Arch Dis Child: first published as 10.1136/adc.48.3.239 on 1 March 1973. Downloaded from

Short reports 239 syndrome may develop well after the treatment of Scott, V., and Clark, E. G. (1946). Syphilitic nephrosis as a manifestation of a renal Herxheimer reaction following penicil- syphilis has been initiated. lin therapy for early ayphilis. American Journal of Syphilis, Scott and Clark (1946) reported what they Gonorrhea and Venereal Diseases, 30, 463. Scully, J. P., and Yamazaki, J. N. (1949). Congenital syphilitic believed to be a possible renal Herxheimer reaction nephrosis successfully treated with penicillin. American in an adult with an acquired syphilis. Their patient Journal of Diseases of Children, 77, 652. had a febrile reaction after the initiation of penicillin therapy and then developed the nephrotic syn- ROBERT SUSKIND,* JERRY A. WINKELSTEIN, and drome 14 days later. Our patient had no known GERALD A. SPEAR initial manifestations of the Herxheimer reaction. The Departments of Pediatrics and Pathology, The One can only speculate as to whether Scott and Johns Hopkins University School of Medicine, Clark's case and our case may indeed represent Baltimore, Maryland, U.S.A. renal Herxheimer reaction. The pathogenesis of the nephrotic syndrome in *Correspondence to Dr. R. Suskind, Anemia and Malnutrition syphilis is obscure. However, the morphological Research Center, P.O. Box 80, Chiang Mai, Thailand. studies of others may afford a clue. Electron dense deposits in the area of the glomerular base- ment membrane have been described in adults with syphilis and the nephrotic syndrome (Falls Severe cutaneous reactions to et al., 1965). Braunstein et al. (1970) have identi- phenytoin fied these as complement-fixing y-G2 heavy chains and A-light chains. Churg (1968) has also identi- Since the first reports of the effectiveness of fied electron dense deposits in the glomerular phenytoin in the treatment of epilepsy (Merrit and capillary wall of an infant with syphilis and the Putnam, 1938), it has established itself as the drug nephrotic syndrome. Poilner (1966), utilizing light of choice in many of the forms of epilepsy. The microscopy, reported glomerular basement mem- many side effects reported are usually attributed to brane thickening in a similar case. Thus the blood levels in excess of 20 .tg/ml (Kutt and copyright. nephrotic syndrome in congenital syphilis appears McDowell, 1968). Signs such as gingival hyper- to be associated with what are ordinarily considered trophy and skin rashes are not usually related to 'immune deposits' in the region of the glomerular phenytoin blood levels but indicate a sensitivity basement membrane: these apparently regress to the drug. with clinical improvement (Falls et al., 1965). The purpose of this paper is to describe a child who developed a fatal skin reaction to the drug when only therapeutic blood levels of the drug Summary were reached, and another case where a severe http://adc.bmj.com/ A 3-month-old infant with congenital syphilis sensitivity reaction was associated with toxic developed the nephrotic syndrome 14 days after blood levels of the drug. having been adequately treated with penicillin. This case is believed to be the first reported Case reports instance of nephrotic syndrome occurring in Case 1. A 10-year-old boy was admitted with a congenital syphilis after treatment with an adequate history of six generalized seizures within 1 year. There dose of penicillin. was no previous history of illness in himself or his on September 25, 2021 by guest. Protected family. He had received no anticonvulsant therapy. REFERENCES Physical examination was normal. EEG indicated an active epileptogenic focus in the right midtemporal Braunstein, G. D., Lewis, E. J., Galvanek, E. G., Hamilton, A., and Bell, W. R. (1970). The nephrotic syndrome associated region, involving the cortex. He was given phenytoin with secondary syphilis. An immune deposit disease. Ameri- 200 mg daily. He had no further convulsions, but 10 can J3ournal of Medicine, 48, 643. days after starting phenytoin he developed a morbilli- Churg, J. (1968). Electron microscopic aspects of renal pathology. In Structural Basis of Renal Disease, p. 132. Ed. by E. L. form rash. Blood phenytoin level on this day was Becker. Hoeber, Harper, New York. 18 * 3 ,ug/ml. Phenytoin was stopped. By the next Falls, W. F., Ford, K. L., Ashworth, C. T., and Carter, N. W. day the rash had extended and became more intense. (1965). The nephrotic syndrome in secondary syphilis: Bullous formation occurred and he became ill and toxic. report of a case with renal biopsy findings. Annals of Internal Medicine, 63, 1047. Rupture of the bullae and leak of serous fluid occurred. Platou, R. V., Hill, A. J., Ingraham, N. R., Goodwin, M. S., Intravenous fluids, antihistamines, and analgesics were Wilkinson, E. E., and Hansen, A. E. (1946). Effect of penicillin given. Dermatological opinion confirmed a diagnosis in the treatment of infantile congenital syphilis; further observa- the rash tions. American J7ournal of Diseases of Children, 72, 635. of Stevens-Johnson syndrome, being confluent, Pollner, P. (1966). Nephrotic syndrome associated with congenital sheets of skin desquamating, and the oral mucosa, by syphilis. Journal of the American Medical Association, 198, 263. now, being affected. Arch Dis Child: first published as 10.1136/adc.48.3.239 on 1 March 1973. Downloaded from

240 Short reports Tetracycline and prednisolone 60 mg/day were given. None of these reports gave blood phenytoin 600 ml whole blood followed by plasma were then levels at the time of the onset of the rash. The required. He was confused and restless, and became child with the fatal reaction reported here had incontinent. therapeutic blood levels of phenytoin throughout Continuous serous fluid loss occurred. By this stage the trunk and abdomen were totally desquamated the period when the rash began, phenytoin being and areas of the upper and lower limbs were involved. measured by the method described by Dawson He became dyspnoeic and cyanosed, and radiology and Jamieson (1971). On the other hand, the confirmed an extensive bronchopneumonia. 13 days child with the less severe reaction had grossly after the onset of the rash he died. At no stage during raised blood levels and the toxic signs of ataxia the illness were there biochemical changes to suggest and nystagmus. The initial dosage of phenytoin hepatitis. Terminally, blood urea rose to 180 mg/100 ml. in this child was excessive. An initial dosage of Necropsy permission was refused. 100 mg twice daily (10 mg/kg) should have been prescribed, then a probable reduction to 5 mg/kg Case 2. This 10-year-old girl was admitted with uncontrolled centrecephalic epilepsy. Numerous anti- monitored by blood phenytoin levels. convulsants had been tried before admission, all with The differing severity and outcome of these two little effect. Phenytoin had not been used previously. cases suggest that skin reactions are indeed a A further EEG showed a greater frequency of discharges sensitivity reaction to the drug and not a toxic and she was given phenytoin. On the first day she reaction associated with raised phenytoin levels. received 400 mg and this was reduced to 300 mg/day Immediate cessation of the drug is indicated. on the following day. She rapidly developed signs of These two children fit into the described pattern toxicity with nystagmus and ataxia. The blood in which the rash develops 8 to 10 days after phenytoin level reached 35*7 ,ug/ml. 9 days after ingestion of the drug and tends to be morbilliform. starting phenytoin a macular rash developed on the trunk and face. Phenytoin was stopped. The rash Both children had negative antibody titres to measles, progressed rapidly and became confluent over the face. in that no rise in titre developed over the period She was pyrexial and confused, with periorbital oedema of their illnesses.

and a severe erythematous morbilliform rash over her copyright. face, trunk, and abdomen and, to a lesser degree, the Summary limbs. She was treated with antihistamines, steroids, Two 10-year-old children are described who were and local therapy. A further 3 days elapsed before the rash showed any improvement. 8 days after the onset, treated with phenytoin for epilepsy, both of whom the rash had almost cleared. The child was apyrexial developed a severe cutaneous reaction, which and alert. Convulsions were partially controlled at proved fatal in one child. The severer reaction this time by diazepam. was accompanied by therapeutic blood levels of while the milder reaction was associated phenytoin, http://adc.bmj.com/ with grossly raised levels. It is suggested that Discussion such skin reactions to phenytoin are a sensitivity Skin reactions occur in about 5% of patients response, rather than a toxic reaction. receiving phenytoin. Reactions usually occur 10 to 14 days after the start of treatment. The classi- cal reaction is a morbilliform rash, but occasionally REFERENCES occur Dawson, K. P., and Jamieson, A. (1971). Value of blood phenytoin. scarlatiniform or urticarial rashes (Living- Estimation in management of childhood epilepsy. Archives of ston, 1956). Disease in Childhood, 46, 386. on September 25, 2021 by guest. Protected Fatal cases are extremely rare, two cases only Gropper, A. L. (1956). Diphenylhydantoin sensitivity. Report of a fatal case with hepatitis and exfoliative dermatitis. New having been reported, both in adults. Gropper England Journal of Medicine, 254, 522. (1956) described a 29-year-old man who developed Heller, G., and Sloane, M. (1950). Erythema bullosum malignans following dilantin therapy. Pediatrics, 5, 836. jaundice, exfoliative dermatitis, eosinophilia, and Kutt, H., and McDowell, F. (1968). Management of epilepsy lymphadenopathy; terminally ulceration extended with diphenylhydantoin sodium. J3ournal of the American to include lips, eyes, oral cavity, and genitalia. Medical Association. 203, 969. Livingston, S. (1956). Treatment of epilepsy with diphenylhydan- Ritchie and Kolb (1942) described a fatal case of toin sodium (dilantin sodium) Postgraduate Medicine, 20, 584. haemorrhagic erythema. Necropsy showed exten- Merrit, H. H., and Putnam, T. J. (1938). A new series of anti- convulsant drugs tested by experiments on animals. Archives sive haemorrhagic changes in the skin, mouth, of Neurology and Psychiatry, 39, 1003. and gastrointestinal tract, and pulmonary oedema Ritchie, E. B., and Kolb, W. (1942). Reaction to sodium diphenyl and oedema ofthe brain. The only child mentioned hydantoinate (dilantin sodium). Archives of Dermatology and in the literature is a nonfatal case of erythema Syphilology, 46, 856. bullosum malignans in a 9-year-old (Heller and K. P. DAWSON Sloane, 1950). Paediatric Unit, Law Hospital, Carluke, Lanarkshire.