Develop. Med. Child Neurol. 1976,18,W-98

Annotations ENCEPHALITIS AND ENCEPHALOPATHY IN CHILDHOOD LEUKAEMIA WHENa child with leukaemia presents with a central nervous system (CNS) disorder it is usual to suspect meningeal or cerebral leukaemic infiltration. Presentation is with headache, lethargy, rapid weight-gain, cranial-nerve palsies or papilloedema'. Usually the diagnosis is readily made by finding blast cells in the CSF, although occasionally these may be difficult to demonstrate unless cytocentrifugation techniques are used2. WESTet aL3 have shown the incidence of CNS leukaemia to be inversely correlated with the platelet count at the time of initial diagnosis. They suggest that leukaemic cells usually enter the CNS from the blood as a result of intracranial petechial haemorrhages occurring around the time of initial diagnosis of leukaemia. The blood-brain barrier then protects these cells from the action of antileukaemic drugs given systemically, allowing them to proliferate even when there is continuing haematological remission. Until recently, some 35 per cent of children treated for acute lymphoblastic leukaemia have shown CNS leukaemia within a year of the original diagnosis4. Using actuarial methods, WESTet aL3 have estimated that, if there were no deaths from other causes, 75 per cent of patients would develop CNS leukaemia within 23 years. Recently several centres have shown that cranial or cranio-spinal x-radiation, usually given together with a course of intrathecal methotrexate soon after the initial remission has been achieved, can largely prevent the occurrence of CNS leukaemia4*5. Following these reports, most treatment regimes routinely include early CNS prophylaxis given in this way. Nowadays meningeal leukaemia is being seen much less commonly, and other conditions may have to be considered when a child with leukaemia presents with a CNS disorder. Children with iatrogenic immunodepression or immune-deficiency diseases are known to be unusually susceptible to viral infections. V U I Ahas ~ reported a child who, three years after diagnosis of acute leukaernia and shortly after successful treatment for a haematological relapse, developed an encephalitic illness with seizures, fever and coma which led to his death two weeks later. Neuropathological studies showed micronodular inflammatory lesions with eosinophil intranuclear inclusions in glial cells, affecting mainly thalamus, substantia nigra, dentate nucleus of the cerebellum, tegmentum of the medulla and ventral pons. He suggests the antileukaemic therapy had, by immunosuppression, allowed viral invasion of the brain to produce the micronodular encephalitis. Children undergoing treatment for leukaemia are at risk for severe generalised infections with cytomegalovirus, varicella-zoster and herpes simplex viruses, and in any of these infections there may be an associated encephalitis'. *. Recently there have been a few reports of atypical subacute sclerosing panencephalitis (SSPE) occurring in children with le~kaemia~-'~. One of the cases reported by BREITFELD' had been in his second remission for eight months when he developed a fairly acute encephalitic illness. Five months earlier his two sibs had had typical measles 90


