Jérome Honnorat

Publications (12)86.45 Total impact

• Article: Comparative assessment of 5 methods (methylation-specific polymerase chain reaction, MethyLight, pyrosequencing, methylation-sensitive high-resolution melting, and immunohistochemistry) to analyze O6-methylguanine-DNA-methyltranferase in a series of 100 glioblastoma patients.

  Véronique Quillien, Audrey Lavenu, Lucie Karayan-Tapon, Catherine Carpentier, Marianne Labussière, Thierry Lesimple, Olivier Chinot, Michel Wager, Jérome Honnorat, Stephan Saikali, Frédéric Fina, Marc Sanson, Dominique Figarella-Branger
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  ABSTRACT: There is a strong need to determine the best technique for O(6) -methylguanine-DNA-methyltranferase (MGMT) analysis, because MGMT status is currently used in clinical trials and occasionally in routine clinical practice for glioblastoma patients. The authors compared analytical performances and predictive values of 5 techniques in a series of 100 glioblastoma patients who received standard of care treatment (Stupp protocol). MGMT promoter was considered methylated in 33%, 33%, 42%, and 60% of patients by methylation-sensitive high-resolution melting, MethyLight, pyrosequencing (with an optimal risk cutoff at 8% for the average percentage of the 5 CpGs tested), and methylation-specific polymerase chain reaction (MS-PCR), respectively. Fifty-nine percent of the samples had <23% (the optimal risk cutoff) of MGMT-positive tumor cells. The best predictive values for overall survival (OS), after adjustment for age and performance status, were obtained by pyrosequencing (hazard ratio [HR], 0.32; P < .0001), MS-PCR (HR, 0.37; P < .0001), and immunohistochemistry (HR, 0.43; P = .0005) as compared with methylation-sensitive high-resolution melting (HR, 0.52 P = .02) and MethyLight (HR, 0.6; P = .05). For progression-free survival (PFS), the best predictive values were obtained with pyrosequencing (HR, 0.35; P < .0001), methylation-sensitive high-resolution melting (HR, 0.46; P = .002), and MS-PCR (HR, 0.49; P = .002). Combining pyrosequencing and immunohistochemistry slightly improved predictive power for OS, but not for PFS. Poor reproducibility and interobserver variability were, however, observed for immunohistochemistry. Good prediction of survival in addition to high reproducibility and sensitivity made pyrosequencing the best among the 5 techniques tested in this study.
  Cancer 01/2012; 118(17):4201-11. · 4.77 Impact Factor
• Source

  Available from: PubMed Central

  Article: Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia.

  Mario U Manto, Christiane S Hampe, Véronique Rogemond, Jérome Honnorat
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  ABSTRACT: To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects. Purified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods. Intra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity. These results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab.
  Orphanet Journal of Rare Diseases 01/2011; 6:3. · 5.83 Impact Factor
• Article: Facial pain as first manifestation of anti-Hu paraneoplastic syndrome.

  Geneviève Demarquay, Adrien Didelot, Véronique Rogemond, Philippe Ryvlin, Michel Gouttard, Paul Garassus, François Mauguière, Jérome Honnorat
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  ABSTRACT: The diagnosis of anti-Hu-associated encephalomyelitis/sensory neuropathy may be particularly difficult when cranial nerve involvement represents the first clinical manifestation of the disease. We report a case of a patient who presented with facial pain as the first manifestation of an anti-Hu paraneoplastic syndrome, which needs a rapid detection and treatment of the underlying tumour. We suggest that paraneoplastic neuropathy should be considered during the management of trigeminal neuropathic pain, especially when brain imagery is normal.
  The Journal of Headache and Pain 04/2010; 11(4):355-7. · 2.43 Impact Factor
• Article: Oncological patterns of care and outcome for 952 patients with newly diagnosed glioblastoma in 2004.

