hypothalamic gliomas in children - bmj

Journal of Neurology, Neurosurgery, and Psychiatry, 1974, 37, 1047-1052

Hypothalamic gliomas in childrenCLIFFORD ROBERSON' AND KENNETH TILL

From the Department of Neurosurgery, The Hospitalfor Sick Children,Great Ormond Street, London

SYNOPSIS Twenty children with gliomas of the hypothalamus were studied. Management was byradiotherapy alone, or operative treatment with or without radiotherapy, and in some cases treat-ment was withheld entirely. One half of the children died within one year of presentation, whereasthe remainder are alive and well after many years. An attempt is made by analysis of the results todetermine when surgery or radiotherapy or a combination of the two may appropriately be employedin the management of this condition.

In most publications concerning optic nervegliomas (a general term for gliomas involving theoptic nerve, chiasm, optic tracts, and hypo-thalamus) lesions confined to the hypothalamusare usually mentioned only incidentally. In thispaper, gliomas involving only the optic nerves orchiasm are excluded. In all the children, the pri-mary lesion involves the hypothalamus, or hypo-thalamus and optic chiasm.

Martin and Cushing (1923) first noted thedifficulty of determining the site of origin ofoptic nerve gliomas, since these tend to extendup and down the optic pathways, often makingit impossible to decide even at postmortemexamination whether the growth originated inthe chiasm and extended to the hypothalamus,or vice versa.

GENERAL CHARACTERISTICS Martin and Cushing(1923) found 0'84% of 823 tumours in all agegroups to be gliomas of the optic pathways. Inthe Vienna series of Koos and Miller (1971) 3%of 700 brain tumours in children and adolescentswere gliomas of the optic pathways, these being8% of the total glioma group. Taveras et al.(1956) found 1 7% of 2,000 gliomas of all agegroups to involve the optic pathways. It isgenerally agreed that about 75% of all opticnerve gliomas occur in patients less than 12 yearsold (Matson, 1969; Koos and Miller, 1971). TheI Present address: Orange County Medical Center, Department ofNeurosurgery, 101 City Drive South, Orange, California, 92680 USA.

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ages of the 20 patients here reported are shownin Table 2. There is no predilection for eithersex, 11 being female and nine male. In mostreports of children with optic nerve gliomas(Udvarhelyi et al., 1965; Matson, 1969) 30 to50% have stigmata of von Recklinghausen'sdisease, but in this more restricted series ofhypothalamic gliomas only one of the 20 hadneurofibromatosis. Matson (1969) found 22%of optic nerve gliomas were intraorbital; 65%involved intracranial portions ofthe optic nerves,and 13% involved both. Different proportionswere reported by Hoyt and Baghdessarian (1969):of 36 patients only 11% were confined to theorbit, the remainder involved intracranial por-tions of the nerves. Twelve of the 36 had signs ofhypothalamic involvement. Approximately 50%/of all optic nerve gliomas at this hospital ap-peared to be hypothalamic in origin.Fowler and Matson (1957) considered optic

nerve gliomas to be a form of astrocytoma,whereas other authors (Koos and Miller, 1971)consider them to be spongioblastomas. Thehistology of the purely hypothalamic gliomas isthe same as those confined to the optic nerves.However, Matson (1969) stressed that primarygliomas of the hypothalamus and chiasm some-times demonstrate a higher degree of malignancymicroscopically when compared with thoseoriginating in the optic nerve. Of our 20 patients,the 14 with positive biopsies all had astrocytomasof grades 1 or 2. In three of the remaining six

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Clifford Roberson and Kenneth Till

children, craniotomy was performed but eitherthe biopsy specimen was inadequate or no biopsywas attempted for fear of needlessly inducingsymptoms; however, the appearance at surgeryin these three cases left no doubt that the tumourwas a glioma of low grade malignancy. Onechild received radiotherapy without previousbiopsy because the neuroradiological studies leftlittle doubt as to the site and histology of thetumour, which was considered inoperable due toextension into the thalamus. Another child notbiopsied presented with the sole finding of pre-cocious puberty at age 6 years. The mass demon-strated by pneumoencephalography was so smallthat it was decided not to institute any treatmentbut to follow up with repeated pneumo-encephalography. The final child not biopsiedwas already in terminal illness at the time ofdiagnosis.

