What is the next best step in diagnosing and managing a patient with worsening cognitive symptoms and suspected autoimmune encephalitis despite a recent negative brain MRI?

Diagnostic Approach for Suspected Autoimmune Encephalitis with Negative MRI

For a patient with worsening cognitive symptoms, word-finding difficulties, brain fog, confusion, and paresthesias despite a negative brain MRI, a lumbar puncture is the next best step to diagnose suspected autoimmune encephalitis, as it can confirm inflammatory etiology and detect neuronal autoantibodies even when MRI is negative. 1

Diagnostic Algorithm for Suspected AE with Negative MRI

Step 1: Confirm Brain Pathology When MRI is Negative

1. Perform EEG

   • Can provide evidence of focal/multifocal brain abnormality when MRI is negative 1
   • Look for findings suggestive of AE:
     • Focal slowing/seizures
     • Lateralized periodic discharges
     • Extreme delta brush (seen in NMDAR-antibody encephalitis)
   • Normal EEG does not exclude AE but helps rule out subclinical seizures 1

2. Consider Brain FDG-PET

   • More sensitive than MRI in detecting abnormalities in AE 1
   • Can confirm focal or multifocal brain abnormality when MRI is negative
   • Essential when there is high clinical suspicion despite negative MRI 2

Step 2: Confirm Inflammatory Etiology (Critical Next Step)

1. Perform Lumbar Puncture

   • CSF analysis should include:
     • Cell count and differential
     • Protein and glucose levels
     • IgG index and oligoclonal bands
     • CSF neuronal autoantibodies panel
     • Infectious studies (PCR for HSV and other viruses)
     • Cytology to rule out malignant cells 1, 2
   • May reveal elevated WBC with lymphocytic predominance and/or elevated protein 1

2. Blood Tests

   • Serum neuronal autoantibody panel
   • Complete blood count, chemistry panel
   • Inflammatory markers (ESR, CRP)
   • Thyroid panel including TPO and thyroglobulin
   • AM cortisol and ACTH
   • Autoimmune panels 1

Step 3: Screen for Associated Neoplasm

• CT chest, abdomen, and pelvis with contrast
• Additional targeted testing based on antibody results:
  • Mammogram/breast MRI
  • Pelvic or testicular ultrasound
  • Whole-body PET if initial screen negative 1

Treatment Considerations

If autoimmune encephalitis is confirmed or strongly suspected after diagnostic workup:

1. First-line therapy:

   • High-dose corticosteroids (IV methylprednisolone 1g daily for 3-5 days)
   • Consider IVIG (2g/kg over 5 days) or plasma exchange if steroids contraindicated or ineffective 1

2. Second-line therapy if no improvement after 2-4 weeks:

   • Rituximab for antibody-mediated autoimmunity
   • Cyclophosphamide for cell-mediated autoimmunity 1

Common Pitfalls to Avoid

1. Delayed diagnosis

   • Don't wait for antibody results to initiate workup
   • Prompt immunotherapy after ruling out infection improves outcomes 2

2. Overreliance on MRI findings

   • Up to 20% of AE cases may have normal MRI findings 2
   • EEG and CSF findings can be diagnostic even with normal MRI 1

3. Inadequate cancer screening

   • Many AE cases are paraneoplastic and require thorough cancer evaluation 1
   • Early tumor detection and treatment significantly improves outcomes 3

4. Missing coexisting antibodies

   • Some patients may have multiple antibodies contributing to clinical presentation 4
   • Comprehensive antibody testing in both serum and CSF is essential

In this patient with progressive cognitive symptoms despite a negative MRI, the lumbar puncture is crucial as the next diagnostic step, as it can provide definitive evidence of inflammation and autoimmunity even when imaging appears normal.