| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Neuroradiology |
1 From the Departments of Diagnostic Imaging and Interventional Radiology (F.G.G., R.F., G.M., G.S.), Pediatrics (A.S.), and Neuroscience (P.C.), University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; Department of Neuroradiology, University of Rome La Sapienza, Italy (A.B.); and Department of Radiology, University of Perugia, Italy (T.L.). Received February 5, 2003; revision requested April 14; final revision received October 27; accepted January 5, 2004. Address correspondence to F.G.G. (e-mail: francescogaraci@tiscali.it).
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
MATERIALS AND METHODS: Diffusion and conventional magnetic resonance (MR) imaging examinations were performed in 18 patients with clinically established tuberous sclerosis complex (10 male and eight female patients; mean age, 20.1 years; range, 12–30 years), as well as in 18 age-matched control subjects (nine male and nine female; mean age, 20.2 years; range, 11–28 years). Apparent diffusion coefficients (ADCs) were generated, and small elliptic regions of interest were manually placed both in perilesional NAWM and in six anatomic locations of NAWM remote from hamartomatous lesions. Perilesional ADCs were compared with those at the same anatomic site on the contralateral side of the brain (generalized linear regression analysis). ADCs from the predetermined sites in patients were compared with those in control subjects (generalized linear regression analysis).
RESULTS: Supratentorial ADCs were higher in patients with tuberous sclerosis complex than in control subjects, and statistically significant differences were observed in the occipital white matter, frontal white matter, centrum semiovale, parietal white matter, and corona radiata (for each location, P < .001). Significant increases were also seen in the perilesional NAWM compared with NAWM at the same anatomic locations on the contralateral side (P < .001). Infratentorial ADCs were normal.
CONCLUSION: Significant ADC increases were measured in the supratentorial NAWM.
© RSNA, 2004
Index terms: Brain, MR, 13.12144 • Brain, white matter • Magnetic resonance (MR), diffusion study • Sclerosis, tuberous, 13.1832
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
Magnetic resonance (MR) imaging plays an important role in the diagnosis of TSC; however, because of heterogeneous phenotypes, a clear correlation between brain lesions and clinical symptoms has not been defined. Diffusion-weighted MR imaging provides information on the motion of water molecules as a consequence of interaction with cellular structures. The trace of apparent diffusion coefficient (ADC) can be altered by pathologic processes that modify the tissue integrity and are undetectable at conventional MR imaging.
The purpose of this prospective study was to evaluate the water diffusivity of normal-appearing white matter (NAWM) in patients with TSC.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
Clinical history and physical examination were used to assess the 18 control subjects. Among the control subjects, 12 underwent MR imaging for a pituitary study, four underwent imaging for cephalalgia, and two were healthy volunteers.
The mean age among patients with TSC was 20.1 years (range, 12–30 years); the mean age was 19.4 years (age range, 12–30 years) among male patients and 21.0 years (age range, 19–27 years) among female patients. Among control subjects, the mean age was 20.2 years (age range, 11–28 years); the mean age was 19.5 years (age range, 14–28 years) among male subjects and 20.8 years (age range, 11–27 years) among female subjects. Written informed consent was obtained from all participants, or, if participants were minors (age, <18 years), consent was obtained from their parents. The study was approved by the local ethics committee.
MR imaging was performed at 1.5 T (Intera; Philips Medical Systems, Best, the Netherlands) and included the following: transverse and sagittal spin-echo T1-weighted sequences (550/10 [repetition time msec/echo time msec]) with two signals acquired, a section thickness of 4 mm, and a gap of 1 mm; transverse spin-echo intermediate- and T2-weighted sequences (3,000/60) with one signal acquired, a section thickness of 4 mm, and a gap of 1 mm; transverse fluid-attenuated inversion-recovery (FLAIR) T2-weighted sequences (8,000/100/2,000 [repetition time msec/echo time msec/inversion time msec]); and single-shot echo-planar diffusion-weighted sequences (b factor, 0–1,000 sec/mm2). Diffusion gradients were applied in each of three orthogonal directions (x, y, z), and ADC maps were generated by using the Stejskal and Tanner equation (9): S = S0exp(–b · ADC), where S is the signal intensity when the maximum diffusion-sensitizing gradient, b, is applied, and S0 is the signal intensity without the diffusion gradient. From ADCx, ADCy, and ADCz, a directionally averaged trace was calculated, as follows: trace ADC = (ADCx + ADCy + ADCz)/3.
