Publications by authors named "Nelly Fabre"

27 Publications

  • Page 1 of 1

Chronic advanced-glycation end products treatment induces TXNIP expression and epigenetic changes in glomerular podocytes in vivo and in vitro.

Life Sci 2021 Apr 13;270:118997. Epub 2021 Jan 13.

Laboratorio de Carboidratos e Radioimunoensaio (LIM-18) do Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil; Programa de Pos-Graduaçao em Medicina, Universidade Nove de Julho (UNINOVE), Sao Paulo, SP, Brazil. Electronic address:

Advanced glycation end products (AGEs) play an important role in oxidative stress and inflammation, processes implicated in the development and progression of kidney dysfunction. In the present study, we investigated the participation of the pro-oxidant protein thioredoxin-interacting protein (TXNIP) and of epigenetic mechanisms on kidney tissue (in vivo, in non-diabetic rats) and on terminally differentiated glomerular podocytes (in vitro) chronically exposed to AGEs. AGEs induced total kidney and glomerular TXNIP expression and decreased H3K27me3 content. Concomitant treatment with the antioxidant N-acetyl-cysteine (NAC) reversed only the increased TXNIP expression. TXNIP expression positively correlated with proteinuria and negatively correlated with H3K27me3 content. In vitro studies in podocytes showed that 72 h exposure to AGEs decreased nephrin expression and increased Txnip, Nox4, Col4a1, and epithelial-to-mesenchymal transition (EMT) markers (Acta2, Snail1, and Tgfb1). Podocytes treatment with NAC reversed Nox4, Col4a1, Acta2, and Tgfb1 increased expression but did not abrogate the reduced expression of nephrin. MiR-29a expression was downregulated by AGEs in vivo, but not in vitro. In conclusion, treatment of non-diabetic rats with AGEs induced TXNIP expression and decreased the contents of the repressive epigenetic mark H3K27me3 and of miR-29a, potentially driving injury to glomerular filtration barrier and podocytes dysfunction.
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http://dx.doi.org/10.1016/j.lfs.2020.118997DOI Listing
April 2021

Cerebral Venous Thrombosis and Subdural Collection in a Comatose Patient: Do Not Forget Intracranial Hypotension. A Case Report.

Headache 2020 Nov 29;60(10):2583-2588. Epub 2020 Sep 29.

Department of Anesthesiology and Critical Care, University Hospital of Toulouse, University Toulouse 3-Paul Sabatier, Toulouse, France.

Background: The typical sign of intracranial hypotension (IH) is postural headache. However, IH can be associated with a large diversity of clinical or radiological signs leading to difficult diagnosis especially in case of coma. The association of cerebral venous thrombosis (CVT) and subdural hemorrhage is rare but should suggest the diagnosis of IH.

Methods: Case report.

Case Description: We report here a case of comatose patient due to spontaneous IH complicated by CVT and subdural hemorrhage. The correct diagnosis was delayed due to many confounding factors. IH was suspected after subdural hemorrhage recurrence and confirmed by magnetic resonance imaging (MRI). After 2 epidural patches with colloid, favorable outcome was observed.

Discussion: The most common presentation of IH is postural orthostatic headaches. In the present case report, the major clinical signs were worsening of consciousness and coma, which are a rare presentation. Diagnosis of IH is based on the association of clinical history, evocative symptomatology, and cerebral imaging. CVT occurs in 1-2% of IH cases and the association between IH, CVT, and subdural hemorrhage is rare. MRI is probably the key imaging examination. In the present case, epidural patch was performed after confounding factors for coma had been treated. Benefit of anticoagulation had to be balanced in this case with potential hemorrhagic complications, especially within the brain.

Conclusion: Association of CVT and subdural hemorrhage should lead to suspect IH. Brain imaging can help and find specific signs of IH.
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http://dx.doi.org/10.1111/head.13977DOI Listing
November 2020

Neuromelanin Locus Coeruleus MRI Contrast in Migraine With Aura.

Headache 2020 04 17;60(4):752-760. Epub 2020 Feb 17.

ToNIC, Toulouse NeuroImaging Center, University of Toulouse, Inserm, UPS, Toulouse, France.

Introduction: The locus coeruleus (LC) is one of the brainstem nuclei that may be activated during migraine attack. As LC contains neuromelanin, a by-product of norepinephrine synthesis, it can be delineated in vivo using neuromelanin sensitive magnetic resonance imaging (MRI). The neuromelanin content in LC has been suggested to reflect previous LC activation. We investigated LC MRI contrast in patients with migraine with aura (MWA) and its correlation with migraine features.

Methods: This matched cohort study compared 23 MWA patients aged 30-55 and without comorbidity, to 23 sex- and age-matched healthy controls. The study was conducted in a University Hospital. LC contrast was measured with T1 neuromelanin-sensitive-weighted 3T MRI. Voxels were manually selected by 2 independent researchers and comparison was made twice using intersection and union of the voxels selected by the 2 observers.

Results: No difference was found in neuromelanin LC contrast between MWA patients and controls with both the INTER method (0.224 ± 0.042 vs 0.228 ± 0.048; difference: 0.0001 (95%CI: -0.032 to 0.026), P = .799) and UNION method (0.218 ± 0.043 vs 0.222 ± 0.047; difference: -0.0012 (95%CI: -0.031 to 0.026), P = .775). Global LC volume was also similar between the 2 groups with INTER method (15.087 ± 3.965 vs 13.739 ± 3.583; difference: 2 (95%CI: -1 to 4), P = .233) and UNION method (17.522 ± 4.440 vs 16.087 ± 4.274; difference: 1 (95%CI: -2 to 4), P = .270). Moreover, no correlations were found between neuromelanin LC contrast and migraine features (duration of migraine and frequency of attacks).

