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.
Chronic inflammatory demyelinating polyneuropathy, disability, impairment, outcome measures, grip strength
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.
December 19, 2016 Accepted
February 17, 2017
Jeffrey A Allen, Department of Neurology, 12–150 Phillips Wangensteen Building, 516 Delaware Street SE, Minneapolis, MN 55455. E: firstname.lastname@example.org
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
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
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
1. Gorson KC, An update on the management of chronic inflammatory demyelinating polyneuropathy, Ther Adv Neurol Disord, 2012;5:359–73.
2. Van den Bergh PY, Hadden RD, Bouche P, et al., European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society first revision, Eur J Neurol, 2010;17:356–63.
3. Hobart JC, Lamping DL, Thompson AJ, Evaluating neurological outcome measures: the bare essentials, J Neurol Neurosurg Psychiatry, 1996;60:127–30.
4. Merkies IS, Lauria G, 131st ENMC international workshop: selection of outcome measures for peripheral neuropathy clinical trials 10 12 December 2004, Naarden, The Netherlands, Neuromuscul Disord, 2006;16:149–56.
5. Merkies IS, Schmitz PI, van der Meche FG, van Doorn PA, Psychometric evaluation of a new sensory scale in immunemediated polyneuropathies. Inflammatory Neuropathy Cause and Treatment (INCAT) Group, Neurology, 2000;54:943–9.
6. Hughes R, Bensa S, Willison H, et al., Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy, Ann Neurol, 2001;50:195–201.
7. Hughes RA, Donofrio P, Bril V, et al., Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial, Lancet Neurology, 2008;7:136–44.
8. Iancu Ferfoglia R, Guimaraes-Costa R, Viala K, et al. Long-term efficacy of rituximab in IgM anti-myelin-associated glycoprotein neuropathy: RIMAG follow-up study, J Peripher Nerv Syst, 2016;21:10–14.
9. Breiner A, Barnett C, Bril V, INCAT disability score: a critical analysis of its measurement properties, Muscle Nerve, 2014;50:164–9.
10. Merkies IS, Schmitz PI, van der Meche FG, et al., Clinimetric evaluation of a new overall disability scale in immune mediated polyneuropathies, J Neurol Neurosurg Psychiatry, 2002;72:596–601.
11. Merkies IS, Schmitz PI, Getting closer to patients: the INCAT Overall Disability Sum Score relates better to patients’ own clinical judgement in immune-mediated polyneuropathies, J Neurol Neurosurg Psychiatry, 2006;77:970–2.
12. Graham RC, Hughes RA, A modified peripheral neuropathy scale: the Overall Neuropathy Limitations Scale, J Neurol Neurosurg Psychiatry, 2006;77:973–6.
13. DeVellis RF, Classical test theory, Med Care, 2006;44(11 Suppl. 3):S50–9.
14. van Nes SI, Vanhoutte EK, van Doorn PA, et al., Rasch-built Overall Disability Scale (R-ODS) for immune-mediated peripheral neuropathies, Neurology, 2011;76:337–45.
15. Vanhoutte EK, Faber CG, van Nes SI, et al., Rasch-built Overall Disability Scale for Multifocal motor neuropathy (MMN-RODS((c))), J Peripher Nerv Syst, 2015;20:296–305.
16. Draak TH, Vanhoutte EK, van Nes SI, et al., Changing outcome in inflammatory neuropathies: Rasch-comparative responsiveness, Neurology, 2014;83:2124–32.
17. Vanhoutte EK, Faber CG, Merkies IS, PeriNom Ssg, 196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies 8-10 February 2013, Naarden, The Netherlands, Neuromuscul Disord, 2013;23:924–33.
18. Muro-de-la-Herran A, Garcia-Zapirain B, Mendez-Zorrilla A, Gait analysis methods: an overview of wearable and non-wearable systems, highlighting clinical applications. Sensors, 2014;14:3362–94.
