Encephalitis is inflammation of the brain tissue, most commonly caused by viral infection or an abnormal autoimmune response directed against neuronal proteins. It is a serious, potentially life-threatening condition that can cause rapid neurological deterioration and requires urgent evaluation and treatment. Outcomes range from full recovery to significant long-term neurological disability — and in the case of untreated HSV encephalitis, death — depending on the cause, severity, and speed of diagnosis and treatment.
Encephalitis represents diffuse brain inflammation without a discrete pus cavity, distinguishing it from a focal brain abscess — though both conditions can coexist and must be considered together in any patient with fever and new neurological symptoms. The characteristic MRI pattern of temporal lobe signal abnormality in HSV encephalitis is one of the most recognizable and clinically important findings in neuroimaging. Autoimmune encephalitis, now recognized as the most common cause of encephalitis overall, frequently presents with prominent psychiatric features that can delay diagnosis — awareness of this condition is essential for early treatment and recovery.
Causes
Viral encephalitis
Viral infection is the most common cause of infectious encephalitis. Herpes simplex virus type 1 (HSV-1) is the most common and most important treatable cause of sporadic encephalitis in immunocompetent adults — it characteristically involves the temporal lobes and limbic system and carries a mortality of 70% if untreated, making empirical acyclovir a neurological emergency. Other viral causes include West Nile virus (causing a flaccid paralysis syndrome distinct from other encephalitides), enteroviruses, arboviruses transmitted by mosquitoes and ticks, varicella-zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). In immunocompromised patients — HIV/AIDS, transplant recipients, those on chemotherapy — opportunistic infections including CMV encephalitis and JC virus (causing progressive multifocal leukoencephalopathy, PML) are critical considerations, producing white matter signal abnormalities that can be difficult to distinguish from other etiologies.
Autoimmune encephalitis
Autoimmune encephalitis — caused by antibodies targeting neuronal surface proteins or intracellular antigens — has been increasingly recognized over the past two decades and is now the most common overall cause of encephalitis in many series. Anti-NMDA receptor encephalitis is the most common subtype, predominantly affecting young women and children. It characteristically presents with a prodromal phase of psychiatric symptoms (anxiety, psychosis, personality change) before overt neurological features — seizures, movement disorders (orofacial dyskinesias), autonomic instability, and decreased consciousness — emerge. It is associated with an underlying ovarian teratoma in approximately 50% of young women, making tumor screening essential. Other important autoimmune subtypes include LGI1, CASPR2, GABA-B, and AMPA receptor antibody encephalitides, each with distinct clinical signatures.
Post-infectious and para-infectious causes
Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating condition triggered by a preceding viral infection or vaccination — most commonly in children — producing multifocal white matter lesions and grey matter involvement on MRI. It can be difficult to distinguish from a first episode of multiple sclerosis and requires careful clinical and MRI follow-up.
Symptoms
Symptom patterns vary significantly by etiology but share common features of brain dysfunction:
- Fever and headache: The typical initial presentation — though absent in a significant proportion of autoimmune cases, where fever may be minimal or absent entirely.
- Altered consciousness and confusion: Ranging from mild disorientation to coma — a key indicator of diffuse brain involvement.
- Behavioral and psychiatric changes: Personality change, agitation, psychosis, and inappropriate behavior — particularly prominent in autoimmune encephalitis, where these features often precede overt neurological signs by days to weeks.
- Seizures: Common in both infectious and autoimmune encephalitis — temporal lobe seizures with déjà vu, emotional changes, and automatisms are characteristic of HSV encephalitis.
- Focal neurological deficits: Language difficulties (aphasia), memory loss, weakness, or sensory changes corresponding to the region of brain inflammation.
- Movement disorders: Orofacial dyskinesias (repetitive involuntary mouth and face movements) are characteristic of anti-NMDA receptor encephalitis.
- Autonomic instability: Fluctuating heart rate, blood pressure, and temperature — a serious complication requiring ICU-level monitoring in severe autoimmune encephalitis.
Diagnosis
MRI with gadolinium contrast is the most sensitive imaging tool and is essential in any patient with suspected encephalitis. In HSV encephalitis, MRI demonstrates characteristic T2/FLAIR hyperintensity in the medial temporal lobes, insula, and cingulate cortex — often asymmetric, with restricted diffusion and occasional cortical enhancement. This temporal lobe pattern on MRI is highly suggestive of HSV and should prompt immediate acyclovir initiation even before CSF results are available. Autoimmune encephalitis may show medial temporal lobe signal abnormality (particularly LGI1 and anti-NMDA receptor) or may have a normal MRI early in the disease course — a normal MRI does not exclude autoimmune encephalitis.
Lumbar puncture with CSF analysis is essential — showing elevated lymphocytes and protein in viral encephalitis, with PCR testing identifying HSV, CMV, VZV, enteroviruses, and other pathogens with high sensitivity. A comprehensive autoimmune antibody panel tested in both serum and CSF identifies autoimmune subtypes — CSF testing is more sensitive than serum for most antibodies and should always be included. EEG detects subclinical seizures, nonconvulsive status epilepticus, and characteristic patterns including extreme delta brush — a highly specific EEG finding for anti-NMDA receptor encephalitis. Whole-body CT or PET imaging screens for an underlying tumor (ovarian teratoma, thymoma, lung or breast cancer) in suspected autoimmune or paraneoplastic cases.
Classification
Encephalitis is classified by its underlying mechanism, which drives treatment strategy:
- Infectious encephalitis: Direct brain invasion by viral, bacterial, fungal, or parasitic pathogens. HSV-1 is the most common and most urgently treatable cause — empirical acyclovir should never be delayed.
- Autoimmune encephalitis: Antibody-mediated neuronal dysfunction — anti-NMDA receptor encephalitis is the most common subtype. Immunotherapy and tumor removal are the treatments of choice.
- Post-infectious / Para-infectious (ADEM): Immune-mediated demyelination triggered by prior infection or vaccination. More common in children. Treated with corticosteroids; must be distinguished from MS.
- Paraneoplastic encephalitis: Encephalitis driven by an immune response to an underlying malignancy — tumor identification and treatment is the essential therapeutic step alongside immunotherapy.
Treatments
Treatment must be initiated promptly — empirically, before a definitive diagnosis is established — as delays in treatment worsen outcomes, particularly for HSV encephalitis where hours matter.
Antiviral therapy:
High-dose intravenous acyclovir (10mg/kg every 8 hours) is initiated immediately in any patient with suspected viral encephalitis — this is a neurological emergency that should not await MRI or CSF results when clinical suspicion is high. Treatment is continued for 14–21 days in confirmed HSV encephalitis. Early acyclovir dramatically reduces HSV encephalitis mortality from 70% untreated to approximately 20–30%, and significantly reduces long-term neurological disability. Specific antiviral or antimicrobial therapy for other identified pathogens (ganciclovir for CMV, acyclovir for VZV) is substituted when culture and PCR results become available.
Immunotherapy for autoimmune encephalitis:
First-line immunotherapy — high-dose intravenous methylprednisolone, intravenous immunoglobulin (IVIG), and plasma exchange — is initiated promptly when autoimmune encephalitis is suspected, often empirically before antibody results are confirmed. Second-line agents — rituximab (anti-CD20 B-cell depletion) and cyclophosphamide — are used for patients who do not respond adequately to first-line treatment. Identifying and surgically removing an underlying tumor is a critical treatment step for paraneoplastic and teratoma-associated cases — tumor removal alone can produce dramatic clinical improvement in anti-NMDA receptor encephalitis. Recovery from autoimmune encephalitis can be prolonged over months but is often remarkable with sustained immunotherapy, even in severely affected patients requiring prolonged ICU care.
Supportive care:
Seizure management with antiepileptic medications, management of autonomic instability, nutritional support, and intensive rehabilitation are essential components of care. Patients with severe encephalitis frequently require ICU-level monitoring and prolonged inpatient rehabilitation. Long-term neuropsychological follow-up assesses cognitive recovery and guides return to work, school, and daily activities.
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