Abstract
Objective: To determine whether edema can be assessed by MRI using T2-weighted signal intensity of hemispheric white matter in cirrhotic patients.
Methods: Fast-FLAIR and magnetization transfer images were obtained before (24) and after (11) liver transplantation. T2-weighted abnormalities on baseline scans and their time-course changes were analyzed and compared with MT ratios (MTR).
Results: Fast-FLAIR baseline images showed faint to substantial, bilateral, symmetric increased signal intensity along the hemispheric white matter in or around the corticospinal tract in 23/24 patients. After liver transplantation the signal abnormalities gradually recovered. This gradual decrease in signal intensity correlated with an increase in MTR values.
Conclusion: Asymptomatic symmetric high-signal intensity in the hemispheric white matter on fast-FLAIR MR images is present in cirrhosis. Normalization of this finding after successful liver transplantation and its correlation with MTR values suggest that this signal abnormality reflects mild edema.
Bilateral symmetric hyperintensity of the globus pallidus is observed on T1-weighted MR images in the majority of patients with chronic liver failure.1-4⇓⇓⇓ The most widely accepted hypothesis explaining this MRI finding is accumulation of manganese in the brain produced by failure of biliary excretion.5,6⇓ Nevertheless, recent reports evaluating the relationship between blood manganese concentration and neurologic symptoms have yielded conflicting results.1,7-11⇓⇓⇓⇓⇓ Results from experimental studies indicate that a more widespread metabolic alteration in the brain could be the cause of hepatic encephalopathy.12 When liver function is impaired, various compounds such as ammonia are present in increased concentrations in the circulation. Hyperammonemia induces accumulation of glutamine inside the astrocytes causing them to swell, and this results in an increase in the water content of the whole brain.13,14⇓ However, although cerebral glutamine increases to a similar extent in both acute and chronic liver failure, brain edema is only rarely a complication of chronic liver failure,5 a fact that can be explained by a compensatory decrease in other osmolytes, such as myoinositol and taurine.12,15-17⇓⇓⇓ Despite this osmoregulatory mechanism, mild astrocytic swelling seems to occur in chronic liver failure and may be partially responsible for the development of hepatic encephalopathy.18,19⇓ This hypothesis is supported by magnetization transfer ratio (MTR) measurements in cirrhotic patients before and after liver transplantation, which show significantly low values in otherwise normal-appearing brain white matter that progressively increase with normalization of liver function.20-22⇓⇓ MTR represents an attempt to quantify the tissue macromolecular environment that is not directly visible using conventional MR techniques.23 Low MTR values indicate a reduction in brain structures that are able to exchange magnetization with the surrounding water molecules, reflecting damage to myelin, cell destruction, or changes in water content. Therefore, the reversible low MTR values observed in cirrhotic patients could be an indication of increased water content.
To test the hypothesis that T2-weighted signal abnormalities suggestive of brain edema may be present in the white matter of patients with chronic liver failure, we assessed this potential abnormality in a group of cirrhotic patients.
Patients and methods.
Characteristics of subjects.
We studied a consecutive series of cirrhotic patients without clinical evidence of hepatic encephalopathy. Twenty-four patients, 14 men and 10 women, with a mean age of 58 years (range, 30 to 68 years), were enrolled in the study while they were being evaluated for liver transplantation in our institution between March 1998 and May 1999. All were nonalcoholic cirrhotic patients and the majority had developed cirrhosis secondary to viral hepatitis. Subjects with a history of drug abuse, those affected by neurologic or psychiatric diseases, and those receiving medications known to have significant effects on the CNS were excluded. The degree of liver failure was mild in four cases (Child-Pugh A), moderate in 18 (Child-Pugh B), and severe in two (Child-Pugh C). All patients underwent laboratory analysis and neurologic and neuropsychological examinations. The neuropsychological assessment consisted in a short battery of tests designed to give a general evaluation of neuropsychological function and to detect the most frequently impaired functions. All subjects were assessed by the same examiner with a structured interview that was completed in approximately 60 minutes, just before performing the MRI study. The neuropsychological evaluation included the following tests: Stroop test, Trail Making test (part A), Symbol Digits (oral version), Grooved Pegboard test (dominant and nondominant hand), Auditory Verbal Learning, Judgment of Line Orientation Hooper test of visual organization, and Controlled Oral Word Association test. Minimal hepatic encephalopathy was arbitrarily defined as two or more neuropsychological tests below 2 SD of the mean.24
Arterial ammonia was not assessed owing to ethical considerations.
