sclerosis (MS). It occurs in up to 50â70% of MS patients during the course of the illness, and 14â21% experience fatigue as the most severe symptom [4, 7, 13].
J Neurol (1999) 246 : 454–458 © Steinkopff Verlag 1999
C. Mainero J. Faroni C. Gasperini M. Filippi E. Giugni O. Ciccarelli M. Rovaris S. Bastianello G. Comi C. Pozzilli
Received: 27 March 1998 Received in revised form: 27 October 1998 Accepted: 9 September 1998 C. Mainero · J. Faroni · E. Giugni · O. Ciccarelli · S. Bastianello · C. Pozzilli (쾷) Department of Neurological Sciences University “La Sapienza” Rome Viale Università 30, I-00185 Rome, Italy Tel.: +39-6-49914716 Fax: +39-6-4457705 C. Gasperini Department of Neurological Sciences University “La Sapienza” Viale Università 30, I-00185 Rome and Department of Neurology S. Camillo Hospital, Via Portuense 332 I-00149 Rome Italy M. Filippi · M. Rovaris Neuroimaging Research Unit Department of Neurosciences Scientific Institute Ospedale S. Raffaele University of Milan, Via Olgettina 60 I-20132 Milan, Italy G. Comi Unit of Clinical Trials Department of Neurosciences Scientific Institute Ospedale S. Raffaele University of Milan, Via Olgettina 60 I-20132 Milan, Italy
O R I G I N A L C O M M U N I C AT I O N
Fatigue and magnetic resonance imaging activity in multiple sclerosis
Abstract Fatigue is a frequent and often severe symptom in multiple sclerosis. Pathogenic mechanisms proposed for fatigue include the release of proinflammatory cytokines, which is thought to have an important effect on changes in the bloodbrain barrier (BBB). To investigate whether fatigue is related to BBB disruption we studied 11 relapsingremitting MS patients participating in a multicenter longitudinal study comparing the sensitivity of monthly enhanced magnetic resonance imaging (MRI) after standard-dose and triple-dose injection of gadoliniumdiethylene triaminopentoacetic acid (Gd-DTPA). Serial Gd-enhanced MRI studies were performed in two separate sessions every 4 weeks for 3 months. An expanded version of the Fatigue Severity Scale, including 29 items, was administered 24 h before each MRI examination. No relationship was found between the number and volume of Gd-enhancing lesions and fatigue scores at any monthly examination over the study
Introduction Fatigue is a common and disabling symptom in multiple sclerosis (MS). It occurs in up to 50–70% of MS patients during the course of the illness, and 14–21% experience fatigue as the most severe symptom [4, 7, 13]. The pathophysiology of fatigue in MS remains unknown. Since MS patients often note an increase in fatigue during relapses
period. Furthermore changes in MRI activity were not significantly related to changes in fatigue scores. These results were obtained on triple-dose delayed scanning, which is more sensitive than standard-dose scanning in detecting areas of BBB disruption. Our preliminary results thus do not support the hypothesis of a relationship between BBB alterations and fatigue severity in multiple sclerosis. Key words Multiple sclerosis · Fatigue · Magnetic resonance imaging
[8], fatigue may depend on cytokines released by inflammatory cells during the acute phases of disease [1, 3]. It is also known that interferon-γ and interferon-α may cause severe fatigue in MS patients and in patients with other diseases [1, 15]. Proinflammatory cytokines are involved in the breakdown of the blood-brain barrier (BBB) in MS [17]. Magnetic resonance imaging (MRI), after the administration of gadolinium-diethylene triaminopentoacetic acid (Gd-DTPA), is a useful tool to evaluate BBB disrup-
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tion [10]. Therefore, if fatigue depends on cytokine activity, a worsening of fatigue should be associated with an increased frequency of lesions enhancement. We investigated the relationship between fatigue and MRI activity in patients with relapsing-remitting MS.
