Herpes Simplex Virus Type 1

Slide 1 · Herpes Simplex

Virus Type 1

Necrotizing encephalitis · neuropathology · clinical interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes: Mechanistic and diagnostic reasoning

Trace HSV-1 from mucosal replication through neuronal latency and CNS injury.

Relate temporal and orbitofrontal involvement to the neurological presentation.

Recognize necrotizing, often hemorrhagic encephalitis and its microscopic correlates.

Integrate clinical recognition, CSF molecular testing, and urgent antiviral treatment.

Slide 3 · HSV-1: Two linked but distinct disease contexts

Primary and recurrent infection

Replication at mucosal or skin surfaces

Vesicular lesions and mucosal shedding

Neuronal latency persists after recovery

Central nervous system disease

Invasion of brain parenchyma

Necrotizing, often hemorrhagic encephalitis

Acute neurologic dysfunction

Most HSV infections do not lead to encephalitis.

Slide 4 · Alpha-herpesvirus biology relevant to pathology

HSV-1 and HSV-2 are closely related human alpha-herpesviruses.

Their genomes consist of double-stranded DNA.

Alpha-herpesviruses replicate in epithelial cells and establish latency in postmitotic neurons.

The ability to alternate between lytic infection and latency is central to recurrence.

Slide 5 · Mucosal entry creates an initial site of replication

Entry at skin or mucosa

Replication in epithelial cells

Production of infectious virions

Vesicular cytopathic injury

HSV establishes infection at the site of entry before neuronal latency.

Slide 6 · Primary mucocutaneous lesions reflect direct cytolysis

Intraepithelial vesicles result from ballooning degeneration and edema of epidermal cells.

Fragile vesicles can rupture, crust, or form superficial ulcerations.

Perioral cold sores commonly involve the skin around the lips and nose.

Mucocutaneous morphology differs from parenchymal brain necrosis.

Slide 7 · Sensory neurons establish the reservoir for latency

Epithelial replication

Entry into sensory axon

Axonal transport to neuronal soma

Latent HSV DNA in nucleus

Movement toward sensory ganglion neuronal cell bodies follows peripheral replication.

Slide 8 · Latency: Persistence without infectious virus production

Latency means viral genomes persist in cells without generating infectious virions.

The neuronal cell nucleus maintains HSV DNA after mucosal disease resolves.

Latency is distinct from ongoing productive lytic replication.

Reactivation can later generate infectious virus despite pre-existing host immunity.

Slide 9 · Lytic replication versus latency

Lytic state

Viral genes expressed in a productive program

Infectious virions are released

Tissue cytopathic changes may develop

Latent state

HSV DNA persists in the neuronal nucleus

Latency-associated transcripts predominate

No infectious virus is produced

Slide 10 · Latency-associated transcripts (LATs)

During latency, transcription is restricted largely to latency-associated RNAs.

LATs may favor neuronal survival by reducing apoptosis.

They may help silence lytic genes through chromatin modifications.

LAT-derived microRNAs may downregulate viral gene expression; These are proposed mechanisms.

Slide 11 · Reactivation reverses the latent state

Neuronal stress-associated pathways

Relief of lytic-gene silencing

Production of viral progeny

Transport toward epithelial surface

Reactivation may produce symptoms—or asymptomatic viral shedding.

Slide 12 · Clinical recurrence does not require repeated new exposure

Primary HSV infection often resolves in immunocompetent individuals.

Persistent neuronal HSV DNA provides a source for later reactivation.

Repeated lesions can arise from reactivation of the same latent infection.

A history of recurrent cold sores cannot be used to establish or exclude encephalitis.

Slide 13 · Immune escape helps HSV persist in an immune host

HSV has evolved several strategies to diminish immune recognition and antiviral effector pathways.

Such evasion helps explain reactivation despite prior adaptive immunity.

Three examples involve MHC class I, IgG Fc interactions, and complement.

These are separate mechanisms: Avoid collapsing them into a single pathway.

Slide 14 · MHC class I interference weakens antiviral CTL recognition

Infected host cell

Reduced MHC I recognition pathway

Less efficient CD8⁺ T-cell recognition

Immune evasion advantage

CD8⁺ cytotoxic T cells usually identify infected cells via peptide–MHC I complexes.

Slide 15 · HSV glycoprotein gE interferes with antibody effector function

HSV gE binds IgG Fc region

Interference with effector access

Reduced C1q / Fc-dependent actions

Binding Fc can limit useful functions of already bound antiviral antibodies.

Slide 16 · HSV glycoprotein gC targets complement

HSV gC interacts with C3

Accelerated loss of active C3 products

Reduced alternative-pathway function

This is distinct from the Fc-binding mechanism involving gE.

Slide 17 · Immune evasion and tissue destruction can coexist

Immune evasion

Latency and recurrence despite immunity

MHC class I, antibody and complement interference

Immune-mediated consequences

Inflammatory recruitment into infected tissue

Parenchymal injury alongside viral cytopathic effects

Neither “direct viral damage” nor “inflammation” alone explains all lesions.

Slide 18 · Host TLR3 signaling is a susceptibility factor

Inherited defects in TLR3 or components of its signaling pathway increase susceptibility to HSV encephalitis.

TLR3 participates in innate antiviral recognition of viral RNA.

A predisposition to CNS infection does not imply every patient has a detectable inherited defect.

This is a mechanistic risk association, not a routine tissue diagnostic biomarker.

Slide 19 · HSV-1 encephalitis is a parenchymal syndrome

Meningitis

Predominantly meningeal inflammation

Clinical meningeal syndrome possible without major parenchymal dysfunction

Encephalitis

Infection and injury within brain tissue

Behavior, memory, consciousness or seizures reflect parenchymal dysfunction

Viral encephalitis commonly coexists with meningeal inflammation (meningoencephalitis).

Slide 20 · HSV-1 is a major cause of sporadic fatal encephalitis

HSV-1 as a major cause of fatal sporadic encephalitis in the United States.

The key teaching signature is limbic/temporal and orbitofrontal involvement.

Untreated destructive infection can lead to extensive parenchymal necrosis.

Antiviral treatment has substantially reduced mortality.

Slide 21 · Anatomic predilection is a central diagnostic clue

Conceptual regions of predilection — schematic, not to anatomical scale

Anterior / orbital frontal cortex

Inferior and medial temporal regions

Additional cingulate involvement in illustrated severe cases

Necrotizing inflammation ± hemorrhage

Distribution is highly suggestive but is not a pathogen-specific diagnostic test.

Slide 22 · Typical involvement begins in specific cerebral regions

The inferior and medial temporal lobes are most prominently involved.

The orbital gyri of the frontal lobes are another classic site.

Gross examples may extend to anterior temporal, inferior frontal and cingulate regions.

Regional predilection is useful but not a standalone etiologic diagnosis.

Slide 23 · Anatomy predicts the clinical pattern

Medial temporal injury

Memory and limbic network dysfunction

Mood, memory and behavior changes

The regional clinicopathologic relationship helps distinguish encephalitis from isolated meningitis.

Slide 24 · Mood and behavior changes can be presenting features

Altered mood and behavior as typical clinical manifestations.

Orbitofrontal and limbic network dysfunction provides a plausible anatomic explanation.

Behavioral disturbance can precede recognition of an infectious CNS process.

Diagnostic reasoning should integrate behavior changes with new neurologic dysfunction.

Slide 25 · Memory impairment points toward temporal-limbic injury

Memory alteration is among the typical presenting features.

Medial temporal injury disrupts circuits important for memory formation.

Memory deficit is a localizing clue rather than a pathogen-specific sign.

The combination with evolving encephalopathy heightens suspicion for HSV encephalitis.

Slide 26 · Seizures signal irritable, damaged cerebral tissue

Seizures are listed among manifestations of the more protracted HSV-1 presentation.

Necrotizing inflammation and neuronal dysfunction create a substrate for epileptic activity.

Seizures may coexist with weakness, lethargy or behavioral disturbance.

An encephalitic syndrome warrants attention to nonconvulsive seizures.

Slide 27 · Subacute HSV-1 encephalitis is recognized

Some cases evolve over a prolonged interval rather than a rapidly fulminant course.

Weakness, lethargy, ataxia and seizures may unfold over four to six weeks.

Slowly evolving cases may show more diffuse brain involvement.

A prolonged history does not exclude infection with HSV-1.

Slide 28 · Two clinically described tempos of HSV-1 encephalitis

Course describes clinical evolution; Time windows are not diagnostic thresholds

Acute encephalitic presentation

Behavior · memory · mood

Subacute course

Weakness · lethargy · ataxia · seizures

Some subacute cases evolve over approximately 4–6 weeks

A prolonged course may correlate with more diffuse parenchymal involvement.

Slide 29 · Prior herpetic lesions are absent in most encephalitis cases

That only about 10% have a history of prior herpetic infection.

A negative history of cold sores does not argue strongly against HSV-1 encephalitis.

Mucocutaneous symptoms are not required for the brain infection to be clinically evident.

Avoid anchoring on the presence or absence of vesicles.

Slide 30 · Age distribution described

The Chapter 28 text states that HSV-1 encephalitis occurs most commonly in children and young adults.

This wording describes the cited textbook—not an age-based rule-out criterion.

Neither older age nor immunocompetence excludes HSV encephalitis.

Age should be integrated with phenotype, localization and laboratory results.

Slide 31 · Encephalitis and ordinary cold sores are not equivalent

Common mucocutaneous infection

Epithelial vesiculation and ulceration

Often self-limited locally

Latent reservoir remains

Rare severe neurologic manifestation

Direct injury within brain parenchyma

Temporal/orbitofrontal necrosis

Urgent diagnostic and treatment response

Slide 32 · Gross neuropathology: Necrotizing encephalitis

The lesion is destructive: Involved parenchyma undergoes tissue necrosis.

Damage predominates in medial/inferior temporal and orbitofrontal regions.

Necrosis corresponds clinically to acute neuronal dysfunction.

The distribution is more informative than simply calling the brain “inflamed.”

Slide 33 · Hemorrhage is a frequent, not obligatory, component

HSV-1 encephalitis as often hemorrhagic in severely affected regions.

Hemorrhage accompanies destructive parenchymal inflammation and vascular injury.

Absence of gross hemorrhage does not exclude HSV infection.

Never infer a specific pathogen from hemorrhage alone.

Slide 34 · Gross damage links topography to neurologic loss

Inferomedial temporal and orbital gyri

Regional necrotizing injury

Hemorrhage in severely damaged regions

Loss of neural tissue function

This sequence summarizes features of the lesion; Hemorrhage is common but not obligatory.

Slide 35 · Microscopic pattern: Inflammation around vessels

Perivascular inflammatory infiltrates are usually found in acute HSV-1 encephalitis.

Lymphocyte-rich perivascular cuffs are a common feature of viral encephalitis in general.

Cuffing demonstrates inflammation but cannot establish HSV-1 by itself.

Interpret the inflammatory pattern together with topography and tissue necrosis.

Slide 36 · Perivascular inflammation: A native schematic

Vessel in brain parenchyma

Lymphocytic perivascular cuff

Adjacent injured neuropil

Schematic only; Not an H&E photomicrograph.

Slide 37 · Neuronophagia marks loss of injured neurons

Neuronophagia is the phagocytic removal of damaged or dead neuronal debris.

This feature in viral meningoencephalitis patterns.

It is a morphologic consequence of neuronal injury, not a virus-specific inclusion.

The extent of neuronal destruction helps explain persistent neurologic deficits.

Slide 38 · Microglial nodules arise during parenchymal injury

Infected or injured neural tissue

Activation and recruitment of microglia

Focal microglial aggregates

Microglial nodules characterize viral encephalitic inflammation, but are not HSV-specific.

Slide 39 · Cowdry type A inclusions: The viral cytopathic clue

Intranuclear inclusions can be seen in HSV-infected neurons and glia.

Cowdry type A inclusions have eosinophilic material with peripheral chromatin margination.

They indicate herpesvirus-type nuclear cytopathic change but do not reliably distinguish HSV-1 from HSV-2.

Their absence in a sample cannot rule out HSV encephalitis.

Slide 40 · Illustrated Cowdry type A nuclear change

Native editable schematic; Not a specimen or a substitute for H&E confirmation

Infected cell

Large intranuclear inclusion

Peripheral chromatin displacement

May occur in neurons and glia

HSV-1 and HSV-2 cannot be typed by inclusion morphology alone.

Slide 41 · Syncytia provide another HSV cytopathic feature

HSV can cause cell-to-cell fusion producing multinucleated syncytia.

Viral inclusion-bearing multinucleated cells may be found in affected tissues.

Syncytia are well illustrated in mucocutaneous HSV disease.

They must not be presented as a substitute for evidence of brain involvement.

Slide 42 · How HSV histology is interpreted

Pattern recognition

Necrosis and sometimes hemorrhage

Perivascular infiltrates

Intranuclear cytopathic change

Etiologic confirmation

Immunohistochemical demonstration in tissue when obtained

Molecular detection in the appropriate specimen

Clinical–radiologic–pathologic concordance

Slide 43 · Protracted cases may involve more diffuse regions

Robbins explicitly contrasts classic focal distribution with slowly evolving encephalitis.

Longer clinical evolution may be associated with more diffuse brain involvement.

Atypical extent reduces the specificity of anatomic pattern alone.

History, microbiology and pathologic data must be interpreted together.

Slide 44 · From molecular infection to observed brain pathology

Productive viral infection in CNS cells

Cellular injury and necrosis

Perivascular inflammatory recruitment

Regional neurologic dysfunction

In severe lesions, necrosis may be accompanied by hemorrhage.

Slide 45 · MRI supports diagnosis through anatomic localization

MRI is preferred to CT when evaluating suspected encephalitis (IDSA guideline).

Temporal-lobe localization strengthens suspicion for HSV encephalitis.

Imaging identifies the affected territory but does not by itself identify viral species.

Imaging should be interpreted together with clinical findings and CSF testing.

Slide 46 · CSF analysis is central to the initial evaluation

Unless contraindicated, obtain CSF in the diagnostic evaluation of encephalitis.

Routine CSF studies assess inflammatory pattern and competing diagnoses.

A CSF nucleic acid amplification test can establish a viral etiology.

CSF microbiology is a clinical diagnostic route; Tissue histology is not routinely required.

Slide 47 · CSF HSV molecular testing: Recommended diagnostic test

Suspected encephalitis

CSF specimen

HSV-1 / HSV-2 NAAT (PCR)

Etiologic interpretation in context

The 2024 IDSA/ASM laboratory guide recommends HSV-1/2 NAAT on CSF.

Slide 48 · CSF HSV NAAT is highly accurate but not infallible

The 2024 IDSA/ASM guide reports CSF HSV NAAT sensitivity and specificity greater than 95%.

An early false-negative result is possible despite a compatible clinical syndrome.

A single negative test should not override highly suggestive clinical and temporal-lobe findings.

The laboratory result must be interpreted against pretest probability.

Slide 49 · What to do when early CSF PCR is negative

Compatible encephalitis persists

Initial HSV PCR negative

Repeat CSF HSV NAAT in 3–7 days

Reassess diagnosis and treatment

This repeat-testing recommendation is in the 2024 IDSA/ASM guide; Do not stop empiric therapy solely because of an early negative result.

Slide 50 · EEG addresses seizures rather than viral identity

EEG may identify nonconvulsive seizures in an encephalopathic patient.

Electrographic abnormalities generally do not establish the HSV etiology.

Seizure detection changes supportive neurologic management.

EEG complements but does not replace CSF virologic testing.

Slide 51 · Clinical evaluation integrates independent evidence

Encephalitic clinical syndrome

Anatomic imaging pattern

CSF HSV-1 / HSV-2 NAAT

Integrated diagnostic conclusion

Treatable viral encephalitis requires rapid parallel evaluation and action.

Slide 52 · Empiric intravenous acyclovir should not wait for PCR

The IDSA encephalitis guideline recommends prompt intravenous acyclovir for suspected encephalitis.

Treatment should begin while diagnostic studies are pending when HSV is plausible.

Delays increase the risk of death or severe neurologic sequelae.

Treatment decisions require individual clinical assessment; This lecture is not a dosing protocol.

Slide 53 · Early antiviral therapy changes the natural history

Substantial mortality reduction with antiviral treatment.

The drug suppresses productive viral replication rather than reversing established necrotic tissue loss.

Therefore rapid recognition matters even before complete etiologic confirmation.

Persistent deficits can remain despite successful control of infection.

Slide 54 · Why brain biopsy is not the routine first test

CSF molecular assays provide etiologic information without neurosurgical tissue sampling.

The IDSA encephalitis guideline does not recommend routine brain biopsy.

Biopsy may be considered in unexplained deterioration despite appropriate treatment.

When tissue is obtained, morphology and targeted immunohistochemistry can be integrated.

Slide 55 · HSV-1 versus HSV-2 in central nervous system disease

Feature

HSV-1

HSV-2

Common CNS phenotype

Necrotizing encephalitis

Adult meningitis; neonatal encephalitis

Site clue

Temporal/orbitofrontal predilection

No equivalent classic temporal predilection in source

Host context

Multiple age groups

Neonates; HIV-associated severe disease

Diagnosis

CSF type-specific NAAT

CSF type-specific NAAT

The viruses overlap; Patterns are tendencies, not absolute rules.

Slide 56 · HSV-2: Important neonatal contrast

HSV-2 acquisition in neonates during delivery from an actively infected genital tract.

Severe neonatal encephalitis is a recognized consequence of infection.

This differs from the classic HSV-1 temporal encephalitis teaching pattern.

Type-specific CSF molecular testing distinguishes the viral types.

Slide 57 · Other neurotropic herpesviruses: Anatomic contrasts

Virus

Typical supplied Robbins context

Distinctive tissue distribution

HSV-1

Sporadic encephalitis

Inferomedial temporal / orbitofrontal

VZV

Latent sensory-neuron infection; zoster

May cause CNS disease; not the classic HSV-1 lesion map

CMV

Congenital or immunosuppressed CNS infection

Periventricular / subependymal regions

Slide 58 · Arbovirus comparison: Shared histology, different context

Many arboviral encephalitides cause lymphocytic cuffs, neuronophagia and microglial nodules.

Those findings are not pathognomonic for HSV-1.

Epidemiology and the distribution of CNS injury help prioritize etiologies.

HSV-1 gains support from temporolimbic necrosis plus appropriate virologic results.

Slide 59 · Interpretation of candidate findings in suspected HSV-1

Finding

What it supports

What it cannot prove

Medial temporal injury

Regional pattern compatible with HSV-1

HSV-1 etiology in isolation

Cowdry A inclusions

Herpesvirus-type nuclear cytopathy

HSV-1 rather than HSV-2

Perivascular lymphocytes

Viral encephalitic inflammation

Any single virus

Positive CSF HSV-1 NAAT

HSV-1 nucleic acid in CSF

Precise severity of tissue necrosis

Slide 60 · Applied case: Acute limbic dysfunction

An adult develops rapidly evolving confusion, memory disturbance, and behavioral change. Brain MRI shows abnormalities in medial temporal regions.

Which diagnosis should be prioritized and what test would establish the suspected viral etiology?

Teaching interpretation · Prioritize HSV-1 encephalitis; Obtain CSF HSV-1/2 NAAT while promptly initiating clinically indicated empiric acyclovir.

Slide 61 · Applied case: A negative early HSV PCR

A patient has focal temporal MRI changes and encephalopathy. The initial CSF HSV PCR is negative early in the course.

Does the initial negative result exclude HSV encephalitis?

Teaching interpretation · No. With continued compatible suspicion, repeat CSF HSV NAAT in 3–7 days and continue clinical management rather than relying on one early result.

Slide 62 · Applied case: Pathology sign interpretation

A cerebral specimen shows necrosis, perivascular inflammatory cells, and occasional intranuclear eosinophilic inclusions.

Which observations favor herpesvirus infection, and what limitation remains?

Teaching interpretation · Cowdry-type nuclear cytopathic change supports herpesvirus infection; The pattern alone does not distinguish HSV-1 from HSV-2 and requires etiologic confirmation.

Slide 63 · A mechanistic chain explains the clinical presentation

HSV infection within brain tissue

Limbic / temporal necrosis and inflammation

Memory, mood, behavior disruption

Possible seizures and neurologic decline

The full pathology pattern links the underlying virus to focal clinical dysfunction.

Slide 64 · High-yield synthesis: Pathogen, site, pathology

HSV-1 is an alpha-herpesvirus with epithelial replication and neuronal latency.

The classic encephalitis pattern preferentially affects inferior/medial temporal and orbitofrontal regions.

Parenchymal necrosis, often with hemorrhage, plus perivascular inflammation are key morphologic features.

Cowdry type A inclusions may occur in neurons and glia.

Slide 65 · High-yield synthesis: Diagnostic and therapeutic action

Suspect HSV encephalitis when progressive encephalopathy includes memory, behavioral change or seizures.

Use MRI localization and CSF type-specific HSV NAAT to refine or confirm the working diagnosis.

Repeat an early negative CSF HSV test when clinical suspicion persists.

Initiate intravenous acyclovir promptly when HSV encephalitis is suspected; Do not await PCR.

Slide 66 · Selected references

Primary textbook

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026). Chapter 28: The Central Nervous System (pp. 1150–1152); Chapter 8: Infectious Diseases (pp. 320–322).

Clinical management (archived)

Tunkel AR, et al. Management of Encephalitis: IDSA Clinical Practice Guidelines. Clin Infect Dis. 2008;47:303–327. doi:10.1086/589747.

Laboratory diagnosis (current 2024)

Miller JM, et al. IDSA/ASM Guide to Utilization of the Microbiology Laboratory, 2024. Clin Infect Dis. doi:10.1093/cid/ciae104.