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Published online before print February 9, 2005, 10.1148/radiol.2351031963
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(Radiology 2005;235:190-196.)
© RSNA, 2005

Pediatric Imaging

Congenital Muscular Dystrophy with Merosin Deficiency: 1H MR Spectroscopy and Diffusion-weighted MR Imaging1

Claudia C. Leite, MD, PhD, Umbertina C. Reed, MD, PhD, Maria C. G. Otaduy, PhD, Maria T. C. Lacerda, MD, PhD, Maria O. R. Costa, MD, PhD, Lúcio G. Ferreira, MD, PhD, Mary S. Carvalho, MD, Maria B. D. Resende, MD, Suely K. N. Marie, MD, PhD and Giovanni G. Cerri, MD, PhD

1 From the Clinics Hospital of the University of São Paulo, Brazil. Received December 10, 2003; revision requested February 19, 2004; revision received May 22; accepted June 28. From the 2002 RSNA Scientific Assembly. M.C.G.O., M.O.R.C., and M.T.C.L. supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo). Address correspondence to C.C.L., Rua Mário Amaral, 81 apto 121M, São Paulo, SP, Brazil 040020–020 (e-mail: claudia.leite@hcnet.usp.br).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To prospectively use hydrogen 1 (1H) magnetic resonance (MR) spectroscopy and apparent diffusion coefficient (ADC) maps to try to explain the discrepancy between the extensive white matter (WM) abnormalities observed at MR imaging and the relatively mild neurocognitive decline in patients with merosin-deficient congenital muscular dystrophy (CMD).

MATERIALS AND METHODS: The hospital ethics committee approved this study, and informed consent was obtained. Nine patients (five boys, four girls; age range, 3–9 years; mean, 6 years ± 2 [standard deviation]) with merosin-deficient CMD underwent T1-weighted, T2-weighted, fluid-attenuated inversion recovery, and diffusion-weighted MR imaging and 1H MR spectroscopy, which was performed in the parieto-occipital WM (POWM) and frontal WM (FWM) by using stimulated-echo acquisition mode. Metabolite (N-acetylaspartate [NAA], choline-containing compounds [Cho], and myo-inositol [mI]) ratios were calculated in relation to creatine/phosphocreatine (Cr) and water (H2O). NAA/Cho was also calculated. ADCs were calculated in approximately the same locations that were studied with spectroscopy. For comparison, 1H MR spectroscopy (n = 10) and ADC mapping (n = 7) were also performed in 10 healthy age- and sex-matched control subjects (three boys, seven girls; age range, 4–9 years; mean, 6 years ± 1). Statistical analysis involved the t test for comparison between different groups; correlation between ADC and spectroscopy results was studied with the Pearson test.

RESULTS: MR imaging revealed evidence of bilateral WM involvement in all patients. Whereas their NAA/Cr and Cho/Cr were normal, their mI/Cr was slightly increased compared with that in control subjects (P = .03 in FWM and P = .07 in POWM), and their NAA/Cho was decreased in POWM (P = .03). NAA/H2O, Cr/H2O, Cho/H2O, and mI/H2O were considerably decreased (P < .05 for all) and ADC values were increased (P < .001) in WM in all patients versus these values in WM in control subjects. There was significant correlation between ADC values and metabolite/water ratios (r = –0.777 to –0.967, P < .05).

CONCLUSION: ADC mapping and 1H MR spectroscopy reveal abnormally high free-water concentrations in the WM of patients with merosin-deficient CMD.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Congenital muscular dystrophies (CMDs) are a heterogeneous group of disorders that are characterized by the early onset of hypotonia, muscular weakness, and dystrophic findings at muscle biopsy; the mode of inheritance is generally autosomal recessive. CMDs can be limited to the muscle or can be associated with central nervous system and eye abnormalities. Many different phenotypes, including some that have been defined on a molecular basis (1–5), have been described during the past decade. Of the four major types of CMD, three (ie, the Fukuyama type, Walker-Warburg syndrome, and muscle-eye-brain disease) are associated with brain malformations and severe mental retardation. CMD without these findings is called "pure" or "classic" CMD and includes merosin-positive and merosin-deficient forms.

