Publications by authors named "Alain Créange"

59 Publications

Testing the validity of a set of diagnostic criteria for sensory neuronopathies: a francophone collaborative study.

J Neurol 2014 Nov 10;261(11):2093-100. Epub 2014 Aug 10.

Centre de Référence Maladies Neuromusculaires Rares Rhône-Alpes, CHU de Saint-Etienne, Saint-Étienne, France,

There are no validated criteria for the diagnosis of sensory neuronopathy (SNN) yet. In a preliminary monocenter study a set of criteria relying on clinical and electrophysiological data showed good sensitivity and specificity for a diagnosis of probable SNN. The aim of this study was to test these criteria on a French multicenter study. 210 patients with sensory neuropathies from 15 francophone reference centers for neuromuscular diseases were included in the study with an expert diagnosis of non-SNN, SNN or suspected SNN according to the investigations performed in these centers. Diagnosis was obtained independently from the set of criteria to be tested. The expert diagnosis was taken as the reference against which the proposed SNN criteria were tested. The set relied on clinical and electrophysiological data easily obtainable with routine investigations. 9/61 (16.4 %) of non-SNN patients, 23/36 (63.9 %) of suspected SNN, and 102/113 (90.3 %) of SNN patients according to the expert diagnosis were classified as SNN by the criteria. The SNN criteria tested against the expert diagnosis in the SNN and non-SNN groups had 90.3 % (102/113) sensitivity, 85.2 % (52/61) specificity, 91.9 % (102/111) positive predictive value, and 82.5 % (52/63) negative predictive value. Discordance between the expert diagnosis and the SNN criteria occurred in 20 cases. After analysis of these cases, 11 could be reallocated to a correct diagnosis in accordance with the SNN criteria. The proposed criteria may be useful for the diagnosis of probable SNN in patients with sensory neuropathy. They can be reached with simple clinical and paraclinical investigations.
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http://dx.doi.org/10.1007/s00415-014-7423-7DOI Listing
November 2014

Association of antibodies to ganglioside complexes and conduction blocks in axonal Guillain-Barré syndrome presenting as acute motor conduction block neuropathy.

J Peripher Nerv Syst 2014 Jun;19(2):115-20

EA 4391, Excitabilité Nerveuse et Thérapeutique, Université Paris EST, Créteil, France; Service de Neurologie, Groupe Hospitalier Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France.

A close relationship between acute motor conduction block neuropathy and antibodies against the complex of GM1 and GalNAc-GD1a has been reported. This study investigates the hypothesis that conduction block at the early phase of axonal Guillain-Barré syndrome (GBS) is also associated with such ganglioside complexes. Sera were obtained from seven French patients with initial evidence of isolated conduction blocks that resolved or progressed to acute motor axonal neuropathy. Serum IgG to asialo-GM1 and gangliosides of LM1, GM1, GM1b, GD1a, GalNAc-GD1a, GD1b, GT1a, GT1b, and GQ1b as well as their complexes were measured. Five of seven patients progressed within the first month of disease to AMAN. One patient had IgG antibodies against the complex of asialo-GM1 and each of the other ganglioside antigens. Another patient carried IgG antibodies against GM1 complex with GM1b, GD1a, and GT1a as well as asialo-GM1 complex with GD1a and GT1a. None had IgG antibodies against GM1/GalNAc-GD1a complex. Six patients had IgG against single antigens GM1, GD1a, GalNAc-GD1a, GD1b, and asialo-GM1. In three patients, a reduced reaction against GM1/GalNAc-GD1a complex was observed. The presence of conduction block in axonal GBS is not always associated with anti-GM1/GalNAc-GD1a complex antibodies.
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http://dx.doi.org/10.1111/jns5.12060DOI Listing
June 2014

Sensory correlates of pain in peripheral neuropathies.

Clin Neurophysiol 2014 May 28;125(5):1048-58. Epub 2013 Oct 28.

Faculté de Médecine, Université Paris Est Créteil, EA 4391, Créteil, France; Service de Physiologie - Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, France. Electronic address:

Objective: To characterize sensory threshold alterations in peripheral neuropathies and the relationship between these alterations and the presence of pain.

Methods: Seventy-four patients with length-dependent sensory axonal neuropathy were enrolled, including 38 patients with painful neuropathy (complaining of chronic, spontaneous neuropathic pain in the feet) and 36 patients with painless neuropathy. They were compared to 28 age-matched normal controls. A standardized quantitative sensory testing protocol was performed in all individuals to assess large and small fiber function at the foot. Large fibers were assessed by measuring mechanical (pressure and vibration) detection thresholds and small fibers by measuring pain and thermal detection thresholds.

Results: Between patients with neuropathy and controls, significant differences were found for mechanical and thermal detection thresholds but not for pain thresholds. Patients with painful neuropathy and those with painless neuropathy did not differ regarding mechanical or thermal thresholds, but only by a higher incidence of thermal or dynamic mechanical allodynia in case of painful neuropathy. Pain intensity correlated with the alteration of thermal detection and mechanical pain thresholds.

Conclusions: Quantitative sensory testing can support the diagnosis of sensory neuropathy when considering detection threshold measurement. Thermal threshold deterioration was not associated with the occurrence of pain but with its intensity.

