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Summary Table

Domain	Detail
Risk Factors	Neonates (HSV-2 via vertical transmission), young adults and elderly (HSV-1 reactivation), immunocompromised patients (HIV/AIDS, transplant recipients), no prior history of cold sores is required
Etiology	HSV-1 in adults and older children (most common cause of sporadic fatal encephalitis); HSV-2 in neonates
Patient Presentation	Acute onset fever, altered mental status, bizarre behavior, seizures (often focal), headache developing over days
Classic Physical Exam	Fever with focal neurologic deficits (aphasia, hemiparesis), personality changes, temporal lobe seizures, +/- nuchal rigidity
Key Diagnostic Results	CSF: lymphocytic pleocytosis, elevated protein, normal glucose, RBCs or xanthochromia; CSF PCR for HSV DNA is the confirmatory test; MRI showing temporal lobe hyperintensity on T2/FLAIR
Management	IV acyclovir started empirically before confirmatory results return; do not wait for PCR
Keywords	"Temporal lobe," "bizarre behavior," "personality changes," "hemorrhagic CSF," "focal seizures," "lymphocytic pleocytosis with RBCs"

1. Pathophysiology

HSV encephalitis is the most common cause of sporadic (non-epidemic) fatal encephalitis in the United States and worldwide. Understanding its tropism is the key to unlocking every question about this disease.

HSV-1 has a strong predilection for the temporal lobes and the inferior frontal lobes. The virus typically reaches the brain through retrograde axonal transport along the olfactory nerve (CN I) or the trigeminal nerve (CN V), both of which have anatomic projections to the temporal and orbitofrontal regions. This is not a random infection of the brain parenchyma; it is a targeted, necrotizing process that destroys temporal lobe tissue preferentially.

This tropism directly explains the clinical picture. The temporal lobes house structures critical for memory (hippocampus), language (Wernicke's area in the dominant hemisphere), and emotional processing (amygdala and limbic cortex). When these structures undergo hemorrhagic necrosis, the patient develops the hallmark triad of fever, altered mental status, and focal neurologic deficits referable to the temporal lobe. Personality changes, olfactory hallucinations, aphasia, and complex partial seizures all trace back to destruction of these regions.

The hemorrhagic nature of the necrosis is what distinguishes HSV encephalitis pathologically from most other viral encephalitides. The virus causes direct cytolytic damage to neurons and glia, triggering an intense inflammatory response with perivascular cuffing, microglial activation, and petechial hemorrhages. This is why the CSF frequently contains red blood cells or xanthochromia in addition to the expected lymphocytic pleocytosis, a finding that should immediately raise suspicion for HSV encephalitis on an exam vignette.

In neonates, the mechanism differs. HSV-2 is acquired during passage through an infected birth canal. The immature immune system allows widespread dissemination, and the encephalitis tends to be more diffuse rather than temporally localized, often presenting as part of a disseminated neonatal HSV syndrome with skin vesicles, hepatitis, and DIC.

In adults, roughly two-thirds of cases represent reactivation of latent HSV-1 residing in the trigeminal ganglion, rather than primary infection. This is why a prior history of oral herpes (cold sores) is neither required nor reliably present. The absence of a herpes history should never be used to exclude HSV encephalitis.

2. Classification and Clinical Manifestation

By Age Group and Viral Subtype

Feature	Neonatal HSV Encephalitis	Adult/Child HSV Encephalitis
Causative Agent	HSV-2 (occasionally HSV-1)	HSV-1 (>90% of cases)
Mechanism	Primary infection via birth canal	Reactivation from trigeminal ganglion (two-thirds); primary infection (one-third)
Brain Involvement	Diffuse, multifocal	Focal: temporal and inferior frontal lobes
Presentation	Lethargy, seizures, poor feeding, vesicular rash, temperature instability	Fever, personality change, aphasia, focal seizures, altered consciousness
Associated Findings	Skin-eye-mouth (SEM) vesicles, hepatitis, coagulopathy	Temporal lobe signs; mucocutaneous lesions often absent
Mortality (untreated)	>80%	~70%
Mortality (with acyclovir)	~30%	~20-30%

Clinical Stages of Progression (Adults)

Stage	Timeline	Clinical Features
Prodromal	Days 1-4	Fever, headache, malaise, subtle behavioral changes
Early Focal	Days 4-7	Aphasia, olfactory/gustatory hallucinations, personality changes, focal seizures
Progressive	Days 7-14	Deepening obtundation, status epilepticus, hemiparesis, increased ICP
Late/Severe	Beyond 14 days	Coma, herniation, death if untreated

The exam will most commonly present a patient in the early focal stage, where behavioral oddities and language dysfunction should trigger immediate suspicion. A vignette describing a previously healthy adult with acute onset fever, confusion, and "strange behavior" or "word-finding difficulty" is the classic setup.

3. Diagnostic Workup

Test	Role	Key Findings
Lumbar Puncture with CSF PCR for HSV DNA	Gold standard / most accurate test	Sensitivity 96-98%, specificity >99%; may be negative in first 24-72 hours
CSF analysis (cell count, protein, glucose)	Supportive	Lymphocytic pleocytosis (10-500 WBC), elevated protein (60-700 mg/dL), normal glucose, RBCs or xanthochromia
MRI Brain (T2/FLAIR)	Best initial imaging test	Hyperintensity in medial temporal lobes, insula, inferior frontal gyri; often asymmetric
CT Head	Rapid triage / rule out mass effect before LP	May be normal early; later shows hypodensity in temporal lobes
EEG	Supportive	Periodic lateralized epileptiform discharges (PLEDs) from the temporal region
Brain biopsy	Historical gold standard; rarely performed now	Reserved for PCR-negative cases with high clinical suspicion and no treatment response

When the exam presents a patient with fever, altered mental status, and focal neurologic signs, the workup follows a logical sequence.

Step 1: Obtain neuroimaging before lumbar puncture if there is concern for elevated intracranial pressure (papilledema, focal deficits, altered consciousness). A CT head is done first to rule out a mass lesion or significant edema that would make LP dangerous. However, CT is often normal in the first 3-5 days of HSV encephalitis, so a normal CT does not exclude the diagnosis.

Step 2: Perform lumbar puncture. The CSF profile in HSV encephalitis is characterized by lymphocytic pleocytosis with elevated protein and a normal glucose. This pattern is shared with other viral meningitides, but the presence of red blood cells or xanthochromia in the CSF, reflecting the hemorrhagic necrosis, is a strong discriminator. The combination of a "viral-pattern CSF" plus RBCs in a febrile patient with temporal lobe signs should lock in HSV encephalitis as the leading diagnosis.

Step 3: Order CSF PCR for HSV DNA. This is the most accurate (confirmatory) test. It has replaced brain biopsy as the gold standard. One critical caveat for exam purposes: PCR can be falsely negative in the first 24-72 hours of illness. If clinical suspicion remains high despite an initial negative PCR, the test should be repeated in 3-7 days. A negative PCR result should never be used as the sole reason to withhold or discontinue acyclovir in a patient with a compatible clinical picture.

Step 4: MRI brain. If obtainable, MRI with T2-weighted and FLAIR sequences is far superior to CT. The classic finding is asymmetric hyperintensity in the medial temporal lobes, insular cortex, and orbitofrontal gyri. This finding on MRI, combined with the clinical picture, is essentially diagnostic even before the PCR returns. On diffusion-weighted imaging (DWI), restricted diffusion in these regions may appear even earlier than T2/FLAIR changes.

Step 5: EEG. While not diagnostic on its own, EEG showing periodic lateralized epileptiform discharges (PLEDs) originating from the temporal lobe strongly supports the diagnosis, particularly in a comatose patient where clinical seizure activity may be subtle.

The overriding principle for exam questions: Do not wait for confirmatory results before treating. The moment HSV encephalitis enters the differential, empiric IV acyclovir must be initiated.

4. Management and Treatment

Phase	Intervention	Details
Empiric / Acute	IV Acyclovir	10 mg/kg IV every 8 hours for 14-21 days in adults; 20 mg/kg IV every 8 hours for 21 days in neonates
Seizure Management	Antiepileptic drugs	Levetiracetam or phenytoin/fosphenytoin for acute seizures; avoid prophylactic AEDs without seizure activity
Supportive	ICU-level care	Airway protection, ICP management, fluid/electrolyte monitoring
After Completion	Repeat CSF PCR	If still positive, extend IV acyclovir; oral valacyclovir suppression considered in neonates
Renal Protection	Aggressive IV hydration	Acyclovir is nephrotoxic (crystalline nephropathy); maintain high urine output

The single most important management principle tested on exams is this: IV acyclovir must be started immediately upon clinical suspicion, before any confirmatory test results are available. Every hour of delay in treatment increases mortality and neurological morbidity. This is the "next best step" that exam questions are built around.

IV acyclovir is dosed at 10 mg/kg intravenously every 8 hours in adults and children over 12 years, infused over 1 hour. The standard duration is 14 to 21 days. In neonates, the dose is higher at 20 mg/kg IV every 8 hours for a minimum of 21 days, reflecting both the higher viral burden and the tolerability profile in this population. Following completion of IV therapy, neonates are typically transitioned to oral acyclovir suppressive therapy (300 mg/m² three times daily for 6 months) to reduce the risk of cutaneous and neurologic relapse.

Monitoring during treatment requires attention to renal function. Acyclovir can precipitate in renal tubules, causing crystalline nephropathy and acute kidney injury. This risk is mitigated by ensuring adequate IV hydration before and during each infusion, and by monitoring serum creatinine every 2-3 days. If renal impairment develops, the dose must be adjusted based on creatinine clearance. This is a commonly tested side effect.

Seizure management follows standard acute seizure protocols. If seizures occur, IV benzodiazepines are first-line for acute termination, followed by a maintenance antiepileptic such as levetiracetam or fosphenytoin. Routine prophylactic antiepileptic therapy without documented seizure activity is not standard practice.

At the end of treatment (day 14-21), current guidelines recommend obtaining a repeat CSF PCR for HSV DNA. If the PCR remains positive, IV acyclovir should be extended until the CSF PCR converts to negative. This step is more commonly tested in neonatal scenarios.

Contraindications and adjustments: In patients with renal insufficiency, acyclovir dosing must be reduced. There are no absolute contraindications to acyclovir when HSV encephalitis is suspected, even in pregnancy (acyclovir is Category B and has an established safety profile in pregnant women). The exam may test whether a student hesitates to treat a pregnant patient. The answer is always to treat.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Bacterial meningitis	Fever, headache, altered mental status, nuchal rigidity	CSF shows neutrophilic pleocytosis with low glucose and very high protein; no focal temporal lobe signs; Gram stain/culture positive
Autoimmune (anti-NMDA receptor) encephalitis	Young patient with psychiatric symptoms, seizures, altered behavior	Subacute onset over weeks; prominent psychiatric features (psychosis, catatonia) and dyskinesias; CSF may show lymphocytic pleocytosis but PCR is negative; associated with ovarian teratoma in young women
Temporal lobe epilepsy	Focal seizures, bizarre behavior, deja vu, automatisms	Afebrile; chronic/recurrent course; MRI may show mesial temporal sclerosis, not acute edema; no CSF pleocytosis
Brain abscess	Fever, focal deficits, altered mental status	Ring-enhancing lesion on contrast CT/MRI; often follows sinusitis, otitis, dental infection, or endocarditis; CSF may show mixed pleocytosis; LP often contraindicated due to mass effect
Arboviral encephalitis (West Nile, Eastern equine)	Fever, encephalitis, CSF lymphocytic pleocytosis	Seasonal (summer/fall); mosquito exposure history; may affect basal ganglia/thalami rather than temporal lobes; no hemorrhagic CSF
Tuberculous meningitis	Subacute meningitis, lymphocytic CSF, cranial nerve palsies	Low CSF glucose (unlike HSV); very high CSF protein; basilar meningeal enhancement on MRI; chronic course over weeks; risk factors (endemic area, immunocompromise)
CNS lymphoma	Focal neurologic deficits, ring-enhancing lesion on imaging	Subacute/chronic course; periventricular location; associated with severe immunocompromise (CD4 <50); biopsy diagnostic
Toxoplasmosis	Focal deficits and ring-enhancing lesions in immunocompromised host	Multiple ring-enhancing lesions in basal ganglia; CD4 count typically <100; responds to empiric pyrimethamine + sulfadiazine

The most commonly tested differential pairing on exams is HSV encephalitis vs. bacterial meningitis. The pivotal distinction is the CSF glucose: normal in HSV, low in bacterial meningitis. Additionally, HSV produces focal temporal lobe findings (aphasia, personality changes, temporal seizures) while bacterial meningitis produces diffuse meningeal irritation without localizing features early on.

The second most dangerous distractor is anti-NMDA receptor encephalitis, which increasingly appears in exam items. The timeline separates them: HSV encephalitis progresses over days, while anti-NMDA receptor encephalitis evolves over weeks with prominent psychiatric and movement disorder features.

6. Traps and High-Yield Pearls

The number one trap with HSV encephalitis questions is hesitation. The entire construct of these questions tests whether you will act on clinical suspicion before diagnostic confirmation. A vignette will present a classic picture and then give you answer choices that include "wait for CSF PCR results," "obtain MRI before starting treatment," or "observe and repeat exam in 12 hours." Every one of these is wrong. The correct answer is start IV acyclovir immediately. Untreated HSV encephalitis carries a mortality rate of approximately 70%, and even survivors suffer devastating neurologic sequelae. No test result justifies delaying treatment.

The second common trap involves the falsely negative early PCR. A question may describe a patient treated empirically with acyclovir whose initial CSF PCR comes back negative. A careless student will choose "discontinue acyclovir." The correct answer is to continue acyclovir and repeat the PCR in 3-7 days, because PCR sensitivity is reduced in the first 72 hours of illness.

The third trap tests awareness that mucocutaneous herpes lesions are often absent. Only about 10% of patients with HSV encephalitis have concurrent oral or genital lesions. The absence of cold sores does not reduce the probability of the diagnosis.

Finally, watch for the renal side effect question. A patient on IV acyclovir who develops a rising creatinine is experiencing crystalline nephropathy. The management is dose adjustment and aggressive hydration, not discontinuation of the drug unless the clinical picture no longer supports HSV encephalitis.

The core competency being tested across all HSV encephalitis questions is the ability to recognize a temporal lobe syndrome in the setting of acute febrile illness, commit to empiric treatment without delay, and interpret CSF findings that combine a viral pattern with hemorrhagic features.

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