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Original Contribution |

Fatigue and Regulation of the Hypothalamo-Pituitary-Adrenal Axis in Multiple Sclerosis FREE

Michaela Gottschalk, MD; Tania Kümpfel, MD; Peter Flachenecker, MD; Manfred Uhr, MD; Claudia Trenkwalder, MD; Florian Holsboer, MD; Frank Weber, MD
[+] Author Affiliations

Author Affiliations: Max Planck Institute of Psychiatry (Drs Gottschalk, Uhr, Holsboer, and Weber) and Institute of Neuroimmunology, Ludwig-Maximilians-University (Dr Kümpfel), Munich, Germany; Hospital Bavaria, Bad Kissingen, Germany (Dr Flachenecker); and Paracelsus-Elena Hospital, Kassel, Germany (Dr Trenkwalder).


Arch Neurol. 2005;62(2):277-280. doi:10.1001/archneur.62.2.277.
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Published online

Background  Fatigue is a common and disabling symptom in patients with multiple sclerosis (MS). Underlying mechanisms postulated so far have involved localization of brain lesions and abnormalities of the neuroendocrine system and cytokine regulation.

Objective  To investigate the relationship between fatigue and the hypothalamo-pituitary-adrenal (HPA) axis in patients with MS.

Design  A prospective survey.

Setting  Outpatient and inpatient study at the Max Planck Institute of Psychiatry, Munich, Germany.

Patients  Thirty-one patients with clinically definite MS, a relapsing-remitting disease course, and without MS-specific treatment.

Interventions  Assessment of fatigue with 3 questionnaires: the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), and the Visual Analog Scale. Assessment of HPA axis regulation with the combined dexamethasone–corticotropin releasing hormone (Dex-CRH) test.

Results  The FSS score was significantly correlated with the MFIS score. Patients with fatigue had significantly elevated adrenocorticotropin (ACTH) levels in the combined Dex-CRH test.

Conclusions  In contrast to results for chronic fatigue syndrome, where a hyporeactivity of the HPA axis has been shown, MS patients with fatigue exhibited a higher activity of the HPA axis than those without fatigue, as evidenced by significantly increased ACTH concentrations. Proinflammatory cytokines, known to be elevated in patients with MS, may cause both HPA axis alterations and fatigue.

Figures in this Article

Fatigue is an overwhelming sense of physical tiredness and lack of energy distinct from sadness and weakness.1 It is a physiologic phenomenon preceding sleep, but it also occurs as a disabling symptom in many patients with multiple sclerosis (MS), most frequently in the early stages of the disease. Although fatigue is common among patients with MS, evaluation of this symptom is difficult because of the subjectivity and variability of the complaints. As a result, many subjective fatigue scales have been developed, and trials have been conducted to measure fatigue quantitatively in terms of muscle strength.2

The pathophysiologic characteristics of fatigue are poorly understood. There is some evidence that peripheral abnormalities such as alterations in muscle metabolism contribute to fatigue in patients with MS.2,3 It has been suggested that abnormalities in the central nervous system (CNS) may play an important role in the pathogenesis of fatigue in MS.4 Inflammatory mediators such as cytokines in the CNS5 or localized damage to specific neuroanatomic regions6 may be the cause. And some investigators have provided evidence that pyramidal tract abnormalities are associated with fatigue in MS.2,7

There is strong evidence in both human and animal studies that MS is an autoimmune disease driven by autoreactive T cells and characterized by an imbalance of proinflammatory T helper (Th) 1 cytokines (eg, tumor necrosis factor α, interferon gamma, interleukin [IL] 2, and lymphotoxin)8,9 and regulatory Th2 cytokines (eg, IL-4 and IL-10).10,11 Because of the background of the interplay of the immune and endocrine systems, the hypothalamo-pituitary-adrenal (HPA) axis has been studied in patients with MS.12 Several investigations suggest a hyperreactivity of the HPA axis in MS related to the clinical course, which might be caused by the well-known elevation of proinflammatory cytokine levels.1214 In contrast, several studies on the relationship between the chronic fatigue syndrome (CFS) and the HPA axis have demonstrated a hyporeactivity of the HPA axis in patients with this disorder.15 The present study was performed to investigate the association between fatigue and HPA-axis activity in patients with MS.

