Postgraduate Medical Journal (1989) 65, 163 - 167

Clinical Reports

Hypothalamic disease in association with dysgenesis of thecorpus callosum

S.R. Page', S.S. Nussey', J.S. Jenkins', S.G. Wilson2 and D.A. Johnson3

'Department ofMedicine II, St. George's Hospital Medical School, Cranmer Terrace, London SW] 7 ORE,Departments of2Neurology and 3Neuropsychology, Atkinson Morley Hospital, Copse Hill, London SE20 ONE,UK.

Summary: We describe two cases of dysgenesis of the corpus cailosum demonstrated by magneticresonance. The first patient presented with chronic hyponatraemia. Investigation demonstrated re-settingof the osmoreceptor and thirst centres. The calculated threshold for arginine vasopressin (AVP) releasewas reduced at 252 mosmol/kg while severe thirst was perceived at a plasma osmolality of260 mosmol/kg.Insulin-induced hypoglycaemia produced an exaggerated AVP response.The second patient presented with hypothermia. The calculated threshold of AVP release was

296 mosmol/kg with increased sensitivity of AVP response to hypertonic saline. The plasma AVPresponse to insulin-induced hypoglycaemia was absent. Both cases had normal anterior pituitary functionand psychological assessment showed a similar prefrontal defect. Specific tests of callosal function werenormal.

These cases illustrate the importance of undertaking complete neuroradiological assessment ofcases ofunexplained hypothalamic disease regardless of the age of presentation to avoid overlooking this rarecongenital association.

Introduction

Dysgenesis of the corpus callosum is a midlinedevelopmental defect. It commonly occurs in associa-tion with other major neurological abnormalitieswhich result in mental retardation, hydrocephalus andepilepsy in childhood.' Isolated dysgenesis is usuallysymptomless and is reported as an occasional inciden-tal finding at post-mortem.' The association ofhypothalamic disease with dysgenesis is rare.2-4We describe two patients with dysgenesis of the

corpus callosum in whom detailed assessment ofanterior and posterior pituitary function has beenperformed.

Case reports

Case I

A 28 year old female secretary developed hyper-thyroidism and at initial presentation the plasmasodium concentration was 130 mmol/l (normal range135-145 mmol/l). Hyperthyroidism recurred twoyears later when therapy with carbimazole was discon-

tinued and she was admitted for a sub-total thyroidec-tomy.The pre-operative plasma sodium concentration

was 128 mmol/l. Two days post-operatively theplasma sodium concentration fell to 108 mmol/l andshe became confused. At this time the plasmaosmolality was 223 mosmol/kg (normal range280-300 mosmol/kg), the urine osmolality was566 mosmol/kg (normal range 100-1400 mosmol/kg)and the urine sodium concentraion was 117 mmol/l.Fluid restriction of 500 ml/day was instituted and theplasma sodium concentration rose to 126 mmol/l over3 weeks. Post-operative hypothyroidism, with a freeserum thyroxine concentration of 7.6 pmol/l (normalrange 9-28 pmol/1) and serum thyroid stimulatinghormone of 19.1 mU/I (normal range 0.3-5.5 mU/l,responded to thyroxine 50 iLg/day. The confusionalstate slowly resolved and recovery was subsequentlyuneventful.

There was a past history of a febrile convulsion atthe age of 2 years. An electroencephalogram (EEG) atthat time showed asymmetrical activity between thetwo cerebral hemispheres but a further EEG per-formed when 10 years ofage for assessment ofenuresiswas normal. Mild systemic hypertension (blood pres-sure 146/95-156/108 mmHg) was diagnosed 1 year

©) The Fellowship of Postgraduate Medicine, 1989

Correspondence: S.R. Page, M.R.C.P.Accepted: 11 October 1988

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164 CLINICAL REPORTS

after the onset of hyperthyroidism. Investigationsincluding urinalysis, an intravenous pyelogram, andurine collections for vanillylmandelic acid were nor-mal. The blood pressure was controlled withnifedipine 10 mg three times daily.Hyponatraemia has persisted (mean plasma sodium

concentration 129 ± 0.65 mmol/l, range 123- 133 mmol/l,n = 9) over 2 years of observation and she maintains afluid restriction of approximately 1000 ml daily.Menstruation is regular, her temperature is normaland she has no neurological symptoms.