PRESENTATION The presenting signs and symp-toms of hypothalamic gliomas depend mainlyupon the location and extent of the tumour.Chiasmal involvement is often heralded by bi-temporal visual field defect, progressive loss ofvisual acuity, or occasionally by signs of hypo-pituitarism if the growth disturbs the pituitarystalk. Hypothalamic involvement may present asdiabetes insipidus, obesity, emaciation, under-development of external genitalia, or precociouspuberty. The tumour may extend along the baseof the brain to reach the interpeduncular region.Frequently the children present with signs of in-creased intracranial pressure due to occlusion ofthe foramina of Monro by tumour filling thethird ventricle anteriorly. Only five of ourpatients did not present with signs and symptomsof increased intracranial pressure.Two patients presented with diabetes insipi-

dus; both were easily controlled with pitressin.None of the children developed diabetes insipidusafter the initial admission. On the other hand,two of the four children who developed sexualprecocity did not do so until two years aftertreatment (conventional radiotherapy in one andimplantation of radioactive gold seed in theother). Precocious puberty is probably the resultof involvement of the median eminence and maybe produced by lesions other than gliomas suchas ectopic pinealomas, teratomas, and hamar-tomas (Matson, 1969). Two of our four patients

with precocious puberty were among thosewhose diagnosis was not verified by biopsy.Of the 20 children with hypothalamic gliomas,

four presented with the diencephalic syndromewhich Russell (1951) originally described as aparadox of skin pallor and extreme body wastingin spite of good appetite and food intake, a senseof well-being sometimes bordering on euphoria,hyperactivity, and normal haemoglobin levels.Our four cases were atypical in that all hadhistories ofpoor feeding and apathy. The wastingis usually the only physical abnormality in thediencephalic syndrome; other indicators ofhypo-thalamic involvement such as diabetes insipidusand electrolyte disturbances are uncommon. Thewasting is so severe that radiographs show acomplete absence of subcutaneous fat, a findingfirst described by Poznanski and Manson (1963),which differentiates it from other causes ofemaciation. The diencephalic syndrome has beenreported in children with primary malignanttumours of the posterior fossa which extendedupwards into the hypothalamic region, but theusual cause is an infiltrating glioma of theanterior hypothalamus and floor of the thirdventricle as in the cases reported here. The lesionmay range from an extremely slow growingglioma resembling a hamartoma to an astro-cytoma of grade 4 malignancy. The commonesttype reported have been astrocytomas grades 1and 2 (Smiih et al., 1965), as were three of thefour cases in our series. The fourth was not veri-fied histologically. The syndrome occurs mostfrequently in children less than 1 year old,although it has been reported in children up to 4years. Our patients were aged 7 months, 2 years,2 years, and 5 years on admission with lengths ofhistory three months, one year, four months, andfour months respectively.

DIAGNOSTIC PROCEDURES The diagnosis canusually be made by plain radiography of theskull followed by lumbar pneumoencephalo-graphy, without the use of angiography. Ifangiography is used, the internal carotid arteries,proximal portions of the posterior communica-ting and anterior choroidal vessels may showlateral displacement. Large hypothalamic massescan elevate and straighten the anterior cerebralvessels and the internal cerebral vein. Angio-graphy was performed on only two of our 20

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patients and in one of these the vessels were re-garded as normal, the diagnosis being madeafterwards by pneumoencephalography.

