Paraneoplastic neuropathy

Handbook of Clinical Neurology, Vol. 115 (3rd series) Peripheral Nerve Disorders G. Said and C. Krarup, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 41

Paraneoplastic neuropathy HARUKI KOIKE AND GEN SOBUE* Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

INTRODUCTION Neurological impairments in patients with malignancies can arise from a variety of factors, including chemotherapy, malnutrition, infection, direct tumor invasion into the nervous system, or a remote effect of the malignancy mediated via the immune system. This latter cause, known as paraneoplastic neurological syndrome, involves neurological symptoms or signs resulting from damage to parts of the nervous system that are remote from the site of a malignancy or its metastases (Denny-Brown, 1948; Henson et al., 1965; Krarup and Crone, 2002; Graus et al., 2004). This derangement can modulate function at any level of the neuromuscular system, including the central nervous system, peripheral nervous system, neuromuscular junction, and muscle itself (Voltz, 2002; Darnell and Posner, 2003; Graus et al., 2004). Thus, these syndromes are actually composed of a number of different clinicopathological entities, including encephalomyelitis, limbic encephalitis, cerebellar degeneration, opsoclonus-myoclonus, sensory neuronopathy, intestinal pseudo-obstruction, Lambert–Eaton myasthenic syndrome, and dermatomyositis, among others (Graus et al., 2004; Giometto et al., 2010). In some of these disorders, neuronal antigens expressed by the malignancy induce an immune response that results in an inappropriate recognition of endogenous nervous system elements as “foreign” (Darnell, 1996; Voltz, 2002; Darnell and Posner, 2003). The antibodies involved in such immune mechanisms are referred to as paraneoplastic or onconeural antibodies. Recent studies have characterized a multitude of new onconeural antibodies. Along with recent progress in serological screening for such onconeural antibodies and diagnostic imaging techniques to detect malignancies, the concept of paraneoplastic neurological

syndromes, including paraneoplastic neuropathy, has been broadened by integrating nonclassic clinical features (Graus et al., 2004). Definitive diagnosis of paraneoplastic neurological syndromes at an early clinical stage is important for a variety of reasons, including detection of occult malignancies, avoidance of unnecessary testing for other diseases, and immediate institution of therapy for cancers and paraneoplastic-mediated neurological compromise (Vedeler et al., 2006). Therefore, recognition of the wide clinical spectrum of paraneoplastic syndromes is important in this context. According to the Paraneoplastic Neurological Syndrome Euronetwork database (Giometto et al., 2010), the peripheral nervous system is the primary site of involvement in one-third of patients with paraneoplastic syndromes. Although a classic syndrome of subacute sensory neuronopathy is often present in patients with paraneoplastic neuropathy, there can also be extensive variation in the progression of neuropathy, pattern of neuropathy, degree of sensory, motor, and autonomic involvement, and presence or absence of specific onconeural antibodies (Graus et al., 2004; Giometto et al., 2010). In this chapter, we provide an overview of paraneoplastic neuropathy, with particular focus on its clinical variation and diagnostic aspects.

TYPES OF NEUROPATHY Sensory neuronopathy The most frequent entities encountered in patients with paraneoplastic neurological syndromes are paraneoplastic cerebellar degeneration and sensory neuronopathy (Giometto et al., 2010). Subacute sensory neuronopathy is the typical presentation and constitutes a classic form of paraneoplastic neurological syndrome (Graus et al., 2004). The primary pathological mechanism for

*Correspondence to: Gen Sobue, M.D., Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Fax: þ81-52-744-2384, E-mail: [email protected]

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subacute sensory neuronopathy is related to autoimmuneinduced impairments in sensory neuronal cell bodies in the dorsal root ganglia (Wanschitz et al., 1997; Ichimura et al., 1998), most often involving onconeural anti-Hu antibodies (Dalmau et al., 1992; Graus et al., 2001; Sillevis Smitt et al., 2002). However, other areas of the nervous system may be involved, resulting in encephalomyelitis, for example (Graus et al., 2001, 2004; Sillevis Smitt et al., 2002). Combined sensory and motor neuropathy, cerebellar degeneration, brainstem and limbic encephalitis, and clinical evidence of the Lambert–Eaton myasthenic syndrome or gastrointestinal pseudo-obstruction have also been reported in patients with anti-Hu antibodies (Heidenreich et al., 1995). Subacute sensory neuronopathy is most commonly associated with small cell lung cancer but may also occur in the context of other malignancies, including breast cancer, ovarian cancer, sarcoma, or Hodgkin lymphoma (Horwich et al., 1977; Gozzard and Maddison, 2010). Like other paraneoplastic syndromes, subacute sensory neuronopathy is seen more frequently in middle-aged and elderly patients (Chalk et al., 1992; Oki et al., 2007), and neuropathic symptoms precede the detection of cancer in a majority of cases (Dalmau et al., 1992; Graus et al., 2001).