but he never developed a rash. He died 1 1 days after the onset of the encephalitic symptoms and autopsy showed Hecht’s giant-cell pneumonia, together with the histological changes of a n inclusion body encephalitis. Serum taken at postmortem showed no elevation of measles antibody titre. BREITFELD’S other case developed a slowly progressive encephalitic illness four months after having measles without a rash. He died in coma two months later. Neuropathological studies showed SSPE changes but without much gliosis, and postmortem serum contained a high titre of measles antibody. SLUCA et al.l0 described a leukaemic child in remission who had an apparently uncomplicated attack of measles and who, two months later, developed an acute encephalitic illness which led to death within two weeks. At autopsy there was evidence of inclusion body encephalitis, without inflammatory reaction. Electronmicroscopy gave evidence of a paramyxovirus infection with disturbed nucleocapside synthesis, the hallmark of a ‘slow-virus’ process. Taken together, these reports suggest that SSPE in children with leukaemia may be acute or subacute, may or may not have a history of previous measles with or without a rash, may or may not produce elevated titres of measles antibody and, histologically, may or may not show perivascular inflammatory reaction. All the cases reported so far seem to lack the characteristic clinical features of SSPE as seen in children without leukaemia. A rare disorder usually associated with malignant disease in adult life, but which has been reported as complicating acute leukaemia in childhood, is progressive multifocal leukoencephalopathys. Scattered areas of demyelination occur, mainly in the cerebral hemispheres. Gradual clinical deterioration occurs, with spastic weakness, visual failure and dementia progressing over a period of three to six months to coma and death. Zu RHEIN and C H O U ’have ~ shown the presence of papova-like viruses in the CNS in this condition. Results of CSF and neuroradiological studies are usually normal but electronmicroscopy of urinary sediment and viral culture may demonstrate papova-like viruses during life. Children with leukaemia are susceptible to infection with Toxoplasma gondii, which produces an atypical ‘glandular fever’ type of illness with a predilection for CNS involvement in patients with malignan~iesl~. Cerebral toxoplasmosis tends to run a subacute course, with headache, drowsiness, seizures, cranial-nerve palsies and spastic weakness. The CSF may have raised protein and pleocytosis, and electroencephalogram (EEG) usually shows diffuse slowing. The Sabin dye test will demonstrate a raised titre, but more definite evidence of a current infection is given by the toxoplasma fluorescent IgM test15. Cerebral toxoplasmosis is usually treated with a combination of pyrimethamine and sulphadiazine given orally. Intrathecal pyrimethamine has been used in some cases but its effectiveness is not clearly defined14. Metabolic encephalopathies associated with leukaemia tend to occur at the time of initial presentation or subsequent haematological relapse. Hyperuricaemia, caused by rapid breakdown of purines during induction or re-induction therapy, may produce uric-acid nephropathy and, less commonly, an encephalopathic illness with vomiting, stupor and convulsionsls. Both these complications can be largely prevented by pre-treatment with allopurinal, which blocks the production of uric acid by inhibition of the enzyme xanthine oxidase. Hypocalcaemia is not uncommon among children acutely ill with leukaemia and may be due to acute renal failure, blood transfusion, sepsis or corticosteriod therapy”. Hypocalcaemic symptoms, which include confusion, weakness, convulsions and stupor, respond dramatically to calcium gluconate, although occasionally an associated hypomagnesaemia requires treatment before this response is seen. Hypercalcaemia, with a normal or elevated 91


