PONTINE GLIOMAS OF CHILDHOOD

913

PONTINE GLIOMAS OF CHILDHOOD L. P. LASSMAN M.B. Lond., F.R.C.S. NEUROLOGICAL SURGEON

V. E.

ARJONA

L.M.S. Seville RESEARCH FELLOW

From the Regional Neurological Centre, Newcastle General Hospital, and the University of Newcastle, Newcastle upon Tyne

of childhood the clinical presentation was cranial-nerve palsies with cerebellar and pyramidal-tract involvement. Early evidence of raised intracranial pressure was present in 6 cases. Characteristic mental changes were found in 8 cases and these symptoms may appear early in the course of the disease. Air studies are essential to confirm the diagnosis and ventriculography is preferred; if necessary, a positive contrast medium is used. Although high-voltage therapy is not curative it increases the survival-time and relieves clinical symptoms.

Summary

In 27

pontine gliomas

most common

Introduction WE describe here a consecutive series of pontine gliomas of childhood in which we have evaluated the effect of high-voltage therapy. These tumours usually originate in the pons, but they tend to invade neighbouring structures, especially the medulla oblongata, and because of this some workers refer to them as brain-stem gliomas. They are more common in children than in adults, but their frequency varies in different series and with the diagnostic criteria used. Buckley (1930), reviewing Cushing’s series, found only 25 pontine tumours out of 1737 verified tumours of the brain; whereas Ingraham and Matson’s (1954) series of 313 brain tumours in children contained 30 brain-stem gliomas, in which the diagnosis had been confirmed by necropsy or at operation. Jackson and Thomson (1959) found 24 verified tumours of the brain stem in a series of 273 intracranial tumours of childhood. Walker and Hopple (1949) reported 100 verified brain tumours in children of which 12 were pontine gliomas. Hare and Woolf (1934) reviewed 432 cases of brain tumours of childhood seen at the Neurological Institute of New York and found that only 7 of the tumours were in the brain stem: Bray et al. (1958) reported a series of 48 cases from the same Institute, but only 40 of them were verified.

Analysis of Clinical Material 265 children with intracranial tumours were admitted to the Newcastle General Hospital between August, 1951,

Fig. 1-Age of childhood.

onset of

symptoms in 27

cases

of

pontine glioma of

and December, 1964. 27 of these were diagnosed as cases of pontine glioma, and the diagnosis confirmed either by ventriculography or at necropsy. 14 were males and 13 females. Their symptoms appeared between the ages of three and thirteen years, with a peak incidence of five years (fig. 1). There was one exception, a four-month-old baby whose clinical picture differed from the remainder of the cases. Mode of Onset The most common clinical presentation was the sudden onset of one or more cranial-nerve palsies, either alone or accompanied by headache or ataxia in a previously healthy child. The presentation was of this type in 13 patients and the sixth cranial nerve was the most frequently involved. 5 patients presented with a unilateral and 2 with a bilateral sixth-nerve palsy. In 4 patients the facial nerve was the first cranial nerve to be involved. In the remaining 2 cases the sixth and the seventh cranial nerves were affected in one, and the ninth and tenth cranial nerves in the other. In 5 patients the illness started with very notable mental changes, which were so profound that they completely altered the personality of the children, and this led the parents to seek medical advice. Hemiparesis was the first symptom in 4 of the cases; the weakness started in the lower limb, progressed to involve the upper limb, and the patient eventually became hemiplegic or even tetraplegic. In these 4 cases the hemiparesis started on the left side. At the onset of the illness in 4 of the patients there was striking cerebellar ataxia and in 1 case this was accompanied by headache and vomiting. The four-month-old baby presented with enlargement of the head and the radiological signs of hydrocephalus; at ventriculography aqueduct stenosis was diagnosed, but at necropsy, a few days later, an infiltrating astrocytoma of the pons was found. The Clinical Syndrome In 24 patients (89%) one or more cranial nerves were involved and our findings confirm that a cranial-nerve palsy is often the earliest and most characteristic sign of the presence of a tumour of the brain stem. The cranial nerves affected were different in almost every case but the abducens and the facial We have not nerves were the most frequently involved. observed improvement of cranial-nerve palsies unless the patient was submitted to high-voltage therapy. Cerebellar signs were present in 22 patients (81%) including ataxia (all the cases) and nystagmus (20 cases). Pyramidal signs were a very common finding and in 22 patients the plantar responses were extensor. In 14 patients there was hemiparesis or hemiplegia; 2 presented with a tetraparesis and 1 with a paraplegia. The hemiparesis was usually contralateral to any cranial-nerve palsy, but on 2 occasions it was ipsilateral. In contrast to the frequent involvement of the pyramidal and cerebellar pathways, only 1 patient presented with sensory

