Neuroradiology (2008) 50:123–129 DOI 10.1007/s00234-007-0325-y

DIAGNOSTIC NEURORADIOLOGY

Prognostic value of high-field proton magnetic resonance spectroscopy in patients presenting with clinically isolated syndromes suggestive of multiple sclerosis Mike P. Wattjes & Michael Harzheim & Götz G. Lutterbey & Manuela Bogdanow & Stephan Schmidt & Hans H. Schild & Frank Träber

Received: 24 July 2007 / Accepted: 28 September 2007 / Published online: 3 November 2007 # Springer-Verlag 2007

Abstract Introduction The aim of this study was to determine the prognostic value of metabolic alterations in the normalappearing white matter (NAWM) of patients presenting with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) with special regard to the prediction of conversion to definite MS. Methods Using a 3T whole-body MR system, a multisequence conventional MRI protocol and single-voxel proton MR spectroscopy (PRESS, repetition time 2000 ms, echo times 38 ms and 140 ms) of the parietal NAWM were performed in 25 patients presenting with CIS at baseline and in 20 controls. Absolute concentrations of N-acetyl-aspartate (tNAA), myo-inositol (Ins), choline (Cho) and creatine (tCr) as well as metabolite ratios were determined. Follow-up including neurological assessment and conventional MRI was performed 3–4 and 6–7 months after the initial event. M. P. Wattjes : G. G. Lutterbey : H. H. Schild : F. Träber Department of Radiology/Neuroradiology, University of Bonn, Bonn, Germany M. P. Wattjes (*) MS Center Amsterdam, Department of Radiology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands e-mail: [email protected] M. Harzheim : S. Schmidt Department of Neurology, University of Bonn, Bonn, Germany M. Bogdanow Department of Medical Biometrics, Informatics and Epidemiology, University of Bonn, Bonn, Germany

Results Nine patients converted to definite MS during the follow-up period. Compared to controls, those patients who converted to MS also showed significantly lower tNAA concentrations in the NAWM (−13.4%, P=0.002) whereas nonconverters (−6.5%, P=0.052) did not. The Ins concentration was 20.2% higher in the converter group and 1.9% higher in the nonconverter group, but these differences did not reach significance. No significant differences could be observed for tCr and Cho in either patient group. Conclusion Axonal damage at baseline in patients presenting with CIS was more prominent in those who subsequently converted to definite MS in the short term follow-up, indicating that tNAA might be a sufficient prognostic marker for patients with a higher risk of conversion to early definite MS. Keywords MRS . NAWM . Clinically isolated syndromes . Multiple sclerosis

Introduction Multiple sclerosis (MS) is the most common idiopathic inflammatory demyelinating disease of the central nervous system in young adults [1]. Although conventional magnetic resonance imaging (MRI) is still the best established paraclinical method for the detection and monitoring of MS, the conventional MRI finding in terms of T2 lesion load does not necessarily correlate with clinical outcome measures such as clinical disability [1–3]. However, in patients presenting with clinically isolated syndromes (CIS) suggestive of MS, MRI has a certain prognostic value in its ability to predict conversion to definite MS and long-term disability [4–6].

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Proton magnetic resonance spectroscopy (1H-MRS) is a well-established quantitative MR method that allows the noninvasive in-vivo assessment of metabolic changes in various parts of the central nervous system (CNS). This is especially important in areas which appear to be normal on conventional MRI, the normal-appearing grey matter (NAGM) and white matter (NAWM) [2]. Several metabolites have been reported to be involved in the disease process of MS. The most clinically relevant metabolites are N-acetyl aspartate (tNAA) which is almost exclusively located in neurons indicating axonal integrity and myoinositol (Ins) which is predominantly found in astroglial cells representing a marker of glial cell activity [7–10]. In the NAWM of MS patients, lower tNAA concentrations and therefore substantial axonal damage can be observed even early in the disease course. Ins is often significantly elevated in the NAWM indicating increased glial cell activity [11–17]. Metabolite changes in definite MS are well known. However, there is only limited experience available in patients presenting with the first clinical demyelinating attack who do not fulfil the criteria of definite MS. One study has provided the first evidence of significantly increased glial cell activity but no substantial axonal damage in the NAWM in patients presenting with CIS [18]. The unanswered question as to whether metabolic alterations at the time of the first clinical episode of a possible MS might have prognostic value in predicting conversion to definite MS is highly relevant in terms of the future disease course and clinical outcome. The aim of the present study was to determine the metabolic alterations in the NAWM of patients presenting with CIS at baseline and to compare the metabolic changes in patients who converted to definite MS over a short follow-up period with those in patients who did not in order to determine the value of metabolic alterations in predicting conversion to definite MS.

