PARANEOPLASTIC SYNDROMES

1. PARANEOPLASTIC SYNDROMES Steven K. Gerhardt, M.D. Neurology Consultants of Dallas

2. DEFINITION • “All neurologic abnormalities not caused by the cancer’s spread to the nervous system are paraneoplastic” • “Remote effects of cancer on the nervous system”

3. PARANEOPLASTIC SYNDROMES • Neurologic symptoms of paraneoplastic syndromes usually precede the identification of the cancer

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

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

6. PARANEOPLASTIC SYNDROMES • Paraneoplastic syndromes are generally, but not always, irreversible

7. Paraneoplastic Syndromes May Affect Any Portion of the Nervous System • Cerebral cortex • Brainstem • Spinal cord • Peripheral nerves • Neuromuscular junction • Muscle

8. 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 syndrome’s onset is while the cancer is small and curable

9. 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

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

11. 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

12. 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

13. 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

14. 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

15. 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.

16. 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

17. 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%

18. “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

19. “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

20. “Classic Paraneoplastic Syndromes”Specific 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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,

28. 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

29. 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

30. 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

31. 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

32. More “Classic” SyndromesSensory Neuronopathy (SN) • <20% paraneoplastic • Also occurs in patients with autoimmune disorders, Sjogren’s 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. Lambert-Eaton Myasthenic Syndrome (LEMS) • Unlike most paraneoplastic syndromes LEMS usually responds to: • plasmapheresis • corticosteroids • azathioprine • intravenous immunoglobin • Long-term treatment often needed

41. 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