Towards a useful and cost-effective workup in chronic polyneuropathy: the EXPRESS study protocol.

BACKGROUND: Knowledge gaps exist about the usefulness and extent of blood tests and nerve conduction studies in the workup of polyneuropathy. We hypothesize that a limited workup improves costs spend on diagnostics without loss of diagnostic reliability or disadvantageous effect on treatment choice in many patients with a clinical diagnosis chronic polyneuropathy. We aim to determine which investigations are necessary in the workup of patients with suspected chronic polyneuropathy clinically diagnosed by neurologists in an outpatient clinic and will perform an early health technology assessment. METHODS: This is a prospective multi-center quality in health care evaluation. We compare two diagnostic strategies, both performed on all participants: the standard care by each patient's neurologist, and the proposed (limited) workup by the study panel members consisting of neurologists with experience in neuromuscular diseases. RESULTS: The primary outcome is effectiveness of a limited workup expressed as concordance between the patient's neurologist diagnosis and the panel diagnosis. This will be related to differences in costs and impact on treatment or patient management otherwise. Other outcomes are burden/gain for the patient in terms of number of investigations, time to diagnosis, hospital visits, sick-leave, loss of productivity, expenses, experienced quality of care. CONCLUSION: This multicenter prospective observational study on quality in healthcare will provide improved evidence about the components of a cost-effective workup for patients with chronic polyneuropathy.

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.

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.

Red flags and adjusted suspicion index for distinguishing hereditary transthyretin amyloid polyneuropathy from idiopathic axonal polyneuropathy.

BACKGROUND: Early diagnosis of hereditary ATTR polyneuropathy (ATTRv-PN) is important since treatment options have become available, which are most effective early in the disease course. ATTRv-PN is likely underdiagnosed as patients might be misdiagnosed with idiopathic polyneuropathy. It is uncertain if it is useful to test for TTR gene mutations in patients with a typical presentation for chronic idiopathic axonal polyneuropathy (CIAP) and which are the distinguishing clinical features. METHODS: We carried out a retrospective cohort study to assess the yield of TTR gene sequencing in patients with polyneuropathy and assessed if the identified patients with ATTRv-PN had a clinical presentation typical of CIAP. Additionally, we assessed which clinical features, including previously defined red flag symptoms, can differentiate between patients with CIAP and ATTRv-PN and assessed the performance of the TTR suspicion index. RESULTS: Out of 338 patients with polyneuropathy, 10 patients had a pathogenic TTR gene mutation (all p.Val50Met) and none had a clinical presentation typical of CIAP. Patients with ATTRv-PN more often had bilateral CTS, motor involvement of arms, cardiac involvement, family history suggestive of hATTRv, and autonomic symptoms than patients with CIAP. All patients with ATTRv-PN as well as 70% of patients with CIAP fulfilled the suspicion index. CONCLUSION: Routine TTR gene sequencing in patients with a typical presentation for CIAP is not useful. However, red flag symptoms can differentiate patients with ATTRv-PN from patients with CIAP. We propose an adjusted version of the TTR suspicion index to increase diagnostic yield.

Clinical relevance of testing for metabolic vitamin B12 deficiency in patients with polyneuropathy.

OBJECTIVE: Determine vitamin B12 threshold levels below which additional testing of methylmalonic acid (MMA) and/or homocysteine (Hcy) is useful to diagnose metabolic vitamin B12 deficiency in patients with polyneuropathy, and how vitamin B12, MMA and Hcy levels relate to the effect of supplementation therapy. METHODS: In a retrospective cohort study of 331 patients with polyneuropathy, vitamin B12, MMA and Hcy were measured. Linear regression models with vitamin B12 as dependent and Hcy or MMA as covariate were compared, to assess which was best related to vitamin B12. Threshold vitamin B12 levels for metabolic deficiency (defined as elevatede metabolites) were determined using logistic regression with elevated metabolites as dependent and vitamin B12 as covariate. A structured interview was conducted in 42 patients to evaluate response to vitamin B12 supplementation. RESULTS: MMA was best related to vitamin B12. Using elevated MMA for metabolic deficiency, we found 90% sensitivity at a vitamin B12 threshold level <264 pmol/L (358 pg/mL) and 95% sensitivity at <304 pmol/L (412 pg/mL). Improvement after supplementation was reported by 19% patients and stabilization by 24%. 88% of patients with improvement and 90% with stabilization either had absolute deficiency (Vitamin B12 < 148 pmol/L) or metabolic deficiency (elevated MMA and vitamin B12 ≥ 148 pmol/L). There were no additional patients with improvement or stabilization with isolated elevated Hcy. CONCLUSION: Testing of MMA has additional value in identifying patients with clinically relevant metabolic deficiency when vitamin B12 is below 304 pmol/L (412 pg/mL). Supplementation can be effective in patients with absolute and metabolic deficiency.

Performance and Self-reported Functioning of People With Chronic Idiopathic Axonal Polyneuropathy: A 4-Year Follow-up Study.

OBJECTIVE: To describe the course of performance of activities (observed and self-reported) of people with chronic idiopathic axonal polyneuropathy (CIAP) over 4 years and to assess the associations with muscle strength, sensory function, and psychological personal factors (intention, perceived behavior control [PBC], and feelings of depression or anxiety). DESIGN: Prospective observational study with measurement at baseline, 6 months, 1 year, and 4 years. SETTING: Outpatient neurology clinic. PARTICIPANTS: People with CIAP (N=92). MAIN OUTCOME MEASURES: Walking was measured using the shuttle-walk test (SWT), a pedometer (mean step count/d), and the "physical functioning" subscale of the Short Form-36 questionnaire. Muscle strength and sensory function were measured using a MicroFET handheld dynamometer and the Sensory Modality Sum score. Personal factors were assessed with the Hospital Anxiety and Depression Scale, and intention and PBC were assessed with a protocolized questionnaire. RESULTS: Multilevel model analysis showed a significant decrease over time in mean scores in performance of activities (SWT, step count), which was associated with older age and loss of muscle strength (SWT: ß=73.392, step count: ß=676.279, P<.001). Limitations in self-reported functioning (physical functioning) significantly increased and were associated with older age (ß=-0.916, P=.001), increased comorbidity (ß=-6.978, P=.024), loss of muscle strength (ß=7.074, P<.001), low PBC (ß=0.744, P<.001), and increased feelings of depression (ß=1.481, P<.001). CONCLUSIONS: Performance of activities of people with CIAP decreased over time (SWT, step count, physical functioning). Older age, loss of muscle strength, comorbidity, feelings of depression, and low perceived behavior control were associated with this decrease. However, there were considerable individual differences.

Serum cytokine patterns in immunoglobulin m monoclonal gammopathy-associated polyneuropathy.

INTRODUCTION: Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM-PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides. METHODS: To test whether B-cell-stimulating cytokines are increased in IgM-PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM-PNP and 113 controls. RESULTS: Median interleukin (IL)-6 concentrations were higher in patients with IgM-PNP, and median IL-10 concentrations were higher in the subgroup with anti-MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy. DISCUSSION: Median IL-6 and IL-10 serum concentrations differ between patients with anti-MAG neuropathy and other patients with IgM-PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune-mediated disease mechanisms. Muscle Nerve 59:694-698, 2019.

Neuropathy associated with immunoglobulin M monoclonal gammopathy: A combined sonographic and nerve conduction study.

INTRODUCTION: We assessed the specific sonographic pattern of structural nerve abnormalities in immunoglobulin M (IgM) neuropathy and disease controls. METHODS: We enrolled 106 incident patients-32 patients with IgM neuropathy, 42 treatment-naive patients with chronic inflammatory demyelinating polyneuropathy, and 32 patients with axonal neuropathies. All patients underwent standardized ancillary testing in addition to standardized sonography of the brachial plexus and the large arm and leg nerves bilaterally. RESULTS: We found widespread nerve enlargement in IgM neuropathy and chronic inflammatory demyelinating polyneuropathy (CIDP), with specific enlargement of brachial plexus and proximal segments of median nerve but not in axonal disease controls (P < .001). Sonographic nerve hypertrophy in IgM neuropathy was not associated with nerve conduction, clinical, or laboratory characteristics. DISCUSSION: Immunoglobulin M neuropathy is characterized by widespread nerve enlargement indistinguishable from CIDP. Our data provide evidence to confirm that the disease process is not confined to the more distal parts of nerves in either classical demyelinating or axonal variants of neuropathy with associated IgM.