signs (hemianssthesia). Evidence of raised intracranial pressure was found in 6 cases headache, vomiting, and papilloedema and 1 enlargement of the head. 10 children vomited in the absence of increased intracranial pressure and this symptom was probably due to involvement of the vagal nuclei. Cairns (1950) drew attention to the presence of mental symptoms: 5 of his 32 cases of verified pontine tumour showed mental symptoms. In our series 8 children had mental symptoms, and in 6 the changes were very similar: there were striking changes in personality and behaviour and two different phases in the change of the behaviour could be distinguished, which succeeded each other alternately for periods of months or weeks. In the first phase the children became withdrawn, apathetic, and lethargic with a general lack of volition. They were easily provoked to tears and there was a very significant deterioration in scholastic ability. This was followed by an aggressive, hyperkinetic phase in which the children had frequent temper tantrums and became physically violent. Their speech became incoherent and the writing of those who could —5having

914 write became illegible. They also had nightmares and nightterrors. The remaining 2 patients presented with a progressive dementia. We noted a degree of dysarthria in all those who presented with mental symptoms.

Radiology Plain X-rays of the skull were taken in all patients and the only abnormality found was signs of increased intracranial pressure, which was present on four occasions. Angiography, either carotid or vertebral, was not performed. We found the most helpful radiological investigation to be air ventriculography-iophendylate (’ Myodil ’) being used when adequate visualisation of the aqueduct and fourth ventricle was not possible with air. Lysholm (1946) described the ventriculographic appearances in these tumours and his findings were confirmed by Sutton (1953) and Bray et al. (1958). In 21 cases the ventriculogram was classical and showed upward displacement of the posterior part of the third ventricle, a bow-shaped upward and backward displacement of the aqueduct and fourth ventricle, and a narrowing of the cisterna pontis. In 5 cases we could not fill the aqueduct and fourth ventricle with either air or iophendylate, and in 1 case

ventriculography was

not

performed.

Surgical Management In the

early cases ventriculography was followed by exploration of the posterior fossa with direct visualisation of the

tumour

and it

was

usual

to carry out a

Torkildsen

(1939) procedure. In the past eight years, surgical exploration has been abandoned and most cases have been given high-voltage therapy. A ventriculoatrial shunt was performed in 3 cases. High-voltage Therapy

Lately, high-voltage therapy has been the treatment of choice and the last 15 patients in our series were treated in this way. The dosage of radiation was about 4500r given over four weeks. Patients given radiotherapy usually started to improve after the first two weeks and this improvement continued. In 10 patients the abnormal neurological signs resolved. In 2 patients the treatment had no effect on the clinical signs but there was a very striking improvement in mental condition. 3 patients did not respond at all. The outstanding effect of high-voltage therapy was the improvement of the cranial-nerve palsies, which disappeared completely in 8 patients, but in other respects

Fig. 2-Survival-time with or without high-voltage therapy.

the response varied from case to case. In 5 patients the pyramidal signs became less striking and this was accompanied by improvement in speech, gait, and mental disorders. The length of the period of improvement was variable but never exceeded eighteen months. 6 patients returned to school and resumed their normal activities until they relapsed and had to be readmitted to hospital. A second course of high-voltage therapy was given to 2 patients but no response was obtained. The

length of survival with and without high-voltage therapy is shown in fig. 2. Necropsy Necropsy was performed in 14 cases. In 9 children, who died suddenly, massive necrosis and haemorrhage present in the tumour. In 3 cases the immediate of death was rupture of the oesophagus, 1 child died of a chest infection and 1 died as a consequence of hydrocephalus. The tumours were examined microscopically : ten were astrocytomas, three spongioblastomas polare, and one a glioblastoma multiforme. was

cause

!

