Repurposing chemotherapy-induced peripheral neuropathy grading.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is perceived differently by patients and physicians, complicating its assessment. Current recommendations advocate combining clinical and patient-reported outcomes measures, but this approach can be challenging in patient care. This multicenter European study aims to bridge the gap between patients' perceptions and neurological impairments by aligning both perspectives to improve treatment decision-making. METHODS: Data were pooled from two prospective studies of subjects (n = 372) with established CIPN. Patient and physician views regarding CIPN were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Total Neuropathy Scale-clinical version (TNSc) items, and the disease-specific quality of life - Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20) from the European Organization for Research and Treatment of Cancer (EORTC). To identify inherent neurotoxic severity patterns, we employed hierarchical cluster analysis optimized with k-means clustering and internally validated by discriminant functional analysis. RESULTS: Both NCI-CTCAE and TNSc demonstrated a significant difference in the distribution of severity grades in relation to QLQ-CIPN20 scores. However, a proportion of subjects with different neurotoxic severity grades exhibited overlapping QLQ-CIPN20 scores. We identified three distinct clusters classifying subjects as having severely impaired, intermediately impaired, and mildly impaired CIPN based on TNSc and QLQ-CIPN20 scores. No differences in demographics, cancer type distribution, or class of drug received were observed. CONCLUSIONS: Our results confirm the heterogeneity in CIPN perception between patients and physicians and identify three well-differentiated subgroups of patients delineated by degree of CIPN impairment based on scores derived from TNSc and QLQ-CIPN20. A more refined assessment of CIPN could potentially be achieved using the calculator tool derived from the cluster equations in this study. This tool, which facilitates individual patient classification, requires prospective validation.

Development, validation and feasibility of a Patient Satisfaction Questionnaire for evaluating the quality performance of a diagnostic small fibre neuropathy service: A qualitative study.

INTRODUCTION AND AIM: Small fibre neuropathy (SFN) is a peripheral neuropathy, leading to neuropathic pain and autonomic dysfunction. An evidence-based standardized patient diagnostic SFN service has been implemented in the Netherlands for improving patient-centred SFN care. However, the quality of care of this diagnostic SFN service has never been assessed from a patient perspective. The aim of this study was to develop and validate an SFN-Patient Satisfaction Questionnaire (SFN-PSQ) to measure the quality performance of a standardized diagnostic SFN service. METHODS: A descriptive qualitative study to create the SFN-PSQ was performed using the (COREQ (Consolidated Criteria for Reporting Qualitative Research) checklist. For item generation and content development, domains and/or items from validated PSQs were selected. The content development and content validity were performed using a Delphi method with SFN expert caregivers with different backgrounds. By using the three-step-test method in individual cognitive interviews, the content validity by patients was finalized. RESULTS: In one online Delphi panel round, the content of the first concept of the SFN-PSQ was validated, which resulted in the second concept of the SFN-PSQ. From July 2019 till March 2020, nine patients consented to participate in the individual cognitive interviews. The most significant changes of the new questionnaire were adding domains and items concerning the waiting list, the diagnostic services and consultation by the hospital psychiatrist. Also, a differentiation was made for both an inpatient and outpatient diagnostic SFN service. Furthermore, the clarity and intelligibility of the domains/items were improved, resulting in an increased comprehension of the SFN-PSQ. Ultimately, the new developed SFN-PSQ consisted of 10 domains and 51 items, suitable for measuring patient satisfaction of the neurological analysis in patients with SFN. CONCLUSION: Through item generation, expert opinions and interviews with patients, the SFN-PSQ was developed and validated, and feasibility was confirmed. The structure of the questionnaire, based on the logistic and diagnostic SFN pathway, could be used as a model in other hospitals to improve the quality, continuity and access of SFN care and other chronic diseases taking into account potential cross-cultural differences. PATIENT OR PUBLIC CONTRIBUTION: Caregivers were involved in the item generation and content development of the questionnaire. Patients were directly involved in testing the content validity and feasibility of the SFN-PSQ. CLINICAL TRIAL REGISTRATION: Not applicable.

IgM anti-MAG± peripheral neuropathy (IMAGiNe) study protocol: An international, observational, prospective registry of patients with IgM M-protein peripheral neuropathies.

BACKGROUND: International consensus on IgM ± anti-MAG ± PNP (IgM PNP) is lacking. Despite increasing interest in clinical trials, validated disease-specific measures are needed to adequately capture limitations and changes over time. The IMAGiNe (IgM ± anti-myelin associated glycoprotein [MAG] peripheral neuropathy) study surges as an international collaboration to create a standardized registry of patients with IgM ± anti-MAG PNP. The consortium, which currently consists of 11 institutions from 7 countries, presents here the IMAGiNe study design and protocol. AIMS: Functional outcome measures will be constructed at the level of impairment, as well as activity and participation. We aim to describe the natural history of the cohort, the role of anti-MAG antibodies, the presence of clinical subtypes, and potential biomarkers. METHODS: The IMAGiNe study is a prospective, observational cohort study with a 3-year follow-up. At each assessment, researchers collect clinical data and subjects complete a list of preselected outcome measures. Among these, the "Pre-Rasch-built Overall Disability Scale (Pre-RODS)" questionnaire will be submitted to Rasch analysis to assess classic and modern clinimetric requirements. RESULTS: The final measures will include the IgM-PNP-specific RODS and Ataxia Rating Scale (IgM-PNP-ARS). Descriptions of the disease course, clinical heterogeneity, treatment regimes, variations in laboratory values, and antibody titers will help reach consensus on diagnosis and follow-up strategies. CONCLUSION: The constructed interval scales will be cross-culturally valid and suitable for use in future clinical trials and daily practice. The ultimate goals are to improve functional individualized assessment, reach international consensus, and lay the foundations for successful designs in future studies.

