Paraneoplastic Syndromes:

Future
Past and Present

Anu Jacob
The Walton Centre NHS FT, Liverpool
 The interface

Neurology Oncology

PNS

Immunology
PNS – paraneoplastic neurological syndrome

(Para –alongside, neo-new, plasis- formation)

 Trousseau’s
syndrome-migratory
thrombophlebitis
-first PNS

Armand Trousseau 1801-

1867
 Paraneoplastic
Sensory
Neuronopathy

Derek-Denny Brown
1901-1981
 Clinical features of PNS

Brain, 88, 1965

Russel Brain
Eaton Lambert
 Pathophysiology and clinical signs of paraneoplastic
rheumatic syndromes

Manger, B. & Schett, G. (2014) Paraneoplastic syndromes in rheumatology

Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2014.138
 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:10.1038/nrrheum.2014.138
Any cancer associated with a neurological
syndrome was thought potentially
paraneoplastic … ?
 Proposed Pathogenesis of Paraneoplastic Neurologic
Disorders.

Darnell RB, Posner JB. N Engl J Med 2003;349:1543-1554.

J Dalmau, F Graus. N Engl J Med 2018;378:840-851.
 Principles of Classification Graus 2004
• Classical vs Non Classical PN syndrome

• Well characterised vs Partially characterised

antibodies

• Definite vs Possible PNS

Definite or Possible PNS
 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 Caspr2 - 30-50% thymoma)

Recoverin AMPAR (rare; 70% SCLC)

AGNA (SOX) GABABR (50% SCLC)

Glycine (10% thymoma)

 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;378:840-851.

 Location of antigen-relationship to
pathogenesis and treatment

• Intracellular antigen associated Ab– T cell

mediated
• Surface antigen associated Ab – B cell
mediated
Syndrome Cancer

Antibody
Neuromyelitis optica Cancer

Aquaporin-4 IgG
Cerebellar Ataxia Pelvic /Breast malignancy

Ant-Yo-Antibody
Archives of
Neurology 2010

July 2011
Relative frequencies of the classical
PNS

238 (24.3)
979 European cases from 20 centres
98 (10.0)

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: 330-225

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

 Relative frequencies of well
characterised onconeural Abs seen in
classical PNS

380 (38.8)

Giometto B, et al, Arch Neurol 2010; 67: 330-225

Treatment and causes of death
 Investigations in PNS
• Aims:
– Define syndrome and regions of involvement
– Exclude alternate causes
– Find the tumour
• Antibodies
• CSF
• Electrophysiology
• MRI
• CT/PET
 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;378:840-851.
PET-CT
 Screening for suspected cancer
Titulaer 2011
Suspected First line Second line Third line
tumour
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)
• 31 patients with
SCLC+LEMS
• 279 with out LEMS
• LEMS offered
survival advantage
HR 1.76 (1.1-2.7)
• Some PNS respond better
– Encephalitis (LGI1,NMDARE),LEMS, OMS, MG
• Some poorly
– PCD, Hu related, myelopathy, autonomic
neuropathy , CARetinopathy
• IPFR fatigue
 Approach to Treatment in PNS
Clinical, neuroimaging, serum Exclusion of other
and CSF evaluation disorders

Antibodies to intra-neuronal Neuronal surface antibodies

proteins – onconeuronal abs (Hu, (NMDAR, AMPAR, GABA(B), GlyR,
Yo, Ma2, CRMP5, amphiphysin etc.) CASPR2, LGI1, etc.)

Tumour present Tumour not present tumour removal +Corticosteroids,

IVIg, plasma exchange

Oncological Intensify Response No response

treatment / tumour
tumour removal surveillance/tre
atment Intensify tumour Rituximab,
+ T-cell surveillance
+ T-cell cyclophosphamide
suppression suppression + chronic
immuno-
suppression
Steroid, Tacrolimus, cyclophos
Mycopheonolate
An illustrative case
 Examination
• No extrapyramidal signs
 Examination
• No extrapyramidal signs
 Diagnosis

• Anti-Ma2 antibody positive PNS

• Mesothelioma
• 66 man
• Opsoclonus and cerebellar signs
• Mesothelioma and anti-Ma 2
• Poor response to IVMP, IVIg and PLEX
• Supportive care
• 37 female
• Sudden onset supranuclear palsy
• Headache and weight gain
• T2 changes hypothalamus, mesial temporal,
midbrain – cleared with chemotherapy
• Died
Future
 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 !
 Prgamatically..
1. Updated /upgraded Classification scheme is
needed

2. New syndromes and antibodies will continue

to evolve
Flanagan et al 2017 Annals of Neurology
Flanagan et al Annal of
Neurology 2017
 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
 GFAP syndrome
• As common as Yo
antibody
• Linear perivascular
enhancement

51
3. It’s all too complex ?
Syndrome Cancer

Antibody
Neurologists delight in H-H approach
Is Arnie more practical ?
Should clinicians cut to the chase ?
• If :
– We can’t conclusively exclude a tumour
Why
– Variable presence of syndrome bother
– Early diagnosis and tumor removal is the with
best treatment for PNS antibodi
es ?

• Should we simply do
– PET-CT whole body + USG Testes or
Mammogram for most suspected PN
syndromes?
 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

5. Immunotherapy for cancer-Implications
• 5th 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
 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
 APC T lymphocyte

Copyrights apply
Immune Check-Point Inhibitors
 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
 6. New treatments and trials in PNS
Title Drug Sponsor

1 Immunotherapy of PNS IVIG Hôpitaux de Paris

2 OMS with or without Dexamethasone/ Institute cure

neuroblastoma cyclophos/rituximab

3, 4 LEMS 3,4 DAP UCSF, Pittsburgh,

California

5 OMS Rituximab Genentech Hôpitaux

de Paris
6 UK SINAPPS-2

Searched 19/3/18
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
 Acknowledgements
• Angela Vincent
• Geoff Keir
• Saiju Jacob
• Paul Maddison
• Immunology diagnostic labs at WCFT
 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
 How often do we find a positive
paraneoplastic antibody?
Antibody Number %
Hu 50 0.8
Yo 26 0.4
Ma2 10 0.16
CV2 5 0.08
Amphiphysin 3 0.05
SOX1 2 0.03
Tr 1 0.02
Ri 1 0.02
120, 000 patients screened
University of Birmingham
2000-2014
6232 patients screened

Data from Saiju Jacob

 Classical and Non Classical Syndromes

Strong
association
with cancer
 Well characterised antibodies
• IHC patterns
• Assoc. with tumours
• Assoc. with syndromes
• Frequency in cancer
• Reproduced by different groups
Definite or Possible
• Oneline – protective effects
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

Schramm 2013 EJNucl Med Mol Imaging
• 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
 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

 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
 Supranuclear gaze palsy in elderly
• Steel Richardson Syndrome/PSP
• Vascular (? Bilateral)
• ?? Paraneoplastic
MRI
Which paraneoplastic antibody
was positive ?
 Classifying antibodies
Group 1 –Intracellular Group 2 - Neuronal
surface/synaptic

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

Encephalitis

NMDAR IgG
Pathogenesis of PNS in general