PATIENTS

Thirty-one patients with clinically definite MS according to the criteria of Poser et al16 and a relapsing-remitting disease course were recruited from the outpatient and inpatient units of the hospital. The patients had been without glucocorticoid treatment for at least 4 weeks. Of the 31 patients, 25 had never had any immunosuppressive or immunomodulatory treatment. Four patients had received treatment with azathioprine, 1 with interferon beta, and 1 with interferon beta and mitoxantrone, all years earlier. None of the patients had taken any centrally acting medications such as antidepressants in the last several years. Patients diagnosed as having a major depressive disorder, those who had a score above 14 on the Hamilton Depression Rating Scale,17 and those with another severe medical disorder were excluded from the study. Written informed consent was obtained from all subjects prior to the investigation.

CLINICAL ASSESSMENT

Subjects were interviewed, and then they completed several standardized self-report fatigue questionnaires: the Fatigue Severity Scale (FSS) of Krupp et al,18 the Modified Fatigue Impact Scale (MFIS) of the Multiple Sclerosis Council,19 and the visual analog scale (VAS).19 A neurologic examination was performed, and the patient’s neurologic disability was assessed using the Kurtzke20 Expanded Disability Status Scale (EDSS).

THE Dex-CRH TEST AND DETERMINATION OF PLASMA HORMONE CONCENTRATIONS

The HPA axis activity was assessed with the combined dexamethasone–corticotropin releasing hormone (Dex-CRH) test on the day the patient completed the questionnaires. The test was performed as described previously.13

Blood was drawn into prechilled tubes containing EDTA and aprotinin and centrifuged. The plasma was stored at –80°C until measurement. Cortisol and adrenocorticotropin (ACTH) concentrations were determined using commercial radioimmunologic assays (Immun Chem Cortisol; ICN Biomedicals, Costa Mesa, Calif; and RIA-ACTH; Nichols Institute Diagnostics, San Juan Capistrano, Calif) with an interassay variation coefficient of less than 8% and an intra-assay variation coefficient of less than 4%.

DATA ANALYSIS

The patients were divided into 2 groups by FSS scores: the fatigue group had FSS scores of 4.0 or higher; the nonfatigue group had FSS scores lower than 4.0. The following variables were calculated: For the Dex-CRH test: maximum rise (deltamax) in levels of cortisol and ACTH after human corticotropin-releasing hormone injections; area under the curve (AUC) from 3 to 4:15 PM using the trapezoidal rule; and the mean location of the curve (ML). Differences in the variables deltamax cortisol, AUC cortisol, ML cortisol, deltamax ACTH, AUC ACTH, and ML ACTH between the 2 groups were tested for significance by means of a 1-factorial multivariate analysis of covariance, with sex, age, and EDSS score as covariates. As the nominal level of significance, P<.05 was accepted. In case of a significant factor effect, univariate F tests were performed to identify the variables contributing significantly to this effect. These tests were performed with a reduced level of significance (Bonferroni correction) to keep the type I error to .05 or lower. Data are given as mean ± SEM or median and range. Pearson r was used to assess the relationship between different fatigue scales.

Of the 31 patients studied with clinically definite MS and a relapsing-remitting disease course, 15 (48%) were assigned to the fatigue group and 16 to the nonfatigue group. Aside from fatigue, the groups had comparable clinical characteristics. The fatigue group consisted of 12 women and 3 men (mean ± SEM age, 39.60 ± 1.84 years) and the nonfatigue group of 10 women and 6 men (mean ± SEM age, 32.38 ± 2.62 years). The median EDSS score was 1.5 (range, 1.0-4.5) in the fatigue group and 2.0 (range, 0.0-6.5) in the nonfatigue group. Age at onset was similar in the 2 groups (fatigue group, 28.73 ± 2.26 years; nonfatigue group, 28.88 ± 1.82 years).

