Paraneoplastic neurological syndromes - Wiley Online Library

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TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES

doi:10.1111/cei.12185

Series originators and editors: Olaf Stu ¨ve and Uwe Zettl

Clinical and Experimental Immunology

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F. Leypoldt*‡ and K.-P. Wandinger† *Department of Neurology, University Medical-Center Hamburg-Eppendorf, Hamburg, † Institute of Clinical Chemistry and Department of Neurology, University Hospital Schleswig-Holstein, Lübeck, Germany, and ‡Josep Dalmau’s Laboratory, Catalan Institution for Research and Advanced Studies (ICREA), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain Accepted for publication 5 August 2013 Correspondence: F. Leypoldt, Department of Neurology, University Medical-Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail: [email protected]

Summary 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 decisionmaking. 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. Keywords:

anti-NMDA receptor encephalitis, paraneoplastic antibodies, paraneoplastic syndromes

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 336

limbic

encephalitis,

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 bestknown member of this group is the anti-N-methyl-Daspartic 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

© 2013 British Society for Immunology, Clinical and Experimental Immunology, 175: 336–348

TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES Paraneoplastic neurological syndromes Table 1. Classical and non-classical paraneoplastic syndromes and diagnostic criteria [4]. Classical syndrome

Non-classical syndrome

Central nervous system Encephalomyelitis Limbic encephalitis Subacute cerebellar degeneration Opsoclonus–myoclonus syndrome

Brain stem encephalitis Optic neuritis Myelitis/necrotizing myelopathy Stiff-person syndrome and variants

Peripheral nervous system Subacute sensory neuronopathy Chronic intestinal pseudo-obstruction

Distal-symmetric sensorimotor neuropathy Polyradiculoneuropathy (acute/chronic) Multiplex mononeuropathy Pure autonomic neuropathies

Neuromuscular junction and muscle Lambert–Eaton myasthenic syndrome Dermatomyositis

Myasthenia gravis Neuromyotonia

Diagnostic criteria

Classical syndrome Non-classical syndrome

Well-characterized onconeural antibodies

Partially characterized onconeural antibodies/no cancer

No antibodies/high cancer risk

Definite Definite

Possible Possible

Possible Not applicable

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]. 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

Cancer detected Definite Possible (definite if improving after cancer treatment)

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 fluidattenuated 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


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TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES F. Leypoldt & K.-P. Wandinger 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 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 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 Vascular Optic neuritis LHON Toxic Alimentary: tobacco–alcohol–amblyopia 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 Metabolic: diabetes mellitus Immune-mediated: GBS, CIDP, Sjögren’s syndrome Hereditary: porphyria, mitochondriopathy Neurodegenerative: MSA-A Immune-mediated: myasthenia gravis Hereditary: episodic ataxia type 2 Toxic: botulism Toxic/metabolic: myopathies, e.g. steroids Immune-mediated: IBM, immune-mediated necrotizing myopathies

Limbic encephalitis (LE)

Opsoclonus–myoclonus syndrome

Retino-/opticopathy

Subacute sensory neuronopathy

Autonomic neuropathy

Lambert–Eaton myasthenic syndrome

Poly-/dermatomyositis

† 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.

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 338

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


TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES Paraneoplastic neurological syndromes Table 3. Syndromes of the central nervous system (CNS) and relevant well-characterized onconeural or neuronal cell-surface antibodies. Syndrome CNS

Subacute cerebellar degeneration 25% Encephalomyelitis 6% Limbic encephalitis 10% Opsoclonus–myoclonus syndrome (adults) 2% Retinopathy 1% Stiff-person syndrome 1%

Relevant antibodies Hu, Yo, CV2/CRMP5, Ri, Tr†, amphiphysin, VGCC Hu, CV2/CRMP5, amphiphysin Hu, Ma2, CV2/CRMP5, Ri, amphiphysin NMDAR, Lgi1‡, CASPR2‡, GABA(b)-, AMPA-, mGluR5, glyR‡, GAD‡ Ri, Hu, Ma/Ta, NMDAR Hu, CV2/CRMP5, recoverin Amphiphysin, glyR‡, GAD‡

†

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.

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. 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 nonCNS 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]. 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 nonimmunoglobulin (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 wellcharacterized antibodies; and (iii) non-classical syndrome and no well-characterized antibodies.


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TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES F. Leypoldt & K.-P. Wandinger 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 Anti-Yo (PCA-1) CDR2, CDR62 Paraneoplastic cerebellar degeneration Anti-CV2/CRMP5 CRMP5 Encephalomyelitis, polyneuropathy, optic neuritis, limbic encephalitis, choreatic syndromes, cerebellar degeneration MA-proteins Limbic encephalitis, rhombencephalitis, male>>female Anti-Ta/Ma2† Anti-Ri (ANNA-2) NOVA-1 Opsoclonus–myoclonus syndrome, rhombencephalitis, cerebellar degeneration, myelitis, jaw dystonia, laryngospasm Anti-amphiphysin Amphiphysin Stiff-person syndrome, limbic encephalitis, rhombencephalitis, cerebellar degeneration, polyneuropathy Anti-recoverin Recoverin Retinopathy Anti-SOX-1 (AGNA) SOX-1 Non-syndrome-specific

Lung cancer (85%), mostly SCLC, neuroblastoma, prostate carcinoma Ovarian, breast cancer SCLC, thymoma Testicular cancer Breast, ovarian carcinoma, SCLC Breast cancer, SCLC

SCLC 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).

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, agedependency and most probable tumour localization are suggested by the clinical syndrome and/or detected antibody (Tables 3, 4 and 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

Table 5. Recommended tumour screening adapted from Titulaer et al. [13]. Diagnostics Tumour

Primary

Secondary

Lung cancer

Thoracic CT (80–85%) thoracic MRI

FDG-PET or FDG-PET/CT

Thymoma Breast cancer Ovarian carcinoma Ovarian teratoma Testicular cancer

Thoracic CT (75–90%), thoracic MRI Mammography (80%), ultrasound Ultrasound (69–90%) + CA-125 Ultrasound (69–90%) Ultrasound (72%) + β-HCG, AFP

Lymphoma Skin tumours (Merkel-cell carcinoma)

Thoracic/abdominal CT, Ultrasound Dermatological examination, biopsy

FDG-PET or FDG-PET/CT Breast MRI Pelvic and abdominal CT MRI (93–98%) Pelvic/abdominal CT (76%), abdominal MRI FDG-PET or FDG-PET/CT

Tertiary Bronchoscopy/EB-US, possibly needle biopsy and/or mediastinoscopy

FDG-PET Thoracic CT (extra-pelvic teratomas) Possibly FDG-PET (malignant teratomas)

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

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© 2013 British Society for Immunology, Clinical and Experimental Immunology, 175: 336–348 30%

40% 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 344

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 antiNMDA 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 chemotherapyassociated 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 pseudochoreoathetotic 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, paraneo-


TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES Paraneoplastic neurological syndromes

plastic 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 (