Materials and methods Patients We studied 11 patients with clinically definite relapsing-remitting MS [16] participating in a multicenter longitudinal study comparing the sensitivity of monthly enhanced MRI after standard-dose (SD) and triple-dose (TD) injection of Gd-DTPA [5]. Patients were excluded if there were clinical relapses or treatment with steroids during the 3 months preceding study initiation. In addition, none of the patients had taken immunosuppressive or immunomodulating treatments for at least 12 months prior to entry in the study. Patients’ mean age was 33.6 ± 5.3 years (range 27–40), median disease duration was 7 years (range 2–10), and median Expanded Disability Status Scale [14] score was 1.5 (range 0–3). In cases of relapse the only allowed schedule treatment was: 1 g methylprednisolone per day administered intravenously for 3 days. MRI assessment Serial MRI of the brain was performed monthly (28 ± 5 days) with a 1.5-T superconductive system (Philips Gyroscan NT 15) over a period of 3 months. At each examination MRI was performed in two sessions, separated by an interval of 12–24 h, using, respectively, a SD (0.1 mmol/kg) and a TD of Gd-DTPA [5]. At the first session the following were obtained: (a) dual echo conventional spin echo scans (TR = 2000–2400), first echo TE = 30–50, second echo TE = 80–100, number of acquisitions = 1; (b) precontrast T1weighted scans (TR = 560–768, TE = 14–15, number of acquisitions = 2); two postcontrast T1-weighted scans (with the same acquisition parameters as before Gd injection) 5 min (early postcontrast scans) and 20 min (delayed postcontrast scans) after the injection of Gd. Since the administration of the two doses of Gd was randomized, in the first sessions the patients could receive either the SD or the TD of Gd. At the second session the following were obtained: (a) precontrast T1-weighted scan (with the same acquisition parameters as during the first session); (b) two postcontrast T1-weighted scans (with the same acquisition parameters as before) 5 min and 20 min after the injection of either the SD or TD of Gd, depending on the administration given on the first session. This means that each month four postcontrast T1-weighted scans were obtained for all the patients, i.e., early and delayed SD scans and early and delayed TD scans. For each scan 24 contiguous interleaved axial slices were obtained (thickness = 5 mm, matrix size = 192–256 and FOV = 220 mm). The same acquisition protocol was used for the entire duration of the study. The postcontrast T1-weighted images from each patient were viewed in a consensual fashion by two neuroradiologists with the films presented in a random order. The observers were unaware of the Gd dose, scanning delay, patient identity, or time point of the acquisition. After a consensus had been obtained, they marked the enhancing lesions on the hardcopies and a single technician measured the lesions volume using a semiautomated local thresholding technique, characterized by high intra- and interrater reproducibility [9, 19]. In the present study the statistical analysis was performed considering the number and volume of enhancing lesions detected on TD delayed postcontrast scans.
Fatigue measurement A fatigue assessment was performed 24 h before each MRI examination using an expanded version of the Fatigue Severity Scale (FSS) [21]. This is a 29-item questionnaire which assesses the effect of fatigue on daily activities and gives information regarding possible triggers of fatigue and conditions which might modify the symptom. The FSS includes four factors which identify distinct dimensions of the symptom. The first factor measures fatigue severity and can be used as a quantitative measure of overall fatigue; the second investigates whether fatigue is situation specific, linked to particular circumstances (i.e., heat, cold, stress); the third addresses possible consequences of fatigue (loss of patience, motivation or ability to concentrate); and the fourth indicates whether fatigue responds to rest or sleep. The response key for each item is a seven-point scale ranging from 1 to 7. The overall fatigue score ranges from 29 to 203; a higher score indicates greater fatigue. All patients had to consider the past 2 weeks when answering the questionnaire. For comparison, FSS was administered to 11 age- and sexmatched healthy subjects. Statisical methods The relationship between the number and volume of enhancing lesions and fatigue scores each month was evaluated by Spearman’s correlation coefficient. The same test was used to evaluate the relationship between absolute changes in FSS and in MRI activity. We also analyzed our data by means of analysis of variance for repeated measurements, considering MRI activity as independent variable and monthly changes in FSS as dependent variable.