Discussion

Pontine glioma usually presents with one or more cranial-nerve palsies, cerebellar and pyramidal signs, and without any evidence of raised intracranial pressure. This i has been the most common mode of presentation in our experience, but in 6 cases raised intracranial pressure was either the first symptom or appeared early in the course of the disease. The frequency and similarity of mental disorders in cases of pontine glioma-which has not been stressed previously, except by Cairns (1950)-is of interest. In our series the mental changes were striking, appearing early in the course of the disease, and in 5 children they started the clinical picture. No patients with I mental symptoms presented with signs of increased intracranial pressure, and this must indicate that the mental changes were produced by the tumour itself. In all cases with mental disorders that came to necropsy the tumour extended to involve the medulla oblongata. It is interesting that Foerster et al. (1939) found mental disorders in 18 out of the 34 cases of tumour of the medulla oblongata. The presence of a pontine glioma must be confirmed by air studies in order to give an adequate prognosis. We have performed ventriculography under general anoes- i thesia in preference to lumbar air encephalography because we believe it is both easier and safer in children. i 8 other cases, not included in this series, were admitted to this hospital in the same period and diagnosed as gliomas on clinical grounds. In most of these cases air studies were not performed, because the clinical picture was so typical of the disease. These cases had a poor prognosis and were not treated. 4 of them are still alive after thirteen, ten, eight, and five years respectively and in almost all of them the symptoms have regressed. The difference between the length of survival in these patients and those in whom a tumour was confirmed by ventriculography suggests that they did not have a pontine glioma. The surgical management of pontine glioma is now limited to the control of hydrocephalus when present, and for this a ventriculoatrial shunt seems to be the most suitable method. We believe that exploration of the posterior fossa and direct visualisation and biopsy of the tumour, as has been advocated by other workers, is "

pontinei

I

unnecessary, because the

diagnosis is satisfactorily confirmed by ventriculography alone. 3 of the patients with papilloedema were given high-voltage therapy-alone in 2 and after insertion of a ventriculoatrial shunt in 1. After high-voltage therapy the papilloedema quickly disappeared in all 3 cases, suggesting that surgical measures to control hydrocephalus may not always be necessary. The histological classification of pontine gliomas has frequently been discussed. Buckley (1930) examined 25 verified cases of glioma of the pons and classified 10 as glioblastoma multiforme, 14 as astrocytoma (of which he named 1 as astroblastoma, 6 as fibrilare astrocytoma, 2

915

CLINICAL AND PATHOLOGICAL SIGNIFICANCE OF ASYMPTOMATIC ATROPHIC THYROIDITIS A Condition of Latent Hypothyroidism

protoplasmic astrocytoma, and 5 as spongioblastoma polare) and 1 unclassified. He reported four months as

being the

average survival-time in the group of and two years in the astrocytomas. In Thomson’s (1959) series 12 were glioblastomas, 10 astrocytomas, 1 spongioblastoma polare, and 1 ganglionneuroma. In Bray et al.’s series (1958) of 10 cases 5 showed varying degrees of glioblastomatous changes arising from an astrocytoma, 3 were astrocytomas, and 2 were spongioblastomas polare. In our series 10 cases were classified as astrocytomas, 3 as spongioblastomas polare, and 1 as glioblastoma multiforme, and this shows the difficulty in classification, especially

as

glioblastomas Jackson and

between glioblastoma and astrocytoma. Ingraham and Matson (1954) suggested that all these tumours should be called mixed gliomas since most of them show areas of glioblastoma multiforme, astrocytoma, and spongioblastoma polare. In our series there was no relation between the type of tumour and length of survival. The commonest cause of death was sudden respiratory and circulatory arrest and in these cases massive necrosis and haemorrhage within the tumour was found. High-voltage therapy improved the clinical condition of the patients and increased the length of survival and its quality. Some workers have reported survival-times of many years after high-voltage therapy; but this has not been our experience, for none of our patients lived longer than two years with or without treatment. The mean survival-time of patients treated with high-voltage therapy was 15-1 months in this series, whereas in the untreated patients it was 4-0 months. The selection of patients for high-voltage therapy was according to the year in which they were admitted and not on clinical grounds and although the patients were not randomised the improved survival of those treated is nevertheless

highly statistically significant. Nearly everybody agrees a high dosage is essential in the treatment of these tumours. Redmond (1961) examined 42 cases (of which 29 were children) and of these, 30 received high-voltage therapy of different dosages. He concluded that less than 2000r is below the optimal range and that the tumour dose should be 4000r in four weeks. Ingraham and Matson (1954) recommended 3000r and the same dose is recommended by Jackson and Thomson (1959). Bray et al. (1958) gave 4000r in adults and scaled down the dose in children. Our radiotherapists have been using a higher dosage than these workers, about 4500r (Finney 1966). We have had little success with further courses of high-voltage therapy after a relapse. that

We thank Mr. R. A. McNay, statistician to the Newcastle Regional for his help and advice. Requests for reprints should be addressed to L. P. L., Regional Neurological Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne 4.

