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.

Tabs Content

Clinical Overview

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

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/brainstem encephalitis, opsoclonus-myoclonus, subacute cerebellar degeneration, autonomic neuropathy, enteric neuropathy (gastrointestinal [GI] dysmotility)	Small cell lung carcinoma (SCLC), neuroblastoma
Yo	Subacute cerebellar degeneration, GI dysmotility (occasionally), chorea	Ovary, breast
CV2/CRMP5	Encephalomyelitis, chorea, limbic encephalitis, sensory neuronopathy, sensorimotor neuropathy, 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, ovary
Ma2/Ta^a	Limbic/diencephalic/brainstem encephalitis, encephalomyelitis, subacute cerebellar degeneration, atypical Parkinsonism	Germ cell tumor (usually testicular), non-SCLC (male predominance)
Amphiphysin^b	Stiff-person syndrome, encephalomyelitis, subacute sensory neuronopathy, sensorimotor neuropathy, limbic encephalitis	SCLC, breast, ovary
Recoverin	Retinopathy	SCLC, melanoma, others
^aBrainstem encephalitis and subacute cerebellar degeneration are usually associated with tumors other than testicular cancer. Sera from these patients also react with the Ma1 protein. ^bSynaptic 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 (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), GABA_BR (γ aminobutyric acid-B receptor), and mGluR1 (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	Small cell lung carcinoma (SCLC)
VGCC N type	Lambert-Eaton, sensorimotor and autonomic neuropathy	SCLC, breast
AChR	Myasthenia gravis	Thymoma
nAChR (α3)	Subacute autonomic neuropathy	SCLC
VGKC complex antibodies	Limbic encephalitis, neuromyotonia (Isaac syndrome), Morvan syndrome (limbic encephalitis and neuromyotonia), gastrointestinal (GI) dysmotility, undulating myeloma, cramp-fasciculation syndrome	Thymoma, SCLC
LGI1^a	Limbic encephalitis	SCLC, neuroendocrine
Caspr2^a	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, thymoma
GABA_B R	Limbic encephalitis (with early prominent seizures)	SCLC
Intracellular Antibody Targets
Amphiphysin^b	Stiff-person syndrome, encephalomyelitis, subacute sensory neuronopathy, sensorimotor neuropathy, limbic encephalitis	SCLC, breast, ovary
GAD	Stiff person syndrome, cerebellar degeneration, limbic encephalitis	Thymoma
^aVGKC-complex antibodies; may also occur independently of VGKC-complex antibodies ^bSynaptic antigenic target; associated with response to treatment AChR, acetylcholine receptor; AMPAR, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; GABA_B R, γ-aminobutyric acid-B receptor; GAD, glutamic acid decarboxylase; LGI1, leucine-rich glioma inactivated 1; 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

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, limbic encephalitis	SCLC
PCCA-2	Encephalomyelitis, subacute cerebellar degeneration	SCLC
Zic4	Subacute cerebellar degeneration	SCLC
Anti-rod/bipolar cell	Optic neuropathy	Melanoma
AGNA-1	Lambert-Eaton myasthenic syndrome	SCLC
AGNA-1, anti-glial nuclear antibody; ANNA, antineuronal nuclear antibody; PCCA, Purkinje cell cytoplasmic antibody; SCLC, small cell lung carcinoma

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	SCLC	Hu, Yo, CV2/CRMP5
Neuropathy	SCLC	Hu, CV2/CRMP5, nAChR (α3)
Encephalomyelitis	SCLC	Hu, CV2/CRMP5
	Testicular	ANNA-3, PCCA-2
	Prostate	Hu
Lambert-Eaton myasthenic syndrome (LEMS)	SCLC	VGCC (P/Q type)
Limbic encephalitis	SCLC	Hu, CV2/CRMP5, amphiphysin, GABA_BR, AMPAR, VGKC
	Testicular	Ma2/Ta, AMPAR, Ri
	Teratoma (ovarian)	NMDAR
	Thymoma	AMPAR, GAD, VGKC (CASPR2, LGI1), CV2/CRMP5
	Breast	AMPAR
	Hodgkin	mGluR
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
Chorea	SCLC	CV2/CRMP-5
Parkinsonism	Testicular	Ma2/Ta
Retinopathy	SLCC	Recoverin, CV2/CRMP5
Retinopathy	Melanoma	Anti-rod/bipolar-cell
Spinal myoclonus	Breast	Amphiphysin
Spinal myoclonus	SCLC	Amphiphysin
Stiff person syndrome	SCLC	Amphiphysin
Stiff person syndrome	Thymoma	GAD
Subacute cerebellar degeneration	Thymoma	GAD
	SCLC	Hu, CV2/CRMP5, PCCA-2, Zic4, Ri, VGKC
	Hodgkin lymphoma	PCCA-Tr
	Testicular	Ma2/Ta
AChR, acetylcholine receptor; AMPAR, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; ANNA, antineuronal nuclear antibody; CV2-CRMP5, collapsin response mediator protein 5; GABA_BR, γ-aminobutyric acid-B receptor; GAD, glutamic acid decarboxylase; Ma2/Ta, intracellular targets; 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

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
- Alcohol abuse (Wernicke-Korsakoff syndrome)
- Immune-mediated nonparaneoplastic
  - CNS vasculitis – primary angiitis of CNS
  - Connective tissue disease
    - Systemic lupus erythematosus
    - Sjögren syndrome
  - Multiple sclerosis
  - Hashimoto encephalopathy
- Psychiatric disorders
- Metabolic encephalopathy
- Infectious encephalitis (eg, Treponema pallidum, HSV, HIV, West Nile virus (WNV), HHV6, Creutzfeldt-Jakob disease)
- Malignancy
  - Metastases
  - CNS gliomas
Retinopathy
- Vascular
- Optic neuritis
- Leber hereditary optic neuropathy (LHON)
- Tobacco-alcohol amblyopia
Lambert-Eaton myasthenic syndrome
- Myasthenia gravis
- Infectious encephalitis (eg, T. botulinum)
- Episodic ataxia type 2
Subacute sensory neuropathy
- Immune-mediated nonparaneoplastic
  - Sjögren syndrome
  - Celiac disease
  - Cryoglobulinemia
  - Autoimmune ganglio neuropathies
- Medications (eg, cisplatinum)
- Vitamin disturbances
  - B₁₂ deficiency
  - B₆ excess
- Infectious encephalitis (eg, HIV)
Opsoclonus-myoclonus
- Infectious encephalitis (eg, HIV, HSV, hepatitis C virus (HCV), Borrelia spp, Creutzfeldt-Jakob disease)
- Postinfectious encephalitis (eg, M. pneumoniae, Streptococcus spp)
- Metabolic encephalopathy (eg, hyperosmolar coma, hypoxia)
- Medications (eg, lithium, tricyclic antidepressants)
- Intracranial hemorrhage
- Systemic disease
  - CNS vasculitis
  - Diabetes mellitus
  - Sarcoidosis
Neurodegenerative disorders
Malignancy
- Cerebral metastases
- Hydrocephalus
- Neuroblastoma (children)

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
- Cancer-associated retinopathy
- Melanoma-associated retinopathy

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

Paraneoplastic Reflexive Panel 2013955

Method: Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot

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

Paraneoplastic Antibodies (PCCA/ANNA) by IFA with Reflex to Titer and Immunoblot 2007961

Method: Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot

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

Autoimmune Neurologic Disease Reflexive Panel, Serum 2013944

Method: Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot/Quantitative Radioimmunoassay/Semi-quantitative Enzyme-Linked Immunosorbent Assay

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

Autoimmune Encephalitis Reflexive Panel, Serum 2013601

Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Radioimmunoassay

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

Autoimmune Encephalitis Extended Panel, Serum 3001431

Method: Semi-Quantitative Indirect Fluorescent Antibody/Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

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

Voltage-Gated Calcium Channel (VGCC) Antibody Panel 3002046

Method: Quantitative Radioimmunoassay

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

P/Q-Type Voltage-Gated Calcium Channel (VGCC) Antibody 0092628

Method: Quantitative Radioimmunoassay

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

N-Type Voltage-Gated Calcium Channel (VGCC) Antibody 3002045

Method: Quantitative Radioimmunoassay

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

Gamma Aminobutyric Acid Receptor, Type B (GABA-BR) Antibody, IgG by IFA with Reflex to Titer, Serum 3001270

Method: Semi-Quantitative Indirect Fluorescent Antibody

Useful for evaluation of classic PNS

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

Method: Qualitative Immunoblot

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

Amphiphysin Antibody, IgG 2008893

Method: Qualitative Immunoblot

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

May aid in diagnosis of occult or recurrent tumor

CV2.1 Screen by IFA with Reflex to Titer 2013956

Method: Semi-Quantitative Indirect Fluorescent Antibody

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

Voltage-Gated Potassium Channel (VGKC) Antibody with Reflex to LGI1 and CASPR2 Screen and Titer, Serum 2009463

Method: Quantitative Radioimmunoassay/Semi-Quantitative Indirect Fluorescent Antibody

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

Voltage-Gated Potassium Channel (VGKC) Antibody, Serum 2004890

Method: Quantitative Radioimmunoassay

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

Leucine-Rich, Glioma-Inactivated Protein 1 Antibody, IgG and Contactin-Associated Protein-2 Antibody, IgG with Reflex to Titers, Serum 2009460

Method: Semi-Quantitative Indirect Fluorescent Antibody

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

Leucine-Rich, Glioma-Inactivated Protein 1 Antibody, IgG with Reflex to Titer, Serum 2009456

Method: Semi-Quantitative Indirect Fluorescent Antibody

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

Contactin-Associated Protein-2 Antibody, IgG with Reflex to Titer, Serum 2009452

Method: Semi-Quantitative Indirect Fluorescent Antibody

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

Voltage-Gated Potassium Channel (VGKC) Complex Antibody Panel with Reflex to Titer, CSF 3001996

Method: Quantitative Radioimmunoassay/Semi-Quantitative Indirect Fluorescent Antibody

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

Leucine-Rich, Glioma-Inactivated Protein 1 Antibody, IgG with Reflex to Titer, CSF 3001992

Method: Semi-Quantitative Indirect Fluorescent Antibody

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

Contactin-Associated Protein-2 Antibody, IgG with Reflex to Titer, CSF 3001986

Method: Semi-Quantitative Indirect Fluorescent Antibody

Rule out metabolic disorder as etiology of neurologic deficits

Comprehensive Metabolic Panel 0020408

Method: Quantitative Ion-Selective Electrode/Quantitative Enzymatic/Quantitative Spectrophotometry

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

Cerebrospinal Fluid (CSF) Culture and Gram Stain 0060106

Method: Stain/Culture/Identification

Rule out infectious process

Cell Count, CSF 0095018

Method: Cell Count/Differential

Aid in infectious evaluation of encephalitis

Protein, Total, CSF 0020514

Method: Reflectance Spectrophotometry

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

Immunoglobulin G, CSF Index 0050676

Method: Quantitative Nephelometry

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

Oligoclonal Bands in CSF and Serum 0081135

Method: Qualitative Isoelectric Focusing/Electrophoresis

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

Paraneoplastic Antibodies (PCCA/ANNA) by IFA with Reflex to Titer and Immunoblot, CSF 2010841

Method: Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot

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

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

Voltage-Gated Potassium Channel (VGKC) Antibody, CSF 3001387

Method: Quantitative Radioimmunoassay

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

Gamma Aminobutyric Acid Receptor, Type B (GABA-BR) Antibody, IgG by IFA with Reflex to Titer, CSF 3001267

Method: Semi-Quantitative Indirect Fluorescent Antibody

Neuronal Cell Antibodies Quantitative, Serum 0099465

Method: Quantitative Enzyme Immunoassay

Neuronal Cell Antibodies, CSF 0098726

Method: Enzyme-Linked Immunosorbent Assay

Test Fact Sheet(s)

Voltage-Gated Potassium Channel Antibody Disorders

Medical Experts

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

Peterson, Lisa K., PhD, D(ABMLI), Medical Director, Immunology, at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

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

References

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

Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger K, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016; 15(4): 391-404. 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

Horta ES, Lennon VA, Lachance DH, Jenkins SM, Smith CY, McKeon A, Klein C, Pittock SJ. Neural autoantibody clusters aid diagnosis of cancer. Clin Cancer Res. 2014; 20(14): 3862-9. 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

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Sweeney M, Galli J, McNally S, Tebo A, Haven T, Thulin P, Clardy SL. Delayed LGI1 seropositivity in voltage-gated potassium channel (VGKC)-complex antibody limbic encephalitis. BMJ Case Rep. 2017; 2017: PubMed

Tebo AE, Haven TR, Jackson BR. Autoantibody diversity in paraneoplastic syndromes and related disorders: The need for a more guided screening approach. Clin Chim Acta. 2016; 459: 162-9. PubMed

Testing Algorithms

Paraneoplastic Neurological Syndromes Testing Algorithm

Read more about Paraneoplastic Neurological Syndromes Testing Algorithm

Educational Videos

Content Review:

December 2016

Last Update: December 2019

Paraneoplastic Neurological Syndromes and Associated Disorders - PNS

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Antibody Tests to Consider

Antibodies, PNS, and Associated Tumors

Differential Diagnosis

Background

Epidemiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Paraneoplastic Neurological Syndromes Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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Paraneoplastic Neurological Syndromes and Associated Disorders - PNS

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Antibody Tests to Consider

Antibodies, PNS, and Associated Tumors

Differential Diagnosis

Background

Epidemiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Paraneoplastic Neurological Syndromes Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult