Association of Global Brain Damage and Clinical Functioning in Neuropsychiatric Systemic Lupus Erythematosus

Transcription

1 ARTHRITIS & RHEUMATISM Vol. 46, No. 10, 2002, pp DOI /art , American College of Rheumatology Association of Global Brain Damage and Clinical Functioning in Neuropsychiatric Systemic Lupus Erythematosus G. P. Th. Bosma, 1 H. A. M. Middelkoop, 2 M. J. Rood, 1 E. L. E. M. Bollen, 1 T. W. J. Huizinga, 1 and M. A. van Buchem 1 Objective. To investigate the relationship between quantitative estimates of global brain damage based on magnetization transfer imaging (MTI) and cerebral functioning, as measured by neurologic, psychiatric, and cognitive assessments, as well as disease duration in patients with a history of neuropsychiatric systemic lupus erythematosus (NPSLE). Methods. In a clinically heterogeneous group of 24 female patients (age range years, mean age 35 years) with a history of NPSLE, the correlation values of several volumetric MTI measures and an estimate of cerebral atrophy, neurologic functioning (Kurtzke s Expanded Disability Status Scale [EDSS]), psychiatric functioning (the Hospital Anxiety and Depression Scale [HADS]), and cognitive functioning (cognitive impairment score [CIS] derived from the revised Wechsler Adult Intelligence Scale), as well as several measures of disease duration were assessed using Pearson s correlation coefficient. Results. Quantitative volumetric estimates of global brain damage based on MTI and a measure of global brain atrophy correlated significantly with the EDSS, HADS, and CIS scores. No significant correlation was found between the quantitative estimates of global brain damage and the measures of disease duration. Conclusion. The results of this study demonstrate that volumetric MTI parameters and cerebral atrophy reflect functionally relevant brain damage in patients 1 G. P. Th. Bosma, MD, M. J. Rood, MD, PhD, E. L. E. M. Bollen, MD, PhD, T. W. J. Huizinga, MD, PhD, M. A. van Buchem, MD, PhD: Leiden University Medical Center, Leiden, The Netherlands; 2 H. A. M. Middelkoop, PhD: Leiden University Medical Center, and Leiden University, Leiden, The Netherlands. Address correspondence and reprint requests to G. P. Th. Bosma, MD, Department of Radiology C2S, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. G.P.T.Bosma@lumc.nl. Submitted for publication September 28, 2001; accepted in revised form July 3, with NPSLE. Furthermore, the absence of a linear relationship between disease duration and results of volumetric MTI measures and atrophy suggests a complicated pattern of accumulating brain damage in patients with NPSLE. In patients with systemic lupus erythematosus (SLE), neurologic, psychiatric, and psychological symptoms often occur. The frequency of nervous system involvement has been reported to range from 11% to 60% (1). Infection, drug side effects, hypertension, or metabolic derangements, as well as an intrinsic brain manifestation of SLE (i.e., neuropsychiatric SLE [NPSLE]), can cause such symptoms. The uncertain pathogenesis and the wide variety of manifestations of NPSLE complicate the development of a uniform diagnostic decision-making protocol and a uniform method of monitoring a patient with this type of SLE. Findings of routine brain imaging studies are often unremarkable in patients with NPSLE, or the studies reveal abnormalities, such as cerebral atrophy and white matter hyperintensities (on magnetic resonance imaging [MRI]), that can also be found in SLE patients without neuropsychiatric symptoms. Furthermore, no correlation has thus far been demonstrated between quantitative measures of such nonspecific abnormalities and measures of brain function (2 5). Recently, magnetization transfer ratio (MTR) histogram analysis, a quantitative MRI technique based on magnetization transfer imaging (MTI), was applied in patients with primary NPSLE but without abnormalities on MRI that could account for the clinical picture. With this technique, cerebral abnormalities were identified in these patients (6,7). Such abnormalities were found in SLE patients who had had episodes of neuropsychiatric symptoms in the past (chronic NPSLE) as well as in patients who were experiencing an active phase of neuropsychiatric symptoms (active NPSLE) (6,7). The 2665

2 2666 GLOBAL BRAIN DAMAGE AND CLINICAL FUNCTIONING IN NPSLE Table 1. MRI Patient characteristics, manifestations of neuropsychiatric systemic lupus erythematosus, and abnormalities detected on conventional Patient/age Neuropsychiatric symptoms* Radiologic abnormalities (no. and mean size of lesions) 1/38 Primary generalized tonic-clonic seizures Small infarction left cerebellar hemisphere; PAIS (2 lesions; 6 mm); cerebral atrophy 2/65 Cerebrovascular disease CAIS 3/27 Primary generalized tonic-clonic seizures NDA 4/41 Chorea PAIS (7 lesions; 4 mm) 5/39 Aseptic meningitis NDA 6/23 Acute confusional state NDA 7/49 Cerebrovascular disease CAIS (2 old lacunar infarctions left corona radiata) 8/34 Cranial neuropathy (second cranial nerve) NDA 9/25 Primary generalized absence seizures PAIS (6 lesions; 4 mm); cerebral atrophy 10/27 Primary generalized tonic-clonic seizures NDA 11/41 Mononeuropathy (single); cognitive dysfunction PAIS (1 lesion; 7 mm) 12/36 Cerebrovascular disease ; cognitive dysfunction NDA 13/26 Transverse myelitis PAIS (8 lesions; 4 mm); cavernoma (9 mm) 14/49 Mood disorder with depressive features PAIS (21 lesions; 3 mm) 15/30 Anxiety disorder NDA 16/32 Cerebrovascular disease PAIS (29 lesions; 6 mm); cerebral atrophy 17/24 Primary generalized tonic-clonic seizures NDA 18/26 Primary generalized absence seizures NDA 19/30 Cognitive dysfunction NDA 20/30 Aseptic meningitis NDA 21/30 Cranial neuropathy (sixth cranial nerve) NDA 22/29 Cerebrovascular disease NDA 23/59 Cognitive dysfunction PAIS (1 lesion; 2 mm) 24/19 Psychosis NDA * According to the American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. CAIS confluent area of increased signal; NDA no detectable abnormalities on conventional magnetic resonance imaging (MRI); PAIS punctate area of increased signal. No infarctions accounting for cerebrovascular disease were found on conventional MRI. abnormal MTI findings in NPSLE patients are presumed to represent diffuse structural brain damage that is too subtle to be detected by conventional qualitative MRI techniques (6,7). Although abnormal MTI findings have been demonstrated in the clinically heterogeneous group of SLE patients with diffuse central nervous system symptoms, there is currently no detailed information on the functional consequences of the structural brain damage detected by MTI. The aim of the present study was to explore the relationship between quantitative estimates of global brain damage based on MTI and clinical data acquired by neurologic, psychiatric, and neuropsychological assessment in patients with a history of NPSLE. To study the influence of disease duration on structural brain damage, the relationship between the MTI data and the patient s age, SLE duration, and the time elapsed since the first occurrence of neuropsychiatric symptoms was investigated. PATIENTS AND METHODS Study subjects. Patients with SLE and a wide variety and severity of diffuse neuropsychiatric symptoms in the past were selected from the patient files of the Department of Rheumatology, Leiden University Medical Center. These patients were invited to participate in the study and, after giving their informed consent, they underwent neuroradiologic, neurologic, psychiatric, and neuropsychological examination. Twenty-four female patients (age range years, mean age 35 years) with a history of NPSLE were enrolled in the present study. Their disease duration since the first manifestation of SLE ranged from 1 year to 29 years (mean 8 years). The duration since the onset of neuropsychiatric manifestations varied from 1 month to 18 years (mean 5 years). All patients fulfilled the American College of Rheumatology (ACR) 1982 revised criteria for the diagnosis of SLE (8). The diagnosis of NPSLE had been made according to clinical findings and after exclusion of other possible causes of the neuropsychiatric symptoms, as required by the ACR criteria for NPSLE (9). Clinical data are shown in Table 1. To avoid the influence of thromboembolic processes on our results, patients with radiologic evidence of infarctions other than an incidental small ( 5-mm) infarct were excluded from the study. Patients with current active disease were also excluded. Image acquisition. MRI was performed with a 1.5T MR system (Philips Medical Systems, Best, The Netherlands). Conventional T1-weighted spin-echo, fluid-attenuated inversion recovery (FLAIR) weighted, and dual (proton density and T2-weighted) imaging was performed on all patients. Images were interpreted by an experienced neuroradiologist

3 BOSMA ET AL 2667 (MAvB). T1-weighted imaging was performed using a spinecho sequence with an echo time (TE) of 20 msec, a repetition time (TR) of 600 msec, and a scanning time of 3 minutes 8 seconds. Dual fast spin-echo imaging was performed using a TE of 23/120 msec, a TR of 2,500 msec, an echo train length factor of 10, and a scanning time of 2 minutes 35 seconds. FLAIR fast spin-echo imaging was performed using a TE of 120 msec, a TR of 8,000 msec, an echo train length of 16, and a scanning time of 3 minutes 28 seconds. All sequences consisted of 22 axial slices with a 6-mm thickness, a field of view of 220 mm, an interslice gap of 0.6 mm, a matrix of pixels; with an acquisition percentage of 80%. In addition to conventional MRI, all patients underwent MTI, which was performed using a 3-dimensional (3-D) gradient-echo pulse sequence with a 106-msec TR, a 6-msec TE, and a flip angle of 12 (10). These scan parameters were chosen to minimize T1 and T2 weighting, resulting in a proton-density contrast in the absence of MT saturation pulses. A matrix of pixels with an acquisition percentage of 50% was used for 28 slices with a thickness of 5 mm, covering the whole brain. The field of view was 220 mm. Two consecutive sets of axial images were acquired. The first set was performed in combination with a radiofrequency saturation pulse, and the second set without. The saturation pulse consisted of a sinc-shaped radiofrequency pulse 1,100 Hz upfield of H 2 O resonance. The flip angle of this pulse was 620, with 3 sinc periods of 1SD over the pulse, which lasted 15 msec. The total scanning time for MTI was 11 minutes 27 seconds. Postprocessing. For postprocessing of the MT images, 3DVIEWNIX semiautomated software (Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA) was used. A detailed description of our MTI data analysis procedure has been previously published (11). Briefly, the following steps were performed: semiautomated segmentation of the intracranial volume (ICV) from the 3-D MTI study, automated calculation of MTRs for every intracranial voxel, and automated display of the 3-D data set of the MTRs as an MTR histogram. The MTR is defined as: MTR M 0 M s 100% M 0 where M s represents the intensity of voxels in the presence of the radiofrequency saturation pulse and M 0 of voxels in the absence of a radiofrequency saturation pulse. Subsequently, within the intracranial compartment, the brain parenchyma was separated from the cerebrospinal fluid (CSF). This was achieved by using an MTR threshold of 20 percentage units (pu), as previously described (6). Brain voxels were defined as intracranial voxels with MTRs 20 pu; intracranial voxels with lower MTRs ( 20 pu) were defined as CSF voxels. This threshold was empirically defined to separate the CSF from the brain parenchyma on a number of data sets from normal controls before we started the analysis of the MTI data included in this study, and it was subsequently used as a fixed threshold in all data sets used in this study. With this threshold, we found an adequate separation of CSF and brain at the interface of these compartments on visual inspection. Furthermore, we found no areas within the boundaries of the brain that had MTRs below 20 pu in any of the patients. From each MTR histogram, we derived the following descriptive measures: the mean MTR (MTR m ) of the brain parenchyma and the MTR corresponding to the peak (MTR p ). These two values are independent because MTR histograms lack a Gaussian distribution. In addition, we assessed the peak height of the MTR histograms. This parameter depends not only on the lesion load in the brain, but also on physiologic differences in brain size. Two types of normalized peak heights were generated. The first (H rpi ) was normalized to correct for physiologic differences in brain size by dividing the individual MTR histogram bins by the total number of intracranial voxels. The value of this parameter reflects atrophy and the integrity of the remaining brain tissue. The peak height normalized for brain volume (H rpb ) was acquired by dividing the individual MTR histogram bins by the total number of brain voxels. This parameter only reflects the integrity of the remaining brain tissue, irrespective of physiologic differences in brain size and atrophy. Finally, as a measure of atrophy, we assessed the CSF:ICV ratio by dividing the number of CSF voxels by the number of all intracranial voxels. Testing clinical functioning. To quantify neurologic functioning, Kurtzke s Expanded Disability Status Scale (EDSS) was assessed for each patient by an experienced neurologist (ELEMB) (12). Neuropsychological assessment was conducted with the Wechsler Adult Intelligence Scale, Revised (WAIS-R), a standardized psychometric test for assessing intelligence (13). Testing lasted 1.5 hours. Since valid tests for premorbid intellectual functioning are lacking, the WAIS-R results (e.g., intelligence quotient) were rated semiquantitatively (0 no impairment, 1 mild impairment, and 2 definite impairment) by an experienced clinical neuropsychologist (HAMM) to derive a cognitive impairment score (CIS) for each patient. To assess psychiatric functioning, all patients completed the Hospital Anxiety and Depression Scale (HADS) questionnaire (14). This questionnaire corrects for the presence of psychiatric deficits due to somatic disease. Anxiety and depression are the main psychiatric abnormalities that can be expected in nonpsychiatric patients (14). To investigate the relationships between volumetric MTI parameters (i.e., H rpi,h rpb, MTR p, MTR m, and CSF: ICV) and clinical data (i.e., the patient s age, disease duration, duration of neuropsychiatric manifestations, and EDSS, HADS, and CIS scores), Pearson s correlation analysis was performed. The nominal level of statistical significance was set at P RESULTS WAIS-R and derived CIS scores, MTI measures, age, disease duration, and duration of neuropsychiatric manifestations were obtained on all 24 NPSLE study patients. HADS and EDSS scores were obtained from 23 of the 24 patients. A relatively large range and even distribution of the various parameters was seen (Table 2). Nonspecific white matter lesions, being either punctate or confluent areas of increased signal on T2,

4 2668 GLOBAL BRAIN DAMAGE AND CLINICAL FUNCTIONING IN NPSLE Table 2. Distribution of radiologic, neurologic, psychiatric, cognitive, and temporal variables in 24 female patients with NPSLE* Range Mean SD H rpi H rpb MTR m MTR p CSF:ICV EDSS CIS WAIS-R HADS Duration of SLE Duration of NPSLE Age, years * Values for Kurtzke s Expanded Disability Status Scale (EDSS) and the Hospital Anxiety and Depression Scale (HADS) are for 23 patients. The duration of neuropsychiatric systemic lupus erythematosus (NPSLE) represents the time since the first occurrence. H rpi histogram peak height corrected for intracranial volume; H rpb histogram peak height corrected for brain volume; MTR m mean magnetization transfer ratio; MTR p peak magnetization transfer ratio; CSF:ICV ratio of cerebrospinal fluid volume to intracranial volume; CIS cognitive impairment score; WAIS-R Wechsler Adult Intelligence Scale, Revised; SLE systemic lupus erythematosus. proton-density, or FLAIR images (white matter hyperintensities), were demonstrated in 10 of the 24 patients (Table 1). With the exception of the MTR m, no significant differences could be established between the 10 patients with and the 14 patients without white matter hyperintensities. The MTR m was lower (P 0.03) in the group with white matter hyperintensities (mean SD ) compared with the group without such lesions ( ). The presence, number, and size of the white matter lesions in both NPSLE groups are shown in Table 1. Functional correlates. Correlations between the MTR histogram parameters and measures of clinical functioning as well as the duration of SLE, duration of neuropsychiatric symptoms, and age are shown in Table 3. On neurologic testing of the NPSLE patients, significant correlations between the EDSS scores and the CSF:ICV ratios, the H rpi values, and the H rpb values were identified. No significant correlation between the EDSS scores and the MTR m or the MTR p values was noted. HADS scores to assess psychiatric functioning correlated significantly with the H rpi values, the H rpb values, the CSF:ICV ratios, and the MTR m values. CIS values, which assess cognition, correlated significantly with the CSF:ICV ratios, the H rpi values, the H rpb values, and the MTR m values. Time correlates. No significant correlations were established between the various structural measures (the CSF:ICV, H rpi,h rpb,mtr p, and MTR m values) and measures of disease duration (age, duration of SLE, and duration of neuropsychiatric manifestations). The results of these analyses are shown in Table 3. DISCUSSION This is the first study in which an association between global cerebral disease burden and various measures of brain functioning was found in patients with a history of NPSLE. Various quantitative estimates of global brain damage correlated significantly with EDSS scores representing neurologic functioning, with HADS values representing psychiatric functioning, as well as with WAIS-R values in combination with subsequent semiquantitative ratings (CIS values) representing global cognitive functioning. The absence of a correla- Table 3. Pearson s correlation coefficients between structural MTR histogram parameters and the various functional parameters in patients with neuropsychiatric sytemic lupus erythematosus* Histogram parameter Neurologic functioning (EDSS) Clinical functioning Cognitive functioning (CIS) Psychiatric functioning (HADS) Duration of SLE Time parameters Duration of NP symptoms H rpi H rpb MTR m CSF:ICV MTR p * MTR magnetization transfer ratio; EDSS Expanded Disability Status Scale; CIS cognitive impairment score; HADS Hospital Anxiety and Depression Scale; SLE systemic lupus erythematosus; NP neuropsychiatric; H rpi relative peak height corrected for intracranial volume; H rpb relative peak height corrected for brain volume; MTR m mean MTR corrected for brain volume; CSF:ICV ratio of cerebrospinal fluid to intracranial volume; MTR p position of MTR peak. P P Age

5 BOSMA ET AL 2669 tion between the quantitative estimates of global brain damage and age, SLE duration, or time elapsed since the first occurrence of neuropsychiatric symptoms suggests that the accumulation of brain damage over time has a nonlinear aspect. In SLE patients with neurologic or psychiatric symptoms or with evidence of cognitive decline, conventional qualitative MRI often detects either no abnormalities or abnormalities that do not provide an explanation for the central nervous system symptoms (2 4). Since in patients with diseases affecting the brain, abnormalities are often not confined to areas that are abnormal on conventional qualitative MRI, quantitative methods have been developed to assess global disease burden, such as MTR histogram analysis (15). It has been demonstrated that MTR histogram analysis is more sensitive to the presence of disease in the brain than is conventional MRI and that it is able to detect abnormalities in brain tissue that appear normal on conventional MRI (16 18). In addition, it has been shown that MTR histogram analysis reflects not only the volume of abnormal brain tissue, but also the degree of tissue destruction (11). In NPSLE, abnormalities have been detected in patients with a history of neuropsychiatric symptoms and in patients with an active phase of neuropsychiatric symptoms in whom conventional MRI revealed no explanatory cerebral abnormalities (6). In the present study, we hypothesized that estimates of structural brain damage based on MTI correlate with quantitative measures of brain function in NPSLE patients due to the sensitivity and quantitative nature of this technique. Cerebral dysfunction in SLE can manifest as a wide spectrum of neurologic, psychiatric, and cognitive symptoms. Seizures, neuropathies, hemiparesis, organic brain syndrome, psychosis, and depression, as well as paresthesias, headaches, anxiety, and mood swings can occur in SLE (9,19). Several groups of investigators have drawn attention to cognitive deterioration as an independent expression of nervous system involvement in SLE, in addition to neurologic and psychiatric manifestations (20 27). Since the whole spectrum of nervous system derangement can occur as a result of SLE, neurologic, psychiatric, and cognitive functioning was assessed in our patients with chronic NPSLE. The current study demonstrates an association between quantitative volumetric estimates of global brain damage based on MTI and the EDSS scores in the NPSLE patients. The H rpb (i.e., the MTR histogram peak height corrected for brain size), reflecting the integrity of the remaining brain tissue, the CSF:ICV ratio, reflecting atrophy, and the H rpi (i.e., the MTR histogram peak height corrected for intracranial volume), reflecting both the integrity of the remaining brain parenchyma and atrophy, were strongly associated with neurologic functioning, as indicated by the EDSS scores. In patients with multiple sclerosis, a similar significant correlation between disease burden (as reflected by volumetric MTI data) and EDSS scores was demonstrated (28). The EDSS score mainly assesses motor skills. These motor skills are affected when lesions occur in the motor tracts that are confined to restricted areas of the brain. Lesions affecting these restricted areas will have an impact on motor skills. In the NPSLE patients evaluated in the present study, conventional MRI revealed no abnormalities in these restricted areas that could explain the neurologic abnormalities. So, the current results suggest that diffuse microscopic cerebral damage in NPSLE seems to affect, among other areas, brain regions that are responsible for motor skills. Psychiatric functioning as assessed by the HADS also correlated with volumetric data for global brain damage derived from MTR histogram analysis. These results suggest that structural brain damage results in disorders such as anxiety and depression. The presence and severity of psychiatric symptoms correlated strongly with the degree of atrophy, as well as with volumetric MTR measures, such as MTR m and H rpb, that are independent of brain volume and atrophy, suggesting that both atrophy and damage of the remaining brain parenchyma contribute to the development of psychiatric symptoms. These observations are consistent with those of recent studies of patients with psychiatric signs but without SLE, in which an association between measures of structural brain damage and the presence and severity of psychiatric symptoms was demonstrated (29 31). Moreover, we also found a strong association between cognitive impairment and measures of structural damage. Similar associations between MTI and cognition have been found in patients with multiple sclerosis (28,32). More and more, cognitive dysfunction is being regarded as an independent presentation of central nervous system involvement in SLE, occurring both in patients with and in patients without neurologic or psychiatric symptoms and in active as well as inactive disease (20 24,33). No single cognitive test is able to quantify global cognitive functioning, but a cognitive test that covers global brain functioning to a high degree is the WAIS-R (13). Similar to the EDSS and HADS,

6 2670 GLOBAL BRAIN DAMAGE AND CLINICAL FUNCTIONING IN NPSLE cognition also correlated significantly with the measures of global disease burden. Correlations were found between cognition and atrophy (CSF:ICV ratio), damage in the remaining brain tissue (H rpb and MTR m ), and a parameter reflecting both atrophy and brain damage otherwise (H rpi ). These data indicate that in addition to atrophy, damage of the remaining brain parenchyma also contributes to cognitive deficits. Our results are consistent with those of a proton magnetic resonance spectroscopy (H-MRS) study that demonstrated a relationship between neurometabolite derangement and cognitive dysfunction in chronic NPSLE (34). In NPSLE patients, the relationship between the abnormalities in metabolism detected by H-MRS and the abnormalities in structure detected by MTI is, thus far, uncertain. In the current study, cerebral atrophy, as indicated by the CSF:ICV ratio, and damage of the remaining brain tissue, as indicated by a decreased H rpb value, were both associated with neurologic, psychiatric, and cognitive measures. In NPSLE, cerebral atrophy and damage of the remaining brain parenchyma as detected by volumetric MTR are probably different manifestations of the same disease process. Cerebral atrophy is associated in NPSLE with neuronal loss, as indicated by decreased N-acetylaspartate ratios detected by H-MRS in otherwise normal-appearing brain tissue (35). Neuronal loss might be associated with demyelination, the probable source of the MTR histogram alterations. Demyelination and neuronal loss might lead to volume loss of cerebral tissue, i.e., cerebral atrophy. Neuronal loss and demyelination might be caused by chronic hypoperfusion, as has been detected by single-photon emission computed tomography (36 38). In turn, hypoperfusion might be the result of vasculopathy, which consists of cuffing of the small blood vessels (39 41). Whether the course of this disease process has a linear or other pattern of progression over time is unknown. In this study, no association between structural brain damage and the 3 time variables (i.e., age, duration of SLE, and the time elapsed since the first occurrence of neuropsychiatric symptoms) could be distinguished. This suggests that accumulation of brain damage is not characterized by a linear pattern in NPSLE. The disease course in NPSLE might be comparable with other manifestations of SLE, such as lupus nephritis, which has a relapsing-remitting or flare-like course (42). Such a flare-like disease course is characterized by periods of active disease in which brain damage can accumulate, followed by periods of relative inactivity in which a steady-state or slowly progressive deterioration occurs. A flare-like disease pattern for NPSLE seems to be in line with the findings of a recent study on the time course of acute psychiatric manifestations in SLE, which was characterized by episodes of acute psychiatric disturbances alternating with intervals of relative rest (43). In addition, it seems unlikely that the demonstrated correlations between quantitative volumetric estimates of global brain damage based on MTI and functional parameters can be explained by increasing age as a confounding factor, since no correlation between MTI measures and age could be shown. A limitation of volumetric MTI analysis is that it does not provide information on the location of the brain abnormalities detected. However, the correlation of volumetric MTI parameters with functional measures as diverse as motor tasks and cognitive tests which presumably require integrity of different areas of the brain suggests that the brain damage detected by volumetric MTI is widespread. Still, to better understand the nature of the underlying disease, more precise knowledge of the anatomic distribution of the abnormalities might be helpful. Assessment of the distribution of MTI abnormalities in NPSLE patients is the focus of ongoing research. In this study, brain damage in NPSLE patients was detected by MTI. In other studies, brain abnormalities in NPSLE patients have been detected with other MRI techniques, such as H-MRS and spin-spin relaxation time measurements (34,44 48). These various MRI techniques might reflect the same underlying histologic changes, different histologic aspects of the same pathologic process, or different pathologic processes. Further studies are required to assess the correlations between the different MRI measures of cerebral damage in NPSLE patients, not only to provide information on the pathogenesis of NPSLE, but also to determine the best combination of methods for diagnosing NPSLE, as has been recommended (49,50). In conclusion, this is the first study to demonstrate an association between global cerebral disease burden as detected by MTI and various measures of brain functioning as detected by neurologic, psychiatric, and neuropsychological assessments in patients with a history of NPSLE. Volumetric MTI analysis therefore seems to reflect functionally relevant brain damage in patients with NPSLE. For this reason, MTI seems a reliable technique for assisting in the diagnosis of NPSLE, studying the natural course of the disease, and using as a surrogate marker for disease in treatment trials.