Plain radiographs of the skull aided by specialviews of the optic foramina may reveal enlarge-ment of the optic canals in those children inwhom there is forward extension of the growth.Often, however, the pre-chiasmatic areas are notinvolved due to the tendency of hypothalamicgliomas to extend more posteriorly thananteriorly (Taveras and Wood, 1964). The size ofnormal optic foramina is not known with cer-tainty, although Fowler and Matson (1957) con-sidered the normal range to be from 4-1 to 4 65mm. Hence, asymmetry of the two foramina isoften a better indication of optic nerve involve-ment in the optic canals than the actual size ofthese canals.The classical radiological sign of chiasmal, and

therefore frequently hypothalamic, gliomas is theJ-shaped sella turcica first described by Martinand Cushing (1923). The anterior aspect of thesella turcica is flattened, and enlargement of thechiasmatic groove leads to a flattened tubercu-lum. The J-shaped sella (more accuratelydescribed as pear-shaped), although highly sug-gestive of chiasmal or hypothalamic glioma, isalso seen in congenital hydrocephalus andgargoylism (Koos and Miller, 1971). It is seen inonly about half the children with confirmeddiffuse chiasmal gliomas (Schuster and Westberg,1967). Nine of the present patients had no sellarchanges.

Suprasellar calcification is very uncommon inprimary tumours of the hypothalamus, in con-trast with an incidence of over 9000 in childrenwith craniopharyngioma. Several of the presentpatients were subjected to craniotomy in thehope that the suprasellar mass was a cranio-pharyngioma, although no calcification hadb_en seen on skull radiographs. One patient withsuprasellar calcification was found at explora-tion to have a hypothalamic glioma instead of acraniopharyngioma.

Hypothalamic gliomas are usually best demon-strated by air contrast radiography. Pneumo-encephalography shows the third ventricle to bedisplaced posteriorly, usually with a bulge intoits anterior portion. The margin of a tumourgrowing downwards may be outlined where itprojects into the cisterna interpeduncularis.

Infiltrating gliomas usually have an irregular sur-face on air study, unlike non-infiltrating masses.Efforts should be made to visualize the surface ofthe tumour adequately, since a non-infiltratinglesion obstructing the foramen of Monro may beoperable (Koos and Miller, 1971).

TREATMENT AND RESULTS

Since hypothalamic gliomas cannot be removed,they are clinically malignant although histo-logically benign. However, the prognosis is oftenunpredictable because the astrocytoma may growextremely slowly. There may be very long-termsurvival, the quality of life in the interim rangingfrom a vegetative existence to a complete lack ofsymptoms. The proper management ofthe patientwill therefore depend upon an assessment of thesigns and symptoms and of the tumour's prob-able rate of growth. In some, simple observationmay be best, while in others combinations ofradiotherapy, craniotomy or burr hole biopsy,sub-total removal, and shunts will be required.The management of all types of optic nervegliomas is still controversial because no largeseries are available for study and because thecommonly long-term natural history has madestatistically valid conclusions difficult.

Since hypothalamic gliomas are of low grademalignancy, they are theoretically unlikely to re-spond to radiotherapy. However, many publica-tions (Taveras and Wood, 1964; MacCarty et al.,1970) have concluded that radiotherapy is oftenof considerable benefit. Others conclude that noimprovement in clinical condition or decrease inthe size of the mass can be attributed to radio-therapy (Fowler and Matson, 1957; Matson,1969; Stein et al., 1971). Matson (1969) con-cluded that, after establishing the inoperabilityof the optic nerve glioma by surgical explora-tion, radiotherapy was warranted in the hopethat it might benefit the patient. Hoyt andBaghdassarian (1969) analysed 36 patients withoptic nerve gliomas, 12 of whom had hypo-thalamic symptoms. They concluded that opticnerve gliomas are non-neoplastic, self-limiting,have a good prognosis, and that even chiasmaticand hypothalamic involvement is compatiblewith long survival and good vision. They felt thatlife could never be prolonged by either radio-therapy or transcranial procedures, and there-

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fore neither radiotherapy nor excision (exceptwhen there is proptosis) is ever justified.Matson (1969) recommended exploration in

children with the diencephalic syndrome only ifa finding such as calcification suggested thepossibility of an extracerebral lesion, since hefeels no treatment can do more than temporarilyarrest the syndrome. However, there are reports(Bain et al., 1966; Girdwood and Ross, 1969)that even gliomas responsible for the diencephalicsyndrome are sufficiently responsive to radio-therapy to be compatible with long-term, high-quality survival. In the series of Bain et al. (1966)remissions were reported in which three patientswere clinically well after four-and-a-half, three,and two years with a return of subcutaneous fatbeginning about five weeks after completion ofradiotherapy. The diagnosis of hypothalamicglioma was confirmed by craniotomy in two ofthese three patients. But the conclusion thatradiotherapy was responsible for these remissionsis clouded by Russell's experience, which hecommunicated to these authors. Ofhis 16 patientswith the diencephalic syndrome, one lived fouryears after radiotherapy, two others were aliveand well four and two years after irradiating, butthree others who did not receive radiotherapywere alive 12, 1 1, and eight years after diagnosis.Bain et al. (1966) have speculated that the gradualtransition to obesity in several of Russell's un-treated patients may be due to extension of theglioma into adjacent areas of the hypothalamus.

MANAGEMENT OF PRESENT SERIES This is sum-marized in Table 1. The child who did not

TABLE 1SUMMARY OF MANAGEMENT AND SURVIVAL IN 20 CASES

OF HYPOTHALMIC GLIOMA IN CHILDREN

Cases Treatment Survival(no.) (yr)

1 None 1I Radiotherapy only 21 Burr-hole biopsy with radiotherapy 122 Burr-hole biopsy without radiotherapy <i* (2)3 Craniotomy-biopsy with radiotherapy 1*, 2, 41 Craniotomy biopsy without radiotherapy 2t2 Craniotomy biopsy, shunt, radiotherapy 4+, 133 Subtotal excision with radiotherapy +*, 4t, 62 Subtotal excision without radiotherapy <i* (2)4 Emergency burr-hole decompression <i* (4)

* Dead. t Unsatisfactory condition.

receive treatment had a small lesion with littleevidence of progression of symptoms and re-mains the same after one year. With one excep-tion, all patients who survived the admissionperiod or who were not in a terminal state onadmission received radiotherapy. The boy whoreceived radiotherapy without previous biopsywas not surgically explored because pneumo-encephalography had shown extensive thalamicinvolvement. In one case radiotherapy was givenafter burr-hole biopsy rather than after cranio-tomy because the tumour was known to belarge, clearly inoperable, and not producing in-creased intracranial pressure. The diagnosis wasconfirmed by burr-hole biopsy in two otherchildren both aged 4 months, who did not thenreceive radiotherapy because of their young age,their poor neurological status, and the size of thegrowth. Three others deteriorated so rapidlyafter diagnosis that radiotherapy could not begiven. A 2 year old girl with the diencephalicsyndrome was admitted comatose with extensorrigidity and was initially decompressed with amarked improvement in her condition, but whenthe nature of the lesion had been ascertained, itwas decided not to intervene further. Two of thethree children who had biopsy at the time ofcraniotomy without any attempt at removal ofthe tumour were thought possibly to havecraniopharyngiomas (since they did not havepear-shaped sellas). Two of these children areclinically well two and four years after radio-therapy, one with objective improvement ofvisual acuity and the other without signs orsymptoms of increased intracranial pressure.The third presented with the diencephalic syn-drome. Her weight increased 50%O in the threemonths after radiotherapy before her excellenthealth deteriorated, culminating in death afterone year. A male baby aged 7 months with alarge porencephalic cyst and hypothalamicglioma who presented with retardation did notreceive radiotherapy after craniotomy because itwas felt at the time that such gliomas were radio-resistent. Two years later he was alive butdebilitated with several seizures a day. Onepatient without changes of the sella turcica wastreated by biopsy through craniotomy, ventriculo-cisternostomy (Torkildsen's procedure), andradiotherapy. He is alive with normal healthfour-and-a-half years later. Another child re-