CLINICAL FEATURES In the classic form of subacute sensory neuronopathy, the typical clinical course is characterized by a subacute onset and a wide range of sensory impairments particularly kinesthetic sensory loss leading to sensory ataxia (Denny-Brown, 1948; Horwich et al., 1977; Dalmau et al., 1992; Camdessanche´ et al., 2002). Sensory signs may be distributed in a symmetrical polyneuropathy pattern or in a multifocal pattern. These disturbances usually start distally and may sometimes mimic a polyneuropathy pattern, but careful history-taking and examination may reveal asymmetry in the neuropathy (Oki et al., 2007). In other cases, symptoms may arise in the face, scalp, trunk, hands, arms, or proximal legs before the feet, or sensory impairment may predominate in the arms rather than the legs. These features reflect the ganglionopathy of the dorsal root ganglia, rather than distally accentuated axonal neuropathy (Koike and Sobue, 2008; Koike et al., 2010a). Typically, sensory ataxia due to loss of proprioceptive and kinesthetic sensation is observed, and reflexes are generally absent. Pseudoathetosis in the hands and fingers and Romberg’s sign are seen, and strength is preserved or only mildly impaired. Although the classic form of subacute sensory neuronopathy is characterized by sensory ataxia, other reports have described patients with sensory symptoms that

manifest as pain, painful dysesthesia, or mechanical hyperalgesia without conspicuous sensory ataxia (Horwich et al., 1977; Dalmau et al., 1992; Oki et al., 2007). Indeed, a previous report of paraneoplastic sensory neuropathy categorized patients into two separate groups: patients that experienced ataxia, and patients that experienced pain (Oki et al., 2007). In the painful group, the primary complaints were severe pain and mechanical hyperalgesia, with some patients reporting impairments in deep sensation or kinesthetic sensation. Further, patients in the ataxic group occasionally complained of painful sensations or painful dysesthesia. These observations suggest that these two forms of paraneoplastic neuropathy may exist over a continuous spectrum of pathophysiological events, with predominant impairment of small sensory neuro-axons or large sensory neuro-axons at the extremes of the spectrum. No obvious differences in age of onset, gender distribution, initial progression rate, distribution pattern of sensory signs, frequency of associated autonomic signs, frequency and nature of autoantibodies, or spectrum and nature of the associated cancers were present when comparing these two forms of paraneoplastic sensory neuropathy, which supports the view that these entities share a common pathophysiological background (Oki et al., 2007). Although typical cases with sensory neuronopathy show pure sensory impairment (Koike et al., 2010a), studies of paraneoplastic neuropathy have shown that concomitant involvement of the motor and autonomic peripheral nervous system is frequent in subacute sensory neuronopathy (Denny-Brown, 1948; Antoine et al., 1998; Camdessanche´ et al., 2002; Nokura et al., 2006; Oki et al., 2007). This may manifest as severe motor weakness due to involvement of motor neurons in the anterior horn of the spinal cord (Nokura et al., 2006) or in the peripheral nerve trunk (Antoine et al., 1998; Camdessanche´ et al., 2002). Thus, involvement of motor functions does not exclude the possibility of subacute sensory neuronopathy (Graus et al., 2004). Autonomic symptoms, such as urinary retention, constipation, or orthostatic hypotension, may also occur in patients with subacute sensory neuronopathy (Oki et al., 2007). In a study of 20 patients with paraneoplastic neuropathy due to anti-Hu antibodies, neuropathy was classified as sensory in 70% of patients, sensorimotor in 25%, and motor in 5% (Camdessanche´ et al., 2002). In this series, somatic neuropathy was the only manifestation in 30% of patients, while autonomic neuropathy or central nervous involvement was present in the remainder of the population. Cerebrospinal fluid analysis in patients with paraneoplastic sensory neuronopathy may reveal elevated protein concentration, pleocytosis, and sometimes oligoclonal

PARANEOPLASTIC NEUROPATHY bands (Vedeler et al., 2006; Oki et al., 2007). Magnetic resonance imaging may show gadolinium enhancement of the spinal roots on T1-weighted images (Gozzard and Maddison, 2010).

ELECTROPHYSIOLOGICAL FEATURES Electrophysiological findings in subacute sensory neuronopathy typically consist of a reduction or an absence of sensory nerve action potential, with a normal or slightly reduced sensory conduction velocity and normal motor conduction velocity (Donofrio et al., 1989). However, more complex electrophysiological abnormalities may be present in patients with anti-Hu antibody neuropathy. In fact, detailed electrophysiological studies of patients with anti-Hu antibodies demonstrated that the typical pattern of subacute sensory neuronopathy was only rarely encountered and that motor nerve involvement and conduction abnormalities were frequently seen, even in the absence of a motor deficit (Camdessanche´ et al., 2002; Oh et al., 2005). Another study of paraneoplastic sensory neuropathy revealed that the reduction of compound muscle action potentials was more prominent in patients with pain symptoms than in those with ataxia (Oki et al., 2007).

PATHOLOGICAL FEATURES (FIGS. 41.1 AND 41.2) As stated earlier, the major lesions associated with subacute sensory neuronopathy are localized within the dorsal root ganglia (Fig. 41.1) (Denny-Brown, 1948; Horwich et al., 1977; Ohnishi and Ogawa, 1986; Donofrio et al., 1989; Dalmau et al., 1992; Ichimura et al., 1998). In a typical case with marked sensory ataxia, autopsy studies have shown marked loss of large sensory neurons in the dorsal root ganglia as well as the loss of predominantly large sensory axons in the central and peripheral rami (Denny-Brown, 1948; Henson et al., 1965; Horwich et al., 1977; Ohnishi and Ogawa, 1986; Donofrio et al., 1989; Dalmau et al., 1992; Ichimura et al., 1998). Lymphocytic infiltration, especially CD8-positive cytotoxic T cells, has also been noted in the dorsal root ganglia (Wanschitz et al., 1997; Ichimura et al., 1998). The severity of pathology may differ among individual dorsal root ganglia, manifesting as variable clinical features among patients (e.g., left–right or segmental difference in sensory impairment) (Ichimura et al., 1998). Even the lesions within the dorsal root ganglia tend to be circumscribed but multifocal (Ichimura et al., 1998). Lymphocytic infiltration into the endoneurium and demyelinated fibers have been found in nerve trunks (Antoine et al., 1998). Findings suggestive of vasculitis have also been reported in the nerve trunk of patients with anti-Hu antibodies and ataxia in the extremities, suggesting concomitant subacute sensory neuronopathy (Younger et al., 1994; Eggers et al.,

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1998). Lesions may extend to the sympathetic ganglia (Wanschitz et al., 1997; Ichimura et al., 1998). Sural nerve biopsy in patients with subacute sensory neuronopathy and marked sensory ataxia tend to show loss of predominantly large myelinated fibers (Fig. 41.2A). In contrast, biopsy in patients with predominant pain and less sensory ataxia symptoms show nerve fiber loss of small myelinated and unmyelinated fibers (Fig. 41.2B) (Oki et al., 2007). In the painful form of paraneoplastic sensory neuropathy, loss of the small dorsal root ganglia neuron occurs, which eventually leads to small fiber loss in peripheral nerves. This notion is consistent with the distribution of sensory impairment that suggests ganglionopathy and with scant regenerating fibers within biopsied specimens (Oki et al., 2007; Koike and Sobue, 2008).

Sensorimotor neuropathies As mentioned above, sensorimotor neuropathy represents a significant proportion of neuropathies associated with anti-Hu antibodies. However, published reports differ according to whether clinical or electrophysiological criteria are used to determine whether motor involvement is present (Lucchinetti et al., 1998; Graus et al., 2001; Camdessanche´ et al., 2002; Sillevis Smitt et al., 2002; Oh et al., 2005). Indeed, lower motor neuron involvement has been reported in patients with anti-Hu-associated paraneoplastic syndrome (Dalmau et al., 1992). Further, motor neuron degeneration in the spinal cord has been noted during autopsy (Dalmau et al., 1992; Verma et al., 1996) and is considered to be a common cause of motor deficit in patients with anti-Hu-associated paraneoplastic neuropathy. Some patients with anti-Hu antibodies may also have anti-CV2/CRMP-5 antibodies (Antoine et al., 2001; Camdessanche´ et al., 2002). According to a previous study of neuropathy associated with anti-Hu and antiCV2/CRMP-5 antibodies, patients with anti-Hu antibodies alone displayed subacute sensory neuronopathy, while those with anti-CV2/CRMP-5 antibodies experienced mixed axonal and demyelinating sensorimotor neuropathy. When both anti-Hu and anti-CV2/CRMP-5 antibodies were present, subacute sensory neuronopathy was superimposed on demyelinating sensorimotor neuropathy (Antoine et al., 2001). A host of other antibodies have been associated with paraneoplastic neuropathies. For example, a subacute motor axonal neuropathy with serum anti-GQ1b antibodies has also been reported in association with recurrent melanoma (Kloos et al., 2003), while a patient with B-cell lymphoma and anti-GM1 and GD1b antibodies had widespread weakness secondary to multifocal motor

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A

B

C

D

E

F

G

H

Fig. 41.1. Autopsy findings in a patient with subacute sensory neuronopathy. L4 dorsal root ganglia (A, B, and C), cervical spinal cord (D), L4 posterior spinal roots (E and F), and thoracic sympathetic ganglia (G and H). Sections were stained with hematoxylin and eosin (A, B, and C), toluidine blue (E and F), and the Kl€ uver–Barrera method (D, G, and H). Although neurons were relatively preserved in one side of the dorsal root ganglion (A), those in the other side were severely depleted and Nageotte’s nodules (arrowheads) were observed (B). Perivascular inflammatory infiltrates were found in the dorsal root ganglia (C). On a cross-section of the cervical spinal cord, the lateral and ventral areas had a normal appearance, while the dorsal tracts were heavily damaged due to the loss of myelinated fibers (D). The degree of the reduction of myelinated fibers in the posterior spinal roots corresponds to the reduction of neurons in the dorsal root ganglia (E to A and F to B). Neurons were preserved in some thoracic sympathetic ganglia (G) but severely reduced in others (H). Scale bars ¼ 50 mm (A, B, G, and H) and 20 mm (C, E, and F).

neuropathy with conduction block (Noguchi et al., 2003). In another report, a patient with pure lower motor neuron syndrome and breast cancer had antibodies against beta IV spectrin in initial axon segments and in nodes

of Ranvier (Berghs et al., 2001). Finally, a patient with small cell lung cancer who experienced rapid onset of tetraplegia and respiratory failure mimicking Guillain– Barre´ syndrome (GBS) did not have anti-Hu antibodies

PARANEOPLASTIC NEUROPATHY

A

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B

Fig. 41.2. Sural nerve biopsy findings in patients with paraneoplastic neuropathy. Transverse sections were stained with toluidine blue. (A) In a patient with subacute sensory neuronopathy and marked sensory ataxia, large myelinated fibers were severely reduced when compared with small myelinated fibers. (B) In a patient with predominant pain and less sensory ataxia symptoms, large myelinated fibers were relatively preserved, while small myelinated fibers were markedly reduced. No axonal sprouting was observed in either A or B. Scale bar ¼20 mm.

or antiganglioside antibodies (Nokura et al., 2006) but did have infiltration of T cells into the dorsal root ganglia and loss of spinal anterior horn cells on autopsy, which suggested the presence of both motor and sensory neuronopathy. In addition to the neuropathies described above, other rare types of neuropathy, including GBS, chronic inflammatory demyelinating polyneuropathy (CIDP), brachial plexopathy, or vasculitic neuropathy, can also occur as paraneoplastic syndrome and manifest as sensory-motor neuropathy.

