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ARTICLES: Gavin Giovannoni, Alan J. Thompson, David H. Miller, and Edward J. Thompson Fatigue is not associated with raised inflammatory markers in multiple sclerosis Neurology 2001; 57: 676-681 [Abstract] [Full text] [PDF]

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Reply to Letter to the Editor

Gavin Giovannoni   (14 November 2001)

Fatigue is not associated with raised inflammatory markers in multiple sclerosis

Jorge Iriarte   (14 November 2001)

Reply to Letter to the Editor 14 November 2001
Gavin Giovannoni Institute of Neurology London United Kingdom Send Correspondence to journal: Re: Reply to Letter to the Editor sandi_moriarity{at}urmc.rochester.edu Gavin Giovannoni	Dr Iriarte raises several valid points on the difficulties facing researchers working on MS-related fatigue. His previous work supports the hypothesis that fatigue is heterogeneous and should be viewed as a symptom -complex or syndrome with different underlying pathogenic mechanisms. [1] Whether or not the percept arising as a result of fatigue at rest (asthenia), with exercise or associated with worsening symptoms is different requires further study. Cognitive neuroscientists may be able to address this question, using for example functional imaging, in normal subjects. A clue that fatigue may be due to focal brain disease was presented in a recent paper by Colombo et al., in which MS patients with fatigue had a significantly higher lesion load in the parietal lobe, internal capsule and periventricular trigone compared to MS patients without fatigue. [2] Although this study needs to be reproduced it may, however, be flawed by the problem highlighted in our paper concerning the validity of current fatigue rating scales. [1] Therefore we recommend that before researchers embark on new experimental paradigms this problem should be addressed by the development of specific and well-validated fatigue outcome measures. References: 1. Giovannoni G, Thompson AJ, Miller DH, Thompson EJ. Fatigue is associated with raised inflammatory markers in multiple sclerosis. Neurology 2001:57:676-681. 2. Iriarte J. Subirá ML, de Castro P. Modalities of multiple sclerosis: correlation with clinical and biological factors. Mult Scler 2000:6:124-130. 3. Colombo B, Martinelli Boneschi F, Rossi P, et al. MRI and motor evoked potential findings in nondisabled multiple sclerosis patients with and without symptoms of fatigue. J Neurol 2000;247:506-509.
Fatigue is not associated with raised inflammatory markers in multiple sclerosis 14 November 2001
Jorge Iriarte Universidad de Navarra Pamplona Spain Send Correspondence to journal: Re: Fatigue is not associated with raised inflammatory markers in multiple sclerosis sandi_moriarity{at}urmc.rochester.edu Jorge Iriarte	Fatigue is an important complaint in patients suffering from multiple sclerosis (MS). It is probably one of the most frequent and sometimes most disabling symptoms. In the course of the last year many groups have increased the research in this important aspect of MS. So far there is no clear explanation for its pathogenesis. Several treatments have been tried, but they are mostly empirical and not completely successful. The recent study of Giovannoni et al. [1] is very interesting, and some considerations may be made. Their results indicate a lack of correlation between fatigue and some inflammatory markers and depression, showing clear differences to other studies. [2, 3, 4] We have studied the pathogenesis of fatigue in MS. [5] Our experience agrees in some aspects with their study, especially in stressing the lack of relationship with depression and in the relevance of fatigue in patients with mild MS. However, we obtained different results in the correlation with the immune activation. One of the reasons for all these discrepancies may be the problem with the concept of “fatigue”. The fact is that patients describe fatigue in many different ways. This was the reason why we addressed the problem of the definition of fatigue when applied to MS patients. In an initial study, we distinguished between “signs of fatigue” (objective signs of lower functioning (speed, strength, potency ...)) and the “symptom fatigue” (subjective feeling of tiredness). [6] In a subsequent paper, we concluded that the symptom fatigue is not a single uniform complaint. [7]. We found that the symptom fatigue has at least three components: asthenia (fatigue at rest), fatigability (fatigue after exercise) and worsening of symptoms with the activity. Our data also supported that the pathogenesis of these modalities may be different: asthenia would be related to the immune activation, while fatigability would be related to the pyramidal deficits. [5] The consideration of fatigue as one single symptom may be the reason for the difference in opinion among the authors. We think that if people working in MS group all types of fatigue as one symptom it loses specificity and the research in the pathogenesis or treatment will be inaccurate. If we call “fatigue” to different symptoms or signs we will probably get different results. If we continue not using a similar definition of fatigue and its subtypes, it will eventually be impossible to obtain homogeneous conclusions in this field. References: 1)Giovannoni G, Thompson AJ, Miller DH, Thompson EJ. Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology 2001:57:676-681. 2.)Bertolone K, Coyle PK, Krupp LB, Doschler C. Cytokine correlates of fatigue in multiple sclerosis. Neurology 1993;45:356. 3)Kroencke DC, Lynch SG, Denney DR. Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern Mult Scler 2000:6:131-136. 4)Bakshi R, Shaikh ZA, Miletich RS et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler 2000:6:181-185. 5)Iriarte J, Subirá ML, de Castro P. Modalities of multiple sclerosis: correlation with clinical and biogogical factors. Mult Scler 2000:6:124-130. 6)Iriarte J, de Castro P. Correlation between the symptom fatigue and muscular fatigue in multiple sclerosis. European Journal of Neurology 1998;5:1-7. 7)Iriarte J, Katsamakis G, de Castro P. The Fatigue Descriptive Scale (FDS): a useful tool to evaluate fatigue in multiple sclerosis. Mult Scler 1999:5:10-16.