American Journal of Neuroradiology 22:773-776 (4 2001)
© 2001 American Society of Neuroradiology
ARTICLE
T2 Relaxation Measurements in X-linked Adrenoleukodystrophy Performed Using Dual-echo Fast Fluid-attenuated Inversion Recovery MR Imaging
Elias R. Melhem
,a,
Theodore F. Gotwalda,
Ryuta Itoha,
S. James Zinreicha and
Hugo W Mosera
a From the Department of Radiology and Radiological Sciences (T.F.G.), The Johns Hopkins Medical Institutions; the F.M. Kirby MR Research Center, Kennedy-Krieger Institute (E.R.M., R.I., S.J.Z.), The Johns Hopkins Medical Institutions; and the Department of Neurogenetics (H.W.M.), Kennedy-Krieger Institute, The Johns Hopkins Medical Institutions, Baltimore, MD.
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Abstract
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Summary: The purpose of this study was to determine whether
dual-echo fast fluid-attenuated inversion recovery MR imaging
and corresponding T2 brain maps can show different zones in
the affected white matter of patients with cerebral X-linked
adrenoleukodystrophy. Ten male patients with cerebral X-linked
adrenoleukodystrophy underwent imaging performed using dual-echo
fast fluid-attenuated inversion recovery and dual-echo conventional
spin-echo MR sequences. Corresponding T2 relaxation maps of
the brain were generated. On the basis of dual-echo fast fluid-attenuated
inversion recovery images and T2 maps, the affected white matter
could be divided into two distinct zones in four patients with
cerebral X-linked adrenoleukodystrophy.
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Introduction
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In cerebral X-linked adrenoleukodystrophy, three different pathologic
zones (Schaumberg's zones) are described in affected white matter:
an outermost zone typified by myelin destruction with preservation
of axons (Schaumberg's zone 1), an intermediate zone that contains
perivascular lymphocytic infiltrates in addition to myelin destruction
(Schaumberg's zone 2), and a central zone, which is typically
irreversible, characterized by axonal destruction, astrogliosis,
and cavitation with absence of oligodendroglia, myelin, and
inflammatory cells (Schaumberg's zone 3) (
1,
2). White matter
injury in zones 1 and 2 may be reversible and has been the prime
target for therapeutic intervention. MR imaging has been effective
in showing different zones in affected white matter that may
correspond to characteristic pathologic zones (
3). Conventional
dual-echo MR imaging has been shown to provide T2 values in
brain tissue that strongly correlate with clinically impractical
16-echo sequence measurements (
4). Recently, normative T2 values
of brain tissue obtained from dual-echo fast fluid-attenuated
inversion recovery (FLAIR) imaging correlated favorably with
conventional spin-echo imaging (
5). The reported advantages
of dual-echo fast-FLAIR imaging include shorter acquisition
times, less motion, fewer susceptibility-related artifacts,
and reduced contamination of the T2 values by CSF signal (
5).
Our purpose was to determine whether dual-echo fast-FLAIR MR
imaging and corresponding T2 brain maps show different zones
in affected white matter of patients with cerebral X-linked
adrenoleukodystrophy.
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Methods
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Ten male patients with biochemically proved X-linked adrenoleukodystrophy
and mild neurologic disability (including personality changes
and visual and auditory deficits) were prospectively included
in the study. The average age of the patients was 7 years, with
a range from 2 to 13 years. Institutional review board approval
and informed consent from all patients were obtained.
MR imaging was performed using a 1.5-T MR system with a maximum gradient capability of 23 mT/m and a slew rate of 103 mT/m. All images of the brain were acquired using a standard quadrature head coil operating in receive mode. Each MR examination of the brain included a dual-echo fast-FLAIR sequence (6000/58, 160/4 [TR/first TEeff, second TEeff/excitations]; inversion time, 2000 ms; three gradient echoes per RF echo; 16 RF refocusing periods; acquisition time, 5 min 24 s) and a dual-echo conventional spin-echo MR sequence ([3000/30, 100/1; acquisition time, 7 min 42 s). Both sequences were matched for section orientation (section number, 22; section thickness, 5 mm; intersection gap, 1 mm; matrix, 182 x 256; field of view, 24 cm). The dual-echo fast-FLAIR and dual-echo conventional spin-echo MR images of the 10 participants were evaluated by a neuroradiologist for the presence of white matter disease and for their ability to show zonal differences in signal intensity.
The images from both sequences were transferred to a UNIX workstation (SUN Enterprise 5500; Sun Microsystems, Mountain View, CA). Numerical calculations and imaging displays were made using IDL (Interactive Data Language; Research Systems, Boulder, CO). For each section, pixel-by-pixel T2 maps (Fig 1) were generated according to the following equation:
where
SI1 and SI2 represent signal intensity from the first and second
echo images, respectively.
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FIG 1. Images of a 13-year-old male patient with X-linked adrenoleukodystrophy.
A, Axial first echo fast FLAIR image (6000/58 [TR/first TEeff]; inversion time, 2000 ms).
B, Axial second echo fast FLAIR image (6000/160 [TR/second TEeff] inversion time, 2000 ms).
C, Axial first echo conventional spin-echo MR image (3000/30 [TR/first TE]).
D, Axial second echo conventional spin-echo MR images (3000/100 [TR/second TE]) of the brain, obtained at the level of the lateral ventricles, show symmetrical and confluent abnormal signal intensity in the deep white matter of the both parietooccipital lobes and splenium of the corpus callosum. The peripheral (arrowheads) and central (asterisks) zones are most distinct on the first echo fast-FLAIR image.
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Regions of interest were placed in the normal-appearing white matter and the affected white matter, guided by visually apparent signal intensity differences on the MR images. T2 values were measured from regions of interest copied onto corresponding T2 maps derived from dual-echo fast-FLAIR and dual-echo conventional spin-echo MR images. For each participant, the T2 values from the normal-appearing white matter and affected white matter were averaged over the multiple sections that covered the cerebral hemispheres.
Using commercially available statistical software (Statview; SAS institute Inc., Cary, NC), repeated measures analysis of variance and paired Bonferonni/Dunn post hoc analyses were performed to compare average T2 values in the different white matter zones. The T2 values in normal-appearing white matter were compared with the published normal range at 1.5 T (6–8). Correlation between T2 values obtained from dual-echo fast FLAIR and dual-echo conventional spin-echo MR images was calculated using Pearson correlation coefficient. For all statistical analyses, the significance level for differences was set at P < .05.
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Results
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In four patients, the first echo of the dual-echo fast-FLAIR
sequence showed two distinct zones in the affected white matter
(
Figs 1A and 2A). The peripherally located zone showed increased
signal intensity compared with normal-appearing white matter,
and the centrally located zone showed decreased signal intensity
compared with normal-appearing white matter. These zones were
difficult to distinguish on the dual-echo conventional spin-echo
MR images and on the second echo fast-FLAIR images (
Fig 1).
In each of six patients, there was only one zone (increased
signal intensity compared with normal-appearing white matter
in the affected white matter on all MR sequences.
Among the four patients with two distinct zones, the average T2 values were 135.3 ± 12.8 ms (FLAIR) and 104.4 ± 3.5 ms (conventional spin-echo) in the zone of increased signal (peripheral zone) and 329.0 ± 62.2 ms (FLAIR) and 207.4 ± 33.8 ms (conventional spin-echo) in the zone of decreased signal intensity (central zone). The average T2 values from the two zones were different (P < .0167). For each of six patients with one zone of affected white matter, the T2 values (137.4 + 9.7 ms [FLAIR] and 107 ± 5.5 ms [conventional spin-echo]) were not different from those of the hyperintense zone (peripheral zone) in the four patients with two zones each (P = .32). The average T2 values in normal-appearing white matter (79.8 ± 3.7 ms [FLAIR] and 69.8 ± 3.3 ms [conventional spin-echo]) were within the published normal range (68–95 ms). There was a very strong correlation between the average T2 values from dual-echo fast-FLAIR and dual-echo conventional spin-echo sequences (r = 0.93) for both normal-appearing white matter and affected white matter.
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Discussion
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Currently, the burden of quantifying CNS disease load and identifying
reversibility in cases of X-linked adrenoleukodystrophy lies
primarily on MR imaging. The ability of the various MR-based
imaging techniques (anatomic, functional, or metabolic) to differentiate
between zones of reversible and zones of irreversible white
matter disease and to identify early white matter derangement
is of the essence (
9).
