What is a paraneoplastic panel for Central Nervous System (CNS)?

Paraneoplastic Panel for CNS

What It Is

A paraneoplastic panel for the CNS is a comprehensive antibody test that screens for both intracellular (onconeural) and neuronal surface antibodies to diagnose autoimmune and paraneoplastic neurological syndromes affecting the central nervous system. 1

Antibodies Included in the Panel

The panel is divided into two major categories based on antigen location:

Intracellular (Onconeural) Antibodies

These antibodies target intracellular antigens and are highly specific markers for paraneoplastic neurological syndromes, though they are not directly pathogenic (T-cell cytotoxicity is the actual mechanism of damage): 1, 2

• Anti-Hu (ANNA1) - Most common, associated with small cell lung cancer (SCLC), causes limbic encephalitis, sensory neuropathy, encephalomyelitis 1
• Anti-Yo (PCA1) - Associated with breast and ovarian cancer, causes cerebellar degeneration 1, 2
• Anti-Ri (ANNA2) - Associated with breast and SCLC, causes brainstem encephalitis and opsoclonus-myoclonus 1, 2
• Anti-Ma2 (Ta) - Associated with testicular cancer, causes limbic and brainstem encephalitis 1, 2
• Anti-CV2 (CRMP5) - Associated with SCLC and thymoma, causes encephalomyelitis and cerebellar ataxia 1, 2
• Anti-Amphiphysin - Associated with breast cancer and SCLC, causes stiff-person syndrome 1, 2
• Anti-Sox1/2 - Associated with SCLC 1

Neuronal Surface (Synaptic) Antibodies

These antibodies target extracellular antigens on neuronal cell membranes and are directly pathogenic, making these syndromes generally responsive to immunotherapy: 1, 2

• Anti-NMDAR - Most common surface antibody, associated with ovarian teratoma (especially in young women), causes severe encephalitis with psychiatric symptoms, seizures, and movement disorders 1
• Anti-LGI1 (part of VGKC complex) - Causes limbic encephalitis with faciobrachial dystonic seizures 1
• Anti-CASPR2 (part of VGKC complex) - Causes Morvan's syndrome and limbic encephalitis 1
• Anti-AMPAR - Causes limbic encephalitis 1, 2
• Anti-GABA-B receptor - Causes limbic encephalitis, often associated with SCLC 1, 2
• Anti-GABA-A receptor - Causes encephalitis with seizures 2
• Anti-Glycine receptor (GlyR) - Causes progressive encephalomyelitis with rigidity and myoclonus (PERM) and stiff-person syndrome 1, 2
• Anti-mGluR1 - Causes cerebellar ataxia, associated with Hodgkin lymphoma 1, 2
• Anti-mGluR5 - Causes limbic encephalitis 1
• Anti-VGCC (P/Q type) - Causes Lambert-Eaton myasthenic syndrome and cerebellar ataxia 1, 2

Additional Markers

• Anti-GAD65 - Targets intracellular antigen but typically indicates non-paraneoplastic autoimmune syndromes (stiff-person syndrome, cerebellar ataxia, limbic encephalitis) 1, 2
• Anti-GFAP - Associated with autoimmune encephalitis 1

Testing Methodology

Sample Requirements

Both serum AND CSF should be tested whenever possible, as sensitivity varies by antibody type: 1, 3

• CSF is more sensitive for: NMDAR, GFAP antibodies 1
• Serum is more sensitive for: Onconeural antibodies (Hu, Yo, Ri, etc.), LGI1, AQP4 antibodies 1

Recommended Dilutions

• Serum: diluted 1:10 or greater 3
• CSF: diluted 1:1 to 1:10 3

Detection Methods

The gold standard combines: 1, 4

• Immunohistochemistry on brain tissue sections (shows characteristic staining patterns)
• Confirmation by immunoblotting or multiplex assays (e.g., Luminex technology) using recombinant purified proteins 4

Clinical Context and Interpretation

Key Differences Between Antibody Types

Intracellular antibodies: 1

• Strongly indicate presence of specific tumor types
• Poor response to immunotherapy alone
• Require aggressive tumor treatment for any neurological improvement
• T-cell mediated pathology causes irreversible neuronal loss

Neuronal surface antibodies: 1

• May or may not be paraneoplastic
• Generally respond well to immunotherapy
• Antibody-mediated pathology is potentially reversible
• Better overall prognosis with early treatment

Critical Pitfalls

Low antibody titers (<1:50) can occur in unrelated conditions and may represent false positives - clinical correlation is essential 1

Positive antibody does not always equal paraneoplastic syndrome - surface antibodies frequently occur without cancer 1

Negative antibody panel does not exclude autoimmune encephalitis - seronegative cases exist and may still respond to immunotherapy 1

When to Order the Panel

Order comprehensive paraneoplastic testing when patients present with: 1

• Acute or subacute (<12 weeks) neurological symptoms
• Evidence of CNS inflammation (CSF pleocytosis, elevated IgG index, oligoclonal bands, or MRI abnormalities)
• Exclusion of infectious, metabolic, and structural causes
• Clinical syndromes including: limbic encephalitis, rapidly progressive cerebellar ataxia, encephalomyelitis, opsoclonus-myoclonus, unexplained seizures, or psychiatric symptoms with neurological features

Cancer Screening After Positive Results

All adults with positive paraneoplastic antibodies require comprehensive cancer screening: 1

• CT chest/abdomen/pelvis with contrast as initial screen 1
• Mammogram and breast MRI for women (especially with anti-Yo, anti-Ri) 1
• Pelvic ultrasound or MRI for ovarian teratoma (especially with anti-NMDAR in young women) 1
• Testicular ultrasound for men (especially with anti-Ma2) 1
• Consider FDG-PET if initial screening negative 1

The most common associated malignancies are: SCLC, ovarian teratoma, breast cancer, thymoma, testicular tumors, and neuroblastoma 1