19. Chin RV, Vo M, Carey B, et al., Spatiotemporal gait parameters as a potential outcome measure for CIDP, Neurology, 2015;84:Supplement P7.338.
20. Vo ML, Chin RL, Carey BT, et al., Spatiotemporal Gait Changes Following IVIG Treatment for CIDP. 68th Annual American Academcy of Neurology (AAN) Meeting; Vancouver, BC, Canada 2016.
21. McDonough AL, Batavia M, Chen FC, et al., The validity and reliability of the GAITRite system's measurements: A preliminary evaluation, Arch Phys Med Rehabil, 2001;82:419–25.
22. Bilney B, Morris M, Webster K, Concurrent related validity of the GAITRite walkway system for quantification of the spatial and temporal parameters of gait, Gait Posture, 2003;17:68–74.
23. Thorpe DE, Dusing SC, Moore CG, Repeatability of temporospatial gait measures in children using the GAITRite electronic walkway, Arch Phys Med Rehabil, 2005;86:2342–6.
24. Mathias S, Nayak US, Isaacs B, Balance in elderly patients: the “get-up and go” test, Arch Phys Med Rehabil, 1986;67:387–9.
25. Podsiadlo D, Richardson S, The timed “Up & Go”: a test of basic functional mobility for frail elderly persons, J Am Geriatr Soc, 1991;39:142–8.
26. Peters DM, Fritz SL, Krotish DE, Assessing the reliability and validity of a shorter walk test compared with the 10-Meter Walk Test for measurements of gait speed in healthy, older adults, J Geriatr Phys Ther, 2001;2013;36:24–30.
27. Erdmann PG, van Meeteren NL, Kalmijn S, et al., Functional health status of patients with chronic inflammatory neuropathies,J Peripher Nerv Syst, 2005;10:181–9.
28. Montes J, McDermott MP, Martens WB, et al., Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy, Neurology, 2010;74:833–8.
29. Draak TH, Gorson KC, Vanhoutte EK, et al., Does ability to walk reflect general functionality in inflammatory neuropathies?, J Peripher Nerv Syst, 2016;21:74–81.
30. Kleyweg RP, van der Meche FG, Schmitz PI, Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barre syndrome, Muscle Nerve, 1991;14:1103–9.
31. Hermans G, Clerckx B, Vanhullebusch T, et al., Interobserver agreement of Medical Research Council sum-score and handgrip strength in the intensive care unit, Muscle Nerve, 2012;45:18–25.
32. Funfgeld EW, [The vigorimeter: for measurement of the strength of the hand and simulation testing], Dtsch Med Wochenschr, 1966;91:2214–6.
33. Draak TH, Pruppers MH, van Nes SI, et al., Grip strength comparison in immune-mediated neuropathies: Vigorimeter vs. Jamar, J Peripher Nerv Syst, 2015;20:269–76.
34. Vanhoutte EK, Latov N, Deng C, et al., Vigorimeter grip strength in CIDP: a responsive tool that rapidly measures the effect of IVIGthe ICE study, Eur J Neurol, 2013;20:748–55.
35. Dimberg EL, Grip strength in CIDP: does one function fit all?, Eur J Neurol, 2013;20:733–4.
36. Andersen H, Jakobsen J, A comparative study of isokinetic dynamometry and manual muscle testing of ankle dorsal and plantar flexors and knee extensors and flexors, Eur Neurol, 1997;37:239–42.
37. Delitto A, Isokinetic dynamometry, Muscle Nerve, 1990;13 Suppl:S53 7.
38. El Mhandi L, Bethoux F, Isokinetic testing in patients with neuromuscular diseases: a focused review, Am J Phys Med, 2013;92:163–78.
39. Harbo T, Brincks J, Andersen H, Maximal isokinetic and isometric muscle strength of major muscle groups related to age, body mass, height, and sex in 178 healthy subjects, Eur J Appl Physiol, 2012;112:267–75.
40. Markvardsen LH, Debost JC, Harbo T, et al., Subcutaneous immunoglobulin in responders to intravenous therapy with chronic inflammatory demyelinating polyradiculoneuropathy, Eur J Neurol, 2013;20:836–42.
41. Markvardsen LH, Harbo T, Sindrup SH, et al. Subcutaneous immunoglobulin preserves muscle strength in chronic inflammatory demyelinating polyneuropathy, Eur J Neurol, 2014;21:1465–70.
42. Markvardsen LH, Sindrup SH, Christiansen I, et al., Subcutaneous immunoglobulin as first-line therapy in treatment-naive patients with chronic inflammatory demyelinating polyneuropathy: randomized controlled trial study, Eur J Neurol, 2017;24:412–18.
43. Merkies IS, Kieseier BC, Fatigue, Pain, Anxiety and Depression in Guillain-Barre Syndrome and Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Eur Neurol, 2016;75:199–206.
44. Merkies IS, Schmitz PI, Samijn JP, et al., Fatigue in immunemediated polyneuropathies. European Inflammatory Neuropathy Cause and Treatment (INCAT) Group, Neurology, 1999;53:1648–54.
45. Valko PO, Bassetti CL, Bloch KE, et al., Validation of the fatigue severity scale in a Swiss cohort, Sleep, 2008;31:1601–7.
46. van Nes SI, Vanhoutte EK, Faber CG, et al., Improving fatigue assessment in immune-mediated neuropathies: the modified Rasch-built fatigue severity scale, J Peripher Nerv Syst, 2009;14:268–78.>
47. Drory VE, Bronipolsky T, Bluvshtein V, et al., Occurrence of fatigue over 20 years after recovery from Guillain-Barre syndrome, Journal of the Neurological Sciences, 2012;316:72–5.
48. Vickrey BG, Hays RD, Beckstrand M, Development of a healthrelated quality of life measure for peripheral neuropathy, Neurorehabil Neural Repair, 2000;14:93–104.
49. Merkies IS, Schmitz PI, van der Meche FG, et al., Quality of life complements traditional outcome measures in immune-mediated polyneuropathies, Neurology, 2002;59:84–91.
50. Gershon RC, Lai JS, Bode R, et al., Neuro-QOL: quality of life item banks for adults with neurological disorders: item development and calibrations based upon clinical and general population testing, Qual Life Res, 2012;21:475–86.
51. Gwathmey KG, Conaway MR, Sadjadi R, et al., Construction and validation of the chronic acquired polyneuropathy patientreported index (CAP-PRI): A disease-specific, health-related quality-of-life instrument, Muscle Nerve, 2016;54:9–17.
52. Merkies IS, Hughes RA, Donofrio P, et al., Understanding the consequences of chronic inflammatory demyelinating polyradiculoneuropathy from impairments to activity and participation restrictions and reduced quality of life: the ICE study, J Peripher Nerv Syst, 2010;15:208–15.
53. Katzberg HD, Rasutis V, Bril V, Home IVIG for CIDP: a focus on patient centred care, Can J Neurol Sci, 2013;40:384 8.
54. Smith AG, Burns TM, Reevaluating clinical measurement tools in therapeutic trials: time to make a Rasch decision?, Neurology, 2014;83(23):2104–5.
55. Ayer G, Christopher-Stine L, Ladha S, et al., Validation of Patient Reported Outcomes in the Home Infusion Setting in the Management of Patients With Neuromuscular Disease. Presented at the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), Savannah, GA 2014.
56. Merkies IS, Schmitz PI, Van Der Meche FG, Van Doorn PA, Comparison between impairment and disability scales in immunemediated polyneuropathies, Muscle Nerve, 2003;28:93–100.
57. GAMUNEX®-C (immune globulin injection [human], 10% caprylate/chromatography purified) Prescribing Information. Grifols.Available at: www.fda.gov.tw/MLMS/ShowFile. aspx?LicId=10000796&Seq=013&Type=9 (accessed October 26, 2016)
Chronic inflammatory demyelinating polyneuropathy, disability, impairment, outcome measures, grip strength