Significance: There is a complex relationship between the loss or functional deficit of large and especially small sensory nerve fibers and the development of pain in peripheral neuropathy.
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http://dx.doi.org/10.1016/j.clinph.2013.09.038DOI Listing
May 2014

The diagnosis of chronic inflammatory demyelinating polyneuropathy: a Delphi-method approach.

J Neurol 2013 Dec 20;260(12):3015-22. Epub 2013 Sep 20.

Service de Neurologie, Groupe Hospitalier Henri Mondor, AP-HP, Centre Hospitalier Universitaire Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010, Créteil, France,

The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) is based on a set of clinical and neurophysiological parameters. However, in clinical practice, CIDP remains difficult to diagnose in atypical cases. In the present study, 32 experts from 22 centers (the French CIDP study group) were asked individually to score four typical, and seven atypical, CIDP observations (TOs and AOs, respectively) reported by other physicians, according to the Delphi method. The diagnoses of CIDP were confirmed by the group in 96.9 % of the TO and 60.1 % of the AO (p < 0.0001). There was a positive correlation between the consensus of CIDP diagnosis and the demyelinating features (r = 0.82, p < 0.004). The European CIDP classification was used in 28.3 % of the TOs and 18.2 % of the AOs (p < 0.002). The French CIDP study group diagnostic strategy was used in 90 % of the TOs and 61 % of the AOs (p < 0.0001). In 3 % of the TOs and 21.6 % of the AOs, the experts had difficulty determining a final diagnosis due to a lack of information. This study shows that a set of criteria and a diagnostic strategy are not sufficient to reach a consensus for the diagnosis of atypical CIDP in clinical practice.
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http://dx.doi.org/10.1007/s00415-013-7100-2DOI Listing
December 2013

Sjögren Syndrome-Associated Small Fiber Neuropathy: Characterization From a Prospective Series of 40 Cases.

Medicine (Baltimore) 2013 Sep;92(5):e10-e18

From the Service de Médecine Interne 2, AP-HP, Hôpital Lariboisière, Université Paris Diderot-Paris 7, Paris (D. Sène, PJG); Service de Médecine Interne 2, AP-HP, Hôpital Pitié-Salpêtrière, Paris, Université, Pierre et Marie Curie-Paris 6, Paris (PC, JH, D. Saadoun, ZA); Centre de Référence des Maladies Neuromusculaire Garches-Necker-Mondor-Hendaye, AP-HP, Hôpital Henri Mondor; INSERM U955, Equipe 10, Université Paris Est-Créteil, Créteil (FJA); and Service de Neurologie (AC) and Service de Physiologie-Explorations Fonctionnelles (JPL), APHP, Hôpital Henri Mondor,Créteil, Université Paris Est-Créteil, Créteil; France.

We conducted the current study to analyze the clinical, immunologic, and neurophysiologic features of primary Sjögren syndrome (pSS)-associated sensory small fiber neuropathies (SFNs). Forty consecutive pSS patients with SFN were included. SFN was defined by the presence of suggestive sensory painful symptoms with normal nerve conduction studies and abnormal neurophysiologic tests for small nerve fibers or a low intraepidermal nerve fiber density at skin biopsy. Included patients were compared to 100 pSS patients without peripheral neuropathy.SFN patients were mainly female (92.5%). Age at pSS diagnosis was 55.3 ± 13.1 years, and at SFN diagnosis, 58.9 ± 11.8 years, with a median time to SFN diagnosis after symptom onset of 3.4 years. Clinical symptoms included burning pains (90%), numbness (87.5%), tingling (82.5%), pins and needles (72.5%), electric discharges (70%), and allodynia (55%). Dysautonomia included vasomotor symptoms (66%) and hyperhidrosis (47%). Abnormal neurophysiologic tests included laser evoked potentials (97.5%), thermal quantitative sensory testing (67.5%), and sympathetic skin reflex (40%). A skin biopsy revealed low intraepidermal nerve fiber density in 76% of the 17 tested patients.Compared to the 100 pSS patients without peripheral neuropathy, the 40 pSS-SFN patients were older at pSS diagnosis (55.3 ± 13.1 vs. 49.5 ± 14.9 yr; p = 0.03), and more often had xerostomia (97.5% vs. 81%; p = 0.01) and arthralgia (82.5% vs. 65.0%; p = 0.04). Immunologically, they were characterized by a lower prevalence of serum B-cell activation markers, that is, antinuclear antibodies (65% vs. 85%; p = 0.01), anti-SSA (42.5% vs. 71%; p = 0.002), and anti-SSB (17.5% vs. 39%; p = 0.017); rheumatoid factor (32.5% vs. 66%; p = 0.0005); and hypergammaglobulinemia (35% vs. 62%; p = 0.005).In conclusion, we report the main features of SFN in patients with pSS, the first such study to our knowledge. Our results show that patients with pSS-associated SFN are characterized by an older age at pSS diagnosis and a distinctive immunologic profile hallmarked by a lower frequency of serum B-cell activation markers.
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http://dx.doi.org/10.1097/MD.0000000000000005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553978PMC
September 2013

Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein neuropathy.

Neurology 2013 Jun 10;80(24):2217-25. Epub 2013 May 10.

Department of Neurology, University Hospital Pitié-Salpêtrière, Paris, France.

Objective: To determine whether rituximab 375 mg/m(2) was efficacious in patients with immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy).

Methods: Fifty-four patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) ≥4 and visual analog pain scale >4 or ataxia score ≥2. The primary outcome was mean change in ISS at 12 months.