Case 2

A 16 year old previously healthy girl presented withdrowsiness, slurring of speech and a deterioration ofher school performance. Menstruation had beenirregular for 3 months. Her oral temperature was340C, falling to a nadir of 31 .50C during her admission.Neurological and general examinations were normal.During attempted warming she experienced extremediscomfort and profuse sweating occurred despite anoral temperature of 35TC. At the end of the warmingperiod her temperature fell rapidly to 32.50C. Theplasma sodium concentration was normal. The EEGshowed generalized slowing consistent with hypother-mia. Her mean temperature during 4 months ofobservation was 32.4°C (range 31'C-340C). Whilsthypothermic she developed an ataxic gait with cerebel-lar incoordination; she experienced two grand malseizures and she remained lethargic, withdrawn anddrowsy. Carbamazepine 200 mg/day was commencedand 3 weeks later her temperature rose to 360C with amarked improvement in her clinical condition.

Investigations and Methods

Anterior pituitary function tests Soluble insulin(0.15 U/kg), thyroliberin (200 pg) and luteoliberin(100 fig) were injected intravenously after baselineblood sampling. Further samples were taken at 30minute intervals for 2 hours. Plasma cortisol estima-tions were performed at 09.00 and 24.00 hours.

Hypertonic saline test Blood samples were collectedbefore, and every 30 minutes during a 2 hour infusionof hypertonic saline (0.45M; 0.1 ml/kg/min).

Plasma renin, aldosterone and catecholamine samp-ling Case 1 maintained a high sodium (> 100 mmol/day) and potassium intake (>70 mmol/day) for 2weeks. Baseline samples were taken after overnightrecumbency and further samples were taken at 5, 10,15 and 30 minutes after standing. All endocrine

investigations in case 2 were performed duringhypothermia (temperature 32°C).

Analyses Plasma osmolality was measured by freez-ing point depression using an Advanced DigimaticOsmometer Model 3D. Plasma glucose was measuredusing a glucose oxidase method. Plasma argininevasopressin (AVP),5 aldosterone,6 cortisol (Amerlexkit, Amersham International plc) and anteriorpituitary hormones were measured by radio-immunoassay. Plasma catecholamines were measuredby high performance liquid chromatography extrac-tion with electrochemical detection.7 Plasma reninactivity (PRA) was measured by the modified methodof Mernard & Catt.8

Neuropsychological assessment Standard clinicalassessments of attention, learning, memory, percep-tion, reasoning and intelligence9 were performed. Inaddition each patient underwent specific tests ofcallosal function using different sensory modalitiesaccording to the method of Bogen.'"

Statistical analysis Plasma AVP and osmolality datafor the patients and 10 normal subjects were subjectedto linear regression analysis. The slope of the regres-sion line was considered abnormal if it was greater orless than the mean ± 2 s.d. of the normal slopes.

Results

Endocrine Anterior pituitary function and diurnalvariation of cortisol was normal in both cases (notshown). The mean ± 2 s.d. for the AVP/osmolalityregression slopes of the 10 normal subjects was0.37 ± 0.54.

Case I The AVP response to 0.45 M saline showednormal sensitivity (slope 0.56) but the calculatedthreshold for AVP release was 252 mosmol/kg (nor-mal range 283 ± 4 mosmol/kg) (Figure 1) and thirstwas experienced at 260 mosmol/kg(278-290 mosmol/kg).Insulin-induced hypoglycaemia produced an exag-gerated rise ofplasma AVP (Figure 2). The supine anderect PRA was abnormally low (0.3 pmol/h/ml supine,normal range 1.1-2.7 pmol/h/ml; 0.6 pmol/h/minerect, normal range 2.8-4.5 pmol/h/ml) but thesupine plasma aldosterone and the response to stand-ing were normal. Supine plasma catecholamine con-centrations were normal but the peak response tostanding (noradrenaline 1774.4 pg/ml, normal range< 1000 pg/ml; adrenaline 3629.3 pg/ml, normal range< 750 pg/ml) was significantly exaggerated.

