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ABSTRACT: Amyotrophic lateral sclerosis is the most common motor neuron disorder in adults. Although the diagnosis appears obvious in theory, clinical practice shows the contrary as diagnosis is delayed in many patients; the average time between symptom onset and diagnosis can reach 12months. The delay can be explained by the variability of the clinical presentation and by the absence of diagnostic markers. In order to standardize diagnosis for enrolment in clinical research, diagnostic criteria for ALS were created and revisited during the last 20years. In 2006, the Awaji criteria for the diagnosis of ALS were proposed, adding two major points to the diagnostic criteria: electromyography is considered equivalent to clinical examination for the identification of LMN signs and fasciculation potentials resume their prominent place in the diagnosis. Comparisons of the accuracy of the revisited El Escorial and Awaji criteria support improved diagnostic sensitivity without any effect on specificity with the new classification. The only weakness of the new classification involves patients with UMN signs in one region and LMN in two regions; these patients were previously classified as laboratory-supported probable ALS and currently as possible ALS, a lower level of diagnostic certainty. In all other instances the accuracy appears to be improved by the Awaji criteria. Nevertheless, there is a body of evidence suggesting the need for a revision of these new criteria, giving more weight to clinical and complementary findings of UMN involvement. The need to diagnose and treat ALS quickly could be facilitated by the inclusion of complementary investigations that detect UMN signs.
Revue Neurologique 12/2012; · 0.49 Impact Factor
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P Corcia,
P Valdmanis,
S Millecamps,
C Lionnet,
H Blasco,
K Mouzat,
H Daoud,
V Belzil,
R Morales,
N Pageot,
V Danel-Brunaud,
N Vandenberghe,
P F Pradat,
P Couratier,
F Salachas,
S Lumbroso,
G A Rouleau,
V Meininger, W Camu
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ABSTRACT: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations.
French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations.
In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months).
Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.
Neurology 04/2012; 78(19):1519-26. · 8.31 Impact Factor
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ABSTRACT: Familial amyotrophic lateral sclerosis (FALS) cases linked to SOD1 mutations may sometimes present with unusual clinical features such as pure lower motor neuron involvement or sensory signs. The authors describe a FALS pedigree with the L144F SOD1 mutation in which all cases had respiratory involvement as a first symptom. Although atypical clinical features are not rare in ALS families, this is the first pedigree with respiratory-onset in three affected members. This unusual presentation led to delayed diagnosis in the proband and highlights the fact that respiratory-onset can occur in familial ALS cases carrying SOD1 mutation.
Journal of neurology, neurosurgery, and psychiatry 07/2011; 82(7):747-9. · 4.87 Impact Factor
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Neurology 05/2011; 76(22):1939-40. · 8.31 Impact Factor
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ABSTRACT: Demyelinating disease affecting both the central and the peripheral nervous systems has rarely been reported.
A 30-year-old man, presented with ataxia and diffuse areflexia due to polyneuropathy fullfilling demyelination criteria. His medical history was notable for central nervous system demyelination compatible with multiple sclerosis. He improved transiently with intravenous immunoglobulin and then stabilized with methotrexate.
This case report distinguishes a new kind of inflammatory disease affecting both central and peripheral nervous system. It seems to be different from multiple sclerosis and chronic immune demyelinating polyneuropathy, because of high hyperproteinorachia and absence of oligoclonal bands in the cerebrospinal fluid.