1976, 18

serum phosphorus and alkaline phosphatase, can occur in acute leukaemia and may indicate a poor prognosis18. Destruction of bone by leukaemic cells is the probable mechanism. Increasing hypercalcaemia produces confusion, muscular weakness and eventual coma. Effective antileukaemic therapy will bring the serum calcium to normal levels and relieve these symptoms. Lactic acidosis may develop in patients with rapidly progressing leukaemia, in whom large aggregates of leukaemic cells are metabolizing a n a e r ~ b i c a l l y Kussmaul ~~. respirations occur, with confusion and lethargy which, with increasing lactic acidosis, may progress to coma. Sodium bicarbonate infusion is required to reduce the metabolic acidosis until antileukaemic therapy has eliminated the source of lactate overproduction. Central pontine myelinolysis has been found a t necropsy in some children with acute leukaemiazO,zl. Pathologically, there is a symmetrical demyelination in the central portion of the basis pontis. A metabolic cause seems likely, as it has also been described in children with hepatic failure and in a variety of chronic debilitating illnesseszz.The clinical manifestations of central pontine myelinolysis are largely unknown, possibly because subtle neurological signs are not obvious in a child with a severe and complicated systemic illness, or because this area of the pons is ielatively ‘silent’ in functional terms. Encephalopathic disturbances can be produced directly by some of the agents used at present in the treatment of acute leukaemia. Coma and convulsions lasting several days may occur during or soon after a course of vincristine therapy in as many as 3 per cent of childrenz3. The mechanism is not usually understood, but a few cases have been associated with hyponatraemia ascribed to inappropriate secretion of antidiuretic hormone2*. The EEG shows generalised slow activity, the CSF is normal and full recovery is the rule. Further vincristine therapy may be possible without subsequent ill-effectsZ3.Methotrexate has been implicated in the pathogenesis of disseminated necrotizing leukoencephalitis, a distinctive degenerative condition which is being seen with increasing frequency in children with acute l e ~ k a e r n i a ~ This ~ - ~ ~complication . arises during or shortly after a course of intrathecal or intravenous methotrexate, given either for prophylaxis or treatment of meningeal leukaemia. Somnolence, ataxia, spasticity and seizures occur and, despite discontinuation of methutrexate therapy, may progress over a period of weeks or months to dementia, coma and death. At necropsy the changes consist of diffuse astrocytosis and multiple necrotic foci in the telencephalic white-matter without inflammatory reaction or inclusion bodies. Calcification may be prominent in cases with a chronic coursez9. Przservatives present in methotrexate used intrathecally have been incriminated30, but PRICEand J A M I E S O N ~feel ~ this is unlikely as the only methotrexate received by seven of their 13 cases before the onset of encephalopathy had been without the usual benzyl alcohol preservative. Almost all reported cases of disseminated necrotizing leukoencephalopathy have received cranial radiation before the intrathecal or intravenous methotrexate. PRICEand JAMIESON believe that this cranial radiation acts to reduce the blood-brain barrier, allowing methotrexate to penetrate readily into the cerebral white-matter and produce the progressive necrotic changes. L-asparaginase is used as a remission-inducing drug in some children failing to respond to vincristine. Symptoms of a mild encephalopathy (lethargy, depression, disorientation and hallucinations) occur in a number of children receiving this drug31. They are accompanied by a diffuse slowing of the EEG and are correlated with elevation of blood-ammonia levels in affected patients. These symptoms clear promptly when the drug is discontinued. The syndrome of increased intracranial pressure with headache, vomiting and papilloedema, following rapid withdrawal of corticosteroids after prolonged therapy,