MR Image Analysis
An experienced neuroradiologist (R.F., more than 5 years of experience) who was aware of each subject’s status (either patient or control subject) independently performed the diffusion-weighted image analyses on a workstation. He identified all the hamartomatous lesions on both FLAIR and spin-echo T2-weighted images. Both FLAIR and spin-echo T2-weighted images were used to determine whether the white matter surrounding the hamartomas appeared to be normal or not. FLAIR images were used as an anatomic reference for the placement and tracing of the regions of interest (ROIs) over the NAWM. Small elliptic ROIs of 20.0–34.5 mm2 were placed on the FLAIR images and automatically superimposed by the software (Easy Vision; Philips Medical Systems) on the ADC maps. ROIs were never placed over hyperintense areas on spin-echo T2-weighted or FLAIR images. Six pairs of ROIs were drawn bilaterally for each subject (in both patients and control subjects) over the NAWM in six predetermined anatomic locations (six per side, 12 total). The white matter locations were frontal, occipital, parietal, corona radiata, centrum semiovale (Fig 1), and brachium pontis. Parietal, frontal, and corona radiata ROIs were drawn away from the ventricles to exclude visibly apparent areas of periventricular white matter hyperintensity. On FLAIR images, ROIs were also placed over the NAWM surrounding the hamartomas and over the contralateral NAWM as a control and were thus automatically superimposed on the ADC maps. The latter ROIs were placed as close as possible to the same anatomic location as the perilesional white matter that did not show any signal intensity abnormality on conventional images (Fig 2).
|
|
= .05 by using a two-sided t test with equal means, unequal variances, and equal number size (Stata version 7.0; Stata, College Station, Tex). For all supratentorial regions, the resulting power was greater than or equal to .99. For the brachium pontis location, the power was equal to .80.
Generalized linear regression analysis was performed by using the Pearson 
2 test for trend to assess differences in values between (a) the NAWM of the TSC group and control subjects (centrum semiovale, frontal area, corona radiata, occipital area, parietal area, brachium pontis) and (b) the perilesional NAWM versus contralateral NAWM in the TSC group.
Differences with a P value less than .05 were considered statistically significant. Data are presented as means (10–6 mm2/sec) ± standard deviations.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
We found statistically significant differences in all supratentorial NAWM locations in the TSC group compared with these values in the same anatomic locations in the control group (Table). In particular, these statistically significant differences were observed between the TSC group and control group, respectively, as follows: centrum semiovale (768 ± 33 vs 699 ± 35, P < .001), frontal white matter (752 ± 25 vs 695 ± 30, P < .001), corona radiata (778 ± 42 vs 709 ± 24, P < .001), occipital white matter (783 ± 39 vs 706 ± 36, P < .001), and parietal white matter (767 ± 37 vs 724 ± 53, P < .001) (Fig 3). No statistically significant differences were observed in the brachium pontis location (696 ± 48 vs 666 ± 50, P = .052).
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
Some neuroastrocytes show partial migration, which results in heterotopic islets of dysplastic cells that may have characteristics of both neurons and glia. More differentiated cells migrate to the cortical plate; this results in clusters of dysplastic cortex (cortical tubers), which are responsible for both epilepsy and mental retardation.
Since results of fetal ultrasonography studies have shown that cranial abnormalities are detectable in TSC patients at as early as 14 weeks of gestation, the cellular effect of TSC gene mutations certainly occurs earlier than middle to late corticogenesis (11).
In the present study, we observed increased ADCs in all supratentorial NAWM of TSC patients, and, in addition, our observations of regions of NAWM surrounding the hamartomatous lesions revealed significant differences in ADCs compared with those of the contralateral side.
ADCs are rotationally invariant measurements of the diffusion of water molecules within a tissue (12). Diffusivity of water molecules is primarily related to microscopic structural barriers that alter the random motion of water on a molecular level (13). Because the degree of biologic membrane permeability is small, the main contribution of the diffusion constant comes from diffusion pathways that move around the cells rather than those that cross cell membranes. Experimental models have revealed that axonal cell membranes account for most of the restriction of water motion in white matter (14). Pathologic disruption of cell membranes, loss of myelin, or any process that may alter the integrity of axons would reduce the restriction of water motion, and, therefore, the ADCs would be expected to increase.
The increase in ADCs in supratentorial NAWM of patients with TSC may be caused by loss of tissue organization or by axonal hypomielination undetectable (unless large enough to be depicted) on conventional MR images.
Results of pathology studies have demonstrated that white matter lesions are invariably present in patients with TSC. On a microscopic level, these foci are characterized by disorganized heterotopic cells and hypomielination (7). They may be seen on spin-echo T2-weighted or FLAIR images as linear or curvilinear regions of hyperintensity (unless heavily calcified) that extend from subependymal nodules to cortical tubers. However, many of these disorganized foci are microscopic and, therefore, are not depicted at imaging (15). In addition, subtle pathologic changes in white matter areas distant from classical lesions have not been studied in detail.
