What is autoimmune encephalitis?

Autoimmune Encephalitis

Autoimmune encephalitis (AE) is a group of non-infectious immune-mediated inflammatory disorders of the brain parenchyma often involving the cortical or deep grey matter with or without involvement of the white matter, meninges or the spinal cord. 1

Definition and Pathophysiology

• AE comprises inflammatory conditions where the immune system mistakenly attacks brain tissue, leading to neurological and psychiatric symptoms 1
• Originally described in the context of paraneoplastic conditions, but now recognized to occur with or without associated tumors 1
• Can be antibody-mediated (targeting cell-surface or synaptic proteins) or cell-mediated (targeting intracellular antigens) 1

Clinical Presentation

• Typically presents with acute or subacute onset (less than 3 months duration) 1
• Chronic presentations are less common but can occur in specific subtypes (LGI1, CASPR2, DPPX, and GAD65-antibody encephalitis) 1
• Often preceded by viral infection, fever, or viral-like prodrome 1
• May be triggered by herpes simplex virus encephalitis or immune-modulating therapies such as TNFα inhibitors and immune-checkpoint inhibitors 1

Common Clinical Features:

• Cognitive dysfunction and memory impairment 1
• Psychiatric symptoms (psychosis, hallucinations, agitation) 2
• Seizures, including new-onset refractory status epilepticus (NORSE) 1
• Movement disorders (dystonia, dyskinesia) 2
• Autonomic dysfunction (blood pressure fluctuations, cardiac arrhythmias) 1
• Speech disorders 2
• Decreased level of consciousness 1

Diagnostic Approach

Step 1: Confirm focal or multifocal brain pathology

• Brain MRI with and without contrast (may show T2/FLAIR hyperintensities in limbic regions or other areas) 1
• EEG if MRI is negative or if patient is encephalopathic/having seizures (may show focal slowing, seizures, lateralized periodic discharges) 1
• Brain FDG-PET if MRI is negative and diagnosis remains uncertain (may show hypermetabolism or hypometabolism patterns specific to certain AE subtypes) 1

Step 2: Confirm inflammatory etiology

• Lumbar puncture for CSF analysis:
  • Cell count, protein, glucose, oligoclonal bands, IgG index 1
  • CSF neuronal autoantibodies panel 1
  • Rule out infectious causes (viral PCR, bacterial culture) 1
• Blood tests:
  • Serum neuronal autoantibodies panel 1
  • Inflammatory markers, antithyroid antibodies, metabolic panel 1
  • Sodium level monitoring (hyponatremia is common in LGI1-antibody encephalitis) 1

Step 3: Screen for associated neoplasm

• CT chest, abdomen, and pelvis with contrast 1
• Mammogram/breast MRI in relevant cases 1
• Pelvic or testicular ultrasound 1
• Whole body FDG-PET if initial screening is negative 1

Treatment

Acute Management

• First-line immunotherapy:

  • Intravenous methylprednisolone (IVMP) is the most commonly used first-line agent (chosen by 84% of specialists for general AE presentation) 1
  • Intravenous immunoglobulin (IVIG) if steroids are contraindicated or ineffective 1
  • Plasma exchange (PLEX) particularly effective in patients with high thromboembolic risk or severe hyponatremia 1
  • Combined first-line therapies may be considered in severe cases (e.g., NMDAR-antibody encephalitis, new-onset refractory status epilepticus) 1

• Second-line immunotherapy (if no response to first-line agents):

  • Rituximab (preferred by 80% of specialists) for antibody-mediated autoimmunity 1
  • Cyclophosphamide for suspected cell-mediated autoimmunity 1
  • Half of specialists recommend adding second-line therapy only after failure of multiple first-line agents, while 32% recommend adding after failure of one first-line agent 1

• For refractory cases:

  • Consider experimental therapies such as IL-6 inhibitors (tocilizumab) or bortezomib 1, 3

Supportive Care

• Antiseizure medications for seizure control 1
• Management of dysautonomia (monitoring blood pressure and heart rate) 1
• Careful correction of hyponatremia if present 1
• Temporary pacemaker may be needed for severe dysrhythmia 1
• Intracranial pressure monitoring in cases with massive inflammation and brain edema 1

Prognosis

• Early aggressive treatment is associated with better functional outcomes and fewer relapses 4
• Approximately half of patients require second-line immunotherapy 4
• A small but significant proportion of patients are refractory to all first- and second-line therapies 3
• Chronic disability is common despite treatment, highlighting the need for comprehensive rehabilitation 5

Common Pitfalls and Caveats

• Delay in diagnosis and treatment can lead to worse outcomes - consider AE early in patients with unexplained neuropsychiatric symptoms 1
• Neuronal autoantibody results are often unavailable during initial evaluation - treatment should not be delayed while waiting for antibody results 1
• Normal CSF studies do not exclude AE - testing for neuronal autoantibodies is still recommended with high clinical suspicion 1
• AE can mimic primary psychiatric disorders, infectious encephalitis, or neurodegenerative conditions 1
• Blood samples for antibody testing should be collected before treatment with IVIG or PLEX to avoid false results 1