is now well known32, but may still occur in some children being treated with these drugs for acute leukaemia. Cerebral radiation therapy given either prophylactically or to treat meningeal leukaemia is commonly followed by a transient cerebral disturbance some six weeks after completion of the course of treatment. FREEMAN et a/.33found that 39 per cent of 28 leukaemic children receiving prophylactic cranial radiation developed somnolence, anorexia and lethargy at about this time and a further 39 per cent developed these features in a mild form. EEGS showed moderate diffuse slowing, but all children went on to make a complete recovery. These workers believe this syndrome represents a transient radiation encephalopathy resulting from inhibition of myelin synthesis. Not all children with acute leukaemia who develop evidence of a CNS disorder will be found to have an encephalopathy or meningeal leukaemia. Other intracranial disorders also occur more frequently and may be amenable to treatment if diagnosed early. Subdural and subarachnoid haemorrhage may occur with minor trauma in the presence of thrombocytopenia. Intracerebral haemorrhages, on the other hand, are commonly associated with leukaemic infiltrations’. 31. Meningitis or cerebral abscess can complicate many of the infections to which children with depressed immunological function are prone. The organisms involved may be bacterial or fungal and in other circumstances are often of low pathogenicity. Modern treatment of leukaemia is complicated and potentially dangerous but does offer the promise of a 50 per cent five-year remission rate35and, in a minority, even the possibility of long-term survival36. With the advent of routine CNS prophylaxis, meningeal leukaemia is becoming much less common, but other CNS disorders are being recognised, many of which are directly or indirectly related to current treatment methods. A leukaemic child with evidence of a CNS disorder requires careful evaluation. DAVID MELLOR City Hospital, Hucknall Road, Nottingham NG5 IPB. REFERENCES I . Lascari, A. D. (1973) Leukenria in Childhood. Springfield, Ill.: Charles C Thomas. 2. Komp, D. M. (1972) ‘Cytocentrifugation in the management of central nervous system leukemia.’ Journal of Pedi(ttrics. 81, 992. 3 . West, R. J., Graham-Pole, J.. Hardisty, R. M., Pike, M. C. (1972) ‘Factors in pathogenesis of central nervous system leukaemia.’ British Meilircrl Journal, 3, 3 1 1. 4. Medical Research Council (1973) ‘Treatment of acute lymph&lastic leukaemia: effect of “prophylactic” therapy against central nervous system leukaemia.’ British Mecliccrl Journal, 2, 381. 5. Aur, R. J. A., Simone, J. V., Hustu, H. O., Verosa, M. S. (1972) ‘A comparative study of central nervous system irradiation and intensive chemotherapy early in remission of childhood acute lymphocytic leukemia.’ Cancer, 29, 381. 6. Vuia, 0. (1975) ‘Micronodular encephalitis and acute leukaemia treated with immunosuppressives in a child.’ Neuropadiatrie, 6, 307. 7. Pierce, M. I. (1962) ‘Neurologic complications in acute leukemia in children.’ Pecliofric Clinics qf North Atnerica, 9, 425. 8. Simone, J. V., Holland, E., Johnson, W. (1972) ‘Fatalities during remission of childhood leukemia.’ Blood, 39,159. 9. Breitfeld, V., Hashida, Y., Sherman, F. E., Odagiri, K., Yunis, E. J. (1973) ‘Fatal measles infection in children with leukemia.’ Lahorafory Investigation, 28, 279. 10. Sluga, E., Budka, H., Pichler, E. (1975) ‘Slow-virus “encephalitis” following measles in a child with cytostatically-treated leukaemia.’ Wiener Klinische Wochenschrif, 87, 248. 1 I . Kay, H. E. M. (1975) Personal communication. 12. Mellor, D. H. (1976) ‘Encephalopathy and encephalitis in childhood leukaemia.’ Paper presented to the Durham meeting of the British Paediatric Neurology Association. 13. Zu Rhein, G . M., Chou, S. M. (1968) ‘Papova virus in progressive multifocal leukoencephalopathy.’ Research Pirblications of the Association .for Research in Nervous and Mental Disease, 44, 307. 14. Vietzke, W. M., Gelderman. A. H., Grimley, P. M., Valsamis, M. P. (1968) ‘Toxoplasmosis complicating malignancy.’ Cancer, 21, 816.



