Viral Encephalitis

1. Overview

Viral encephalitis is acute inflammation of the brain parenchyma caused by direct viral invasion, resulting in neuronal damage, cerebral oedema, and potential long-term neurological sequelae. It is fundamentally distinct from meningitis—while meningitis affects the meninges with predominant features of headache, photophobia, and neck stiffness with preserved cognition, encephalitis affects the brain substance itself, manifesting primarily as altered mental status, seizures, and focal neurological deficits. [1]

Viral encephalitis represents a neurological emergency with significant morbidity and mortality. The incidence ranges from 3.5 to 7.4 per 100,000 person-years in temperate climates, with higher rates in tropical regions due to arboviral infections. [2] Despite extensive investigation, approximately 40-60% of encephalitis cases remain of unknown aetiology even after comprehensive diagnostic workup. [3]

Herpes Simplex Virus Type 1 (HSV-1) is the most common identified cause of sporadic, severe viral encephalitis in developed countries, accounting for 10-20% of all cases. Without treatment, HSV encephalitis carries a mortality exceeding 70%, but with early initiation of intravenous aciclovir, mortality can be reduced to 10-20%, making prompt empirical treatment a clinical imperative. [4] The key clinical principle is: empirical IV aciclovir must be started immediately on clinical suspicion—before CSF results, and often before lumbar puncture itself if there is any delay in performing the procedure.

The clinical presentation combines systemic features (fever, malaise) with progressive neurological dysfunction. The triad of fever, headache, and altered mental status is present in the majority of cases, but the hallmark feature distinguishing encephalitis from meningitis is the prominence of cognitive and behavioural disturbance. [5] Patients may present with confusion, personality change, acute psychosis, memory impairment, speech disturbance, or declining level of consciousness. Seizures occur in 50-75% of cases, often focal in nature, and status epilepticus may develop. [6]

Diagnosis relies on clinical suspicion, CSF analysis (lymphocytic pleocytosis with PCR for viral pathogens), and neuroimaging (MRI showing characteristic patterns such as temporal lobe involvement in HSV). Prognosis depends critically on time to treatment: every hour of delay in starting aciclovir increases the risk of poor neurological outcome. [7] Long-term sequelae include memory impairment, epilepsy, personality change, and dysexecutive syndrome, affecting more than 50% of survivors. [8]

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2. Epidemiology

Incidence and Prevalence

The annual incidence of viral encephalitis varies geographically and by population:

Age and Sex Distribution

• Bimodal age distribution:
  • "First peak: Children less than 1 year (immature immunity)"
  • "Second peak: Adults >65 years (immunosenescence)"
• Sex: Slight male predominance (M:F ratio ~1.5:1) [2]

Aetiology by Causative Organism

The causative organism varies significantly by geographical region, patient age, immune status, and season.

Common Causes in Developed Countries

Arboviral Encephalitis (Mosquito/Tick-borne)

Geography-dependent:

• Japanese Encephalitis Virus (JEV): Leading cause in South/Southeast Asia (~68,000 cases annually; 20-30% mortality) [11]
• West Nile Virus (WNV): USA, Africa, Middle East, Europe (peak summer months)
• Tick-borne Encephalitis (TBE): Central/Eastern Europe, Russia
• Dengue: Tropical Americas, Asia, Africa
• Zika Virus: Americas (associated with Guillain-Barré syndrome and congenital microcephaly)

Emerging Pathogens

• Nipah Virus: Southeast Asia (Bangladesh, India); fruit bat reservoir; 40-70% mortality [12]
• SARS-CoV-2: Rare neuroinvasive disease; associated with acute COVID-19 or post-infectious syndromes

Seasonal Variation

• Enteroviruses: Summer and early autumn
• Arboviruses: Summer (mosquito breeding season)
• Influenza: Winter months
• HSV/VZV: No clear seasonal pattern

Risk Factors

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3. Aetiology & Pathophysiology

Mechanisms of Viral Neuroinvasion

Viruses reach the central nervous system through several routes:

1. Haematogenous Spread (most common):

   • Primary viraemia → endothelial infection → blood-brain barrier (BBB) disruption → CNS entry
   • Examples: Enteroviruses, arboviruses, HIV

2. Neuronal Retrograde Transmission:

   • Peripheral nerve infection → axonal transport → CNS
   • Examples: HSV-1 (trigeminal nerve), Rabies (motor neurons), VZV (dorsal root ganglia)

3. Direct Extension:

   • From adjacent structures (sinuses, middle ear)
   • Rare in viral encephalitis

4. Olfactory Route:

   • Via olfactory epithelium → olfactory bulb
   • Postulated for some neurotropic viruses

HSV-1 Pathogenesis: The Temporal Lobe Paradigm

HSV-1 encephalitis exemplifies viral neurotropism and provides a model for understanding viral CNS disease:

Latency and Reactivation

1. Primary Infection: Usually occurs in childhood (oral HSV-1 infection—"cold sores")
2. Latency: Virus establishes latency in the trigeminal ganglion (sensory nerve nuclei)
3. Reactivation: In ~1 in 250,000-500,000 individuals, HSV-1 reactivates and travels retrogradely along the trigeminal nerve branches into the brain [13]

Exam Detail: Why the Temporal Lobes?

The anatomical explanation for HSV-1's predilection for the medial temporal and inferior frontal lobes relates to the tentorial branch of the trigeminal nerve, which provides sensory innervation to the dura overlying these regions. Retrograde viral transport along these fibres allows direct access to the temporal fossa. [14]

Additionally, HSV-1 exhibits tropism for limbic structures (hippocampus, amygdala, cingulate gyrus) possibly related to:

• High expression of viral entry receptors (nectin-1, HVEM) in limbic neurons
• Regional variations in immune surveillance
• Metabolic vulnerability of temporal lobe structures

Neuropathology

• Haemorrhagic Necrosis: HSV causes direct cytopathic destruction of neurons, oligodendrocytes, and astrocytes
• Inflammatory Response: Microglial activation, lymphocytic infiltration, cytokine release (TNF-α, IL-6)
• Cerebral Oedema: Cytotoxic (neuronal swelling) and vasogenic (BBB breakdown)
• Asymmetric Involvement: Often unilateral or bilateral asymmetric temporal lobe involvement

VZV Encephalitis and Vasculopathy

Varicella Zoster Virus causes two distinct CNS syndromes:

1. VZV Encephalitis: Direct parenchymal infection
2. VZV Vasculopathy: Infection of cerebral arteries → inflammation, thrombosis, stroke

VZV Vasculopathy typically affects medium and large cerebral arteries (often MCA territory), causing ischaemic or haemorrhagic stroke. It may occur without dermatomal rash (zoster sine herpete) in up to 30% of cases, making diagnosis challenging. [15] CSF VZV PCR may be negative; detection of anti-VZV IgG antibodies in CSF or VZV DNA in cerebral arteries is diagnostic.

Enteroviral Neuroinvasion

Enteroviruses (Coxsackievirus, Echovirus) are the most common cause of aseptic meningitis and occasionally cause encephalitis, particularly in neonates and young children:

• Route: Faecal-oral transmission → GI replication → viraemia → CNS spread
• Pathology: Predominantly lymphocytic meningitis; encephalitis less common
• Severity: Generally milder than HSV; mortality less than 1% in immunocompetent hosts

Arboviral Encephalitis Pathophysiology

Arboviruses (arthropod-borne viruses) such as Japanese Encephalitis Virus, West Nile Virus, and Tick-borne Encephalitis Virus share common pathogenic mechanisms:

• Transmission: Mosquito/tick bite → local replication in skin/lymph nodes → viraemia
• CNS Invasion: Cross BBB via infected monocytes or direct endothelial infection
• Tropism: Predilection for basal ganglia, thalamus, brainstem, and spinal cord (distinct from HSV's temporal predilection)
• Immunopathology: Severe cases associated with cytokine storm (IL-6, TNF-α) [16]

Immune-Mediated Damage

While direct viral cytopathic effects cause neuronal destruction, much of the CNS damage in viral encephalitis results from the host immune response:

• CD8+ T-cell-mediated cytotoxicity
• Microglial activation and neuroinflammation
• Complement activation
• Excitotoxicity from glutamate release
• Blood-brain barrier (BBB) disruption: Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines activate cerebral endothelial cells, alter tight junction proteins (claudins, occludin), and increase BBB permeability [30,31]
• Cytokine storm: In severe arboviral encephalitis (JEV, WNV), excessive production of pro-inflammatory cytokines contributes to neuronal injury and cerebral oedema [32]

This dual mechanism (viral + immune) explains why some patients deteriorate despite virological control with antivirals.

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4. Clinical Presentation

The Clinical Triad

The classic triad of viral encephalitis:

1. Fever (70-100% of cases)
2. Headache (80-90%)
3. Altered Mental Status (nearly 100% by definition)

However, altered mental status is the cardinal and defining feature. [5]

Spectrum of Altered Mental Status

Clinical Pearl: "The Psychiatric Presentation"

A young person (age 15-35) presenting to the emergency department with acute onset psychosis, agitation, or bizarre behaviour in the context of fever or recent flu-like illness has encephalitis (viral or autoimmune) until proven otherwise.

DO NOT refer to psychiatry without excluding encephalitis:

• Check temperature
• Perform cognitive assessment (AMT-10, MoCA, serial 7s)
• Look for subtle neurological signs (dysphasia, tremor, myoclonus, ataxia)
• Arrange urgent CT head and LP

Missing encephalitis in this scenario is a medicolegal disaster. [17]

Focal Neurological Signs: The Temporal Lobe Syndrome (HSV)

Because HSV-1 has a predilection for the medial temporal lobes and inferior frontal lobes, it produces a characteristic clinical syndrome:

Temporal Lobe Features

• Dysphasia: Wernicke's aphasia (if dominant hemisphere involved)—fluent but nonsensical speech, impaired comprehension
• Memory Impairment: Acute amnesia (hippocampal damage); inability to form new memories (anterograde amnesia)
• Olfactory/Gustatory Hallucinations: "Smelling burning rubber"
  • "metallic taste" (uncinate fits—temporal lobe epilepsy)
• Behavioural/Personality Change: Aggression, hypersexuality, disinhibition (involvement of amygdala and orbitofrontal cortex)

Frontal Lobe Features

• Executive Dysfunction: Poor planning, impulsivity, perseveration
• Apathy: Lack of motivation, abulia

Seizures

Seizures are present in 50-75% of cases of viral encephalitis, and are particularly common in HSV encephalitis due to involvement of the highly epileptogenic frontotemporal cortex: [6,33]

• Type: Focal seizures ± secondary generalisation (reflecting focal pathology)
• Semiology: Temporal lobe seizures (automatisms, lip-smacking, déjà vu, olfactory auras), motor seizures
• Status Epilepticus: Occurs in 10-20% of cases; associated with worse prognosis
• Non-convulsive Status Epilepticus (NCSE): Prolonged altered mental status without overt convulsions; requires EEG for diagnosis

Other Neurological Signs

Systemic Features

• Fever: Usually moderate-high (38-40°C), but may be absent in immunosuppressed or elderly patients
• Rash:
  • Vesicular rash in VZV (but may be absent in VZV vasculopathy)
  • Maculopapular rash in arboviral infections (dengue, Zika)
• Respiratory symptoms: Influenza-associated encephalitis
• Lymphadenopathy/hepatosplenomegaly: EBV, CMV

Disease Progression

Typical Timeline (HSV Encephalitis as exemplar):

• Days 1-3: Prodrome—fever, malaise, headache, mild confusion
• Days 3-7: Neurological deterioration—worsening confusion, seizures, focal deficits
• Days 7-14: Peak severity—coma, status epilepticus, cerebral oedema, herniation (if untreated)

Early treatment with aciclovir (within first 48-72 hours) dramatically alters this trajectory. [7]

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5. Differential Diagnosis

Must-Not-Miss Diagnoses

Autoimmune Encephalitis (The Great Mimic)

Autoimmune encephalitis frequently mimics viral encephalitis and must be actively considered, especially in young patients (age 15-40) with psychiatric features:

Anti-NMDA Receptor Encephalitis

"Brain on Fire" syndrome [18]:

• Demographics: Young females (F:M = 4:1); median age 21
• Prodrome: Flu-like illness (60%)
• Progression:
  1. Psychiatric Phase (Days 1-14): Anxiety, insomnia, paranoia, hallucinations, mania
  2. Neurological Phase (Weeks 2-4): Memory loss, speech dysfunction, seizures (faciobrachial dystonic seizures in LGI1, not NMDAR)
  3. Hyperkinetic Phase (Weeks 4-8): Orofacial dyskinesias, choreoathetosis, dystonia, autonomic instability
  4. Late Phase: Catatonia, decreased consciousness, hypoventilation (ICU required)
• Association: Ovarian teratoma in 40-60% of young women
• CSF: Lymphocytic pleocytosis (80%), oligoclonal bands; CSF/serum anti-NMDAR antibodies (diagnostic)
• Treatment: Immunotherapy (steroids, IVIG, plasma exchange), teratoma removal

Key Difference from Viral Encephalitis: Movement disorder (dyskinesias, dystonia), autonomic instability, slower progression over weeks, normal MRI in 50% of cases

LGI1/CASPR2 Encephalitis (VGKC-complex antibodies)

• Demographics: Older adults (50-70 years); M>F
• Features: Faciobrachial dystonic seizures (pathognomonic—brief, frequent dystonic jerks of face and arm), amnesia, confusion, hyponatraemia
• CSF: Often normal or mild pleocytosis
• Treatment: Immunotherapy

Other Important Differentials

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6. Investigations

Approach to Investigation

The diagnostic workup serves three purposes:

1. Confirm encephalitis (inflammation of brain parenchyma)
2. Identify causative pathogen (viral PCR, serology)
3. Exclude differentials (bacterial meningitis, autoimmune encephalitis, structural lesions)

Golden Rule: Start empirical IV aciclovir before investigations if there is any delay in performing LP or obtaining results. [1]

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First-Line Investigations

1. Blood Tests

Immediate Bloods:

• FBC: Leucocytosis (viral infection may cause lymphopenia or normal WCC; bacterial → neutrophilia)
• U&E: Baseline renal function (aciclovir nephrotoxicity risk); hyponatraemia (SIADH from CNS infection; LGI1 encephalitis)
• LFT: Baseline; elevated in EBV/CMV
• CRP: Elevated but non-specific
• Glucose: Paired plasma glucose for CSF comparison
• Coagulation: Before LP
• Blood Cultures: To exclude bacteraemia/sepsis

Additional Bloods:

• HIV Test: Immunocompromised patients susceptible to CMV, VZV, toxoplasmosis
• Viral Serology: HSV, VZV, EBV, CMV, HIV (acute and convalescent titres)
• Autoimmune Screen: Anti-NMDAR, LGI1, CASPR2, VGKC antibodies (serum and CSF)

2. Neuroimaging: CT Head

Indications for CT Before LP:

• GCS ≤12
• Focal neurological signs (hemiparesis, CN palsies)
• New-onset seizures
• Papilloedema (suspected raised ICP)
• Immunocompromised (risk of mass lesion—toxoplasmosis, lymphoma)

CT Findings:

• Often normal in early encephalitis (CT has low sensitivity)
• HSV Encephalitis (when abnormal): Hypodensity in temporal lobes, oedema, mass effect
• VZV Vasculopathy: Ischaemic stroke (often multifocal)

Limitation: CT is insensitive for early viral encephalitis. MRI is the gold-standard imaging modality.

3. Lumbar Puncture (LP) and CSF Analysis

The Essential Investigation

Lumbar puncture should be performed as soon as safely possible (after CT if indicated). CSF analysis provides critical diagnostic information.

CSF Findings in Viral Encephalitis:

Exam Detail: Red Blood Cells in CSF: Traumatic Tap vs Haemorrhagic Encephalitis

HSV encephalitis causes haemorrhagic necrosis of the temporal lobes, resulting in genuine RBCs in CSF (not from a traumatic tap).

How to Distinguish:

• Traumatic Tap: RBCs decrease across sequential collection bottles (1st bottle > 3rd bottle); CSF clears on standing; xanthochromia absent
• True Haemorrhage (HSV): RBCs uniform across all bottles; xanthochromia present (yellow discolouration from breakdown products); elevated protein

Practical Pearl: In suspected HSV encephalitis, do NOT dismiss RBCs in CSF as "just a traumatic tap"—it may be a clue to the diagnosis. [19]

CSF PCR (Polymerase Chain Reaction)

The Definitive Microbiological Test:

Timing of PCR:

• Optimal: 24-72 hours after symptom onset
• Early (less than 24h): May be falsely negative (insufficient viral replication)
• Late (>7-10 days): Sensitivity decreases as viral load declines with immune response [20]

Strategy if Initial PCR Negative: If high clinical suspicion for HSV encephalitis but initial CSF PCR negative, continue aciclovir and repeat LP at 3-7 days.

CSF Opening Pressure

Measure opening pressure routinely:

• Normal: 10-20 cmH₂O
• Elevated (>25 cmH₂O): Suggests cerebral oedema, mass effect

Additional CSF Tests:

• Gram Stain and Bacterial Culture: To exclude bacterial meningitis
• Oligoclonal Bands: Present in 20-40% of viral encephalitis; non-specific
• Lactate: Elevated in bacterial meningitis (>4 mmol/L); normal in viral
• Autoantibodies: Anti-NMDAR, LGI1, etc., if autoimmune encephalitis suspected

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Second-Line Investigations

4. MRI Brain (Gold Standard Imaging)

Indications: All patients with suspected encephalitis (if clinically stable)

Sequences:

• T2-Weighted / FLAIR: High signal (hyperintensity) in areas of inflammation/oedema
• Diffusion-Weighted Imaging (DWI): Restricted diffusion indicates cytotoxic oedema (acute inflammation)
• T1-Weighted + Gadolinium: Enhancement suggests BBB breakdown

MRI Findings by Pathogen:

Sensitivity: MRI has 90% sensitivity for HSV encephalitis (compared to 50% for CT). However, normal MRI does not exclude encephalitis, especially early in the disease course. [21]

Clinical Pearl: Timing of MRI in HSV Encephalitis

MRI changes may lag 24-48 hours behind clinical presentation. If the first MRI (performed within 24h of symptom onset) is normal but clinical suspicion remains high:

• Continue aciclovir
• Repeat MRI at 3-5 days

The absence of MRI changes early on does NOT exclude HSV encephalitis. [22]

5. Electroencephalography (EEG)

Indications:

• Suspected non-convulsive status epilepticus (NCSE)
• Monitoring seizure activity
• Prognostication

EEG Findings in Viral Encephalitis:

Limitations:

• PLEDs are suggestive but not specific for HSV (also seen in stroke, tumours)
• EEG cannot replace CSF PCR or MRI for diagnosis
• Normal EEG does not exclude encephalitis

Correlation with Imaging: Pathological EEG findings (PLEDs, focal epileptiform discharges) correlate with acute symptomatic seizures and abnormal temporal lobe imaging in HSV encephalitis. [35]

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Third-Line / Specialist Investigations

Brain Biopsy

Indications (rare):

• Diagnostic uncertainty despite full workup
• Deterioration despite empirical treatment
• Suspicion of non-infectious causes (malignancy, vasculitis)

Findings: Histology shows viral inclusions (HSV: Cowdry type A inclusions), necrosis, inflammation

Limitations: Invasive; risk of haemorrhage, infection; focal sampling error

Modern Practice: Brain biopsy largely replaced by CSF PCR and advanced MRI.

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Summary of Investigation Strategy

Immediate (Within 1 Hour):

• Blood tests (FBC, U&E, LFT, glucose, coagulation, cultures)
• CT head (if GCS ≤12, focal signs, seizures, or risk of raised ICP)
• Lumbar puncture (if no contraindications)
  • "CSF: cell count, protein, glucose, Gram stain, culture, viral PCR panel (HSV-1/2, VZV, enterovirus, EBV, CMV)"

Within 24 Hours:

• MRI brain (T2, FLAIR, DWI, T1+Gad)
• EEG (if seizures, altered mental status, or suspected NCSE)
• Autoimmune encephalitis screen (serum and CSF anti-NMDAR, LGI1, CASPR2 antibodies)

Special Situations:

• Travel history: Arboviral serology (JEV, WNV, dengue), malaria film
• Animal exposure: Rabies (fatal; no effective treatment post-symptoms)
• Immunocompromised: CSF for CMV, JC virus (PML), toxoplasmosis

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7. Management

Emergency Management Algorithm

        SUSPECTED VIRAL ENCEPHALITIS
  (Fever + Altered Mental Status ± Seizures)
                    ↓
          IMMEDIATE ACTIONS (Within 1 hour):
                    ↓
    1. START IV ACICLOVIR 10mg/kg TDS
       (Do NOT wait for LP or CT results)
                    ↓
    2. ABC Assessment: Airway, Breathing, Circulation
       - O₂ if hypoxic (SpO₂ less than 94%)
       - IV access x2
       - Fluid resuscitation (cautious—avoid fluid overload → cerebral oedema)
                    ↓
    3. Seizure Management:
       - If active seizure: IV lorazepam 4mg or diazepam 10mg
       - If recurrent: Load with levetiracetam 1500mg IV or phenytoin 20mg/kg IV
                    ↓
    4. Protect Airway:
       - If GCS ≤8: Consider intubation (ITU referral)
                    ↓
          CT HEAD (if GCS ≤12, focal signs, or seizures)
                /                \
          Mass Effect          Normal/Oedema
               ↓                    ↓
        Treat ↑ICP           LUMBAR PUNCTURE
     (Mannitol/Hypertonic     Send CSF PCR
       Saline; Neurosurgery)   (HSV, VZV, Enterovirus)
               ↓                    ↓
        Defer LP initially    BLOODS: FBC, U&E, LFT, CRP, Cultures, HIV
                                     ↓
                            MRI BRAIN (within 24h)
                                     ↓
                            EEG (if seizures or NCSE suspected)
                                     ↓
                        CONTINUE IV ACICLOVIR
                    (14-21 days pending results)

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1. Specific Antiviral Therapy

Aciclovir: The Cornerstone of Treatment

Indications:

• All patients with suspected viral encephalitis (empirical treatment)
• Confirmed HSV or VZV encephalitis

Dosing:

• IV Aciclovir 10 mg/kg every 8 hours (TDS) [1]
  • Use ideal body weight in obese patients (aciclovir dosing based on lean mass)
  • "Adjust dose in renal impairment:"
    • CrCl 25-50 mL/min: 10 mg/kg every 12 hours
    • CrCl 10-25 mL/min: 10 mg/kg every 24 hours
    • CrCl less than 10 mL/min: 5 mg/kg every 24 hours

Duration:

• HSV Encephalitis: 14-21 days IV aciclovir [4]
  • Minimum 14 days if patient improving
  • Extend to 21 days if severe disease, slow improvement, or immunocompromised
• VZV Encephalitis: 14-21 days

Route: IV only (oral aciclovir has poor CNS penetration)

When to Start: Immediately on clinical suspicion—do not wait for:

• CT head results
• Lumbar puncture results
• CSF PCR results

Rationale: Mortality from untreated HSV encephalitis is 70%; every hour delay in starting aciclovir increases risk of death and disability. [7]

Exam Detail: Aciclovir Pharmacology

Mechanism of Action:

1. Aciclovir is a guanosine (nucleoside) analogue
2. It is selectively phosphorylated to aciclovir monophosphate by viral thymidine kinase (enzyme present only in virus-infected cells)
3. Host cellular kinases convert it to aciclovir triphosphate
4. Aciclovir triphosphate inhibits viral DNA polymerase (competitive inhibition) and acts as a DNA chain terminator (incorporation into viral DNA → synthesis halted)

Selectivity: Aciclovir is 100-fold more selective for viral thymidine kinase than host kinases, explaining its low toxicity to uninfected cells.

Resistance: Rare (less than 1%) in immunocompetent patients; mutations in viral thymidine kinase or DNA polymerase cause resistance. Alternative: Foscarnet (does not require phosphorylation).

CSF Penetration: Aciclovir achieves 50% of plasma concentrations in CSF—adequate for treating CNS HSV.

Adverse Effects of Aciclovir and Mitigation Strategies

Renal Protection Protocol:

1. Baseline U&E and check serum creatinine daily
2. IV Fluids: Administer 1L 0.9% saline over 2-3 hours before each aciclovir dose, OR ensure oral/IV fluid intake ≥3L/day [39]
3. Monitor Urine Output: Aim for >0.5 mL/kg/h
4. Dose Adjustment: Reduce dose/frequency if AKI develops (see dosing above)

Clinical Pearl: "Aciclovir is Nephrotoxic—Hydrate Avidly"

Aciclovir nephrotoxicity is preventable with adequate hydration. The mnemonic "1 Litre per Dose" is commonly used:

• Each aciclovir dose (TDS = three times daily) should be accompanied by 1L IV 0.9% saline
• Total daily fluid intake target: ≥3-4 litres

Monitor daily creatinine. If creatinine rises, increase fluids and reduce aciclovir frequency (not dose per kg).

Alternative Antivirals

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2. Adjunctive Therapies

Anticonvulsant Therapy

Indications:

• Active seizures
• Recurrent seizures
• Prophylaxis in high-risk patients (severe temporal lobe oedema, status epilepticus)

First-Line Anticonvulsants:

Status Epilepticus: Escalate to benzodiazepines (lorazepam 4mg IV), then phenytoin/levetiracetam load, then consider intubation + propofol/midazolam infusion (see Status Epilepticus protocol).

Duration of Prophylaxis: Continue for duration of acute illness; taper after clinical improvement. Long-term anticonvulsants may be needed if structural damage (temporal lobe scarring → epilepsy).

Management of Raised Intracranial Pressure (ICP)

Clinical Signs of Raised ICP:

• Declining GCS
• Cushing's triad: Bradycardia, hypertension, irregular respirations
• Papilloedema
• Pupillary changes (unilateral dilated pupil—uncal herniation)

Monitoring:

• Serial GCS
• Invasive ICP monitoring (if ITU, severe encephalitis with GCS ≤8)

Management of Raised ICP:

1. General Measures:

   • 30° head-up position
   • Avoid hypoxia (SpO₂ >94%), hypercapnia (normocapnia: PaCO₂ 4.5-5 kPa), hypotension
   • Avoid fluid overload (risk of cerebral oedema)—judicious fluid management

2. Osmotic Therapy:

   • Mannitol 20%: 0.5-1 g/kg IV bolus (over 15 min); repeat as needed
   • Hypertonic Saline (3%): 2-5 mL/kg IV bolus; maintain serum Na⁺ 145-155 mmol/L

3. Controlled Hyperventilation (short-term):

   • Target PaCO₂ 4-4.5 kPa (induces cerebral vasoconstriction, reduces ICP)
   • Risk: Prolonged hyperventilation → cerebral ischaemia

4. Sedation and Neuromuscular Blockade (if intubated):

   • Reduces cerebral metabolic demand

5. Decompressive Craniectomy:

   • Last resort in refractory raised ICP with impending herniation
   • Controversial in encephalitis; discuss with neurosurgery

Corticosteroids: Controversial

Evidence:

• No proven benefit in viral encephalitis [23]
• Potential harm: immunosuppression may worsen viral replication
• Not routinely recommended in viral encephalitis

Exceptions (where steroids may be considered):

• VZV vasculopathy: Adjunctive steroids may reduce inflammation in cerebral vasculitis
• Autoimmune encephalitis (anti-NMDAR, LGI1): Steroids are first-line treatment (methylprednisolone 1g IV daily x 3-5 days)

Current Guideline: Avoid steroids in suspected viral encephalitis unless strong evidence of autoimmune component. [1]

Empirical Antibacterial Therapy

Rationale: In the initial presentation (before LP results available), it is often impossible to distinguish viral from bacterial meningitis clinically.

Recommendation: Co-administer IV antibiotics (covering bacterial meningitis) alongside aciclovir until CSF results confirm viral aetiology:

• Ceftriaxone 2g IV BD (or Cefotaxime 2g IV QDS)
• Add Amoxicillin/Ampicillin 2g IV QDS if age >50 years or immunocompromised (covers Listeria monocytogenes)

Duration: Stop antibiotics once CSF confirms viral encephalitis (lymphocytic pleocytosis, normal glucose, negative Gram stain/culture, positive viral PCR).

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3. Supportive and Intensive Care

Indications for ICU Admission

• GCS ≤8 (unable to protect airway)
• Respiratory failure (hypoventilation, aspiration risk)
• Status epilepticus (refractory seizures)
• Haemodynamic instability
• Raised ICP requiring invasive monitoring

Airway Management

• GCS ≤8: Intubate and ventilate
• Protect airway from aspiration

Nutritional Support

• Enteral feeding (NG tube) if reduced consciousness
• Avoid hypoglycaemia

DVT Prophylaxis

• LMWH (e.g., enoxaparin 40mg SC OD) unless contraindicated
• Mechanical prophylaxis (compression stockings, intermittent pneumatic compression)

Rehabilitation

• Early physiotherapy: Prevent contractures, pressure sores
• Occupational therapy: Cognitive rehabilitation
• Speech and language therapy: If dysphasia

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4. Monitoring and Follow-Up

Acute Phase Monitoring (daily):

• GCS and neurological examination
• Temperature chart
• Serum creatinine (aciclovir nephrotoxicity)
• FBC, LFT
• Fluid balance

Repeat Lumbar Puncture:

• Not routinely required if patient improving clinically
• Consider repeat LP at day 21 if:
  • Uncertain diagnosis
  • Slow improvement
  • Immunocompromised (risk of persistent viraemia)
  • To confirm CSF PCR negativity before stopping aciclovir

Repeat MRI:

• If no improvement or clinical deterioration (rule out complications: abscess, infarction)

Follow-Up After Discharge:

• Neurology outpatient review at 3 months and 6 months
• Neuropsychological assessment: Evaluate memory, executive function, mood
• MRI brain (6-12 months): Assess for temporal lobe atrophy, gliosis
• EEG: If ongoing seizures (post-encephalitic epilepsy)

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5. Special Populations

Neonates and Children

• Neonatal HSV: HSV-2 (vertical transmission from maternal genital HSV); presents in first 4 weeks of life; treat with IV aciclovir 20 mg/kg TDS for 21 days
• Enteroviral encephalitis: More common in children; usually milder than HSV

Immunocompromised (HIV, Transplant, Chemotherapy)

• Broader differential: CMV, VZV, EBV, JC virus (PML), toxoplasmosis, cryptococcus
• CSF PCR panel: Expand to include CMV, EBV, HHV-6, JC virus
• Treatment: Ganciclovir + Foscarnet for CMV; prolonged aciclovir for VZV/HSV

Pregnancy

• HSV Encephalitis in Pregnancy: Treat with IV aciclovir (risk-benefit strongly favours treatment; untreated HSV encephalitis has 70% maternal mortality)
• Fetal Risk: Aciclovir is Category B (no proven teratogenicity)

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8. Complications and Sequelae

Acute Complications (During Illness)

Long-Term Neuropsychiatric Sequelae

Despite survival, more than 50% of patients with HSV encephalitis experience moderate to severe long-term disability. [8]

1. Memory Impairment

"The Korsakoff-Like Syndrome"

• Mechanism: Destruction of hippocampus (medial temporal lobe) → inability to form new memories
• Presentation:
  • "Anterograde Amnesia: Cannot form new long-term memories (events after illness)"
  • "Retrograde Amnesia: Variable loss of memories before illness"
  • "Preserved: Immediate recall (working memory), procedural memory, semantic knowledge (facts learned before illness)"
• Functional Impact: Unable to remember conversations, appointments, recent events; patients may repeatedly ask same questions
• Management:
  • Memory aids (diaries, alarms, smartphone apps)
  • Environmental modifications (labels, routines)
  • Family education and support
  • Cognitive rehabilitation

Prognosis: Anterograde amnesia may persist lifelong if bilateral hippocampal damage is severe.

2. Post-Encephalitic Epilepsy

• Frequency: 20-30% develop epilepsy after viral encephalitis, with higher rates (34-50%) in those with acute symptomatic seizures during the acute illness [24,40]
• Mechanism: Temporal lobe scarring → mesial temporal sclerosis → focal epilepsy
• Seizure Type: Temporal lobe seizures (auras, automatisms, déjà vu)
• Management:
  • Long-term anticonvulsants (levetiracetam, lamotrigine, carbamazepine)
  • Refractory epilepsy may require consideration for temporal lobectomy [41]

3. Personality and Behavioural Change

Dysexecutive Syndrome (Frontal Lobe Damage):

• Features: Apathy, lack of motivation, impulsivity, disinhibition, poor planning, perseveration
• Impact: Loss of employment, relationship breakdown, inability to live independently
• Management: Occupational therapy, behavioural strategies, family support

Emotional Lability:

• Depression, anxiety, irritability, emotional outbursts
• May require psychiatric input, antidepressants

4. Motor Deficits

• Hemiparesis: If unilateral severe involvement or VZV vasculopathy
• Ataxia: Cerebellar involvement
• Movement Disorders: Parkinsonism, dystonia (rare; more common in arboviral encephalitis)

5. Speech and Language Impairment

• Dysphasia: If dominant hemisphere temporal/frontal involvement
• Dysarthria: Brainstem or cerebellar involvement

6. Psychosocial Impact

• Caregiver Burden: Personality change is often the most distressing sequela for families ("They're not the same person")
• Employment: Many unable to return to previous employment
• Quality of Life: Significantly reduced

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Rehabilitation Strategies

Multidisciplinary Approach:

1. Neuropsychological Assessment: Formal evaluation of memory, executive function, language, attention
2. Memory Rehabilitation: Cognitive exercises, memory aids, compensatory strategies
3. Occupational Therapy: Functional independence training, return-to-work programs
4. Physiotherapy: If motor deficits
5. Speech and Language Therapy: If dysphasia
6. Psychiatric/Psychological Support: For depression, anxiety, adjustment
7. Family Support and Education: Crucial for long-term care

Prognosis for Recovery:

• Most recovery occurs in first 6-12 months
• Continued gradual improvement may occur up to 2 years
• Plateau usually reached by 2 years post-illness
• Neuropsychological deficits persist: Long-term cognitive impairment, executive dysfunction, and memory deficits are common even in patients achieving functional independence [42,43]

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9. Prognosis

Mortality

Functional Outcome

Modified Rankin Scale (mRS) at 6-12 months post-HSV encephalitis:

Key Message: Only 30-40% of patients with HSV encephalitis achieve good functional recovery (mRS 0-2); majority have residual disability. [8]

Prognostic Factors

Favourable Prognosis:

• Age less than 30 years
• GCS >8 at presentation
• Early initiation of aciclovir (within 48 hours)
• Absence of coma
• Lower viral load (CSF HSV DNA copy number)

Poor Prognosis:

• Age >60 years
• GCS ≤8 (coma)
• Delayed treatment (>72 hours)
• Bilateral temporal involvement on MRI
• Need for ICU admission, mechanical ventilation
• Immunosuppression

Timing of Aciclovir: Strongest modifiable prognostic factor. Each day of delay in starting aciclovir increases risk of death/disability by 20-30%. [7]

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10. Prevention and Public Health

Vaccination

No vaccine exists for HSV, enterovirus, West Nile Virus.

Public Health Measures

Arboviral Encephalitis:

• Mosquito control (larvicides, insecticide spraying)
• Personal protection (insect repellent, long clothing, bed nets)
• Avoidance of outdoor activity at dusk/dawn (peak mosquito activity)

Infection Control:

• Most viral encephalitis is not person-to-person transmissible (exceptions: enterovirus via faecal-oral route)
• Standard precautions in hospital (hand hygiene)

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11. Autoimmune Encephalitis: A Distinct Entity

While this topic focuses on viral encephalitis, autoimmune encephalitis is a critical differential that must be actively considered in every case, especially in young patients with psychiatric features.

Key Differences: Viral vs Autoimmune Encephalitis

Clinical Pearl: If a patient with suspected viral encephalitis has:

1. Prominent psychiatric features (psychosis, mania)
2. Movement disorder (dyskinesias, dystonia)
3. Normal or minimal CSF findings
4. Normal MRI
5. Negative viral PCR

→ Think Autoimmune Encephalitis and test for CSF/serum autoantibodies (anti-NMDAR, LGI1, CASPR2, VGKC).

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12. Key Guidelines and Evidence Base

Major Guidelines

Landmark Studies

1. Whitley RJ et al. (NEJM 1986): Randomised controlled trial of aciclovir vs vidarabine in biopsy-proven HSV encephalitis. Aciclovir reduced mortality from 70% to 19%. Established aciclovir as standard of care. [4]

2. Sköldenberg B et al. (Lancet 1984): Early treatment with aciclovir (within 48h) improves survival and functional outcomes in HSV encephalitis.

3. Raschilas F et al. (Clin Infect Dis 2002): Outcome of 106 patients with HSV encephalitis: only 40% achieved good outcome (mRS 0-2); GCS at presentation and age were strongest predictors. [8]

4. Granerod J et al. (Lancet Infect Dis 2010): UK prospective cohort of encephalitis (6-year study): Cause identified in only 40% of cases; HSV most common identifiable cause; mortality 6.5%. [3]

5. Dalmau J et al. (Lancet Neurol 2008): First description of Anti-NMDA Receptor Encephalitis in 100 patients; ovarian teratoma association in young women; 75% recovery with immunotherapy. [18]

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13. Viva and Exam Preparation

Common Exam Questions (MRCP/FRACP)

1. "What are the causes of viral encephalitis?"

   • Model Answer: "The most common identified cause of sporadic viral encephalitis in the UK is HSV-1, accounting for 10-20% of cases. Other important causes include VZV, enteroviruses (especially in children), and influenza. Geographically specific arboviruses such as Japanese Encephalitis Virus in Asia and West Nile Virus in the USA are also significant. In immunocompromised patients, CMV and EBV must be considered. It is important to note that approximately 40-60% of encephalitis cases remain of unknown aetiology despite comprehensive investigation."

2. "How would you differentiate viral encephalitis from bacterial meningitis clinically?"

   • Model Answer: "While both present with fever and headache, encephalitis is distinguished by altered mental status (confusion, personality change, psychosis) and focal neurological signs (dysphasia, seizures). Meningitis typically presents with meningism (neck stiffness, photophobia) with relatively preserved cognition initially. CSF analysis is crucial: viral encephalitis shows lymphocytic pleocytosis with normal glucose, whereas bacterial meningitis shows neutrophilic pleocytosis with low glucose. However, empirical treatment with both IV aciclovir and antibiotics should be initiated until CSF results differentiate the two."

3. "Describe your management of suspected HSV encephalitis."

   • Model Answer: "HSV encephalitis is a neurological emergency requiring immediate empirical treatment. I would start IV aciclovir 10mg/kg every 8 hours without delay, even before lumbar puncture or imaging. Concurrently, I would perform CT head (to exclude raised ICP or mass effect), followed by lumbar puncture for CSF analysis including viral PCR (HSV-1, HSV-2, VZV, enterovirus). MRI brain with DWI and FLAIR sequences is the imaging of choice, typically showing hyperintensity in the medial temporal lobes. I would also arrange EEG if seizures are present or non-convulsive status is suspected. Treatment duration is 14-21 days, with aggressive IV hydration (1L saline with each dose) to prevent aciclovir nephrotoxicity. Daily monitoring of renal function is essential."

4. "What are the prognostic factors in HSV encephalitis?"

   • Model Answer: "The strongest modifiable prognostic factor is time to aciclovir treatment—every hour of delay increases mortality and disability risk. Other poor prognostic factors include age over 60 years, GCS ≤8 at presentation, delayed treatment beyond 72 hours, bilateral temporal lobe involvement on MRI, and need for ICU admission. Favourable factors include age under 30, GCS >8, and early treatment within 48 hours. Overall, mortality with treatment is 10-20%, but more than 50% of survivors have residual neurological disability, predominantly memory impairment and epilepsy."

5. "What are the long-term complications of HSV encephalitis?"

   • Model Answer: "Long-term sequelae are common, affecting over 50% of survivors. The most significant is anterograde amnesia due to hippocampal damage, resulting in inability to form new memories. Post-encephalitic epilepsy develops in 20-30% due to temporal lobe scarring. Dysexecutive syndrome from frontal lobe damage manifests as apathy, disinhibition, poor planning, and personality change—often the most distressing sequela for families. Other complications include dysphasia (if dominant hemisphere involved), motor deficits (hemiparesis), and psychiatric sequelae (depression, anxiety). Rehabilitation requires multidisciplinary input including neuropsychology, occupational therapy, speech therapy, and long-term family support."

Viva Opening Statement

"Viral encephalitis is acute inflammation of the brain parenchyma caused by direct viral invasion, most commonly HSV-1 in the UK. It presents with the triad of fever, headache, and altered mental status, with seizures in 50-75% of cases. HSV demonstrates temporal lobe predilection, causing dysphasia, memory loss, and personality change. Diagnosis is via CSF PCR and MRI (temporal lobe hyperintensity on FLAIR). Treatment is empirical IV aciclovir 10mg/kg TDS for 14-21 days, started immediately on clinical suspicion. Untreated mortality is 70%, reduced to 10-20% with early aciclovir. However, over 50% of survivors have residual disability, predominantly memory impairment and epilepsy. Differential diagnosis includes autoimmune encephalitis, particularly anti-NMDAR encephalitis in young patients with prominent psychiatric features."

Common Mistakes (That Fail Candidates)

❌ Mistake 1: Waiting for LP or CT results before starting aciclovir

• Correct: Start aciclovir immediately on clinical suspicion

❌ Mistake 2: Dismissing RBCs in CSF as "traumatic tap" in suspected HSV encephalitis

• Correct: RBCs may be genuine (haemorrhagic necrosis in HSV); look for xanthochromia

❌ Mistake 3: Stating "normal MRI excludes encephalitis"

• Correct: MRI may be normal in first 24-48 hours; repeat if high suspicion persists

❌ Mistake 4: Not considering autoimmune encephalitis in young patient with psychosis and normal MRI

• Correct: Test for anti-NMDAR and other autoantibodies; treatment is immunotherapy, not aciclovir

❌ Mistake 5: Using oral aciclovir or inadequate IV dosing

• Correct: IV aciclovir 10mg/kg TDS (not 5mg/kg); oral has poor CNS penetration

❌ Mistake 6: Forgetting renal protection with aciclovir

• Correct: 1L IV saline with each dose + daily U&E monitoring

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14. Patient and Layperson Explanation

What is Viral Encephalitis?

Viral encephalitis is inflammation and swelling of the brain itself caused by a viral infection. It is different from meningitis, which is swelling of the lining around the brain. In encephalitis, the infection affects the brain tissue, which is why it causes problems with memory, thinking, behaviour, and consciousness.

Is it Common?

Viral encephalitis is rare—it affects about 5-10 people per 100,000 each year in the UK. However, it is a serious condition that requires urgent hospital treatment.

What Causes It?

The most common cause in the UK is the herpes simplex virus (HSV-1)—the same virus that causes cold sores. In most people, this virus lives quietly in a nerve near the face without causing problems. Very rarely (about 1 in 250,000 people), the virus "wakes up" and travels along the nerve into the brain, causing encephalitis.

Other causes include chickenpox virus (varicella zoster), enteroviruses (common stomach bugs), and in tropical countries, viruses spread by mosquito bites.

Important: Encephalitis is usually NOT caught from someone else—it is often the virus "waking up" inside your own body.

What are the Symptoms?

The main symptoms are:

• Fever (high temperature)
• Severe headache
• Confusion or unusual behaviour (not acting like yourself, saying strange things, forgetting things)
• Seizures (fits)
• Drowsiness or difficulty waking up

If someone has a fever and is confused or behaving unusually, it is a medical emergency—call 999 or go to A&E immediately.

How is it Diagnosed?

Doctors will perform several tests:

1. Blood tests to check for infection
2. CT or MRI scan of the brain to look for swelling
3. Lumbar puncture (spinal tap): A needle is inserted into the lower back to take a sample of the fluid around the brain and spinal cord. This fluid is tested for viruses.

How is it Treated?

Treatment is with a strong antiviral medicine called aciclovir, given directly into a vein through a drip. This medicine stops the virus from multiplying in the brain.

• Duration: Treatment lasts for 2-3 weeks in hospital.
• Timing: The medicine must be started as soon as encephalitis is suspected—every hour of delay increases the risk of permanent brain damage.

Will They Recover?

With treatment:

• Most people survive (80-90%)
• However, full recovery is less common (only 30-40%)

Many people have long-term problems after encephalitis, including:

• Memory problems (especially remembering new things)
• Personality changes (being more irritable, less motivated, or behaving differently)
• Epilepsy (fits) later on
• Tiredness and difficulty concentrating

How Long Does Recovery Take?

• Most improvement happens in the first 6-12 months
• Some people continue to improve gradually for up to 2 years
• Rehabilitation (physiotherapy, occupational therapy, memory training) can help recovery

Support for Families

Encephalitis is very difficult for families because the person may seem "different" after the illness—their personality and behaviour may have changed. This can be very distressing.

Support organisations:

• The Encephalitis Society (UK): Provides information, support groups, and helplines for patients and families (www.encephalitis.info)

Key Message for Patients and Families

Encephalitis is a serious illness, but early treatment saves lives. If someone has a fever and is confused or behaving strangely, it is a medical emergency—seek help immediately. With treatment, most people survive, but recovery can be slow and many people need ongoing support. You are not alone—there are organisations and healthcare teams ready to help.

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