Journal ofNeurology, Neurosurgery, and Psychiatry 1996;61:369-375

Hypothermia in multiple sclerosis

K D White, D J Scoones, P K Newman

AbstractFive patients with clinically definite mul-tiple sclerosis are reported who presentedwith acute relapses associated withhypothermia. Repeated episodes ofhypothermia were seen in four.Thrombocytopenia was associated withthe hypothermia in four patients. Furtherinvestigation disclosed a tendency tochronic hypothermia and suggested an

altered thermoregulatory set point in one

patient, when MRI, endocrine, and auto-nomic studies failed to localise a lesion inthe hypothalamus, but subsequentnecropsy showed hypothalamic lesions.In such patients a predisposition toaltered thermoregulation may occur dueto direct involvement of the hypothala-mus or from combined lesions affectinghypothalamic outflow to the brainstemand spinal cord.

(3 Neurol Neurosurg Psychiatry 1996;61:369-375)

Keywords: hypothermia; multiple sclerosis; thrombo-cytopaenia; hypothalamus

Department ofNeurology,MiddlesbroughGeneral Hospital,Cleveland, UKK D WhiteDepartment ofNeuropathology,Newcastle GeneralHospital, Newcastleupon Tyne, UKD J ScoonesMiddlesbroughGeneral Hospital,Middlesbrough,Cleveland, UKP K NewmanCorrespondence to:Dr K D White, Departmentof Neurology,Middlesbrough GeneralHospital, Middlesbrough,Cleveland, UK.Received 29 January 1996and in revised form23 May 1996Accepted 4 June 1996

The ability of humans to precisely thermoregu-late body temperature around 37°C is a com-

plex process.' 2 Simplified, the system consistsof peripheral thermoreceptors that relay affer-ent signals to central integrating mechanisms.Central and peripheral thermal informationare thought to be integrated at various CNSsites, each of which can facilitate or inhibitother sites, which are hierarchically arranged.Integrators compare the information with thatfrom internal thermosensitive cells and if nec-essary activate behavioural and autonomicmechanisms via efferent channels.3 4 Animalstudies have shown that lower centres includ-ing the brainstem and cervical cord have thecapability to mount independent responses tothermal stimuli.5-8 The hypothalamus acts as

the chief integrator which coordinates theactivity of the other centres. Discrete lesions ofthe anterior hypothalamus can lead to eitherhyperthermia or hypothermia, whereas lesionsin the posterior hypothalamic nucleus tend toproduce hypothermia. Hypothermia may alsooccur when there is damage to the reflex ther-moregulatory pathways traversing the brain-stem or spinal cord.7 9 Reports of disordersof control of temperature in patients with mul-tiple sclerosis are few.'5-2' Although plaques ofdemyelination affecting the hypothalamushave been described at necropsy, this occurs

only rarely22 and there has only been indirectevidence implicating disturbance of this struc-ture in patients with hypothermia.'6 In thisreport we present five cases of multiple sclero-sis in which hypothermia was associated withrelapses in the condition and additionallynecropsy evidence of involvement of the hypo-thalamus in one patient with recurrenthypothermia.

Case reportsCASE 1A 48 year old man with clinically definite mul-tiple sclerosis for five years (Kurtzke disabilityscale 6)23 was admitted in December 1991.Since diagnosis he had experienced severalrelapses with clinical involvement of the spinalcord and brainstem with some response tosteroid treatment. During a two year period ofazathioprine treatment, there had been areduction in the number of relapses and nohaematological abnormality had beendetected. After this two year period the aza-thioprine was discontinued. Three monthslater he required admission because of threeweeks of deteriorating mobility, with slurredspeech, confusion, and disorientation. For 10days before admission, he had becomeincreasingly withdrawn and drowsy. In retro-spect his wife had noticed that he had startedto snore at night and that his feet were unusu-ally cold.On admission he was in stupor; there was

increased tone in the upper limbs and a flaccidparaparesis. The axillary temperature was36°C. An initial diagnosis of acute relapse ofmultiple sclerosis was made and he wastreated with intravenous methylprednisolone.Haemoglobin was 12-7 g/dl, white blood cells8-7 x 109/1, platelets 27 x 109/1, serumsodium 140 mmol/l, and urea 8-9 mmol/l.Treatment was started with cefuroxime on theassumption that there may have been a precip-itating infection from the urinary tract. Over48 hours he steadily deteriorated, becomingmute, with neck stiffness, agitation, repetitivefacial twitching, left lower motor facial weak-ness, and decerebrate posturing. Haemoglobinwas 9-9 g/dl, white blood cells 5-8 x 109/1, andplatelets 19 x 109/1. Brain CT showed a mod-erate degree of cerebral atrophy; CSF was nor-mal. A fall in respiratory rate was followed byperiods of apnoea, whereupon ventilatory sup-port was commenced and continued for 11days. At the start of assisted ventilation rectaltemperature was 31°C. Rewarming returnedthe core temperature to normal within 48

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hours and a return to normal conscious leveloccurred after four days. Thrombocytopaeniapersisted for 10 days. Excessive bleeding fromaround central and peripheral lines (pro-thrombin time (PT) ranging from 13-16 sec-onds and kaolin cephalin clotting time(KCCT) 49-56 seconds, platelet antibodiesabsent) necessitated transfusion of packedcells, platelets, and plasma protein fraction.Vitamin B 12 was normal (690 nmol/l) butblood folate (1 4,ug/i) and red cell folate(66 pg/l) were low. The bone marrow showedincreased megakaryocytes and features whichwere consistent with folate deficiency.Autoantibody titres (including antinuclear fac-tor, rheumatoid factor, antimitochondrial, gas-tric parietal cell, smooth muscle, reticulin,thyroid microsomal, thyroglobulin antibodies)were negative.

Recovery rapidly ensued but the patient wasleft with a residual spastic paraparesis and sen-sory level to T 12, mild upper limb weakness,and incoordination. He returned home 30days after admission and within two weeks hadreturned to work and was able to walk shortdistances with a stick. On discharge haemoglo-bin was 13-2 g/dl, white blood cells 7-6 x 109/l,platelets 208 x 109/l.

Six weeks after discharge the patient wasreadmitted after a recurrence of the originalsymptoms, with slurred speech, forgetfulness,and lethargy. Rectal temperature was 32 3°C.Neurologically there was facial asymmetry, leftupper limb incoordination, and a worsening ofthe spastic paraparesis. Thrombocytopeniaand clotting abnormalities were again docu-mented (platelets 84 x 1 09/1, prothrombintime 13 s, KCCT 60 s) which corrected withrewarming. Close observation of rectal tem-perature over six days disclosed an inversion ofthe normal circadian rhythm, with a peak of37'C between 6 00 and 10 00 am and lowesttemperatures between 6 00 and 10 00 pm.More detailed thermoregulatory studies weredeclined by the patient. At discharge 14 dayslater platelets had risen to 294 x 109/l andwhite blood cells to 9-9 x 109/1, but a slightfall in haemoglobin to 10-3 g/dl was noted.Over subsequent months rectal temperaturemeasured at home ranged from 35 to 36 5°C.At temperatures above this there was a pro-nounced decline in functional lower limbpower, from weight bearing to non-weightbearing.

Brain MRI in 1987 had been normal.Repeat imaging after both episodes ofhypothermia, including administration ofgadolinium on the second occasion, showedmultiple high signal lesions in the periventricu-lar white matter, but no plaques were detectedin the region of the hypothalamus. No evi-dence of hypopituitarism was detected on for-mal dynamic endocrinological assessment.Blood pressure and heart rate response toValsalva's manoeuvre and blood pressureresponse to standing were normal. There wereborderline abnormalities of the 30:15 heartrate response to standing and beat to beat vari-ation on deep breathing was reduced to a heartrate change of 8-5 beats per minute.

For the first year after these episodes thepatient's condition remained stable. However,hypothermia became a recurrent problem inthe winter months followed by further deterio-ration with dysmnesia, periods of confusion,hypersomnolence leading to dementia, apha-gia, and subsequent death. At necropsy thebrain weighed 1350 g and showed no externalabnormality. Plaques of demyelination werefound in the typical periventricular distribu-tion as well as in the midbrain, pons, andmedulla. In addition there were plaquesthroughout the hypothalamus including thearea of the posterior hypothalamic nucleus(figure).

CASE 2A 59 year old man with a 30 year history ofmultiple sclerosis (clinically definite and labo-ratory supported, Kurtzke disability score 7),who was previously noted to have a spasticparaparesis, cerebellar signs, and milddysarthria, presented in November 1993 withan insidious onset over four weeks of increas-ing fatigue, lethargy, and slowness of thought,which progressed to increasing drowsiness,dysphagia, and dysarthria. On admission hewas in stupor with a rectal temperature of33°C. Investigations showed a platelet countof 94 x 1 09/1, haemoglobin 11 5 g/dl, whitecell count 7 0 x 109/l, and serum sodium 142mmol./l. He was treated with passive rewarm-ing and intravenous fluids and normothermiawas achieved within 36 hours. Despite a fur-ther fall in platelets to 79 x 10/l after 24hours, the platelet count returned to normalwithin four days. His clinical recovery wascomplicated by a paranoid psychosis andconfusion for 17 days, severe left ventricular

.*- pn

v

mb

Section through half of the hypothalamus at the level of themammillary bodies. (Luxolfast blue and cresylfast violetoriginally x 5.) Section shows two areas of demyelination.p = Plaques; pn = posterior nucleus of hypothalamus; v =

third ventricle; mb = mammillary body.

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failure, and myocardial infarction. Core tem-perature remained normal throughout thistime. The disability status at discharge hadincreased to Kurtzke scale 8 and mentally heremained rather vague and intermittently con-fused. One further episode of hypothermia hassince been treated.

CASE 3A 57 year old woman with a 20 year history ofclinically definite multiple sclerosis (Kurtzkedisability scale 7) was admitted in March 1992with deteriorating mobility, lethargy, andintermittent dysphagia. On admission she wasoriented but over two weeks her consciouslevel deteriorated. Skin temperature was nor-mal. On transfer to the neurology unit shewould open her eyes spontaneously andlocalise pain, but the only verbal response wasgrunting. There was bilateral optic atrophyand absence of oculocephalic responses but noother specific cranial nerve abnormalities. Shehad pronounced neck stiffness, general rigid-ity, and a spastic tetraparesis. Her core tem-perature was 35°C. She was rewarmed, givenintravenous fluids, methylprednisolone, andantibiotics for respiratory and urinary infec-tions. The temperature returned to normalwithin 24 hours. On admission haemoglobinwas 12K1 g/dl, white cells 11-5 x 109/l, andplatelets 141 x 109/l. Mild hyponatraemiawas noted (serum sodium concentration130 mmol/l). Plasma viscosity was increased at2 17 cp. Clotting was abnormal with a slightprolongation of KCCT of 52 seconds and aminor increase in fibrin degradation productsat 1 0 ug/ml (normal < 0 5 ug/ml). A tran-sient thrombocytopenia of 99 x 109/l becameapparent 24 hours after admission andreturned to normal within 48 hours. An EEGwas abnormal at the time of reduced consciouslevel, with diffuse delta and theta slow waveactivity. Brain CT disclosed bilateral periven-tricular low density lesions in keeping with herlongstanding multiple sclerosis. Protein inCSF was normal. Platelet associated antibodywas raised at a level of 2-2 (normal < 1-6),antinuclear factor was positive with a speckledpattern at a titre of 1:160, with DNA antibod-ies negative and rheumatoid factor positive ata titre of > 1:320. IgM anticardiolipin anti-body binding was borderline positive but IgGwas negative. After improvement in consciouslevel she remained confused for nine daysbefore regaining her premorbid mental state.A return to her previous physical level of func-tion was achieved after one month. A secondepisode of hypothermia occurred nine monthslater and was detected after one week of pro-gressive lethargy and dysarthria. Her rectaltemperature was 34°C and she was consciousand oriented, although slightly slow inresponses and confused. Neck stiffness wasabsent. There was evidence of a right internu-clear ophthalmoplegia, cerebellar dysarthria,spastic tetraparesis, and upper limb cerebellarsigns, all of which were longstanding. Withrewarming there was an improvement in men-tal function and she was discharged after onlysix days. This patient's disease was of long