Materials and methods Patients and healthy controls Included in the study were 25 patients (17 female, 8 male; median age 35 years, range 18–55 years) and 20 healthy controls (11 female, 9 male; median age 29 years, range 22 to 40 years). The inclusion criteria were age between 18 and 56 years, presentation with a CIS of the CNS according to the International Panel (IP) criteria on the diagnosis of MS [19], no other immunological, malignant or vascular diseases in the present and/or past medical history, and no immune-modifying treatment during the last 4 weeks. All

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patients were selected by the MS outpatient clinic of the local Department of Neurology. The complete study protocol was approved by the local Institutional Review Board. Written informed consent was obtained from all participants. Study protocol All patients underwent combined baseline 1H-MRS and conventional multisequence MRI examination shortly after the first clinical event. Follow-up visits including a neurological assessment and conventional multisequence MRI were scheduled for 3–4 and 6–7 months after initial presentation. The assessment of conversion to definite MS was performed clinically (new clinical attack) and by MRI (new T2 hyperintense lesion and/or new contrast-enhancing lesion) according to the IP criteria [19]. Neurological assessment Prior to each MR examination, a neurological examination was performed by an experienced neurologist including application of the Expanded Disability Status Scale (EDSS) [20]. Further neurological work-up included CSF parameters (assessment of cellularity, protein level, intrathecal IgG synthesis and oligoclonal bands by isoelectric focusing) as well as visual evoked potentials.

Conventional MRI protocol All MR examinations were performed on a 3.0T wholebody MR system (Gyroscan Intera, Philips Medical Systems, Best, The Netherlands) using an eight-element phased array sensitivity-encoding (SENSE) head coil. The MR system was equipped with standard gradients (maximum slew rate of 150 mT/m per ms, maximum strength of 30 mT/m). The multisequence protocol included 21 contiguous sagittal sections of a T2 turbo spin echo sequence (repetition time 3575 ms, echo time 100 ms, measured voxel size 0.9×0.9×2 mm) and 24 contiguous axial sections of a T2 turbo spin echo sequence (repetition time 4100 ms, echo time 100 ms, measured voxel size 0.9×0.9×5 mm), fluid-attenuated inversion recovery sequence (repetition time 12,000 ms, echo time 140 ms, inversion delay 2850 ms, measured voxel size 0.9×0.9×5 mm) and a T1-weighted spin echo sequence (repetition time 500 ms, echo time 12 ms, measured voxel size 0.9×0.9×5mm) before and after administration of contrast agent (gadolinium diethylene-triaminepentaacetic acid, DTPA). Details of the MR acquisition parameters, scan orientation and repositioning have been described previously [21, 22].

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1

H-MRS acquisition

H-MRS acquisitions were obtained at baseline within the same session as the conventional MR imaging, prior to the administration of gadolinium-DTPA. Localized single voxel 1 H-MRS was acquired from the parietal NAWM using a protocol similar to recently described 1H-MRS acquisition protocols [15, 18]. The MRS voxel size was 8 ml in all examinations. An example of voxel positioning and size is given in Fig. 1. The 1H-MRS acquisitions were based on point-resolved spectroscopy (PRESS) localization using a repetition time of 2,000 ms, echo times of 38 ms and 140 ms, 1,024 samples, a bandwidth of 2 Hz/pixel, and 96 signal averages. We performed automated “high-order” B0 shimming. In order to obtain absolute concentrations the tNAA signal was referenced to the internal water signal in unsuppressed spectra (repetition time 3,500 ms, echo time 140 ms, 32 signal averages). Unsuppressed T2 relaxometry (repetition time 5,000 ms, seven different echo times ranging from 40 to 750 ms) was performed to correct for partial CSF volume within the selected voxel. The T2 relaxation times of tNAA, creatine (tCr), and choline (Cho) were measured with a water-suppressed acquisition (repetition time 2,500 ms, six sets of different echo times ranging from 50 to 425 ms, 16 signal averages). A time-domain analysis using the MRUI software package was performed during postprocessing, and 22 spectral components were quantified within the water-suppressed data obtained at the shorter echo time and analyzed using the AMARES algorithm [23, 24]. The absolute concentrations of tNAA, Ins, Cho and tCr were determined as well as their relative signal ratios. Additionally, the ratio of Glx (summation of glutamate and glutamine) to tCr was determined. The Glx/tCr ratio was calculated using the sum of the four peaks from the CH2multiplets of Glx visible in the frequency range 2.1–2.4 ppm in the example spectra (Fig. 2). The accuracy and reproducibility of the absolute concentration measure-