  Luc Bauchet, Hélène Mathieu-Daudé, Pascale Fabbro-Peray, Valérie Rigau, Michel Fabbro, Olivier Chinot, Loreleï Pallusseau, Charlotte Carnin, Karl Lainé, Aline Schlama, [......], Chantal Campello, Christine Kerr, Hugues Duffau, Monique Reme-Saumon, Brigitte Trétarre, Jean-Pierre Daures, Dominique Henin, François Labrousse, Philippe Menei, Jérome Honnorat
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  ABSTRACT: This report, an audit requested by the French government, describes oncological patterns of care, prognostic factors, and survival for patients with newly diagnosed and histologically confirmed glioblastoma multiforme (GBM) in France. The French Brain Tumor DataBase, which is a national multidisciplinary (neurosurgeons, neuropathologists, radiotherapists, neurooncologists, epidemiologists, and biostatisticians) network, prospectively collected initial data for the cases of GBM in 2004, and a specific data card was used to retrospectively collect data on the management and follow-up care of these patients between January 1, 2004, and December 1, 2006. We recorded 952 cases of GBM (male/female ratio 1.6, median age 63.9 years, mean preoperative Karnofsky performance status [KPS] 79). Surgery consisted of resection (RS; n = 541) and biopsy (n = 411); 180 patients did not have subsequent oncological treatment. After surgery, first-line treatment (n = 772) consisted of radiotherapy (RT) and temozolomide (TMZ) concomitant +/- adjuvant in 314 patients, RT alone in 236 patients, chemotherapy (CT) alone in 157 patients, and other treatment modalities in 65 patients. Median overall survival was 286 days (95% CI, 266-314) and was significantly affected by age, KPS, and tumor location. Median survival (days, 95% CI) associated with these main strategies, when analyzed by a surgical group, were as follows: RS + RT-TMZ((n=224)): 476 (441-506), biopsy + RT-TMZ((n=90)): 329 (301-413), RS + RT((n=147)): 363 (331-431), biopsy + RT((n=89)): 178 (153-237), RS + CT((n=61)): 245 (190-361), biopsy + CT((n=96)): 244 (198-280), and biopsy only((n=118)): 55 (46-71). This study illustrates the usefulness of a national brain tumor database. To our knowledge, this work is the largest report of recent GBM management in Europe.
  Neuro-Oncology 04/2010; 12(7):725-35. · 5.72 Impact Factor
• Article: Microarray gene expression profiling in meningiomas: differential expression according to grade or histopathological subtype.

  Michelle Fèvre-Montange, Jacques Champier, Anne Durand, Anne Wierinckx, Jérome Honnorat, Jacques Guyotat, Anne Jouvet
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  ABSTRACT: Meningiomas, one of the largest subgroup of intracranial tumours are generally benign, but can progress to malignancy. They are classified into the three World Health Organization grades: benign, atypical and anaplastic meningiomas. Various histopathological features have been associated with aggressiveness or recurrence. Several genes have been suggested as prognostic factors, but molecular signatures have not permitted the classification of the tumours into the three grades. We have performed a microarray transcriptomic study on 17 meningiomas of different malignancy using CodeLink Uniset Human Whole Genome Bioarrays to try to distinguish the different grades and histopathological subtypes. Unsupervised hierarchical clustering classified the meningiomas into groups A, B and C, which corresponded to the three grades except for 3 benign meningiomas with higher proliferation indexes and/or recurrence, included in the atypical group. Several genes involved in cell adhesion (CD44, LOX), cell division (CKS2, BIRC5 and UBE2C), cell differentiation (Notch1) or signal transduction (ARHGAP28) were upregulated, whereas tumour suppressor genes (LR1B, DRR1, PLZF, GPX3, SYNPO, TIMP3 and HOPS) and genes involved in cell adhesion (PROS1), proliferation (SERPINF1 and PDGFD) and differentiation (AOX1) were downregulated in groups B and C compared to group A. In the benign tumours, we identified genes with signatures specific for fibroblastic meningiomas (FBLN1, Tenascin C and MMP2 encoding extracellular matrix proteins) and for meningothelial meningiomas (MLPH, DEFB1 and FAT3), suggesting different mechanisms involved in the tumorigenesis of these subtypes. This microarray-based expression profiling study revealed candidate genes and pathways that may contribute to a better understanding of the recurrence of a benign meningioma. Our results might make it possible to determine which benign meningiomas might recur despite complete resection, and will provide helpful information for neurosurgeons in the follow-up of the patients.
  International Journal of Oncology 12/2009; 35(6):1395-407. · 2.40 Impact Factor
• Article: CRMP3 is required for hippocampal CA1 dendritic organization and plasticity.

