An Approach to Autoimmune Encephalitis

PATHCHAT Edition No. 81
Published: April 2023
Please contact your local Ampath pathologist for more information.

Authors:

• Dr. Lizelle Nagel
• Dr. Mark da Silva

Background

✅ What is Autoimmune Encephalitis (AE)?

• AE is caused by autoantibodies against intracellular, membrane, or synaptic neuronal proteins.
• Its prevalence and incidence are comparable to infectious encephalitis, with increasing detection.
• It presents with a wide range of clinical syndromes and diagnostic variants, often leading to confusion in classification.

✅ Limbic Encephalitis as a Primary Manifestation

• Limbic encephalitis is the most frequent clinical subtype of AE.
• It involves autoimmune inflammation of limbic structures, including:
  • Hippocampus.
  • Amygdala.
  • Hypothalamus.
  • Cingulate gyrus.
  • Limbic cortex.
• Symptoms evolve over days to weeks and include:
  • Acute or subacute mood and behavioural changes.
  • Short-term memory impairment.
  • Complex partial seizures.
  • Cognitive dysfunction.
  • Hypothalamic dysfunction.

✅ Paraneoplastic Autoimmune Encephalitis

• AE may be associated with an underlying cancer (paraneoplastic encephalitis).
• Common presentations include limbic encephalitis, brainstem encephalitis, or encephalomyelitis.
• In some cases, AE develops weeks to months before a cancer diagnosis.
• Early recognition and treatment with:
  • Anti-cancer therapy.
  • Immunosuppression.
  • Apheresis or intravenous immunoglobulins (IVIG).

📌 Timely diagnosis and intervention can stabilize or improve patient outcomes.

Diagnostic Approach

✅ Making a Definitive Clinical Diagnosis

• All diagnostic criteria must be met, and alternative causes excluded.
• Key investigations include:
  • Magnetic Resonance Imaging (MRI).
  • Electroencephalography (EEG).
  • Cerebrospinal fluid (CSF) analysis.
  • Serological antibody testing.

✅ MRI Findings Suggestive of AE

• Hyperintensities on FLAIR or T2-weighted images in specific brain regions:
  • Medial temporal lobes (limbic encephalitis).
  • Subcortical regions (brainstem or cerebellum).

✅ EEG Utility

• Used to exclude non-convulsive seizures.
• Findings are often non-specific.

📌 MRI and EEG are valuable diagnostic tools but must be used in conjunction with clinical and serological findings.

Cerebrospinal Fluid (CSF) Findings in AE

✅ Key CSF Parameters to Assess:

• Cell count.
• Protein levels.
• Glucose concentration.
• IgG index and oligoclonal bands.
• Viral PCR studies.
• Bacterial and fungal cultures.
• VDRL (for syphilis).
• Cytology (to assess malignancy-related encephalitis).

✅ Typical CSF Findings in AE:

• Normal or inflammatory CSF profile.
• Mildly increased protein (<1 g/L).
• Pleocytosis (increased white cell count).
• Elevated IgG index or presence of oligoclonal bands.

📌 A normal CSF profile does not exclude AE, as inflammation may be subtle or absent in some cases.

Serological Testing for Autoimmune Encephalitis

✅ Detecting Autoantibodies

• Specific autoantibodies in serum and CSF confirm AE diagnosis.
• Autoantibodies can be intrathecal (produced in the CNS) or systemic.
• Testing in both CSF and serum improves diagnostic accuracy.

✅ Key Considerations for Antibody Testing:

• High antibody titres are more likely to be neurologically relevant.
• Negative results do NOT exclude AE, as not all causative antibodies have commercially available tests.
• Some patients remain seronegative despite having AE.

✅ Diagnosing Paraneoplastic Encephalitis

• Paraneoplastic AE is confirmed when high-risk (≥70%) or intermediate-risk (30–70%) onconeuronal antibodies are present.
• Common associated cancers include:
  • Lung cancer.
  • Breast cancer.
  • Thymoma.
  • Hodgkin’s lymphoma.
  • Ovarian cancer.
  • Testicular cancer.
• Patients with positive onconeuronal antibodies but no known cancer should undergo intensive cancer screening.
• Negative cancer screening should be repeated every six months for two years.

📌 Serological antibody testing is crucial but should always be interpreted in the appropriate clinical context.

Key Messages for Clinicians

✅ Phenotype Does Not Predict the Antibody

• Testing all three neural antibody profiles is essential to avoid misdiagnosis.

✅ Both CSF and Serum Should Be Tested

• Dual testing optimizes sensitivity and specificity.

✅ Correlation Between Antibody and Clinical Picture is Crucial

• If the clinical symptoms do not align with the detected antibody, consider a false-positive result.

✅ Positive Onconeuronal Antibodies Require Cancer Investigation

• Patients with antibodies like anti-Hu should undergo intensive malignancy screening.

✅ Negative Results Do Not Exclude AE

• Commercial testing is not available for all autoantigens.
• Some AE patients remain seronegative.

📌 A systematic and multi-modal approach is required to diagnose autoimmune encephalitis accurately.

Autoimmune Encephalitis Testing at Ampath

✅ Neural Antibody Panels Available:

• Neuronal antibodies (Serum + CSF) → NEUR + NEURC.
• Anti-NMDA and other glutamate receptor antibodies (Serum + CSF) → NMDA + NMDAC.
• Aquaporin and anti-MOG antibodies (Serum + CSF) → NMO + NMOC.

📌 Ampath’s neural antibody tests are available under the Central Nervous System section on the Immunology Autoimmunity request form.

Key Takeaways for Clinicians

✅ Autoimmune encephalitis is an increasingly recognized disorder with varied clinical presentations.
✅ Limbic encephalitis is the most common subtype and presents with behavioural and cognitive changes.
✅ Both MRI and EEG are helpful but not definitive for diagnosis.
✅ CSF findings may be normal or mildly inflammatory.
✅ Antibody testing in both serum and CSF is essential for accurate diagnosis.
✅ A negative antibody test does not exclude AE, as some patients remain seronegative.
✅ Paraneoplastic AE requires thorough malignancy screening, even in the absence of a known cancer diagnosis.

📌 Early detection and intervention are critical for improving patient outcomes in autoimmune encephalitis.