Thermoregulation In Multiple Sclerosis

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Thermoregulation in multiple sclerosisScott L. Davis, Thad E. Wilson, Andrea T. White and Elliot M. FrohmanJ Appl Physiol 109:1531-1537, 2010. First published 29 July 2010; doi:10.1152/japplphysiol.00460.2010You might find this additional info useful.This article cites 86 articles, 26 of which can be accessed free at:/content/109/5/1531.full.html#ref-list-1This article has been cited by 11 other HighWire hosted articles, the first 5 are:Brain temperature in multiple sclerosisAnna Pietroboni, Andrea Arighi, Milena Deriz, Elio Scarpini, Daniela Galimberti, NereoBresolin and Mario RangoMult Scler, June , 2014; 20 (7): 894-896.[Full Text] [PDF]Brain temperature in multiple sclerosisAnna Pietroboni, Andrea Arighi, Milena Deriz, Elio Scarpini, Daniela Galimberti, NereoBresolin and Mario RangoMult Scler, October 24, 2013; .[Full Text] [PDF]Heat sensitive persons with multiple sclerosis are more tolerant to resistance exercise thanto endurance exerciseAnders G Skjerbæk, Andreas B Møller, Ellen Jensen, Kristian Vissing, Henrik Sørensen, LarsNybo, Egon Stenager and Ulrik DalgasMult Scler, June , 2013; 19 (7): 932-940.[Abstract] [Full Text] [PDF]Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathyLindsay Horton, Amy Conger, Darrel Conger, Gina Remington, Teresa Frohman, ElliotFrohman and Benjamin GreenbergNeurology, May 14, 2013; 80 (20): 1862-1866.[Abstract] [Full Text] [PDF]Updated information and services including high resolution figures, can be found at:/content/109/5/1531.full.htmlAdditional material and information about Journal of Applied Physiology can be found at: information is current as of June 11, 2014.Journal of Applied Physiology publishes original papers that deal with diverse areas of research in applied physiology, especiallythose papers emphasizing adaptive and integrative mechanisms. It is published 12 times a year (monthly) by the AmericanPhysiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2010 by the American Physiological Society.ISSN: 0363-6143, ESSN: 1522-1563. Visit our website at from on June 11, 2014Heat sensitivity and exerciseAndrea T WhiteMult Scler, June , 2013; 19 (7): 833-834.[Full Text] [PDF]

J Appl Physiol 109: 1531–1537, 2010.First published July 29, 2010; doi:10.1152/japplphysiol.00460.2010.HIGHLIGHTED TOPICReviewMechanisms and Modulators of Temperature RegulationThermoregulation in multiple sclerosisScott L. Davis,1,2 Thad E. Wilson,3,4 Andrea T. White,5,6 and Elliot M. Frohman2,71Department of Applied Physiology and Wellness, Southern Methodist University, Dallas, Texas; Departments of 2Neurologyand 7Ophthalmology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; Departments of 3BiomedicalSciences and 4Specialty Medicine, Ohio University College of Osteopathic Medicine, Athens, Ohio; and 5Department ofExercise and Sport Science and 6The Brain Institute, University of Utah, Salt Lake City, UtahSubmitted 29 April 2010; accepted in final form 22 July 2010Downloaded from on June 11, 2014Davis SL, Wilson TE, White AT, Frohman EM. Thermoregulation in multiplesclerosis. J Appl Physiol 109: 1531–1537, 2010. First published July 29, le sclerosis (MS) is a progressiveneurological disorder that disrupts axonal myelin in the central nervous system.Demyelination produces alterations in saltatory conduction, slowed conductionvelocity, and a predisposition to conduction block. An estimated 60 – 80% of MSpatients experience temporary worsening of clinical signs and neurological symptoms with heat exposure. Additionally, MS may produce impaired neural control ofautonomic and endocrine functions. This review focuses on five main themesregarding the current understanding of thermoregulatory dysfunction in MS: 1) heatsensitivity; 2) central regulation of body temperature; 3) thermoregulatory effectorresponses; 4) heat-induced fatigue; and 5) countermeasures to improve or maintainfunction during thermal stress. Heat sensitivity in MS is related to the detrimentaleffects of increased temperature on action potential propagation in demyelinatedaxons, resulting in conduction slowing and/or block, which can be quantitativelycharacterized using precise measurements of ocular movements. MS lesions canalso occur in areas of the brain responsible for the control and regulation of bodytemperature and thermoregulatory effector responses, resulting in impaired neuralcontrol of sudomotor pathways or neural-induced changes in eccrine sweat glands,as evidenced by observations of reduced sweating responses in MS patients.Fatigue during