Skip to main content

Advertisement

SpringerLink
Log in

Hypothalamic Dysfunction and Multiple Sclerosis: Implications for Fatigue and Weight Dysregulation

  • Demyelinating Disorders (DN Bourdette and M Cameron, Section Editors)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Signs and symptoms of multiple sclerosis are usually attributed to demyelinating lesions in the spinal cord or cerebral cortex. The hypothalamus is a region that is often overlooked yet controls many important homeostatic functions, including those that are perturbed in multiple sclerosis. In this review we discuss how hypothalamic dysfunction may contribute to signs and symptoms in people with multiple sclerosis. While dysfunction of the hypothalamic-pituitary-adrenal axis is common in multiple sclerosis, the effects and mechanisms of this dysfunction are not well understood. We discuss three hypothalamic mechanisms of fatigue in multiple sclerosis: (1) general hypothalamic-pituitary-adrenal axis hyperactivity, (2) disordered orexin neurotransmission, (3) abnormal cortisol secretion. We then review potential mechanisms of weight dysregulation caused by hypothalamic dysfunction. Lastly, we propose future studies and therapeutics to better understand and treat hypothalamic dysfunction in multiple sclerosis. Hypothalamic dysfunction appears to be common in multiple sclerosis, yet current studies are underpowered and contradictory. Future studies should contain larger sample sizes and standardize hormone and neuropeptide measurements.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as • Of importance •• Of major importance

  1. Who gets MS? National MS Society. http://www.nationalmssociety.org/About-the-Society/MS-Prevalence. 2016.

  2. Sbardella E, Petsas N, Tona F, Prosperini L, Raz E, Pace G, et al. Assessing the correlation between grey and white matter damage with motor and cognitive impairment in multiple sclerosis patients. PLoS One. 2013;8(5):e63250. doi:10.1371/journal.pone.0063250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vita G, Carolina Fazio M, Milone S, Blandino A, Salvi L, Messina C. Cardiovascular autonomic dysfunction in multiple sclerosis is likely related to brainstem lesions. J Neurol Sci. 1993;120(1):82–6. doi:10.1016/0022-510X(93)90029-X.

  4. Araki I, Matsui M, Ozawa K, Takeda M, Kuno S. Relationship of bladder dysfunction to lesion site in multiple sclerosis. J Urol. 2003;169(4):1384–7. doi:10.1097/01.ju.0000049644.27713.c8.

    Article  PubMed  Google Scholar 

  5. Mirone L, Altomonte L, D’Agostino P, Zoli A, Barini A, Magaro M. A study of serum androgen and cortisol levels in female patients with rheumatoid arthritis. Correlation with disease activity. Clin Rheumatol. 1996;15(1):15–9.

    Article  CAS  PubMed  Google Scholar 

  6. Stasi C, Orlandelli E. Role of the brain-gut axis in the pathophysiology of Crohn’s disease. Dig Dis. 2008;26(2):156–66. doi:10.1159/000116774.

    Article  PubMed  Google Scholar 

  7. Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev. 1999;79(1):1–71.

    CAS  PubMed  Google Scholar 

  8. Scarlett JM, Jobst EE, Enriori PJ, Bowe DD, Batra AK, Grant WF, et al. Regulation of central melanocortin signaling by interleukin-1 beta. Endocrinology. 2007;148(9):4217–25. doi:10.1210/en.2007-0017.

    Article  CAS  PubMed  Google Scholar 

  9. Shibata M. Hypothalamic neuronal responses to cytokines. Yale J Biol Med. 1990;63(2):147–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. McCann SM, Kimura M, Karanth S, Yu WH, Mastronardi CA, Rettori V. The mechanism of action of cytokines to control the release of hypothalamic and pituitary hormones in infection. Ann N Y Acad Sci. 2000;917:4–18.

    Article  CAS  PubMed  Google Scholar 

  11. Burfeind KG, Michaelis KA, Marks DL. The central role of hypothalamic inflammation in the acute illness response and cachexia. Semin Cell Dev Biol. 2016;54:42–52. doi:10.1016/j.semcdb.2015.10.038.

    Article  PubMed  Google Scholar 

  12. Tan CR, Yaffee PM, Jamil LH, Lo SK, Nissen N, Pandol SJ, et al. Pancreatic cancer cachexia: a review of mechanisms and therapeutics. Front Physiol. 2014;5:88. doi:10.3389/fphys.2014.00088.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Imrich R, Rovensky J. Hypothalamic-pituitary-adrenal axis in rheumatoid arthritis. Rheum Dis Clin N Am. 2010;36(4):721–7. doi:10.1016/j.rdc.2010.09.003.

    Article  Google Scholar 

  14. Lovelock JD, Coslet S, Johnson M, Rich S, Gomberg-Maitland M. Relative adrenal insufficiency in severe congestive heart failure with preserved systolic function: a case report. J Cardiovasc Med. 2007;8(9):754–7. doi:10.2459/JCM.0b013e328011c256 (Hagerstown, Md).

    Article  Google Scholar 

  15. Zietz B, Lock G, Plach B, Drobnik W, Grossmann J, Scholmerich J, et al. Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis. Eur J Gastroenterol Hepatol. 2003;15(5):495–501. doi:10.1097/01.meg.0000059115.41030.e0.

    CAS  PubMed  Google Scholar 

  16. Dorfman MD, Thaler JP. Hypothalamic inflammation and gliosis in obesity. Curr Opin Endocrinol Diabetes Obes. 2015;22(5):325–30. doi:10.1097/med.0000000000000182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ysrraelit MC, Gaitan MI, Lopez AS, Correale J. Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis. Neurology. 2008;71(24):1948–54. doi:10.1212/01.wnl.0000336918.32695.6b.

    Article  CAS  PubMed  Google Scholar 

  18. Michelson D, Stone L, Galliven E, Magiakou MA, Chrousos GP, Sternberg EM, et al. Multiple sclerosis is associated with alterations in hypothalamic-pituitary-adrenal axis function. J Clin Endocrinol Metab. 1994;79(3):848–53. doi:10.1210/jcem.79.3.8077372.

    CAS  PubMed  Google Scholar 

  19. Then Bergh F, Kumpfel T, Trenkwalder C, Rupprecht R, Holsboer F. Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS. Neurology. 1999;53(4):772–7.

    Article  CAS  PubMed  Google Scholar 

  20. Reder AT, Makowiec RL, Lowy MT. Adrenal size is increased in multiple sclerosis. Arch Neurol. 1994;51(2):151–4.

    Article  CAS  PubMed  Google Scholar 

  21. Huitinga I, De Groot CJ, Van der Valk P, Kamphorst W, Tilders FJ, Swaab DF. Hypothalamic lesions in multiple sclerosis. J Neuropathol Exp Neurol. 2001;60(12):1208–18.

    Article  CAS  PubMed  Google Scholar 

  22. Melief J, de Wit SJ, van Eden CG, Teunissen C, Hamann J, Uitdehaag BM, et al. HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter. Acta Neuropathol. 2013;126(2):237–49. doi:10.1007/s00401-013-1140-7.

    Article  PubMed  Google Scholar 

  23. Nagaraj K, Taly AB, Gupta A, Prasad C, Christopher R. Prevalence of fatigue in patients with multiple sclerosis and its effect on the quality of life. J Neurosci Rural Pract. 2013;4(3):278–82. doi:10.4103/0976-3147.118774.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol. 1988;45(4):435–7.

    Article  CAS  PubMed  Google Scholar 

  25. Flachenecker P, Kumpfel T, Kallmann B, Gottschalk M, Grauer O, Rieckmann P, et al. Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters. Mult Scler. 2002;8(6):523–6.

    Article  CAS  PubMed  Google Scholar 

  26. Rosenberg JH, Shafor R. Fatigue in multiple sclerosis: a rational approach to evaluation and treatment. Curr Neurol Neurosci Rep. 2005;5(2):140–6.

    Article  PubMed  Google Scholar 

  27. Bamer AM, Johnson KL, Amtmann D, Kraft GH. Prevalence of sleep problems in individuals with multiple sclerosis. Mult Scler. 2008;14(8):1127–30. doi:10.1177/1352458508092807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Attarian HP, Brown KM, Duntley SP, Carter JD, Cross AH. The relationship of sleep disturbances and fatigue in multiple sclerosis. Arch Neurol. 2004;61(4):525–8. doi:10.1001/archneur.61.4.525.

    Article  PubMed  Google Scholar 

  29. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung H-P, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819–28. doi:10.1016/S0140-6736(12)61769-3.

  30. Neilley LK, Goodin DS, Goodkin DE, Hauser SL. Side effect profile of interferon beta-1b in MS: results of an open label trial. Neurology. 1996;46(2):552–4.

    Article  CAS  PubMed  Google Scholar 

  31. Hoepner R, Faissner S, Salmen A, Gold R, Chan A. Efficacy and side effects of natalizumab therapy in patients with multiple sclerosis. J Cent Nerv Syst Dis. 2014;6:41–9. doi:10.4137/jcnsd.s14049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cantor F. Central and peripheral fatigue: exemplified by multiple sclerosis and myasthenia gravis. PM R. 2010;2(5):399–405. doi:10.1016/j.pmrj.2010.04.012.

  33. Crofford LJ, Young EA, Engleberg NC, Korszun A, Brucksch CB, McClure LA, et al. Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun. 2004;18(4):314–25. doi:10.1016/j.bbi.2003.12.011.

  34. Murialdo G, Barreca A, Nobili F, Rollero A, Timossi G, Gianelli MV, et al. Dexamethasone effects on cortisol secretion in Alzheimer’s disease: some clinical and hormonal features in suppressor and nonsuppressor patients. J Endocrinol Investig. 2000;23(3):178–86. doi:10.1007/bf03343703.

    Article  CAS  Google Scholar 

  35. Vreeburg SA, Hoogendijk WG, van Pelt J, et al. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch Gen Psychiatry. 2009;66(6):617–26. doi:10.1001/archgenpsychiatry.2009.50.

    Article  CAS  PubMed  Google Scholar 

  36. Schmidt ME, Semik J, Habermann N, Wiskemann J, Ulrich CM, Steindorf K. Cancer-related fatigue shows a stable association with diurnal cortisol dysregulation in breast cancer patients. Brain Behav Immun. 2016;52:98–105. doi:10.1016/j.bbi.2015.10.005.

  37. Crofford LJ, Pillemer SR, Kalogeras KT, Cash JM, Michelson D, Kling MA, et al. Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheum. 1994;37(11):1583–92.

    Article  CAS  PubMed  Google Scholar 

  38. Bower JE, Ganz PA, Dickerson SS, Petersen L, Aziz N, Fahey JL. Diurnal cortisol rhythm and fatigue in breast cancer survivors. Psychoneuroendocrinology. 2005;30(1):92–100. doi:10.1016/j.psyneuen.2004.06.003.

    Article  CAS  PubMed  Google Scholar 

  39. Generaal E, Vogelzangs N, Macfarlane GJ, Geenen R, Smit JH, Penninx BW, et al. Reduced hypothalamic-pituitary-adrenal axis activity in chronic multi-site musculoskeletal pain: partly masked by depressive and anxiety disorders. BMC Musculoskelet Disord. 2014;15(1):1–11. doi:10.1186/1471-2474-15-227.

    Article  Google Scholar 

  40. Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ. Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiology. 2007;55(2):112–20. doi:10.1159/000104468.

    Article  CAS  Google Scholar 

  41. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332(20):1351–62. doi:10.1056/nejm199505183322008.

    Article  CAS  PubMed  Google Scholar 

  42. Han KS, Kim L, Shim I. Stress and sleep disorder. Exp Neurobiol. 2012;21(4):141–50. doi:10.5607/en.2012.21.4.141.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Gottschalk M, Kumpfel T, Flachenecker P, Uhr M, Trenkwalder C, Holsboer F, et al. Fatigue and regulation of the hypothalamo-pituitary-adrenal axis in multiple sclerosis. Arch Neurol. 2005;62(2):277–80. doi:10.1001/archneur.62.2.277.

    Article  PubMed  Google Scholar 

  44. Heesen C, Nawrath L, Reich C, Bauer N, Schulz KH, Gold SM. Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? J Neurol Neurosurg Psychiatry. 2006;77(1):34–9. doi:10.1136/jnnp.2005.065805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron. 2003;38(5):701–13. doi:10.1016/S0896-6273(03)00331-3.

  46. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18(23):9996–10015.

    CAS  PubMed  Google Scholar 

  47. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci. 2007;8(3):171–81. doi:10.1038/nrn2092.

    Article  CAS  PubMed  Google Scholar 

  48. Fronczek R, van Geest S, Frölich M, Overeem S, Roelandse FWC, Lammers GJ, et al. Hypocretin (orexin) loss in Alzheimer’s disease. Neurobiol Aging. 2012;33(8):1642–50. doi:10.1016/j.neurobiolaging.2011.03.014.

  49. Long-Biao C, Bo-Wei L, Xiao-Hang J, Lin Z, Juan S. Progressive changes of orexin system in a rat model of 6-hydroxydopamineinduced Parkinson’s disease. Neurosci Bull. 2010;26(5):381–7. doi:10.1007/s12264-010-0410-9.

    Article  CAS  Google Scholar 

  50. Irving EA, Harrison DC, Babbs AJ, Mayes AC, Campbell CA, Hunter AJ, et al. Increased cortical expression of the orexin-1 receptor following permanent middle cerebral artery occlusion in the rat. Neurosci Lett. 2002;324(1):53–6. doi:10.1016/S0304-3940(02)00176-3.

  51. Grossberg AJ, Zhu X, Leinninger GM, Levasseur PR, Braun TP, Myers Jr MG, et al. Inflammation-induced lethargy is mediated by suppression of orexin neuron activity. J Neurosci. 2011;31(31):11376–86. doi:10.1523/JNEUROSCI.2311-11.2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kato T, Kanbayashi T, Yamamoto K, Nakano T, Shimizu T, Hashimoto T, et al. Hypersomnia and low CSF hypocretin-1 (orexin-A) concentration in a patient with multiple sclerosis showing bilateral hypothalamic lesions. Intern Med. 2003;42(8):743–5.

    Article  PubMed  Google Scholar 

  53. Oka Y, Kanbayashi T, Mezaki T, Iseki K, Matsubayashi J, Murakami G, et al. Low CSF hypocretin-1/orexin-A associated with hypersomnia secondary to hypothalamic lesion in a case of multiple sclerosis. J Neurol. 2004;251(7):885–6. doi:10.1007/s00415-004-0442-z.

    Article  PubMed  Google Scholar 

  54. Nozaki H, Shimohata T, Kanbayashi T, Sagawa Y, Katada S, Satoh M, et al. A patient with anti-aquaporin 4 antibody who presented with recurrent hypersomnia, reduced orexin (hypocretin) level, and symmetrical hypothalamic lesions. Sleep Med. 2009;10(2):253–5. doi:10.1016/j.sleep.2007.11.022.

    Article  PubMed  Google Scholar 

  55. Küçükali Cİ, Haytural H, Benbir G, Coban A, Ulusoy C, Giriş M, et al. Reduced serum orexin-A levels in autoimmune encephalitis and neuromyelitis optica patients. J Neurol Sci. 2014;346(1–2):353–5. doi:10.1016/j.jns.2014.08.041.

  56. Papuc E, Stelmasiak Z, Grieb P, Pawel G, Rejdak K. CSF hypocretin-1 concentrations correlate with the level of fatigue in multiple sclerosis patients. Neurosci Lett. 2010;474(1):9–12. doi:10.1016/j.neulet.2010.02.062.

    Article  CAS  PubMed  Google Scholar 

  57. Constantinescu CS, Niepel G, Patterson M, Judd A, Braitch M, Fahey AJ, et al. Orexin A (hypocretin-1) levels are not reduced while cocaine/amphetamine regulated transcript levels are increased in the cerebrospinal fluid of patients with multiple sclerosis: no correlation with fatigue and sleepiness. J Neurol Sci. 2011;307(1-2):127–31. doi:10.1016/j.jns.2011.04.024.

    Article  CAS  PubMed  Google Scholar 

  58. Dalal MA, Schuld A, Haack M, Uhr M, Geisler P, Eisensehr I, et al. Normal plasma levels of orexin A (hypocretin-1) in narcoleptic patients. Neurology. 2001;56(12):1749–51.

    Article  CAS  PubMed  Google Scholar 

  59. Salomon RM, Ripley B, Kennedy JS, Johnson B, Schmidt D, Zeitzer JM, et al. Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects. Biol Psychiatry. 2003;54(2):96–104.

    Article  CAS  PubMed  Google Scholar 

  60. Boddum K, Hansen MH, Jennum PJ, Kornum BR. Cerebrospinal fluid hypocretin-1 (orexin-A) level fluctuates with season and correlates with day length. PLoS One. 2016;11(3):e0151288. doi:10.1371/journal.pone.0151288.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Kiyashchenko LI, Mileykovskiy BY, Maidment N, Lam HA, Wu MF, John J, et al. Release of hypocretin (orexin) during waking and sleep states. J Neurosci. 2002;22(13):5282–6. 20026541.

    CAS  PubMed  Google Scholar 

  62. Dinneen S, Alzaid A, Miles J, Rizza R. Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans. J Clin Invest. 1993;92(5):2283–90. doi:10.1172/jci116832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5(3):243–51.

    Article  CAS  PubMed  Google Scholar 

  64. Chapotot F, Gronfier C, Jouny C, Muzet A, Brandenberger G. Cortisol secretion is related to electroencephalographic alertness in human subjects during daytime wakefulness. J Clin Endocrinol Metab. 1998;83(12):4263–8. doi:10.1210/jcem.83.12.5326.

    CAS  PubMed  Google Scholar 

  65. do Lee Y, Kim E, Choi MH. Technical and clinical aspects of cortisol as a biochemical marker of chronic stress. BMB Rep. 2015;48(4):209–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst. 2000;92(12):994–1000.

    Article  CAS  PubMed  Google Scholar 

  67. Sephton SE, Lush E, Dedert EA, Floyd AR, Rebholz WN, Dhabhar FS, et al. Diurnal cortisol rhythm as a predictor of lung cancer survival. Brain Behav Immun. 2013;30(Suppl):S163–70. doi:10.1016/j.bbi.2012.07.019.

    Article  CAS  PubMed  Google Scholar 

  68. Lara VP, Caramelli P, Teixeira AL, Barbosa MT, Carmona KC, Carvalho MG, et al. High cortisol levels are associated with cognitive impairment no-dementia (CIND) and dementia. Clin Chim Acta. 2013;423:18–22. doi:10.1016/j.cca.2013.04.013.

  69. Clow A, Hucklebridge F, Stalder T, Evans P, Thorn L. The cortisol awakening response: more than a measure of HPA axis function. Neurosci Biobehav Rev. 2010;35(1):97–103. doi:10.1016/j.neubiorev.2009.12.011.

    Article  CAS  PubMed  Google Scholar 

  70. Papadopoulos AS, Cleare AJ. Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol. 2012;8(1):22–32. doi:10.1038/nrendo.2011.153.

    Article  CAS  Google Scholar 

  71. Powell DJ, Liossi C, Moss-Morris R, Schlotz W. Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis. Psychoneuroendocrinology. 2013;38(11):2405–22. doi:10.1016/j.psyneuen.2013.07.004.

    Article  CAS  PubMed  Google Scholar 

  72. Powell DJ, Moss-Morris R, Liossi C, Schlotz W. Circadian cortisol and fatigue severity in relapsing-remitting multiple sclerosis. Psychoneuroendocrinology. 2015;56:120–31. doi:10.1016/j.psyneuen.2015.03.010. Powell et al. investigated the relationship between circadian cortisol and fatigue in 76 individuals (38 RRMS and 38 healthy controls). They found that RRMS patients with fatigue had increased cortisol awakening response (CAR) compared to individuals without MS. This paper presents CAR as a solid measure of HPA axis function, and implicates hypothalamic dysfunction in fatigue in MS.

    Article  CAS  PubMed  Google Scholar 

  73. Knutsson U, Dahlgren J, Marcus C, Rosberg S, Bronnegard M, Stierna P, et al. Circadian cortisol rhythms in healthy boys and girls: relationship with age, growth, body composition, and pubertal development. J Clin Endocrinol Metab. 1997;82(2):536–40. doi:10.1210/jcem.82.2.3769.

    CAS  PubMed  Google Scholar 

  74. Burke CW. Biologically active cortisol in plasma of oestrogen-treated and normal subjects. Br Med J. 1969;2(5660):798–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Turpeinen U, Hämäläinen E. Determination of cortisol in serum, saliva and urine. Best Pract Res Clin Endocrinol Metab. 2013;27(6):795–801. doi:10.1016/j.beem.2013.10.008.

  76. Arafah BM. Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods. J Clin Endocrinol Metab. 2006;91(10):3725–45. doi:10.1210/jc.2006-0674.

    Article  CAS  PubMed  Google Scholar 

  77. Ng SM, Agwu JC, Dwan K. A systematic review and meta-analysis of Synacthen tests for assessing hypothalamic-pituitary-adrenal insufficiency in children. Arch Dis Child. 2016. doi:10.1136/archdischild-2015-308925.

    PubMed  Google Scholar 

  78. Jensen MA, Mortier L, Koh E, Keevil B, Hyttinen S, Hansen AM. An interlaboratory comparison between similar methods for determination of melatonin, cortisol and testosterone in saliva. Scand J Clin Lab Invest. 2014;74(5):454–61. doi:10.3109/00365513.2014.900693.

    Article  CAS  PubMed  Google Scholar 

  79. Alexandraki KI, Grossman AB. Is urinary free cortisol of value in the diagnosis of Cushing’s syndrome? Curr Opin Endocrinol Diabetes Obes. 2011;18(4):259–63. doi:10.1097/MED.0b013e3283487193.

    Article  CAS  PubMed  Google Scholar 

  80. Russell E, Koren G, Rieder M, Van Uum S. Hair cortisol as a biological marker of chronic stress: current status, future directions and unanswered questions. Psychoneuroendocrinology. 2012;37(5):589–601. doi:10.1016/j.psyneuen.2011.09.009.

  81. Thomson S, Koren G, Fraser LA, Rieder M, Friedman TC, Van Uum SH. Hair analysis provides a historical record of cortisol levels in Cushing’s syndrome. Exp Clin Endocrinol Diabetes. 2010;118(2):133–8. doi:10.1055/s-0029-1220771.

    Article  CAS  PubMed  Google Scholar 

  82. Patejdl R, Penner IK, Noack TK, Zettl UK. Multiple sclerosis and fatigue: a review on the contribution of inflammation and immune-mediated neurodegeneration. Autoimmun Rev. 2016;15(3):210–20. doi:10.1016/j.autrev.2015.11.005 . Patejdl et al. described the differences between primary fatigue (caused by the disease itself) and secondary fatigue (resulting from other side effects of the disease or drugs) in MS. They summarize literature supporting the claim that damage to the CNS and/or cytokines derived from immune cells leads to neuroendocrine dysfunction and neuronal damage, which subsequently causes fatigue.

  83. Zellini F, Niepel G, Tench CR, Constantinescu CS. Hypothalamic involvement assessed by T1 relaxation time in patients with relapsing-remitting multiple sclerosis. Mult Scler. 2009;15(12):1442–9. doi:10.1177/1352458509350306.

    Article  PubMed  Google Scholar 

  84. Gershon AS, Margulies M, Gorczynski RM, Heathcote EJ. Serum cytokine values and fatigue in chronic hepatitis C infection. J Viral Hepat. 2000;7(6):397–402.

    Article  CAS  PubMed  Google Scholar 

  85. Bower JE, Ganz PA, Aziz N, Fahey JL. Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med. 2002;64(4):604–11.

    Article  PubMed  Google Scholar 

  86. Meyers CA, Albitar M, Estey E. Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer. 2005;104(4):788–93. doi:10.1002/cncr.21234.

    Article  CAS  PubMed  Google Scholar 

  87. Martins TB, Rose JW, Jaskowski TD, Wilson AR, Husebye D, Seraj HS, et al. Analysis of proinflammatory and anti-inflammatory cytokine serum concentrations in patients with multiple sclerosis by using a multiplexed immunoassay. Am J Clin Pathol. 2011;136(5):696–704. doi:10.1309/ajcp7ubk8ibvmvnr.

    Article  CAS  PubMed  Google Scholar 

  88. Malekzadeh A, Van de Geer-Peeters W, De Groot V, Elisabeth Teunissen C, Beckerman H, Group T-AS. Fatigue in patients with multiple sclerosis: is it related to pro- and anti-inflammatory cytokines? Dis Markers. 2015;2015:758314. doi:10.1155/2015/758314.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Beurskens AJ, Bultmann U, Kant I, Vercoulen JH, Bleijenberg G, Swaen GM. Fatigue among working people: validity of a questionnaire measure. Occup Environ Med. 2000;57(5):353–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Braun TP, Zhu X, Szumowski M, Scott GD, Grossberg AJ, Levasseur PR, et al. Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis. J Exp Med. 2011;208(12):2449–63. doi:10.1084/jem.20111020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Schmidt FM, Weschenfelder J, Sander C, Minkwitz J, Thormann J, Chittka T, et al. Inflammatory cytokines in general and central obesity and modulating effects of physical activity. PLoS One. 2015;10(3):e0121971. doi:10.1371/journal.pone.0121971.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Khurana SR, Bamer AM, Turner AP, Wadhwani RV, Bowen JD, Leipertz SL, et al. The prevalence of overweight and obesity in veterans with multiple sclerosis. Am J Phys Med Rehabil. 2009;88(2):83–91. doi:10.1097/PHM.0b013e318194f8b5.

    Article  PubMed  Google Scholar 

  93. Pinhas-Hamiel O, Livne M, Harari G, Achiron A. Prevalence of overweight, obesity and metabolic syndrome components in multiple sclerosis patients with significant disability. Eur J Neurol. 2015;22(9):1275–9. doi:10.1111/ene.12738. Pinhas-Hamiel et al. reported a decreased prevalence of obesity in MS patients compared to the general population. However, these patients had high rates of abdominal obesity and metabolic syndrome. This highlights the shortcomings in using BMI as the sole measure of body composition. The findings from this paper suggest MS patients are vulnerable to metabolic dysregulation.

    Article  CAS  PubMed  Google Scholar 

  94. Marrie R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. High frequency of adverse health behaviors in multiple sclerosis. Mult Scler. 2009;15(1):105–13. doi:10.1177/1352458508096680.

    Article  PubMed  Google Scholar 

  95. Marrie RA, Horwitz R, Cutter G, Tyry T, Vollmer T. Association between comorbidity and clinical characteristics of MS. Acta Neurol Scand. 2011;124(2):135–41. doi:10.1111/j.1600-0404.2010.01436.x.

    Article  CAS  PubMed  Google Scholar 

  96. Garner DJ, Widrick JJ. Cross-bridge mechanisms of muscle weakness in multiple sclerosis. Muscle Nerve. 2003;27(4):456–64. doi:10.1002/mus.10346.

    Article  CAS  PubMed  Google Scholar 

  97. Kent-Braun JA, Ng AV, Castro M, Weiner MW, Gelinas D, Dudley GA, et al. Strength, skeletal muscle composition, and enzyme activity in multiple sclerosis. J Appl Physiol. 1997;83(6):1998–2004.

    CAS  PubMed  Google Scholar 

  98. Formica CA, Cosman F, Nieves J, Herbert J, Lindsay R. Reduced bone mass and fat-free mass in women with multiple sclerosis: effects of ambulatory status and glucocorticoid Use. Calcif Tissue Int. 1997;61(2):129–33.

    Article  CAS  PubMed  Google Scholar 

  99. Stenholm S, Harris TB, Rantanen T, Visser M, Kritchevsky SB, Ferrucci L. Sarcopenic obesity: definition, cause and consequences. Curr Opin Clin Nutr Metab Care. 2008;11(6):693–700. doi:10.1097/MCO.0b013e328312c37d.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Dominguez LJ, Barbagallo M. The cardiometabolic syndrome and sarcopenic obesity in older persons. J Cardiometab Syndr. 2007;2(3):183–9.

    Article  PubMed  Google Scholar 

  101. Aubertin-Leheudre M, Lord C, Goulet ED, Khalil A, Dionne IJ. Effect of sarcopenia on cardiovascular disease risk factors in obese postmenopausal women. Obesity (Silver Spring). 2006;14(12):2277–83. doi:10.1038/oby.2006.267.

    Article  Google Scholar 

  102. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489–95. doi:10.1016/s1470-2045(10)70218-7.

    Article  PubMed  Google Scholar 

  103. Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer. 2002;2(11):862–71.

    Article  CAS  PubMed  Google Scholar 

  104. Von Roenn JH, Roth EL, Craig R. HIV-related cachexia: potential mechanisms and treatment. Oncology. 1992;49 Suppl 2:50–4.

    Google Scholar 

  105. Plauth M, Schutz ET. Cachexia in liver cirrhosis. Int J Cardiol. 2002;85(1):83–7.

    Article  PubMed  Google Scholar 

  106. Poehlman ET, Dvorak RV. Energy expenditure, energy intake, and weight loss in Alzheimer disease. Am J Clin Nutr. 2000;71(2):650s–5s.

    CAS  PubMed  Google Scholar 

  107. Roubenoff R, Roubenoff RA, Cannon JG, Kehayias JJ, Zhuang H, Dawson-Hughes B, et al. Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J Clin Invest. 1994;93(6):2379–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kamalian N, Keesey RE, ZuRhein GM. Lateral hypothalamic demyelination and cachexia in a case of “malignant” multiple sclerosis. Neurology. 1975;25(1):25–30.

    Article  CAS  PubMed  Google Scholar 

  109. van Waesberghe JH, Kamphorst W, De Groot CJ, van Walderveen MA, Castelijns JA, Ravid R, et al. Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol. 1999;46(5):747–54.

    Article  PubMed  Google Scholar 

  110. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. The Canadian MS Research Group. Can J Neurol Sci. 1987;14(3):273-8.

  111. Murray TJ. Amantadine therapy for fatigue in multiple sclerosis. Can J Neurol Sci. 1985;12(03):251–4.

    Article  CAS  PubMed  Google Scholar 

  112. Krupp LB, Coyle PK, Doscher C, Miller A, Cross AH, Jandorf L, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology. 1995;45(11):1956–61.

    Article  CAS  PubMed  Google Scholar 

  113. Pucci E, Branas P, D’Amico R, Giuliani G, Solari A, Taus C. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2007(1):Cd002818. doi:10.1002/14651858.CD002818.pub2.

  114. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803–39.

    Article  CAS  PubMed  Google Scholar 

  115. Wisor JP. Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions. Front Neurol. 2013;4:139. doi:10.3389/fneur.2013.00139.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Sheng P, Hou L, Wang X, Wang X, Huang C, Yu M, et al. Efficacy of modafinil on fatigue and excessive daytime sleepiness associated with neurological disorders: a systematic review and meta-analysis. PLoS One. 2013;8(12):e81802. doi:10.1371/journal.pone.0081802.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Zifko UA, Rupp M, Schwarz S, Zipko HT, Maida EM. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol. 2002;249(8):983–7. doi:10.1007/s00415-002-0765-6.

    Article  CAS  PubMed  Google Scholar 

  118. Rammohan K, Rosenberg J, Lynn D, Blumenfeld A, Pollak C, Nagaraja H. Efficacy and safety of modafinil (Provigil(®)) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002;72(2):179–83. doi:10.1136/jnnp.72.2.179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Asano M, Finlayson ML. Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication. Mult Scler Int. 2014;2014:798285. doi:10.1155/2014/798285.

    PubMed  PubMed Central  Google Scholar 

  120. Dobryakova E, Genova HM, DeLuca J, Wylie GR. The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders. Front Neurol. 2015;6:52. doi:10.3389/fneur.2015.00052.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Yadav V, Bever Jr C, Bowen J, Bowling A, Weinstock-Guttman B, Cameron M, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014;82(12):1083–92. doi:10.1212/wnl.0000000000000250.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler. 2004;10(4):434–41.

    Article  CAS  PubMed  Google Scholar 

  123. Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet. 2003;362(9395):1517–26. doi:10.1016/S0140-6736(03)14738-1.

  124. Fatemi I, Shamsizadeh A, Ayoobi F, Taghipour Z, Sanati MH, Roohbakhsh A, et al. Role of orexin-A in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2016;291:101–9. doi:10.1016/j.jneuroim.2016.01.001.

    Article  CAS  PubMed  Google Scholar 

  125. Equihua AC, De La Herrán-Arita AK, Drucker-Colin R. Orexin receptor antagonists as therapeutic agents for insomnia. Front Pharmacol. 2013;4:163. doi:10.3389/fphar.2013.00163.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Morairty SR, Revel FG, Malherbe P, Moreau J-L, Valladao D, Wettstein JG, et al. Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone. PLoS One. 2012;7(7):e39131. doi:10.1371/journal.pone.0039131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Herring WJ, Connor KM, Snyder E, Snavely DB, Zhang Y, Hutzelmann J, et al. Suvorexant in patients with insomnia: pooled analyses of three-month data from phase-3 randomized controlled clinical trials. J Clin Sleep Med. 2016 [Epub ahead of print].

  128. Panzica G, Melcangi RC. Structural and molecular brain sexual differences: a tool to understand sex differences in health and disease. Neurosci Biobehav Rev. 2016;67:2–8. doi:10.1016/j.neubiorev.2016.04.017.

Download references

Author information

Authors and Affiliations

  1. MD/PhD Program, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA

    Kevin G. Burfeind

  2. Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA

    Vijayshree Yadav

  3. Papé Family Pediatric Research Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, L 481, Portland, OR, 97239, USA

    Daniel L. Marks

Authors
  1. Kevin G. Burfeind
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vijayshree Yadav
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel L. Marks
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel L. Marks.

Ethics declarations

Conflict of Interest

Kevin G. Burfeind, Vijayshree Yadav, and Daniel L. Marks declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Demyelinating Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Burfeind, K.G., Yadav, V. & Marks, D.L. Hypothalamic Dysfunction and Multiple Sclerosis: Implications for Fatigue and Weight Dysregulation. Curr Neurol Neurosci Rep 16, 98 (2016). https://doi.org/10.1007/s11910-016-0700-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-016-0700-3

Keywords

Search

Navigation