Paraneoplastic Neurologic Syndromes and Associated Disorders - PNS

Paraneoplastic 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

How do paraneoplastic neurologic syndromes present clinically?

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). 

Does antibody testing for paraneoplastic neurologic syndromes provide clinically actionable information?

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. 

Is it more effective to order a panel test or individual antibody tests to investigate paraneoplastic neurologic syndromes?

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. 

Diagnostic Criteria for PNS
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

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

Source: Graus, 2004 

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. 

Well-Characterized Antibodies
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

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

Sources: de Beukelaar, 2006 ; Graus, 2004 

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. 

Neural Surface Antibodies

Antibodies Against Cell Surface (Extracellular) and Synaptic Antigens

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

AChR, acetylcholine receptor; DPPX, dipeptidyl aminopeptidase-like protein 6; gAChR, ganglionic acetylcholine receptor; GAD, glutamic acid decarboxylase; VGCC, voltage-gated calcium channel

Sources: de Beukelaar, 2006 , Graus, 2004 

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. 

Partially Characterized Antibodies (Target Intracellular Antigens)
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

Sources: de Beukelaar,2006 , Graus, 2004 

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.

Strategies for Testing for Neural Autoantibodies
  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 and CSF Testing for PNS
  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.

ARUP PNS and Related Disorders Panel Testing

Serum Antibodies

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 IFA with Reflex to Titer 2013956    
SOX1 Antibody, IgG by Immunoblot, Serum 3002885    
NMDA Receptor Antibody, IgG, Serum with Reflex to Titer 2004221    
GAD Antibody 2001771    
VGKC Antibody, Serum 2004890    
LGI1 Antibody, IgG with Reflex to Titer, Serum 2009456   Reflex
CASPR2 Antibody, IgG with Reflex to Titer, Serum 2009452   Reflex
AQP4, IgG by IFA with Reflex to Titer, Serum 2013320    
AMPA Receptor Antibody, IgG by IFA with Reflex to Titer, Serum 3001260    
GABA-BR Antibody, IgG by IFA with Reflex to Titer, Serum 3001270    
MOG Antibody, IgG by 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 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.

ARUP PNS Panel Testing

CSF Antibodies

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 IFA with Reflex to Titer, CSF 3002257  
SOX1 Antibody, IgG by Immunoblot, CSF 3002886  
N-methyl-D-Aspartate Receptor Antibody, IgG, 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 with Reflex to Titer, CSF 3001992  
Contactin-Associated Protein-2 Antibody, IgG 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 IFA with Reflex to Titer, CSF 3001257  
Gamma Aminobutyric Acid Receptor, Type B (GABA-BR) Antibody, IgG by IFA with Reflex to Titer, CSF 3001267  
Dipeptidyl Aminopeptidase-Like Protein 6 (DPPX) Antibody, IgG by IFA With Reflex to Titer, CSF 3004512  
aReflex: Neuronal Nuclear Antibodies (Hu, Ri, Yo, Tr/DNER) IgG by Immunoblot, CSF

ARUP Laboratory Tests

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.

Panel Testing

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

Comprehensive panel for the evaluation of paraneoplastic and neuromuscular junction disorders, and/or encephalitis, in the presence or absence of malignancy

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

Use for differential evaluation of neuromuscular junction disorders

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

Comprehensive panel for the evaluation of paraneoplastic and neuromuscular junction disorders, and/or encephalitis, in the presence or absence of malignancy

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

Related Testing

Use to rule out metabolic disorder as etiology of neurologic deficits

Aids in evaluation of infectious encephalitis

Use for assessment of multiple sclerosis

Use to detect unique IgG oligoclonal bands in CSF in conjunction with a matched serum specimen

Medical Experts

Author

References