Table 2.
Studies assessing the relationship between multiple sclerosis fatigue and peripheral inflammation
| Study | Population | Fatigue assessment | Method | Results |
|---|---|---|---|---|
|
Studies assessing peripheral cytokines
| ||||
| Rudick and Barna44 | Eight fatigued MS patients (disease details NA, 6F/2M); 50 HCs | NA | Serum levels of IL2 and its receptor (using ELISA) | No group difference with regard to IL2 or its receptor level Correlation NA |
| Flachenecker et al45 | 26 fatigued MS patients; 11 unfatigued MS patients; cohort characteristics, 29 RR, 8 SP, 27F/10M, 54% treated | FSS | Serum mRNA expression of IFNγ, TNFα, and IL10 (using RT-PCR) | Higher TNFα (but not IFNγ or IL10) mRNA expression among fatigued patients Correlation analysis between fatigue and cytokine mRNA expression NA |
| Heesen et al49 | 23 fatigued MS patients (19 RR, 3 SP, 1 PP, 18F/5M, 60.9% treated); 25 HCs (sex-matched, 20F/5M) | MFIS | Whole-blood stimulatory capacity for TNFα, IFNγ, and IL10 (using ELISA); cognitive task to examine the immunoresponse (cytokines) to psychological stress | No significant group difference in baseline cytokines Blunted response of IFNγ among MS patients following psychological stress (no group difference in TNFα or IL10 responses) No correlation between fatigue and cytokine levels |
| Heesen et al25 | 15 fatigued MS patients (6 RR, 8 SP, 1 PP, 9F/6M, 66.7% treated); 15 unfatigued MS patients (11 RR, 2 SP, 2 PP, sex-matched, 9F/6M, 60% treated) | MFIS, FSS | Whole-blood stimulatory capacity for TNFα, IFNγ, and IL10 (using ELISA) | Higher levels of TNFα and IFNγ (but not IL10 levels) in fatigued MS patients Correlation between fatigue scores of TNFα and IFNγ |
| Gold et al27 | 44 MS patients (all RR, all female, 59% treated) | MFIS, FSS | Serum intracellular levels of cytokines IFNγ and TNFα (using flow cytometry) | Frequency of IFNγ-producing CD8+ T cells predicted of fatigue scores (regression analysis) |
| Pokryszko-Dragan et al50 | 20 fatigued MS patients; 20 unfatigued MS patients; cohort characteristics, 30 RR, 10 SP, 30F/10M, untreated; 25 HCs (sex NA) | MFIS, FSS | Levels of IFNγ (using flow cytometry) | Higher IFNγ production among fatigued MS A trend toward correlation between fatigue and IFNγ |
| Malekzadeh et al53 | 21 fatigued MS patients (15 RR, 5 PP/SP, 1 missing, 10F/7M, 47.6% treated); 14 unfatigued MS patients (11 RR, 3 PP/SP, sex-matched, 10F/4M, 50% treated) | Self-reported checklist: individual strength, fatigue subscale | Serum levels of IL1β, IL2, IL6, IL8, IL12p70, IL17, TNFα, and IFNγ, IL4, IL5, IL10, and IL13 (using electrochemiluminescence-based multiplex immunoassay) | No group differences with regard to variables measured Association between fatigue and IL6 levels (regression analysis) |
| Mulero et al51 | Seven fatigued MS patients (all RR, 5F/2M, 85.7% treated); 7 HCs (details NA) | MFIS | Whole-blood gene expression (using microarrays and RT-PCR) | Activation of IFN-response genes among fatigued MS patients Correlation NA |
| Alvarenga-Filho et al47 | 18 MS patients (all RR, 15F/3M, untreated); 10 HCs (age-matched 8F/2M) | FSS | In vivo and in vitro assessment of peripheral levels of IL6, IL10, IL21, IL22, IL17, TNFα, and IFNγ (using ELISA) | Higher IFNγ, IL6, TNFα, IL17, and IL22 among MS patients In vivo: correlation between fatigue and each of IL6 and TNFα and a trend toward a correlation with IFNγ In vitro: correlation between fatigue and of IL6, TNFα, IFNγ, and IL22 levels |