Hospital Board,

REFERENCES

Bray, P. F., Carter, S., Taveras, S. M. (1958) Neurology, 8, 1. Buckley, R. C. (1930) Archs Path. 9, 779. Cairns, H. (1950) Fol. psychiat. neurol. neurochirurg. neerl. 53, 193. Finney, R. (1966) Personal communication. Foerster, O., Gagel, O., Mahoney, W. (1939) Arch Psychiat. Nervenkr. 110, 1. C. C., Woolf,

Hare,

A. (1934) Arch Neurol. Psychiat. 32, 1230. D., Matson, D. D. (1954) Neurosurgery of Infancy and Childhood. Springfield, Illinois. Jackson, I. J., Thomson, R. K. (1959) Pediatric Neurosurgery. Springfield,

Ingraham,

F.

Illinois.

Lysholm, E. (1946) Br. J. Radiol. 19, 437. Redmond, S. S., Jr. (1961) Am. J. Rœntegnol. 86, 644. Sutton, D. (1953) Acta radiol. 40, 234. Torkildsen, A. (1939) Acta chir. scand. 82, 117. Walker, A. E., Hopple, T. L. (1949) J. Pediat. 35, 671.

P. A. BASTENIE

P. NEVE

M.D. Brussels

M.D. Brussels

PROFESSOR OF MEDICINE

RESIDENT IN MEDICINE

M. BONNYNS

L. VANHAELST

M.D. Brussels

M.D. Brussels

RESIDENT IN MEDICINE

RESEARCH FELLOW

M. CHAILLY M.D. Brussels ASSISTANT IN PATHOLOGICAL ANATOMY

From the

Departments of Medicine and Pathological Anatomy, University Hospital St. Pierre, Brussels, Belgium

Summary

By the Boyden tanned-red-cell test, thyro-

globulin antibodies (T.G.A.) have been detected in a large percentage of over 2000 patients admitted to hospital for various diseases. Post-mortem controls in nearly 250 cases with and without circulating T.G.A. have indicated a very high correspondence of these antibodies with the presence of a process of atrophic asymptomatic thyroiditis. This condition, which is to be distinguished from Hashimoto’s thyroiditis, is prevalent in

and its incidence increases with age. Its development is associated with other autoimmune diseases, with diabetes, and with obesity. Although clinical signs of hypothyroidism are absent, biological signs are indicative of latent thyroid failure. women

Introduction LYMPHOCYTIC thyroiditis is often found at necropsy of patients who during life had neither goitre nor clinical signs of thyroid disease and who had died from various causes (Simmonds 1923, Bastenie 1937, 1944, Goudie et al. 1959, Williams and Doniach 1962). This conditionwhich is known as focal thyroiditis, Hashimoto’s thyroiditis without struma, incipient Hashimoto’s thyroiditis, among others-is probably best called " asymptomatic atrophic thyroiditis ". The affected thyroid is of normal or, in most cases, decreased size and weight. The focal or diffuse lesions comprise lymphoplasmatocytic infiltrations and characteristic lesions of the parenchyma, often indistinguishable from those in the remnants of thyroid tissue observed in the atrophic thyroid of myxoedema (Simmonds 1923, Bastenie 1944). The discovery of antithyroid antibodies in the serum of most patients with Hashimoto’s struma lymphomatosa or myxoedema (Doniach and Roitt 1957) has been correlated with the inflammatory lesions found in the thyroid of these patients (Smart and Owen 1963). The presence of the same thyroglobulin and thyroid microsomal antibodies in the serum of patients without clinical signs of thyroid disease has led to the notion that the presence of these circulating antibodies reflects the existence in the thyroid of an asymptomatic inflammatory process (Goudie et al. 1959, Bastenie et al. 1965). We have attempted to determine the pathological and clinical significance of this asymptomatic atrophic

thyroiditis.

Patients and Patients and Methods Methods

Thyroglobulin antibodies (T.G.A.) have been systematically looked for in male and female patients admitted with various diseases to the medical wards of this hospital. Patients with a detectable goitre or with a recent history of thyroid disease were excluded. The only screening method used was the