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Encephalitis due to Epstein-Barr virus
Journal of Infection (199o)
20, 69-72
CASE REPORT E n c e p h a l i t i s d u e to E p s t e i n - B a r r v i r u s N. Bhatti,* E. Larson,*$ M. Hickey~ and D. Sealt Microbial Pathogenicity Research Group, * Division of Communicable Diseases, Clinical Research Centre, Northwick Park Hospital and t Department of Microbiology, Northwick Park Hospital, Watford Road, Harrow, Middlesex H A I 3 UJ, U.K. Accepted for publication 25 September 1989 Summary Acute encephalitis due to Epstein-Barr virus is described. The initial diagnosis was based on clinical features and a positive Monospot test. Early treatment with intravenous acyclovir was given; steroids were not used. The patient made a rapid and complete recovery from a comatose state. The effectiveness of acyclovir in this condition remains unproven but early treatment is recommended in severely ill patients whose prognosis is uncertain.
Introduction Encephalitis due to E p s t e i n - B a r r virus (EBV) is infrequently reported. 1-8 It has been suggested that mortality can be as high as 33 %, although this m a y be associated with other features, i.e. myocarditis. T h e use of steroids is controversial while any beneficial effects of acyclovir remain unproven. W e have recently treated a patient who had E p s t e i n - B a r r virus encephalitis and report a successful o u t c o m e without the use of steroids.
Case report A 17-year-old man, previously well, was admitted to hospital in an unconscious state with choreiform m o v e m e n t s of all four limbs. D u r i n g the previous 2 weeks he had been tired and unwell, and 4 days before admission had developed a sore throat for which he was treated with oral penicillin V. O n the morning of admission the patient was noticed to be behaving in an aggressive manner. His father came h o m e that afternoon, to find him unconscious and writhing on the floor. O n examination the patient was pyrexial to 37"8 °C and unresponsive to painful stimuli b u t m o v e d his limbs in a choreiform manner. His neck was stiff and pupils pinpoint, while all four limbs were hyperreflexic. A p u r p u r i c rash was noted on the right side of the face. Because meningococcal meningitis could not be excluded, he was at once given six megaunits of benzylpenicillin intravenously. After urgent c o m p u t e d ~t A u t h o r to w h o m all correspondence should be addressed. o 1 6 3 - 4 4 5 3 / 9 o / o i o o 6 9 + o 4 $o2.oo/o 4
© 199 ° T h e British Society for the Study of Infection JIN 20
7°
N. B H A T T I
ET AL.
tomography was found to be normal, lumbar puncture was performed which yielded clear cerebrospinal fluid (CSF). Microscopy showed 26 white cells per /zl, all of which were lymphocytes. No organisms were seen. T h e CSF protein was raised (I'O7 g/l) but glucose was normal (4"6 mmol/1, blood glucose 6"5 mmol/1). T h e peripheral WBC's were raised at 20. 9 × IO9/1 with a differential count of 67 % lymphocytes and 32 % neutrophils. Other routine haematological and biochemical tests were normal apart from a serum aspartate transaminase of I46 IU/1. T h e Monospot test was positive. A diagnosis of Epstein-Barr virus encephalitis was made and treatment with intravenous acyclovir (700 mg 8 hourly) commenced. Intravenous benzylpenicillin (2 megaunits 4 hourly) was continued for 2 days when Neisseria meningitidis group C was isolated from a throat swab. Neisseria meningitidis was not isolated from blood or CSF and group C antigen could not be detected using latex agglutination and countercurrent immunoelectrophoresis. T h e patient was sedated with papaveretum and ventilated overnight. When extubated he was unconscious, irritable, twitching and hyperreflexic with a pyrexia of 39"3 °C. On the following day h e could respond to commands but was unable to talk, while his reflex responses were normal. He became fully conscious on the third day and had no focal neurological abnormality. His pyrexia persisted for a further 3 days. Acyclovir was continued for a total of 7 days after which he was discharged home. Although there was some initial impairment of intellectual function (serial sevens), this had resolved on followup. He was able to return to college after three weeks.
Virological investigations A Paul Bunnell test was positive, all heterophil agglutinins being removed by ox red cell absorption. Acute EBV infection was confirmed by finding serum IgG antibody to early antigen (EA) at a titre of 25oo and viral capsid antigen (VCA) at a titre of I6o, with IgM to VCA at a titre of i6oo; Serum IgG antibody titres to EBV nuclear antigens (EBNA) I and 2 were less than IO. IgM to VCA could be detected in CSF at a titre of IO but IgG antibody to VCA and EA remained undetectable. Titres in serum were similar after r week, but a repeat lumbar puncture was not performed. Discussion Epstein-Barr virus should be considered in the differential diagnosis of acute encephalitis even though it is an unusual cause. In our patient there was a preceding history of sore throat, but the finding of a purpuric rash required us to exclude a diagnosis of meningococcal infection. T h e positive Monospot screening test was confirmed by the Paul Bunnell test and by finding specific antibodies to EBV capsid antigen in serum and CSF. EA and VCA are produced in B lymphocytes as viral lyric cycle products and are therefore specific for viral replication. T h e Monospot test can thus be useful in rapidly establishing the cause of acute encephalitis. 1'3 It has been suggested that the mortality rate of EBV encephalitis can be as high as 33 %,8 and that those who survive may have long-term after affects, but others have described the disease as relatively benign with few sequelae. 2 It is
71
Encephalitis due to E B virus
perhaps more common than has been reported and subacute or mild encephalitis due to EBV may be missed. This may be relevant to the prolonged lassitude which sometimes follows EBV infection. We were not able to perform a convalescent CSF examination but did find an IgM titre of io in the acute stage. Follow-up CSF antibody studies would clearly be useful but are unlikely to be available in most cases. T h e value of acyclovir and steroids in EBV infections is controversial and unproven, but both are currently recommended. 8 T h r e e double-blind controlled studies and one matched control trial have shown significant reduction in both fever and pharyngitis during corticosteroid treatment without unacceptable side-effects. Despite this the use of steroids in infectious mononucleosis has not been generally accepted. 9' 10 It has been found that the combination of intravenous acyclovir and prednisolone causes not only cessation of virus shedding, but a dramatic improvement of fever and symptoms in uncomplicated glandular fever. 6 This apparent response to steroids was not involved in the rapid recovery seen in our patient treated with acyclovir alone. Acyclovir is an analogue of guanosine which depends for its activity on being phosphorylated by the virus specific enzyme thymidine kinase. Such selective phosphorylation results in few side-effects, allows the drug to target virus-infected cells, but results in much less activity against EBV than herpes simplex virus (HSV). 11 However, it has been demonstrated in the EBV-permissive cell line, B95-8, that concentrations of acyclovir of 5 and 5 o # g / m l inhibited EBV replication, while hydrocortisone at 2 to 2oo # g / m l had no effect. 6 T h e authors also showed that in the early stages of infectious mononucleosis, acyclovir caused a dramatic but reversible inhibition of oropharyngeal EBV replication. Acyclovir only affects active replication of EBV in B lymphocytes which are selectively infected via their surface receptor 'CR2'. It has no effect on their latent infection. If acyclovir was effective in treating our patient's encephalitis, the viral replication must have been an essential part of the disease process. In the normal individual there is a cytotoxic EBV-specific T lymphocyte response to the infected B lymphocytes that can be aggressive, but which prevents EBV positive lymphoproliferative lesions. 12 Steroids are known to be effective in limiting this T cell response. If solitary use of steroids induced early recovery of encephalitis, it could be postulated that the encephalitis had a n immunological (lymphocytic) basis as its cause. T h e early diagnosis of acute viral encephalitis is a clinical one and the cause may not be immediately apparent. Clinical trials of acyclovir have shown that survival is increased and neurological damage reduced if treatment of herpes encephalitis is started within 4 days of onset. 13'~4 Such trials have not been possible for EBV encephalitis because of the small number of diagnosed cases. Some authors have reported a satisfactory outcome to EBV encephalitis without chemotherapy 1' 3,4 but Lange et al. 2 reported a patient who died on day I0, and D e m e y et al. 7 one with severe memory loss. All patients, including our own, have had transitory deficits of CNS function following the encephalitis. Our patient was prescribed acyclovir within I2 h of onset of neurological symptoms but it is clearly impossible to know if he might have made a complete recovery without it. Present data suggest that it is prudent to 4-2
72
N. B H A T T I E T A L .
prescribe acyclovir for early treatment of possible EBV/HSV encephalitis, e s p e c i a l l y w h e n p a t i e n t s a r e s e v e r e l y ill, p r o g n o s i s is u n c e r t a i n a n d t o x i c i t y c a n b e e x p e c t e d to b e m i n i m a l . (We thank Professor D o r o t h y Crawford, D e p a r t m e n t of Virology, H a m m e r s m i t h Hospital, for carrying out the serology tests for EBV infection.)
References 1. Joncas JH, Chicoine L, Thivieige R, Bertrand M. Epstein-Barr virus antibodies in the cerebrospinal fluid, a case of infectious mononucleosis with encephalitis. A m ff Dis Child I974; 127: 282--285. 2. Lange BJ, Berman PH, Bender J, Henle W, Hewetson JF. Encephalitis in infectious mononucleosis: diagnostic considerations. Paediatrics 1976; 58: 877-88o. 3. Halstead CC, Shihman Chang R. Infectious mononucleosis and encephalitis: recovery of Epstein-Barr Virus from spinal fluid. Paediatrics I979; 64: 257--258. 4. Cleary T G , Henle W, Pickering LK: Acute cerebellar ataxia associated with Epstein-Barr virus infection. J A M A 198o; 143: 148-149. 5. Piadines S, Francois P, Joannaid A, Gout JP, Baccand C, Beaudoing A. Encephalite a virus d'Epstein-Barr. Pediatric 1986; xxxxl : 481-484. 6. Andersson J, Eirnberg I. Management of Epstein-Barr virus infections. A m J Med 1988; 85 (suppl 24): IO7-II 5. 7- Demey HE, Martin JJ, Lens RM, Moeremans CJ, Bossaert LL. Coma as a presenting sign of Epstein-Barr encephalitis. Arch Intern Med 1988; I48: 1459-1461. 8. Juel-Jensen BE. Infectious mononucleosis : Epstein-Barr virus disease. In : Weatherall D J, Ledingham JGG, Warrell DA, Eds. Oxford textbook of medicine. Oxford: Oxford University Press, 1987; 572-575. 9. Bender CE. The value of corticosteroids in the treatment of infectious mononucleosis. J A M A 1967; I99:529-53 I. zo. Bolden KJ. Corticosteroids in the treatment of infectious mononucleosis. ] R Coll Gen Prac I972; 21: 87-95. I I. Wood MJ, Geddes AM. Infection today- antiviral therapy. Lancet I987; ii: I I89-I 192. I2. Anon. (editorial). Epstein-Barr virus silver anniversary. Lancet 1989, i: I I 7 I - I 1 7 3 . I3. Skoldenberg B, Forsgren M, Alestig K et al. Acyclovir versus vidarabine in herpes simplex encephalitis. Lancet I984; ii: 707-71 I. I4. Whitley RJ, Alford CJ, Hirsch MS et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N E n g l J ivied 1986; 314: I44-I49.
20, 69-72
CASE REPORT E n c e p h a l i t i s d u e to E p s t e i n - B a r r v i r u s N. Bhatti,* E. Larson,*$ M. Hickey~ and D. Sealt Microbial Pathogenicity Research Group, * Division of Communicable Diseases, Clinical Research Centre, Northwick Park Hospital and t Department of Microbiology, Northwick Park Hospital, Watford Road, Harrow, Middlesex H A I 3 UJ, U.K. Accepted for publication 25 September 1989 Summary Acute encephalitis due to Epstein-Barr virus is described. The initial diagnosis was based on clinical features and a positive Monospot test. Early treatment with intravenous acyclovir was given; steroids were not used. The patient made a rapid and complete recovery from a comatose state. The effectiveness of acyclovir in this condition remains unproven but early treatment is recommended in severely ill patients whose prognosis is uncertain.
Introduction Encephalitis due to E p s t e i n - B a r r virus (EBV) is infrequently reported. 1-8 It has been suggested that mortality can be as high as 33 %, although this m a y be associated with other features, i.e. myocarditis. T h e use of steroids is controversial while any beneficial effects of acyclovir remain unproven. W e have recently treated a patient who had E p s t e i n - B a r r virus encephalitis and report a successful o u t c o m e without the use of steroids.
Case report A 17-year-old man, previously well, was admitted to hospital in an unconscious state with choreiform m o v e m e n t s of all four limbs. D u r i n g the previous 2 weeks he had been tired and unwell, and 4 days before admission had developed a sore throat for which he was treated with oral penicillin V. O n the morning of admission the patient was noticed to be behaving in an aggressive manner. His father came h o m e that afternoon, to find him unconscious and writhing on the floor. O n examination the patient was pyrexial to 37"8 °C and unresponsive to painful stimuli b u t m o v e d his limbs in a choreiform manner. His neck was stiff and pupils pinpoint, while all four limbs were hyperreflexic. A p u r p u r i c rash was noted on the right side of the face. Because meningococcal meningitis could not be excluded, he was at once given six megaunits of benzylpenicillin intravenously. After urgent c o m p u t e d ~t A u t h o r to w h o m all correspondence should be addressed. o 1 6 3 - 4 4 5 3 / 9 o / o i o o 6 9 + o 4 $o2.oo/o 4
© 199 ° T h e British Society for the Study of Infection JIN 20
7°
N. B H A T T I
ET AL.
tomography was found to be normal, lumbar puncture was performed which yielded clear cerebrospinal fluid (CSF). Microscopy showed 26 white cells per /zl, all of which were lymphocytes. No organisms were seen. T h e CSF protein was raised (I'O7 g/l) but glucose was normal (4"6 mmol/1, blood glucose 6"5 mmol/1). T h e peripheral WBC's were raised at 20. 9 × IO9/1 with a differential count of 67 % lymphocytes and 32 % neutrophils. Other routine haematological and biochemical tests were normal apart from a serum aspartate transaminase of I46 IU/1. T h e Monospot test was positive. A diagnosis of Epstein-Barr virus encephalitis was made and treatment with intravenous acyclovir (700 mg 8 hourly) commenced. Intravenous benzylpenicillin (2 megaunits 4 hourly) was continued for 2 days when Neisseria meningitidis group C was isolated from a throat swab. Neisseria meningitidis was not isolated from blood or CSF and group C antigen could not be detected using latex agglutination and countercurrent immunoelectrophoresis. T h e patient was sedated with papaveretum and ventilated overnight. When extubated he was unconscious, irritable, twitching and hyperreflexic with a pyrexia of 39"3 °C. On the following day h e could respond to commands but was unable to talk, while his reflex responses were normal. He became fully conscious on the third day and had no focal neurological abnormality. His pyrexia persisted for a further 3 days. Acyclovir was continued for a total of 7 days after which he was discharged home. Although there was some initial impairment of intellectual function (serial sevens), this had resolved on followup. He was able to return to college after three weeks.
Virological investigations A Paul Bunnell test was positive, all heterophil agglutinins being removed by ox red cell absorption. Acute EBV infection was confirmed by finding serum IgG antibody to early antigen (EA) at a titre of 25oo and viral capsid antigen (VCA) at a titre of I6o, with IgM to VCA at a titre of i6oo; Serum IgG antibody titres to EBV nuclear antigens (EBNA) I and 2 were less than IO. IgM to VCA could be detected in CSF at a titre of IO but IgG antibody to VCA and EA remained undetectable. Titres in serum were similar after r week, but a repeat lumbar puncture was not performed. Discussion Epstein-Barr virus should be considered in the differential diagnosis of acute encephalitis even though it is an unusual cause. In our patient there was a preceding history of sore throat, but the finding of a purpuric rash required us to exclude a diagnosis of meningococcal infection. T h e positive Monospot screening test was confirmed by the Paul Bunnell test and by finding specific antibodies to EBV capsid antigen in serum and CSF. EA and VCA are produced in B lymphocytes as viral lyric cycle products and are therefore specific for viral replication. T h e Monospot test can thus be useful in rapidly establishing the cause of acute encephalitis. 1'3 It has been suggested that the mortality rate of EBV encephalitis can be as high as 33 %,8 and that those who survive may have long-term after affects, but others have described the disease as relatively benign with few sequelae. 2 It is
71
Encephalitis due to E B virus
perhaps more common than has been reported and subacute or mild encephalitis due to EBV may be missed. This may be relevant to the prolonged lassitude which sometimes follows EBV infection. We were not able to perform a convalescent CSF examination but did find an IgM titre of io in the acute stage. Follow-up CSF antibody studies would clearly be useful but are unlikely to be available in most cases. T h e value of acyclovir and steroids in EBV infections is controversial and unproven, but both are currently recommended. 8 T h r e e double-blind controlled studies and one matched control trial have shown significant reduction in both fever and pharyngitis during corticosteroid treatment without unacceptable side-effects. Despite this the use of steroids in infectious mononucleosis has not been generally accepted. 9' 10 It has been found that the combination of intravenous acyclovir and prednisolone causes not only cessation of virus shedding, but a dramatic improvement of fever and symptoms in uncomplicated glandular fever. 6 This apparent response to steroids was not involved in the rapid recovery seen in our patient treated with acyclovir alone. Acyclovir is an analogue of guanosine which depends for its activity on being phosphorylated by the virus specific enzyme thymidine kinase. Such selective phosphorylation results in few side-effects, allows the drug to target virus-infected cells, but results in much less activity against EBV than herpes simplex virus (HSV). 11 However, it has been demonstrated in the EBV-permissive cell line, B95-8, that concentrations of acyclovir of 5 and 5 o # g / m l inhibited EBV replication, while hydrocortisone at 2 to 2oo # g / m l had no effect. 6 T h e authors also showed that in the early stages of infectious mononucleosis, acyclovir caused a dramatic but reversible inhibition of oropharyngeal EBV replication. Acyclovir only affects active replication of EBV in B lymphocytes which are selectively infected via their surface receptor 'CR2'. It has no effect on their latent infection. If acyclovir was effective in treating our patient's encephalitis, the viral replication must have been an essential part of the disease process. In the normal individual there is a cytotoxic EBV-specific T lymphocyte response to the infected B lymphocytes that can be aggressive, but which prevents EBV positive lymphoproliferative lesions. 12 Steroids are known to be effective in limiting this T cell response. If solitary use of steroids induced early recovery of encephalitis, it could be postulated that the encephalitis had a n immunological (lymphocytic) basis as its cause. T h e early diagnosis of acute viral encephalitis is a clinical one and the cause may not be immediately apparent. Clinical trials of acyclovir have shown that survival is increased and neurological damage reduced if treatment of herpes encephalitis is started within 4 days of onset. 13'~4 Such trials have not been possible for EBV encephalitis because of the small number of diagnosed cases. Some authors have reported a satisfactory outcome to EBV encephalitis without chemotherapy 1' 3,4 but Lange et al. 2 reported a patient who died on day I0, and D e m e y et al. 7 one with severe memory loss. All patients, including our own, have had transitory deficits of CNS function following the encephalitis. Our patient was prescribed acyclovir within I2 h of onset of neurological symptoms but it is clearly impossible to know if he might have made a complete recovery without it. Present data suggest that it is prudent to 4-2
72
N. B H A T T I E T A L .
prescribe acyclovir for early treatment of possible EBV/HSV encephalitis, e s p e c i a l l y w h e n p a t i e n t s a r e s e v e r e l y ill, p r o g n o s i s is u n c e r t a i n a n d t o x i c i t y c a n b e e x p e c t e d to b e m i n i m a l . (We thank Professor D o r o t h y Crawford, D e p a r t m e n t of Virology, H a m m e r s m i t h Hospital, for carrying out the serology tests for EBV infection.)
References 1. Joncas JH, Chicoine L, Thivieige R, Bertrand M. Epstein-Barr virus antibodies in the cerebrospinal fluid, a case of infectious mononucleosis with encephalitis. A m ff Dis Child I974; 127: 282--285. 2. Lange BJ, Berman PH, Bender J, Henle W, Hewetson JF. Encephalitis in infectious mononucleosis: diagnostic considerations. Paediatrics 1976; 58: 877-88o. 3. Halstead CC, Shihman Chang R. Infectious mononucleosis and encephalitis: recovery of Epstein-Barr Virus from spinal fluid. Paediatrics I979; 64: 257--258. 4. Cleary T G , Henle W, Pickering LK: Acute cerebellar ataxia associated with Epstein-Barr virus infection. J A M A 198o; 143: 148-149. 5. Piadines S, Francois P, Joannaid A, Gout JP, Baccand C, Beaudoing A. Encephalite a virus d'Epstein-Barr. Pediatric 1986; xxxxl : 481-484. 6. Andersson J, Eirnberg I. Management of Epstein-Barr virus infections. A m J Med 1988; 85 (suppl 24): IO7-II 5. 7- Demey HE, Martin JJ, Lens RM, Moeremans CJ, Bossaert LL. Coma as a presenting sign of Epstein-Barr encephalitis. Arch Intern Med 1988; I48: 1459-1461. 8. Juel-Jensen BE. Infectious mononucleosis : Epstein-Barr virus disease. In : Weatherall D J, Ledingham JGG, Warrell DA, Eds. Oxford textbook of medicine. Oxford: Oxford University Press, 1987; 572-575. 9. Bender CE. The value of corticosteroids in the treatment of infectious mononucleosis. J A M A 1967; I99:529-53 I. zo. Bolden KJ. Corticosteroids in the treatment of infectious mononucleosis. ] R Coll Gen Prac I972; 21: 87-95. I I. Wood MJ, Geddes AM. Infection today- antiviral therapy. Lancet I987; ii: I I89-I 192. I2. Anon. (editorial). Epstein-Barr virus silver anniversary. Lancet 1989, i: I I 7 I - I 1 7 3 . I3. Skoldenberg B, Forsgren M, Alestig K et al. Acyclovir versus vidarabine in herpes simplex encephalitis. Lancet I984; ii: 707-71 I. I4. Whitley RJ, Alford CJ, Hirsch MS et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N E n g l J ivied 1986; 314: I44-I49.