Paraneoplastic neurological syndromes

Abstract

Paraneoplastic neurological syndromes are immune-mediated erroneous attacks on the central or peripheral nervous systems, or both, directed originally against the tumour itself. They have been known for more than 40 years, but recently the discovery of new subgroups of paraneoplastic encephalitis syndromes with a remarkably good response to immune therapy has ignited new clinical and scientific interest. Knowledge of these subgroups and their associated autoantibodies is important in therapeutic decision-making. However, the abundance of new autoantibodies and syndromes can be confusing. This review paper summarizes current knowledge and new developments in the field of paraneoplastic neurological syndromes, their classification, pathophysiology and treatment.

Other Articles published in this series.

Diagnosis, pathogenesis and treatment of myositis: recent advances. Clinical and Experimental Immunology 2014, 175: 349–58.

Disease-modifying therapy in multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy: common and divergent current and future strategies. Clinical and Experimental Immunology 2014, 175: 359–72

Monoclonal antibodies in treatment of multiple sclerosis. Clinical and Experimental Immunology 2014, 175: 373–84.

CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. Review of an increasingly recognized entity within the spectrum of inflammatory central nervous system disorders. Clinical and Experimental Immunology 2014, 175: 385–96.

Requirement for safety monitoring for approved multiple sclerosis therapies: an overview. Clinical and Experimental Immunology 2014, 175: 397–407.

Myasthenia gravis: an update for the clinician. Clinical and Experimental Immunology 2014, 175: 408–18.

Cerebral vasculitis in adults: what are the steps in order to establish the diagnosis? Red flags and pitfalls. Clinical and Experimental Immunology 2014, 175: 419–24.

Multiple sclerosis treatment and infectious issues: update 2013. Clinical and Experimental Immunology 2014, 175: 425–38.

Introduction

Immune-mediated syndromes affecting different levels of the central, peripheral or autonomic nervous system and associated with cancer are called paraneoplastic neurological syndromes. They are often therapy-refractive and relentlessly progressive syndromes. Several associated antibodies have been discovered since the first description of anti-Hu antibodies in 1985 [1]. These antibodies recognize mainly intracellular antigens, e.g. Hu, CV2/collapsing response mediator protein 5 (CRMP5) and Yo, expressed in nervous tissue and tumours, and hence have been called onconeural antibodies. Their presence indicates underlying tumours with a very high probability [2].

In recent years, several new treatment responsive subtypes of paraneoplastic encephalitis, limbic encephalitis and peripheral nervous system manifestations have been identified. They are defined by the presence of antibodies directed against channels, receptors or associated proteins located at the synaptic or extra-synaptic neuronal cell membrane. These antibodies are referred to collectively as synaptic or neuronal cell-surface antibodies in this review. The best-known member of this group is the anti-N-methyl-D-aspartic acid (NMDA) receptor encephalitis. Unlike syndromes associated with onconeural antibodies, which in most cases are paraneoplastic, these syndromes and the respective antibodies may occur with and without associated cancer [3].

This paper summarizes current knowledge on the most common paraneoplastic neurological syndromes and antibodies, taking into account these new syndromes. The first part offers a practical approach while the second part describes common syndromes in more detail. The third part of the paper reviews pathophysiology and therapeutic strategies.

Practical approach

Clinical syndromes occurring in a paraneoplastic context can be divided into those with a high likelihood of paraneoplastic aetiology and those associated only rarely with underlying cancer, termed ‘classical’ and ‘non-classical syndromes’ respectively (Table 1) [4]. Most ‘non-classical syndromes’, e.g. brain stem encephalitis or optic neuritis, and also many ‘classical syndromes’, are in fact caused by other diseases, necessitating a thorough differential work-up in any suspected case. The specific differential diagnosis depends on the clinical syndrome and history (Table 2). Red flags pointing towards a paraneoplastic syndrome besides the presence of a ‘classical syndrome’ are the presence of a subacute, relentlessly progressive syndrome, consecutive or simultaneous affection of different areas of the central and/or peripheral nervous system and a high individual tumour risk (e.g. smoking, weight loss, etc.). In addition to the ‘classical’ syndrome of limbic encephalitis, the recently described and unique syndrome of anti-NMDA receptor encephalitis (described in more detail below) is also highly predictive of underlying cancer in certain age groups (up to 50%) and should trigger antibody and tumour screening in all suspected cases [5].

Table 1.

Classical and non-classical paraneoplastic syndromes and diagnostic criteria [4]

Classical syndrome	Non-classical syndrome
Central nervous system
Encephalomyelitis	Brain stem encephalitis
Limbic encephalitis	Optic neuritis
Subacute cerebellar degeneration	Myelitis/necrotizing myelopathy
Opsoclonus–myoclonus syndrome	Stiff-person syndrome and variants
Peripheral nervous system
Subacute sensory neuronopathy	Distal-symmetric sensorimotor neuropathy
Chronic intestinal pseudo-obstruction	Polyradiculoneuropathy (acute/chronic)
	Multiplex mononeuropathy
	Pure autonomic neuropathies
Neuromuscular junction and muscle
Lambert–Eaton myasthenic syndrome	Myasthenia gravis
Dermatomyositis	Neuromyotonia

Diagnostic criteria
	Well-characterized onconeural antibodies	Partially characterized onconeural antibodies/no cancer	No antibodies/high cancer risk	Cancer detected
Classical syndrome	Definite	Possible	Possible	Definite
Non-classical syndrome	Definite	Possible	Not applicable	Possible (definite if improving after cancer treatment)

Table 2.

Differential diagnosis of classical and some non-classical paraneoplastic syndromes

Syndrome	Differential diagnoses
Subacute cerebellar degeneration	Metastatic
	Alcoholic
	Toxic (lithium, anti-convulsives, 5-FU, araC‡)
	Vitamin deficiency (B1, B12, E, folic acid)
	Immune-mediated non-paraneoplastic Miller–Fisher syndrome Gluten-sensitive enteropathy Antibody-associated†
	Infectious (VZV, EBV, Lues, Whipple's disease, CJD)
	Other: meningeal siderosis, MSA-C, hereditary
Limbic encephalitis (LE)	Infectious HSV-1, VZV, WNV, HIV/PML, Lues, CJD HHV6 (in immunocompromised patients)
	Immune-mediated non-paraneoplastic GAD, SLE, Sjögren's syndrome, SREAT PACNS
	Glioma
Opsoclonus–myoclonus syndrome	Infectious (HIV, hepatitis C, WNV, Whipple's disease, borreliosis, CJD)
	Postinfectious (mycoplasma, salmonellosis, streptococci)
	Toxic (e.g. lithium and tricyclic anti-depressants)
	Hereditary
	Epileptic
	Metabolic, hypoxic encephalopathy
	Neurodegenerative diseases
Retino-/opticopathy	Vascular
	Optic neuritis
	LHON
	Toxic
	Alimentary: tobacco–alcohol–amblyopia
Subacute sensory neuronopathy	Immune-mediated Sjögren's syndrome, coeliac disease, cryoglobulinaemia Autoimmune autonomic ganglionopathies (ganglionic AcHR antibodies), dysautonomia with peripherin antibodies
	Toxic (cisplatin)
	Alimentary: hypervitaminosis B6, vitamin B12 deficiency
	Infectious: HIV
Autonomic neuropathy	Metabolic: diabetes mellitus
	Immune-mediated: GBS, CIDP, Sjögren's syndrome
	Hereditary: porphyria, mitochondriopathy
	Neurodegenerative: MSA-A
Lambert–Eaton myasthenic syndrome	Immune-mediated: myasthenia gravis
	Hereditary: episodic ataxia type 2
	Toxic: botulism
Poly-/dermatomyositis	Toxic/metabolic: myopathies, e.g. steroids
	Immune-mediated: IBM, immune-mediated necrotizing myopathies

^†e.g. GAD (gadolinium); RhoGTPase-activating protein 26, Homer-3, mGluR1.

^‡Cytosine arabinoside. 5-FU, 5-fluorouracil; CIDP: chronic inflammatory demyelinating polyneuropathy; CJD: Creutzfeld–Jakob's disease; EBV: Ebstein–Barr virus; GBS: Guillain–Barré syndrome; HIV: human immunodeficiency syndrome virus; IBM: inclusion body myositis; HIV/PML: progressive multifocal leucoencephalopathy in HIV; MSA: multi-system atrophy; NMO: neuro-myelitis optica; LHON: Liebers optic neuropathy; PACNS: primary angiitis of the CNS; SREAT: steroid-responsive encephalopathy with autoantibodies to thyroid; SLE; systemic lupus erythematosus; VZV: varicella zoster virus; WNV: West Nile virus.

The first step in the diagnostic work-up of a neurological syndrome suspected to be paraneoplastic in origin is to prove its immune-mediated nature and rule out obvious differential diagnoses such as meningeal disease, metastasis, toxic or metabolic causes. Next, if clinical suspicion of paraneoplastic aetiology remains high, screening for relevant onconeural or neuronal cell-surface antibodies should be initiated. Their presence or absence helps to further predict the probability and location of underlying cancer. The last step would be a tumour screening guided by the clinical information and antibody status.

Initial work-up

Magnetic resonance imaging (MRI) of the brain and/or spinal cord is warranted in central nervous system (CNS) syndromes and, together with cerebrospinal fluid (CSF) analysis, is especially helpful in excluding differential diagnoses; for example, meningeal diseases and T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities can be observed [6,7]. Significant gadolinium (GAD) enhancement is not a hallmark of these diseases, and should raise doubts of this diagnosis. Completely normal MRI scans do not exclude paraneoplastic syndromes of the CNS. Also, for some encephalitic syndromes with neuronal cell-surface antibodies (e.g. anti-NMDA receptor encephalitis), MRI imaging is very often without abnormal results [8]. In paraneoplastic cerebellar degeneration (PCD) an initial abnormal MRI of the brain or cerebellum is even more unusual, although cerebellar atrophy occurs in later stages [2]. MRI imaging of the CNS in suspected peripheral nervous system paraneoplastic syndromes, e.g. sensory neuronopathy, can sometimes show changes suggestive of limbic encephalitis and also aid in diagnosis. MRI of the peripheral nervous system, e.g. in plexopathies, helps to exclude metastatic affection.

CSF analysis is advisable in all patients suspected to suffer from paraneoplastic syndromes. In paraneoplastic syndromes affecting the CNS, nerve roots or spinal sensory ganglia, inflammatory changes in CSF are found in most cases: lymphocytic pleocytosis and/or oligoclonal bands, in some cases elevated protein. In 90% of paraneoplastic syndromes at least one of these three parameters is abnormal. As in most autoimmune diseases, incidence of lymphocytic pleocytosis decreases with time (50% during the first 3 months, 30% afterwards), while the incidence of elevated CSF proteins increases. Sixty per cent of patients harbour oligoclonal bands. The observations in peripheral or autonomic nervous system manifestation are not significantly different. However, in 7% of paraneoplastic cases with onconeural antibodies, CSF is entirely normal [9]. Similar numbers apply for paraneoplastic disorders associated with neuronal cell-surface antibodies, e.g. anti-NMDA receptor encephalitis [9].

Antibodies

Detecting antibodies against onconeural antigens, e.g. Hu, CV2/CRMP5, Yo and amphiphysin, together with a compatible neurological syndrome, has a very high specificity for paraneoplastic syndromes. In contrast, antibodies against neuronal cell-surface antigens, e.g. NMDA receptor antibodies, are syndrome-specific but can occur in paraneoplastic and idiopathic cases [10]. Antibodies against onconeural and/or neuronal cell-surface antigens are present in serum and/or CSF of the majority of patients with paraneoplastic syndromes (Table 3). However, even in patients with definite paraneoplastic syndromes in a large European network study, only 80% harboured onconeural antibodies [6]. While this percentage is likely to increase in the future, with the discovery of further onconeural antibodies, in clinical routine seronegative cases often pose a considerable diagnostic challenge.

Table 3.

Syndromes of the central nervous system (CNS) and relevant well-characterized onconeural or neuronal cell-surface antibodies

	Syndrome	Relevant antibodies
CNS	Subacute cerebellar degeneration	Hu, Yo, CV2/CRMP5, Ri, Tr†, amphiphysin, VGCC
	25%
	Encephalomyelitis	Hu, CV2/CRMP5, amphiphysin
	6%
	Limbic encephalitis	Hu, Ma2, CV2/CRMP5, Ri, amphiphysin
	10%	NMDAR, Lgi1‡, CASPR2‡, GABA(b)-, AMPA-, mGluR5, glyR‡, GAD‡
	Opsoclonus–myoclonus syndrome (adults)	Ri, Hu, Ma/Ta, NMDAR
	2%
	Retinopathy	Hu, CV2/CRMP5, recoverin
	1%
	Stiff-person syndrome	Amphiphysin, glyR‡, GAD‡
	1%

^†Tr antibodies are not considered well-characterized but should raise a high suspicion of underlying cancer.

^‡Lgi1: leucine-rich, glioma-inactivated 1; gadolinium (GAD) glycine-receptor antibody associated syndromes are rarely paraneoplastic. VGCC: voltage-gated calcium channel; CV2/CRMP5: collapsing response mediator protein 5; NMDAR: N-methyl-D-aspartate receptor; CASPR2: contactin-associated protein-like 2; GAD: gadolinium; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid; mGluR5: metabotrophic glutamate receptor 5; glyR: α1-glycine receptor; GABA: γ-amino-butyric acid.

It is generally advisable to test serum and CSF, as failure to do so might result in false-negative and false-positive results. The relevant antibodies for testing vary according to the clinical syndrome. For syndromes involving the CNS, Table 2 provides suggestions. Relevant antibodies in non-CNS syndromes are discussed in more detail below in the sections on peripheral nervous system and neuromuscular junction disorders. Onconeural antibodies characterized in large and independent patient cohorts are called ‘well characterized’. Partially characterized antibodies have not been studied in large patient cohorts or their antigen is unknown (Table 4). Their detection increases the suspicion of underlying tumour, but diagnosis of a paraneoplastic syndrome should not be based solely on their finding (Table 1) [4].

Table 4.

Onconeural antibodies found in paraneoplastic syndromes. Alternative names are given in parentheses

Antibody	Antigen	Associated syndromes and symptoms	Most common tumours
Onconeural antibodies (well-characterized, paraneoplastic antibodies tumour in >90%)
Anti-Hu (ANNA-1)	HuD	Encephalomyelitis, limbic encephalitis, cerebellar degeneration, brain stem encephalitis, multi-segmental myelitis, sensory neuronopathy, sensory motor neuropathy, autonomic neuropathy	Lung cancer (85%), mostly SCLC, neuroblastoma, prostate carcinoma
Anti-Yo (PCA-1)	CDR2, CDR62	Paraneoplastic cerebellar degeneration	Ovarian, breast cancer
Anti-CV2/CRMP5	CRMP5	Encephalomyelitis, polyneuropathy, optic neuritis, limbic encephalitis, choreatic syndromes, cerebellar degeneration	SCLC, thymoma
Anti-Ta/Ma2†	MA-proteins	Limbic encephalitis, rhombencephalitis, male>>female	Testicular cancer
Anti-Ri (ANNA-2)	NOVA-1	Opsoclonus–myoclonus syndrome, rhombencephalitis, cerebellar degeneration, myelitis, jaw dystonia, laryngospasm	Breast, ovarian carcinoma, SCLC
Anti-amphiphysin	Amphiphysin	Stiff-person syndrome, limbic encephalitis, rhombencephalitis, cerebellar degeneration, polyneuropathy	Breast cancer, SCLC
Anti-recoverin	Recoverin	Retinopathy	SCLC
Anti-SOX-1 (AGNA)	SOX-1	Non-syndrome-specific	Sensitivity 67%, specificity 95% for SCLC in LEMS
Partially characterized onconeural antibodies (antigen not characterized or positive predictive value for tumour unknown)
Anti-Tr (PCA-Tr)	DNER	Cerebellar degeneration	Hodgkin lymphoma, non-Hodgkin lymphoma
Anti-Zic4	ZIC1-4	Cerebellar degeneration	SCLC
PCA-2	280 kD	Encephalitis, Lambert–Eaton myasthenic syndrome, polyneuropathy	SCLC
ANNA-3	170 kD	Neuropathy, cerebellar degeneration, limbic encephalitis	SCLC

DNER: delta/notch-like epidermal growth factor-related receptor.

^†In some patients co-existing Ma1 antibodies, in which case brain stem syndromes and non-testicular tumours often predominate. SCLC: small-cell lung cancer; LEMS: Lambert–Eaton myasthenic syndrome (LEMS).

Most syndromes can be associated with several different antibodies, and different syndromes can occur with the same antibody (Tables 3 and 4). However, most importantly, antibody findings have to be interpreted together with the clinical syndrome. Onconeural antibodies such as Hu antibodies occur in patients with tumours but without neurological syndromes [11], and occasionally even in other immune-mediated non-paraneoplastic diseases [12]. In the following situations, serum and CSF samples should be sent to reference laboratories for retesting: seronegative cases with a high clinical suspicion or a known tumour, antibodies not compatible with the clinical syndrome and non-immunoglobulin (Ig)G isotype antibody findings.

Tumour screening

In most paraneoplastic cases, neurological symptom onset precedes tumour diagnosis [5,6]. The main difficulty in screening arises from the fact that tumours are often too small to detect while still triggering the immune reaction. There are three common clinical situations: (i) classical or non-classical syndrome and a compatible onconeural (Hu, Yo, etc.) or neuronal cell-surface antibody (e.g. NMDA receptor antibodies); (ii) classical syndrome and no well-characterized antibodies; and (iii) non-classical syndrome and no well-characterized antibodies.

In situations (i) and (ii), clinical suspicion of a paraneoplastic syndome is very high. Tumour screening should be carried out according to recently published European guidelines (Table 5) [13]. The frequency, age-dependency and most probable tumour localization are suggested by the clinical syndrome and/or detected antibody (Tables 6). It is advisable to perform a sequential approach, e.g. if an initial thoracic computed tomography (CT) in suspected small-cell lung cancer (SCLC) is negative, it should be followed by fluordeoxy glucose-positron emission tomography (FDG-PET). The expected tumour type influences the diagnostic sequence, e.g. an ovarian teratoma can be searched for by transvaginal or abdominal ultrasound and if negative by abdominal MRI or CT scanning. If no tumour is found with available methods, close oncological follow-up every 3–6 months for at least 5 years is suggested by the guidelines for syndromes associated with onconeural antibodies [13]. The majority (90%) of tumours will become evident within the first year. Also, clinical relapse should trigger repeated tumour screening. In Lambert–Eaton myasthenic syndrome, a screening period of 2 years appears to be sufficient [14]. No clear guidelines exist for syndromes with synaptic or neuronal cell-surface antibodies. Currently, they are screened similarly to syndromes with onconeural antibodies.

Table 5.

Recommended tumour screening adapted from Titulaer et al. [13]

Tumour	Diagnostics
	Primary	Secondary	Tertiary
Lung cancer	Thoracic CT (80–85%) thoracic MRI	FDG-PET or FDG-PET/CT	Bronchoscopy/EB-US, possibly needle biopsy and/or mediastinoscopy
Thymoma	Thoracic CT (75–90%), thoracic MRI	FDG-PET or FDG-PET/CT
Breast cancer	Mammography (80%), ultrasound	Breast MRI
Ovarian carcinoma	Ultrasound (69–90%) + CA-125	Pelvic and abdominal CT	FDG-PET
Ovarian teratoma	Ultrasound (69–90%)	MRI (93–98%)	Thoracic CT (extra-pelvic teratomas)
Testicular cancer	Ultrasound (72%) + β-HCG, AFP	Pelvic/abdominal CT (76%), abdominal MRI	Possibly FDG-PET (malignant teratomas)
Lymphoma	Thoracic/abdominal CT, Ultrasound	FDG-PET or FDG-PET/CT
Skin tumours (Merkel-cell carcinoma)	Dermatological examination, biopsy

Sensitivity in parentheses. EB-US: endobronchial ultrasound; CT: computerized tomography; HCG: human chorionic gonadotropin; AFP: alpha-fetoprotein; MRI: magnetic resonance imaging; FDG-PET: fluordeoxy glucose-positron emission tomography.

Table 6.

Encephalitic syndromes associated with antibodies against synaptic or neuronal cell-surface antigens

Antigen	NMDA receptor NR1	Lgi1	CASPR2	AMPA receptor	GABA(b) receptor	Glycine receptor α1	mGluR5
Age (median)/gender female : male	0·6–85 (21) 4:1	30–80 (60) 1:2	46–77 (60) 1:4	38–87 (60) 9:1	24–75 (62) 1:1	5–69 (43) 6:5	46, 15 1:1
Clinical syndrome	Prodomal syndrome Psychiatric syndrome, seizures, amnesia Movement disorders catatonia, autonomic instability	Limbic encephalitis, tonic or facio-brachial dystonic seizures, myoclonus	Morvan syndrome, encephalitis, neuromyotonia	Limbic encephalitis, psychiatric syndromes	Limbic encephalitis	Encephalomyelitis with rigidity and myoclonus, hyperekplexia, stiff-person syndrome, (retinopathy)	Limbic encephalitis, myoclonus
MRI T2/FLAIR hyperintensities medial-temporal	25% (only 33% abnormal)	>80%	40%	90%	70%	10%	≈ 50%
CSF: pleocytosis or ocb	95% (at onset 80%)	40%	25%	90%	90%	Some ocb	2/2
Tumour	Age-dependent 10–50% ovarian teratomas	<10%† (lung, thymoma)	<20%† (lung, thymoma)	70% (lung, breast, thymoma)	60% (lung)	Rare ≈ 10%	2/2 Hodgkin lymphoma
Miscellaneous	EEG in 90% abnormal, 30% ‘extreme delta brush’	Hyponatraemia (60%)	Limbic encephalitis	Common relapses	Prominent seizures and status epilepticus	Few cases known	Only 2 cases known
Estimated relative frequency	55%	30%	4%	4%	5%	2%	<1%

^†True tumour incidence unknown; ocb: oligoclonal bands; EEG: electroencephalograph; NMDA: N-methyl-D-aspartate; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid; GABA: γ-amino-butyric acid receptor; CASPR2: contactin-associated protein-like 2; Lgi1: leucine-rich, glioma-inactivated 1; mGluR5: metabotrophic glutamate receptor 5.

Situation (iii) has a low a priori chance of paraneoplastic aetiology. The method of tumour screening and surveillance depends on the level of clinical suspicion, and no clear guidelines exist. It is good clinical practice to perform close clinical follow-up visits and possibly repeat tumour screening, but alternative diagnoses have to be considered frequently.

Pathophysiology

Many tumours, and especially tumours of neuro-ectodermal lineage, e.g. SCLC, can express central or peripheral nervous system antigens. In patients with SCLC but without neurological symptoms, up to 29% harbour Hu antibodies [11]. However, only a minority of these develop a paraneoplastic neurological syndrome. Host factors, e.g. major histocompatibility complex (MHC) haplotypes [human leucocyte antigen (HLA)-DQ2 and HLA-DR3], contribute [15,16], but the main factors are still unclear. Intrinsic tumour properties are considered to be important in breaking central or peripheral immune tolerance to self-antigens [17].

Recent years have shown that the subcellular localization of the detected antigen plays a major role for disease mechanisms. As already mentioned, onconeural antibodies (Table 4) are directed against intracellular antigens, which are not directly accessible to the antibodies. The main pathogenic effect is carried out most probably by cytotoxic T cells, resulting in neuronal cell death [10]. However, the newly discovered neuronal cell-surface antibodies (Table 6) can reach their target antigen directly. The mechanism of action in some of these involves cross-linking and internalization of their antigen, which leads to functional inactivation while retaining neuronal integrity. This dichotomy is currently considered to be the basis for the differing reversibility and immunotherapy responsiveness of syndromes with onconeural versus synaptic or neuronal cell-surface antibodies [10].

However, many aspects are still unclear. The contribution of host and tumour factors to initiation of systemic immune reaction, factors involved in establishing the immune reaction beyond the blood–brain barrier and effector function of neuronal cell-surface antibodies, remain to be elucidated [8].

Paraneoplastic disorders of the CNS

It is necessary for therapeutic and prognostic purposes to differentiate paraneoplastic CNS syndromes into those associated with onconeural antibodies (e.g. Hu, CV2/CRMP5, amphiphysin) and those with synaptic neuronal cell-surface antibodies. Syndromes with these latter antibodies are generally more responsive to immunotherapy, and they occur with or without cancer [3]. The antibodies are directed against functional relevant antigens on neuronal surfaces and have become known by the name of their target: N-methyl-D-aspartate-(NMDA, NR1)-receptor antibody, α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid receptor (AMPA-receptor) [18], γ-amino-butyric acid (GABA)(b)-receptor [19], α1-glycine receptor (GlyR) [20], metabotrophic glutamate receptor 5 (mGluR5) [21], leucine-rich, glioma-inactivated 1 (Lgi1) [22,23] and contactin-associated protein-like 2 (CASPR2) [23,24] (Table 6).

Paraneoplastic CNS syndromes with onconeural antibodies (Hu, amphiphysin, etc.) are rare (0·1–1% of tumour patients) [25,26], although reliable data on true incidence are missing. In large centres, two to three patients are diagnosed annually. The most common paraneoplastic CNS manifestations are paraneoplastic cerebellar degeneration (PCD), followed by limbic encephalitis (PLE) and encephalomyelitis (PEM) (Table 3). Brain stem encephalitis, opsoclonus–myoclonus syndrome, stiff-person syndrome and myelitis are considerably less common [6].

Syndromes associated with neuronal cell-surface antibodies (e.g. anti-NMDA receptor encephalitis) occur considerably more frequently [27]. One per cent of young patients in a large German intensive care unit [28] and 4% of patients suffering from encephalitis in England were diagnosed with anti-NMDA receptor encephalitis [29]. It was more prevalent than any single viral form of encephalitis in a centre specializing in encephalitis [30]. However, only 30–50% of anti-NMDA receptor encephalitis cases are associated with underlying tumours [5]. Data on the incidence of the other neuronal cell-surface antibody-associated syndromes are missing; however, Lgi1 antibody-associated syndromes are considered the second largest group (Table 6).

Below, the most relevant paraneoplastic CNS syndromes are listed in the order of their estimated relative frequency. Arguably, the syndrome of anti-NMDAR encephalitis is the most frequent, followed by paraneoplastic limbic encephalitis and paraneoplastic cerebellar degeneration.

Anti-NMDA receptor encephalitis

Recognizing the clinical picture of anti-NMDA-receptor encephalitis is important, because it is extremely pathognomonic. However, it should not be referred to as limbic, because the syndrome reflects diffuse encephalitis.

The disease predominates in women (81%) and young patients (37% <18 years, 95% <45 years); however, in the age groups younger than 12 years and older than 45 years, almost 50% of patients are male. Approximately 50% of patients have prodromal symptoms: fever, headache, nausea, vomiting and upper gastrointestinal symptoms [5,8]. In adults, this is followed a few days or weeks later by psychiatric symptoms and behavioural abnormalities (>95%) often overshadowing other symptoms, such as memory deficits (60–80%). Affective, psychotic and obsessive–compulsive syndromes can occur. Seizures and status epilepticus are common (70%); they are often the initial symptoms in children (>30%), and pose a problem in differentiating them from non-epileptic abnormal movements (70–90%) [5,8]. The latter typically include repetitive oro-facio-lingual dyskinesias, pseudo-rhythmic arm and leg movements, choreoathetosis, oculogyric crisis, opisthotonus, dystonia and generalized rigidity [8,31]. These symptoms are usually accompanied by progressive loss of consciousness (60–70%) and autonomic instability (50%). While adults are more prone than children to develop central hypoventilation the latter may exhibit atypical symptoms (ataxia, hemiparesis) [5].

The MRI of the brain is often normal (at onset 67%) or shows non-specific abnormalities. In contrast, the CSF is abnormal in most patients, including mild to moderate lymphocytic pleocytosis (96%), oligoclonal bands (65%), or both [5,32]. The electroencephalogram (EEG) of these patients shows generalized diffuse (90%), focal slowing (30%) or seizure activity (24–60%). A highly characteristic pattern, described as ‘extreme delta brush’, occurs in 30% of adults (and some children) with this disorder. It consists of diffuse generalized slowing 1–3 Hz with superimposed beta-activity (20–30 Hz) ‘on top’ of the slow delta waves [5,33,34].

The paraneoplastic aetiology is age-dependent: uni-or bilateral ovarian teratomas can be found in 50% of patients older than 12 years, but in only 6% in younger patients [5,8]. Tumours other than teratomas are rare, but found preferentially in patients older than 45 years. Of male patients, only 6% have underlying tumours; lymphoma has been reported occasionally [8,35]. The clinical syndromes do not differentiate between paraneoplastic or idiopathic variants; however, relapses (12% of all NMDA-receptor antibody encephalitis within 24 months) are more common in idiopathic (55% of these) than in paraneoplastic variants (45% of these) [5,8,32].

Recovery in adequately treated patients is mostly favourable (78–97%); however, incapacitating residual symptoms remain in up to 22% of these and approximately 4–7% of cases are fatal, usually due to complications of intensive care [5,8].

Limbic encephalitis

Core symptoms of limbic encephalitis (epileptic seizures, short-term memory deficits, behavioural and psychiatric disturbances) occur associated with onconeural (e.g. Hu; Table 4) and neuronal cell-surface antibodies [e.g. AMPAR, GABA(b)R, etc.; Table 6]. In patients with Hu antibodies, the syndrome can evolve eventually into an encephalomyelitis [36]. Most patients with paraneoplastic limbic encephalitis will have at least minor involvement of other areas of the nervous system. Peripheral and/or autonomic nervous system involvement can precede or follow limbic encephalitis syndromes. The antibody associates strongly with SCLC and the prognosis is unfavourable.

Optic neuritis and chorea can be associated in patients with CV2/CRMP5-antibodies [37–40]. Associated tumours are especially SCLC and thymomas, and the prognosis is slightly better than for Hu antibody syndromes [41]. In young male patients, the presence of Ma2 antibodies (also known as anti-Ta) is highly associated with testis tumours, and responds considerably better to immunosuppression than limbic encephalitis with Hu antibodies [42].

Of the previously considered seronegative paraneoplastic limbic encephalitis cases, up to 40% might harbour GABA(b) receptor antibodies [43]. The syndrome is characterized by frequent epileptic seizures and status epilepticus in older patients with lung cancer or younger patients without associated tumours [19,43]. Some associated symptoms are indicative of certain neuronal cell-surface antibodies (Table 6), e.g. hyponatraemia and myoclonus in Lgi1 antibody encephalitis, or neuromyotonia in CASPR2 antibody limbic encephalitis (Morvan's syndrome). Glycine receptor antibodies can be found in stiff-person syndromes plus limbic encephalitis and hyperekplexia [44]. In very few cases, metabotrophic glutamate receptor 5 (mGluR5) antibodies have been found in limbic encephalitis and Hodgkin lymphoma (Ophelia's syndrome) [21]. The outcome of paraneoplastic limbic encephalitis associated with these synaptic or neuronal cell-surface antibodies is generally considered to be more favourable than paraneoplastic syndromes with onconeural antibodies.

In most cases (>95%), syndromes associated with onconeural antibodies (e.g. Hu; Table 4) are paraneoplastic; however, in limbic encephalitis with neuronal cell-surface antibodies, the tumour frequency varies considerably (Table 6). Most commonly associated tumours with onconeural antibodies are lung cancer, especially SCLC [6]. However, breast and ovarian cancer are common in women, and in young male patients one has to consider testicular cancer (anti-Ma2). Rarely, neuro-ectodermal skin cancer (Merkel-cell carcinoma) has been described. Furthermore, thymomas and lymphomas have to be considered in onconeural and neuronal cell-surface antibody-associated syndromes (Table 6).

Paraneoplastic cerebellar degeneration

Paraneoplastic cerebellar degeneration (PCD) is the most common CNS paraneoplastic neurological syndrome (24% [6]) with onconeural antibodies (e.g. Yo; Table 4). Within days to a few weeks, a severe cerebellar syndrome with dystaxia, loss of ambulation, dysarthria, saccadic gaze, pursuit and nystagmus develops. Usually the neurological syndrome stabilizes after several months but functionally on a very poor level, with 90% of patients being wheelchair-bound [45]. Usually, no abnormalities are found on MRI early during the disease. Within months atrophy may develop. In a few cases FDG-PET showed cerebellar hypermetabolism early during the disease [46].

The most common onconeural antibodies found in PCD are anti-Yo, anti-Hu, anti-VGCC and anti-CV2/CRMP5, and less often anti-Tr. Anti-Yo and anti-Tr are more syndrome-specific for PCD than the other antibodies. Most commonly associated tumours are listed in Table 4. Patients with Yo antibodies have a significantly longer median survival than Hu-associated PCD (13 versus 7 months, respectively) [47]. While anti-Yo is found in the context of breast or ovarian cancer, anti-Tr is usually found coincident with lymphomas [48]. Patients with PCD and VGCC antibodies should be examined for the presence of Lambert–Eaton myasthenic syndrome [49].

Recently, the antigen detected by anti-Tr antibodies was identified as delta/notch-like epidermal growth factor-related receptor (DNER) [50]. PCD with this antibody have the best median survival of these syndromes (median >113 months) [8,36,47,51].

New antibodies associated with PCD and idiopathic cerebellitis have been described in single cases and small case series, but their relevance and tumour association is currently unclear [anti-protein kinase Cγ in PCD and adenocarcinoma [36,52], anti-RhoGTPase-activating protein 26 (ARHGAP26) in PCD with ovarian cancer [47,53,54]; voltage-gated potassium channel (VGKC)-complex antibodies, GAD, mGluR1 and Homer-3 in idiopathic cerebellitis].

Rare paraneoplastic syndromes of the CNS

Several rare classical and non-classical paraneoplastic syndrome are known. The ‘classical’ syndrome of opsoclonus–myoclonus syndrome (POMS) (2·3%) is paraneoplastic in around 20% of cases, with the remainder being mainly post-infectious. The paraneoplastic variant is more common in patients above 50 years with signs of an encephalopathy [5,55,56]. In children, 50% of cases are associated with neuroblastoma and no antibodies have been characterized. In single cases, NMDA-receptor antibodies have been reported [48,57–60].

Stiff-person syndrome (SPS) occurs in a paraneoplastic and idiopathic context; women are affected more often (7:3) and variants exist, e.g. stiff-limb syndrome and progressive encephalomyelitis with rigor and myoclonus (PERM). Antibodies against GAD and, recently discovered, glycine receptor can be found in idiopathic SPS (50–90%) [5,44,61,62]. Its paraneoplastic form (5% of SPS) can be associated with anti-amphiphysin antibodies alone or in combination with the other antibodies [5,6,63].

Myelitis not occurring in the context of encephalomyelitis is a non-classical syndrome (Table 1). Necrotizing myelitis with multi-segmental affection of anterior horns has been described in few cases. No clear tumour or antibody association has been documented [64–66]. However, recently a case series of 31 patients with multi-segmental myelitis preferentially symmetrically involving the grey matter showed association with amphiphysin or CV2/CRMP5 antibodies and SCLC or breast cancer [67,68]. Some cases of aquaporin4 antibody-positive paraneoplastic neuromyelitis optica have also been described [69,70].

Extrapyramidal syndromes are only rarely caused by a paraneoplastic syndrome with onconeural antibodies; they are more common in syndromes with antibodies against synaptic or neuronal cell-surface antigens (especially anti-NMDA receptor encephalitis) [4,6,71]. However, generalized chorea, focal and segmental dystonias and hemiballism can be the primary manifestation of paraneoplastic encephalitis with onconeural antibodies (e.g. Hu, CV2/CRMP5). In cases with anti-CV2/CRMP5 antibodies, up to 70% present initially with an asymmetric or unilateral chorea, although eventually more widespread affection of the central nervous system develops in 90% [13,71].

While 10% of tumour patients suffer from visual loss, true paraneoplastic retinopathy (classical syndrome) is very rare (1% of paraneoplastic syndromes) [6]. It can be associated with various carcinomas or melanoma.

Paraneoplastic syndromes of the peripheral nervous system

Metabolic, metastatic and especially chemotherapy-associated toxic damage of peripheral nerves are responsible for the majority of neuropathies manifesting in cancer patients. Importantly, demyelinating proximal and/or distal polyneuropathies can occur in the setting of monoclonal gammopathy. Its presence should trigger screening for lymphoma, plasma cell dyscrasias or amyloidosis. However, the review of these important paraneoplastic neuropathies lies beyond the scope of this paper.

The occurrence of a classical paraneoplastic syndrome of the peripheral nervous system, neuromuscular junction (NMJ) or muscle (Table 1) in a patient with or without known cancer should raise the suspicion of paraneoplastic aetiology. Most paraneoplastic syndromes precede the tumour diagnosis. Classical paraneoplastic syndromes of the peripheral nervous system include paraneoplastic sensory neuronopathy (PSN) and autonomic neuropathy (chronic intestinal pseudo-obstruction). PSN is characterized by asymmetric, often painful hyp-and paraesthesias of arms, legs, trunk and face together with severe dysfunction of proprioception, sensory ataxia and pseudo-choreoathetotic movements. Recently, diagnostic criteria have been published [41].

Distal symmetric sensory and sensorimotor polyneuropathies (non-classical syndrome) can be paraneoplastic; however, special care has to be taken not to overlook other more common differential diagnoses. Generally, paraneoplastic syndromes of the peripheral nervous system can affect it at any level and mimic most other diseases [72], e.g. Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, brachial plexopathy or small fibre neuropathy [73,74]. Mononeuritis multiplex patterns of involvement and rapid-onset painful neuropathies can be suggestive of vasculitis, which can also occur associated with underlying cancer [75].

Red flags for including paraneoplastic syndromes in the differential are: rapidly progressive and debilitating syndromes, high individual tumour risk and isolated or combined autonomic involvement. The latter is suggested by the presence of chronic intestinal pseudo-obstruction, orthostatic dysregulation, cardiac arrhythmias, dry mouth, dry eyes, erectile dysfunction in males and dyshidrosis [76]. Patients with paraneoplastic autonomic neuropathy have an unfavourable prognosis [6].

Onconeural antibodies found in paraneoplastic peripheral nervous system involvement are anti-Hu, anti-CV2/CRMP5 or anti-amphiphysin [36,77]. However, the majority of patients with non-classical paraneoplastic syndromes will have no detectable antibodies [74].

Recently, CASPR2 and less frequently Lgi1 antibodies have been identified in patients with neuromyotonia with or without limbic encephalitis (Table 6). Neuromyotonia (Isaac syndrome) manifests with muscle pain, cramps, fasciculations, stiffness and weakness of trunk and extremities with or without autonomic symptoms. Repetitive discharges of motoneurones with high intraburst frequency can be found on electromyography. In particular, CASPR2 may be associated with thymomas in up to 20%, although this has not been reproduced in other cohorts [24,78,79].

Paraneoplastic syndromes of the neuromuscular junction

Lambert–Eaton myasthenic syndrome (LEMS) is associated with cancer in half of the cases. Progressive proximal weakness, autonomic symptoms (dry mouth, erectile dysfunction and constipation) and diminished tendon reflexes with fatigability are the typical presentation. Detection of VGCC-P/Q-antibodies (85–90%) and the typical electrophysiological properties support the diagnosis [66]. Several parameters [age, smoking, weight loss, Karnofsky performance status, bulbar symptoms, male sexual impotence, SOX1 (Sry-related HMG box 1) antibodies] predict an underlying SCLC with a probability higher than 80% [80]. SOX1 antibodies alone have a specificity of 95% for SCLC underlying LEMS, but unfortunately a sensitivity of only 65% [81]. New data also suggest that tumour screening in LEMS is needed only for a period of up to 2 years [14].

Myasthenia gravis is non-paraneoplastic in the majority of cases (90%) [82]. Thymoma are responsible for most paraneoplastic cases; very rarely, thymus and other carcinomas can be associated. Elevated striational antibodies in younger patients (<50 years) have a specificity of 60% for an underlying thymoma. However, antibodies against titin or ryanodine receptors are more specific: their absence in young patients (<50 years) with myasthenia gravis and positive AchR antibodies make a thymoma very unlikely and their presence very likely [83].

Paraneoplastic syndromes in muscle: dermatomyositis

Dermatomyositis can be paraneoplastic in around 25% of cases [84]. Unfortunately, while some syndrome-specific antibodies exist (Mi2, Jo1, SRP), antibodies or other biomarkers indicating underlying cancer are not known. In contrast to the other syndromes in this review, dermatomyositis is not associated preferentially with certain tumour types. Most common are ovarian, lung, pancreatic, stomach and colorectal cancers and lymphomas [85]. Therefore, a broad tumour screen has to be considered upon initial diagnosis and annually for 3 years. Relapses should trigger repeated screening [13].

Treatment

Treatment of paraneoplastic syndromes can be differentiated into tumour and immunosuppressive treatment. Prompt initiation of therapy upon diagnosis can stabilize symptoms and prevent spreading to further areas in syndromes with onconeural antibodies. However, most of these syndromes respond poorly to immunotherapy. Syndromes with synaptic or neuronal cell-surface antibodies mainly show a marked improvement upon immunosuppression and tumour removal, even in severely affected patients.

Tumour therapy

Elimination of tumour tissue in common paraneoplastic syndromes with onconeural antibodies (Hu, Yo) or neuronal surface antigen antibodies (anti-NMDA receptor encephalitis) has been shown in large case series to be beneficial [8,36,47,51]. For example, in patients with a paraneoplastic encephalomyelitis associated with anti-Hu, tumour treatment was associated with recovery or stabilization with an odds ratio of 4·56 (95% confidence interval 1·62–12·86) [36]. Patients with a paraneoplastic cerebellar degeneration with onconeural antibodies lived significantly longer if their tumour was treated [47]. Patients with a teratoma-associated NMDA-receptor antibody encephalitis are less likely to suffer from relapses [5].

Tumour therapy should be instituted according to current oncological guidelines; there is no evidence suggesting a different tumour treatment in paraneoplastic neurological syndromes. However, tumour therapy should be instituted as quickly as possible.

Immunotherapy

The efficacy of immunosuppression in paraneoplastic neurological syndromes with onconeural antibodies is not supported by higher-level evidence [49,57,59]. However, it is good clinical practice to institute an immunosuppression in these syndromes in the absence of a detectable tumour or in combination with a tumour therapy in cases not improving or stabilizing. No systematic studies exist concerning the type of immunosuppression. Usually, steroids, plasmapheresis, intravenous immunoglobins (IVIG) or immunoadsorption are the first line of treatment. Plasmapheresis has not been shown to be effective and especially in syndromes with onconeural antibodies, e.g. Hu, Yo does not target the cell-mediated autoimmunity directly. Nevertheless, it is commonly utilized in initiation of immunosuppression. Therapy-refractive cases are treated with cyclophosphamide-based immunosuppression. Immunosuppressants (Azathioprin, methotrexate, cyclosporin A, tacrolimus, mycophenolate mofetile) are used commonly as steroid-sparing agents.

Anti-NMDA receptor encephalitis patients often (50%) respond to first-line treatment with steroid, IVIG or plasmapheresis. Of those who do not respond, around 75% benefit from second-line treatment with cyclophosphamide, rituximab or both. Factors related to a good outcome included lower severity of symptoms not necessitating intensive care treatment, prompt initiation of immunosuppression/tumour removal and second-line immunotherapy in patients failing first-line therapy [5]. Most patients with prompt tumour removal do not need second-line therapy [5]. Lgi1 and CASPR2 antibody-associated syndromes are considered to respond favourably to immunosuppression (e.g. steroids, plasmapheresis, IVIG), but often cause residual memory impairment. However, large case series on long-term outcome are currently missing. Even less is known on treatment and prognosis of other neuronal cell-surface antibody syndromes [e.g. GABA(b), AMPAR]. They are usually treated similarly to anti-NMDA receptor encephalitis.

In LEMS, treatment with steroids and azathioprine and in some cases immunoglobins can be considered [64,66]. The idiopathic variant of stiff-person syndrome can be treated with immunoglobins as well; however, this has not been shown for the paraneoplastic form [67]. Rituximab has been utilized with encouraging results in childhood opsoclonus–myoclonus syndrome [69].

Take-home messages

1. Paraneoplastic neurological syndromes are tumour-associated, immune-mediated syndromes potentially affecting any level of the nervous system.

2. Syndromes with a high probability of underlying cancer are called ‘classical’ neurological syndromes.

3. Paraneoplastic cerebellar degeneration, encephalomyelitis, encephalitis and limbic encephalitis as well as sensory neuronopathy are the most common classical paraneoplastic syndromes.

4. Antibodies with a high specificity of underlying cancer are called paraneoplastic or onconeural antibodies.

5. Antibodies against synaptic or neuronal cell-surface antibodies have been discovered. In contrast to onconeural antibodies, they occur with and without underlying cancer.

6. Encephalitis syndromes can occur with onconeural and neuronal cell-surface antibodies.

7. Treatment consists of prompt tumour treatment and immunotherapy. Syndromes with neuronal cell-surface antibodies usually respond to immunotherapy and have a better prognosis.

Disclosure

FL has received speaker honoraria from Grifols and scientific funding from Euroimmun, Lübeck, Germany. KPW was an employee of Euroimmun.