Paraneoplastic Antibodies

175 Pages·2016·3.23 MB·English

Paraneoplastic Antibodies
Molecular and clinical studies
Peter Maat
Paraneoplastic Antibodies
Molecular and clinical studies
Peter Maat
Copyright: P. Maat, 2016
All rights reserved. No part of this thesis may be reproduced, stored in a retrieval
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ISBN: 978-94-91602-45-0
Ontwerp omslag: J. Maat
Gebruikte uurwerk: skeletklok gemaakt door M. Van Manen, 2001
Vomgeving en druk; Proefschriftenprinten.nl
Paraneoplastic Antibodies
Molecular and clinical studies
Paraneoplastische antistoffen
Moleculaire en klinische studies
Proefschrift
ter verkrijging van de graad van doctor aan de
Erasmus Universiteit Rotterdam
op gezag van de
rector magnificus
Prof.dr. H.A.P. Pols
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
donderdag 24 maart 2016 om 11.30 uur
door
Peter Maat
geboren te Rijssen
Promotiecommissie:
Promotor: Prof.dr. P.A.E. Sillevis Smitt
Overige leden: Prof.dr. J.M. Rozemuller
Prof.dr. M.J. van den Bent
Prof.dr. J.M. Kros
Copromotor: Dr. T.M. Luider
TAble Of COnTenTs
Chapter 1 Introduction 7
Chapter 2 Paraneoplastic Neurologic Syndromes 15
Based on:
Paraneoplastic Neurologic Syndromes. In: Encyclopedia of Life
Sciences(ELS) 2009. John Wiley & Sons, Ltd: Chichester.
Chapter 3 Mass spectrometric detection of antigen-specific 37
immunoglobulin peptides in paraneoplastic patient sera
Journal of Autoimmunity 2012;38(4):354-360.
Chapter 4 Multiplex serology of paraneoplastic 59
antineuronal antibodies
Journal of Immunological Methods, 2013; 398(1-2):125-132.
Chapter 5 Identification of delta/notch-like epidermal growth factor- 81
related receptor as the Tr antigen in paraneoplastic
cerebellar degeneration
Annals of Neurology, 2012; 71: 815-824
Chapter 6 Psychiatric phenomena as initial manifestation of 105
encephalitis by anti-NMDA receptor antibodies
Acta Neuropsychiatrica 2013; 25(3): 128-136
Chapter 7 Pathologically confirmed autoimmune encephalitis in 123
suspected Creutzfeldt-Jakob disease
Neurology Neuroimmunology Neuroinflammation, December
2015; 2(6) no. 6 e178
summary and discussion 149
Appendices 159
- Samenvatting 160
- List of abbreviations 164
- Dankwoord 167
- PhD portfolio 170
- Curriculum vitae 172
- List of publications 173

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1
Introduction
Paraneoplastic neurological syndromes (PNS) are remote effects of cancer. These are
not caused by invasion of the tumor or its metastasis nor by other direct effects of the
tumor or its treatment, such as infection, ischemia, metabolic and nutritional deficits,
drug neurotoxicity or surgery.1
PNS are rare, affecting less than 0.1% of all cancer patients.2 PNS generally have a
subacute course, leaving the patient severely disabled in weeks to months. Often the
patient is not yet known to suffer from cancer and the rapid neurological deterioration
can present a diagnostic challenge.1 The discovery of paraneoplastic antineuronal
antibodies not only facilitated the diagnosis of PNS but also resulted in the general
belief that these disorders are triggered by the often aberrant expression of neuronal
antigens in the associated tumor.3
Several classification systems for antineuronal antibodies have been deployed. In
chapter 2 we classify antibodies by their level of characterization.4 In this classification,
‘well characterized onconeural antibodies’ are defined by (a) recognizable patterns on
routine rat brain immunohistochemistry and positive immunoblotting on recombinant
antigen proteins; (b) the number of cases antibody-positive reported associated with
tumors; (c) the description of well characterized neurological syndromes associated
with the antibodies; (d) the unambiguous identification of the Abs among different
studies, and (e) the frequency of these Abs in patients without cancer.4 These ‘well-
characterized’ onconeural antibodies are by definition almost exclusively found in
patients with cancer and include anti-Hu, Yo, CV2, Ri, Ma2 and amphiphysin.4 Most
of the ‘well-characterized’ onconeural antibodies are directed against intracellular
antigen. Studies of patients’ brain tissues obtained at autopsy, cancer, CSF and blood
suggest that these disorders are mediated by a cytotoxic T cell response, explaining the
generally poor response to treatment and poor prognosis. The ‘onconeural’ antibodies
are probably not pathogenic and markers of neoplasia. The other antibody categories
included the ‘partially characterized paraneoplastic antibodies’ and ‘antibodies that
occur with and without cancer’.4
More recently a still growing number of autoantibodies directed against synaptic
or neuronal cell-surface antigens has been identified, such as the metabotropic
glutamate receptors 1 and 5 (mGluR1,5), N-methyl-D-aspartate receptors (NMDAR),
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) or
gamma-aminobutyric acid receptors (GABAR) (Table 1).5-8 These autoantibodies have
direct access to their target antigen and are potentially pathogenic.5,9 The associated
clinical syndromes may be paraneoplastic (with underlying tumor) or may represent
an autoimmune encephalitis (without underlying tumor). In general, patients harboring
autoantibodies directed against synaptic or neuronal cell-surface antigens respond
favorably to immunotherapy with a good outcome in up to 80%.7,10
8
Table 1. Autoantibodies associated with paraneoplastic neurological syndromes and 1
autoimmune encephalitis
Intracellular antigens int
r
o
Antigen Main clinical syndrome Tumor d
u
Hu (ANNA-1) Encephalomyelitis, sensory neuronopathy, limibic SCLC, neuroblastoma, ct
io
encephalitis, subacute cerebellar degeneration, prostate carcinoma14-17 n
autonomic neuropathy
Yo (PCA-1) Subacute cerebellar ataxia Ovary, breast, fallopian tube,
endometrium carcinoma16,18,19
CV2 (CRMP-5) Encephalomyelitis, limbic encephalitis, chorea, optic SCLC, thymoma, renal
neuritis, sensory and sensorimotor neuropathy, cel land tyroid gland
subacute cerebellar degeneration carcinoma16,20
Ri (ANNA-2) Opsoclonus-myoclonus, brainstem encephalitis Breast carcinoma, SCLC16,21
Ma2 (Ta) Limbic/diencephalic/brainstem encephalitis, subacute Testis (men), ovary, breast,
cerebellar ataxia lung carcinoma16,22-24
Intracellular synaptic antigens
GAD65 Subacute cerebellar ataxia, limbic encephalitis Rarely lung, colon, pancreas,
breast, thyroid, renal cell
carcinoma, thymoma25
Amphiphysin Stiff-person syndrome, encephalomyelitis, subacute Breast carcinoma, SCLC,
sensory neuronopathy, sensorimotor neuropathy melanoma16,26
Synaptic or cell-surface antigens
NMDAR Anti-NMDAR encephalitis (complex neuropsychiatric Ovarian teratoma27,28
syndrome) (Age related)
AMPAR Limbic encephalitis, psychosis Lung, breast carcinoma,
thymoma29
GABAR Limbic encephalitis with prominent seizures SCLC30
B
GABAR Status epilepticus, refractory seizures Rarely thymoma31
A
LGI1 Limbic encephalitis, faciobrachial dystonic seizures, <10% thymoma32,33
hyponatremia
Caspr2 Neuromyotonia, Morvan’s syndrome Rarely thymoma34,35
DNER/Tr Subacute cerebellar ataxia Hodgkin lymphoma13,36
VGCC Subacute cerebellar ataxia, Lambert-Eaton myasthenic SCLC37-40
syndrome
GlyR Stiff-person syndrome, hyperekplexia, PERM Rarely Hodgkin lymphoma,
breast, lung carcinoma41-43
mGluR1 Subacute cerebellar degeneration Hodgkin lymphoma44
mGluR5 Limbic encephalitis (Ophelia syndrome) Hodgkin lymphoma45
Dopamine-2R Basal ganglia encephalitis, Sydenham’s chorea No tumors reported46,47
DPPX Hallucinations, agitation, myoclonus, tremor, seizures, No tumors reported48
diarrhea
IgLON5 NREM/REM parasomnia, sleep breathing disorder No tumors reported49
9