This case was originally published in 2017. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 60-year-old man presents with acute confusion, aggressive behavior, and aphasia. Imaging reveals a heterogeneously enhancing mass (5 x 2 x 2 cm) in the left medial temporal lobe with extensive peripheral edema (Image A), but no significant contrast enhancement. A subtotal temporal lobectomy was performed on suspicion of a low-grade glioma.

Tissue Site
Left temporal lobe

Image A: MRI, axial. T2-weighted FLAIR.

Image A: MRI, axial. T2-weighted FLAIR.

The whole slide image provided is an H&E stained slide of left temporal lobe from an excision.

  1. What is the MOST likely diagnosis?

    1. Acute bacterial infection

    2. Anaplastic astrocytoma, WHO grade III

    3. Herpes simplex virus type 1 (HSV1) encephalitis

    4. Herpes simplex virus type 2 encephalitis

    5. Ischemic infarct

  2. Histologic features MOST characteristic of the diagnosis include:

    1. Focal collection of neutrophils and cellular debris with a fibrotic capsule

    2. Hemorrhage, necrosis, mixed inflammatory infiltrate, and cells harboring viral inclusions

    3. Ischemic red neurons, reactive astrocytes, and neuropil edema

    4. Pleomorphic astrocytes, mitotic figures, microvascular proliferation, and palisading necrosis

    5. Visible organisms with a muted host response

  3. Herpes simplex virus belongs to which of the following?

    1. Adenovirus

    2. DNA virus

    3. Retrovirus

    4. RNA virus

    5. Slow virus

View Answer Key

The diagnosis is herpes simplex encephalitis. PCR amplification of tissue from the specimen more specifically identified the causative agent as herpes simplex virus, type 1 (HSV1). The most common identifiable cause of viral encephalitis in hospitalized patients, HSV1 infection classically exhibits tropism for the orbitofrontal and temporal lobes bilaterally and asymmetrically, but can on occasion present as a unifocal mass mimicking neoplasm as exemplified in this case. Untreated cases have a mortality rate of up to 70%, while in patients treated with a 14- to 21-day course of acyclovir the mortality rate is less than 10%. Although the patient in this case clinically improved while on a four-week course of acyclovir, he did not return to baseline functioning and was discharged to a nursing home.

Primary infection with HSV1 is usually subclinical. Symptomatic primary infection may manifest as gingivostomatitis, pharyngitis, or a mononucleosis-like syndrome. During the initial infection, the virus undergoes retrograde transport along sensory axons and becomes established in latent form in sensory ganglia, especially the trigeminal ganglion. Reactivation of latent virus produces recurrent mucocutaneous lesions most commonly involving the vermilion border of the lips (herpes labialis) that are recognized as cold sores or fever blisters. About one-third of herpes encephalitis cases are associated with primary infection, while the remainder result from reactivation of latent virus. It remains unclear whether viral reactivation occurs within the brain itself (herpes simplex viral DNA has been detected in normal brain) or in peripheral sensory ganglia, such as the trigeminal ganglion, with secondary axonal transport to the CNS. Olfactory pathways are also likely routes of retrograde viral transport. In contrast, HSV2 infection is more commonly encountered in newborns, acquired via genital infection from the mother during vaginal birth.

A hypercellular specimen with reactive astrocytes and occasional mitotic figures can raise the specter of astrocytoma (Image B). However, demonstration of extravasated blood and ischemic necrosis with infiltration by neutrophils, lymphocytes (Image C, Image D, and Image E), and CD68-positive macrophages (Image F) leads to a diagnosis of hemorrhagic necrotizing encephalitis. Although the presence of haloed Cowdry A viral inclusions (Image G) provides diagnostic reassurance, they are not always seen and are not specific to HSV. IHC for HSV1/2 is positive in infected cells (Image H). But since IHC can lack sensitivity, PCR testing of tissue in cases with high clinical suspicion of HSV infection can confirm the diagnosis.

Image B: H&E stain, high magnification.

Image B: H&E stain, high magnification.

Image C: H&E stain, low magnification.

Image C: H&E stain, low magnification.

Image D: H&E stain, intermediate magnification.

Image D: H&E stain, intermediate magnification.

Image E: H&E stain, high magnification.

Image E: H&E stain, high magnification.

Image F: IHC CD68, intermediate magnification.

Image F: IHC CD68, intermediate magnification.

Image G: H&E stain, high magnification.

Image G: H&E stain, high magnification.

Image H: IHC HSV1/2, high magnification.

Image H: IHC HSV1/2, high magnification.

Herpesviridae are divided into three subfamilies (alpha, beta, and gamma) based on genomic organization and homology, viral host range, and other biologic properties. HSV1, HSV2, varicella-zoster virus (VZV), and herpes simian B virus are neurotropic viruses in the alpha subgroup. HSV1 and HSV2 are the most closely related, sharing roughly 83% genomic homology and expressing similar proteins that result in partial antigenic cross-reactivity. HSV molecular assays of cerebrospinal fluid, most prominently PCR methods, outperform both culture and direct antigen detection methods by a substantial margin, including primary infection, reactivation, or reinfection. Loop-mediated isothermal amplification (LAMP) is an alternative method that has the advantage of not requiring a thermocycler or other expensive equipment. Another nucleic acid amplification-based and isothermal method that has been applied to the diagnosis of HSV infection is helicase-dependent amplification (HDA).

Herpes simplex virus type 1 (HSV1) encephalitis


Take Home Points

  • Herpes encephalitis classically involves bilateral asymmetric orbitofrontal and temporal lobes, but can have atypical presentations - including that of a unifocal mass mimicking a neoplasm.
  • Histologic evaluation of herpes infection of the brain reveals hemorrhagic and necrotizing encephalitis, sometimes with cells harboring Cowdry type A intranuclear viral inclusions.
  • HSV1 encephalitis may occasionally be confused with infiltrative gliomas leading to diagnostic surgical procedures and requiring intraoperative consultations.
  • IHC coupled with molecular methods can establish the specific etiologic agent in herpes encephalitis.

References

  1. George BP, Schneider EB, Venkatesan A. Encephalitis hospitalization rates and inpatient mortality in the United States, 2000-2010. PLoS One. 2014;9(9):e104169.
  2. Levin MJ, Weinberg A, Schmid DS. Herpes simplex virus and varicella-zoster virus. Microbiol Spectrum. 2016;4(3):1-20.
  3. Steiner I, Benninger F. Update on herpes virus infections of the nervous system. Curr Neurol Neurosci Rep. 2013;13(12):414.
  4. Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. Lancet. 2002;359(9305):507-14.

Answer Key

  1. What is the MOST likely diagnosis?
    A. Acute bacterial infection
    B. Anaplastic astrocytoma, WHO grade III
    C. Herpes simplex virus type 1 (HSV1) encephalitis
    D. Herpes simplex virus type 2 encephalitis
    E. Ischemic infarct
  2. Histologic features MOST characteristic of the diagnosis include:
    A. Focal collection of neutrophils and cellular debris with a fibrotic capsule
    B. Hemorrhage, necrosis, mixed inflammatory infiltrate, and cells harboring viral inclusions
    C. Ischemic red neurons, reactive astrocytes, and neuropil edema
    D. Pleomorphic astrocytes, mitotic figures, microvascular proliferation, and palisading necrosis
    E. Visible organisms with a muted host response
  3. Herpes simplex virus belongs to which of the following?
    A. Adenovirus
    B. DNA virus
    C. Retrovirus
    D. RNA virus
    E. Slow virus