Seizures in children during interferon alpha therapy

Correspondence achieved. In contrast, HCV-RNA levels decreased in seven IFNtreated patients (mean 105 genome equivalents/ml before, 102 at the end of treatment) and HCV-RNA became undetectable in the remaining six patients on IFN, including the two patients who responded. However, 12 months after the end of therapy, one of these latter two patients again had HCV-RNA detectable in her serum. Our results demonstrate that no effective therapy is available for the majority of patients with HCV-RNA-positive and LKM 1-positive chronic hepatitis, no pretreatment data are helpful in predicting the outcome, and serum HCV-RNA levels do not necessarily correlate with disease activity on liver biopsy (as already suggested by others) (7). Further studies with larger numbers of patients are needed before interferon can be considered the treatment of choice for these patients. Sandro Vento 1, Francesca Cainelli 1, Ercole Concia I and Teresa Ferraro 2

2.

3.

4.

5.

lDepartment of Infectious Diseases, University of Verona, via Locchi, 12 37124 Verona and 21nfectious Diseases Unit, "'A. Pugliese'" Hospital Catanzaro, Italy 6.

References

7.

1. Homberg JC, A b u a f N, Bernard O, Islam S. Alvarez E Khalil SH, Poupon R, Darnis E I_~vy VG, Grippon E Opolon P, Bernuau J, Benhamou JP, Alagille D. Chronic active hepatitis associated with anti-liver/kidney microsome antibody type 1:

a second type of "autoimmune" hepatitis. Hepatology 1987; 7: 1333-39. Lenzi M, Ballardini G, Fusconi M, Cassani E Selleri L, Volta U, Zauli D, Bianchi FB. Type 2 autoimmune hepatitis and hepatitis C virus infection. Lancet 1990; 335: 258-59. Lunel E A b u a f N, Frangeul L, Grippon P, Perrin M, Le Coz Y, Valla D, Borotto E, Yamamoto AM, Huraux JM, Opolon P, Homberg JC. Liver kidney microsome antibody type 1 and hepatitis C virus infection. Hepatology 1992; 16: 630-36. Todros L, Saracco G, Durazzo M, Abate ML, Touscoz G, Scaglione L, Verme G, Rizzetto M. Efficacy and safety of interferon alfa therapy in chronic hepatitis C with autoantibodies to liver-kidney microsomes. Hepatology 1995; 22: 1374-78. Calleja JL, Albillos A, Cacho G, Iborra J, Abreu L, Escartin E Interferon and prednisone therapy in chronic hepatitis C with non-organ-specific antibodies. J Hepatol 1996; 24: 30812. Chomczinsky P, Sacchi N. Single-step method of R N A isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-59. Booth JC, Foster GR, Kumar U, Galassini R, Goldin RD, Brown JL, Thomas HC. Chronic hepatitis C virus infections: predictive value of genotype and level of viraemia on disease progression and response to interferon alpha. Gut 1995; 36: 427-32.

Seizures in children during interferon alpha therapy To the Editor: Interferon is widely used in hepatitis B treatment. Most side effects are well known, but there are some that are not so common. In the Journal of Hepatology, in January 1996, Dr. Obaid Shakil et al. described the occurrence of seizures in patients during alpha interferon therapy (1). In a group of 311 patients treated with alpha interferon, grand mal seizures occurred in four (1.3%) patients. The observations were made in adults, which explains the low percentage of seizures. In children treated with alpha interferon, seizures may occur more often. Between 1990 and 1995, 225 children aged 10 months-18 years with chronic hepatitis B were treated in the Child Health Center in Warsaw. In this group, 131 patients were under 5 years of age. Interferon had been given in doses of 3 MU three times weekly for 20 weeks (total dose 180 MU). Neurological symptoms (seizures or tremors) occurred in ten (4%) patients, all of them aged under 5. In the group of children aged under 5, neurological symptoms occurred in 7.6%. The clinical data of the patients are given in Table 1. In the group of ten children with neurological symptoms, five patients had low weight at birth (less than 2500 g), two had Apgar scores -<5, three were born by cesarian section, two had a previous history of seizures, one had hypocalcemic seizures in infancy and the other

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had a history of fever and convulsions, a complicated neonatal period (sixth pregnancy, cesarian section, Apgar 5) and abnormal EEG. Nine children had grand mal seizures. In seven children these occurred during high fever, shortly after interferon administration. Seizures were usually observed at about the middle of the period of interferon therapy. Seizures without high temperature were observed in three children. In one child tremors without accompanying fever were noted. In five children EEG was carried out shortly after the seizures, and in all cases the results were abnormal. During a further observation in children with abnormal EEG, epilepsy was diagnosed in three of them and only in those children did seizures recur after stopping interferon treatment. In all cases, except one, alpha interferon combined with phenobarbital anticonvulsant therapy was continued shortly after seizures. One year after the end of treatment, seven out of ten children had HBe/anti-HBe seroconversion and one of them also had HBs/anti-HBs seroconversion. Both antigens were still present only in two children. We have no information on one child. At the end of treatment both HBs and HBe antigens were positive in this child. In our experience the frequency of seizures in patients treated with alpha interferon is higher than described by Dr. Shakil et al. Our group of patients, however, differs considerably from that described

Correspondence TABLE 1 Clinical features of patients who developed seizures during alfa interferon therapy Initials Sex Age

Neonatal history

IFN dose (MU/m 2)

Initial ALT

Final ALT (12 mo after IFN)

Serological profile (12 mo after IFN)

Type of seizures

Duration and total dose of IFN before onset of seizures

JM

F

2.2/12

5.00

474

22

13 weeks (117 MU)

M

2.4/12

5.00

79

36

HBs+, H B e - , antiHBe+ HBs+, HBe+

tremors

MM

P II, BW 2980, APGAR 9 P V, BW 3500, APGAR 9

10 weeks (90 MU)

KZ

M

4.2/12

5.46

65

17

KW

M

6.37

185

5

fever, convulsions

7 weeks (63 MU)

KG

M

P II, BW 2900, APGAR 9 1.6/12 P III, prematurity, CC, placenta praecox, BW 1420, APGAR 1 1.11/12 P VI, CC, BW 3250, APGAR 5

EPI, seizures occurred before and after IFN fever, convulsions

4.84

171

13

HBs-, HBe-

AB

F

4.18

23

18

BM

F

5.07

130

13

HBs+, H B e - , antiHBe+ HBs+, H B e - , antiHBe+

AP

M

5.25

39

26

RN

M

5.95

27

ND

HBs+, H B e - , antyHBe+ ND

DP

M

6.25

157

98

HBs+, HBe+

4.2/12

P II, CC prematurity, BW 2470, APGAR 9 2.8/12 P IV, twins, prematurity, BW 2300, APGAR 6 1.9/12 P V, BW 4350, APGAR 9 1.10/12 P III, BW 2400, APGAR 10 2.7/12 P II, prematurity, BW 1780, APGAR 6

HBs+, H B e - , antiHBe+ HBs+, H B e - , antiHBe+

seizures in the patient's history, fever, convulsions, EPI convulsions without fever convulsions during fever, EPI, convulsions following IFN fever, convulsions

11 weeks (99 MU)

11 weeks (102 MU)

one week (9 MU) 10 weeks (90 MU)

19 weeks (179 MU)

fever, convulsions

12 weeks (108 MU)

fever, convulsions

8 weeks (72 MU)

P - pregnancy, CC - cesarean section, BW - body weight at birth, APGAR - Apgar score, ND - not done.

by Dr. Shakil. Seizures occurred only in children under 5 years of age, and in 70% they were accompanied by high temperature. In patients from this group, high temperature is the risk factor for seizures, and about 3-4% of children with high fever develop seizures (2). Seizures during high fever in children of this age are considered to be connected with the immaturity of the central nervous system and a low convulsant threshold. Another factor which may lead to seizures is perinatal central nervous system damage. In the group analyzed, risk factors for central nervous system injury were present in six out of ten children (prematurity/low birth weight, complicated delivery, poor postnatal state) while seizures before starting interferon treatment were observed in only two children. In all children who underwent EEG shortly after the seizures episode, abnormal results were obtained. Nevertheless, a diagnosis of epilepsy was made in only three cases and only in these children was anticonvulsant therapy continued after discontinuing IFN. Dr Shakil explains that seizures occur as a result of small vessel damage in the central nervous system. Our observations suggest that in small children immaturity or perinatal central nervous system damage may be an additional factor inducing seizures. Our observations suggest that seizures are a relatively common side effect of interferon therapy in children aged under 5. Seizures cannot

be neglected and in each case neuroinfection should be excluded. It seems that phenobarbital administration during interferon therapy can prevent seizures, and HBe/antiHBe seroconversion in 70% of our patients justifies the administration of interferon in chronic hepatitis B in small children (3). Marek Woynarowski and Jerzy Socha Child Health Memorial Institute, Department o f Gastroenterology and Nutrition, AI. Dzieci Polskich 20, 04-736 Warsaw, Poland Tel: 4822 15 73 86. Fax: 4822 15 31 54.

References 1. Obai Shakil A, Di Bisceglie AM, Hoofnagle JH. Seizures during interferon therapy. J Hepatol 1996; 24: 48-51. 2. Haslam RHA. Seizures in childhood. In: Nelson Textbook of Pediatrics, 14th Edn. Philadelphia: W.B. Saunders Company, 1992: 1495-6. 3. Woynarowski M, Pawtowska J, Nat¢cz A, Madaliriski K, Wo~niewicz B, Socha J. Interferon treatment in children aged below 3 years. J Pediatr Gastroenterol Nutr 1995; 20:450 (abstract).

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