Results: Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m(2) rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 ± 2.7 in the rituximab group, and 1.0 ± 2.8 in the placebo group. However, changes were observed, in per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p = 0.027), the self-evaluation scale (p = 0.016), and 2 subscores of the Short Form-36 questionnaire.

Conclusions: Although primary outcome measures provide no evidence to support the use of rituximab in IgM anti-MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per protocol analysis.

Level Of Evidence: This study provides Class I evidence that rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy.
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http://dx.doi.org/10.1212/WNL.0b013e318296e92bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721095PMC
June 2013

A clinical pattern-based etiological diagnostic strategy for sensory neuronopathies: a French collaborative study.

J Peripher Nerv Syst 2012 Sep;17(3):331-40

Département de Neurologie, Centre de Référence Maladies Neuromusculaires Rares Rhône-Alpes, CHU de Saint-Etienne, France.

Sensory neuronopathies (SNNs) encompass paraneoplastic, infectious, dysimmune, toxic, inherited, and idiopathic disorders. Recently described diagnostic criteria allow SNN to be differentiated from other forms of sensory neuropathy, but there is no validated strategy based on routine clinical investigations for the etiological diagnosis of SNN. In a multicenter study, the clinical, biological, and electrophysiological characteristics of 148 patients with SNN were analyzed. Multiple correspondence analysis and logistic regression were used to identify patterns differentiating between forms of SNNs with different etiologies. Models were constructed using a study population of 88 patients and checked using a test population of 60 cases. Four patterns were identified. Pattern A, with an acute or subacute onset in the four limbs or arms, early pain, and frequently affecting males over 60 years of age, identified mainly paraneoplastic, toxic, and infectious SNN. Pattern B identified patients with progressive SNN and was divided into patterns C and D, the former corresponding to patients with inherited or slowly progressive idiopathic SNN with severe ataxia and electrophysiological abnormalities and the latter to patients with idiopathic, dysimmune, and sometimes paraneoplastic SNN with a more rapid course than in pattern C. The diagnostic strategy based on these patterns correctly identified 84/88 and 58/60 patients in the study and test populations, respectively.
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http://dx.doi.org/10.1111/j.1529-8027.2012.00411.xDOI Listing
September 2012

Clinical and radiological characteristics in multiple sclerosis patients with large cavitary lesions.

Eur Neurol 2012 14;68(3):156-61. Epub 2012 Aug 14.

Department of Neurology, Centre Hospitalier Universitaire, Nimes, France.

Background: Large cavitary lesions are not typical for multiple sclerosis (MS). Cavitary white matter changes may be seen in megalencephalic leukoencephalopathy with subcortical cysts, Alexander disease, mitochondrial leukoencephalopathies, vanishing white matter disease, leukoencephalopathy with calcifications and cysts, cytomegalovirus infection, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Objective: To analyze clinical and radiological characteristics in MS patients with large cavitary lesions.

Methods: We studied MS patients with large cavitary brain lesions. Patient characteristics, disease onset/duration/subtype, expanded disability status scale (EDSS), mini mental state (MMS), corpus callosum lesions, history of segmental myelitis, CSF oligoclonal bands (OCB), visual evoked potentials (VEP), vanishing white matter disease genetic analysis, and characteristics of the cavitary lesions were analyzed.

Results: Nine patients were analyzed, 1 man and 8 women. Mean age of disease onset was 38.5 years. Mean disease duration was 9 years. Three patients had initial relapsing-remitting MS and 6 patients had primary-progressive MS. Mean EDSS was 4.5. Mean MMS was 20/30. Segmental myelitis was present in 6 cases. OCB were found in 6 patients. VEP was performed in 6 patients, and pathological in all but one. Vanishing white matter disease genetic analysis was performed and negative in 5 patients. Inferior corpus callosum lesions were seen in all patients with available sagittal FLAIR sequences. Cavitary lesions were strictly supratentorial, and located inside the diffuse leukoencephalopathy, with often a posterior predominance.

Conclusion: MS patients with large cavitary lesions seem to represent an MS subgroup, predominantly women, with relatively late disease onset, predominantly primary-progressive type, relatively high EDSS scores, and severe cognitive dysfunction.
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http://dx.doi.org/10.1159/000338476DOI Listing
March 2013

Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease.

Mult Scler 2012 Dec 28;18(12):1721-36. Epub 2012 Mar 28.

GeNeuro, Geneva, Switzerland.

Background: The envelope protein from multiple sclerosis (MS) associated retroviral element (MSRV), a member of the Human Endogenous Retroviral family 'W' (HERV-W), induces dysimmunity and inflammation.

Objective: The objective of this study was to confirm and specify the association between HERV-W/MSRV envelope (Env) expression and MS.

Methods: 103 MS, 199 healthy controls (HC) and controls with other neurological diseases (28), chronic infections (30) or autoimmunity (30) were analysed with an immunoassay detecting Env in serum. Env RNA or DNA copy numbers in peripheral blood mononuclear cells (PBMC) were determined by a quantitative polymerase chain reaction (PCR). Env was detected by immunohistology in the brains of patients with MS with three specific monoclonals.

