Journal ofNeurology, Neurosurgery, and Psychiatry 1981 ;44:1094-1099

Spontaneous periodic hypothermia with lipoma of thecorpus callosumGD SUMMERS, AC YOUNG, RA LITTLE, HB STONER, WSTC FORBES,RAC JONES

From the Department of Neurosciences, Salford Royal Hospital anid the MRC Trauma Uniit, University ofAManchester

SUMMARY A patient with spontaneous periodic hypothermia who had both a lipoma and agenesisof the corpus callosum is described. Spontaneous periodic hypothermia associated with corpuscallosum abnormalities is a distinct entity and although the mechanism underlying the hypothermicepisodes is unexplained, the term "diencephalic autonomic epilepsy" does not seem appropriate.

Spontaneous periodic hypothermia is a rare conditionin which episodes of severe hypothermia areprecipitated by profuse sweating. Penfield' intro-Juced the term "diencephalic autonomic epilepsy"to describe a patient with attacks of hypothermia,headache, hiccough, sweating and salivation ina terminal illness from a third ventricular tumour.This term has been applied to patients with spon-taneous periodic hypothermia. However, only12 cases have been described (table) and a stereotypedsyndrome emerges differing substantially fromPenfield's patient. This syndrome is a chronic one,often beginning in childhood or early adult life andprogressing very slowly. Agenesis of the corpuscallosum is almost the hallmark of the condition,being found in seven out of nine patients who hadadequate investigations. The association of callosalagenesis and periodic hypothermia has been termed"Shapiro's'syndrome".6 We report a patient with thissyndrome in whom a lipoma and agenesis of thecorpus callosum were demonstrated by a computedtomographic scan (CT scan).

Case history

A 44-year-old unmarried man was admitted in January1980 for the investigation of recurrent episodes of stuporassociated with profuse sweating and hypothermia.Sweating attacks started in his teens and from 1969 therewere numerous admissions to general and psychiatrichospitals. During three years in this region he had sevenhospital admissions because of hypothermia. Admissionswere mainly in winter and recovery took 2-6 weeks.

Address for reprint requests: AC Young, Salford RoyalHospital, Chapel Street, Salford M60 9EP, UK.Received 3 June 1981. Accepted 7 August 1981

Profuse sweating for several days had been noted duringone of them.When two years old he had sustained a fractured skull

in a road traffic accident. His physical development wasnormal but he was mentally slow and had attended aspecial school. He had worked in a furniture factory fornearly 20 years, eventually being forced to retire by illhealth. For at least 6 years he had major seizures treatedwith Phenytoin 100 mg twice daily. On examination hewas thin with a normal male distribution of body hair.He was alert and orientated but below average intelligence(WAIS IQ= 75). He had mild dysarthria with exag-gerated reflexes in the left arm and bilateral extensorplantar responses. After three weeks in hospital, duringwhich he was well and ambulant with an oral temperaturebetween 35 0°C and 36 5°C, blood pressure 120/80mmHg and pulse rate 60 per minute, he suddenlydeveloped profuse sweating accompanied by cutaneousvasodilatation which affected the whole body surface. Hecomplained of feeling hot and after 2 hours continuoussweating his oral temperature was 31 0°C. Any rise inbody temperature provoked further attacks of sweatinglasting 30 minutes to several hours and with each attackthe rectal temperature fell, often as low as 29 5°C (fig 1).Two days after the onset of sweating the patient becamelethargic and withdrawn. His dysarthria increased, hehad marked truncal ataxia and flapping tremor of theoutstretched hands. After 4 days he was unresponsive andincontinent. Systolic blood pressure varied between75-100 mmHg with marked bradycardia, sometimes asslow as 40 per minute. The ECG showed typical J-waves.Five days later his body temperature returned abruptlyto his normal level. His physical and mental staterecovered after two days. Seven days later he had asimilar sudden episode of sweating and hypothermiawhich lasted 8 days. His hospital course was marked byalternating periods of relative normality and sweatingwith hypothermia. Shivering was never seen. Severalmajor and left sided focal motor attacks occurred during

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36-35-

Y 34-a4,E 33.E 32-A,

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Fig I showing that episcdes of severe sweatingcoincided ivith each rise in body temperature producintga set-point which is lower than normal.

Sweating Sweating

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Fig 2 (continued in next column)

the hypothermic periods. When cellulitis developed inthe left buttock the temperature rose to 40°C, but he didnot sweat.