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ments were evaluated and controlled using a phantom containing NAA, Ins, Cho, Cr, glutamate and lactate in known concentrations as previously described [25]. Metabolite T2 measurements were performed in 17 of the 25 CIS patients and in 15 of the 20 healthy controls. In those patients and controls in whom the metabolite T2 values were not measured individually, the respective group mean value for T2 was applied in the calculation of the absolute concentrations. Statistical analysis All statistical analyses were performed by the SPSS software package (SPSS, Chicago, Ill.). P values <0.05 were considered statistically significant. The significance of the differences in the NAWM metabolite concentrations between the two groups of CIS patients and the healthy controls was evaluated by the nonparametric Mann-Whitney test for unpaired samples.

Results Clinical characteristics at baseline Among the 25 patients presenting with CIS, the initial clinical event was unilateral optic neuritis in 16, brainstem syndromes in 4, spinal cord syndromes in 3, and polysymptomatic CIS in 2. At baseline, the median EDSS was 1.5 (range 0–3) and the median disease duration was 30 days (range 2–48 days). Conversion to definite MS Nine patients (36%) converted to definite MS during the 7-month follow-up period. Among these, three patients showed a new contrast-enhancing lesion, one patient a new T2-hyperintense lesion on MRI at 3–4 months and another

Fig. 1 Voxel positioning within the NAWM. Axial and sagittal T2-weighted images (right, left) and coronal T1-weighted image (centre) obtained from a healthy control demonstrating the positioning of the MRS voxel within the parietal NAWM

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Fig. 2 1H-MR spectra (repetition time 2,000 ms, echo time 38 ms) from the NAWM of two age- and gender-matched patients presenting with CIS (unilateral optic neuritis) at baseline, one who did not convert to definite MS (a) and one who did convert (b) during the

follow-up period. Note the markedly lower tNAA value and higher Ins value in the patient who converted to definite MS (b) compared to the patient who did not convert (a)

patient at 6–7 months after the initial clinical event. The remaining four patients had a second clinical event and converted to clinically definite MS (two patients at 3 months, one patient at 5 months, and one patient at 6 months after the initial event).

lesion dissemination in space. One patient in the converter group did not have dissemination in space on the baseline scan, but showed new lesions on the follow-up scan, thus fulfilling the criteria for dissemination in space and in time.

Conventional MRI at baseline

Metabolic changes at baseline

Among the 25 patients presenting with CIS, 24 (96%) showed inflammatory brain lesions on MRI, and 16 fulfilled the criteria for lesion dissemination in space according to the IP criteria [19]. One patient had a normal MRI scan without any inflammatory brain lesions. The findings in terms of fulfilled diagnostic MRI criteria are summarized in Table 1. Eight patients in the converter group and eight in the nonconverter group had

The metabolite concentrations and relative signal ratios of the CIS patients compared to healthy controls are given in Table 2. Compared with healthy controls, the CIS patients who converted to definite MS within the follow-up period showed significantly lower tNAA concentrations at baseline (−13.4%, P=0.002), whereas slightly but not significantly lower tNAA concentrations were observed in the nonconverter group. This difference was even obvious in a direct comparison between the converter and nonconverter group (−13.4% vs. −6.5%), but did not reach a statistically significant level (P=0.084). Spectra from two CIS patients indicating the markedly lower tNAA concentrations in the patient group who converted to definite MS are given in Fig. 2. None of the other metabolites showed significantly different absolute concentrations either in the complete CIS group or in the two subgroups. The CIS patients who converted showed markedly higher Ins concentrations than the nonconverter group (20.2% vs. 1.9%), but this difference was not significant (P=0.081).