Results: Env antigen was detected in a serum of 73% of patients with MS with similar prevalence in all clinical forms, and not in chronic infection, systemic lupus, most other neurological diseases and healthy donors (p<0.01). Cases with chronic inflammatory demyelinating polyneuropathy (5/8) and rare HC (4/103) were positive. RNA expression in PBMC and DNA copy numbers were significantly elevated in patients with MS versus HC (p<0.001). In patients with MS, DNA copy numbers were significantly increased in chronic progressive MS (secondary progressive MS vs relapsing-remitting MS (RRMS) p<0.001; primary progressive MS vs RRMS -<0.02). Env protein was evidenced in macrophages within MS brain lesions with particular concentrations around vascular elements.

Conclusion: The association between MS disease and the MSRV-type HERV-W element now appears quite strong, as evidenced ex-vivo from serum and PBMC with post-mortem confirmation in brain lesions. Chronic progressive MS, RRMS and clinically isolated syndrome show different ELISA (Enzyme-Linked Immunosorbent Assay) and/or PCR profiles suggestive of an increase with disease evolution, and amplicon sequencing confirms the association with particular HERV-W elements.
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http://dx.doi.org/10.1177/1352458512441381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573672PMC
December 2012

Injection of interferon-beta in the morning decreases flu-like syndrome in many patients with multiple sclerosis.

Clin Neurol Neurosurg 2011 May 26;113(4):316-22. Epub 2011 Jan 26.

Service de Neurologie, Hôpital Henri Mondor, AP-HP, Université Paris Est, Créteil, France.

Background: Although it is recommended that interferon-beta (IFNβ) injections be administered in the evening, it is possible that morning injections could more effectively decrease interleukin 6 secretion.

Methods: This study evaluated the effects of switching from an evening injection of IFNβ to a morning injection on the intensity of flu-like syndrome in patients with multiple sclerosis (MS). We performed an intervention study that consisted of a quantitative evaluation of IFNβ-related flu-like syndrome in a cohort of 105 MS patients. Patients with persistent flu-like reactions who injected IFNβ in the evening were encouraged to switch to morning injections. After one month, we evaluated various quantitative and qualitative changes (e.g., severity of flu-like syndrome, sleep quality, antipyretic drug use).

Results: Of the 98 patients (93%) who injected IFNβ in the evening, 88 (85%) had a persistent flu-like syndrome (the severity score was 3.92±0.26). A total of 50 (57%) patients switched to morning injections. One month after changing the injection time, 29 patients (58%) reported that their flu-like syndrome was decreased, 11 (24%) thought that it was unchanged and 9 (18%) thought that it was increased (p=0.014). In addition, 23 patients (48%) reported improved sleep (p=0.001), and 33 (68%) patients chose to continue morning injections, whereas 17 (32%) patients switched back to evening injections (p=0.024). Quantitative measures, however, indicated that there was no change in the severity of flu-like syndrome or the number of antipyretic doses taken for its management.

Conclusion: Morning injections qualitatively improved IFNβ-related flu-like syndrome and sleep. A change in IFNβ injection time from evening to morning could benefit a significant proportion of patients with MS.
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http://dx.doi.org/10.1016/j.clineuro.2010.12.013DOI Listing
May 2011

Nerve excitability changes after intravenous immunoglobulin infusions in multifocal motor neuropathy and chronic inflammatory demyelinating neuropathy.

J Neurol Sci 2010 May 10;292(1-2):63-71. Epub 2010 Mar 10.

Service de Physiologie, Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique, Hôpitaux de Paris, Créteil, France.

Intravenous immunoglobulin (IVIg) infusions may provide clinical benefits in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). The short delay in the clinical response to IVIg therapy is not consistent with a process of remyelination or axonal regeneration. We assessed whether or not the efficacy of IVIg infusions in MMN and CIDP could reflect changes in axonal membrane properties and nerve excitability. Ulnar motor nerve excitability was studied before and after three to five consecutive days of IVIg infusions (0.4 g/kg/day) in 10 patients with MMN, 10 patients with CIDP, and 10 neurological controls (CTRLs). Excitability recovery cycle, stimulus-response and strength-duration properties were investigated. The recovery cycle parameters (absolute and relative refractory period durations, refractoriness and supernormality) were similar in all groups and did not change after IVIg infusions. At baseline, patients with CIDP, but not with MMN, showed a reduced strength-duration time constant (chronaxie) and increased rheobase when compared to CTRLs. After IVIg infusions, strength-duration time constant remained stable in CTRLs, but decreased in patients with MMN or CIDP. Rheobase increased in the three groups after treatment. The decreased strength-duration time constant after IVIg infusions in patients with MMN or CIDP could reflect a reduction of persistent Na(+) current, able to limit intraaxonal Na(+) accumulation and then to produce neuroprotective effects. However, this could also reflect compensatory mechanisms that did not directly underlie the therapeutic effect. Whatever the underlying process, this result revealed that IVIgs were able to produce early nerve excitability changes.
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http://dx.doi.org/10.1016/j.jns.2010.02.002DOI Listing
May 2010

[Multiple sclerosis physiopathology].

Authors:
Alain Créange

Soins 2009 Nov(740):32-5

Service de Neurologie, Groupe Hospitalier Universitaire Albert-Chenevier/Henri-Mondor (AP-HP).

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November 2009

Cervical spondylotic amyotrophy presenting as dropped head syndrome.

Clin Neurol Neurosurg 2009 Dec 3;111(10):874-6. Epub 2009 Aug 3.

Service de Physiologie - Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, France.

We report a case of acute-onset dropped head syndrome in a 65-year-old patient in whom the diagnosis of amyotrophic lateral sclerosis (ALS) was initially proposed based on electromyographic signs of neck and shoulder muscle denervation. There were no signs of pyramidal involvement and the clinical and electromyographic signs of motor denervation never evolved beyond the neck and shoulder girdle muscles after a 6-year follow-up period, which argued against ALS. Other causes of dropped head syndrome were carefully ruled out based on clinical findings, electrodiagnostic studies and blood investigations. The restriction of muscle denervation to a few cervical myotomes, the presence of C3-C4 spondylotic changes without associated root or spinal cord compression, and the absence of an alternative explanation to the patient's symptoms strongly supported the diagnosis of cervical spondylotic amyotrophy (CSA). CSA is thought to result from spinal cord microcirculatory disturbances and secondary anterior horn cell degeneration due to ischemia. Our case enlarges the clinical spectrum of focal cervical anterior horn disease, which classically results in more distal monomelic atrophy affecting one or both upper limbs.
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http://dx.doi.org/10.1016/j.clineuro.2009.07.005DOI Listing
December 2009

Motor cortex stimulation for the treatment of refractory peripheral neuropathic pain.

Brain 2009 Jun 31;132(Pt 6):1463-71. Epub 2009 Mar 31.

Service Physiologie, Explorations Fonctionnelles, Hôpital Henri Mondor, 51 avenue de Lattre de Tassigny, Créteil Cedex, France.

Epidural motor cortex stimulation (MCS) has been proposed as a treatment for chronic, drug-resistant neuropathic pain of various origins. Regarding pain syndromes due to peripheral nerve lesion, only case series have previously been reported. We present the results of the first randomized controlled trial using chronic MCS in this indication. Sixteen patients were included with pain origin as follows: trigeminal neuralgia (n = 4), brachial plexus lesion (n = 4), neurofibromatosis type-1 (n = 3), upper limb amputation (n = 2), herpes zoster ophthalmicus (n = 1), atypical orofacial pain secondary to dental extraction (n = 1) and traumatic nerve trunk transection in a lower limb (n = 1). A quadripolar lead was implanted, under radiological and electrophysiological guidance, for epidural cortical stimulation. A randomized crossover trial was performed between 1 and 3 months postoperative, during which the stimulator was alternatively switched 'on' and 'off' for 1 month, followed by an open phase during which the stimulator was switched 'on' in all patients. Clinical assessment was performed up to 1 year after implantation and was based on the following evaluations: visual analogue scale (VAS), brief pain inventory, McGill Pain questionnaire, sickness impact profile and medication quantification scale. The crossover trial included 13 patients and showed a reduction of the McGill Pain questionnaire-pain rating index (P = 0.0166, Wilcoxon test) and McGill Pain questionnaire sensory subscore (P = 0.01) when the stimulator was switched 'on' compared to the 'off-stimulation' condition. However, these differences did not persist after adjustment for multiple comparisons. In the 12 patients who completed the open study, the VAS and sickness impact profile scores varied significantly in the follow-up and were reduced at 9-12 months postoperative, compared to the preoperative baseline. At final examination, the mean rate of pain relief on VAS scores was 48% (individual results ranging from 0% to 95%) and MCS efficacy was considered as good or satisfactory in 60% of the patients. Pain relief after 1 year tended to correlate with pain scores at 1 month postoperative, but not with age, pain duration or location, preoperative pain scores or sensory-motor status. Although the results of the crossover trial were slightly negative, which may have been due to carry-over effects from the operative and immediate postoperative phases, observations made during the open trial were in favour of a real efficacy of MCS in peripheral neuropathic pain. Analgesic effects were obtained on the sensory-discriminative rather than on the affective aspect of pain. These results suggest that the indication of MCS might be extended to various types of refractory, chronic peripheral pain beyond trigeminal neuropathic pain.
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http://dx.doi.org/10.1093/brain/awp035DOI Listing
June 2009

A case of POEMS syndrome treated by autologous hematopoietic stem-cell transplantation.

Nat Clin Pract Neurol 2008 Dec;4(12):686-91

Service de Neurologie, Hôpital Henri-Mondor, Créteil Cedex, France.

Background: A 55-year-old woman with no remarkable medical history presented to a neurology ward with a 17-week history of rapidly progressive gait difficulties that confined her to a wheelchair.

Investigations: Electroneuromyography, immunoelectrophoresis, bone radiography, lesion-targeted bone-marrow examination, blood tests.

Diagnosis: Neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome.

Management: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation.
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http://dx.doi.org/10.1038/ncpneuro0942DOI Listing
December 2008

Image of the month. Diagnosis of endoneural sciatic nerve invasion by uterine cervical epidermoid cancer using [18F]FDG-PET/CT.

Eur J Nucl Med Mol Imaging 2007 Oct 3;34(10):1711-2. Epub 2007 Aug 3.

Department of Nuclear Medicine, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.

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http://dx.doi.org/10.1007/s00259-007-0510-6DOI Listing
October 2007

[Nerve conduction blocks and peripheral neuropathies].

J Soc Biol 2006 ;200(4):307-21

Service de Physiologie-Explorations Fonctionnelles, Hôpital Henri Mondor, Créteil Cedex, France.

A motor nerve conduction block is defined as a reduction of either amplitude or area of the compound motor action potential elicited by proximal vs. distal motor nerve stimulation. The pathophysiological mechanisms leading to a figure of conduction block include segmental demyelination, recent axonal interruption, or various axonal excitability abnormalities due to ion channel dysfunction or membrane potential changes. These processes can be related to compressive, ischemic or dysimmune inflammatory causes. The etiologic diagnosis is established on the combination of clinical, electrophysiological, and biological data. Among the neuropathies that feature nerve conduction blocks, there is a group of particular dysimmune multifocal neuropathies characterized by long-term persistent conduction blocks, including pure motor forms and sensori-motor forms. The clinical, electrophysiological, biological, and therapeutic specificities of these two types of neuropathy will be discussed.
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http://dx.doi.org/10.1051/jbio:2006036DOI Listing
September 2007

[Inflammatory demyelinating neuropathies: classification, evolution and prognosis].

J Soc Biol 2006 ;200(4):301-6

Service de Neurologie, Hôpital Henri Mondor, Créteil Cedex, France.

Inflammatory demyelinating neuropathies can be classified according to the topography of the nervous lesion. Acute and chronic polyradiculoneuritis are characterized by diffuse and multifocal, but predominantly proximal lesions, multifocal motor and sensory-motor neuropathies with persistent conduction blocks are restricted to some nerve trunks, while neuropathies due to monoclonal IgM with anti-MAG (Myelin Associated Glycoprotein) activity show distal and symmetric distribution. The clinical characteristics of inflammatory demyelinating neuropathies vary according to the type of neuropathy. Their course can be remittent or progressive but is especially marked by the risk of definitive axonal lesions, source of permanent neurological deficits. These neuropathies correspond to various mechanisms, which can be differentiated according to the antigenic target, the type of immunological disorder (with respect to cellular or humoral predominance), and the adapted therapeutic strategy. The inflammatory process is accompanied by energetic failure, leading to Na+/K+ pump impairment and intra-axonal Na+ accumulation. This failure results in Na+/Ca2+ exchanger activation, provoking neuronal Ca2+ influx, enzymatic proteolysis and axonal degeneration.
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http://dx.doi.org/10.1051/jbio:2006035DOI Listing
September 2007

Alteration of motor nerve recovery cycle in multiple sclerosis.

Clin Neurophysiol 2007 Aug 18;118(8):1753-8. Epub 2007 Jun 18.

Service de Physiologie, Explorations Fonctionnelles, Hôpital Henri Mondor, AP-HP, 51 avenue de Lattre de Tassigny, 94010 Créteil cedex, France.

Objective: To study peripheral motor nerve excitability in patients with multiple sclerosis (MS).

Methods: Twenty MS patients with normal nerve conduction parameters and no predisposing factors for peripheral neuropathy were included. Compound muscle action potentials were recorded from the abductor digiti minimi muscle to paired-pulse stimulation of the ulnar nerve at the wrist, with various interstimuli intervals (ISIs) ranging from 1 to 7 ms. The motor nerve recovery cycle was studied using a subtraction method. We measured the durations of the absolute and relative refractory periods (ARP, RRP) and the percentages of refractoriness and supernormality at 2.6 and 7 ms ISIs. The results obtained in MS patients were compared to normative values established in 20 age-matched healthy subjects. Correlations were made between excitability parameters and MS type (relapsing-remitting or progressive), EDSS score, disease duration, and motor evoked potential (MEP) abnormalities.

Results: Supernormality was extremely reduced, refractoriness was increased and both ARP and RRP were prolonged in MS patients vs. healthy controls. These alterations did not correlate to clinical features or to the presence of MEP abnormalities.

Conclusions: Changes in motor nerve recovery cycle revealed the existence of subtle impairment in the peripheral nervous system of MS patients, mainly characterized by a reduced supernormality.

Significance: Peripheral nerve excitability alterations in MS may be due to axoglial paranodal dysjunction or juxtaparanodal dysfunction.
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http://dx.doi.org/10.1016/j.clinph.2007.04.025DOI Listing
August 2007

Devic disease with brainstem lesions.

Arch Neurol 2006 Apr;63(4):591-3

Medical Reanimation Service, Pathology Department, Henri Mondor Hospital, 51 Avenue du Maréchal de Lattre de Tassigny, 94000 Créteil, France.

We describe a patient who suffered from an unusually severe form of neuromyelitis optica with a hyperacute time-course evolution requiring mechanical ventilation within 3 days. The patient died after 72 days and autopsy showed major spinal cord, optic nerve, and brainstem necrosis, and multifocal necrotic lesions on the cerebellum and cerebral white matter.
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http://dx.doi.org/10.1001/archneur.63.4.591DOI Listing
April 2006

Macrophage migration inhibitory factor (MIF) seems crucially involved in Guillain-Barré syndrome and experimental allergic neuritis.

J Neuroimmunol 2005 Nov;168(1-2):168-74

Department of Biomedical Sciences, School of Medicine, University of Catania, Italy.