Conclusion: These negative findings do not support the use of neuromelanin LC contrast as a biomarker of MA.
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http://dx.doi.org/10.1111/head.13771DOI Listing
April 2020

Cluster Headache in Subjects With Substance Use Disorder: A Case Series and a Review of the Literature.

Headache 2019 04 7;59(4):576-589. Epub 2019 Apr 7.

Service de Psychiatrie et Psychologie, INSERM UMR 1043, Université de Toulouse III, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

Objective: To describe a case series of 7 patients presenting cluster headache (CH) criteria and a substance use disorder, reported to a French Addictovigilance center. Then, to assess clinical, pharmacological, and neurobiological linkages between substance use and CH onset.

Background: CH patients are presenting a higher prevalence of comorbidities, among which the use of psychoactive substances, licit or illicit, have been explored by a few authors. Recently, 3 cases of CH in patients seen in the hospital-based addiction care center have been reported to the Toulouse addictovigilance center.

Methods: Other cases have been identified in the same tertiary hospital after a collaborative investigation done with the departments of neurology and psychiatry and included in the case series. A narrative review was performed to assess the potential of psychoactive substance consumption to induce or facilitate CH.

Results: From 2016 to 2018, 6 males and 1 female aged between 26 and 54 years old, presenting CH criteria and a substance use disorder, were included in our case series. Among substances used, there are: (1) daily use of tobacco and alcohol in 5/7 subjects; (2) daily or almost daily use of cocaine in 5/7 subjects; (3) regular use of cannabis before attacks beginning in 4/7 subjects; and (4) opioids, as a substitutive medication or abused, in 5/7 subjects. The intranasal route administration is reported by all the subjects and precedes the beginning of attacks for 5/7 subjects.

Conclusions: We have found a CH prevalence of 0.9% in our studied population, while it is estimated at 0.1% in the general population. The coexistence of cluster headache and addiction behaviors reflects possible common neurobiological pathways, which would include the hypothalamus. Research could be conducted on the potential of hypothalamic therapeutic targets.
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http://dx.doi.org/10.1111/head.13516DOI Listing
April 2019

Functional connectivity of hypothalamus in chronic migraine with medication overuse.

Cephalalgia 2019 06 5;39(7):892-899. Epub 2019 Mar 5.

1 Department of Neurology, University Hospital of Toulouse, Toulouse, France.

Objective: To investigate the functional connectivity of the hypothalamus in chronic migraine compared to interictal episodic migraine in order to improve our understanding of migraine chronification.

Methods: Using task-free fMRI and ROI-to-ROI analysis, we compared anterior hypothalamus intrinsic connectivity with the spinal trigeminal nucleus in patients with chronic migraine (n = 25) to age- and sex-matched patients with episodic migraine in the interictal phase (n = 22). We also conducted a seed-to-voxel analysis with anterior hypothalamus as a seed.

Results: All patients with chronic migraine had medication overuse. We found a significant connectivity (T = 2.08, p = 0.024) between anterior hypothalamus and spinal trigeminal nucleus in the chronic group, whereas these two regions were not connected in the episodic group. The strength of connectivity was not correlated with pain intensity (rho: 0.09, p = 0.655). In the seed-to-voxel analysis, three regions were more connected with the anterior hypothalamus in the chronic group: The spinal trigeminal nuclei (MNI coordinate x = 2, y = -44, z = -62), the right dorsal anterior insula (MNI coordinate x = 10, y = 10, z = 18), and the right caudate (MNI coordinate x = 12, y = 28, z = 6). However, these correlations were no longer significant after whole brain FWE correction.

Conclusion: An increased functional connectivity between the anterior hypothalamus and the spinal trigeminal nucleus, as previously reported in preictal episodic migraine, was demonstrated in chronic migraine with medication overuse. This finding confirms a major role of the anterior hypothalamus in migraine and suggests that chronic migraineurs are locked in the preictal phase.
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http://dx.doi.org/10.1177/0333102419833087DOI Listing
June 2019

Cerebral autoregulation in migraine with aura: A case control study.

Cephalalgia 2019 04 8;39(5):635-640. Epub 2018 Oct 8.

1 Department of Neurology, University Hospital of Toulouse, Toulouse, France.

Background: Migraine with aura is independently associated with increased risk of ischemic stroke, especially in younger subjects. This association might be related to an impairment of cerebral autoregulation, which normally maintains cerebral blood flow independent of arterial blood pressure variations.

Methods: Patients aged 30-55, fulfilling ICHD-3 beta criteria for migraine with aura, were prospectively enrolled and compared with gender- and age-matched healthy controls without a history of migraine. Patients and controls with a history of stroke or any disease potentially impairing cerebral autoregulation were excluded. We assessed cerebral autoregulation with two different methods: Transfer function analysis, and the correlation coefficient index Mx. The transfer function phase and gain reflect responses of cerebral blood flow velocities to relatively fast fluctuations of arterial blood pressure, whereas Mx also reflects responses to slower arterial blood pressure fluctuations.

Results: A total of 22 migraine with aura patients (median age [IQR]: 39.5 [12.5] years) and 22 controls (39 [9.75] years) were included. Transfer function parameters and Mx were not different between patients and controls. However, Mx was inversely correlated with age in patients (ρ = -0.567, p = 0.006) and not in controls (ρ = -0.084, p = 0.509). Mx was also inversely correlated with migraine with aura duration (ρ = -0.617, p = 0.002), suggesting improvement of cerebral autoregulation efficiency with disease duration.

