PARANEOPLASTIC SYNDROMES

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PARANEOPLASTIC SYNDROMES

• Steven K. Gerhardt, M.D.
• Neurology Consultants of Dallas

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DEFINITION

• All neurologic abnormalities not caused by the
  cancers spread to the nervous system are
  paraneoplastic
• Remote effects of cancer on the nervous system

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PARANEOPLASTIC SYNDROMES

• Neurologic symptoms of paraneoplastic syndromes
  usually precede the identification of the cancer

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PARANEOPLASTIC SYNDROMES

• Usually when the paraneoplastic-related cancer is
  identified, it is small, nonmetastatic, and
  indolently growing

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PARANEOPLASTIC SYNDROMES

• Neurologic disability caused by paraneoplastic
  syndromes is often profound in the absence of any
  other cancer symptoms

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PARANEOPLASTIC SYNDROMES

• Paraneoplastic syndromes are generally, but not
  always, irreversible

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Paraneoplastic Syndromes May Affect Any Portion
of the Nervous System

• Cerebral cortex
• Brainstem
• Spinal cord
• Peripheral nerves
• Neuromuscular junction
• Muscle

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Importance of Paraneoplastic Syndromes

• Although rare, recognition by the physician is
  important
• Neurologic symptoms precede and prompt the
  diagnosis of systemic cancer in about 50 of
  patients
• Some syndromes direct search to particular organs
• In many cases the syndromes onset is while the
  cancer is small and curable

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Pathogenesis

• Onconeuronal Immunity
• Tumor expression of proteins that normally are
  restricted to the nervous system triggers an
  immune response against the tumor that also
  affects the nervous system
• Only a small amount of tumor may trigger response

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Pathogenesis continued

• Tests for antibodies against the cancer-expressed
  neuronal proteins
• Some disorders caused by antibodies
• Myasthenia gravis
• LEMS
• Other disorders most likely caused by B and T
  cell mechanisms of neuronal injury

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Diagnosis

• Paraneoplastic syndromes occur in patients
• not known to have cancer (most common)
• with active cancer
• in remission after treatment
• exclude other cancer-associated process

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Diagnosis with Known Cancer

• Search for metastases
• MRI of involved site
• CSF cytology
• Search for nonmetastatic disorders
• Vascular, infectious, metabolic disorders,
  chemotherapy, radiation therapy
• Serum/CSF for autoantibodies

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Diagnosis without Known Cancer

• Exclude other causes of nervous system
  dysfunction
• Search for Cancer
• CXR, pelvic examination,
• mammograms, examine lymph nodes, serum cancer
  markers (CEA)
• CSF for cells, IgG, OCB, cytology examination
• Serum/CSF for autoantibodies
• If CSF or autoantibodies positive then follow and
  search again

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Diagnosis

• Suggestive clinical features
• Subacute onset, progress over weeks to months
• Severe neurologic disability
• One portion of nervous system more than
  widespread involvement
• Some syndromes present stereotypically

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DiagnosisAutoantibodies

• Presence of autoantibodies
• helps to confirm the clinical diagnosis
• focus the search for an underlying malignancy
• Anti-Hu, Anti-Yo, Anti-Ri, Anti-Tr, Anti-CV2, etc.

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Treatment

• Unrewarding in general
• Most patient left with severe neurologic
  disability
• Immunosuppression ineffective in most, except
  LEMS
• ? rapid onset without diagnosis or treatment
  before irreversible neuronal damage has occurred

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Frequency of Paraneoplastic Syndromes

• Clinically significant paraneoplastic syndromes
  probably occur in fewer than 1 of patients with
  cancer
• If a patient without a known cancer presents with
  one of the classic paraneoplastic syndromes the
  likelihood he/she has cancer is considerable
• i.e., LEMS 60 paraneoplastic
• Subacute cerebellar degeneration 50

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Classic Paraneoplastic Syndromes

• A group of disorders, when present, strongly
  suggests an underlying cancer
• Lambert-Eaton myasthenic syndrome (LEMS)
• Opsoclonus/myoclonus found in children
• Subacute cerebellar degeneration
• Encephalomyelitis
• Subacute motor neuronopathy
• Sensory neuronopathy

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Non-classic Paraneoplastic Syndromes

• Second group of clinical syndromes sometimes
  associated with cancer
• More often appearing in the absence of a neoplasm
• Polymyositis
• Amyotrophic lateral sclerosis
• Sensorimotor polyneuropathy
• Extensive search for a neoplasm is generally
  unwarranted

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Classic Paraneoplastic SyndromesSpecific
Syndromes

• Paraneoplastic cerebellar degeneration
• Most common
• Best characterized
• Rare disorder
• 300 cases report by 1995
• A group of related disorders that differ in
  clinical features, prognosis, and types of
  malignancies

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Paraneoplastic Cerebellar Degeneration

• Disorders can be separated by characteristic
  antibodies to particular tumor-associated
  antibodies
• PCD can be associated with any cancer, but most
  common
• lung cancer (small-cell)
• ovarian
• uterine
• lymphomas

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Paraneoplastic Cerebellar Degeneration

• Neurologic symptoms prompt patient to see doctor
  before cancer is symptomatic
• Cancer is usually found months to 2-4 years after
  onset of neurologic symptoms
• Sometimes only at autopsy

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Paraneoplastic Cerebellar Degeneration

• Clinical features
• slight incoordination in walking
• rapidly evolving over weeks to months with
  progressive gait ataxia
• incoordination in arms, legs and trunk
• dysarthria
• nystagmus with oscillopsia

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Paraneoplastic Cerebellar Degeneration

• Within a few months it reaches its peak and then
  stabilizes
• most cannot walk without support
• cannot sit unsupported
• handwriting is impossible
• eating independently difficult
• speech very difficult to understand
• oscillopsia may prevent reading
• diplopia vertigo

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Paraneoplastic Cerebellar Degeneration

• Neurologic signs always bilateral, usually
  symmetric
• Deficits frequently limited to cerebellar
  dysfunction
• Other neurologic deficits (mild)
• sensorineural hearing loss
• dysphagia
• hyperreflexia
• extrapyramidal signs
• peripheral neuropathy
• dementia

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Paraneoplastic Cerebellar Degeneration

• Laboratory evaluation
• diffuse cerebellar atrophy months to years after
  onset on head imaging
• CSF (early)
• increased lymphocytes
• slightly elevated protein and IgG concentrations
• Pleocytosis resolves with time

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Paraneoplastic Cerebellar Degeneration

• Autoantibodies in serum and CSF
• found in a subset of patients
• number is unknown
• react with Purkinje cells of cerebellum tumor
• well characterized
• anti-Yo, anti-Hu, anti-Ri, anti-Tr, anti-CV2,
  anti-Ma proteins,

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Paraneoplastic Cerebellar Degeneration

• Autoantibodies in serum and CSF/cancer
• anti-Yo ovary, breast
• anti-Hu SCLC
• anti-Ri Breast, SCLC,
• anti-Tr Hodgkins lymphoma
• anti-CV2 SCLC
• anti-Ma proteins Testicular

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Paraneoplastic Cerebellar Degeneration

• Pathology
• CNS may be normal at autopsy
• usually the cerebellum is atrophic with
  abnormally widened sulci and small gyri
• microscopic
• extensive/complete loss of Purkinje cells of the
  cerebellar cortex
• pathologic changes sometimes involving other
  parts of nervous system

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Paraneoplastic Cerebellar Degeneration

• Diagnosis
• recognize characteristic clinical syndrome
• exclude other causes of late-onset cerebellopathy
• Leptomeningeal metastasis
• infections
• toxicity of chemotherapies
• viral brainstem encephalitis
• demyelinating disease
• Creutzfeld-Jakob disease
• infarction, hypothyroidism
• alcoholic and hereditary cerebellar degenerations

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Paraneoplastic Cerebellar Degeneration

• Once the disease peaks it doesnt usually change
• Treatment or cure of underlying cancer usually
  doesnt help
• Immune suppression (steroids) or plasmapheresis
  is not effective
• ? clonazepam for ataxia

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More Classic SyndromesSensory Neuronopathy (SN)

• lt20 paraneoplastic
• Also occurs in patients with autoimmune
  disorders, Sjogrens syndrome
• 2/3 of paraneoplastic SN have small-cell lung
  cancer
• Neurologic syndrome usually precedes diagnosis of
  cancer
• dysesthetic pain and numbness of distal
  extremities
• severe sensory ataxia
• all sensory modalities affected, loss of DTRs
• motor nerve action potentials are normal

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Subacute Motor Neuronopathy(Spinal Muscular
Atrophy)

• Rare complication of Hodgkins and other
  lymphomas
• Subacute, progressive, painless, patchy lower
  motor neuron weakness
• Affects legs more than arms
• Profound weakness
• Degeneration of neurons in the anterior horns of
  the spinal cord

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Encephalomyelitis

• Cancer patients with clinical signs of damage to
  more than one area of the nervous system
• Limbic encephalitis
• rare complication of small-cell lung cancer
• personality/mood changes develop over days or
  weeks
• severe impairment of recent memory
• sometimes with agitation, confusion,
  hallucinations, seizures
• brain MRI normal or signal changes in the
  medial temporal lobe(s)
• may improve with treatment of underlying tumor

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Opsoclonus/Myoclonus Found in Children

• Opsoclonus
• involuntary, arrhythmic, multidirectional,
  high-amplitude conjugate saccades
• associated with myoclonus
• may have cerebellar signs
• 50 of children harbor a neuroblastoma
• Neurologic signs precede discovery of tumor in
  50
• Anti-Ri antibody associated with opsoclonus

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Photoreceptor Degeneration

• Cancer-associated retinopathy (CAR)
• Rare syndrome
• Small-cell lung cancer, melanoma, gynecologic
  tumors
• Episodic visual obscurations, night blindness,
  light-induced glare, photosensitivity, impaired
  color vision progressing to painless vision loss
• Typically precedes diagnosis of cancer
• ? prednisone

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Lambert-Eaton Myasthenic Syndrome (LEMS)

• Presynaptic disorder of neuromuscular
  transmission
• Proximal weakness, areflexia or hyporeflexia,
  autonomic dysfunction
• 45 to 60 associated with SCLC, reported also
  with renal cell carcinoma, lymphoma and breast
• Syndrome precedes tumor diagnosis by several
  months to years

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Lambert-Eaton Myasthenic Syndrome (LEMS)

• Onset with proximal lower extremity weakness
• Later proximal upper extremity weakness
• Respiratory and craniobulbar involvement uncommon
• Autonomic dysfunction prominent
• dry mouth, dry eyes, impotence, orthostatic
  hypotension, hyperhidrosis
• Facilitation with sustained contraction
• gt100 CMAP increase with repetitive stimulation

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Lambert-Eaton Myasthenic Syndrome (LEMS)

• gt92 with antibodies against P/Q-type
  voltage-gated calcium channels (presynaptic)
• Impaired influx of calcium into nerve terminal
  with reduced neuromuscular junction transmission
• A LEMS diagnosis warrants a thorough
  investigation for underlying carcinoma, SCLC
• Careful observation and serial evaluations until
  tumor found

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Lambert-Eaton Myasthenic Syndrome (LEMS)

• Unlike most paraneoplastic syndromes LEMS usually
  responds to
• plasmapheresis
• corticosteroids
• azathioprine
• intravenous immunoglobin
• Long-term treatment often needed

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Summary

• Paraneoplastic syndromes are rare
• Often precede the diagnosis of cancer
• Thought to result from cross-reactivity of
  antibodies to a common antigen within tumor and
  nervous tumor
• Disability persists despite treatment of
  underlying tumor