Macrophage migration inhibitory factor (MIF) is a proinflammatory type 1 cytokine that plays a pathogenic role in several inflammatory and autoimmune diseases. The role of this cytokine in peripheral nerve inflammatory disease has not been evaluated. Therefore, to evaluate the role of macrophage migration inhibitory factor (MIF) in Guillain-Barré syndrome (GBS) and experimental allergic neuritis (EAN), we determined MIF circulating levels in a series of patients with GBS and healthy subjects with ELISA and evaluated the effect of two specific inhibitors of MIF, a neutralizing monoclonal antibody or a chemical inhibitor ISO1 on the course of murine EAN. The data show increased MIF plasma levels in GBS patients as compared to healthy controls (p<0.0001) and a progressive increase of MIF circulating concentration with patient's disability (p<0.0001). Both anti-MIF mAb and ISO1 favorably influenced the course of EAN. Treated mice had a lower cumulative severity score (p=0.001) and reduced disease duration than the control mice (p<0.03). MIF may promote immune reaction in GBS. Therapeutic effects of both anti-MIF mAb and ISO1 in EAN suggest that MIF could be a promising therapeutic target in inflammatory demyelinating peripheral nerve disorders.
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http://dx.doi.org/10.1016/j.jneuroim.2005.07.019DOI Listing
November 2005

Human endogenous retrovirus (HERV)-W ENV and GAG proteins: physiological expression in human brain and pathophysiological modulation in multiple sclerosis lesions.

J Neurovirol 2005 Feb;11(1):23-33

bioMérieux, R&D, Chemin de l'Orme, 69280 Marcy L'Etoile, France.

Antigen expression of a human endogenous retrovirus family, HERV-W, in normal human brain and multiple sclerosis lesions was studied by immunohistochemistry by three independent groups. The HERV-W multicopy family was identified in human DNA from the previously characterized multiple sclerosis-associated retroviral element (MSRV). A panel of antibodies against envelope (ENV) and capsid (GAG) antigens was tested. A physiological expression of GAG proteins in neuronal cells was observed in normal brain, whereas there was a striking accumulation of GAG antigen in axonal structures in demyelinated white matter from patients with MS. Prominent HERV-W GAG expression was also detected in endothelial cells of MS lesions from acute or actively demyelinating cases, a pattern not found in any control. A physiological expression of ENV proteins was detected in microglia in normal brain; however,a specific expression in macrophages was apparently restricted to early MS lesions. Thus, converging results from three groups confirm that GAG and ENV proteins encoded by the HERV-W multicopy gene family are expressed in cells of the central nervous system under normal conditions. Similar to HERV-W7q ENV (Syncitin), which is expressed in placenta and has been shown to have a physiological function in syncytio-trophoblast fusion, HERV-W GAG may thus also have a physiological function in human brain. This expression differs in MS lesions, which may either reflect differential regulation of inherited HERV-W copies, or expression of "infectious" MSRV copies. This is compatible with a pathophysiological role in MS, but also illustrates the ambivalence of such HERV antigens, which can be expressed in cell-specific patterns, under physiological or pathological conditions.
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http://dx.doi.org/10.1080/13550280590901741DOI Listing
February 2005

A reappraisal of various methods for measuring motor nerve refractory period in humans.

Clin Neurophysiol 2005 Apr 11;116(4):969-76. Epub 2005 Jan 11.

Service de Physiologie-Explorations Fonctionnelles, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, AP-HP, Créteil 94010, France.

Objective: To compare various techniques of stimulation and methods of analysis to estimate absolute (ARP) and relative (RRP) refractory periods in motor nerve trunks of humans.

Methods: Double collision (DC) technique and two types of paired pulse (PP) technique, with test stimulation of supramaximal (PP(supra)) or submaximal (PP(sub)) intensity, were applied to 32 healthy subjects. The ulnar nerve was stimulated either at a single site (wrist) for the PP techniques or at two sites (wrist and elbow) for the DC technique, with various distal interstimuli intervals (ISIs). The elicited compound muscle action potentials (CMAPs) were recorded from the abductor digitorum minimi muscle. The DC technique provided estimates of minimal and maximal ARPs, whereas maximal RRP values were obtained with the PP techniques. Data were analyzed using three methods: a visual reading of the raw ISI-CMAP curves and two computer-aided analyses of the regression curve fitting the ISI-CMAP plots. Pain induced by each technique was assessed on a 0-10 visual analogue scale. A test-retest study was performed with the PP techniques in 12 subjects.

Results: RP estimates varied with both the stimulation technique and the analysis method. The DC technique was more painful than the PP techniques, but provided shorter and more accurate ARP values, whereas the PP(sub) technique provided longer, but valid RRP values. Computer-aided methods of data analysis gave the lowest coefficients of test-retest variation.

Conclusions: Compared to the PP techniques, the DC technique allowed the evaluation of the whole distribution of ARP estimates, not distorted by muscle fiber RPs. For RRP estimation, the PP(sub) technique can be preferred to the PP(supra) technique. Finally, computer-aided methods are preferable to analyze ISI-CMAP curves.

Significance: The distribution of RP estimates can be easily and reliably assessed in whole motor nerve trunks of humans, providing valuable information to assess peripheral nerve excitability.
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http://dx.doi.org/10.1016/j.clinph.2004.11.018DOI Listing
April 2005

Correlation between disease severity and in vitro cytokine production mediated by MSRV (multiple sclerosis associated retroviral element) envelope protein in patients with multiple sclerosis.

J Neuroimmunol 2005 Mar 8;160(1-2):195-203. Epub 2004 Dec 8.

Laboratoire d'Immunochimie, CEA/ INSERM-U548, 17 rue des Martyrs 38054 Grenoble, France.