| Alvarenga-Filho et al56 | 15 fatigued MS patients (all RR, 11F/4M, untreated); 15 unfatigued MS (all RR, sex-matched, 10F/5M, untreated) | FSS | In vivo and in vitro assessment of peripheral levels of IL6, IL10, IL12, IL17, IL21, IL22, IL23, TNFα, and IFNγ (using ELISA) | Higher IL6 and TNFα levels in fatigued MS patients In vivo: correlation between fatigue and IL6 and TNFα levels and a trend toward a correlation between fatigue and IFNγ In vitro: correlation between fatigue and IL1β, IL6, IL17, IL22, and IL23 levels |
| Akcali et al28 | 26 fatigued MS patients (14F/12M); 28 unfatigued MS patients (15F/13M); cohort characteristics, all RR, 87.1% treated; 26 HCs (13F/13M); sex-matched groups | FSS, NFI-MS | Serum IL1β, TNFα, IL35, IL2, and IL10 (using ELISA) | Higher IL35 and IL2 (but not IL1β, IL10, or TNFα) in the patient group compared to HCs No group differences between fatigued and unfatigued patients for any measure No correlation between fatigue and any cytokines studied |
|
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|
Studies assessing peripheral blood-cell populations
| ||||
| Yaldizli et al57 | 20 fatigued MS patients (13 RR, 6 SP, 1 PP, 13F/7M, untreated); 20 unfatigued MS patients (12 RR, 7 SP, 1PP, 12F/8M, untreated); 19 HCs; sex-matched groups | FSS | Lymphocyte subsets in peripheral blood mononuclear cell cultures (using flow cytometry); suppressive function of regulatory T cells (using antigen stimulation) | No difference in leukocyte and lymphocyte subsets, including regulatory T cells between fatigued and unfatigued MS patients The entire patient group tended to have lower suppressive regulatory T-cell activity compared to HCs, with no differences between fatigued and unfatigued patients Correlation NA |
| Pokryszko-Dragan et al50 | 20 fatigued MS patients; 20 unfatigued MS patients; cohort characteristics, 30 RR, 10 SP, 30F/10M, untreated; 25 HCs (sex NA) | MFIS, FSS | Percentage of IFNγ-positive CD3+CD4+ T lymphocytes (using flow cytometry) | No group difference with regard to percentage of IFNγ-positive CD3+CD4+ T lymphocytes No correlation between fatigue and percentage of IFNγ-positive CD3+CD4+ T lymphocytes |
|
| ||||
|
Studies assessing other peripheral markers
| ||||
| Giovannoni et al58 | 38 MS patients (16 RR, 9 SP, 13 PP, 17F/21M, all untreated) | FQS, FSS | Serum CRP and sICAM-1 levels; urinary neopterin excretion (measured daily for 2 weeks) | Patients with raised serum CRP had higher FSS (but not FQS) scores than patients with normal CRP levels No correlation between fatigue (FSS, FQS) and any variable measured |
| Flachenecker et al45 | 26 fatigued MS patients; 11 unfatigued MS patients; cohort characteristics, 29 RR, 8 SP, 27F/10M, 54% treated | FSS | Serum ESR | No group differences in ESR values Correlation analysis NA |
| Adamczyk-Sowa et al59 | 102 MS patients (85 RR, 17 PP/SP, 67F/35M, 79.4% treated); 20 HCs (sex-matched) | MFIS | Plasma lipid hydroxyperoxides and homocysteine concentrations | Higher lipid-hydroxyperoxide levels among MS patients compared to HCs No correlation between fatigue and biochemical measures |
Abbreviations: ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte-sedimentation rate; F, female; FSS, Fatigue Severity Scale; FQS, Fatigue Questionnaire Scale; HCs, healthy controls; M, male; MFIS, Modified Fatigue Impact Scale; MS, multiple sclerosis; NA, not available, NFI, Neurological Fatigue Index; PP, primary progressive; RR, relapsing–remitting; RT-PCR, real-time polymerase chain reaction; SP, secondary progressive.