duration and clinically typical of multiple scle-rosis with early relapses and remissions.Whether the presence of the autoantibodies isrelevant is uncertain given the patient's age,but the pattern of early relapses and remis-sions was considered to be more in keepingwith a diagnosis of multiple sclerosis thancerebral lupus erythematosus. Cerebral lupuserythematosus seemed less likely in view of thenegative double stranded DNA antibodies,negative IgG anticardiolipin antibody, normalcompliment levels, and the distribution of thelesions on CT. Extraneurological features,particularly polyarthropathy, had never beenpresent.

CASE 4A 64 year old woman with clinically definitemultiple sclerosis for 30 years (Kurtzke dis-ability scale 9) was admitted in November1993. Since diagnosis she had had manyrelapses and remissions with involvement ofoptic nerves, spinal cord, and brainstem. Overthe previous eight years there had been a pro-gressive physical decline. On this occasion shepresented with a three month history of deteri-orating upper and lower limb function,episodes of speech disturbance, and peripheraloedema. Three days before admission she wasfound unconscious and at her local hospitalher conscious level remained depressed for 12hours before there was a spontaneous, fluctu-ating, improvement. On transfer the rectaltemperature was 34-7°C, she was alertalthough disoriented, with peripheral and peri-orbital oedema, optic atrophy, and nystagmus.Impaired palatal movement was a new featureand there had been a significant deteriorationin the tetraparesis. Mild hyponatraemia(sodium concentration 130 mmol/l) was notedwith normal urinary and plasma osmolalities,which corrected with fluid restriction. Cortisoland thyroid function were normal. Full bloodcount was normal. An EEG showed diffusedelta and theta activity which improved onrewarming. Temperature returned to normalwithout active treatment within 24 hours,although her mental state did not return tonormal for seven days. Her functional capacityhad returned to its previous level by the timeof discharge. No further episodes of hypother-mia have occurred.

CASE 5A 47 year old woman was admitted to a med-ical unit with a few days history of withdrawal,lethargy, and then lapsing into coma. She hadled a reclusive existence, and 12 years earlierhad been admitted to a psychiatric unit withblurred vision, sensory symptoms, and diffi-culty in walking, labelled as hysterical in viewof associated psychological disability. On thecurrent admission she was unrousable, hadneck stiffness, generalised hypertonia, and arectal temperature of 290C. There was no evi-dence of drug overdose and her biochemistry,including thyroid function and cortisol, wasnormal. Haemoglobin concentration was10-2 g/dl, white cell count 8-5 x 109/l,platelets 33 x 109/l, and serum sodium con-

