Definition and epidemiology
Encephalitis is inflammation of the brain parenchyma, distinguished from meningitis (inflammation of the meninges) by the presence of altered mental status, seizures, or focal neurologic deficits. Many patients have overlapping features termed meningoencephalitis.
- Incidence is roughly 5-10 per 100,000 person-years worldwide, varying by region and surveillance.
- Bimodal age distribution: young children and adults over 65 are most commonly affected.
- Herpes simplex virus (HSV-1) is the leading identified cause of sporadic, non-epidemic encephalitis in high-income countries.
- Globally, arboviruses (e.g., Japanese encephalitis virus, West Nile virus, tick-borne encephalitis virus) are major causes, with geographic and seasonal clustering.
- Autoimmune encephalitis (e.g., anti-NMDA receptor encephalitis) is increasingly recognized and may be as common as viral causes in some case series, particularly in young women and in association with ovarian teratoma.
- In up to 40-50% of cases, no causative organism is identified despite extensive workup.
- Empiric IV acyclovir should be started immediately whenever HSE is suspected, before CSF PCR confirms the diagnosis.
- HSV encephalitis classically localizes to the medial temporal and inferior frontal lobes on MRI.
- CSF in viral encephalitis typically shows lymphocytic pleocytosis with normal glucose.
- Confirmed HSV encephalitis requires a full 14-21 day course of IV acyclovir; oral step-down is not recommended due to poor CSF penetration.
- Anti-NMDA receptor encephalitis presents with psychiatric symptoms, seizures, and movement disorders, often with an ovarian teratoma in young women.
- PLEDs on EEG over the temporal lobe support a diagnosis of HSV encephalitis.
- Untreated HSV encephalitis has roughly 70% mortality; early treatment markedly reduces this.
- Low CSF glucose points away from viral encephalitis toward bacterial, tuberculous, or fungal infection.
Etiology and risk factors
Infectious causes
- Herpesviruses: HSV-1 (most common sporadic cause), HSV-2 (more often meningitis, but can cause encephalitis especially in neonates), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV, especially in immunocompromised), human herpesvirus 6 (HHV-6, especially post-transplant).
- Arboviruses: West Nile virus, Japanese encephalitis virus, St. Louis encephalitis virus, tick-borne encephalitis virus, Eastern/Western equine encephalitis viruses.
- Enteroviruses: more common in children.
- Rabies virus: via animal bite, long incubation, almost universally fatal once symptomatic.
- Bacterial/other: Listeria monocytogenes, Mycobacterium tuberculosis, Treponema pallidum, Mycoplasma pneumoniae, Bartonella henselae.
- Parasitic/fungal: Toxoplasma gondii and Cryptococcus neoformans in HIV/AIDS; Naegleria fowleri (primary amebic meningoencephalitis) after freshwater exposure.
Non-infectious (autoimmune/paraneoplastic) causes
- Anti-NMDA receptor encephalitis (associated with ovarian teratoma in young women).
- Limbic encephalitis associated with anti-LGI1, anti-CASPR2, or classic paraneoplastic antibodies (anti-Hu, anti-Ma2).
- Acute disseminated encephalomyelitis (ADEM), typically post-infectious or post-vaccination in children.
Risk factors
- Age extremes (young children, older adults).
- Immunosuppression (HIV, transplant, chemotherapy) increases risk of opportunistic causes (CMV, Toxoplasma, HHV-6).
- Geographic/seasonal exposure (mosquito or tick season, endemic regions).
- Animal or insect bites (rabies, arboviruses).
- Unvaccinated status (measles, Japanese encephalitis, rabies where vaccines are available).
Pathophysiology
Viral encephalitis results from direct viral invasion and replication within neurons and glial cells, triggering neuronal injury, perivascular inflammation, and microglial activation. HSV-1 classically reactivates from latency in the trigeminal ganglion and spreads along olfactory and temporal pathways, producing hemorrhagic necrosis preferentially in the medial temporal lobes, insular cortex, and inferior frontal lobes — the pathologic basis for the characteristic MRI and EEG findings.
Autoimmune encephalitis involves antibody-mediated dysfunction of neuronal surface or synaptic proteins (e.g., NMDA receptor internalization) rather than direct cytotoxic destruction, which is why many cases are reversible with immunotherapy and recovery can be more complete than after necrotizing viral infection.
Secondary injury in both forms arises from cerebral edema, blood-brain barrier breakdown, and in severe cases, raised intracranial pressure and herniation.
Clinical features
The classic triad is fever, headache, and altered mental status, but presentations vary widely by etiology and age.
- Fever (variable, may be absent in autoimmune cases)
- Headache, nausea, vomiting
- Altered consciousness: confusion, lethargy, coma
- Seizures (focal or generalized), often early and prominent in HSE
- Focal neurologic deficits: aphasia, hemiparesis, cranial nerve palsies
- Behavioral and personality changes, psychosis (classic for anti-NMDA receptor encephalitis, especially in young women)
- Movement disorders (orofacial dyskinesias, choreoathetosis) suggest autoimmune etiology
- Autonomic instability (tachycardia, hyperthermia, hypoventilation) in severe autoimmune encephalitis
- Meningismus (neck stiffness, photophobia) if meningeal involvement coexists
Diagnosis
Diagnosis combines clinical suspicion, neuroimaging, CSF analysis, and etiology-specific testing. Empiric treatment should not be delayed while awaiting results.
CSF analysis (lumbar puncture, after excluding contraindications)
- Lymphocytic pleocytosis (typically 10-500 cells/mm3)
- Normal or mildly elevated protein
- Normal or mildly low glucose (markedly low glucose suggests bacterial, fungal, or tuberculous process instead)
- CSF HSV PCR is the gold standard for HSE; sensitivity is high but can be falsely negative very early in illness, warranting repeat testing if suspicion remains
Neuroimaging
- MRI brain (preferred over CT): T2/FLAIR hyperintensity in medial temporal lobes, insula, and inferior frontal lobes is classic for HSE
- CT may be normal early and is mainly used to exclude mass effect before lumbar puncture
EEG
- Periodic lateralized epileptiform discharges (PLEDs) over the temporal lobe support HSE
- Diffuse slowing is nonspecific but common
Other
- Serum and CSF autoimmune antibody panels (e.g., anti-NMDA receptor antibody) when autoimmune etiology suspected
- Blood cultures, serologies, and travel/exposure history to guide testing for arboviruses, rabies, or opportunistic infections
- Imaging for underlying tumor (e.g., pelvic ultrasound/MRI for ovarian teratoma) in suspected anti-NMDA receptor encephalitis
- Brain biopsy is rarely needed, reserved for atypical or progressive cases of unclear etiology
Differential diagnosis
| Condition | Distinguishing feature |
|---|---|
| Bacterial meningitis | Markedly low CSF glucose, neutrophilic pleocytosis, nuchal rigidity prominent |
| Autoimmune encephalitis | Subacute psychiatric symptoms, movement disorder, often normal/mild MRI |
| Acute disseminated encephalomyelitis (ADEM) | Multifocal white matter lesions, recent infection/vaccination, mostly children |
| Toxic-metabolic encephalopathy | No fever/CSF pleocytosis, history of drug/toxin exposure or organ failure |
| Brain abscess | Focal ring-enhancing lesion on imaging, often with sinus/ear source |
| Nonconvulsive status epilepticus | EEG shows ongoing seizure activity, no CSF pleocytosis |
| Stroke | Sudden onset, vascular territory on imaging, no fever/pleocytosis |
| CNS vasculitis | Multifocal infarcts, abnormal vessel imaging |
Management
Empiric and supportive measures
- Start IV acyclovir empirically in any patient with suspected encephalitis as soon as the diagnosis is considered, before CSF PCR results return, because untreated HSE carries very high mortality
- Supportive care: airway protection, seizure control with antiepileptics, ICU-level monitoring for raised intracranial pressure or autonomic instability
- Treat raised intracranial pressure if present using standard neurocritical care measures
Etiology-directed therapy
- HSV encephalitis: a full course of IV acyclovir (14-21 days) is required; guidelines (including IDSA) explicitly recommend against switching to oral agents such as valacyclovir, because oral antivirals achieve inadequate CSF penetration and carry a high risk of relapse. Treatment is stopped only if PCR is negative and an alternative diagnosis is confirmed
- VZV encephalitis: IV acyclovir for the guideline-recommended duration
- CMV: ganciclovir or foscarnet, mainly in immunocompromised patients
- Bacterial causes identified or suspected: empiric antibacterial coverage (e.g., ceftriaxone plus vancomycin, with ampicillin added if Listeria is a concern) pending culture results
- Autoimmune encephalitis: immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange as first line), escalating to rituximab or cyclophosphamide if refractory; tumor removal (e.g., teratoma resection) is essential when an underlying neoplasm is found
- Rabies: supportive care only once symptomatic; prevention via post-exposure prophylaxis is key
- Guideline consensus (IDSA, European and WHO recommendations) agrees on early empiric acyclovir, a full IV course for confirmed HSE, and supportive ICU care as the universal foundation of management; second-line immunotherapy choices for autoimmune encephalitis vary somewhat by society and local protocol
Complications and prognosis
- Mortality for untreated HSE approaches 70%; with early acyclovir, mortality falls substantially but significant long-term morbidity remains common
- Residual deficits: memory impairment (especially with temporal lobe/hippocampal damage), seizures/epilepsy, personality change, aphasia
- Autoimmune encephalitis has a more variable course; many patients, especially with anti-NMDA receptor encephalitis, show substantial recovery with timely immunotherapy and tumor treatment, though relapse can occur
- Children with ADEM generally have a favorable prognosis with corticosteroid treatment
- Delayed diagnosis and delayed initiation of acyclovir are the strongest modifiable predictors of poor outcome in HSE
HSE localization — think "TIE" lobes: Temporal, Insular, inferior frontal (Extratemporal) regions are classically affected on MRI.
Practice questions
1. A 45-year-old man presents with 2 days of fever, headache, and progressive confusion. He has a witnessed focal seizure involving the right arm. MRI shows T2 hyperintensity in the left medial temporal lobe and insula. CSF shows 80 WBC/mm3 (lymphocyte-predominant), normal glucose, and mildly elevated protein. What is the most appropriate immediate next step?
2. A 24-year-old woman is brought in for new-onset psychosis, agitation, and orofacial dyskinesias over the past two weeks, followed by a generalized seizure. MRI is largely unremarkable. CSF shows mild lymphocytic pleocytosis. Which of the following is most likely to be found on further workup?
3. A 6-year-old boy develops fever and multifocal neurologic deficits (ataxia, weakness, confusion) two weeks after a documented viral upper respiratory infection. MRI shows multiple bilateral white matter lesions in the brain and spinal cord. CSF shows mild lymphocytic pleocytosis. What is the most likely diagnosis?
Frequently asked questions
What causes encephalitis?
Encephalitis is most often caused by viral infection, with herpes simplex virus being the leading identifiable cause in sporadic cases, though arboviruses, other herpesviruses, and enteroviruses are also common. Autoimmune processes, such as anti-NMDA receptor encephalitis, are an increasingly recognized non-infectious cause. Bacterial, fungal, and parasitic causes occur mainly in specific exposure or immunocompromised settings. In nearly half of cases, no specific cause is ever identified.
What are the first symptoms of encephalitis?
The earliest symptoms are usually fever, headache, and a flu-like prodrome, followed within hours to days by altered mental status such as confusion or lethargy. Seizures and focal neurologic signs like weakness or speech difficulty often develop next. In autoimmune encephalitis, early symptoms may instead be psychiatric, such as new-onset agitation, hallucinations, or personality change, which can delay recognition.
How is encephalitis diagnosed?
Diagnosis relies on a combination of brain MRI, lumbar puncture with CSF analysis and PCR testing, and EEG, interpreted alongside the clinical picture. CSF typically shows lymphocytic pleocytosis, and PCR for herpes simplex virus is the key confirmatory test for HSV encephalitis. MRI showing temporal lobe changes strongly supports this diagnosis. Additional antibody testing is used when autoimmune encephalitis is suspected.
Is encephalitis curable?
Many cases of encephalitis are treatable and patients can recover, especially when caused by herpes simplex virus and treated promptly with a full course of IV acyclovir, or when autoimmune in origin and treated with immunotherapy. However, recovery is not guaranteed, and delayed treatment, particularly in HSV encephalitis, is linked to significant mortality and lasting neurologic deficits such as memory loss or epilepsy. Some causes, like rabies, remain almost universally fatal once symptoms appear.
Encephalitis vs meningitis — what is the difference?
Meningitis is inflammation limited to the meninges, presenting mainly with fever, headache, and neck stiffness without altered brain function, while encephalitis involves inflammation of the brain tissue itself, producing confusion, seizures, or focal neurologic deficits in addition to those symptoms. Many patients have features of both, called meningoencephalitis. The presence of altered mental status or focal deficits is the key clinical clue pointing toward brain parenchymal involvement.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: A86
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.