revue neurologique 170 (2014) 570–576
Available online at
International meeting of the French society of neurology 2014
Peripheral neuropathies associated with antibodies directed to intracellular neural antigens Neuropathies pe´riphe´riques associe´es aux anticorps dirige´s contre des antige`nes intracellulaires neuronaux J.-C. Antoine Service de neurologie, CHU de Saint-E´tienne, 42055 Saint-E´tienne cedex, France
Antibodies directed to intracellular neural antigens have been mainly described in
Received 18 July 2014
paraneoplastic peripheral neuropathies and mostly includes anti-Hu and anti-CV2/
Accepted 31 July 2014
CRMP5 antibodies. These antibodies occur with different patterns of neuropathy. With
Available online 4 September 2014
anti-Hu antibody, the most frequent manifestation is sensory neuronopathy with frequent autonomic involvement. With anti-CV2/CRMP5 the neuropathy is more frequently
sensory and motor with an axonal or mixed demyelinating and axonal electrophysiolo-
gical pattern. The clinical pattern of these neuropathies is in keeping with the cellular
distribution of HuD and CRMP5 in the peripheral nervous system. Although present in
high titer, these antibodies are probably not directly responsible for the neuropathy.
Pathological and experimental studies indicate that cytotoxic T-cells are probably the
main effectors of the immune response. These disorders contrast with those in which
antibodies recognize a cell surface antigen and are probably responsible for the disease.
The neuronal cell death and axonal degeneration which result from T-cell mediated
immunity explains why treating these disorders remains challenging. # 2014 Elsevier Masson SAS. All rights reserved.
Immunology Mots cle´s : Neuropathie periphe´rique Neuronopathie sensitive Syndromes neurologiques parane´oplasiques Anticorps anti-Hu Anticorps anti-CV2 Anticorps anti-CRMP5 Cellules T Immunologie
r e´ s u m e´ Des anticorps dirige´s contre des antige`nes intracellulaires du syste`me nerveux pe´riphe´rique ont e´te´ principalement de´crits dans le cadre des syndromes neurologiques parane´oplasiques et incluent les anticorps anti-Hu et anti-CV2/CRMP5. Avec l’anticorps anti-Hu la neuropathie sensitive est la plus fre´quente des manifestations cliniques. Elle est fre´quemment associe´e a` une atteinte du syste`me nerveux autonome. Avec l’anticorps anti-CV2/ CRMP5 la neuropathie est fre´quemment sensitivomotrice avec un profil e´lectrophysiologique axonal ou axono-mye´linique. Les manifestions cliniques de ces neuropathies sont conformes a` la distribution cellulaire dans le syste`me nerveux pe´riphe´rique d’HuD et de CRMP5. Bien que pre´sents en titre e´leve´, ces anticorps ne sont probablement pas directement responsables de la neuropathie. Des e´tudes anatomopathologies et expe´rimentales
E-mail address: [email protected]
. http://dx.doi.org/10.1016/j.neurol.2014.07.002 0035-3787/# 2014 Elsevier Masson SAS. All rights reserved.
revue neurologique 170 (2014) 570–576
indiquent que les cellules T cytotoxiques sont probablement les principaux effecteurs de la re´ponse immune. Ces maladies s’opposent donc a` celles au cours desquelles des anticorps reconnaissant des antige`nes de la surface cellulaire provoquent probablement le processus pathologique. La mort neuronale et la de´ge´ne´rescence axonale qui re´sultent de l’activation de l’immunite´ cellulaire me´die´e par les cellules T expliquent que le traitement de ces neuropathies reste difficile. # 2014 Elsevier Masson SAS. Tous droits re´serve´s.
