokkaido University Hospital during 1996 to 2001 were included in the study. All patients fulfilled the American College of Rheumatology (ACR) criteria for SLE classification [23]. The study population comprised 40 females and two males, mean age 30 yr [range 15–57]. The records of all patients were carefully reviewed, retrospectively. The mean disease duration was 28 months (range 0–204) and disease activity was assessed in all the patients by the SLE disease activity index (SLEDAI). The diagnosis of NPSLE was made according to clinical findings and after exclusion of other causes of neuropsychiatric symptoms as required by the ACR criteria [6]. NPSLE comprised depressive state, psychosis, conscious disorder, manic state, meningitis, paranoia and ataxia. During the study, all patients received high-dose prednisolone, defined as 60 mg daily for more than 1 month. According to the presence of CNS manifestations, patients were divided into three groups; group 1 and group 2 included patients with CNS manifestations before and after starting steroid therapy, respectively, and group 3 comprised patients without CNS manifestations during the whole course of the disease.

Laboratory investigations
As part of their initial evaluation, all patients had routine haematological and laboratory tests. Sera were also tested for anti-double-stranded DNA antibodies (anti-dsDNA) by Farr assay, anti-Sm antibodies by enzyme-linked immunosorbent assay (ELISA) and levels of serum complement C3, C4 and CH50 by nephelometry. IgG and IgM anticardiolipin antibodies (aCL) were determined in our laboratory by ELISA as ß2-glycoprotein I (ß2GPI)-dependent aCL [24]. Lupus anticoagulant was evaluated in plasma according to the standard criteria [25].

MRI and SPECT
MRI was performed at the time of admission in all the patients and SPECT in 31, regardless of the existence of CNS manifestations.

MRI was performed utilizing a Diasonics MT/S system (Magnetom Vision/Magnetom Symphony; Siemens, Germany) employing a superconducting 0.5 tesla (T) magnet operating at 0.35 T. All images were obtained with a multislice, spin-echo technique imaging hydrogen nuclei; sections with a thickness of 7 mm at 10-mm intervals were obtained, with 1.7 mmx1.7 mm resolution. Spin lattice relaxation time (T1) and spin-spin transverse relaxation time (T2) abnormalities were examined.

SPECT was performed using [123I]-N-isopropyl-p-iodoamphetamine hexamethylpropylene (9300A/DI, Toshiba, Japan). Brain imaging experts in the Departments of Neuroradiology and Nuclear Medicine at Hokkaido University Hospital, who were partially blinded to the patients' clinical symptoms and serological profile, analysed and commented on the image findings.

Cerebral atrophy and fixed foci of T1 low/T2 high were diagnosed as abnormal MRI findings. Diffuse and partial hypoperfusion were diagnosed as abnormal SPECT findings (Fig. 1Go).



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FIG. 1. Typical MRI and SPECT pictures of cerebral lesions in patients with SLE. (A) T2 axial MRI shows the atrophic brain of a 33-yr-old female. Cerebral atrophy and fixed foci of T1 low/T2 high were diagnosed as abnormal findings. (B) A 123I-SPECT image in a patient with SLE shows diffuse hypoperfusion of the brain. Diffuse and partial hypoperfusion were diagnosed as abnormal SPECT findings.

 

Statistical analysis
The relative risk was approximated by odds ratio (OR) and P values determined by Fisher's exact test. P<0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Twenty-one (48%) patients had CNS manifestations; seven had them before the initiation of high-dose steroid therapy (group 1) while in 14 they appeared after the high-dose steroid treatment (group 2). No CNS manifestations were found in 23 (52%) patients (group 3).

Abnormal MRI findings were found in 19 patients (43%), 16% of whom had cerebral atrophy, 58% fixed foci of T1 low/T2 high and 26% had both patterns. Among 31 patients in whom SPECT was performed, 22 (71%) had abnormalities, 82% of whom showed partial and 18% diffuse hypoperfusion. Twelve patients (39%) had abnormal images in both techniques. There was no correlation between focal high-signal lesions in MRI and hypoperfusion on SPECT (data not shown).

The frequency of MRI abnormalities was significantly higher in patients with CNS manifestations than in those without (group 1+2 vs group 3; 71 vs 17%). After the initiation of steroids, patients with CNS manifestations also had an elevated frequency of abnormal MRI findings compared with those without CNS complications (group 2 vs group 3). No relationship was found between SPECT findings and CNS manifestations in any of the groups analysed. However, a higher frequency of abnormal findings in both MRI and SPECT was observed in patients with CNS manifestations than in those without (group 1+2 vs group 3; 69 vs 7%). In addition, patients with CNS manifestations after high-dose steroid therapy had a markedly elevated frequency of abnormal MRI and SPECT (80%). Table 1Go summarizes the correlations between MRI and/or SPECT abnormalities and CNS manifestations in patients with SLE with the statistical parameters.