In the merosin-deficient form of CMD, patients have a total or partial deficiency of the protein merosin (laminin {alpha}2). This type of CMD is characterized by a severe clinical course and is associated with a genetic defect on locus 6q2 (6). Affected children generally show severe congenital hypotonia, an inability to achieve independent walking, severe and early joint contractures, normal or near-normal intelligence, and white matter (WM) changes at magnetic resonance (MR) imaging (7–9). These WM changes may not be apparent until 6 months of age. Children with the merosin-positive form of CMD generally have a less severe phenotype and no MR imaging abnormalities at presentation (6).

Hydrogen 1 (1H) MR spectroscopy and diffusion-weighted imaging are MR imaging techniques that yield information about the cerebral biochemical status and the molecular motion of water, respectively. The purpose of our study was to prospectively use proton MR spectroscopy and apparent diffusion coefficient (ADC) maps to try to explain the discrepancy between the extensive WM abnormalities observed at MR imaging and the relatively mild neurocognitive decline in patients with merosin-deficient CMD.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Control Subjects
From March 2001 to February 2002, we prospectively examined nine patients with merosin-deficient CMD that was proved with muscle biopsy. These patients were consecutively selected from the congenital muscular disorders group in the neurology department of our hospital. Five patients were male and four were female; their ages ranged from 3 to 9 years (mean age, 6 years ± 2 [standard deviation]). This was the first MR imaging examination for five patients and was a follow-up examination in the remaining four patients. The cognitive function of the children was also assessed with standard psychological tests (Stanford-Binet intelligence scale or Brunet-Lezine infant test). Table 1 summarizes the patients’ clinical characteristics, laboratory data, and merosin statuses (as determined with muscle biopsy).


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  		TABLE 1. Nine Patients with CMD: Clinical Characteristics, Laboratory Findings, and Merosin Status

 
An age- and sex-matched control group was examined with the same imaging protocols used to examine the patient group, with the exception that the control subjects did not receive a gadolinium chelate. In addition, the diffusion study was performed in only seven of the 10 control subjects. This control group consisted of healthy children (three boys and seven girls) from the community who ranged in age from 4 to 9 years (mean age, 6 years ± 1). These children were healthy and did not have any neurologic symptoms or signs. There was no statistically significant difference in age or sex between the patient group and the control group, as confirmed with the t test (P = .394) and the Fisher exact test (P = .673), respectively.

Our hospital ethics committee approved this study, and the parents of the children in the patient and the control groups provided written informed consent for participation.

MR Imaging
All MR imaging examinations were performed with the same 1.5-T MR imaging unit (Signa Horizon LX; GE Medical Systems, Milwaukee, Wis). The MR imaging protocol included acquisition of the following transverse images: T1-weighted images (repetition time msec/echo time msec, 466/19), T2-weighted images (4500/120; echo train length, eight), and fluid-attenuated inversion recovery images (repetition time msec/echo time msec/inversion time msec, 11 002/148/2200). The section thickness was 5 mm, and the field of view varied between 18 and 24 cm. We also obtained transverse, coronal, and sagittal T1-weighted images after the administration of 0.1 mmol per kilogram of body weight of a gadolinium chelate; the brand of gadolinium chelate used varied during the course of this investigation. Two radiologists (C.C.L. and M.T.C.L.; 11 and 5 years of experience, respectively) independently evaluated the MR imaging results and described the location of WM involvement and classified it as focal (consisting of sparse lesions) or diffuse (consisting of confluent lesions that sometimes extended to the arcuate fibers). The presence or absence of brain malformations was also recorded.