Of the 31 patients, 15 had a fatigue score of 4 or higher on the FSS, indicating fatigue (mean ± SEM FSS scores: fatigue group, 5.27 ± 0.20; nonfatigue group, 2.72 ± 0.23). The FSS score was highly significantly correlated (P<.001; Pearson r = 0.65) with the MFIS score (MFIS scores: fatigue group, 1.91 ± 0.13; nonfatigue group, 1.40 ± 0.28). In contrast, it was not correlated with the severity of fatigue as measured by the VAS (VAS scores: fatigue group, 0.58 ± 0.05; nonfatigue group, 0.66 ± 0.37). But the VAS and MFIS scores had a significant correlation (P<.001; Pearson r = 0.51).

There was a significant effect of fatigue on the HPA axis activity (P<.03, Wilks multivariate tests of significance). The patients with fatigue had significantly increased ACTH levels compared with those without fatigue (univariate F tests, P<.05; Figure, A). However, their cortisol levels were not significantly elevated (Figure, B). None of the covariates age, sex, EDSS score, or duration of disease were found to have influence on fatigue.

Place holder to copy figure label and caption
Figure.

Reactivity of the hypothalamo-pituitary-adrenal axis in multiple sclerosis patients with and without fatigue. A, Adrenocorticotropin (ACTH) levels were significantly higher in the patients with fatigue than in those without fatigue. B, Cortisol levels did not differ statistically between patients with and without fatigue. Error bars indicate standard error of the mean; AUC, area under the curve; deltamax, greatest increase; and ML, mean location of the curve.

Graphic Jump Location

Fatigue is a common symptom in MS and is reported by more than one third of patients.1,21,22 Using the FSS, we found that 48% of our patients experienced fatigue. The FSS is the most widely accepted unidimensional scale.18 Multidimensional assessment of fatigue is possible with the MFIS,19 which showed a highly significant correlation with the FSS in our study. In line with recently published results,23 the VAS was less powerful in detecting fatigue in patients with MS. We found no correlation between fatigue and neurologic disability as determined with the EDSS in our study population, which is in line with several other publications.21,22,24 This reflects the observation that fatigue often occurs in the early stages of the disease and is often the leading symptom despite a low EDSS score. However, other investigators have reported an association between physical disability and fatigue.2527 Fatigue was independent of age, sex, and duration of disease.

In our study, the MS patients with fatigue showed a dysregulation of the HPA axis, as demonstrated by significantly elevated plasma ACTH levels. In contrast, Heesen et al28 recently found no correlation between fatigue and HPA axis activity in 40 patients with MS. A possible explanation is differences between the MS populations studied: Heesen et al investigated 32 patients with a chronic progressive course and 8 with a relapsing-remitting course. In support of our findings, several studies have shown correlations between HPA axis function and both disease activity and course of disease. Patients with a chronic progressive MS course showed increasing HPA axis activity.1214 Another reason why the findings are inconsistent may be that the study population of Heesen et al28 received immunomodulatory and immunosuppressive agents such as interferons, glatiramer acetate, methotrexate, and mitoxantrone, whereas patients being treated with such medications were excluded from other studies, including ours, because some of these therapies influence cytokines, which have an effect on HPA axis activity.29,30 Furthermore, Heesen et al28 did not divide patients into subgroups with and without fatigue as we did, and fatigue as determined by the FSS was lower than in our group.

In contrast to our study, which demonstrates a hyperreactivity of the HPA axis in MS patients with fatigue, several studies of non-MS patients with CFS showed a hyporeactivity.15 Our patients with MS had fatigue scores similar to those of the patients with CFS. However, in 1 study, non-MS patients with CFS had significantly higher somatization scores than patients with MS, which reflects strong focusing on bodily sensations.22 Patients with MS are more likely than healthy individuals to report that their fatigue is easily triggered, worsened by heat, and that it prevents sustained physical functioning.21 Therefore, CFS seems to be different from fatigue in MS both clinically and with respect to HPA axis activation.

Immune activation is known to be elevated in patients with MS, and the proinflammatory cytokines involved may be the cause of the HPA axis alterations and a strong feeling of fatigue in patients with MS. Studies in patients and animals with MS found an association between fatigue and some proinflammatory cytokines, including tumor necrosis factor α and IL-1,5,31,32 which are known to activate the HPA axis. Increased serum levels of IL-1 affect the hypothalamus and cause fever, fatigue, and myalgia.33 Other markers, including urinary neopterin excretion (a marker of interferon gamma–activated macrophage activity) and excretion levels of serum C-reactive protein (CRP) and soluble intercellular adhesion molecule-1, showed no significant association with fatigue in MS.34 However, in 1 study, patients with higher CRP levels had higher FSS scores, which correlated with a more severe course of disease.34 Wei and Lightman14 found higher CRP levels in MS patients with a hyperreactivity of the HPA axis.14 C-reactive protein is induced by IL-6, which is known to be a strong activator of the HPA axis.35 Flachenecker et al36 found significantly higher median levels of tumor necrosis factor α messenger RNA expression in MS patients with fatigue than in those without fatigue. In 1 study, aspirin caused a reduction in fatigue severity in patients with MS.37

Taken together, these findings support the hypothesis of an association between proinflammatory cytokines and both fatigue and up-regulation of the HPA axis in patients with MS, and we postulate that cytokine-induced impairment of corticoid receptor signaling accounts for this effect.38 We further postulate that successful reinstatement of corticosteroid receptor function by appropriate drugs such as antidepressants will have a positive influence on both MS-associated HPA axis dysfunction and fatigue.39,40

Correspondence: Frank Weber, MD, Max Planck Institute of Psychiatry, Kraepelinstr 10, 80804 Munich, Germany (fweber@mpipsykl.mpg.de).

Accepted for Publication: April 29, 2004.

Acknowledgment: We acknowledge the assistance of Alexander Yassouridis, PhD, who was very helpful with the statistical analysis. We also thank Heike Staufer for her excellent technical assistance.

