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Depressive state and chronic fatigue in multiple sclerosis and neuromyelitis optica
Journal of Neuroimmunology 283 (2015) 70–73
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Short communication
Depressive state and chronic fatigue in multiple sclerosis and neuromyelitis optica Tetsuya Akaishi a, Ichiro Nakashima a,⁎, Tatsuro Misu b, Kazuo Fujihara b, Masashi Aoki a a b
Department of Neurology, Tohoku University School of Medicine, Sendai, Japan Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan
a r t i c l e
i n f o
Article history: Received 8 April 2015 Received in revised form 6 May 2015 Accepted 7 May 2015 Keywords: Neuromyelitis optica Depression Fatigue Carnitine Levocarnitine
a b s t r a c t Depression and chronic fatigue are frequently present in multiple sclerosis (MS); however, the prevalence rates have not been investigated in neuromyelitis optica (NMO). Thirty-nine consecutive NMO and 75 MS patients were compared using self-rating questionnaires for depressive states, daily activity, and fatigue, as well as serum carnitine levels. A subgroup of patients with low carnitine levels were re-evaluated regarding depression and fatigue after levocarnitine treatment. Depression and fatigue were equally prevalent in MS and NMO and were strongly correlated with one another. Measurement of the serum carnitine levels and the administration of levocarnitine did not appear to be beneficial. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Depression and chronic fatigue are present in most patients with multiple sclerosis (MS) and are often described as two of the most debilitating symptoms (Tomassini et al., 2004; Tejani et al., 2012). These symptoms are thought to be caused by the disseminated demyelination. Low serum carnitine levels have been suggested to cause these symptoms, especially in MS patients treated with disease-modifying therapies (DMT) (Fukazawa et al., 1996; Lebrun et al., 2006). Carnitine is associated with transport and catabolism of fatty acids in muscle cells. By supporting transport and oxidative catabolism of fatty acids in mitochondria, carnitine contributes to muscular endurance and tolerance to fatigue. Deficiency of carnitine either by reduced intake or impaired endogenous synthesis is thought to cause easy fatigability and chronic fatigue. Oral acetyl levocarnitine (L-carnitine), administered for disabling fatigue in MS, has been investigated in various studies. In contrast, depression, chronic fatigue and serum carnitine levels have not been assessed in patients with neuromyelitis optica (NMO), in which astrocytes are the primary target of anti-aquaporin-4 (AQP4) antibody. The effectiveness of L-carnitine for these symptoms in NMO is also unknown. 2. Methods Seventy-five consecutive patients with MS and 39 patients with NMO who regularly visit the outpatient clinic at Tohoku University ⁎ Corresponding author.
http://dx.doi.org/10.1016/j.jneuroim.2015.05.007 0165-5728/© 2015 Elsevier B.V. All rights reserved.
Hospital were collected between June and September 2014 to assess self-rating questionnaires for depressive states (self-reported quick inventory of depressive symptomatology: QIDS-SR) (Rush et al., 2003), daily activity (performance status: PS), and chronic fatigue (Chalder fatigue scale: ChFS) (Chalder et al., 1993). The QIDS-SR scores ranged from 0 to 27 (0 to 5: no depression; 6 to 10: mild depression; 11 to 15: moderate depression; 16 to 20: severe depression; and 21 to 27: very severe depression), whereas the PS ranged from 0 to 4 and the ChFS ranged from 0 to 56. The serum free-carnitine, acylcarnitine, and total-carnitine levels were measured for once at the same time of the questionnaires. The scores regarding gait disturbance (GD) and optic neuritis (ON), and the final expanded disability status scale (EDSS) were also collected. The GD-score scales were as follows: 0: normal; 1: only slight GD without impaired ADL; 2: possible to walk but with impaired daily activities; 3: wheelchair-bound; and 4: bedridden. The ON-score scales in each side of the eye were as follows: 0: normal; 1: possible to read; 2: counting finger; 3: hand motion or light perception; and 4: blindness. In NMO, the dose of oral prednisolone (PSL) was also collected. Pearson correlation coefficients or Spearman rank correlation coefficients (R) were comprehensively compared between all pairs of datasets to identify mutual relations and confounders. Pearson's R was adopted for the variables with normal distributions, and Spearman's R was adopted for the other pairs. Eleven patients with low carnitine levels (six MS and five NMO patients) who agreed to L-carnitine (1800 mg/day) treatment were followed, and their questionnaire scores were assessed after one month of administration.