Investigations revealed a normo-hromic, normozyticanaemia with a haemoglobin between 8 and 12 g/dl.There was an intermittent leucopenia (2 x 109/l) anda mild thrombocytopenia (137 x 109/l). Serum iron, totaliron binding capacity, folate and B12 levels were normaland marrow aspiration showed dyserythropoiesis similarto that seen in the anaemia of chronic disorders. Sweatingepisodes were associated with a marked hyponatraemia(serum sodium 124-126 mmol/l) and a fall in serumosmolality. There was a corresponding fall in urineosmolality, urine sodium, urine volume and creatinineclearance with improvement as the sweating subsided(fig 2). Liver enzymes rose in parallel with the severity and

Fig 2 (continued)150

Creatinine 100clearancee(ml/min) 50

500Osmolality 400(mO s ml kg) 300

200100

14 21 28

N..Plasma /R

osmolality _

/,

14 21 28251

Urine volume 2-0(litre/24hrs) 1.5

1.005

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Urine sodium 300' _(mmol/24hrs) 2004

100Cc I5C

14 21February

Fig 2 showing changes in the serum and urineparameters during episodes of hypothern;ia.

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length of the hypothermic episode. Before one episode ofhypothermia, some additional metabolic and physio-logical tests were carried out. Mean skin and coretemperatures were already lower than normal, 30-1°Cand 35 2°C respectively, giving a whole body temperatureof 32 5°C. The resting energy expenditure was 34-6kcal m-2 h-1 which was 4-4% below his predicted rate butwas higher than that rate corrected for the lower bodytemperature. Tests of autonomic cardiac control showedthat his pulse rate was not altered by such stimuli as deepinspiration, a head up tilt or a Valsalva manoeuvre. Atthe time of these tests the plasma glucose, lactate andinsulin concentrations were 4-4 mmol/l, 1 36 mmol/l and22 ,AU/ml respectively. Later while the temperature wasfalling these values were 5-72 mmol/l, 2-10 mmol/l and27 /AU/ml (expected changes). An oral glucose tolerancetest between episodes was within normal limits. Theurinary normetanephrine and 5-hydroxyindole aceticacid concentrations were repeatedly normal. There wasno evidence of abnormality of the hypothalamic pituitaryaxis as judged by the results of TRH and FSH/LHRHstimulation tests and there was a normal circadian rhythmof the plasma cortisol.

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Summers, Young, Little, Stoner, Forbes, Jones

Table Reported cases ofspontaneous periodic hypothermia

Author(s) Lesion Sex Age of Seizures Pituitaryonset o dwvarfismswveating

Hines and Bannick (1934)2 ? M 12 yr - -Hoffman and Pobirs (1942)3 ? M 33 yr - -

Duff et al (I1961)4 ? M 10 yr - -Shapiro et al (1969)5 Agenesis of corpus callosum F 19 yr - -

Shapiro et al (1969)5 Agenesis of corpus callosum F 9 yr - -

Guihard et al(1971)6 Agenesis of corpus callosum M 11 yrFox et al (1973)' Normal pneumoenceph F 46 yrNoel et al (1973)8 Agenesis of corpus callosum M 25 yrThomas and Green (1973)9 Normal pneumoenceph. F 38 yrDutau et al (1975)"° Agenesis of corpus callosum M 6 mth tSadowsky and Reeves (1975)" Agenesis of corpus callosum M 18 yrCarr-Locke and Millac (1977)12 Agenesis of corpus callosum F 8 yrPresent case Lipoma and agenesis of corpus callosum M 16 yr

The EEG during an episode of hypothermia showeddiffuse symmetrical delta activity but between attacksthere was only a slight excess of theta activity. Chest andskull radiographs, including coned lateral views of thepituitary fossa were normal. A CT brain scan showeda discrete area of fat density just to the right of themidline at the anterior end of the corpus callosum in theposition normally occupied by the genu. There wasevidence of agenesis of the corpus callosum (fig 3). A rightcarotid arteriogram showed the branches of the anterior

Fig 3 CT Brain scan (a) axial view (b) sagittalreconstruction. Area offat density immediately to theright of the midline with widely separated and abnormalbodies of the lateral ventricles. The lipoma is shown to bein the position of the genu.

cerebral complex to be more separate and straighter thannormal and coursing superiorly in a diagonal radiatingpattern towards the convexity. The pericallosal arterywas shown to be very low in position and the internalcerebral vein high (fig. 4).

In attacks the patient was wrapped in blankets and thesweat removed frequently to prevent evaporation on theskin. The severe hyponatraemia was treated with normalsaline given intravenously. To finally exclude any remedi-able lesion a neuro-surgical exploration of the area usinga microsurgical technique was carried out via a coronalincision and restricted sagittal approach by division of thefalx anteriorly. No true corpus callosum was identifiedand no mass lesion could be seen. The exploration wastherefore terminated without biopsy or other procedure.Post-operatively there was no change and he continuedto suffer frequent episodes of prolonged hypothermia.

Discussion

This patient is an example of a rare but increasinglyrecognised syndrome which is one cause of spontan-eous hypothermia. Clinically it is characterised byattacks of profuse sweating and hypothermia oftenleading to stupor or coma. Investigation of themajority of patients reveals agenesis of the corpuscallosum. This is the first recorded case of spontan-eous hypothermia associated with a lipoma andagenesis of the corpus callosum. Lipoma of thecorpus callosum is a rare tumour accounting for lessthan 0 05% of all brain tumours13 and in nearly 50%of cases there is associated agenesis of the corpuscallosum.14 The tumour is asymptomatic in approxi-mately 50% of cases'5 16 but epilepsy, hemiplegia,dementia and headaches are common modes ofpresentation.13-16 There are no previously recordedcases of lipoma of the corpus callosum with periodichypothermia but Zettner and Netsky14 record thatdiencephalic syndromes such as dystrophia adiposo-genitalis, hypothermia and irregularities of menstru-ation may occur.

Agenesis of the corpus callosum is not believed tobe the cause of the spontaneous hypothermia217

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Diabetes Precocious Mental Hypotonia Cranio-facial Abnormlal Response toinsipilus puberty retardation dysmiorphismit external anti-convulsants

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and similarly the lipoma in the present case seemsunlikely to be the cause per se. Both lesions point todiffuse developmental abnormalities.18 The mechan-ism of attacks in this syndrome has never beensatisfactorily explained. Previous authors have

accepted these attacks as examples of diencephalicepilepsy5-8 12 as described by Penfield' but there aregood reasons for abandoning this term.9 11 19 Penfieldin his detailed account emphasised the brief natureof his patient's attacks which lasted for 5-12 minutes.

Fig 4 Right car-otid arteriogram. Subtraction films. (a) Anteroposterior projection. (b) lateral projection The anteriorcerebral artery complex is abnormal in position with the peri-callosal arterY low and the branches of the peri-callosalare shown coulr.sing in a diagonal fashion towards the convexity.

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The patient had raised intracranial pressure and allthe features could be explained by acute intermittenthydrocephalus caused by a ball valve action of theintra-ventricular tumour. In contrast, patients suchas the present case with spontaneous periodichypothermia have attacks lasting hours or days andnone have had raised intra-cranial pressure.2 12Occurrence of seizures in three patients5 9 10 hasbeen cited as evidence of an epileptic mechanism forthe sweating and hypothermia6 12 but other factorssuch as the associated brain damage and severehyponatraemia as in the present case, would inthemselves be sufficient to produce seizures. Failureof anti-convulsants to control sweating and hypo-thermia in almost all the cases does not favouran epileptic mechanism.Our patient's main disability is a disturbance of

thermoregulation characterised by episodes of severehypothermia due to increased heat loss from excessivesweating. The trouble is not due to inability tothermoregulate but stems from his abnormal"target" temperatures. Body temperature is normallycontrolled around 37°C but in this patient thermo-regulation is aimed at achieving a lower temperature.The patient's condition could be described in theterms of the moveable set-point theory of thermo-regulation,20 as one in which the set-point was usuallylower than normal (about 35 5°C) and which under-went episodes of reduction to an even lower levelabout 31 V0C). Reduction to this level was achievedby excessive sweating. This explanation postulatesepisodic and inappropriate changes in the intra-hypothalamic neuronal equivalent of a referencesignal generator. There is no direct evidence for theexistence of such a neurone and it may be easier to

Summers, Young, Little, Stoner, Forbes, Jones

explain our patient's disorder in terms of Bligh's2'recent updating of Vendrik's22 hypothesis, showndiagrammatically in fig 5. In this model a set-point isproduced by the inputs from hot and cold sensors,with the temperature-activity characteristics shown,acting on the reflex effectors both directly andthrough crossed inhibitory fibres. The final drive tothe effector pathways to heat loss and heat pro-duction can be modulated by additional excitatoryand inhibitory influences as shown which willproduce changes in the apparent set-point.The association between thermal sensation and

the effector responses is obscure. Although thepatient felt hot during the attacks, tests of thermalsensation gave normal results and it is unlikely thatthe excessive sweating was due to a change in thecharacteristics of the sensor neurones. A more likelyexplanation would be an increase in the off-lineexcitatory input to the heat loss neurone (fig 5). Thiswould lower the resting set-point and if subject toepisodes of further increases in activity, would causeperiods of hypothermia due to increased sweating.An advantage of this hypothesis is that it increasesthe number of possible cerebral sites of origin of theexcitatory impulses and extends them beyond thehypothalamus. Except possibly for the changes inthe autonomic nervous system there is little evidenceof damage to the hypothalamus of this patient whilethere are lesions in other regions, namely the frontallobes and corpus callosum.Spontaneous periodic hypothermia with corpus

callosum abnormalities is a distinct clinical entity.In many reported cases hypothermia has beenoverlooked for several years and the symptomsattributed to some other medical or psychiatric

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Fig 5 The diagram (after Bligh21 1979) shows how a neuronal network of the layout shown centrewith warm and cold sensors of the temperature activity relationships shown left will produce a set-pointshown right. This set-point could be raised or lowered by excitatory and inhibitory inputs toneurones A and B by input from elsewhere in the central nervous system or from peripheralthermosensors. The situation in the present case could be explained by an increase in the excitatoryinput a.

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condition.4 12 Routine use of a low readingthermometer would avoid this error. If the syndromeis recognised then a CT scan and tests of autonomicand thermoregulatory function are obligatory.Although no specific treatment exists, it may be thatprompt symptomatic treatment consisting of heatconservation and sodium replacement would reducethe severity of episodes and prevent further cerebraldamage which may be responsible for the progressionnoted in some cases. Total sympathectomy hasproved effective in one case7 and this may be possiblein similar cases with transient thermoregulatoryabnormalities and absence of generalised autonomicdysfunction.

We thank the staff of the Departments of MedicalIllustration, Salford Area Health Authority (T) andthe University of Manchester, and Mrs D Ogden forpreparation of the manuscript.

References

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2 Hines EA, Bannick EG. Intermittent hypothermia withdisabling hyperhidrosis: Report of a case withsuccessful treatment. Proc Mayo Clinic 1934 ;9 :705-8.

3 Hoffman AM, Pobirs FW. Intermittent hypothermiawith disabling hyperhidrosis. JAMA 1942;120:445-7.

4 Duff, RS, Farrant PC, Leveaux VM, Wray SM.Spontaneous periodic hypothermia. QJ Med1961 ;30:329-38.

a Shapiro WR, Williams GH, Plum F. Spontaneousrecurrent hypothermia accompanying agenesis ofthe corpus callosum. Brain 1969;92:423-36.

6 Guihard J, Velot-Lerou A, Poitrat C, Laloum D,L'Hirondel J. Hypothermie spontanee recidivanteavec agenesie du corps calleux. Syndrome deShapiro (nouvelle observation). Ann Pediat 1971;

18:645-56.7Fox RH, Wilkins DC, Bell JA et al. Spontaneous

periodic hypothermia: Diencephalic epilepsy. BrMed J 1973 ;2 :693-5.

8 Noel P, Hubert JP, Ectors M, Franken L, Flament-Durand J. Agenesis of the corpus callosum associ-ated with relapsing hypothermia. Brain 1973 ;96:359-68.

9 Thomas DJ, Green ID. Periodic hypothermia. Br MedJ 1973;2:696-7.

10 Dutau G, Carriere J-P, Rochiccioli P. Hypothermiespontanee recidivante avec hypoplasie du corpscalleux. Pediatrie 1975 ;30 :117-27.

1 Sadowsky C, Reeves AG. Agenesis of the corpus cal-losum with hypothermia. Arch Neurol 1975 ;32 :774-6.

12 Carr-Locke D, Millac P. Diencephalic epilepsy in apatient with agenesis of the corpus callosum con-firmed by computerised axial tomography. J NeurolNeurosurg Psychiatry 1977;40:808-14.

13 Suemitsu T, Nakajima S, Kumajima K, Nihei K,Kamoshita S. Lipoma of the corpus callosum:Report of a case and review of the literature. Child'sBrain 1979 ;5 :476-83.

14 Zettner A, Netsky MG. Lipoma of the corpus callosum.J Neuropathol Exp Neurol 1960;19:305-19.

15 Wallace D. Lipoma of the corpus callosum. J NeurolNeurosurg Psychiatry 1976 ;39:1179-85.

16 Tahmouresie A, Kroll G, Shucart W. Lipoma of thecorpus callosum. Surg Neurol 1979;11:31-4.

17 Editorial. Episodic hypothermia. Lancet 1973 ;2 :246-7.Ettlinger G. Agenesis of the corpus callosum. In:Vinken PJ, Bruyn GW, eds. Handbook of ClinicalNeurology. Amsterdam: Elsevier/North HollandBiomedical Press, 1977;30:285-97.

9Thomas DJ. Episodic hypothermia. Lancet 1973;22:449.

20 Hammel HT. Regulation of internal body temperature.Annu Rev Physiol 1968;30:641-710.

21 Bligh J. The central neurology of mammalian thermo-regulation. Neuroscience 1979;4 :1213-36.

22 Vendrik AJH. The regulation of body temperature inman. Ned Tijdschr Geneeskd 1959;103:240-4.

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