Diagnostic value of symptoms in chronic polyneuropathy: The Erasmus Polyneuropathy Symptom Score.

In this study, we evaluated the diagnostic value of symptoms of chronic polyneuropathy and to construct and validate a simple questionnaire that can help diagnose chronic polyneuropathy. In a multi-step procedure, we initially compiled a 12-item questionnaire concerning polyneuropathy symptoms. The questionnaire was completed by 117 polyneuropathy patients and 188 controls (headache, transient ischemic attack, multiple sclerosis). First, we calculated sensitivity, specificity and likelihood ratios of each symptom. Next, we used multi-variable logistic regression to create a model that could discriminate patients from controls, using only the most informative symptoms and their frequency of occurrence. Based on the regression coefficients, we developed a simple scoring system (Erasmus Polyneuropathy Symptom Score, E-PSS), which was externally validated in 140 cases with chronic idiopathic axonal polyneuropathy and 96 controls without polyneuropathy. We assessed performance with discrimination (area under the curve, AUC) and calibration analyses. Numb and tingling feet were most frequently reported by polyneuropathy patients and had the highest sensitivity. Walking on cotton wool and allodynia had the highest specificity. Logistic regression yielded a model that contained these four symptoms, complemented with balance problems and tingling hands. Based on this analysis, the E-PSS was created, ranging from 0 to 14. The E-PSS had a good performance (AUC = 0.92) in the derivation set and proved to be valid in the external population (AUC = 0.95). In conclusion, the Erasmus Polyneuropathy Symptom Score (E-PSS) is a simple, validated six-item score that takes the presence and frequency of six different symptoms into account and it may be a helpful tool to screen individuals for the presence of chronic polyneuropathy.

Clinical relevance of serum antibodies to GD1b in immune-mediated neuropathies.

Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster.

Protocol of a dose response trial of IV immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (DRIP study).

High peak levels of serum IgG may not be needed for maintenance treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with intravenous immunoglobulin (IVIg). More frequent dosing of IVIg leads to more stable IgG levels and higher trough levels which may be related with improved clinical efficacy. More frequent lower dosing leads to lower peak levels and may induce less systemic side-effects. The DRIP study is a double-blind randomized controlled cross-over intervention study. CIDP patients ≥18 years old, proven IVIg dependent and receiving an individually established but stable maintenance dose and interval of IVIg (Kiovig) can be included. One group (A) will be treated with their normal dosage and interval of IVIg and receive a placebo (albumin 0.5%) infusion in between their regular IVIg infusions, for a total of four infusions. The other group (B) will be treated with half their normal IVIg dosage (with the same volume of placebo to maintain the total volume) at half their interval (double their frequency) for four infusions. After a wash-out phase (2 infusions), patients will cross-over to the other treatment group. During the study the total dose of IVIg administered will remain unchanged as before start of the trial. The main objective is to investigate whether high frequent low dosage IVIg treatment is more effective than low frequent high dosage IVIg treatment as maintenance treatment for CIDP. Hand grip strength, as measured by the Martin Vigorimeter, will be used as the primary outcome measure. Secondary objective is to investigate whether high frequent low dosage of IVIg results in less adverse events compared to low frequent high dosage treatment. The DRIP study is currently ongoing and the protocol is presented.

The role of nutrition as risk factor for polyneuropathy: a case-control study.

The aim of this case-control study is to investigate the role of nutrition as risk factor for polyneuropathy. Three hundred eighteen patients with chronic idiopathic axonal polyneuropathy and 636 matched controls completed a validated food frequency questionnaire that covered nutrient intake and alcohol consumption. As risk estimates, we calculated adjusted odds ratios for the intake of energy and nutrients. Energy and nutrient intake did not differ between patients and controls, regardless of moderate alcohol consumption. Nutrition is not a risk factor for chronic idiopathic axonal polyneuropathy.

Maintenance IV immunoglobulin treatment in chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients treated with intravenous immunoglobulin (IVIg) usually start with a standard dosage of 2 g/kg bodyweight. Only a minority of patients has a sustained improvement, and most require ongoing maintenance treatment. Preferred IVIg regimens, however, vary considerably between doctors and at present it is unknown which is optimal. As there are also large differences in IVIg dosage and interval requirements between patients, optimal IVIg maintenance treatment of CIDP is even more complex. The lack of evidence-based guidelines on how IVIg maintenance treatment should be administered may potentially lead to under- or overtreatment of this expensive therapy. We provide an overview of published practical IVIg maintenance treatment regimens, IVIg maintenance schedules used in randomized controlled trials and one based upon our own long-term experience on how this treatment could be given in CIDP.

Drug therapy for chronic idiopathic axonal polyneuropathy.

BACKGROUND: Chronic idiopathic axonal polyneuropathy (CIAP) is an insidiously progressive sensory or sensorimotor polyneuropathy that affects elderly people. Although severe disability or handicap does not occur, CIAP reduces quality of life. CIAP is diagnosed in 10% to 25% of people referred for evaluation of polyneuropathy. There is a need to gather and review emerging evidence on treatments, as the number of people affected is likely to increase in ageing populations. This is an update of a review first published in 2004 and previously updated in 2006, 2008, 2011 and 2013. OBJECTIVES: To assess the effects of drug therapy for chronic idiopathic axonal polyneuropathy for reducing disability and ameliorating neurological symptoms and associated impairments, and to assess any adverse effects of treatment. SEARCH METHODS: In July 2016, we searched Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews in the Cochrane Library, MEDLINE, Embase, and the Web of Science. We searched two trials registries for ongoing trials. We also handsearched the reference lists of relevant articles, reviews and textbooks identified electronically, and we would have contacted authors and other experts in the field to identify additional studies if this seemed useful. SELECTION CRITERIA: We sought all randomised or quasi-randomised (alternate or other systematic treatment allocation) trials that examined the effects of any drug therapy in people with CIAP at least one year after the onset of treatment. People with CIAP had to fulfil the following criteria: age 40 years or older, distal sensory or sensorimotor polyneuropathy, absence of systemic or other neurological disease, chronic clinical course not reaching a nadir in less than two months, exclusion of any recognised cause of the polyneuropathy by medical history taking, clinical or laboratory investigations, and electrophysiological studies in agreement with axonal polyneuropathy, without evidence of demyelinating features. The primary outcome was the proportion of participants with a significant improvement in disability. Secondary outcomes were change in the mean disability score, change in the proportion of participants who make use of walking aids, change in the mean Medical Research Council sum score, degree of pain relief and/or reduction of other positive sensory symptoms, change in the proportion of participants with pain or other positive sensory symptoms, and frequency of adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed the results of the literature search and extracted details of trial methodology and outcome data of all potentially relevant trials. MAIN RESULTS: We identified 39 studies and assessed them for possible inclusion in the review, but we excluded all of them because of insufficient quality or lack of relevance. We summarised evidence from non-randomised studies in the Discussion. AUTHORS' CONCLUSIONS: Even though CIAP has been clearly described and delineated, no adequate randomised or quasi-randomised controlled clinical treatment trials have been performed. In their absence there is no proven efficacious drug therapy.

Chronic obstructive pulmonary disease is not a risk factor for polyneuropathy: A prospective controlled study.

Polyneuropathy has been observed in patients with chronic obstructive pulmonary disease (COPD). If polyneuropathy occurs as a complication or extrapulmonary manifestation of COPD, one would expect an increased prevalence among patients with a cryptogenic axonal polyneuropathy. This case-control study aimed to investigate the association between COPD and polyneuropathy. We prospectively included 345 patients with cryptogenic axonal polyneuropathy and 465 controls. A standardized questionnaire assessed the presence of COPD and we verified this diagnosis by contacting the family physician. The severity of COPD was based on the Global Initiative for Chronic Obstructive Lung Disease classification. The prevalence of COPD did not differ between patients with polyneuropathy and controls (15/345 vs. 12/465 respectively; odds ratio (OR) 1.7; 95% confidence interval (CI) [0.8-3.7]). Adjusting for age, gender and possible confounders did not affect these results (adjusted OR 1.7, 95% CI 0.7-4.1). The severity of COPD was similar between patients with polyneuropathy and controls. This study does not support the hypothesis that COPD is a risk factor for polyneuropathy.

Recent advances in outcome measures in IgM-anti-MAG+ neuropathies.

PURPOSE OF REVIEW: This review aims to provide an overview of all randomized trials performed in IgM Anti-Myelin Associated Glycoprotein related peripheral neuropathy (MGUSP) with emphasis on the applied outcome measures including the rationale for their choice and possible limitations, emphasizing new advances in modern clinimetrics. RECENT FINDINGS: All clinical trials performed in patients with MGUSP have been negative, which raises many unanswered questions: were the sample sizes too small, the duration of the trials too short, the chosen medical interventions not aggressive enough, the definition of being a responder inadequate, and, last but not least, the outcome measures used improper? Only recently has attention been directed towards the possibility of using suboptimal outcome measures as a potential factor that may have contributed to the negative results in MGUSP. SUMMARY: Since there is no international consensus on how to assess and treat patients with MGUSP, the current study addresses new advances in the field of modern clinimetrics and recommendations for future outcome measure studies in MGUSP before proceeding with new interventional trials.

Impairment measures versus inflammatory RODS in GBS and CIDP: a responsiveness comparison.

This study aimed to 'define responder' through the concept of minimum clinically important differences using the individually obtained standard errors (MCID-SE) and a heuristic 'external criterion' responsiveness method in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). One hundred and fourteen newly diagnosed or relapsing patients (GBS: 55, CIDP: 59) were serially examined (1-year follow-up). The inflammatory Rasch-built overall disability scale (I-RODS), Rasch-transformed MRC sum score (RT-MRC), and Rasch-transformed modified-INCAT-sensory scale (RT-mISS) were assessed. Being-a-responder was defined as having a MCID-SE cut-off ≥1.96. Also, the correlations between patients' scores on each scale and the EuroQoL health-status 'thermometer' (external criterion) were determined (higher correlation indicated better responsiveness). In both diseases, the SEs showed a characteristic 'U'-shaped dynamic pattern across each scales' continuum. The number of patients showing a meaningful change were higher for the I-RODS > RT-MRC > RT-mISS and were in GBS higher than CIDP patients. The MCID-SE concept using Rasch-transformed data demonstrated an individual pattern of 'being-a-responder' in patients with immune-mediated neuropathies, and the findings were validated by the external criterion responsiveness method. The I-RODS showed greater responsiveness compared with the MRC and INCAT-sensory scales, and its use is therefore recommended in future trials in GBS and CIDP.

Grip strength comparison in immune-mediated neuropathies: Vigorimeter vs. Jamar.

The Jamar dynamometer and Vigorimeter have been used to assess grip strength in immune-mediated neuropathies, but have never been compared to each other. Therefore, we performed a comparison study between these two devices in patients with immune-mediated neuropathies. Grip strength data were collected in 102 cross-sectional stable and 163 longitudinal (new diagnoses or changing condition) patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), gammopathy-related polyneuropathy (MGUSP), and multifocal motor neuropathy (MMN). Stable patients were assessed twice (validity/reliability studies). Longitudinal patients were assessed 3-5 times during 1 year. Responsiveness comparison between the two tools was examined using combined anchor-/distribution-based minimum clinically important difference (MCID) techniques. Patients were asked to indicate their preference for the Jamar or Vigorimeter. Both tools correlated highly with each other (ρ = 0.86, p < 0.0001) and showed good intra-class correlation coefficients (Jamar [Right/Left hands]: ICC 0.997/0.96; Vigori: ICC 0.95/0.98). Meaningful changes were comparable between the two instruments, being higher in GBS compared to CIDP patients. In MGUSP/MMN poor responsiveness was seen. Significant more patients preferred the Vigorimeter. In conclusion, validity, reliability, and responsiveness aspects were comparable between the Jamar dynamometer and Vigorimeter. However, based on patients' preference, the Vigorimeter is recommended in future studies in immune-mediated neuropathies.

Comparing the NIS vs. MRC and INCAT sensory scale through Rasch analyses.

