Paraneoplastic Neurological Syndromes and Associated Disorders - PNS

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.

Quick Answers for Clinicians

Which testing algorithms are related to this topic?

Diagnosis

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

  • 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 polymerase chain reaction (PCR) testing (eg, herpes simplex virus [HSV], human herpesvirus 6 [HHV6], varicella-zoster virus [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 electromyography (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 voltage-gated potassium channel (VGKC) complex antibodies, N-methyl-D-aspartate receptor (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, blood urea nitrogen [BUN]/creatinine, hepatic enzymes, calcium)
          • EMG, muscle biopsy, MRI, positron emission tomography (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
    • Target 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])
      • ≥1 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 nonparaneoplastic 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, Epstein-Barr virus (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
  • Neurodegenerative disorders
  • Malignancy

Background

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

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

ARUP Lab Tests

Aid in the diagnosis of paraneoplastic neurological syndromes (PNS) associated with ANNA-1 (Hu), ANNA-2 (Ri), PCCA-1 (Yo), amphiphysin, and CV2.1 antibodies

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; Amphiphysin by immunoblot; and CV2.1 by IFA

Reflex pattern: if Purkinje cell/neuronal nuclear IgG IFA screen is indeterminate, then immunoblot will be added; if IFA screen is positive at ≥1:10, then a titer (PCCA or ANNA) and immunoblot will be added; if CV2.1 antibody IgG screen by IFA is positive, then CV2.1 antibody IgG titer by IFA will be added

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 indeterminate, then immunoblot will be added; if IFA screen is positive at ≥1:10, then a titer (PCCA or ANNA) and immunoblot will be added

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

Panel includes Purkinje cell (PCCA) antibody and neuronal nuclear (ANNA) antibody IgG by IFA with reflex to titer and immunoblot (Hu, Ri, Yo); amphiphysin antibody IgG; CV2.1 antibody IgG by IFA with reflex to titer; 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 (LGI1) antibody, IgG with reflex to titer; contactin-associated protein-2 (CASPR2) antibody, IgG with reflex to titer; P/Q type VGCC antibody; N-type VGCC antibody; acetylcholine receptor binding antibody with reflex to acetylcholine receptor modulating antibody; titin antibody; and striated muscled antibody

Individual tests in panel may also be ordered separately

Differential evaluation of encephalitis of unknown origin with subacute onset of seizures, confusion, memory loss, and/or behavioral change

For extended version of this panel, refer to autoimmune encephalitis extended panel

For adults and patients with suspicion of cancer, additional evaluation of paraneoplastic autoantibodies is recommended; refer to paraneoplastic antibodies (PCCA/ANNA) reflexive panel

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

Reflex patterns: if AQP4 antibody IgG by ELISA is positive, then AQP4 antibody IgG by IFA will be added; if AQP4 antibody IgG by IFA is positive, then an AQP4 antibody IgG titer will be added

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

If NMDA antibody IgG is positive, then an NMDA antibody IgG titer is reported

Differential evaluation of encephalitis of unknown origin with subacute onset of seizures, confusion, memory loss, and/or behavioral change

Detect antibodies in addition to those included in the autoimmune encephalitis reflexive panel 

Testing for LGI1 and CASPR2 antibodies is always performed rather than only as a reflex

For adults and patients with suspicion of cancer, additional evaluation of paraneoplastic autoantibodies is recommended; refer to the paraneoplastic reflexive panel

Components include NMDA receptor antibody, IgG, glutamic acid decarboxylase antibody, VGKC antibody, aquaporin-4 receptor antibody, LG1 antibody, CASPR2 antibody, AMPA receptor antibody, GABA receptor antibody, and MOG antibody

Detect N-type and P/Q-type VGCC antibodies

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

Aid in diagnosis of limbic encephalitis

May be used in monitoring treatment response in individuals who are antibody-positive

The presence of GABA-BR antibodies may be associated with seizures; GABA-BR encephalitis may be paraneoplastic as about 50% of cases are associated with small-cell lung cancer

Useful for evaluation of classic PNS

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

Consider ordering for individuals with PEM, chorea, cerebellar degeneration, optic neuritis, and peripheral neuropathy

May aid in diagnosis of occult or recurrent tumor

Reflex pattern: if CV2.1 antibody IgG is positive, then CV2.1 antibody IgG titer will be added

Screening test for VGKC receptor complex-associated autoantibodies with test reflex to CASPR2 and LGI1 antibodies

Antibodies are associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, Morvan syndrome, and rare tumors (eg, thymoma, small cell lung cancer)

Results are not intended to be used as the sole means for clinical diagnosis or patient management decisions

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

Screening test for VGKC receptor complex-associated autoantibodies

Assay does not identify CASPR2 antibody or LGI1 antibodies

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

Results are not intended to be used as the sole means for clinical diagnosis or patient management decisions

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

Disorders are rarely associated with tumors

Aid in diagnosis of CASPR2 antibody disorders associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, and 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

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

Disorders are rarely associated with tumors

Aid in diagnosis of CASPR2 antibody disorders associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, and Morvan syndrome

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

Aid in diagnosis of CASPR2 antibody disorders associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, and 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

Related Tests

Screening test for VGKC receptor complex-associated autoantibodies with test reflex to CASPR2 and LGI1 antibodies

Antibodies are associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, Morvan syndrome, and rare tumors (eg, thymoma, small cell lung cancer)

Serum is the preferred specimen

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

Disorders are rarely associated with tumors

Aid in diagnosis of CASPR2 antibody disorders associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, and Morvan syndrome

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

Serum is the preferred specimen type

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

Aid in diagnosis of CASPR2 antibody disorders associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, and Morvan syndrome

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

Serum is the preferred specimen type

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

Rule out metabolic disorder as etiology of neurologic deficits

Panel includes albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin, calcium, carbon dioxide, creatinine, chloride, glucose, potassium, protein, sodium, and urea nitrogen

Identify bacteria in CSF

Rule out infectious process

Aid in infectious evaluation of encephalitis

Preferred test is oligoclonal band profile; index test aids in workup of suspected multiple sclerosis

Use for assessment of multiple sclerosis

Detect unique IgG oligoclonal bands in CSF in conjunction with a matched serum specimen

Preferred test is oligoclonal band profile testing

Aid in the diagnosis of paraneoplastic neurologic syndromes associated with malignancy for CSF specimens only

Includes Purkinje cell/neuronal nuclear IgG, CSF; neuronal nuclear antibody titer, IgG, CSF; Purkinje cell antibody titer, CSF; and neuronal nuclear abs IgG immunoblot CSF

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

Consider ordering for individuals with paraneoplastic encephalomyelitis, chorea, cerebellar degeneration, optic neuritis, and peripheral neuropathy

May aid in diagnosis of occult or recurrent tumor

Serum is the preferred specimen

Screening test for VGKC receptor complex-associated autoantibodies

Does not identify CASPR2 antibody or LGI1 antibodies

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

Results are not intended to be used as the sole means for clinical diagnosis or patient management decisions

Serum is the preferred specimen type

Aid in diagnosis of limbic encephalitis

May be used in monitoring treatment response in individuals who are antibody-positive

The presence of GABA-BR antibodies may be associated with seizures; GABA-BR encephalitis may be paraneoplastic as about 50% of cases are associated with small-cell lung cancer

Medical Experts

Contributor

Hill

Harry R. Hill, MD
Professor of Clinical Pathology, Pediatrics, and Medicine, University of Utah
Medical Director, Cellular and Innate Immunology, ARUP Laboratories
Contributor
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®