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TABLE 1. Brain imaging in patients with SLE

 
The resulting positive predictive values of MRI, SPECT or both techniques for predicting CNS manifestations after starting steroid therapy (excluding patients with CNS manifestations before starting steroids) were 71, 50 and 89%, respectively (group 2 vs group 3).

No association was found among complement levels, anti-dsDNA, anti-Sm, aPL and CNS manifestations, nor among those and the imaging findings.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study evaluates the results of MRI and SPECT of the brain in SLE patients and the correlation between imaging findings and CNS manifestations before or after the initiation of high-dose steroid therapy. We show that abnormalities in both MRI and SPECT strikingly correlate with CNS manifestations after initiating steroid therapy.

MRI is currently the preferred anatomical imaging modality for evaluating SLE-associated brain lesions with high sensitivity [22]. We found abnormal MRI in 48% of SLE patients, but only in 13% of the patients without CNS manifestations. These data contrast with those reported by Kozora et al. [26] that showed abnormal findings in MRI in 35% of SLE patients without overt CNS disease. The difference in prevalence might be due to the use of a more sensitive quantitative MRI technique by these authors. Using MRI, it is extremely difficult to differentiate lesions that indicate active NPSLE from chronic lesions related to NPSLE or changes unrelated to SLE [16]. Recently, it has been demonstrated that magnetization transfer imaging (MTI), an MRI technique more sensitive to structural brain damage that the conventional method, can detect CNS damage in patients with a history of NPSLE and also cerebral changes in the active phase of CNS lupus [27, 28]. Although, MTI might be a diagnostic aid, more research is needed before it can be applied in a clinical setting.

Hyperintensity foci on T2 was the most frequent MRI abnormality in our population. A similar MRI pattern has been described in patients with aPL, implying a possible pathogenic link between abnormal white matter lesions and aPL (29, 30). We did not find an association between the presence of aPL and imaging abnormalities, suggesting that CNS manifestations are multifactorially related to SLE.

SPECT scanning has been used in the assessment of CNS involvement in SLE [3137] and proved highly sensitive, detecting abnormalities in up to 90% of patients with clinical neuropsychiatric involvement [13]. However, SPECT has low specificity and comparable abnormalities have been described in patients with acute stroke, transient ischaemic attacks, epilepsy and other neurological conditions [31]. We observed SPECT abnormalities in 22/31 (71%) patients. We did not find a correlation between those image findings and CNS manifestations, which is in agreement with data reported by Waterloo et al. [38] of lack of association between neuropsychological dysfunction in SLE patients and SPECT findings. Thus, SPECT scanning may be used mainly to support a clinical diagnosis of neuropsychiatric involvement.

The interpretation of SPECT images is difficult, and the importance of combining neuroimaging studies has been emphasized in order to assess both brain structure and function. SPECT and MRI may be complementary and useful examinations in the evaluation of neurological involvement in patients with juvenile SLE [39] and in the adult SLE population [36]. We combined SPECT and MRI in 31 patients and found abnormalities in both techniques in 12. Patients with image abnormalities in both techniques had a higher risk for neuropsychiatric involvement than those with normal image findings in at least one technique. Interestingly, we found a markedly higher frequency of MRI and SPECT abnormalities in patients with CNS manifestations after the steroid therapy. SPECT coupled with MRI might increase the diagnostic value of MRI. The combination of these two image techniques may be useful in predicting CNS manifestations after the initiation of high-dose steroid therapy. CNS manifestations after steroid treatment may comprise not only NPSLE but also ‘steroid psychosis’. In this study, we did not discriminate these two concepts since ‘steroid psychosis' is poorly defined. Thus, the strong correlation between MRI and SPECT abnormalities in these patients suggests that ‘steroid psychosis' is based on some organic brain lesions related to SLE.

No correlation was found between any specific MRI pattern and hypoperfusion in SPECT, therefore the alteration in brain metabolism reflected by SPECT cannot alone be responsible for NPSLE.

In conclusion, MRI clearly correlated with CNS manifestations in patients with SLE, and the combination of MRI and SPECT might be useful in predicting the CNS manifestations after steroid therapy in some patients. Therefore, performing MRI in conjunction with SPECT may contribute to the better management of NPSLE.


    Notes
 
Correspondence to: T. Atsumi. E-mail: at3tat{at}med.hokudai.ac.jp Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 4 July 2002; Accepted 28 November 2002





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