Paraneoplastic Neurological Syndromes and Associated Disorders - PNS

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
    • Paraneoplastic neurological syndromes (PNS) are rare
      • If testing is pursued – initial antibody testing should be targeted toward well-characterized antibodies
  • Rule out central nervous system (CNS) infection
    • Cerebrospinal fluid analysis
      • Protein, glucose, cell count
      • Viral PCR testing (HSV, HHV6, VZV)
      • Oligoclonal band profile
      • Bacterial culture and Gram stain
      • Fungal culture
    • Electrolyte panel
    • CBC
  • If initial evaluations for infection, metabolic abnormalities are negative
    • Follow up testing – consider based on clinical presentation, age, and history
      • Autoimmune serologies for ANA, ANCA, APS
      • Paraneoplastic antibody evaluation
      • N-methyl-D-aspartate receptor (NMDAR) antibody, serum, and CSF
      • Autoimmune channelopathies evaluation
        • Anti-voltage-gated potassium channel (VGKC)-complex antibodies
        • Anti-LGI1 antibodies
        • Anti-CASPR2 antibodies

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

  • 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
      • Rule out metabolic disorder(s) as etiology
        • Electrolyte testing – comprehensive metabolic screening (electrolytes, BUN/creatinine, hepatic enzymes, calcium)
      • Rule out CNS infection
        • CSF studies – spinal tap with cell count, protein level, culture with gram stain; also consider immunoglobulin G (CSF) and oligoclonal bands testing
      • If above 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) such as 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

  • 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
    • Well-characterized antibodies by clinical syndromes and associated tumors

      Well-Characterized Antibodies (Target Intracellular Antigens)

      Antibody

      Clinical syndromes

      Associated tumors

      Hu

      Sensory neuronopathy, encephalomyelitis, limbic encephalitis, opsoclonus-myoclonus, subacute cerebellar degeneration, autonomic neuropathy, enteric neuropathy (GI dysmotility)

      Small-cell lung carcinoma (SCLC), neuroblastoma

      Yo

      Subacute cerebellar degeneration, occasional GI dysmotility, chorea

      Ovary, breast

      CV2/CRMP-5

      Encephalomyelitis, chorea, limbic encephalitis, sensory neuronopathy, sensorimotor neuropathy, optic neuropathy, subacute cerebellar degeneration, autonomic neuropathy, GI dysmotility

      SCLC, thymoma

      Ri

      Opsoclonus-myoclonus, brainstem encephalitis, cerebellar degeneration

      SCLC, breast, ovary

      Ma2/Ta*

      Limbic/diencephalic/brainstem encephalitis, encephalomyelitis, subacute cerebellar degeneration, atypical Parkinsonism

      Germ cell tumor (usually testicular), non-SCLC (male predominance)

      Amphiphysin**

      Stiff-person syndrome, encephalomyelitis, subacute sensory neuronopathy, sensorimotor neuropathy, limbic encephalitis

      SCLC, breast, ovary

      Recoverin

      Cancer-associated retinopathy

      SCLC, melanoma, others

      *Brainstem encephalitis and subacute cerebellar degeneration are usually associated with tumors other than testicular cancer. Sera from these patients also react with the Ma1 protein.

      **Synaptic antigenic target; associated with response to treatment

  • 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 such as 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 mGluR (metabotropic glutamate receptor) antibodies
    • Cell surface and synaptic antibodies by clinical syndromes and associated tumors

      Antibodies Against Cell Surface and Synaptic Antigens

      Antibody

      Clinical syndromes

      Associated tumors

      Extracellular Antibody Targets

      VGCC P/Q type

      Lambert-Eaton myasthenic syndrome, subacute cerebellar degeneration

      SCLC

      VGCC N type

      Lambert-Eaton, sensorimotor and autonomic neuropathy

      SCLC, breast

      mGluR3

      Rasmussen encephalitis

      Non-neoplastic

      AChR

      Myasthenia gravis

      Thymoma

      nAChR

          α3

      Subacute autonomic neuropathy

      SCLC

          Muscarinic (M3)

      Sjögren syndrome

      Non-neoplastic

      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 encephalitisSCLC, neuroendocrine

      Caspr2*

      Limbic encephalitis, Morvan syndromeThymoma

      NMDAR (NR1)

      Limbic encephalitis

      Ovarian teratoma

      AMPAR

      Limbic encephalitis, agitation

      SCLC, breast, thymoma

      GABAB R

      Limbic encephalitis

      SCLC

      Intracellular Antibody Targets

      Amphiphysin**

      Stiff-person syndrome, encephalomyelitis, subacute sensory neuronopathy, sensorimotor neuropathy, limbic encephalitis

      SCLC, breast, ovary

      GAD

      Stiff person syndrome, cerebellar degeneration, limbic encephalitis

      Thymoma

      *VGKC-complex antibodies; may also occur independently of VGKC-complex antibodies

      **Synaptic antigenic target; associated with response to treatment

      Abbreviations: AChR = acetylcholine receptor; nAChR = nicotinic acetylcholine receptor; NMDAR = N-methyl-D-aspartate receptor; SCLC = small cell lung carcinoma; VGCC = voltage-gated calcium channel; VGKC = voltage-gated potassium channel; GluR3 = glutamate receptor type 3; GAD = glutamic acid decarboxylase; AMPAR = alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; GABAB R = γ-aminobutyric acid-B receptor

  • 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
    • Partially characterized antibodies by clinical syndromes and associated tumors

      Partially Characterized Antibodies (Target Intracellular Antigens)

      Antibody

      Clinical syndromes

      Associated tumors

      PCCA-Tr

      Subacute cerebellar degeneration

      Hodgkin lymphoma

      ANNA-3

      Encephalomyelitis, subacute sensory neuronopathy

      SCLC

      PCCA-2

      Encephalomyelitis, subacute cerebellar degeneration

      SCLC

      Zic4

      Subacute cerebellar degeneration

      SCLC

      mGluR1

      Subacute cerebellar degeneration

      Hodgkin lymphoma

      Anti-rod/bipolar cell

      Optic neuropathy

      Melanoma

      AGNA-1

      Lambert-Eaton myasthenic syndrome

      SCLC

      Abbreviations: ANNA = antineuronal nuclear antibody; mGluR1 = metabotropic glutamate receptor type 1; PCCA = Purkinje cell cytoplasmic antibody; SCLC = small-cell lung carcinoma; AGNA-1 = anti-glial nuclear antibody

  • 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

  • PNS and antibody association

    PNS and Antibody Association

    Syndrome

    Most common
    tumor

    Most-frequent antibodies

    Autonomic dysfunction

    GI dysmotility

    SCLCHu, Yo, CV2/CRMP5

    Neuropathy

    SCLCHu, CV2/CRMP5, nAChR (α3)
    EncephalomyelitisSCLCHu, CV2/CRMP5
    Germ cell (testis)ANNA-3, PCCA-2
    ProstateHu
    Lambert-Eaton myasthenic syndrome (LEMS)SCLCVGCC (P/Q type)
    Limbic encephalitisSCLCHu, CV2/CRMP5, Amphiphysin
    Germ cell (testis)Ma2/Ta, GABABR, VGKC, AMPAR, Ri
    Teratoma (ovarian)NMDAR
    ThymomaAMPAR, GAD, VGKC (CASPR2, LGI1)
    BreastAMPAR
    Neuropathy

    Subacute sensory

    SCLCHu, CV2/CRMP5, Amphiphysin, ANNA-3

    Sensorimotor

    SCLCCV2/CRMP5, Hu
    NeuromyotoniaSCLCVGKC
    Opsoclonus-myoclonus  NeuroblastomaHu
    BreastRi
    SCLCRi
    Other movement disorders

    Dystonia

    Teratoma (ovarian)NMDAR

    Chorea

    BreastYo
    SCLCCV2/CRMP-5

    Parkinsonism

    Germ cell (testis)Ma2/Ta
    RetinopathySLCCRecoverin, CV2/CRMP5
    MelanomaAnti-rod/bipolar-cell
    Spinal myoclonusBreastAmphiphysin
    SCLCAmphiphysin
    Stiff person syndromeSCLCAmphiphysin
    ThymomaGAD
    Subacute cerebellar degenerationOvary, breastYo
    ThymomaGAD
    SCLCHu, CV2/CRMP5, PCCA-2, Zic4, Ri, VGKC
    Hodgkin lymphomaPCCA-Tr, mGluR1
    Germ cell (testis)Ma2/Ta
    Abbreviations: AChR = acetylcholine receptor; ANNA = antineuronal nuclear antibody; mGluR1 = metabotropic glutamate receptor type 1; nAChR = nicotinic acetylcholine receptor; NMDAR = N-methyl-D-aspartate receptor; PCCA = Purkinje cell cytoplasmic antibody; SCLC = small cell lung carcinoma; VGCC = voltage-gated calcium channels; VGKC = voltage-gated potassium channel; GAD = glutamic acid decarboxylase

Differential Diagnosis

Clinical Background

Paraneoplastic neurological syndromes (PNS) are diseases occurring due to remote effects of usually malignant tumors. 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
  • 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

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Paraneoplastic Antibodies (PCCA/ANNA) by IFA with Reflex to Titer and Immunoblot 2007961
Method: Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot

Aid in the diagnosis of PNS associated with malignancy

Order based on clinical presentation

PCCA/ANNA antibodies are screened by IFA; if IFA screen positive at 1:10, a specific titer (PCCA or ANNA) and immunoblot will be added

Negative result does not rule out PNS

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

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

Aids in discriminating between a PNS and other encephalitis of unknown origin

   
Amphiphysin Antibody, IgG 2008893
Method: Qualitative Immunoblot

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

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

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

Screening test for VGKC receptor complex-associated autoantibodies 

Associated with

  • Acquired neuromyotonia
  • Limbic encephalitis
  • Painful neuropathy
  • Morvan syndrome
  • Rare tumors – thymoma, small-cell lung cancer

Reflexes to CASPR2 and LGI1 antibodies individually

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

Should not be used as the sole criterion for diagnosis

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

Use to evaluate

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

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

Does not identify CASPR2 or LGI1 separately

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

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

Management of antibody-positive (LGI1 or CASPR2) individual following immunotherapy and/or plasmapheresis

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

Aids in diagnosis of LGI1 disorders

Associated with

  • Limbic encephalitis
  • Hyponatremia
  • Myoclonic movements

Rarely associated with tumors

Management of antibody-positive (LGI1) individual following immunotherapy and/or plasmapheresis

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

Aids in diagnosis of CASPR2 disorders

Associated with

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

Management of antibody-positive (CASPR2) individual following immunotherapy and/or plasmapheresis

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

Aid in the diagnosis of PNS associated with malignancy, or consider in pediatric patients with severe acute encephalitis

Order based on clinical presentation

 

Dependent upon clinical history

Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Comprehensive Metabolic Panel 0020408
Method: Quantitative Ion-Selective Electrode/Quantitative Enzymatic/Quantitative Spectrophotometry

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

Cell Count, CSF 0095018
Method: Cell Count/Differential

Rule out infectious process

Cerebrospinal Fluid (CSF) Culture and Gram Stain 0060106
Method: Stain/Culture/Identification

Rule out presence of infectious process

Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

Aid in infectious evaluation for neurologic deficit

Immunoglobulin G, CSF Index 0050676
Method: Quantitative Nephelometry

Nonspecific testing in neurologic evaluation

May help rule out diseases such as multiple sclerosis

Oligoclonal Bands in CSF and Serum 0081135
Method: Qualitative Isoelectric Focusing/Electrophoresis

Nonspecific testing in neurologic evaluation

May help rule out diseases such as multiple sclerosis

Comprehensive Metabolic Panel 0020408
Method: Quantitative Ion-Selective Electrode/Quantitative Enzymatic/Quantitative Spectrophotometry

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

Cell Count, CSF 0095018
Method: Cell Count/Differential

Rule out infectious process

Cerebrospinal Fluid (CSF) Culture and Gram Stain 0060106
Method: Stain/Culture/Identification

Rule out presence of infectious process

Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

Aid in infectious evaluation for neurologic deficit

Immunoglobulin G, CSF Index 0050676
Method: Quantitative Nephelometry

Nonspecific testing in neurologic evaluation

May help rule out diseases such as multiple sclerosis

Oligoclonal Bands in CSF and Serum 0081135
Method: Qualitative Isoelectric Focusing/Electrophoresis

Nonspecific testing in neurologic evaluation

May help rule out diseases such as multiple sclerosis

Paraneoplastic Antibodies (PCCA/ANNA) by IFA with Reflex to Titer and Immunoblot, CSF 2010841
Method: Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot

PCCA/ANNA antibodies are screened by IFA; if IFA screen is positive at 1:1, then a specific titer (PCCA or ANNA) will be added

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

Neuronal Cell Antibodies, CSF 0098726
Method: Enzyme-Linked Immunosorbent Assay
Neuronal Cell Antibodies Quantitative, Serum 0099465
Method: Quantitative Enzyme Immunoassay
Gamma-Aminobutyric Acid-B (GABA-B) Receptor Antibody, CSF (Temporary Delay as of 10/21/14 - no referral available) 2011021
Method: Qualitative Immunofluorescence

May be useful in evaluation of certain types of new-onset cryptogenic epilepsy (eg, associated with movement disorders, psychiatric manifestations, history of autoimmune diseases)

AMPA-Receptor (GluR1/2) Antibody IgG, CSF (Temporary Delay as of 10/21/14 - no referral available) 2011048
Method: Qualitative Immunofluorescence 

May be useful in evaluation of certain types of new-onset cryptogenic epilepsy (eg, associated with movement disorders, psychiatric manifestations, history of autoimmune diseases)