What is autoimmune encephalitis?

What is Autoimmune Encephalitis?

Autoimmune encephalitis (AE) is a group of non-infectious immune-mediated inflammatory disorders of the brain parenchyma caused by a misdirected immune response against self-antigens in the central nervous system, often involving cortical or deep grey matter with or without involvement of white matter, meninges, or spinal cord. 1

Core Definition and Pathophysiology

• AE represents inflammatory brain disorders characterized by the immune system attacking neuronal or glial antigens, resulting in diffuse brain inflammation 1, 2
• The immune reaction typically causes multifocal brain inflammation that may extend to the meninges, spinal cord, and/or peripheral nervous system 1
• These disorders are at least as common as infectious causes of encephalitis 2

Classification Systems

AE can be classified in three practical ways 1:

Anatomical Classification

• Limbic (affecting memory and temporal lobe structures)
• Cortical/subcortical (affecting outer brain layers)
• Striatal (affecting basal ganglia)
• Diencephalic (affecting thalamus/hypothalamus)
• Brainstem
• Encephalomyelitis (brain and spinal cord)
• Meningoencephalitis (brain and meninges) 1

Serological Classification

• Antibodies to intracellular antigens (classical onconeuronal antibodies) 1
• Antibodies to surface antigens with high clinical relevance (NMDAR, AMPAR, LGI1, CASPR2, GABA receptors, DPPX, glycine receptor, AQP4, MOG, GFAP) 1
• Antibodies to surface antigens with low clinical relevance (VGKC, VGCC) 1

Etiological Classification

• Idiopathic (no identifiable trigger)
• Paraneoplastic (associated with underlying malignancy)
• Postinfectious (triggered by viral infections like HSV, VZV, or EBV) 1, 3
• Iatrogenic (caused by immune checkpoint inhibitors or TNFα inhibitors) 1

Clinical Presentation

Temporal Pattern

• Acute or subacute onset with symptom duration typically less than 3 months 1
• Chronic presentations occur only with specific antibodies (LGI1, CASPR2, DPPX, GAD65) and should otherwise raise suspicion for neurodegenerative disease 1
• Hyperacute presentations are atypical and suggest vascular etiology 1
• Relapses are rare and usually result from insufficient treatment or rapid immunotherapy interruption 1

Characteristic Features

• Polysyndromic presentation is a clinical hallmark, with multiple neurological domains affected simultaneously 1
• Preceding viral infection, fever, or viral-like prodrome is common 1
• Neurological manifestations in children include seizures, movement disorders, and focal neurological deficits more prominently than psychiatric symptoms 4
• Psychiatric symptoms in children manifest as temper tantrums, aggression, and agitation rather than psychosis 4

Antibody-Specific Syndromes

While significant symptom overlap exists between all antibodies, some have stereotypical presentations 1:

• NMDAR-antibody encephalitis: oromandibular dyskinesia, cognitive/behavioral changes, speech and autonomic dysfunction 1
• LGI1-antibody encephalitis: faciobrachial dystonic seizures (highly steroid-responsive), hyponatremia in ~55% of cases 1, 5

Risk Factors

• For paraneoplastic AE: known cancer, smoking, elderly age, rapid unintentional weight loss 1
• For idiopathic AE: personal or family history of other autoimmune disorders 1
• Triggers: HSV encephalitis, immune checkpoint inhibitors (causing accelerated paraneoplastic encephalitis), TNFα inhibitors 1

Diagnostic Approach

Initial Workup

• Brain MRI with contrast to identify anatomical patterns and exclude alternative diagnoses 1
• CSF analysis including cell count, protein, glucose, viral PCR studies, oligoclonal bands, and IgG index 3
• EEG to detect abnormalities supporting the diagnosis 3
• Brain FDG-PET for confirming focal or multifocal brain pathology 3

Diagnostic Criteria

Major criterion: Altered mental status (decreased consciousness, lethargy, or personality change) lasting ≥24 hours with no alternative cause 3

Minor criteria (supporting probable/confirmed diagnosis) 3:

• Documented fever ≥38°C within 72 hours of presentation
• New onset seizures
• New focal neurological findings
• CSF white blood cell count ≥5/cubic mm
• Brain MRI abnormalities
• EEG abnormalities

Key Diagnostic Principle

• Clinicians must approach AE initially as a clinical entity when deciding on investigations and treatment, as antibody results are often unavailable during early evaluation 1
• Bilateral limbic encephalitis on MRI is the only imaging finding sufficient to diagnose definite AE in the correct clinical setting (with negative CSF viral studies), even without antibody confirmation 1

Prognosis and Treatment Implications

• Most patients respond within weeks to immunotherapy with good outcomes when treatment is prompt 5
• Early immunotherapy is crucial for better outcomes and prevention of cognitive dysfunction 5
• Monophasic course is more common in idiopathic AE, while progressive course may occur in paraneoplastic syndromes 1
• Prompt diagnosis and early treatment lead to substantial recovery in most patients despite severity of symptoms 6