[Show abstract][Hide abstract] ABSTRACT: Recent studies in multiple sclerosis (MS) showed longer survival times from clinical onset than older hospital-based series. However estimated median time ranges widely, from 24 to 45 years, which makes huge difference for patients as this neurological disease mainly starts around age 20 to 40. Precise and up-to-date reference data about mortality in MS are crucial for patients and neurologists, but unavailable yet in France.
Estimate survival in MS patients and compare mortality with that of the French general population.
We conducted a multicenter observational study involving clinical longitudinal data from 30,413 eligible patients, linked to the national deaths register. Inclusion criteria were definite MS diagnosis and clinical onset prior to January, 1st 2009 in order to get a minimum of 1-year disease duration.
After removing between-center duplicates and applying inclusion criteria, the final population comprised 27,603 MS patients (F/M sex ratio 2.5, mean age at onset 33.0 years, 85.5% relapsing onset). During the follow-up period (mean 15.2 +/- 10.3 years), 1569 deaths (5.7%) were identified; half related to MS. Death rates were significantly higher in men, patients with later clinical onset, and in progressive MS. Overall excess mortality compared with the general population was moderate (Standardized Mortality Ratio 1.48, 95% confidence interval [1.41-1.55]), but increased considerably after 20 years of disease (2.20 [2.10-2.31]).
This study revealed a moderate decrease in life expectancy in MS patients, and showed that the risk of dying is strongly correlated to disease duration and disability, highlighting the need for early actions that can slow disability progression.
PLoS ONE 07/2015; 10(7):e0132033. DOI:10.1371/journal.pone.0132033 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Immunological mechanisms are suspected in sensory neuropathy (SN) occurring with systemic autoimmune diseases and in some idiopathic cases, but so far there are no antibodies (Abs) identifying these neuropathies.
Methods In the search for such specific antibodies, serum samples were collected from 106 patients with SN of these 72 fulfilled the diagnosis criteria of sensory neuronopathy (SNN) and 211 control subjects including patients with sensorimotor neuropathies, other neurological diseases (ONDs), systemic autoimmune diseases and healthy blood donors.
Results In the first step, a protein array with 8000 human proteins allowed identification of the intracellular domain of the fibroblast growth factor receptor 3 (FGFR3) as a target of Abs in 7/16 SNN and 0/30 controls. In the second step, an ELISA method was used to test the 317 patients and controls for anti-FGFR3 Abs. Abs were detected in 16/106 patients with SN and 1/211 controls (p<0.001). Among the 106 patients with SN, anti-FGFR3 Abs were found in 11/38 patients with autoimmune context, 5/46 with idiopathic neuropathy and 0/22 with neuropathy of other aetiology (p=0.006). The only control patient with anti-FGFR3 Abs had lupus and no recorded neuropathy. Sensitivity, specificity, and positive and negative predictive values of anti-FGFR3 Abs for a diagnosis of idiopathic or dysimmune SN were 19%, 99.6%, 94.1% and 77.3%, respectively. A cell-based assay confirmed serum reactivity against the intracellular domain of FGFR3. The neuropathy in patients with anti-FGF3 Abs was non-length dependent in 87% of patients and fulfilled the criteria of probable SNN in 82%. Trigeminal nerve involvement and pain were frequent features.
Conclusions A anti-FGFR3 Abs identify a subgroup of patients with SN in whom an underlying autoimmune disorder affecting sensory neurons in the dorsal root and trigeminal nerve ganglia is suspected.
[Show abstract][Hide abstract] ABSTRACT: Sensory neuronopathy (SNN) depends on a pathophysiological process that targets the sensory neuron in the posterior root ganglia.
These rare diseases are sometimes difficult to diagnose because the site of impairment is not directly assessable by conventional neurophysiological techniques.
After recalling the general data concerning SNN, we propose an easy to use clinical and electrophysiological diagnosis criteria and guidelines for clinicians in their search for an etiology in a patient with NNS.
La Presse Médicale 11/2014; 43(11). DOI:10.1016/j.lpm.2014.02.034 · 1.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our objective was to examine the strength of evidence in support of the paraneoplastic syndrome (PNS) as one cause of ALS and, if the association appears more likely than chance, determine which features of ALS imply concurrent malignancy. We reviewed the literature on concurrent ALS and neoplasia assessing the strength of evidence for the association. Most accounts of ALS and neoplasm are case reports or small uncontrolled series. In order of strength of evidence, three clinical situations that support a paraneoplastic aetiology for ALS are: 1) laboratory evidence of well-characterized onconeuronal antibodies, most often anti-Hu, anti-Yo or anti-Ri; 2) co-occurrence of ALS and a neoplasm known to cause PNS, usually lymphoma or cancer of the breast; and 3) combined ALS and a neoplasm not classically associated with PNS, without detectable onconeuronal antibodies. Clinical features that warrant evaluation of neoplasm include upper motor neuron disease in elderly females, rapid progression, non-motor signs, and young onset. In conclusion, most examples of ALS and neoplasm do not constitute a classically established PNS. Rare instances of elevated onconeuronal antibody titres or typical neoplasm, implies that, albeit rare, the PNS is one of a multitude of causes of ALS.
