Paraneoplastic syndromes of the nervous system

1
Paraneoplastic syndromes of the nervous system

• Loosely defined as a neurologic condition
  associated with malignancy that is not directly
  due to mets, vascular compromise, opportunistic
  infection, or side effects of Rx
• Immunologic factors (auto-antibodies) are thought
  to be the primary cause
• These antibodies can be detected in serum and
  also CSF of pts and in some cases can be highly
  specific for a specific syndrome or a specific
  tumor

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Animal models exist for three types

• P/Q type voltage gated Ca channel antibodies in
  Lambert-Eaton
• Acetylcholine receptor antibodies in Myasthenia
  gravis
• Voltage gated K channel antibodies in
  neuromyotonia

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Other factors

• Hyponatremia due to SIADH
• Hypercalcemia of malignancy due to PTHrP
• Hypoglycemia due to IGF-II
• Depletion of CNS substrate (tryptophan in the
  case of carcinoid)
• Synthesis of immunoglobulins by the tumor that
  may cause peripheral neuropathy (Waldenstroms
  macroglobulinemia)

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Diagnostic Strategies

• Many times the paraneoplastic syndrome will
  develop before the presence of a tumor is known.
• Search for malignancy thorough HP, risk
  factors
• MRI can assist in Dx of encephalomyelitis
  enhancement on T2 weighted images.
• Examine CSF malignant cells (leptomeningeal
  carcinomatosis), inflammatory changes
  (pleocytosis, oligoclonal bands), antibodies
• Characteristic EMG findings exist for
  Lambert-Eaton, Myasthenia Gravis, neuromyotonia,
  and dermatomyositis.

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Diagnostic Strategies Specific Antibodies

• anti-Hu (also called antineuronal nuclear
  antibodies or ANNA-1) associated with a sensory
  neuropathy as well as encephalomyelitis.
  Underlying tumor is small cell lung Ca in 75 of
  cases.
• anti-Ma2 (also called anti-Ta) can cause
  encephalomyelitis and is associated with
  testicular cancer
• anti-Yo (aby against purkinje cells) causes
  cerebellar findings and occur with breast and GYN
  cancers
• Anti-MaI causes brainstem and cerebellar
  dysfunction and is associated with breast, colon,
  parotid

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Diagnostic Strategies Specific Antibodies

• Anti-Tr (directed against an Ag in the cytoplasm
  of purkinje cells) causes cerebellar degeneration
  in association with Hodgkins disease
• Antibody against glutamate receptor can cause
  cerebellar ataxia in Hodgkins disease
• Anti-CV2 aby acts against glial cells and
  peripheral nerve antigens small cell lung ca,
  thymoma, uterine sarcoma

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Prognostic Factors

• Anti-Hu, anti-Yo typically does not improve
  with control of tumor or immune suppression
• Others (anit-Tr, anti-CV2) can stabilize with
  immune suppression

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Specific syndromes

• Paraneoplastic encephalomyelitis involvement of
  several areas of the nervous system, including
  temporal-limbic systems, brainstem, cerebellum,
  dorsal root ganglia, ANS
• Paraneoplastic cerebellar degeneration
  dizziness, nausea, vomiting, progressive atazia
• Paraneoplastic visual syndromes
  melanoma-associated retinopathy, optic neuropathy

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Specific syndromes

• Motor subacute motor neuronopathy, disorders
  resembling ALS, Stiff Man Syndrome
• Sensory subacute sensory neuronopathy (pins and
  needles, electric shocks)
• Peripheral nervous system acute (Guillain-Barre)
  or chronic sensorimotor neuropathy (CIDP),
  amyloid neuropathy
• Autonomic neuropathy
• Neuromyotonia
• Necrotizing myopathy (inc. CK)
• Cachectic myopathy

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Specific syndromes

• Myasthenia gravis antibody directed against the
  acetylcholine receptor. Seen in thymoma, but
  also breast, small cell, Hodgkins). Bulbar
  symptoms predominate first (diplopia, dysphagia)
  and worsens with use/fatigue
• Lambert-Eaton gradual onset of limb girdle
  weakness (hip then shoulder) then generalized
  weakness. Worse in the morning, improves
  throughout the day. Autonomic dysfunction
  frequently seen.