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15. Remington, J. S., Miller, M. J., Brownlee, I. (1968) ‘IgM antibodies in acute toxoplasmosis: 1. Diagnostic significance in congenital cases, and a method for their rapid demonstration.’ Pediatrics, 41, 1082. 16. Sinks, L. F., Newton, W. A., Nagi, N. A., Stevenson, T. D. (1966) ‘A syndrome associated with extreme hyperuricemia in leukemia.’ Journal of Pediatrics, 68, 578. 17. Jaffe, N., Kim, B. S., Vawter, G. F. (1972) ‘Hypocalcemia-a complication of childhood leukemia.’ Cancer, 29, 392. 18. Stein, R. C. (1971) ‘Hypercalcemia in leukemia.’ Journal of Pediatrics, 78, 861. 19. Field, M., Block, J. B., Levin, R., Hall, D. P. (1966) ‘Significance of blood lactate elevations among patients with acute leukemia and other neoplastic proliferative disorders.’ American Journal of Medicine, 40, 528. 20. Rosman, N. P., Kokulas, B. A., Richardson, E. P. (1966) ‘Central pontine myelinolysis in a child with leukemia.’ Archives of Neurology, 14, 273. 21. Cadman, T. E., Rorke, L. B. (1969) ‘Central pontine myelinolysis in childhood and adolescence.’ Archives of Disease in Childhood, 44, 342. 22. Valsamis, M . P., Peress, N. S., Wright, L. D. (1971) ‘Central pontine myelinolysis in childhood.’ Archives of Neurology, 25, 307. 23. Martin, J., Mainwaring, D. (1973) ‘Coma and convulsions associated with vincristine therapy.’ British Medical Journal, 4, 782. 24. Whittaker, J. A., Parry, D. H., Bunch, C., Weatherall, D. J. (1973) ‘Coma associated with vincristine therapy.’ British Medical Journal, 4, 335. 25. Kay, H. E. M., Knapton, P. J., OSullivan, J. P., Wells, D. G., Harris, R. F., Innes, E. M., Stuart, J., Schwartz, F. C. M., Thompson, E. N. (1972) ‘Encephalopathy in acute leukaemia associated with methotrexate therapy.’ Archives of Disease in Childhood, 47, 344. 26. Duttera, M. J., Bleyer, M. A., Pomeroy, T. C., Leventhal, C. M., Leventhal, B. G. (1973) ‘Irradiation, methotrexate toxicity and the treatment of meningeal leukaemia.’ Lancet, ii, 703. 27. Price, R. A., Jamieson, P. A. (1975) ‘The central nervous system in childhood leukemia. 11. Subacute leukoencephalopathy.’ Cancer, 35, 306. 28. Rubinstein, L. J., Herman, M. M., Long, T. F., Wilbur, J. R. (1975) ‘Disseminated necrotizing leukoencephalopathy :A complication of treated central nervous system leukemia and lymphoma.’ Cancer, 35, 29 1. 29. Flament-Durand, J., Ketelbant-Balasse, P., Maurus, R., Regnier, R., Spehl, M. (1975) ‘Intracerebral calcifications appearing during the course of acute lymphocytic leukemia treated with methotrexate and x-rays.’ Cancer, 35, 319. 30. Saiki, J. H., Thompson, S., Smith, F., Atkinson, R. (1972) ‘Paraplegia following intrathecal chemotherapy.’ Cancer, 29, 370. 31. Pratt, C. B., Choi, S. I., Holton, C. P. (1971) ‘Low-dosage asparaginase treatment of childhood acute lymphocytic leukemia.’ American Journal of Diseases of Children, 121,406. 32. Walker, A. E., Adamkiewiez, J. J. (1964) ‘Pseudo-tumor cerebri associated with prolonged corticosteroid therapy: Reports of four cases.’ Journal of the American Medical Association, 188, 779. 33. Freeman, J. E., Johnston, P. G. B., Voke, J. M. (1973) ‘Somnolence after prophylactic cranial irradiation in children with acute lymphoblastic leukaemia.’ British Medical Journal, 4, 523. 34. Nieri, R. L., Burgert, E. O., Groover, R. V. (1968) ‘Central nervous system complications of leukemia: A review.’ Mayo Clinic Proceedings, 43, 70. 35. Aur, R. J. A. (1974) rn Cleyton, F. J., Crowther, D., Malpas, J. S. (Eds.) Reviews in Leukaemia and Lymphoma, Vol. 1. Advances in Acute Leukaemia. Amsterdam: North Holland. 36. Burchenal, J. H., Murphy, M. L. (1965) ‘Long term survivors in acute leukemia.’ Cancer Research, 25, 1491.

BEHAVIOUR DISORDER: A PREVENTABLE LATE SEQUEL OF ILLNESS IN CHILDHOOD A recent paper by SIGAL and GAGNON’ discusses the effects of parental and medical worry about a child’s acute and serious illness on that child’s subsequent behaviour. As it stands, the paper is rather hard to absorb using as it does criteria for (and descriptions ot) behavioural disturbance which are based on other papers which readers may not have readily to hand. It does, however, give several important reminders which are worthy of further comment. Firstly: Parents know when they are worriers and their children know it too. Secondly: Paediatricians usually know when a child is seriously ill, and what is the likely prognosis in terms of length of acute illness and subsequent progress. Thirdly: Paediatricians have a good idea which illnesses are likely to worry parents most and in which of these the worry may persist inappropriately.


Encephalitis and encephalopathy in childhood leukaemia.

Develop. Med. Child Neurol. 1976,18,W-98 Annotations ENCEPHALITIS AND ENCEPHALOPATHY IN CHILDHOOD LEUKAEMIA WHENa child with leukaemia presents with...
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