Autonomic symptom burden is an independent contributor to multiple sclerosis related fatigue

  • Magdalena Krbot Skorić
  • Luka Crnošija
  • Ivan Adamec
  • Barbara Barun
  • Tereza Gabelić
  • Tomislav Smoljo
  • Ivan Stanić
  • Tin Pavičić
  • Ivan Pavlović
  • Jelena Drulović
  • Tatjana Pekmezović
  • Mario HabekEmail author
Research Article



To investigate a possible association between autonomic dysfunction and fatigue in people with multiple sclerosis.


In 70 people with multiple sclerosis early in the disease course (51 females, mean age 33.8 ± 9.1), quantitative sudomotor axon reflex tests, cardiovascular reflex tests (heart rate and blood pressure responses to the Valsalva maneuver and heart rate response to deep breathing), and the tilt table test were performed. Participants completed the Composite Autonomic Symptom Score 31, the Modified Fatigue Impact Scale, and the Epworth Sleepiness Scale, as well as the Beck Depression Inventory. Cutoff scores of ≥ 38 or ≥ 45 on the Modified Fatigue Impact Scale were used to stratify patients into a fatigued subgroup (N = 17 or N = 9, respectively).


We found clear associations between fatigue and scores in subjective tests of the autonomic nervous system: fatigued patients scored significantly worse on Composite Autonomic Symptom Score 31, and there was a strong correlation between the Modified Fatigue Impact Scale and the Composite Autonomic Symptom Score 31 (rs = 0.607, p < 0.001). On the other hand, we found only modest associations between fatigue and scores in objective tests of the autonomic nervous system: there was a clear trend for lower sweating outputs at all measured sites, which reached statistical significance for the distal leg and foot. We found weak correlations between the Modified Fatigue Impact Scale and the Valsalva ratio (rs = − 0.306, p = 0.011), as well as between the Modified Fatigue Impact Scale and quantitative sudomotor axon reflex tests of the forearm, proximal, and distal lower leg (rs = − 0.379, p = 0.003; rs = − 0.356, p = 0.005; and rs = − 0.345, p = 0.006, respectively). A multiple regression model showed that the Composite Autonomic Symptom Score 31, Beck Depression Inventory, and Epworth Sleepiness Scale were independent predictors of fatigue (p = 0.005, p = 0.019, and p = 0.010, respectively).


These results suggest that—even early in the course of the disease—people with multiple sclerosis suffer from objective and subjective impairments of the autonomic nervous system. The results also point to an association between autonomic nervous system impairment and multiple sclerosis related fatigue.


Fatigue Depression Sleep Multiple sclerosis 


Author contributions

Study concept and design: MH. Acquisition of data: MKS, LC, IA, BB, TG, TS, IS, TP, IP, JD, TP, MH. Analysis and interpretation of data: MKS, LC, IA, BB, TG, TS, IS, TP, IP, JD, TP, MH. Drafting of the manuscript: MH. Critical revision of the manuscript for important intellectual content: MKS, LC, IA, BB, TG, TS, IS, TP, IP, JD, TP, MH. Administrative, technical, and material support: MKS, LC, IA, BB, TG, TS, IS, TP, IP, JD, TP, MH.


This study was funded by the Installation Research project HRZZ UIP-11-2013-2622 of the Croatian Science Foundation and University of Zagreb research support for the academic years 2017/2018.

Compliance with ethical standards

Conflict of interest

None of the authors have relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Supplementary material

10286_2018_563_MOESM1_ESM.docx (20 kb)
Supplementary material 1 (DOCX 20 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Magdalena Krbot Skorić
    • 1
    • 2
  • Luka Crnošija
    • 1
  • Ivan Adamec
    • 1
  • Barbara Barun
    • 1
    • 3
  • Tereza Gabelić
    • 1
    • 3
  • Tomislav Smoljo
    • 3
  • Ivan Stanić
    • 3
  • Tin Pavičić
    • 3
  • Ivan Pavlović
    • 3
  • Jelena Drulović
    • 4
  • Tatjana Pekmezović
    • 5
  • Mario Habek
    • 1
    • 3
    Email author
  1. 1.Department of Neurology, Referral Center for Autonomic Nervous System DisordersUniversity Hospital Center ZagrebZagrebCroatia
  2. 2.Faculty of Electrical Engineering and ComputingUniversity of ZagrebZagrebCroatia
  3. 3.School of MedicineUniversity of ZagrebZagrebCroatia
  4. 4.Clinic of Neurology, CCS, Faculty of MedicineUniversity of BelgradeBelgradeSerbia
  5. 5.Institute of Epidemiology, Faculty of MedicineUniversity of BelgradeBelgradeSerbia

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