Paraneoplastic syndromes2013

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Paraneoplastic syndromes2013

  1. 1. PARANEOPLASTIC SYNDROMES Prof. Ashraf Abdou Neuropsychiatry department 12/14/2013
  2. 2. Objectives • Definition • Pathogenesis • Incidence • Diagnosis • Common paraneolastic syndromes 12/14/2013
  3. 3. DEFINITION All neurological abnormalities Not Caused By:  Invasion by the tumor or its metastases  Infections  Ischemia, metabolic or nutritional deficits  Surgery or other treatment modalities • “Remote effects of cancer on the nervous system” 12/14/2013
  4. 4. PARANEOPLASTIC SYNDROMES • Neurological symptoms of paraneoplastic syndromes usually precede the identification of the cancer • Usually when the paraneoplastic-related cancer is identified, it is small, nonmetastatic, and indolently growing • Neurological disability caused by paraneoplastic syndromes is often profound in the absence of any other cancer symptoms • Paraneoplastic syndromes are generally, but not 12/14/2013 always, irreversible
  5. 5. Paraneoplastic Syndromes May Affect Any Portion of the Nervous System • Cerebral cortex • Brainstem • Spinal cord • Peripheral nerves • Neuromuscular junction • Muscle 12/14/2013
  6. 6. Importance of Paraneoplastic Syndromes Although rare, recognition by the physician is important:  Neurological 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 syndrome’s onset is while the cancer is small and curable 12/14/2013
  7. 7. 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% 12/14/2013
  8. 8. 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 12/14/2013
  9. 9. Autoimmunity 12/14/2013
  10. 10. 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 12/14/2013
  11. 11. Pathogenesis • Pathologically: loss of neurons + inflammatory infiltrates • CSF: pleocytosis – intrathecal synthesis of IgG – oligoclonal band 12/14/2013
  12. 12. Antibody Target Hu Pan-neuronal SCLC nuclei Yo Purkinje cytoplasm Ri As Hu but not Breast PNS POM Tr As with Yo but M layer Hodgkin’s PCD GluR1 mGluR1 receptor Hodgikin’s PCD CV2 Oligo cytoplasm SCLC, uterine LEMS, PCD, sarcoma LE 12/14/2013 Tumor Syndrome PEM/PSN, PCD Ovary, breast PCD
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  14. 14. Diagnosis • PNS is the differential diagnosis of unexplained neurological syndromes • NOT A WAIST BASKET FOR UNEXPLAINED CASES 12/14/2013
  15. 15. Relation of the PND to tumor • 70% of cases PND proceed the diagnosis of cancer • 70% of cases identification of the tumor in the 1st screening • Screening:  CT chest, abdomen and pelvis  FDG-PET whole body 12/14/2013
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  19. 19. Paraneoplastic syndromes Classic Brain, cranial n, retina •Cerebellar deg •Limbic encephalitis •Encephalomyelitis •Ospoclonus-myoclonus Spinal cord Non-classic •Brainstem encephalitis •Optic neuritis •Cancer-related retinopathy •Melanoma-associated retinopathy •Stiff-person syndrome •Myelitis •Necrotizing myelopathy •Motor-neuro syndromes NMJ Lambert-Eaton myasthenic synd Myasthenia gravis Peripheral nerves or muscle •Sensory neuronopathy •Dermatomyositis •Intestinal pseudoobstruction •Sensorimotor neuropathy •Acquired neuromyotonia •Autonomic neuropathy •Polymyositis •Acute necrotising myopathy 12/14/2013
  20. 20. Diagnosis Paraneoplastic syndromes occur in patients:  not known to have cancer (most common)  with active cancer  in remission after treatment exclude process 12/14/2013 other cancer-associated
  21. 21. Diagnostic criteria of PND
  22. 22. Suspected PND Know cancer Abs -ve Rule out other Neuro complications Of cancer 12/14/2013 No cancer diag Abs +ve Abs -ve Ab +ve Search of tumor
  23. 23. 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 12/14/2013
  24. 24. Diagnosis without Known Cancer • Exclude other causes of nervous system dysfunction • Search for Cancer      12/14/2013 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
  25. 25. Diagnosis Suggestive clinical features:  Subacute onset, progress over weeks to months  Severe neurological disability  One portion of nervous system more than widespread involvement  Some syndromes present stereotypically 12/14/2013
  26. 26. Diagnosis Autoantibodies 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. 12/14/2013
  27. 27. Treatment • Unrewarding in general • Most patient left with severe neurological disability • Immunosuppression ineffective in most, except LEMS • ? rapid onset without diagnosis or treatment before irreversible neuronal damage has occurred • Treatment of underlying tumor; stabilization of the condition 12/14/2013
  28. 28. “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 12/14/2013
  29. 29. “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 12/14/2013
  30. 30. “Classic Paraneoplastic Syndromes” Specific Syndromes 12/14/2013
  31. 31. 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 12/14/2013
  32. 32. 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 12/14/2013
  33. 33. Paraneoplastic Cerebellar Degeneration • Neurological symptoms prompt patient to see doctor before cancer is symptomatic • Cancer is usually found months to 2-4 years after onset of neurological symptoms • Sometimes only at autopsy 12/14/2013
  34. 34. 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 12/14/2013
  35. 35. 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 12/14/2013
  36. 36. Paraneoplastic Cerebellar Degeneration • Neurological 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 12/14/2013
  37. 37. Paraneoplastic Cerebellar Degeneration Investigations  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 Oligoclonal band 12/14/2013
  38. 38. Ovarian carcinoma
  39. 39. 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, antiCV2, anti-Ma proteins 12/14/2013
  40. 40. Paraneoplastic Cerebellar Degeneration Autoantibodies in serum and CSF/cancer  anti-Yo ovary, breast  anti-Hu SCLC  anti-Ri Breast, SCLC,  anti-Tr Hodgkin’s lymphoma  anti-CV2 SCLC  anti-Ma proteins Testicular 12/14/2013
  41. 41. 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 the cerebellar cortex  pathologic loss of Purkinje cells of changes sometimes involving other parts of nervous system 12/14/2013
  42. 42. 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 12/14/2013
  43. 43. Paraneoplastic Cerebellar Degeneration • Once the disease peaks it doesn’t usually change • Treatment or cure of underlying cancer usually doesn’t help • Immune suppression (steroids) or plasmapheresis is not effective • ? clonazepam for ataxia 12/14/2013
  44. 44. Classical paraneoplastic syndromes 12/14/2013
  45. 45. More “Classic” Syndromes Sensory Neuronopathy (SN) • <20% paraneoplastic • Also occurs in patients with autoimmune disorders, Sjogren’s syndrome • 2/3 of paraneoplastic SN have small-cell lung cancer • Neurological 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 12/14/2013
  46. 46. • Onset    Painful paresthesias & dysesthesias Asymmetric; Distal or Proximal No tumor at initial workup: 50% • Sensory loss (95%)  All modalities involved Proprioceptive loss: Prominent  Ataxia: Sensory  Pseudoathetosis   Distribution Proximal & Distal  Asymmetric (35%) or Symmetric  Upper limb only (25%)  Lower limb only (45%)  • Discomfort: Pain (80%); Paresthesias • Motor 12/14/2013
  47. 47. Motor • Normal (75%)     Occasional sensory-motor involvement (25%): May be subclinical Weakness may be proximal or distal Rare (5%): Amyotrophy; Fasciculations Course Progression    Over days to 6 months Distribution: To diffuse sensory loss Then plateau with little improvement • Occasional improvement with treatment-induced remission of neoplasm • Less common outcomes    Mild course Acute (< 24 hrs; 3%) Chronic (> 6 mo; 15% to 40%) • Survival: Mean 28 months; Range 6 to 96 months 12/14/2013
  48. 48. Subacute Motor Neuronopathy (Spinal Muscular Atrophy) • Rare complication of Hodgkin’s 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 12/14/2013
  49. 49. Classical paraneoplastic syndromes 12/14/2013
  50. 50. 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 12/14/2013
  51. 51. Classical paraneoplastic syndromes 12/14/2013
  52. 52. Opsoclonus/Myoclonus Found in Children • Opsoclonus    involuntary, arrhythmic, multidirectional, highamplitude 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 12/14/2013
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  54. 54. 12/14/2013
  55. 55. Classical paraneoplastic syndromes 12/14/2013
  56. 56. 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 12/14/2013
  57. 57. 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 • >100% CMAP increase with repetitive stimulation 12/14/2013
  58. 58. Lambert-Eaton Myasthenic Syndrome (LEMS) • >92% 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 12/14/2013
  59. 59. Lambert-Eaton Myasthenic Syndrome (LEMS) • Unlike most paraneoplastic syndromes LEMS usually responds to:  plasmapheresis  corticosteroids  azathioprine  intravenous immunoglobin • Long-term treatment often needed 12/14/2013
  60. 60. Summary • Paraneoplastic syndromes are rare • Often precede the diagnosis of cancer • Thought to result from crossreactivity of antibodies to a common antigen within tumor and nervous tumor [Onconeural Ab] • Disability persists despite treatment of underlying tumor 12/14/2013

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