Search

Abstract: Left precordial chest pain (LPCP) evokes above all angina. Eliminating a cardiac origin is then always the first priority. When cardiac causes are eliminated, non-cardiac causes are sought in order to avoid leaving patients with undiagnosed or undifferentiated chest pain. There is a myriad of non-cardiac causes ranging from heartburn, panic attacks, pleurisy, pulmonary embolism, pneumothorax, Tietze syndrome, bruises and fractures of the ribs, to spine meningioma, neuroma, herniated disk and impairment of the nerve roots. Although clinical presentation and characteristics of the pain are usually helpful in diagnosing the cause, conducting magnetic resonance imaging of the spine may be of a high utility in some situations. Here we report a case of chronic angina-like LPCP, caused by a thoracic meningioma. [Copyright &y& Elsevier]

Background: Charcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3). Methods: 80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes. Results: This trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group. Conclusions: These results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults. Trial registration EudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257. The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13). Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0199-0) contains supplementary material, which is available to authorized users.

Recessive X-linked amyotrophic spinobulbar muscular atrophy (SBMA) or Kennedy disease is a neuroendocrine disorder with a slowly progressive phenotype, caused by an expansion of a polymorphic tandem CAG repeat of the androgen receptor gene. Classical clinical hallmarks include onset in the third decade of life, weakness and wasting predominantly in proximal extremity muscles, variable weakness of bulbar muscles, abundant muscle fasciculations, sensory nerve action potential abnormalities and signs of androgen insensitivity such as gynecomastia and testicular atrophy. The diagnosis has been recently made easier by the availability of genetic testing but Kennedy disease is probably still underdiagnosed because of phenotypic variability. We report 11 new cases, of which seven had atypical initial manifestations presenting respectively with myasthenia, cramps and fasciculation syndrome, polyneuropathy, post-trauma monomelic neuronopathy, effort-dependent muscle intolerance and/or muscular dystrophy, with the aim to enlarge the phenotypic spectrum of the published series.

Binding of monoclonal IgM antibodies in serum to antigens of the peripheral nervous system such as MAG and SG(L)PG was measured by various non standardised methods. In this study we evaluated a new commercially available IgM anti-SGPG ELISA (Bühlmann Laboratories AG, Switzerland). The results were compared with three different markers and methods: (1) an in-house thin-layer overlay chromatography for IgM reactivity against sulfated glucuronosyl paragloboside (SGPG) antibodies (gold standard), (2) an indirect immunofluorescent assay for detecting IgM antibodies against myelin, and (3) IgM anti-MAG antibodies, a commercially available Kit based on ELISA technology, manufactured by Bühlmann Laboratories AG. 147 patient sera with anti-MAG/SGPG neuropathy and 121 control sera from patients with peripheral neuropathy were analysed. The anti-SGPG autoantibody ELISA turned out to be a very reliable commercially available test with no technical difficulties and both, excellent sensitivity (0.98), and specificity (0.98) for detecting MAG/SGPG antibody-mediated demyelinating neuropathies. Anti-SGPG antibody titers have pratical implications for both, management and follow-up of neuropathies treated with rituximab.

The neuropathies associated with monoclonal IgM gammopathy reacted with glycoconjugated targets on a very antigenic epitope on the sulfated glucuronic glycolipids corresponding to SGPG and SGLPG (sulfoglucuronyl paragloboside and sulfoglucuronyl lactosaminyl paragloboside), myelin-associated glycoprotein (MAG) and sulfatide. Sometimes monoclonal IgM binds to a broad spectrum of gangliosides. The detection of targets of autoantibodies has considerable importance in the diagnosis and management of patients. It is not known whether the results of antibody tests are equally sensitive and specific for identification of involved auto-antigens. In this study we evaluated the results obtained using IgM reactivity against MAG by enzyme-linked immunosorbent assay (ELISA Bühlmann) with IgM reactivity against SGPG/SGLPG obtained by overlay thin-layer chromatography. We selected 117 patients with anti-SGPG/SGLPG monoclonal gammopathy and peripheral neuropathy and a control group of 102 peripheral neuropathies with 24 having IgM high titres of monoclonal IgM anti-ganglioside antibodies. The anti-MAG sensitivity was 0.97, specificity was 0.86. There is a crossreactivity between 8 (57%) monoclonal IgM antibodies anti-MAG and anti-ganglioside GM1 and 2 (28%) anti-disialylated gangliosides. These results indicate that in clinical practice, anti-MAG ELISA is useful for eliminating anti-MAG neuropathy, as well as for positive diagnosis for titres upper than 10,000 BTU. It is also alpha good test to appreciate clinical improvement after Rituximab treatment.

