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Neuroradiology |
1 From the Departments of Radiology (M.K.L., C.H.S., H.J.K., Y.K.C., S.H.C., J.H.K.) and Internal Medicine (W.P.), Inha University College of Medicine, 7-206 3rd St, Shinheung-Dong, Choong-Gu, Incheon 400-103, Korea; and the NMR Laboratory, Asan Institute for Life Sciences, Seoul, Korea (J.H.L.). Received August 27, 1999; revision requested October 8; final revision received March 7, 2000; accepted March 24. Address correspondence to M.K.L. (e-mail: kanlim@chollian.net).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Twenty-six patients who had SLE with (n = 17) or without (n = 9) neuropsychiatric symptoms were examined at MR imaging and 1H MR spectroscopy. The voxel was placed in the basal ganglia and peritrigonal white matter. Eight healthy volunteers were included.
RESULTS: Five of nine patients with major neuropsychiatric symptoms and one of eight patients with minor neuropsychiatric symptoms had abnormal MR imaging findings. 1H MR spectroscopy showed a significantly decreased N-acetylaspartate–creatine (Cr) ratio in the basal ganglia and an increased choline-Cr ratio in the peritrigonal white matter in patients with major symptoms compared with those with minor symptoms, those without symptoms, and healthy control subjects. Among patients with major symptoms, there was no difference in metabolite ratios between those with and those without abnormal MR imaging findings. Among patients with normal MR imaging findings, abnormal spectral changes were observed only in those with major neuropsychiatric symptoms. In patients without neuropsychiatric symptoms, results of 1H MR spectroscopy and MR imaging were normal.
CONCLUSION: In patients with SLE, 1H MR spectroscopic findings seem to reflect the cerebral metabolic disturbance related to the severity of the neuropsychiatric symptoms and are not related to the presence of abnormal MR imaging findings.
Index terms: Brain, diseases, 10.61, 10.78, 10.83 • Brain, metabolism • Brain, MR, 10.121411, 10.121415, 10.12145 • Lupus erythematosus, 10.61 • Magnetic resonance (MR), spectroscopy, 10.12145
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Magnetic resonance (MR) imaging is known to be more sensitive than computed tomography (CT) for the detection of anatomic brain abnormalities in patients with neuropsychiatric SLE because of the higher quality of the anatomic images due to excellent soft-tissue contrast and the ability to acquire multiplanar images at MR imaging (6). Large infarcts, cortical atrophy, and multifocal gray matter and/or white matter lesions are frequently observed at MR imaging in patients with SLE; the most common finding is a multifocal lesion in the white matter. However, a substantial population of patients with SLE do not have abnormal brain MR images and have only neuropsychiatric symptoms because the metabolic and/or functional alterations of the disease usually precede the anatomic disturbance, which cannot be depicted at conventional MR imaging.
Therefore, at present, positron emission tomography (PET) or single photon emission computed tomography (SPECT) is the modality of choice for use in establishing the diagnosis on the basis of findings of functional or metabolic tests that are used to measure underlying hemodynamics and metabolic disturbances. However, these modalities have a few limitations, as follows: SPECT lacks sufficient spatial resolution, and the quantification of change is not straightforward; PET has rigid technical requirements and considerable expense (7,8).
Localized hydrogen 1 MR spectroscopy can depict the alterations in brain metabolism in various diseases (9–14); special attention has been paid to its use in subclinical diseases such as hepatic encephalopathy in which the clinical symptoms and cerebral anatomic changes are not yet developed (15–18). Recently, 1H MR spectroscopy has been performed in an attempt to detect the early changes of central nervous system involvement in neuropsychiatric SLE (19,20). Other studies of 1H MR spectroscopy with SLE (5,21–23) demonstrated spectral abnormalities in some patients with neuropsychiatric SLE in whom MR imaging failed to show any focal changes.
Recently, Friedman et al (24) suggested that the cerebrovascular abnormalities may be the basis of diffuse cerebral injury in SLE; the small-vessel injury is primarily associated with a decreased N-acetylaspartate (NAA)–creatine (Cr) ratio, while the medium-vessel injury is primarily associated with an increased choline (Cho)-Cr ratio. However, none of the previous studies of SLE with MR imaging and 1H MR spectroscopy involved examination of the relationship between these MR findings and the degree of neuropsychiatric symptoms.