Krupp  LBPollina  DA Mechanisms and management of fatigue in progressive neurological disorders. Curr Opin Neurol 1996;9456- 460
PubMed
Djaldetti  RZiv  IAchiron  AMelamed  E Fatigue in multiple sclerosis compared with chronic fatigue syndrome: a quantitative assessment. Neurology 1996;46632- 635
PubMed
Sheean  GLMurray  NMFRothwell  JCMiller  DH An electrophysiological study of the mechanism of fatigue in multiple sclerosis. Brain 1997;120299- 315
PubMed
Comi  GLeocani  LRossi  PColombo  B Physiopathology and treatment of fatigue in multiple sclerosis. J Neurol 2001;248174- 179
PubMed
Natelson  BHLaManca  JJDenny  TN  et al.  Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis. Am J Med 1998;10543S- 49S
PubMed
Colombo  BMartinelli Boneschi  FRossi  P  et al.  MRI and motor evoked potential findings in nondisabled multiple sclerosis patients with and without symptoms of fatigue. J Neurol 2000;247506- 509
PubMed
Iriarte  JDe Castro  P Correlation between symptom fatigue and muscular fatigue in multiple sclerosis. Eur J Neurol 1998;5579- 585
PubMed
Beck  JRondot  PCatinot  LFalcoff  EKirchner  HWietzerbin  J Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand 1988;78318- 323
PubMed
Wekerle  HKojima  KLannes-Vieira  JLassmann  HLinington  C Animal models. Ann Neurol 1994;36(suppl)S47- S53
PubMed
Ramirez  FMason  D Induction of resistance to active experimental allergic encephalomyelitis by myelin basic protein-specific Th2 cell lines generated in the presence of glucocorticoids and IL-4. Eur J Immunol 2000;30747- 758
PubMed
Rott  OFleischer  BCash  E Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur J Immunol 1994;241434- 1440
PubMed
Then Bergh  FKümpfel  TTrenkwalder  CRupprecht  RHolsboer  F Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS. Neurology 1999;53772- 777
PubMed
Grasser  AMöller  ABackmund  HYassouridis  AHolsboer  F Heterogeneity of hypothalamic-pituitary-adrenal system response to a combined dexamethasone-CRH test in multiple sclerosis. Exp Clin Endocrinol Diabetes 1996;10431- 37
PubMed
Wei  TLightman  SL The neuroendocrine axis in patients with multiple sclerosis. Brain 1997;1201067- 1076
PubMed
Scott  LVDinan  TG The neuroendocrinology of chronic fatigue syndrome: focus on the hypothalamic-pituitary-adrenal axis. Funct Neurol 1999;143- 11
PubMed
Poser  CMPaty  DWScheinberg  L  et al.  New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13227- 231
PubMed
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed
Krupp  LBLaRocca  NGMuir-Nash  JSteinberg  AD The fatigue severity scale: application to patients with multiple sclerosis and systemic lupus erythematodes. Arch Neurol 1989;461121- 1123
PubMed
Zimmermann  CHohlfeld  R ”Fatigue” bei multipler Sklerose. Nervenarzt 1999;70566- 574
PubMed
Kurtzke  JF Disability rating scales in multiple sclerosis. Ann N Y Acad Sci 1984;436347- 360
PubMed
Krupp  LBAlvarez  LALaRocca  NGScheinberg  LC Fatigue in multiple sclerosis. Arch Neurol 1988;45435- 437
PubMed
Vercoulen  JHHommes  ORSwanik  CMA  et al.  The measurement of fatigue in patients with multiple sclerosis. Arch Neurol 1996;53642- 649
PubMed
Flachenecker  PKümpfel  TKallmann  B  et al.  Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters. Mult Scler 2002;8523- 526
PubMed
Fisk  JDPontefract  ARitvo  PGArchibald  CJMurray  TJ The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994;219- 14
PubMed
Bergamaschi  RRomani  AVersino  MPoli  RCosi  V Clinical aspects of fatigue in multiple sclerosis. Funct Neurol 1997;12247- 251
PubMed
Colosimo  CMillefiorini  EGrasso  MG  et al.  Fatigue in MS is associated with specific clinical features. Acta Neurol Scand 1995;92353- 355
PubMed
Kroencke  DCLynch  SGDenney  DR Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern. Mult Scler 2000;6131- 136
PubMed
Heesen  CGold  SMRaji  AWiedemann  KSchulz  KH Cognitive impairment correlates with hypothalamo-pituitary-adrenal axis dysregulation in multiple sclerosis. Psychoneuroendocrinology 2002;27505- 517
PubMed
Weber  FPolak  TGunther  A  et al.  Synergistic immunomodulatory effects of interferon-beta 1 b and the phosphodiesterase inhibitor pentoxifylline in patients with relapsing-remitting multiple sclerosis. Ann Neurol 1998;4427- 34
PubMed
Dunn  AJ Cytokine activation of the HPA axis. Ann N Y Acad Sci 2000;917608- 617
PubMed
Bertolone  KCoyle  PKKrupp  LB  et al.  Cytokine correlates of fatigue in multiple sclerosis. Neurology 1993;43A356
Chao  CCDeLaHunt  MHu  SClose  KPeterson  PK Immunologically mediated fatigue: a murine model. Clin Immunol Immunopathol 1992;64161- 165
PubMed
Krupp  LBPollina  D Neuroimmune and neuropsychiatric aspects of chronic fatigue syndrome. Adv Neuroimmunol 1996;6155- 167
PubMed
Giovannoni  GThompson  AJMiller  DHThompson  EJ Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology 2001;57676- 681
PubMed
Mortensen  RF C-reactive protein, inflammation, and innate immunity. Immunol Res 2001;24163- 176
PubMed
Flachenecker  PBihler  IWeber  F  et al.  Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Mult Scler 2004;10165- 169
PubMed
Wingerchuk  DMScottsdale  AZBenarroch  EE  et al.  Aspirin for multiple sclerosis-related fatigue: results of a double-blind, placebo-controlled study. Neurology 2002;58(suppl 3)A492
De Kloet  EROitzl  MSSchöbitz  B Cytokines and the brain corticosteroid receptor balance: relevance to pathophysiology of neuroendocrine-immune communication. Psychoneuroendocrinology 1994;19121- 134
PubMed
Holsboer  FBarden  N Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev 1996;17187- 205
PubMed
Then Bergh  FKümpfel  TGrasser  ARupprecht  RHolsboer  FTrenkwalder  C Combined treatment with corticosteroids and moclobemide favors normalization of hypothalamo-pitiutary-adrenal axis dysregulation in relapsing-remitting multiple sclerosis: a randomized, double blind trial. J Clin Endocrinol Metab 2001;861610- 1615
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Reactivity of the hypothalamo-pituitary-adrenal axis in multiple sclerosis patients with and without fatigue. A, Adrenocorticotropin (ACTH) levels were significantly higher in the patients with fatigue than in those without fatigue. B, Cortisol levels did not differ statistically between patients with and without fatigue. Error bars indicate standard error of the mean; AUC, area under the curve; deltamax, greatest increase; and ML, mean location of the curve.

