Multisystem Processes & Disorders

Herpes simplex virus: oral, genital, encephalitis

Clinical Overview and When to Suspect HSV

— HSV-1: classically orolabial (gingivostomatitis, herpes labialis), but now causes >50% of new genital herpes in US adolescents/young adults due to oral-genital contact.

— HSV-2: predominantly genital, recurs more often than genital HSV-1 (~4x/year vs ~1x/year).

— Recurrent grouped vesicles on an erythematous base at the lip vermilion, genitals, buttocks, or sacrum

— Painful genital ulcers with tender inguinal lymphadenopathy, dysuria, prodromal tingling

— Fever, altered mentation, focal temporal lobe findings, or new seizure in any adult → HSV encephalitis until proven otherwise

— Neonate (≤6 weeks) with vesicles, sepsis-like illness, seizures, or pneumonitis

— Eczema herpeticum: monomorphic punched-out erosions in atopic dermatitis

— Herpetic whitlow on a finger (classic in dentists, healthcare workers, thumb-suckers)

— Keratoconjunctivitis with dendritic corneal ulcer on fluorescein

HSV-1 and HSV-2 are double-stranded DNA alphaherpesviruses that establish lifelong latency in sensory ganglia (trigeminal for orolabial; sacral for genital) with periodic reactivation.

Transmission: direct mucocutaneous contact with lesions or asymptomatic shedding (the majority of transmissions). Seroprevalence in US adults: HSV-1 ~48%, HSV-2 ~12%.

When to suspect on Step 3:

Risk factors: multiple/new sexual partners, HIV, immunosuppression (transplant, chemo), atopic dermatitis, infancy, advanced age (encephalitis bimodal: <3 and >50).

Step 3 management: the single most important reflex is empiric IV acyclovir in any patient with fever + AMS + focal neuro signs before waiting for CSF PCR—delay >6 hours worsens mortality and morbidity.

Board pearl: Most genital HSV is transmitted by asymptomatic shedders who don't know they're infected; this drives counseling about chronic suppressive therapy and condom limitations.

Presentation Patterns and Key History

— High fever, drooling, refusal to eat/drink, foul breath, painful vesicles/ulcers on gingiva, tongue, buccal mucosa, palate, and lips; tender cervical adenopathy; lasts 10–14 days.

— Key distinction: HSV gingivostomatitis involves the anterior mouth and gingiva; herpangina (coxsackie A) spares the gingiva and clusters on the posterior pharynx/soft palate.

— Multiple bilateral painful ulcers, constitutional symptoms (fever, myalgia, headache), tender inguinal nodes, dysuria, urinary retention (sacral radiculopathy in women), aseptic meningitis (~10–20%).

— Lasts up to 3 weeks if untreated.

— Acute fever, personality/behavioral change, aphasia, anosmia, hallucinations (olfactory/gustatory), focal seizures, hemiparesis—reflecting temporal lobe predilection.

— Subacute progression over 1–7 days; any age; not classically a "sex history" question.

— SEM (skin-eye-mouth): vesicles, keratoconjunctivitis

— CNS: seizures, lethargy, poor feeding, temperature instability

— Disseminated: sepsis, DIC, hepatitis, pneumonitis—highest mortality

Primary orolabial (gingivostomatitis): typically children 6 months–5 years.

Recurrent herpes labialis: prodrome of tingling/burning → grouped vesicles at the vermilion border → crusting in 4–7 days. Triggers: UV light, fever, stress, menses, dental work.

Primary genital herpes:

Recurrent genital herpes: unilateral, fewer lesions, prodrome of sacral/buttock tingling, no systemic symptoms, heals in 5–10 days. HSV-2 recurs more than HSV-1.

HSV encephalitis:

Neonatal HSV: presents at days 5–21 of life in three patterns:

History essentials: sexual partners and protection, last partner change, prior outbreaks, recent oral sex (HSV-1 genital), pregnancy status/EDD, immune status (HIV, steroids, transplant), atopic dermatitis, recent dental work or sun exposure, occupational exposures.

Board pearl: A college student with first-episode genital ulcers PLUS aseptic meningitis is the classic primary HSV-2 vignette—LP shows lymphocytic pleocytosis; treat with IV acyclovir.

Physical Exam Findings (and Neuro Assessment when relevant)

— Key distinction: Aphthous ulcers occur on non-keratinized mucosa (buccal, labial, soft palate) and lack vesicles or systemic symptoms.

— Women: vulva, labia, perineum, cervix (cervicitis with friable mucosa in primary); often bilateral in primary disease.

— Men: penile shaft, glans, perianal region (especially MSM).

— Tender, shallow ulcers with scalloped borders, may coalesce; vesicles often unroofed by the time of presentation.

— Bilateral tender inguinal lymphadenopathy with primary infection.

— Fever + disorientation, aphasia (often expressive), memory deficits, behavioral changes

— Focal seizures (especially complex partial with olfactory aura)

— Hemiparesis, cranial nerve findings, sometimes papilledema

— Meningismus less prominent than bacterial meningitis

Orolabial: clustered 1–3 mm vesicles on erythematous base at the vermilion border; when intraoral, ulcers on keratinized mucosa (hard palate, attached gingiva).

Genital lesions:

Herpetic whitlow: painful vesicles/pustules on a distal finger pulp, often misdiagnosed as bacterial paronychia—do not I&D (worsens disease, risk of viral dissemination).

Eczema herpeticum: monomorphic punched-out hemorrhagic erosions superimposed on atopic dermatitis; can be life-threatening.

Herpes gladiatorum: wrestlers with vesicles on head/neck/trunk from skin-to-skin contact.

Ocular HSV: unilateral red eye, photophobia, foreign body sensation, decreased vision; fluorescein staining reveals a branching dendritic ulcer—pathognomonic.

HSV encephalitis neuro exam:

Neonatal exam: scattered vesicles (50% lack skin findings at presentation!), conjunctivitis, hepatomegaly, seizures, hypotension.

CCS pearl: In a febrile adult with new altered mental status, document a focused neuro exam (orientation, language, cranial nerves, motor) before sedation/intubation; this anchors the temporal-lobe picture pointing to HSV encephalitis and justifies LP + empiric acyclovir on the order sheet.

Diagnostic Workup — Initial Labs, Imaging, and PCR

— HSV PCR from lesion swab is the test of choice—highest sensitivity and specificity, types HSV-1 vs HSV-2 (prognostically important for recurrence counseling).

— Viral culture: lower sensitivity, especially in crusted lesions; mostly historical.

— Tzanck smear: multinucleated giant cells; cannot distinguish HSV from VZV and is rarely used now.

— Direct fluorescent antibody (DFA): faster than culture, decent sensitivity, types virus.

— Type-specific glycoprotein G serology (HSV-1 IgG, HSV-2 IgG): useful for partner discordance counseling, recurrent culture-negative lesions, pregnancy screening in select cases—but not routine screening in asymptomatic adults (USPSTF: do not screen asymptomatic adolescents/adults, including pregnant women).

— CSF HSV PCR: ~95% sensitive, ~99% specific; can be falsely negative if performed <72 hours of symptoms—repeat LP at 3–7 days if clinical suspicion remains and initial PCR was negative.

— CSF profile: lymphocytic pleocytosis (10–500 cells, predominantly lymphocytes), elevated RBCs/xanthochromia (hemorrhagic temporal necrosis), elevated protein, normal/slightly low glucose.

— MRI brain with contrast: T2/FLAIR hyperintensity in medial temporal lobes, insula, inferior frontal cortex, often bilateral asymmetric—most sensitive imaging.

— CT (if MRI unavailable or contraindicated): temporal lobe hypodensity/edema, but often normal early.

— EEG: periodic lateralized epileptiform discharges (PLEDs/LPDs) over temporal lobes—classic but nonspecific.

— Routine labs: CBC, BMP (acyclovir nephrotoxicity baseline), LFTs, HIV test, pregnancy test.

Mucocutaneous HSV (oral or genital):

Suspected HSV encephalitis — order in parallel:

Neonatal HSV workup: surface swabs (mouth, nasopharynx, conjunctivae, anus), blood HSV PCR, CSF HSV PCR, LFTs, CBC.

Step 3 management: Do not delay IV acyclovir waiting for PCR results in suspected encephalitis or neonatal HSV—empiric therapy on clinical suspicion is the standard, with de-escalation if PCR negative and clinical course favors an alternative.

Diagnostic Workup — Confirmatory and Adjunctive Studies

— Genital HSV-2: average 4 recurrences/year in year 1

— Genital HSV-1: average <1 recurrence/year; recurrence rate falls sharply after year 1

— This drives the suppression vs episodic decision.

— Recurrent or atypical genital symptoms with negative PCR

— Clinical diagnosis of genital herpes without lab confirmation

— Partner of a person with known genital HSV (sero-discordance)

— Not recommended: routine screening of asymptomatic general population (high false-positive rate, psychological harm).

— Examine for active lesions at onset of labor; type-specific serology can clarify whether a lesion at delivery is primary (high risk) vs recurrent (lower risk) when history is unclear.

— Routine antenatal HSV serologic screening is NOT recommended (USPSTF, ACOG).

— Also test for syphilis (RPR/treponemal), gonorrhea/chlamydia NAAT, hepatitis B; consider hepatitis C and trichomonas per risk.

Repeat CSF PCR at 3–7 days if initial result negative but clinical and MRI features still suggest HSV encephalitis; viral load may be below detection limit early.

Quantitative CSF HSV PCR at end of treatment: some centers use it to confirm clearance before stopping IV acyclovir in encephalitis—persistent positivity → extend therapy.

HSV typing (HSV-1 vs HSV-2) on lesion PCR: prognostic counseling

Type-specific serology indications:

Pregnancy considerations:

HIV coinfection workup: every patient newly diagnosed with genital HSV-2 should be offered HIV testing—HSV-2 increases HIV acquisition risk ~3-fold and is a syndemic STI.

Ophthalmology referral and slit-lamp exam with fluorescein for suspected HSV keratitis—do not prescribe topical steroids without ophtho input (can perforate cornea in epithelial disease).

Brain biopsy: historical gold standard for HSV encephalitis; now reserved for atypical cases, immunocompromised hosts, or PCR-negative cases not improving.

Board pearl: A hemorrhagic CSF (elevated RBCs without trauma) + lymphocytic pleocytosis + temporal lobe MRI lesion triad is HSV encephalitis on the exam—start IV acyclovir before the PCR returns.

Risk Stratification and First-Line Management Logic

— Mucocutaneous (oral/genital) in an immunocompetent host → oral antiviral, outpatient.

— Severe mucocutaneous, eczema herpeticum, disseminated, ocular, or immunocompromised → consider IV acyclovir, hospitalize.

— Encephalitis or neonatal HSV → IV acyclovir immediately, inpatient/ICU.

— Episodic (treat each outbreak): infrequent recurrences (<6/year), able to recognize prodrome, start within 24 hours.

— Suppressive (daily): ≥6 outbreaks/year, severe outbreaks, significant psychosocial distress, HIV coinfection, serodiscordant partners (reduces transmission ~50%), pregnancy after 36 weeks, immunocompromised.

— HIV: more frequent, prolonged, atypical (deep ulcerative) HSV; lower threshold for IV therapy and suppression.

— Pregnancy near term: any genital HSV history → start suppression at 36 weeks to reduce shedding and C-section need.

— Atopic dermatitis with vesicular flare → assume eczema herpeticum until proven otherwise; IV acyclovir if extensive or systemic features.

— GCS, seizure burden, ICP signs (papilledema, posturing, Cushing triad), renal function (acyclovir dosing), age, time-to-treatment (the single strongest mortality predictor).

— Untreated mortality ~70%; with timely acyclovir mortality drops to ~20–30%, but morbidity remains high (memory, personality, seizures).

— Outpatient oral therapy: standard for typical recurrences.

— Hospitalize for: encephalitis, neonatal HSV, disseminated HSV, eczema herpeticum, urinary retention from sacral radiculopathy requiring catheterization, severe primary genital HSV with systemic illness, ocular HSV with stromal involvement.

Decision tree for any HSV presentation:

Genital herpes — choose episodic vs suppressive:

Risk modifiers:

Severity assessment in HSV encephalitis:

Resource decisions:

CCS pearl: On a CCS case of fever + AMS, your first three orders should be: (1) IV access + labs/blood cultures, (2) empiric IV acyclovir + ceftriaxone + vancomycin (± ampicillin if elderly/immunocompromised), (3) MRI brain and LP—do not wait on imaging to start antimicrobials.

Pharmacotherapy — First-Line Antiviral Regimens

— Valacyclovir 2 g PO BID × 1 day OR famciclovir 1500 mg PO × 1 OR acyclovir 400 mg 5x/day × 5 days

— Start at first prodromal symptom; benefit lost if delayed >72 hours.

— Primary gingivostomatitis (children): acyclovir 15 mg/kg 5x/day × 7 days if started within 72 hours—reduces duration, viral shedding, and oral intake problems.

— Valacyclovir 1 g PO BID × 7–10 days

— Acyclovir 400 mg PO TID × 7–10 days

— Famciclovir 250 mg PO TID × 7–10 days

— Valacyclovir 500 mg PO BID × 3 days OR 1 g daily × 5 days

— Acyclovir 800 mg PO BID × 5 days or 800 mg TID × 2 days

— Famciclovir 1 g PO BID × 1 day

— Valacyclovir 500 mg or 1 g PO daily (1 g preferred if ≥10 outbreaks/year)

— Acyclovir 400 mg PO BID

— Reassess annually for ongoing need.

— IV acyclovir 10 mg/kg (ideal body weight) IV q8h × 14–21 days

— Confirm clearance with end-of-treatment CSF PCR in some protocols; minimum 21 days is preferred.

— Crystalline nephropathy (esp. with rapid IV push, dehydration) → hydrate aggressively, infuse over ≥1 hour, dose by ideal body weight in obesity

— Neurotoxicity (tremor, myoclonus, confusion, hallucinations)—especially in renal impairment

— Phlebitis at IV site

Mechanism: acyclovir, valacyclovir (prodrug, better oral bioavailability), and famciclovir are guanosine analogs activated by viral thymidine kinase → incorporated into viral DNA → chain termination. Selective for HSV/VZV-infected cells.

Orolabial HSV (herpes labialis recurrence):

Genital HSV — first episode (any of):

Genital HSV — episodic recurrence:

Suppressive therapy:

HSV encephalitis:

Neonatal HSV: IV acyclovir 20 mg/kg q8h × 14 days (SEM) or 21 days (CNS or disseminated), then oral acyclovir suppression × 6 months to improve neurodevelopmental outcomes.

Severe/disseminated/immunocompromised mucocutaneous HSV: IV acyclovir 5–10 mg/kg q8h until clinical improvement, then oral step-down.

Acyclovir toxicities:

Step 3 management: For any patient starting IV acyclovir, order IV fluids at 1–1.5x maintenance and a baseline + daily creatinine—a renal AKI question with acyclovir nearly always traces to under-hydration or weight-based overdosing.

Expanded Pharmacology — Resistance, Topicals, and Adjuncts

— Mostly via thymidine kinase mutations (loss of viral TK → cannot phosphorylate acyclovir).

— Suspect in immunocompromised patients (HIV/AIDS, HSCT) with non-healing ulcers despite ≥7–10 days of appropriate acyclovir.

— Treatment: foscarnet IV (does not require TK activation; directly inhibits viral DNA polymerase). Toxicities: nephrotoxicity, electrolyte derangements (hypocalcemia, hypomagnesemia, hypokalemia), seizures, genital ulcers.

— Alternative: cidofovir (also TK-independent; severe nephrotoxicity, requires probenecid and saline pre-hydration).

— Topical acyclovir, penciclovir, docosanol cream—minor reduction in herpes labialis duration (~half a day).

— Topical antivirals are inadequate for genital herpes management—use systemic.

— Trifluridine or ganciclovir gel ophthalmic drops for HSV epithelial keratitis (managed by ophthalmology); add oral acyclovir for stromal disease.

— Pain control for primary genital HSV: acetaminophen/NSAIDs, topical lidocaine, sitz baths, voiding in warm water; catheterize for retention.

— Adjunctive dexamethasone in HSV encephalitis: data mixed; not routinely recommended outside trials—may consider for significant cerebral edema. Do not delay acyclovir for steroids.

— Seizure prophylaxis in encephalitis: treat clinical/electrographic seizures with levetiracetam; not routine prophylaxis.

— Acyclovir + nephrotoxins (NSAIDs, aminoglycosides, contrast) → additive AKI.

— Probenecid increases acyclovir levels.

Acyclovir resistance:

Topical agents (limited efficacy; not substitutes for systemic therapy in serious disease):

Adjuncts:

Counseling on outbreak triggers: UV exposure (sunscreen for herpes labialis), stress, illness, menses, trauma.

Vaccines: no licensed HSV vaccine exists; multiple candidates in trials.

Drug interactions:

Key distinction: Acyclovir failure in an immunocompetent host is almost always inadequate dose, late initiation, or poor adherence—true resistance is rare outside immunosuppression. Verify these before switching to foscarnet.

Special Populations — Elderly and Renal/Hepatic Impairment

— Acyclovir is renally cleared; standard doses cause acute crystalline nephropathy and neurotoxicity (encephalopathy, myoclonus, hallucinations, seizures) in CKD/AKI.

— Dose adjust by CrCl:

— CrCl >50: standard q8h

— CrCl 25–50: q12h

— CrCl 10–25: q24h

— CrCl <10 or HD: 50% of dose q24h, give after dialysis (acyclovir is dialyzable)

— Use ideal body weight in obese patients—dosing by total body weight causes overdose and toxicity.

— Hydrate to UOP ≥75–100 mL/hr; infuse over at least 1 hour.

— Daily creatinine while on IV acyclovir.

— Both cause confusion in a treated patient.

— Acyclovir neurotoxicity: occurs in renal impairment, often with myoclonus and tremor, EEG nonspecific, resolves with drug discontinuation ± hemodialysis, no temporal lobe MRI lesion.

— HSV encephalitis: temporal lobe MRI findings, CSF PCR positive.

— Watch for combined nephrotoxins (NSAIDs, ACEi/ARB during AKI, contrast, vancomycin, aminoglycosides).

— Avoid concurrent zoster live vaccine while on chronic antiviral suppression (theoretical—use recombinant Shingrix).

Renal impairment is the highest-yield Step 3 dosing trap with acyclovir:

Acyclovir neurotoxicity vs HSV encephalitis — the differential is the high-yield trap:

Valacyclovir in elderly: associated with TTP/HUS at very high doses in immunocompromised; standard doses safe but adjust for CrCl.

Hepatic impairment: no specific dose adjustment for acyclovir/valacyclovir (renally cleared).

Drug-drug interactions in elderly:

Encephalitis in elderly: bimodal age distribution of HSV encephalitis includes adults >50; outcomes worse with age, delayed treatment, and lower presenting GCS. Aggressive early therapy still warranted regardless of age.

Frailty considerations: long-term suppression is generally safe in elderly with normal renal function; reassess CrCl annually.

Step 3 management: A renally impaired elderly inpatient on IV acyclovir who develops new myoclonus and confusion → check creatinine, hold acyclovir, consider hemodialysis rather than escalating presumed CNS infection workup.

Special Populations — Pregnancy, Pediatrics, and Immunocompromised

— Primary (first-episode) HSV in 3rd trimester is the highest-risk scenario—high viral shedding, no maternal antibodies transferred to neonate → 30–50% vertical transmission risk during vaginal delivery.

— Recurrent HSV at delivery: vertical transmission ~3% (maternal antibodies protective).

— Acyclovir and valacyclovir are safe in pregnancy (category B-equivalent; extensive data).

— Treat any first episode during pregnancy with full-course oral therapy.

— Suppressive therapy from 36 weeks until delivery in any woman with a history of genital HSV (even one prior outbreak) → reduces outbreaks, viral shedding, and C-section rate.

— Cesarean delivery indicated for active genital lesions OR prodromal symptoms at onset of labor.

— Avoid invasive fetal monitoring (scalp electrodes) in women with HSV history.

— Presents days 5–21; SEM, CNS, disseminated patterns.

— High-dose IV acyclovir 20 mg/kg q8h × 14 days (SEM) or 21 days (CNS/disseminated), followed by oral acyclovir suppression × 6 months (improves neurodevelopmental outcomes; monitor ANC—neutropenia risk).

— Mortality: disseminated ~30%, CNS ~6% with treatment; long-term neurologic morbidity high.

— Primary gingivostomatitis: hydration is the main complication driver—admit for IV fluids if poor PO intake.

— Acyclovir within 72 hours shortens course.

— Eczema herpeticum: hospitalize, IV acyclovir, ophtho if periorbital involvement, avoid topical steroids on active lesions.

— Atypical, chronic, ulcerative, sometimes hyperkeratotic lesions.

— Higher rates of dissemination, esophagitis, pneumonitis, hepatitis.

— HSV esophagitis: odynophagia + small volcano-like punched-out ulcers on EGD (vs CMV's deep linear ulcers; vs Candida's white plaques).

— Treat with IV acyclovir; consider chronic suppression. Suspect acyclovir resistance if non-healing → foscarnet.

Pregnancy and genital HSV:

Neonatal HSV:

Pediatric considerations:

Immunocompromised hosts (HIV, transplant, chemo):

Board pearl: A pregnant patient at 38 weeks with active genital vesicles in labor → proceed with C-section, regardless of duration of membrane rupture; document active lesions and counseling.

Complications and Adverse Outcomes

— Bacterial superinfection (Staph/Strep) of denuded skin.

— Urinary retention from sacral autonomic radiculopathy in primary genital HSV (Elsberg syndrome)—may require catheterization.

— Aseptic meningitis with primary genital HSV (often HSV-2): self-limited; treat with IV/oral acyclovir.

— Mollaret meningitis: recurrent benign lymphocytic meningitis, HSV-2 most common cause.

— Proctitis (especially MSM): tenesmus, anorectal pain, discharge.

— Dendritic epithelial keratitis → stromal keratitis → corneal scarring, leading infectious cause of corneal blindness in developed countries.

— Acute retinal necrosis in immunocompromised.

— HSV encephalitis sequelae: anterograde amnesia, anomic/Wernicke aphasia, personality change, complex partial seizures (mesial temporal sclerosis), Klüver-Bucy syndrome (hyperorality, hypersexuality, placidity—bilateral temporal damage).

— Even with timely treatment, ~60% of survivors have residual neurologic deficits.

Mucocutaneous complications:

Ocular complications:

CNS complications:

Disseminated HSV: hepatitis (often anicteric with very high transaminases), pneumonitis, DIC, multi-organ failure—mortality >80% if untreated; classic in pregnancy (3rd trimester) and immunocompromised.

Eczema herpeticum: bacteremia, sepsis, ocular involvement, scarring.

Erythema multiforme: HSV is the most common trigger of recurrent erythema multiforme minor—targetoid lesions 1–2 weeks after HSV outbreak; treat with chronic acyclovir suppression to prevent recurrences.

Bell palsy: HSV-1 reactivation in geniculate ganglion implicated; treat with steroids ± antivirals if severe.

Psychosocial morbidity: depression, anxiety, fear of disclosure, relationship strain—often more impactful than physical symptoms; address explicitly in counseling.

HIV acquisition: genital HSV-2 increases HIV acquisition risk ~3x via mucosal disruption and CD4 trafficking.

Drug complications: acyclovir AKI/neurotoxicity, foscarnet electrolyte derangements and renal failure.

Key distinction: Recurrent erythema multiforme without a clear etiology should prompt HSV suppression trial—even when no preceding lesions are visible—often diagnostic and therapeutic.

When to Escalate Care — ICU, Consults, and Inpatient Triage

— Suspected or confirmed HSV encephalitis (always)

— Neonatal HSV (always)

— Disseminated HSV (any organ involvement: hepatitis, pneumonitis, sepsis)

— Eczema herpeticum with extensive involvement, systemic symptoms, or periocular disease

— Severe primary genital HSV with urinary retention, severe pain, dehydration, or aseptic meningitis with significant headache

— Immunocompromised patients with progressive, ulcerative, or non-healing HSV

— Pregnant patient with primary HSV near term or with systemic disease

— Pediatric gingivostomatitis with inability to maintain hydration

— Encephalitis with GCS ≤8, status epilepticus, signs of elevated ICP, or need for airway protection

— Disseminated HSV with septic shock, DIC, or respiratory failure

— Neonatal disseminated HSV

— Infectious disease: encephalitis, disseminated disease, immunocompromised hosts, acyclovir failure, neonatal HSV, pregnancy management

— Neurology: encephalitis (seizure management, prognostication), EEG interpretation

— Ophthalmology: any ocular HSV—do not initiate topical steroids without ophtho (risk of corneal perforation in epithelial disease)

— Obstetrics: pregnant patient with active lesions at labor onset—delivery planning

— Dermatology: eczema herpeticum, atypical presentations

— Pediatrics/Neonatology: any neonatal HSV

— Tertiary care if no neuro ICU, neurosurgery (rare need for decompression in malignant edema), or pediatric ICU on site.

— Transfer should not delay empiric IV acyclovir—start before transport.

— Completion of IV acyclovir course (14–21 days)

— Hemodynamic and neurologic stability

— Seizure control on a stable regimen

— Rehab disposition plan (likely acute inpatient rehab given cognitive deficits)

Admit to hospital:

ICU criteria:

Consults:

Transfer considerations:

Discharge criteria from encephalitis admission:

CCS pearl: On a CCS case of fever + new aphasia, the highest-yield actions in the first hour are: place IV, draw CSF/blood cultures, start IV acyclovir + broad-spectrum antibiotics, MRI brain, consult ID and neurology; failing to give acyclovir within 6 hours is the single most common scored error.

Key Differentials — Other Causes of Vesicles/Ulcers and Encephalitis

— Syphilis (T. pallidum): painless, indurated, clean-based chancre, non-tender adenopathy; dark-field microscopy, RPR/treponemal serology.

— Chancroid (H. ducreyi): painful, deep, ragged ulcer with purulent base, tender suppurative adenopathy ("buboes"); rare in US.

— Lymphogranuloma venereum (C. trachomatis L1–L3): small painless ulcer that heals → tender, matted inguinal/femoral adenopathy with "groove sign," proctocolitis in MSM.

— Granuloma inguinale/donovanosis (Klebsiella granulomatis): painless, beefy-red, friable ulcers; Donovan bodies on biopsy.

— HSV (your topic): multiple painful vesicles → shallow ulcers, tender bilateral adenopathy, systemic symptoms in primary.

— Aphthous ulcers: non-keratinized mucosa, no vesicles, no systemic symptoms, recurrent.

— Herpangina (coxsackie A): posterior pharynx vesicles, spares gingiva.

— Hand-foot-mouth (coxsackie A16, enterovirus 71): oral ulcers + palmar/plantar lesions.

— Erythema multiforme/SJS: target lesions, drug or HSV trigger, mucosal involvement.

— Primary VZV: diffuse vesicles in different stages of healing (vs HSV's uniform/grouped).

— Arboviral (West Nile, EEE, La Crosse, Powassan): seasonal, mosquito exposure, flaccid paralysis (WNV), basal ganglia/thalamic MRI (WNV/EEE/Japanese).

— Enteroviral: summer/fall, often milder.

— VZV encephalitis/vasculopathy: stroke-like syndrome, often with prior shingles.

— CMV (immunocompromised): periventricular enhancement.

— HIV encephalopathy: subacute dementia.

— Rabies: hydrophobia, animal bite history, near-universal mortality.

Genital ulcer differential (same category — STIs):

Oral ulcer differential:

Encephalitis differential (same category — viral):

Key distinction: Painless genital ulcer = syphilis until proven otherwise; painful grouped vesicles = HSV. Co-testing for both (and HIV) is standard since coinfection is common.

Key Differentials — Non-Infectious and Other-Category Causes

— Behçet disease: recurrent oral AND genital aphthous ulcers + uveitis ± skin pathergy; HLA-B51; biopsy non-specific; HSV PCR negative.

— Lipschütz ulcer: acute genital ulceration in adolescent girls, often after EBV or other viral illness; HSV-negative, self-limited.

— Crohn disease: "knife-cut" linear fissures and fistulae in vulvar/perianal region.

— Fixed drug eruption: recurrent, same-site lesion with drug exposure (NSAIDs, sulfa, tetracyclines).

— Squamous cell carcinoma: chronic non-healing ulcer, indurated edges, biopsy diagnostic.

— Trauma/excoriation: history-dependent.

— Autoimmune encephalitis (anti-NMDA receptor): psychiatric prodrome, orofacial dyskinesias, autonomic instability, seizures, often follows HSV encephalitis (post-infectious autoimmune trigger)—suspect if patient relapses neurologically 2–8 weeks after recovery from HSV encephalitis.

— Paraneoplastic limbic encephalitis (anti-Hu, anti-Ma2): older patients, malignancy workup.

— Hashimoto encephalopathy: anti-TPO antibodies, steroid-responsive.

— Wernicke encephalopathy: ophthalmoplegia, ataxia, confusion; alcohol/malnutrition; treat with thiamine.

— Toxic-metabolic: hepatic, uremic, hyponatremic, hypoglycemic encephalopathy; no focal neurologic findings classically.

— Stroke: sudden onset, focal deficit, no fever.

— Status epilepticus / postictal state: EEG-defined.

— CNS lymphoma, abscess, tumor: ring-enhancing or mass effect on imaging.

— Bullous pemphigoid, pemphigus vulgaris, dermatitis herpetiformis—usually not grouped vesicles on erythematous base; chronicity and biopsy/IF differentiate.

— Contact dermatitis: linear/geographic distribution following exposure.

Non-infectious genital ulcer differential:

Non-infectious encephalopathy/encephalitis differential:

Other vesicular skin differentials:

Board pearl: A patient who improved on acyclovir and then deteriorated with new psychiatric symptoms, dyskinesias, and seizures has anti-NMDA receptor encephalitis post-HSV—send NMDA antibodies and treat with steroids, IVIG, plasmapheresis, ± rituximab. This is increasingly tested.

Secondary Prevention, Discharge Plan, and Long-Term Management

— Lifelong infection with asymptomatic shedding is the rule, not the exception (driver of transmission).

— Disclosure to current and future sexual partners: ethical, often legally relevant in some jurisdictions.

— Condoms reduce transmission but don't eliminate it (lesions on uncovered areas).

— Daily suppressive antivirals reduce transmission ~50% in heterosexual serodiscordant couples.

— Avoid sexual contact during prodrome or active lesions.

— Outbreak frequency typically declines over years.

— ≥6 outbreaks/year, significant psychosocial impact, serodiscordant partnership, immunocompromise, HIV coinfection, recurrent erythema multiforme triggered by HSV, pregnancy from 36 weeks.

— Reassess annually—many can step down to episodic therapy.

— Complete the full 14–21 day IV acyclovir course before discharge (or arrange OPAT if stable for home IV).

— Antiepileptics (levetiracetam most common) if seizures occurred—taper decision by neurology after seizure-free interval.

— Outpatient neurology follow-up within 1–2 weeks.

— Cognitive/speech therapy referrals.

— Watch for post-HSV anti-NMDA receptor encephalitis at 2–8 weeks.

— Test for HIV (offer PrEP if at ongoing risk), syphilis, gonorrhea, chlamydia, hepatitis B/C.

— Hepatitis B vaccination if non-immune.

— HPV vaccination if age-eligible.

— Sun protection (SPF lip balm) for herpes labialis.

— Stress reduction, sleep hygiene.

— Treat eczema aggressively to prevent eczema herpeticum recurrence.

Counseling for genital herpes (cornerstone of long-term management):

Suppressive therapy candidates:

Discharge medications after HSV encephalitis:

STI panel and prevention:

Lifestyle and trigger management:

Recurrent erythema multiforme: chronic acyclovir suppression × 6–12 months.

Step 3 management: Patients on daily valacyclovir suppression for genital HSV should be reassessed annually for ongoing need, partner status, and renal function (basic metabolic panel)—not indefinite refills without review.

Follow-Up, Monitoring, and Counseling Cadence

— Follow-up at 2–4 weeks after first episode to address questions, reinforce counseling, review STI panel results.

— Annual visit if on suppression: review outbreak frequency, side effects, renal function (BMP), reconsider need for ongoing suppression.

— Test of cure not needed.

— Initiate suppression at 36 weeks with valacyclovir 500 mg BID or acyclovir 400 mg TID.

— Examine perineum and ask about prodromal symptoms at onset of labor.

— Postpartum counseling on neonatal HSV signs (lethargy, poor feeding, vesicles, seizures) and strict handwashing if mother has active orolabial lesions.

— Neurology follow-up at 1–2 weeks for seizure management and cognitive assessment.

— Neuropsychological testing at 1–3 months to characterize deficits (memory, language, executive function).

— Speech/language therapy, occupational therapy, cognitive rehabilitation referrals.

— Driving assessment before resumption; counsel about state-specific seizure reporting laws.

— Repeat MRI at 1–3 months to assess residual injury.

— Watch for post-HSV anti-NMDA receptor encephalitis at 2–8 weeks—new psychiatric, movement, or seizure symptoms warrant antibody testing and re-imaging.

— Phone or in-person check at 48–72 hours to confirm adequate hydration and PO intake.

— Resolution expected by 10–14 days.

— HIV testing at diagnosis, repeat in 3 months if exposure ongoing.

— Annual STI screening (gonorrhea, chlamydia, syphilis) if risk factors.

— Hepatitis B vaccine series, HPV vaccine if age-eligible.

— Pap smear per routine guidelines (HSV does not alter cervical cancer screening cadence).

Uncomplicated genital herpes (outpatient):

Pregnancy with HSV history:

HSV encephalitis post-discharge:

Pediatric gingivostomatitis:

Ocular HSV: ophthalmology follow-up at 1 week then every few weeks; long-term recurrence risk warrants chronic acyclovir 400 mg BID after stromal keratitis.

Vaccinations and screening to address at follow-up:

Patient education materials: written, language-appropriate; address disclosure, transmission, suppression options.

Board pearl: A child recovering from HSV encephalitis with new dystonia and behavioral regression 4 weeks later → send anti-NMDA receptor antibodies (serum + CSF) and start immunotherapy; do not assume "residual" encephalitis damage.

Ethical, Legal, and Patient Safety Considerations

— HSV is not a reportable STI in most US jurisdictions (unlike syphilis, gonorrhea, chlamydia, HIV).

— Strongly encourage patient-led disclosure to current and future sexual partners; some states permit civil liability for known nondisclosure with transmission.

— Document counseling about transmission risk, asymptomatic shedding, and suppression options.

— In most states, minors can consent to STI diagnosis and treatment without parental consent—know your state's law.

— Confidentiality protections may be breached by EHR portal disclosures or insurance EOBs; counsel adolescents about these limits.

— Suspected child sexual abuse (e.g., genital HSV in a prepubescent child without clear non-sexual transmission route) triggers mandated reporting to child protective services.

— Neonatal HSV requires careful tracing of maternal exposure but is not itself reportable as abuse.

— Pregnant patient declining recommended C-section for active genital HSV at term: respect autonomy after thorough documentation of risk discussion (neonatal HSV mortality, disseminated risk), offer ethics consult; ultimately patient retains decision-making capacity unless impaired.

— Patient with encephalitis lacking capacity → identify surrogate decision-maker per state hierarchy; obtain consent for LP, intubation, and procedures from surrogate; document.

— HSV encephalitis survivors with cognitive impairment have high readmission and medication error risk; ensure med reconciliation, caregiver education, and clear seizure action plan at discharge.

— IV acyclovir patients transitioning to outpatient parenteral therapy (OPAT): set up weekly CBC, BMP, and home health monitoring; clear escalation criteria.

— Verify weight-based acyclovir dosing using ideal body weight in obesity—a high-risk medication error.

— Ensure adequate hydration order (1–1.5x maintenance) and infusion over ≥1 hour to prevent crystalline nephropathy.

— Healthcare worker with herpetic whitlow: restrict from direct patient contact, especially with neonates and immunocompromised, until lesions crusted.

Confidentiality and partner notification:

Adolescent confidentiality:

Mandatory reporting overlap:

Informed consent edge cases:

Transition-of-care safety:

Patient safety in inpatient orders:

Occupational exposures:

Step 3 management: A pregnant patient with active genital lesions at term who refuses C-section requires documented capacity assessment, ethics consult, neonatology counseling, and detailed informed-refusal documentation—you do not override maternal autonomy for fetal benefit in the US.

High-Yield Associations and Rapid-Fire Clinical Facts

HSV-1: trigeminal ganglion latency; orolabial classic, but causes >50% of new genital HSV in young US adults; encephalitis classically HSV-1.

HSV-2: sacral ganglion latency; genital classic; aseptic meningitis (Mollaret), neonatal disease more often.

Test of choice: lesion PCR; CSF PCR for encephalitis (95% sens, 99% spec).

Imaging signature of HSV encephalitis: bilateral asymmetric medial temporal lobe + inferior frontal + insular T2/FLAIR hyperintensity, often hemorrhagic.

CSF signature of HSV encephalitis: lymphocytic pleocytosis + elevated RBCs/xanthochromia + elevated protein + positive HSV PCR.

EEG: PLEDs over temporal lobe.

Empiric therapy: IV acyclovir 10 mg/kg q8h × 14–21 days for encephalitis—do not delay for PCR.

Acyclovir AKI: crystalline nephropathy; prevent with hydration, slow infusion, IBW dosing in obese.

Acyclovir neurotoxicity: tremor, myoclonus, confusion in renal failure → distinguish from worsening encephalitis.

Resistance: thymidine kinase mutation in immunocompromised → foscarnet (nephrotoxic, electrolyte derangements).

Pregnancy: any history → suppression from 36 weeks; active lesions/prodrome at labor → C-section.

Neonatal HSV: IV acyclovir 20 mg/kg q8h × 14 (SEM) or 21 (CNS/disseminated) days, then oral suppression × 6 months.

Gingivostomatitis (HSV) vs herpangina (coxsackie): anterior + gingival vs posterior pharynx.

HSV vs aphthous: keratinized mucosa with vesicles vs non-keratinized without vesicles.

Painless genital ulcer → syphilis; painful → HSV (or chancroid: deep, suppurative adenopathy).

Dendritic corneal ulcer on fluorescein = HSV keratitis; never start topical steroids without ophthalmology.

Eczema herpeticum: monomorphic punched-out erosions in atopic dermatitis → IV acyclovir.

Recurrent erythema multiforme → suspect HSV trigger → suppression.

Bell palsy: HSV-1 in geniculate ganglion implicated; treat with steroids ± antivirals.

Post-HSV encephalitis relapse with psychiatric/movement symptoms → anti-NMDA receptor encephalitis.

No vaccine available; condoms partially protective; chronic suppression reduces transmission ~50%.

HSV-2 + HIV: ~3-fold increased HIV acquisition; co-test always.

Board pearl: Hemorrhagic temporal lobe lesion + fever + aphasia = HSV-1 encephalitis—the single most testable image-stem in this topic.

Board Question Stem Patterns

— Best next step: IV acyclovir 10 mg/kg q8h immediately; confirm with CSF HSV PCR.

— Cause: crystalline nephropathy from inadequate hydration / dosing on total body weight in obesity.

— Action: increase IV fluids, slow infusion, redose by IBW, recheck Cr.

— Action: check renal function, renally adjust acyclovir, consider hemodialysis; do not escalate antibiotics.

— Action: cesarean delivery.

— Action: treat with oral acyclovir/valacyclovir × 7–10 days; plan suppression from 36 weeks.

— Diagnosis: primary syphilis (not HSV); RPR/treponemal test; treat with benzathine penicillin G 2.4 million units IM × 1.

— Action: chronic acyclovir suppression.

— Diagnosis: anti-NMDA receptor encephalitis; treat with steroids, IVIG, plasmapheresis, ± rituximab.

— Action: IV acyclovir, admit, ophthalmology if periorbital, avoid topical steroids on lesions.

— Action: foscarnet; monitor renal function, electrolytes (Ca/Mg/K).

Stem 1 — Encephalitis classic: 55-year-old with 3 days of fever, headache, then word-finding difficulty and a witnessed focal seizure; MRI shows bilateral asymmetric temporal lobe edema with hemorrhage; CSF: WBC 80 (90% lymphs), RBC 200, protein 90, glucose 60.

Stem 2 — Acyclovir AKI: Patient on IV acyclovir for encephalitis develops Cr rise from 0.9 to 2.4 on day 3.

Stem 3 — Acyclovir neurotoxicity vs disease progression: CKD patient on standard-dose IV acyclovir develops new myoclonus and confusion.

Stem 4 — Pregnancy at term: 38-week pregnant patient with history of recurrent genital HSV presents in labor with prodromal vulvar tingling and a small vesicle.

Stem 5 — First-trimester management: pregnant patient with first episode of genital HSV at 14 weeks.

Stem 6 — Painful vs painless ulcer: young man with single painless indurated genital ulcer and non-tender inguinal node.

Stem 7 — Recurrent EM: patient with recurrent target lesions every few months after lip "cold sores".

Stem 8 — Post-HSV encephalitis relapse: child recovered from HSV encephalitis returns 5 weeks later with psychiatric symptoms, orofacial dyskinesias, and seizures.

Stem 9 — Eczema herpeticum: child with atopic dermatitis develops monomorphic punched-out erosions, fever.

Stem 10 — Acyclovir-resistant HSV in HIV: AIDS patient with CD4 30 has chronic non-healing perianal ulcer despite 14 days IV acyclovir.

Step 3 management: Recognize the decision phrasing—"best next step" with fever + AMS + focal findings is always start IV acyclovir before imaging and LP.

One-Line Recap

Herpes simplex virus is a lifelong, latency-establishing neurotropic alphaherpesvirus whose orolabial, genital, ocular, neonatal, and encephalitic presentations are diagnosed primarily by PCR and treated with acyclovir/valacyclovir—with immediate empiric IV acyclovir for any suspected encephalitis or neonatal disease being the single highest-yield action.

— Mucocutaneous: lesion PCR (gold standard); typing distinguishes HSV-1 vs HSV-2 for recurrence counseling.

— Encephalitis: CSF HSV PCR + temporal-lobe MRI; CSF often shows lymphocytic pleocytosis with elevated RBCs.

— Never delay empiric therapy for confirmatory testing.

— Genital/orolabial: oral valacyclovir/acyclovir/famciclovir, episodic or suppressive.

— Encephalitis: IV acyclovir 10 mg/kg q8h × 14–21 days.

— Neonatal: IV acyclovir 20 mg/kg q8h × 14–21 days, then oral suppression × 6 months.

— Pregnancy: suppression from 36 weeks; C-section for active lesions or prodrome at labor.

— Renal dosing, IBW dosing in obesity, and aggressive hydration prevent crystalline nephropathy and neurotoxicity.

— Acyclovir-resistant HSV (immunocompromised) → foscarnet.

— Painful grouped vesicles (HSV) vs painless indurated ulcer (syphilis) vs painful deep ulcer with suppurative buboes (chancroid).

— HSV gingivostomatitis (anterior + gingiva) vs herpangina (posterior pharynx).

— Recurrent erythema multiforme → consider HSV trigger and suppress.

— Post-HSV encephalitis relapse with psychiatric/movement symptoms → anti-NMDA receptor encephalitis.

Diagnosis:

Treatment essentials:

High-yield distinctions:

Board pearl: The instant a stem combines fever, altered mentation, and any focal neurologic feature, your reflex order is empiric IV acyclovir—this single decision drives the correct answer on most HSV encephalitis vignettes and is the cornerstone Step 3 CCS action for this topic.