BACKGROUND AND OBJECTIVESKappa free light chains (KFLC) seem to efficiently diagnose MS. However, extensive cohort studies are lacking to establish consensus cut-offs, notably to rule out non-MS ...autoimmune CNS disorders. Our objectives were to (1) determine diagnostic performances of CSF KFLC, KFLC index, and KFLC intrathecal fraction (IF) threshold values that allow us to separate MS from different CNS disorder control populations and compare them with oligoclonal bands' (OCB) performances and (2) to identify independent factors associated with KFLC quantification in MS. METHODSWe conducted a retrospective multicenter study involving 13 French MS centers. Patients were included if they had a noninfectious and nontumoral CNS disorder, eligible data concerning CSF and serum KFLC, albumin, and OCB. Patients were classified into 4 groups according to their diagnosis: MS, clinically isolated syndrome (CIS), other inflammatory CNS disorders (OIND), and noninflammatory CNS disorder controls (NINDC). RESULTSOne thousand six hundred twenty-one patients were analyzed (675 MS, 90 CIS, 297 OIND, and 559 NINDC). KFLC index and KFLC IF had similar performances in diagnosing MS from nonselected controls and OIND (p = 0.123 and p = 0.991 for area under the curve AUC comparisons) and performed better than CSF KFLC (p < 0.001 for all AUC comparisons). A KFLC index of 8.92 best separated MS/CIS from the entire nonselected control population, with better performances than OCB (p < 0.001 for AUC comparison). A KFLC index of 11.56 best separated MS from OIND, with similar performances than OCB (p = 0.065). In the multivariate analysis model, female gender (p = 0.003), young age (p = 0.013), and evidence of disease activity (p < 0.001) were independent factors associated with high KFLC index values in patients with MS, whereas MS phenotype, immune-modifying treatment use at sampling, and the FLC analyzer type did not influence KFLC index. DISCUSSIONKFLC biomarkers are efficient tools to separate patients with MS from controls, even when compared with other patients with CNS autoimmune disorder. Given these results, we suggest using KFLC index or KFLC IF as a criterion to diagnose MS. CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that KFLC index or IF can be used to differentiate patients with MS from nonselected controls and from patients with other autoimmune CNS disorders.
Abstract Respiratory Muscle Endurance (RME) is an alternative way to assess respiratory muscle impairment but normal values are lacking to use this test in a clinical perspective. Our objective was ...then to determine reference values of RME in healthy subjects. We recruited 161 healthy subjects (25-80 years old) who were distributed within 5 groups with a 10-year range. We measured vital capacity (VC) and maximal respiratory pressure (MIP, MEP). The RME test consisted of isocapnic hyperpnea at increasing levels of ventilation until exhaustion to determine Tlim (expressed in minutes and as percentage of maximal voluntary ventilation, MVV). A significant difference between age-groups was observed for both VC and MEP expressed as percentage of predicted value. Mean Tlim was 21.8 ± 5.9 minutes 95% confidence interval 20.9-22.8, 74.4 ± 15.9% of predicted MVV 95% CI 71.8-76.9. Tlim was similar among age groups. Tolerance to the RME test was excellent. This study provides normal values of RME in a large age range of healthy subjects and demonstrates that RME is preserved in the elderly.
To identify and characterize autoantibodies (Abs) as novel biomarkers for an autoimmune context in patients with central and peripheral neurologic diseases.
Two distinct approaches ...(immunoprecipitation/mass spectrometry-based proteomics and protein microarrays) and patients' sera and CSF were used. The specificity of the identified target was confirmed by cell-based assay (CBA) in 856 control samples.
Using the 2 methods as well as sera and CSF of patients with central and peripheral neurologic involvement, we identified Abs against the family of Argonaute proteins (mainly AGO1 and AGO2), which were already reported in systemic autoimmunity. AGO-Abs were mostly of immunoglobulin G 1 subclass and conformation dependent. Using CBA, AGO-Abs were detected in 21 patients with a high suspicion of autoimmune neurologic diseases (71.4% were women; median age 57 years) and only in 4/856 (0.5%) controls analyzed by CBA (1 diagnosed with small-cell lung cancer and the other 3 with Sjögren syndrome). Among the 21 neurologic patients identified, the main clinical presentations were sensory neuronopathy (8/21, 38.1%) and limbic encephalitis (6/21, 28.6%). Fourteen patients (66.7%) had autoimmune comorbidities and/or co-occurring Abs, whereas AGO-Abs were the only autoimmune biomarker for the remaining 7/21 (33.3%). Thirteen (61.9%) patients were treated with immunotherapy; 8/13 (61.5%) improved, and 3/13 (23.1%) remained stable, suggesting an efficacy of these treatments.
AGO-Abs might be potential biomarkers of autoimmunity in patients with central and peripheral nonparaneoplastic neurologic diseases. In 7 patients, AGO-Abs were the only biomarkers; thus, their identification may be useful to suspect the autoimmune character of the neurologic disorder.
This study provides Class III evidence that AGO-Abs are more frequent in patients with autoimmune neurologic diseases than controls.
Even if nerves and muscles are the principal targets of intensive care unit-acquired weakness, the neuromuscular junction may be as well involved. In intensive care units, neuromuscular blocking ...agents are classically used, and side effects are possible. Sepsis, immobilization, and denervation which are common in intensive care units may be the cause of neuromuscular junction disorders and participate to the pathophysiology of weakness. We propose here a review of end-plate disorders in intensive care units to highlight their mechanisms and propose diagnosis tools.
Highlights • We describe the largest series of co-occurence of ALS and myasthenia gravis. • This association is rare and requires strict diagnostic criteria. • It may be triggered by a dysfunction of ...the adaptive immune system in both disorders. • False positivity for anti-AChR antibodies is encountered in some ALS patients. • Transient response to acetylcholinesterase inhibitors is also possible in ALS.
