Optimizing the Use of Outcome Measures in Chronic Inflammatory Demyelinating Polyneuropathy

US Neurology, 2017;13(1):26–34 DOI: https://doi.org/10.17925/USN.2017.13.01.26


The challenges encountered during the assessment of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) are many. Ideally, CIDP outcome measures capture impairments in disability, strength, and sensory dysfunction, and quality of life (QoL). A number of outcome measures have been validated for this purpose. Disability outcomes include the adjusted inflammatory neuropathy cause and treatment (INCAT) disability score, INCAT overall disability sum score (ODSS), and overall neuropathy limitations scale (ONLS). A more sensitive disability score, the inflammatory Rasch-built overall disability scale (I-RODS), has also been validated for use in clinical trials and may better capture clinically meaningful changes in those with CIDP. Strength and sensory impairment can be assessed in a number of ways, including the INCAT sensory subscore (ISS), Medical Research Council sum score, and Martin vigorimeter or Jamar dynamometer grip strength. However, the feasibility of applying and interpreting these measures during routine daily practice has been questioned. Furthermore, these outcome measures may not reflect other factors that can impair QoL in those affected by CIDP, such as pain and fatigue. A valid, reliable, and responsive composite measure that addresses all aspects of impairment faced by patients with CIDP remains an unmet need in clinical practice.
Keywords: Chronic inflammatory demyelinating polyneuropathy, disability, impairment, outcome measures, grip strength
Disclosure: Jeffrey A Allen is a consultant for, and has received clinical trial support, from: Axelacare, CSL Behring, and Grifols. Deborah F Gelinas is an employee of Grifols, and is on the Avanir Speaker Bureau for Nuedexta. Richard A Lewis is a consultant for Axelacare, CSL Behring, Biotest Pharma, Kedrion, and Pharnext. Richard J Nowak is a speaker and advisor/consultant for Grifols. Gil I Wolfe participated in Shire and Grifols advisory boards and received research support from CSL Behring.

Compliance with Ethics:This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.

AuthorshipAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.

Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.

Read more about CIPD here
Received: December 19, 2016 Accepted February 17, 2017
Correspondence: Jeffrey A Allen, Department of Neurology, 12–150 Phillips Wangensteen Building, 516 Delaware Street SE, Minneapolis, MN 55455. E: jeffrey.allen@nm.org
Support: The publication of this article was supported by Grifols. The views and opinions expressed in the article are those of the authors and not necessarily those of Grifols. US/ GX/1016/0386

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated disease that evolves in a progressive or relapsing pattern over months to years. Although “typical” CIDP is characterized by symmetric proximal and distal motor and sensory deficits, it is now recognized that multifocal (asymmetric), distally predominant, pure sensory, and pure motor variants also fall within the CIDP spectrum. First-line treatment options for CIDP include corticosteroids, intravenous immunoglobulin (IVIG), and plasmapheresis (plasma exchange).1 For patients refractory to first-line options or those chronically dependent on high-dose first-line therapy, no evidence-based treatment recommendations exist. Cytotoxic immunosuppressant drugs are sometimes utilized.2 Close follow-up care is essential for treatment administration and optimization. Patients treated with IVIG or plasma exchange need regular treatment visits to maintain therapeutic efficacy, typically every few weeks. Many patients with CIDP remain on such treatment for years. While, in some, chronic immunotherapy is justified on the basis of well-defined clinical changes indicative of active disease (e.g., treatment-related fluctuations or relapse); in many patients, treatment is driven by subjective feelings of benefit without objective evidence of improvement in motor and sensory deficits or disability.3 There is an opportunity to supplement periodic outpatient clinical visits with currently available objective measures as a means to improve confidence in treatment-induced disease modification, optimize therapy, and justify treatment dependence for those on chronic therapy.

Evaluating responses to treatment in CIDP may be difficult. The absence of a clear definition of treatment response, in part due to the heterogeneous nature of CIDP and its variants, is one challenge. The many scales that have

been developed to measure strength impairment, sensory dysfunction, and disability emphasize the many modalities in which treatment response can be objectively assessed.4 Established outcome measures are typically employed in clinical studies in order to ensure comparability between trials. Outcome measures are considered appropriate for use if they demonstrate high validity (i.e. they are able to measure the intended parameter) and reliability (i.e., they measure the parameter in a reproducible manner) and are sensitive to change.3 However, many measures used in clinical trials are not accessible or feasible for daily practice. This is a critical factor when evaluating patients with CIDP. This article aims to review currently used and validated outcome tools in CIDP, assess their suitability for use in everyday clinical practice, and highlight other potential tools that might be helpful in the routine clinical settling. Validated scales for assessing outcomes in CIDP A number of different outcome measures that are appropriate for use in CIDP are summarized in Table 1 and described in detail below.

Inflammatory neuropathy cause and treatment disability scale and sensory subscore
From a consensus meeting on outcome measures in inflammatory neuropathies, the level of disability emerged as the primary measure for assessing treatment efficacy.4 The inflammatory neuropathy cause and treatment (INCAT) disability scale captures upper and lower limb dysfunction separately on a scale of 0 to 5, which are then added together for a total composite score ranging between 0 and 10.5 Lower scores indicate no or minimal disability (no arm dysfunction or walking abnormality); higher scores indicate more disability (no purposeful arm movement or restricted to wheelchair). An adjusted INCAT disability score has been used in multiple clinical trials, including the largest CIDP trial performed to date, the immune globulin intravenous CIDP efficacy (ICE) study.6,7 The adjusted INCAT disability score is identical to the INCAT disability score with the exception that changes in upper limb function from 0 (normal) to 1 (minor symptoms) are excluded. This exclusion was made because upper limb changes from 0 to 1 (minor symptoms in the fingers which do not impair any functional activities) were not judged by regulatory agencies to be clinically significant in all patients. This measure showed statistically significant differences in favor of patients treated with human IVIG, 10% caprylate/chromatography purified, compared with patients who received placebo. The most common adverse reactions were headache, fever, chills, hypertension, rash, nausea, and asthenia, and the most serious adverse reactions in clinical studies was pulmonary embolism (PE) in 1 subject with a history of PE.7

The INCAT sensory subscore (ISS) has been evaluated for uniformity in assessing sensory deficit in immune-mediated polyneuropathies.5 The scale assesses light touch, pin-prick, vibration, and joint position sense in distal and proximal upper and lower limb areas as well as 2-point discrimination at the index finger. In a psychometric validation study, moderate to good validity was obtained for the ISS combined with acceptable internal consistency and inter- and intra-observer reliability. Standardized response mean scores for the ISS were high, indicating favorable responsiveness.5 Although the ISS has been recommended for evaluation of sensory deficit in clinical practice and in trials, it may not be the optimal choice for all types of inflammatory neuropathy. In clinical trials of rituximab for anti-myelinassociated glycoprotein (anti-MAG) neuropathy, no ISS changes were found, suggesting either treatment failure or lack of ISS sensitivity to change.8 The major strengths of the INCAT disability scale and the INCAT ISS are validity and reliability. Although the INCAT disability can be obtained quickly (good feasibility in clinical practice), the same cannot be said with the ISS.5 Other advantages include the ability to evaluate both upper and lower limb dysfunction (INCAT disability) and to quantify sensory impairments (ISS). The weaknesses of both, as with all multi-item composite ordinal measures, are that the individual components of the sum scores do not have equal weight and cannot be represented linearly. A 1-point change in score may have different clinical significance depending upon where in the scale that change occurs. Concerns have also been raised regarding the methodologic quality of validation studies, including their failure to fully capture activity limitations. The INCAT disability scale poorly measures proximal arm weakness and fails to capture subtle changes in gait stability and running. As such, the scale has poor sensitivity for detection of subtle but clinically meaningful change,9 which is again highlighted in a study of anti-MAG neuropathy.8 Such changes may be better addressed by the overall disability sum score (ODSS) or the overall neuropathy limitations scale (ONLS).

Overall disability sum score and overall neuropathy limitations scale
The ODSS was the first scale designed to quantify the limitations of patients with immune-mediated peripheral neuropathies.10 The ODSS focuses on the function of the upper and lower limbs and consists of a checklist for interviewing patients. It is scored from 0 to 5 on upper limb function and from 0 to 7 on lower limb function, where a score of 0 indicates no limitations (the ceiling of the scale) and a score of 5 or 7 indicates no purposeful movement. Unlike the 10-point INCAT disability score, the ODSS better captures lower limb disability at both ends of the severity spectrum, effectively broadening the floor and ceiling of the scale.4

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Keywords: Chronic inflammatory demyelinating polyneuropathy, disability, impairment, outcome measures, grip strength