GUILLAIN–BARRE´ SYNDROME GBS is an immune-mediated neuropathy characterized by rapidly ascending muscle weakness or paralysis accompanied by absent or depressed deep tendon reflexes and elevated cerebrospinal fluid protein levels (Hughes and Cornblath, 2005). Most cases of GBS are preceded by vaccination or by respiratory or gastrointestinal infections, but this phenomenon may also occur in the setting of malignancies. Whether GBS arises as a result of the underlying cancer or whether this is simply a chance association is still under debate (Giometto et al., 2010). Regardless, GBS has been more commonly associated with lymphomas (Lisak et al., 1977; Vallat et al., 1995; Grigg et al., 1998) as well as various kinds of solid tumors, such as small cell lung cancer (Nokura et al., 2006), breast cancer (Rojas-Marcos et al., 2003), renal cell carcinoma (Alimonti et al., 2003), hepatocellular carcinoma (Camdessanche´ et al., 2002), tongue carcinoma (Antoine et al., 1999), ovarian dysgerminoma (Ivanaj et al., 2003), and esophageal carcinoma (Zilli and Allal, 2011).

In one report, nine of 435 patients with GBS had been diagnosed with cancer in the 6 months preceding or following onset of the neurological disorder (Vigliani et al., 2004), which is a higher rate of cancer than expected. Five patients had electrophysiological findings consistent with acute inflammatory demyelinating polyneuropathy, two with acute motor axonal neuropathy, one with acute motor sensory axonal neuropathy, and one was not characterized. Three patients had non-small cell lung cancer, and the remainder of the patients had chronic lymphocytic leukemia, Hodgkin lymphoma, metastatic disease of unknown primary, kidney cancer, esophageal cancer, or vocal cord cancer. Acute mortality was significantly higher in patients with GBS and cancer when compared with those with GBS alone.

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a demyelinating disorder defined as chronically progressive, stepwise, or recurrent neuropathy manifesting with symmetrically proximal and distal weakness and sensory dysfunction of all extremities, developing over at least 2 months (Joint Task Force of the EFNS and the PNS, 2010a). Some patients with paraproteinemia due to plasma cell dyscrasias develop demyelinating neuropathy that is indistinguishable from CIDP, and there is no consensus as to whether these entities should be considered the same or different disease processes (Joint Task Force of the EFNS and the PNS, 2010b).

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Paraneoplastic neuropathy with anti-CV2/CRMP-5 antibodies may develop demyelinating neuropathy with slow progression (Antoine et al., 2001). Patients manifesting findings compatible with CIDP without anti-CV2/CRMP-5 antibodies have been reported in association with adenocarcinoma of the pancreas, colon, and liver (Antoine et al., 1996), breast cancer (RojasMarcos et al., 2003), malignant melanoma (Bird et al., 1996), and renal cell carcinoma (Allen et al., 2011). CIDP-like neuropathies have also been reported in patients with hematological malignancies (Griggs et al., 1997; Viala et al., 2008; Isoda et al., 2009).

BRACHIAL PLEXOPATHY Some cases of brachial plexopathy are believed to be immune-mediated (van Alfen and van Engelen, 2006), with a small number of cases occurring in the context of paraneoplastic syndromes (Pezzimenti et al., 1973; Lachance et al., 1991; Enright et al., 1995; Lucchinetti et al., 1998; Coppens et al., 2006). Brachial plexopathy may occur with hematological malignancies, particularly Hodgkin’s lymphoma (Pezzimenti et al., 1973; Lachance et al., 1991; Enright et al., 1995), and has been reported as an initial neurological manifestation in two of 143 patients with anti-Hu antibodies (Lucchinetti et al., 1998). Other studies have documented brachial plexopathy followed by sensorimotor neuropathy and associated with anti-amphiphysin antibodies (Coppens et al., 2006). However, brachial plexopathy (or lumbosacral plexopathy) may arise from direct invasion by tumors or secondary to antineoplastic radiation therapy (Krarup and Crone, 2002).

VASCULITIC NEUROPATHY Vasculitis can occur in association with malignancies (Greer et al., 1988). In a study of 60 patients with vasculitides associated with malignancies, observed clinical manifestations were, in order of frequency: cutaneous involvement, arthralgias, fever, peripheral neuropathy, renal involvement, and positive anti-neutrophil cytoplasmic antibody (Fain et al., 2007). Further, peripheral neuropathy was seen in 19 of 60 patients. Although vasculitis is more frequent with hematological malignancies than with solid malignancies, vasculitisassociated peripheral neuropathy is more common in solid tumors than in hematological malignancies (Fain et al., 2007). In a retrospective study of 40 patients with histopathologically proven vasculitic neuropathy, a relatively high incidence of various types of malignancies was observed; six patients with vasculitic neuropathies developed a malignancy within 2 years from the onset of neuropathy, which suggests an association between these two entities (Zivkovic´ et al., 2007). Although paraneoplastic vasculitic neuropathy usually occurs in a mononeuritis multiplex pattern

(Johnson et al., 1979; Oh et al., 1991; Blumenthal et al., 1998; Antoine et al., 1999; Turner et al., 2003), it can also occur in a symmetrical polyneuropathy pattern in a minority of cases (Vincent et al., 1986). Concomitant autonomic dysfunction or sensory ataxia may be present (Younger et al., 1994; Eggers et al., 1998), as may anti-Hu antibodies in some cases (Younger et al., 1994; Eggers et al., 1998; Ansari et al., 2004), but not in others (Oh et al., 1991; Antoine et al., 1999).