Before gadolinium chelate administration, two single-voxel 1H MR spectroscopic acquisitions were performed in regions containing affected WM. One acquisition was performed in the frontal WM (FWM) and one was performed in the parieto-occipital WM (POWM) (Fig 1) in both the patients and the control subjects. The voxel was always positioned by the same radiologist (M.O.R.C.; 5 years of experience), and its size was 2 x 2 x 2 cm3. The 1H MR spectroscopic sequence was a 90°-90°-90° stimulated-echo acquisition mode pulse sequence with the following parameters: 1500/30; mixing time, 13.7 msec; number of acquisitions, 128; and number of phase cycle steps, eight. The stimulated-echo acquisition mode sequence was preceded by an automatic preacquisition procedure that included adjustment of transmitter and receiver gains, optimization of the flip angle for water suppression, and shimming for the chosen voxel, which was graphically selected on a T2-weighted localizer image (3000/88; echo train length, 22; section thickness, 5 mm). The water peak line width was never broader than 5 Hz after the preacquisition procedure.



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  		Figure 1. Patient 5.  Transverse T2-weighted MR image (3000/88; echo train length, 22) shows where voxel was obtained at 1H MR spectroscopy in FWM (1) and POWM (2).

 
Sixteen unsuppressed water reference acquisitions, followed by 128 water-suppressed acquisitions, were acquired for each voxel, while transmitter and receiver gains were kept constant. Water suppression was achieved with the application of three chemical shift–selective Gaussian pulses (10). A total of 2048 data points were collected over a spectral width of 2500 Hz.

Spectral analysis was performed off-line with public-domain MR user interface software (available at: www.mrui.uab.es) by an experienced spectroscopist (M.C.G.O.). The 16 unsuppressed water reference acquisitions were used to measure the water signal, and the 128 water-suppressed acquisitions were used to measure the metabolite signals. In the water-suppressed spectra, the residual water signal was used as a reference for the chemical shift at 4.7 ppm before a Hankel-Lanczos singular value decomposition, or HLSVD, filter (11) in the region of 4.3–5.2 ppm was applied. After the water signal was filtered out (and with the assumption that all evaluated metabolites had the same line width), the advanced method for accurate, robust, and efficient spectral fitting, or AMARES (12), algorithm was used to fit the time-domain data to the following resonances: N-acetylaspartate (NAA) at 2.02 ppm, creatine/phosphocreatine (Cr) at 3.02 ppm, choline-containing compounds (Cho) at 3.22 ppm, and myo-inositol (mI) at 3.56 ppm. Because the fitting algorithm was applied to the time-domain data, we used (for quantification purposes) the amplitude values, which would correspond to integral values in the frequency domain. The obtained amplitude values were used to calculate metabolite ratios relative to the Cr resonance. The NAA/Cho ratio was also calculated. The water signal was measured from the unsuppressed reference acquisitions by using the HLSVD algorithm (13). Metabolite/water (H2O) ratios were calculated after dividing the corresponding amplitude values by the total number of acquisitions (128 and 16, respectively).

Diffusion-weighted images were obtained in the transverse plane by using a sequence that was based on the Stejskal and Tanner pulsed field gradient method (14), combined with an echo-planar imaging sequence with 10 000/100 and one signal acquired. For each section, four acquisitions were performed with b = 0, bx = 1000, by = 1000, and bz = 1000 sec/mm2. A trace image was generated by averaging the three diffusion-weighted images: bx, by, and bz. For each section, ADC maps were created from the corresponding T2-weighted image (b = 0 sec/mm2) and the trace image (b = 1000 sec/mm2), and the ADC pixel intensity was calculated according to the following equation: ADC = [–ln(b1000/b0)]/1000 sec/mm2.

We measured only two b values for time-saving reasons, a practice that has been proved to yield accurate enough results when compared with methods involving a higher number of b values (15). Mean ADC values were determined for the FWM and POWM by placing a 2 x 2-cm2 square region of interest on a 5-mm transverse section. Care was taken to position these regions of interest at the same locations where the 1H MR spectroscopic data were obtained by using the region-of-interest coordinates of the 1H MR spectroscopic voxel as a guide (Fig 2). The same experienced radiologist (M.O.R.C.; 5 years of experience) who placed the 1H MR spectroscopic voxels also placed the ADC regions of interest.



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  		Figure 2. Patient 5.  ADC map shows locations in FWM (1) and POWM (2) in which ADC values were measured.