Revue Neurologique 05/2011; 167(12):921-5. · 0.49 Impact Factor
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I De Vidi,
G Boursier,
N Delouche,
P Portalès,
E Cadars,
M Bouthier,
C Mettling,
Y L Lin,
E Thouvenot,
B Carlander, W Camu,
J P Antel,
A Bar-Or,
H Zephir,
P Vermersch,
J De Seze,
P Corbeau,
J F Eliaou,
T Vincent
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ABSTRACT: NMO-IgG is a specific biomarker of neuromyelitis optica (NMO) that targets the aquaporin-4 (AQP4) water channel protein. The current gold standard for NMO-IgG identification is indirect immunofluorescence (IIF). Our aim in this study was to develop a new quantitative cell-based assay (CBA) and to propose a rational strategy for anti-AQP4 Ab identification and quantification. We observed an excellent correlation between the CBA and IIF for NMO-IgG/anti-AQP4 detection. The CBA appeared more sensitive than IIF but on the other hand, IIF allows the simultaneous detection of various auto-Abs, underlining the complementarity between both methods. In conclusion, we propose to use IIF for the screening of patients at diagnosis in order to identify auto-Abs targeting the central nervous system. A highly sensitive, AQP4 specific and quantitative assay such as our CBA could be used thereafter to specifically identify the target of the Ab and to monitor its serum concentration under treatment.
Clinical Immunology 03/2011; 138(3):239-46. · 4.05 Impact Factor
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N Collongues,
R Marignier,
H Zéphir,
F Blanc,
S Vukusic,
O Outteryck,
M Fleury,
A Ruet,
F Borgel,
E Thouvenot, [......],
B Audoin,
M Debouverie,
P Labauge,
O Gout, W Camu,
D Brassat,
B Brochet,
P Vermersch,
C Confavreux,
J de Seze
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ABSTRACT: Neuromyelitis optica (NMO) frequently begins with a monofocal episode of optic neuritis or myelitis. A concept named high-risk syndrome (HRS) for NMO has been proposed for patients with monofocal episodes and NMO-IgG antibodies.
To describe HRS patients and compare them with NMO patients.
We identified 30 patients with HRS: 18 with extensive myelitis (HRM) and 12 with optic neuritis (HRON), in a database pooling patients from 25 centres in France. Clinical, laboratory/magnetic resonance imaging (MRI) data and outcome were analysed and compared with a national cohort of 125 NMO patients extracted from the same database.
Mean follow-up was 4.8 years. Mean age at onset was 42.8 years (range: 12.4-70) with a female:male ratio of 0.9. Asymptomatic lesions were report on visual evoked potentials in 4/8 tested HRM patients and on spinal cord MRI in 2/7 HRON patients. Three patients died, two owing to a cervical lesion. HRS and NMO patients had similar clinical/paraclinical data, except for a predominance of men in the HRS group and a later mean age at onset in the HRM subgroup.
The description of HRS patients is compatible with a monofocal form of NMO. Asymptomatic lesions could be included in a new set of NMO diagnostic criteria.
Multiple Sclerosis 01/2011; 17(6):720-4. · 4.26 Impact Factor
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ABSTRACT: Several association studies have identified possible susceptibility factors for sporadic amyotrophic lateral sclerosis (SALS). Studies on the APOE gene provided conflicting results, especially about the effect on bulbar onset. We assessed the possible role of APOE gene in a large cohort of patients with ALS and matched controls.
The APOE alleles were determined in 1482 patients with SALS and 955 controls and analysed by univariate and multivariate statistics, taking into account gender, site-of-onset and age-at-onset.
Patients with bulbar onset were more likely to be women [odds ratio (OR)=2.17; 95% CI: 1.74-2.72] and to be older (OR=3.47; 95% CI: 2.58-4.67). The ε4-carriers were more frequent in the bulbar-onset group than in the limb-onset group (OR=1.39 bulbar onset versus limb onset; 95% CI: 1.08-1.80) but this association was observed amongst men (OR=1.78; 95% CI: 1.25-2.53) and not women (OR=1.09; 95% CI: 0.75-1.59).
Our study provides evidence for a contribution of the ε4 allele in the occurrence of bulbar-onset ALS amongst men. We propose that men are normally protected by androgens against bulbar onset and that the ε4 allele inhibits this protection, perhaps by interfering with the androgen pathway.