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centration 143 mmol./l. Gentle rewarming ledto a gradual return to normothermia overthree days, at which time she was consciousbut confused and neurological evaluationshowed bilateral optic disc pallor, mild limbincoordination, mild paraparesis, and bilateralextensor plantar responses. The platelet countreturned to normal. Subsequent investigationshowed bilateral delay of P,00 latency of visualevoked potentials and a high CSF IgG indexwith oligoclonal bands in the CSF but not inthe serum. Brain MRI showed diffuse corticalatrophy with multiple hyperintense periven-tricular lesions on T2 weighted sequences butwithout abnormality in the region of the hypo-thalamus. Initially EEG showed a generalisedencephalopathic picture with widespread thetaand delta activity, but this subsequentlyimproved to a mixture of alpha and theta com-ponents. Chest radiography was normal andautoantibodies were negative.On discharge from hospital after one month

the patient was normothermic, disinhibited,and garrulous with mild cognitive blunting.She had slight gait ataxia, pale optic discs, anda right extensor plantar response.Thus this patient had presented with

hypothermia and a new diagnosis of multiplesclerosis was made after a review of the his-tory, the current neurological findings, andresults of investigations. A second episode ofhypothermia occurred 11 months later afterone week of increasing drowsiness, anorexia,and unsteadiness. Her rectal temperature was34°C and she was drowsy and confused.There was nystagmus on horizontal gaze,decorticate posturing of the upper limbs, and aspastic tetraparesis with bilateral extensorplantar responses. Core temperature returnedto normal after 48 hours and she was dis-charged eight days later with return to her pre-vious neurological status.

DiscussionImpairment of consciousness in multiple scle-rosis is well recognised, ifuncommon, but pre-viously only seven patients have been reportedwith relapses of their multiple sclerosis withobtundation which has been associated withhypothermia. 15-1820 We present four patientsseen in a three year period from one neurologyunit and a fifth case from a nearby unit, whichled us to believe that it is probably more com-mon than previously recognised. The patientsshare common features which might suggestwhich are more at risk of this complication. Allof our patients presented with an insidiousneurological decline, associated withdepressed conscious level and considerablehypothermia. Each had multiple sclerosis of atleast five years duration and all but one werevery disabled (Kurtzke EDSS > 6). All dis-played signs during the acute relapse suggest-ing an active lesion in the brain stem and infour patients signs consistent with brainsteminvolvement had previously been noted. Fromthe available histories it is likely that the peri-ods of hypothermia exceeded one week. Allresponded to rewarming within 48 hours.

Improvement in cognitive function laggedbehind establishment of normothermia, withconfusion persisting for up to 17 days. Fourpatients had repeated episodes of hypothermiaand in two chronic hypothermia developed.Normal thermoregulation relies on periph-

eral thermoreceptors in skin and the uppergastrointestinal tract, which send afferent sig-nals via the cervical cord, brainstem, and thal-amocortical system to the cortex for consciousappreciation of ambient temperature.'Thermoregulation occurs at several levels orcentres, the hypothalamus, including the pre-optic area, the anterior and posterior hypothal-amus, brainstem, and cervical cord.'-6 Afferentcold impulses synapse in the posterior hypo-thalamic heat maintenance centre, not onlywith efferent pathways initiating heat produc-tion but also with cells which receiveinhibitory impulses from the anterior hypo-thalamus in response to local warming. Theanterior hypothalamic heat loss centre is situ-ated near the preoptic nuclei and destructionof this area in animals results in normal tem-perature in cold but overheating in hotenvironments.7 8 The anterior hypothalamicefferent impulses for heat dissipation aremediated by the sympathetic nervous system,which induces sweating and vasodilatation.The site of the thermostat in humans has beenvariously considered to be in either the ante-rior or posterior hypothalamus and even thewhole brainstem.' Reflex thermoregulatorypathways that function independently of thiscentral control have been shown to passthrough the brainstem and cervical cord.4 Theraphe nuclei are key sites for the integration ofperipheral and central thermal stimuli, and inprocessing information ascending to the pre-optic/anterior hypothalamic area (POAH).Many of these neurons seem to be warm sensi-tive.9 Animal studies provide evidence for pre-dominantly cold responsive neurons in thepontine dorsomedial reticular formation of theguinea pig'° and in the rat the medulla itselfhas cold receptors, which when damagedresult in chronic hypothermia.7 Thermo-regulation studies on lesions in rat brains con-cluded that communication between thepreoptic(PO) and anterior hypothalamic(AH)nuclei is necessary for normal thermoregula-tion at extremes of temperatures and similareffects to those seen with destruction of thePO/AH could be produced by cutting theneural connections between the PO/AH andother brain structures. However, a secondarycentral temperature control system was indi-cated by the ability of the rats to maintainregulation of temperature in a neutral environ-ment despite large lesions destroying themedial preoptic region and the anterior hypo-thalamic tissue. Isolated lesions of the medullaresulted in a profound fall in body tempera-ture in some animals, inability to regulateagainst cold rather than heat in others, and areduction of resting body temperature in someanimals.7 Other studies in rats suggested thatlesions which prevented cold induced vaso-constriction but did not impair heat inducedvasodilatation must be separately controlled at