 
MR Image Analysis and Comparisons
Two experienced radiologists (C.C.L. and M.T.C.L.) independently reviewed the T1-weighted, T2-weighted, and transverse fluid-attenuated inversion recovery images obtained in the patients and classified the WM involvement as focal or diffuse. The 1H MR spectroscopic and diffusion-weighted imaging data, which were obtained before gadolinium chelate administration, were used to determine ratios of other metabolites to Cr, metabolite/water ratios, and ADC values. The mean ratios of other metabolites to Cr, metabolite/water ratios, and ADC values in regions of interest in the FWM and POWM of patients were then compared with those in control subjects.

Statistical Analysis
Statistical analysis was performed by using the software SPSS for Windows 10 (SPSS, Chicago, Ill).

The normal distribution of the data was confirmed with the Anderson-Darling test, with which a P value of .01 was considered to indicate a statistically significant difference. The two-tailed t test was used for comparisons between different groups, and the Levene test was applied to determine whether or not variances were equal. The Pearson correlation test was used to evaluate the relationship between ADC values and metabolite/water ratios in the patients. P < .05 was considered to be statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
All patients had bilateral and symmetric WM involvement, which was characterized by hypointensity on T1-weighted MR images and hyperintensity on T2-weighted and fluid-attenuated inversion recovery images without gadolinium enhancement on T1-weighted images (Fig 3).In all patients, the frontal, parietal, temporal, and occipital lobes were involved. The corpus callosum was spared in all cases. The cerebellar WM was affected in two patients, the brainstem was affected in one patient, and the external capsules were affected in one patient. The degree of WM involvement varied, and there was diffuse involvement in eight patients but focal involvement in only one (patient 5). There was no disagreement between the two radiologists (C.C.L., M.T.C.L.). None of the patients presented with evidence of brain malformations, including cortical developmental abnormalities. All patients had normal or near-normal neurocognitive development, as determined by a pediatric neurologist (U.C.R.), who used standard psychological tests.



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  		Figure 3a. Patient 3.  Transverse (a) T2-weighted (4500/120; echo train length, eight), (b) T1-weighted (466/19), and (c) fluid-attenuated inversion recovery (11 002/148/2200) MR images show abnormal signal intensity in FWM and POWM that extends to the arcuate fibers (arrows).

 


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  		Figure 3b. Patient 3.  Transverse (a) T2-weighted (4500/120; echo train length, eight), (b) T1-weighted (466/19), and (c) fluid-attenuated inversion recovery (11 002/148/2200) MR images show abnormal signal intensity in FWM and POWM that extends to the arcuate fibers (arrows).

 


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  		Figure 3c. Patient 3.  Transverse (a) T2-weighted (4500/120; echo train length, eight), (b) T1-weighted (466/19), and (c) fluid-attenuated inversion recovery (11 002/148/2200) MR images show abnormal signal intensity in FWM and POWM that extends to the arcuate fibers (arrows).

 
Table 2 lists mean metabolite ratios ± standard deviations in the FWM and POWM of patients versus those in control subjects. It was not possible to measure metabolite ratios in the FWM of one patient (patient 7).


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  		TABLE 2. Metabolite Ratios in FWM and POWM of Patients with CMD versus Those in Control Subjects

 
The NAA/Cr and Cho/Cr in the WM (both frontal and parieto-occipital) of the patients did not differ significantly from those in the control group. However, there was a slight but statistically significant increase in mI/Cr in the FWM of the patients and a decrease in NAA/Cho in the POWM of the patients compared with these values in the control subjects (Table 2, Fig 4). Table 3 shows that the NAA/H2O, Cho/H2O, Cr/H2O, and mI/H2O in the FWM and POWM of patients were decreased compared with these ratios in control subjects. In the FWM, there was a 45% decrease in NAA/H2O, a 46% decrease in Cr/H2O, a 41% decrease in Cho/H2O, and a 36% decrease in mI/H2O (Table 3). In the POWM, NAA/H2O, Cr/H2O, Cho/H2O, and mI/H2O decreased by 43%, 37%, 33%, and 27%, respectively (Table 3).



