1. 2011 Diagnostic Slide Session Case 7 Aditya Raghunathan Suzanne Z. Powell

2. Presentation 47 year old woman Altered mental status Altered mental status HIV diagnosed in 1993 HIV diagnosed in 1993 NOT taken therapy ~ 14 yrs Past medical history: Shingles Past medical history: Shingles On admission: CD4 20 cells/ μL On admission: CD4 20 cells/ μL Mediastinal mass

3. MRIT2FLAIR

4. Mediastinal Mass Adenomatous hyperplasia (Multinodular goiter)

5. Subsequently, frontal lobe lesions were biopsied...

6. Intra-Operative Cytology

14. DIAGNOSIS?

15. LFB-PAS

16. GFAP

17. Additional Studies HSV 1, HSV2, CMV, EBV, Enterovirus IHC & culture : Negative HSV 1, HSV2, CMV, EBV, Enterovirus IHC & culture : Negative BK virus IHC, JC virus-ISH: Negative BK virus IHC, JC virus-ISH: Negative Toxoplasma IHC: Negative Toxoplasma IHC: Negative Bacterial/ fungal stains & cultures: Negative Bacterial/ fungal stains & cultures: Negative

18. HHV3 (VZV) Immunostain

20. Electron Microscopy

22. VZV Immunostain positive VZV Immunostain positive PCR: VZV DNA detected PCR: VZV DNA detected Measles IHC/ PCR: Negative Measles IHC/ PCR: Negative

23. Human herpes virus 3 encephalitis/ vasculopathy (HHV3, Varicella zoster virus) In the context of an HIV+ patient, untreated for 14 years In the context of an HIV+ patient, untreated for 14 years

24. HIV in the HAART Era Epidemiologically ↓ “main” opportunistic inf. e.g. Toxoplasmosis, Cryptococcal meningitis Epidemiologically ↓ “main” opportunistic inf. e.g. Toxoplasmosis, Cryptococcal meningitis ↑ Nonspecific/ nonlethal CNS diseases ↑ Nonspecific/ nonlethal CNS diseases ↑ Uncommon CNS infections ↑ Uncommon CNS infections VZV & HSV VZV & HSV Gray F et al. (2003)

25. CNS Symptoms & CSF VZV Load Immunocompromised: Deeper sites Immunocompromised: Deeper sites Small-vessel vasculopathy, meningoencephalitis, ventriculitis & myelitis Small-vessel vasculopathy, meningoencephalitis, ventriculitis & myelitis 97 cases: ↑ CSF VZV DNA load in encephalitis & acute aseptic meningitis 97 cases: ↑ CSF VZV DNA load in encephalitis & acute aseptic meningitis > Cranial nerve disease > Cranial nerve disease Kleinschmidt-DeMasters BK et al. (2001) Persson A et al. (2009)

26. VZV Detection Highly cell associated Highly cell associated Present in low titers Present in low titers Culture from CSF rarely + Culture from CSF rarely + In CSF, diagnostic value of detecting In CSF, diagnostic value of detecting anti-VZV IgG antibodies > VZV DNA Nagel et al. (2007)

27. VZV Genotypes 4021 patients w. ? CNS VZV infection 4021 patients w. ? CNS VZV infection 43 + VZV DNA in CSF by PCR 43 + VZV DNA in CSF by PCR CNS disease frequently w/o rash CNS disease frequently w/o rash Can resemble HSV encephalitis Can resemble HSV encephalitis 7 genotypes identified at CDC 7 genotypes identified at CDC 1 Oka vaccine strain 1 Oka vaccine strain  ? Vaccine - associated CNS disease Pahlud et al. (2011)

28. References Pahud BA, Glaser CA, Dekker CL, Arvin AM, Schmid DS. Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine. J Infect Dis. 2011 Feb 1;203(3):316-23. Pahud BA, Glaser CA, Dekker CL, Arvin AM, Schmid DS. Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine. J Infect Dis. 2011 Feb 1;203(3):316-23. Gray F, Chrétien F, Vallat-Decouvelaere AV, Scaravilli F. The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol. 2003 May;62(5):429-40. Gray F, Chrétien F, Vallat-Decouvelaere AV, Scaravilli F. The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol. 2003 May;62(5):429-40. Kleinschmidt-DeMasters BK, Gilden DH. Varicella-Zoster virus infections of the nervous system: clinical and pathologic correlates. Arch Pathol Lab Med. 2001;125:770-80 Kleinschmidt-DeMasters BK, Gilden DH. Varicella-Zoster virus infections of the nervous system: clinical and pathologic correlates. Arch Pathol Lab Med. 2001;125:770-80 Nagel MA, Forghani B, Mahalingam R, et al.: The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology 2007, 68:1069–1073. Nagel MA, Forghani B, Mahalingam R, et al.: The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology 2007, 68:1069–1073. Persson A, Bergström T, Lindh M, Namvar L, Studahl M. Varicella-zoster virus CNS disease--viral load, clinical manifestations and sequels. J Clin Virol. 2009 Nov;46(3):249- 53. Persson A, Bergström T, Lindh M, Namvar L, Studahl M. Varicella-zoster virus CNS disease--viral load, clinical manifestations and sequels. J Clin Virol. 2009 Nov;46(3):249- 53.

29. Thank You!