t
Chronic Enteroviral Meningoencephalitis in Agammaglobulinemia: Case Report and Literature Review S. A. MISBAH, 1'5 G. P. SPICKETT, 1 P. C. J. RYBA, 2 J. M. HOCKADAY, 2 J. S. KROLL, 2 C. SHERWOOD, 4 J. B. KURTZ, 3 E. R. MOXON, 2 and H. M. C H A P E L 1
Accepted: January 14, 1992
INTRODUCTION
Chronic enteroviral meningoencephalitis is a wellrecognized complication in patients with X-linked agammaglobulinemia (XLA). The majority of published cases refers to its occurrence in patients on no replacement therapy or on only intramuscular immunoglobulin. The advent of intravenous immunoglobulin (IVIg) in the early 1980s and its widespread use in XLA was thought to have virtually eradicated enteroviral meningoencephalitis in these patients. We describe the development of echovirus meningoencephalitis in an l 1-year-old boy on regular IVIg replacement whose serum IgG levels were maintained at between 6 and 8 g/L (NR 6-13 g/L). Treatment with daily high-dose IVIg was commenced, with significant clinical improvement being noted within a few weeks in association with a reduction in blood--brain barrier permeability. The persistence of live virus, however, necessitated the use of intraventricular immunoglobulin. The virus proved resistant to two courses of specific intraventricular immunoglobulin and a 6-week course of oral ribavirin and eventually proved fatal 5 months after presentation. In view of the therapeutic uncertainties we have reviewed the use of immunogtobulin in the treatment of enteroviral meningoencephalitis over the past 6 years.
Chronic enteroviral meningoencephalitis is a wellrecognized complication in patients with X-linked agammaglobulinemia (XLA) (1). In the majority of patients it proves to be fatal and reports of successful treatment with intravenous immunoglobulin (IVIg) and/or intraventricular immunoglobulin are rare. Hitherto most published reports have referred to its occurrence in patients on no replacement therapy or on only intramuscular immunoglobulin replacement (IMIg). We report the development of chronic enteroviral meningoencephalitis in an l 1year-old boy on regular IVIg replacement whose serum IgG levels were maintained at between 6 and 8 g/L (NR 6-13 g/L) and review the use of immunoglobulin in its treatment over the past 6 years (Table I). CASE REPORT KL, a Caucasian male child of unrelated parents, was diagnosed as having X L A in 1982, at the age of 4 years. Investigation showed panhypogammaglobulinemia and no circulating B cells. Weekly IMIg therapy was commenced, and 2 years later K L was converted to regular IVIg (0.4 g/kg/3 weekly). Apart from an occasional mild ear or chest infection (1-2 per year), he remained well and grew normally. Behavioral problems were noted in 1989, and in January 1990 he was hospitalized with acute lymphocytic meningitis. No virus was isolated from cultures of CSF, stools, or throat washings. He was treated empirically with intravenous Acyclovir, and after an initial recovery, he deteriorated steadily over 2 months. In May 1990, K L presented with progressive apathy, headache, drowsiness, and a
KEY WORDS: Enterovirus meningoencephalitis; X-linked agammaglobulinemia immunoglobulin; ribavirin.
1Department of Immunology, John Radcliffe Hospital, Oxford,
UK.
2Department of Paediatrics, John Radcliffe Hospital, Oxford,
UK.
3Department of Virology, John Radcliffe Hospital, Oxford, UK. 4Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, California 92037. ~To whom correspondence should be addressed at Department of Immunology, Level 7, John Radcliffe Hospital, Oxford OX3 9DU, UK.
266 0271-9142/92/0700-0266506.50/0© 1992PlenumPublishingCorporation
9 yr Echo 11 9 yr Echo 17
2 yr
10 mo
7 yr
6 mo
4. McKinney e t at. (29)b 5. MeKinney e t aL (31) 6. Bernatowska e t
7. Van Maldergem e t
6 mo
2 yr 9 mo
3 mo
5 yr
3 yr 4 mo (CVI)
6 yr 4 mo (CVI)
2 yr 6 mo
35 yr CVI with thymoma NK 3 yr
4 yr
9. McKinney e t aL
10. D~cer et al.
l l . Dwyer et al.
12. Dw'yer e t at.
13. Lau e t aL
14. Lau e t al.
15. Kondoh e t aL
16. Hadfield e t aL
17. Johnson e t aL 18. Roberton e t al.
19. Misbah et aL
11 3q" Echo 11 9.5 yr Untypable plcorna Villas 12 yr Echo 11
35 yr Echo 11
7 yr Echo 11
4 yr 8 mo Echo 11 8 yr 7 mo Echo 11 3 yr 5 mo Echo 11 & adeno 6 yr 4 mo
3.5 yr Echo 5
5.5 yr Echo 7
7.5 yr Echo 9,7
8.5 yr Echo 13
32 yr Echo 11
IVIg
NK IVIg
Prednisotone
IVIg
Nil
? route of Ig replacement IVIg
IVIg
IMIg
IMIg
Plasma, IMlg
Mg
Plasma
NK
NK
IMIg
IMIg
IMIg
Before o n s e t of encephalitis
2 mo
NK NK NK ?
IVIg
Plasma, IVIg IVIg Plasma, IVIg High-dose IVIg
1:32
1 mo
NK 2 wk
IVIg, 1 mo IVenIg, 3 wk IVenlg, 2 wk IVIg IVenIg, 2 wk
NK 1:64 1:100-1:1000 1:64-1:128 1:8-1:32
1:32
NK 12 mo 18 days Continuous 2.5 yr
Continuous
IVenlg, 3 days IVIg Acyclovir IVIg (high dose) I.T. ez-inf~ I.T. lg, 5 m Hi,h-dose IVIg, 18 uays IVenIg, 22 days IVenIg, IVIg ttigh-dose IVIg Plasma, transfer factor, IVenIg, IVen r-c~inf High-dose IVIg IVenIg. Oral nbavirin
NK
5 wk
>1:32
IVenIg, 3 days IVIg
iVlg
1:16
5 mo
IVIg, 2 mo IVenIg
1:64
10 yr (CSF) Neg. cultures with IVenlg
NK
1:8
NK
NK
NK
1:32
1:8
1:64
T i t e r of antiecho " a b " i n Ig
tVIg, 10 yr IVenIg, 5 daysNvk for 6 mo
IVIg
Only on one occaslon Continuous
S i nc e
D u r a t i o n of v i r u s isolation
Plasma, M g
Treatment
ONot k n o w n . b N u m b e r s in p a r e n t h e s e s refer to p a t i e n t n u m b e r s in M c K i n n e y e t a L p a p e r (1). CAlpha-interferon.
(25)
3 yr 9 mo
8, McKianey e t al. (21)
al.
at.
15 yr Echo 24
NK °
3. Mease et aL
29 yr Echo 11
19 mo
2. Crennan e t aL
24 yr Echo 3
Encephalitis
10 mo
Agamma
1. Prentice e t al.
P a t i e n t no. and Ref.
A g e at diagnosis
Ta bl e L E n t e r o v i r a l M e n i n g o e n c e p h a l i t i s in A g a m m a g l o b u l i n e m i a
Died 6 wk; CSF sterile. Entero- and adenovirus in stools. Poor response to IVIg. Marked improvement with I.T. lg; well at 21 mo f/u. Dead at 4 too. No response to IVenIg. Initial clinical improvement. Dead at 2.5 yr. Temp. clinical improvement at 6 wk with high-dose Wig. No response to IVenIg and ribavirin, Died at 5 mo.
$ in protein cone. and cell et. NK NK NK
No change
Virus cleared but poor clinical response Well at 2 yr; attending normal school. Echo 29 in stools.
No response to high-dose IVIg (peak s.IgG, 13 g/L). Good response to IVenlg. "Doing well" at school at 5.5 yr f/u. Well at 16 mo flu. CSF free of virus.
NK
Normalization
Normalization
Normalization
$ in protein cone. and celt ct. with IVenIg $ in protein cone. and cell ct. with IVenlg Normalization
Disease progression halted at 14 mo f/u
Improved after 6 mo of IVIg. At 2 yr f/u improvement maintained. Initial dramatic improvement at 1 mo. Lost to f/u after 10 mo. Fatal relapse 6 wk later. IVlg slowed progression. No response to IVenIg.
Normalization NK
Alive 7 mo after diagnosis.
Improved at 3 mo. Remained stable at review at 23 too. Died at Day 29. Treated with steroids and methotrexate for presumed polymyositis previously. Complete recovery at 7 too. Two relapses duringnoncompliance and when intervalbetween IVIg infusion was lengthened. Well at 4 yr. Alive 2 yr after diagnosis.
Outcome and comments
NK
NK
Increase in protein cone. and cell ct. NK
No change
CSF changes with treatment
7.
(gl
r~
.
Chronic Enteroviral Meningoencephalitis in Agammaglobulinemia: Case Report and Literature Review S. A. MISBAH, 1'5 G. P. SPICKETT, 1 P. C. J. RYBA, 2 J. M. HOCKADAY, 2 J. S. KROLL, 2 C. SHERWOOD, 4 J. B. KURTZ, 3 E. R. MOXON, 2 and H. M. C H A P E L 1
Accepted: January 14, 1992
INTRODUCTION
Chronic enteroviral meningoencephalitis is a wellrecognized complication in patients with X-linked agammaglobulinemia (XLA). The majority of published cases refers to its occurrence in patients on no replacement therapy or on only intramuscular immunoglobulin. The advent of intravenous immunoglobulin (IVIg) in the early 1980s and its widespread use in XLA was thought to have virtually eradicated enteroviral meningoencephalitis in these patients. We describe the development of echovirus meningoencephalitis in an l 1-year-old boy on regular IVIg replacement whose serum IgG levels were maintained at between 6 and 8 g/L (NR 6-13 g/L). Treatment with daily high-dose IVIg was commenced, with significant clinical improvement being noted within a few weeks in association with a reduction in blood--brain barrier permeability. The persistence of live virus, however, necessitated the use of intraventricular immunoglobulin. The virus proved resistant to two courses of specific intraventricular immunoglobulin and a 6-week course of oral ribavirin and eventually proved fatal 5 months after presentation. In view of the therapeutic uncertainties we have reviewed the use of immunogtobulin in the treatment of enteroviral meningoencephalitis over the past 6 years.
Chronic enteroviral meningoencephalitis is a wellrecognized complication in patients with X-linked agammaglobulinemia (XLA) (1). In the majority of patients it proves to be fatal and reports of successful treatment with intravenous immunoglobulin (IVIg) and/or intraventricular immunoglobulin are rare. Hitherto most published reports have referred to its occurrence in patients on no replacement therapy or on only intramuscular immunoglobulin replacement (IMIg). We report the development of chronic enteroviral meningoencephalitis in an l 1year-old boy on regular IVIg replacement whose serum IgG levels were maintained at between 6 and 8 g/L (NR 6-13 g/L) and review the use of immunoglobulin in its treatment over the past 6 years (Table I). CASE REPORT KL, a Caucasian male child of unrelated parents, was diagnosed as having X L A in 1982, at the age of 4 years. Investigation showed panhypogammaglobulinemia and no circulating B cells. Weekly IMIg therapy was commenced, and 2 years later K L was converted to regular IVIg (0.4 g/kg/3 weekly). Apart from an occasional mild ear or chest infection (1-2 per year), he remained well and grew normally. Behavioral problems were noted in 1989, and in January 1990 he was hospitalized with acute lymphocytic meningitis. No virus was isolated from cultures of CSF, stools, or throat washings. He was treated empirically with intravenous Acyclovir, and after an initial recovery, he deteriorated steadily over 2 months. In May 1990, K L presented with progressive apathy, headache, drowsiness, and a
KEY WORDS: Enterovirus meningoencephalitis; X-linked agammaglobulinemia immunoglobulin; ribavirin.
1Department of Immunology, John Radcliffe Hospital, Oxford,
UK.
2Department of Paediatrics, John Radcliffe Hospital, Oxford,
UK.
3Department of Virology, John Radcliffe Hospital, Oxford, UK. 4Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, California 92037. ~To whom correspondence should be addressed at Department of Immunology, Level 7, John Radcliffe Hospital, Oxford OX3 9DU, UK.
266 0271-9142/92/0700-0266506.50/0© 1992PlenumPublishingCorporation
9 yr Echo 11 9 yr Echo 17
2 yr
10 mo
7 yr
6 mo
4. McKinney e t at. (29)b 5. MeKinney e t aL (31) 6. Bernatowska e t
7. Van Maldergem e t
6 mo
2 yr 9 mo
3 mo
5 yr
3 yr 4 mo (CVI)
6 yr 4 mo (CVI)
2 yr 6 mo
35 yr CVI with thymoma NK 3 yr
4 yr
9. McKinney e t aL
10. D~cer et al.
l l . Dwyer et al.
12. Dw'yer e t at.
13. Lau e t aL
14. Lau e t al.
15. Kondoh e t aL
16. Hadfield e t aL
17. Johnson e t aL 18. Roberton e t al.
19. Misbah et aL
11 3q" Echo 11 9.5 yr Untypable plcorna Villas 12 yr Echo 11
35 yr Echo 11
7 yr Echo 11
4 yr 8 mo Echo 11 8 yr 7 mo Echo 11 3 yr 5 mo Echo 11 & adeno 6 yr 4 mo
3.5 yr Echo 5
5.5 yr Echo 7
7.5 yr Echo 9,7
8.5 yr Echo 13
32 yr Echo 11
IVIg
NK IVIg
Prednisotone
IVIg
Nil
? route of Ig replacement IVIg
IVIg
IMIg
IMIg
Plasma, IMlg
Mg
Plasma
NK
NK
IMIg
IMIg
IMIg
Before o n s e t of encephalitis
2 mo
NK NK NK ?
IVIg
Plasma, IVIg IVIg Plasma, IVIg High-dose IVIg
1:32
1 mo
NK 2 wk
IVIg, 1 mo IVenIg, 3 wk IVenlg, 2 wk IVIg IVenIg, 2 wk
NK 1:64 1:100-1:1000 1:64-1:128 1:8-1:32
1:32
NK 12 mo 18 days Continuous 2.5 yr
Continuous
IVenlg, 3 days IVIg Acyclovir IVIg (high dose) I.T. ez-inf~ I.T. lg, 5 m Hi,h-dose IVIg, 18 uays IVenIg, 22 days IVenIg, IVIg ttigh-dose IVIg Plasma, transfer factor, IVenIg, IVen r-c~inf High-dose IVIg IVenIg. Oral nbavirin
NK
5 wk
>1:32
IVenIg, 3 days IVIg
iVlg
1:16
5 mo
IVIg, 2 mo IVenIg
1:64
10 yr (CSF) Neg. cultures with IVenlg
NK
1:8
NK
NK
NK
1:32
1:8
1:64
T i t e r of antiecho " a b " i n Ig
tVIg, 10 yr IVenIg, 5 daysNvk for 6 mo
IVIg
Only on one occaslon Continuous
S i nc e
D u r a t i o n of v i r u s isolation
Plasma, M g
Treatment
ONot k n o w n . b N u m b e r s in p a r e n t h e s e s refer to p a t i e n t n u m b e r s in M c K i n n e y e t a L p a p e r (1). CAlpha-interferon.
(25)
3 yr 9 mo
8, McKianey e t al. (21)
al.
at.
15 yr Echo 24
NK °
3. Mease et aL
29 yr Echo 11
19 mo
2. Crennan e t aL
24 yr Echo 3
Encephalitis
10 mo
Agamma
1. Prentice e t al.
P a t i e n t no. and Ref.
A g e at diagnosis
Ta bl e L E n t e r o v i r a l M e n i n g o e n c e p h a l i t i s in A g a m m a g l o b u l i n e m i a
Died 6 wk; CSF sterile. Entero- and adenovirus in stools. Poor response to IVIg. Marked improvement with I.T. lg; well at 21 mo f/u. Dead at 4 too. No response to IVenIg. Initial clinical improvement. Dead at 2.5 yr. Temp. clinical improvement at 6 wk with high-dose Wig. No response to IVenIg and ribavirin, Died at 5 mo.
$ in protein cone. and cell et. NK NK NK
No change
Virus cleared but poor clinical response Well at 2 yr; attending normal school. Echo 29 in stools.
No response to high-dose IVIg (peak s.IgG, 13 g/L). Good response to IVenlg. "Doing well" at school at 5.5 yr f/u. Well at 16 mo flu. CSF free of virus.
NK
Normalization
Normalization
Normalization
$ in protein cone. and celt ct. with IVenIg $ in protein cone. and cell ct. with IVenlg Normalization
Disease progression halted at 14 mo f/u
Improved after 6 mo of IVIg. At 2 yr f/u improvement maintained. Initial dramatic improvement at 1 mo. Lost to f/u after 10 mo. Fatal relapse 6 wk later. IVlg slowed progression. No response to IVenIg.
Normalization NK
Alive 7 mo after diagnosis.
Improved at 3 mo. Remained stable at review at 23 too. Died at Day 29. Treated with steroids and methotrexate for presumed polymyositis previously. Complete recovery at 7 too. Two relapses duringnoncompliance and when intervalbetween IVIg infusion was lengthened. Well at 4 yr. Alive 2 yr after diagnosis.
Outcome and comments
NK
NK
Increase in protein cone. and cell ct. NK
No change
CSF changes with treatment
7.
(gl
r~
.
