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
    • Initial testing should be targeted toward well-characterized 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 voltage-gated potassium channel (VGKC)-complex antibodies, N-methyl-D-aspartate receptor antibody (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)
    Amphyphysin**	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) and GABA_BR (γ aminobutyric acid-B receptor), GlyR (glycine 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 encephalitis	SCLC, neuroendocrine
    Caspr2*	Limbic encephalitis, Morvan syndrome	Thymoma
    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
  • Onconeuronal antibody panels by component and positivity rates (based on 3 years of ARUP Laboratories’ data)

    Onconeuronal Antibody Panels and Positivity Rates (based on 3 years of ARUP Laboratories’ data)
    Test	Test Description	Positivity Rates
    Neuronal Nuclear Antibody (ANNA) IgG by IFA with Reflex to Titer & Immunoblot, Serum	Hu and Ri are screened by immunofluorescence and confirmed by immunoblot	0.55%
    Neuronal Nuclear Antibodies (ANNA) IgG, Immunoblot, Serum	Hu and Ri are confirmed by immunoblot	Hu – 3.10% Ri – 0.88%
    Paraneoplastic Syndrome Antibody Panel with Reflex to ANNA Titer, PCCA Titer and Neuronal Immunoblot	ANNA abs are screened by IFA; if IFA screen is positive at 1:10, then titer and immunoblot (Hu and Ri) will be added If Purkinje cell screen is positive at 1:10, then titer and immunoblot (Yo) will be added	ANNA IFA – 0.51% PCCA IFA – 0.32%
    Neuronal Antibodies (Hu, Ri, Yo, Amphiphysin) IgG by Immunoblot	Amphiphysin, Hu, Ri, and Yo are screened by immunoblot	Amphiphysin – 0.10% Hu – 0.55% Ri – 0.10% Yo – 0.38%
    Purkinje Cell Cytoplasmic Antibody by IFA with Reflex to Titer & Immunoblot	If Purkinje cell screen is 1:10, then titer and immunoblot will be added	0.87%

Antibodies, PNS, and Associated Tumors

• PNS and antibody association

  PNS and Antibody Association
  Syndrome	Most common tumor	Most-frequent antibodies
  Autonomic dysfunction
  GI dysmotility	SCLC	Hu, Yo, CV2/CRMP5
  Neuropathy	SCLC	Hu, CV2/CRMP5, nAChR (α3)
  Encephalomyelitis	SCLC	Hu, CV2/CRMP5
  	Germ cell (testis)	ANNA-3, PCCA-2
  	Prostate	Hu
  Lambert Eaton Myasthenic Syndrome (LEMS)	SCLC	VGCC (P/Q type)
  Limbic encephalitis	SCLC	Hu, CV2/CRMP5, Amphiphysin
  	Germ cell (testis)	Ma2/Ta, GABABR, VGKC, AMPAR, Ri
  	Teratoma (ovarian)	NMDAR
  	Thymoma	AMPAR, GAD, VGKC
  	Breast	AMPAR
  Neuropathy
  Subacute sensory	SCLC	Hu, CV2/CRMP5, Amphiphysin, ANNA-3
  Sensorimotor	SCLC	CV2/CRMP5, Hu
  Neuromyotonia	SCLC	VGKC
  Opsoclonus-myoclonus	Neuroblastoma	Hu
  	Breast	Ri
  	SCLC	Ri
  Other movement disorders
  Dystonia	Teratoma (ovarian)	NMDAR
  Chorea	Breast	Yo
  	SCLC	CV2/CRMP-5
  Parkinsonism	Germ cell (testis)	Ma2/Ta
  Retinopathy	SLCC	Recoverin, CV2/CRMP5
  	Melanoma	Anti-rod/bipolar-cell
  Spinal myoclonus	Breast	Amphiphysin
  	SCLC	Amphiphysin
  Stiff person syndrome	SCLC	Amphiphysin
  	Thymoma	GAD
  Subacute cerebellar degeneration	Ovary, breast	Yo
  	Thymoma	GAD
  	SCLC	Hu, CV2/CRMP5, PCCA-2, Zic4, Ri, VGKC
  	Hodgkin lymphoma	PCCA-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

• Paraneoplastic cerebellar degradation
  • Alcohol abuse 
  • Vitamin deficiency (thiamine, vitamin E)
  • Toxins
  • Infectious encephalitis – HIV, HSV
  • Creutzfeldt-Jakob disease
  • Glutamic acid decarboxylase (GAD)-associated cerebellar ataxia
  • Cerebrovascular accident
  • Identified malignancy present
    • Cerebellar metastases
    • Chemotherapy toxicity
• Opsoclonus-myoclonus
  • Infectious encephalitis – HIV, HSV
  • Metabolic encephalopathy (hyperosmolar coma)
  • Drug effect
  • Intracranial hemorrhage
  • Systemic disease
    • CNS vasculitis
    • Diabetes mellitus
    • Sarcoidosis
  • Identified malignancy present
    • Cerebral metastases
    • Hydrocephalus
• Limbic encephalitis and variants
  • Wernicke-Korsakoff syndrome (alcohol abuse)
  • Systemic disease
    • CNS vasculitis (primary angiitis of CNS)
    • Connective tissue disease
      • Systemic lupus erythematosus
      • Sjögren syndrome
    • Diabetes mellitus
    • Sarcoidosis
  • Multiple sclerosis
  • Psychiatric disorders
  • Metabolic encephalopathy
  • Treponema pallidum
  • Identified malignancy present
    • Metastases
    • HHV6 limbic encephalitis
    • CNS gliomas
• Infectious
  • Encephalitis
  • HIV
  • HSV

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
  • Cancer-associated retinopathy
  • Melanoma-associated retinopathy

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Purkinje Cell (Yo) Antibody by IFA with Reflex to Titer and Western Blot, CSF 2006167 Method: Qualitative Immunofluorescence Assay/Quantitative Western Blot (Indirect Fluorescent Antibody/Western Blot)	If positive, titer and immunoblot will be added
Neuronal Nuclear Antibody (Hu) by IFA with Reflex to Titer and Western Blot, CSF 2006162 Method: Qualitative Immunofluorescence Assay/Quantitative Western Blot (Indirect Fluorescent Antibody/Western Blot)	If positive, titer and immunoblot will be added
Neuronal Cell Antibodies, CSF 0098726 Method: Enzyme-Linked Immunosorbent Assay
Neuronal Cell Antibodies, Serum 0099465 Method: Enzyme Immunoassay

Diagnostic Algorithm

  Paraneoplastic Neurological Syndromes Testing