revue neurologique 170 (2014) 570–576

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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

info article

abstract

Article history:

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

Keywords:

sensory and motor with an axonal or mixed demyelinating and axonal electrophysiolo-

Peripheral neuropathy

gical pattern. The clinical pattern of these neuropathies is in keeping with the cellular

Sensory neuronopathy

distribution of HuD and CRMP5 in the peripheral nervous system. Although present in

Paraneoplastic neurological

high titer, these antibodies are probably not directly responsible for the neuropathy.

syndromes

Pathological and experimental studies indicate that cytotoxic T-cells are probably the

Anti-Hu antibodies

main effectors of the immune response. These disorders contrast with those in which

Anti-CV2 antibodies

antibodies recognize a cell surface antigen and are probably responsible for the disease.

Anti-CRMP5 antibodies

The neuronal cell death and axonal degeneration which result from T-cell mediated

T-cells

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

571

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.

1.

Introduction

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 [1]. 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 [2]. 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 [3]. 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 [4], 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 [5]. It also interacts with SMN in motor neurons, which may facilitate the localization of mRNAs into motor axons [6]. HuD is expressed by most of small cell lung cancers in a normal non-mutated form [7] 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 [8]. However, HuD although belonging to the repertory of antigens normally recognized by circulating T-cells [9] shows a high degree of immune tolerance [10] 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 [11]. Patients with anti-Hu antibodies show a wide spectrum of neurological disorders involving the central, peripheral and autonomic nervous systems [12] 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 [13]. SNN was first identified and recognized as a PNS by Denny-Brown in 1948 [14] 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 [16]. Paraneoplastic SNN has a highly suggestive clinical presentation [17]. 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 [19]. 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 [20]. 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 [21]. Although paraneoplastic SNN occurs with different tumors including breast cancer and Hodgkin’s disease [22], 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 [23] occur in about 78% of patients followed by anti-CV2/ CRMP5 and amphiphysin antibodies [16]. Other PNS disorders occur with anti-Hu antibodies [12]. 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 [24]. 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 [25]. Nerve vasculitis [26] and demyelinating neuropathy [27] 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 [28]. In the peripheral nervous system, CRMP5 is expressed in sensory neurons and their satellite cells [29] and in axons and Schwann cells where it plays different functions in Schwann cell differentiation and axon repair [30]. As HuD, CRMP5 is universally expressed by SCLCs [31]. CRMP5 also belongs to the repertory of thymus self-antigens [32], 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 [33]. 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 [33]. 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 [34].

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 [38]. 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 [39]. 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 [40]. 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 [41] 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 [37]. 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 [42]. 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 [43] 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 [44]. 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 [45]

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 [46] while a similar action of anti-Hu antibodies has not been demonstrated although the results of Greenlee et al. [42] needs to be verified. On the clinical point of view, a reduction of the level of antibodies usually follows clinical improvement in antiNMDAR encephalitis [47], which is not the case in patients with anti-Hu antibodies [48].

5.

Treatment implications

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 [49]. 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 [50]. 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 [51]. 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 [12] so that when an onconeural antibody is detected, all the efforts should be made to obtain an early tumor diagnosis [52]. 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

Anti-Hu antibodies

Anti-NMDAR antibodies

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 [53]. However, it should be kept in mind that if the method is highly sensitive it is not specific [54]. 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 [52]. 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 [49]. 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 [55], 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.

references

[1] Honnorat J, Viaccoz A. New concepts in paraneoplastic neurological syndromes. Rev Neurol (Paris) 2011;167:729–36. [2] Antoine JC, Camdessanche JP. Paraneoplastic disorders of the peripheral nervous system. Presse Med 2013;42:e235–44. [3] Querol L, Nogales-Gadea G, Rojas-Garcia R, MartinezHernandez E, Diaz-Manera J, Suarez-Calvet X, et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013; 73:370–80. [4] Chung S, Jiang L, Cheng S, Furneaux H. Purification and properties of HuD, a neuronal RNA-binding protein. J Biol Chem 1996;271:11518–24. [5] Fornaro M, Raimondo S, Lee JM, Giacobini-Robecchi MG. Neuron-specific Hu proteins sub-cellular localization in primary sensory neurons. Ann Anat 2007;189:223–8. [6] Fallini C, Zhang H, Su Y, Silani V, Singer RH, Rossoll W, et al. The survival of motor neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons. J Neurosci 2011;31:3914–25.