thermal stress is common in MS and results in decreased motorfunction and increased symptomatology likely due to impairments in centralconduction. Although not comprehensive, some evidence exists concerning treatments (cooling, precooling, and pharmacological) for the MS patient to preservefunction and decrease symptom worsening during heat stress.demyelination; core temperature; sweating; skin blood flow; fatigueMULTIPLE SCLEROSIS (MS) is a disabling progressive neurologicaldisorder affecting 400,000 individuals in the United States.The pathophysiology of MS results in a disruption or loss ofaxonal myelin in the central nervous system (CNS), leading tothe formation of scar tissue (sclerosis). MS is thoughtto involve a number of autoimmune injury cascades that appearto be dependent on the interaction of complex epigenetic andenvironmental factors. Immune responses in individuals withMS are skewed toward a proinflammatory state, resulting ininflammation, demyelination, and ultimately loss of axons anddisorganization of normal tissue architecture within the CNS(23). Demyelination is associated with corresponding changesin axonal physiology, including a loss of saltatory properties ofelectrical conduction, reduction in conduction velocity, and aAddress for reprint requests and other correspondence: S. L. Davis, Dept. ofApplied Physiology and Wellness, Annette Caldwell Simmons School ofEducation and Human Development, Southern Methodist Univ., P.O. Box750382 Dallas, TX 75275-0382 (e-mail: [email protected]).http://www.jap.orgpredisposition to conduction block. These pathophysiologicalmechanisms underlie the myriad of symptoms (Table 1) inindividuals with MS and are contingent on the neuroanatomiclocalization of lesions (23).Autonomic dysfunction involving the genitourinary, gastrointestinal, cardiovascular, and thermoregulatory systems iscommonly observed in MS (29). In addition to autonomicdysfunction, the majority of MS patients experience transientand temporary worsening of clinical signs and neurologicalsymptoms in response to a number of factors, the most prominent of which are increased ambient or core body temperatureand exercise. However, the assessment and understanding ofautonomic dysfunction in individuals with MS is problematicdue to the variability of early clinical symptoms and theheterogeneity in the clinical course over time (Fig. 1). Withthese limitations in mind, this review will focus on our currentunderstanding of the thermoregulatory dysfunction in MSwhile characterizing five main topical themes: 1) heat sensitivity; 2) central regulation of body temperature; 3) thermo-8750-7587/10 Copyright 2010 the American Physiological Society1531

Review1532MS AND THERMOREGULATIONTable 1. Common symptoms of multiple sclerosisMost Common SymptomsFatigueWalking (gait), balance, andcoordination problemsBowel dysfunctionDizziness and vertigoPainEmotional changesSpasticityNumbnessBladder dysfunctionVision problemsSexual dysfunctionCognitive dysfunctionDepressionLess Common SymptomsSpeech disordersSwallowing problemsHeadacheHearing lossSeizuresTremorRespiration/breathing problemsItchingBased on information from National Multiple Sclerosis Society (Ref. 73).regulatory effector responses; 4) heat-induced fatigue; and5) countermeasures to improve function in MS patients duringa thermal stress.HEAT SENSITIVITY IN MSJ Appl Physiol VOLFig. 1. Clinical courses of multiple sclerosis (MS). Adapted from Confavreux andVukusic (11) with permission from Lippincott Williams and Wilkins/WoltersKluwer Health.109 NOVEMBER 2010 www.jap.orgDownloaded from on June 11, 2014The earliest medical reports of thermal sensitivity in MS arederived from Charles Prosper Ollivier d’Angers who noted in1824 that a hot bath induced numbness in the right leg andreduced feeling and dexterity in the hands of a patient with MS(56). However, Wilhelm Uhthoff’s description of this phenomenon occurring after a hot bath or with exercise in MS patientswith a history of optic neuritis has most commonly been citedas the landmark observation of the pathophysiological principle of temperature-induced conduction block in demyelinatedaxonal segments (Uhthoff’s phenomenon) (77). It is estimatedthat 60 – 80% of the MS population experience transient andtemporary worsening of clinical signs and neurological symptoms as a result of elevated body temperature by immersion inwarm water (41– 43 C) or exposure to infrared heating lamps(27, 46, 50, 51).Symptom worsening can result from passive heat exposure,exercise (increase in metabolism), or a combination of heatexposure and increases in