Increases in ADCs within hamartomatous lesions have been described previously (16). In our study, the increase in ADCs observed in all white matter supratentorial locations, remote from any hyperintense area, suggests widespread ultrastructural changes and, therefore, may reflect diffuse microstructural damage.
Increased diffusivity of NAWM in patients with TSC may be caused by subtle radial hypomyelinated tracts, which usually extend from subependymal areas to the cortex. These tracts may be seen as linear areas of increased signal intensity on T2-weighted images. However, because we never placed ROIs on ADC maps over areas that were hyperintense either on spin-echo T2-weighted or on FLAIR images, the increased diffusivity of water molecules in NAWM could be more diffused than expected. Conversely, our findings might also indicate the presence of subtle disorganized white matter with heterotopic neurons, which is undetectable on conventional MR images.
Since ROIs had not been drawn below and/or between tubers and subependymal areas, the axonal microstructural damage demonstrated in our study would not be exclusively related to the linear band of cell migration but rather to the migration, differentiation, and organization of the white matter as a whole.
Whatever the explanation, we believe these findings are of interest, given the difficulty in diagnosis because of the absence of a reliable molecular marker and the great variability in clinical expression.
In a report of a combined study of functional magnetoencephalography and MR imaging, it was suggested that neuronal malfunctioning may not be restricted to the area of cortical tubers but may also affect functionally correlated regions (17). In addition, positron emmision tomography with fluorine 18 fluorodeoxyglucose demonstrated that cortical tubers represent areas of hypometabolism (18). Rintahaka and Chugani (19) confirmed that these areas correspond to cortical tubers on MR images. Furthermore, it has been demonstrated that hypometabolic areas are larger than lesions observed on MR images (20). Our results are congruent with those of this latter study in that we also clearly demonstrated that areas surrounding tubers, which appear normal on FLAIR images, show the greatest increases in ADCs. However, the most important result of our study is that there were widespread increases in ADCs for all white matter locations within the supratentorial regions in the TSC group. In addition, since it is well known that tubers rarely occur in the cerebellum (6), it is not surprising that we found no significant differences in ADCs within the infratentorial location (brachium pontis).
Our results might add clinically useful information in the diagnostic evaluation of patients with minor symptoms and the explanation of the variable clinical symptoms, and the results might also provide hints on the real extension of the epileptogenic zone. Finally, our findings might also help in understanding the physiopathogenesis of TSC in general.
One limitation of this study is that we did not evaluate the extent of the NAWM changes with other techniques, such as magnetization transfer and diffusion tensor MR imaging, which might have resulted in more detailed information on such subtle abnormalities. Further studies with other MR techniques are needed to confirm our findings.
Since the genetic mutation, which likely occurs in a dysplastic stem cell, represents the principal cause of events leading to hamartomatous lesions, diffuse ultrastructural changes reported herein may represent an important binding link between the molecular biologic events and the neurologic phenotype.
|
FOOTNOTES |
|---|
Author contributions: Guarantors of integrity of entire study, F.G.G., G.S.; study concepts and design, F.G.G., R.F., A.B.; literature research, G.M., A.S., P.C.; clinical studies, G.M., A.S., P.C.; data acquisition and analysis/interpretation, F.G.G., G.M., T.L.; statistical analysis, A.B., F.G.G.; manuscript preparation, F.G.G., A.B., P.C., R.F., T.L.; manuscript editing, F.G.G., R.F.; manuscript definition of intellectual content, revision/review, and final version approval, all authors
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  B. N. Kalantari and N. Salamon Neuroimaging of Tuberous Sclerosis: Spectrum of Pathologic Findings and Frontiers in Imaging Am. J. Roentgenol., May 1, 2008; 190(5): W304 - W309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.I. Makki, D.C. Chugani, J. Janisse, and H.T. Chugani Characteristics of Abnormal Diffusivity in Normal-Appearing White Matter Investigated with Diffusion Tensor MR Imaging in Tuberous Sclerosis Complex AJNR Am. J. Neuroradiol., October 1, 2007; 28(9): 1662 - 1667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.L. White, W.L. Hadley, Y. Zhang, and M.A. Dogar Analysis of Central Nervous System Vasculitis with Diffusion-Weighted Imaging and Apparent Diffusion Coefficient Mapping of the Normal-Appearing Brain AJNR Am. J. Neuroradiol., May 1, 2007; 28(5): 933 - 937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yamada, H. Matsuzawa, M. Uchiyama, I. L. Kwee, and T. Nakada Brain Developmental Abnormalities in Prader-Willi Syndrome Detected by Diffusion Tensor Imaging Pediatrics, August 1, 2006; 118(2): e442 - e448. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| RADIOLOGY | RADIOGRAPHICS | RSNA JOURNALS ONLINE |
