Encephalitis: A Comprehensive Approach to Suspicion and Management

Dr Neeraj Manikath , claude.ai

Abstract

Encephalitis remains a diagnostic and therapeutic challenge in internal medicine, with significant morbidity and mortality despite advances in neuroimaging and molecular diagnostics. This review synthesizes current evidence on recognizing, investigating, and managing encephalitis, emphasizing practical clinical pearls for the post-graduate physician. We explore the subtle clinical presentations that may precede obvious neurological deterioration, discuss the evolving diagnostic landscape, and provide evidence-based management strategies with attention to time-critical interventions.

Introduction

Encephalitis, defined as inflammation of the brain parenchyma with associated neurological dysfunction, affects approximately 5-10 cases per 100,000 individuals annually in developed countries, though the true incidence is likely underestimated.[1] Despite extensive investigation, 40-50% of cases remain without an identified etiology even in well-resourced settings.[2] The mortality rate ranges from 5-30% depending on the causative agent, and survivors frequently experience long-term neurological sequelae including cognitive impairment, personality changes, and epilepsy.[3]

The clinical presentation of encephalitis exists on a spectrum from subtle cognitive changes to fulminant neurological collapse. Early recognition and prompt empirical therapy are crucial, as delayed treatment—particularly for herpes simplex virus (HSV) encephalitis—is associated with significantly worse outcomes.

Clinical Suspicion: The Art of Early Recognition

The Classic Triad and Beyond

The textbook presentation of encephalitis includes fever, altered mental status, and headache. However, Pearl #1: This complete triad is present in fewer than 50% of patients at initial presentation.[4] Relying solely on this triad will result in missed or delayed diagnoses.

Subtle Harbingers of Encephalitis

Clinical Hack #1: The "Pre-Encephalitic Syndrome"

Many patients experience a prodromal phase lasting 1-7 days characterized by non-specific symptoms:

Behavioral changes noticed by family members (personality alteration, social withdrawal, uncharacteristic behavior)
Subtle cognitive slowing or word-finding difficulties
New-onset psychiatric symptoms in previously healthy individuals
Unexplained seizures, particularly in adults without epilepsy risk factors

Oyster: A 45-year-old presenting with new-onset confusion and "bizarre behavior" over 48 hours without fever may have autoimmune encephalitis rather than primary psychiatric disease. The absence of fever does not exclude encephalitis.

Red Flags Demanding Immediate Attention

Certain clinical features should trigger immediate encephalitis workup:

The Fever-Seizure Combination: New-onset seizures with concurrent fever in adults is encephalitis until proven otherwise[5]
Focal Neurological Signs: Aphasia, hemiparesis, or visual field defects suggest focal inflammation
Movement Disorders: Orofacial dyskinesias, choreoathetosis, or dystonia (particularly suggestive of anti-NMDA receptor encephalitis)
Rapid Deterioration: Any patient with declining level of consciousness over hours to days
CSF Pleocytosis with Altered Mental Status: Even mild lymphocytosis (10-20 cells/μL) in the context of encephalopathy warrants aggressive investigation

Diagnostic Approach: Maximizing Yield While Minimizing Delay

The Emergency Department Protocol

Clinical Hack #2: The "60-Minute Rule"

From suspicion to treatment initiation should ideally occur within 60 minutes for possible HSV encephalitis. This requires a streamlined protocol:

Minute 0-15:

Blood cultures, complete blood count, comprehensive metabolic panel, liver function tests
Blood PCR for HSV, VZV if available
Serum for autoimmune encephalitis panel (hold at -80°C if testing not immediately available)

Minute 15-30:

Non-contrast CT head to exclude mass lesion, abscess, or contraindications to lumbar puncture

Minute 30-45:

Lumbar puncture with opening pressure
CSF studies: cell count with differential, protein, glucose, Gram stain, bacterial culture, HSV-1/2 PCR, VZV PCR, enterovirus PCR
Hold additional CSF at 4°C for additional testing

Minute 45-60:

Initiate empirical therapy (discussed below)
MRI brain with and without contrast (if patient stable enough for transport)

Lumbar Puncture: Interpreting the Cellular Response

Pearl #2: CSF pleocytosis is present in 90% of viral encephalitis cases, but 10% may have normal initial CSF, particularly if sampled very early in the disease course.[6] A normal initial CSF should not prevent empirical treatment if clinical suspicion is high, and repeat lumbar puncture after 12-24 hours is often diagnostic.

Oyster: A lymphocytic pleocytosis with elevated protein and normal glucose is classic for viral encephalitis, but remember that HSV encephalitis can show red blood cells (often >500/μL) in CSF due to hemorrhagic necrosis of temporal lobes, mimicking subarachnoid hemorrhage.

The Evolving Role of Advanced Diagnostics

Metagenomic Next-Generation Sequencing (mNGS)

This technology, while expensive and not universally available, has revolutionized diagnosis of cryptic encephalitis cases, identifying pathogens in up to 20% of previously undiagnosed cases.[7] Consider requesting mNGS for:

Immunocompromised patients
Cases with CSF pleocytosis but negative standard PCR testing
Atypical presentations or travel to endemic areas
Failure to improve on empirical therapy

Autoimmune Encephalitis Panels

The recognition of autoimmune encephalitis as a major diagnostic category has expanded dramatically. Pearl #3: Anti-NMDA receptor encephalitis is now more common than any individual viral cause of encephalitis in patients under 30 years old.[8]

Key antibodies to test:

Serum AND CSF: anti-NMDA receptor, anti-LGI1, anti-CASPR2, anti-GABA-B receptor
Testing both serum and CSF increases sensitivity; some antibodies are CSF-specific

Clinical Hack #3: The "Young Female with Psychiatric Symptoms and Seizures" Pattern

If you encounter a young woman with subacute onset of psychiatric symptoms, seizures, movement disorders, and autonomic instability, think anti-NMDA receptor encephalitis. Consider:

Ovarian teratoma screening (present in 40% of cases in women >18 years)
Immunotherapy should not wait for antibody confirmation if clinical suspicion is high

Neuroimaging: Beyond Lesion Detection

MRI Patterns and Their Diagnostic Implications

Pearl #4: Normal initial MRI occurs in up to 10% of proven encephalitis cases—do not let a normal scan dissuade you from treatment.[9]

Characteristic MRI findings:

HSV encephalitis: Medial temporal lobe T2/FLAIR hyperintensity, often with hemorrhagic transformation
Autoimmune encephalitis: Variable; may show medial temporal lobe changes (limbic encephalitis pattern), or be normal
West Nile virus: Deep gray matter involvement (thalamus, basal ganglia)
Japanese encephalitis: Thalamus and substantia nigra involvement
Eastern equine encephalitis: Basal ganglia with cortical involvement

Clinical Hack #4: FLAIR and DWI sequences are most sensitive for early parenchymal changes—ensure these are included in your MRI protocol.

Management: Time-Critical Interventions

Empirical Therapy: What, When, and for How Long?

The Standard Empirical Regimen:

Acyclovir 10 mg/kg IV every 8 hours (adjust for renal function)
Consider adding ceftriaxone 2g IV every 12 hours and vancomycin (dose by weight and renal function) if bacterial meningitis cannot be excluded
Dexamethasone 10mg IV every 6 hours remains controversial in viral encephalitis but may be considered for severe cerebral edema

Pearl #5: Continue acyclovir for 14-21 days even if HSV PCR returns negative if clinical suspicion remains high or if the sample was obtained very early. PCR sensitivity increases with repeat testing after 3-7 days.[10]

HSV Encephalitis: The Treatment Paradigm

HSV encephalitis remains the most important treatable cause of sporadic encephalitis. Mortality without treatment approaches 70%, reduced to 20-30% with acyclovir therapy.[11] Critically, outcome is directly correlated with neurological status at treatment initiation—every hour counts.

Oyster: Acyclovir is both nephrotoxic and neurotoxic. Ensure adequate hydration (500mL normal saline before each dose), monitor renal function daily, and watch for acyclovir-induced neurotoxicity (confusion, myoclonus) particularly in patients with renal impairment.

Autoimmune Encephalitis: Immunotherapy Protocols

Once autoimmune encephalitis is suspected:

First-Line Immunotherapy:

Methylprednisolone 1g IV daily for 5 days, OR
IVIG 0.4 g/kg daily for 5 days, OR
Combination of both

Clinical Hack #5: Response to immunotherapy is the strongest confirmatory test while awaiting antibody results. Improvement within 7-10 days strongly supports autoimmune etiology.

If no response after 10-14 days:

Second-Line Immunotherapy:

Rituximab 375 mg/m² weekly for 4 weeks, OR
Cyclophosphamide 750 mg/m² monthly

Pearl #6: In anti-NMDA receptor encephalitis, earlier immunotherapy (within 4 weeks of symptom onset) is associated with better outcomes.[12] Do not delay treatment for antibody confirmation.

Seizure Management

Seizures occur in 60-75% of encephalitis cases. Clinical Hack #6: Load with an antiepileptic drug even if seizures have not occurred yet in a patient with encephalitis, as seizures worsen cerebral edema and metabolic stress.

Recommended: Levetiracetam 1000-1500mg IV load, then 500-1000mg twice daily (fewer drug interactions, no hepatic metabolism).

Consider continuous EEG monitoring, as non-convulsive status epilepticus occurs in up to 20% of encephalitis patients.[13]

Supportive Care and Complications

Intracranial Pressure Management:

Monitor for signs of elevated ICP: worsening headache, vomiting, papilledema, Cushing's triad
Consider ICP monitoring in comatose patients
Hyperosmolar therapy with hypertonic saline (preferred over mannitol for sustained control)

Complications to Anticipate:

SIADH (monitor sodium every 6-12 hours initially)
Aspiration pneumonia
Venous thromboembolism (prophylaxis essential)
Autonomic dysregulation in anti-NMDA receptor encephalitis

Prognosis and Long-Term Outcomes

Full neurological recovery occurs in approximately 40-50% of HSV encephalitis survivors, with cognitive impairment being the most common residual deficit.[14] Autoimmune encephalitis generally has better outcomes, with 70-80% achieving good recovery, though relapse occurs in 12-35% of cases, necessitating long-term follow-up.[15]

Pearl #7: All encephalitis survivors require neuropsychological assessment at 3-6 months post-discharge to identify cognitive deficits requiring rehabilitation.

Conclusion

Encephalitis diagnosis and management demands vigilance, rapid decision-making, and willingness to treat empirically while investigations proceed. The expanding recognition of autoimmune causes has transformed our diagnostic approach, but HSV encephalitis remains a critical treatable emergency. Success depends on maintaining high clinical suspicion, initiating early empirical therapy, pursuing comprehensive yet targeted diagnostics, and providing meticulous supportive care.

The dictum remains: When in doubt, treat. The consequences of undertreating encephalitis far outweigh the risks of short-term empirical acyclovir and immunotherapy.

References

Granerod J, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010;10(12):835-844.
Glaser CA, et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis. 2006;43(12):1565-1577.
Bradshaw MJ, Venkatesan A. Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management. Neurotherapeutics. 2016;13(3):493-508.
Tunkel AR, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47(3):303-327.
Solomon T, et al. Management of suspected viral encephalitis in adults. J Infect. 2012;64(4):347-373.
Tyler KL. Acute viral encephalitis. N Engl J Med. 2018;379(6):557-566.
Wilson MR, et al. Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis. N Engl J Med. 2019;380(24):2327-2340.
Dubey D, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018;83(1):166-177.
Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013;310(17):1842-1850.
Steiner I, et al. Viral encephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol. 2010;17(8):999-e57.
Whitley RJ, et al. Herpes simplex encephalitis: clinical assessment. JAMA. 1982;247(3):317-320.
Titulaer MJ, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.
Claassen J, et al. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology. 2004;62(10):1743-1748.
Sili U, et al. Herpes simplex virus encephalitis: clinical manifestations, diagnosis and outcome in 106 adult patients. J Clin Virol. 2014;60(2):112-118.
Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med. 2018;378(9):840-851.

Word count: ~2000 words

Search This Blog

Internal medicine