Recent developments have identify a series of antibodies directed toward cell surface antigens such as ion channels, neurotransmitter receptors or proteins associated with them leading to the characterization of new clinical entities. The most fascinating aspect of these developments is that there is an increasing number of evidences demonstrating that these antibodies play a crucial role in the pathophysiology of these disorders . Antibodies directed toward cell surface antigens have long ago been identified in diseases of the neuromuscular junction (anti-Acetylcholine receptors antibodies in myasthenia gravis or anti-voltage gated calcium channel antibodies in the Lambert-Eaton myasthenic syndrome) and in several forms of dysimmune peripheral neuropathies . Such is the case of monoclonal IgM directed to the myelin associated glycoprotein (MAG) or IgG or IgM antibodies reacting with gangliosides. All these antigens are located on myelin or axonal membranes and can be accessible to auto-antibodies. Animal models have similarly demonstrated that for both the neuromuscular junction and the peripheral nerve, these antibodies are responsible for the disorder. More recently antibodies reacting with surface proteins of the nodal and paranodal regions have been identified in variants of chronic of inflammatory demyelinating polyneuropathies but it is not known whether these antibodies are pathogenic or not . In opposition with cell surface-antibodies there exist another category of antibodies, which recognize intracellular antigens. These antibodies have been described in the context of paraneoplastic neurological syndromes (PNS). In contrast with the previous category, more than 90% of patients harboring these antibodies have a tumor, mostly a small cell lung cancer (SCLC), while cancer is inconstant or absent with the previous group. Another striking difference is that it was not possible to demonstrate that these antibodies are pathogenic living open the question as to whether they are only biomarkers of the underlying tumor. Two main antibodies reacting with intracellular antigens are associated with peripheral nervous system disorders, namely the anti-Hu and anti-CV2/CRMP5 antibodies.
2. Sensory neuronopathy and other peripheral nervous system disorders associated with anti-Hu antibodies Anti-Hu antibodies react with HuD a neuronal specific mRNA binding protein, which is expressed in all categories of
neurons in the central and peripheral nervous system , and in autonomic structures including the digestive tract. In sensory neurons HuD is located in the nucleus and in the cytoplasm in mitochondria and the Golgi apparatus where it may enable mRNA interactions with sub-cellular organelles and regulate their cellular localization . It also interacts with SMN in motor neurons, which may facilitate the localization of mRNAs into motor axons . HuD is expressed by most of small cell lung cancers in a normal non-mutated form  and it is commonly admitted that it is the recognition of the protein by the immune system in a tumor context that leads to the development of the neurological syndrome. This may be facilitated by an expression of the protein at the cell surface both in tumors and neurons as it has at least been showed in vitro . However, HuD although belonging to the repertory of antigens normally recognized by circulating T-cells  shows a high degree of immune tolerance  which probably explains that only a very few patients with SCLC develop a PNS and that autoimmune disorders directed against HuD are extremely rare in patients, mainly children, who never develop cancer even after several years of follow-up . Patients with anti-Hu antibodies show a wide spectrum of neurological disorders involving the central, peripheral and autonomic nervous systems  but the most frequent manifestation occurring in more than half of the patients is sensory neuronopathy (SNN) (Graus et al., 2001). This disorder depends on the destruction of sensory neurons in dorsal root ganglia . SNN was first identified and recognized as a PNS by Denny-Brown in 1948  but a paraneoplastic origin is only one of the etiologies of SNN which may depend on autoimmune diseases, viral infections, toxic or genetic causes [13,15]. In our series, paraneoplastic SNN represent 11% of all SN cases but 17.5% of patients with an acute or subacute form (Antoine et al., to be published). However, in the PNSEuro network database, SN occurs in 24% of patients making it one of the most frequent PNS . Paraneoplastic SNN has a highly suggestive clinical presentation . The onset is usually subacute or rapidly progressive with paraesthesia and pain. Sensory loss is frequently multifocal or asymmetrical, and the upper limbs are almost invariably involved [12,18]. The face, the chest, or the abdomen may also be concerned. Pain is frequent and sensory loss, affecting especially deep sensation often leads to severe sensory ataxia in the four limbs. Although usually present in most patients with an equal intensity, small or large sensory fiber involvement may predominate in some cases . If diagnosed late in the evolution, SSN can be a very disabling disorder, but in the PNSEuro network database patients are frequently only mildly disabled with a mean