In this study, dual-echo fast-FLAIR MR imaging (specifically the first echo) showed two distinct zones in the affected white matter of four patients with X-linked adrenoleukodystrophy, which may correspond to well-established irreversible and potentially reversible pathologic zones. However, this radiologic-pathologic correlation requires confirmation if dual-echo fast-FLAIR imaging is to assume an important role in differentiating between pathologic zones.
The low signal intensity in the central zone within the affected white matter on first echo fast-FLAIR images is probably due to marked prolongation of T1 relaxation, approaching that of CSF. The low signal is the result of short effective TE (58 ms) and CSF-nulling inversion pulse (10). On the other hand, the central zone is hyperintense on the second echo fast-FLAIR images because of marked prolongation of T2 relaxation, which is emphasized by the long effective TE (160 ms).
For the remaining six patients, the absence of central low signal intensity on the first echo fast-FLAIR images and the moderate prolongation of T2 relaxation may imply that axonal destruction, astrogliosis, and cavitation have not yet occurred in potentially reversibly affected white matter. This again awaits radiologic-pathologic confirmation. Determination of T2 values in the affected white matter of patients with cerebral X-linked adrenoleukodystrophy provides a quantitative measure that is intrinsic to the diseased white matter and devoid of MR weighting effects. These intrinsic measures allow normalization across participants and MR imagers and help better define thresholds for segmentation algorithms. The ability to normalize becomes critical for conducting multicenter trials (necessary for uncommon diseases such as adrenoleukodystrophy). Furthermore, once spatial matching between pathologic zones and T2 value zones is confirmed, we anticipate an improvement in the correlation between disease burden, as defined by MR imaging, and clinical disability. Also, if future work shows the ability of dual-echo fast-FLAIR images and T2 maps to distinguish between reversibly and irreversibly affected white matter, these maps may provide a better guide for experimental therapies.
A limitation of our study is the lack of contrast-enhanced T1-weighted MR images of the participants. The presence of contrast enhancement in affected white matter has been attributed to the inflammatory process in Schaumberg's zone 2 and has been shown to be a predictor of disease progression (11). Combining contrast-enhanced T1-weighted MR imaging and dual-echo fast FLAIR MR imaging with corresponding T2 maps may improve in vivo delineation of the different pathologic zones.
It is important to emphasize that the two MR imaging sequences implemented in this study do not fully account for the multiexponential nature of the T2 decay in brain tissue or for the effects of molecular diffusion, stimulated echoes, and magnetization transfer on the T2 relaxation values (12, 13). However, multiple echo MR imaging sequences designed for accurate in vivo T2 relaxation measurements remain impractical for clinical use because of time and brain coverage constraints (4). Additionally, for the purpose of generating total brain T2 maps of our patients with X-linked adrenoleukodystrophy, we feel restricted to dual-echo MR imaging. Furthermore, the effects of molecular diffusion, stimulated echoes, and magnetization transfer on T2 relaxation values are influenced by the type of MR read-out implemented. This is the likely reason for the wide range of published normative brain T2 values and the differences in T2 values of both affected white matter and normal-appearing white matter generated from the two dual-echo techniques used in this study (5).
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Conclusion
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On the basis of dual-echo fast-FLAIR imaging and T2 maps, the
affected white matter can be divided into distinct zones in
patients with cerebral X-linked adrenoleukodystrophy.
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FIG 2. Images of an 8-year-old male patient with X-linked adrenoleukodystrophy.
A, Axial view first echo fast-FLAIR image (6000/58 [TR/first TEeff]; inversion time, 2000 ms).
B, Axial view second echo fast-FLAIR image (6000/160 [TR/second TEeff]; inversion time, 2000 ms).
C, Corresponding T2 maps of the brain, obtained at the level of the lateral ventricles, show symmetrical and confluent abnormal signal intensity in the deep white matter of the both parietooccipital lobes. Note that regions of highest signal intensity on the T2 map (ie, highest T2 values) correspond to the central zone of low signal intensity on the first echo FLAIR image.
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Footnotes
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101 Address reprint requests to Elias R. Melhem, MD, Department
of Radiology and Radiological Sciences, The Johns Hopkins Medical
Institutions, 600 North Wolfe Street, Baltimore, MD 21287.
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References
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Received June 2, 2000;
accepted after revision October 4, 2001.
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Abstract
Introduction