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Clinicalfeatures ofpatients with hypothermia and multiple sclerosis

Reference Kurtzke Rectal temp Neck Conscious Brain stem Platelet count RecurrentPatient No No Agelsex score (OC) stiffness Myoclonus level signs x 109/l hypothermia

1 15 61/F 10 29-4 NK NK + + + Yes 19 No2 16 41/F 7 32-9 No No + NK 61 Yes3 16 52/F 8 31-0 No No + + + NK 50 Yes4 17 55/F 6 33-0 Yes Yes + + + No 80 Yes5 17 52/M 7 32-5 No No + Yes 100 Yes6 17 49/F 6 32-0 Yes Yes + No Normal Yes7 18 38/F 6 32-0 No No + + Yes Normal Yes8 20 63/F 4 32-4 NK No + + NK Normal No9 20 68/F 6 31-6 NK No + + Yes Normal No

10 * 48/M 6 31-0 Yes Yes + + Yes 27 Yes11 * 59/M 7 33-0 No No + + Yes 95 Yes12 * 57/F 7 35-0 Yes No + + Yes 99 Yes13 * 64/F 9 34-7 No No + Yes 172 No14 * 47/F 3 29-0 Yes No + + + Yes 33 Yes

*Patients in current series. Conscious level: + = confused, + + = stupor, + ++ = coma; NK = not known.

a site more caudal than the POAH, possibly inthe medulla.8 Based on electrical stimulationof the CNS and lesion studies it has been pro-posed that thermoregulation involves the con-nection of multiple integrators and multiplethermostats at many levels of the neuraxiswhich have evolved to enable very fine controlof temperature regulation.2 That this is likelyin humans is suggested by the array of differ-ent neuroanatomical sites associated withhypothermia. It is well documented thatpatients with high cervical cord injury candevelop hypothermia due to impaired periph-eral sensitivity to ambient temperature, lack ofshivering response, and lack of vasoconstric-tion when lesions above Ti are present.25Hypothermia is recognised in various neuro-logical disorders other than multiple sclero-sis.2"0

O'Brien et al'5 reported a patient with ter-minal multiple sclerosis and hypothermia,stressing the haematological effects of hypo-thermia, but not the possible causative linkwith multiple sclerosis. Sullivan et al'6 firstreported hypothermia associated with multiplesclerosis in two patients. Lammens et al 17reported three patients with whom hypother-mia was associated with both exacerbation ofpre-existing and the development of new neu-rological signs. Geny et a120 reported hypother-mia in two patients with multiple sclerosis.Both had cerebellar and pyramidal signs, con-fusion, and psychomotor slowing and one alsodeveloped a partial lateral rectus palsy.Neither had any history of alcoholism orsevere dietary restriction, although one hadrefused meat for a month. Despite the fact thatthese signs could be accounted for by a combi-nation of multiple sclerosis and hypothermia,Geny et al concluded that both patients hadWernicke's encephalopathy.20 Further evi-dence for this was proposed by the poor initialresponse to passive rewarming and subsequentnormalisation of temperature on day two aftertreatment with thiamine. It could be arguedthat this was a coincidence as normalisation ofcore temperature after pronounced hypother-mia does not occur in 24 hours and may haveoccurred despite the thiamine. However, inone patient when thiamine was withdrawnthere was a pronounced drop in core tempera-ture which returned to normal with the rein-troduction of thiamine. This has been notedpreviously.37

