Paraneoplastic Neurological Syndromes and Associated Disorders - PNS

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Neurologic disease of unknown etiology without evidence of malignancy
  • Neurologic disease with high suspicion of malignancy or known risk factors for malignancy

Criteria for Diagnosis

  • Paraneoplastic neurological syndromes (PNS) can be classified based on consensus criteria (Graus et al, 2004)
    • Presence or absence of tumors
    • Presence of classic symptoms
    • Characterization of onconeuronal antibodies

Laboratory Testing

  • PNS are rare
    • Initial antibody testing should be targeted toward well-characterized antibodies
  • Rule out central nervous system (CNS) infection or metabolic abnormality before testing for PNS
    • Cerebrospinal fluid (CSF) analysis
      • Protein, glucose, cell count
      • Viral PCR testing (eg, HSV, HHV6, VZV)
      • Oligoclonal band profile
      • Bacterial culture and Gram stain
      • Fungal culture
    • CBC
    • Electrolyte panel/metabolic profile
  • If initial evaluations for infection and metabolic abnormalities are negative
    • Follow-up testing should be based on clinical presentation, age, and history – consider workup based on presence or absence of malignancy
      • No known malignancy – consider antibody tests based on their characterization, patient’s specific clinical manifestations (central versus peripheral nervous system; neuromuscular system), age, and sex
        • Characterization of antibodies – dependent on the number of studies describing their clinical relevance as well as the nature of antibodies and their effect on the disease process
        • PNS and some defined autoimmune neurologic diseases – may be confirmed by the presence of specific antibodies in the presence of clinically defined symptoms
        • No antibodies present – evaluate for other disorders associated with neurological symptoms
          • If infectious and metabolic evaluations are negative – proceed with further neurologic evaluation, including EMG, muscle biopsy, CT, MRI
            • Negative neurologic testing – reevaluate in 6 months or sooner depending on symptoms
            • Positive neurologic testing – further evaluation based on test results
        • In children with encephalitis of unknown origin, PNS is very rare
          • Consider testing for VGKC-complex antibodies, NMDAR, and glutamic acid decarboxylase (GAD) autoantibodies
      • Known malignancy – antibody testing based on clinical symptoms and tumor type
        • Antibodies present – PNS confirmed
          • Titers may correlate with severity of neurological symptoms
          • Correlation between response to treatment and decline in antibody titer is antibody-dependent
            • Antibodies to Hu (ANNA-1), Yo (PCCA-1), Ri (ANNA-2), CV2/CRMP5 (collapsin response mediator protein 5), Ma2/Ta (intracellular targets) – may not decline with treatment
            • Neuronal surface antibodies (NSAbs) (eg, NMDAR) – may decline
            • Decline associated with positive treatment response
        • Antibodies not present – evaluate for other cancer-related complications
          • CSF studies – spinal tap with cell count, protein level, culture with gram stain; also consider immunoglobulin G (CSF) and oligoclonal bands testing
            • Expected results in PNS – lymphocytic pleocytosis, increased protein concentration, change in oligoclonal bands (may be positive)
          • Electrolyte testing – comprehensive metabolic screening (electrolytes, BUN/creatinine, hepatic enzymes, calcium)
          • EMG, muscle biopsy, MRI, PET (may be the most sensitive imaging for detecting occult malignancy)

Antibody Tests to Consider

  • Most antibodies have low positivity rates – initial testing should take these rates into account
    • Comprehensive panels – generally not cost effective due to low rate of positivity of less commonly observed antibodies
  • Well-characterized antineuronal (also referred to as onconeuronal) antibodies
    • Targets intracellular nuclear and cytoplasmic antigens
    • Neurologic symptoms and survival vary with both types of antibodies and tumors
      • Hu, Yo, Ri, CV2/CRMP5, Ma2/Ta, amphiphysin – all considered classic and diagnostic for PNS
        • Hu, Ri, Yo – most commonly observed antibodies
        • Hu and CV2/CRMP5  – may coexist
        • Yo and Ma2/Ta – associated with specific clinical manifestations and gender specific tumors
          • Warrant customized testing based on suspected tumor
        • Amphiphysin – synaptic target with a strong association for breast cancer and treatment response
  • Cell surface and synaptic autoantibody targets
    • Antibodies target cell surface (extracellular) or synaptic antigens
    • Not age dependent
    • May or may not be associated with malignancy
    • Generally thought to be pathogenic
    • Usually treatment-responsive
    • NSAb syndromes – may be indistinguishable at presentation from classical PNS (eg, limbic encephalitis [LE])
      • One or more autoantibodies can be considered in the differential based on age and sex
      • NMDAR encephalitis – frequent in individuals of both genders and age groups and may mimic LE
        • Frequently non-paraneoplastic patients do respond to immunotherapy with a good chance for substantial recovery
      • LGI1 (leucine-rich glioma-inactivated 1) and CASPR2 (contactin-associated protein-like 2) – previously thought to be VGKC
      • Less common – AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), GABABR (γ aminobutyric acid-B receptor), and mGluR1 (metabotropic glutamate receptor) antibodies
  • Partially characterized antibodies
    • ANNA-3, PCCA-2, PCCA-Tr, anti-glial nuclear antibody (AGNA-1, also referred to as SOX-1)
      • Autoantibodies are very rare and poorly characterized
      • Not recommended as first-line tests for PNS evaluation
      • Unlike Hu, Ri, amphiphysin, CV2/CRMP5, and Ma2/Ta antibodies, the presence of these antibodies is not sufficient to make a diagnosis of PNS
  • Most antibodies have low positivity rates – initial testing should take these rates of positivity into account
    • Comprehensive panels – generally not cost effective due to low rate of positivity of less commonly observed antibodies

Antibodies, PNS, and Associated Tumors

Differential Diagnosis

  • Subacute cerebellar degradation
    • Alcohol abuse
    • Vitamin deficiency (eg, B1 (thiamine), B12, vitamin E)
    • Medications (eg, lithium, anticonvulsants, 5-fluorouracil, and arabinofuranosyl cytidine [araC])
    • Infectious encephalitis – HIV, HSV, Creutzfeldt-Jakob disease, VZV, EBV, Whipple disease
    • Immune-mediated nonparaneoplastic
      • GAD-associated cerebellar ataxia
      • Miller Fisher syndrome (anti-GQ1b antibodies)
      • Gluten sensitivity enteropathy (anti-gliadin antibodies)
    • Cerebrovascular accident
    • Malignancy – cerebellar metastases
    • Hypothyroidism, hypoparathyroidism
  • Limbic encephalitis and variants
  • Retinopathy
    • Vascular
    • Optic neuritis
    • Leber hereditary optic neuropathy (LHON)
    • Tobacco-alcohol amblyopia
  • Lambert-Eaton myasthenic syndrome
  • Subacute sensory neuropathy
  • Opsoclonus-myoclonus
    • Infectious encephalitis (eg, HIV, HSV, HCV, Borrelia spp, Creutzfeldt-Jakob disease)
    • Post-infectious encephalitis (eg, M. pneumoniae, Streptococcus spp)
    • Metabolic encephalopathy (eg, hyperosmolar coma, hypoxia)
    • Medications (eg, lithium, tricyclic antidepressants)
    • Intracranial hemorrhage
    • Systemic disease
  • Neurodegenerative disorders
  • Malignancy

Paraneoplastic neurological syndromes (PNS) are diseases that occur due to the remote effects of tumors (usually malignant). Although many tumors have been associated with PNS, the most common include small cell lung cancer (SCLC), thymoma, neuroblastoma, ovarian, breast, testicular, and Hodgkin lymphoma.

Epidemiology

  • Incidence – rare (Didelot, 2014)
  • Exceptions
    • 3% of patients with SCLC are affected by Lambert-Eaton myasthenic syndrome (LEMS)
    • ~10% of patients who have plasma cell disorders with malignant monoclonal gammopathy may be affected by paraneoplastic peripheral neuropathy
    • 15% of patients with myasthenia gravis (MG) have thymoma

Pathophysiology

  • Etiology
    • Some forms are autoimmune-mediated
    • Immune response against tumors ectopically expressing neuronal antigens is provided by onconeuronal antibodies
    • Except in a very few cases (eg, LEMS and recoverin) the direct role of antibodies in the pathogenesis of a PNS has not been proven
  • Classification of antibodies based on immunohistochemical staining pattern – refer to tables in Diagnosis section

Clinical Presentation

  • Central nervous system syndromes
    • Encephalomyelitis – brainstem, motor dysfunction
    • Limbic encephalitis – short-term memory loss, seizures, confusion, dementia
    • Subacute cerebellar degeneration – ataxia, slurred speech
    • Opsoclonus-myoclonus – involuntary saccadic eye movements may have truncal myoclonus
  • Peripheral nervous system syndromes
    • Subacute sensory neuropathy
    • Chronic gastrointestinal pseudo-obstruction
  • Neuromuscular junction, muscle, joint, bone syndromes
    • LEMS – less ocular involvement and more lower limb involvement than classic MG
    • Peripheral nerve hyperexcitability (neuromyotonia, Morvan syndrome)
    • Dermatomyositis
  • Visual afferent system (neuro-ophthalmologic PNS) syndromes
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Paraneoplastic Antibodies (PCCA/ANNA) by IFA with Reflex to Titer and Immunoblot 2007961
Method: Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot

Recommended Use 

Aid in the diagnosis of PNS associated with malignancy

Order based on clinical presentation

Panel includes Purkinje cell/neuronal nuclear IgG screen; neuronal nuclear antibody (ANNA) IFA titer, IgG; Purkinje cell antibody, titer; neuronal nuclear antibodies (Hu, Ri, Yo) IgG by immunoblot

Reflex pattern – if IFA screen is positive at 1:10, then a specific titer (PCCA or ANNA) and immunoblot will be added

Limitations 

Negative result does not rule out PNS

Consider patient’s clinical presentation, results of CSF evaluation, imaging and cancer history

Autoimmune Encephalitis Reflexive Panel 2013601
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Radioimmunoassay

Recommended Use 

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 paraneoplastic antibodies (PCCA/ANNA) reflex test

Panel includes NDMA receptor antibody, IgG with reflex to titer; GAD antibody; VGKC antibody; aquaporin-4 receptor antibody; aquaporin-4 receptor antibody, IgG by IFA with reflex to titer; leucine-rich, glioma-inactivated protein 1 antibody, IgG with reflex to titer; and contactin-associated protein-2 antibody, IgG with reflex to titer

Neuronal Nuclear Antibodies (Hu, Ri, Yo) IgG by Immunoblot 2007963
Method: Qualitative Immunoblot

Recommended Use 

Useful for evaluation of classic PNS

Detects antibodies to Hu, Ri, and Yo, which are associated with a diagnosis of classic PNS

Limitations 

Negative result does not rule out PNS

Amphiphysin Antibody, IgG 2008893
Method: Qualitative Immunoblot

Recommended Use 

Consider ordering in individuals with stiff-person syndrome, paraneoplastic encephalomyelitis (PEM), or sensory neuronopathy (SN)

May aid in diagnosis of occult tumor, recurrence of tumor, or second tumor

Limitations 

Negative result does not rule out PNS

Voltage-Gated Potassium Channel (VGKC) Antibody with Reflex to LGI1 and CASPR2 Screen and Titer 2009463
Method: Quantitative Radioimmunoassay/Semi-Quantitative Indirect Fluorescent Antibody

Recommended Use 

Screening test for VGKC receptor complex-associated autoantibodies 

Evaluation of

  • Limbic encephalitis
  • Faciobrachial dystonic seizures
  • Peripheral nerve hyperexcitability disorders
  • Neuromyotonia (Issacs syndrome)
  • Variant form (Morvan syndrome)

Use to manage antibody-positive (VGKC, LGI1, or CASPR2) individual following immunotherapy and/or plasmapheresis

Reflex pattern – if VGKC is indeterminate or positive, LGI1 antibody IgG and CASPR2 antibody IgG will be added; if LGI1 antibody IgG is positive, then LGI1 antibody IgG titer will be added; if CASPR2 antibody IgG is positive, then CASPR2 antibody IgG titer will be added

Limitations 

Should not be used as the sole criterion for diagnosis

Negative result does not rule out PNS

The presence of VGKC antibodies should be used in conjunction with clinical manifestations for the neuromyotonia spectrum of disorders and VGKC antibody-associated limbic encephalitis

VGKC receptor-complex proteins may be coprecipitated by anti-VGKC antibodies, including LGI1, CASPR2, other unidentified targets

Voltage-Gated Potassium Channel (VGKC) Antibody 2004890
Method: Quantitative Radioimmunoassay

Recommended Use 

Screening test for VGKC receptor complex-associated autoantibodies

Use to evaluate

  • Limbic encephalitis
  • Faciobrachial dystonic seizures
  • Peripheral nerve hyperexcitability disorders
  • Neuromyotonia – Isaacs syndrome
  • Variant form – Morvan syndrome

Use to manage antibody-positive (VGKC, LGI1, or CASPR2) individual following immunotherapy and/or plasmapheresis

Limitations 

Should not be used as the sole criterion for diagnosis

Negative result does not rule out PNS

The presence of VGKC antibodies should be used in conjunction with clinical manifestations for the neuromyotonia spectrum of disorders and VGKC antibody-associated limbic encephalitis

VGKC receptor-complex proteins may be coprecipitated by anti-VGKC antibodies, including LGI1, CASPR2, other unidentified targets

Does not identify CASPR2 or LGI1 antibodies individually

Follow-up 

Dependent on clinical history

Leucine-Rich, Glioma-Inactivated Protein 1 Antibody, IgG and Contactin-Associated Protein-2 Antibody, IgG with Reflex to Titers 2009460
Method: Semi-Quantitative Indirect Fluorescent Antibody

Recommended Use 

Aids in diagnosis of CASPR2/LGI1 disorders

LGI1 associated with

  • Limbic encephalitis
  • Hyponatremia
  • Myoclonic movements
  • Rarely associated with tumors

CASPR2 associated with

  • Acquired neuromyotonia
  • Limbic encephalitis
  • Painful neuropathy
  • Morvan syndrome

Use to manage antibody-positive (LGI1 or CASPR2) individual following immunotherapy and/or plasmapheresis

Reflex pattern – if LGI1 antibody IgG is positive, then LGI1 antibody IgG titer will be added; if CASPR2 antibody IgG is positive, then CASPR2 antibody IgG titer will be added

Limitations 

Negative result does not rule out PNS

Leucine-Rich, Glioma-Inactivated Protein 1 Antibody, IgG with Reflex to Titer 2009456
Method: Semi-Quantitative Indirect Fluorescent Antibody

Recommended Use 

 Aid in diagnosis of LGI1 antibody disorders associated with limbic encephalitis, hyponatremia, and myoclonic movements

Disorders are rarely associated with tumors

Use to manage antibody-positive LGI1 individual following immunotherapy and/or plasmapheresis

Reflex pattern – if LGI1 antibody IgG is positive, then LGI1 antibody IgG titer will be added

Limitations 

Negative result does not rule out PNS

Contactin-Associated Protein-2 Antibody, IgG with Reflex to Titer 2009452
Method: Semi-Quantitative Indirect Fluorescent Antibody

Recommended Use 

Aids in diagnosis of CASPR2 disorders

Associated with

  • Acquired neuromyotonia
  • Limbic encephalitis
  • Painful neuropathy
  • Morvan syndrome

Use to manage antibody-positive (CASPR2) individual following immunotherapy and/or plasmapheresis

Reflex pattern – if CASPR2 antibody IgG is positive, then CASPR2 antibody IgG titer will be added

Limitations 

Negative result does not rule out PNS

Voltage-Gated Calcium Channel (VGCC) Antibody 0092628
Method: Quantitative Radioimmunoassay

Recommended Use 

Aid in the evaluation of muscle weakness in the context neuromuscular junction disorder with or without cancer, or the diagnosis of paraneoplastic neurological syndromes

Limitations 

Negative result does not rule out PNS

Follow-up 

Dependent upon clinical history

Guidelines

Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, Honnorat J, Smitt S, Vedeler C, Verschuuren JJ, Vincent A, Voltz R. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004; 75(8): 1135-40. PubMed

Titulaer MJ, Soffietti R, Dalmau J, Gilhus NE, Giometto B, Graus F, Grisold W, Honnorat J, Smitt PA, Tanasescu R, Vedeler CA, Voltz R, Verschuuren JJ, European Federation of Neurological Societies. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol. 2011; 18(1): 19-e3. PubMed

Zuliani L, Graus F, Giometto B, Bien C, Vincent A. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J Neurol Neurosurg Psychiatry. 2012; 83(6): 638-45. PubMed

General References

Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008; 7(4): 327-40. PubMed

Davies E, Connolly DJ, Mordekar SR. Encephalopathy in children: an approach to assessment and management. Arch Dis Child. 2012; 97(5): 452-8. PubMed

Didelot A, Honnorat J. Paraneoplastic disorders of the central and peripheral nervous systems. Handb Clin Neurol. 2014; 121: 1159-79. PubMed

Grant R, Graus F. Paraneoplastic movement disorders. Mov Disord. 2009; 24(12): 1715-24. PubMed

Graus F, Saiz A, Dalmau J. Antibodies and neuronal autoimmune disorders of the CNS. J Neurol. 2010; 257(4): 509-17. PubMed

Hacohen Y, Wright S, Waters P, Agrawal S, Carr L, Cross H, De Sousa C, Devile C, Fallon P, Gupta R, Hedderly T, Hughes E, Kerr T, Lascelles K, Lin J, Philip S, Pohl K, Prabahkar P, Smith M, Williams R, Clarke A, Hemingway C, Wassmer E, Vincent A, Lim MJ. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry. 2013; 84(7): 748-55. PubMed

Jammoul A, Li Y, Rae-Grant A. Autoantibody-mediated encephalitis: Not just paraneoplastic, not just limbic, and not untreatable. Cleve Clin J Med. 2016; 83(1): 43-53. PubMed

Lancaster E, Dalmau J. Neuronal autoantigens--pathogenesis, associated disorders and antibody testing. Nat Rev Neurol. 2012; 8(7): 380-90. PubMed

Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011; 77(2): 179-89. PubMed

Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies Ann N Y Acad Sci. 2015; 1338: 94-114. PubMed

Leypoldt F, Wandinger K. Paraneoplastic neurological syndromes. Clin Exp Immunol. 2014; 175(3): 336-48. PubMed

Lim M, Hacohen Y, Vincent A. Autoimmune encephalopathies Pediatr Clin North Am. 2015; 62(3): 667-85. PubMed

Panzer J, Dalmau J. Movement disorders in paraneoplastic and autoimmune disease. Curr Opin Neurol. 2011; 24(4): 346-53. PubMed

Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010; 85(9): 838-54. PubMed

Rosenfeld MR, Dalmau J. Update on paraneoplastic and autoimmune disorders of the central nervous system. Semin Neurol. 2010; 30(3): 320-31. PubMed

Sioka C, Fotopoulos A, Kyritsis AP. Paraneoplastic immune-mediated neurological effects of systemic cancers. Expert Rev Clin Immunol. 2014; 10(5): 621-30. PubMed

Tampoia M, Zucano A, Antico A, Giometto B, Bonaguri C, Alessio MG, Radice A, Platzgummer S, Bizzaro N. Diagnostic accuracy of different immunological methods for the detection of antineuronal antibodies in paraneoplastic neurological syndromes. Immunol Invest. 2010; 39(2): 186-95. PubMed

Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol. 2011; 10(8): 759-72. PubMed

Vincent A. Developments in autoimmune channelopathies. Autoimmun Rev. 2013; 12(6): 678-81. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Paxton CN, Rowe LR, South ST. Observations of the genomic landscape beyond 1p19q deletions and EGFR amplification in glioma Mol Cytogenet. 2015; 8: 60. PubMed

Medical Reviewers

Haven, Thomas, R&D Investigator I, R&D Immunology Group at ARUP Laboratories

Hill, Harry R., MD, Medical Director, Immunology and Infectious Disease at ARUP Laboratories; Professor of Clinical Pathology and Pediatrics; Adjunct Professor, Internal Medicine, University of Utah

Tebo, Anne E., PhD, D(ABMLI), Medical Director, Immunology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Last Update: September 2016

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