A subgroup of patients (n = 11) with good evolution after liver transplantation was serially studied by MRI at 1 month (30 ± 1 day) and 1 year (360 ± 7 days) after the procedure. All the patients were receiving tacrolimus-based immunosuppression and had a satisfactory postoperative course.
A group of 12 healthy volunteers (three men and nine women) with a mean age of 57 years (range 46 to 66 years) were used as controls. The local institutional review board approved the study and all patients gave written consent for participation.
MRI studies.
MRI studies were performed on a 1.5-T Magnetom Vision-plus superconductive magnet (Siemens, Erlangen, Germany) using a quadrature transmit/receive head coil. The initial conventional MRI of the brain included the following pulse sequences: transverse T2-weighted fast spin-echo (3000 ms/85 ms/2 = repetition time [TR]/echo time [TE]/number of acquisitions), fast-fluid attenuation inversion recovery (FLAIR) (9900 ms/110 ms/2500 ms/1 = TR/TE/inversion time/number of acquisitions), and T1-weighted spin-echo (600 ms/15 ms/2 = TR/TE/number of acquisitions). The sequences were registered using the following parameters: section thickness 5 mm, interleaved imaging mode, intersection gap 1.5 mm, pixel size approximately 1 × 1 mm, and acquisition matrix 256 × 256 mm.
Magnetization transfer (MT) imaging studies were also performed in the 24 patients. The MT study was obtained with a two-dimensional gradient-echo (2d-GE) pulse sequence (714 ms/12 ms/20°/1 = TR/TE/flip angle/number of acquisitions) with the same slice parameters and position used in the conventional sequences. This gradient-echo sequence was repeated using the same imaging parameters, but with an additional off-resonance preparation pulse to saturate the macromolecular protons to obtain MT contrast. The saturation pulse had the following parameters: off-resonance frequency selective gaussian radiofrequency pulse centered 1.5 kHz below the water frequency, bandwidth 250 Hz, and length 7.68 ms. The MTRs were quantified as a percentage of signal loss according to the following equation: MTR = (So − Ss)/So × 100, where So is the mean signal intensity for a given region obtained from the 2d-GE sequence without the saturation pulse and Ss is the mean signal intensity for the same region with the saturation pulse. Pixel-by-pixel MTR maps were constructed from the two sets of two-dimensional gradient-echo images with the NUMARIS software (Siemens, Erlangen, Germany). To avoid misregistration between the two sets, a visual analysis that excluded mismatching of the MTR maps was conducted before calculating the MTR in selected areas. In case of mismatch, the two sets of images were repeated.
In the subgroup of 11 patients that were serially reassessed after successful liver transplantation the same MRI protocol was performed using the same scanner. Repositioning was achieved using a protocol based on identification of standardized anatomical landmarks.25
MRI analysis.
Fast spin-echo and fast-FLAIR T2-weighted images from the baseline and follow-up examinations were visually assessed simultaneously and independently by two of the authors (A.R. and J.A.) who had not been provided with the clinical information. The two observers were aware of the study hypothesis and the potential signal changes on T2-weighted images, but they did not know how many of the participants were patients. All baseline scans from patients and healthy subjects were reviewed on two separate occasions by each observer under normal scan-reporting conditions to assess intraobserver and interobserver variation. These 4 independent assessments (2 × 2) were done in each patient and healthy volunteer. Thus, a total of 96 and 48 assessments were obtained in patients and volunteers. Films were reviewed in random order, changing the order on each review. Focal high-signal lesions located in the subcortical or periventricular white matter attributable to involutive changes or small-vessel disease were not included in the analysis.
We noted the presence and degree of T2 signal abnormalities along the hemispheric white matter. The maximum degree of signal intensity was scored with a four-point scale (no hyperintensity, faint hyperintensity, moderate hyperintensity, and substantial hyperintensity), based on a subjective assessment of signal intensity in the area of interest relative to the normal-appearing anterior frontal subcortical white matter (figure 1).
Figure 1. Brain transverse T2-weighted fast-FLAIR image (9900 ms/110 ms/2500 ms/1 = repetition time/echo time/ inversion time/number of acquisitions) showing no signal abnormality (A), faint high-signal intensity (B), moderate high-signal intensity (C), and substantial high-signal intensity (D) in the white matter close to or within the expected course of the corticospinal tract in four different subjects. The first two subjects (A, B) are healthy volunteers, while the other two (C, D) are patients with liver cirrhosis without overt hepatic encephalopathy.