Ghawache and Destee'8 reported a patientwho had three separate episodes of hypother-mia 14 years after the onset of multiple sclero-sis. Hypothermic episodes correlated closelywith aggravation of spastic paraparesis and aconsistent inappropriate antidiuretic hormonesecretion. Brain MRI did not show any evi-dence of hypothalamic plaques and there wasno other endocrine evidence of hypothalamicdisturbance. Unlike our patients, there was nosignificant deterioration in clinical status afterthe hypothermic episodes. By contrast, ther-moregulatory abnormality resulting in hyper-thermia has been reported in multiple sclerosisand in one case pathological evidence wasfound of plaques involving the lateral and pos-terior hypothalamus.19 The table summarisesclinical data from patients with multiple scle-rosis and hypothermia.

In a condition in which there are known tobe multiple lesions it is difficult to implicate asingle anatomical site as being responsible forthe thermoregulatory abnormality. Sullivan eta!20 presented evidence of a central thermoreg-ulatory centre lesion with a fall in core temper-ature and a restricted skin vasoconstrictorresponse to cooling in their patients. Thehyponatraemia seen in one patient suggestedthat the lesion was likely to lie in the hypothal-amus. In our patients thermoregulatory stud-ies were not possible. An inversion of thenormal circadian rhythm of temperature wasseen in the first case, suggesting a central dis-turbance but MRI on two occasions afterepisodes of hypothermia did not show anylesions in the region of the hypothalamus, anegative finding also noted by Geny et al 20 andLammens et al. l7 Furthermore, postmortemexamination in one of the patients failed toshow any hypothalamic plaques. Similarly in apostmortem report by Nagashi et al2' of apatient with coexistent pituitary hypothy-roidism and Devic's disease no lesions wereseen involving the hypothalamus. As far as weare aware patient 1 is the first reported patientin which hypothermia has occurred with multi-ple sclerosis and subsequent necropsy hasshown direct involvement of the hypothalamusby plaques of demyelination. We think that itis possible that in some patients the ther-moregulatory abnormalities are due to brainstem disease, for which clinical evidence wasseen in all of our patients. In patient 1 therewere also borderline abnormalities of auto-

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nomic function. Previous studies of autonomicfunction in patients with multiple sclerosishave shown that abnormalities of cardiovascu-lar regulation and thermoregulatory sweatingare common, and abnormal sweatingresponses correlate with more severe diseaseor presence of impotence44143 and brainstemdisease.44 In syringomyelia and syringobulbiasubclinical disturbances of autonomic func-tion were commonly found when there wasevidence of brainstem involvement.45 Isolatedlesions of the brainstem producing hypother-mia have occurred with central pontine myeli-nolysis" and mesodiencephalic haematoma.1'Brainstem involvement was a common featureof our patients, not in itself unusual, butsuggesting that such patients with widespreaddisease may have a predisposition to hypother-mia, related to brainstem disease, impairedperipheral response, lack of shivering with cer-vical cord involvement, and possibly involve-ment of the preoptic/anterior hypothalamicjunction and are associated with a poor out-come.

Thrombocytopenia as seen in patients withhypothermia and multiple sclerosis has beenreported in other cases of accidental and spon-taneous hypothermia.4647 Initially noted inearly cardiac surgery patients who were cooledto 20°C, it is thought to occur due to seques-tration of platelets in the spleen as was shownin studies of labelled platelets in dogs.4849However, in patients with recurrent hypother-mia there may be a deleterious effect onhaemopoiesis causing thrombocytopenia.'5Information on patients in intensive care unitssuggests that hypothermia may contribute tothe multifactorial coagulopathy seen in thecritically ill multiple transfused patient.50 Atemperature effect on the enzyme coagulationcascade is implied. In a patient with multiplesclerosis and thrombocytopenia occulthypothermia should be considered.