Conclusions: Cerebral autoregulation did not differ between patients and controls aged 30-55. However, cerebral autoregulation efficiency was strongly correlated with migraine with aura duration. Further studies in younger patients are needed to determine whether cerebral autoregulation is impaired early in the course of disease.

Trial Registration: NCT02708797.
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http://dx.doi.org/10.1177/0333102418806861DOI Listing
April 2019

Advanced glycation end products-induced insulin resistance involves repression of skeletal muscle GLUT4 expression.

Sci Rep 2018 05 25;8(1):8109. Epub 2018 May 25.

Departament of Physiology and Biophysics, Institute of Biomedical Sciences, Universidade de São Paulo, São Paulo, Brazil.

Little is known about advanced glycation end products (AGEs) participation in glucose homeostasis, a process in which skeletal muscle glucose transporter GLUT4 (Scl2a4 gene) plays a key role. This study investigated (1) the in vivo and in vitro effects of AGEs on Slc2a4/GLUT4 expression in skeletal muscle of healthy rats, and (2) the potential involvement of endoplasmic reticulum and inflammatory stress in the observed regulations. For in vivo analysis, rats were treated with advanced glycated rat albumin (AGE-albumin) for 12 weeks; for in vitro analysis, soleus muscles from normal rats were incubated with bovine AGE-albumin for 2.5 to 7.5 hours. In vivo, AGE-albumin induced whole-body insulin resistance; decreased (~30%) Slc2a4 mRNA and GLUT4 protein content; and increased (~30%) the nuclear content of nuclear factor NF-kappa-B p50 subunit (NFKB1), and cellular content of 78 kDa glucose-regulated protein (GRP78). In vitro, incubation with AGE-albumin decreased (~50%) the Slc2a4/GLUT4 content; and increased cellular content of GRP78/94, phosphorylated-IKK-alpha/beta, nuclear content of NFKB1 and RELA, and the nuclear protein binding into Slc2a4 promoter NFKB-binding site. The data reveal that AGEs impair glucose homeostasis in non-diabetic states of increased AGEs concentration; an effect that involves activation of endoplasmic reticulum- and inflammatory-stress and repression of Slc2a4/GLUT4 expression.
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http://dx.doi.org/10.1038/s41598-018-26482-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970140PMC
May 2018

N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats.

Front Physiol 2017 22;8:723. Epub 2017 Sep 22.

Laboratorio de Lipides, LIM-10, Faculdade de Medicina, Hospital das Clinicas, Universidade de São PauloSão Paulo, Brazil.

Advanced glycation endproducts elicit inflammation. However, their role in adipocyte macrophage infiltration and in the development of insulin resistance, especially in the absence of the deleterious biochemical pathways that coexist in diabetes mellitus, remains unknown. We investigated the effect of chronic administration of advanced glycated albumin (AGE-albumin) in healthy rats, associated or not with N-acetylcysteine (NAC) treatment, on insulin sensitivity, adipose tissue transcriptome and macrophage infiltration and polarization. Male Wistar rats were intraperitoneally injected with control (C) or AGE-albumin alone, or, together with NAC in the drinking water. Biochemical parameters, lipid peroxidation, gene expression and protein contents were, respectively, determined by enzymatic techniques, reactive thiobarbituric acid substances, RT-qPCR and immunohistochemistry or immunoblot. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/mass spectrometry (LC-MS/MS) and ELISA. CML and PYR were higher in AGE-albumin as compared to C. Food consumption, body weight, systolic blood pressure, plasma lipids, glucose, hepatic and renal function, adipose tissue relative weight and adipocyte number were similar among groups. In AGE-treated animals, insulin resistance, adipose macrophage infiltration and mRNA were increased with no changes in M1 and M2 phenotypes as compared to C-albumin-treated rats. Total GLUT4 content was reduced by AGE-albumin as compared to C-albumin. NAC improved insulin sensitivity, reduced urine TBARS, adipose macrophage number and and and increased and . CD11b, CD206, , expressions were similar among groups. AGE-albumin sensitizes adipose tissue to inflammation due to macrophage infiltration and reduces GLUT4, contributing to insulin resistance in healthy rats. NAC antagonizes AGE-albumin and prevents insulin resistance. Therefore, it may be a useful tool in the prevention of AGE action on insulin resistance and long-term complications of DM.
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http://dx.doi.org/10.3389/fphys.2017.00723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5616024PMC
September 2017

Hormetic modulation of hepatic insulin sensitivity by advanced glycation end products.

Mol Cell Endocrinol 2017 05 24;447:116-124. Epub 2017 Feb 24.

Laboratório de Carboidratos e Radioimunoensaios (Laboratório de Investigações Médicas, LIM-18), Faculdade de Medicina, Universidade de São Paulo (FMUSP), Brazil. Electronic address:

Because of the paucity of information regarding metabolic effects of advanced glycation end products (AGEs) on liver, we evaluated effects of AGEs chronic administration in (1) insulin sensitivity; (2) hepatic expression of genes involved in AGEs, glucose and fat metabolism, oxidative stress and inflammation and; (3) hepatic morphology and glycogen content. Rats received intraperitoneally albumin modified (AlbAGE) or not by advanced glycation for 12 weeks. AlbAGE induced whole-body insulin resistance concomitantly with increased hepatic insulin sensitivity, evidenced by activation of AKT, inactivation of GSK3, increased hepatic glycogen content, and decreased expression of gluconeogenesis genes. Additionally there was reduction in hepatic fat content, in expression of lipogenic, pro-inflamatory and pro-oxidative genes and increase in reactive oxygen species and in nuclear expression of NRF2, a transcription factor essential to cytoprotective response. Although considered toxic, AGEs become protective when administered chronically, stimulating AKT signaling, which is involved in cellular defense and insulin sensitivity.
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http://dx.doi.org/10.1016/j.mce.2017.02.035DOI Listing
May 2017

N-Acetyl Cysteine Attenuated the Deleterious Effects of Advanced Glycation End-Products on the Kidney of Non-Diabetic Rats.