For the qualitative analysis, regions of interest (ROIs) were selected from four different supratentorial locations identified in four consecutive slices, along the white matter in or around the corticospinal tract in each hemisphere, following a line that connected the subcortical precentral white matter and the posterior limb of the internal capsule. Selection of these areas was based on findings from the qualitative assessment, which revealed abnormal signal abnormalities within the areas. As reference for each image we also selected four different locations of anterior frontal subcortical white matter in each hemisphere (figure 2).
Figure 2. Consecutive transverse T2-weighted fast-FLAIR images (9900 ms/110 ms/2500 ms/1 = repetition time/echo time/inversion time/number of acquisitions) from a patient with liver cirrhosis and considered to have substantial high-signal abnormalities. The location of regions of interest (ROIs) in the right hemisphere are shown in four slices at the level of the subcortical precentral white matter (A), upper corona radiata (B), lower corona radiata (C), and posterior limb of the internal capsule (D). Reference ROIs are located in each slice at the normal-appearing subcortical anterior frontal white matter.
In the subgroup of 11 patients that entered the longitudinal study, we performed serial qualitative and quantitative analysis of the baseline, 1-month and 12-month studies. Based on the expected decreased signal intensity after successful liver transplantation, the same two observers that had visually assessed the baseline studies tried to independently and blindly (to the examination time-point) identify the order in which the three examinations were carried out in each patient. Afterwards, the same two observers performed a consensus visual analysis to define the degree of signal change along the corticospinal tract at the 1-month and 12-month exams, as compared with the baseline examination. The signal change was scored with a 3-point scale (no change, minimal or equivocal changes, and obvious changes), based on subjective assessment of signal change in the area of interest relative to the baseline examination. Window level and width were kept constant for the serial qualitative analysis. The qualitative analysis was performed in each the follow-up studies in the same manner as in the baseline examinations, attempting to be as precise as possible in locating the ROIs within the same position.
Statistical analysis.
Data analysis was performed with the SPSS software package version 7.5 (SPSS Inc., Chicago, IL, USA). The Wilcoxon test for paired samples was used to compare the baseline and 12-month data. Spearman’s rank correlation coefficient was used to evaluate the correlations between relative T2-signal intensity and mean MTR values. Inter- and intraobserver agreement was calculated with the κ test. Results are expressed as mean ± SD. A p value < 0.05 was accepted as significant for all the analyses.
Results.
Baseline study.
All patients were clinically stable at the time of the study. None showed signs of overt hepatic encephalopathy; all were perfectly alert, without flapping tremor, and oriented in space, person, and time. Neuropsychological tests revealed signs of minimal hepatic encephalopathy in 17 patients (70%).
In the consensus review of the MRI scans from the 24 cirrhotic patients, the hemispheric white matter high-signal intensity was graded as substantial in 5, moderate in 7, faint in 11, and absent in one. When present, the hemispheric white matter high-signal intensity was always symmetric and located in or around the corticospinal tract. These signal abnormalities did not correlate with the presence of corresponding clinical abnormalities (pyramidal signs) in any of the patients. In the consensus review of the MRI scans from the 12 healthy volunteers, eight showed symmetric high-signal intensity within the hemispheric white matter in or around the corticospinal tract. This signal was graded as faint in five and moderate in three. No substantial changes were observed in any of them.
Intraobserver agreement between the first and second scan assessments was good for both observers. Overall concordances were 72% for the first observer and 75% for the second observer with corresponding κ coefficients of 0.71 and 0.67. Interobserver agreement was also good, with an overall concordance of 69% and a κ coefficient of 0.74.
In all patients and healthy volunteers, hemispheric high-signal intensities were more conspicuous on fast-FLAIR than on fast spin-echo T2-weighted images.
There were no statistical differences regarding the presence of symmetric hemispheric white matter high-signal intensities on fast-FLAIR images between cirrhotic patients and healthy volunteers, but there was a trend toward signal abnormalities in the patients. Substantial signal changes were only observed in patients. The comparison between patients with moderate or substantial high-signal intensity (n = 12) and those with no or faint high-signal intensity (n = 12) showed no differences in clinical parameters of liver function or neuropsychological function, as defined by the presence or absence of minimal hepatic encephalopathy.
The mean MTR in the selected deep hemispheric white matter of the 24 patients showed a correlation with relative T2 signal intensity in this region (r = −0.673; p < 0.0001). The mean MTR in frontal subcortical white matter also correlated with relative T2 signal intensity (r = −0.571; p < 0.0001). Moreover there were strong correlations in MTR values between the deep hemispheric white matter and frontal subcortical white matter (r = 0.895; p < 0.0001) and in T2 signal intensity values between these regions (r = 0.803; p < 0.0001).
