Evaluation of Symptom-Oriented Selection of Computed Tomography or Magnetic Resonance Imaging for Neuropsychiatric Systemic Lupus Erythematosus

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1 J Radiol Sci 2015; 40: Evaluation of Symptom-Oriented Selection of Computed Tomography or Magnetic Resonance Imaging for Neuropsychiatric Systemic Lupus Erythematosus Hung-Wen Kao 1,2 Chao-Jan Wang 3 Shy-Chyi Chin 3 Department of Radiology 1, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Department of Biomedical Imaging and Radiological Sciences 2, National Yang-Ming University, Taipei, Taiwan Department of Medical Imaging and Intervention 3, Linkou Chang-Gung Memorial Hospital, School of Medicine, Chang Gung University, Taoyuan, Taiwan ABSTRACT The purpose of this study is to assess the value of computed tomography (CT) and magnetic resonance imaging (MRI) for patients with symptoms of neuropsychiatric systemic lupus erythematosus (NPSLE) that vary in severity. Seventy-one patients with NPSLE were enrolled and divided into two groups based on symptom severity: (1) those with mild symptoms including mania, depression, intermittent headache, movement disorders and cognitive impairment, and (2) those with severe symptoms including focal/generalized seizures, hemiparesis and delirium. Cranial CT was performed as a primary screening tool in all cases. Medical charts and imaging findings were reviewed to determine whether CT and MRI findings were sufficient to explain the observed symptoms. Statistical significance was evaluated using the Chi-Square and McNemar tests. For patients with mild symptoms, no differences in positive rates were observed between CT and MRI findings (p = 0.996). Positive rates for both CT and MRI findings were higher in patients with severe symptoms than those with mild symptoms (p < 0.001). For patients with severe symptoms, however, higher positive rates were observed for MRI as compared to CT (p = 0.016). Modern brain imaging permits NPSLE symptoms to be categorized concisely. Not every patient with NPSLE symptoms should receive MRI; when symptoms are mild, the utility of CT is equivalent to that of MRI. When symptoms are severe, however, MRI is superior to CT for explanation of symptoms and guidance in selection of treatment. Neuropsychiatric symptoms are now recognized as sequel of the effects of systemic lupus erythematosus (SLE) on central nervous system (CNS). Findings of Petri and colleagues support the possibilities that the brain is affected extremely early in the course of the disease and that CNS manifestations of the disease may be present prior to diagnosis [1]. However, clinical manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE) are remarkably diverse. To date, the criteria for classification of NPSLE symptoms are based mainly on the guidelines of the American College of Rheumatology (ACR) agreement of 1999 [2]. In 2004, the ACR criteria for symptoms of NPSLE were revised for further classification of twelve clinical presentations [3]. Brain magnetic resonance imaging (MRI) was initially found to be abnormal in approximately 25% of patients with newly diagnosed SLE [1]. With the increased recognition of symptoms associated with NPSLE, however, brain MRI abnormalities are now reported for 53-67% of patients with SLE; findings from both Chinese and western cohort studies support these higher percentages [4-6]. Nonetheless, in this setting, at least 30-40% of patients with NPSLE symptoms do not display abnormal brain MRI findings, and some patients with positive MRI findings also display Correspondence Author to: Shy-Chyi Chin Department of Medical Imaging and Intervention, Linkou Chang Gung Memorial Hospital, School of Medicine, Chang Gung University, Taoyuan, Taiwan No. 5, Fu-Hsing Street, Guei-Shan, Taoyuan 333, Taiwan 75

2 positive computed tomography (CT) findings. In general, brain MR images tend to be abnormal in patients with focal neurologic deficits (e.g., hemiparesis) whereas findings in patients with vague clinical symptoms (e.g., cognitive decline, headache) tend to be normal or nonspecific atrophic changes [6]. We assumed that MRI is not requisite as the first-line imaging modality in patients with symptoms of NPSLE. On the other hand, though CT is long considered an insensitive method for the evaluation of NPSLE symptoms, the correlation between MRI findings and NPSLE symptoms have not been found satisfactory as expected [1, 7-10]. The present study was therefore performed to evaluate the utilities of CT and MRI as imaging modalities for patients with varying degrees of NPSLE severity. We hypothesized that imaging modalities would provide different positive findings depending on the severity of NPSLE symptoms and that selection of the appropriate modality would more effectively guide the choice of treatment for the patient with NPSLE. MATERIALS AND METHODS Patients Institutional review board approval was obtained for this retrospective review of clinical and imaging findings. Seventy-one patients with neuropsychiatric symptoms were grouped on the basis of classified clinical symptoms ranging from mild neuropsychiatric symptoms, neurological deficits and seizures to a seriously deteriorating level of consciousness. All patients underwent CT studies and 36 patients underwent MRI studies. Symptoms were classified according to the 1999 and 2003 ACR case definitions for NPSLE syndromes [2, 11]. Demographic findings and principal NPSLE symptoms were recorded prior to performance of the requested imaging studies. The twelve CNS/ NPSLE syndromes of the 2004 revised ACR criteria were simplified into 4 categories of symptoms as follows: A, psychiatric symptoms (depression, mania); B, mild neurological symptoms (headache, tremor); C, seizures, persistent headache (with sign of increased intracranial pressure) and focal neurologic deficits; and D, delirium and altered mental status. Each patient was followed closely at the clinic for at least six months to ascertain whether the imaging findings were appropriate. CT and MRI as imaging modalities The CT protocol involved a non-enhanced axial scan without angiography or perfusion. The MRI protocol included fluid-attenuation-inverse-recovery sequence, T1-, T2- and diffusion-weighted sequences, and time-of-flight MR angiography (with or without venography). CT was often selected in emergency situations or for patients in whom MRI was contraindicated. Imaging interpretation Positive CT and MRI findings were defined as salient focal or diffuse lesions such as edema, infarction and hemorrhage. Brain atrophy was not considered a positive finding. In general, CT is used to exclude the presence of acute hemorrhage or major infarction but is considered less sensitive for detection of acute lacunar infarction or microhemorrhage. For brain inflammation or infection, MRI is considered superior to CT because MRI inherently offers better tissue characteristics and readily to provide diverse scan protocol for the validation of the abnormalities. In general, MRI findings often provide a better understanding of abnormal findings seen on CT. Such abnormal findings include infarction with stenosis of the internal or middle cerebral artery (MR angiography), vasogenic edema with posterior reversible encephalopathy syndrome (PRES; diffusion weighted sequence), and lobar hematoma resulting from venous thrombosis (MR venography). In the present study, CT and MRI findings were reviewed and discordance of the positive findings between the two imaging modalities was resolved through discussion. Statistical analysis After binary scoring of the positive rates for both CT and MRI findings, the McNemar test was used to compare the positive rates between CT and MRI and the Chi-square test was employed to compare the positive rates between mild (categories A and B) and severe (categories C and D) symptoms. A p value < 0.05 was considered to indicate statistical significance. All the statistical analyses were performed with an IBM SPSS Statistics (version 20; IBM Corp., Armonk, NY). RESULTS The demographic characteristics and major NPSLE symptoms are presented in Table 1. Of the 71 patients included in this study, 60 (84.5%) were female. Of the categories of NPSLE symptoms displayed by these patients, C Table 1. The demographic characteristics and major NPSLE symptoms Patient characteristics CT performed MRI performed (n = 71) (n = 36) Sex, M/F 11/60 7/29 Age (SD) 39.5 (13.2) 37.5 (13.1) Symptom A, n (%) 15 (21.1) 7 (19.4) Symptom B, n (%) 15 (21.1) 6 (16.7) Symptom C, n (%) 33 (46.5) 18 (50) Symptom D, n (%) 8 (11.3) 5 (14) 76

3 was the most common (46.5%), followed by A (21.1%), B (21.1%), and D (11.3%). Table 2 provides the positive rates of MRI and CT findings for patients with different categories of symptoms. Positive imaging rates for patients with mild symptoms (categories A and B) did not differ between the two imaging modalities (p = 0.996). For patients with severe symptoms (categories C and D), however, higher positive rates were observed for MRI as compared to CT (p = 0.016; Fig. 1). Furthermore, positive rates for both CT and MRI findings were significantly higher (p < 0.001) for patients with severe symptoms (categories C and D) as compared to those with mild symptoms (categories A and B) (Table 3). DISCUSSION The present study supports the value of symptomoriented selection of CT or MRI as the imaging modality for patients with NPSLE. CT was found to have utility Table 2. Comparison between positive rates of CT and MRI for different symptoms CT positive rate MRI positive rate p value* Symptom A, n (%) 0/15 (0.0%) 0/7 (0.0%) NA Symptom B, n (%) 1/15 (6.7%) 2/6 (33.3%) Symptom A+B, n (%) 1/30 (3.3%) 2/13 (15.4%) Symptom C, n (%) 12/33 (36.4%) 14/18 (77.8%) Symptom D, n (%) 5/8 (62.5%) 4/5 (80.0%) Symptom C+D, n (%) 17/41 (41.5%) 18/23 (78.3%) * McNemar test Table 3. Comparison of the CT and MRI positive rates between symptom A+B and symptom C+D Symptom A+B Symptom C+D p value* CT positive rate, % <0.001 MRI positive rate, % <0.001 * Chi-square test Figure 1 1a 1b 1c Figure 1. A 42-year-old female with diplopia (symptom C). Noncontrast brain CT a. showed no obvious abnormal finding while MR fluid-attenuation-inversion-recovery b. and post-contrast T1-weighted images c. depicted a non-enhancing lesion in the midbrain (arrow), corresponding to the clinical symptom. 77

