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Herpes simplex encephalitis

MedGen UID:
75794
Concept ID:
C0276226
Disease or Syndrome
Synonym: Herpetic encephalitis
SNOMED CT: Herpes encephalitis (428638009); Encephalitis caused by Herpesvirus (428638009); Encephalitis caused by Herpesviridae (428638009)
Modes of inheritance:
Non-Mendelian inheritance
MedGen UID:
109109
Concept ID:
C0600599
Genetic Function
Source: Orphanet
A mode of inheritance that depends on genetic determinants in more than one gene.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
HPO: HP:0012302
Monarch Initiative: MONDO:0012521
Orphanet: ORPHA1930

Definition

Infection of the brain parenchyma with herpes simplex virus, resulting in inflammation of the brain parenchyma with neurologic dysfunction. [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHerpes simplex encephalitis

Conditions with this feature

Granulocytopenia with immunoglobulin abnormality
MedGen UID:
383874
Concept ID:
C1856263
Disease or Syndrome
Immunodeficiency-59 and hypoglycemia (IMD59) is an autosomal recessive primary immunologic disorder characterized by combined immunodeficiency and recurrent septic infections of the respiratory tract, skin, and mucous membranes, as well as disturbed glucose metabolism. Granulocytopenia and B-cell and dendritic cell deficiency are present (Haapaniemi et al., 2017).
Herpes simplex encephalitis, susceptibility to, 1
MedGen UID:
413772
Concept ID:
C2750180
Finding
Herpes simplex virus (HSV)-1 is most often associated with infection of the oral mucosa. Primary infection is most commonly asymptomatic, but it may lead to symptoms usually involving the mucosa and skin. Following replication at the infection site, HSV-1 enters the epithelial endings of sensory neurons and travels up the trigeminal cranial nerves to the trigeminal ganglia, where latent infection is established. Reactivation of HSV-1, usually in the form of herpes labialis (cold sores), may occur in 20 to 40% of the population. HSV-1 seroprevalence is high, with over 85% of adults between the ages of 20 and 40 years infected. HSV-1 rarely infects the central nervous system (CNS), resulting in herpes simplex encephalitis (HSE), with an incidence of 2 to 4 per 1,000,000 people per year. In HSE, HSV-1 invades and replicates in neurons and glial cells, where focal necrotizing infections occur, primarily affecting the temporal and subfrontal regions of the brain. Untreated, HSE is fatal in at least 70% of cases, although the mortality and morbidity have been drastically reduced with antiviral therapy. Approximately one-third of all HSE cases are due to primary infections, and 30% of all HSE cases occur in children under the age of 20 years. Among children, HSE peaks between 3 months and 3 years of age, coinciding with the time of primary infection. In a subset of children, HSE results from a series of monogenic primary immunodeficiencies that impair UNC93B1- and TLR3 (603029)-dependent production of IFNA (147660)/IFNB (147640) and IFNG (147570) in the CNS (summary by Sancho-Shimizu et al., 2007). Genetic Heterogeneity of Susceptibility to Acute Infection-Induced Encephalopathy, including Herpes Simplex Encephalitis (HSE) For other forms of susceptibility to acute infection-induced encephalopathy, see herpes-specific IIAE2 (613002), caused by mutation in the TLR3 gene (603029) on chromosome 4q35; IIAE3 (608033), caused by mutation in the RANBP2 gene (601181) on chromosome 2q12; IIAE4 (614212), caused by mutation in the CPT2 gene (600650) on chromosome 1p32; herpes-specific IIAE5 (614849), caused by mutation in the TRAF3 gene (601896) on chromosome 14q32; herpes-specific IIAE6 (614850), caused by mutation in the TICAM1 gene (607601) on chromosome 19p13; herpes-specific IIAE7 (616532), caused by mutation in the IRF3 gene (603734) on chromosome 19q13; herpes-specific IIAE8 (617900), caused by mutation in the TBK1 gene (604834) on chromosome 12q14; IIAE9 (618426), caused by mutation in the NUP214 gene (114350) on chromosome 9q34; herpes-specific IIAE10 (619396), caused by mutation in the SNORA31 (619378) on chromosome 13q14; IIAE11 (619441), caused by mutation in the DBR1 gene (607024) on chromosome 3q22; and IIAE12 (620461), caused by mutation in the RNH1 gene (173320) on chromosome 11p15.
Immunodeficiency 83, susceptibility to viral infections
MedGen UID:
416638
Concept ID:
C2751803
Disease or Syndrome
Immunodeficiency-83 (IMD83) is characterized by increased susceptibility to severe viral infections, including herpes simplex virus (HSV), varicella zoster virus (VZV), influenza A virus (IAV), hantavirus, and possibly respiratory syncytial virus (RSV). The age at onset varies widely from infancy to adulthood, and there is incomplete penetrance. The susceptibility to encephalitis or pneumonitis appears to result from impaired TLR3-dependent interferon production by nonhematopoietic cells that reside within the central nervous system (CNS) or lung epithelial cells (review by Zhang et al., 2013; summary by Mork et al., 2015; Sironi et al., 2017, Lim et al., 2019, Partanen et al., 2020). For a general phenotypic description of herpes simplex encephalitis (HSE) and a discussion of genetic heterogeneity of acute infection-induced encephalopathy, see 610551.
Immunodeficiency 31B
MedGen UID:
462438
Concept ID:
C3151088
Disease or Syndrome
Immunodeficiency-31B (IMD31B) results from autosomal recessive (AR) STAT1 deficiency. STAT1 is crucial for cellular responses to IFNA (147660)/IFNB (147640) (type I interferon) and IFNG (147570) (type III interferon). AR STAT1 deficiency affects both the IFNA/IFNB and the IFNG pathways, resulting in susceptibility to mycobacteria, Salmonella, and viruses, with a severe disease course and often fatal outcome (review by Al-Muhsen and Casanova, 2008).
Herpes simplex encephalitis, susceptibility to, 3
MedGen UID:
766782
Concept ID:
C3553868
Finding
A Mendelian susceptibility or predisposition to herpes simplex infection induced encephalitis in which the cause of the diseas is a mutation in the TRAF3 gene.
Herpes simplex encephalitis, susceptibility to, 4
MedGen UID:
766783
Concept ID:
C3553869
Finding
A Mendelian susceptibility or predisposition to herpes simplex infection induced encephalitis in which the cause of the diseas is a mutation in the TICAM1 gene.
Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency
MedGen UID:
862387
Concept ID:
C4013950
Disease or Syndrome
Immunodeficiency-31A (IMD31A) results from autosomal dominant (AD) STAT1 deficiency. STAT1 is crucial for cellular responses to IFNA (147660)/IFNB (147640) (type I interferon) and IFNG (147570) (type III interferon). AD STAT1 deficiency selectively affects the IFNG pathway, but not the IFNA/IFNB pathway, and confers a predisposition to mycobacterial infections. Pathogens reported in IMD31A patients include bacillus Calmette-Guerin (BCG) and Mycobacterium avium complex, as well as Mycobacterium tuberculosis. IMD31A has low penetrance and a mild clinical phenotype with good prognosis for recovery (review by Al-Muhsen and Casanova, 2008). Two patients with heterozygous STAT1 mutations have been reported with increased susceptibility to adult-onset herpes simplex encephalitis (HSE) without a history of other significant infections (Mork et al., 2015).
Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 7
MedGen UID:
901850
Concept ID:
C4225294
Finding
A Mendelian susceptibility or predisposition to herpes simplex infection induced encephalitis in which the cause of the diseas is a mutation in the IRF3 gene.
Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8
MedGen UID:
1646997
Concept ID:
C4693542
Finding
Immunodeficiency 72 with autoinflammation
MedGen UID:
1749856
Concept ID:
C5436540
Disease or Syndrome
Immunodeficiency-72 with autoinflammation and lymphoproliferation (IMD72) is an autosomal recessive immunologic disorder characterized by onset of recurrent infections or systemic inflammation in the first year of life. Affected individuals develop bacterial and viral infections that can be severe, including bacteremia, recurrent pneumonia, and meningitis, consistent with an immunodeficiency. There is also an autoimmune and hyperinflammatory aspect to the disorder, manifest as atopy or allergies, hepatosplenomegaly, and lymphoproliferation, including hemophagocytic lymphohistiocytosis (HLH). Immunologic workup shows variable abnormalities, including low or high Ig subsets, increased B cells, irregular T-cell activation and cytokine response, impaired immune synapse formation, and defective cellular migration. At the cellular level, these defects are related to abnormal F-actin polymerization and altered intracellular signaling (summary by Cook et al., 2020).
Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 10
MedGen UID:
1782836
Concept ID:
C5543600
Finding
Susceptibility to infection-induced acute encephalopathy-10 (IIAE10) presents as neurologic deficits in response to acute infection, particularly with herpes simplex virus-1 (HSV-1), which leads to inflammation of the brain and herpes simplex encephalitis (HSE). The age at onset ranges from infancy to adulthood. However, some mutation carriers do not develop encephalopathy even if exposed to the virus, indicating incomplete penetrance (summary by Lafaille et al., 2019). For a phenotypic description of herpes simplex encephalitis (HSE) and a discussion of genetic heterogeneity of susceptibility to acute infection-induced encephalopathy, see 610551.

Professional guidelines

PubMed

Nosadini M, Thomas T, Eyre M, Anlar B, Armangue T, Benseler SM, Cellucci T, Deiva K, Gallentine W, Gombolay G, Gorman MP, Hacohen Y, Jiang Y, Lim BC, Muscal E, Ndondo A, Neuteboom R, Rostásy K, Sakuma H, Sharma S, Tenembaum SN, Van Mater HA, Wells E, Wickstrom R, Yeshokumar AK, Irani SR, Dalmau J, Lim M, Dale RC
Neurol Neuroimmunol Neuroinflamm 2021 Jul;8(5) Epub 2021 Jul 22 doi: 10.1212/NXI.0000000000001052. PMID: 34301820Free PMC Article
Aksamit AJ Jr
Neurol Clin 2021 Feb;39(1):197-207. Epub 2020 Nov 7 doi: 10.1016/j.ncl.2020.09.011. PMID: 33223083
Solomon T, Michael BD, Smith PE, Sanderson F, Davies NW, Hart IJ, Holland M, Easton A, Buckley C, Kneen R, Beeching NJ; National Encephalitis Guidelines Development and Stakeholder Groups
J Infect 2012 Apr;64(4):347-73. Epub 2011 Nov 18 doi: 10.1016/j.jinf.2011.11.014. PMID: 22120595

Recent clinical studies

Etiology

Bloch KC, Glaser C, Gaston D, Venkatesan A
Clin Infect Dis 2023 Sep 11;77(5):e14-e33. doi: 10.1093/cid/ciad306. PMID: 37485952
Armangué T, Olivé-Cirera G, Martínez-Hernandez E, Rodes M, Peris-Sempere V, Guasp M, Ruiz R, Palou E, González A, Marcos MÁ, Erro ME, Bataller L, Corral-Corral Í, Planagumà J, Caballero E, Vlagea A, Chen J, Bastard P, Materna M, Marchal A, Abel L, Cobat A, Alsina L, Fortuny C, Saiz A, Mignot E, Vanderver A, Casanova JL, Zhang SY, Dalmau J
Brain 2023 Oct 3;146(10):4306-4319. doi: 10.1093/brain/awad238. PMID: 37453099
Piret J, Boivin G
Clin Microbiol Rev 2020 Mar 18;33(2) Epub 2020 Feb 12 doi: 10.1128/CMR.00105-19. PMID: 32051176Free PMC Article
Armangue T, Spatola M, Vlagea A, Mattozzi S, Cárceles-Cordon M, Martinez-Heras E, Llufriu S, Muchart J, Erro ME, Abraira L, Moris G, Monros-Giménez L, Corral-Corral Í, Montejo C, Toledo M, Bataller L, Secondi G, Ariño H, Martínez-Hernández E, Juan M, Marcos MA, Alsina L, Saiz A, Rosenfeld MR, Graus F, Dalmau J; Spanish Herpes Simplex Encephalitis Study Group
Lancet Neurol 2018 Sep;17(9):760-772. Epub 2018 Jul 23 doi: 10.1016/S1474-4422(18)30244-8. PMID: 30049614Free PMC Article
Pinninti SG, Kimberlin DW
Semin Perinatol 2018 Apr;42(3):168-175. Epub 2018 Mar 12 doi: 10.1053/j.semperi.2018.02.004. PMID: 29544668

Diagnosis

Li F, Wang Y, Zheng K
Autophagy 2023 Feb;19(2):734-736. Epub 2022 Jul 23 doi: 10.1080/15548627.2022.2102309. PMID: 35849507Free PMC Article
Venkatesan A, Murphy OC
Neurol Clin 2018 Nov;36(4):705-724. Epub 2018 Sep 20 doi: 10.1016/j.ncl.2018.07.001. PMID: 30366550
Armangue T, Spatola M, Vlagea A, Mattozzi S, Cárceles-Cordon M, Martinez-Heras E, Llufriu S, Muchart J, Erro ME, Abraira L, Moris G, Monros-Giménez L, Corral-Corral Í, Montejo C, Toledo M, Bataller L, Secondi G, Ariño H, Martínez-Hernández E, Juan M, Marcos MA, Alsina L, Saiz A, Rosenfeld MR, Graus F, Dalmau J; Spanish Herpes Simplex Encephalitis Study Group
Lancet Neurol 2018 Sep;17(9):760-772. Epub 2018 Jul 23 doi: 10.1016/S1474-4422(18)30244-8. PMID: 30049614Free PMC Article
Sabah M, Mulcahy J, Zeman A
BMJ 2012 Jun 6;344:e3166. doi: 10.1136/bmj.e3166. PMID: 22674925
Kennedy PG, Chaudhuri A
J Neurol Neurosurg Psychiatry 2002 Sep;73(3):237-8. doi: 10.1136/jnnp.73.3.237. PMID: 12185148Free PMC Article

Therapy

Bloch KC, Glaser C, Gaston D, Venkatesan A
Clin Infect Dis 2023 Sep 11;77(5):e14-e33. doi: 10.1093/cid/ciad306. PMID: 37485952
Piret J, Boivin G
Clin Microbiol Rev 2020 Mar 18;33(2) Epub 2020 Feb 12 doi: 10.1128/CMR.00105-19. PMID: 32051176Free PMC Article
Stahl JP, Mailles A
Curr Opin Infect Dis 2019 Jun;32(3):239-243. doi: 10.1097/QCO.0000000000000554. PMID: 30921087
Bewersdorf JP, Koedel U, Patzig M, Dimitriadis K, Paerschke G, Pfister HW, Klein M
Infection 2019 Apr;47(2):267-273. Epub 2018 Dec 1 doi: 10.1007/s15010-018-1257-7. PMID: 30506479
Bradshaw MJ, Venkatesan A
Neurotherapeutics 2016 Jul;13(3):493-508. doi: 10.1007/s13311-016-0433-7. PMID: 27106239Free PMC Article

Prognosis

Armangué T, Olivé-Cirera G, Martínez-Hernandez E, Rodes M, Peris-Sempere V, Guasp M, Ruiz R, Palou E, González A, Marcos MÁ, Erro ME, Bataller L, Corral-Corral Í, Planagumà J, Caballero E, Vlagea A, Chen J, Bastard P, Materna M, Marchal A, Abel L, Cobat A, Alsina L, Fortuny C, Saiz A, Mignot E, Vanderver A, Casanova JL, Zhang SY, Dalmau J
Brain 2023 Oct 3;146(10):4306-4319. doi: 10.1093/brain/awad238. PMID: 37453099
Nosadini M, Thomas T, Eyre M, Anlar B, Armangue T, Benseler SM, Cellucci T, Deiva K, Gallentine W, Gombolay G, Gorman MP, Hacohen Y, Jiang Y, Lim BC, Muscal E, Ndondo A, Neuteboom R, Rostásy K, Sakuma H, Sharma S, Tenembaum SN, Van Mater HA, Wells E, Wickstrom R, Yeshokumar AK, Irani SR, Dalmau J, Lim M, Dale RC
Neurol Neuroimmunol Neuroinflamm 2021 Jul;8(5) Epub 2021 Jul 22 doi: 10.1212/NXI.0000000000001052. PMID: 34301820Free PMC Article
Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, Geis C, Lancaster E, Titulaer MJ, Rosenfeld MR, Graus F
Lancet Neurol 2019 Nov;18(11):1045-1057. Epub 2019 Jul 17 doi: 10.1016/S1474-4422(19)30244-3. PMID: 31326280
Pinninti SG, Kimberlin DW
Semin Perinatol 2018 Apr;42(3):168-175. Epub 2018 Mar 12 doi: 10.1053/j.semperi.2018.02.004. PMID: 29544668
Guasp M, Dalmau J
Med Clin (Barc) 2018 Jul 23;151(2):71-79. Epub 2017 Nov 26 doi: 10.1016/j.medcli.2017.10.015. PMID: 29183618

Clinical prediction guides

Cleaver J, Jeffery K, Klenerman P, Lim M, Handunnetthi L, Irani SR, Handel A
Brain 2024 Apr 4;147(4):1130-1148. doi: 10.1093/brain/awad419. PMID: 38092513Free PMC Article
Armangué T, Olivé-Cirera G, Martínez-Hernandez E, Rodes M, Peris-Sempere V, Guasp M, Ruiz R, Palou E, González A, Marcos MÁ, Erro ME, Bataller L, Corral-Corral Í, Planagumà J, Caballero E, Vlagea A, Chen J, Bastard P, Materna M, Marchal A, Abel L, Cobat A, Alsina L, Fortuny C, Saiz A, Mignot E, Vanderver A, Casanova JL, Zhang SY, Dalmau J
Brain 2023 Oct 3;146(10):4306-4319. doi: 10.1093/brain/awad238. PMID: 37453099
Zhu S, Viejo-Borbolla A
Virulence 2021 Dec;12(1):2670-2702. doi: 10.1080/21505594.2021.1982373. PMID: 34676800Free PMC Article
Armangue T, Spatola M, Vlagea A, Mattozzi S, Cárceles-Cordon M, Martinez-Heras E, Llufriu S, Muchart J, Erro ME, Abraira L, Moris G, Monros-Giménez L, Corral-Corral Í, Montejo C, Toledo M, Bataller L, Secondi G, Ariño H, Martínez-Hernández E, Juan M, Marcos MA, Alsina L, Saiz A, Rosenfeld MR, Graus F, Dalmau J; Spanish Herpes Simplex Encephalitis Study Group
Lancet Neurol 2018 Sep;17(9):760-772. Epub 2018 Jul 23 doi: 10.1016/S1474-4422(18)30244-8. PMID: 30049614Free PMC Article
Guasp M, Dalmau J
Med Clin (Barc) 2018 Jul 23;151(2):71-79. Epub 2017 Nov 26 doi: 10.1016/j.medcli.2017.10.015. PMID: 29183618

Recent systematic reviews

Whitfield E, White B, Denaxas S, Lyratzopoulos G
Br J Gen Pract 2023 Sep;73(734):e702-e709. Epub 2023 Aug 31 doi: 10.3399/BJGP.2023.0044. PMID: 37308303Free PMC Article
Rocha ND, de Moura SK, da Silva GAB, Mattiello R, Sato DK
BMC Infect Dis 2023 Jan 26;23(1):55. doi: 10.1186/s12879-023-08007-3. PMID: 36703115Free PMC Article
Vaugon E, Mircescu A, Caya C, Yao M, Gore G, Dendukuri N, Papenburg J
Clin Microbiol Infect 2022 Dec;28(12):1547-1557. Epub 2022 Jun 17 doi: 10.1016/j.cmi.2022.06.004. PMID: 35718347
Patoulias D, Koutras C
Folia Med Cracov 2017;57(4):97-105. PMID: 29337981
Nosadini M, Mohammad SS, Corazza F, Ruga EM, Kothur K, Perilongo G, Frigo AC, Toldo I, Dale RC, Sartori S
Dev Med Child Neurol 2017 Aug;59(8):796-805. Epub 2017 Apr 25 doi: 10.1111/dmcn.13448. PMID: 28439890

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