19 Full-1

Review
Paraneoplastic neurological
Pract Neurol: first published as 10.1136/practneurol-2021-003073 on 11 September 2021. Downloaded from http://pn.bmj.com/ on June 29, 2023 by guest. Protected by copyright.
syndromes: a practical approach to
diagnosis and management
Sophie Binks,1,2 Christopher Uy,1,3 Jerome Honnorat ‍ ‍ ,4,5
Sarosh R Irani ‍ ‍ 1,2
vigilance.1 3 A key feature of PNS is that

1
Oxford Autoimmune Neurology ABSTRACT
Group, Nuffield Department of
Paraneoplastic neurological syndromes (PNS) the cancer triggers the immune response,
Clinical Neurosciences, Oxford
University, Oxford, UK are the immune-mediated effects of a remote and so it should express the autoantigen
2
Department of Neurology, cancer and are characterised by an autoantibody to which the immune response (including
Oxford University Hospitals NHS response against antigens expressed by an autoantibody) is directed: this ensures
Foundation Trust, Oxford, UK
3
Department of Medicine
the tumour. Classically, well-characterised a direct biological link between the cancer
(Division of Neurology), ‘onconeuronal’ antibodies target intracellular and PNS.
University of British Columbia, antigens and hence cannot access their Expert guidelines in 2021 have rede-
Vancouver, British Columbia, antigens across intact cell membranes. The fined aspects of these disorders in light
Canada
4
French Reference Centre on
pathogenic mediators are likely to be neuronal- of the description of novel antibodies
Paraneoplastic Neurological specific T cells. There is a variable response to and the most robust emergent clinical–
Syndromes and Autoimmune immunotherapies and the clinical syndrome serological–oncological associations.4
Encephalitis, Hospices Civils helps to direct the search for a specific set of
de Lyon, Hopital Neurologique,
Among other benefits, these observed
Lyon, France tumours. By contrast, many newly emerging relationships avoid the spurious attribu-
5
SynatAc Team, Institute autoantibodies with oncological associations tion of common cancers to neurological
NeuroMyoGene INSERM U1217/ target cell surface epitopes and can exert presentations with an alternative expla-
CNRS UMR 5310, Universite de direct pathogenic effects on both the central
Lyon, Universit Claude Bernard nation, and hence encourage accurate
Lyon 1, Lyon, France and peripheral nervous systems. Patients with diagnosis and prognostication. In this
these cell-surface directed autoantibodies often classification, clinical presentations and
Correspondence to clearly respond to immunotherapies. Overall, the
Prof Sarosh R Irani, Oxford associated autoantibodies may be broadly
clinical, serological and oncological features in an defined as ‘high’ or ‘intermediate’ risk of
Autoimmune Neurology
Group, Nuffield Department of individual patient help to determine the clinical paraneoplastic aetiology (box 1).4 5 High-
Clinical Neurosciences, Oxford relevance of the syndrome and hence guide its
University, Oxford OX3 9DS, UK;
risk clinical presentations are reflected
management. We summarise current knowledge by epidemiological studies which consis-
sarosh.irani@ndcn.ox.ac.uk
and a practical approach to the investigation,
tently identify autoantibody patterns with
Accepted 15 July 2021 diagnosis, treatment and outcomes of patients
subacute cerebellar degeneration, enceph-
Published Online First with suspected PNS.
11 September 2021 alomyelitis, limbic encephalitis and
sensory neuronopathy as the leading PNS
in European cohorts.1–3 The intermediate-
INTRODUCTION risk groups show recognised, but less reli-
Paraneoplastic neurological syndromes able, clinical–serological associations.
pn.bmj.com (PNS) describe the remote neurolog-
ical immune- mediated consequences of
a systemic cancer. They affect ~1:300 PARANEOPLASTIC ANTIBODIES IN
patients with tumours, yet population- CONTEXT
level epidemiology suggests an incidence Traditionally, PNS have been associated
rate of only between ~1 and 8/100 000 with ‘well- defined onconeuronal’ anti-
person-years,1 2 indicating ongoing under- bodies, which almost always target intra-
© Author(s) (or their recognition. Distinctive clinical and sero- cellular proteins and hence show limited
employer(s)) 2022. No direct pathogenic significance. Never-
commercial re-use. See rights
logical features (tables 1–3) typically
and permissions. Published direct the search for a tumour, which is theless, their presence often indicates a
by BMJ. subsequently detected in around 65% of robust (sometimes nearly 100%) associa-
To cite: Binks S, Uy C, cases. Rarely this tumour emerges only tion with a tumour in addition to distinct
Honnorat J, et al. Pract Neurol months or years after the neurological clinical links (table 1), for example, Yo
2022;22:19–31. syndrome, demanding ongoing clinical antibodies and cerebellar degeneration.6
Binks S, et al. Pract Neurol 2022;22:19–31. doi:10.1136/practneurol-2021-003073 1 of 15

Table 1 Demographic, tumour, clinical, treatment response and prognosis in onconeuronal antibody-associated syndromes
Antibody (alternative Demographics and tumour
2 of 15
Review
names) frequency Main associated tumour types Predominant associated syndromes IT responsive? Life expectancy
Hu (ANNA-1) Median age 60s, men ~75% SCLC in ~75% Sensory neuropathy (~50%), of which sensory Limited evidence of symptomatic benefit with Median survival ~11.8 months
24 39 57 70
Tumour frequency up to 98% with Others include other lung, prostate, neuronopathy ~30% early use in patients with sensory neuropathy, no in a cohort with ~80% receiving
4-year follow-up after onset of breast, bladder, GI tract, ovary, Cerebellar ataxia/PCD (~20%) evidence of survival benefit oncological treatment and ~45% IT
paraneoplastic syndrome neuroendocrine, unknown origin Limbic or cortical encephalitis (up to ~20%)
Rhombencephalitis (up to ~20%)
Sensorimotor neuropathy (~5%)
Autonomic dysfunction (up to ~24%)
Multifocal deficits (~20%)
Myeloneuropathy – newly reported
Yo (PCA-1)6 50 54 67 70 Almost always women with median Breast (~20%) PCD (at onset or within disease course ~90%) No evidence of sustained symptomatic or survival Overall median survival ~24 months.
age 60s, and at least ~90%– Gynaecological (ovary/fallopian tube Peripheral neuropathy (10%) benefit An analysis of 25 oncologically treated
100% tumour ~60%) Myeloneuropathy—newly reported patients showed survival significantly
Rarely in men: upper GI adenocarcinoma longer in breast cancer (~100 months)
or prostate than ovarian (~22 months) cancer.
Ri (ANNA-2)52 61 Mainly (~80%) women, median age Mainly breast (up to 70%) and lung (up Cerebellar syndrome (~66%) Reports of improved jaw dystonia with early Survival ~70% at 12 months,
mid-60s, ~90% with a tumour to 25%) Opsoclonus±myoclonus (~30%) aggressive cancer/IT ~60% at 24 months, and ~50% at
Dystonia and parkinsonism, ~20% each; with No evidence of survival benefit in a mixed cohort 36 months, with all patients receiving
jaw dystonia specifically up to 20% depending antitumour therapy and 58% IT
on cohort
Ma1 (PNMA1 and 2)55 56 M: ~40%–75%, median age ~60, Various including lung/pleural (~30%), Limbic and/or brainstem encephalitis ~45%– Little or no effect of IT on outcomes Reported in small cohorts only,
tumour in 77%–100%, cohort testicular, Gl tract, non-HL, breast cancer, 65% 36%–38% death due to tumour
dependent renal cancer and melanoma Cerebellar/brainstem syndrome (up to ~75%) or neurological progression with
Peripheral neuropathy ~10% oncological/IT in ~50% where
ascertainable
Ma2/Ta (PNMA2 only) Consistently ~75% M, median age Most commonly testicular germ cell (up Encephalitis—limbic, diencephalic, and/or Some tumour and syndrome response to 14% death reported in one cohort
25 42 55 56
younger in M (mid-30s) than mixed to ~70%) or lung tumours (non-SCLC) brainstem (95%) but ‘classic’ limbic ~25% orchidectomy±IT (steroids, intravenous of 28 patients (treatment details not
or F (early 60s) cohorts, tumour Distinctive aspects include excessive daytime immunoglobulins, plasma exchange) especially specified)
~90% sleepiness (~30%) and eye movement men<45
abnormalities in encephalitis patients (~90%)
Amphiphysin M:F 40:60, higher F (~90%) Lung cancer (mainly SCLC)~70%, breast Common associations include neuropathies Reported with chemotherapy and steroids in In mixed phenotypes, survival ~7–9
62 65 70 87
in neuropathy, mean age ~65, cancer ~25% (~60%) and stiff-person-spectrum disorders stiff-person syndrome, and with IT especially months,~50% of patients receiving
malignancy in ~80% (~30%–40%), but also myelopathy, cyclophosphamide in neuropathy oncological and/or IT; in mainly treated
(in patients with only amphiphysin encephalitis/encephalopathy, cerebellar ataxia neuropathy cases~30% mortality at
antibodies) and myeloneuropathy 5 years
Zic422 90 Median mid-60s, nearly 90% SCLC in ~90% of patients with PCD most common in both isolated Zic4 and Limited to case reports, 50% of which improved Not systematically reported
M,~90% with tumour (in patients Zic4±other immunities Zic4+other onconeuronal antibodies with chemotherapy+IT, including rituximab
with only Zic4 antibodies and no
other immunities)
KELCH11 (KLHL11) In clinical cohorts, all patients are ~65% testicular cancer (mainly Rhombencephalitis, with ataxia (~80%), ~60% achieved neurological improvement or ~25% mortality at median of 55
37 43 44
M, with median age mid-40s, and seminoma) in clinical cohorts. In diplopia (~60%), vertigo (~50%) and stability with IT, trend to better outcomes with months in a cohort in which almost all
cancer found in ~70% serological studies, also found with auditory symptoms (hearing loss and testicular cancer received oncological and IT
teratoma (ovarian or testicular) and tinnitus ~40% each, tinnitus often an early
NMDAR-Ab-E manifestation), dysarthria (~30%), and seizures
(~20%)
Continued
Binks S, et al. Pract Neurol 2022;22:19–31. doi:10.1136/practneurol-2021-003073

Table 1 Continued
Antibody (alternative Demographics and tumour
names) frequency Main associated tumour types Predominant associated syndromes IT responsive? Life expectancy
mGluR1 Median age ~55, ~2:1 M:F, ~11% HL, cutaneous T lymphoma Cerebellar syndrome (~90%)+cognitive/ With IT, ~50% stabilisation and ~40% 2/25 published patients, mainly IT-
58
with tumour psychiatric features improvement treated, died
mGluR5 Median age ~30, including HL, SCLC Neuropsychiatric and cognitive deficits, poor Complete recovery in more than 50%, mostly No deaths in a contemporary cohort
49
paediatric cases, M=F, ~60% with sleep, seizures; Ophelia syndrome treated with cancer±IT; relapse responded to
tumour same
Tr/DNER51 72 Median age ~60, ~80% M HL (~90%), occasionally also non-HL Predominantly a cerebellar syndrome, frequently Often irreversible. Remission in ~15% of patients No systematic data; in one small
pure in HL mainly under-40 treated for HL (no patients observational cohort, 2/16 patients
without tumour improved) with a cerebellar syndrome and HL, of
which 10 had Tr/DNER, died.
CV2/CRMP5 Median age ~60, ~75% men, SCLC and thymoma Varied including neuropathy (largely an Neuropathy may be responsive to high dose Median survival 48 months if CRMP5/

57 63 66
~90% with tumour asymmetric painful polyradiculopathy), intravenous steroids. CV2 antibodies in isolation, death in
cerebellar ataxia, chorea, uvea/retinal ~40%
involvement, LEMS, myeloneuropathy
LEMS–VGCC: In paraneoplastic and non- SCLC Patients with VGCC antibodies may present with The myasthenic syndrome, but not the cerebellar Median survival of 12 months in
P/Q type59 68 93 paraneoplastic LEMS, median age LEMS alone, or LEMS+PCD; VGCC antibodies syndrome, responds well to IT. patients with PCD (mostly with tumour
LEMS–Sox1 (AGNA1) is in the early 60s; ~70% of LEMS may also denote ataxia without LEMS in treatment, but some with only IT or
69 94
have underlying cancer; and ~2/3 ~40% lung cancer PCD none)
paraneoplastic patients are M. Sox1 Indicates paraneoplastic LEMS (seen in With Sox1 positivity, SCLC and LEMS,
~60% paraneoplastic but not in idiopathic median survival of ~15 months in
cases); background Sox positivity rate of mostly oncologically treated patients
~20%–30% in SCLC±Hu antibodies
Retinopathies: Mean age mid-50s, >80% M Mainly cutaneous melanoma Night blindness, photopsias, visual field deficit Case series only, benefit in some of varied IT Average survival 5.9 years after
MAR74 and reduced visual acuity regimes+cytoreduction melanoma onset
Recoverin/CAR:75 76 91 Mean age early 60s, ~40% to 60% SCLC, prostate and endometrial cancers, Painless visual loss and uveitis Cancer therapy alone does not abate visual loss, Not systematically reported
women but also found in retinitis pigmentosa benefit of various IT in some case reports
AGNA1, antiglial nuclear antibody; ANNA, antineuronal nuclear antibody; CAR, cancer-associated retinopathy; CRMP5, collapsin response-mediator protein-5; DNER, delta and notch-like epidermal growth factor-related receptor; F, female; GI, gastrointestinal; HL, Hodgkin's
lymphoma; IT, immunotherapy; KELCH11, Kelch-like protein 11; LEMS, Lambert-Eaton myasthenic syndrome; M, male; MAR, melanoma-associated retinopathy; mGluR1/5, metabotropic glutamate receptor 1/5; NMDAR-Ab-E, NMDAR-antibody encephalitis; PCA, Purkinje cell
cytoplasmic antibody; PCD, paraneoplastic cerebellar degeneration; PNMA1/2, paraneoplastic antigen Ma1/2; SCLC, small cell lung cancer; VGCC, voltage-gated calcium channel.
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Table 2 Demographic, tumour, clinical, treatment response and prognosis in cell surface antibody-mediated syndromes where an underlying tumour is
often detected in a minority of cases
Predominant
Antibody Demographics and Main associated associated
(alternative names) tumour frequency tumour types syndromes IT responsive? Life expectancy
NMDAR antibodies ~80% female, Mainly ovarian NMDAR-Ab-E: Yes, good outcomes In a large cohort, of which 94%
7 45–48
median age 27, teratoma, psychiatric with early (<40 days) was treated with IT and/or
~30% with teratoma especially in features, seizures, IT (steroids+at least tumour removal, ~5% mortality,
women aged movement disorder, one other immune almost all patients had an mRS
<45 dysautonomia treatment) and early score of 5 before death.
oophorectomy, in
teratoma cases
GABAA/B receptor antibodies: Male=female, median Thymoma Acute encephalitis Partial or complete In same cohort death in ~15%,
GABAA81 age ~40 (but can with prominent (~30%) recovery in 2/3 had status epilepticus and
affect paediatric seizures, including ~85% of patients 1/3 had sepsis
population), tumour status epilepticus and undergoing IT
in 60% of adults epilepsia partialis
(10% children) continua
9 77 79
GABAB Male ~80% and SCLC Limbic encephalitis Response of Median survival of ~15 months,
median age mid-60s predominant in neurological syndrome death in patients with tumour
in paraneoplastic paraneoplastic to IT in up to ~90% of due to cancer progression or
cases (tumour in patients treated paraneoplastic chemotherapy complications
~50% of GABAB, patients, often partial (death rare in patients without
often with additional tumour)
onconeuronal
positivities)
AMPA receptor antibodies8 Median age ~55, Lung, breast, Encephalitis, often Median mRS score of Death occurred in ~50% of the
women ~70%, thymus, ovarian severe and acute 2 in mainly IT-treated fulminant encephalitis cases but
tumour in ~50% Confusion and patients; worse was rare with other presentations.
memory deficits outcomes reported in
prominent, may those with fulminant
present with or encephalitis
without seizures
CASPR2 antibodies41 Median age 60s, men Thymoma Morvan’s syndrome ~50% of patients ~50% death rate among IT-
~90%, tumour in up predominant in with tumour had treated patients with Morvan’s
to 40% (Morvan’s the paraneoplastic a neurological syndrome and tumour
syndrome) group. Other improvement in mRS
presentations include score with IT.
limbic encephalitis,
cerebellar
syndrome, isolated
neuromyotonia/
myokymia, painful
peripheral nerve
syndrome
AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CASPR2, contactin-associated protein-like 2; GABAA/B, γ-amino butyric acid (alpha/beta
subunit); IT, immunotherapy; mRS, modified Rankin Scale; NMDAR, N-methyl-D-aspartate receptor; NMDAR-Ab-E, NMDAR-antibody encephalitis; SCLC, small
cell lung cancer.
Such associations clinically guide cancer identification young children or men; α-amino-3-hydroxy-5-methyl-
and can expedite and focus treatments. 4-isoxazolepropionic acid (AMPA) receptor-antibodies
More recently, an explosion of scientific discovery which are associated with ~50% rate of cancers, espe-
in the field of cell surface- directed neuroglial anti- cially small cell lung cancer (SCLC and thymoma),
bodies, which show clear pathogenic potential, has but mainly in the older patients8; and γ-aminobutyric
yielded several further clinical–serological associations acid (GABA)B receptor-autoantibodies which associate
amongst PNS. However, the frequency of cancer asso- with a ~50% rate of SCLC in patients more than 50
ciated with these newer autoantibodies varies substan- years of age (table 1).9 Also, several surface neuroglial
tially according to the antigenic target, and the age antibodies are associated with very low overall rates
and sex of the patients. Examples include N-methyl- of cancer.10
D-aspartate receptor (NMDAR)- autoantibodies and By contrast to intracellular- directed antibodies,
ovarian teratomas,7 which occur in young women those targeting cell- surface proteins—which have
between ~18 and 35 years of age, but very rarely in access to their native targets in the blood/cerebrospinal
4 of 15 Binks S, et al. Pract Neurol 2022;22:19–31. doi:10.1136/practneurol-2021-003073

Table 3 Paraclinical features of onconeuronal and surface antibody-associated syndromes

Investigation
CSF inflammatory Intrathecal CSF antibodies MRI abnormal Temporal lobe Cerebellar Predominant pattern nerve
Antibody and syndrome (pleocytosis, OCBs) synthesis? detected acute high signal Multifocal/other atrophy EEG abnormal conduction studies/EMG
Onconeuronal
Hu (ANNA1) LE
Hu (ANNA1) BE
Hu (ANNA1) PCD Late Late
Hu (ANNA1) neuropathy SN, SMN, A, (D)
Yo (PCA1) PCD Late SN, SMN, PRN, A
Ri (ANNA2)
Ma (PNMA1/2) (Ma2) (Ma2)
Ma2/Ta (PNMA2)
Amphiphysin * * CMU activity in SPS
Amphiphysin neuropathy SN, SMN, PRN, A
Zic4 * * * *
KELCH11
mGLuR1 Late

mGLuR5
Tr/DNER PCD * Late
CRMP5/CV2 mixed If LE* SN, SMN, PRN, A
CRMP5/CV2 chorea BG Slowing*
CRMP5/CV2 neuropathy SN, SMN, PRN, A
VGCC LEMS ↓ CMAPs
VGCC PCD ˄ LEMS in ~40%
Surface neuronal
NMDAR-Ab-E
GABAA
GABAB
AMPAR +
CASPR2–Morvan’s Neuromyotonia
CASPR2–LE + Myokimia
Paraclinical features of onconeuronal and surface antibody-associated syndromes compiled from references cited in this review—key: ‍ ‍not delineated, ‍ ‍usually absent, ‍ ‍sometimes (up to ~30%), ‍ ‍quite frequent (~30% to 60%),
‍ ‍frequent (more than ~60%).
+Tested on a subset of patients.
˄Isolated case reports of VGCC and LE.
*Based on small reports (typically ~5 or fewer).
A, axonal; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA, antineuronal nuclear antibody; BE, brainstem encephalitis; CASPR2, contactin-associated protein-like 2; CMAP, compound muscle action potential; CMU,
continuous motor unit; CRMP5, collapsin response-mediator protein-5; CSF, cerebrospinal fluid; D, demyelinating; DNER, delta and notch-like epidermal growth factor-related receptor; EEG, electroencephalogram; GABAA/B, γ-amino butyric acid
(alpha/beta subunit); GI, gastrointestinal; IT, immunotherapy; KELCH11, Kelch-like protein 11; LE, limbic encephalitis; LEMS, Lambert-Eaton myasthenic syndrome; mGluR1/5, metabotropic glutamate receptor 1/5; Morvan’s, Morvan’s syndrome;
NMDAR, N-methyl-D-aspartate receptor; NMDAR-Ab-E, NMDAR-antibody encephalitis; OCB, oligoclonal band; PCA, Purkinje cell cytoplasmic antibody; PCD, paraneoplastic cerebellar degeneration; PNMA1/2, paraneoplastic antigen Ma1/2; PRN,
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polyradicular neuropathy; SMN, sensory motor neuropathy; SN, sensory neuropathy; SPS, stiff-person syndrome; VGCC, voltage-gated calcium channel.
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closely associated with Hodgkin’s lymphoma and have
Box 1 Classic paraneoplastic presentations4 5
been recognised to target the extracellular portion of
A. High risk, frequently associated with tumours the delta and notch-like epidermal growth factor-related
Central nervous system receptor (DNER).20
► Encephalomyelitis.
The relatively high rate of many of these antibodies
► Limbic encephalitis.
in patients with tumours but no accompanying neuro-
► Subacute cerebellar degeneration.
logical syndrome, for example, ~16% of patients with
► Opsoclonus–myoclonus.
SCLC with Hu- 21 or Zic4-antibodies,22 and the frequent
Peripheral nervous system and neuromuscular junction/ co-occurrence of more than one paraneoplastic anti-
muscle body in an individual,3 cautions against interpretation
► Subacute sensory neuronopathy.
of the antibody result in isolation. It may also suggest
► Chronic gastric pseudo-obstruction.
that the polyclonal immune response protects against
► Lambert-Eaton myasthenic syndrome.
tumour growth. Indeed, tumours may be more indolent
► Dermatomyositis.
in patients with a PNS.23
In PNS, the likely origin of immunisation is the tumour
B. Intermediate risk, less frequently associated with itself, given immunohistochemical evidence of relevant
tumours antigen expression in cancers including SCLC,24 testic-
Central nervous system ular seminoma25 and ovarian carcinoma.26 The accom-
► Encephalitis. panying peripheral immune response may translocate to
► Brainstem encephalitis. the central nervous system (CNS) in some patients with,
► Isolated myelopathy. overall, CSF studies indicating intrathecal synthesis of
Peripheral nervous system and neuromuscular junction/ antibodies6 22 25 in CNS- predominant syndromes (vs
muscle absent intrathecal synthesis in those with PNS- only
► Polyradiculopathy. involvement).27 This suggests an influx of lymphocytes
► Stiff-person syndrome. to the CSF is a key triggering event for CNS syndromes,
► Myasthenia gravis. a finding that aligns with clonal CD8+ T cells and
restricted T- cell receptor repertoires in postmortem
brain pathology.28 It is likely that these cell types are key
fluid (CSF)—are considered directly pathogenic as disease effectors.
they bind in vivo and can trigger deleterious effects,
including complement fixation, receptor internali- Genetic contributions
sation and induce direct functional modifications to Major histocompatibility complex (MHC) molecules are
their target proteins.11 12 We have detailed these caus- considered essential to antigen presentation, T-cell acti-
ative antibodies in our sister review.13 Also, herein, vation and autoantibody generation. Early—although
we will neither focus on autoantibodies in inflamma- limited—immunohistochemical observations suggested
tory myopathies, which have recently been reviewed that tumours of patients with Hu-antibody PNS might
in this journal,14 nor the potential triggering of PNS have increased expression of MHC proteins, when
after checkpoint inhibitor drugs,15 as these likely show compared with tumours in patients without autoan-
different underlying mechanisms to traditional PNS.16 tibodies.29 More recently, it was demonstrated that
Myasthenia gravis may be associated with an under- patients with Hu- antibody with PNS were signifi-
lying tumour, typically a thymoma, but also is not cantly more likely to carry the class II molecules HLA-
further considered herein due to its absence from the DQ2 and HLA- DR3 than ethnically- matched healthy
updated 2021 guidelines.4 controls.30 By contrast, with Yo-antibodies, a risk haplo-
type DQA1*01:03-DQB1*06:03-DRB1*13:01, was
PATHOPHYSIOLOGY reported as tumour- specific and observed mainly in
Role of onconeuronal antibodies patients with ovarian but not breast cancer, whereas
The exact role of intracellular- directed antibodies there is a protective effect of DRB1*04:01 across all
remains unresolved, but they are unlikely to be direct patients.31
mediators of disease. Although uptake and patholog- A different genetic predisposition has been suggested
ical effects of Hu-antibodies by Purkinje cells have been by somatic mutations in antigenic proteins. Taking
shown in vitro,17 their infusion into various in vivo Yo-antibody cerebellar degeneration, it has been shown
models does not consistently replicate disease despite that associated ovarian tumours, but not those found
achieving high antibody titres in the experimental in patients without Yo-antibodies, expressed numerous
animals.18 Experiments with Ma2- antibodies yielded genetic lesions in the antigenic cerebellar degeneration-
similar negative results.19 However, some antibodies clas- related protein 2- like (or Yo) protein. It is plausible
sically denoted as ‘onconeuronal’ do recognise extracel- that these create neoantigens that drive the disease.26
lular domains of neuroglial proteins and thus could have A differing mechanism has been elucidated in patients
a direct role in causation: for example, Tr antibodies are harbouring NMDAR- autoantibodies and ovarian

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teratoma. Pieces (‘explants’) of tissue from these—
AUTOANTIBODY TESTING: PRACTICAL
usually benign—tumours, and isolated intrateratoma CONSIDERATIONS
B cells, were able to secrete NMDAR- autoantibodies Commercial testing for specific onconeuronal anti-
in vitro. Furthermore, tumour immunohistochemistry bodies is typically performed using immunodot or
revealed structures housing T cells, B cells and the blot methods.33 34 With these techniques, the antigens
NR1 subunit—the key autoantibody epitope.32 In this of interest are immobilised within a fixed band on a
scenario, the tumours may act as ectopic lymphoid nitrocellulose paper, patient serum or CSF is applied,
organs and initiate the directly pathogenic autoantibody and if ‘antibody-positive’, an intensity is visualised at
response. the known location of the antigen (figure 1). Several
Taken together, these early observations support a local recent studies have cast doubt on the accuracy of
tumour response, facilitated by genetic and other as-yet this approach, consistently showing only ~40% of
confirmed factors in at-risk patients, which gains trac- line blot-positive results are verified by more robust
tion in the CNS with either autoantibodies or cytotoxic methods such as immunofluorescence or cell- based
33 34
T cells as the key pathogenic effector. Future efforts to assays. Positive predictive values have been as low
map steps along this pathogenic pathway systematically as 39%.35 While bleak, these overall results mask some
will offer clearer insights into disease pathogenesis and even more worrying findings for individual antigens—
biology. for example, Déchelotte et al almost never confirmed
Figure 1 Detection of paraneoplastic antigens. Use of commercial line or dot blots miss clinically relevant reactivities identified
by immunohistochemistry or cell-based assay. (A) Immunohistochemistry on sections of paraformaldehyde-perfused rat
cerebellum incubated with a CV2-positive serum (dilution 1:5000) that did not react with commercial immunoblots despite robust
immunoreactivity with the cytoplasm and processes of oligodendrocytes in the GCL and WM. Scale bar=25 µm. (B) Line blot
neuronal antigen profile. Antigens by columns: a, titin; b, SOX1; c, recoverin; d, Hu; e, Yo; f, Ri; g, Ma2; h, CV2; and i, amphiphysin.
Strips were incubated with the sera of patients with CV2 antibodies determined by immunohistochemistry, two positives and
one negative control. Serum 3 showed very mild immunoreactivity at 1/200 dilution but was negative at the manufacturer’s
recommended dilution (1/1000). This serum was also immunoreactive with amphiphysin. (C) Serum of patients with CV2 antibodies
by immunohistochemistry, diluted at 1/2000 and 1/200, did not react with blot strips. The localisation of the appropriate CV2
band detected with the positive control (+) is indicated with an arrowhead. Serum 3 showed a weak immunoreactivity with SOX1
and amphiphysin. (D) HEK293 cells transfected to express GFP-tagged CRMP5 were incubated with serum of patients with CV2
antibodies that did not react with commercial immunoblots or control (−) serum. Patient’s serum, but not control serum, stained
the cells (red) that specifically express CRMP5 (seen in green). Both reactivities are shown merged in the bottom row (yellow). Nuclei
counterstained with 4′,6-diamidino-2-phenylindole (DAPI) . Scale bar=20 µm. Reproduced from Sabater et al36 with permission from
Elsevier. GCL, granular cell layer; GFP, green fluorescent protein; WM, white matter.

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positive line dots for amphiphysin, Ma1- and Yo-an- Typically, patients are in their mid-60s with a slight
tibodies, whereas for Hu-antibodies, confirmation by male predominance, but Hu- antibodies also have
other methods was observed in up to ~88%.34 A recent been detected in children with neuroblastoma in
investigation into patients with collapsin response- connection with a brainstem syndrome including
mediator protein-5 (CRMP5)/CV2-antibodies showed opsoclonus–myoclonus29 40 and an aggressive—but
commercial kits failed to detect ~8% of patient sera non- paraneoplastic—paediatric limbic encephalitis
found positive by immunofluorescence or cell-based with a limited response to immunotherapies.40
assay (figure 1).36 Two of these samples were from Several surface neuronal antibodies associate
individuals with SCLC, showing a crucial diagnosis with autoimmune encephalitis and tumours. Again,
could have been missed. these patients show clinical characteristics that help
Therefore, expert consensus suggests that a posi- refine the pretest probabilities of a tumour. In addi-
tive onconeuronal result by commercial kits should be tion to the age/sex bias of teratomas in patients
reinforced by a second method, and that both positive with NMDAR- antibody encephalitis, patients with
and negative results are interpreted in the context of Morvan’s syndrome and contactin-associated protein-
the patient presentation. Research laboratories with an like 2 (CASPR2) autoantibodies have a 40% rate of
interest in these disorders and routine laboratories with thymoma compared with a <5% rate in patients with
close links to experienced clinicians may be able to help CASPR2-autoantibodies and limbic encephalitis.41 A
with difficult cases. The importance of research-level diencephalic/brainstem-centred encephalitis is a hall-
assays is further emphasised by the rapid expansion of mark of Ma- antibodies, particularly antibodies to
in newer entities (eg, Kelch-like protein 11 (KLHL11)), Ma2, also known as Ta. Almost all affected patients
for which availability remains on a research-only basis are male and commonly have testicular germ cell
despite its description in 2019.37 Overall, to maximise tumours. A distinctive aspect of this disease localises
sensitivity and specificity, we recommend sending both to the hypothalamus with features including gelastic
serum and CSF for antibody testing as both biosamples seizures and daytime somnolence (~30%), and even
show differing diagnostic characteristics across CNS frank narcolepsy/cataplexy.19 42
autoimmune illnesses and, in combination, provide KLHL11-antibody encephalitis was first described
optimised diagnostic accuracy.38 as a rhombencephalitis with prominent features of
vertigo, diplopia, dysarthria, ataxia and auditory
Practical approach to testing: which antibodies should I dysfunction (tinnitus and sensorineural hearing loss).
suspect… The syndrome was originally described exclusively in
…at the population level men with a typical age of onset in the mid-40s and
Among 979 cases in a 2010 European cohort, the a strong association with testicular tumours (~65%).
most frequently detected antibodies were against Hu An early association has been proposed with the class
(~39%), Yo (~13%), CRMP5/CV2 (~6%) and Ri II HLA alleles DQB1*02:01 and DRB1*03:01.37 43
(~5%). The rate of seronegative PNS in the cohort By contrast, a laboratory- based study using only a
was ~18%, and—overall—the most common tumours cell-based assay detected KLHL-11 positivity in equal
were SCLC (~38%), ovarian (~10%) and breast proportions of men and women with a wider pheno-
(~9%).3 More recently, a 2020 population- based type including isolated germ cell tumours and patients
Italian study identified Yo (30%), Hu (26%) and Ma2 with NMDAR-antibody encephalitis.44 Hence, the full
(22%) as the leading antigenic specificities.1 Overall, clinical spectrum associated with KLH11- antibodies
these authors found PNS coexisted with 1 in 334 requires further study.
cancers, most commonly lung (17%), breast (16%) and
lymphoma (12%). Modest variations between these …if the patient has prominent psychiatric features
two cohorts may be ascribed to ancestry, chronolog- NMDAR- antibody encephalitis is the exemplar of
ical trends or local environmental factors. However, it antibody- mediated neuropsychiatry, and its most
is important to note that, although some are especially prominent characteristics include behavioural changes,
typical, a variety of tumours can be associated with psychosis mood disturbances, catatonia and sleep
PNS (tables 1 and 2). disturbances.7 The diagnosis should be suspected in
new-onset acute to subacute psychopathology, espe-
…if the patient has (forms of) encephalitis cially in young women (~80%), typically with neuro-
Onconeuronal antibodies that target the ‘Hu’ anti- logical accompaniments such as memory disturbances,
gens are classically associated with a limited ‘limbic’ seizures and/or movement disorders.45–48 Initial presen-
encephalitis. These patients can also develop a multi- tation to psychiatric services remains common,and
focal neurological presentation, including spinal cord patients may have received prior erroneous diagnoses
involvement and rhombencephalitis.24 A striking of primary psychosis, bipolar disorder or depression.
peripheral manifestation is a sensory neuronopathy, The Ophelia syndrome is associated with surface-
with clinical and electrophysiological studies also directed mGluR5-antibodies and seen in patients with
showing sensory or sensorimotor neuropathies.24 39 Hodgkin’s lymphoma. Psychosis, hallucinations, mood

Review
disorder, behavioural and personality change, and compromise.61 Amphiphysin- antibodies are associ-
sleep disturbance are among the psychiatric features ated with a paraneoplastic stiff-person syndrome and
reported.49 a female bias (~60%).62 In contrast, chorea should
Overall, we recommend antibody screens in new- prompt consideration of CRMP5/CV2- antibodies,
onset pyschosis for individuals fitting the aforemen- which show a male bias (~75%).57 63 Table 1 describes
tioned descriptions, as well as others with atypical other features associated with these antibodies.
demographic, phenotypical or clinical features when Autoantibody-associated movement disorders have
compared with primary psychiatric diagnostic catego- been reviewed in greater detail elsewhere and provide
ries, in particular, those with additional traditionally valuable clues as to the nature of the autoimmune
‘neurological’ features. illness.64
…if the patient has a cerebellar syndrome

…if the patient has a peripheral nerve or muscle problem
Several onconeuronal antibodies are strongly associ-
Two classic peripheral PNS are sensory neuronopathy
ated with paraneoplastic cerebellar degeneration. In
(or Denny-Brown syndrome) and LEMS.5 More than
this condition, the deterioration is usually acute to
50% of patients with Hu-antibodies have a sensory
subacute, pancerebellar—causing limb and truncal
neuronopathy or peripheral neuropathy, character-
ataxia plus nystagmus—and is frequently irrevers-
istically involving both large and small fibres with
ible even with successful treatment of the underlying
dominant axonal involvement and only upper limb
neoplasm, likely secondary to established Purkinje
involvement in ~25%,24 39 with or without addi-
cell destruction.6 50 51 A cerebellar ataxia developing
tional neurological features. The neuropathy occur-
over the time course of a neurodegenerative process
ring in connection with amphiphysi-antibodies may
is rarer but can be observed, for example in patients
be immunotherapy-responsive, increasing the urgency
with Ri- or glutamic acid decarboxylase- (GAD)
of early and accurate detection.65 In CRMP5/CV2-
antibodies although GAD- antibodies are rarely
antibody disease, the neuropathy is often a painful,
tumour-associated.52 53 Yo- antibodies are the most
asymmetrical, sensorimotor polyradiculopathy which
well-established association of a subacute cerebellar
may be steroid- responsive and commonly found
syndrome, almost always occuring in women with
alongside additional features such as cerebellar
breast or gynaecological tumours,6 50 but one case
ataxia and myelopathy.66 A few (~10%) women with
series reported seven men, five of whom had gastro-
Yo-antibodies may present with a peripheral neurop-
intestinal malignancy.54 Also, paraneoplastic cere-
athy of upper limb onset,67 and a painful periph-
bellar degeneration may occur with Zic4-antibodies,
eral neuropathy is recognised in association with
frequently detected alongside other onconeural anti-
CASPR2-autoantibodies.41
bodies in SCLC,22 and with Tr- antibodies, mainly
LEMS is accompanied by VGCC- antibodies in
detected in male patients with Hodgkin’s lymphoma.51
~85% of patients and is paraneoplastic in ~70%.68
Further, around 20% of patients with Hu-antibodies
SOX1- antibodies are a useful biomarker of malig-
develop a cerebellar syndrome,24 in addition to ~60%
nancy in patients with LEMS, being found in as many
of those with Ri-antibodies, particularly women with
as ~60% of tumour cases but far less commonly in
breast cancer.52 Also to be considered in this setting
non-paraneoplastic cases.69 Paraneoplastic myeloneu-
are Ma1-antibodies (between 27% and 77% in small
ropathy70 is a syndromic description associated chiefly
cohorts),55 56 CRMP5/CV2-antibodies57 and mGluR1-
with antibodies to amphiphysin, Hu and CRMP5/
antibodies, the latter with superadded psychiatric and
CV2, and in smaller numbers with other specificities
cognitive features.58 Finally, a subgroup of patients
(table 1).
with voltage- gated calcium channel (VGCC) anti-
bodies (P/Q type) have ataxia with SCLC, both with
and without Lambert- Eaton myasthenic syndrome …if the patient has lymphoma
(LEMS).59 Whereas limbic encephalitis (eg, with mGluR5-
antibodies) and paraneoplastic cerebellar degener-
…if the patient has another movement disorder ation (eg, with antibodies to Tr/DNER or mGluR1)
Ri-antibodies may occur in combination with opso- mainly occur with Hodgkin’s lymphoma,49 51 58
clonus–myoclonus60 and, more recently, movement the more frequent associations of non- Hodgkin's
disorder presentations including tremor, parkinsonism lymphoma are sensorimotor neuropathies and
and stiff-person syndrome, mainly in female (~80%) dermatomyositis, although Tr/DNER and Ma2 speci-
patients. Some have a stepwise progression and are ficities may occur in this context.71 72 It is noteworthy
misdiagnosed with atypical Parkinson’s disease, that histopathological efforts did not find DNER
multiple sclerosis or a functional disorder.52 An was expressed by the malignant cells of Hodgkin’s
important ‘not-to-miss’ association of Ri-antibodies is lymphoma, suggesting these patients represent a
jaw dystonia and laryngospasm, which may be severe potential exception to the paradigm of tumour-driven
enough to precipitate nutritional deficiency or airway immunisation.51

Review
…if the patient has dysautonomia
Dysautonomia can cause potentially dangerous compli-
cations in several of the paraneoplastic syndromes. For
example, in patients with Ri-antiboies, dysautonomia
may lead to cardiac arrhythmias and central respira-
tory failure.52 Another manifestation is gastric pseudo-
obstruction, especially seen with Hu-antibodies.5
Of the cell-surface antibodies, autonomic features
are prominent in LEMS where they typically include
dry mouth/eyes, visual disturbance, erectile dysfunc-
tion, constipation, impaired sweating and ortho-
static hypotension, and are rarely life-threatening.73 Figure 2 Body imaging in paraneoplastic encephalitides. (A,B)
Dysautonomia is a prominent feature of patients with Pelvic MRI of a 19-year-old woman with N-methyl-D-aspartate
receptor-antibody encephalitis. A right ovarian teratoma
NMDAR-antibodies. This tends to occur in ~50% of
is visible as a dark cystic area (arrow) on a fat suppressed
cases and characteristically becomes apparent 2–4 sequence (A). This was previously seen on T1 imaging (B)
weeks into the illness, with manifestations including (arrow) but required fat suppressed sequences for the lesion to
tachycardia–bradycardia, labile blood pressure and be clearly identifiable as a dermoid, rather than haemorrhagic,
cardiac asystole.46–48 Finally, almost all (>90%) patients cyst.
with Morvan’s syndrome, seen with CASPR2- ±LGI1-
autoantibodies, have dysautonomia, most commonly (MR) scanning in young women with NMDAR-
hyperhidrosis (>85%) and cardiovascular instability antibody encephalitis.38 Selection of ultrasound scan
(tachycardia, labile blood pressure in ~50%).41 or MRI to visualise an ovarian teratoma depends on
local expertise and the mental state of patients, who
…if the patient has visual loss
are often extremely agitated in the acute phase of
Among their many manifestations, antibodies to their illness. In our experience, some ovarian tera-
CRMP5/CV2 have a recognised association with tomas can be radiologically small and challenging to
paraneoplastic optic neuropathy, as well as posterior detect (figure 2). Expert radiological help is strongly
uveitis.57 63 Other antibodies can be more closely asso- recommended with equivocal scans. However,
ciated purely with visual syndromes. For example, without the radiological suggestion of a teratoma, we
melanoma- associated retinopathy has a character- do not recommend empirical oophrectomy as overall
istic presentation of night blindness, photopsias and yields appear low. In some cases, such as in women
reduced visual acuity, often occuring in patients with a with subacute cerebellar ataxia, confirmed circulating
pre-existing diagnosis of cutaneous melanomas and its Yo-antibodies and negative radiological explorations, a
appearance may signal a relapse. Onset can be abrupt surgical examination may be warranted.73
and antibodies are found against bipolar layer retinal To detect delayed tumour presentations, it is often
cells, with—as yet—undefined targets.74 Another recommended to follow-up a negative body CT with
syndrome with antibodies to retinal tissue, recoverin FDG-PET scan and surveillance imaging for several
or cancer-associated retinopathy, causes painless visual years thereafter.73 This decision – and the duration
loss in patients with known cancer of various types of follow-up - should rest with clinical acumen and
(table 1), as well as in some non-paraneoplastic cases.75 perceived likelihood of detecting a tumour.
76
Paraclinical investigations: neurological

INVESTIGATIONS Cerebrospinal fluid
Overall, the early recognition of a paraneoplastic cause CSF is recommended to explore important differen-
is essential to guide oncological investigation and opti- tials. CSF autoantibodies are frequently detected in
mise tumour management, which is also a cornerstone PNS.38 77–79 In certain syndromes, such as NMDAR-
in addressing the associated PNS.73 Imaging forms the antibody encephalitis, CSF NMDAR-autoantibodies
mainstay of investigations—as directed by the clinico- are highly specific and often considered mandatory
serological associations (tables 1–3). Tumour markers for a diagnosis.38 In most of the antibodies discussed
(eg, CA125 where ovarian cancer is suspected) may within this review, broader CSF markers are
also be measured, especially when tumours are small abnormal (table 3) with common themes including
and not definitively detected with imaging.6 As an lymphocytic pleocytosis, CSF-specific (‘unmatched’)
overview, recommendations suggest body imaging to oligoclonal bands and elevated protein. Over
include CT of the chest, abdomen and pelvis,73 with the range of these conditions, glucose is usually
additional—more focused—modalities based on the normal, and cytospin does not reveal malignant
specific predicted associations, for example, testicular cells (table 3). One notable aspect in Ma2-antibody
ultrasound scanning in men with Ma2-antibodies42 or encephalitis is the possible finding of reduced hypo-
pelvic/transvaginal ultrasound or magnetic resonance cretin in patients with narcolepsy/somnolence.42

Review
However, it should be highlighted that a bland CSF Electromyography is a valuable investigation in
does not rule out PNS and, in certain entities such patients with CASPR2-autoantibodies where frank
as CASPR2- autoantibodies with Morvan’s and in neuromyotonia is common.41 85 Peripheral neuro-
GABAAR-antibody encephalitis, CSF is quite often physiology in PNS may delineate relevant findings
unremarkable (table 3). as described previously, but less specific findings of
sensory or sensorimotor neuropathy are also possible
Neuroimaging (table 2). In suspected LEMS, decreased compound
MRI appearances of the brain or spinal cord are muscle action potentials are expected; and the elec-
often characteristic in particular syndromes (table 3). trical hallmark is increment after high- frequency
For example, abnormalities in hypothalamus, dien- repetitive nerve stimulation.73 Specific abnormalities
cephalon and rhombencephalon in patients with consistent with bipolar cell dysfunction on electro-
Ma2-antibody encephalitis,42 basal ganglionitis in retinogram may assist in the diagnosis of patients
those with chorea and CRMP5/CV2- antibodies,80 with melanoma-associated retinopathy antibodies.74
and multifocal cortical and subcortical abnormal-
ities in patients with GABAAR-antibodies.81 In the OUTCOMES
spinal syndromes, paraneoplastic myelopathies often Tumour identification and appropriate oncological
show a predominance for corticospinal tracts and are management are key to medical and neurological
frequently longitudinally extensive.82 stabilisation, especially as many PNS associated with
Again, as with CSF studies, it is important to note cancers display a limited immunotherapy response.73
that MR scan of the brain and spine can be normal Median survival is frequently aligned to the under-
in PNS. This is an especially common scenario in lying tumour prognosis and delineated for the indi-
NMDAR-antibody encephalitis,46 47 in patients with vidual antibodies within tables 1 and 2. However,
amphiphysin-antibodies52 and in Morvan’s syndrome the PNS field is limited by small and highly selected
with CASPR2-autoantibodies.41 Therefore, in a clini- cohorts, few randomised trials, reports of spontaneous
cally and serologically appropriate setting, an unre- improvement and frequently biased interpretations of
markable MRI should not deter from the diagnosis treatment benefits.86 An analysis of deaths in 403 para-
of some PNS. Moreover, in most cases of paraneo- neoplastic patients with differing antibody specificities
plastic cerebellar degeneration, initial MRI or CT is concluded that 109 (27%) died of their neurological
unrevealing with cerebellar atrophy visible only in syndrome, 150 (37%) of tumour progression and the
later scans (figure 3). remainder of unknown or other causes. The risk of
death from the paraneoplastic syndrome was highest
Electrophysiology for patients with dysautonomic features; in this
Patients with encephalopathies will typically mani- subgroup, nearly 60% died of neurological disease.3
fest electrophysiological abnormalities (table 3). One More than one comparative observational cohort
distinctive electroencephalogram (EEG) pattern is study has shown that patients with Hu- antibodies
extreme delta brush in NMDAR-antibody encepha- have a worse prognosis than those with CRMP5/CV2-
litis83—but is usually apparent only in the profoundly antibodies.57 66
encephalopathic patient, hence having limited
diagnostic value.46 An EEG study in patients with Treatment and immunotherapy outcomes: onconeuronal
Hu-antibody showed surprisingly widespread abnor- antibodies
malities including in those without overt seizures or While many cases with onconeuronal antibodies are
focal clinical signs.84 immunotherapy-resistant or only partially responsive,
Figure 3 Central nervous system imaging in paraneoplastic encephalitides. (A) CT scan of the head showing chronic cerebellar
atrophy in a patient with Yo antibodies. (B–D) FLAIR hyperintensities in a patient with AMPAR-antibody encephalitis with a thymoma.
The images demonstrate multifocal inflammatory T2 hyperintensities of bilateral hippocampi with other discrete cortical lesions in
the right orbitofrontal cortex, left anterior cingulate, right posterior superior temporal sulcus, right anterior and inferior insula, right
temporal operculum, left posterior temporal region, left occipital and left calcarine cortex. AMPAR, α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptor; FLAIR, fluid-attenuated inversion recovery.

Review
it is important to recognise certain syndromes in which associated thymomas show demonstrably worse
there is stronger evidence for immune-directed treat- outcomes compared with non-
paraneoplastic
ment. For example, young men with Ma2-antibodies patients.41 In an observational cohort, the mortality
and testicular cancer may show some recovery with rate of the thymoma group was 50%, mainly due
tumour removal and immunotherapy,42 and an immu- to tumour-related causes such as respiratory failure
notherapy response is also documented in CRMP5/ and tumour invasion, and the modified Rankin Scale
CV2- and amphiphysin- antibody- associated neurop- score was static despite immunotherapies. However,
athies.65 66 Women with amphiphysin-antibody stiff- recently in our centres, we have experienced some
person syndrome can also make worthwhile functional clinical benefits with rituximab in such patients (SR
gains with cancer treatment and corticosteroids.87 Irani and J Honnorat, unpublished data, 2021).
On the other hand, there is limited evidence for a The syndromes associated with surface antibodies
symptomatic benefit of immunotherapy in Hu-anti- to mGluR1 and mGluR5, despite common associa-
body neuropathy, and the main predictors of outcome tions with lymphoma, are typically immunotherapy
among all patients with this specificity are disability/ responsive, and >50% of patients with mGluR5-
performance status, age and multifocal disease.24 One autoantibodies can make a full recovery.49 58 In VGCC
trial of triple immunotherapy (intravenous meth- antibody-positive patients, the LEMS—but less so the
ylprednisolone, intravenous immunoglobulin and cerebellar syndrome—responds to immunotherapy
cyclophosphamide) in patients with Hu- and Yo-anti- and 3,4-diaminopyridine can be used for symptomatic
bodies harbouring a variety of presentations achieved treatment.73 A report of global improvement following
transient stabilisation in neuropathy patients but no rituximab of a patient with VGCC with LEMS and
improvement in other symptomatic groups.88 There cerebellar degeneration again highlights the possible
were similarly disappointing results in a trial of intra- opportunities of newer therapies in recalcitrant disease
venous immunoglobulin alone.89 Many cases of para-
neoplastic cerebellar degeneration remain refractory
to treatment even if the underlying malignancy is Key points
successfully addressed, a situation which is particularly
► Early recognition of paraneoplastic syndromes is
observed with Yo-antibodies.6 50 67 Treatment response
crucial for successful identification and management
in some of the rarer syndromes is available only in
of the underlying tumour.
case reports.90 The literature for treatment in para-
► Serum results should be interpreted with a critical,
neoplastic retinopathies is dominated by case reports,
clinical eye, given the pitfalls of line blot/immunodot
but it is generally believed that in cancer-associated
testing.
retinopathy, cancer treatment alone is ineffective for
► Syndromes mediated by surface neuronal
visual recovery, and that additional immune treat-
autoantibodies usually respond to prompt
ments are beneficial.91
immunotherapy, in addition to oncological therapies;
some syndromes associated with ‘onconeuronal’
Treatment and immunotherapy outcomes: surface
antibodies may not respond, but there are important
neuronal antibodies
exceptions.
In marked contrast, overall, the vast majority of patients
► There is limited high-quality trial evidence, meaning
with surface neuronal antibodies are immunotherapy-
much practice is based on observational or cohort
sensitive. In addition to oncological management,
studies.
these patients merit a trial of immunotherapy, often
extending to second- line or even third- line agents
based on initial responses (table 2, Uy et al13). More
than 80% of treated NMDAR- antibody encepha- Further reading
litis can be expected to have a good outcome at 24
► Graus F, Vogrig A, Muñiz-Castrillo S, et al.
months,47 a figure likely to have increased since better
Updated diagnostic criteria for paraneoplastic
recognition and more effective treatment protocols are
neurologic syndromes. Neurol - Neuroimmunol
commonplace. In this condition, paraneoplastic and
Neuroinflammation 2021;8:e1014. doi:10.1212/
non-paraneoplastic cases are likely to do equally well,
nxi.0000000000001014
but shorter time to oophorectomy is key in securing
► Makuch M, Wilson R, Al-Diwani A, et al. N-methyl-D-
clinical improvement in patients with a teratoma.46
aspartate receptor antibody production from germinal
In our experience, this benefits from close multidis-
centre reactions: Therapeutic implications. Ann Neurol
ciplinary discussions between radiology and gynae-
2018;83:553–61. doi:10.1002/ana.25173
cology colleagues to provide a balanced approach
► Ruiz-García R, Martínez-Hernández E, Saiz A, et al. The
regarding considerations around fertility preservation
diagnostic value of onconeural antibodies depends
in young women of childbearing potential.
on how they are tested. Front Immunol 2020;11:1–6.
There is a contrasting situation for patients
doi:10.3389/fimmu.2020.01482
with CASPR2- autoantibodies, where patients with

Review
entities.92 Within this group, the poorest outlook is
4 Graus F, Vogrig A, Muñiz-Castrillo S, et al. Updated diagnostic
reserved for patients with GABABR-autoantibodies, criteria for paraneoplastic neurologic syndromes. Neurol
whose functional improvement is in many cases partial Neuroimmunol Neuroinflamm 2021;8:e1014.
5 Graus F, Delattre JY, Antoine JC, et al. Recommended
and, despite immunotherapy gains, many die due to
diagnostic criteria for paraneoplastic neurological syndromes. J
an underlying SCLC and its related complications.77 79
Neurol Neurosurg Psychiatry 2004;75:1135–40.
6 Peterson K, Rosenblum MK, Kotanides H, et al. Paraneoplastic
Twitter Sarosh R Irani @ANG_Oxford
cerebellar degeneration. I. A clinical analysis of 55 anti-Yo
Contributors SRI and SB conceived the study and produced the antibody-positive patients. Neurology 1992;42:1931–7.
first draft. CU and JH edited the manuscript for intellectual
content. All authors approved the final text. doi:10.1212/wnl.42.10.1931
7 Al-Diwani A, Handel A, Townsend L, et al. The
Funding SRI is supported by the Wellcome Trust
psychopathology of NMDAR-antibody encephalitis in adults: a
(104079/Z/14/Z), Medical Research Council(MR/V007173/1),
BMA Research Grants - Vera Down grant (2013), Margaret systematic review and phenotypic analysis of individual patient
Temple (2017), Epilepsy Research UK (P1201), the Fulbright data. Lancet Psychiatry 2019;6:235–46.
UK-US commission (MS Society research award) and by 8 Joubert B, Kerschen P, Zekeridou A, et al. Clinical spectrum
the National Institute for Health Research (NIHR) Oxford of encephalitis associated with antibodies against the
Biomedical Research Centre. This research was funded in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
whole, or in part, by the Wellcome Trust (grant number
receptor: case series and review of the literature. JAMA Neurol
104079/Z/14/Z). JH is supported by a public grant overseen
by the French National Research Agency (ANR), as part of the 2015;72:1163–9.
second 'Investissements d'Avenir' programme called BETPSY 9 van Coevorden-Hameete MH, de Bruijn MAAM, de Graaff
(reference ANR-18-RHUS-0012, https://www.rhu-betpsy.fr/). E, et al. The expanded clinical spectrum of anti-GABABR
For the purpose of open access, the author has applied a CC encephalitis and added value of KCTD16 autoantibodies. Brain
BY public copyright licence to any author accepted manuscript 2019;142:1631–43.
version arising from this submission. SB has received salary
10 Ramanathan S, Al-Diwani A, Waters P, et al. The autoantibody-
support from the NIHR and is currently supported by the
Wellcome Trust. CU is supported by the Friedman Award for mediated encephalitides: from clinical observations to
Health Scholars (University of British Columbia) and received molecular pathogenesis. J Neurol 2021;268:1689–707.
salary support from the UBC Division of Neurology. doi:10.1007/s00415-019-09590-9
Disclaimer The views expressed are those of the authors 11 Sun B, Ramberger M, O'Connor KC, et al. The B cell
and not necessarily those of the NHS, the National Institute immunobiology that underlies CNS autoantibody-mediated
for Health Research, the Department of Health, UBC, or diseases. Nat Rev Neurol 2020;16:481–92.
Vancouver Coastal Health. The funders had no role in the 12 Varley J, Taylor J, Irani SR. Autoantibody-mediated
preparation, review or approval of the manuscript, and
decision to submit the manuscript for publication. diseases of the CNS: structure, dysfunction and therapy.
Neuropharmacology 2018;132:71–82.
Competing interests SRI is a coapplicant and receives royalties
on patent application WO/2010/046716 (UK patent number, 13 Uy CE, Binks S, Irani SR. Autoimmune encephalitis: clinical
PCT/GB2009/051441) entitled ‘Neurological Autoimmune spectrum and management. Pract Neurol 2021. doi:10.1136/
Disorders’. The patent has been licensed commercially for the practneurol-2020-002567. [Epub ahead of print: 09 Jun
development of assays for LGI1 and other VGKC complex 2021].
antibodies. SRI and SB are coapplicants on a patent application
entitled 'Diagnostic Strategy to Improve Specificity of CASPR2 14 Rietveld A, Lim J, de Visser M, et al. Autoantibody testing
Antibody Detection' (PCT/GB2019/051257, publication in idiopathic inflammatory myopathies. Pract Neurol
number WO/2019/211633 and UK1807410.4). SRI has 2019;19:284–94.
received honoraria from UCB, MedImmun, ADC therapeutics 15 Vogrig A, Muñiz-Castrillo S, Joubert B, et al. Central nervous
and Medlink Neurology, and research support from CSL
system complications associated with immune checkpoint
Behring, UCB and ONO Pharma. CU and JH declare no
competing interests with respect to this publication. inhibitors. J Neurol Neurosurg Psychiatry 2020;91:772–8.
16 Vogrig A, Fouret M, Joubert B, et al. Increased frequency of
Patient consent for publication Not required.
anti-Ma2 encephalitis associated with immune checkpoint
Provenance and peer review Commissioned. Externally peer
inhibitors. Neurol Neuroimmunol Neuroinflamm 2019;6.
reviewed by Neil Anderson, Auckland, New Zealand.
doi:10.1212/NXI.0000000000000604. [Epub ahead of print:
ORCID iDs 07 Aug 2019].
Jerome Honnorat http://orcid.org/0000-0002-4721-5952 17 Greenlee JE, Clawson SA, Hill KE, et al. Neuronal uptake of
Sarosh R Irani http://orcid.org/0000-0002-7667-9748 anti-Hu antibody, but not anti-Ri antibody, leads to cell death
in brain slice cultures. J Neuroinflammation 2014;11:1–15.
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Review

vigilance.1 3 A key feature of PNS is that

Binks S, et al. Pract Neurol 2022;22:19–31. doi:10.1136/practneurol-2021-003073 1 of 15

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closely associated with Hodgkin’s lymphoma and have

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teratoma. Pieces (‘explants’) of tissue from these—

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…if the patient has a cerebellar syndrome

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Paraclinical investigations: neurological

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However, it should be highlighted that a bland CSF Electromyography is a valuable investigation in

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entities.92 Within this group, the poorest outlook is

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