Abstract
Relapse of herpes simplex virus (HSV) encephalitis following acyclovir therapy has
been reported infrequently in children beyond the neonatal period. The pathogenic
mechanism of the recurrence is not fully understood. We report two new cases that
support a mechanism of latent HSV infection with reactivation of the disease. Our
patients were 2 years (#1) and 8 months (#2) old at initial infection. Both presented
with fever, lethargy, focal seizures, and focal motor abnormalities. Serum HSV antibodies
(Abs) were negative. The patients were treated with acyclovir for 14 and 21 days,
respectively. They were readmitted at 1 month, and 4 days after discharge, respectively,
with recurrent lethargy, seizures, and choreo-athetoid movements. Serum and CSF HSV
Abs were significantly increased. CSF PCR was positive. In patient # 2 acyclovir-sensitive
HSV was isolated from a brain biopsy. Both patients were re-treated with acyclovir,
but progressed to a neurovegetative state. In our cases, latent HSV infection and
reactivation is the most likely explanation for recurrent encephalitis. The immuno-pathogenic
mechanisms of the infection recurrence are discussed. Based on the reported cases
in the literature, patients younger than 2 years of age and with lower total dose
of acyclovir treatments have a higher risk of recurrence.
Key words
Herpes - encephalitis - relapse - pediatrics - latent
References
- 1
Abramson J S, Roach E S, Levy H B.
Postinfectious encephalopathy after treatment of herpes simplex encephalitis with
acyclovir.
Pediatr Infect Dis.
1984;
3
146-147
- 2 American Academy of Pediatrics .
Herpes Simplex. Pickering LK 2003 Red Book: Report of the Committee On Infectious Diseases. Elk Grove
Village, IL; American Academy of Pediatrics 2003 346-349 729
- 3
Barthez M A, Billard C, Santini J J, Ruchoux M M, Grangeponte M C.
Relapse of herpes simplex encephalitis.
Neuropediatrics.
1987;
18
3-7
- 4
Barthez-Carpentier M A, Rozenberg F, Dussaix E, Lebon P, Goudeau A, Billard C. et
al .
Relapse of herpes simplex encephalitis.
J Child Neurol.
1995;
10
363-368
- 5
Bergstrom T, Trollfors B.
Recurrent herpes simplex virus type 2 encephalitis in a preterm neonate. Favourable
outcome after prolonged acyclovir treatment.
Acta Paediatr Scand.
1991;
80
878-881
- 6
Bourgeois M, Vinikoff L, Lellouch-Tubiana A, Sainte-Rose C.
Reactivation of herpes virus after surgery for epilepsy in a pediatric patient with
mesial temporal sclerosis: case report.
Neurosurgery.
1999;
44
633-635
- 7
Dalai S K, Pesnicak L, Miller G F, Straus S E.
Prophylactic and therapeutic effects of human immunoglogbulin pathobiology of HSV-1
infection, latency and reactivation in mice.
J Neurovirol.
2002;
8
35-44
- 8
Dankner W M, Spector S A.
Recurrent herpes simplex in a neonate.
Pediatr Infect Dis.
1986;
5
582-586
- 9
Davis L E, McLaren L C.
Relapsing herpes simplex encephalitis following antiviral therapy.
Ann Neurol.
1983;
13
192-195
- 10
Dennett C, Klapper P E, Cleator G M.
Polymerase chain reaction in the investigation of “relapse” following herpes simplex
encephalitis.
J Med Virol.
1996;
48
129-132
- 11
Domjan J, Millar J.
The MRI appearances of anterior opercular syndrome in a child with recurrent herpes
simplex encephalitis.
Clin Radiol.
2000;
55
574-575
- 12
Erlandsson A C, Bladh L G, Stierna P, Yucel-Lindberg T, Hammarsten O, Modeer T. et
al .
Herpes simplex virus type 1 infection and glucocorticoid treatment regulate viral
yield, glucocorticoid receptor and NF-kappa B levels.
J Endocrinol.
2002;
175
165-176
- 13
Field H J, Tewari D, Sutton D, Thackray A M.
Comparison of efficacies of famciclovir and valaciclovir against herpes simplex virus
type 1 in a murine immunosuppression model.
Antimicrob Agents Chemother.
1995;
39
1114-1119
- 14
Field H J, Thackray A M.
Early therapy with valaciclovir or famciclovir reduces but does not abrogate herpes
simplex virus neuronal latency.
Nucleosides Nucleotides Nucleic Acids.
2000;
19
461-470
- 15
Gascon G G, al-Jarallah A A, Okamoto E, al Ahdal M, Kessie G, Frayha H.
Chorea as a presentation of herpes simplex encephalitis relapse.
Brain Dev.
1993;
15
178-181
- 16
Ito Y, Kimura H, Yabuta Y, Ando Y, Murakami T, Shiomi M. et al .
Exacerbation of herpes simplex encephalitis after successful treatment with acyclovir.
Clin Infect Dis.
2000;
30
185-187
- 17
Jones C.
Herpes simplex virus type 1 and bovine herpesvirus 1 latency.
Clinical Microbiology Reviews.
2003;
16
79-95
- 18
Kimberlin D, Powell D, Gruber W, Diaz P, Arvin A, Kumar M. et al .
Administration of oral acyclovir suppressive therapy after neonatal herpes simplex
virus disease limited to the skin, eyes and mouth: results of a phase I/II trial.
Pediatr Infect Disease J.
1996;
15
247-254
- 19 Kimberlin D W, Prober C G.
Antiviral agents. Long SS, Pickering LK, Prober CG Principles and Practice of Pediatric Infectious
Diseases. Philadelphia; Churchill Livingstone 2003: 1527-1542
- 20
Kimura H, Aso K, Kuzushima K, Hanada N, Shibata M, Morishima T.
Relapse of herpes simplex encephalitis in children.
Pediatrics.
1992;
89
891-894
- 21
Knezevic W, Carroll W M.
Relapse of herpes simplex encephalitis after acyclovir therapy.
Aust NZ J Med.
1983;
13
625-626
- 22
LeBlanc R A, Pesnicak L, Cabral E S, Godleski M, Straus S E.
Lack of interleukin-6 (IL-6) enhances susceptibility to infection but does not alter
latency or reactivation of herpes simplex virus type 1 in IL-6 knockout mice.
J Virol.
1999;
73
8145-8151
- 23
Mandyla H, Anagnostakis D, Koutsovitis P, Siahanidou T, Youroukos S.
Late recurrence of herpes simplex virus meningoencephalitis in two infants.
Eur J Pediatr.
2001;
160
732-735
- 24
Martin J R, Suzuki S.
Targets of infection in a herpes simplex-reactivation model.
Acta Neuropathol.
1989;
77
402-411
- 25
Nicolaidou P, Iacovidou N, Youroukos S, Liacopoulou-Tsitsipi T, Kattamis C.
Relapse of herpes simplex encephalitis after acyclovir therapy.
Eur J Pediatr.
1993;
152
737-738
- 26
Norose K, Yano A, Zhang X M, Blankenhorn E, Heber-Katz E.
Mapping of genes involved in murine herpes simplex virus keratitis: identification
of genes and their modifiers.
J Virol.
2002;
76
3502-3510
- 27
Opitz J C, Kettrick M A, Sullivan B J.
Recurrent neonatal herpes presenting initially with hoarseness.
Am J Perinatol.
1989;
6
307-309
- 28
Paillard C, Vanhulle C, Devaux A M, Ensel P, Monroc-Morval M, Blanc T.
[Recurrence of herpes simplex encephalitis].
Arch Pediatr.
1999;
6
1081-1085
- 29
Pavone P, Trobia G L, Ruggieri M, Greco F, D'Agata A, Musumeci S.
[Early relapse of herpes simplex encephalitis. Clinical and therapeutic implications].
Minerva Pediatr.
1999;
51
395-398
- 30
Pike M G, Kennedy C R, Neville B G, Levin M.
Herpes simplex encephalitis with relapse.
Arch Dis Child.
1991;
66
1242-1244
- 31 Prober C G.
Herpes simplex virus. Long SS, Pickering LK, Prober CG Principles and Practice of Pediatric Infectious
Diseases. Philadelphia; Churchill Livingstone 2003: 1032-1040
- 32
Seto A, Morikawa S, Isono T, Ogawa K, Inubushi T.
Genetic susceptibility to herpetic encephalitis of inbred rabbits of B/Jas strain.
J Med Virol.
1995;
46
224-229
- 33
Shanks D E, Blasco P A, Chason D P.
Movement disorder following herpes simplex encephalitis.
Dev Med Child Neurol.
1991;
33
348-352
- 34
Stanberry L R.
Herpes. Vaccines for HSV.
Dermat Clin.
1998;
16
811-816
- 35
Taskinen E, Koskiniemi M L, Vaheri A.
Herpes simplex virus encephalitis. Prolonged intrathecal IgG synthesis and cellular
activity in the cerebrospinal fluid with transient impairment of blood-brain barrier.
J Neurol Sciences.
1984;
63
331-338
- 36
Thackray A M, Field H J.
Comparison of effects of famciclovir and valaciclovir on pathogenesis of herpes simplex
virus type 2 in a murine infection model.
Antimicrob Agents Chemother.
1996;
40
846-851
- 37
Thackray A M, Field H J.
Famciclovir and valaciclovir differ in the prevention of herpes simplex virus type
1 latency in mice: a quantitative study.
Antimicrob Agents Chemother.
1998;
42
1555-1562
- 38
Thackray A M, Field H J.
Persistence of infectious herpes simplex virus type 2 in the nervous system in mice
after antiviral chemotherapy.
Antimicrob Agents Chemother.
2000;
44
97-102
- 39
VanLandingham K E, Marsteller H B, Ross G W, Hayden F G.
Relapse of herpes simplex encephalitis after conventional acyclovir therapy.
JAMA.
1988;
259
1051-1053
- 40
Wang H S, Kuo M F, Huang S C, Chou M L.
Choreoathetosis as an initial sign of relapsing of herpes simplex encephalitis.
Pediatr Neurol.
1994;
11
341-345
- 41
Yamada S, Kameyama T, Nagaya S, Hashizume Y, Yoshida M.
Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation.
J Neurol Neurosurg Psychiatry.
2003;
74
262-264
M.D. Ignacio Valencia
Department of Pediatrics
Section of Neurology
St. Christopher's Hospital for Children
Erie Avenue at Front Street
Philadelphia, PA 19134
USA
Email: Ignacio.Valencia@drexel.edu