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  		Figure 4a. Average 1H MR spectroscopic data for POWM in (a) patients and (b) control subjects and for FWM in (c) patients and (d) control subjects. Note that the differences between patients and control subjects are minimal. There is a decrease in NAA/Cho in the POWM and an increase in mI/Cr in the FWM of the patients compared with these values in the control subjects.

 


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  		Figure 4b. Average 1H MR spectroscopic data for POWM in (a) patients and (b) control subjects and for FWM in (c) patients and (d) control subjects. Note that the differences between patients and control subjects are minimal. There is a decrease in NAA/Cho in the POWM and an increase in mI/Cr in the FWM of the patients compared with these values in the control subjects.

 


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  		Figure 4c. Average 1H MR spectroscopic data for POWM in (a) patients and (b) control subjects and for FWM in (c) patients and (d) control subjects. Note that the differences between patients and control subjects are minimal. There is a decrease in NAA/Cho in the POWM and an increase in mI/Cr in the FWM of the patients compared with these values in the control subjects.

 


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  		Figure 4d. Average 1H MR spectroscopic data for POWM in (a) patients and (b) control subjects and for FWM in (c) patients and (d) control subjects. Note that the differences between patients and control subjects are minimal. There is a decrease in NAA/Cho in the POWM and an increase in mI/Cr in the FWM of the patients compared with these values in the control subjects.

 

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  		TABLE 3. Metabolite/Water Ratios in FWM and POWM of Patients versus Those in Control Subjects

 
Table 4 lists the ADC values. The mean ADC for the FWM of the patients (1366 x 10–6 m2/sec ± 206) was significantly greater than that for the control subjects (874 x 10–6 m2/sec ± 17) (P < .001). The mean ADC for the POWM of the patients (1404 x 10–6 m2/sec ± 248) was also increased compared with that for the control subjects (848 x 10–6 m2/sec ± 30) (P < .001) (Table 4). The Pearson correlation test revealed a strong correlation between these increases in ADC values and the decreases in the metabolite/water ratios (Table 5).


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  		TABLE 4. ADCs in FWM and POWM of Patients versus Those in Control Subjects

 

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  		TABLE 5. Results of Correlation between ADC Values and Metabolite/Water Ratios in Patients

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
Tomé et al (16) originally described a subtype of CMD with merosin (laminin {alpha}2) deficiency. In addition to the muscle abnormalities, which are characterized by a marked increase in the connective tissue of endomysium that is associated with some necrosis and regeneration of muscle fibers, patients with this type of CMD have abnormal findings at cranial MR imaging, polyneuropathy, and, sometimes, congestive cardiomyopathy (8,9,16,17). The brain involvement in these patients manifests as abnormal signal intensity in the supratentorial WM and external capsules (7–9,16–22). The diagnosis of merosin-deficient CMD is based on the clinical findings of severe congenital hypotonia, weakness with high blood levels of creatine kinase, WM abnormalities, and dystrophy associated with negative immunostaining of biopsied muscle for merosin.

The extent of WM involvement at MR imaging in these patients does not appear to correlate with the clinical phenotype or the degree of merosin expression (21). The WM involvement has been described as diffuse and symmetric in the cerebral hemispheres (7,20). The WM lesions are hypointense on T1-weighted images, hyperintense on T2-weighted and fluid-attenuated inversion recovery images, and do not show enhancement after gadolinium chelate administration. Some authors (22–26) have reported associated cortical migrational disorders. We did not observe any cortical migrational disorders, vermian abnormalities, or brainstem atrophy among our patients.

Proton MR spectroscopy has been used as a diagnostic tool for noninvasive biochemical analysis of the brain. Yet, to our knowledge, there is no prior report of proton MR spectroscopy or ADC measurement (diffusion-weighted imaging) in patients with merosin-deficient CMD. A compelling reason to use such techniques is that they have provided additional information regarding some metabolic and demyelinating processes involving children. For example, Canavan disease, Alexander disease, Cockayne syndrome, Pelizaeus-Merzbacher disease, vanishing WM disease, metachromatic leukodystrophy, and X-linked adrenoleukodystrophy are associated with abnormal findings at 1H MR spectroscopy (27–37). In most of these diseases, the metabolic changes detected at 1H MR spectroscopy correlate with the neuropathologic findings (29,33–35).

In contrast to the findings it reveals in most WM diseases, 1H MR spectroscopy in our patients with merosin-deficient CMD revealed normal NAA/Cr and Cho/Cr and a slightly increased mI/Cr. Given the extent of the abnormalities observed at MR imaging, it is somewhat surprising that, when Cr was used as a reference, mI/Cr was the only metabolite ratio that was different between our patient and control groups. In addition, we must take into account the fact that the way we measured metabolite concentrations allowed us to obtain only relative concentrations. This means that, although NAA/Cr and Cho/Cr were preserved in our patients, the absolute concentrations of metabolites might not necessarily have been the same between patients and control subjects. As a matter of fact, when we calculated NAA/Cho, we observed significant changes in the POWM between patients and control subjects.

In an attempt to compare our 1H MR spectroscopic data independently of Cr, we decided to calculate metabolite ratios relative to the internal water signal, as measured from the unsuppressed water reference acquisitions. We found that all metabolite/water ratios were considerably lower in patients than in control subjects. For example, Cr/H2O was an average of about 42% lower in patients (46% lower in the FWM and 37% lower in the POWM) than in control subjects. This could be explained either by an increase in water content or a decrease in metabolite content.

The main osmolyte regulating osmotic pressure in cells is mI (38). When metabolites in cells become strongly diluted, the concentration of mI increases to maintain the osmotic pressure. Therefore, the increased mI/Cr could reflect strong dilution of the other metabolites in the cells of patients compared with the dilution in control subjects. To summarize, our results indicate that the major difference between patients and control subjects was the greater dilution of metabolites in the WM of the patients; this led to a relative increase in mI/Cr in patients, which is explainable by the role of mI in maintaining osmotic pressure.

Diffusion-weighted imaging yields image contrast that depends on the molecular motion of water in tissue. This MR imaging technique has been widely used to depict acute brain infarction; in pediatric neuroimaging, it has also been used in the diagnosis of hypoxic-ischemic injuries. Diffusion in WM is believed to be affected by the tissue’s structural organization at the microscopic level and to reflect the extent to which the molecular displacement of water is free or restricted. There are also reports that developing myelination can alter diffusion; a decrease in ADC values has been observed during myelination (39–42).

Using proton spectroscopy and diffusion tensor MR imaging, Eichler et al (36) examined patients with X-linked adrenoleukodystrophy. They found a correlation between increased free extracellular water and decreased metabolite concentrations in the affected WM of these patients. This relative increase in the free extracellular water content could also explain the increase in ADC values observed by Engelbrecht et al (42) in cases of adrenoleukodystrophy and Krabbe disease. The possible explanations for this increased water concentration have included: an increase in the water content, a decrease in the cellular component, and/or a myelin abnormality resulting in more free water. Increased ADC values have also been correlated with increased free extracellular water content in cases of vasogenic edema (43). Similarly, on the basis of the strong correlation found between metabolite/water ratios and ADC values, we hypothesize that the increased ADC values in the affected WM of our patients reflected increased free extracellular water.

The pathogenesis of changes in brain WM in patients with CMD and merosin deficiency has yet to be completely defined. Merosin (laminin {alpha}2) is a protein linking the extracellular matrix to the dystrophin-glycoprotein complex of striated muscle cells. Villanova et al (44,45) have described merosin as a major component of the basal membrane. In the central nervous system, merosin is present in the basal lamina of the walls of intraparenchymal blood vessels. This basal lamina constitutes part of the blood-brain barrier, which actively selects molecules that are allowed to reach the brain. Thus, a deficiency in merosin could lead to impaired selective filtration (vascular hyperpermeability), allowing normal plasma components or even toxic substances to reach the central nervous system (44,45).

