Develop.Med. Child ,Veiirol. 1975, 17, 493-51 6

Case Reports Neonatal Disseminated Herpes Simplex Virus Infection with Encephalitis Treated with Cytosine Arabinoside R. S. Brown

B. D . Bower cases reported only one had evidence suggestive of encephalitis and this was unproven. The case report which follows appears to be the first proven case of herpes simplex encephalitis in a neonate treated with cytosine arabinoside (Ara C ) .

Introduction The incidence of herpes simplex virus (HSV) infections in the newborn has been estimated at between 1 in 3500 and 1 in 30,000 in the United States (Nahmias et al. 1970). No estimate has been published in Britain, but the paucity of reported cases suggests that the infection is less common. Until fairly recently no therapy has been available for the specific treatment of herpes virus infections. Since the first report of the use of 5-iodo-2’-deoxyuridine (IDU) by Breeden et al. (1966), other modes of specific drug therapy have been tried, including interferon inducers (Bellanti et al. 1971) and cytosine arabinoside. After initial enthusiastic reports of the results of IDU, more careful analysis of the data has shown that this agent has little effect on the generalised disease or on its prognosis (Juel-Jensen 1973). Cytosine arabinoside has been used in the treatment of several adults with HSV infections (Juel-Jensen 1970, 1973; Hryniuk er a/. 1972, Chow et al. 1973) but there are very few reports of the use of this agent in neonatal herpes virus infections. To our knowledge there are only two reports of its use in the neonate (Chow ef al. 1973, John and Tobin 1973) and of the four

Case Report E.W. was delivered at term to an unmarried 39-year-old primipara. Pregnancy and delivery were uneventful and the infant had normal Apgar scores at birth. Birthweight was 1778g. She became mildly jaundiced on the second day of life, the maximum bilirubin being 9.0mg/100mI on the third day of life. She fed well and was discharged on the n i n t h day. From the 12th day of life her mother noticed that the infant had become drowsy and apathetic and would not feed as well as previously. In addition she developed a rather high-pitched cry. She was admitted on the 13th day of life to the Taunton and Somerset Hospital, under the care of Dr. D. Chatlacombe. On admission the infant was pyrexial and irritable and the anterior fontanelle was tense. A cluster of clear vesicles was present over the right scapular area. A lumbar puncture was performed: the CSF contained nine lymphocytes and one polymorph per mm3,and a protein of 90nig/100ml. A clinical diagnosis of septicaeinia was made and intravenous antibiotics were given. There was an initial improvement in the child‘s behaviour and feeding but the pyrexia persisted. On the 16th day of life, left-sided twitching was seen and two days later a generalised convulsion occurred. She remained drowsy thereafter and the anterior fontanelle remained tense. The CSF at this stage contained 40 red cells and 120 white cells (90 per cent lymphocytes) per mn? and a protein

Correspondence to Dr. B. D. Bower, Department of Paediatrics. Radcliffe Infirmary, Oxford OX2 6HE.

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of 90mg/100mI. Subdural taps were negative and an EEG done on the first day was normal. Herpes encephalitis seemed the probable diagnosis and the infant was transferred to the Radcliffe Infirmary, Oxford. On arrival she was found to have athetoid limb movements, poor head control, generalised hypotonia and depressed neonatal reflexes. She sucked poorly. Hepatosplenomegaly was present and there was a cluster of vesicles on the back. Vesicles were also present on the palate and the anterior nares. The CSF contained 38 polymorphs, 48 lymphocytes and 3600 red cells per mms, with a protein of 240mg/ 100ml. A diagnosis of disseminated herpes virus infection with encephalitis was made and a cerebral aspiration biopsy from the right parietal lobe was performed. Positive herpes simplex immunofluorescence of brain tissue and of vesicles from the back and nose, and histological evidence of necrotising encephalitis (Figs. 1 and 2) confirmed the diagnosis. Antibody titres to herpes virus were as follows: less than 1 in 10 on day 10; 1 in 128 on day 35; and 1 in 512 at four months. The mother's titre was 1 in 128, and though there was no growth from cervical and vaginal smears, the virus grown from the infant was type 1 (genital strain). Cytosine arabinoside (Ara C) was started o n the 20th day of life and was given by daily IV infusions for 12 days. Anticonvulsant therapy, dexamethasone and frusemide were also given. The response to the start of treatment was dramatic: the convulsions stopped, the fontanelle tension became normal and the baby became more alert. The hepatosplenomegaly improved by the 10th day of therapy, at which stage the skin and oral lesions had healed. After the 1 1th day virus