metabolism (exercise-heat stress).Both physical (walking, running, driving, writing, etc.) andcognitive (memory retrieval, processing speed, multitasking,etc.) functions can be impaired by heat exposure, greatlyimpacting overall patient safety as well as the ability ofindividuals with MS to perform routine activities of dailyliving, even in mildly affected individuals (57, 59). Symptomworsening has been reported with exercise (78), hot shower(81), and sunbathing (2). Even fluctuations in circadian bodytemperature from the morning to the afternoon can elicitchanges in symptoms (62).In the past, physicians and health care providers instructedMS patients to minimize their exposure to high ambient temperatures and to avoid exercise or intense physical work inorder to avoid symptom worsening. However, lack of exerciseoften results in deconditioning, reduced functional capabilities,increased risk of injury, and less weight-bearing movement,which has consequences on bone and mineral metabolism (59,88). Evidence now indicates that exercise is beneficial toindividuals with MS by improving fitness and sense of wellbeing, reducing fatigue, and increasing strength and safety ofwalking and should be incorporated into their overall diseasemanagement plan (57).Typically, deficits caused by increases in temperature arereversible by removing heat stressors and allowing subsequentcooling. Davis et al. (15) quantified Uhthoff’s phenomenonduring indirect whole body heating and its reversibility withthe subsequent application of active cooling by objectivelymeasuring horizontal eye movement velocities in a group ofMS patients with internuclear ophthalmoparesis, an abnormality characterized by the slowing of the eye moving toward thenose (adduction) during horizontal eye movements. The speedof horizontal eye movements in MS patients with internuclear ophthalmoparesis was slowed from baseline when corebody temperature was raised 0.8 C with whole bodyheating and returned to baseline following 1 h of wholebody cooling (Fig. 2) (15).The precise mechanisms for impaired neural function indemyelinated axons due to increases in temperature are notcompletely understood but are likely due to a combination ofstructural and physiological changes within axons in the CNS(75). With demyelination, increases in temperature can affectthe propagation of action potentials. Increased temperaturemay also influence the electrical properties of the nerve fiber byincreasing the refractory period (partly mediated by potassiumchannel activation and sodium channel inactivation), which

ReviewMS AND THERMOREGULATIONFig. 2. Data from healthy controls (Control; n 8), MS patients withoutinternuclear opthalmoparesis (MS-Control; n 8), and MS patients diagnosedwith internuclear ophthalmoparesis (MS-INO; n 8) showing ocular functionresponses [velocity-versional dysconjugacy index (VDI)] during whole bodyheat stress (increase internal temperature 0.8 C) and subsequent whole bodycooling (return to normothermic baseline). A significant slowing (P 0.001)of horizontal eye movements (increasing velocity-VDI) was observed in MSpatients with INO during whole body heating. However, ocular function wasrestored to preheating baseline with subsequent whole body cooling. Data areexpressed as means SD. Reproduced from Davis et al. (15) with permissionfrom Lippincott Williams and Wilkins/Wolters Kluwer Health.CENTRAL REGULATION OF BODY TEMPERATURE IN MSCompounding temperature-related nerve conduction problems, individuals with MS may have impaired neural control ofautonomic and endocrine functions (30). Thermosensitive neurons of the preoptic anterior hypothalamus process afferentthermal information (central and peripheral) to integrate anddirect autonomic thermoeffector responses (6, 63). Areas of theJ Appl Physiol VOLsympathetic nervous system (hypothalamic area and interomediolateral columns of the spinal cord) that are responsible forcontrolling thermoregulatory function are susceptible to disease-related pathology in individuals with MS (1).Hypothermia has been documented in a small number of MSpatients (18, 42, 44, 74, 83, 87) with core temperatures rangingfrom 30 to 35 C. Hypothermia can be profound but tolerated inMS patients. Lesions within the CNS, specifically the hypothalamus, may impair the homeostatic control of body temperature in individuals with MS and allow for atypical fluctuationsin body temperature (45). Hypothermia may be more commonthan reported and be indicative of more severe disease (87).Fluctuations in body temperature can be problematic for MSpatients when infections have bee