T. Akaishi et al. / Journal of Neuroimmunology 283 (2015) 70–73
All statistical analyses in this study were conducted using SPSS (Statistical Package for the Social Sciences) Statistics Base 22 software (IBM, Armonk, New York, USA) and Microsoft Excel Statistical Analysis (ver. 6.0; Esumi Co., Ltd., Tokyo, Japan). This study was approved by the local research ethics committees of Tohoku University School of Medicine and of Tohoku University Hospital. Each patient voluntary gave written informed consent before participating in the study and also before treatment.
3. Results 3.1. Demographic and laboratory data Of the 75 MS patients, 13 (17.3%) patients were male and 62 (82.7%) patients were female (Table 1). All 39 NMO patients were female. The mean present age was increased in NMO compared with MS (p b 0.0001). The median disease duration was similar in MS and NMO (p ≥ 0.10). The median of the final EDSS was increased in NMO compared with MS (p b 0.0001). In the MS patients, there was a significant correlation between the disease duration and the final EDSS (R = 0.29, p b 0.01). Eight of the 75 MS patients (10.7%) and 16 of the 39 NMO patients (41.0%) were taking anti-depressant medications at the timing of this study.
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3.4. Correlations between carnitine levels and questionnaires The correlation coefficients between the serum carnitine levels and the three self-rated questionnaires were not significant (p ≥ 0.10) between any pairs. 3.5. Correlative coefficients with clinical information The QIDS-SR (R = 0.331, p b 0.05) and ChFS (R = 0.397, p b 0.05) exhibited weak to moderate correlations with disease duration in NMO (Fig. 2A, B), but not in MS (Fig. 2C, D). In contrast, the QIDS-SR (R = 0.373, p b 0.05) and ChFS (R = 0.307, 0.05 ≤ p b 0.10) exhibited weak to moderate correlations with the GD-score in MS, but not in NMO. There was no significant correlation between ON-score and selfrating questionnaires including QIDS-SR both in MS and NMO patients. Strong correlations between the final EDSS and PS were identified in both MS and NMO. A moderate correlation between the free-carnitine level and present age was identified only in NMO (R = 0.485, p b 0.01). The final EDSS exhibited weak correlations with disease duration in MS (R = 0.306, p b 0.01) and present age in NMO (R = 0.399, p b 0.05). In NMO patients, QIDS-SR score was significantly higher in those with anti-depressants than in those without anti-depressants (p ≤ 0.01). However, results did not change even among patients without antidepressants. 3.6. Carnitine levels and self-rating questionnaires by treatment types
3.2. Self-rated questionnaires More severe than mild levels of depression (QIDS-SR ≥ 5) were identified in 47 MS patients (62.7%) and 29 NMO patients (74.4%). Impaired daily activity (PS ≥ 1) was identified in 42 MS patients (56.0%) and 30 NMO patients (76.9%) (Table 1). If the cut-off level of the ChFS was set at a conventional score of 26, abnormal chronic fatigue (ChFS ≥ 26) was suggested in 53 MS patients (70.7%) and 30 NMO patients (76.9%). There was no significant difference between MS and NMO in the QIDS-SR (p ≥ 0.10) or ChFS (p ≥ 0.10); however, the PS was increased in NMO (p b 0.05). Strong correlations were identified between depression (QIDS-SR) and fatigue (ChFS) in both MS and NMO (Fig. 1).
In the MS patients, the free-carnitine level was lower in the patients receiving no treatment (n = 7; 36.6 ± 8.5 μmol/l) compared with the patients receiving disease-modifying treatments (DMT) (n = 68; 45.1 ± 9.6 μmol/l; p b 0.05). QIDS-SR was significantly lower in the MS patients administered IFN-β (median: 4; range: 0–17) compared with the patients administered fingolimod (7; 1–20) (p b 0.05), most likely because of the selection-bias for fingolimod in patients with depressive symptoms who avoid IFN-β. In NMO, 36 patients (92.3%) were administered low dose oral PSL therapy. There was no significant correlation between the PSL dose and the carnitine levels (p ≥ 0.05 for both free- and acyl-carnitine). No correlation was identified between the PSL dose and the questionnaires.