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ceived a craniotomy for gold seed implantationand remained well for 13 years apart from pre-cocity until recently requiring a shunt for pro-gressive obstructive hydrocephalus. This wasfollowed by radiotherapy. His vision improvedbut it is not clear whether this is the result of theshunt or the irradiation. Two patients weretreated by subtotal removal of the tumours with-out radiotherapy. The first was rapidly deteriora-ting at the time of diagnosis, the mass protrudingthrough the foramen of Monro. It was hopedthat a satisfactory decompression could beachieved by partial removal, but the child died inthe postoperative period. The other patient, whohad the diencephalic syndrome, had a midlinetumour filling the pituitary fossa which re-sembled a large craniopharyngioma. At cranio-tomy a partial removal was achieved, but deathoccurred in the postoperative period. Anotherdiencephalic patient had partial removal andradiotherapy but led a vegetative existence tilldeath occurred five months later. Surgery wasundertaken in another patient because thetumour was considered to be partially accessiblesince the optic foramina were enlarged. She iswell four years later apart from mental retarda-tion, making it impossible to assess her visualacuity. The final patient presented with de-creasing visual acuity and raised intracranialpressure. His huge tumour, extending from theoptic canals to the cerebral peduncles andblocking the foramen of Monro, was partiallyexcised. Six years after radiotherapy he is in goodhealth with restoration of normal vision to hisright eye.

TABLE 2RELATIONSHIP OF SURVIVAL TO AGE AT PRESENTATION

Cases Age Survival(no.) (yr) (yr)

3 < 2t1 1 23 2 < i* (2), 4t1 3 132 4 <i*5 5 <i(2), 1*,6, 121 7 11 9 412 11 <i*, 41 13 2

* Dead. t Unsatisfactory.

DISCUSSION

Of the 20 patients, 10 did not receive radio-therapy either as a matter of deliberate policy orbecause they died before therapy could begin.One patient continued a downhill course inspite of radiotherapy. The remaining nine alldemonstrated objective improvement and arestill alive and well except one who showedinitial response to irradiation before succumb-ing. The improvement in five of these nine can bedirectly attributed to radiotherapy since they hadno other treatment.

TABLE 3RELATIONSHIP OF PRESENTING CONDITION TO SURVIVAL

Cases Presenting Survival(no.) condition (yr)

4 Good 1, 2, 6, 127 Fair < i* (2), 2t, 4t, 4, 41, 137 Poor < i* (5), i*, 12 Critical <i* (2)

* Dead. t Unsatisfactory condition.

Of the five patients with partial removal of thetumour, two died in the postoperative period andone five months later. The other two presentedwith hydrocephalus and are now long-term sur-vivors without the problems plaguing childrenwith shunts. There are not enough patientstreated by subtotal excision and radiotherapy orcontrols with partial excision without suchtherapy to judge whether or not subtotal removaladds to the improvement achievable by radio-therapy alone. However, most children present-ing with hydrocephalus need more immediaterelief from their symptoms than radiotherapycan provide, and therefore require either a shuntor partial excision in addition to radiotherapy.Because the natural history of hypothalamicglioma is so variable and frequently favourable,craniotomy should not be performed except tocarry out partial removal of the growth in orderto relieve increased intracranial pressure or toexplore if there is some doubt about the diagnosisand the possibility exists that the mass may beeither extracerebral or a non-gliomatous hypo-thalamic lesion.

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Satisfactory long-term survival appears to bemore related to the patient's presenting condition(Table 3) than to his age (Table 2). Criteria usedin Table 3 are as follows:

Good: alert and oriented but with a mild de-crease of visual acuity, mild symptoms of in-creased intracranial pressure, precocious puberty,etc.

Fair: alert, oriented but with severer symp-toms.Poor: debilitated, or disabled by severe neuro-

logical abnormality but conscious.Critical: consciousness and general condition

deteriorated to an extent requiring emergency de-compression.

Table 3 thus suggests that (1) if the child pre-sents in sufficiently good condition to survivesix months, he can expect a good long-term sur-vival, and (2) children presenting in either pooror critical condition should not be treated at all.

This second conclusion implies that no chil-dren with the diencephalic syndrome should betreated, but because of the encouraging resultsreported by Bain et al. (1966), this conclusionshould probably be modified for the time being.Such children who present in an alert mentalstate should receive radiotherapy sometimespreceded by decompression and only those incritical condition left untreated.