Table 1 Conventional MRI findings in terms of diagnostic MRI criteria MR imaging criteria

0 1 2 3 4

CIS patients (n=25) Nonconversion to MS (n=16)

Conversion to MS (n=9)

2 7 3 2 2

– 3 – 3 3

0.084 0.081 0.598 0.121 0.76 0.76 0.013 0.032 0.329 0.065 0.002 0.062 0.562 0.945 0.049 0.005 0.035 0.002 0.234 0.82 −13.4 +20.2 +5.3 −2.9 −17.8 −11 +22.2 +41.1 +11.7 −4 12.56±1.22 4.52±1.00 2.18±0.46 6.97±0.63 2.12±0.52 2.50±0.19 0.66±0.16 0.35±0.10 1.24±0.26 1.45±0.24 0.052 0.825 0.089 0.158 0.011 0.007 0.211 0.695 0.814 0.03 −6.5 +1.9 +8.2 +7.9 −13.2 −11 −5.6 +8.9 +0.9 −15.9 0.002 0.147 0.066 0.166 0.003 <0.001 0.492 0.048 0.229 0.048 tNAA (mM) Ins (mM) Cho (mM) tCr (mM) tNAA/Cho tNAA/tCr Ins/tCr Ins/tNAA Cho/tCr Glx/tCr

13.21±1.37 4.06±0.90 2.22±0.37 7.33±1.02 2.20±0.39 2.50±0.30 0.56±0.14 0.29±0.09 1.16±0.18 1.33±0.25

−9 +3.6 +7.2 +4.9 −14.7 −11 +3.7 +16.9 +4.5 −11.9

13.57±1.35 3.83±0.78 2.24±0.32 7.54±1.15 2.24±0.31 2.50±0.35 0.51±0.11 0.27±0.08 1.12±0.12 1.27±0.24

Versus nonconverters Versus healthy controls

P values

Difference vs. healthy controls (%) Value P value vs. healthy controls P value vs. healthy controls Difference vs. healthy controls (%)

Difference vs. healthy controls (%) Value Value

Patients with conversion to MS (n=9) Patients without conversion to MS (n=16) All patients (n=25) Metabolite

Table 2 Metabolite concentrations and relative signal ratios at baseline. Values are means±SD. Signal ratios correspond to an echo time of 140 ms, except those involving Ins or Glx, which were obtained at the short echo time of 38 ms. P values were obtained with the Mann-Whitney U-test (values <0.05 were considered significantly different)

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Concerning the relative metabolite ratios, the higher Ins concentrations in the converter group compared to the nonconverter group were mirrored in the Ins/tCr ratio which was statistically significant (P=0.013). The higher Ins concentrations and lower tNAA concentrations in the converter group in comparison to the non-converter group were also reflected in a significant difference in the Ins/tNAA ratio (+41.1% vs. +8.9%, P=0.032). The whole CIS group showed a significantly lower Glx/tCr ratio than the healthy controls. This difference was more pronounced in the non-converter group (−15.9%, P=0.03) than in the converter group (−4%, P=0.82, not significant).

Discussion Several quantitative MR methods have been established to quantify changes in areas of the CNS which appear normal on conventional MR images including magnetization transfer ratio, T1 relaxation time measurements, diffusion tensor imaging and 1H-MRS [11–18, 26–28]. However, these methods are more time-consuming and are currently not used routinely for prognostic purposes in patients presenting with the first clinical demyelinating event suggestive of MS. Therefore, conventional MRI in terms of diagnostic MRI criteria still remains the most clinically relevant tool to predict conversion to definite MS [29]. Since the approval of the US Food and Drug Administration for high-field MR systems up to 8 T, whole-body high-field MR systems primarily operating at 3 T are increasingly incorporated into the clinical setting of neuroimaging. They provide a substantially increased signalto-noise ratio (SNR) which consequently offers the possibility of scanning with an improved spatial resolution and better image quality. In patients with CIS as well as in those with definite MS, imaging at higher field strengths leads to an increased rate of detection of inflammatory lesions in various anatomic regions of the brain which can lead to higher classifications according to diagnostic imaging criteria [30–32]. Considering 1H-MRS, higher magnetic field strengths offer further advantages such as higher spectral resolution and improved accuracy in the absolute quantification of metabolites. In the past few years, experience has been gained in the application of high-field 1 H-MRS of the brain to various disease entities including MS. However, there is limited experience available particularly in patients presenting with CIS [16, 33, 34]. In the present study we performed a high-field 1H-MRS protocol in patients with CIS directly after the first clinical event in order to obtain first experience regarding the possible value of metabolic changes at baseline in predicting conversion to definite MS. To provide optimal

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conditions for a precise and reproducible quantification of both clinically relevant metabolites, tNAA and Ins, we performed acquisitions with short (Ins) and long (tNAA) echo times. A recently published study comparing metabolite alterations in patients with CIS with various disease durations and patients with a very early course of definite MS using high-field MR spectroscopy demonstrated that axonal damage had already occurred in the patients with CIS [25]. Considering the metabolite alterations found in the NAWM of this CIS cohort, it becomes obvious that the absolute concentration of tNAA, and therefore axonal damage at baseline, may be an important prognostic marker. The lower tNAA concentration was the only metabolite change in the whole CIS group that is significant compared to healthy controls. This is in contrast to previous results obtained from studies at 1.5 T, in which no significant difference in tNAA concentration could be observed [18, 35]. However, we have to take into account that these studies used either metabolite ratios instead of absolute quantifications or a single short echo time acquisition. These methodological differences hamper direct comparison with our results. Regarding the subgroups of the whole CIS cohort, tNAA was significantly lower only in the group of patients who converted to definite MS, and not in the nonconverter group, indicating that higher disease activity in the NAWM in terms of axonal damage might have a value in predicting conversion to definite MS. Interestingly, recently presented data obtained at 1.5 T has also shown significantly decreased levels of tNAA in CIS patients who developed clinically definite MS during a 1-year follow-up. However, the most impressive finding in this study was a significantly higher Ins concentration in CIS patients, especially in those who developed definite MS within 3 years [36]. Using high-field MR spectroscopy, it has been shown that Ins is elevated in the NAWM of patients fulfilling the diagnostic criteria for definite MS early in the disease course but not in patients presenting with CIS not meeting the criteria for definite MS [25]. In this study, Ins was clearly higher in those CIS patients who converted to MS than in normal controls and the nonconverter group, albeit not significantly. However, this effect might have been due to a higher spread of the Ins concentrations in our study. In a larger patient group, the increase in Ins concentration will probably become more assured. Another group of metabolites also significantly altered in the whole CIS group was Glx. Unfortunately, our MRS acquisition protocol did not allow a precise quantification of the different components of the Glx signal. The glutamate component in particular is of special interest since recent histopathological investigations and studies using special 1H-MRS acquisition protocols have provided evidence that glutamate might play an important role in the

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disease process of MS [16, 37, 38]. In terms of MRS, however, the data from recently performed studies are inconclusive. Some studies have shown a significant decrease in Glx, whereas others have shown an increase in Glx especially in those with longer disease courses [14, 16, 18]. Interestingly, the significantly lower in Glx concentrations were only prominent in the nonconverter group, and not in the converter group. The reason for this finding remains speculative and has to be further evaluated by larger 1H-MRS studies at high magnetic fields specifically focusing on the precise and reproducible quantification of glutamate and glutamine in patients with CIS and early MS.

Conclusion Axonal damage as indicated by significantly lower absolute tNAA concentrations within the NAWM of patients presenting with CIS suggestive of MS is more prominent in those patients who show an early conversion to definite MS. Thus, in accordance with recently presented data obtained at lower field strengths, metabolite changes observed at the time of the first clinical event might be important as prognostic markers for the future clinical course and clinical outcome measures. Therefore, in addition to conventional MRI, 1H-MRS should be considered for the baseline assessment of patients presenting with CIS to gain important additional information for an accurate prognostic classification. Acknowledgements The authors would like to thank all patients and control subjects who took part in this study. MPW was supported by the European Exchange Program provided by the European Society of Neuroradiology (ESNR). Conflict of interest statement of interest.

We declare that we have no conflict

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