The presence of anti-glycolipid specific antibodies have been found to be associated with acute and chronic immune-mediated peripheral neuropathies. Recently a number of anti-glycolipid antibody assays have became commercially available. In this study we established specific anti-glycolipid antibody profiles in a series of sera by the Dotzen Ganglio Profile antibodies. This kit screens for the simultaneous detection of ten anti-glycolipid antibodies against GM3, GM2, GM1, GD3, GD1a, GD1b, GT1a, GT1b, GQ1b gangliosides and sulfatides of the IgM and IgG classes. Sera from 89 patients with acute and chronic neuropathies were selected in a well-characterized cohort of banked sera with anti-glycolipid antibody profiles identified by in-house immunodot assay. Serum from 52 clinical variants of Guillain-Barré syndrome with IgG autoantibody profiles and 37 chronic acquired peripheral neuropathy with IgM autoantibody profiles were tested. The assay correctly identified with good agreement 50 of 52 IgG antibody profiles and 32 of 37 IgM antibody profiles. The assay compared well with in-house immunodot assay. It is easy to screen 10 crossreacting glycolipid antibodies to establish specific antibody profiles to define different subgroups of immune-mediated peripheral neuropathies for classification and immune management.

While employment appears to be among major concerns for epileptic patients, these are confronted with a very high rate of unemployment, especially when epilepsy is pharmacoresistant. However, the persistence of seizures is not the only factor bearing on vocational training or employment; other factors may intervene as well: cognitive dysfunctions, psychological/behavioral disturbances, impact of AEDs, education, vocational training, family members and relatives' attitude, school teams' attitude, employers' attitude, occupational physicians' attitude. Educational level is lower when epilepsy started at school-age; persisting seizures together with other problems may lead the epileptic child or teenager to attend specialized schools. In France, there are few institutions dedicated to children or teenagers with severe epilepsy, and these are very unevenly distributed over the French territory. The main social measures regarding children with epilepsy in France are mentioned. Besides being seizure-free and able to drive, work is one major expectation of patients from epilepsy surgery. The results of epilepsy surgery regarding employment are somewhat controversial; in some studies, temporal lobe surgery may not raise the employment rate; other studies point out that operated-on patients need a long time (up to 6 years) to find a job after surgery. The vocational level or the previous work experiences appear to be as important factors for further employment as being seizure-free, a condition which may not be met in all favourable work outcomes. The medico-social support to patients with pharmacoresistant partial epilepsies has to deal with all the factors mentioned previously; the opportunity for epilepsy surgery may have to be considered early in order to try and prevent the detrimental impact of pharmacoresistant epilepsy on school achievement and vocational training; adult patients with pharmacoresistant epilepsy often cumulate a low qualification level, an absence of a solid work experience, a lack of motivation and a social deprivation. Neurologists may have an insufficient knowledge of social and work regulations: in this paper we describe the main possibilities for epileptic patients to obtain social supports in France. Likewise, occupational physicians seldom know much about epilepsies. We have a positive experience of a multidisciplinary approach combining neurologists, occupational physicians and insertion teams. We are convinced that a personalized follow-up of the epileptic person is useful and often

We established anti-ganglioside antibody profiles in GBS and studied the frequency, fine specificity and clinical correlate. IgG and IgM antibodies to 8 gangliosides were tested by immunodot-blot in 249 consecutive patients with Guillain-Barré syndrome with large variability in clinical expression, referred to our laboratory over a 8-year period. IgG and IgM anti-GM1 antibodies were measured by Elisa. Thin-layer chromatography overlayed by serum was used to control positivity. 89/249 GBS (36%) had characteristic anti-ganglioside antibody profile. Isotypes were, IgG (62%), IgG + IgM (26%) and IgM (12%). Antecedent infections were found in 62% of GBS included more frequently Campylobacter jejuni and cytomegalovirus. Various autoantibody profiles were described with an immunodominant ganglioside. We detected 6 characteristic anti-ganglioside profiles with fine specificity and immunodominant ganglioside corresponding to 6 immuno-clinical variants of GBS: 1) anti-GM1 and GD1b IgG and IgG > IgM in the acute motor axonal neuropathy after Campylobacter jejuni infection in 41 GBS; 2) anti-GD1a IgG in 6 severe motor axonal GBS after Campylobacter jejuni infection; 3) selectively anti-GQ1b IgG in 17 typical Miller Fisher syndrome with areflexia, ataxia and ophthalmoplegia; 4) anti- GT1b ganglioside and polysialogangliosides IgG (n = 9) in two separate cranial nerve variants, ophthalmoplegic SGB and lower cranial nerve variants depending upon the presenting deficit; 5) anti-GD1b IgG in 5 pure ataxic sensory GBS (4%); 6) anti-GM2 IgM in 11 severe GBS with antecedent CMV infection (8%). 34 GBS (14%) had low levels of anti-GM1 and GD1b IgM antibodies which are not disease specific and may simply represent part of the naturally occurring autoantibody population or a secondary response to disease. 126 GBS (50%) had no antibodies, predominantly in classical form. Associations between isotype, fine specificity and clinical presentation permit the definition of homogeneous immuno-clinical variants. Various autoantibody profiles with diagnostic and prognostic value are easy to perform by immunodot blot in acute peripheral neuropathies.

Serum IgM and IgG autoantibodies against carbohydrate epitopes on glycolipids and glycoproteins have been determined in a series of 112 neuropathies associated with monoclonal IgM (M-IgM) by different immunological techniques. The M-IgM anti-myelin sheath antibodies were determined by indirect immunofluorescence microscopy, the M-IgM anti-myelin associated glycoprotein (MAG) antibodies by western-blot analysis, the M-IgM anti-SGPG and SGLPG antibodies by immunodetection on thin-layer chromatography, the M-IgM anti-ganglioside GM3, GM2, GD3, GM1, GD1a, GD1b, GT1b, GQ1b and anti-sulfatide antibodies by immunodot-blot assay on membrane. Among the 112 M-IgM, 81 had autoantibody activity against nerve glycolipid antigens concentrated in peripheral nerve (72%). M-IgM bound strongly to myelin sheath in 34,5% of cases, to MAG in 38% of cases, to SGPG/SGLPG in 52% of cases, to gangliosides in 21.5% of cases and to sulfatide in 26 % of cases. Six M-IgM autoantibody activity profiles have been described in correlation with distinct clinical syndromes: - the M-IgM autoantibody activity profile against the carbohydrate epitope common to the glycolipids SGPG and SGLPG and myelin associated glycoprotein (MAG) in chronic demyelinating sensitive and sensorimotor peripheral neuropathies (58 patients, 52%); - the M-IgM autoantibody activity profile against immunodominant GM1 in demyelinating pure motor neuropathies (9 patients, 8%); - the M-IgM autoantibody activity profile against immunodominant disialosylgangliosides in chronic demyelinating sensitive ataxic neuropathies (8 patients, 7%); - the M-IgM autoantibody activity profile against immunodominant GM2 in demyelinating motor polyneuropathies (3 patients, 2.5%); - the M-IgM autoantibody activity profile against immunodominant GD1a in pure motor polyneuropathies (2 patients, 2%); - the M-IgM autoantibody activity profile against immunodominant GT1b and polysialosylgangliosides in one acute polyradiculoneuropathy (1%). The M-IgM recognized all gangliosides except GM1 and GM2. The neuropathies associated with IgM monoclonal gammopathy with autoreactive specificity form distinct syndromes. In 27.5% of cases, M-IgM had no identifiable activity autoantibodies.

Background and Purpose: Aging is recognized to originate from a diversity of mechanisms that blur the limits between normal and pathologic processes. The purpose of this study was to determine the early effect of normal aging on the regional distribution of brain metabolite concentrations, including N-acetylaspartate (NAA), a major neuronal marker, choline (Cho), and creatine (Cr)., Methods: Thirty-two healthy participants, ages 21 to 61 years, were examined by proton MR spectroscopic (1H MRS) imaging. 1H MRS imaging acquisitions were performed in two brain locations: the centrum semiovale and the temporal lobe. Thirty voxels were selected in four cerebral regions, cortical, semioval, temporal, and hippocampal, and 1H MR spectra were processed to determine the metabolite ratios., Results: With advancing age of the participants, the ratios of %NAA, NAA:Cho, and NAA:Cr were significantly decreased, whereas the ratios of %Cho and %Cr were significantly increased in the cortical, semioval, and temporal regions. On the basis of the significant metabolic difference determined by cluster analysis, two groups of 16 participants with ages ranging from 21 to 39 years (younger group) and 40 to 61 years (older group) were compared. Repeated measures analysis of variance tests, with multiple comparison procedures between the two age groups and among the four brain region groups, showed significant decreases of the %NAA, NAA:Cho, and NAA:Cr ratios in the semioval and temporal regions of the older group compared with the younger group. When compared with other cerebral regions, %NAA and %Cho ratios were significantly decreased in the hippocampal and cortical regions, respectively., Conclusion: These metabolic changes suggest that brain aging is characterized by a reduction in neuronal viability or function associated with an accelerated membrane degradation and/or an increase in glial cell numbers.

We retrospectively evaluated measurement data and clinical relevance of autoantibodies to gangliosides in peripheral neuropathies (PN). The IgG and IgM antiganglioside autoantibodies were determined by our own immunodot-blot assay on membrane and by enzyme-linked immunosorbent assay (Elisa) in sera of 1,342 patients with peripheral neuropathies. Anti-GM1 and anti-GD1b autoantibodies formed a part of the normal autoantibody repertoire and were common place in 12% of normal subjects and in 14% of disease control groups. Polyclonal IgM antiganglioside autoantibodies were detected in chronic PN, polyclonal IgG antiganglioside autoantibodies were detected in acute PN. Polyclonal IgM anti-GM1 and anti-GD1b autoantibodies were detected in 35 patients out of 48 with treatable multifocal motor neuropathy with persistent conduction blocks. These autoantibodies well discriminated between suspected motor peripheral neuropathies and motor neuron diseases (sensitivity 73%, specificity 83%, positive predictive value 60%, negative predictive value 91%). Monoclonal IgM autoantibodies reacted strongly with gangliosides in 15 patients out of 77 with M-IgM neuropathy (19%). M-IgM autoantibodies differed in their fine specificities with different principal target antigens as demonstrated with cross-reactivity. Such findings provide further evidence for a relationship between neurological syndromes and antiganglioside antibody profiles and also suggest that different gangliosides could be principal target antigens such as GM1, GD1b, GT1b, GD1a or GM2. Polyclonal IgG anti-GM1 and anti-GD1b autoantibodies were detected in 21 patients out of 22 with acute motor axonal Guillain-Barré syndrome with antecedent of infection by Campylobacter jejuni, polyclonal IgG anti-GQ1b autoantibodies in 9 patients out of 10 with Miller-Fisher syndrome. Detection of antiganglioside autoantibodies by immunodot-blot assay which is simple and quick in testing a large panel of gangliosides has become very important in the diagnosis and in the choose of expensive therapeutic strategies in chronic or acute autoimmune neuropathies.

This report describes a case of paraneoplastic neurological syndrome associating a subacute sensory neuronopathy and an intestinal pseudo-obstruction in a 64-year old man with a small cell lung cancer. Various paraneoplastic neurological syndromes have been described in association with small cell lung cancer. In our patient anti-Hu antibodies were identified by indirect immunohistochemistry and western-blot analysis. This antibody constitutes an informative tool in assessing the paraneoplastic origin of neurologic symptoms when the etiological inquiry is negative. Its positivity is important in promoting the search for an underlying malignancy and should lead to repeat investigations if the first investigations are normal.

Charcot-Marie-Tooth (CMT) type-1 (CMT1) neuropathy is characterized by peripheral nerve demyelination and has been divided into several subtypes. The most frequent among these, subtype 1A, is related to a microduplication of the region p11.2 of chromosome 17. This region contains the PMP-22 gene which is involved in peripheral nerve myelination. Since motor nerve conduction velocity (MNCV) is closely related to nerve myelination, we compared type-1A patient MNCVs versus non-A CMT1 patient MNCVs, in 57 CMT1A patients and 21 non-A type-1 patients. Patients with the 17p11.2 duplication have MNCVs that are significantly more reduced (about 20 m/s) compared to patients without the 17p11.2 duplication (about 30 m/s). This study also permits a model of the MNCV in the median nerve (MedMNCV) of CMT1 patients, with age, gender and molecular status as parameters. Furthermore, in order to help clinicians to diagnose subtypes of CMT1 patients, the probability for type 1A is modeled as a function of MedMNCV only.