Caro et al (17) hypothesized that the hyperintense signal on T2-weighted MR images in the WM observed in their MR imaging–based study of merosin-deficient CMD was attributable to increased water content caused by a defect in the blood-brain barrier rather than to decreased or abnormal myelination. Reinforcing the hypothesis that there is no destruction of myelin, Gilhuis et al (8) did not find myelin-specific protein in the cerebrospinal fluid of patients with merosin deficiency; this is in contrast to findings in patients with demyelinating diseases. Furthermore, in our patients, we did not observe any alteration in Cho/Cr, which appears to be augmented in patients with active demyelinating diseases (36).

An important limitation of this study was that we were not able to obtain absolute metabolite concentrations in the cerebral tissue of patients and control subjects. For such calculations it would have been necessary to correct for the T1 and T2 relaxation behavior of each metabolite. To measure metabolites’ T1 and T2 in our patients, several spectra would have had to be obtained with different echo times and repetition times, and this process would have resulted in too prolonged an imaging time for anesthetized patients. We did not measure water relaxation times either.

And because we acquired our 1H MR spectroscopic data with a repetition time of 1500 msec, we did not allow complete longitudinal relaxation of metabolites and water signals. This implies a partial saturation of the MR signal, and this effect becomes stronger the longer the T1 of the compound. MR imaging abnormalities in the WM suggest that water T1 and T2 were considerably increased in our patients in the studied areas (17). An increase in water T1 would have resulted in a stronger saturation (reduction) of the water signal in the spectra of patients; this would not explain the reduced Cr/H2O in patients compared with this ratio in control subjects. However, an increase in water T2 could partly account for this observation in that the longer the T2 of the compound, the larger its MR signal for a given echo time. Taking into account the short echo time used in our spectra, it is unlikely that different relaxation properties of water between patients and control subjects is the only reason for the large differences observed in the metabolite/water ratios.

Another limitation was that it was not possible to perform pathologic examination for confirmation of our hypothesis that myelin was preserved in the patients in this series.

The decreased metabolite/water ratios and increased ADC suggest increased free extracellular water concentrations in the affected WM of patients with merosin-deficient CMD. In conclusion, our findings support the hypothesis that WM changes in patients with merosin-deficient CMD are not related to destruction of brain myelin but rather reflect the leakage of plasma into the brain. These findings may explain why most children with this type of CMD have normal or near-normal intelligence and do not present with neurologic symptoms or signs, despite the extensive WM abnormalities observed at MR imaging.


   ACKNOWLEDGMENTS
 
The MR user interface software package was kindly provided by the participants of the following European Union Network programs: Human Capital and Mobility, grant number CHRX-CT94–0432, and Training and Mobility of Researchers, grant number ERB-FMRX-CT970160.


   FOOTNOTES
 
Abbreviations: ADC = apparent diffusion coefficient, Cho = choline-containing compounds, CMD = congenital muscular dystrophy, Cr = creatine/phosphocreatine, FWM = frontal WM, mI = myo-inositol, NAA = N-acetylaspartate, POWM = parieto-occipital WM, WM = white matter

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, C.C.L., U.C.R., S.K.N.M., G.G.C.; study concepts, C.C.L., U.C.R., M.C.G.O.; study design, C.C.L., U.C.R.; literature research, C.C.L., M.C.G.O., U.C.R., L.G.F.; clinical studies, U.C.R., L.G.F., S.K.N.M., M.S.C., M.B.D.R.; data acquisition and analysis/interpretation, C.C.L., M.C.G.O., M.T.C.L., M.O.R.C.; statistical analysis, M.T.C.L., M.C.G.O., M.O.R.C.; manuscript preparation and editing, C.C.L., M.C.G.O.; manuscript definition of intellectual content and revision/review, C.C.L., U.C.R., M.C.G.O.; manuscript final version approval, U.C.R., S.K.N.M., G.G.C.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 

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A. Alkan, A. Sigirci, R. Kutlu, M. Aslan, S. Doganay, and C. Yakinci
Merosin-Negative Congenital Muscular Dystrophy: Diffusion-Weighted Imaging Findings of Brain
J Child Neurol, May 1, 2007; 22(5): 655 - 659.
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