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Rankin score of 2.3 while very indolent and protracted courses over several years have been reported . CSF analysis usually shows elevated protein concentration, pleocytosis or oligoclonal bands. The electrophysiological hallmark of SSN is a severe and diffuse alteration of sensory nerve action potentials with frequently non-excitable sensory nerves. Motor conduction velocities are classically normal but are in fact frequently mildly altered, which may be confusing and lead to an inappropriate diagnosis of axonal sensory-motor neuropathy . Although paraneoplastic SNN occurs with different tumors including breast cancer and Hodgkin’s disease , SCLC represents 70–80% of cases. About 90% of patients with paraneoplastic SNN have an onconeural antibody, which means that the absence of such antibodies does not rule out the possibility of a paraneoplastic disorder. In the PNSEuro network database, anti-Hu antibodies, which have 99% specificity and 82% sensitivity for the diagnosis of cancer  occur in about 78% of patients followed by anti-CV2/ CRMP5 and amphiphysin antibodies . Other PNS disorders occur with anti-Hu antibodies . The most frequent is dysautonomia, which is frequently associated with SNN. It affects the cardiovascular and digestive systems. Orthostatic hypotension can be very severe and arrhythmia may explain cases of sudden death. Digestive pseudo-obstruction is also a severe disease that results from the destruction of autonomic neurons in myenteric plexuses . Lesion of lower motor neurons induces motor deficit, muscle atrophy and fasciculations. As in most cases, patients simultaneously have SNN. The resulting presentation is that of a sensory-motor polyneuropathy which since the evolution is usually rapid and the distribution asymmetrical, may be confused with a mononeuropathy multiplex. More symmetrical case with an extensive progression may resemble Guillain-Barre´ syndrome. A predominant or pure motor neuron involvement mimicking amyotrophic lateral sclerosis is quite exceptional . Nerve vasculitis  and demyelinating neuropathy  have been reported but they are very unusual in the anti-Hu syndrome.
3. Peripheral neuropathy with anti-CV2/ CRMP5 and other onconeural antibodies CRMP5 the protein recognized by anti-CV2 antibodies belongs to a family of developmentally regulated neural proteins which are expressed in the adult in regions of the central nervous system undergoing postnatal plasticity . In the peripheral nervous system, CRMP5 is expressed in sensory neurons and their satellite cells  and in axons and Schwann cells where it plays different functions in Schwann cell differentiation and axon repair . As HuD, CRMP5 is universally expressed by SCLCs . CRMP5 also belongs to the repertory of thymus self-antigens , which suggests that it may undergo an immune tolerance, which can only be broken in some specific conditions. Peripheral neuropathy is the most frequent manifestation in patients with anti-CV2/CRMP5 antibodies occurring in 57% of them . It is frequently associated with cerebellar ataxia, limbic encephalitis or ocular involvement. The neuropathy is different from that of patients with anti-Hu antibodies [29,33].
It is sensory or sensorimotor and predominates in the lower limbs. Pain is less frequent. Nerve conduction studies shows an axonal or mixed axonal and demyelinating pattern, but as a common rule the slowing of motor conduction velocities does not reached the values usually observed in chronic inflammatory demyelinating polyneuropathies and conduction blocs are never seen. Nevertheless, when performed, nerve biopsy may show demyelinated fibers and onion bulb formations [29,33]. The association of anti-Hu and anti-CV2/ CRMP5 antibodies is not rare. It is the most frequent association in the PNSEuro network database. Patients with both antibodies may develop a neuropathy blending the characteristics of the two disorders, in particular SNN with a mild demyelinating pattern on the ENMG. Finally, there is a good correlation between the patterns of neuropathy and the distribution of the target protein in sensory neurons, Schwann cells and axons in the anti-CV2/CRMP5 disorder, which suggest that CRMP5 is the actual target of the autoimmune process. SCLC and thymoma are the most frequent tumors in patients with anti-CV2/CRMP5 antibodies but the prognosis of SCLC is better with anti-CV2/CRMP5 antibodies than with anti-Hu antibodies . PNS disorders occur only occasionally with anti-Yo, anti-Ma2, and antiamphiphysin antibodies and the clinical pattern of the neuropathy in these cases has not been well established .
