Paraneoplastic Neurological Syndromes

Clinical Background

Paraneoplastic neurological syndromes (PNS) are diseases that occur as remote effects of tumors. Although many tumors have been associated with PNS, the most commonly encountered include: small cell lung cancer (SCLC), thymoma, neuroblastoma, ovarian, breast, testicular and Hodgkins lymphoma.

Epidemiology

Prevalence - rare, less than 1% of all cancers
Exceptions
- 3% of patients with SCLC are affected by Lambert-Eaton myasthenic syndrome (LEMS)
- About 10% of patients with plasma cell disorders with malignant monoclonal gammopathy may be affected by paraneoplastic peripheral neuropathy
- 15% of patients with myasthenia gravis have thymoma

Pathophysiology

The etiology of some cases of PNS is believed to be autoimmune-mediated
- Immune response against tumors that ectopically express neuronal antigens referred to as onconeuronal antigens
Except for very few cases (eg, LEMS and Recoverin) a direct role of antibodies in the pathogenesis of a PNS has not been proven
In a significant number of cases, the neurologic symptoms precede the detection of tumor
Classification of antibodies based on immunohistochemical staining pattern
- Anti-neuronal nuclear antibodies (ANNA) - ANNA-1, ANNA2, ANNA-3
- Cytoplasmic antibodies - Purkinje cell cytoplasmic antibody 1 (PCCA-1), PCCA-2, PCCA-Tr, and mGLuR1
- Others, which include plasma membrane cation channel antibodies -CV2/CRMP-5, Ma1, Ma2/Ta, amphiphysin, striational, voltage-gated calcium channel (VGCC) and voltage-gated potassium channel (VGKC) antibodies
Antibodies associated with PNS can occur independently of tumor presence
The presence of well characterized antibodies associated with PNS may be useful in the following circumstances:
- Characterization of disease as being definite PNS
- Search for the presence of an underlying tumor or development of a second tumor in patients with known history
PNS may also occur in the absence of autoantibodies

Clinical Presentation

Syndromes of the central nervous system
- Encephalomyelitis (PEM) - brainstem, motor dysfunction
- Limbic encephalitis (LE) - short-term memory loss, seizures, confusion
- Subacute cerebellar degeneration (PCD) - ataxia, slurred speech
- Opsoclonus-myoclonus (OM) - involuntary saccadic eye movements may have truncal myoclonus
Syndromes of the peripheral nervous system
- Subacute sensory neuropathy (PSN)
- Chronic gastrointestinal pseudoobstruction
Syndromes of the neuromuscular junction, muscle, joint, bone
- LEMS - less ocular involvement and more lower limb involvement than classic myasthenia gravis
- Peripheral nerve hyperexcitability
- Dermatomyositis
Syndromes of the visual afferent system (neuro-ophthalmologic PNS)
- Cancer-associated retinopathy
- Melanoma-associated retinopathy

See Also

Human T-Lymphotrophic Virus Types I, II - HTLV I, II

Lung Cancer

Multiple Sclerosis

Myasthenia Gravis - MG

Neuropathic Disease

Paraneoplastic Pemphigus

Plasma Cell Dyscrasias

Diagnosis

PNS can be classified based on consensus criteria, which include:
- Presence or absence of tumors
- Presence of any classical syndrome symptoms
- Characterization of onconeuronal antibodies
Laboratory testing
- Order autoantibody tests based on clinical presentation

Antibodies, Paraneoplastic Neurological Syndromes, and Associated Tumors
Antibody	Clinical syndromes	Associated tumors
Well-characterized paraneoplastic antibodies
Anti-Hu (ANNA-1)	Encephalomyelitis, limbic encephalitis, sensory neuronopathy, subacute cerebellar degeneration, autonomic neuropathy	SCLC, neuroblastoma, prostate
Anti-Yo (PCCA-1)	Subacute cerebellar degeneration	Ovary, breast
Anti-CV2 (CRMP5)	Encephalomyelitis, chorea, limbic encephalitis, sensory neuronopathy, sensorimotor neuropathy, optic neuropathy, subacute cerebellar degeneration, autonomic neuropathy	SCLC, thymoma
Anti-Ri (ANNA-2)	Opsoclonus-myoclonus, brainstem encephalitis	Breast, ovary, SCLC
Anti-Ma2 (Ta)*	Limbic/diencephalic/brainstem encephalitis, subacute cerebellar degeneration	Testicular, lung
Anti-amphiphysin	Stiff person syndrome, encephalomyelitis, subacute sensory neuronopathy, sensorimotor neuropathy, limbic encephalitis	Breast, ovary, SCLC
Anti-recoverin	Cancer-associated retinopathy	SCLC/melanoma/others
Partially characterized antibodies
Anti-Tr (PCCA-Tr)	Subacute cerebellar degeneration	Hodgkins disease
ANNA-3	Encephalomyelitis, subacute sensory neuronopathy	SCLC
PCCA-2	Encephalomyelitis, subacute cerebellar degeneration	SCLC
Anti-Zic4	Subacute cerebellar degeneration	SCLC
Anti-mGluR1	Subacute cerebellar degeneration	Hodgkins disease
Antibodies that occur with and without cancer
Anti-VGCC	Lambert-Eaton myasthenic syndrome, subacute cerebellar degeneration	SCLC
Anti-GUIR 3	Rasmussen's encephalitis
Anti-AchR	Myasthenia gravis	Thymoma
Anti-nAChR	Subacute autonomic neuropathy	SCLC
Anti-VGKC	Limbic encephalitis, neuromyotonia, Morvan's syndrome	Thymoma, SCLC
Anti NMDAR (NR2)	Limbic encephalitis	Ovarian teratoma
*Brainstem encephalitis and subacute cerebellar degeneration are usually associated with tumors other than testicular cancer and sera from these patients also react with the Ma1 protein. Abbreviations: AChR, acetylcholine receptor; ANNA, antineuronal nuclear antibody; GUIR3; mGluR1, metabotropic glutamate receptor type 1; nAChR, nicotinic acetylcholine receptor; NMDAR, N-methy-D-aspartate receptor; PCCA, Purkinje cell cytoplasmic antibody; SCLC, small cell lung carcinoma; VGCC, voltage-gated calcium channels; VGKC, voltage-gated potassium channel.
(de Beukelaar, et al., 2006, 295) Modified

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Paraneoplastic Syndrome Antibody Panel with Reflex to ANNA Titer, PCCA Titer & Neuronal Immunoblot

ARUP #: 0051226

Methodology: Refer to individual components

Use:

For research purposes

Aid in the diagnosis of paraneoplastic syndromes associated with carcinoma of lung, breast, ovary, thymoma or Hodgkin lymphoma

Limitations:

Not recommended as a general screening test for lung, breast or gynecologic malignancies

Follow-up:

An immunoblot assay should be completed for confirmation of ANNA-1 or ANNA-2 or PCCA positive IFA test

Test name: Neuronal Nuclear Antibody (ANNA) IgG by IFA with Reflex to Titer & Immunoblot, Serum

ARUP #: 0050904

Methodology: Indirect Fluorescent Antibody/Immunoblot

Use:

For research purposes

Aid in the diagnosis of paraneoplastic syndromes associated with carcinoma of lung, breast, ovary or thymoma

Limitations:

Not recommended as a general screening test for lung, breast or gynecologic malignancies

Follow-up:

Consider ordering Purkinje cell cytoplasmic antibody (PCCA) IFA with reflex to titer and confirmation by immunoblot

Test name: Neuronal Nuclear Antibody (ANNA) Titer IgG by IFA, Serum

ARUP #: 0050912

Methodology: Indirect Fluorescent Antibody

Use:

For research purposes

Aid in the diagnosis of paraneoplastic syndromes associated with carcinoma of lung, breast, ovary, thymoma or Hodgkin lymphoma

Limitations:

Not recommended as a general screening test for lung, breast or gynecologic malignancies

Follow-up:

An immunoblot assay should be completed for confirmation of ANNA-1 or ANNA-2

Test name: Neuronal Nuclear Antibodies (ANNA) IgG, Immunoblot, Serum

ARUP #: 0051088

Methodology: Immunoblot

Use:

For research purposes

Aid in the diagnosis of paraneoplastic syndromes associated with carcinoma of lung, breast, ovary or thymoma

Limitations:

Not recommended as a general screening test for lung, breast or gynecologic malignancies

Follow-up:

Consider ordering Purkinje cell cytoplasmic antibody (PCCA) IFA with reflex to titer and Western Blot

Test name: Neuronal Antibodies (Hu, Ri, Yo, Amphiphysin) IgG by Immunoblot

ARUP #: 0051090

Methodology: Immunoblot

Use:

For research purposes

Aid in the diagnosis of paraneoplastic syndromes associated with carcinoma of lung, breast, ovary or thymoma

Limitations:

Not recommended as first line test for neuronal antibodies (Hu, Ri, Yo, Amphiphysin)

The presence of amphiphysin antibodies does not necessarily indicate the presence of a tumor; absence of these antibodies does not rule out PNS

Test name: Purkinje Cell Cytoplasmic Antibody by IFA with Reflex to Titer & Immunoblot

ARUP #: 0059444

Methodology: Indirect Fluorescent Antibody/Immunoblot

Use:

For research purposes

Aid in the diagnosis of paraneoplastic syndromes associated with carcinoma of lung, breast, ovary, thymoma or Hodgkin lymphoma

Test name: Voltage-Gated Calcium Channel (VGCC) Antibody

ARUP #: 0092628

Methodology: Radiobinding Assay

Use:

For research purposes

Aid in the diagnosis of paraneoplastic syndromes associated with carcinoma of lung or thymoma

Limitations:

May be present in the absence of cancer

Additional Tests Available

Test name: Purkinje Cell Cytoplasmic Antibody by IFA with Reflex to Titer & Western Blot, CSF

ARUP #: 0098510

Methodology: Western Blot/Immunofluorescence Assay

Comments:

Test name: Neuronal Nuclear Antibody (ANNA) with Reflex to Titer and Western Blot, CSF

ARUP #: 0098761

Methodology: Indirect Fluorescent Antibody/Western Blot

Comments:

References

Cited References

de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic neurological disorders. Oncologist. 2006;11(3):292-305.

General References

Alabduljalil T, Behbehani R. Paraneoplastic syndromes in neuro-ophthalmology. Curr Opin Ophthalmol. 2007;18(6):463-469.

Darnell RB, Posner JB. Paraneoplastic syndromes affecting the nervous system. Semin Oncol. 2006;33(3):270-298.

Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med. 2003;349(16):1543-1554.

Eichmuller SB, Bazhin AV. Onconeural versus paraneoplastic antigens?. Curr Med Chem. 2007;14(23):2489-2494.

Graus F, Dalmau J. Paraneoplastic neurological syndromes: diagnosis and treatment. Curr Opin Neurol. 2007;20(6):732-737.

Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, Honnorat J, Smitt PS, Vedeler Ch, Verschuuren JJ, Vincent A, Voltz R. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75(8):1135-1140.

Molina-Garrido MJ, Guillen-Ponce C, Martinez S, Guirado-Risueno M. Diagnosis and current treatment of neurological paraneoplastic syndromes. Clin Transl Oncol. 2006;8(11):796-801.

Storstein A, Vedeler CA. Paraneoplastic neurological syndromes and onconeural antibodies: clinical and immunological aspects. Adv Clin Chem. 2007;44:143-185.

Vernino S. Autoimmune and paraneoplastic channelopathies. Neurotherapeutics. 2007;4(2):305-314.

Medical Reviewers

Hill, Harry R., M.D. Group Medical Director, Laboratory of Immunology, ARUP Laboratories, and Executive Director of the ARUP Institute for Clinical and Experimental Pathology; Professor and Division Head, Clinical Pathology, University of Utah

Litwin, Christine, M.D. Medical Director, Immunology at ARUP Laboratories; Professor, Clinical Pathology, University of Utah

Tebo, Anne E., Ph.D. Assistant Medical Director, Immunology at ARUP Laboratories; Clinical Assistant Professor, Clinical Pathology, University of Utah

Comprehensive Review: May 2008
Last Update: July 2008