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250 260 270 280 290 300 310Plasma osmolality (mosmol/kg)

Figure 1 The relationship between plasma AVP andplasma osmolality during hypertonic saline infusion incase 1 (@) and case 2 (0) compared with 10 normalcontrol subjects (-). The linear regression equation forthe normal subjects is y = 0.37 (x-283); r = 0.74P <0.001. The mean ± 2s.d. of the slopes of 10 normalsubjects is 0.37 ± 0.54. For case I the equation is y = 0.56( x - 252) r = 0.85, P < 0.05 and case 2 the equation isy = 1.37 ( x -296) r = 0.95, P < 0.05.

Case 2 The plasma AVP response showed increasedsensitivity (slope 1.37) and the calculated threshold ofAVP release was elevated at 296 mosmol/kg (Figure1). Insulin-induced hypoglycaemia failed to produce arise of plasma AVP (Figure 2).

0- I I I0 30 60

Time (minutes)

I 190 120

Figure 2 The AVP response to insulin-induced hypo-glycaemia. Case 1 = *; case 2 = 0; control subjects-= E (Means ± s.e.m. Student's t-test, n = 10). Bloodglucose nadir: case 1 = 1.0 mmol/l, case 2 = 1.2 mmol/l.

Radiology Magnetic resonance imaging (SiemansMagnetom 1.5T) showed dysgenesis of the corpuscallosum in both cases (Figure 3). Case 2 had a highdensity area on both Ti and T2 weighted scans,anteriorly placed between the lateral ventricles consis-tent with a lipoma of the corpus callosum (Figure 3).

Figure 3 Cranial magnetic resonance imaging of normal corpus callosum (left), case I (centre) and case 2 (right).CC = corpus callosum, L = lipoma (case 2).

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166 CLINICAL REPORTS

Neuropsychological assessment Verbal IQ (case 1,83; case 2, 93), performance IQ (case 1, 75; case 2, 87)and full-scale IQ (case 1, 75; case 2, 90) were com-parable though both patients demonstrated a markedslowing of information processing speed. Motor reac-tion speeds were significantly slowed in case 2 consist-ent with the degree of hypothermia. Immediate recallfrom memory, and learning ability were impaired withprimary difficulties in selectivity and inhibitory con-trol. All object naming, reading and writing wereperformed without error.

Discussion

The anterior hypothalamus plays a major role inosmoregulation in man by control of both the secre-tion of AVP from the neurohypophysis and theperception of thirst around set-points which maintaina normal plasma osmolality." Case 1 had resetting ofthe osmoreceptor threshold leading to AVP release atinappropriately low plasma osmolality but with aqualitatively normal AVP response to hypertonicsaline infusion assessed by the slope of the AVP/osmolality linear regression. The abnormal thirstset-point further maintains hypotonic plasma byencouraging drinking at low plasma osmolality andboth mechanisms entirely account for the chronicsymptomless hyponatraemia. The exaggerated AVPresponse to insulin-induced hypoglycaemia providesfurther confirmation of abnormalities ofAVP regula-tion although the mechanism remains unknown. Bothsurgery" and hypothyroidism'2 are potent non-osmotic stimuli to AVP secretion and would furtherreduce the threshold for AVP secretion. These addi-tional factors, together with the administration ofintravenous fluids post-operatively, may account forthe rapid onset of severe post-operative dilutionalhyponatraemia following sub-total thyroidectomy.The exaggerated plasma catecholamine response to

standing in case 1 suggests an abnormal neurogenicreflex arc which is most readily explained by additionalhypothalamic disease affecting nuclei which controlthe sympathetic nervous system. The significance ofthis with regard to the mild 'essential' hypertension incase 1 is unknown. The discordant PRA andaldosterone concentrations demonstrated in case 1 aresimilar to those reported in unrelated conditionscomplicated by inappropriate AVP secretion.'3 It islikely therefore that the discordancy results from themetabolic effects of inappropriate AVP secretionrather than hypothalamic disease though themechanism is unknown.