We performed a comparison between Neuropathy Impairment Scale-sensory (NISs) vs. the modified Inflammatory Neuropathy Cause and Treatment sensory scale (mISS), and NIS-motor vs. the Medical Research Council sum score in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and IgM monoclonal gammopathy of undetermined significance-related polyneuropathy (MGUSP). The ordinal data were subjected to Rasch analyses, creating Rasch-transformed (RT)-intervals for all measures. Comparison between measures was based on validity/reliability with an emphasis on responsiveness (using the patient's level of change related to the individually obtained varying SE for minimum clinically important difference). Eighty stable patients (GBS: 30, CIDP: 30, and MGUSP: 20) were assessed twice (entry: two observers; 2-4 weeks later: one observer), and 137 newly diagnosed or relapsing patients (GBS: 55, CIDP: 59, and IgM-MGUSP: 23) were serially examined with 12 months follow-up. Data modifications were needed to improve model fit for all measures. The sensory and motor scales demonstrated approximately equal and acceptable validity and reliability scores. Responsiveness scores were poor but slightly higher in RT-mISS compared to RT-NISs. Responsiveness was equal for the RT-motor scales, but higher in GBS compared to CIDP; responsiveness was poor in patients with MGUSP, suggesting a longer duration of follow-up in the latter group of patients.

Treatment for IgG and IgA paraproteinaemic neuropathy.

BACKGROUND: Paraproteinaemic neuropathy refers to those neuropathies associated with a monoclonal gammopathy or paraprotein. The most common of these present with a chronic, predominantly sensory, symmetrical neuropathy, similar to chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but with relatively more sensory involvement, both clinically and neurophysiologically. The optimal treatment for neuropathies associated with IgG and IgA monoclonal gammopathy of uncertain significance is not known. This is an update of a review first published in 2007. OBJECTIVES: To assess the effects of any treatment for IgG or IgA paraproteinaemic peripheral neuropathy. SEARCH METHODS: On 18 January 2014 we searched the Cochrane Neuromuscular Disease Group Trials Specialized Register, CENTRAL, MEDLINE and EMBASE. We also checked bibliographies for controlled trials of treatments for IgG or IgA paraproteinaemic peripheral neuropathy. We checked clinical trials registries for ongoing studies in November 2014. SELECTION CRITERIA: We considered for inclusion randomised controlled trials (RCTs) and quasi-RCTs using any treatment for IgG or IgA paraproteinaemic peripheral neuropathy. We excluded people with IgM paraproteins. We excluded people where the monoclonal gammopathy was considered secondary to an underlying disorder. We included participants of any age with a diagnosis of monoclonal gammopathy of uncertain significance with a paraprotein of the IgG or IgA class and a neuropathy. Included participants were not required to fulfil specific electrophysiological diagnostic criteria. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology to select studies, extract data and analyse results. One trial author provided additional data and clarification. MAIN RESULTS: We identified one RCT, with 18 participants, that fulfilled the predetermined inclusion criteria. The trial compared plasma exchange to sham plasma exchange in participants with IgG or IgA paraproteinaemic neuropathy over a three-week follow-up period. We identified four other studies but these were not RCTs or quasi-RCTs. The included RCT did not report our predefined primary outcome measure, change in disability six months after randomisation. The trial revealed a modest benefit of plasma exchange in the weakness component of the Neuropathy Disability Score (NDS, now the Neuropathy Impairment Score); the mean improvement with plasma exchange was 17 points (95% confidence interval (CI) 5.2 to 28.8 points) versus 1 point (95% CI -7.7 to 9.7 points) in the sham exchange group at three weeks' follow-up (mean difference (MD) 16.00; 95% CI 1.37 to 30.63, low quality evidence). There was no statistically significant difference in the overall NDS (MD 18.00; 95% CI -2.03 to 38.03, low quality evidence), vibration thresholds or neurophysiological indices. Adverse events were not reported. The trial was at low risk of bias overall, although limitations of trial size and duration reduce the quality of the evidence in support of its conclusions. AUTHORS' CONCLUSIONS: The evidence from RCTs for the treatment of IgG or IgA paraproteinaemic neuropathy is currently inadequate. More RCTs of treatments are required. These should have adequate follow-up periods and contain larger numbers of participants, perhaps through multicentre collaboration, considering the relative infrequency of this condition. Observational or open trial data provide limited support for the use of treatments such as plasma exchange, cyclophosphamide combined with prednisolone, intravenous immunoglobulin, and corticosteroids. These interventions show potential therapeutic promise but the potential benefits must be weighed against adverse effects. Their optimal use and the long-term benefits need to be considered and validated with well-designed RCTs.