CONCLUSIONS

Twenty children with hypothalamic gliomasfrom the Hospital for Sick Children, GreatOrmond Street, were reviewed in an attempt todetermine the appropriate management. If thechild's condition at the time of diagnosis is suchthat survival for several months is likely, thelong-term prognosis for good survival is excellentand is enhanced by treatment. It is concluded thatradiotherapy has a definite beneficial effect andshould be given to every child not presenting inpoor or critical condition. These are best leftuntreated. An exception is a child with the di-encephalic syndrome whose general condition ispoor but there is little or no impairment ofconsciousness; such a child should be treated byradiotherapy sometimes preceded by a shuntoperation.

If there is increased intracranial pressure withradiological evidence to suggest that the obstruc-

tion may be relieved by operation, then partialremoval should be carried out. If it is judged thatobstruction cannot be relieved, a shunting pro-cedure is required. Craniotomy is also indicatedif there is anything in the clinical or radiologicalexamination to suggest that the lesion may beextracerebral. Otherwise, biopsy through a burrhole may be adequate for confirmation of thediagnosis.

REFERENCES

Bain, H. W., Darte, J. M. M., Keith, W. S., and Kruyff, E.(1966). The diencephalic syndrome of early infancy due tosilent brain tumor: with special reference to treatment.Pediatrics, 38, 473-482.

Chutorian, A. M., Schwartz, J. F., Evans, R. A., and Carter,S. (1964). Optic gliomas in children. Neurology (Minneap.),14, 83-95.

Fowler, F. D., and Matson, D. D. (1957). Gliomas of theoptic pathways in childhood. Journal of Neurosurgery, 14,515-528.

Girdwood, T. G., and Ross, E. M. (1969). The diencephalicsyndrome of early infancy. British Journal ofRadiology, 42,847-850.

Hoyt, W. F., and Baghdassarian, S. A. (1969). Optic gliomaof childhood. Natural history and rationale for conserva-tive management. British Journal of Ophthalmology, 53,793-798.

Koos, W. T., and Miller, M. H. (1971). Intracranial Tumoursof Infants and Children, pp. 172-188. Churchill: London.

MacCarty, C. S., Boyd, A. S., Jr, and Childs, D. S., Jr (1970).Tumors of the optic nerve and optic chiasm. Journal ofNeurosurgery, 33, 439-444.

Martin, P., and Cushing, H. (1923). Primary gliomas of thechiasm and optic nerves in their intracranial portion.Archives of Ophthalmology, 52, 209-241.

Matson, D. D. (1969). Neurosurgery of Infancy and Child-hood, 2nd edn. Thomas: Springfield, Ill.

Poznanski, A. K., and Manson, G. (1963). Radiographicappearance of the soft tissues in the diencephalic syndromeof infancy. Radiology, 81, 101-106.

Russell, A. (1951). A diencephalic syndrome of emaciation ininfancy and childhood. (Abstract.) Archives of Diseases ofChildhood, 26, 274.

Schuster, G., and Westberg, G. (1967). Gliomas of the opticnerve and chiasm. Acta Radiologica, Diagnosis, 6, 221-232.

Smith, K. R., Jr, Weinburg, W. A., and McAlister, W. H.(1965). Failure to thrive: the diencephalic syndrome ofinfancy and childhood. A case report. Journal of Neuro-surgery, 23, 348-351.

Stein, B. M., Fraser, R. A. R., and Tenner, M. S. (1971).Radiological characteristics and surgical management ofthird ventricular tumors in children. Acta NeurologicaLatinoamericana, 17, 131-140.

Taveras, J. M., Mount, L. A., and Wood, E. H. (1956). Thevalue of radiation therapy in the management of glioma ofthe optic nerves and chiasm. Radiology, 66, 518-528.

Taveras, J. M., and Wood, E. H. (1964). Diagnostic Neuro-radiology. Williams and Wilkins: Baltimore.

Udvarhelyi, G. B., Khodadoust, A. A., and Walsh, F. B.(1965). Gliomas of the optic nerve and chiasm in children:an unusual series of cases. Clinical Neurosurgery, 13, 204-237.

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