4. The respective role of cellular immunity and antibodies in patients with antibodies to intracellular neural antigens Although patients harbor very high titer of anti-Hu or CV2/ CRMP5 IgG antibodies in their serum and CSF it has not been possible to demonstrate that these antibodies are pathogenic. Most of our knowledge on the question relies on studies performed in the anti-Hu syndrome. The pathological hallmark of SNN consist of a loss of sensory neurons in the dorsal root ganglia with a compensatory proliferation of satellite cells, the glial cells that compose the capsule of sensory neurons, forming Nageotte’s nodules. As a consequence, the central and peripheral process of sensory neurons degenerates without any possibility of regeneration. In paraneoplastic cases an inflammatory mononuclear cell reaction is found around sensory neurons but also in the spinal cord and the brain where they may more or less extend. Inflammatory cells can also spread into the posterior roots and in some case in the peripheral nerves [26,27]. Immunopathological studies [13,35–38] have been performed in several patients with anti-Hu antibodies. The inflammatory cells mostly consist of T-cells. CD8+ cytotoxic T-cells come in close contact with sensory neurons while CD4+ helper-cells and macrophages gather in the interstitial space between neurons. Cytotoxic T-cells express perforin or TIA-1 the agents of cellular toxicity. There is also an overexpression of major histocompatibility complex classes I and II molecules by sensory neurons and their satellite cells together with adhesion molecules such as ICAM-1. In contrast, Fas, Fasligand, C9neo, and activated caspase-3 are not expressed which indicates that neuron cell death more probably results from cytotoxicity rather than apoptosis . Due to the
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difficulty of identifying antigens recognized by T-cell receptors it was not possible to demonstrate that HuD is the actual target of the cytotoxic T-cell reaction. However, circulating T-cells or tissue infiltrating T-cells display an oligoclonal pattern with a restricted repertoire of TCR genes suggesting that these cells are specifically directed toward one or few antigens . In addition circulating CD4+ probably Th1 cells more strongly react in vitro with HuD in patients with anti-Hu antibodies than in those with SCLC and no antibodies . Taken together these results have led to the hypothesis that SNN in particular and PNS in general depend on cellular immunity in patients with anti-Hu antibodies. Is there a place for a role of auto-antibodies in this disorder? Pathological studies have found IgG deposits around sensory neurons in the dorsal root ganglia of patients with anti-Hu antibodies [35,41] and elution of IgGs from tissue lesions have showed that they contain anti-Hu antibodies  indicating that antibodies can reach their target in the dorsal root ganglion. In situ IgGs are of the IgG1 and 3 classes which can activate the complement and natural killer (NK) cells. However, complement deposits and NK cells are scarce or absent in lesions which does not support the hypothesis of an antibody dependent cytotoxicity . Conversely, in vitro antiHu antibodies have been showed to induce short-term neuron lysis in presence of complement while delayed cytotoxicity also occurs which does not require complement . These important results have not been controlled by other studies. The blood-nerve barrier is known to be weak in the dorsal root and autonomic ganglia  which may facilitate the access of antibodies – and T-cells as well – to this structure and explain why SNN and dysautonomia are so frequent in patients with anti-Hu antibodies. Transfer of the disease by antibodies is an important argument in favor of their role in immunology. Immunization with HuD in rodents led to the production of high titer of antibodies in these animals but without development of clinical manifestation . Table 1 shows a comparison of what occurs in vivo and vitro in patients with anti-Hu antibodies and in patients with anti-NMDAR antibodies and encephalitis, a disorder which is now thought to be antibody mediated. Interestingly, the main difference in the two disorders is the presence numerous Bcells and plasma cells in the nervous system in the later 
while in the former these cells are only scarcely found. If in both situations complement deposits are absent, anti-NMDAR IgGs interfere in vitro with the normal functioning of their target receptor without the presence of complement  while a similar action of anti-Hu antibodies has not been demonstrated although the results of Greenlee et al.  needs to be verified. On the clinical point of view, a reduction of the level of antibodies usually follows clinical improvement in antiNMDAR encephalitis , which is not the case in patients with anti-Hu antibodies .
That cellular immunity plays the main role in PNS involving intracellular antigens and that this results in neuron cell death or axonal degeneration explains why treating these disorders remains challenging. Another important factor to take into account in the management of patients with antibodies to intracellular neural antigens is that the available therapeutic window does not exceed a few months, probably less than 3 to 5 months, before that the inflammatory reaction resolves spontaneously and leaves irreversible neuronal damages . To this must be added the fact that the rarity of PNS is a limiting factor for the development of good quality therapeutic trials. A Cochrane review found that so far no randomized or quasi randomized trials are available . Several open and uncontrolled studies used immunomodulatory or immunosuppressant treatments including high dose steroids, intravenous immunoglobulins (IVIg), plasma exchanges, cyclophosphamide, rituximab or a combination of them in patients with paraneoplastic disorders associated with intracellular antigen antibodies . Their results are equivocal although they suggest that some patients may stabilize or improve with these treatments. In a retrospective study, tumor treatment was the only predictor of stabilization in patients with anti-Hu antibodies  so that when an onconeural antibody is detected, all the efforts should be made to obtain an early tumor diagnosis . In patients with anti-Hu or anti-CV2/CRMP5 SCLC must be suspected first while with CV2/CRMP5 antibodies, thymoma is an alternative possibility. The SCLC is frequently limited to
Table 1 – Comparison of the immunological perturbations in patients with anti-Hu and anti-NMDAR antibodies.
IgG Classes AB synthesis in CSF AB titer evolution follows clinical symptoms In vitro complement activation In vitro AB activity Tissus lesions B-cells Plasmocytes T-cells TIA-1/perphorin Macrophages IgGs Complement
IgG 1 and 3 + (serum > CSF) – + Cytotoxicity complement dependent and non-dependent
IgG1 (2 and 3) + (CSF & serum) + + NMDAR modulation non complement dependent
+ – +++ CD3/CD4/CD8 + + + –
+++ +++ + CD3 – + + –
AB: antibodies; IgG: G immunoglobulins; CSF: cerebrospinal fluid.
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small metastatic lymph nodes that may escape detection by CT-scan or lung fibroscopy so that a FDG-PET scanner is recommended and should be systematically performed in acute or subacute SNN negative for onconeural antibodies particularly if the CSF is inflammatory . However, it should be kept in mind that if the method is highly sensitive it is not specific . When a first careful workup is negative, it is recommended to renew it after 3 to 6 months and then every 6 months for a period of at least 4 years . Steroids or IgIV are usually used during the time period necessary to perform investigations and organize the oncological treatment. In patients with a progression of the neurological disorder cyclophosphamide may be an alternative therapeutic . Obviously there is a need for future therapeutic trial in these disorders targeting T-lymphocytes and drugs such as natalizumab or alentezumamb may be good candidates.
6. Non paraneoplastic T-cell mediated sensory neuronopathy Sensory neurons degeneration in presence of mononuclear cell infiltration is not specific of paraneoplastic SNN. It has also been observed with HIV infection , Sjo¨gren’s syndrome, unclassified connective diseases and in idiopathic cases [56,57]. When an immunohistochemical analysis was performed, T-cells predominate around sensory neurons [56,58]. Thus there probably exist a spectrum of autoimmune T-cell mediated disorders targeting sensory neurons. So far specific antibodies have not been identified in non-paraneoplastic cases but the similarity with paraneoplastic SNN suggests that some of them may exist and are to be discovered.
Disclosure of interest The author declares that he has no conflicts of interest concerning this article.
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