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was no longer cultured from the skin. Associated with the use of Ara C, the platelets dropped to 40,000 and the haemoglobin to 7,4g/100mI. No bleeding occurred and there was no evidence at any stage of disseminated intravascular coagulation. There was a transient rise in liver enzymes in the blood. When discharged at the age of 6+ weeks there were signs of generalised hypotonia and difficulty with feeding, which persisted until the child's death from an overdose of sedative at the age of eight months. Tube-feeding was required almost constantly and the neurological and developmental status remained poor, the infant being microcephalic and showing little attempt to grasp objects, smile or roll over. Post-mortem showed a very small brain weighing 230g (normal weight for age 950g); this was due to loss of much of the cortex and white matter of the cerebral hemispheres, the lost brain being replaced by multiple thin-walled cavities and membranes. There was histological evidence of necrosis of the neuronal layers of the hippocampus and replacement of damaged tissue by calcification (Figs. 3 and 4).

Discussion Neonatal HSV infections are usually the result of type 2 (genital strain) HSV (Nahmias et a/. 1970). Typing may be useful in isolating the infecting contact, for the isolation of type 1 suggests postnatal acquisition of the virus, although transplacental spread of type 1 has been suggested (Sieber et al. 1966, Florman el

c

Fig. 1. Photomicrograph of smear from aspiration biopsy of right parietal lobe, showing marked perivascular cellular infiltrate (H & E x 165).

Fig. 2. Haemorrhagic necrosis with margination of nuclear chromatin (arrowed) in parietal-lobe cells ( H & E x 400).

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a/. 1973). The usual mode of infection is via the mother's genital tract, either ascending infection following rupture of membranes or, more usually, by contamination during passage through the birth canal (Nahmias et al. 1970). Our case was infected by type 2 herpes. This type is almost exclusively confined to the genital tract and therefore i t is likely that transmission in our patient occurred during delivery. This hypothesis is not nullified by the negative swabs from the mother, as these were not taken until the 21st day of the puerperium. Neonatal HSV infections can be divided into three groups with different manifestations and considerable differences in prognosis. The disseminated form, with or without encephalitis, has an extremely poor outcome. 94 out of 98 cases dying and only 2 of the 98 cases surviving with no sequelae (Nahmias et al. 1970). Infants with disseminated disease may present with respiratory, liver, skin or eye manifestations, and involvement of many organs has been described. Intravascular coagulation, splenomegaly and jaundice are commonly found in this group. I n the localised group, mortality and morbidity depends on the organ involved. Those with

encephalitis as the main site of infection have a very poor prognosis. while other organ involvement has a less severe outlook. Evidence of birth damage in the survivors of the so-called 'localised' infections suggests that subclinical encephalitis can occur even in these cases. Occasional cases have been reported in which the virus has been isolated from an asymptomatic infant. suggesting that infants may be infected with HSV without showing any ill-effects. Because of the generally very poor outcome of disseminated HSV infections, any therapy which may possibly improve these figures is worth attempting. 5-iodo-2'-deoxyuridine ( I D U ) was first used in adults by Breeden e t al. in 1966. Partridge and Millis (1968) and Tuffli and Nahmias (1969) were the first to use it in the neonate. The early reports seemed promising, but it appears that death in those in whom it has been tried was unrelated to the stage of the illness when therapy was begun. to the dose or to the duration of therapy (Juel-Jensen 1973), despite good in rifro evidence of efficacy (Buthala 1964). It is used extensively in the local treatment of herpetic infections of the eye and skin. It is toxic, is difficult to prepare and administer, especially to

Fig. 3. Post-mortem photomicrograph of histological section of temporal lobe, cut coronally. bhowing laminar necrosis of neuronal layers of hippocampus, with replacement of damaged 50:. tissue by calcification ( H & E

Fig. 4. Detail of Calcified area (arrowed) seen in Fig. 3 ( H & E A 100).

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both had the disseminated form without encephalitis. In view of the poor outcome of disseminated HSV infection, even without CNS involvement, it would seem that Ara C may have been of use, though the number of cases treated is small. The use of corticosteroids in this disease is the subject of some controversy. The main reason for their use is to decrease cerebral oedema, but their action may be elsewhere (Rappel 1973). Several possible disadvantages have been postulated, including interfiron inhibition, enhancement of virus replication and decrease in antibody production (Longson and Beswick 1971, Illis and Gostling 1972). Some experimental and clinical evidence suggests that results may be worse if steroids are used (B0e et al. 1965), but it has been suggested that they are safer and more valuable if used in conjunction with antiviral agents. Illis and Merry (1972) analysed a series of their own cases and those from the literature and found that the effect appeared to be beneficial. We feel that the significant initial response of our case was likely to have been the result of steroid and diuretic treatment and not to the Ara C. Disseminated intravascular coagulation has been described in several cases and must be anticipated and treated when indicated. It did not occur in this case.

neonates, and virus resistance has been clearly shown (Tomlinson and MacCallum 1973). Interferon inducers have been used in a limited number of cases, with little benefit, and it is suggested that they may be toxic (Levy 1970, Bellanti et af. 1971). Cytosine arabinoside (1-B-D-arabinofuranosylcytosine) (Ara C ) was used in our case because of the report of its efficiency in several adult patients. The dosage suggested is lOmg per kg to start, followed by 8mg per kg per day for four days, then 6.5mg per kg per day for two days by daily intravenous infusion (Juel-Jensen 1973). We continued with the lower dose for a longer period than is recommended, because of the persistence of virus growth in the skin lesions. Experimentally, Ara C has been shown to be much more effective than IDU (Panitch and Baringer 1973), though in some cases there has been little effect on the virus by either agent (Tomlinson and MacCallum 1973). The advantage of Ara C over IDU is its relative safety, its easier preparation and the absence of reported virus resistance. Several adult cases of HSV infections have been treated with Ara C, with varying degrees of success. Assessment of its efficacy is difficult because of the small number of cases available to each investigator and because of doubt in some cases about the diagnosis of encephalitis. HSV encephalitis can only be diagnosed with certainty by brain biopsy, with positive viral culture or immunofluorescence. Inclusion bodies are non-specific. In neonatal HSV encephalitis, any success with Ara C would be evidence of efficacy, as the prognosis, once encephalitis is diagnosed, is almost invariably poor. Of the four reported cases of HSV infections in the neonate treated with Ara C, one died, one had cerebral damage and two were subsequently found to be normal. The two cases with a normal outcome

Acknowledgements: We should like to thank Mr. R. Gye, Dr. F. 0. MacCallum,, Dr. A. H. Tomlinson and Dr. T. Hughes for assisting in the diagnosis of this infant. We should also like to thank Dr. D. Challacombe. for referring the case, and Dr. J. Oxbury and Dr. B. Juel-Jensen for helpful advice. This report was presented in part at the clinical meeting of the Section of Paediatrics of the Royal Society of Medicine on 24th May 1974.

AUTHORS’ APPOINTMENTS

Dr. R. S. Brown, Senior Registrar; Dr. B. D. Bower, Consultant Paediatrician; Department of Paediatrics, The Radcliffe Infirmary, Oxford OX2 6HE.

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SUMMARY

Herpes simplex encephalitis was diagnosed by immunofluorescence and histology of a brain biopsy on the 19th day of life in a neonate in whom symptoms had begun at 12 days. Treatment with steroid, diuretic and cytosine arabinoside was begun and initially there was dramatic improvement in the symptoms. This improvement was not sustained, however. and the infant developed evidence of severe brain-damage. Disseminated herpes simplex virus infection is discussed and available therapy for this severe disease is outlined. RESUME

Infection \*iralefierphtique disshtnin@ea vec enct:plialite sio'i'eiiant ti la nnissance et traithe pur cytosine arabinoside Une encephalite herpitique a C t i diagnostiqute par immunofluorescence et etude histologique d'une biopsie cirebrale au 19eme jour de la vie d'un nourrisson ayant prisente des anomalies ;i partir du douzieme jour. U n traitement avec steroide, diuretiques et cytosine arabinoside a C t e debut6 et il y eut au depart une amklioration spectaculaire. Cette amelioration ne s'est pas maintenue et le nourrisson a prisente des symptomes d'atteinte ciribrale grave. L'infection virale herpetique dissiminee est discutie et la thirapeutique disponible pour cette grave maladie est soulignee. 2 USA M MEN FASSU NG

Die Behandlung der neonatalen dissetninierten Herpes Virus Infektion riiit Encephalitis niii Zytosin Arabinosid Bei einem Neugeborenen, bei dem am 12. Tag Symptome aufgetreten waren, wurde am 19. Lebenstag durch Immunfluoreszenz und die Histologie einer Hirnbiopsie eine Herpes Simplex Encephalitis diagnostiziert. Die Behandlung mit Steroiden, Diuretica und Zytosin Arabinosid wurde eingeleitet und anfanglich zeigte sich eine deutliche Besserung der Symptome. Diese Besserung hielt jedoch nicht an und das Kind entwickelte Anzeichen eines schweren Hirnschadens. Die disseminierte Herpes Simplex Virus Infektion wird diskutiert und es werden die vorhandenen Therapiemoglichkeiten f u r diese schwere Erkrankung dargestellt. RESUMEN

Infeccidn diseminada neonatal por virus herpr'tico coil encefalitis tratada con citosina arabinosido Se diagnostic6 una encefalitis por herpes simple, por inmunofluorescencia e histologia de biopsia cerebral, en el 19 dia de vida en u n recitn nacido en el cual 10s sintomas habian aparecido a 10s 12 dias. Se inicio un tratamineto con esteroides, diurtticos y citosina arabinbsido, con una mejoria teatral inicial de 10s sintomas. Esta mejoria no se mantuvo y el niiio desarrollo evidencia de una lesion cerebral grave. Se discute la infeccion diseminada por el virus del herpes simple, asi como la posible terapeutica de esta grave enfermedad.

REFERENCES Bellanti, J. A,, Catalano, L. W., Chambers, R . W. (1971) 'Herpes simplex encephalitis. Virologic and serologic study of a patient with an interferon inducer.' Journal of Pediafrics, 78, 136. B m , J., Solberg, C. O., Saeter, T. (1965) 'Corticosteroid therapy for acute meningoencephalitis: a retrospective study of 346 cases.' British Medical Journa!. 1, 1094. Breeden, C. J., Hall, T. C., Tyler. R. H. (1966) 'Herpes simplex encephalitis treated with systemic 5-iOdOZ'deoxyuridine.' Annals of Infernal Medicine, 65, 1050. F

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Buthala, D. A. (1964) ‘Cell culture studies on antiviral agents: 1. Action of cytosine arabinoside and some comparisons with 5-iodo-2’deoxyuridine.’ Proceedings of the Society for Experimental Biology and Medicine, 115, 69. Chow, A. W., Ronald, A., Fiala, M., Hryniuk, W., Weil, M. L., St. Geme, J., Guze, L. B. (1973) ‘Cytosine arabinoside therapy for herpes simplex encephalitis-clinical experience with six patients.’ .4ntimicrobial Areents and Chemotherapy, 3,412. Florman, A. L., Gershon, A. A., Blackett, P. R., Nahmias, A. J. (1973) ‘Intrauterine infection with herpes simplex virus. Resultant congenita! malformations.’ Journal ofthe American Medical Associa‘ion, 225, 129. Hryniuk, W., Foerster, J., Shojania, M., Chow, A. (1972) ’Cytarabine for herpes virus infections.’ Joiirnal of the American Medical Association, 219, 715. Illis, L. S., Gostling. J. V. T. (1972) Herpes Simplex Dicephalitis. Bristol: Scientechnica. p. 94. - Merry, R. T. G. (1972) ‘Treatment of herpes simplex encephalitis.’ Journal s f the Royal College of‘ Physicians,7, 34. John. R. W., Tobin. J. O’H. (1973) ‘Neonatal herpesvirus hominis infections.’ Postgradirate Medical Journal, 49, 380. Juel-Jensen, B. E. (1970) ‘Severe generalised primary herpes treated with cytarahine.’ British MedicafJoirrnal, 2, 154.

- (1974) ‘The use of idoxuridine, cytarabine and vidarahine in herpes simplex, varicella zoster, vaccinia and other DNA diseases.’ In Daikos, G. K . (Ed.)Pr0gres.r in Chemotherapy, Vol. 1, p. 932. Levy, H. B. (1970) ‘Interferon and interferon-inducers in the treatment of malignancies.’ Archives of Internal Medicine. 126, 78. Longson, M., Beswick, T. S. L. (1971) ‘Dexamethasone treatment in herpes simplex encepha!itis.’ Lancer, 1, 749. Nahmias, A. J., Alford, C. A., Korones, S. B. (1970) ‘Infection of the newborn with herpes virus hominis.’ Advances in Pediatrics, 17, 185. Panitch, H . S., Baringer, J. R. (1973) ‘Experimental herpes virus simplex encephalitis. Treatment with pyrimidine nucleosides.’ Archives of Neurology, 28, 371. Partridge, J. W., Millis, R. R. (1968) ‘Systemic herpes simplex infection in a newborn treated with intravenous idoxuridine.’ .4rchives of Disease in Childhood, 43, 377. Rappel, M. (1973) ‘The management of acute necrotising encephalitis: a review of 369 cases.’ Postgruduilte Medical Journal, 49,4 19. Sieber, 0. F., Jr., Fulgitini, V. A., Brazie, J., Umlauf, H. J., Jr. (1966) ‘In ufero infection of the fetus by herpes simplex virus.’ Journal of Pediatrics, 69, 30. Tomlinson, A. H., MacCallum, F. 0. (1973, ‘Pyrimidine analogues in the treatment of experimental herpes infeztions.’ Postgraduate Medical Journrrl, 49,4 16. Tumi, G. A., Nahmias, A. J. (1969) ‘Neonatal herpetic infection.’ American Journal qf Diseases of Children. 118,909.

Unilateral Arhinencephaly in Goldenhar-Gorlin Syndrome S. Aleksic G . Budzilovich R. Reuben J. Laguna M . Finegold J . McCarthy J . M . Converse I. Feigin related to the degree of severity of the cerebral malformations; thus the facial characteristics may predict the cerebral deformities (DeMyer et al. 1964). Recently we have had the opportunity to examine the brain of a child with the clinical features of oculo-auriculo-vertebral dysplasia and hemifacial microsomia (Goldenhar-Gorlin syndrome) who had died following corrective surgery for a cleft palate. At autopsy the brain showed unilateral absence of the olfactory bulb and tract and there were associated cerebral malformations (ipsilateral hypoplasia of the orbital gyri, hypothalamus

Introduction Arhinencephaly is the term which indicates a group of cerebral malformations in which the most characteristic feature is a bilateral absence of the olfactory tracts (Kundrat 1882, Yakovlev 1959, DeMyer and Zemen 1963). Usually the cerebral malformations are associated with facial abnormalities such as median cleft lip and palate, absence of the philtrum, and hypotelorism (Currarino and Silverman 1960, DeMyer and Zeman 1963). The type of facial abnormalities appear to be __ Correspondence to Dr. S . Aleksic, Bellevue Hospital, New York, N.Y. 10016. ~

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Neonatal disseminated herpes simplex virus infection with encephalitis treated with cytosine arabinoside.

Herpes simplex encephalitis was diagnosed by immunofluorescence and histology of a brain biopsy on the 19th day of life in a neonate in whom symptoms ...
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