Serial MRI study.
At the baseline examinations, the 11 patients that entered the serial study were considered by consensus to have faint signal abnormalities within the deep hemispheric white matter in six, moderate signal abnormalities in four and substantial signal abnormalities in one. Both observers reported progressive reduction of deep white matter high signal intensity on fast-FLAIR images for all patients. Moreover, both observers were able to independently identify the time-point of the three examinations in each of the patients. On consensus review of the scans, signal reduction was considered minimal/equivocal in six patients and obvious in five patients at the 1-month scan, while changes in all 11 patients were considered obvious at the 12-month scan, as compared with the baseline scan (figures 3 and 4⇓). Mean MTR in the selected hemispheric white matter increased from 29.6% (±3.8) at baseline, to 31.6% (±2.5) at 1 month, and 34.4% (±2.2) at 12 months after liver transplantation. Mean subcortical frontal white matter MTRs also showed significant increases from 31.4% (±3.6) at baseline to 33.4%(±2.4) at 1 month and 35.3% (±2.1) at 12 months. MTR values were not significantly more decreased at each time point in the deep hemispheric white matter when compared to subcortical frontal white matter, although a trend to lower values was observed within the deep white matter (table 1). In this subgroup of 11 patients a negative correlation was also observed between mean baseline MTR values and mean, relative T2 signal intensity along the deep hemispheric white matter (r = −0.643; p < 0.05). Mean MTRs and T2 ratios showed significant increases and decreases, from the baseline to the 12-month examinations (p = 0.002; p = 0.02). Moreover, the differences between the 12-month and baseline examinations for MTRs and relative T2 signals showed a negative correlation (r = −0.769; p < 0.005) (figure 5).
Figure 3. Serial transverse T2-weighted fast-FLAIR images (9900 ms/110 ms/2500 ms/1 = repetition time/echo time/inversion time/number of acquisitions) at the level of the centrum semiovale in a patient with liver cirrhosis before (A), at 1 month (B), and at 12 months (C) after successful liver transplantation. The substantial high signal intensity within the deep hemispheric white matter seen at baseline shows progressive normalization from the 1-month to the 12-month examinations.
Figure 4. Serial transverse T2-weighted fast-FLAIR images (9900 ms/110 ms/2500 ms/1 (repetition time/echo time/inversion time/number of acquisitions) at the level of the basal ganglia in a patient with liver cirrhosis before (A), at 1 month (B), and at 12 months (C) after successful liver transplantation. Bilateral moderate high-signal intensity in the posterior limb of the internal capsule is seen initially. Signal reduction is minimal or equivocal at the 1-month examination, but obvious at the 12-month examination as compared to the baseline examination.
Table 1 Serial relative T2 (rT2) signal and MTR changes along the hemispheric white matter in or around the corticospinal tract obtained in 11 patients with cirrhosis before and after liver transplantation
Figure 5. Serial changes in relative T2 signal intensity and magnetization transfer ratios (MTR) from the hemispheric white matter in or around the corticospinal tract before and after liver transplantation. Baseline relative T2 signal intensity (A) was significantly decreased and MTR values (B) were significantly increased at the 12-month examination (p = 0.02; p = 0.002). A significant correlation was observed in baseline and serial changes between relative T2 signal intensity and MTR (r = −0.643, p = <0.05; r = −0.769, p = < 0.005). Black bars = pretransplant; dark gray bars = 1 month post-transplant; light gray bars = 12 months post-transplant.
Discussion.
It has been suggested that mild astrocytic swelling occurs in chronic liver failure and may be partially responsible for the development of hepatic encephalopathy.18,19⇓ MRI data seem to support the presence of a slight increase in brain water content in patients with chronic liver failure. MTR measurements show significantly lower MTRs in otherwise normal-appearing white matter in these patients as compared to healthy controls,20,21⇓ and these values return to normal with normalization of liver function.22
The current study describes a previously undetected MRI finding in patients with chronic liver failure: high-signal intensity along the hemispheric white matter in or around the corticospinal tract on T2-weighted images. This feature may reflect the presence of mild brain edema, as suggested by its reversibility after successful liver transplantation. In fact, half our cirrhotic patients showed diffuse, symmetric, moderate, or substantial hyperintensity on T2-weighted images, mimicking the signal abnormalities described in ALS.26 Moreover, all the eleven patients in the serial study showed a progressive decrease in signal intensity on the examinations after liver transplantation, despite the fact that most were considered to have only faint signal abnormalities on the baseline assessment.