Cell Physiol Biochem 2016 30;40(3-4):608-620. Epub 2016 Nov 30.

Laboratório de Carboidratos e Radioimunoensaios (LIM-18), Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil.

Aim: To assess the renal effects of chronic exposure to advanced glycation end-products (AGEs) in the absence of diabetes and the potential impact of concomitant treatment with the antioxidant N-acetyl cysteine (NAC).

Methods: Wistar rats received intraperitoneally 20 mg/kg/day of albumin modified (AlbAGE) or not (AlbC) by advanced glycation for 12 weeks and oral NAC (600mg/L; AlbAGE+NAC and AlbC+NAC, respectively). Biochemical, urinary and renal morphological analyses; carboxymethyl-lysine (CML, an AGE), CD68 (macrophage infiltration), and 4-hydroxynonenal (4-HNE, marker of oxidative stress) immunostaining; intrarenal mRNA expression of genes belonging to pathways related to AGEs (Ager, Ddost, Nfkb1), renin-angiotensin system (Agt, Ren, Ace), fibrosis (Tgfb1, Col4a1), oxidative stress (Nox4, Txnip), and apoptosis (Bax, Bcl2); and reactive oxidative species (ROS) content were performed.

Results: AlbAGE significantly increased urine protein-to-creatinine ratio; glomerular area; renal CML content and macrophage infiltration; expression of Ager, Nfkb1, Agt, Ren, Tgfb1, Col4a1, Txnip, Bax/Bcl2 ratio; and 4-HNE and ROS contents. Some of these effects were attenuated by NAC concomitant treatment.

Conclusion: Because AGEs are highly consumed in modern diets and implicated in the progression of different kidney diseases, NAC could be a therapeutic intervention to decrease renal damage, considering that long-term restriction of dietary AGEs is difficult to achieve in practice.
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http://dx.doi.org/10.1159/000452574DOI Listing
February 2017

Delayed-onset Friedreich's ataxia revisited.

Mov Disord 2016 Jan 21;31(1):62-9. Epub 2015 Sep 21.

Département de Neurologie, Hôpital de Hautepierre, CHU de Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France; and Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

Background: Friedreich's ataxia usually occurs before the age of 25. Rare variants have been described, such as late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, occurring after 25 and 40 years, respectively. We describe the clinical, functional, and molecular findings from a large series of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia and compare them with typical-onset Friedreich's ataxia.

Methods: Phenotypic and genotypic comparison of 44 late-onset Friedreich's ataxia, 30 very late-onset Friedreich's ataxia, and 180 typical Friedreich's ataxia was undertaken.

Results: Delayed-onset Friedreich's ataxia (late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia) had less frequently dysarthria, abolished tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, ganglionopathy, cerebellar atrophy, scoliosis, and cardiomyopathy than typical-onset Friedreich's ataxia, along with less severe functional disability and shorter GAA expansion on the smaller allele (P < 0.001). Delayed-onset Friedreich's ataxia had lower scale for the assessment and rating of ataxia and spinocerebellar degeneration functional scores and longer disease duration before wheelchair confinement (P < 0.001). Both GAA expansions were negatively correlated to age at disease onset (P < 0.001), but the smaller GAA expansion accounted for 62.9% of age at onset variation and the larger GAA expansion for 15.6%. In this comparative study of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, no differences between these phenotypes were demonstrated.

Conclusion: Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as "delayed-onset Friedreich's ataxia." As the most frequently inherited ataxia, Friedreich's ataxia should be considered facing compatible pictures, including atypical phenotypes (spastic ataxia, retained reflexes, lack of dysarthria, and lack of extraneurological signs), delayed disease onset (even after 60 years of age), and/or slow disease progression.
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http://dx.doi.org/10.1002/mds.26382DOI Listing
January 2016

Prevalence and pharmacological factors associated with impulse-control disorder symptoms in patients with Parkinson disease.

Clin Neuropharmacol 2012 Nov-Dec;35(6):261-5

Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, Toulouse, France.

Background: Impulse-control disorders (ICDs) occur in patients with Parkinson disease (PD), especially in younger patients on dopamine therapies.

Objective: To assess the prevalence of ICD symptoms and its pharmacological correlations in a sample of French patients with PD and without PD (poststroke).

Methods: Outpatients with PD and without PD (poststroke) were screened for compulsive behaviors related to hypersexuality, compulsive shopping, pathological gambling, or compulsive eating by means of the Questionnaire for Impulse-Control Disorders--short version. Full medical history and Unified Parkinson's Disease Rating Scale scores were also recorded. Dose of dopamine agonists were converted to defined daily doses (DDDs), according to the World Health Organization Anatomical Therapeutic Chemical classification system classification system.

