Hsv encephalitis final

Herpes Simplex ENCEPHALITISWAFAA AL SHEHHI

R5 PEDIATRIC NEUROLOGY RESIDENT

JANUARY 2015

Road Map

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

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.

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.

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.

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.

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.

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


• Neonatal HSV infection categorized as:5

1.Skin,eyes and mouth disease43%.

2.Disseminated disease 23%.

3.Encephalitis 34%

5 Kenneth F. Swaiman, Pediatric neurology principles and practice, fifth edition, chapter 81, p 1271-1273.


• 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


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

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.

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.

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.

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.

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

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.

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


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.

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.


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.

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.

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.

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

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.

• A 2 weeks old baby with HSV-2 encephalitis.

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

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

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.



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.


PLEDs

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


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.

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

16.Jennifer G. et al, Drugs (2014) 16:229-234.

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.

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


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.

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.

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).

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

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.

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.

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.

Prophlaxis • Oral acyclovir is recommended for neonates and

valacyclovir for older children requiring long-term prophylaxis.


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


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.

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.

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.

Thank you

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.

References5.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.

References8. 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.

References11. 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.

References13.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/v7c09.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.

References17.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.

References19. 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.

References22.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.

References28.http://pmj.bmj.com/ on January 12, 2015.

29.Hye Kyung Lim,neurology 83 Nov 2014, 1888-1897

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Hsv encephalitis final