This document provides an overview of herpes simplex encephalitis (HSE). It discusses the etiology, epidemiology, pathophysiology, clinical manifestations, diagnosis and treatment of HSE. Key points include: HSE is most commonly caused by HSV-1 and is a leading cause of viral encephalitis in children; presentation varies from non-specific symptoms to seizures, altered mental status and focal neurological deficits; diagnosis involves CSF analysis, neuroimaging and PCR testing; and treatment involves high-dose intravenous acyclovir administered for at least 21 days. Recurrence of HSE is possible due to viral reactivation or immune-mediated processes.

1. Herpes Simplex
ENCEPHALITIS
WAFAA AL SHEHHI
R5 PEDIATRIC NEUROLOGY RESIDENT
JANUARY 2015

2. Road Map
• Introduction.
• Etiology.
• Epidemiology.
• Pathophysiology.
• Clinical manifestations.
• Differential diagnosis.
• Diagnosis.
• Treatment.
• Prognosis.

3. Herpes Simplex Encephalitis
• Herpes simplex encephalitis is the most common
single cause of viral encephalitis in infants and
children.1
• It is important due to its frequency, high mortality
reaching 20% of patients and its long term
morbidity.2
1.Le Doare K, et al, Child Educ Pract Ed August 2014,BMJ.
2.Javier Riancho,Neurol Sci 2013.

4. Etiology
• Herpes simplex viruses are members of herpes virus
family.3
• Genome consist of a single double stranded DNA
molecule.
• Type 1 virus associated with orofacial herpes infections.
• Type 2 virus identified in genital herpes and causes
most of the congenital or perinatally acquired infections.
3.John H.Menkes, child neurology, 7th
edition, chapter 7.

5. Epidemiology
• Neonatal disease is more common than childhood
disease.
• The incidence of severe disease in infants is 1 in 64 000
infants per year.
• In children over 1 year, HSE is nearly four times less
common, occurring in 1 in 230 000 children per year.4
4.Ward KN,Ohrling A, Bryant NJ, et al. Arch Dis Child 2012;97:162-5.

6. Pathophysiology
• The pathogenesis of HSE in humans is poorly
understood.
• The exact mechanism of cellular damage is unclear, but it
may involve both direct virus-mediated and indirect
immune-mediated processes.28
28.http://pmj.bmj.com/ on January 12, 2015.

7. Pathophysiology
• The ability of HSV-1 to induce apoptosis in neuronal cells,
a property not shared by HSV-2, might explain why the
former causes virtually all cases of herpes simplex
encephalitis in immunocompetent older children and
adults.
• Brain infection is thought to occur by means of direct
neuronal transmission of the virus from a peripheral site to
the brain via the trigeminal or olfactory nerve.

9. What are the presenting features of
neonatal and childhood HSV
encephalitis?
• Neonatal HSV disease presents in the first 4 weeks of
life.1
• Almost always acquired by perinatal exposure to HSV.
• Illness symptoms often begin between the first 7-21
days of life.
1 Le Doare K, et al. Arch Dis Child Educ Pract Ed 2014;0:1-
6.doi:10.1136/archdischild-2014-306321

10. What are the presenting features of
neonatal and childhood HSV encephalitis?
• Neonatal HSV infection categorized as:5
1.Skin,eyes and mouth disease43%.
2.Disseminated disease 23%.
3.Encephalitis 34%
5 Kenneth F. Swaiman, Pediatric neurology principles and practice, fifth
edition, chapter 81, p 1271-1273.

11. What are the presenting features of
neonatal and childhood HSV encephalitis?
• Non specific clinical features as poor oral intake,
behavioral changes or fever.
• Focal or generalized seizures, apnea, lethargy or coma.
• Can accompanied by pneumonitis,hepatitis or
disseminated intravascular coagulopathy.
• 60 to 70% have associated skin vesicles.1
1 Le Doare K, et al. Arch Dis Child Educ Pract Ed 2014;0:1-

12. 6-AAP 2005, Herpes Simplex, p 309-318. In L.K. Pickering (ed.) 2005 Red Book.

13. Clinical manifestations
• Childhood HSE presents with:7
1.Alternation of consciousness (97%).
2.Fever (92%).
3.Headache (81%).
4.Dysphasia (76%).
5.Ataxia (40%).
6.Seizures (38%)- focal (28%); generalized (10%)
7.Focal weakness (38%).
8.Cranial nerve defect (32%)
9.Visual field loss (14%).
10.Papilledema (14%).
7.Whitley RJ,Soong SJ, Linneman C Jr, Liu C, Pazin G, Alford CA. JAMA.
Jan 15 1982;247 (3): 317-20.

14. Clinical manifestations
• Atypical presentation in both HSV-1 &HSV-2:1
1.Sub acute encephalitis.
2.Apparent psychiatric syndromes.
3.Recurrent meningitis.
4.HSV-1: brainstem encephalitis.
5.HSV-2: a myelitis.

15. Clinical manifestations
6. Global aphasia for 1 language but retained most of his birth
language ability.8
7. Anterior opercular syndrome.9
8. Lingual epilepsia partialis continua.10
8- Ku A,Lachmann EA, Nagler W. Pediatr Neurol.Sep 1996;15(2):169-71.
9-De Kleermaeker FG, J Child Neurol, 2014 Apr; 29(4):560-3.
10-Iyer RS1, Ramalingam Ramakrishnan TCNeurol India. 2014 Jul-Aug;62(4):439-41.
doi: 10.4103/0028-3886.141230.

16. Clinical manifestations
9. Extrapyramidal symptoms and basal ganglia
involvement.11
10. HSE- associated cerebral hemorrhage in an HIV-
positive person.12
11- Mondal G, Kumar R, Ghosh JK, Basu K, Chatterejee S. India J Pediatr. Jul
2009;76(7): 749-50.
12- Li JZ,Sax , AIDS Read. Apr 2009;19(4): 153-5.

17. Differential Diagnosis
• Acute Disseminated Encephalomyelitis.
• Aseptic meningitis.
• Childhood epilepsy syndrome.
• Migrain varients.
• Neuro- Behcet disease.

18. Does a child with HSE have to have
external lesions for the diagnosis to be
likely?
• In neonates, skin lesions may be present, it may appear later
in clinical course.13
13-Pediatric in review, volume 17 number 12,Herpes simplex virus infections by: Paula W.
Annunziato, MD and Anne Gershon.

19. Does a child with HSE have to have
external lesions for the diagnosis to be
likely?
• In childhood HSE, only 10% have a prior history of
mucosal symptoms such as cold sores or conjunctivitis.1
1 Le Doare K, et al. Arch Dis Child Educ Pract Ed 2014;0:1-
6.doi:10.1136/archdischild-2014-306321

20. Should a lumbar puncture always be
attempted in HSE?
• CSF is an essential component of the diagnostic work up.
• Patients typically have mononuclear pleocytosis.
• RBC count may be elevated.
• Protein levels are elevated.
• Glucose values may be normal or mildly decreased.
• In about 5-10% of patients, especially children, initial CSF
results may be normal.5
5.Kenneth F. Swaiman, Pediatric neurology principles and practice, fifth
edition,chapter 81, p 1271-1273.

21. Does it make a difference if the PCR is
positive for HSV-1 or for HSV-2?
• No, not really.
• HSV-1 is more common in childhood HSE.1
• HSV-2 tends to be associated with genital herpes and is
more common in neonatal HSE.
1 Le Doare K, et al. Arch Dis Child Educ Pract Ed 2014;0:1-
6.doi:10.1136/archdischild-2014-306321

22. HSV PCR test
• PCR is highly sensitive (94-98%) and specific (98-100%)26
• Results become positive within 24 hours of the onset of
symptoms and remain positive for at least 5-7 days after
the start of antiviral therapy.
26.Mc Dermott SS, Neurology, 2000 Feb;54(3):746-9.

23. HSV PCR test
• Negative CSF HSV PCR tests can occur within first 72 h of
illness.26
• Patients with HSV encephalitis will typically have a negative
CSF HSV PCR after 14 days of acyclovir treatment.
26.Mc Dermott SS, Neurology, 2000 Feb;54(3):746-9.

24. HSV PCR test
• False positive HSV PCR reported in patients with temporal lobe
glioblastoma.26
• A breakdown of the blood-brain barrier (e.g., in severe
bacterial meningitis) or contamination of the CSF with blood
give false positive HSV PRC result.27
26.Mc Dermott SS, Neurology, 2000 Feb; 54(3):746-9.
27.Reborta L. DeBiasi,Clin Micobiol.Rev. Oct 2004;17(4):903-925.

25. What is the best neuroimaging
modality?
• CT scan with contrast.
• MRI is better than CT for the diagnosis of encephalitis.

26. Neuroimaging
• In neonate:5
• MRI and CT usually reveal diffuse edema during the acute
stage and later exhibit atrophy, parynchymal calcification
or cystic encephalomalacia.
• MRI can reveal a watershed distribution of abnormalities.
5- Kenneth F. Swaiman, Pediatric neurology princeples and practice, fifth
edition,chapter 81, p 1271-1273.

27. • A 2 weeks old baby with HSV-2 encephalitis.
14-http://www.hawaii.edu/medicine/pediatrics/pemxray/v7c09.html

31. 24.Okanishi T et al. Diffusion-weighted MRI for early dignosis of neonatal herpes simplex
encephalitis. Brain Dev (2014).

32. Neuroimaging
• In children:5
• Edema and hemorrhages may be present. After 1 week,
contrast enhancement may be detectable.
• Unilateral or bilateral abnormalities consisting of T2
prolongation in the temporal lobe or insula .
• Enhancement of the insula, temporal cortex and cingulate
gyrus on T1- weighted, gadolinum –enhanced images.
5- Kenneth F. Swaiman, Pediatric neurology princeples and practice, fifth
edition,chapter 81, p 1271-1273.

33. 14-http://www.hawaii.edu/medicine/pediatrics/pemxray/v7c09.html

34. 14-http://www.hawaii.edu/medicine/pediatrics/pemxray/v7c09.html

35. Is an EEG required?
• An EEG may provide additional diagnostic clues.1
• The typical pattern is of periodic lateralizing epileptiform
discharges in the temporal lobe, with slow wave
complexes occurring at intervals of 2-3 s.
• This pattern can be seen in other disorders.
1 Le Doare K, et al. Arch Dis Child Educ Pract Ed 2014;0:1-
6.doi:10.1136/archdischild-2014-306321

36. PLEDs

37. What therapy is recommended while
waiting for the investigation results?
• Clinical overlap between patients with encephalitis,
meningitis and septic shock.
• Broad spectrum antibiotics and high dose acyclovir until
test results are available.1
1 Le Doare K, et al. Arch Dis Child Educ Pract Ed 2014;0:1-
6.doi:10.1136/archdischild-2014-306321

38. What is adequate treatment?
• High dose intravenous acyclovir is most effective when
started early.
• Neonatal HSE: 60mg/kg/day in three divided doses every
8 h,assuming that renal function is normal.
• Treatment should be 14 days if the disease is limited to
the skin, eyes or mouth and a minimum of 21 days if the
infection involved the CNS or is disseminated.15
15. Upton D Allen,Joan L Robinson; Canadian Paediatric
Society,pediatric child health Vol 19 No 4 April 2014.

39. Treatment
• In 2006, the American Academy of Pediatrics updated its
dosing recommendations for children aged 3 months to
12 years to receive high-dose acyclovir (60 mg/kg/day).
• The incidence of renal injury or failure was similar
between children who received standard- dose and high-
dose acyclovir.16

40. Is acyclovir resistance an issue?
• In immunocompetent patients, viral resistance to acyclovir
occur rarely , the reported prevalence less than 1 %.17
• In immunocompromised patients, raises to 6%.
17-Piret J, Boivin G. Antimicrob agents chemother 2011;55:459-72.

41. If HSE is unlikely, when is it safe to
stop acyclovir?
• Where clinical suspicion of HSE is low, it is usually
appropriate to stop acyclovir if:
1.Negative CSF HSV PCR and cell count (<5cells/mm3)
and.
2.Normal brain MRI and.
3.Normal EEG and.
4.A full and rapid clinical recovery with normal level of
consciousness or
5.An alternative diagnosis becomes apparent.1
1 Le Doare K, et al. Arch Dis Child Educ Pract Ed 2014;0:1-
6.doi:10.1136/archdischild-2014-306321

42. Does a negative LP rule-out HSE?
• Acyclovir should not be stopped if the CSF is negative on
PCR for HSV when other features are consistent with
HSE.
• HSV PCR is a highly sensitive and specific test (94 and
96%), except during the first 24 h of the disease, when
as many as 10% of HSE CSF samples can be falsely
negative.18
18-Lakeman FD, Whitley RJ. National institute of allergy and infectious
diseases collaborative antiviral study group. J infect Dis 1995; 171:857-63.

43. Can neonatal and childhood HSE
recur?
• Children presenting with features suggestive of HSV relapse
need repeat cultures of blood and CSF, including CSF PCR for
HSV and autoantibody quantification.
• After neonatal HSE, HSV can reactivate months to years after
the initial infection.
• Presenteing as dermal flares or an encephalitis as the initial
illness.

45. HSV relapse
•Abnormal movements as chorea, seizures, focal neurological
deficits and psychiatric symptoms.
•May be immune mediated.
•Autoantibodies against N-methyl-D-aspartate receptor
(NMDAR).

46. Genetic factors
• Childhood-onset HSE is due to TLR3 deficiency in a
traceable fraction of patients, in particular the ones with HSE
recurrence.29
• TLR3 deficiency is a ssociated with insufficient virus
control in the brain, leading to incomplete viral latency in the
CNS itself in turn leading to a high rate of HSE recurrence
due to virus reactivation.
29.Hye Kyung Lim,neurology 83 Nov 2014, 1888-1897

47. HSV relapse
• Both neonatal and childhood HSE predispose to
subsequent autoimmune encephalitis with new
neurological symptoms including:
• Aphasia.
• Behavioral changes.
• Choreoathetoid movements.
• Opercular syndrome.19
19 De Tiege X,Rozenberg F,Heron B. Europ J Paediatr Neurol
2008; 12:72-81.

48. HSV recurrence
• Individuals with HSV-2 infection generally have high rates of
recurrence in the first and second years followed by a
substantial decrease in subsequent years.25
25.Kimberlin DW. Semin Pediatr Infect Dis. Oct 2005;16(4):271-81.

49. What about prophylaxis after HSE?
• A small patient series proposed doses of 1340 mg/m2
acyclovir given twice daily (total daily dose 2680 mg/m2),
based on CSF penetrating data.20
• Placebo-controlled RCT validated oral acyclovir given at
300 mg/m2 three times daily (900 mg/m2) as adequate at
improving neurodevelopmental outcome.21
20- Rudd C, Rivadeneira ED, Gutman LT. Acta Pediatrica
1994;83:1237-43.
21-Kimkberlin DW. J Paeditr Infect Dis 2013;2:179-82.

50. Prophlaxis
• Oral acyclovir is recommended for neonates and
valacyclovir for older children requiring long-term
prophylaxis.
1 Le Doare K, et al. Arch Dis Child Educ Pract Ed 2014;0:1-
6.doi:10.1136/archdischild-2014-306321

52. What onward referral is needed?
• If there is family history of invasive HSV disease and/or
consanguinity, children should be referred to an
immunology center.
• Children with HSE will require long-term multidisciplinary
neurodevelopmental follow up and possible psychological
and educational rehabilitation.
• Treatment of long term complications including epilepsy,
spasticity and dystonia.1
1 Le Doare K, et al. Arch Dis Child Educ Pract Ed 2014;0:1-
6.doi:10.1136/archdischild-2014-306321

53. Prognosis
• 70% mortality in untreated HSE patients.23
• Mortality in patients treated with acyclovir 11%.
• Mortality of neonatal HSE, 6% in patients with isolated HSE and
31% in patients with disseminated infection.
23.Whitley RJ, Cobbs CG,Alford CA Jr,Soong SJ, Hirsch MS, Connor JD, et al.
JAMA,Jul 14 1989;262(2):234-9.

54. Prognosis
• Neurologic outcomes in survivors treated with acyclovir
are as follows:23
1.No deficits or mild deficits-38%.
2.Moderate deficits -9%.
3.Severe deficit- 53%.
• Squeal among survivors depend on the patients age and
neurologic status at the time of diagnosis.
23-Whitley RJ, Cobbs CG,Alford CA Jr,Soong SJ, Hirsch MS, Connor JD, et al.
JAMA,Jul 14 1989;262(2):234-9.

55. Take home message
HSE represent medical emergency.
PCR is the golden standard diagnostic tool but
negative result can happen in early illness.
 EARLY INITIATION of therapy within 3 days of
illnes improve the outcome with 21 days duration.
 CHOREOATHETOTIC movement was reported
as first sign of HSE relapse.
Prophylaxis important in children less than 2
years.
Genetics play a role especially in recurrent
cases.

56. Thank you

57. References
1.Le Doare K, et al, managing neonatal and childhood
herpes encephalitis, Child Educ Pract Ed August
2014,BMJ.
2.Javier Riancho,HSV encephalitis,Neurol Sci 2013.
3.John H.Menkes, child neurology, 7th
edition, chapter
7/infections of nervous system.
4.Ward KN,Ohrling A, Bryant NJ, et al. Herpes simplex
serious neurological disease in young children: incidence
and long term outcome. Arch Dis Child 2012;97:162-5.

58. References
5.Kenneth F. Swaiman, Pediatric neurology princeples and
practice, fifth edition,chapter 81, p 1271-1273.
6. AAP 2005, Herpes Simplex, p 309-318. In L.K. Pickering (ed.)
2005 Red Book.
7. Whitley RJ,Soong SJ, Linneman C Jr, Liu C, Pazin G,
Alford CA. Herpes simplex encephalitis. Clinical
assessment. JAMA. Jan 15 1982;247 (3): 317-20.

59. References
8. Ku A,Lachmann EA, Nagler W. Selective language
aphasia from herpes simplex encephalitis. Pediatr
Neurol.Sep 1996;15(2):169-71.
9.McGrath NM,Anderson NE,Hope JK,Croxson MC, Powell
KF. Anterior opercular syndrome,caused by herpes simplex
encephalitis. Neurology. Aug 1997;49(2):494-7.
10.Iyer RS1, Ramalingam Ramakrishnan TCNeurol India.
2014 Jul-Aug;62(4):439-41. doi: 10.4103/0028-
3886.141230.

60. References
11. Mondal G, Kumar R, Ghosh JK, Basu K, Chatterejee S.
Basal ganglia involvement in a child with herpes simplex
encephalitis. India J Pediatr. Jul 2009;76(7): 749-50.
12.Li JZ,Sax PE. HSV-1 encephalitis complicated by
cerebral hemorrhage in an HIV- positive person. AIDS
Read. Apr 2009;19(4): 153-5.

61. References
13.Pediatric in review, volume 17 number 12,Herpes
simplex virus infections by: Paula W. Annunziato, MD and
Anne Gershon.
14.http://www.hawaii.edu/medicine/pediatrics/pemxray/v7c
09.html
15. Upton D Allen,Joan L Robinson; Canadian Paediatric
Society,pediatric child health Vol 19 No 4 April 2014.
16.Jennifer G. et al, standerd dose versus high dose
acyclovir in children treated emprically for
encephalitis,Pediatr Drugs (2014) 16:229-234.

62. References
17.Piret J, Boivin G. Resistance of herpes simplex viruses to
nucleoside analogues: mechanisms, prevalence, and
management . Antimicrob agents chemother 2011;55:459-72.
18.Lakeman FD, Whitley RJ. Diagnosis of herpes simplex
encephalitis: application of polymerase chine reaction to
cerebrospinal fluid from brain-biopsaied patients and correlation
with disease. National institute of allergy and infectious diseases
collaborative antiviral study group. J infect Dis 1995; 171:857-63.

63. References
19. De Tiege X,Rozenberg F,Heron B. The spectrum of
herpes simplex encephalitis in children. Europ J Paediatr
Neurol 2008; 12:72-81.
20.Rudd C, Rivadeneira ED, Gutman LT.Dosing
considerations for oral acyclovir following neonatal herpes
disease. Acta Pediatrica 1994;83:1237-43.
21.Kimkberlin DW. Acyclovir Dosing in the neonatal period
and beyond. J Paeditr Infect Dis 2013;2:179-82.

64. References
22.Royal College of Obstetricians and Gynaecologists.
Management of genital herpes in pregnancy. 2007.
23.Whitley RJ, Cobbs CG,Alford CA Jr,Soong SJ, Hirsch
MS, Connor JD, et al. HSV encephalitis, diagnosis,
presentation and outcome.JAMA,Jul 14 1989;262(2):234-9.
24.Okanishi T et al. Diffusion-weighted MRI for early
dignosis of neonatal herpes simplex encephalitis. Brain Dev
(2014).
25.Kimberlin DW. Semin Pediatr Infect Dis. Oct
2005;16(4):271-81.
26.Mc Dermott SS, Neurology, 2000 Feb; 54(3):746-9.
27.Reborta L. DeBiasi,Clin Micobiol.Rev. Oct
2004;17(4):903-925.

65. References
28.http://pmj.bmj.com/ on January 12, 2015.
29.Hye Kyung Lim,neurology 83 Nov 2014, 1888-1897