  Tam T Quach, Guy Massicotte, Marie-Françoise Belin, Jérome Honnorat, Erica R Glasper, Anne C Devries, Lyn B Jakeman, Michel Baudry, Anne-Marie Duchemin, Pappachan E Kolattukudy
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  ABSTRACT: In vitro studies have pointed to the collapsin response mediator proteins (CRMPs) as key regulators of neurite outgrowth and axonal differentiation. CRMP3 is expressed mostly in the nervous system during development but remains at high levels in the hippocampus of adults. To explore CRMP3 function in vivo, we generated mice with targeted disruption of the CRMP3 gene. Immunohistochemistry and Golgi staining of CA1 showed abnormal dendrite and spine morphogenesis in the hippocampus of CRMP3-deficient mice. Apical dendrites displayed an increase in undulation and a reduction in length and branching points. Basal dendrites also exhibited a reduction in length with an alteration in soma stem distribution and an increased number of thick dendrites localized in stratum oriens (SO). Long-term potentiation (LTP) was impaired in this area. These data indicate an important role for CRMP3 in dendrite arborization, guide-posts navigation, and neuronal plasticity.
  The FASEB Journal 03/2008; 22(2):401-9. · 5.71 Impact Factor
• Article: French brain tumor data bank: methodology and first results on 10,000 cases.

  Luc Bauchet, Valérie Rigau, Hélène Mathieu-Daudé, Dominique Figarella-Branger, Delphine Hugues, Loreleï Palusseau, Fabienne Bauchet, Michel Fabbro, Chantal Campello, Laurent Capelle, Anne Durand, Brigitte Trétarre, Didier Frappaz, Dominique Henin, Philippe Menei, Jérome Honnorat, François Segnarbieux
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  ABSTRACT: This work aims to prospectively record all primary central nervous system tumors (PCNST), in France, for which histological diagnosis is available. The objectives are to create a national registry and a network to perform epidemiological studies, to implement clinical and basic research protocols, and to harmonize the healthcare of patients affected by PCNST. Following a feasibility study, including an estimate of the gross incidence of PCNST (15.8/100,000 person-years) in France, all French neuropathology and neurosurgery departments decided to participate in the program. For each patient, the neurosurgeon and the neuropathologist complete a data file containing socio-demographic, clinical, radiologic and anatomopathologic information. The Tumor Registry from Herault is authorized to compile the data files with personal identifiers. In 2.5 years, 10,093 cases of newly diagnosed PCNST have been recorded. Tumor resections were performed in 75.3%, while biopsies accounted for 24.7%. Histological diagnoses included glioma (49.6%), other neuroepithelial tumors (3.8%), meningioma (30.9%), neurinoma (8.7%), lymphoma (2.9%) and others (4.1%). Cryopreservation was reported for 2,261 PCNST specimens. Clinical and radiological aspects were also recorded. Preliminary results are encouraging and stimulating for the long-term goal of creating a National Registry and a National Network for patients affected by PCNST. To our knowledge, this is the first European databank dedicated to PCNST, with collection of clinical, radiological and histological data (including cryopreservation of the specimen). The creation of this registry and this database may have major clinical and fundamental implications.
  Journal of Neuro-Oncology 10/2007; 84(2):189-99. · 3.21 Impact Factor
• Source

  Available from: Marie-Aline A Laute

  Article: Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases.

  Mario-Ubaldo Manto, Marie-Aline Laute, Michèle Aguera, Véronique Rogemond, Massimo Pandolfo, Jérome Honnorat
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  ABSTRACT: Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid into GABA. GAD autoantibodies (GAD-Ab) have been described in diabetes mellitus and in diseases involving the central nervous system such as stiff-person syndrome and cerebellar ataxia. However, the pathogenic role of GAD-Ab in neurological diseases remains a matter of debate. Using neurophysiological and neurochemical methods, we analyzed the effects of intracerebellar and paraspinal administration of GAD-Ab in rats. Intracerebellar administration of IgG from patients with GAD-Ab and neurological involvement (IgG-GAD) blocked the potentiation of the corticomotor response normally associated with trains of repetitive peripheral nerve stimulation. When injected in the lumbar paraspinal region, IgG-GAD induced continuous motor activity with repetitive discharges, abnormal exteroceptive reflexes, and increased excitability of anterior horn neurons, as assessed by F/M ratios. Furthermore, IgG-GAD significantly reduced the N-methyl-D-aspartate-mediated production of nitric oxide in cerebellar nuclei and impaired the synaptic regulation of glutamate after N-methyl-D-aspartate administration. These effects were not observed after administration of IgG from the following groups: (1) patients with GAD-Ab, diabetes mellitus, and without neurological complications; and (2) control patients. These results indicate that stiff-person syndrome and cerebellar ataxia are the direct consequence of antibody-mediated neuronal dysfunction.
  Annals of Neurology 07/2007; 61(6):544-51. · 11.09 Impact Factor
• Article: Effects of anti–glutamic acid decarboxylase antibodies associated with neurological diseases