European Journal of Neurology 01/2011; 18(8):1046-52. · 3.69 Impact Factor
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ABSTRACT: Health related quality of life (HRQOL) is often affected in multiple sclerosis (MS). Nevertheless, to our knowledge, there is no longitudinal study in the literature about the correlation between MRI parameters and HRQOL in MS patients.
We included 28 patients with clinically definite relapsing remitting MS. All patients initiated subcutaneous interferon beta-1a therapy. To assess HRQOL, we used the SEP-59 scale, the French validated translation of MSQOL-54, and the MusiQoL scale. Conventional MRI was performed every year. Lesion load (LL) and brain atrophy were automatically measured using SepINRIA, a free software developed by INRIA in Sophia Antipolis.
The mean EDSS score was 1.7 and disease duration was 2.5 years. Our results revealed that HRQOL was significantly correlated to T1 and T2-LL with both SEP-59 and MusiQoL scales. T1-LL was better correlated with physical dimensions and T2-LL was better correlated with mental components. At 1-year follow-up, patients whose MRI showed either an increase of T1 LL or at least one gadolinium enhancing lesion had a worse HRQOL at the end of the study. Initial brain parenchymal fraction (BPF) measure was also correlated with the long-term follow-up HRQOL. EDSS scored at the end of the study had not significantly changed (1.3; P>0.05).
Our study revealed pertinent clinicoradiological correlations between HRQOL and MRI parameters in our cohort.
Revue Neurologique 11/2010; 166(11):894-900. · 0.49 Impact Factor
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N Collongues,
R Marignier,
H Zéphir,
C Papeix,
B Fontaine,
F Blanc,
D Rodriguez,
M Fleury,
S Vukusic,
J Pelletier,
B Audoin,
E Thouvenot, W Camu,
B Barroso,
A Ruet,
B Brochet,
P Vermersch,
C Confavreux,
J de Seze
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ABSTRACT: Neuromyelitis optica (NMO) is a rare inflammatory disease. Average age at onset is 35 years. Few data exist on patients with pediatric-onset NMO (p-NMO), with disease onset before age 18 years. We report the clinical and paraclinical features and long-term outcome of patients with p-NMO and compare them with a large adult-onset NMO (a-NMO) cohort.
We performed a retrospective, multicenter study of patients with p-NMO in pediatric and adult medical centers. We identified 125 patients with NMO (12 p-NMO; 113 a-NMO) fulfilling the 2006 criteria. Data were collected using hospital files and standardized assessment forms for NMO.
Patients with p-NMO were followed up during a mean 19.3 years. Median age at onset was 14.5 years (4.1-17.9) with a female:male ratio of 3:1. Three patients (25%) fulfilled Paty criteria for multiple sclerosis on first brain MRI, including one patient with acute disseminated encephalomyelitis. Median interval between onset and residual Expanded Disability Status Scale (EDSS) score 4 was 20.7 years, score 6 was 26 years, and score 7 was 28.7 years. Median interval between onset and residual visual loss ≤1/10 was 1.3 years. Compared with a-NMO, p-NMO showed a longer time to EDSS scores 4 and 6, largely explained by the severity of the first myelitis in the a-NMO group. Time to first treatment was longer in the p-NMO group (13.1 vs 3.4 years).
Patients with p-NMO can present a diffuse inflammatory process on first brain MRI and have a longer time to disability than patients with a-NMO.
Neurology 09/2010; 75(12):1084-8. · 8.31 Impact Factor
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N Collongues,
R Marignier,
H Zéphir,
C Papeix,
F Blanc,
C Ritleng,
M Tchikviladzé,
O Outteryck,
S Vukusic,
M Fleury, [......],
D Rodriguez,
S Wiertlewski,
D Laplaud,
F Borgel,
P Tourniaire,
J Grimaud,
B Brochet,
P Vermersch,
C Confavreux,
J de Seze
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ABSTRACT: There have been few epidemiologic studies on neuromyelitis optica (NMO) and none used the recent 2006 diagnostic criteria. Here we describe the clinical, laboratory, MRI, and disability course of NMO in a French cohort of 125 patients.
We performed an observational, retrospective, multicenter study. Data were collected from September 2007 through August 2008, corresponding to the endpoint of the study. We identified 125 patients fulfilling the 2006 NMO criteria. Selection was made using hospital files and a specific clinical questionnaire for NMO.
Mean age at onset was 34.5 years (range 4-66) with a mean disease duration of 10 +/- 7.8 years at the endpoint. The patients were mainly (87%) Caucasian, with a female:male ratio of 3:1. In 90% of cases, the association of optic neuritis, longitudinal extensive myelitis, and a Paty-negative initial brain MRI was sufficient to fulfill the supportive criteria. Eighty-eight percent of patients were treated with immunosuppressive therapies. Median delay from onset to Expanded Disability Status Scale (EDSS) score 4 was 7 years; score 6, 10 years; and score 7, 21 years. The first episode of myelitis was immediately followed by an EDSS score > or = 4 in 37.3% of cases, and a severe residual visual loss was observed in 22% of patients after the first episode of optic neuritis. Multivariate analysis did not reveal any predictors of a poor evolution other than a high number of MRI brain lesions at diagnosis, which were predictive of a residual visual acuity < or = 1/10.
Our demographic data provide new data on disability in patients with neuromyelitis optica, most of whom were receiving treatment.
Neurology 03/2010; 74(9):736-42. · 8.31 Impact Factor
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V V Belzil,
P N Valdmanis,
P A Dion,
H Daoud,
E Kabashi,
A Noreau,
J Gauthier,
P Hince,
A Desjarlais,
J-P Bouchard,
L Lacomblez,
F Salachas,
P-F Pradat, W Camu,
V Meininger,
N Dupré,
G A Rouleau
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ABSTRACT: The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease.
To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported.
In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS.
Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.
Neurology 10/2009; 73(15):1176-9. · 8.31 Impact Factor
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I Le Ber,
A Camuzat,
E Berger,
D Hannequin,
A Laquerrière,
V Golfier,
D Seilhean,
G Viennet,
P Couratier,
P Verpillat, [......],
M Didic,
C Thomas-Anterion,
M Puel,
B-F Michel,
C Besse,
C Duyckaerts,
V Meininger,
D Campion,
B Dubois,
A Brice
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ABSTRACT: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3).
Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics.
We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 +/- 10.3 years (range, 41-84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients.
This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.
Neurology 06/2009; 72(19):1669-76. · 8.31 Impact Factor
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Journal of the European Academy of Dermatology and Venereology 05/2009; 23(11):1332-3. · 2.98 Impact Factor
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V Meininger,
J-C Antoine,
M C Arne-Bes,
E Broussolle,
G Bruneteau,
J P Camdessanche, W Camu,
L Carluer,
P Cintas,
P Clavelou, [......],
J Pouget,
P F Pradat,
E Rousso,
F Salachas,
M H Soriani,
C Tranchant,
N Vandenberghe,
A Verschueren,
F Viader,
C Vial
Revue Neurologique 03/2009; 165(3):207-10. · 0.49 Impact Factor
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ABSTRACT: Devic's neuromyelitis optica (NMO) is a severe demyelinating disease of the central nervous system, often misdiagnosed as multiple sclerosis, and involving mainly optic nerves and the spinal cord. We report on a peculiar case of relapsing NMO with severe recurrent dysautonomia and hypersomnia, in which we had the opportunity to observe a dramatic decrease in hypocretin/orexin cerebrospinal fluid level.
Case Reports 01/2009; 2009.
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J Gil,
B Funalot,
A Verschueren,
V Danel-Brunaud, W Camu,
N Vandenberghe,
C Desnuelle,
N Guy,
J P Camdessanche,
P Cintas,
L Carluer,
S Pittion,
G Nicolas,
P Corcia,
M-C Fleury,
C Maugras,
G Besson,
G Le Masson,
P Couratier
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ABSTRACT: To prospectively investigate causes of death and the circumstances surrounding death in 302 patients with amyotrophic lateral sclerosis (ALS). The functional status of patients immediately before death was also determined.
Information was obtained from neurologists at ALS centres, patients' files, and, when deaths occurred outside a medical facility, attending physicians.
Most patients (63%) died in a medical facility. The most frequently reported cause of death was respiratory failure (77%), including terminal respiratory insufficiency (58%), pneumonia (14%), asphyxia due to a foreign body (3%) and pulmonary embolism (2%). Ten per cent of patients died from other causes: post-surgical or traumatic conditions (5%), cardiac causes (3.4%), suicide (1.3%) and sudden death of unknown origin (0.7%). The cause of death could not be determined in 13% of cases (6% inside a medical facility and 25% outside). At the time of death, only 55% of patients were receiving riluzole, 33% were undergoing non-invasive ventilation, 3% had a tracheotomy and 37% a gastrostomy.
The information provided by this study helps to improve our understanding of the natural history of the disease and may help optimize the quality of care we can offer patients at the end of life.
European Journal of Neurology 12/2008; 15(11):1245-51. · 3.69 Impact Factor
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P N Valdmanis,
E Kabashi,
A Dyck,
P Hince,
J Lee,
P Dion,
M D'Amour,
F Souchon,
J-P Bouchard,
F Salachas,
V Meininger,
P M Andersen, W Camu,
N Dupré,
G A Rouleau
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ABSTRACT: The paraoxonase gene cluster on chromosome 7 comprising the PON1-3 genes is an attractive candidate for association in amyotrophic lateral sclerosis (ALS) given the role of paraoxonase genes during the response to oxidative stress and their contribution to the enzymatic break down of nerve toxins. Oxidative stress is considered one of the mechanisms involved in ALS pathogenesis. Evidence for this includes the fact that mutations of SOD1, which normally reduce the production of toxic superoxide anion, account for 12% to 23% of familial cases in ALS. In addition, PON variants were shown to be associated with susceptibility to ALS in several North American and European populations.
We extended this analysis to examine 20 single nucleotide polymorphisms (SNPs) across the PON gene cluster in a set of patients from France (480 cases, 475 controls), Quebec (159 cases, 95 controls), and Sweden (558 cases, 506 controls).
Although individual SNPs were not considered associated on their own, a haplotype of SNPs at the C-terminal portion of PON2 that includes the PON2 C311S amino acid change was significant in the French (p value 0.0075) and Quebec (p value 0.026) populations as well as all three populations combined (p value 1.69 x 10(-6)). Stratification of the samples showed that this variation was pertinent to ALS susceptibility as a whole, and not to a particular subset of patients.
These findings contribute to the increasing weight of evidence that genetic variants in the paraoxonase gene cluster are associated with amyotrophic lateral sclerosis.
Neurology 09/2008; 71(7):514-20. · 8.31 Impact Factor
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ABSTRACT: The diagnostic process of sensory-motor neuropathies is difficult. Atypical variants and rare etiologies also contribute to delay the diagnosis. We report the case of a 70-year-old woman with slowly progressive asymmetric axonal sensory-motor neuropathy. Leprosy was identified after an eight-year delay. Nerve biopsy was required to establish the diagnosis: electron microscopy revealed debris of Hansen's bacillus in the nerve. Treatment was fully curative after several months. Leprosy is a rare cause of neuropathy in Europeans. Systematic inquiry about travel to endemic areas would be helpful in establishing the diagnosis. In such cases, nerve biopsy is crucial.
Revue Neurologique 06/2008; 164(11):964-8. · 0.49 Impact Factor
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Journal of neurology, neurosurgery, and psychiatry 04/2008; 79(3):333-4. · 4.87 Impact Factor