3.3. Serum carnitine levels
3.7. Changes after L-carnitine therapy
A low-level of total-carnitine (normal range: 45–91 μmol/L) was identified in 17 MS patients (22.7%) and 8 NMO patients (20.5%) (Table 1). A low-level of free-carnitine (normal range: 36–74 μmol/L) was identified in 13 MS patients (17.3%) and 7 NMO patients (17.9%). A low-level of acylcarnitine (normal range: 6–23 μmol/L) was identified in 13 MS patients (17.3%) and 4 NMO patients (10.3%).
Six MS patients and five NMO patients with a low-level of serum carnitine were administered L-carnitine. There was no significant improvement in any questionnaire after the treatment as shown in Fig. 3 (p ≥ 0.10).
Table 1 Comparisons of the clinical and laboratory information between MS and NMO.
Present age (mean ± SD) Duration [years] (median, range) ON-score (median, range) GD-score (median, range) Final EDSS (median, range) QIDS-SR (median, range) PS (median, range) ChFS (median, range) Total-carnitine [μmol/l] (mean ± SD) Free-carnitine [μmol/l] (mean ± SD) Acyl-carnitine [μmol/l] (mean ± SD)
MS (n = 75)
NMO (n = 39)
p-Value
36.4 ± 3.1 6 (1–31) 0 (0–4) 1 (0–3) 2 (0–8) 6 (0–24) 1 (0–3) 31 (16–54) 53.8 ± 10.9 44.3 ± 9.8 9.6 ± 3.8
51.9 ± 13.6 8 (0–35) 2 (0–8) 1 (0–4) 4.75 (0–8.5) 6 (1–23) 1 (0–4) 32 (18–55) 53.3 ± 9.0 44.2 ± 8.2 9.1 ± 2.4
b0.0001 n.s. b0.0001 n.s. b0.0001 n.s. 0.0106 n.s. n.s. n.s. n.s.
Abbreviations; MS: multiple sclerosis, NMO: neuromyelitis optica, SD: standard deviation, n.s.: not significant with p ≥ 0.05, QIDS-SR: quick inventory of depressive symptomatology (self-reported), PS: performance status, ChFS: Chalder fatigue scale.
4. Discussion This study demonstrated for the first time that NMO patients experience comparable levels of depressive state and chronic fatigue as MS patients. Because few reports have described cerebral demyelinating lesions in NMO, other mechanisms are needed to explain this finding. The oral PSL dose and present age are not likely mechanisms because they did not exhibit correlations with the scores although, longer disease duration would contribute to the advent of chronic depression and fatigue in NMO. Although the same levels of depression and fatigue were identified in MS and NMO, the mechanisms of these symptoms could be different between the diseases. For example, gait disturbances exhibited significant correlations with the QIDS-SR and close to significant correlations with the ChFS in MS, but not in NMO. In contrast, disease duration exhibited significant correlations with the QIDS-SR and ChFS in NMO, but not in MS. These findings suggest that chronic depression and fatigue in MS could be caused by the same pathomechanism of
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T. Akaishi et al. / Journal of Neuroimmunology 283 (2015) 70–73
Fig. 1. Correlations between the QIDS-SR and ChFS in MS (A) and NMO (B). The correlation coefficient (R) values are denoted below the plots. ***: p b 0.001 in the test of no correlation.
demyelinating lesions as motor disturbances; however, these symptoms in NMO could be caused by other factors that accumulate with time. A strong correlation between the QIDS-SR and ChFS in both MS and NMO suggested that the management of each symptom would be important to control other symptoms. Unfortunately, the administration of L-carnitine therapy failed to significantly improve the scores. We conclude that oral L-carnitine therapy is unfounded for the management of these symptoms in MS and NMO. In conclusion, NMO patients can exhibit the same levels of depression and fatigue as MS patients regardless of the present PSL dose.
Carnitine is occasionally low in the sera of MS and NMO, but does not seem to play a major role in depression and fatigue in these diseases. Measurement of the serum carnitine levels and administration of oral L-carnitine seem not to be beneficial. Author contributions I.N. conceptualized and designed the study, I.N., T.M. and K.F. recruited the patients and collected the clinical data, and T.A. and I.N. performed data analysis and contributed to the interpretation of the results. M.A. and K.F. supervised the interpretation of the results. T.A.