The purpose of this study was to determine the usefulness of 1H MR spectroscopy with MR imaging in the evaluation of central nervous system involvement in patients who have SLE with or without neuropsychiatric symptoms and to investigate a potential role of 1H MR spectroscopy in the diagnosis of SLE in relation to the degree of neuropsychiatric symptoms.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Major neuropsychiatric symptoms included clinical symptoms and signs related to acute stroke, neuropathy, movement disorder, transverse myelitis, seizure, meningitis, dementia, delirium, major cognitive defects, atypical psychosis, or major affective disorder. Minor neuropsychiatric symptoms included headache, anxiety, mood swings, or minor cognitive complaints such as difficulties in concentration, memory, and finding words.
Neuropsychiatric symptoms were evaluated within 0–1 days prior to MR examination, and other clinical parameters that may have affected the 1H MR spectroscopic findings, such as serum sodium level and serum osmolarity, were carefully reviewed during patient selection. The history and duration of steroid medication use were recorded for each patient. Results in all patients examined in this study were in the normal ranges for those variables. Eight healthy age-matched control subjects (all female subjects; age range, 24–35 years; mean age, 27 years + 7) were also included for comparison.
Informed consent for 1H MR spectroscopy was obtained from all patients, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in a priori approval by the institutional human research committee.
MR Imaging and MR Spectroscopy
MR imaging and single-voxel 1H brain spectroscopic examinations were performed with a 1.5-T whole-body MR imaging and spectroscopic system (version 5.5; GE Medical Systems, Milwaukee, Wis) equipped with actively shielded gradients and a quadrature head coil. Before spectroscopy, we performed MR imaging using a transverse and sagittal T1-weighted spin-echo sequence (484/8–9 [repetition time msec/echo time msec]; two signals acquired; matrix size, 256 x 192; section thickness, 7 mm; intersection gap, 0 mm) and a transverse T2-weighted fast spin-echo sequence (4,000/98; two signals acquired; matrix size, 256 x 256; section thickness, 7 mm; intersection gap, 0 mm). In no patient was contrast enhancement used. MR images were evaluated on the basis of the presence or absence of the following radiologic findings: (a) high-signal-intensity lesions in periventricular white matter, (b) cortical atrophy or ventricular dilatation (atrophy), and (c) large infarct.
For all spectra, a stimulated-echo acquisition method, or STEAM, localization sequence with a three-pulse chemical shift selective, or CHESS, sequence was used to suppress the water signal; the following acquisition parameters were used: 3,000/30; mixing time, 13.7 msec; spectral width, 2,500 Hz; size, 2,048 points; average, 36; and two signals acquired. The voxel of localization was placed in the basal ganglia and left peritrigonal periventricular white matter in all patients (Fig 1). The size of the voxel was approximately 8 cm3 (2 x 2 x 2 cm). The location in which the voxels should be located was determined mainly by using transverse MR images. To avoid tissue contamination from the adjacent structures and to keep the localization consistent, all voxels were positioned by a single experienced neuroradiologist (M.K.L.). Restricting the edge of the voxels to positions of approximately 5–10 mm from the inner table of the skull helped us to prevent the spectrum from becoming contaminated by strong signals originating from the scalp fat, which can mask lactate resonance.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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In patients with abnormal MR imaging findings, the statistical difference between patients with major neuropsychiatric symptoms and those with minor neuropsychiatric symptoms could not be evaluated because only one patient with minor neuropsychiatric symptoms had abnormal MR imaging findings.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The region of interest at MR spectroscopic examination in patients with SLE should best reflect the area where the metabolic changes might precede the morphologic changes. In this study, the morphologic changes were depicted on MR images in the periventricular and subcortical white matter rather than in the basal ganglia in patients with major neuropsychiatric symptoms. In previous studies (24,30), small focal lesions depicted on MR images were almost entirely restricted to the white matter rather than the gray matter in patients with SLE. The specific susceptibility of the white matter to small vascular lesions is thought to be due to the unique vascularization of this tissue. Although blood is supplied to the cortical gray matter through the interdigitated vessels that provide multiple, interconnecting sources of blood flow to a single region; blood is supplied to the deep white matter by means of a single source. This single source renders the deep white matter especially vulnerable to vascular insult because no collateral flow is possible.
On the contrary, the basal ganglia region is frequently subjected to deposition of various paramagnetic trace metals within the brain in patients after total parenteral nutrition and in those with hepatocellular degeneration or manganese intoxication. This region is also thought to be one of the areas most vulnerable to hypoxic brain damage (31,32).
Interestingly, according to our results, the basal ganglia seemed to be one of the most metabolically active areas in the brain in patients with SLE, although it does not usually show anatomic disturbance at MR imaging. The precise biochemical mechanism that explains the morphologic disturbance depicted on MR images of neuropsychiatric SLE is still unknown. For this reason, we chose the basal ganglia and periventricular white matter regions as localization sites, with the hypothesis that ongoing or early metabolic changes might occur in these areas with neuropsychiatric SLE. Our results in this study support this hypothesis. Therefore, the basal ganglia and periventricular white matter seem to be the optimal localization sites for 1H MR spectroscopy in the evaluation of the biochemical changes that accompany neuropsychiatric SLE.
MR imaging has been used extensively in the evaluation of neuropsychiatric SLE and has been proved to be more sensitive than CT (6). The most common findings noted on MR images include infarct, cortical atrophy, white matter lesions, and periventricular areas of high signal intensity (21–23). Histopathologic findings suggest that these abnormalities are caused by microinfarct, hemorrhage, ischemic demyelination, multiple sclerosis–like demyelination, and bland vasculopathy (24). However, most histopathology reports of SLE are surprisingly unremarkable, with predominantly normal findings in the brain and nonspecific changes. In this study, MR imaging revealed morphologic brain abnormalities in five of the nine patients with major neuropsychiatric symptoms and in one of the eight patients with minor neuropsychiatric symptoms. These results are believed to suggest that MR imaging findings are well correlated with the severity of clinical signs and symptoms. However, MR imaging is somewhat insensitive in the evaluation of neuropsychiatric SLE because many patients with major or minor neuropsychiatric symptoms have no abnormal findings on MR images.
Whereas MR imaging primarily depicts the gross morphologic change that accompanies the disease process, MR spectroscopy takes advantage of the MR phenomenon to provide access to living chemistry in situ (9–14). MR spectroscopy is the only physical technique routinely used in clinical research that allows for the assessment of in vivo metabolism at the molecular level; molecular changes usually occur prior to the morphologic changes. Accordingly, MR spectroscopy might be more sensitive in the detection of the early changes of brain injuries in neuropsychiatric SLE.
Among patients with SLE in this study, the decreased NAA-Cr ratio in the basal ganglia and increased Cho-Cr ratio in the periventricular white matter at 1H MR spectroscopy directly correlate with the severity of the neuropsychiatric symptoms and bear no relation to the presence of abnormal MR imaging findings. A decrease in NAA level, which is known to be a neuronal marker, indicates not only a loss of neurons or neuronal activity but also neuronal dysfunction or impairment as a result of myelin breakdown. The concentration of Cho reflects cellular density or total membrane content. The Cho signal that appeared in the 1H MR spectrum is known to contain contributions from phosphorylcholine and glycerophosphorylcholine, which are a precursor to the cell membrane and a breakdown product of cell membrane, respectively. Therefore, an increased Cho signal can be thought of as an indicator of active demyelination or of changes in cell signaling activities (14,16,33). Decreased NAA-Cr ratios in basal ganglia may represent indirect evidence that extensive small-vessel injury had happened in the normal-appearing basal ganglia region on MR images. These spectroscopic findings suggest that clinical presentation of the major neuropsychiatric symptoms indicate a severe cerebral insult, which resulted in substantial neuronal injury.
