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FeedbackParaneoplastic neurologic syndromes (PNSs) are rare disorders that occur due to the remote effects of tumors (usually malignant). The most frequent tumor type associated with PNSs is small cell lung cancer (SCLC). Other tumors related to PNSs include thymoma, neuroblastoma, Hodgkin lymphoma, and ovarian, breast, and testicular tumors. Researchers believe that PNSs are caused by cancer-fighting components of the immune system, particularly antibodies and specific white blood cells, known as T cells. Instead of attacking only the cancer cells, these immune agents also attack the normal cells of the nervous system and cause neurologic disorders.
PNSs might be suspected in cases of neurologic disease of unknown etiology without evidence of malignancy, or neurologic disease with high suspicion of malignancy or known risk factors for malignancy. Clinical presentation, age, history, and the presence or absence of malignancy guide the selection of paraneoplastic autoantibody testing.
Quick Answers for Clinicians
Paraneoplastic neurologic syndromes (PNSs) occur as a remote effect of a tumor and may present as focal (eg, paraneoplastic cerebellar degeneration [PCD]) or multifocal (eg, limbic and brainstem encephalitis with sensory neuronopathy). The diagnosis of PNS may be challenging because presenting signs of PNS often occur before the malignancy becomes clinically overt. PNSs may present with multiple clinical manifestations (eg, encephalitis, autonomic failure, peripheral neuropathy, cerebellar ataxia, and visual complaints).
In some cases, yes. Certain well-characterized antibodies (eg, Hu, Ri, and Yo) are strongly associated with cancer and provide valuable information about which malignancies might need to be screened for in a patient. The detection of an antibody can also guide treatment decisions. However, some antibodies have an uncertain prevalence and significance and are markedly rarer than others.
In recent years, antibodies associated with paraneoplastic neurologic syndromes (PNSs) have been characterized and added to commercially available PNS diagnostic panels. However, many of these antibodies are extremely rare, and most antibodies have low positivity rates. Also, the majority of patients tested for autoimmune neurologic disease have a single autoantibody. Comprehensive panels are generally not cost-effective due to the low positivity rates of less commonly observed antibodies. Initial antibody testing should take these factors into account.
Indications for Testing
PNS testing may be indicated for any of the following purposes:
- Diagnose paraneoplastic neurologic disease associated with certain cancers (carcinoma of the lung, breast, or ovary, thymoma, or Hodgkin lymphoma) and/or related disorders such as autoimmune encephalitis
- Direct a focused search for cancer
- Differentiate autoimmune neuropathies from neurotoxic effects of chemotherapy
- Monitor the immune response of seropositive patients during the course of cancer therapy
- Detect early evidence of cancer recurrence in previously seropositive patients
Criteria for Diagnosis
Diagnostic criteria for PNS were established in 2004 by an international expert group that divided patients with suspected PNS into definite and probable categories. These criteria are based on the presence or absence of malignancy, the type of antibody present, and the type of clinical syndrome.
| Definite PNS | Possible PNS |
|---|---|
|
A classical syndromea with cancer that develops within 5 yrs of the diagnosis of the neurologic disorder A nonclassicalb syndrome that resolves or significantly improves after cancer treatment without concomitant immunotherapy, provided that the syndrome is not susceptible to spontaneous remission A nonclassicalb syndrome with onconeural antibodies (well characterized or not) and cancer that develops within 5 yrs of the diagnosis of the neurologic disorder A neurologic syndrome (classical or not) with well-characterized onconeural antibodies (anti-Hu, Yo, CV2, Ri, Ma2, or amphiphysin) and no cancer |
A classical syndrome,a no onconeural antibodies, and no cancer but high risk of having an underlying tumor A neurologic syndrome (classical or not) with partially characterized onconeural antibodies and no cancer A nonclassical syndrome,b no onconeural antibodies, and cancer present within 2 yrs of diagnosis |
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aClassical syndromes include encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, opsoclonus-myoclonus, subacute sensory neuronopathy, chronic GI pseudo-obstruction, LEMS, and dermatomyositis. bThe most common nonclassical syndromes include brainstem encephalitis, autonomic neuropathies, myasthenia gravis, subacute/chronic sensorimotor neuropathies, motor neuron disease, and necrotizing myelopathy. GI, gastrointestinal; LEMS, Lambert-Eaton myasthenic syndrome |
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Laboratory Testing
Diagnosis
Central nervous system infections or metabolic abnormalities should be ruled out before testing for PNS. If initial evaluations for infection and metabolic abnormalities are negative, follow-up antibody testing should be based on clinical presentation, age, history, and the presence or absence of malignancy.
