Paraneoplastic Neurological Syndromes

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

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

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

Lung Cancer

Multiple Sclerosis

Myasthenia Gravis - MG

Neuropathic Disease

Paraneoplastic Pemphigus  

Plasma Cell Dyscrasias  

Indications for Ordering

• 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 on number for test-specific information in the ARUP Laboratory Test Directory