Randomized trial of three IVIg doses for treating chronic inflammatory demyelinating polyneuropathy.

Intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy usually starts with a 2.0 g/kg induction dose followed by 1.0 g/kg maintenance doses every 3 weeks. No dose-ranging studies with intravenous immunoglobulin maintenance therapy have been published. The Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) study was a prospective, double-blind, randomized, parallel-group, multicentre, phase III study investigating the efficacy and safety of 10% liquid intravenous immunoglobulin (Panzyga®) in patients with active chronic inflammatory demyelinating polyneuropathy. Patients were randomized 1:2:1 to receive the standard intravenous immunoglobulin induction dose and then either 0.5, 1.0 or 2.0 g/kg maintenance doses every 3 weeks. The primary end point was the response rate in the 1.0 g/kg group, defined as an improvement ≥1 point in adjusted Inflammatory Neuropathy Cause and Treatment score at Week 6 versus baseline and maintained at Week 24. Secondary end points included dose response and safety. This trial was registered with EudraCT (Number 2015-005443-14) and clinicaltrials.gov (NCT02638207). Between August 2017 and September 2019, the study enrolled 142 patients. All 142 were included in the safety analyses. As no post-infusion data were available for three patients, 139 were included in the efficacy analyses, of whom 121 were previously on corticosteroids. The response rate was 80% (55/69 patients) [95% confidence interval (CI): 69-88%] in the 1.0 g/kg group, 65% (22/34; CI: 48-79%) in the 0.5 g/kg group, and 92% (33/36; CI: 78-97%) in the 2.0 g/kg group. While the proportion of responders was higher with higher maintenance doses, logistic regression analysis showed that the effect on response rate was driven by a significant difference between the 0.5 and 2.0 g/kg groups, whereas the response rates in the 0.5 and 2.0 g/kg groups did not differ significantly from the 1.0 g/kg group. Fifty-six per cent of all patients had an adjusted Inflammatory Neuropathy Cause and Treatment score improvement 3 weeks after the induction dose alone. Treatment-related adverse events were reported in 16 (45.7%), 32 (46.4%) and 20 (52.6%) patients in the 0.5, 1.0 and 2.0 g/kg dose groups, respectively. The most common adverse reaction was headache. There were no treatment-related deaths. Intravenous immunoglobulin (1.0 g/kg) was efficacious and well tolerated as maintenance treatment for patients with chronic inflammatory demyelinating polyneuropathy. Further studies of different maintenance doses of intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy are warranted.

Withdrawal of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy.

Intravenous immunoglobulins are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy. Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment and high health-care costs. Our objective was to determine whether intravenous immunoglobulin withdrawal is non-inferior to continuing intravenous immunoglobulin treatment and to determine how often patients are overtreated. We performed a randomized, double-blind, intravenous immunoglobulin-controlled non-inferiority trial in seven centres in the Netherlands (Trial registration: ISRCTN 13637698; www.isrctn.com/ISRCTN13637698). Adults with clinically stable chronic inflammatory demyelinating polyradiculoneuropathy using intravenous immunoglobulin maintenance treatment for at least 6 months were included. Patients received either intravenous immunoglobulin withdrawal (placebo) as investigational treatment or continuation of intravenous immunoglobulin treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-week follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale. The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse end point according to predefined criteria. Patients with a relapse end point after intravenous immunoglobulin withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable were included in an open-label extension phase of 52 weeks. We included 60 patients, of whom 29 were randomized to intravenous immunoglobulin withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change Inflammatory Rasch-Overall Disability Scale scores was -0.47 (95% CI -1.24 to 0.31), indicating that non-inferiority of intravenous immunoglobulin withdrawal could not be established. In the intravenous immunoglobulin withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the intravenous immunoglobulin continuation group (-17%; 95% CI -39 to 8). Of the intravenous immunoglobulin withdrawal group, 28% remained stable at the end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether intravenous immunoglobulin withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of intravenous immunoglobulin-treated patients experienced a relapse end point, emphasizing the need for more objective measures for disease activity in future trials, as the patient-reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients.

Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies.

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.

Small fiber neuropathies: expanding their etiologies.

PURPOSE OF REVIEW: Several conditions have been associated with the development of small fiber neuropathy (SFN). The list of metabolic, immune-mediated, infectious, toxic, drugs-related, and hereditary conditions is still growing and various hypotheses are made about the underlying pathophysiological mechanisms. Understanding these processes is important to provide new targets for treatment. In addition, the specific SFN phenotype can provide direction for the underlying etiology. This review discusses the latest developments concerning the expanding etiologies in SFN. RECENT FINDINGS: In the past 18 months, special attention has been paid to immunological etiologies, partly due to the coronavirus disease 2019 pandemic, but also new auto-antibodies in SFN have been demonstrated. Identifying patients with immune-mediated SFN can be challenging, since contrary to the classical distal sensory phenotype, a nonlength-dependent pattern is more common.Besides the etiologies of classical SFN, small fiber pathology is increasingly described in diseases without the typical neuropathic pain features of SFN, sometimes called syndromic SFN. However, the clinical relevance is not yet fully understood. SUMMARY: The expansion of the etiologies of SFN continues and brings more insight in possible targets for treatment. The clinical presentation may vary as a result of the underlying condition.

Assessing deterioration using impairment and functional outcome measures in chronic inflammatory demyelinating polyneuropathy: A post-hoc analysis of the immunoglobulin overtreatment in CIDP trial.

It is unclear whether frequently used cutoff values for outcome measures defining minimal clinically important differences (MCIDs) can accurately identify meaningful deterioration in chronic inflammatory demyelinating polyneuropathy (CIDP). We used data from the immunoglobulin overtreatment in CIDP (IOC) trial, in which 60 clinically stable patients with CIDP were randomized to intravenous immunoglobulin (IVIg) withdrawal or continuation. We calculated change scores of the Inflammatory Rasch-Built Overall Disability Scale (I-RODS), grip strength, and Medical Research Council-sum score (MRC-SS) and classified visits based on a treatment anchor (ie, decision to restart/increase treatment after reaching a predefined early endpoint of deterioration). The variability of scores in patients without deterioration was calculated using the limits of agreement. We defined optimized MCIDs for deterioration and specific combinations of MCIDs from different outcome measures, and subsequently calculated the accuracies of the (combined) MCIDs. Substantial variability was found in scores of the I-RODS, grip strength and MRC-SS in patients without deterioration over time, and most MCIDs were within the limits of the variability observed in patients without deterioration. Some MCID cut-offs were insensitive but highly specific for detecting deterioration, for example, the MCID-SE of -1.96 of the I-RODS and -2 point on the MRC-SS. Others were sensitive, but less specific, for example, -4 centiles of the I-RODS. Some combined MCIDs resulted in high specificities and moderate sensitivities. Our results suggest that clinically important deterioration cannot be distinguished from variability over time with currently used MCIDs on the individual level. Combinations of MCIDs might improve the accuracy of determining deterioration, but this needs validation.

Analysis of relapse by inflammatory Rasch-built overall disability scale status in the PATH study of subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy.

Clinical trials in chronic inflammatory demyelinating polyneuropathy (CIDP) often assess efficacy using the ordinal Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Here, data from the PATH study was reanalyzed using change in Inflammatory Rasch-built Overall Disability Scale (I-RODS) to define CIDP relapse instead of INCAT. The PATH study comprised an intravenous immunoglobulin (IVIG) dependency period and an IVIG (IgPro10 [Privigen]) restabilization period; subjects were then randomized to weekly maintenance subcutaneous immunoglobulin (SCIG; IgPro20 [Hizentra]) 0.2 g/kg or 0.4 g/kg or placebo for 24 weeks. CIDP relapse was defined as ≥1-point deterioration in adjusted INCAT, with a primary endpoint of relapse or withdrawal rates. This retrospective exploratory analysis redefined relapse using I-RODS via three different cut-off methods: an individual variability method, fixed cut-off of ≥8-point deterioration on I-RODS centile score or ≥4-point deterioration on I-RODS raw score. Relapse or withdrawal rates were 47% for placebo, 34% for 0.2 g/kg IgPro20 and 19% for 0.4 g/kg IgPro20 using the raw score; 40%, 28% and 15%, respectively using the centile score, and 49%, 40% and 27%, respectively using the individual variability method. IgPro20 was shown to be efficacious as a maintenance therapy for CIDP when relapse was defined using I-RODS. A stable response pattern was shown for I-RODS across various applied cut-offs, which could be applied in future clinical trials.

The facioscapulohumeral muscular dystrophy Rasch-built overall disability scale (FSHD-RODS).

BACKGROUND AND OBJECTIVES: Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient-reported Rasch-built interval scale on activity and participation for FSHD. METHODS: A pre-phase FSHD-Rasch-built overall disability scale (pre-FSHD-RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease-related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2-4 weeks; reliability studies). The pre-FSHD-RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure. RESULTS: The pre-FSHD-RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38-inquiry (originating from 32 items; six items split) FSHD-RODS was constructed achieving Rasch model expectations. Adequate test-retest reliability and (cross-cultural and external) validity scores were obtained. CONCLUSIONS: The FSHD-RODS is a disease-specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD.