Scandinavian Journal of Infectious Diseases
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Cytarabine Treatment of Herpes Simplex Encephalitis in Infants and Small Children: A Report on Three Cases with a Short Review of the Literature Bengt Lagerkvist & Hans Ekelund To cite this article: Bengt Lagerkvist & Hans Ekelund (1975) Cytarabine Treatment of Herpes Simplex Encephalitis in Infants and Small Children: A Report on Three Cases with a Short Review of the Literature, Scandinavian Journal of Infectious Diseases, 7:2, 81-84, DOI: 10.3109/ inf.1975.7.issue-2.01 To link to this article: http://dx.doi.org/10.3109/inf.1975.7.issue-2.01
Published online: 02 Jan 2015.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [UQ Library]
Date: 30 April 2016, At: 08:11
Scand J Infect Dis 7: 81-84, 1975
Cytarabine Treatment of Herpes Simplex Encephalitis in Infants and Small Children A Report on Three Cases with a Short Review of the Literature
BENGT LAGERKVIST and HANS EKELUND
Downloaded by [UQ Library] at 08:11 30 April 2016
From S:t Goren's Children's Hospital, Stockholm, and the Department of Pediatrics, General Hospital, Malmo, Sweden
ABSTRACT. Three cytarabine-treated infants and children with herpes simplex encephalitis are presented. The effect of the treatment was excellent in 2 cases. One boy who had a CP syndrome died. It is assumed that the treatment with cytarabine should be started as early as possible with a dosage of 3 mg/kg body weight given intravenously once a day in a single injection for 5 days. No serious side effects have been noted. The advantage of cytarabine over idoxuridine, especially when treating small children and herpetic infections in the central nervous system, are emphasized.
INTRODUCTION
CASE REPORTS
When treating herpes simplex encephalitis the therapeutic trials have hitherto mostly been limited to 3 measures: decompression, administration of ACTH or corticosteroids and the antiviral drug idoxuridine. The last one lowers mortality to about 30% (2, 5, 6), but has serious side effects and low solubility. The drug is thus difficult to use especially in the pediatric age group. However, since a few years it is possible to use another antiviral drug, cytarabine (cytosine arabinoside, Cytosar'") which is an easily soluble pyrimidine nucleoside mainly acting as a DNA-inhibitor. In 1963, it was found to be active against herpes simplex virus and was then used in the treatment of herpetic keratitis. It fell into disuse as an antiviral agent because of the local side effects. It is now mainly utilized as an antileukemic drug. In 1970, however, Juel-Jensen (3) reported very good results with cytarabine treatment of adults with severe infections caused by herpes simplex virus, and in 1972 other cases with favourable outcomes were presented by Farris and Blaw (1) and Juel-Jensen and McCallum.(4). The purpose of this paper is to report 3 cases of herpes simplex encephalitis in small children treated with cytarabine and to present a short review of the literature.
Case 1
6-751958
A boy, 13 months old, with normal physical and mental development fell ill on August 12, 1972 with fever 39°C as the only presenting symptom. He was seen by a pediatrician 4 days later because of remaining high fever and was said to suffer from herpangina because of vesicles on the oral mucosa. On August 19 he was admitted to a children's hospital. The fever had ranged between 39-40°C. He was in a bad condition with light stiffness of the neck. He was pale, had conjunctivitis, oedema of the eyelids and vesicles on the oral mucosa. The lymph nodes of the neck were enlarged. The cerebrospinal fluid (CSF) and white blood cell (WBC) count were normal. Three days later, on August 22, he became worse with increasing irritability, myoclonic jerks and increasing neck stiffness. A second lumbar puncture showed a puncture bleeding with CSF containing 12000 erythrocytes, 6 polymorphonuclear and 8 mononuclear leukocytes. The protein content was 46 mg/IOO ml. Ampicillin treatment was started. The next day he was transported to another children's hospital with the diagnosis of herpes simplex encephalitis. He was drowsy, had gastric retention and slight breathing difficulties. He had several vesicles of typical herpes simplex appearance in the mouth, the face and on the buttocks. The liver and spleen were enlarged. He was very stiff in the neck, irritable and had a shrilly and monotonous cry. The ampicillin dose was increased and cloxacillin was added, corresponding to treatment of septicemia. The following days he became deeply comatose and did not recognize his mother. He had no seizures or signs of paralysis. The hemoglobin value, WBC and platelet count Scand J Infect Dis 7
82
B. Lagerkvist and H. Ekelund
Table I. Previously published and own cases of cytarabine-treated herpes simplex encephalitis
Downloaded by [UQ Library] at 08:11 30 April 2016
Age No. (y.) Sex
Referenee no.
Diagnosis
Days of disease Dosage a day before and no. of treatment days
Neurological symptoms
21
M
3
Brain biopsy
10
2 3
20 68
M M
3 3
Probable Brain biopsy
14
10 mg/kgx I 8 mg/kgx4 6.5 rng/kgx Z 5 mg/kgx? 5 mg/kgx4
4
35
M
3
Brain biopsy
8
6.6 mg/kgx6
Coma
5
14
F
Brain biopsy
12
4 mg/kgx I 6 mg/kgx I 8 mg/kgX4
Semicomatose Aphasia Hemiparesis
6
I!
M
reported case I
13
3 mg/kgx5
7
2!
M
reported case 2
EEG, virus isolation, serological findings Brain biopsy with virus isolation
16
3 mg/kg x S
Semicomatose Signs of meningeal irritation Coma Brain oedema
8
6w M
reported case 3
14
3 mg/kgx5
As in case 6
were all normal. Micro ESR was 36 mrn/h, SGOT and SGPT 500 E each. Bilirubin, thrombotest, urea and electrolytes in serum were all normal. An EEG was abnormal with low frequency of 1-1 1/ 2 cps and amplitude up to 200 mV with no focal findings. Herpes simplex virus (typing not done) was isolated from the mouth but not from CSF. The titer of complement-fixing antibodies against herpes simplex virus increased from 64 on August 23 to 256 on Nov. 21. Cytarabine treatment was started on August 25 with 3 mg/kg body weight in a single rapid intravenous injection daily, continued for the next following 4 days to a total of 5 doses. On the second day of cytarabine treatment he became afebrile for the first time in 2 weeks. After another 24 hours he began to follow objects with his eyes again, move his head towards sounds and became much less irritable with an obviously more modulated cry. Two days later he began to be interested in toys, to babble and to recognize his mother. His recovery proceeded very well and his EEG was very much improved on the third day after therapy was started. SGOT and SGPT were then 120 E and 275 E, respectively. He was discharged from the hospital 3 weeks later in a quite normal condition with normal blood values including SGOT and SGPT, normal EEG and no signs of sequelae. Follow-up investigations during 15 months have shown normal development. No brain biopsy was done. The diagnosis herpes simpScand J Infect Dis 7
Coma Incontinence Hemiplegia Semicomatose Coma
Convulsions Signs of meningeal irritation
Outcome
Post-mortem findings
Recovered with minimal defects Total recovery Death after 4 days treatment Recovered with slight mental changes Recovered with semantic aphasia
Virus not particu larly resistant
Total recovery
Death
Cerebral degeneration (CPl. For H.S. encephalitis typical cellular changes
Total recovery
lex encephalitis was based on the clinical picture of encephalitis together with pathological EEG findings and simultaneous herpes simplex virus infection proved by virus isolation and significantly increased titer of complement-fixing antibodies. The quick response to cytarabine treatment corresponds well to case 5, Table 1. The side effects of the drug were a fall in the polymorphonuclear leukocytes to a minimum of 600//L1 (total WBC count 5300) on the 11th day after treatment was started, an anemia with Hb 8.6 g/Ioo ml and a slight peripheral oedema during the first 5 days of treatment. Case 2 A boy, 2 years old, with cerebral palsy of athetoid type of unknown origin. His gross motor development and speech were delayed, but otherwise his development was adequate for age. He had only had a few minor infections when he fell ill on November 19, 1972 with high fever (40°C). He was seen by a pediatrician 3 days later and was treated with penicillin because of enlarged and inflamed tonsils and enlarged lymph nodes. Two days later he was examined in a clinic for infectious diseases because of remaining high fever and a number of vesicles on the oral mucosa. Penicillin was discharged. On November 30 he was hospitalized because of high fever, feeding difficulties and increasing amount of vesicles in the mouth, on the lips and on the cheeks. He was slightly dehydrated, but had no additional neurological signs except his CP syndrome.
Downloaded by [UQ Library] at 08:11 30 April 2016
Herpes simplex encephalitis Three days later his mother noticed a slight squint. The following day, 15 days after he fell ill, he quickly got worse. He was drowsy and lay with his head bent backwards. He had breathing difficulties and a left-sided eye muscle paralysis. 24 hours later he was comatose with bilateral oculomotor paresis and neck stiffness as signs of brain swelling. The temperature was 39"C, Hb 10.2 g/l00 ml, ESR 44 rnm, WBC count normal and EEG pattern abnormal with irregular frequency 2-6 cps and amplitude max.40mV. Cytarabine treatment was started with 3 mg/kg body weight in a single rapid intravenous injection daily and diuretic treatment with mannitol (Mannitol's) and furosemide (Lasix'P), The cytarabine treatment was continued in the same manner for 5 consecutive days. 16 hours after starting the cytarabine treatment he was afebrile for the first time since he fell ill. The ophthalmological signs of brain swelling had rapidly disappeared, but he still had neck stiffness. After 2 days of cytarabine and diuretic treatment he was still better. He listened a little to his mother's voice and tried to answer, and his neck stiffness had disappeared. The mucocutaneous changes had improved a little as had the EEG. There was no clinical change during the following 2 days of treatment with cytarabine and diuretics. Then he slowly deteriorated with less contact, low temperature, slight peripheral oedema, an urticaria-like exanthema for one day and once again ophthalmological signs of brain swelling and neck stiffness. ACTH injections were then added together with the same diuretics as before. There was, however, no significant change and he died 4 days after cytarabine treatment was finished. The brain autopsy showed no signs of increased intracranial pressure. There were no signs of necrotizing encephalitis, but hypoplasia of the cerebellum and right occipitallobe probably corresponding to his cerebral palsy. Herpes simplex virus (typing not done) was isolated from the hippocampus. All over the brain, the brain stem and medulla oblongata cellular changes typical for herpes simplex encephalitis were found. A lymph node showed cellular depletion which was thought to be caused by the ACTH treatment. It was remarkable that the titre of complement-fixing antibodies against herpes simplex in autopsy blood was below 5 (the first blood sample was lost). The immunoglobulins 5 days before death were normal. When he was 9 months old he had a serum albumin level of 4.6 g/IOO ml and IgG 400 mg/l00 ml. A lung X-ray picture at the same age showed a rather small thymus. This might indicate a slight defect in the immunological defence though it was not clinically apparent. His brain defects might also explain why the treatment failed. (His parents and sister have no immunological abnormalities.)
Case 3 A boy, 2 months of age, born on March 10, 1973, the first child of healthy parents. Pregnancy and delivery were normal as was the development of the infant. Five weeks of age he had an uncomplicated upper respiratory infection. Almost 2 months old (April 29) he was admitted to hospital because of increasing troubles of wheezy bronchitis. He was treated initially with betamethasone
83
(Betapred'P) in a short course together with bronchodilating agents (adrenaline, theophyllamine) and penicillin. In spite of this therapy he had recurrent fever bouts between 38°C and 39°C. From May 10, an increasing number of small vesicles were noted in the face and scalp. On May 14 he was irritable with neck stiffness and a temperature of 39"C. A lumbar puncture showed a clear CSF, containing 211 mononuclear and 86 polynuclear leukocytes per ILl. The total protein content was 64 mg/IOO ml and the CSF sugar 53 mg/l00 ml. In the next 24 hours he had 2 right-sided convulsions lasting a few minutes. EEG on May 15 showed a generalized slow activity of high voltage mixed up with sharp waves of changing but mainly left-sided predominance. He was still listless and irritable with moderate neck stiffness but conscious and without any gross abnormal findings on neurological examination. There were no feeding difficulties. The left eye was irritated and ophthalmological examination showed a dendritic keratitis and an irregular large pupil that responded slowly to light. On May 15 it was reported that herpes simplex virus type 1 had been cultured from the vesicles in the skin. With the assumption that the meningoencephalitis was caused by this agent cytarabine in a dose of 3 mg/kg body weight was given intravenously in one single injection daily during 5 consecutive days (total dose 75 mg), During the first days of this treatment the boy cried monotonously, like "brain cry", but otherwise no change could be demonstrated in his general condition. The cry got normal within another few days and he improved successively. There were no more convulsions and EEG controls showed marked regression of the pathological changes. No haematological side effects were noted. There was a significant rise in the titre of complement-fixing antibodies against herpes simplex virus from 128 (May 29). A repeated lumbar puncture on May 23 showed only 22 mononuclear cells in the CSF. The boy could be discharged in a completely normal state of gross and psychomotor development without any neurological sequelae. His left pupil was still irregular and somewhat larger than the right one. Last seen in November 1973 at the age of 8 months his general condition was excellent and he had continued to develop normally. This case represents a primary herpes simplex virus infection confirmed by clinical signs of cutaneous herpes vesicles from which virus was cultured, together with a significant increase in CF antibodies. At the same time there appeared an aseptic meningoencephalitis with negative virus culture from CSF but probably representing a manifestation of the herpes simplex infection. Signs of meningeal irritation dominated, encephalitic symptoms being moderate. It is possible that this case would have run a favourable course without any treatment but the improvement in close temporal relationship to the cytarabine administration speaks in favour of this agent contributing to the outcome.
DISCUSSION Up to now, 8 cases of probable or proved herpes simplex encephalitis treated with cytarabine have Scand J Infect Dis 7
Downloaded by [UQ Library] at 08:11 30 April 2016
84
B. Lagerkvist and H. Ekelund
been reported. Three patients recovered completely, 3 recovered with minor or moderate defects and 2 died (Table I). The result of treatment certainly depends on the number of days passing before treatment is started and on the total dosage. The two deaths occurred in patients where 14 days or more passed before antiviral treatment was started. The boy reported by us, and who died, might very well have died even with earlier onset of treatment and a higher dosage because of his CP syndrome and suspected immunodeficiency. The dosage has varied between 2.5-10 mg/kg body weight and the duration of the treatment from 5-7 days (Table I). In our cases the dosage has been 3 mg/kg unchanged during 5 days. In the various reports treatment has started or ended up with a higher dosage or it has been unchanged. It does not seem to influence the outcome. The improvement occurred in all survivors within a few days. The side effects of cytarabine are numerous. In our cases leukopenia, anemia, thrombocytopenia, slight peripheral oedema and skin reactions appeared. Nevertheless, they were all mild or moderate and in our opinion do not contraindicate a therapeutic trial. Cytarabine has several striking advantages over idoxuridine as summarized by Weinstein and Chang (7). The antiviral spectrum is similar for both drugs but viruses in the herpes group, especially type 2 herpes simplex virus, are more sensitive to cytarabine than to idoxuridine. Also, cytarabine is not deaminated in the brain, as is idoxuridine, making cytarabine theoretically more effective in the management of herpes simplex encephalitis. Moreover cytarabine is poorly, if at all, incorporated into DNA as is idoxuridine which must be looked upon as a potential mutagen. Finally the inactivation of the drugs speaks in favour of cytarabine which is undetectable in the blood about 15 min after a single intravenous injection which is half the .time for idoxuridine. Although several spontaneous recoveries from herpes simplex encephalitis are reported, the results in general are improved when using antiviral drugs. Our experiences with cytarabine in small children with herpes simplex encephalitis are encouraging as are others in adults. It may also be the best available antiviral drug when the agent is type 2 herpes simplex virus, in neonates predominantly associated with generalized herpetic infection. Scand J Infect Dis 7
REFERENCES I. Farris, W. A. & Blaw, M. E.: Cytarabine treatment of
herpes simplex encephalitis. Arch Neurol27: 99, 1972. 2. Illis, L. S. & Merry, R. T. G.: Treatment of herpes simplex encephalitis. J R ColI Physicians Lond 7: 34, 1972. 3. Juel-Jensen, B. E.: Severe generalized primary herpes treated with cytarabine. Br Med J 2: 154, 1970. 4. Juel-Jensen, B. E.& McCallum, F. 0.: Herpes simplex, variceUae and zoster. Clinical manifestations and treatment. W. Heinemann Medical Books Ltd, London 1972. 5. Nolan, D. C., Carrithers, M. M., Lerner, A. M.: Herpes virus hominis encephalitis in Michigan. Report of thirteen cases including six treated with idoxuridine. N Engl J Med 282: 10, 1970. 6. Nolan, D. C., Lauter, C. B. & Lerner, A. M.: Idoxuridine in herpes simplex virus (type I) encephalitis. Experience with 29 cases in Michigan, 1966 to 1971. Ann Intern Med 78: 243, 1973. 7. Weinstein, L. & Chang, T.-W.: The chemotherapy of viral infections. N Engl J Med 289: 725, 1973. Address/or reprints: B. Lagerkvist, M.D., S:t Giirans sjukhus, Barnklinikerna, Box /2500, S-l/28/ Stockholm, Sweden
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Cytarabine Treatment of Herpes Simplex Encephalitis in Infants and Small Children: A Report on Three Cases with a Short Review of the Literature Bengt Lagerkvist & Hans Ekelund To cite this article: Bengt Lagerkvist & Hans Ekelund (1975) Cytarabine Treatment of Herpes Simplex Encephalitis in Infants and Small Children: A Report on Three Cases with a Short Review of the Literature, Scandinavian Journal of Infectious Diseases, 7:2, 81-84, DOI: 10.3109/ inf.1975.7.issue-2.01 To link to this article: http://dx.doi.org/10.3109/inf.1975.7.issue-2.01
Published online: 02 Jan 2015.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [UQ Library]
Date: 30 April 2016, At: 08:11
Scand J Infect Dis 7: 81-84, 1975
Cytarabine Treatment of Herpes Simplex Encephalitis in Infants and Small Children A Report on Three Cases with a Short Review of the Literature
BENGT LAGERKVIST and HANS EKELUND
Downloaded by [UQ Library] at 08:11 30 April 2016
From S:t Goren's Children's Hospital, Stockholm, and the Department of Pediatrics, General Hospital, Malmo, Sweden
ABSTRACT. Three cytarabine-treated infants and children with herpes simplex encephalitis are presented. The effect of the treatment was excellent in 2 cases. One boy who had a CP syndrome died. It is assumed that the treatment with cytarabine should be started as early as possible with a dosage of 3 mg/kg body weight given intravenously once a day in a single injection for 5 days. No serious side effects have been noted. The advantage of cytarabine over idoxuridine, especially when treating small children and herpetic infections in the central nervous system, are emphasized.
INTRODUCTION
CASE REPORTS
When treating herpes simplex encephalitis the therapeutic trials have hitherto mostly been limited to 3 measures: decompression, administration of ACTH or corticosteroids and the antiviral drug idoxuridine. The last one lowers mortality to about 30% (2, 5, 6), but has serious side effects and low solubility. The drug is thus difficult to use especially in the pediatric age group. However, since a few years it is possible to use another antiviral drug, cytarabine (cytosine arabinoside, Cytosar'") which is an easily soluble pyrimidine nucleoside mainly acting as a DNA-inhibitor. In 1963, it was found to be active against herpes simplex virus and was then used in the treatment of herpetic keratitis. It fell into disuse as an antiviral agent because of the local side effects. It is now mainly utilized as an antileukemic drug. In 1970, however, Juel-Jensen (3) reported very good results with cytarabine treatment of adults with severe infections caused by herpes simplex virus, and in 1972 other cases with favourable outcomes were presented by Farris and Blaw (1) and Juel-Jensen and McCallum.(4). The purpose of this paper is to report 3 cases of herpes simplex encephalitis in small children treated with cytarabine and to present a short review of the literature.
Case 1
6-751958
A boy, 13 months old, with normal physical and mental development fell ill on August 12, 1972 with fever 39°C as the only presenting symptom. He was seen by a pediatrician 4 days later because of remaining high fever and was said to suffer from herpangina because of vesicles on the oral mucosa. On August 19 he was admitted to a children's hospital. The fever had ranged between 39-40°C. He was in a bad condition with light stiffness of the neck. He was pale, had conjunctivitis, oedema of the eyelids and vesicles on the oral mucosa. The lymph nodes of the neck were enlarged. The cerebrospinal fluid (CSF) and white blood cell (WBC) count were normal. Three days later, on August 22, he became worse with increasing irritability, myoclonic jerks and increasing neck stiffness. A second lumbar puncture showed a puncture bleeding with CSF containing 12000 erythrocytes, 6 polymorphonuclear and 8 mononuclear leukocytes. The protein content was 46 mg/IOO ml. Ampicillin treatment was started. The next day he was transported to another children's hospital with the diagnosis of herpes simplex encephalitis. He was drowsy, had gastric retention and slight breathing difficulties. He had several vesicles of typical herpes simplex appearance in the mouth, the face and on the buttocks. The liver and spleen were enlarged. He was very stiff in the neck, irritable and had a shrilly and monotonous cry. The ampicillin dose was increased and cloxacillin was added, corresponding to treatment of septicemia. The following days he became deeply comatose and did not recognize his mother. He had no seizures or signs of paralysis. The hemoglobin value, WBC and platelet count Scand J Infect Dis 7
82
B. Lagerkvist and H. Ekelund
Table I. Previously published and own cases of cytarabine-treated herpes simplex encephalitis
Downloaded by [UQ Library] at 08:11 30 April 2016
Age No. (y.) Sex
Referenee no.
Diagnosis
Days of disease Dosage a day before and no. of treatment days
Neurological symptoms
21
M
3
Brain biopsy
10
2 3
20 68
M M
3 3
Probable Brain biopsy
14
10 mg/kgx I 8 mg/kgx4 6.5 rng/kgx Z 5 mg/kgx? 5 mg/kgx4
4
35
M
3
Brain biopsy
8
6.6 mg/kgx6
Coma
5
14
F
Brain biopsy
12
4 mg/kgx I 6 mg/kgx I 8 mg/kgX4
Semicomatose Aphasia Hemiparesis
6
I!
M
reported case I
13
3 mg/kgx5
7
2!
M
reported case 2
EEG, virus isolation, serological findings Brain biopsy with virus isolation
16
3 mg/kg x S
Semicomatose Signs of meningeal irritation Coma Brain oedema
8
6w M
reported case 3
14
3 mg/kgx5
As in case 6
were all normal. Micro ESR was 36 mrn/h, SGOT and SGPT 500 E each. Bilirubin, thrombotest, urea and electrolytes in serum were all normal. An EEG was abnormal with low frequency of 1-1 1/ 2 cps and amplitude up to 200 mV with no focal findings. Herpes simplex virus (typing not done) was isolated from the mouth but not from CSF. The titer of complement-fixing antibodies against herpes simplex virus increased from 64 on August 23 to 256 on Nov. 21. Cytarabine treatment was started on August 25 with 3 mg/kg body weight in a single rapid intravenous injection daily, continued for the next following 4 days to a total of 5 doses. On the second day of cytarabine treatment he became afebrile for the first time in 2 weeks. After another 24 hours he began to follow objects with his eyes again, move his head towards sounds and became much less irritable with an obviously more modulated cry. Two days later he began to be interested in toys, to babble and to recognize his mother. His recovery proceeded very well and his EEG was very much improved on the third day after therapy was started. SGOT and SGPT were then 120 E and 275 E, respectively. He was discharged from the hospital 3 weeks later in a quite normal condition with normal blood values including SGOT and SGPT, normal EEG and no signs of sequelae. Follow-up investigations during 15 months have shown normal development. No brain biopsy was done. The diagnosis herpes simpScand J Infect Dis 7
Coma Incontinence Hemiplegia Semicomatose Coma
Convulsions Signs of meningeal irritation
Outcome
Post-mortem findings
Recovered with minimal defects Total recovery Death after 4 days treatment Recovered with slight mental changes Recovered with semantic aphasia
Virus not particu larly resistant
Total recovery
Death
Cerebral degeneration (CPl. For H.S. encephalitis typical cellular changes
Total recovery
lex encephalitis was based on the clinical picture of encephalitis together with pathological EEG findings and simultaneous herpes simplex virus infection proved by virus isolation and significantly increased titer of complement-fixing antibodies. The quick response to cytarabine treatment corresponds well to case 5, Table 1. The side effects of the drug were a fall in the polymorphonuclear leukocytes to a minimum of 600//L1 (total WBC count 5300) on the 11th day after treatment was started, an anemia with Hb 8.6 g/Ioo ml and a slight peripheral oedema during the first 5 days of treatment. Case 2 A boy, 2 years old, with cerebral palsy of athetoid type of unknown origin. His gross motor development and speech were delayed, but otherwise his development was adequate for age. He had only had a few minor infections when he fell ill on November 19, 1972 with high fever (40°C). He was seen by a pediatrician 3 days later and was treated with penicillin because of enlarged and inflamed tonsils and enlarged lymph nodes. Two days later he was examined in a clinic for infectious diseases because of remaining high fever and a number of vesicles on the oral mucosa. Penicillin was discharged. On November 30 he was hospitalized because of high fever, feeding difficulties and increasing amount of vesicles in the mouth, on the lips and on the cheeks. He was slightly dehydrated, but had no additional neurological signs except his CP syndrome.
Downloaded by [UQ Library] at 08:11 30 April 2016
Herpes simplex encephalitis Three days later his mother noticed a slight squint. The following day, 15 days after he fell ill, he quickly got worse. He was drowsy and lay with his head bent backwards. He had breathing difficulties and a left-sided eye muscle paralysis. 24 hours later he was comatose with bilateral oculomotor paresis and neck stiffness as signs of brain swelling. The temperature was 39"C, Hb 10.2 g/l00 ml, ESR 44 rnm, WBC count normal and EEG pattern abnormal with irregular frequency 2-6 cps and amplitude max.40mV. Cytarabine treatment was started with 3 mg/kg body weight in a single rapid intravenous injection daily and diuretic treatment with mannitol (Mannitol's) and furosemide (Lasix'P), The cytarabine treatment was continued in the same manner for 5 consecutive days. 16 hours after starting the cytarabine treatment he was afebrile for the first time since he fell ill. The ophthalmological signs of brain swelling had rapidly disappeared, but he still had neck stiffness. After 2 days of cytarabine and diuretic treatment he was still better. He listened a little to his mother's voice and tried to answer, and his neck stiffness had disappeared. The mucocutaneous changes had improved a little as had the EEG. There was no clinical change during the following 2 days of treatment with cytarabine and diuretics. Then he slowly deteriorated with less contact, low temperature, slight peripheral oedema, an urticaria-like exanthema for one day and once again ophthalmological signs of brain swelling and neck stiffness. ACTH injections were then added together with the same diuretics as before. There was, however, no significant change and he died 4 days after cytarabine treatment was finished. The brain autopsy showed no signs of increased intracranial pressure. There were no signs of necrotizing encephalitis, but hypoplasia of the cerebellum and right occipitallobe probably corresponding to his cerebral palsy. Herpes simplex virus (typing not done) was isolated from the hippocampus. All over the brain, the brain stem and medulla oblongata cellular changes typical for herpes simplex encephalitis were found. A lymph node showed cellular depletion which was thought to be caused by the ACTH treatment. It was remarkable that the titre of complement-fixing antibodies against herpes simplex in autopsy blood was below 5 (the first blood sample was lost). The immunoglobulins 5 days before death were normal. When he was 9 months old he had a serum albumin level of 4.6 g/IOO ml and IgG 400 mg/l00 ml. A lung X-ray picture at the same age showed a rather small thymus. This might indicate a slight defect in the immunological defence though it was not clinically apparent. His brain defects might also explain why the treatment failed. (His parents and sister have no immunological abnormalities.)
Case 3 A boy, 2 months of age, born on March 10, 1973, the first child of healthy parents. Pregnancy and delivery were normal as was the development of the infant. Five weeks of age he had an uncomplicated upper respiratory infection. Almost 2 months old (April 29) he was admitted to hospital because of increasing troubles of wheezy bronchitis. He was treated initially with betamethasone
83
(Betapred'P) in a short course together with bronchodilating agents (adrenaline, theophyllamine) and penicillin. In spite of this therapy he had recurrent fever bouts between 38°C and 39°C. From May 10, an increasing number of small vesicles were noted in the face and scalp. On May 14 he was irritable with neck stiffness and a temperature of 39"C. A lumbar puncture showed a clear CSF, containing 211 mononuclear and 86 polynuclear leukocytes per ILl. The total protein content was 64 mg/IOO ml and the CSF sugar 53 mg/l00 ml. In the next 24 hours he had 2 right-sided convulsions lasting a few minutes. EEG on May 15 showed a generalized slow activity of high voltage mixed up with sharp waves of changing but mainly left-sided predominance. He was still listless and irritable with moderate neck stiffness but conscious and without any gross abnormal findings on neurological examination. There were no feeding difficulties. The left eye was irritated and ophthalmological examination showed a dendritic keratitis and an irregular large pupil that responded slowly to light. On May 15 it was reported that herpes simplex virus type 1 had been cultured from the vesicles in the skin. With the assumption that the meningoencephalitis was caused by this agent cytarabine in a dose of 3 mg/kg body weight was given intravenously in one single injection daily during 5 consecutive days (total dose 75 mg), During the first days of this treatment the boy cried monotonously, like "brain cry", but otherwise no change could be demonstrated in his general condition. The cry got normal within another few days and he improved successively. There were no more convulsions and EEG controls showed marked regression of the pathological changes. No haematological side effects were noted. There was a significant rise in the titre of complement-fixing antibodies against herpes simplex virus from 128 (May 29). A repeated lumbar puncture on May 23 showed only 22 mononuclear cells in the CSF. The boy could be discharged in a completely normal state of gross and psychomotor development without any neurological sequelae. His left pupil was still irregular and somewhat larger than the right one. Last seen in November 1973 at the age of 8 months his general condition was excellent and he had continued to develop normally. This case represents a primary herpes simplex virus infection confirmed by clinical signs of cutaneous herpes vesicles from which virus was cultured, together with a significant increase in CF antibodies. At the same time there appeared an aseptic meningoencephalitis with negative virus culture from CSF but probably representing a manifestation of the herpes simplex infection. Signs of meningeal irritation dominated, encephalitic symptoms being moderate. It is possible that this case would have run a favourable course without any treatment but the improvement in close temporal relationship to the cytarabine administration speaks in favour of this agent contributing to the outcome.
DISCUSSION Up to now, 8 cases of probable or proved herpes simplex encephalitis treated with cytarabine have Scand J Infect Dis 7
Downloaded by [UQ Library] at 08:11 30 April 2016
84
B. Lagerkvist and H. Ekelund
been reported. Three patients recovered completely, 3 recovered with minor or moderate defects and 2 died (Table I). The result of treatment certainly depends on the number of days passing before treatment is started and on the total dosage. The two deaths occurred in patients where 14 days or more passed before antiviral treatment was started. The boy reported by us, and who died, might very well have died even with earlier onset of treatment and a higher dosage because of his CP syndrome and suspected immunodeficiency. The dosage has varied between 2.5-10 mg/kg body weight and the duration of the treatment from 5-7 days (Table I). In our cases the dosage has been 3 mg/kg unchanged during 5 days. In the various reports treatment has started or ended up with a higher dosage or it has been unchanged. It does not seem to influence the outcome. The improvement occurred in all survivors within a few days. The side effects of cytarabine are numerous. In our cases leukopenia, anemia, thrombocytopenia, slight peripheral oedema and skin reactions appeared. Nevertheless, they were all mild or moderate and in our opinion do not contraindicate a therapeutic trial. Cytarabine has several striking advantages over idoxuridine as summarized by Weinstein and Chang (7). The antiviral spectrum is similar for both drugs but viruses in the herpes group, especially type 2 herpes simplex virus, are more sensitive to cytarabine than to idoxuridine. Also, cytarabine is not deaminated in the brain, as is idoxuridine, making cytarabine theoretically more effective in the management of herpes simplex encephalitis. Moreover cytarabine is poorly, if at all, incorporated into DNA as is idoxuridine which must be looked upon as a potential mutagen. Finally the inactivation of the drugs speaks in favour of cytarabine which is undetectable in the blood about 15 min after a single intravenous injection which is half the .time for idoxuridine. Although several spontaneous recoveries from herpes simplex encephalitis are reported, the results in general are improved when using antiviral drugs. Our experiences with cytarabine in small children with herpes simplex encephalitis are encouraging as are others in adults. It may also be the best available antiviral drug when the agent is type 2 herpes simplex virus, in neonates predominantly associated with generalized herpetic infection. Scand J Infect Dis 7
REFERENCES I. Farris, W. A. & Blaw, M. E.: Cytarabine treatment of
herpes simplex encephalitis. Arch Neurol27: 99, 1972. 2. Illis, L. S. & Merry, R. T. G.: Treatment of herpes simplex encephalitis. J R ColI Physicians Lond 7: 34, 1972. 3. Juel-Jensen, B. E.: Severe generalized primary herpes treated with cytarabine. Br Med J 2: 154, 1970. 4. Juel-Jensen, B. E.& McCallum, F. 0.: Herpes simplex, variceUae and zoster. Clinical manifestations and treatment. W. Heinemann Medical Books Ltd, London 1972. 5. Nolan, D. C., Carrithers, M. M., Lerner, A. M.: Herpes virus hominis encephalitis in Michigan. Report of thirteen cases including six treated with idoxuridine. N Engl J Med 282: 10, 1970. 6. Nolan, D. C., Lauter, C. B. & Lerner, A. M.: Idoxuridine in herpes simplex virus (type I) encephalitis. Experience with 29 cases in Michigan, 1966 to 1971. Ann Intern Med 78: 243, 1973. 7. Weinstein, L. & Chang, T.-W.: The chemotherapy of viral infections. N Engl J Med 289: 725, 1973. Address/or reprints: B. Lagerkvist, M.D., S:t Giirans sjukhus, Barnklinikerna, Box /2500, S-l/28/ Stockholm, Sweden