Results Two patients had a clinical relapse during the study period and were treated with intravenous methylprednisolone. In neither patient did the FSS assessed during the relapse differ significantly from those evaluated in the absence of relapse. The mean FSS each month was, respectively, 119 ± 6.7, 130 ± 9.3, 128 ± 8.1, 131 ± 9.9. Fatigue in MS patients was significantly higher than in healthy controls (FSS 86 ± 6.7; P < 0.005). The mean number and volume of TD Gd-enhancing lesions were, respectively, 4.4 ± 1.4, 4.8 ± 1.7, 6.2 ± 2.2, and 6.0 ± 2.2; and 244 ± 113 ml, 323 ± 136 ml, 400 ± 160 ml, and 350 ± 121 ml. Figure 1 presents the number of enhancing lesions detected on TD scans and absolute FSS per month per patient over the whole study period. No correlation was found between the number and volume of Gd-enhancing lesions and FSS at any monthly examination over the study period. We examined the possible correlation between FSS and the number and volume of enhancing lesions detected on the scans performed at the same time and 1 month before fatigue assessment. The relationships between fatigue scores and number of enhancing lesions at baseline are shown in Fig. 2. We also did not find any relationship between monthly changes in FSS and monthly changes in number and volume of MRI enhancing lesions over the study period. These results were confirmed by using analysis of variance for re-
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Fig. 1 Number of TD Gd-enhancing lesions (a) and absolute fatigue scores (b) per month per patient over the entire study period
a
b
peated-measures statistical analysis. In addition, none of the four factors of the FSS was significantly related to MRI activity. According to the TD findings, all scans examined were divided into three subgroups: inactive scans (no enhancing lesions, n = 10), scans with low activity (from one to five enhancing lesions, n = 18), scans with high activity (more than five enhancing lesions, n = 16). The corresponding mean FSS for the individual subgroups was 141 ± 11.3, 120 ± 6.9, and 128 ± 4.5. No significant differences between the three subgroups were found (analysis of variance test).
Discussion A variety of pathogenic mechanisms have been proposed for fatigue in MS; these include impaired capacity of demyelinated fibers to conduct, impaired muscular oxidative capacity, physical deconditioning, psychological factors, reduced glucose metabolism in the frontal cortex and
basal ganglia, and immune dysfunction with release of proinflammatory cytokines [12, 18, 20]. The mechanisms of action of proinflammatory cytokines in the development of fatigue are still poorly understood. Previous studies have shown that prolonged administration of interferons, interleukins, and tumor necrosis factor is accompanied by several adverse effects including fatigue [1, 3, 15]. It is known that BBB endothelial cells have receptors on their luminal surface which are the first to bind circulating interferon, interleukin-1, interleukin-2, and tumornecrosis factor, and it is clear that these cytokines are powerful agents capable of inducing the synthesis of factors which are able to play a role in the breakdown of the BBB [17, 23]. Patients with MS often experience increased fatigue during relapses and may present isolated acute episodes of fatigue which are similar to typical relapses [8]. Several brain MRI studies have shown a significant association between the number of enhancing lesions and relapse rate [22]. It has also been demonstrated that BBB breakdown may occur before the development of symptoms [11].
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Thus if there is any relationship between fatigue and cytokines release, it should be possible to detect a correlation with disease activity as measured by enhanced MRI. This study demonstrates that the number and volume of enhancing lesions are not significantly related to fatigue. Our results were obtained on TD delayed scanning, which is more sensitive than SD scanning in detecting areas of BBB disruption [6]. Nevertheless, some methodological limitations of this study should also be considered. These include the limited number of patients studied and the difficulty in obtaining objective correlates for fatigue assessment. The FSS clearly discriminates between physiological fatigue and fatigue associated with disease [21]; however, it may not be sufficiently sensitive to changes over time. In conclusion, our preliminary results do not support the hypothesis of a relationship between BBB alterations and fatigue, suggesting that this symptom is not related to the action of proinflammatory cytokines on the central nervous system. However, we cannot exclude an action of cytokines on the peripheral nervous system. There is evidence that an effect of cytokines on neuromuscular junctions, including change in end-plate activity, decrease muscle transmembrane potential difference and increased prostaglandins release [2]. Further investigations with newer MRI techniques with greater pathological specificity might provide new insights into the pathogenesis of fatigue in MS.
a
Acknowledgements We thank Prof. C. Fieschi for his continuous support and Drs. M. Frontoni, C. Buttinelli, and E. Millefiorini for allowing us to study their patients.
b Fig. 2 Scatterplot showing the relationships between number of enhancing lesions seen on TD delayed scans at baseline and both the fatigue scores assessed at the same time (Rho = 0.002; p = 0.95) (a) and 1 month after MRI examination (Rho = –0.007; p = 0.98) (b)
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