Fig. 2. (A, B) Correlations between the QIDS-SR and disease duration (A) and between the ChFS and disease duration (B) in NMO patients. Both scores exhibited weak to moderate correlations with the disease duration in NMO. (C, D) Correlations between the QIDS-SR and disease duration (C) and between the ChFS and disease duration (D) in MS patients. Differing from NMO, neither score exhibited a significant correlation with the disease duration in MS.
T. Akaishi et al. / Journal of Neuroimmunology 283 (2015) 70–73
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Fig. 3. Changes in the QIDS-SR and ChFS by L-carnitine administration. There was no significant change in either score in both MS and NMO.
drafted the manuscript and all authors substantively revised the document for intellectual content.
Technology of Japan and as the secondary investigator by the Grants-inAid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan.
Conflict of interest Acknowledgments I.N. reports personal fees from Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Japan, and grants from LSI Medience Corporation. T.M. has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co., and Astellas Pharma Inc. and research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. K.F. has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical and research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The ChemoSero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; he is funded as the secondary investigator (#22229008, 2010–2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and
We thank Brent Bell for reading the manuscript, and Kaori Tobise and Mayumi Hirose for their help in collecting samples. References Chalder, T., Berelowitz, G., Pawlikowska, T., Watts, L., Wessely, S., Wright, D., Wallace, E.P., 1993. Development of a fatigue scale. J. Psychosom. Res. 37 (2), 147–153. Fukazawa, T., Sasaki, H., Kikuchi, S., Hamada, T., Tashiro, K., 1996. Serum carnitine and disabling fatigue in multiple sclerosis. Psychiatry Clin. Neurosci. 50 (6), 323–325 (Dec). Lebrun, C., Alchaar, H., Candito, M., Bourg, V., Chatel, M., 2006. Levocarnitine administration in multiple sclerosis patients with immunosuppressive therapy-induced fatigue. Mult. Scler. 12 (3), 321–324 (Jun). Rush, A.J., Trivedi, M.H., Ibrahim, H.M., Carmody, T.J., Arnow, B., Klein, D.N., Markowitz, J.C., Ninan, P.T., Kornstein, S., Manber, R., Thase, M.E., Kocsis, J.H., Keller, M.B., 2003. The 16-item inventory of depressive symptomatology (QIDS), clinical rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol. Psychiatry 54 (5), 573–583 (Sep). Tejani, A.M., Wasdell, M., Spiwak, R., Rowell, G., Nathwani, S., 2012. Carnitine for fatigue in multiple sclerosis. Cochrane Database Syst. Rev. 5, CD007280 (pub3, May). Tomassini, V., Pozzilli, C., Onesti, E., Pasqualetti, P., Marinelli, F., Pisani, A., Fieschi, C., 2004. Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomized, double-blind, crossover trial. J. Neurol. Sci. 218 (1–2), 103–108 (Mar).
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Short communication
Depressive state and chronic fatigue in multiple sclerosis and neuromyelitis optica Tetsuya Akaishi a, Ichiro Nakashima a,⁎, Tatsuro Misu b, Kazuo Fujihara b, Masashi Aoki a a b
Department of Neurology, Tohoku University School of Medicine, Sendai, Japan Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan
a r t i c l e
i n f o
Article history: Received 8 April 2015 Received in revised form 6 May 2015 Accepted 7 May 2015 Keywords: Neuromyelitis optica Depression Fatigue Carnitine Levocarnitine
a b s t r a c t Depression and chronic fatigue are frequently present in multiple sclerosis (MS); however, the prevalence rates have not been investigated in neuromyelitis optica (NMO). Thirty-nine consecutive NMO and 75 MS patients were compared using self-rating questionnaires for depressive states, daily activity, and fatigue, as well as serum carnitine levels. A subgroup of patients with low carnitine levels were re-evaluated regarding depression and fatigue after levocarnitine treatment. Depression and fatigue were equally prevalent in MS and NMO and were strongly correlated with one another. Measurement of the serum carnitine levels and the administration of levocarnitine did not appear to be beneficial. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Depression and chronic fatigue are present in most patients with multiple sclerosis (MS) and are often described as two of the most debilitating symptoms (Tomassini et al., 2004; Tejani et al., 2012). These symptoms are thought to be caused by the disseminated demyelination. Low serum carnitine levels have been suggested to cause these symptoms, especially in MS patients treated with disease-modifying therapies (DMT) (Fukazawa et al., 1996; Lebrun et al., 2006). Carnitine is associated with transport and catabolism of fatty acids in muscle cells. By supporting transport and oxidative catabolism of fatty acids in mitochondria, carnitine contributes to muscular endurance and tolerance to fatigue. Deficiency of carnitine either by reduced intake or impaired endogenous synthesis is thought to cause easy fatigability and chronic fatigue. Oral acetyl levocarnitine (L-carnitine), administered for disabling fatigue in MS, has been investigated in various studies. In contrast, depression, chronic fatigue and serum carnitine levels have not been assessed in patients with neuromyelitis optica (NMO), in which astrocytes are the primary target of anti-aquaporin-4 (AQP4) antibody. The effectiveness of L-carnitine for these symptoms in NMO is also unknown. 2. Methods Seventy-five consecutive patients with MS and 39 patients with NMO who regularly visit the outpatient clinic at Tohoku University ⁎ Corresponding author.
http://dx.doi.org/10.1016/j.jneuroim.2015.05.007 0165-5728/© 2015 Elsevier B.V. All rights reserved.
Hospital were collected between June and September 2014 to assess self-rating questionnaires for depressive states (self-reported quick inventory of depressive symptomatology: QIDS-SR) (Rush et al., 2003), daily activity (performance status: PS), and chronic fatigue (Chalder fatigue scale: ChFS) (Chalder et al., 1993). The QIDS-SR scores ranged from 0 to 27 (0 to 5: no depression; 6 to 10: mild depression; 11 to 15: moderate depression; 16 to 20: severe depression; and 21 to 27: very severe depression), whereas the PS ranged from 0 to 4 and the ChFS ranged from 0 to 56. The serum free-carnitine, acylcarnitine, and total-carnitine levels were measured for once at the same time of the questionnaires. The scores regarding gait disturbance (GD) and optic neuritis (ON), and the final expanded disability status scale (EDSS) were also collected. The GD-score scales were as follows: 0: normal; 1: only slight GD without impaired ADL; 2: possible to walk but with impaired daily activities; 3: wheelchair-bound; and 4: bedridden. The ON-score scales in each side of the eye were as follows: 0: normal; 1: possible to read; 2: counting finger; 3: hand motion or light perception; and 4: blindness. In NMO, the dose of oral prednisolone (PSL) was also collected. Pearson correlation coefficients or Spearman rank correlation coefficients (R) were comprehensively compared between all pairs of datasets to identify mutual relations and confounders. Pearson's R was adopted for the variables with normal distributions, and Spearman's R was adopted for the other pairs. Eleven patients with low carnitine levels (six MS and five NMO patients) who agreed to L-carnitine (1800 mg/day) treatment were followed, and their questionnaire scores were assessed after one month of administration.
T. Akaishi et al. / Journal of Neuroimmunology 283 (2015) 70–73
All statistical analyses in this study were conducted using SPSS (Statistical Package for the Social Sciences) Statistics Base 22 software (IBM, Armonk, New York, USA) and Microsoft Excel Statistical Analysis (ver. 6.0; Esumi Co., Ltd., Tokyo, Japan). This study was approved by the local research ethics committees of Tohoku University School of Medicine and of Tohoku University Hospital. Each patient voluntary gave written informed consent before participating in the study and also before treatment.
3. Results 3.1. Demographic and laboratory data Of the 75 MS patients, 13 (17.3%) patients were male and 62 (82.7%) patients were female (Table 1). All 39 NMO patients were female. The mean present age was increased in NMO compared with MS (p b 0.0001). The median disease duration was similar in MS and NMO (p ≥ 0.10). The median of the final EDSS was increased in NMO compared with MS (p b 0.0001). In the MS patients, there was a significant correlation between the disease duration and the final EDSS (R = 0.29, p b 0.01). Eight of the 75 MS patients (10.7%) and 16 of the 39 NMO patients (41.0%) were taking anti-depressant medications at the timing of this study.