Graphic Jump Location

Tables

References

Krupp  LBPollina  DA Mechanisms and management of fatigue in progressive neurological disorders. Curr Opin Neurol 1996;9456- 460
PubMed
Djaldetti  RZiv  IAchiron  AMelamed  E Fatigue in multiple sclerosis compared with chronic fatigue syndrome: a quantitative assessment. Neurology 1996;46632- 635
PubMed
Sheean  GLMurray  NMFRothwell  JCMiller  DH An electrophysiological study of the mechanism of fatigue in multiple sclerosis. Brain 1997;120299- 315
PubMed
Comi  GLeocani  LRossi  PColombo  B Physiopathology and treatment of fatigue in multiple sclerosis. J Neurol 2001;248174- 179
PubMed
Natelson  BHLaManca  JJDenny  TN  et al.  Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis. Am J Med 1998;10543S- 49S
PubMed
Colombo  BMartinelli Boneschi  FRossi  P  et al.  MRI and motor evoked potential findings in nondisabled multiple sclerosis patients with and without symptoms of fatigue. J Neurol 2000;247506- 509
PubMed
Iriarte  JDe Castro  P Correlation between symptom fatigue and muscular fatigue in multiple sclerosis. Eur J Neurol 1998;5579- 585
PubMed
Beck  JRondot  PCatinot  LFalcoff  EKirchner  HWietzerbin  J Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand 1988;78318- 323
PubMed
Wekerle  HKojima  KLannes-Vieira  JLassmann  HLinington  C Animal models. Ann Neurol 1994;36(suppl)S47- S53
PubMed
Ramirez  FMason  D Induction of resistance to active experimental allergic encephalomyelitis by myelin basic protein-specific Th2 cell lines generated in the presence of glucocorticoids and IL-4. Eur J Immunol 2000;30747- 758
PubMed
Rott  OFleischer  BCash  E Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur J Immunol 1994;241434- 1440
PubMed
Then Bergh  FKümpfel  TTrenkwalder  CRupprecht  RHolsboer  F Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS. Neurology 1999;53772- 777
PubMed
Grasser  AMöller  ABackmund  HYassouridis  AHolsboer  F Heterogeneity of hypothalamic-pituitary-adrenal system response to a combined dexamethasone-CRH test in multiple sclerosis. Exp Clin Endocrinol Diabetes 1996;10431- 37
PubMed
Wei  TLightman  SL The neuroendocrine axis in patients with multiple sclerosis. Brain 1997;1201067- 1076
PubMed
Scott  LVDinan  TG The neuroendocrinology of chronic fatigue syndrome: focus on the hypothalamic-pituitary-adrenal axis. Funct Neurol 1999;143- 11
PubMed
Poser  CMPaty  DWScheinberg  L  et al.  New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13227- 231
PubMed
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed
Krupp  LBLaRocca  NGMuir-Nash  JSteinberg  AD The fatigue severity scale: application to patients with multiple sclerosis and systemic lupus erythematodes. Arch Neurol 1989;461121- 1123
PubMed
Zimmermann  CHohlfeld  R ”Fatigue” bei multipler Sklerose. Nervenarzt 1999;70566- 574
PubMed
Kurtzke  JF Disability rating scales in multiple sclerosis. Ann N Y Acad Sci 1984;436347- 360
PubMed
Krupp  LBAlvarez  LALaRocca  NGScheinberg  LC Fatigue in multiple sclerosis. Arch Neurol 1988;45435- 437
PubMed
Vercoulen  JHHommes  ORSwanik  CMA  et al.  The measurement of fatigue in patients with multiple sclerosis. Arch Neurol 1996;53642- 649
PubMed
Flachenecker  PKümpfel  TKallmann  B  et al.  Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters. Mult Scler 2002;8523- 526
PubMed
Fisk  JDPontefract  ARitvo  PGArchibald  CJMurray  TJ The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994;219- 14
PubMed
Bergamaschi  RRomani  AVersino  MPoli  RCosi  V Clinical aspects of fatigue in multiple sclerosis. Funct Neurol 1997;12247- 251
PubMed
Colosimo  CMillefiorini  EGrasso  MG  et al.  Fatigue in MS is associated with specific clinical features. Acta Neurol Scand 1995;92353- 355
PubMed
Kroencke  DCLynch  SGDenney  DR Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern. Mult Scler 2000;6131- 136
PubMed
Heesen  CGold  SMRaji  AWiedemann  KSchulz  KH Cognitive impairment correlates with hypothalamo-pituitary-adrenal axis dysregulation in multiple sclerosis. Psychoneuroendocrinology 2002;27505- 517
PubMed
Weber  FPolak  TGunther  A  et al.  Synergistic immunomodulatory effects of interferon-beta 1 b and the phosphodiesterase inhibitor pentoxifylline in patients with relapsing-remitting multiple sclerosis. Ann Neurol 1998;4427- 34
PubMed
Dunn  AJ Cytokine activation of the HPA axis. Ann N Y Acad Sci 2000;917608- 617
PubMed
Bertolone  KCoyle  PKKrupp  LB  et al.  Cytokine correlates of fatigue in multiple sclerosis. Neurology 1993;43A356
Chao  CCDeLaHunt  MHu  SClose  KPeterson  PK Immunologically mediated fatigue: a murine model. Clin Immunol Immunopathol 1992;64161- 165
PubMed
Krupp  LBPollina  D Neuroimmune and neuropsychiatric aspects of chronic fatigue syndrome. Adv Neuroimmunol 1996;6155- 167
PubMed
Giovannoni  GThompson  AJMiller  DHThompson  EJ Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology 2001;57676- 681
PubMed
Mortensen  RF C-reactive protein, inflammation, and innate immunity. Immunol Res 2001;24163- 176
PubMed
Flachenecker  PBihler  IWeber  F  et al.  Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Mult Scler 2004;10165- 169
PubMed
Wingerchuk  DMScottsdale  AZBenarroch  EE  et al.  Aspirin for multiple sclerosis-related fatigue: results of a double-blind, placebo-controlled study. Neurology 2002;58(suppl 3)A492
De Kloet  EROitzl  MSSchöbitz  B Cytokines and the brain corticosteroid receptor balance: relevance to pathophysiology of neuroendocrine-immune communication. Psychoneuroendocrinology 1994;19121- 134
PubMed
Holsboer  FBarden  N Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev 1996;17187- 205
PubMed
Then Bergh  FKümpfel  TGrasser  ARupprecht  RHolsboer  FTrenkwalder  C Combined treatment with corticosteroids and moclobemide favors normalization of hypothalamo-pitiutary-adrenal axis dysregulation in relapsing-remitting multiple sclerosis: a randomized, double blind trial. J Clin Endocrinol Metab 2001;861610- 1615
PubMed

Correspondence

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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
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Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
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