Antibody Testing
The association between specific autoantibodies in PNS and autoimmune neurologic diseases can be classified based on their clinical and analytical characterization and/or the cellular location of the recognized antigen.
Initial antibody tests should target well-characterized antibodies. Well-characterized antibodies target intracellular antigens and are found in patients with cancer and different types of PNSs. These antibodies have a high positive predictive value for tumors and are considered classical and diagnostic for PNS. Hu, Yo, CV2/CRMP5, Ri, Ma2/Ta, and amphiphysin are all considered classical and diagnostic for PNS. Of these antibodies, Hu, Ri, and Yo are the most commonly observed.
| Antibody | Clinical Syndromes | Common Cancer Associations |
|---|---|---|
| Hua | Sensory neuronopathy, encephalomyelitis, limbic/brainstem encephalitis, opsoclonus-myoclonus, subacute cerebellar degeneration, autonomic neuropathy, enteric neuropathy (GI dysmotility) | SCLC, neuroblastoma, prostate cancer |
| Yob | Subacute cerebellar degeneration, GI dysmotility (occasionally), chorea | Ovarian and breast cancer |
| CV2/CRMP5a | Encephalomyelitis, chorea, limbic encephalitis, sensory neuronopathy, optic neuropathy (retinitis, optic neuritis, uveitis), subacute cerebellar degeneration, autonomic neuropathy, GI dysmotility | SCLC, thymoma |
| Ri | Opsoclonus-myoclonus, brainstem encephalitis, subacute cerebellar degeneration, myelitis, jaw dystonia | SCLC, breast cancer, ovarian cancer |
| Ma2/Tabc | Limbic/diencephalic/brainstem encephalitis, encephalomyelitis, subacute cerebellar degeneration, atypical Parkinsonism | Germ cell tumor (usually testicular), NSCLC (male predominance) |
| Amphiphysind | Stiff-person syndrome, encephalomyelitis, subacute sensory neuronopathy, sensorimotor neuropathy, limbic encephalitis | SCLC, breast cancer, ovarian cancer |
| Recoverin | Retinopathy | SCLC, melanoma, others |
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aHu and CV2/CRMP5 may coexist. bYo and Ma2/Ta are associated with specific clinical manifestations and gender-specific tumors and warrant customized testing based on the suspected tumor. cBrainstem encephalitis and subacute cerebellar degeneration are usually associated with tumors other than testicular cancer. Sera from patients with these syndromes also react with the Ma1 protein. dSynaptic antigenic target; associated with response to treatment. NSCLC, non-small cell lung cancer |
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Antibodies against cell surfaces (extracellular) or synaptic antigens are collectively known as neural surface antibodies (NSAbs). These antibodies are generally thought to be pathogenic, are usually treatment responsive, are not age dependent, and may or may not be associated with malignancy. NSAb syndromes may be indistinguishable at presentation from classical PNS (eg, limbic encephalitis). More than one autoantibody can be considered in the differential based on age and sex. N-methyl-D-aspartate receptor (NMDAR) encephalitis is frequent in individuals of both sexes and age groups and may mimic limbic encephalitis. Frequently, patients with nonparaneoplastic conditions do respond to immunotherapy and have a good chance of substantial recovery. Leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) were previously thought to be voltage-gated potassium channel (VGKC) antibodies. Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR), gamma (γ)-aminobutyric acid-B receptor (GABABR), and metabotropic glutamate receptor 1 (mGluR1) antibodies are less common.