7 BOSMA ET AL 2671 REFERENCES 1. West SG. Neuropsychiatric lupus. Rheum Dis Clin North Am 1994;20: Lim L, Ron MA, Ormerod IE, David J, Miller DH, Logsdail SJ, et al. Psychiatric and neurological manifestations in systemic lupus erythematosus. Q J Med 1988;66: Baum KA, Hopf U, Nehrig C, Stover M, Schorner W. Systemic lupus erythematosus: neuropsychiatric signs and symptoms related to cerebral MRI findings. Clin Neurol Neurosurg 1993;95: Stimmler MM, Coletti PM, Quismorio FP Jr. Magnetic resonance imaging of the brain in neuropsychiatric systemic lupus erythematosus. Semin Arthritis Rheum 1993;22: Cauli A, Montaldo C, Peltz MT, Nurchis P, Sanna G, Garau P, et al. Abnormalities of magnetic resonance imaging of the central nervous system in patients with systemic lupus erythematosus correlate with disease severity. Clin Rheumatol 1994;13: Bosma GPTh, Rood MJ, Zwinderman AH, Huizinga TWJ, van Buchem MA. Evidence of central nervous system damage in patients with neuropsychiatric systemic lupus erythematosus demonstrated by magnetization transfer imaging. Arthritis Rheum 2000;43: Bosma GPTh, Rood MJ, Huizinga TWJ, De Jong BA, Bollen ELEM, van Buchem MA. Detection of cerebral involvement in patients with active neuropsychiatric systemic lupus erythematosus using magnetization transfer imaging. Arthritis Rheum 2000;43: Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25: ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42: Dousset V, Grossman RI, Ramer KN, Schnall MD, Young LH, Gonzalez-Scarano F, et al. Experimental allergic encephalomyelitis and multiple sclerosis: lesion characterization with magnetization transfer imaging. Radiology 1992;182: Van Buchem MA, Udupa JK, McGowan JC, Miki Y, Heyning FH, Boncoeur-Martel MP, et al. Global volumetric estimation of disease burden in multiple sclerosis based on magnetization transfer imaging. AJNR Am J Neuroradiol 1997;18: Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983;33: Wechsler D. Wechsler Adult Intelligence Scale, Revised: manual. New York: Psychological Corporation; Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67: Van Buchem MA, McGowan JC, Kolson DL, Polansky M, Grossman RI. Quantitative volumetric magnetization transfer analysis in multiple sclerosis: estimation of macroscopic and microscopic disease burden. Magn Reson Med 1996;36: Grossman RI, Gomori JM, Ramer KN, Lexa FJ, Schnall MD. Magnetization transfer: theory and clinical applications in neuroradiology. Radiographics 1994;14: Loevner LA, Grossman RI, Cohen JA, Lexa FJ, Kessler D, Kolson DL. Microscopic disease in normal-appearing white matter on conventional MR images in patients with multiple sclerosis: assessment with magnetization-transfer measurements. Radiology 1995; 196: Hiehle JF Jr, Grossman RI, Ramer KN, Gonzalez Scarano F, Cohen JA. Magnetization transfer effects in MR-detected multiple sclerosis lesions: comparison with gadolinium-enhanced spin-echo images and nonenhanced T1-weighted images. AJNR Am J Neuroradiol 1995;16: Bluestein HG. Neuropsychiatric manifestations of systemic lupus erythematosus. N Engl J Med 1987;317: Carbotte RM, Denburg SD, Denburg JA. Prevalence of cognitive impairment in systemic lupus erythematosus. J Nerv Ment Dis 1986;174: Denburg SD, Carbotte RM, Denburg JA. Cognitive impairment in systemic lupus erythematosus: a neuropsychological study of individual and group deficits. J Clin Exp Neuropsychol 1987;9: Hanly JG, Fisk JD, Sherwood G, Jones E, Jones JV, Eastwood B. Cognitive impairment in patients with systemic lupus erythematosus. J Rheumatol 1992;19: Hay EM, Black D, Huddy A, Creed F, Tomenson B, Bernstein RM, et al. Psychiatric disorder and cognitive impairment in systemic lupus erythematosus. Arthritis Rheum 1992;35: Ginsburg KS, Wright EA, Larson MG, Fossel AH, Albert M, Schur PH, et al. A controlled study of the prevalence of cognitive dysfunction in randomly selected patients with systemic lupus erythematosus. Arthritis Rheum 1992;35: Denburg SD, Denburg JA, Carbotte RM, Fisk JD, Hanly JG. Cognitive deficits in systemic lupus erythematosus. Rheum Dis Clin North Am 1993;19: Denburg SD, Carbotte RM, Denburg JA. Psychological aspects of systemic lupus erythematosus: cognitive function, mood, and self-report. J Rheumatol 1997;24: Carlomagno S, Migliaresi S, Ambrosone L, Sannino M, Sanges G, Di Iorio G. Cognitive impairment in systemic lupus erythematosus: a follow-up study. J Neurol 2000;247: Van Buchem MA, Grossman RI, Armstrong C, Polansky M, Miki Y, Heyning FH, et al. Correlation of volumetric magnetization transfer imaging with clinical data in MS. Neurology 1998;50: Soares JC, Mann JJ. The anatomy of mood disorders: review of structural neuroimaging studies. Biol Psychiatry 1997;41: Hickie I, Scott E, Wilhelm K, Brodaty H. Subcortical hyperintensities on magnetic resonance imaging in patients with severe depression: a longitudinal evaluation. Biol Psychiatry 1997;42: O Brien J, Ames D, Chiu E, Schweitzer I, Desmond P, Tress B. Severe deep white matter lesions and outcome in elderly patients with major depressive disorder: follow up study. BMJ 1998;317: Rovaris M, Filippi M, Falautano M, Santuccio G, Martinelli V, Rocca MA, et al. Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis. Neurology 1998;50: Glanz BI, Slonim D, Urowitz MB, Gladman DD, Gough J, MacKinnon A. Pattern of neuropsychologic dysfunction in inactive systemic lupus erythematosus. Neuropsychiatry Neuropsychol Behav Neurol 1997;10: Brooks WM, Jung RE, Ford CC, Greinel EJ, Sibbitt WL Jr. Relationship between neurometabolite derangement and neurocognitive dysfunction in systemic lupus erythematosus. J Rheumatol 1999;26: Sibbitt WL Jr, Haseler LJ, Griffey RH, Hart BL, Sibbitt RR, Matwiyoff NA. Analysis of cerebral structural changes in systemic lupus erythematosus by proton MR spectroscopy. AJNR Am J Neuroradiol 1994;15: Kushner MJ, Tobin M, Fazekas F, Chawluk J, Jamieson D, Freundlich B, et al. Cerebral blood flow variations in CNS lupus. Neurology 1990;40: Nossent JC, Hovestadt A, Schonfeld DH, Swaak AJG. Singlephoton emission computed tomography of the brain in the evaluation of cerebral lupus. Arthritis Rheum 1991;34: Falcini F, De Cristofaro MT, Ermini M, Guarnieri M, Massai G, Olmastroni M, et al. Regional cerebral blood flow in juvenile systemic lupus erythematosus: a prospective SPECT study. Single photon emission computed tomography. J Rheumatol 1998;25:583 8.

8 2672 GLOBAL BRAIN DAMAGE AND CLINICAL FUNCTIONING IN NPSLE 39. Johnson RT, Richardson EP. The neurological manifestations of systemic lupus erythematosus. Medicine (Baltimore) 1968;47: Ellis SG, Verity MA. Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, Semin Arthritis Rheum 1979;8: Zvaifler NJ, Bluestein HG. The pathogenesis of central nervous system manifestations of systemic lupus erythematosus. Arthritis Rheum 1982;25: Ponticelli C, Moroni G. Flares in lupus nephritis: incidence, impact on renal survival and management. Lupus 1998;7: Ward MM, Studenski S. The time course of acute psychiatric episodes in systemic lupus erythematosus. J Rheumatol 1991;18: Davie CA, Feinstein A, Kartsounis LD, Barker GJ, McHugh NJ, Walport MJ, et al. Proton magnetic resonance spectroscopy of systemic lupus erythematosus involving the central nervous system. J Neurol 1995;242: Sibbitt WL Jr, Brooks WM, Haseler LJ, Griffey RH, Frank LM, Hart BL, et al. Spin-spin relaxation of brain tissues in systemic lupus erythematosus: a method for increasing the sensitivity of magnetic resonance imaging for neuropsychiatric lupus. Arthritis Rheum 1995;38: Chinn RJS, Wilkinson ID, Hall-Craggs MA, Paley MNJ, Shortall E, Carter S, et al. Magnetic resonance imaging of the brain and cerebral proton spectroscopy in patients with systemic lupus erythematosus. Arthritis Rheum 1997;40: Sibbitt WL Jr, Haseler LJ, Griffey RR, Friedman SD, Brooks WM. Neurometabolism of active neuropsychiatric lupus determined with proton MR spectroscopy. AJNR Am J Neuroradiol 1997;18: Petropoulos H, Sibbitt WL Jr, Brooks WM. Automated T2 quantitation in neuropsychiatric lupus erythematosus: a marker of active disease. J Magn Reson Imaging 1999;9: West SG, Emlen W, Wener MH, Kotzin BL. Neuropsychiatric lupus erythematosus: a 10-year prospective study on the value of diagnostic tests. Am J Med 1995;99: Sibbitt WL Jr, Sibbitt RR, Brooks WM. Neuroimaging in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 1999; 42: