What are the characteristic clinical features of autoimmune encephalitis and the recommended diagnostic workup and treatment approach?

Autoimmune Encephalitis: Clinical Features and Management Approach

Start high-dose intravenous methylprednisolone (IVMP) immediately once infection is ruled out by basic CSF analysis, as early immunotherapy is critical for preventing permanent neurological damage and improving functional outcomes. 1

Clinical Features

Core Presenting Symptoms

Autoimmune encephalitis manifests with a characteristic constellation of neuropsychiatric symptoms that typically evolve subacutely over days to weeks:

• Cognitive impairment (90% of cases) - confusion, memory deficits, disorientation 2, 3
• Psychiatric symptoms (74%) - psychosis, behavioral changes, mood disorders, catatonia 3
• Seizures (65%) - including new-onset refractory status epilepticus (NORSE) in severe cases 1, 3
• Movement disorders (71%) - abnormal involuntary movements, faciobrachial dystonic seizures (particularly with LGI1 antibodies) 3
• Dysautonomia (58%) - blood pressure/heart rate fluctuations, requiring intensive monitoring 1, 3
• Decreased consciousness (32%) - ranging from lethargy to coma 4

Critical pitfall: The psychiatric symptoms often lead to initial misdiagnosis as primary psychiatric illness. Any patient with acute psychiatric symptoms plus seizures, movement disorders, or altered consciousness should trigger consideration of autoimmune encephalitis.

Diagnostic Workup Algorithm

Step 1: Initial Evaluation

Brain MRI and EEG are essential first-line tests to identify focal or multifocal brain abnormalities 1. However, normal imaging does not exclude the diagnosis - many cases show minimal inflammatory damage on conventional imaging 5.

Step 2: Lumbar Puncture (unless contraindicated)

Perform LP to:

• Rule out infectious/neoplastic causes
• Document inflammatory CSF profile
• Test for neuronal autoantibodies in CSF

Expected CSF findings:

• Elevated protein (56% of cases) 4
• Lymphocytic pleocytosis (71%) 4
• Oligoclonal bands, elevated IgG index/synthesis rate 1

Step 3: Antibody Testing

• Serum AND CSF neuronal autoantibodies (CSF more sensitive for many antibodies) 1
• Test for: NMDAR, LGI1, CASPR2, GABA-B, AMPA, GAD, VGKC, and others 6
• Important: 41% may be seronegative - do not withhold treatment if clinical suspicion is high 4

Step 4: Advanced Imaging When Initial Tests Uninformative

Brain FDG-PET should be considered when clinical suspicion remains high despite negative MRI/EEG 1

Step 5: Cancer Screening

Perform CT chest/abdomen/pelvis with contrast in all cases to identify potential paraneoplastic etiology 1. If negative and suspicion remains, add:

• Mammogram/breast MRI
• Pelvic ultrasound
• Whole body FDG-PET based on specific cancer risk factors 1

Treatment Algorithm

First-Line Immunotherapy

Initiate immediately once infection excluded - do not wait for antibody results 1

Standard approach:

1. High-dose IVMP (typically 1g daily × 3-5 days) is first choice for 84% of experts 1
2. Alternative if steroids contraindicated: IVIG or plasma exchange (PLEX) 1

Relative contraindications to steroids:

• Uncontrolled hypertension/diabetes
• Acute peptic ulcer
• Severe behavioral symptoms that worsen with steroids 1

When to Use Combination First-Line Therapy from the Start

Start combined steroids + IVIG or steroids + PLEX immediately (rather than sequentially) in severe presentations 1:

• Severe NMDAR-antibody encephalitis
• New-onset refractory status epilepticus (NORSE)
• Severe dysautonomia
• Rapidly progressive symptoms

Choosing between IVIG vs PLEX as add-on:

• IVIG first in: agitated patients, bleeding disorders 1
• PLEX first in: severe hyponatremia, high thromboembolic risk (cancer, smoking, hypertension, diabetes), associated demyelination 1

Escalation Strategy

If no improvement after first-line therapy:

1. Add second agent (IVIG or PLEX) if not already using combination 1

2. After 2-4 weeks of combined first-line therapy without improvement, escalate to second-line agents 1:

   • Rituximab - preferred (80% of experts) for antibody-mediated disease (e.g., NMDAR, LGI1, CASPR2) 1
   • Cyclophosphamide - for cell-mediated/paraneoplastic syndromes with intracellular antigens 1

3. If conventional second-line fails, consider experimental therapies:

   • Tocilizumab (IL-6 inhibitor)
   • Bortezomib
   • Ocrelizumab (in clinical trials) 1

Maintenance/Bridging Therapy

After acute treatment, initiate bridging therapy to prevent relapse 1:

• Gradual oral prednisone taper, OR
• Monthly IVIG, OR
• Monthly IV methylprednisolone

Critical Management Considerations

Supportive Care Priorities

• Dysautonomia monitoring: Continuous cardiac monitoring, temporary pacemaker may be needed for severe dysrhythmia 1
• Hyponatremia management: Usually SIADH-related; fluid restriction typically sufficient. Correct slowly to avoid central pontine myelinolysis 1
• Seizure management: Aggressive antiepileptic therapy; may require ICU-level care for status epilepticus
• ICP monitoring: Rarely needed but consider if massive inflammation/edema present 1

Common Pitfalls to Avoid

1. Delaying treatment while awaiting antibody results - antibodies may take weeks and 35-41% are seronegative 4
2. Single negative HSV PCR - if temporal lobe involvement present, repeat LP in 3-7 days as early HSV PCR can be falsely negative 6
3. Assuming normal MRI excludes diagnosis - many cases have minimal visible inflammation 5
4. Stopping at first-line monotherapy in severe cases - combination therapy from onset improves outcomes in severe presentations 1

Prognostic Factors

Poor functional outcome associated with:

• Older age at presentation 3
• Status epilepticus 3
• Delayed treatment initiation
• Absence of headache (paradoxically) 3

Despite aggressive treatment, only 58-82% achieve good functional recovery, with incomplete recovery and residual symptoms common 2, 3. This underscores the critical importance of early recognition and immediate immunotherapy initiation to optimize neurological outcomes and quality of life.