Brit. J. Ophthal. (I975) 59, 362

Treatment of malignant meningitis in retinoblastoma

CLARE E. STANNARD*, R. SEALY*, D. SEVELt, AND F. A. BRINTON$From the Departments of *Radiotherapy, tOphthalmology, and tObstetrics and Gynaecology (Cytology Service), GrooteSchuur Hospital and University ofCape Town, South Africa

It has long been known that retinoblastoma canspread along the optic nerve and into the spinal cordvia the subarachnoid space (Knapp, I869).Merriam (1950) described I 7 necropsies on

children with retinoblastoma in three of whom therewas widespread involvement of the subarachnoidspace of the spinal cord by the retinoblastoma. Intwo of these cases, the tumour cells were detected inthe cerebrospinal fluid (CSF) before death.

Intracranial extension of advanced retinoblastomais a common occurrence and was found to be the onlysite of tumour dissemination in i i out of 24 necropsiesreported on by Reese (I963). Death in the remainingI3 cases was due to haematogenous spread.

Berkeley, Fuller, Sears, and Tapley (I967) statedthat intracranial spread ofretinoblastoma representedadvanced and incurable disease for which onlypalliative treatment in the form of oral endoxan andintrathecal methotrexate could be offered. Theyfound that this was effective in relieving symptoms,clearing the CSF of tumour cells, and possibly in-creasing the survival time of these patients.

In the following case reports it can be seen that thediagnosis of malignant meningitis may be suspectedon clinical examination, but is confirmed by thedemonstration of malignant cells in the CSF.The fluid is processed as soon as possible after

withdrawal. If there is likely to be any delay at all intransit, it is first fixed with an equal quantity of 50per cent ethyl alcohol. Where there is a large quantityof fluid, it is first spun down. When a button forms,the supematant liquid is gently removed to leaveabout i ml. The cells are then re-suspended and passedthrough a Millepore filter or a cytocentrifuge. Whereno button forms or where the volume of fluid is lessthan I ml, the whole specimen is either filtered orcytocentrifuged. At least four slides are preparedfrom the sample, fixed in 96 per cent ethyl alcoholand stained by the Papanicolaou method.The cytological aspects of retinoblastoma have

been described by Wieczorek (I964), Ifekwunigwe,Pulvertaft, and Williams (I966), and Spriggs andBoddington (I968). Wieczorek mentions a high

Address for reprints: C. E. Stannard, Department of Radiotherapy,Groote Schuur Hospital, Observatory, Cape Town, Cape, SouthAfrica

nucleocytoplasmic ratio and prominent nucleoli,while Spriggs and Boddington describe one case intheir series showing abundant, small, poorly-differentiated cells forming clusters. Ifekwunigwedemonstrated the cells of retinoblastoma by means ofphase-contrast.The treatment of malignant meningitis is similar to

the prophylactic treatment of the central nervoussystem in acute lymphoblastic leukaemia with cranialirradiation and intrathecal methotrexate. In thisseries, there is one survivor.No cases of retinoblastoma treated this way can

be found in the literature.

Material and methodsDuring the period February I972 to February I974, 22patients with retinoblastoma were assessed at the OcularTumour Clinic at Groote Schuur Hospital. The majorityof these patients presented with either optic nerve in-volvement or bilateral disease. Six of these patients werefound to have malignant cells in the CSF, though only twohad the clinical signs of meningitis. Five of these sixpatients were known to have had optic nerve involvement.An attempt was made initially to treat the meningitis withintrathecal methotrexate (i 2 mg/M2) and later with wholehead irradiation when the meningitis recurred.Three of the children treated this way died approxi-

mately 6 months after the beginning of the treatment,although they did achieve clinical and cytological re-mission for a period. The temporary success of this regimesuggested the more aggressive approach which was adoptedin the other cases described.

CASE I

A three-year-old African boy presented at anotherhospital with pulmonary tuberculosis in November 1971.The following February, a leucocoria of the right eye wasnoticed and an enucleation was performed. Histologicalstudies showed the features of a retinoblastoma withextension of the tumour along the optic nerve. The patientwas referred to the Ocular Tumour Clinic at GrooteSchuur Hospital and was found to be well systemnically.

Chest x ray showed collapse and consolidation withdestruction of the right upper lobe in keeping withtuberculosis. No lung metastases were noted. Orbitalx rays showed an enlarged right optic foramen. Exam-ination under general anaesthesia (EUA) showed a normal

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Treatment of malignant meningitis in retinoblastoma 363

left eye, but in the right socket there was a firm posteriororbital mass. This was biopsied and the histological studiesshowed a retinoblastoma.The patient continued the antituberculous therapy that

he had been receiving for the previous 3 months. He alsoreceived deep x-ray therapy to the right orbit (3520 r/26days) together with intravenous endoxan (three fort-nightly injections of 50 mg/kg).EUA 8 weeks after the completion of treatment showed

a contracted socket but no orbital mass. The left eyewas again normal.Two months later the patient became drowsy and was

found to have neck stiffness and clonic movements of hisarms and legs. Examination of the CSF showed clusters ofcells highly suspicious of malignancy as well as scantyinflammatory cells. Brain scan showed an area of in-creased uptake in the region of the optic chiasma. EUAshowed a raised white nodule on the temporal side of theleft disc. The patient was then treated with intrathecalmethotrexate (12 mg/M2 weekly x 6) and intravenousendoxan (30 mg/kg fortnightly). His general conditionimproved, the CSF became clear of malignant cells, buthe lost the sight in his left eye. A further EUA showedperipapillary oedema and slight disc pallor, and it wasassumed that the left optic nerve was also involved by thetumour.Three weeks after the methotrexate was stopped he

again became drowsy and ataxic. There was no neck

stiffness and no malignant cells were found in the CSF.He was treated with deep x-ray therapy to the whole head(3000 r/3I days) together with weekly intrathecalmethotrexate, and fortnightly intravenous injections ofendoxan and vincristine.The patient again recovered and remained well for 2

months, but then developed headaches and neck stiffness.x ray of the skull showed signs of raised intracranialpressure. He was treated with endoxan but continued todeteriorate and he died in April I973, I4 months after theinitial diagnosis and 6 months after the initial treatmentfor malignant meningitis.

CASE 2

A nine-year-old African boy was seen at anotherhospital in October 1972, complaining of 'progressiveswelling of the right eye' for IO months. The eye wasenucleated and the histology showed a retinoblastomawith infiltration of the optic nerve.The tumour recurred locally, and in November 1972 he

was referred to the Ocular Tumour Clinic at GrooteSchuur Hospital. On examination, the entire right orbitwas filled by a mass and the eyelids were oedematous andpainful. The left eye was normal and there was no neckstiffness. The CSF showed atypical cells (Figure) and thebrain scan showed increased uptake behind the rightorbit, compatible with spread of the tumour. Tomographs

:: :::;. SM

..s.

FIGURE Case no. 2, December I972. CSF large clusters ofpoorly differentiated malignant cells (Papanicolaou stain x 400)

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364 British Journal of Ophthalmology

of the optic canal showed marked enlargement of theright optic foramen and the optic canal throughout itslength.The patient was initially treated with intravenous

endoxan, but as the tumour continued to grow rapidly, hewas treated with deep x-ray therapy to the right orbit(4150 r/33 days), intravenous vincristine (0-5 mg weekly),and intrathecal methotrexate (12 mg/M2 weekly for 6weeks). He responded remarkably well, the tumourregressing completely, and the CSF becoming clear ofmalignant cells after 4 weeks. Brain scan at this stage alsoshowed tumour regression.He was discharged and returned for follow-up 6 weeks

later. Although symptomatically well, with no clinicalevidence of tumour, the CSF showed numerous clusters ofmalignant cells. He was treated again with intrathecalmethotrexate and deep x-ray therapy to the whole headwas started. He then developed weakness of the right armand leg and at the second intrathecal injection, there wasevidence ofa spinal block. Xrays ofthe dorso-lumbar spineshowed attenuation of the right pedicles of the twelfththoracic and first lumbar vertebrae. Deep x-ray therapy tohis head was discontinued and the spine was irradiated.He then developed glands in the right groin and a swellingof the left supraorbital ridge. Treatment was abandonedand the patient died in March 1973, I5 months after theinitial symptoms and 5 months after the initial treatmentfor malignant meningitis.

CASE 3

A two-year-old African boy had the right eye enucleatedat another hospital in April 1972. No histological studywas available. In August 1972, he had a local recurrencewhich was initially treated with methotrexate, but as therewas no response, he was then given deep x-ray therapy(3 000 r) to the right orbit.

In November 1972, the patient developed recurrenceson the forehead and was referred to the Ocular TumourClinic at Groote Schuur Hospital. There was a largefluctuant mass on the forehead and a hard mass over theright temporal region. The right socket and the left eyeshowed no sign of tumour. The CSF showed an atypicalcell and on the brain scan there was increased uptake in thefrontal area indicating metastatic spread. The aspiratefrom the fluctuant lump showed undifferentiated malignantcells.The patient was treated with deep x-ray therapy to the

whole head (3000 r/43 days), intrathecal methotrexate(i 2 mg/M2 weekly for I 0 weeks), and intravenous endoxan(30 mg/kg x 4).The masses on the forehead decreased in size. Seven

weeks after the cytotoxic therapy was discontinued, thefrontal mass again increased in size and a 6 x 5 cm massdeveloped over the ramus of the right mandible. Thepatient was not given any further treatment and died 5weeks later; I 3 months after the beginning of treatment, 2years after the initial symptoms, and 5 months after theinitial treatment with methotrexate.

CASE 4

A two-year-old African girl presented in March 1973,with gross tumour filling both eyes. The right eye was

enucleated and histological studies confirmed a retino-blastoma. As the intraocular contents of the left eye werereplaced by tumour tissue, it was also enucleated. Histo-logical studies of both eyes showed an endophytic typeof retinoblastoma, with infiltration of the right opticnerve only. The CSF showed a single cluster of degenerateatypical cells and the brain scan showed increased uptakeon the left side over the supraorbital and retro-orbitalregions.The patient was treated with intrathecal methotrexate

(I 2 mg/M2 for 6 weeks), intravenous endoxan (threefortnightly injections of 30 mg/kg), and deep x-ray therapyto the whole head (I 785 r midplane over 2 I days) followedby planned fields to the orbits (i625 r/14 days). Thebrain scan after treatment was normal, and the CSFbecame clear.

She remained well for 8 months but then had twogeneralized convulsions. There was no clinical evidence ofa recurrence, the brain scan was normal, and the CSFwas clear of malignant cells. She was given I-(2-chloro-ethyl)-3-cyclohexyl-l-nitroso-urea (CCNU) I00 mg/M2orally and continues to receive this every 2 months. Shehas remained well since and the CSF has now been clearfor 20 months.

CASE 5

A three-year-old Cape coloured girl presented inFebruary I974 with a left buphthalmos which had beenprogressive for one year after the appearance of a whitedisc in the eye. The eye was enucleated and histologicalstudies showed that it was filled with retinoblastomawhich had also infiltrated the choroid, the sclera, and theoptic nerve up to the line of excision.

Clusters of highly atypical cells were seen in the CSF.The brain scan was normal. She was treated with deepx-ray therapy to the whole head (2500 r/32 days) followedby planned fields to the left orbit (3240 r/26 days), thusgiving a maximum tumour dose of 4050 r/7i days. Shealso received CCNU 50 mg orally every 6 weeks, togetherwith six intrathecal injections of methotrexate (I 2 mg/M2)at weekly intervals.The CSF became clear, but about 3 weeks later, she

became irritable, had neck stiffness, and developed aflaccid paralysis of the legs and a hypotonic bladder.There were scanty atypical cells in the CSF, the bone scanshowed increased uptake in the upper lumbar spine, and amyelogram revealed an intramedullary mass extendingfrom the level of the second lumbar vertebra to the sacralsac.

She was treated with deep x-ray therapy to the lumbarspine (4000 r/27 days) and recovered bladder function andsome movements in the legs. She then developed a 2 cmleft submandibular gland, which contained malignantcells. Further treatment was abandoned and she died ofbronchopneumonia in July 1974.Necropsy findings showed tumour infiltration of the

arachnoid over the frontal and temporal lobes, tumourdeposits around the medulla, cerebellum, and attached tothe whole length of the cord dura. There were alsoparavertebral tumour masses associated with but notinvolving the eleventh and twelfth dorsal and first andsecond lumbar vertebrae. The left orbit volume treatedshowed no neoplasm.

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Treatment of malignant meningitis in retinoblastoma 365

CASE 6

A i6-month-old African boy presented in February1974 at another hospital with recent swelling of the righteye and a white spot, which had been present since birth.An enucleation was performed and histological studies

showed an eye filled with retinoblastoma which had alsoinfiltrated the sclera, muscular tissue, and the optic nerveas far as the line of excision. The CSF and the brain scanwere normal. EUA showed a hard tumour palpable in theposterior part of the socket. This was biopsied and thehistological studies showed a recurrence of retinoblastoma.He was treated with deep x-ray therapy to the right

orbit (3960 r/29 days) and intravenous endoxan (threefortnightly injections of 30 mg/kg). This was followed byexenteration of the right orbit and histological studies ofthe specimen showed no recurrence of the tumour.Two weeks after exenteration he became irritable and

developed neck stiffness. Lumbar puncture revealedxanthochromic and blood-stained fluid, in which therewere poorly differentiated malignant cells and mitoticfigures. Brain scan showed signs of intracranial spread.He was treated with weekly intrathecal methotrexate(I2 mg/M2) CCNU 40 mg orally and deep x-ray therapyto the whole head (ig20 r/23 days). Two weeks after theonset of meningitis, he became paraplegic with retentionof urine and developed a lump over the left temple. Bonescan showed a deposit in the mid-thoracic region and inthe left and right temporo-orbital regions. He receivedpalliative irradiation to the dorsal spine and left temple,but thereafter there was continuous deterioration in thehaematological picture, hepatomegaly, and finallybronchopneumonia.Necropsy findings revealed disseminated retinoblastoma

which had spread to many organs including the bonemarrow and spinal cord, with the notable exception of thebrain. The tumour had recurred and filled the orbit,spreading also into the extraorbital optic nerve.

DiscussionThe presence of malignant cells in the CSF is usuallyassociated with an abnormal brain scan. However,in Case 5, the brain scan was normal and in retrospectone should have looked for tumour tissue in thespinal cord, since the lesion in the dorso-lumbarregion was almost certainly present from the beginningand responsible for producing malignant cells in theCSF.

The necropsy of Case 6 was remarkable in thatthere were no intracranial metastases despite wide-spread dissemination elsewhere. It is assumed that thelow dose of cranial irradiation had been effectivewhereas intrathecal methotrexate was not so successful.As malignant meningitis due to retinoblastoma

may not be clinically overt, it is suggested that allpatients who have tumour spread along the opticnerve or orbital recurrence should have the CSFexamined for malignant cells on several occasions,and a brain and cord scan. Once a patient has beenfound to have malignant cells in the CSF, radicaltreatment should be considered. This should comprisewide field cranial and spinal irradiation, togetherwith cytotoxic therapy, at present intrathecalmethotrexate combined with suitable systemicalkylating agents. Regular follow-up examination ofthe CSF is necessary as well as other follow-upmeasures. More attention should be given to thedesign of cytotoxic schedules intended to cross theblood-brain barrier.

It is clear that prolonged survival and perhapscure (Case 4) can be attained even at a late stage ofthe disease.

Summary

Six patients with meningitis due to retinoblastomaare described. The diagnosis may be suspected onclinical examination but is made by the demonstrationof malignant cells in the CSF. These patients havebeen treated with cranial irradiation together withsystemic and intrathecal cytotoxic drugs. There isone survivor.

It is suggested that the CSF should be examined inall cases at risk so that the appropriate treatment canbe started promptly and thus improve the prognosis.

Thanks are due to Dr J. G. Burger, Medical Superinten-dent, Groote Schuur Hospital, for his permission topublish this paper.The follow-up of these cases was made possible by a

grant from the Cancer Research Trust and the Radio-therapy Research Fund.

ReferencesBERKELEY, R. G., FULLER, L. M., SEARS, M. E., and TAPLEY, N. DU V. (I967) In 'Cancer of the Head and Neck', ed.W. S. MacComb and G. H. Fletcher, p. 408. Williams & Wilkins, Baltimore

IFEKWUNIGWE, A. E., PULVERTAFT, R. J. v., and WILLIAMS, A. 0. (I966) Brit. J. Cancer, 20, 250KNAPP, H. (I869) Cited by Merriam (I950)MERRIAM, G. R. (1950) Arch. Ophthal., 44, 7IREESE, A. B. (I963) 'Tumors of the Eye', 2nd ed., p. IoI. Harper & Row, New YorkSPRIGGS, A. I., and BODDINGTON, M. M. (I968) 'The Cytology of Effusions', 2nd ed., p. 48. Heinemann, LondonWIECZOREK, V. (I964) Dtsch. Z. Nervenheilk., I86, 410

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