[Show abstract][Hide abstract] ABSTRACT: Sensory neuronopathy (SNN) depends on a pathophysiological process that targets the sensory neuron in the posterior root ganglia. These rare diseases are sometimes difficult to diagnose because the site of impairment is not directly assessable by conventional neurophysiological techniques. After recalling the general data concerning SNN, we propose an easy to use clinical and electrophysiological diagnosis criteria and guidelines for clinicians in their search for an etiology in a patient with NNS.
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Neurology 08/2014; 261(11). DOI:10.1007/s00415-014-7423-7 · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Patients with peripheral neuropathy and anti-MAG monoclonal IgM may respond to Rituximab, a humanized monoclonal anti-CD20 antibody. Methods: We report on three patients with peripheral neuropathy and anti-MAG monoclonal IgM who deteriorated under Rituximab and reviewed seven previously published cases. Results: Worsening was acute and severe, and occurred during the treatment period. All the patients improved after deterioration but at final evaluation only one was improved comparatively to baseline, five were worsened and four were stabilized. Deterioration was not clearly associated with an increase of the anti-MAG antibody titer. Two patients received Rituximab prior or after the course which induced worsening without adverse reaction. Conclusion: Although rare, acute worsening of the neuropathy can occur after Rituximab. The deterioration is however reversible within some weeks to several months.
Journal of the Neurological Sciences 08/2014; 345(1-2). DOI:10.1016/j.jns.2014.07.055 · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a degenerative disease which prognosis is poor. Early diagnosis permits to set up immediately adapted treatment and cares.
Available diagnostic criteria are based on the detection of both the central and peripheral motor neuron injury in bulbar, cervical, thoracic and lumbar regions.
Electromyographic study is the key tool to identify peripheral motor neuron involvement.
Conduction velocities are systematically performed to rule out differential diagnosis.
Needle examination records abnormal activities at rest and looks for neurogenic pattern during muscle contraction.
Motor unit potentials morphology is modified primary to recruitment.
Motor evoked potentials remain the test of choice to identify impairment of central motor neurons.
For the monitoring of ALS patients, the MUNE technique (motor unit number estimation) seems the most interesting.
La Presse Médicale 05/2014; 43(5). DOI:10.1016/j.lpm.2014.03.003 · 1.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a degenerative disease which prognosis is poor. Early diagnosis permits to set up immediately adapted treatment and cares. Available diagnostic criteria are based on the detection of both the central and peripheral motor neuron injury in bulbar, cervical, thoracic and lumbar regions. Electromyographic study is the key tool to identify peripheral motor neuron involvement. Conduction velocities are systematically performed to rule out differential diagnosis. Needle examination records abnormal activities at rest and looks for neurogenic pattern during muscle contraction. Motor unit potentials morphology is modified primary to recruitment. Motor evoked potentials remain the test of choice to identify impairment of central motor neurons. For the monitoring of ALS patients, the MUNE technique (motor unit number estimation) seems the most interesting.
[Show abstract][Hide abstract] ABSTRACT: Paraneoplastic neurological syndromes are rare but can affect any part of the peripheral nervous system (PNS) including motor neurons, sensory ganglia, nerve roots, plexuses, cranial and peripheral nerves, and neuromuscular junctions. The type of cancer, lymphoma or solid tumour, is a determinant factor of the underlying mechanism. With solid tumour, antibodies directed to intracellular (anti-Hu or anti-CV2/CRMP5 antibodies) or surface antigens (anti-VGCC,or LGI1 and Caspr2 antibodies) have been identified while with lymphoma, the neuropathy is usually linked to a monoclonal gammopathy. This review discusses the different etiologies and mechanisms of paraneoplastic disorders of the PNS in patients emphasising their evaluation, diagnosis and treatment.
La Presse Médicale 04/2013; 42(6). DOI:10.1016/j.lpm.2013.01.059 · 1.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:This study aimed to assess factors which predict good tolerance of noninvasive ventilation (NIV), in order to improve survival and quality of life in amyotrophic lateral sclerosis (ALS) patients.METHODS:We conducted a prospective study on ALS patients requiring NIV. The study's primary endpoint was NIV tolerance at one month. Patients, several of whom failed to complete the study, were classified as 'tolerant' or 'poorly tolerant' according to the number of hours of NIV use (more or less than 4 hours per night, respectively).RESULTS:81 patients, 73 of whom also attended the one-month follow-up visit, participated over 34 months. NIV tolerance after the first day of utilisation predicted tolerance at 1 month (77.6 % and 75.3 % of patients, respectively). Multivariate analysis disclosed three factors predicting good NIV tolerance: 1° absence of airway secretion accumulation prior to NIV onset (odds ratio, OR=11.5); 2° normal bulbar function at initiation of NIV (OR= 8.5) and 3° older age (weakly significant, OR=1.1).CONCLUSION:Our study reveals three factors which are predictive of good NIV tolerance, in particular the absence of airway secretion accumulation, which should prompt NIV initiation before its appearance.
Respiratory care 01/2013; 58(9). DOI:10.4187/respcare.02103 · 1.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OPINION STATEMENT: Paraneoplastic disorders of the peripheral nervous system (PNS) are the most frequent manifestation of paraneoplasia. As with the central nervous system, two categories of immune mechanisms are distinguished. On one side, antibodies toward intracellular antigens (HuD and CV2-CRMP5) occur with subacute sensory neuronopathy or sensorimotor neuropathy probably depending on a T cell mediated disorder (group 1). On the other side, the Lambert-Eaton myasthenic syndrome (LEMS) and peripheral nerve hyperexcitability (PNH) occur with antibodies to cell membrane antigens, respectively, the voltage gated calcium channel and CASPR2 proteins, which are responsible for the disease (group 2). Treatment recommendation mostly depends on class IV studies. Three lines of therapeutics can be proposed, namely tumor, immunomodulatory and symptomatic treatments. Cancer treatment is crucial since an early tumor cure is the best way to stabilize patients in group 1 and improve those in group 2. This implies the use of an efficient strategy for cancer diagnosis. With group 2 symptomatic treatment including 3,4 diaminopyridine for LEMS and carbamazepine for PNH may suffice to obtain good quality remission. Immunomodulatory treatments like IVIg and plasma exchange, which have a well-established efficacy in antibody dependent diseases, may be used as second line treatments. Rituximab, for which there is only little evidence in this context, may be kept in a third line for severe refractory patients. With group 1 patients, who frequently develop an evolving and disabling disorder, bolus of methylprednisolone and or IVIg may be recommended while searching for and treating the tumor. If the tumor is not found and the patient deteriorates, monthly pulses of cyclophosphamide may stabilize the patients. Antidepressants and antiepileptic drugs efficacious in the treatment of neuropathic pain are to be used as symptomatic treatment when necessary. The choice is then based on the cost effectiveness and tolerance of these drugs.
Current Treatment Options in Neurology 01/2013; DOI:10.1007/s11940-012-0210-9 · 2.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of the Peripheral Nervous System 09/2012; 17(3):331-340. DOI:10.1111/j.1529-8027.2012.00411.x · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report the case of a 75-year-old female who had a trismus as the first, long-lasting and, isolated symptom of ALS. We discuss also therapeutic possibilities.
[Show abstract][Hide abstract] ABSTRACT: Collapsin response mediator protein 5 (CRMP5) is one of the rare peripheral nerve antigens that is a target of autoantibodies in a paraneoplastic peripheral neuropathy. The pattern of axonal and myelin alterations suggests that CRMP5 is involved in axon-Schwann cell interaction. We examined CRMP5 expression and function in primary cultures of Schwann cells and neurons and at various developmental and regenerating stages of rat sciatic nerve and in CRMP5-deficient mice in vivo. Collapsin response mediator protein 5 was strongly expressed during postnatal development and regeneration and decreased with myelination. It was mainly expressed by immature Schwann cells and persisted in Remak cells in the adult; however, a subpopulation of Schwann cells that were induced to myelinate also expressed CRMP5. We identified 2 axonal molecular cues regulating CRMP5 expression: human neuregulin type 1, which induces CRMP5 expression in immature and premyelinating Schwann cells, and cyclic adenosine monophosphate, which inhibits CRMP5 expression when Schwann cells begin myelination. Collapsin response mediator protein 5-deficient mice showed abnormal Schwann process extension resulting in abnormal cell-axon segregation, indicating that CRMP5 is involved in the morphologic adaptation of Schwann cells to surround axons. These results demonstrate the importance of CRMP5 in axon-Schwann cell cooperation during development and regeneration.
Journal of Neuropathology and Experimental Neurology 04/2012; 71(4):298-311. DOI:10.1097/NEN.0b013e31824d1df2 · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Collapsin Response Mediator Proteins (CRMPS) are highly expressed in the developing brain, and in adult brain areas that retain neurogenesis, ie: the olfactory bulb (OB) and the dentate gyrus (DG). During brain development, CRMPs are essentially involved in signaling of axon guidance and neurite outgrowth, but their functions in the adult brain remain largely unknown. CRMP5 has been initially identified as the target of auto-antibodies involved in paraneoplasic neurological diseases and further implicated in a neurite outgrowth inhibition mediated by tubulin binding. Interestingly, CRMP5 is also highly expressed in adult brain neurogenic areas where its functions have not yet been elucidated. Here we observed in both neurogenic areas of the adult mouse brain that CRMP5 was present in proliferating and post-mitotic neuroblasts, while they migrate and differentiate into mature neurons. In CRMP5(-/-) mice, the lack of CRMP5 resulted in a significant increase of proliferation and neurogenesis, but also in an excess of apoptotic death of granule cells in the OB and DG. These findings provide the first evidence that CRMP5 is involved in the generation and survival of newly generated neurons in areas of the adult brain with a high level of activity-dependent neuronal plasticity.
PLoS ONE 10/2011; 6(10):e23721. DOI:10.1371/journal.pone.0023721 · 3.23 Impact Factor