J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.2.204 on 1 February 1998. Downloaded from 204 J Neurol Neurosurg Psychiatry 1998;64:204–212 1H-MRS in patients with multiple sclerosis undergoing treatment with interferon â-1a: results of a preliminary study P Sarchielli, O Presciutti, R Tarducci, G Gobbi, A Alberti, G P Pelliccioli, A Orlacchio, V Gallai Abstract Conclusions—IFN â-1a has an impact on Background—In vivo magnetic resonance metabolite concentrations in multiple spectroscopy (MRS) has been widely used sclerosis lesions measured by proton to assess biochemical changes which MRS. The increase in Cho, Cho/NAA, and occur in demyelinating lesions in white Cho/Cr ratios in multiple sclerosis lesions matter of patients with multiple sclerosis. reinforces the view that they are an index It has been suggested that metabolic vari- of active or recent demyelination and ations evidenced by MRS are sensitive could support the clinical, neuroradio- indicators of the eVects of immunomodu- logical and immunological evidence latory treatments in this disease. showing an increase in disease activity Given the recent finding of an increase during the first period of treatment with in the disease activity in patients with IFN â-1a. On the other hand, the increase multiple sclerosis treated with interferon in the Cho peak could be indicative of a (IFN) â-1a in the first period of rise in membrane turnover in multiple treatment,1H MRS was used to investigate sclerosis lesions or a remodelling of further the modification in brain meta- plaques which is not necessarily due to a bolic indices, particularly in the first de novo immune mediated demyelination. phase of IFN â treatment. Methods—A 1H MRS study was performed (J Neurol Neurosurg Psychiatry 1998;64:204–212) on five patients with relapsing-remitting multiple sclerosis who were being treated Keywïrds: proton magnetic resonance spectroscopy; multiple sclerosis; interferon â-1a with intramuscular IFN â-1a (6 million units/week) for six months and on five untreated patients. The mean age, dura- In the past few years, the development of local- tion of the disease, and expanded disabil- ised proton magnetic resonance spectroscopy Neurologic Clinic, ity status scores (EDSS) of the two groups (1H MRS) has allowed the in vivo study of University of Perugia, were similar. Patients were evaluated at Via E dal Pozzo 06126, some cerebral metabolites in various diseases the beginning of the study and in the first, 1–6 Perugia, Italy of the CNS, including multiple sclerosis. The P Sarchielli third, and sixth months of treatment. recent progress in MRS study, with localisation http://jnnp.bmj.com/ A Alberti Results—In the multiple sclerosis white of small volumes of interest, permits a more A Orlacchio matter lesions, N-acetylaspartate (NAA), accurate assessment of changes in cerebral V Gallai choline (Cho), inositol (Ins), and creatine metabolites in lesional areas, reducing, at least (Cr) peaks did not vary significantly over Department of in part, the contamination of spectroscopic Medical Physics, the entire period of the study in the results by white and grey matter surrounding Perugia General untreated group. the demyelinating lesions. Hospital, Perugia, In the treated group there was a signifi- The principal finding with 1H MRS in on September 26, 2021 by guest. Protected copyright. Italy cant increase in the Cho peak area at the patients with multiple sclerosis was a decrease O Presciutti first month compared with the pretreat- R Tarducci in the N-acetyl aspartate (NAA) peak area, G Gobbi ment period, and this increase continued whereas contrasting results were obtained for in the third and sixth months (p<0.001). A other metabolites.7–13 Department of slight but not significant rise in the Cho Although the results of some proton MRS Neuroradiology, peak was also found in normal appearing studies on patients with multiple sclerosis were Perugia General white matter in the patient group under- Hospital, Perugia, contrasting, a common issue was a decrease in Italy going treatment with IFN â-1a. The axonal density in lesional areas, particularly in G P Pelliccioli increase in Cho and the lack of significant chronic lesions, due to the combination of changes in Cr and NAA peaks induced a axonal loss and gliosis associated with demyeli- Correspondence to: significant rise in Cho/Cr and Cho/NAA nating lesions, as well as the presence of Dr Paola Sarchielli, ratios over the entire period of treatment Neurologic Clinic, biochemical abnormalities in the normal ap- Policlinico Monteluce, Via E compared with those at the beginning of pearing white matter of patients with multiple Dal Pozzo 06126, Perugia, the study (p<0.02 and p<0.005 respec- sclerosis, not