[7] Carpentier AF, Voltz R, DesChamps T, Posner JB, Dalmau J, Rosenfeld MR. Absence of HuD gene mutations in paraneoplastic small cell lung cancer tissue. Neurology 1998;50:1919. [8] Tora M, Graus F, de Bolos C, Real FX. Cell surface expression of paraneoplastic encephalomyelitis/sensory neuronopathy-associated Hu antigens in small-cell lung cancers and neuroblastomas. Neurology 1997;48:735–41. [9] Rousseau A, Benyahia B, Dalmau J, Connan F, Guillet JG, Delattre JY, et al. T cell response to Hu-D peptides in patients with anti-Hu syndrome. J Neurooncol 2005; 71:231–6. [10] DeLuca I, Blachere NE, Santomasso B, Darnell RB. Tolerance to the neuron-specific paraneoplastic HuD antigen. PLoS One 2009;4:e5739. [11] Honnorat J, Didelot A, Karantoni E, Ville D, Ducray F, Lambert L, et al. Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer. Neurology 2013;80:2226–32. [12] Graus F, Keime-Guibert F, Rene R, Benyahia B, Ribalta T, Ascaso C, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138–48. [13] Kuntzer T, Antoine JC, Steck AJ. Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies). Muscle Nerve 2004;30:255–68. [14] Denny-Brown D. Primary sensory neuropathy with muscular changes associated with carcinoma. J Neurol Neurosurg Psychiatry 1948;11:73–87. [15] Sghirlanzoni A, Pareyson D, Lauria G. Sensory neuron diseases. Lancet Neurol 2005;4:349–61. [16] Giometto B, Grisold W, Vitaliani R, Graus F, Honnorat J, Bertolini G. Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol 2010;67:330–5. [17] Camdessanche JP, Jousserand G, Ferraud K, Vial C, Petiot P, Honnorat J, et al. The pattern and diagnostic criteria of sensory neuronopathy: a case-control study. Brain 2009;132:1723–33. [18] Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu – associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 1992;71:59–72. [19] Oki Y, Koike H, Iijima M, Mori K, Hattori N, Katsuno M, et al. Ataxic vs painful form of paraneoplastic neuropathy. Neurology 2007;69:564–72. [20] Graus F, Bonaventura I, Uchuya M, Valls-Sole J, Rene R, Leger JM, et al. Indolent anti-Hu-associated paraneoplastic sensory neuropathy. Neurology 1994;44:2258–61. [21] Camdessanche JP, Antoine JC, Honnorat J, Vial C, Petiot P, Convers P, et al. Paraneoplastic peripheral neuropathy associated with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients. Brain 2002;125:166–75. [22] Horwich MS, Cho L, Porro RS, Posner JB. Subacute sensory neuropathy: a remote effect of carcinoma. Ann Neurol 1977;2:7–19. [23] Molinuevo JL, Graus F, Serrano C, Rene R, Guerrero A, Illa I. Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann Neurol 1998;44:976–80. [24] Condom E, Vidal A, Rota R, Graus F, Dalmau J, Ferrer I. Paraneoplastic intestinal pseudo-obstruction associated with high titres of Hu autoantibodies. Virchows Arch A Pathol Anat Histopathol 1993;423:507–11. [25] Verma A, Berger JR, Snodgrass S, Petito C. Motor neuron disease: a paraneoplastic process associated with anti-hu antibody and small-cell lung carcinoma. Ann Neurol 1996;40:112–6.

revue neurologique 170 (2014) 570–576

[26] Younger DS, Dalmau J, Inghirami G, Sherman WH, Hays AP. Anti-Hu-associated peripheral nerve and muscle microvasculitis. Neurology 1994;44:181–3. [27] Antoine JC, Mosnier JF, Honnorat J, Convers P, Absi L, Lapras J, et al. Paraneoplastic demyelinating neuropathy, subacute sensory neuropathy, and anti-Hu antibodies: clinicopathological study of an autopsy case. Muscle Nerve 1998;21:850–7. [28] Veyrac A, Giannetti N, Charrier E, Reymond-Marron I, Aguera M, Rogemond V, et al. Expression of collapsin response mediator proteins 1, 2 and 5 is differentially regulated in newly generated and mature neurons of the adult olfactory system. Eur J Neurosci 2005;21:2635–48. [29] Antoine JC, Honnorat J, Camdessanche JP, Magistris M, Absi L, Mosnier JF, et al. Paraneoplastic anti-CV2 antibodies react with peripheral nerve and are associated with a mixed axonal and demyelinating peripheral neuropathy. Ann Neurol 2001;49:214–21. [30] Camdessanche JP, Ferraud K, Boutahar N, Lassabliere F, Mutter M, Touret M, et al. The collapsin response mediator protein 5 onconeural protein is expressed in Schwann cells under axonal signals and regulates axon-Schwann cell interactions. J Neuropathol Exp Neurol 2012;71:298–311. [31] Meyronet D, Massoma P, Thivolet F, Chalabreysse L, Rogemond V, Schlama A, et al. Extensive Expression of Collapsin Response Mediator Protein 5 (CRMP5) is a specific marker of high-grade lung neuroendocrine carcinoma. Am J Surg Pathol 2008;1699–708. [32] Camdessanche JP, Lassabliere F, Meyronnet D, Ferraud K, Absi L, Honnorat J, et al. Expression of the onconeural CV2/ CRMP5 antigen in thymus and thymoma. J Neuroimmunol 2006;174:168–73. [33] Honnorat J, Cartalat-Carel S, Ricard D, Camdessanche JP, Carpentier AF, Rogemond V, et al. Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry 2009;80:412–6. [34] (a) Waragai M, Chiba A, Uchibori A, Fukushima T, Anno M, Tanaka K. Anti-Ma2 associated paraneoplastic neurological syndrome presenting as encephalitis and progressive muscular atrophy. J Neurol Neurosurg Psychiatry 2006;77:111–3. (b) Tracy J, Lennon V, Pittock SJ. Purkinje cell antibody type 1 (PCA-1, Anti-Yo): peripheral nerve manifestations. Neurology 2006;66(Suppl. 2):A188. (c) Taieb G, Renard D, Deverdal M, Honnorat J, Labauge P, Castelnovo G. Pure monomelic sensory neuronopathy associated with anti-yo antibodies. Muscle Nerve 2012;45:297–8. [35] Graus F, Ribalta T, Campo E, Monforte R, Urbano A, Rozman C. Immunohistochemical analysis of the immune reaction in the nervous system in paraneoplastic encephalomyelitis. Neurology 1990;40:219–22. [36] Wanschitz J, Hainfellner JA, Kristoferitsch W, Drlicek M, Budka H. Ganglionitis in paraneoplastic subacute sensory neuronopathy: a morphologic study. Neurology 1997;49:1156–9. [37] Jean WC, Dalmau J, Ho A, Posner JB. Analysis of the IgG subclass distribution and inflammatory infiltrates in patients with anti-Hu-associated paraneoplastic encephalomyelitis. Neurology 1994;44:140–7. [38] Bernal F, Graus F, Pifarre A, Saiz A, Benyahia B, Ribalta T. Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. Acta Neuropathol (Berl) 2002;103:509–15. [39] (a) Voltz R, Dalmau J, Posner JB, Rosenfeld MR. T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis. Neurology 1998;51:1146–50.

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

575

(b) Plonquet A, Gherardi RK, Creange A, Antoine JC, Benyahia B, Grisold W, et al. Oligoclonal T-cells in blood and target tissues of patients with anti-Hu syndrome. J Neuroimmunol 2002;122:100–5. Benyahia B, Liblau R, Merle-Beral H, Tourani JM, Dalmau J, Delattre JY. Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies. Ann Neurol 1999;45:162–7. Dalmau J, Furneaux HM, Rosenblum MK, Graus F, Posner JB. Detection of the anti-Hu antibody in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronopathy. Neurology 1991;41:1757–64. Greenlee JE, Parks TN, Jaeckle KA. Type IIa (‘anti-Hu’) antineuronal antibodies produce destruction of rat cerebellar granule neurons in vitro. Neurology 1993;43:2049–54. Allen DT, Kiernan JA. Permeation of proteins from the blood into peripheral nerves and ganglia. Neuroscience 1994;59:755–64. Sillevis Smitt PA, Manley GT, Posner JB. Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice. Neurology 1995;45:1873–8. (a) Tuzun E, Zhou L, Baehring JM, Bannykh S, Rosenfeld MR, Dalmau J. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol 2009;118:737–43. (b) Camdessanche JP, Streichenberger N, Cavillon G, Rogemond V, Jousserand G, Honnorat J, et al. Brain immunohistopathological study in a patient with antiNMDAR encephalitis. Eur J Neurol 2010;929–31. (c) Martinez-Hernandez E, Horvath J, Shiloh-Malawsky Y, Sangha N, Martinez-Lage M, Dalmau J. Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology 2011;77:589–93. (a) Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010;30:5866–75. (b) Manto M, Dalmau J, Didelot A, Rogemond V, Honnorat J. In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction. Orphanet J Rare Dis 2010;5:31. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10:63–74. Llado A, Mannucci P, Carpentier AF, Paris S, Blanco Y, Saiz A, et al. Value of Hu antibody determinations in the followup of paraneoplastic neurologic syndromes. Neurology 2004;63:1947–9. Antoine JC, Camdessanche JP. Treatment options in paraneoplastic disorders of the peripheral nervous system. Curr Treat Options Neurol 2013;15:210–23. Giometto B, Vitaliani R, Lindeck-Pozza E, Grisold W, Vedeler C. Treatment for paraneoplastic neuropathies. Cochrane Database Syst Rev 2012;12:CD007625. (a) Graus F, Vega F, Delattre JY, Bonaventura I, Rene R, Arbaiza D, et al. Plasmapheresis and antineoplastic treatment in CNS paraneoplastic syndromes with antineuronal autoantibodies. Neurology 1992;42:536–40. (b) Keime-Guibert F, Graus F, Fleury A, Rene R, Honnorat J, Broet P, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000;68:479–82. (c) Uchuya M, Graus F, Vega F, Rene R, Delattre JY. Intravenous immunoglobulin treatment in paraneoplastic