There are two possible reasons why we were able to identify this previously undescribed signal abnormality in patients with liver cirrhosis. First, the current study used fast-FLAIR, a sequence that (at least in the supratentorial compartment) has demonstrated higher sensitivity than conventional T2-weighted sequences for depicting white matter lesions.27 Second, in other studies these abnormalities might have been interpreted as normal involutive or chronic ischemic changes, but their progressive normalization with improvement of liver function seen in the current study excludes this misinterpretation.
The most plausible explanation for the T2 signal hyperintensity along the hemispheric white matter in or around the corticospinal tract is the existence of mild cerebral edema. The pathologic bases for signal abnormalities along the corticospinal tract in ALS are axonal loss, demyelination, or wallerian degeneration.28 However, none of these abnormalities has been described in the brain of cirrhotic patients. In addition, the progressive normalization of the high signal abnormalities in cirrhotic patients after successful liver transplantation supports the hypothesis that edema is the main cause, since resolution of demyelination and axonal loss would not be expected after normalization of liver function.
It seems unlikely that therapy would have confounding effects on signal alterations in the serial study. Tacrolimus-based immunosuppression was (of course) applied only after liver transplantation, when T2 high-signal abnormalities were demonstrated to decrease, not to increase, as would be expected if therapy had produced white matter signal changes.
The significant negative correlation observed at baseline examinations between relative T2 signal and mean MTR, and between serial changes in relative T2 signal intensity and mean MTR, further support the existence of mild cerebral edema as the cause of signal abnormalities. It has been proposed that the MTR decrease in normal-appearing white matter in cirrhosis probably reflects mild cerebral edema, because MTR restores to normal after successful liver transplantation, with a time-course that follows the normalization of the osmotic disturbances detected with MRS.22 Although the main contributor to MTR decrease in brain white matter is demyelination and axonal loss, purely edematous lesions may also significantly decrease MTR values.29,30⇓
Using a qualitative (visual) analysis we demonstrated selective involvement of the hemispheric white matter in or around the corticospinal tract, although diffuse involvement would have been expected. Widespread involvement is supported in previous studies that demonstrate decreased MTR and MRS abnormalities in white matter far from the corticospinal tract.20-22⇓⇓ Our quantitative analysis also supports widespread abnormality. In the 11 patients in the serial study the mean MTR values obtained from normal-appearing frontal white matter outside the corticospinal tract also showed a significant increase after liver transplantation. Moreover, we demonstrated a strong correlation between T2 signal intensity and MTR values from the deep white matter and anterior subcortical frontal white matter in the baseline examinations.
Fast-FLAIR is able to trace the corticospinal tract as a faint symmetric signal increase in approximately half of normal adults.31-32⇓ Therefore, the selective involvement of the white matter within or close to the corticospinal tract that we observed in cirrhotic patients may be simply due to a diminished threshold for visual detection of a widespread white matter alteration. Accordingly, we found a faint to moderate increase in the hemispheric white matter in or around the corticospinal signal in 66% of the healthy volunteer group. However, none of the controls showed the substantial hyperintensity seen in 21% of the cirrhotic patients. Alternatively, selective involvement of the corticospinal tract in our patients may reflect a higher vulnerability of this white matter for the development of edema secondary to liver failure. In fact, pyramidal signs are frequently observed in hepatic encephalopathy,8,33,34⇓⇓ thus selective involvement of the corticospinal tract in a preclinical state of hepatic encephalopathy could be expected. The reasons for this greater vulnerability of the corticospinal tract are unknown but they may include higher energy demands and higher susceptibility for excitotoxicity.35-39⇓⇓⇓⇓
Longitudinal MRI studies that include diffusion-weighted images in patients with and without overt liver encephalopathy could better define the nature of brain edema, which is supposed to be predominantly cytotoxic,13 and would determine quantitatively if the edema involves the brain white matter diffusely or predominantly the corticospinal tract. Such studies would increase our knowledge of the pathophysiology of liver encephalopathy and define the potential use of MR for assessing the effect of therapy in patients with this condition.
Acknowledgments
Supported by a grant from Spain’s Fondo de Investigación sanitaria (FIS-Health Research Fund) 98/231 awarded by the Ministry of Health and Welfare.
Acknowledgment
The authors thank Celine L. Cavallo for English language support.
- Received December 31, 2001.
- Accepted May 13, 2002.
References
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