DEFINITION

4. DEFINITION

5. Paraneoplastic neurological disorders (PNDs) refer to an extensive group of syndromes that can affect any part of the nervous system by mechanisms that are primarily immune mediated.

6. INCIDENCE

7. - Rare, < 1% patients with cancer - 3% in SCLC - 30% in thymoma and 50% in sclerotic myeloma - LEMS occurs in approximately 3% of patients with SCLC and 1/1000 in gynaecological tumours - Some specific cancers may have associations with certain disorders more frequently

8. In neuromyopathy - 4% of women with breast cancer - 16% of men with lung cancer - 66% of patients with all cancers

9. Age & Sex: - In UK M:F 1:3.2 - In USA 3:1 - Median age 66y (30-77) - 11% below 50y - lymphoproliferative diseases and testicular tumours in younger

10. - In 60% of patients, symptoms of PND develop before the presence of a tumor is known. - In 40% of patients, symptoms of PND develop after the tumor diagnosis or at tumor recurrence. - In 40% of patients, ther is no detected antibodies - In 15% of cancer patients showed antibodies without having neurologic syndromes.

11. PATHOGENESIS

12. Different etiologies postulated: • - Toxins, viruses, nutritional deficiency, autoimmune • - Autoimmune theory strongest: • “molecular mimicry” • Antibodies react with shared protein antigens: • - Not the cause of damage • -CytotoxicT-cells involved

13. Non metastatic complications of cancers

14. Pathological findings: -Perivascular space filled with T helper (CD4+)& B cells -Interstitial infilterate with cytotoxic T cells (CD8+)

16. CLSSIFICATION

25. DIAGNOSIS

26. Recognition of the paraneoplastic antibodies Recognition of the associated cancer Recognition of the Neurological Syndrome

27. Recognition of the Neurological Syndrome

28. Recognition of the associated cancer • Carcinomas • Lung • Small Cell • Non-small Cell • Gynecologic • Ovarian • Fallopian tube • Endometrial • Breast • GI • Colon • Gastric • Esophageal • Pancreas • GU • Prostate • Renal Cell • Testicular • Lymphomas • Hodgkin’s Disease • Non-Hodgkin’s Disease • Miscellaneous • Sarcoma • Carcinoid • Melanoma • Thymoma/Malignant Thymoma

29. Recognition of the associated cancer Blood tests for PSA, CEA and CA 125,15.3; these are sometimes helpful in progressivePEM • Chest MRI/CT where lung cancer is suspected. • Abdominal and pelvic MRI/CT in PCD. • Mammography in cases of PCD or OMA • Skeletal survey must be considered if myeloma is a possibility with a motor neuropathy,CIDP or the LEMS

30. Recognition of the associated cancer Bone marrow may also be required if myeloma is suspected. • Bronchoscopy if there is a mass on chest imaging or the patient is ANNA-1 (anti-Hu) positive but the chest CT/MRI is negative • Laparoscopy if imaging of the pelvis is positive, or mammography and pelvic imaging are negative but PCA-1 (anti-Yo) antibody is positive. • FDG Positron Emission Tomography (PET) can sometimes identify a primary site when all the above investigations are negative.

31. Recognition of the paraneoplastic antibodies

32. Recognition of the paraneoplastic antibodies (1) Antibodies are present in approximately 60% of patients with PND of the CNS; therefore, the absence of antibodies does not rule out that a syndrome could be paraneoplastic. (2) Paraneoplastic antibodies may be identified (usually at low titer) in the serum of a variable proportion of patients with cancer but without PND (ie, anti-Hu and anti-CV2/CRMP5 in 20% and 10% of patients with SCLC, respectively) (3) In PND of the CNS the antibodies are found in serum and CSF; detection of CSF antibodies is a strong indicator that the associated neurological syndrome is paraneoplastic. (4) Most PNDs of the peripheral nerve or muscle do not associate with paraneoplastic antibodies, except for anti-Hu and anti-CV2/ CRMP5 antibodies. (5) Not all paraneoplastic antibodies have the same sensitivity and specificity.

33. Recognition of the paraneoplastic antibodies Antibodies That Occur with and without Cancer Association

34. Recognition of the paraneoplastic antibodies

35. Recognition of the paraneoplastic antibodies

36. Recognition of the paraneoplastic antibodies

37. DIAGNOSTIC CRITERIA

38. Diagnostic criteria for PND Definite PND: 1. A classical syndrome and cancer that develops within five years of the diagnosis of the neurological disorder. 2. A non-classical syndrome that resolves or significantly improves after cancer treatment without concomitant immunotherapy, provided that the syndrome is not susceptible to spontaneous remission. 3. A non-classical syndrome with onconeural antibodies (well characterized or not) and cancer that develops within five years of the diagnosis of the neurological disorder. 4. A neurological syndrome (classical or not) with well characterized onconeural antibodies (anti-Hu, Yo, CV2, Ri, Ma2, or amphiphysin), and no cancer.

39. Diagnostic criteria for PND Possible PND 1. A classical syndrome, no onconeural antibodies, no cancer but at high risk to have an underlying tumour. 2. A neurological syndrome (classical or not) with partially characterized onconeural antibodies and no cancer. 3. A non-classical syndrome, no onconeural antibodies, and cancer present within two years of diagnosis.

40. Diagnostic criteria for PND Neurological syndrome Classical Non-Classical Tm +ve Tm +ve Tm -ve Tm -ve -ve onconeural Ab +ve onconeural Ab -ve onconeural Ab ±ve onconeural Ab Improvement after cancer therapy or +ve onconeural Ab Well characterized Ab Partially characterized Ab High risk cancer Possible Possible Possible Definite Definite Definite

41. PARANEOPLASTIC SYNDROMES

42. Historic context • First description – peripheral neuropathy in lung Ca patient, Oppenheim, 1888 • Myasthenia with thymoma – Weigert, 1901 • Cerebellar degeneration with ovarian and SCLC – Brain et al, 1951 • Lambert-Eaton myasthenic syndrome and SCLC – Lambert et al, 1956 • Cancer associated retinopathy – Sawyer et al, 1976 • Croft & Wilkinson 1965- Carcinomatous neuromyopathy Dr Edward H Lambert (1915-2003)

43. Encephalomyelitis • Immune-mediated inflammatory disorder that can affect any part of the CNS, dorsal root ganglia, and autonomic nerves. • main areas involved include the hippocampus (limbic encephalitis), the Purkinje cells of the cerebellum cerebellar degeneration), the lower brain stem (brain stem encephalitis),dorsal root ganglia (sensory neuronopathy), spinal cord (myelitis) • Symptoms usually precede tumour detection (SCLC) • Brain MRI often normal, except limbic encephalitis • CSF - ↑ protein, mild pleocytosis; may be N • Most common antibodies: Anti-Hu (ANNA-1), anti-amphiphysin, anti-CV2 • Rare improvement despite tumour treatment • Immunosuppressive Rx, PLEX, IVIG rarely successful

44. Limbic Encephalitis • Majority have SCLC, occ testicular, thymoma, other carcinoma • Usually part of encephalomyelitis syndrome • Symptoms: subacute amnestic syndrome, affective disorder, antero- and retrograde amnesia, hallucinations or delusions, seizures common, abnormal sleep/wake, labile BP, SIADH • MRI: increased T2 signal medial temporal lobes/amygdala, occ hypothalamus, basal forebrain • CSF: N or mild pleocytosis, ↑ protein • Path: non-spec neuronal loss, gliosis, perivasc infiltrates, microglial nodules • Anti-Hu (ANNA-1) (other Ab’s occ) • Workup: Look for SCLC – CT Chest, other CT • Course variable: many may improve after tumour Rx, frequently stabilize at moderate/severe disability

45. Cerebellar degeneration • Majority have SCLC, ovarian Ca (other female genital Ca), breast Ca or Hodgkin’s • Symptoms usually predate cancer dx: • Diffuse dysfunction of cerebellum: • Dysarthria, oculomotor dysfunction • Appendicular and gait ataxia • Many superimposed signs of multifocal encephalomyelitis • May also have LEMS or PN • Deficits worsen for weeks-months then stabilize • Few can walk, feed selves or sit • Anti-Yo (PCA-1) (anti-Tr, anti-Ri, anti-Ma, anti-Hu)

46. Cerebellar degeneration • Path: diffuse loss of Purkinje cells • MRI scans N early, later diffuse atrophy • CSF: mild ↑ protein, pleocytosis • Work-up: Tumour search guided by type of antibody; if –ve, repeat q3-4 mos • Few improve with tumour Rx or with immunosuppressive Rx

47. Cerebellar degeneration

48. Cerebellar degeneration

49. Opsoclonous - myoclonus • Usually disorder of children, ½ have neuroblastoma • Symptoms develop before or after tumour found, fluctuate • Respond to tumour Rx and ACTH, profound deficits freq • Adult syndrome also ass’d with ataxia/falls, precedes tumour Dx – SCLC, Ca breast • Paraneoplastic clinically worse than idiopathic, does not respond as well to Rx, progresses more • MRI normal, CSF protein ↑ • Antibodies: Anti-Ri (ANNA-2), occ PCA-1, anti-Hu • Adult work-up: mammo, pelvic exam & imaging, CEA, CA-125; smokers  CT or MRI chest • Better outcome than PCD or encephalomyelitis • Rx with steroids, ACTH, tumour Rx

50. Lambert – Eaton mysthenic syndrome • Associated with cancer in 40-70%, SCLC • Presynaptic inhib release of quanta of ACh at NMJ • Syndrome precedes tumour discovery in most, by up to 5y • fatigue, proximal weakness, muscle aches, autonomic dysfunction(dry mouth, constipation, impotence), paresthesias • Reflexes absent, improve after voluntary contraction (facilitation)