detectable with standard spin Italy. Tel 0039 75 5783568; tively). echo MRI. Fax 0039 75 5783583; 1 email: [email protected] In the treated group there was a slight The discrepancy among the results of H but significant increase in the Ins peak in MRS studies in multiple sclerosis could be due Received 2 January 1997 the first month (p<0.05) but in the third to the diVerent patient selection and inclusion and in revised form 13 August 1997 and sixth months of treatment the Ins val- criteria, the diVerent techniques used, the Accepted 22 August 1997 ues returned to the pretreatment range. diVerent areas selected (active or chronic J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.2.204 on 1 February 1998. Downloaded from 1H-MRS in patients with multiple sclerosis treated with IFN â-1a 205 lesions), and the diVerence in the size of 37.6 (SD 4.7) years; the disease duration was selected volumes of interest which do not com- three to eight (mean: 3.9 (SD 1.8)) years; and pletely exclude surrounding normal white and the EDSS ranged from 1.5 to 3 (2.0 (SD 1.0)). grey matter. Despite the diYculties in inter- The mean relapse rate was 0.8/year and preting data obtained in vivo, MRS provides 0.9/year in treated and untreated multiple scle- direct information concerning metabolic varia- rosis groups respectively. tions and damage to or integrity of myelin and Patients were evaluated at the beginning of axons, which cannot be evidenced with the study and in the first, third, and sixth traditional MRI, and it has been suggested that months of treatment. All patients signed it may play an important part in studies on the informed consent forms according to the natural history of the disease and the assess- declaration of Helsinki.20 ment of immunosuppressive or immunomodu- At the beginning of the study MRI and 1H latory treatment in clinical trials.11 14 15 MRS were also performed on six healthy, age In particular, metabolic variations evidenced matched control subjects (mean age 33.5 (SD by MRS have been proposed as sensitive indi- 3.7)) years with no systemic or neurological cators of the eVects of immunomodulatory diseases. treatment in multiple sclerosis. Until now, few data have been available MRI regarding the cerebral metabolic changes Evaluations with MRI and 1H MRS were evidenced by 1H MRS due to immunosuppres- performed at the above mentioned times in a sive or immunomodulatory treatments, includ- single session with a clinical, 1.5T, whole body ing IFN â, in patients with multiple sclerosis.16 MR system (Signa Advantage, GE Medical The purpose of the present research was to Systems) with a standard head coil. use 1H MRS to assess the modifications in the To quantify the lesional load and number of cerebral metabolite concentration in lesional active lesions, MRI examination was per- areas and in the normal appearing white matter formed in a separate session preceding 1H of patients with multiple sclerosis treated with MRS. T1 weighting (650/15 TR ms/TE ms), IFN â-1a in the first six months of treatment, proton density (2000/15 TR ms/TE ms), and comparing them with the same indices ob- T2 weighting (200/70 TR ms/TE ms) images tained in untreated patients with multiple scle- were obtained in the axial plane. Gd-DTPA rosis matched for age and disability. was given intravenously in a dose of 0.2 ml/kg body weight (0.1 mmol/kg) followed by a Patients and methods postinjection flush with 10 ml saline. T1 PATIENTS weighted sequences were obtained starting five The 1H MRS analysis was performed on 10 to 10 minutes after Gd-DTPA injection, with patients with relapsing-remitting multiple scle- an in plane resolution of 1.0×1.3 mm2 and a rosis. Five of them (four women and one man) slice thickness of 5 mm (gap 1.25 mm). had undergone IFN â-1a treatment, and five The quantification of MRI abnormalities (three women and two men) were untreated. was performed as previously described.21 The For both treated and untreated patients the assessment of lesions was performed on 15 inclusion criteria was definite multiple anatomically defined brain sites (seven periv- sclerosis17 for at least two years, a baseline entricular and separated from the ventricles). http://jnnp.bmj.com/ expanded disability status score (EDSS)18 of An arbitrary scoring system weighted for lesion 1.0 to 3.5 inclusive, at least two documented size was used to estimate the regional lesional exacerbations of the disease in the two years load. One point was given for each lesion with before the study, but no exacerbation in the a diameter<5 mm; two points for 6 –10 mm past three months. None of the patients had lesions, and three points for lesions >10 mm. undergone immunosuppressant therapy within Confluent lesions were scored one extra point.