Results: Two hundred three patients with PD and 52 patients without PD were recruited (mean ± SD age, 67 ± 1 vs 69 ± 2, P= 0.4; males: 62% vs 55% P= 0.2). Symptoms of ICDs were reported by 0% of poststroke patients and 25% of the patients with PD (P < 0.001). Hypersexuality was reported by 10% of the patients with PD, compulsive shopping by 6%, pathological gambling by 3%, and compulsive eating by 14%. A logistic regression analysis found that age younger than 68 years (odds ratio [OR], 3.3; 95% confidence interval, 1.6-6.6) and exposure to dopamine agonists (OR, 20.3; 95% confidence interval, 2.7-65.0) or monoaminooxidase-B inhibitor (OR, 3.7; 95% confidence interval, 1.1-12.6) were significant factors associated with increased ICD frequency. Patients with ICD symptoms were exposed to higher dopamine doses than those without them (1.6 ± 0.1 vs 1.0 ± 0.1 daily-defined doses; P < 0.001). A dose-response pharmacodynamic model disclosed a significant nonlinear dose-response relationship between dopamine agonists and frequency of ICD symptoms (P < 0.01).

Conclusions: Impulse-control disorder symptoms were more frequent in the patients with PD than in the poststroke patients with PD. Impulse-control disorder symptoms were related to younger age and exposure to monoaminooxidase-B inhibitors, and showed a nonlinear dose-response relationship with dopamine agonists.
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http://dx.doi.org/10.1097/WNF.0b013e31826e6e6dDOI Listing
August 2013

Factors related to orthostatic hypotension in Parkinson's disease.

Parkinsonism Relat Disord 2012 Jun 13;18(5):501-5. Epub 2012 Feb 13.

Laboratoire de Pharmacologie Médicale et Clinique, INSERM U 1027 Equipe de PharmacoEpidémiologie, l'Université de Toulouse, Toulouse, France.

Introduction: Orthostatic hypotension (OH), a frequent feature of Parkinson's disease (PD) can contribute to falls and is usually related to the disease itself and/or to drugs.

Objectives: To explore factors related to OH and to assess the concordance between abnormal blood pressure (BP) fall after standing and the presence of orthostatic symptoms.

Methods: Non-demented, non-operated idiopathic PD out-patients were questioned about the presence of orthostatic symptoms. Afterward, BP was measured 5-min after lying down and for 3-min after standing up. OH was defined as systolic and/or diastolic BP fall ≥ 20 and/or 10 mmHg after standing. Patients were further evaluated by the Unified PD Rating Scale (UPDRS) and their medications were recorded.

Results: 103 patients were included in this study (mean age = 66 ± 1 years, mean disease duration = 9 ± 1 years; mean UPDRS II+III in ON-state = 37 ± 2 points). Forty-one subjects (40%) reported the presence of orthostatic symptoms during the previous week and 38 (37%) had OH according to manometric definition. Independent factors related to OH, as assessed by logistic regression were age >68 years (OR, 95% CI=3.61, 1.31-9.95), polypharmacy (defined as intake of >5 medications, OR = 3.59, 1.33-9.69), amantadine (7.45, 1.91-29.07) or diuretics (5.48, 1.10-54.76), whereas the consumption of entacapone was protective (0.20, 0.05-0.76). The agreement between abnormal BP fall and presence of orthostatic symptoms was poor (kappa = 0.12 ± 0.1, p = 0.23).

Conclusion: OH was significantly related to older age, polypharmacy and amantadine or diuretics intake, while entacapone exposure appeared to reduce the risk of OH. Low concordance between OH and orthostatic symptoms was observed.
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http://dx.doi.org/10.1016/j.parkreldis.2012.01.012DOI Listing
June 2012

Do Parkinson's disease patients disclose their adverse events spontaneously?

Eur J Clin Pharmacol 2012 May 29;68(5):857-65. Epub 2011 Dec 29.

Laboratoire de Pharmacologie Médicale et Clinique, INSERM U 1027 Equipe de PharmacoEpidémiologie, Faculté de Médecine, Université de Toulouse, Toulouse, France.

Background: Underreporting of adverse drug reactions is common but has been rarely studied in Parkinson's disease (PD).

Objective: To compare the prevalence of adverse events (AEs) in relation to antiparkinsonian drugs in PD patients using two different data collection methods: patient's spontaneous reporting versus a predefined investigator-driven structured interview. Secondary objectives were to assess factors related to spontaneous reporting and to compare the rate of AE reporting in PD patients with that of a group of non-parkinsonian post-stroke patients.

Study Design: Cross-sectional study.

Patients: Ambulatory, cognitively intact PD or post-stroke outpatients.

Interventions: None.

Outcome Measures: Patients were first asked by means of an an open question to disclose any unpleasant effects in connection with their current medications that had occurred during the previous week. Afterwards, a predefined questionnaire listing the most common AEs known to be related to antiparkinsonian drugs was used to question the same patients in a systematic manner about the presence of any AE during the same week. Chronological and semiological criteria were used to classify the reported AEs as "unrelated" or "possibly/plausibly related" to the antiparkinsonian treatment.

Results: A total of 203 PD and 52 post-stroke patients of comparable age and sex were recruited. Eighty-five PD and five post-stroke patients reported spontaneously at least one AE (42 vs. 10%, p < 0.01), while 203 PD and 47 post-stroke patients reported at least one AE following the structured questionnaire (100 vs. 90%, p < 0.001). In PD patients, there were a total of 112 spontaneously reported AEs as compared with 1,574 according to the structured questionnaire (7%). Spontaneous disclosure of AEs was associated with experiencing >2 AEs [OR = 1.2 (1.1-3.2)], logistic regression). Seventy-four percent of PD patients had ≥1 AE possibly/plausibly related to antiparkinsonian drugs.

Conclusions: Results showed that only 7% of AEs were reported spontaneously by patients, thus underscoring the importance of systematically asking about AEs in PD patients.
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http://dx.doi.org/10.1007/s00228-011-1198-xDOI Listing
May 2012

Treatment of refractory chronic cluster headache by chronic occipital nerve stimulation.