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.
Although paraneoplastic subacute sensory neuronopathy is the most frequent presentation of peripheral neuropathy in patients with anti-Hu antibodies, other neuropathies have been reported. In order ...to investigate the clinical and electrophysiological manifestations of neuropathies associated with anti-Hu antibodies, we conducted a retrospective study of 20 patients. For the electrophysiological study, each nerve was classified as normal, demyelinating, axonal/neuronal or axonal/demyelinating. Peripheral neuropathy was the presenting symptom in 95% of patients. CNS and autonomic neuropathy were present in 40% and 30% of patients, respectively. The course of the neuropathy was acute, mimicking Guillain-Barré syndrome in one patient (5%), and subacute (55%) or progressive (40%) in the others. Clinically, the neuropathy was sensory (70%), sensorimotor (25%) or motor (5%). At onset, symptoms were symmetrical (65%), asymmetrical (25%) or multifocal (10%). Pain was a predominant manifestation (80%). Amyotrophia and fasciculations were rare. The median Rankin's score was 2, three patients having an indolent form. Electrophysiology showed the axonal/neuronal pattern to be the most frequent (46.9% of studied nerves); an axonal/demyelinating or demyelinating pattern being seen in 18.3% and 4.9% of nerves, respectively. The axonal/neuronal pattern was more frequent in sensory nerves and the mixed axonal/demyelinating pattern more frequent in motor nerves (P < 0.01). A higher proportion of abnormal nerves correlated with a progressive course (P < 0.05) or a Rankin's score between 3 and 5 (P < 0.01). In patients with sensory neuropathy, 88.5% of sensory nerves were abnormal, mostly with an axonal/neuronal pattern. In addition, 47% of motor nerves were abnormal so that only four out of 14 patients with a clinically pure sensory neuropathy (28.6%) had an electrophysiological pattern typical of sensory neuronopathy. In patients with a sensorimotor neuropathy, 96.6% of sensory and 71% of motor nerves were abnormal. The only statistical difference between sensory and sensorimotor neuropathies was that patients with sensorimotor neuropathy had more frequent motor nerve involvement (P < 0.05) without differences concerning the distribution of the abnormal patterns. Needle neuromyography showed only limited evidence of motor neurone degeneration in both sensory and sensorimotor neuropathy. The present work shows that the typical clinical and electrophysiological pattern of subacute sensory neuronopathy is rarely encountered in patients with anti-Hu antibody and that motor nerve involvement is frequently seen, even in the absence of a motor deficit. In addition to their potential pathophysiological involvement in the mechanism of the paraneoplastic neuropathy, these findings have practical consequences for the diagnosis of the disorder.
Subacute sensory neuronopathy with anti‐Hu antibodies is the best‐characterized paraneoplastic peripheral neuropathy associated with carcinoma. Anti‐CV2 antibodies, another group of paraneoplastic ...antibodies, react with a 66‐kd brain protein belonging to the family of Ulip/CRMP proteins. The manifestations associated with anti‐CV2 antibodies include cerebellar degeneration, uveitis, and peripheral neuropathy. Some of these patients also have anti‐Hu antibodies. We have compared the clinical, electrophysiological, and pathological characteristics of the peripheral neuropathy in 9 patients with anti‐CV2 antibodies (3 of whom also had anti‐Hu antibodies) and 12 patients with only anti‐Hu antibodies. Data for patients with anti‐Hu antibodies alone indicated subacute sensory neuronopathy. Patients with anti‐CV2 antibodies had a mixed axonal and demyelinating sensory motor neuropathy that was sometimes superimposed on subacute sensory neuronopathy when both anti‐CV2 and anti‐Hu antibodies were present. Unlike anti‐Hu antibodies, anti‐CV2 antibodies reacted with peripheral nerve antigens, as shown by their ability to bind to a 66‐kd protein in human and rat nerve on Western blot analysis and to immunolabel peripheral nerve axons and sensory neurons on immunohistochemical study. Ann Neurol 2001;49:214–221
Introduction
IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic inflammatory ...demyelinating polyradiculoneuropathy (CIDP). Our objective was to assess, in a real-life practice, the incidence, the clinical features and the response to treatment of these forms of CIDP.
Methods
1500 sera of patients suspected of having CIDP from France, Belgium and Switzerland were prospectively tested using a flow cytometry technique. The characteristics of patients with antibodies against the node of Ranvier were compared to 100 seronegative CIDP from our department.
Results
IgG4 antibodies against Nfasc155, CNTN1, and Caspr1 were, respectively, detected in 15 (prevalence 1%), 10 (0.7%) and 2 (0.2%) sera. Antibodies specific of the Nfasc140/186 were not detected.
All subjects with antibodies against the node of Ranvier fulfilled diagnostic criteria for CIDP.
CIDP with anti-Nfasc155 were younger, had more sensory ataxia and postural tremor than seronegative CIDP. CIDP with anti-CNTN1 had more frequent subacute onset and facial paralysis, commoner renal involvement with membranous glomerulonephritis and greater disability, than seronegative CIDP. CIDP with anti-Caspr1 had more frequent respiratory failure and cranial nerve involvement but not more neuropathic pain than seronegative CIDP. Intravenous immunoglobulins were ineffective in most seropositive patients. Rituximab produced dramatic improvement in disability and decreased antibodies titres in 13 seropositive patients (8 with anti-Nfasc155 and 5 with anti-CNTN1 antibodies).
Conclusions
Although rare, anti-paranodal antibodies are clinically valuable, because they are associated with specific phenotypes and therapeutic response.
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