| Targets | Antibody | Clinical Syndromes | Common Cancer Associations |
|---|---|---|---|
| Extracellular antibody targets | VGCC P/Q type | LEMS, subacute cerebellar degeneration | SCLC |
| VGCC N type | LEMS, sensorimotor and autonomic neuropathy | SCLC, breast cancer | |
| AChR | Myasthenia gravis | Thymoma | |
| gAChR (α3) | Subacute autonomic neuropathy | SCLC | |
| VGKC complex antibodies | Limbic encephalitis, neuromyotonia (Isaac syndrome), Morvan syndrome (limbic encephalitis and neuromyotonia), GI dysmotility, undulating myeloma, cramp-fasciculation syndrome | Thymoma, SCLC | |
| LGI1 | Limbic encephalitis | SCLC, neuroendocrine cancer | |
| CASPR2 | Limbic encephalitis, Morvan syndrome (limbic encephalitis and peripheral nerve hyperexcitability), neuromyotonia | Thymoma | |
| NMDAR (NR1) | Limbic/brainstem encephalitis, psychiatric syndromes | Ovarian teratoma | |
| AMPAR | Limbic encephalitis, agitation/psychiatric disturbances (not reported in children) | SCLC, breast cancer, thymoma | |
| GABABR | Limbic encephalitis (with early prominent seizures) | SCLC | |
| DPPX | Limbic encephalitis (with hyperexcitability, pleocytosis, and frequent diarrhea | Hematologic malignancies | |
| Synaptic antibody targets | GAD | Stiff-person syndrome, cerebellar degeneration, limbic encephalitis | Thymoma |
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AChR, acetylcholine receptor; DPPX, dipeptidyl aminopeptidase-like protein 6; gAChR, ganglionic acetylcholine receptor; GAD, glutamic acid decarboxylase; VGCC, voltage-gated calcium channel |
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Partially characterized antibodies are rare and poorly characterized. Unlike Hu, Ri, amphiphysin, CV2/CRMP5, and Ma2/Ta antibodies, the presence of these antibodies is not sufficient to make a diagnosis of PNS.
| Antibody | Clinical Syndromes | Associated Tumors |
|---|---|---|
| PCCA-Tr/DNER | Subacute cerebellar degeneration | Hodgkin lymphoma |
| ANNA-3 | Encephalomyelitis, subacute sensory neuronopathy, limbic encephalitis | SCLC |
| PCCA-2 | Encephalomyelitis, subacute cerebellar degeneration | SCLC |
| Zic-4 | Subacute cerebellar degeneration | SCLC |
| Anti-rod/bipolar cell | Optic neuropathy | Melanoma |
| SOX1/AGNA-1 | LEMS | SCLC |
| mGluR1 | Subacute cerebellar degeneration | Hodgkin lymphoma |
|
AGNA-1, antiglial nuclear antibody; ANNA, antineuronal nuclear antibody; DNER, delta/notch-like epidermal growth factor-related receptor; PCCA, Purkinje cell cytoplasmic antibody; SOX1, sex-determining region Y-box 1 |
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Testing Strategies
In recent years, antibodies associated with PNS have been characterized and added to commercially available PNS diagnostic panels. However, many of these antibodies are extremely rare and most antibodies have low positivity rates. Also, the majority of patients tested for autoimmune neurologic disease have a single autoantibody. Comprehensive panels are generally not cost-effective due to the low positivity rates of less commonly observed antibodies. Initial antibody testing should take these factors into account.
| Targeted or Single | Comprehensive | |
|---|---|---|
| Advantages |
Faster Treatment can be initiated sooner More cost-effective Clusters of antibodies tend to include similar antigens Focus on antibodies relevant for specific patients (based on age, sex, tumor, clinical symptoms) |
Can identify multiple antibodies Can rule out multiple antibodies |
| Disadvantages |
Negative result does not rule out autoimmune neurologic disease Testing for antibodies one at a time can delay diagnosis and treatment |
Can take weeks to receive results, which can delay treatment Not all antibodies are relevant for all patients (relevance is affected by age, sex, tumor, clinical symptoms) Many of the antibodies are very rare, so it’s not cost-effective to test for every one Negative result does not rule out autoimmune neurologic disease Expensive Overlap between comprehensive panels |
Serum and Cerebrospinal Fluid Testing
Testing for many antibodies is available for both cerebrospinal fluid (CSF) and serum. These specimen types have advantages and disadvantages.
| Serum | CSF | |
|---|---|---|
| Advantages |
Less invasive More suitable for monitoring response to treatment Antibodies are present at higher titers |
Less nonspecific binding, which leads to fewer false-positive results Can be more sensitive and specific than serum for neuronal cell antibodies |
| Disadvantages |
Nonspecific binding may cause false-positive results Serum may be falsely negative because some antibodies are produced intrathecally |
More invasive Antibodies can be present at a lower titer or not at all, compared with serum, which may cause false-negative results |
ARUP offers several combinations of serum and CSF antibody tests. The tables below show a comparison of the different options available. Refer to Paraneoplastic Neurologic Syndromes Testing Algorithm - Serum and Paraneoplastic Neurologic Syndromes Testing Algorithm - CSF for reflex patterns.
| Test Component(s) | Paraneoplastic Reflexive Panel 3002929 | Autoimmune Neurologic Disease Reflexive Panel, Serum 3004070 | Autoimmune Encephalitis Extended Panel, Serum 3001431 | Autoimmune Neuromuscular Junction Reflexive Panel 3003017 |
|---|---|---|---|---|
| PCCA/ANNA by IFA with Reflex to Titer and Immunoblot 2007961a | ✔ | ✔ | ||
| Amphiphysin Antibody, IgG 2008893 | ✔ | ✔ | ||
| CV2.1 Screen by CBA-IFA with Reflex to Titer 2013956 | ✔ | ✔ | ||
| SOX1 Antibody, IgG by Immunoblot, Serum 3002885 | ✔ | ✔ | ||
| NMDA Receptor Antibody, IgG CBA-IFA, Serum with Reflex to Titer 2004221 | ✔ | ✔ | ||
| GAD Antibody 2001771 | ✔ | ✔ | ||
| VGKC Antibody, Serum 2004890 | ✔ | ✔ | ||
| LGI1 Antibody, IgG CBA-IFA with Reflex to Titer, Serum 2009456 | ✔ | ✔ | Reflex | |
| CASPR2 Antibody, IgG CBA-IFA with Reflex to Titer, Serum 2009452 | ✔ | ✔ | Reflex | |
| AQP4, IgG by CBA-IFA with Reflex to Titer, Serum 2013320 | ✔ | ✔ | ||
| AMPA Receptor Antibody, IgG by CBA-IFA with Reflex to Titer, Serum 3001260 | ✔ | ✔ | ||
| GABA-BR Antibody, IgG by CBA-IFA with Reflex to Titer, Serum 3001270 | ✔ | ✔ | ||
| MOG Antibody, IgG by CBA-IFA with Reflex to Titer, Serum 3001277 | ✔ | ✔ | ||
| N-Type VGCC Antibodyb | ✔ | |||
| P/Q-Type VGCC Antibody 0092628b | ✔ | ✔ | ||
| AChR Binding Antibody 0080009c | ✔ | ✔ | ||
| AChR Blocking Antibody 0099580c | ✔ | |||
| Titin Antibody 2005636 | ✔ | |||
| Striated Muscle Antibodies, IgG with Reflex to Titer 0050746 | ✔ | |||
| Ganglionic AChR Antibody 3003020 | ✔ | |||
| DPPX Antibody IgG by CBA-IFA with Reflex to Titer, Serum 3004359 | ✔ | ✔ | ||
|
aReflex: Neuronal Nuclear Antibodies (Hu, Ri, Yo, Tr/DNER) IgG by Immunoblot, Serum 3002917. bN-Type Voltage-Gated Calcium Channel (VGCC) Antibody test is available in a panel with the P/Q-Type VGCC test (VGCC Antibody Panel 3002046). cReflex: For Autoimmune Neuromuscular Junction Reflexive Panel 3003017, this component reflexes to Acetylcholine Receptor Modulating Antibody 0099521 if positive; for Autoimmune Neurologic Disease Reflexive Panel, Serum, the component test is performed only as a reflex if CV2.1 is positive. |
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| Test Component(s) | Paraneoplastic Reflexive Panel, CSF 3004517 | Autoimmune Neurologic Disease Reflexive Panel, CSF 3002887 | Autoimmune Encephalitis Reflexive Panel, CSF 3002787 |
|---|---|---|---|
| Paraneoplastic Antibodies (PCCA/ANNA) by IFA with Reflex to Titer and Immunoblot, CSF 2010841a | ✔ | ✔ | |
| Amphiphysin Antibody, IgG, CSF 3004510 | ✔ | ✔ | |
| CV2.1 Screen by CBA-IFA with Reflex to Titer, CSF 3002257 | ✔ | ✔ | |
| SOX1 Antibody, IgG by Immunoblot, CSF 3002886 | ✔ | ✔ | |
| N-methyl-D-Aspartate Receptor Antibody, IgG CBA-IFA, CSF with Reflex to Titer 2005164 | ✔ | ✔ | |
| Glutamic Acid Decarboxylase Antibody, CSF 3002788 | ✔ | ✔ | |
| Voltage-Gated Potassium Channel (VGKC) Antibody, CSF 3001387 | ✔ | ✔ | |
| Leucine-Rich, Glioma-Inactivated Protein 1 Antibody, IgG CBA-IFA with Reflex to Titer, CSF 3001992 | ✔ | ✔ | |
| Contactin-Associated Protein-2 Antibody, IgG CBA-IFA with Reflex to Titer, CSF 3001986 | ✔ | ✔ | |
| Aquaporin-4 Receptor Antibody, IgG by IFA, CSF with Reflex to Titer 2013327 | ✔ | ||
| Alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antibody, IgG by CBA-IFA with Reflex to Titer, CSF 3001257 | ✔ | ✔ | |
| Gamma Aminobutyric Acid Receptor, Type B (GABA-BR) Antibody, IgG by CBA-IFA with Reflex to Titer, CSF 3001267 | ✔ | ✔ | |
| Dipeptidyl Aminopeptidase-Like Protein 6 (DPPX) Antibody, IgG by CBA-IFA With Reflex to Titer, CSF 3004512 | ✔ | ✔ | |
| aReflex: Neuronal Nuclear Antibodies (Hu, Ri, Yo, Tr/DNER) IgG by Immunoblot, CSF | |||
ARUP Laboratory Tests
Aids in the diagnosis of PNS associated with ANNA-1 (Hu), ANNA-2 (Ri), PCCA-1 (Yo), PCCA-Tr/DNER, amphiphysin, SOX1, and CV2.1 antibodies
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Qualitative Immunoblot
Comprehensive panel for the evaluation of paraneoplastic and neuromuscular junction disorders, and/or encephalitis, in the presence or absence of malignancy
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Qualitative Immunoblot/Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Use for differential evaluation of encephalitis of unknown origin with subacute onset of seizures, confusion, memory loss, and/or behavioral change
For adults and patients with suspicion of cancer, additional evaluation of paraneoplastic autoantibodies is recommended; refer to the paraneoplastic reflexive panel
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Use for differential evaluation of neuromuscular junction disorders
Quantitative Radioimmunoassay/Qualitative Radiobinding Assay/Semi-Quantitative Flow Cytometry/Semi-Quantitative Indirect Fluorescent Antibody
Aids in the diagnosis of PNS associated with ANNA-1 (Hu), ANNA-2 (Ri), PCCA-1 (Yo), PCCA-Tr/DNER, amphiphysin, SOX1, and CV2.1 antibodies
Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot
Comprehensive panel for the evaluation of paraneoplastic and neuromuscular junction disorders, and/or encephalitis, in the presence or absence of malignancy
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Qualitative Immunoblot/Quantitative Radioimmunoassay/Semi-quantitative Enzyme-Linked Immunosorbent Assay
Use for differential evaluation of encephalitis of unknown origin with subacute onset of seizures, confusion, memory loss, and/or behavioral change
Serum is the preferred sample type for most of the antibodies included in the panel
For adults and patients with suspicion of cancer, additional evaluation of paraneoplastic autoantibodies is recommended; refer to paraneoplastic antibodies (PCCA/ANNA) by IFA with reflex to titer and immunoblot, CSF
Refer to the Paraneoplastic Neurologic Syndromes Testing Algorithm - CSF for reflex pattern
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Use to rule out metabolic disorder as etiology of neurologic deficits
Quantitative Ion-Selective Electrode/Quantitative Enzymatic Assay/Quantitative Spectrophotometry
Aids in evaluation of infectious encephalitis
Reflectance Spectrophotometry
Use for assessment of multiple sclerosis
Use to detect unique IgG oligoclonal bands in CSF in conjunction with a matched serum specimen
Qualitative Isoelectric Focusing/Electrophoresis/Quantitative Immunoturbidimetry
References
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Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol. 2011;18(1):19-e3.
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de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic neurological disorders. Oncologist. 2006;11(3):292-305.
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Tebo AE, Haven TR, Jackson BR. Autoantibody diversity in paraneoplastic syndromes and related disorders: the need for a more guided screening approach. Clin Chim Acta. 2016;459:162-169.
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Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75(8):1135-1140.
For a detailed list of panel components, please refer to the serum and CSF antibody test tables above. For reflex patterns, please refer to the Paraneoplastic Neurologic Syndromes Serum and CSF algorithms.