Cephalalgia 2011 Jul 4;31(10):1101-5. Epub 2011 Jul 4.

Centre Hospitalier Universitaire de Nice, France.

Background: Greater occipital nerve stimulation (ONS) has been recently proposed to treat severe chronic cluster headache patients (CCH) refractory to medical treatment. We report the results of a French multidisciplinary cohort study.

Methods: Thirteen CCH patients were operated and data were collected prospectively. All of them suffered from CCH according to the International Headache Society classification, lasting for more than 2 years, refractory to pharmacological prophylactic treatment with adequate trials, with at least one daily attack. Chronic ONS was delivered through a subcutaneous occipital electrode connected to an implanted generator, in order to induce paraesthesias perceived locally in the lower occipital region.

Results: After surgery (mean follow-up 14,6 months), the mean attack frequency and intensity decreased by 68% and 49%, respectively. At last follow-up, 10/13 patients were considered as responders (improvement >50%). Prophylactic treatment could be stopped or reduced in 8/13 cases. Local infection occurred in one patient, leading to hardware removal.

Conclusions: Our data confirmed the results of the 36 similar cases reported in the literature, suggesting that ONS may act as a prophylactic treatment in chronic CH. Considering their respective risks, ONS should be proposed before deep brain stimulation in severe refractory CCH patients.
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http://dx.doi.org/10.1177/0333102411412086DOI Listing
July 2011

Photophobia in migraine: an interictal PET study of cortical hyperexcitability and its modulation by pain.

J Neurol Neurosurg Psychiatry 2010 Sep 30;81(9):978-84. Epub 2010 Jun 30.

Service de Neurologie et Explorations Fonctionnelles du Système Nerveux, CHU Rangueil, 31059 Toulouse Cedex 9, France.

Objective: Photophobia is an abnormal sensitivity to light experienced by migraineurs and is perhaps caused by cortical hyperexcitability. In clinical studies, an inter-relation between light perception and trigeminal nociception has been demonstrated in migraineurs but not in controls. The purpose of the study was to verify this interaction by functional imaging.

Methods: The authors used H(2)O(15) positron emitting tomography (PET) to study the cortical responses of seven migraineurs between attacks and the responses of seven matched control subjects to luminous stimulations at three luminance intensities: 0, 600 and 1800 Cd/m(2). All three intensities were both with and without concomitant trigeminal pain stimulation. In order to facilitate habituation, the stimulations were started 30 s before PET acquisitions.

Results: When no concomitant pain stimulation was applied, luminous stimulations activated the visual cortex bilaterally in migraineurs (specifically in the cuneus, lingual gyrus and posterior cingulate cortex) but not in controls. Concomitant pain stimulation allowed visual cortex activation in control subjects and potentiated its activation in migraineurs. These activations by luminous stimulations were luminance-intensity-dependent in both groups. Concomitant stimulation by pain was associated with activation of the posterior parietal cortex (BA7) in migraineurs and controls.

Interpretation: The study shows the lack of habituation and/or cortical hyperexcitability to light in migraineurs. Moreover, the activation by light of several visual cortex areas (including the primary visual cortex) was potentiated by trigeminal pain, demonstrating multisensory integration in these areas.
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http://dx.doi.org/10.1136/jnnp.2009.190223DOI Listing
September 2010

Anatomical location of effective deep brain stimulation electrodes in chronic cluster headache.

Brain 2010 Apr 17;133(Pt 4):1214-23. Epub 2010 Mar 17.

Centre Hospitalier Universitaire de Nice-Neurosurgery, Nice, France.

Deep brain stimulation of the posterior hypothalamus is a therapeutic approach to the treatment of refractory chronic cluster headache, but the precise anatomical location of the electrode contacts has not been clearly assessed. Our aim was to study the location of the contacts used for chronic stimulation, projecting each contact centre on anatomic atlases. Electrodes were implanted in a series of 10 patients (prospective controlled trial) in the so-called 'posteroinferior hypothalamus' according to previously described coordinates, i.e. 2 mm lateral, 3 mm posterior and 5 mm below the mid-commissural point. The coordinates of the centre of each stimulating contact were measured on postoperative computed tomography or magnetic resonance imaging scans, taking into account the artefact of the electrode. Each contact centre (n=10; left and right hemispheres pooled) was displayed on the Schaltenbrand atlas and a stereotactic three dimensional magnetic resonance imaging atlas (4.7 tesla) of the diencephalon-mesencephalic junction for accurate anatomical location. Of the 10 patients with 1-year follow-up, 5 responded to deep brain stimulation (weekly frequency of attacks decrease >50%). In responders, the mean (standard deviation) coordinates of the contacts were 2.98 (1.16) mm lateral, 3.53 (1.97) mm posterior and 3.31 (1.97) mm below the mid-commissural point. All the effective contacts were located posterior to the hypothalamus. In responders, structures located <2 mm from the centres of effective contacts were: the mesencephalic grey substance (5/5), the red nucleus (4/5), the fascicle retroflexus (4/5), the fascicle longitudinal dorsal (3/5), the nucleus of ansa lenticularis (3/5), the fascicle longitudinal medial (1/5) and the thalamus superficialis medial (1/5). The contact coordinates (Wilcoxon test) and the structures (Fisher's exact test) were not significantly different between responders and non-responders. These findings suggest that failure of deep brain stimulation treatment in cluster headache may be due to factors unrelated to electrode misplacement. They also suggest that the therapeutic effect is probably not related to direct hypothalamic stimulation. Deep brain stimulation might modulate either a local cluster headache generator, located in the hypothalamus or in the mesencephalic grey substance, or non-specific anti-nocioceptive systems.
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http://dx.doi.org/10.1093/brain/awq041DOI Listing
April 2010

Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension.

