The effect of tremor on disability assessment in chronic inflammatory demyelinating polyradiculoneuropathy.

Tremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is common, often unresponsive to treatment, and may contribute to disability. We aim to investigate whether tremor is associated with disability as measured in daily practice and clinical trials, independent of other impairments. We included 76 CIDP patients in this cross-sectional study. We assessed tremor with the Tremor Research Group essential tremor rating assessment scale (TETRAS) and the Fahn-Tolosa-Marin clinical rating scale (FTM). Disability was measured with the inflammatory Rasch-built overall disability scale (I-RODS) and the adjusted Inflammatory Neuropathy Cause and Treatment disability scale (INCAT-DS, categorized separately in arm score, or total score). Impairments including strength, sensory impairment, and fatigue were measured using specific impairment scales. We tested whether "the presence of a clinically relevant tremor" (based on TETRAS and FTM) or "tremor severity" (FTM part B sum score) was associated with disability scores (I-RODS, INCAT-DS total score, and INCAT-DS arm score), independent of the impairment scores, using multivariate regression. Both "the presence of a clinically relevant tremor" and "tremor severity" were significantly associated with disability measured by the INCAT-DS (arm score and total score), but not the I-RODS, independent of strength, sensory impairment, and fatigue. The explained variances were low. Clinically relevant tremor can (partly) explain disability in CIDP, as measured with the INCAT-DS, independent of muscle strength, sensory deficits, and fatigue. To assess disease activity in CIDP patients with tremor, both impairment and disability outcomes should be assessed, as disability is caused partly by tremor while the effect of immunotherapy on tremor seems limited.

Randomized trial of intravenous immunoglobulin maintenance treatment regimens in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: High peak serum immunoglobulin G (IgG) levels may not be needed for maintenance intravenous immunoglobulin (IVIg) treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and such high levels may cause side effects. More frequent lower dosing may lead to more stable IgG levels and higher trough levels, which might improve efficacy. The aim of this trial is to investigate whether high frequent low dosage IVIg treatment is more effective than low frequent high dosage IVIg treatment. METHODS: In this randomized placebo-controlled crossover trial, we included patients with CIDP proven to be IVIg-dependent and receiving an individually established stable dose and interval of IVIg maintenance treatment. In the control arm, patients received their individual IVIg dose and interval followed by a placebo infusion at half the interval. In the intervention arm, patients received half their individual dose at half the interval. After a wash-out phase patients crossed over. The primary outcome measure was handgrip strength (assessed using a Martin Vigorimeter). Secondary outcome indicators were health-related quality of life (36-item Short-Form Health Survey), disability (Inflammatory Rasch-built Overall Disability Scale), fatigue (Rasch-built Fatigue Severity Scale) and side effects. RESULTS: Twenty-five patients were included and were treated at baseline with individually adjusted dosages of IVIg ranging from 20 to 80 g and intervals ranging from 14 to 35 days. Three participants did not complete the trial; the main analysis was therefore based on the 22 patients completing both treatment periods. There was no significant difference in handgrip strength change from baseline between the two treatment regimens (coefficient -2.71, 95% CI -5.4, 0.01). Furthermore, there were no significant differences in any of the secondary outcomes or side effects. CONCLUSIONS: More frequent lower dosing does not further improve the efficacy of IVIg in stable IVIg-dependent CIDP and does not result in fewer side effects.

