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Published in: Current Neurology and Neuroscience Reports 11/2016

01-11-2016 | Demyelinating Disorders (DN Bourdette and M Cameron, Section Editors)

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

Authors: Kevin G. Burfeind, Vijayshree Yadav, Daniel L. Marks

Published in: Current Neurology and Neuroscience Reports | Issue 11/2016

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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.
Literature
3.
go back to reference 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. 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.
5.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
7.
go back to reference 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.PubMed 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.PubMed
10.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
14.
go back to reference 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).CrossRef 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).CrossRef
15.
go back to reference 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.PubMed 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.PubMed
18.
go back to reference 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.PubMed 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.PubMed
19.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
20.
go back to reference Reder AT, Makowiec RL, Lowy MT. Adrenal size is increased in multiple sclerosis. Arch Neurol. 1994;51(2):151–4.PubMedCrossRef Reder AT, Makowiec RL, Lowy MT. Adrenal size is increased in multiple sclerosis. Arch Neurol. 1994;51(2):151–4.PubMedCrossRef
21.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
22.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
24.
go back to reference Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol. 1988;45(4):435–7.PubMedCrossRef Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol. 1988;45(4):435–7.PubMedCrossRef
25.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
26.
go back to reference Rosenberg JH, Shafor R. Fatigue in multiple sclerosis: a rational approach to evaluation and treatment. Curr Neurol Neurosci Rep. 2005;5(2):140–6.PubMedCrossRef Rosenberg JH, Shafor R. Fatigue in multiple sclerosis: a rational approach to evaluation and treatment. Curr Neurol Neurosci Rep. 2005;5(2):140–6.PubMedCrossRef
29.
go back to reference 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. 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.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
33.
go back to reference 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. 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.
go back to reference 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.CrossRef 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.CrossRef
36.
go back to reference 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. 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.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
39.
go back to reference 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.CrossRef 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.CrossRef
40.
go back to reference 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.CrossRef 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.CrossRef
45.
go back to reference 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. 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.
go back to reference 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.PubMed 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.PubMed
49.
go back to reference 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.CrossRef 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.CrossRef
50.
go back to reference 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. 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.
52.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
53.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
54.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
55.
go back to reference 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. 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.
57.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
58.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
59.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
61.
go back to reference 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.PubMed 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.PubMed
63.
go back to reference Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5(3):243–51.PubMedCrossRef Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5(3):243–51.PubMedCrossRef
64.
go back to reference 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.PubMed 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.PubMed
65.
66.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
68.
go back to reference 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. 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.
71.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
72.•
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
73.
go back to reference 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.PubMed 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.PubMed
78.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
80.
go back to reference 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. 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.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
82.••
go back to reference 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. 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.
84.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
85.
go back to reference Bower JE, Ganz PA, Aziz N, Fahey JL. Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med. 2002;64(4):604–11.PubMedCrossRef Bower JE, Ganz PA, Aziz N, Fahey JL. Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med. 2002;64(4):604–11.PubMedCrossRef
86.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
87.
go back to reference 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.PubMedCrossRef 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​.PubMedCrossRef
88.
89.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
93.•
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
97.
go back to reference 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.PubMed 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.PubMed
98.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
100.
go back to reference Dominguez LJ, Barbagallo M. The cardiometabolic syndrome and sarcopenic obesity in older persons. J Cardiometab Syndr. 2007;2(3):183–9.PubMedCrossRef Dominguez LJ, Barbagallo M. The cardiometabolic syndrome and sarcopenic obesity in older persons. J Cardiometab Syndr. 2007;2(3):183–9.PubMedCrossRef
101.
go back to reference 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.CrossRef 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.CrossRef
104.
go back to reference Von Roenn JH, Roth EL, Craig R. HIV-related cachexia: potential mechanisms and treatment. Oncology. 1992;49 Suppl 2:50–4. Von Roenn JH, Roth EL, Craig R. HIV-related cachexia: potential mechanisms and treatment. Oncology. 1992;49 Suppl 2:50–4.
106.
go back to reference Poehlman ET, Dvorak RV. Energy expenditure, energy intake, and weight loss in Alzheimer disease. Am J Clin Nutr. 2000;71(2):650s–5s.PubMed Poehlman ET, Dvorak RV. Energy expenditure, energy intake, and weight loss in Alzheimer disease. Am J Clin Nutr. 2000;71(2):650s–5s.PubMed
107.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
108.
go back to reference Kamalian N, Keesey RE, ZuRhein GM. Lateral hypothalamic demyelination and cachexia in a case of “malignant” multiple sclerosis. Neurology. 1975;25(1):25–30.PubMedCrossRef Kamalian N, Keesey RE, ZuRhein GM. Lateral hypothalamic demyelination and cachexia in a case of “malignant” multiple sclerosis. Neurology. 1975;25(1):25–30.PubMedCrossRef
109.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
110.
go back to reference 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. 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.
go back to reference Murray TJ. Amantadine therapy for fatigue in multiple sclerosis. Can J Neurol Sci. 1985;12(03):251–4.PubMedCrossRef Murray TJ. Amantadine therapy for fatigue in multiple sclerosis. Can J Neurol Sci. 1985;12(03):251–4.PubMedCrossRef
112.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
114.
go back to reference Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803–39.PubMedCrossRef Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803–39.PubMedCrossRef
118.
119.
121.
go back to reference 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.PubMedPubMedCentralCrossRef 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​.PubMedPubMedCentralCrossRef
122.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
123.
go back to reference 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. 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.
127.
go back to reference 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]. 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].
Metadata
Title
Hypothalamic Dysfunction and Multiple Sclerosis: Implications for Fatigue and Weight Dysregulation
Authors
Kevin G. Burfeind
Vijayshree Yadav
Daniel L. Marks
Publication date
01-11-2016
Publisher
Springer US
Published in
Current Neurology and Neuroscience Reports / Issue 11/2016
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI
https://doi.org/10.1007/s11910-016-0700-3

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