MSRV is a retroviral element previously isolated in cell cultures from patients with multiple sclerosis. It is part of a new multi-copy endogenous retrovirus family named HERV-W and displays pro-inflammatory properties both in vitro in human PBMC cultures and in vivo in a humanized SCID mice model. In the present study, we have evaluated potential links between the pro-inflammatory properties of MSRV envelope protein and MS disease. Thus, cytokine productions mediated by the surface unit of MSRV envelope protein were evaluated in PBMC of MS patients and compared with healthy controls. Divergent reactivity to ENV-SU between MS and control PBMC was observed and was reflected by a significant increase of IFN-gamma, IL-6 and IL-12p40 production by the tested MS population. Interestingly, the overproduction of IL-6 and IL-12p40 was found to correlate with disease severity (EDSS) in most patients. Altogether our data suggest that MSRV envelope protein may induce an abnormal cytokine secretion, thus contributing to the inflammatory process in MS.
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http://dx.doi.org/10.1016/j.jneuroim.2004.10.019DOI Listing
March 2005

Neurofibromatosis 1-associated neuropathies: a reappraisal.

Brain 2004 Sep 2;127(Pt 9):1993-2009. Epub 2004 Aug 2.

Service de Neurologie, Hôpital d'Instruction des Armées Desgenettes, Lyon, France.

Neurofibromatosis 1 (NF1) is a common disease which is a source of various multisystemic manifestations related either to the accumulation of neurofibromas or to specific developmental abnormalities. The neurofibroma is the hallmark lesion of NF1 and develops from peripheral nerves. However, to date, the description of peripheral neuropathies of NF1 has not been investigated. To examine this question, we have evaluated 688 NF1 patients for the presentation, prognosis and associated morbidity of peripheral neuropathies in two hospital-based series. We collected 18 patients (four women and 14 men) with diffuse peripheral neuropathy (2.3%). Eight patients had a paucisymptomatic or an asymptomatic neuropathy detected only on electrophysiological study, two had minor sensory manifestations, five had moderate motor and sensory manifestations and three had severe motor and sensory manifestations. Superimposed radicular changes were observed in seven cases. Two patients had a subacute and 16 a chronic polyneuropathy. Fourteen patients had a demyelinating neuropathy with either severe axonal changes (three), moderate or minor axonal changes (four) or no axonal changes (seven). Four patients had axonal neuropathies. There was a strong association between the presence of a peripheral neuropathy and large root diffuse neurofibromas (P < 0.03) and subcutaneous neurofibromas (P < 0.0001). Severe morbidity and mortality of patients with NF1 and peripheral neuropathies was 50%, much higher than what is observed in the general population of patients with NF1, and 100% in patients with the most severe symptoms and electrophysiological changes (demyelination with severe axonal features). Four patients out of 18 (22%) developed a malignant peripheral nerve sheath tumour (MPNST), a much higher proportion than in the whole population of NF1. Two patients died. Peripheral neuropathy constitutes a potentially severe complication in patients with NF1 associated with a frequent morbidity related to spinal complications and MPNSTs. Association of proximal large neurofibromas, peripheral neuropathies and subcutaneous neurofibromas may constitute a phenotype of NF1 with a severe prognosis.
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http://dx.doi.org/10.1093/brain/awh234DOI Listing
September 2004

Prognostic factors of CNS tumours in Neurofibromatosis 1 (NF1): a retrospective study of 104 patients.

Brain 2003 Jan;126(Pt 1):152-60

INSERM Unité 421, Faculté de Médecine, Villejuif, France.

In addition to multiple peripheral neurofibromas, Neurofibromatosis 1 (NF1) predisposes to CNS tumours. Most of them are pilocytic astrocytomas, arise in children and are located in the optic pathways or in the brainstem. The majority are indolent, but factors predictive of poor prognosis have yet to be identified. Furthermore, the incidence and natural history of gliomas of a higher grade, arising in adults or involving other locations are largely unknown in NF1. In order to address these issues, we performed a retrospective study of 104 patients followed in seven French centres between 1982 and 2000. Inclusion criteria were a diagnosis of NF1, according to the National Institutes of Health criteria, and the presence of a CNS tumour, regardless of type, location or age of onset. The series included 88 children (age range 3 months to 17 years) and 16 adults (age range 19-52 years). The median follow-up was 5.6 years. One hundred and twenty-seven CNS tumours were observed in the 104 patients. Eighty-four (66%) were optic pathway tumours (OPT) and 43 (34%) extra-optic pathway tumours (extra-OPT) (brainstem: n = 21; other locations: n = 22). Twenty-one patients (20%) had multiple CNS tumours. OPT were symptomatic in 50 patients and extra-OPT in 19. Main clinical findings at presentation included visual loss (n = 29; 58%) and precocious puberty (n = 5; 10%) for OPT, increased intracranial pressure (n = 9; 48%) for extra-OPT. Fourteen out of the 27 symptomatic tumours with histology were pilocytic astrocytomas. The overall survival rate was 90% at 5 years (95% confidence interval 82-95%). Extra-optic location, tumour diagnosis in adulthood and symptomatic tumours were independent factors associated with shorter survival time (P < 0.05, Cox model). Radiotherapy for OPT was associated with vascular complications (ischaemic strokes) and growth hormone deficiency in 32 and 46% of patients, respectively. In conclusion, mortality is high in extra-OPT, particularly in adults, whereas OPT are only exceptionally life-threatening. Radiotherapy of OPT is associated with an important morbidity in NF1.
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http://dx.doi.org/10.1093/brain/awg016DOI Listing
January 2003