Overview
Definition:
Herpes Simplex Virus (HSV) encephalitis is a severe, often focal, necrotizing inflammation of the brain parenchyma, most commonly caused by HSV-1
In neonates, HSV-2 is more frequently implicated, often acquired during passage through an infected birth canal.
Epidemiology:
It is the most common cause of sporadic, severe, focal encephalitis in immunocompetent individuals, with an incidence of approximately 1 in 250,000 to 1 in 500,000 person-years
In neonates, the incidence is higher, around 1 in 3,000 to 1 in 5,000 births
Untreated, it carries a high mortality rate.
Clinical Significance:
HSV encephalitis is a medical emergency requiring prompt diagnosis and aggressive antiviral therapy
Neurological sequelae, including cognitive deficits, seizures, and motor impairments, are common even with treatment, highlighting the importance of timely intervention and appropriate dosing.
Clinical Presentation
Symptoms:
Sudden onset of fever
Headache
Altered mental status, including lethargy, confusion, personality changes, and irritability
Focal neurological deficits, such as hemiparesis, aphasia, or visual field defects
Seizures, which can be focal or generalized
In infants, poor feeding, irritability, lethargy, and seizures are prominent
In neonates, symptoms can be non-specific, including lethargy, poor feeding, fever, or hypothermia, progressing to seizures, rash, and shock.
Signs:
Fever
Altered level of consciousness
Focal neurological signs mirroring temporal lobe involvement (e.g., olfactory or gustatory hallucinations, memory impairment)
Signs of meningeal irritation (nuchal rigidity, Kernig's, Brudzinski's signs) may be present but are often less pronounced than in bacterial meningitis
Papilledema may be seen
In neonates, vesicular rash may be present if disseminated disease is involved.
Diagnostic Criteria:
Diagnosis is typically based on a combination of clinical presentation, neuroimaging findings, and laboratory confirmation
Definitive diagnosis relies on detecting HSV DNA in cerebrospinal fluid (CSF) via PCR
While clinical suspicion is high with characteristic symptoms and signs, especially temporal lobe involvement, prompt CSF analysis is crucial
Consensus guidelines recommend empirical treatment in all suspected cases pending definitive confirmation.
Diagnostic Approach
History Taking:
Detailed history of recent febrile illness, onset and progression of neurological symptoms, presence of focal deficits, and any history of cold sores or genital herpes in the patient or close contacts
For neonates, birth history, presence of maternal genital herpes, and mode of delivery are critical
Rule out recent travel or exposure to other infectious agents.
Physical Examination:
Complete neurological examination to assess mental status, cranial nerves, motor and sensory function, reflexes, and coordination
Assess for meningeal signs
Funduscopic examination for papilledema
Skin examination for herpetic vesicular rash, particularly in neonates.
Investigations:
Cerebrospinal fluid (CSF) analysis: PCR for HSV DNA (highly sensitive and specific), cell count (lymphocytic pleocytosis typical, may be hemorrhagic or neutrophilic early on), protein elevation, and glucose levels (usually normal)
Blood tests: complete blood count, electrolytes, glucose, liver function tests, coagulation profile
Electroencephalogram (EEG): can show diffuse or focal slowing, periodic lateralized epileptiform discharges (PLEDs), particularly in temporal lobe involvement
Neuroimaging: MRI brain with contrast is the investigation of choice, demonstrating characteristic temporal lobe lesions (edema, hemorrhage, enhancement)
CT scan may show hypodensity but is less sensitive, especially in early stages.
Differential Diagnosis:
Bacterial meningitis
Other viral encephalitides (e.g., enterovirus, arbovirus, West Nile virus)
Autoimmune encephalitis (e.g., anti-NMDA receptor encephalitis)
Metabolic encephalopathy
Intracranial hemorrhage or stroke
Brain tumors
Abscesses.
Management
Initial Management:
Immediate empirical treatment with intravenous acyclovir is paramount upon suspicion, even before definitive diagnosis
Airway, breathing, and circulation (ABC) support
Seizure management with anticonvulsants (e.g., lorazepam, levetiracetam)
Management of increased intracranial pressure (ICP) if present, using measures like head elevation, mannitol, or hypertonic saline.
Medical Management:
Intravenous Acyclovir: Standard regimen for both children and neonates is 10-20 mg/kg per dose administered intravenously every 8 hours for a minimum of 14-21 days
For neonates, the dose is often 20 mg/kg/dose IV every 8 hours
Longer durations (up to 21 days) are recommended for severe disease or disseminated neonatal infection
Monitoring renal function is crucial due to potential nephrotoxicity
adequate hydration should be maintained
Resistance to acyclovir is rare but should be considered in refractory cases, and alternative agents like foscarnet may be used under specialist guidance.
Surgical Management:
Surgical intervention is generally not indicated for HSV encephalitis itself, but may be required for managing complications such as refractory status epilepticus or large focal lesions with mass effect, typically involving neurosurgical consultation.
Supportive Care:
Intensive care unit (ICU) monitoring for neurological status, hemodynamic stability, and respiratory function
Fluid and electrolyte balance
Nutritional support
Physical and occupational therapy for rehabilitation
Long-term neurodevelopmental follow-up.
Complications
Early Complications:
Status epilepticus
Increased intracranial pressure and brain herniation
Hemorrhagic lesions and stroke
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Disseminated intravascular coagulation (DIC) in neonates.
Late Complications:
Neurological sequelae, including cognitive impairment, memory deficits, behavioral changes, personality disorders, seizures, focal neurological deficits (e.g., hemiparesis, visual impairment), and developmental delay in children
Hydrocephalus.
Prevention Strategies:
In neonates, prevention involves careful management of maternal genital herpes during pregnancy and labor, including prophylactic antiviral therapy and considering Cesarean section if active lesions are present
In immunocompromised patients, prophylactic oral acyclovir may be used in select circumstances, though this is not routine for prevention of primary HSV encephalitis.
Prognosis
Factors Affecting Prognosis:
Early diagnosis and prompt initiation of IV acyclovir treatment are the most critical factors
Age at onset (neonates have a worse prognosis than older children and adults), severity of initial illness, extent of neurological involvement on imaging, and presence of complications like seizures or coma significantly influence outcomes.
Outcomes:
With prompt treatment, mortality rates have decreased significantly from over 70% to around 10-20%
However, a substantial proportion of survivors (30-50%) experience significant long-term neurological deficits
Neonatal HSV encephalitis has a higher mortality and morbidity rate compared to immunocompetent older children and adults.
Follow Up:
Lifelong neurological and neurodevelopmental follow-up is recommended for all survivors, particularly children, to monitor for cognitive, behavioral, and motor deficits
Regular assessment of seizure control and management of any ongoing neurological issues are essential.
Key Points
Exam Focus:
Empirical IV acyclovir (10-20 mg/kg/dose IV q8h) for a minimum of 14-21 days is the cornerstone of management
CSF PCR for HSV is diagnostic
Temporal lobe involvement on MRI is classic
Neonatal HSV has a worse prognosis
Prompt initiation of treatment is critical.
Clinical Pearls:
Always consider HSV encephalitis in a child with sudden onset fever and altered mental status or focal neurological deficits
Do not delay antiviral therapy while awaiting test results
Monitor renal function closely during acyclovir therapy
Suspect disseminated neonatal HSV if fever, lethargy, rash, and seizures are present.
Common Mistakes:
Delaying empirical acyclovir treatment due to uncertainty or waiting for definitive diagnosis
Inadequate duration of acyclovir therapy
Underestimating the neurological sequelae and the need for long-term follow-up
Misinterpreting early CSF findings which may be non-specific.