Paraneoplastic Syndromes: Future Past and Present. Anu Jacob The Walton Centre NHS FT, Liverpool

Transcription

1 Paraneoplastic Syndromes: Future Past and Present Anu Jacob The Walton Centre NHS FT, Liverpool

2 The interface Neurology Oncology PNS Immunology PNS paraneoplastic neurological syndrome (Para alongside, neo-new, plasis- formation)

3 Trousseau s syndrome-migratory thrombophlebitis -first PNS Armand Trousseau

4 Paraneoplastic Sensory Neuronopathy Derek-Denny Brown

5 Clinical features of PNS Brain, 88, 1965 Russel Brain

6 Eaton Lambert

7 Pathophysiology and clinical signs of paraneoplastic rheumatic syndromes Manger, B. & Schett, G. (2014) Paraneoplastic syndromes in rheumatology Nat. Rev. Rheumatol. doi: /nrrheum

8 R3SPE Remitting seronegative symmetrical synovitis with pitting oedema in a patient with non-hodgkin lymphoma Manger, B. & Schett, G. (2014) Paraneoplastic syndromes in rheumatology Nat. Rev. Rheumatol. doi: /nrrheum

9 Any cancer associated with a neurological syndrome was thought potentially paraneoplastic?

10 Proposed Pathogenesis of Paraneoplastic Neurologic Disorders. Darnell RB, Posner JB. N Engl J Med 2003;349: J Dalmau, F Graus. N Engl J Med 2018;378:

11 Principles of Classification Graus 2004 Classical vs Non Classical PN syndrome Well characterised vs Partially characterised antibodies Definite vs Possible PNS

12 Definite or Possible PNS

13 The antibodies Characterized Partially characterized Only occasionally paraneoplastic Hu (ANNA1) Tr (PCA-Tr) AChR (15% thymoma) Yo (PCA-1) ANNA-3 MuSK CV2/CRMP5 PCA-2 VGCC (50% SCLC) Ri (ANNA2) Zic4 NMDAR (35% ovarian teratoma) Ma2 (Ta) mglur1 VGKC complex (LGI1 - rare, Amphiphysin Caspr % thymoma) Recoverin AGNA (SOX) AMPAR (rare; 70% SCLC) GABA B R (50% SCLC) Glycine (10% thymoma)

14 Antibody Reactivity and Pathological Features of Encephalitis Associated with Antibodies against Neuronal Cell-Surface Antigens as Compared with Encephalitis Associated with Antibodies against Intracellular Antigens. J Dalmau, F Graus. N Engl J Med 2018;378:

15 Location of antigen-relationship to pathogenesis and treatment Intracellular antigen associated Ab T cell mediated Surface antigen associated Ab B cell mediated

16 Syndrome Cancer Antibody

17 Neuromyelitis optica Cancer Aquaporin-4 IgG

18 Cerebellar Ataxia Pelvic /Breast malignancy Ant-Yo-Antibody

19 Archives of Neurology 2010 July 2011

20 Relative frequencies of the classical PNS 238 (24.3) 98 (10.0) 979 European cases from 20 centres 91% had a single, pure syndrome (99% definite PNS, 1% possible PNS) 238 (24.3) 65% developed PNS before the tumour 43 (4.4) Giometto B, et al, Arch Neurol 2010; 67:

21 Relative frequencies of the tumour types seen in classical PNS 345 (38.4) SCLC was the most common tumour Giometto B, et al, Arch Neurol 2010; 67: 330

22 Relative frequencies of well characterised onconeural Abs seen in classical PNS 380 (38.8) Giometto B, et al, Arch Neurol 2010; 67:

23 Treatment and causes of death

24 Investigations in PNS Aims: Define syndrome and regions of involvement Exclude alternate causes Find the tumour Antibodies CSF Electrophysiology MRI CT/PET

25 MRI Findings in Antibody-Mediated Encephalitis. Dopamine 2 receptors NMDAR Limbic Encephalitis GABA-A AMPA MOG J Dalmau, F Graus. N Engl J Med 2018;378:

26 PET-CT

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28 Suspected tumour Screening for suspected cancer Titulaer 2011 First line Second line Third line SCLC/Thymoma CT Chest or FDG-PET Breast Ca. Mammography MRI Breast FDG-PET Ovarian teratoma TV USS CT/MRI pelvis Ovarian Ca. TV USS and Ca-125 CT/MRI pelvis FDG-PET Testicular tumour USS, β-hcg, AFP CT/MRI pelvis Biopsy (if >50; or calcification in US) Deramtomyositis CT/Thorax USG pelvis + Mammography/Testes USG If initial screen negative Repeated after 3-6 months and Every 6 months for 4-5 years (2 years may be sufficient for LEMS)

29 31 patients with SCLC+LEMS 279 with out LEMS LEMS offered survival advantage HR 1.76 ( )

30 Some PNS respond better Encephalitis (LGI1,NMDARE),LEMS, OMS, MG Some poorly PCD, Hu related, myelopathy, autonomic neuropathy, CARetinopathy IPFR fatigue

31 Approach to Treatment in PNS Clinical, neuroimaging, serum and CSF evaluation Exclusion of other disorders Antibodies to intra-neuronal proteins onconeuronal abs (Hu, Yo, Ma2, CRMP5, amphiphysin etc.) Neuronal surface antibodies (NMDAR, AMPAR, GABA(B), GlyR, CASPR2, LGI1, etc.) Tumour present Tumour not present tumour removal +Corticosteroids, IVIg, plasma exchange Oncological treatment / tumour removal + T-cell suppression Intensify tumour surveillance/tre atment + T-cell suppression Steroid, Tacrolimus, cyclophos Mycopheonolate Response Intensify tumour surveillance + chronic immunosuppression No response Rituximab, cyclophosphamide

32 An illustrative case

33 Examination No extrapyramidal signs

34 Examination No extrapyramidal signs

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36 Diagnosis Anti-Ma2 antibody positive PNS Mesothelioma

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38 66 man Opsoclonus and cerebellar signs Mesothelioma and anti-ma 2 Poor response to IVMP, IVIg and PLEX Supportive care

39 37 female Sudden onset supranuclear palsy Headache and weight gain T2 changes hypothalamus, mesial temporal, midbrain cleared with chemotherapy Died

40 Future

41 Wish List Understanding the immune response against the intracellular antigens Reasons for BBB breach T cell specific treatments Long term: Prevention and cure of cancers Targeted immunsuppression within the CNS Salvation of immunologic disorders may come from understanding genetics!

42 Prgamatically.. 1. Updated /upgraded Classification scheme is needed 2. New syndromes and antibodies will continue to evolve

43 Flanagan et al 2017 Annals of Neurology

44 Flanagan et al Annal of Neurology 2017

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46 Cancers in GFAP syndrome Neoplasia was diagnosed in 35 patients (34%) (within 2 years in 66%) Ovarian teratoma, prostate and gastroesophageal adenocarcinomas, myeloma, melanoma, colonic carcinoid, parotid pleomorphic adenomas 50

47 GFAP syndrome As common as Yo antibody Linear perivascular enhancement 51

48 3. It s all too complex?

49 Syndrome Cancer Antibody

50 Neurologists delight in H-H approach

51 Is Arnie more practical?

52 Should clinicians cut to the chase? If : We can t conclusively exclude a tumour Variable presence of syndrome Early diagnosis and tumor removal is the best treatment for PNS Should we simply do PET-CT whole body + USG Testes or Mammogram for most suspected PN syndromes? Why bother with antibodi es?

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54 4. We need uniform antibody testing panels and algorithms? Patients first seen in general neurology clinics Testing based on syndrome knowledge Paraneoplastic antineuronal antibody tests depends on lab (type of test, cut offs)* Unrequested tests are not done Add on tests as afterthoughts No clear guidance with what to do with +ve result *National External quality asessment service (NEQAS) in place

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56 5. Immunotherapy for cancer-implications 5 th pillar of cancer treatment after Surgery, Chemo, Radiation and Targeted therapy drugs: homing in on cells with specific molecular changes Imatinib (Glivec) tyrosine kinase inhibitor Trastuzumab (Herceptin) HER2 receptors Immunotherapy enhances own immune system to fight cancer

57 Immunotherapy 2 categories Adoptive cell transfers CAR T cells (chimeric antigen transfer) patients own T cells that apheresed and genetically engineered, multiplied and then reinfused to target cancer cell proteins (e.g CD-19 on B cells) Check point inhibitors Check points are regulatory pathways of immune system CTLA-4 cytotoxic T lymphocyte associated protein-4( CD-152) ipilimumab, (metastatic melanoma) PD-1 and PD-L1 (programmed cell death/ligand protein) nivoulumab (melanoma, NSCLC, Renal cell cancer, Hodgkin s, urothelial cancer

58 APC T lymphocyte Copyrights apply

59 Immune Check-Point Inhibitors

60 Immune checkpoint inhibitors can induce worsen autoimmune diseases and paraneoplastic diseases Mechanism? similar to PNS; anti-tumour response, cross reacts with CNS antigens Hypophysitis- hypopituitarism Encephalitis within weeks (NMDAR -IgG+ve) Transverse myelitis GBS CIDP MG like CIS to MS Treat- stop ICI drugs temporarily Steroids, IVIG

61 6. New treatments and trials in PNS Title Drug Sponsor 1 Immunotherapy of PNS IVIG Hôpitaux de Paris 2 OMS with or without neuroblastoma Dexamethasone/ cyclophos/rituximab Institute cure 3, 4 LEMS 3,4 DAP UCSF, Pittsburgh, California 5 OMS Rituximab Genentech Hôpitaux de Paris 6 UK SINAPPS-2 Searched 19/3/18

62 Have we made true progress in treating PNS? Why? Rare disorders are not any simpler than common ones Larger numbers of patients needed Only national/international collaborative efforts will provide numbers Only well defined cohorts can offer biologic samples for promoting research Only demonstration of a cohort of well characterised and accessible patients and will attract pharmaceutical trials 20 regional neurological centres in UK Are neurologists unable to do true collaborative research and develop treatment pathways? Each of these require interested experts-champions- to dedicate decades of their career

63 Acknowledgements Angela Vincent Geoff Keir Saiju Jacob Paul Maddison Immunology diagnostic labs at WCFT

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65 Clinicians Dilemma All clinicians cant keep up with DDPX clinician then reads up Refs time Labs or clinicians will have to guide Poor prognosis hesitant to take on MDT approach Immunotherapy Regional centres

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68 How often do we find a positive Data from Saiju Jacob paraneoplastic antibody? 120, 000 patients screened Antibody Number % Hu Yo Ma CV Amphiphysin SOX Tr Ri University of Birmingham patients screened

69 Classical and Non Classical Syndromes Strong association with cancer

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71 Well characterised antibodies IHC patterns Assoc. with tumours Assoc. with syndromes Frequency in cancer Reproduced by different groups

72 Definite or Possible

73 Oneline protective effects

74 Cancer survival in LEMS (hypothesis) Anti-VGCC binds to Ca channels on the surface of SCLC Reduces Ca ++ influx Reduction in neuropeptide release Decline in autocrine/paracrine stimulation Reduction in cancer cell proliferation

75 Schramm 2013 EJNucl Med Mol Imaging

76 32 Anti-Ma 27 had tumours Testicular tumours (11) Lung/pleural adenocarcinoma (6) GI tract (4) Ovarian (2) Renal, Bladder, NHL, Cervical 78% had MRI changes

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78 71 year old man Referred from Ophthalmology April 2017 Sudden onset (?subtle problems prior) Difficulty looking down Difficulty with focus/depth perception Courtesy : Mark Doran, Brython Hywell, Dan Menzies

79 Other relevant history Slightly apathetic Sleeping a lot No amnesia No falls No REM sleep disorder PMH : Ischaemic heart disease MI 2 stents Hypertension Benign prostatic hypertrophy 50 pack year smoking history

80 Supranuclear gaze palsy in elderly Steel Richardson Syndrome/PSP Vascular (? Bilateral)?? Paraneoplastic

81 MRI

82 Which paraneoplastic antibody was positive?

83 Classifying antibodies Group 1 Intracellular Group 2 - Neuronal surface/synaptic 1a cancer associated 1b cancer specific- but not pathogenically related 1c Non PNS syndromes 2a Typical CNS syndromes. But not necessarily paraneoplastic Hu (ANNA1) Sox GAD AMPA P/Q type Ca+ channels (lung Ca) Yo (PCA1) Zic Adenylate Kinase GABAb Ri (ANNA2) Homer 3 Glycine CV2 (CRM5), Amphiphysin Ma2 NMDAR 2b MGlur1 (hodgkins)

84 Definite Vs Possible Definite paraneoplastic syndrome Neurological syndrome Antibody Cancer Any Well characterised None Classic syndrome None Develop within 5 years Non-classic syndrome Any paraneoplastic Ab Develop within 5 years Possible paraneoplastic syndrome Neurological syndrome Antibody Cancer Any Partially characterised None Classic syndrome None None; but at high risk Non-classic syndrome None Develop within 2 years

85 Ovarian Teratoma Encephalitis NMDAR IgG

86 Pathogenesis of PNS in general