Patient-reported outcomes with subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy: the PATH study.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyneuropathy (CIDP) causes weakness which adversely impacts function and quality of life (QOL). CIDP often requires long-term management with intravenous or subcutaneous immunoglobulin. The Polyneuropathy and Treatment with Hizentra® (PATH) study showed that subcutaneous immunoglobulin (SCIG) was efficacious in CIDP maintenance. Here, patient-reported outcomes in patients on SCIG are assessed. METHODS: Subjects stabilized on intravenous immunoglobulin were randomly allocated to receive weekly 0.2 or 0.4 g/kg bodyweight of 20% SCIG (IgPro20) or placebo. Overall QOL/health status was assessed using the EuroQoL 5-Dimension (EQ-5D) health profile and visual analog scale, treatment satisfaction was assessed with the Treatment Satisfaction Questionnaire for Medicine (TSQM) and work-related impact was assessed with the Work Productivity and Activity Impairment Questionnaire for General Health (WPAI-GH). The EQ-5D health profile was assessed in terms of the percentage of subjects maintained or improved at week 25 of SCIG therapy on each of the EQ-5D domains versus baseline after intravenous immunoglobulin stabilization. TSQM and WPAI-GH were assessed by median score changes from baseline to week 25. RESULTS: In total, 172 subjects were randomized to placebo (n = 57), 0.2 g/kg IgPro20 (n = 57) and 0.4 g/kg IgPro20 (n = 58). Significantly higher proportions of IgPro20-treated subjects improved/maintained their health status on the EQ-5D usual activities dimension, and in additional dimensions (mobility and pain/discomfort) in sensitivity analyses. TSQM and WPAI-GH scores were more stable with IgPro20 treatment compared with placebo. CONCLUSIONS: IgPro20 maintained or improved QOL in most subjects with CIDP, consistent with the PATH study findings that both IgPro20 doses were efficacious in maintaining CIDP.

The minimum clinically important difference: which direction to take.

Over the past decades in modern medicine, there has been a shift from statistical significance to clinical relevance when it comes to interpreting results from clinical trials. A concept that is increasingly being used as a surrogate for clinical relevance and effect size calculation is the minimum clinically important difference (MCID). In this paper, an overview is presented of the most important aspects of the MCID concept used in research trials and a discussion of what this means for the neurological patient in clinical trials and daily practice is given. Is the MCID the best outcome measure cut-off to be implemented?

Associated conditions in small fiber neuropathy - a large cohort study and review of the literature.

BACKGROUND AND PURPOSE: Small fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals. METHODS: A total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings. RESULTS: No associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients. CONCLUSIONS: Based on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral.

Correlation of the patient's reported outcome Inflammatory-RODS with an objective metric in immune-mediated neuropathies.

BACKGROUND AND PURPOSE: There is increasing interest in using patient-reported outcome measures (PROMs) in clinical studies to capture individual changes over time. However, PROMs have also been criticized because they are entirely subjective. Our objective was to examine the relationship between a subjective PROM and an objective outcome tool in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and gammopathy-related polyneuropathy (MGUSP). METHODS: The Inflammatory Rasch-built Overall Disability Scale (I-RODS©, a multi-item scale that examines functionality) was completed by 137 patients with newly diagnosed (or relapsing) GBS (55), CIDP (59) and MGUSP (23) who were serially examined (GBS/CIDP, T0/T1/T3/T6/T12 months; MGUSP, T0/T3/T12). Possible association between the I-RODS findings and the vigorimeter scores, an objective linear instrument to assess grip strength, was examined. RESULTS: A significant correlating trend was found between the I-RODS and grip strength scores for the overall group and in each illness, independently. CONCLUSION: The objectivity of patients' subjective report on their functional state based on a strong correlation between the I-RODS and grip strength in patients with GBS, CIDP and MGUSP has been demonstrated. These findings provide further support to use the I-RODS and grip strength in future clinical studies in these conditions.

Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation.

Gain-of-function missense mutations in voltage-gated sodium channel Nav1.7 have been linked to small-fiber neuropathy, which is characterized by burning pain, dysautonomia and a loss of intraepidermal nerve fibers. However, the mechanistic cascades linking Nav1.7 mutations to axonal degeneration are incompletely understood. The G856D mutation in Nav1.7 produces robust changes in channel biophysical properties, including hyperpolarized activation, depolarized inactivation, and enhanced ramp and persistent currents, which contribute to the hyperexcitability exhibited by neurons containing Nav1.8. We report here that cell bodies and neurites of dorsal root ganglion (DRG) neurons transfected with G856D display increased levels of intracellular Na(+) concentration ([Na(+)]) and intracellular [Ca(2+)] following stimulation with high [K(+)] compared with wild-type (WT) Nav1.7-expressing neurons. Blockade of reverse mode of the sodium/calcium exchanger (NCX) or of sodium channels attenuates [Ca(2+)] transients evoked by high [K(+)] in G856D-expressing DRG cell bodies and neurites. We also show that treatment of WT or G856D-expressing neurites with high [K(+)] or 2-deoxyglucose (2-DG) does not elicit degeneration of these neurites, but that high [K(+)] and 2-DG in combination evokes degeneration of G856D neurites but not WT neurites. Our results also demonstrate that 0 Ca(2+) or blockade of reverse mode of NCX protects G856D-expressing neurites from degeneration when exposed to high [K(+)] and 2-DG. These results point to [Na(+)] overload in DRG neurons expressing mutant G856D Nav1.7, which triggers reverse mode of NCX and contributes to Ca(2+) toxicity, and suggest subtype-specific blockade of Nav1.7 or inhibition of reverse NCX as strategies that might slow or prevent axon degeneration in small-fiber neuropathy.

Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin.

BACKGROUND: The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. PATIENTS AND METHODS: A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). RESULTS: Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. CONCLUSION: None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.

Rasch-built Overall Disability Scale for patients with chemotherapy-induced peripheral neuropathy (CIPN-R-ODS).

Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side-effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN.

The Rasch-built Pompe-specific activity (R-PAct) scale.

We constructed a patient-based interval scale using Rasch analysis, specifically suited to quantify the effects of Pompe disease on patient's ability to carry out daily life activities and their social participation: Rasch-built Pompe-specific Activity scale. Between July 2005 and April 2011, 186 patients aged 16 or older, participated to develop this scale. External construct validity was determined through correlations with the MRC sumscore and Rotterdam Handicap Scale. Furthermore, test-retest reliability was determined in a subgroup of 44 patients. Finally, individual person-level responsiveness was used to determine the proportion of patients demonstrating significant improvement or deterioration during their natural disease course, or during treatment with enzyme replacement therapy. Of the original 49 items, 31 were removed after investigation of model fit, internal reliability, threshold examination, item bias, and local dependency. The remaining 18 items were ordered on a linearly weighted scale and demonstrated good discriminative ability (Person Separation Index 0.96), external construct validity (intraclass correlation coefficient (ICC) for MRC sumscore 0.82, and for the Rotterdam handicap scale 0.86), reliability of person's location (ability comparison: ICC 0.95), and responsiveness. We therefore conclude that the R-PAct scale enables us to accurately detect limitations in activities and social participation throughout the entire disease spectrum in patients with Pompe disease.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS: After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS: Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION: Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

Vigorimeter grip strength in CIDP: a responsive tool that rapidly measures the effect of IVIG--the ICE study.

BACKGROUND AND PURPOSE: In a recent trial in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), the ICE study, grip strength measurement captured significantly more improvement in patients receiving immune globulin (IGIV-C) intravenously than in those receiving placebo. METHODS: We conducted a systematic analysis to determine the sensitivity of grip strength as an indicator of meaningful clinical changes in CIDP. RESULTS: A randomized double-blind trial was undertaken in 117 CIDP patients who received IGIV-C or placebo every 3 weeks for up to 24 weeks. Grip strength and inflammatory neuropathy cause and treatment (INCAT) disability scores were assessed at each visit, and the responsiveness of each scale was compared. A minimum clinically important difference cut-off value for grip strength (>8 kPa) and INCAT score (>1 point) was applied to assess the proportion of responders to IGIV-C versus placebo. This analysis showed that grip strength demonstrated significant improvement earlier (as early as day 16) than the INCAT disability scale in patients receiving IGIV-C compared with placebo. A significantly higher proportion of improvers were seen in the IGIV-C group (37.5%-50.9%) than in the placebo group (21.1%-25.9%) for grip strength at day 16, week 3, week 6 and the end of the first period. Also, grip strength showed within the first 6 weeks in the placebo group significantly more patients with a clinically meaningful deterioration (>8 kPa), compared with the INCAT (>1-point deterioration) findings. CONCLUSIONS: Grip strength can be considered a sensitive tool for assessing clinically relevant changes in patients with CIDP. Its use in daily practice is suggested.

Pain relief and quality-of-life improvement after spinal cord stimulation in painful diabetic polyneuropathy: a pilot study.

BACKGROUND: Painful diabetic polyneuropathy (PDP) is associated with high pain scores and is difficult to treat. Therefore, spinal cord stimulation (SCS) has been suggested as second-line treatment. In this study, the feasibility and efficacy of SCS in PDP were investigated, as well as the predictive value of clinical sensory testing for the treatment outcome. METHODS: Fifteen patients with intractable PDP in the lower limbs were recruited. During lead implantation, the feasibility of achieving adequate paraesthesia coverage using one stimulation lead was investigated. If trial stimulation was successful, a definitive neurostimulator was implanted. Pain intensity was scored using an 11-point numeric rating scale and patients' global impression of change scale. Additionally, neuropathic pain characteristics, quality of life, sleep quality and mood were assessed. The predictive value of clinical sensory testing for the treatment outcome was analysed. RESULTS: Adequate paraesthesia coverage was achieved in 14 out of 15 patients. Clinically relevant pain relief was present in 11 patients after trial stimulation and 10 patients at 12 months. The quality of life was significantly increased at 2 weeks and 3 months in patients with successful SCS treatment. Several neuropathic pain characteristics and quality of sleep were improved at 2 weeks and 12 months. Preoperative clinical sensory testing did not differentiate between treatment responders from non-responders. CONCLUSIONS: SCS seems to be an efficacious and feasible treatment for intractable PDP. In this exploratory study, it was not possible to predict the treatment outcome using clinical sensory testing. These results justify performing a randomized clinical trial.

Genetic aspects of sodium channelopathy in small fiber neuropathy.

Small fiber neuropathy (SFN) is a disorder typically dominated by neuropathic pain and autonomic dysfunction, in which the thinly myelinated Aδ-fibers and unmyelinated C-fibers are selectively injured. The diagnosis SFN is based on a reduced intraepidermal nerve fiber density and/or abnormal thermal thresholds in quantitative sensory testing. The etiologies of SFN are diverse, although no apparent cause is frequently seen. Recently, SCN9A-gene variants (single amino acid substitutions) have been found in ∼30% of a cohort of idiopathic SFN patients, producing gain-of-function changes in sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons. Functional testing showed that these variants altered fast inactivation, slow inactivation or resurgent current and rendered dorsal root ganglion neurons hyperexcitable. In this review, we discuss the role of Na(V)1.7 in pain and highlight the molecular genetics and pathophysiology of SCN9A-gene variants in SFN. With increasing knowledge regarding the underlying pathophysiology in SFN, the development of specific treatment in these patients seems a logical target for future studies.

Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability.

OBJECTIVES: Although small fiber neuropathy (SFN) often occurs without apparent cause, the molecular etiology of idiopathic SFN (I-SFN) has remained enigmatic. Sodium channel Na(v)1.7 is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons and their small-diameter peripheral axons. We recently reported the presence of Na(v)1.7 variants that produce gain-of-function changes in channel properties in 28% of patients with painful I-SFN and demonstrated impaired slow-inactivation in one of these mutations after expression within HEK293 cells. Here we show that the I739V Na(v)1.7 variant in a patient with biopsy-confirmed I-SFN impairs slow-inactivation within DRG neurons and increases their excitability. METHODS: A patient with SFN symptoms including pain, and no identifiable underlying cause, was evaluated by skin biopsy, quantitative sensory testing, nerve conduction studies, screening of genomic DNA for variants in SCN9A, and functional analysis. RESULTS: Voltage-clamp analysis following expression within DRG neurons revealed that the Na(v)1.7/I739V substitution impairs slow-inactivation, depolarizing the midpoint (V(1/2)) by 5.6 mV, and increasing the noninactivating component at 10 mV from 16.5% to 22.2%. Expression of I739V channels within DRG neurons rendered these cells hyperexcitable, reducing current threshold and increasing the frequency of firing evoked by graded suprathreshold stimuli. CONCLUSIONS: These observations provide support, from a patient with biopsy-confirmed SFN, for the suggestion that functional variants of Na(v)1.7 that impair slow-inactivation can produce DRG neuron hyperexcitability that contributes to pain in SFN. Na(v)1.7 channelopathy-associated SFN should be considered in the differential diagnosis of cases of SFN in which no other cause is found.

Morphometry of dermal nerve fibers in human skin.

OBJECTIVE: We aimed to assess the innervation density of dermal nerves in human skin biopsies by bright-field immunohistochemistry. METHODS: The size of dermal area where nerve length was quantified was validated in 30 skin biopsy sections (5 controls and 5 patients with small-fiber neuropathy [SFN]). It was obtained dividing an area of 200-µm depth from the dermal-epidermal junction into 4 equal portions. The length of dermal nerves (DNFL) was measured into 150 sections (25 controls and 25 patients with SFN) and values per millimeter of epidermis (DNFL/mm) and dermal area (DNFL/mm2) were obtained. Age- and gender-matched normative values of intraepidermal nerve fiber (IENF) density were used as gold standard to calculate the performance of dermal nerve morphometry. RESULTS: Patients showed significantly lower DNFL (1.96 mm ± 0.96 SD), DNFL/mm (0.65 ± 0.29 SD), and DNFL/mm2 (3.75 ± 1.7 SD) than controls (DNFL 3.52 mm ± 1.31 SD, 5th percentile 2.05; DNFL/mm 1.25 ± 0.39, 5th percentile 0.71; DNFL/mm2 7.07 ± 2.41 SD, 5th percentile 3.95). Sensitivity, specificity, and percentage of individuals correctly classified were 75.8%, 73.9%, and 74.8% for DNFL, 75%, 80%, and 77.7% for DNFL/mm, and 75.8%, 80.2%, and 78.1% for DNFL/mm2. Receiver operator characteristic area analysis confirmed the excellent discrimination (0.8-0.9) between patients and controls. Dermal nerve morphometry significantly correlated with IENF density. Spearman rank correlation demonstrated good agreement for interobserver analysis (0.87-0.89), and between DNFL and IENF densities (0.71-0.73; p < 0.0001). CONCLUSIONS: We provided a reliable method to quantify the innervation density of dermal nerves that might improve the diagnostic yield of skin biopsy.

Rasch-built Overall Disability Scale (R-ODS) for immune-mediated peripheral neuropathies.

OBJECTIVE: To develop a patient-based, linearly weighted scale that captures activity and social participation limitations in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and gammopathy-related polyneuropathy (MGUSP). METHODS: A preliminary Rasch-built Overall Disability Scale (R-ODS) containing 146 activity and participation items was constructed, based on the WHO International Classification of Functioning, Disability and Health, literature search, and patient interviews. The preliminary R-ODS was assessed twice (interval: 2-4 weeks; test-retest reliability studies) in 294 patients who experienced GBS in the past (n = 174) or currently have stable CIDP (n = 80) or MGUSP (n = 40). Data were analyzed using the Rasch unidimensional measurement model (RUMM2020). RESULTS: The preliminary R-ODS did not meet the Rasch model expectations. Based on disordered thresholds, misfit statistics, item bias, and local dependency, items were systematically removed to improve the model fit, regularly controlling the class intervals and model statistics. Finally, we succeeded in constructing a 24-item scale that fulfilled all Rasch requirements. "Reading a newspaper/book" and "eating" were the 2 easiest items; "standing for hours" and "running" were the most difficult ones. Good validity and reliability were obtained. CONCLUSION: The R-ODS is a linearly weighted scale that specifically captures activity and social participation limitations in patients with GBS, CIDP, and MGUSP. Compared to the Overall Disability Sum Score, the R-ODS represents a wider range of item difficulties, thereby better targeting patients with different ability levels. If responsive, the R-ODS will be valuable for future clinical trials and follow-up studies in these conditions.

Hereditary muscular dystrophies and the heart.

Cardiac disease is a common clinical manifestation of neuromuscular disorders, particularly of muscular dystrophies. Heart muscle cells as well as specialized conducting myocardial fibres may be affected by the dystrophic process. The incidence and nature of cardiac involvement vary with different types of muscular dystrophies. Some mainly lead to myocardial disease, resulting in cardiomyopathy and heart failure, while others particularly affect the conduction system, leading to arrhythmias and sudden death. As prognosis of muscular dystrophy patients may be directly related to cardiac status, surveillance and timely management of cardiac complications are important. However, recognition of cardiac involvement requires active investigation and remains challenging since typical signs and symptoms of cardiac dysfunction may not be present and progression is unpredictable. In this review, we present a comprehensive overview of hereditary muscular dystrophies associated with cardiac disease to provide an efficient strategy for the expertise and management of these diseases.

European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.

BACKGROUND: Revision of the guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy, published in 2005, has become appropriate owing to publication of more relevant articles. Most of the new studies focused on small fiber neuropathy (SFN), a subtype of neuropathy for which the diagnosis was first developed through skin biopsy examination. This revision focuses on the use of this technique to diagnose SFN. METHODS: Task force members searched the Medline database from 2005, the year of the publication of the first EFNS guideline, to June 30th, 2009. All pertinent articles were rated according to the EFNS and PNS guidance. After a consensus meeting, the task force members created a manuscript that was subsequently revised by two experts (JML and JVS) in the field of peripheral neuropathy and clinical neurophysiology, who were not previously involved in the use of skin biopsy. RESULTS AND CONCLUSIONS: Distal leg skin biopsy with quantification of the linear density of intraepidermal nerve fibers (IENF), using generally agreed upon counting rules, is a reliable and efficient technique to assess the diagnosis of SFN (Recommendation Level A). Normative reference values are available for bright-field immunohistochemistry (Recommendation Level A) but not yet for confocal immunofluorescence or the blister technique. The morphometric analysis of IENF density, either performed with bright-field or immunofluorescence microscopy, should always refer to normative values matched for age (Recommendation Level A). Newly established laboratories should undergo adequate training in a well-established skin biopsy laboratory and provide their own stratified for age and gender normative values, intra- and interobserver reliability, and interlaboratory agreement. Quality control of the procedure at all levels is mandatory (Good Practice Point). Procedures to quantify subepidermal nerve fibers and autonomic innervated structures, including erector pili muscles, and skin vessels, are under development but need to be confirmed by further studies. Sweat gland innervation can be examined using an unbiased stereologic technique recently proposed (Recommendation Level B). A reduced IENF density is associated with the risk of developing neuropathic pain (Recommendation Level B), but it does not correlate with its intensity. Serial skin biopsies might be useful for detecting early changes of IENF density, which predict the progression of neuropathy, and to assess degeneration and regeneration of IENF (Recommendation Level C). However, further studies are warranted to confirm its potential usefulness as an outcome measure in clinical practice and research. Skin biopsy has not so far been useful for identifying the etiology of SFN. Finally, we emphasize that 3-mm skin biopsy at the ankle is a safe procedure based on the experience of 10 laboratories reporting absence of serious side effects in approximately 35,000 biopsies and a mere 0.19% incidence of non-serious side effects in about 15 years of practice (Good Practice Point).

Confirming the efficacy of intravenous immunoglobulin in CIDP through minimum clinically important differences: shifting from statistical significance to clinical relevance.

BACKGROUND: The ICE trial demonstrated the efficacy of immune globulin intravenous (IGIV-C) over placebo in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, improving the interpretability of the results by analysing the minimum clinically important difference (MCID) had not been considered. OBJECTIVES: To identify MCID thresholds of various outcome measures using different methods and to test treatment differences (IGIV-C vs placebo) using these thresholds. METHODS: One anchor-based (Short Form-36 question 2) and three distribution-based (½ SD, 1 SE of measurement, and effect size) techniques were employed to identify MCID cut-offs for various impairments (electromyographic parameters, Medical Research Council (MRC) sum score, grip strength, inflammatory neuropathy cause and treatment (INCAT) sensory sum score), disability (INCAT scale score, Rotterdam handicap scale (RHS) score) and quality of life (SF-36). IGIV-C or placebo was administered every 3 weeks for up to 24 weeks to 117 CIDP patients. Patients who did not improve by ≥1 point on the INCAT scale received alternate treatment. The proportion of patients with results exceeding identified MCID thresholds was compared. Results MCID cut-offs for outcomes were determined using each method. For the INCAT disability scale (primary ICE-trial outcome), all MCID methods identified significantly more responders with IGIV-C than placebo. Significant differences favouring IGIV-C were also demonstrated for various nerve conduction parameters, MRC sum score, grip strength, RHS score and SF-36 physical component summary score. CONCLUSION: In addition to being statistically significant, all MCID analyses showed that CIDP improvements with IGIV-C are clinically meaningful. Consideration of MCID is recommended in future therapeutic trials. Trial Registration Number NCT00220740 (http://ClinicalTrials.gov).