An Update on Autoimmune (Limbic) Encephalitis

by Dr. Mark Cruz da Silva – Clinical Microbiologist, Immunology Department

PATHCHAT Edition No. 12
Please contact your local Ampath pathologist for more information.

Understanding Encephalitis

🔹 Definition & Diagnosis:

• Encephalitis refers to inflammation of the brain, typically diagnosed clinically.
• Diagnosis is based on:
  • Neurologic dysfunction (e.g., altered consciousness, seizures).
  • Corroborating findings from CSF analysis, EEG, and neuroimaging.
• Common causes include:
  • Infections (HSV, enteroviruses).
  • Seizures.
  • Metabolic encephalopathy.
  • Toxic causes (e.g., overdose).
  • Cerebrovascular accidents.

🔹 Why Autoimmune Encephalitis (AE) Matters:

• Some patients have no clear infectious or metabolic cause.
• AE is increasingly recognized and may mimic infectious encephalitis.
• Early diagnosis is critical, as delayed treatment can cause irreversible brain damage.

What is Autoimmune Encephalitis (AE)?

🔹 Definition & Prevalence:

• AE is an immune-mediated encephalitis, caused by either humoral (antibody-mediated) or cellular immune pathways.
• Previously considered rare, AE is now diagnosed as often as HSV and enteroviral encephalitis, particularly NMDAR encephalitis.
• Timely treatment leads to better outcomes, emphasizing the need for early recognition.

Types of Autoimmune Encephalitis

1. T-Lymphocyte Mediated Neurological Syndromes

Example: Paraneoplastic Limbic Encephalitis (PLE)

• Mechanism:
  • Onconeuronal autoantibodies attack intracellular neuronal antigens.
  • CD8+ T-cells induce cytotoxic damage, leading to neurodegeneration.
• PLE is often associated with cancer, particularly:
  • Small cell lung carcinoma (SCLC) → Anti-Hu (ANNA-1) and Anti-CV2 (CRMP5) antibodies.
  • Thymoma → Anti-CV2 antibodies.
  • Paraneoplastic stiff-person syndrome → Anti-amphiphysin antibodies.
  • Testicular seminoma → Anti-Ma2 antibodies.

🔹 Key Facts About PLE:

• In 70–80% of cases, PLE is diagnosed BEFORE cancer is detected.
• Severe neurological deficits often persist despite treatment.
• Treatment:
  • Tumor resection (if present).
  • Immunotherapy (IVIG, corticosteroids, or both).

2. Autoantibody-Mediated Neurological Syndromes

Example: Anti-NMDA Receptor (NMDAR) Encephalitis

🔹 Mechanism:

• Autoantibodies target cell surface antigens that regulate neuronal function and plasticity.
• Unlike PLE, neurological recovery is more likely with treatment.

🔹 Clinical Presentation of NMDAR Encephalitis:

• Prodromal viral-like illness followed by:
  • Psychiatric symptoms (hallucinations, aggression, paranoia).
  • Insomnia and memory loss.
  • Seizures and movement disorders (dyskinesias).
  • Autonomic instability.
  • Language dysfunction.

🔹 Epidemiology:

• Primarily affects young women (<30 years old).
• Two-thirds of cases occur in individuals under 18.
• Often associated with ovarian teratomas (50% of women >18 years old with NMDAR encephalitis).
• In patients >45 years old, often linked to carcinoma.

🔹 Diagnosis:

• Detection of NR1 subunit antibodies in CSF or serum.
• Key study (California Encephalitis Project):
  • NMDAR encephalitis is more common in young patients than HSV or enterovirus encephalitis.
  • MRI, EEG, and CSF findings differ from viral encephalitis.

🔹 Treatment:

• First-line:
  • Tumor resection (if applicable).
  • Immunotherapy (IVIG, corticosteroids, or both).
• Second-line (if non-responsive):
  • Rituximab or cyclophosphamide.
• Early treatment improves recovery (up to 80% response rate).

Other Autoimmune Encephalitides & Associated Antibodies

🔹 Other Antibody-Associated Syndromes:

• LGI1 (Leucine-Rich Glioma-Inactivated 1) → Limbic encephalitis, seizures, and hyponatremia.
• CASPR2 (Contactin-Associated Protein-Like 2) → Encephalitis, neuropathy, and Morvan syndrome.
• AMPA receptor → Autoimmune epilepsy and encephalitis.
• GABA receptor → Autoimmune epilepsy and encephalitis.

🔹 Diagnostic Approach:

• CSF and serum antibody testing for NMDAR, LGI1, CASPR2, AMPA, and GABA receptors.
• CSF titers correlate better with clinical severity in NMDAR encephalitis.
• For LGI1-associated limbic encephalitis, serum titers are typically higher than CSF titers.

Key Clinical Takeaways

✅ Autoimmune encephalitis should be considered in any case of unexplained encephalitis.
✅ Patients with suspected limbic encephalitis should undergo a tumor screen, even if autoantibodies are absent.
✅ Some encephalitides (e.g., NMDAR and LGI1) respond well to early immunotherapy.
✅ NMDAR antibody testing should be requested alongside HSV and enteroviral PCR in young patients with encephalitis symptoms.
✅ CSF and serum samples should be tested for neuronal and GAD65 antibodies.

Recommended Diagnostic Tests at Ampath

🔹 For Paraneoplastic Encephalitis:

• Immunofluorescence for anti-Hu, Ri, and Yo antibodies.
• Line immunoassay for anti-Hu, Ri, Yo, Ma2, CV2, and amphiphysin.
• ELISA for anti-GAD65 antibodies (ordered separately).

🔹 For Autoimmune Encephalitis:

• NMDAR antibodies (CSF and serum).
• LGI1, CASPR2, AMPA, and GABA receptor antibodies.

References

1. Dalmau J, Lancaster E, Martinez-Hernandez E, et al. (2011). Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurology, 10:63–74.
2. Gable MS, Sheriff H, Dalmau J, et al. (2012). The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clinical Infectious Diseases, 54: 899–904.
3. Rose N, Mackay I. (2014). The Autoimmune Diseases (5th edition). Academic Press.
4. Shoenfeld Y, Meroni PL. (2012). The General Practice Guide to Autoimmune Diseases. Pabst Science Publishers.