J Headache Pain 2010 Feb;11(1):23-31

Department of Neurosurgery, Centre Hospitalier Universitaire de Nice, Nice, France.

Chronic cluster headache (CCH) is a disabling primary headache, considering the severity and frequency of pain attacks. Deep brain stimulation (DBS) has been used to treat severe refractory CCH, but assessment of its efficacy has been limited to open studies. We performed a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic DBS in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity,sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions.During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation(weekly frequency of attacks decrease [50%), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies (clinicaltrials.gov number NCT00662935).
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http://dx.doi.org/10.1007/s10194-009-0169-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3452182PMC
February 2010

One or several types of triptan overuse headaches?

Headache 2009 Apr 25;49(4):519-28. Epub 2009 Feb 25.

Department of Neurology, Saint-Etienne Hospital, Saint-Etienne University, INSERM U879, Saint-Etienne, France.

Background: Whereas the clinical features of pure triptan overuse headache (TOH) are well known, there are insufficient data regarding the semiological pattern of headaches when triptan overuse is associated with other types of medication overuse.

Objective: To investigate and compare the clinical characteristics of patients with pure TOH and those with medication overuse headaches associating triptan and other medication overuses (combined TOH).

Methods: This cross-sectional, observational study was conducted in 7 tertiary-care headache centers participating in the French Observatory of Migraine and Headaches. From 2004 to 2006, data from 163 patients with TOH were collected in face-to-face structured interviews (according to the International Classification of Headache Disorders, 2nd edition criteria).

Results: Eighty-two patients fulfilled criteria for pure TOH (pTOH patients) and 81 for combined TOH (cTOH) patients. Continuous headaches were reported in 76% of cTOH patients compared with 32% of pTOH patients. Significantly more frequent and severe headaches and more intense phono-/photophobia between attacks were noted in cTOH patients. More cTOH than pTOH patients reported a history of tension-type headaches and a long-standing history of chronic headaches. Finally, compared with pTOH patients, cTOH patients were characterized by stronger dependence on acute treatments of headaches according to the DSM-IV criteria.

Conclusions: Combined therapy with analgesics and/or the total number of drug units taken per day may cause a shift from a pattern of clear-cut headache attacks in patients with pTOH toward more severe clinical presentation in patients with cTOH. These patients should receive more intensive prophylactic therapy and specific behavioral management.
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http://dx.doi.org/10.1111/j.1526-4610.2009.01365.xDOI Listing
April 2009

Behavioral dependence in patients with medication overuse headache: a cross-sectional study in consulting patients using the DSM-IV criteria.

Headache 2008 Jul 11;48(7):1026-36. Epub 2007 Dec 11.

Department of Treatment of Chronic Pain Patients, Pellegrin University Hospital, Bordeaux, France.

Objective: The aim of this study was to assess behavioral dependence on migraine abortive drugs in medication-overuse headache (MOH) patients and identify the predisposing factors.

Background: It is common occurrence that MOH patients relapse after medication withdrawal. Behavioral determinants of medication overuse should therefore be identified in MOH patients.

Methods: This was a cross-sectional, multicenter study that included 247 MOH patients (according to International Classification of Headache Disorders, 2nd edition criteria) consulting in French headache specialty centers. Face-to-face interviews were conducted by senior neurologists using a structured questionnaire including the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for the evaluation of dependence, Hospital Anxiety and Depression Scale for the evaluation of anxiety and depression, and 6-item short-form Headache Impact Test scale for the determination of functional impact.

Results: Most MOH patients had pre-existing primary migraine (87.4%) and current migraine-type headaches (83.0%). Treatments overused included triptans (45.8%), opioid analgesics alone or in combination (43.3% of patients), and analgesics (27.9%). Nonmigraine abortive substances (tobacco, caffeine, sedatives/anxiolytics) were overused by 13.8% of patients. Two-thirds of MOH patients (66.8%) were considered dependent on acute treatments of headaches according to the DSM-IV criteria. Most dependent MOH patients had migraine as pre-existing primary headache (85.7%) and current migraine-type headaches (87.9%), and most of them overused opioid analgesics. More dependent than nondependent MOH patients were dependent on psychoactive substances (17.6% vs 6.1%). Multivariate logistic analysis indicated that risk factors of dependence on acute treatments of headaches pertained both to the underlying disease (history of migraine, unilateral headaches) and to drug addiction (opioid overuse, previous withdrawal). Affective symptoms did not appear among the predictive factors of dependence.

Conclusion: In some cases, MOH thus appears to belong to the spectrum of addictive behaviors. In clinical practice, behavioral management of MOH should be undertaken besides pharmacological management.
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http://dx.doi.org/10.1111/j.1526-4610.2007.00999.xDOI Listing
July 2008

Hypothalamic activation in spontaneous migraine attacks.

Headache 2007 Nov-Dec;47(10):1418-26

Neurology Service, Rangueil Hospital, Toulouse Cedex 9, France.

Background: Migraine sufferers experience premonitory symptoms which suggest that primary hypothalamic dysfunction is a likely trigger of the attacks. Neuroendocrine and laboratory data also support this hypothesis. To date, positron emission tomography (PET) scans of migraine sufferers have demonstrated activation of brainstem nuclei, but not of the hypothalamus.

Objective: To record cerebral activations withH2 15OPET during spontaneous migraine without aura attacks.