The spectral changes at 1H MR spectroscopy in the patients with major neuropsychiatric symptoms were also well correlated with the brain abnormalities depicted on MR images. Recently, Friedman et al (24) reported that major independent relationship existed between decreased NAA-Cr ratio and small focal lesions other than cerebral infarction in patients with neuropsychiatric SLE. They also demonstrated that an elevated Cho-Cr ratio was primarily related to the presence of an infarct rather than to the presence of small focal lesions. According to them, the findings of simultaneous analyses of MR imaging and 1H MR spectroscopic results suggest that the overriding process of brain injury in SLE is pervasive small-vessel disease with a superimposed demyelinating or inflammatory process in those patients with cerebral infarction. In our study, the result of the decreased NAA-Cr ratios in the patients with small focal lesions was similar to those of the previous study (22–24); however, the result of increased Cho-Cr ratios was as not prevalent as that shown in other studies (22, 24) because definite large infarctions were not shown on MR images of the patients examined in this study.
Among the eight patients with minor neuropsychiatric symptoms, MR imaging revealed morphologic abnormalities in only one, and the MR spectroscopic findings of those eight patients were not different from the findings of patients without neuropsychiatric symptoms and normal volunteers. These results were somewhat disappointing because 1H MR spectroscopy was expected to reveal occult brain injuries before the clinical signs and symptoms became obvious. This result may have occurred because the classification of neuropsychiatric symptoms was sometimes complicated, and the number of the patients included in this study was small.
Nevertheless, the present study is a good start in the use of 1H MR spectroscopy in the diagnosis of SLE. 1H MR spectroscopy is sensitive in the detection of metabolic changes that may occur prior to anatomic changes and is, thus, useful in making a diagnosis at the subclinical stage of the disease. A productive future direction might be to investigate, with a prospective study of a large group of patients, the early metabolic changes in patients with SLE. In addition, it is worthwhile to investigate other regions, such as the hippocampus, frontal cortex, and cingulate gyrus, which might be related to the specific neuropsychiatric symptoms of SLE. Also, it may be useful to use diffusion MR imaging in addition to T2-weighted MR imaging for better delineation of the lesions at the early stage of the disease and to use MR spectroscopic imaging techniques in addition to single-voxel MR spectroscopic techniques to visualize the metabolic changes of the whole brain at once. The results of diffusion MR imaging and MR spectroscopy can be compared with those of SPECT in the diagnosis of SLE.
Both MR imaging and 1H MR spectroscopy are useful in the evaluation of neuropsychiatric SLE. On a clinical basis, 1H MR spectroscopy is known to be sensitive in the detection of early metabolic changes that might occur prior to the anatomic changes that are detectable only at MR imaging. This knowledge was assumed in this study. Although we did not directly measure the sensitivity of 1H MR spectroscopy in the detection of early metabolic changes, four patients had normal MR imaging findings among the nine with neuropsychiatric symptoms, and seven patients had normal MR imaging findings among the eight with minor neuropsychiatric symptoms.
In patients with SLE and neuropsychiatric symptoms, early treatment with steroids and cyclophosphamide seems essential in the reduction of mortality and morbidity. Therefore, the patients with SLE and clinical central nervous system involvement who have normal MR imaging findings and abnormal 1H MR spectroscopy findings should be receive medical treatment. However, clinicians must be cautious in their interpretation of the spectroscopic data acquired with a manually placed spectroscopic voxel. In this study, the metabolic ratios did not correlate with the severity of signal intensity changes on MR images in this study, which might have been due to placement of the spectroscopic voxel irrespective of sites with abnormal signal intensity. In later studies, the use of spectroscopic imaging techniques might be helpful to minimize the limitation of the single-voxel technique used in this study.
In conclusion, the decreased NAA-Cr ratio in the basal ganglia and increased Cho-Cr ratio in the periventricular white matter of patients with SLE examined at 1H MR spectroscopy directly correlate with the severity of neuropsychiatric symptoms and bear no relation to the presence of abnormal MR imaging findings.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, M.K.L.; study concepts, M.K.L.; study design, M.K.L.; definition of intellectual content, M.K.L., C.H.S.; literature research, H.J.K.; clinical studies, W.P.; data acquisition, S.H.C.; data analysis, S.H.C., J.H.K.; statistical analysis, S.H.C.; manuscript preparation, M.K.L.; manuscript editing, Y.K.C.; manuscript review, J.H.L., M.K.L.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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