Autonomic neuropathies Autoimmune autonomic ganglionopathy and chronic intestinal pseudo-obstruction have been established as a subgroup of autonomic neuropathies and may sometimes be associated with malignancies (Vernino et al., 2008; Sandroni and Low, 2009). Like other paraneoplastic neuropathies, autonomic neuropathy may overlap with other entities. For example, autonomic dysfunction may be seen in patients with subacute sensory neuronopathy (Oki et al., 2007). Anti-Hu, anti-CV2/CRMP-5, and anti-ganglionic acetylcholine receptor (AchR) antibodies are frequently associated with autonomic neuropathy. In fact, features suggestive of autonomic neuropathy are seen in approximately 30%, 31%, and 21% of patients seropositive for these antibodies, respectively (Lucchinetti et al., 1998; Yu et al., 2001; McKeon et al., 2009). Recognition of paraneoplastic autonomic neuropathy is also important for prognostic reasons. Although malignancy is the main cause of death in patients with paraneoplastic neurological syndromes, patients with autonomic dysfunction tend to have a poorer prognosis (Giometto et al., 2010).

AUTOIMMUNE AUTONOMIC GANGLIONOPATHY Before being established as a defined disease entity, autoimmune autonomic ganglionopathy was variably referred to as acute pandysautonomia, autoimmune autonomic neuropathy, idiopathic autonomic neuropathy, or subacute autonomic neuropathy (Klein et al., 2003; Vernino et al., 2008). The anti-ganglionic AchR antibody is a serological marker for autoimmune autonomic ganglionopathy, and 50% of patients with autoimmune autonomic ganglionopathy are positive for anti-ganglionic AchR antibody (Klein et al., 2003; Vernino et al., 2008). This disease is frequently associated with paraneoplastic syndrome (Vernino et al., 2000), but standard autonomic testing is unable to differentiate paraneoplastic autoimmune autonomic ganglionopathy from nonparaneoplastic autoimmune autonomic ganglionopathy (Vernino, 2009). Patients with autoimmune autonomic ganglionopathy typically show monophasic progression evolving to peak severity within a few days to weeks (Vernino et al., 2008; Sandroni and Low, 2009). While most cases of

PARANEOPLASTIC NEUROPATHY autoimmune autonomic ganglionopathy show an acute or subacute course to reach its nadir similar to the somatic counterpart, GBS, some cases can occur with a chronic course resembling that of pure autonomic failure (Klein et al., 2003; Vernino et al., 2008; Sandroni and Low, 2009; Koike et al., 2010b).

CHRONIC INTESTINAL PSEUDO-OBSTRUCTION Chronic intestinal pseudo-obstruction is a dysmotility syndrome that presents with signs and symptoms of intestinal obstruction and radiographical evidence of dilated bowels without any evidence of anatomical obstruction (Chinn and Schuffler, 1988; Lennon et al., 1991). Features can include severe gastroparesis, intestinal pseudoobstruction, esophageal dysmotility (including achalasia), or any combination of these (Lucchinetti et al., 1998; Vernino, 2009), and clinical presentation often consists of nausea, vomiting, early satiety, bloating, abdominal pain, constipation, and secondary weight loss (Vernino, 2009). Pathologically, paraneoplastic enteric neuropathy has been associated with a destructive inflammatory process affecting the myenteric ganglia. In postmortem or surgical samples of the gut, examination of the enteric plexus has revealed lymphocytic infiltration as well as a reduction in the numbers of neurons and axons (Chinn and Schuffler, 1988; Jun et al., 2005). Five to 10% of patients with chronic gastrointestinal pseudo-obstruction test positive for the anti-ganglionic AchR antibody (Vernino et al., 2000, 2008). Patients with anti-ganglionic AchR antibody positivity have more prominent cholinergic dysfunction and gastrointestinal symptoms than seronegative patients, which suggests that chronic gastrointestinal pseudo-obstruction could be yet another autonomic variant of autoimmune autonomic ganglionopathy (Sandroni and Low, 2009). In a previous study of 24 patients who presented with gastrointestinal dysmotility as the major symptom and were found to have one or more autoantibody on serological testing, 11 of the 24 were seropositive for the anti-ganglionic AchR antibody (Dhamija et al., 2008). Serological positivity was present in either the paraneoplastic or idiopathic forms. Among patients with antiHu antibodies, more than 10% had a paraneoplastic syndrome manifesting only as gastrointestinal dysmotility (Lucchinetti et al., 1998). Thymoma-associated gastric pseudo-obstruction with antibodies to voltage-gated potassium channels and neuromyotonia has also been reported (Viallard et al., 2005).

ANTIBODIES ASSOCIATED WITH PARANEOPLASTIC NEUROPATHY Onconeural antibodies can be associated with a number of different neurological manifestations but are typically highly specific for the presence of cancer and

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predictive of the type of cancer (Pittock et al., 2004). Different onconeural antibodies may also be present within a single patient (Pittock et al., 2004), but no onconeural antibody may be identified in patients with paraneoplastic neurological syndromes (Candler et al., 2004). The Paraneoplastic Neurological Syndrome Euronetwork defined six antibodies (anti-Hu, Yo, CV2/CRMP-5, Ri, Ma2, or amphiphysin) as being “well characterized,” and recommended that a patient with idiopathic neurological symptoms and seropositivity for any of these antibodies should be defined as having a definite paraneoplastic syndrome, regardless of whether an underlying malignancy is found (Graus et al., 2004). Among these antibodies, anti-Hu and CV2/CRMP-5 antibodies deserve particular attention, because they are much more frequently associated with paraneoplastic neuropathy.

Anti-Hu antibodies Anti-Hu antibody (also known as antineuronal nuclear antibody-type 1, ANNA-1) was the first recognized autoantibody marker of small cell lung cancer (Graus et al., 1985). In a previous study of 162 consecutive patients with anti-Hu antibodies, malignancy was present in 88% of patients, being small cell lung cancer in 93% (Lucchinetti et al., 1998). Although patients with antiHu antibodies show a wide range of paraneoplastic neurological manifestations, including cerebellar ataxia, limbic encephalitis, myelopathy, Lambert–Eaton syndrome, and myopathy, peripheral neuropathy is the most common manifestation and present in 60 to 80% of patients (Dalmau et al., 1992; Lucchinetti et al., 1998; Graus et al., 2001; Sillevis Smitt et al., 2002). In fact, the estimated specificity and sensitivity of antiHu antibody for sensory neuropathy of paraneoplastic etiology is 99% and 82%, respectively (Molinuevo et al., 1998). Aside from the conventional sensory ataxic form of paraneoplastic sensory neuronopathy, the painful form of paraneoplastic sensory neuropathy may also be associated with anti-Hu antibody positivity (Oki et al., 2007). Furthermore, approximately 30% of patients with anti-Hu antibodies have some features of dysautonomia, the most common being chronic gastrointestinal pseudoobstruction (Lucchinetti et al., 1998).

Anti-CV2/CRMP-5 antibodies Collapsing-response mediator proteins (CRMP) are a family of neuronal cytoplasmic proteins present in adult central and peripheral neurons and in small cell lung carcinomas (Honnorat et al., 1996; Yu et al., 2001). Antibodies against these proteins are associated with a wide variety of paraneoplastic syndromes, such as neuropathy, cerebellar ataxia, dementia, and Lambert– Eaton syndrome (Yu et al., 2001). According to a previous study of 116 patients seropositive for anti-CV2/

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CRMP-5 antibodies, peripheral neuropathy, usually axonal sensorimotor type, was the most common form of neurological derangement and was present in 47% of patients (Yu et al., 2001). By contrast, autonomic neuropathy was present in 31% of patients. Lung carcinoma, mostly small cell type, was ultimately found in 77% of patients with anti-CV2/CRMP-5 antibodies. Unlike anti-Hu antibodies, anti-CV2/CRMP-5 antibodies cross-react with antigens in the peripheral nerve trunk (Antoine et al., 2001). Findings suggestive of demyelination and axonal degeneration have also been reported in biopsy specimens from patients with antiCV2/CRMP-5 antibodies (Antoine et al., 2001).

Other antibodies In a study of 55 patients with paraneoplastic cerebellar degeneration associated with anti-Yo antibody, 26 had hyporeflexia or mild distal sensory complaints, suggesting the superimposition of neuropathy (Peterson et al., 1992). In contrast to the pan-neuronal cross-reactivity of anti-Hu antibody, Anti-Ri antibody (also known as ANNA-2) immunoreactivity has not been detected in peripheral neurons. Regardless, one study reported that seven of 31 patients with anti-Ri antibodies had peripheral neuropathy (Pittock et al., 2003). Three among these seven patients were also seropositive for ANNA-1 autoantibodies. Another study reported that patients with antiamphiphysin antibody had the following neurological manifestations (in order of decreasing frequency): neuropathy, encephalopathy, myelopathy, stiff-man phenomena, and cerebellar syndrome (Pittock et al., 2005). In 63 patients with anti-amphiphysin antibodies, sensory neuropathy was present in 14, sensorimotor neuropathy was present in 11, motor neuropathy was present in two, and polyradiculopathy was present in four. There has also been progress in characterizing the involvement of anti-ganglionic AchR antibody in autonomic neuropathies. The anti-ganglionic AchR antibody recognizes the alpha3 subunit of AchR, which is expressed in neurons of the sympathetic, parasympathetic, and enteric ganglia (Vernino et al., 2008). Although this antibody has been recognized as a marker for autonomic neuropathy, especially autoimmune autonomic ganglionopathy, malignancy is found in about 30% of seropositive patients (Vernino et al., 2000; McKeon et al., 2009). In a study of 155 patients who were seropositive for anti-ganglionic AchR antibodies, 21% of patients manifested autonomic dysfunction (McKeon et al., 2009). Other neurological findings included those consistent with central nervous system involvement (17%), sensorimotor neuropathy (28%), and myasthenia gravis (3%)

(McKeon et al., 2009). Further, patients with high antibody titers tended to show more profound autonomic neuropathy (Vernino et al., 2000; Klein et al., 2003). Other paraneoplastic-related autoantibodies have been characterized. For example, sensorimotor neuropathy was also reported in four of 11 patients who were seropositive for ANNA-3 (Chan et al., 2001). AntiSOX1 antibodies were found in five of 32 patients with paraneoplastic sensory or sensorimotor neuropathy, and three of these patients were seropositive for the anti-Hu antibody (Tschernatsch et al., 2010). Case reports have also suggested an association between the anti-Trk (high-affinity nerve growth factor receptor) antibody and sensory neuropathy in a patient with non-Hodgkin lymphoma (Mutoh et al., 2005), and between synaptophysin and sensorimotor and autonomic neuropathy in a patient with small cell lung cancer (Tschernatsch et al., 2008). Finally, in a study of 72 patients with antibodies to voltage-gated potassium channels, clinical signs of peripheral neuropathy were observed in 10 patients (Tan et al., 2008). Four of these 10 patients simultaneously manifested peripheral nerve hyperexcitability, and autonomic dysfunction was present in 24 patients out of the entire study population.

PATHOGENESIS Most or all paraneoplastic neurological disorders are immune-mediated (Darnell and Posner, 2003) and arise from tumors that express neuronal proteins or crossreacting antigens (Voltz, 2002). Onconeural antibodies likely underlie the pathogenesis of paraneoplastic neurological disorders by inducing cell-mediated damage to neurons and axons (Darnell, 2004). The histological features of tumors in paraneoplastic neurological disorders may have heavier infiltration of lymphocytes (Cooper et al., 2001). Previous reports have suggested that some paraneoplastic neurological disorders were associated with a better prognosis when compared with patients with histologically identical tumors that were not associated with paraneoplastic neurological disorders (Altman and Baehner, 1976; Keime-Guibert et al., 1999; Maddison et al., 1999). In patients with paraneoplastic sensory neuronopathy, inflammatory cell infiltration in the dorsal root ganglia (Denny-Brown, 1948; Henson et al., 1965; Horwich et al., 1977; Dalmau et al., 1992; Antoine et al., 1998; Ichimura et al., 1998) and peripheral nerve endoneurium (Antoine et al., 1998), as well as the findings suggestive of vasculitis in the nerves and muscles (Younger et al., 1994; Eggers et al., 1998), strongly suggests an immune-mediated mechanism. Destruction of dorsal root ganglion cells due to lymphocytic infiltration, especially CD8-positive cytotoxic T cells, has been

PARANEOPLASTIC NEUROPATHY postulated as a cause of characteristic sensory ataxia in subacute sensory neuronopathy (Wanschitz et al., 1997; Ichimura et al., 1998; Tanaka et al., 1999). Observations from Graus et al. (1985) that high titers of anti-Hu antibodies were present in patients with subacute sensory neuronopathy suggest that Hu antigens expressed in tumor cells may trigger immune-mediated damage to the dorsal root ganglia. However, passive transfer of these antibodies or immunization has failed to reproduce the disease in animals (Sillevis Smitt et al., 1995). In addition, in spite of a wide expression of Hu antigen in the nervous system, including the brain, spinal cord, dorsal root ganglia, and sympathetic ganglia (Dalmau et al., 1991; Yamada et al., 1994; Ichimura et al., 1998), lesions tend to be confined to rather restricted areas in the nervous system depending on the individual patients (Ichimura et al., 1998). A recent study found two types of CD8-positive T cells specific to Hu antigen in patients with anti-Hu antibodies: classic cytotoxic CD8-positive T cells and atypical noncytotoxic CD8-positive T cells (Roberts et al., 2009). Further, small cell lung cancer produced cytokines that caused naive CD8-positive T cells to adopt the atypical noncytotoxic phenotype. These observations suggest that small cell lung cancer may evade tumor immune surveillance by skewing tumor antigen-specific T cells to this unusual noncytotoxic phenotype, providing an explanation for variation of clinicopathological features in anti-Hu antibody-associated paraneoplastic neurological syndromes.

DIAGNOSIS In 2004, the Paraneoplastic Neurological Syndrome Euronetwork suggested two levels of diagnostic evidence to define a neurological syndrome as paraneoplastic: “definite” and “possible” (Graus et al., 2004). Criteria for definite paraneoplastic neurological syndromes were: (1) a classic syndrome and cancer that develops within 5 years of the diagnosis of the neurological disorder; (2) a nonclassic syndrome that resolves or significantly improves after cancer treatment without concomitant immunotherapy, provided that the syndrome is not susceptible to spontaneous remission; (3) a nonclassic syndrome with onconeural antibodies (well characterized or not) and cancer that develops within 5 years of the diagnosis of the neurological disorder; and (4) a neurological syndrome (classic or not) with well-characterized onconeural antibodies (anti-Hu, Yo, CV2, Ri, Ma2, or amphiphysin) and no cancer. Criteria for possible paraneoplastic neurological syndromes were: (1) a classic syndrome, no onconeural antibodies, no cancer but at high risk of having an underlying tumor; (2) a neurological syndrome (classic or not) with partially

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characterized onconeural antibodies and no cancer; and (3) a nonclassic syndrome, no onconeural antibodies, and cancer present within 2 years of diagnosis. With regard to paraneoplastic neuropathy, only subacute sensory neuronopathy and chronic intestinal pseudo-obstruction were classified as “classic” (Graus et al., 2004). Multiple autoantibodies may be found within a single patient, and the distinct profile of autoantibodies may aid to predict the site of cancer, rather than a specific neurological syndrome (Pittock et al., 2004). For example, anti-Hu antibodies are strongly associated with small cell lung cancer (Lucchinetti et al., 1998).

Detection of malignancy Tumor detection is frequently difficult in patients with paraneoplastic neurological syndromes, most of whom have either small tumors or tumors limited to metastatic lymph nodes (Dalmau et al., 1992; Lucchinetti et al., 1998). For example, thoracic computed tomography (CT) imaging or magnetic resonance imaging is commonly used to detect the tumor in patients with anti-Hu antibodies, but no tumor can be identified at the initial evaluation in 50 to 60% of cases, probably because the tumor is too small to be detected by these methods (Chartrand-Lefebvre et al., 1998; Lucchinetti et al., 1998). When paraneoplastic neurological syndromes are suspected and no cancer is found in response to routine investigation, a whole body fluorodeoxyglucose positron emission tomography (FDG-PET) scan may reveal the malignancy (Antoine et al., 2000; Rees et al., 2001; Younes-Mhenni et al., 2004; Titulaer et al., 2011). A recent review recommends that if initial thoracic CT imaging is negative, then FDG-PET should be conducted to screen for small cell lung cancer in patients with classic paraneoplastic neurological syndrome and onconeural antibodies (Titulaer et al., 2011). If this screening is negative, repeat screening should be conducted at 3 or 6 months and then every 6 months for 4 years (Titulaer et al., 2011).

TREATMENT Recognition and diagnosis of paraneoplastic neurological syndrome is important as neurological symptoms usually predate direct symptoms of the primary tumor, and treatment at an earlier stage provides better chances of a good outcome (Graus et al., 2001; Titulaer et al., 2011). Treatment of malignancy is the mainstay of the management of paraneoplastic syndromes, and a complete response to this treatment has a favorable influence on the course of neurological symptoms (Keime-Guibert et al., 1999; Durmus¸ et al., 2010; Murakami et al., 2010; Allen et al., 2011; Zilli and Allal, 2011). To directly address neuropathic symptoms, immunomodulatory

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treatment may also be indicated (Oh et al., 1997; KeimeGuibert et al., 2000; Graus et al., 2001), and has been used even when the underlying malignancy cannot be identified (Sadeghian and Vernino, 2010). Although there have been no placebo-controlled clinical trials, previous reports suggested the efficacy of intravenous immunoglobulin (Graus et al., 2001; Uchuya et al., 1996), plasma exchange (Vernino et al., 2004), corticosteroids (Oh et al., 1997), rituximab (Shams’ili et al., 2006), a combination of intravenous immunoglobulin, cyclophosphamide, and methylprednisolone (Keime-Guibert et al., 2000). Patients presenting with subacute sensory neuronopathy tend to show better response to immunomodulatory treatment when compared with patients with other classic paraneoplastic neurological syndromes (Uchuya et al., 1996; Keime-Guibert et al., 2000; Graus et al., 2001; Vernino et al., 2004). A recent study suggested that human chorionic gonadotropin also has immunomodulatory activity and improves the course of paraneoplastic neurological syndromes associated with anti-Hu antibodies, including sensory neuronopathy (van Broekhoven et al., 2010). Patients presenting with features of GBS or CIDP should be treated according to the established guidelines for these diseases (Voltz, 2002). Treatment of GBS includes intravenous immunoglobulin and plasma exchange (Hughes and Cornblath, 2005). Response to therapy in GBS patients with malignancy was similar to that seen in those without malignancy (Antoine et al., 1999). Patients with features of CIDP responded to immunosuppressive therapy (Antoine et al., 1996, 1999). In patients with paraneoplastic vasculitic neuropathy, response to immunosuppressive therapy also has been reported (Oh et al., 1991; Antoine et al., 1999). Symptomatic treatment should also be considered in patients with neuropathic pain, sensory ataxia, and dysautonomic manifestations, such as orthostatic hypotension (Voltz, 2002; Vedeler et al., 2006).

CONCLUSIONS Recent progress in serological screening of paraneoplastic antibodies and in diagnostic imaging techniques to detect malignancies has enabled a broadening of the concept of paraneoplastic neurological syndromes, including paraneoplastic neuropathy, by integrating nonclassic clinical features. The classic feature of paraneoplastic neuropathy is subacute sensory neuronopathy. Destruction of dorsal root ganglion cells due to lymphocytic infiltration, especially with CD8-positive cytotoxic T cells, has been postulated to mediate subacute sensory neuronopathy. In addition, sensorimotor neuropathies, such as GBS, CIDP, brachial plexopathy, and vasculitic neuropathy,

are sometimes observed. Some studies also describe the occurrence of autonomic neuropathies, including autoimmune autonomic ganglionopathy and chronic intestinal pseudo-obstruction. Various onconeural antibodies, including anti-Hu, anti-CV2/CRMP-5, and anti-ganglionic AchR antibodies, are associated with neuropathy. Somatic neuropathy is the most common manifestation in patients with anti-Hu and anti-CV2/CRMP-5 antibodies, while antiganglionic AchR antibody is associated with autonomic neuropathies. A whole-body FDG-PET scan may be useful to detect malignancy in patients with unremarkable conventional radiological findings. Recognition of the variable manifestations of paraneoplastic neuropathy is important, as neuropathic symptoms usually precede the identification of the primary tumor, and treatment at an earlier stage provides better chances of good outcomes. Immunomodulatory treatment before, during, or after antineoplastic therapy may be of benefit for patients with paraneoplastic neuropathy and has been used even when the underlying malignancy cannot be identified.

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