Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2

Area of Science:

• Neuroimmunology
• Autoimmune Neurology
• Clinical Diagnostics

Background:

• Autoantibodies targeting voltage-gated potassium channels (VGKC) are associated with distinct neurological syndromes.
• Leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) autoantibodies are implicated in limbic encephalitis and other conditions.
• However, 'double-negative' VGKC antibodies lack pathogenic potential and are found in healthy individuals.

Purpose of the Study:

• To evaluate the diagnostic utility of current VGKC antibody testing.
• To determine the clinical relevance of LGI1 and CASPR2 autoantibodies versus other VGKC reactivities.
• To recommend optimized antibody testing strategies for autoimmune neurological disorders.

Main Methods:

• Analysis of autoantibody specificities in patients with neurological syndromes.
• Correlation of antibody targets (LGI1, CASPR2, or other VGKC epitopes) with clinical presentations.
• Assessment of antibody pathogenic potential based on target epitope.

Main Results:

• LGI1 and CASPR2 autoantibodies are directly pathogenic and linked to specific immunotherapy-responsive syndromes.
• VGKC antibodies lacking LGI1/CASPR2 reactivity are common in controls and clinically non-specific.
• LGI1/CASPR2 antibodies constitute only ~15% of VGKC-positive results, with potential for missed diagnoses with broad VGKC testing.

Conclusions:

• Current broad VGKC antibody testing is often misleading and can miss critical diagnoses.
• Laboratories should cease VGKC antibody testing and focus exclusively on LGI1 and CASPR2 autoantibodies.
• This diagnostic shift promises significant improvements in patient care and management of autoimmune neurological disorders.