Methods: We scanned 7 patients with migraine without aura (6 females and 1 male) in each of 3 situations: within 4 hours of headache onset, after headache relief by sumatriptan injection (between the fourth and the sixth hour after headache onset), and during an attack-free period.

Results: During the headache we found not only significant activations in the midbrain and pons, but also in the hypothalamus, all persisting after headache relief by sumatriptan.

Conclusion: Hypothalamic activity, long suspected by clinical and experimental arguments as a possible trigger for migraine, is demonstrated for the first time during spontaneous attacks.
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http://dx.doi.org/10.1111/j.1526-4610.2007.00776.xDOI Listing
March 2008

Does ageing influence deep brain stimulation outcomes in Parkinson's disease?

Mov Disord 2007 Jul;22(10):1457-63

Department of Neurology, University Hospital CHU, Toulouse, France.

We sought to define the influence of ageing in clinical, cognitive, and quality-of-life outcomes after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). We performed motor assessment (UPDRS), mood tests, cognitive, and quality of life evaluation (PDQ-39) on PD patients before surgery, and 12 and 24 months after, and we recorded adverse events. The variations of these parameters after surgery were correlated with age using regression statistical tests. Cerebral bleeding risk was evaluated by a nonparametric test. We enrolled 45 patients (mean age 60 +/- 9 years, range 40-73). No significant correlation was found between age and motor scores and PDQ-39 improvements at 12 months. At 24 months, there was a significant negative correlation between age and the improvement of three dimensions of PDQ 39 (mobility, activities of daily life, and cognition). Cognitive impairment showed no correlation, but apathy and depression were positively correlated with age. Significant statistical difference was observed between cerebral bleeding and age. STN-DBS is an effective treatment for elderly patients with advanced PD. A longer follow-up duration and a larger population seem necessary to better assess the quality of life perception in elderly patients and to determinate the real risk of hemorrage.
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http://dx.doi.org/10.1002/mds.21547DOI Listing
July 2007

Cerebral autoregulation is preserved in multiple system atrophy: A transcranial Doppler study.

Mov Disord 2006 Dec;21(12):2122-6

Laboratory of Autonomic Nervous System and Neurosonology, Vascular Neurology Department, Hopital Rangueil, Toulouse, France.

Patients with multiple system atrophy (MSA) present large changes in blood pressure (BP) due to autonomic disturbances. We analyzed how this change may influence dynamic cerebral autoregulation (DCA). Simultaneous recordings of arterial BP (Finapres) and middle cerebral artery (MCA) blood flow velocity (BFV) (transcranial Doppler) were performed in 10 patients with MSA (61 +/- 12 yr of age) and 12 healthy volunteers (61 +/- 11 yr of age): cerebral BFV response to oscillations in mean BP was studied in the supine position by cross-spectral analysis of mean BP and mean MCA BFV. The DCA was also studied during the decrease in BP the first seconds when standing up from a sitting position by the assessment of the cerebrovascular resistance index (CR; mean BP/mean MCA BFV ratio). The MCA BFV/BP cross-spectral analysis showed a phase for the mid-frequency band (0.07-0.2 Hz) significantly larger in MSA, suggesting more active autoregulation in response to larger changes in BP. Changes in CR reflecting the rate of autoregulation, when standing did not differ between the two groups. These data suggest that dynamic cerebral autoregulation is preserved in MSA.
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http://dx.doi.org/10.1002/mds.21130DOI Listing
December 2006

[Triptan use in general practice: a French pharmacoepidemiological study].

Therapie 2004 Sep-Oct;59(5):533-9

Service de Pharmacologie Clinique, INSERM U586, Toulouse, France.

This French pharmacoepidemiological study describes triptan use in general practice for triptan 'naive' (never treated by a triptan before study inclusion) and 'non-naive' (already treated by a triptan) patients. Data from 1774 patients were analysed (81% women). The mean age of the patients was 41 years (+/-12.8). This study showed that 95% of the patients had a diagnosis of migraine according to the International Headache Society (IHS) criteria. This result confirmed the effective use of triptans by general practitioners. Migraines in patients treated with triptans in the present study were more severe than in subjects reporting migraine in the general population. 'Naive' and 'non-naive' patients had similar IHS diagnoses and severity profiles but, for 'non-naive' patients, the migraine history was longer and the disability (quality of life) reported was worse than for the 'naive' patients. The reasons for the treatment switch were the need for improved efficacy, a faster onset of action, fewer recurrences and better tolerability.
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http://dx.doi.org/10.2515/therapie:2004091DOI Listing
February 2005

Cortical motor activation in akinetic schizophrenic patients: a pilot functional MRI study.

Mov Disord 2004 Jan;19(1):83-90

INSERM U 455, and PET Center, University Hospital of Toulouse, France.

Akinesia is associated with supplementary motor area (SMA) dysfunction in Parkinson's disease. We looked for a similar association in patients with schizophrenia. Using functional magnetic resonance imaging (fMRI), we compared motor activation in 6 akinetic neuroleptic-treated schizophrenic patients and 6 normal subjects. Schizophrenic patients had a defective activation in the SMA, left primary sensorimotor cortex, bilateral lateral premotor and inferior parietal cortices, whereas the right primary sensorimotor cortex and a mesial frontal area were hyperactive. SMA was hypoactive in akinetic schizophrenic patients, emphasizing the role of this area in motor slowness. Other abnormal signals likely reflect schizophrenia-related abnormal intracortical connections.
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http://dx.doi.org/10.1002/mds.10598DOI Listing
January 2004

[Acute and chronic headache].

Rev Prat 2002 Feb;52(4):435-42

Service de neurologie, centre hospitalier universitaire Rangueil, Toulouse.

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February 2002