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3.4. Correlations between carnitine levels and questionnaires The correlation coefficients between the serum carnitine levels and the three self-rated questionnaires were not significant (p ≥ 0.10) between any pairs. 3.5. Correlative coefficients with clinical information The QIDS-SR (R = 0.331, p b 0.05) and ChFS (R = 0.397, p b 0.05) exhibited weak to moderate correlations with disease duration in NMO (Fig. 2A, B), but not in MS (Fig. 2C, D). In contrast, the QIDS-SR (R = 0.373, p b 0.05) and ChFS (R = 0.307, 0.05 ≤ p b 0.10) exhibited weak to moderate correlations with the GD-score in MS, but not in NMO. There was no significant correlation between ON-score and selfrating questionnaires including QIDS-SR both in MS and NMO patients. Strong correlations between the final EDSS and PS were identified in both MS and NMO. A moderate correlation between the free-carnitine level and present age was identified only in NMO (R = 0.485, p b 0.01). The final EDSS exhibited weak correlations with disease duration in MS (R = 0.306, p b 0.01) and present age in NMO (R = 0.399, p b 0.05). In NMO patients, QIDS-SR score was significantly higher in those with anti-depressants than in those without anti-depressants (p ≤ 0.01). However, results did not change even among patients without antidepressants. 3.6. Carnitine levels and self-rating questionnaires by treatment types
3.2. Self-rated questionnaires More severe than mild levels of depression (QIDS-SR ≥ 5) were identified in 47 MS patients (62.7%) and 29 NMO patients (74.4%). Impaired daily activity (PS ≥ 1) was identified in 42 MS patients (56.0%) and 30 NMO patients (76.9%) (Table 1). If the cut-off level of the ChFS was set at a conventional score of 26, abnormal chronic fatigue (ChFS ≥ 26) was suggested in 53 MS patients (70.7%) and 30 NMO patients (76.9%). There was no significant difference between MS and NMO in the QIDS-SR (p ≥ 0.10) or ChFS (p ≥ 0.10); however, the PS was increased in NMO (p b 0.05). Strong correlations were identified between depression (QIDS-SR) and fatigue (ChFS) in both MS and NMO (Fig. 1).
In the MS patients, the free-carnitine level was lower in the patients receiving no treatment (n = 7; 36.6 ± 8.5 μmol/l) compared with the patients receiving disease-modifying treatments (DMT) (n = 68; 45.1 ± 9.6 μmol/l; p b 0.05). QIDS-SR was significantly lower in the MS patients administered IFN-β (median: 4; range: 0–17) compared with the patients administered fingolimod (7; 1–20) (p b 0.05), most likely because of the selection-bias for fingolimod in patients with depressive symptoms who avoid IFN-β. In NMO, 36 patients (92.3%) were administered low dose oral PSL therapy. There was no significant correlation between the PSL dose and the carnitine levels (p ≥ 0.05 for both free- and acyl-carnitine). No correlation was identified between the PSL dose and the questionnaires.
3.3. Serum carnitine levels
3.7. Changes after L-carnitine therapy
A low-level of total-carnitine (normal range: 45–91 μmol/L) was identified in 17 MS patients (22.7%) and 8 NMO patients (20.5%) (Table 1). A low-level of free-carnitine (normal range: 36–74 μmol/L) was identified in 13 MS patients (17.3%) and 7 NMO patients (17.9%). A low-level of acylcarnitine (normal range: 6–23 μmol/L) was identified in 13 MS patients (17.3%) and 4 NMO patients (10.3%).
Six MS patients and five NMO patients with a low-level of serum carnitine were administered L-carnitine. There was no significant improvement in any questionnaire after the treatment as shown in Fig. 3 (p ≥ 0.10).
Table 1 Comparisons of the clinical and laboratory information between MS and NMO.
