Paraneoplastic Neurological Disorders

1. Paraneoplastic Neurological Disorders Dr Ashwin Pinto Wessex Neurological Centre

2. Structure of Talk • Basic facts and definition • The rules…. and the exceptions • Pathogenesis • Common clinical syndrome • Specific anti-neuronal antibodies

3. Incidence of paraneoplastic disorders Varies with neurological syndrome and tumour • myasthenia gravis – 15% of patients with thymoma • LEMS – 2-3% of patients with SCLC • Other syndromes with solid tumours - <1% • Rare with haematological malignancies except: • Hodgkin’s disease • osteosclerotic myeloma and POEMS syndrome

4. Definition …… non-metastatic remote effect of cancer on nervous system • But how can we be sure that the two are linked? • Cancer is common ? chance association • Tumour often post-dates neurological symptoms by months-years • Affects <1% people with cancer • Syndromes and antibodies frequently overlap

5. Evidence • There are recognised associations between certain malignancies and defined neurological syndromes • In some cases the neurological condition remits when the cancer is treated • Identification of ‘marker’ antibodies that recognise proteins expressed by the tumour and by neurones

6. The Rules • Most tumours are associated with more than one type of PND • Paraneoplastic syndromes frequently co-exist • Antibody ‘markers’ are generally not specific for a single disease • Response to treatment of PND is poor

7. Abs causative Transfer of abs / T cells transfers disease E.g. LEMS, MG, neuromyotonia Treatment of immune process is effective Abs disease markers Transfer of abs does not cause disease E.g. Limbic encephalitis, PCD, PSN Treatment of immune process generally not helpful. Two different types of PND?

8. Cancer-associated retinopathy Melanoma-associated retinopathy Paraneoplastic optic neuropathy Motor neuron syndromes Subacute motor neuronopathy Other motor neuron syndromes Encephalomyelitis Limbic encephalitis Brainstem encephalitis Subacute cerebellar degeneration Opsoclonus-myoclonus Stiff-person syndrome Paraneoplastic visual syndromes CNS PND syndromes

9. PNS PND syndromes • Subacute sensory neuronopathy • Acute sensorimotor neuropathy • Chronic sensorimotor neuropathy • Association with M-proteins • Subacute autonomic neuropathy • Paraneoplastic peripheral nerve vasculitis

10. NMJ and muscle PND syndromes • Lambert-Eaton myasthenic syndrome • Myasthenia gravis • Neuromyotonia • Dermatomyositis • Acute necrotizing myopathy • Cachectic myopathy

11. Pathogenesis - antibodies • Most, but not all, PND are associated with anti-neuronal antibodies • Antigens are expressed by tumour cells (mutated or identical?) • Target antigens generally transcriptional proteins which often interact with oncogenes.

12. Detection of Anti-Neuronal Antibodies by Indirect Immunofluorescence Cerebellar Folia Tissue Stellate cell Molecular layer Basket cell Purkinje cell layer Golgi cell Granular layer Granular cell White matter Climbing fiber Mossy fiber

13. Anti-VGCC Depolarisation Crosslinkage - LEMS Nerve (Fab)2 - LEMS Muscle Fab – No LEMS Lambert-Eaton Myasthenic Syndrome and Anti-VGCCs Ca++

14. Are antibodies pathogenic in PND? • Most antigens are cytoplasmic or nuclear rather than extra-cellular • Antibodies do not transfer disease • Animals immunised against Hu etc develop antibodies but no disease • Response to immunosuppressant treatment is disappointing • Antigens are expressed by tumours in patients without PND

15. Cell-mediated immunity in PNDs • Histology shows numerous inflammatory cells in CNS of affected patients • Cytotoxic T lymphocytes specific for the Yo antigen, cdr2, have been identified in patients with PCD • Analysis of TCR gene usage suggests that invading CTL cells are oligoclonal (ie antigen driven)

16. Blood brain barrier cytotoxic killing tumour Cytotoxic killing CTL apoptotic tumour cell cdr2 peptide CTL Dendritic cell T cell receptor MHC Class I Purkinje cell after Albert et al., 1998

17. Pathogenic Abs in Central PNDs anti-mGluR1 antibdies in two patients with HD functional effect on ligand-gated ion channel passive transfer reproduced ataxia

18. Paraneoplastic encephalomyelitis Presenting features: • involvement of several areas of the nervous system • limbic and brainstem encephalitis, myelitis, DRG, autonomic • Majority of patients have underlying SCLC • Investigations • MRI brain may be normal or show limbic signal change • CSF pleocytosis, OCBs and raised protein • anti-neuronal Abs

19. Paraneoplastic encephalomyelitis • Anti-neuronal antibodies • anti-Hu: commonest, assoc with SCLC • also anti-CV2/CRMP5, anti-amphiphysin, anti-ANNA3 and anti-PCA2 • Treatment and prognosis • tumour treatment may stabilise condition • no benefit from immunomodulatory Rx • median survival time is approx 1 year

20. Limbic encephalitis Presenting features: • subacute confusion, seizures, psychiatric symptoms, hallucinations (v variable) Three groups can be identified • patients with SCLC and anti-HU • older median=62yr, smokers, F>M • young males with testicular cancer • anti-Ma2 positive • no anti-neuronal antibodies • 40% of patients • median age 57 • associated lung cancer

21. Limbic encephalitis • Investigations • Anti-neuronal Abs positive in 60% • anti-Hu, anti-Ma2 and anti-CV2 • Signal change in medial temporal lobes on MRI (not invariable) • EEG abnormal (slow, paroxysmal spikes) • CSF abnormal in 80%: pleocytosis, OCB, intrathecal syn HuAb

22. Limbic encephalitis Associations:SCLC, testes, breast, thymoma • Treatment: • Look for primary tumour • Response to immunosuppression poor • Treatment of primary tumour may stabilise the condition (remain very disabled) or rarely improve neurology (Hodgkins, thymoma)

23. Cerebellar degeneration Presenting features • Often abrupt onset with dramatic cerebellar signs before tumour diagnosed. May stabilise at level of severe disability • May be in assoc with PEM, LEMS, peripheral neuropathy • Investigations • MRI may show cerebellar atrophy at the later stages • Anti-neuronal antibodies in serum • CSF mildly abnormal in 2/3rd

24. Cerebellar degeneration Associations: • 90% associated with gynae (anti-Yo), Hodgkins (anti-Tr), SCLC (anti-Hu) • Finding anti-Yo ab predicts gynae malignancy with close to 100% certainty, though may post date the neurological syndrome by as much as a year. • Treatment: • Anti-Yo positive: poor prognosis from tumour (mets common) and from PCD • Anti-Tr positive: treatment of tumour may stabilise the condition though remain v disabled

25. Motor Neurone Syndromes Three groups have been identified: • anti-Hu positive pts who subsequently develop more extensive CNS symtoms/signs • women with primary lateral sclerosis and breast carcinoma – no serological marker • patients with ALS and various cancer – probably coincidental

26. Sensory neuronopathy Presenting features: • Patchy numbness, dysaesthesia, paraesthesiae, lacinating pain, proprioceptive loss occ with autonomic dysfunction • may be assoc with other PND eg paraneoplastic encephalomyelitis • Investigations • CSF - increased protein and pleocytosis • small / absent SNAPs • abnormal blink reflex (more likely in PNS form) Histology Pathology in dorsal root ganglia (similar to Sjogrens)

27. Sensory neuronopathy Associations: • Anti-Hu most common ab • SCLC most common Ca • Anti-Hu positive 99% specific and 82% sensitive [rarely reported in idiopathic disease] • 18% neg for all known abs even with SCLC • Rarely associated with anti-CV2, amphiphysin

28. Sensory neuronopathy Treatment: • Immunosuppression disappointing. • Treatment of tumour may stabilise Dx or lead to mild symptom improvement • Generally eventually associated with paraneoplastic encephalomyelitis. Prognosis of this is awful

29. Opsoclonus/myoclonus (children) Presenting features: • Abrupt onset • Chaotic eye movements • Often assoc with ataxia, vomiting and irritability • Investigations: • Imaging often normal, • CSF may be mildly abnormal (protein, cells, OCB) • No antibody markers (anti-Hu seen equally frequently in children with tumour but no PND)

30. Opsoclonus/myoclonus (children) • Associations: • 2-3% cases of neuroblastoma • Generally precedes tumour Treatment: • Good prognosis in children, respond to immunosuppressant treatment (ACTH, IVIg) • Generally some residual symptoms (motor deficits, speech delay)

31. Opsoclonus/myoclonus (adults) Presenting features: • Less common than children • May be associated with cerebellar disease, myoclonus, mental changes • Associations: • SCLC, breast account for 70% in adults • Also thymoma, non-small cell, thyroid Ca • Breast Ca may be associated with anti-Ri antibodies • Most negative for all known antibodies

32. Opsoclonus/myoclonus (adults) Treatment: • Better prognosis than PCD, limbic encephalitis • May improve with treatment of primary tumour • Some reports of response to immunosuppressant Tx • Valproate, clonazepam may help • Anti-Ri antibodies: • Specific for neurone specific RNA binding proteins NOVA1 and 2 • NOVA1 neg mice have similar symptoms due to apoptosis of brainstem neurons

33. Stiff person syndrome Presenting features: • Stiffness, spasms triggered by movement and emotional upset • Rare with respect to the non-PND form. • Associations: • SCLC, thymoma, breast, colon

34. Stiff person syndrome Humoral response: • May have antibodies against amphiphysin +/- GAD • Amphiphysin ?involved in synaptic transmission • Treatment: • May improve with removal of tumour and steroids

35. Paraneoplastic retinal degeneration Presenting features: • Bilateral asymmetric blurring of vision, night blindness, obscurations, positive symptoms (sparkles, shimmering, distortion) • Progressive deterioration • Examination and Investigations: • Decreased acuity and colour vision • 50% have afferent pupillary defect • Narrowing of retinal vessels (relatively normal fundoscopy) • Central / ring scotomas on visual field testing

36. Paraneoplastic retinal degeneration Association with SCLC: • 90% assoc with SCLC • Tends to precede tumour diagnosis by over 2 years • Flat ERG • Associated with anti-retinal antibodies • Heterogeneous, stain outer layers of retina • Recoverin the most common antigen (Ca binding protein) • May show moderate improvement with high dose steroids

37. Paraneoplastic retinal degeneration Association with melanoma: • Second most common • Case reports of other tumours • Postdates melanoma by up to 10 years • Generally signals metastases • ERG abnormal but not flat • Antibodies react against bipolar cells in retina • May improve with steroids

40. Anti-Hu antibodies • commonly assoc with limbic encephalitis, cerebellar degeneration and sensory neuronopathy • React with group of neuronal proteins • RNA-binding proteins thought to have a role in post-transcriptional processing • Some Hu proteins bind to oncogenes c-fos and c-myc • Hu proteins widely expressed in SCLC • Recent study found low titre in 16% of SCLC pts without PND

41. Anti-Yo antibodies • found (almost) exclusively in women with PCD and gynaecological malignancy • antibodies recognise cdr2 / pcd17 • cytoplasmic protein with helix-leucine zipper motif • cdr2 has restricted expression normally to immune privileged sites • widely expressed in gynaecological tumours

42. Anti-Ma antibodies • anti-Ma2 Abs are highly specific for young men with paraneoplastic LE and germ-cell tumour of testis • reactivity with other Ma proteins seen In older patients with PCD or rhombencephalitis assoc with several different tumours

43. Anti-Tr antibody • found in patients with PCD assoc with Hodgkin’s disease • reacts with unidentified antigen in cytoplasm of Purkinje cells • characteristic punctate pattern in molecular layer of cerebellum • Only 50 patients identified worldwide to date

44. anti-CV2 / CRMP5 Abs • assoc with variety of PNDs • cerebellar ataxia – 26% • dementia – 25% • cranial neuropathy – 17% • chorea – 11% • SCLC identified in 77% of pts • thymoma in 7%

45. Case presentation • M.L. • 40 yrs male, right handed • presented in status epilepticus - 30/3/2000 • Background • safari in Kenya over Xmas • took mefloquine for malarial prophylaxis until late Jan • prodromal illness • headaches from Feb

46. single generalised seizure 18/3/2000 • assessed in A+E with plan for neurological F/U • mild personality change • olfactory hallucinations and episodes of altered consciousness • unsteady with weak legs • admitted with second seizure 30/3/2000 which developed into status epilepticus

47. FH/SH • smokes 20-a-day for many years • father has LEMS (also smoker but no SCLC) Examination • marked anterograde amnesia • retrograde amnesia • no limb weakness or focal neurology • sluggish/absent reflexes • plantars flexor

48. CT Brain – normal • CT venogram – normal • Lumbar puncture • RBC 1, WBC 6 (lymphs) • Protein 398 mg/l • CSF glucose 5.0, blood glucose 6.5 • Oligoclonal bands – negative • PCR for HSV and enterovirus – negative • EEG (3/4/2000) – abnormal record with slowing most evident over R temporal area. Slowing less severe than typical for viral encephalitis. Discrete electrographic discharges over R temporal area suggestive of temporal lobe seizures