4 equivalent to that of MRI in the evaluation of patients with mild NPSLE symptoms. Higher positive rates were obtained with both modalities when patients exhibited severe as opposed to mild symptoms. Most importantly, for patients with severe, more objective NPSLE symptoms, MRI was found to be superior to CT for providing findings that readily explain the observed symptoms. In such situations, therefore, MRI should prove more helpful than CT for guidance of treatment. CNS involvement, reported to be present in 14-75% of patients, is one of the notable complications of SLE and is manifested by widely diverse symptoms, which are subject to change over time. Furthermore, the percentages of NPSLE patients with different symptoms vary widely with respect to the patient cohort examined. Selection of the patient cohort in the present study was based on the radiological information system available to the authors. In this setting, the patient group with severe symptoms (e.g., categories C and D) was inevitably larger than the group with mild symptoms (e.g., categories A and B). Manifestations of NPSLE usually precede imaging findings, with the diversity of these manifestations dependent on the site(s) of involvement. MRI is currently considered the gold standard among available anatomic imaging modalities for defining the site(s) and extent of CNS lesions and for visualizing brain abnormalities not detected by CT. Nonetheless CT remains valuable for identifying hemorrhage, large infarction and cortical atrophy. In the present study, CT was found to be equivalent to MRI for identifying lesions in patients with mild NPSLE symptoms and, for both modalities, findings were unremarkable. These observations provide assurance that grave brain abnormalities will not be underestimated and that progression to more severe symptoms within the subsequent 6 months is not likely to occur when CT is used as the imaging modality for patients with mild symptoms. For patients in the present study, CT merely served as an auxiliary tool of exclusion and, as such, CT findings alone should have been sufficient for patients with mild symptoms. Management is expected to involve minimum intervention when mild NPSLE symptoms are present whereas urgent intervention is expected when focal or severe diffuse symptoms are present. When specific neuropsychiatric symptoms (e.g., categories C and D) appear, it is suggested that more sophisticated imaging work-ups such as MRI be performed to define the underlying cause(s) of symptoms and to guide treatment. In cases with severe NPSLE symptoms, MRI is useful for identifying underlying etiologies such as acute arterial infarction, venous thrombus or PRES and for guiding treatment accordingly. Inappropriate and potentially detrimental treatments, such as augmentation of immunosuppression in patients with PRES, can therefore be avoided. In the present study MRI was associated with a 78.3% positive rate for elucidation of symptoms in categories C and D; the more definite diagnoses led to appropriate treatments including administration of steroids, anticoagulants, or cytotoxic agents. CT findings were also positive (e.g., PRES and intracerebral hemorrhage) for patients with symptoms in categories C and D but were not as clear as those obtained with MRI. Furthermore, MRI is preferable to CT for such patients because conventional MRI protocols usually include sequences, such as diffusion-weighted imaging, MR angiography and MR venography, which highlight the associated abnormalities. Nevertheless, it is advisable that MRI be used in conjunction with hematological, serological, and immunological testing for better elucidation of ongoing pathologic processes [12]. A number of studies have been performed with the goal of demonstrating a clear relationship between brain imaging abnormalities (e.g., brain volume or demyelinating lesions) and NPSLE symptoms but the results varied, particularly with respect to the psychiatric and more subjective neurological symptoms [1, 9, 10, 13]. Clinical radiological correlations are barely obvious. In this setting, the practical utility of an imaging modality in the occurrence of mild NPSLE symptoms is to exclude more imminent or reversible disease. Based on our results, it appears that correlations between symptoms of movement disorders and psychiatric and cognitive impairments and structural CT or MR images are not significant, in contrast to the correlations in patients with focal neurological deficits, such as infarction and hemorrhage. In patients with symptoms in the categories C and D, a considerable number of patients (21.7%) showed normal MRI findings in our study. Explanations for this observation include the following possibilities. First, the underlying brain abnormalities associated with severe NPSLE symptoms might be inconspicuous on conventional MR images. Second, NPSLE symptoms might result from spinal cord or SLE-related nonstructural comorbidities such as systemic infection, drug effects, electrolyte imbalances or metabolic encephalopathy. In our study, both CT and MRI underestimated the severity of NPSLE symptoms. In a study of 41 British patients, those with normal brain MRI findings were found more likely than those with abnormal brain MRI findings to exhibit diffuse phenomena such as headache, meningism, memory impairment, confusion, and generalized seizures [6]. However, 36% of the patients with normal MRI findings also experienced focal events such as monoparesis, hemiparesis, and hemisensory symptoms and, for some of these patients, their symptoms were compatible with later spinal MRI findings. Similar to the findings of the present report, the reliability of imaging findings for exclusion of more severe disease was found to be much higher than for the diagnosis of psychiatric symptoms, regardless of selection of CT or MRI as the imaging modality. Two limitations of the present study should be noted. Firstly, the positive rates for imaging findings for NPSLE symptoms were prone to a certain degree of subjective 78

5 evaluation and may therefore varied among clinicians and radiologists. Secondly, the patient number in this study was small that might bias the statistical results. However, the decision to concisely categorize patients with NPSLE symptoms into 4 groups and the concept of the symptomoriented selection of the imaging modalities indicate the importance of the CT and MRI in the diagnosis of NPSLE and suggest the modern imaging modality to be integrated as part of classification of NPSLE symptoms in the future revision of the ACR criteria. Larger and prospective studies are recommended to verify that the image-assisted classification employed in this disease will serve to predict more accurately the outcomes for patients with symptoms of NPSLE. In summary, our results suggested that MRI is not mandatory for every patient with NPSLE symptoms. When patients have mild symptoms including headache, mood disorders, and defects in cognitive function, CT findings serve to explain symptoms and to exclude the presence of serious conditions. However, MRI findings are more sensitive to explain severe and objective NPSLE symptoms and are therefore more helpful for guidance of treatment. REFERENCES 1 Petri M, Naqibuddin M, Carson KA, et al. Brain magnetic resonance imaging in newly diagnosed systemic lupus erythematosus. J Rheumatol 2008; 35: The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999; 42: Hanly JG. ACR classification criteria for systemic lupus erythematosus: limitations and revisions to neuropsychiatric variables. Lupus 2004; 13: Steup-Beekman GM, Zirkzee EJ, Cohen D, et al. Neuropsychiatric manifestations in patients with systemic lupus erythematosus: epidemiology and radiology pointing to an immune-mediated cause. Ann Rheum Dis 2013; 72: Zhou HQ, Zhang FC, Tian XP, et al. Clinical features and outcome of neuropsychiatric lupus in Chinese: analysis of 240 hospitalized patients. Lupus 2008; 17: Joseph FG, Lammie GA, Scolding NJ. CNS lupus: a study of 41 patients. Neurology 2007; 69: Abreu MR, Jakosky A, Folgerini M, et al. Neuropsychiatric systemic lupus erythematosus: correlation of brain MR imaging, CT, and SPECT. Clin Imaging 2005; 29: Waterloo K, Omdal R, Jacobsen EA, et al. Cerebral computed tomography and electroencephalography compared with neuropsychological findings in systemic lupus erythematosus. J Neurol 1999; 246: Ainiala H, Dastidar P, Loukkola J, et al. Cerebral MRI abnormalities and their association with neuropsychiatric manifestations in SLE: a population-based study. Scand J Rheumatol 2005; 34: Driver CB, Wallace DJ, Lee JC, et al. Clinical validation of the watershed sign as a marker for neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 2008; 59: Nived O, Sturfelt G, Liang MH, et al. The ACR nomenclature for CNS lupus revisited. Lupus 2003; 12: Sanna G, Bertolaccini ML, Khamashta MA. Neuropsychiatric involvement in systemic lupus erythematosus: current therapeutic approach. Curr Pharm Des 2008; 14: Appenzeller S, Rondina JM, Li LM, et al. Cerebral and corpus callosum atrophy in systemic lupus erythematosus. Arthritis Rheum 2005; 52: