Autoimmune Encephalitis: Symptoms, Types, Causes and Treatment

Autoimmune encephalitis (AE) is a rapidly advancing and often misunderstood set of disorders in which the body's own immune system attacks the brain, leading to a wide range of neurological and psychiatric symptoms. Early recognition and treatment are crucial, as many cases are highly responsive to immunotherapy. In this article, we’ll break down the core features of AE, including its symptoms, main types, underlying causes, and current treatment strategies, using the latest evidence from clinical research.

Symptoms of Autoimmune Encephalitis

Autoimmune encephalitis presents with a variety of neurological and psychiatric symptoms that can be subtle or dramatic. Understanding the symptom profile is crucial for early recognition and effective intervention.

Symptom	Description	Prevalence/Group	Source(s)
Psychiatric	Behavioral changes, psychosis, delusions	Most common; up to 82% of cases	2 4 5
Seizures	New-onset or refractory	~60% in anti-NMDAR encephalitis	3 4 2
Memory/Cognition	Deficits, confusion, disorientation	Common in adults	3 6
Movement	Chorea, dystonia, hyperkinesia, catatonia	More frequent in children	1 5
Autonomic	Instability, dysfunction	Up to 58% with anti-NMDAR	4 2
Sleep	Disturbances, insomnia	About 45% in some cohorts	4

Table 1: Key Symptoms

Overview of Symptom Presentation

Autoimmune encephalitis often begins with a subacute onset, developing over days to weeks. The most frequent initial symptoms are psychiatric, such as behavioral disturbances, mood changes, hallucinations, or psychosis. In some studies, psychiatric symptoms are the presenting feature in up to 60–80% of cases, often leading to misdiagnosis as primary psychiatric disorders 2 4. Memory loss and cognitive decline are also common, especially in adults 3 6.

Psychiatric and Behavioral Symptoms

• Psychosis, hallucinations, and delusions are hallmark features, particularly in adults and adolescents.
• Catatonia and severe agitation may occur, and can be mistaken for primary psychiatric disorders.

Seizures and Neurological Signs

• Seizures are frequent, especially with anti-NMDA receptor (NMDAR) encephalitis, affecting around 60% of patients 4.
• Movement disorders such as choreoathetosis (involuntary writhing), dystonia, or hyperkinesia are more common in children 1 5.
• Speech disorders and mutism are seen in both children and adults.

Autonomic and Systemic Features

• Autonomic dysfunction can manifest as heart rate or blood pressure fluctuations, temperature instability, and breathing problems 4.
• Sleep disturbances are also reported, including insomnia or excessive sleepiness.

Red Flags for Early Diagnosis

• Clinical warning signs ("red flags") such as new-onset seizures, catatonia, autonomic instability, and movement abnormalities should prompt consideration of AE, especially if psychiatric symptoms are prominent 2.

Types of Autoimmune Encephalitis

Autoimmune encephalitis is not a single disease, but a group of related disorders defined by specific autoantibodies and clinical features. Recognizing the different types is essential for diagnosis and treatment.

Type	Target Antigen / Feature	Common Group Affected	Source(s)
Anti-NMDAR	N-methyl-D-aspartate receptor	Children, young adults	4 8 7 1
Anti-LGI1	Leucine-rich glioma-inactivated 1	Older adults	4 7
Anti-GABABR	GABA-B receptor	Adults, often with seizures	4 7
Anti-CASPR2	Contactin-associated protein-like 2	Adults	4 7
Onconeural	Intracellular antigens (paraneoplastic)	Associated with tumors	3 7
Post-infectious	After viral encephalitis (e.g., HSV)	All ages	1 5 9

Table 2: Main Types of Autoimmune Encephalitis

Antibody-Mediated Encephalitides

Anti-NMDAR Encephalitis

• The most common type, especially in children and young adults.
• Presents with psychiatric symptoms, seizures, movement disorders, and autonomic instability 4 8.
• Frequently follows a viral infection, especially herpes simplex virus (HSV) 1 9.

Anti-LGI1, Anti-GABABR, Anti-CASPR2

• Anti-LGI1: More common in older adults, often manifests as limbic encephalitis (memory loss, confusion, seizures).
• Anti-GABABR: Marked by frequent seizures, sometimes associated with lung tumors 4 7.
• Anti-CASPR2: Associated with neuromyotonia, insomnia, and sometimes tumors.

Onconeural and Paraneoplastic Types

• Target intracellular antigens, commonly associated with underlying cancers 3 7.
• Often less responsive to immunotherapy.

Post-Infectious and Other Rare Forms

• Postviral Autoimmune Encephalitis: Can occur after HSV, SARS-CoV-2, or other infections; characterized by relapsing symptoms and autoantibody production 1 5 9 10.
• Newly recognized subtypes include those targeting mGluR5, DPPX, and GABAAR 7.

Causes of Autoimmune Encephalitis

Understanding why the immune system attacks the brain is a complex and evolving area. The causes span genetic, infectious, and paraneoplastic (tumor-related) mechanisms.

Cause	Mechanism	Key Details	Source(s)
Post-infectious	Immune response after viral infection	HSV, COVID-19, others	1 5 9 10
Paraneoplastic	Immune response to tumor antigens	Tumor triggers autoimmunity	3 7
Idiopathic	Unknown/primary autoimmunity	No clear trigger	6 7
Genetic	Genetic predisposition (rarely identified)	Under investigation	8

Table 3: Causes of Autoimmune Encephalitis

Post-Infectious Triggers

A significant number of AE cases follow viral infections, most notably herpes simplex virus (HSV) encephalitis 1 5 9. After the acute infection, new neurological symptoms may develop weeks later, often associated with autoantibodies such as anti-NMDAR. Other viruses, including SARS-CoV-2 (COVID-19), have also been linked to autoimmune processes in the brain 10.

• Mechanism: Infection may disrupt the blood-brain barrier and expose neuronal antigens, triggering a misdirected immune response 5 8.
• Clinical clues: Relapse or worsening after initial improvement from viral encephalitis should prompt suspicion for post-infectious AE 1 5.

Paraneoplastic Mechanisms

Some AE cases are associated with tumors (paraneoplastic syndrome). The immune system’s attempt to attack tumor antigens inadvertently targets similar proteins in the brain 3 7.

• Common tumors: Ovarian teratomas (especially in young women), small cell lung cancer, and thymomas.
• Screening: Tumor search is essential in new AE diagnosis, especially in adults.

Idiopathic and Genetic Factors

In some cases, no clear trigger is identified. Genetic predisposition is suspected but not well-defined 6 8. Research continues into potential environmental and genetic risk factors.

Treatment of Autoimmune Encephalitis

Early and aggressive treatment is vital for improving outcomes in autoimmune encephalitis. A range of immunotherapies are used, tailored to disease severity and response.

Treatment	Description	Use/Indication	Source(s)
Corticosteroids	Reduce inflammation	First-line	14 16 5
IVIG/Plasma Exchange	Remove autoantibodies	First-line, severe cases	14 16 5
Rituximab	B-cell depletion therapy	Second-line	14 16
Cyclophosphamide	Broad immunosuppression	Second-line, refractory	14 16
Tumor removal	Surgery/oncology	Paraneoplastic cases	3 14
Advanced therapies	Cytokine inhibitors, plasma cell therapies, etc.	Refractory cases	16

Table 4: Treatment Options

First-Line Therapies

• Corticosteroids: Administered intravenously to rapidly suppress inflammation.
• Intravenous immunoglobulin (IVIG) and plasma exchange: Remove circulating autoantibodies, especially useful in severe or rapidly progressing cases 14 16 5.

Second-Line and Advanced Therapies

If first-line treatments fail or only partially succeed:

• Rituximab: Targets and depletes B cells that produce pathogenic antibodies 14 16.
• Cyclophosphamide: A potent immunosuppressant, used for resistant cases.

For a small group of patients with refractory AE (not responding to standard treatments), options include:

• Cytokine inhibitors: Drugs like tocilizumab or anakinra, targeting inflammatory pathways.
• Plasma cell-depleting agents: Such as bortezomib, especially for antibody-driven disease.
• Intrathecal therapies: Direct administration of drugs into the spinal fluid 16.

Tumor Screening and Treatment

For paraneoplastic AE, identifying and treating the underlying tumor is essential. Tumor removal can sometimes lead to dramatic neurological improvement 3 14.

Importance of Early and Ongoing Intervention

• Early diagnosis and treatment are strongly associated with better functional outcomes and fewer relapses 14 4.
• Relapse monitoring is important, as AE can recur, necessitating long-term follow-up 3.

Conclusion

Autoimmune encephalitis is a diverse group of treatable brain disorders that require timely recognition and intervention. As our understanding grows, so does the spectrum of antibodies, triggers, and targeted treatments.

Key takeaways:

• AE can present with a combination of psychiatric, cognitive, and neurological symptoms, often mimicking psychiatric or infectious disorders.
• The disorder includes several subtypes, most notably anti-NMDAR encephalitis, and can be triggered by infections (especially HSV), tumors, or remain idiopathic.
• Prompt initiation of immunotherapy—corticosteroids, IVIG, plasma exchange, and second-line agents—is critical for optimal recovery.
• Tumor screening is mandatory in many cases, and ongoing follow-up is essential to detect relapses or manage long-term effects.
• Increased awareness among clinicians and the public can reduce diagnostic delays, improving outcomes and quality of life for those affected.

Autoimmune encephalitis is a medical emergency but, with early intervention, one with a high potential for recovery.