In conclusion we have reported five patientswith multiple sclerosis who presented over athree year period and had relapses associatedwith subacute hypothermia followed bychronic hypothermia in two cases. This com-plication may be more widespread than previ-ously recognised and relates to duration ofdisease and possibly presence of brainsteminvolvement. Complaints of drowsiness, con-fusion, and snoring should lead to recording oftemperature with a low reading rectal ther-mometer. Thrombocytopenia may be an indi-cator of unsuspected hypothermia.We thank Dr RA Shakir, Dr P Tilley, and Dr TJ Walls forallowing us to report on their patients and to Dr DJ Burn forhis helpful comments on this manuscript.

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2 Hensel H. Principles of temperature regulation. In:Thermoreception and temperature regulation. London:Academic Press, 1981:5-17. (Monographs of the Physio-logical Society No 38.)

3 Satinoff E. Neural organization and evolution of tempera-ture regulation in mammals. Science 1978;201:16-22.

4 Hensel H. Central thermoregulatory connections. In:Thermoreception and temperature regulation. London:Academic Press, 1981:139-54. (Monographs of thePhysiological Society No 38.)

5 Jessen C. Thermal afferents in the control of body tempera-ture. In: E Schoonbaum, P Lomax, eds. Thermo-regulation, physiology, and biochemistry. London:

Pergamon Press, 1990:153-84.6 Crawshaw LI, Wollmnuth LP, O'Connor CS, Rausch RN,

Simpson L. Body temperature regulation in vertebrates:comparative aspects and neuronal elements. In: ESchoonbaum, P Lomax, eds. Thermoregulation, physiol-ogy, and biochemistry. Pergamon Press, 1990:153-84.

7 Upton JM, Dwyer PE, Fossler DE. Effects of brainstemlesions on temperature regulation in hot and cold envi-ronments. Am J Physiol 1974;226: 1356-7.

8 Gilbert T, Blatteis CM. Hypothalamic thermoregulatorypathways in the rat. JApplPhysiol 1977;43:770-7.

9 Gordon CJ, Heath JE. Integration and central processing intemperature regulation. Ann Rev Physiol 1986;48:595-612.

10 Hinkel P, Schroder-Rosenstock K. Responses of pontineunits to skin-temperature in the guinea pig. Jf Physiol1981;314:189-94.

11 D'Anglejan Chatillon J, Broussier PM, Boukobza M,Pannier I. Hypothermie au cours d'un syndrome deGayet-Wemicke et myelinoysee centropontine infraclin-ique. La presse medicale, 1988;17:1858.

12 Gaymard G, Cambon H, Dormont D, Richard A,Derouesne C. Hypothermia in a mesodiencephalichaematoma. J7 Neurol Neurosurg Psychiatry 1990;53:1014-7.

13 Pledger HG. Disorders of temperature regulation in acutetraumatic tetraplegia. J7Bone Joint Surg 1962;44: 110-3.

14 Menard MR, Hahn G. Acute and chronic hypothermia in aman with spinal cord injury: environmental and pharma-cologic causes. Arch Phys Med Rehabil 1991;72:421-4.

15 O'Brien H, Amess JAL, Mollin DL. Recurrent thrombocy-topenia, erythroidhypoplasia and sideroblastic anaemiaassociated with hypothermia. Br 7 Haematol 1982;51:451-6.

16 Sullivan F, Hutchinson M, Bahandeka S, Moore RE.Chronic hypothermia in multiple sclerosis. J NeurolNeurosurg Psychiatry 1987;50:813-5.

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