Hypothermia is a well recognized feature ofhypothalamic disease'4 but an association with cal-losal dysgenesis is rare. Of the 10 previously reportedcases all had intermittent hypothermia with episodes

lasting up to 4 weeks. Persistence ofhypothermia for 4months has not been previously reported. Five caseshad temperature related cerebellar ataxia.4 The pro-fuse sweating experienced in response to warming andthe absence of shivering in case 2 suggest abnormalcontrol of heat conservation rather than dissipationthough we cannot differentiate between an abnor-mality in heat conservation or lowering of the thermo-regulating set point.'5

Both the absent AVP response to insulin-inducedhypoglycaemia and the abnormalities of AVP res-ponse to hypertonic saline infusion may be due toadditional hypothalamic disease. However, all inves-tigations in case 2 were performed during hypother-mia. Continuation of carbamazepine therapy and thehistory of seizures prevented further assessment ofAVP secretion following clinical improvement and wecannot therefore exclude an effect of hypothermia onAVP secretion.The cause of the hypothalamic disease remains

obscure. Water homeostasis and temperature regula-tion are unaffected in patients undergoing surgicalsection of the corpus callosum for intractableepilepsy'6 and the occasional incidental finding ofcallosal dysgenesis at post-mortem' suggests dys-genesis alone is not responsible. Midline lipomasare a recognized association of callosal dysgenesis'7but only one of the 10 previously reported cases ofcallosal dysgenesis with associated hypothermia hadevidence of a lipoma.'8 Histological evidence of non-specific gliosis of the anterior hypothalamus has beenreported in 2 cases ofintermittent hypothermia,4"9 oneof which had associated callosal dysgenesis. No causeof the gliosis was found. The magnetic resonance(MR) scans of the hypothalamus in our reported caseswere normal and the presence of hypothalamic gliosisremains speculative. Previous authors have suggesteddiencephalic epilepsy as a cause of intermittenthypothermia both with20 and without2' associatedcallosal dysgenesis. The apparent clinical improve-ment after commencing anticonvulsant therapy in case2 is interesting but must be interpreted with caution.Previous reports suggest a poor overall response toanticonvulsant therapy4 and the prolonged durationof hyponatraemia in case 1 and hypothermia in case 2argues against diencephalic epilepsy. Furthermore,periods of remission occasionally lasting for years,independent of anticonvulsant therapy characterizethe hypothermia in association with callosaldysgenesis and the apparent improvement in case 2may be coincidental.

It is interesting that both patients could performapparently normal activities before presentation des-pite significant impairment of many aspects of pre-frontal cognition. Furthermore, the lack of evidencefor classical disconnection signs22 contrasts with thesevere defects resulting from surgical section of the

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CLINICAL REPORTS 167

corpus callosum or the presence of a callosal gliomaand is consistent with previous reports.23 The timing ofthe developmental insult may be crucial in this respect,allowing greater functional development of non-callosal pathways, or the development of bilateralrepresentation of important cortical function.24

In conclusion both cases illustrate the importance ofundertaking complete neuroradiological assessmentof cases of unexplained hypothalamic disease regard-

less of the age of presentation to avoid overlookingthis rare congenital association.

Acknowledgements

We thank Dr J. Britten for interpretation of the MR scansand Dr Paget Davis for referring one of the patients. S.R.Page is supported by the St George's Hospital SpecialTrustees and S.S. Nussey was a Wellcome Trust Lecturer.

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