576

[52]

[53]

[54]

[55]

revue neurologique 170 (2014) 570–576

neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry 1996;60:388–92. (d) Shams’ili S, de Beukelaar J, Gratama JW, Hooijkaas H, van den Bent M, van’t Veer M, et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol 2006;253:16–20. Titulaer MJ, Soffietti R, Dalmau J, Gilhus NE, Giometto B, Graus F, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 2011;18:19–23. Camdessanche JP, Jousserand G, Franques J, Pouget J, Delmont E, Creange A, et al. A clinical pattern-based etiological diagnostic strategy for sensory neuronopathies: a French collaborative study. J Peripher Nerv Syst 2012;17:331–40. Younes-Mhenni S, Janier MF, Cinotti L, Antoine JC, Tronc F, Cottin V, et al. FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain 2004;127:2331–8. (a) Scaravilli F, Sinclair E, Arango JC, Manji H, Lucas S, Harrison MJ. The pathology of the posterior root ganglia in AIDS and its relationship to the pallor of the gracile tract. Acta Neuropathol (Berl) 1992;84:163–70. (b) Esiri MM, Morris CS, Millard PR. Sensory and sympathetic ganglia in HIV-1 infection: immunocytochemical demonstration of HIV-1 viral antigens, increased MHC class II antigen expression and mild reactive inflammation. J Neurol Sci 1993;114:178–87.

[56] (a) Griffin JW, Cornblath DR, Alexander E, Campbell J, Low PA, Bird S, et al. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjogren’s syndrome. Ann Neurol 1990;27:304–15. (b) Hainfellner JA, Kristoferitsch W, Lassmann H, Bernheimer H, Neisser A, Drlicek M, et al. T-cell-mediated ganglionitis associated with acute sensory neuronopathy. Ann Neurol 1996;39:543–7. [57] (a) Colli BO, Carlotti Jr CG, Assirati Jr JA, Lopes LD, Junior WM, Chimelli L, et al. Dorsal root ganglionectomy for the diagnosis of sensory neuropathies. Surgical technique and results. Surg Neurol 2007. (b) Sobue G, Yanagi T, Hashizume Y. Chronic progressive sensory ataxic neuropathy with polyclonal gammopathy and disseminated focal perivascular cellular infiltrations. Neurology 1988;38:463–7. (c) Okajima T, Yamamura S, Hamada K, Kawasaki S, Ideta T, Ueno H, et al. Chronic sensory and autonomic neuropathy. Neurology 1983;33:1061–4. (d) Kurokawa K, Noda K, Mimori Y, Watanabe C, Katayama S, Nakamura S, et al. A case of pandysautonomia with associated sensory ganglionopathy. J Neurol Neurosurg Psychiatry 1998;65:278–9. [58] Mori K, Iijima M, Koike H, Hattori N, Tanaka F, Watanabe H, et al. The wide spectrum of clinical manifestations in Sjogren’s syndrome-associated neuropathy. Brain 2005;128:2518–34.