  Mario-Ubaldo Manto MD, Marie-Aline Laute LT, Michèle Aguera LT, Véronique Rogemond PhD, Massimo Pandolfo MD, PhD Jérome Honnorat MD
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  ABSTRACT: Objective Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid into GABA. GAD autoantibodies (GAD-Ab) have been described in diabetes mellitus and in diseases involving the central nervous system such as stiff-person syndrome and cerebellar ataxia. However, the pathogenic role of GAD-Ab in neurological diseases remains a matter of debate.Methods Using neurophysiological and neurochemical methods, we analyzed the effects of intracerebellar and paraspinal administration of GAD-Ab in rats.ResultsIntracerebellar administration of IgG from patients with GAD-Ab and neurological involvement (IgG-GAD) blocked the potentiation of the corticomotor response normally associated with trains of repetitive peripheral nerve stimulation. When injected in the lumbar paraspinal region, IgG-GAD induced continuous motor activity with repetitive discharges, abnormal exteroceptive reflexes, and increased excitability of anterior horn neurons, as assessed by F/M ratios. Furthermore, IgG-GAD significantly reduced the N-methyl-D-aspartate–mediated production of nitric oxide in cerebellar nuclei and impaired the synaptic regulation of glutamate after N-methyl-D-aspartate administration. These effects were not observed after administration of IgG from the following groups: (1) patients with GAD-Ab, diabetes mellitus, and without neurological complications; and (2) control patients.InterpretationThese results indicate that stiff-person syndrome and cerebellar ataxia are the direct consequence of antibody-mediated neuronal dysfunction. Ann Neurol 2007;61:544–551
  Annals of Neurology 05/2007; 61(6):544 - 551. · 11.09 Impact Factor
• Article: Anti-GAD antibodies and periodic alternating nystagmus.

  Caroline Tilikete, Alain Vighetto, Paul Trouillas, Jérome Honnorat
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  ABSTRACT: Autoantibodies directed against glutamic acid decarboxylase (GAD-Ab) have recently been described in a few patients with progressive cerebellar ataxia, suggesting an autoimmune physiopathologic mechanism. To determine the exact role of GAD-Ab and gamma-aminobutyric acid (GABA)-ergic neurotransmission in the pathogenesis of cerebellar ataxia. Case report. University neurological hospital. We report the case of a patient with subacute cerebellar ataxia associated with GAD-Ab showing periodic alternating nystagmus (PAN). Baclofen, a GABAergic medication, was given to the patient. Eye movement recording of spontaneous nystagmus and postrotatory vestibular responses. Baclofen was effective in suppressing PAN and improving postrotatory vestibular responses but not for improving cerebellar ataxia. The presence of PAN and the response to baclofen provide a unique opportunity to suggest a direct role of GAD-Ab in cerebellar dysfunction in this patient.
  Archives of Neurology 09/2005; 62(8):1300-3. · 7.58 Impact Factor
• Article: Potential role of anti-GAD antibodies in abnormal eye movements.

  Caroline Tilikete, Alain Vighetto, Paul Trouillas, Jérome Honnorat
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  ABSTRACT: Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid to gamma-aminobutyric acid (GABA). Autoantibodies directed against GAD (antiGAD-Ab) have been described in patients with insulin-dependent diabetes mellitus, stiff-man syndrome, and in a few patients with progressive cerebellar ataxia. The presence of these autoantibodies suggests an autoimmune pathophysiological mechanism for the neurological manifestations in these disorders. However, the exact role of antiGAD-Ab and GABAergic neurotransmission in the pathogenesis of the neurological manifestations, particularly in progressive cerebellar ataxia, is not fully understood. The cases of two patients with subacute cerebellar ataxia associated with antiGAD-Ab presenting with abnormal eye movements are reported. One patient presented a periodic alternating nystagmus (PAN), whereas the other presented a downbeat nystagmus (DBN) and slow vertical saccades. The potential role of antiGAD-Ab and the resultant GABAergic neurotransmission deficit in oculomotor manifestations is discussed.
  Annals of the New York Academy of Sciences 05/2005; 1039:446-54. · 3.15 Impact Factor
• Article: Beware of optic neuritis!

  Pierre Krolak-Salmon, Géraldine Androdias, Jérome Honnorat, Christiane Caudie, Philippe Bret, Denis Hernette, Alain Vighetto
  The Lancet Neurology 01/2003; 1(8):516-7. · 23.46 Impact Factor