Present age (mean ± SD) Duration [years] (median, range) ON-score (median, range) GD-score (median, range) Final EDSS (median, range) QIDS-SR (median, range) PS (median, range) ChFS (median, range) Total-carnitine [μmol/l] (mean ± SD) Free-carnitine [μmol/l] (mean ± SD) Acyl-carnitine [μmol/l] (mean ± SD)
MS (n = 75)
NMO (n = 39)
p-Value
36.4 ± 3.1 6 (1–31) 0 (0–4) 1 (0–3) 2 (0–8) 6 (0–24) 1 (0–3) 31 (16–54) 53.8 ± 10.9 44.3 ± 9.8 9.6 ± 3.8
51.9 ± 13.6 8 (0–35) 2 (0–8) 1 (0–4) 4.75 (0–8.5) 6 (1–23) 1 (0–4) 32 (18–55) 53.3 ± 9.0 44.2 ± 8.2 9.1 ± 2.4
b0.0001 n.s. b0.0001 n.s. b0.0001 n.s. 0.0106 n.s. n.s. n.s. n.s.
Abbreviations; MS: multiple sclerosis, NMO: neuromyelitis optica, SD: standard deviation, n.s.: not significant with p ≥ 0.05, QIDS-SR: quick inventory of depressive symptomatology (self-reported), PS: performance status, ChFS: Chalder fatigue scale.
4. Discussion This study demonstrated for the first time that NMO patients experience comparable levels of depressive state and chronic fatigue as MS patients. Because few reports have described cerebral demyelinating lesions in NMO, other mechanisms are needed to explain this finding. The oral PSL dose and present age are not likely mechanisms because they did not exhibit correlations with the scores although, longer disease duration would contribute to the advent of chronic depression and fatigue in NMO. Although the same levels of depression and fatigue were identified in MS and NMO, the mechanisms of these symptoms could be different between the diseases. For example, gait disturbances exhibited significant correlations with the QIDS-SR and close to significant correlations with the ChFS in MS, but not in NMO. In contrast, disease duration exhibited significant correlations with the QIDS-SR and ChFS in NMO, but not in MS. These findings suggest that chronic depression and fatigue in MS could be caused by the same pathomechanism of
72
T. Akaishi et al. / Journal of Neuroimmunology 283 (2015) 70–73
Fig. 1. Correlations between the QIDS-SR and ChFS in MS (A) and NMO (B). The correlation coefficient (R) values are denoted below the plots. ***: p b 0.001 in the test of no correlation.
demyelinating lesions as motor disturbances; however, these symptoms in NMO could be caused by other factors that accumulate with time. A strong correlation between the QIDS-SR and ChFS in both MS and NMO suggested that the management of each symptom would be important to control other symptoms. Unfortunately, the administration of L-carnitine therapy failed to significantly improve the scores. We conclude that oral L-carnitine therapy is unfounded for the management of these symptoms in MS and NMO. In conclusion, NMO patients can exhibit the same levels of depression and fatigue as MS patients regardless of the present PSL dose.
Carnitine is occasionally low in the sera of MS and NMO, but does not seem to play a major role in depression and fatigue in these diseases. Measurement of the serum carnitine levels and administration of oral L-carnitine seem not to be beneficial. Author contributions I.N. conceptualized and designed the study, I.N., T.M. and K.F. recruited the patients and collected the clinical data, and T.A. and I.N. performed data analysis and contributed to the interpretation of the results. M.A. and K.F. supervised the interpretation of the results. T.A.
Fig. 2. (A, B) Correlations between the QIDS-SR and disease duration (A) and between the ChFS and disease duration (B) in NMO patients. Both scores exhibited weak to moderate correlations with the disease duration in NMO. (C, D) Correlations between the QIDS-SR and disease duration (C) and between the ChFS and disease duration (D) in MS patients. Differing from NMO, neither score exhibited a significant correlation with the disease duration in MS.
T. Akaishi et al. / Journal of Neuroimmunology 283 (2015) 70–73
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Fig. 3. Changes in the QIDS-SR and ChFS by L-carnitine administration. There was no significant change in either score in both MS and NMO.
drafted the manuscript and all authors substantively revised the document for intellectual content.
Technology of Japan and as the secondary investigator by the Grants-inAid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan.
Conflict of interest Acknowledgments I.N. reports personal fees from Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Japan, and grants from LSI Medience Corporation. T.M. has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co., and Astellas Pharma Inc. and research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. K.F. has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical and research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The ChemoSero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; he is funded as the secondary investigator (#22229008, 2010–2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and
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