Paraneoplastic Syndromes: Classic Syndromes and Diagnosis
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Semelhante a Paraneoplastic Syndromes: Classic Syndromes and Diagnosis
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Paraneoplastic Syndromes: Classic Syndromes and Diagnosis
- 1. PARANEOPLASTIC SYNDROMES Prof. Ashraf Abdou Neuropsychiatry department 12/14/2013
- 2. Objectives • Definition • Pathogenesis • Incidence • Diagnosis • Common paraneolastic syndromes 12/14/2013
- 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. 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. Paraneoplastic Syndromes May Affect Any Portion of the Nervous System • Cerebral cortex • Brainstem • Spinal cord • Peripheral nerves • Neuromuscular junction • Muscle 12/14/2013
- 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. 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. 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
- 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. Pathogenesis • Pathologically: loss of neurons + inflammatory infiltrates • CSF: pleocytosis – intrathecal synthesis of IgG – oligoclonal band 12/14/2013
- 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. Diagnosis • PNS is the differential diagnosis of unexplained neurological syndromes • NOT A WAIST BASKET FOR UNEXPLAINED CASES 12/14/2013
- 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. 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. 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. Diagnostic criteria of PND
- 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. 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. 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. 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. 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. 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. “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. “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. “Classic Paraneoplastic Syndromes” Specific Syndromes 12/14/2013
- 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. 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. 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. 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. 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. 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. 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
- 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. 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. 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. 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. 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
- 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. • 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. 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. 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
- 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
- 54. 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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- 58. 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
- 59. 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
- 60. 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
- 61. 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
- 62. 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