medical research council sum score pdf

MRC Muscle Scale - MRC

The MRC scale for muscle power was first published in 1943 in a document called ‘Aids to the Investigation of Peripheral Nerve Injuries (War Memorandum No. 7)’.  This became a standard text resource which was reprinted many times, and is referred to widely in a number of documents and papers. In the 1970s the document was republished with the title ‘Aids to the Examination of the Peripheral Nervous System (Memorandum No. 45)’.

The muscle scale grades muscle power on a scale of 0 to 5 in relation to the maximum expected for that muscle. In a recent comparison to an analogue scale the MRC scale is more reliable and accurate for clinical assessment in weak muscles (grades 0-3) while an analogue scale is more reliable and accurate for the assessment of stronger muscles (grades 4 and 5).

Permission to reuse the MRC Muscle Scale

The MRC Muscle Scale is licensed under the Open Government Licence .

© Crown Copyright

Aids to the Examination of the Peripheral Nervous System (Memorandum No. 45) is licensed under the Open Government Licence 3.0.

You must give appropriate credit (“Used with the permission of the Medical Research Council”) and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests that the MRC endorses you or your use.

Aids to the examination of the peripheral nervous system – MRC Memorandum No.45 (superseding War Memorandum No.7)

Contact information

Ask a question, or get further information about any of the MRC scales. Email: [email protected]

For information about licensing

To view the full Open Government Licence, visit National Archives: Open Government Licence Version two .

Further context, best practice and guidance can be found in the National Archives: UK Government Licensing Framework .

LifeArc manages MRC’s intellectual property rights and commercialises findings by licensing them to industry. They can be contacted for support via the contact information on their website .

Last updated: 16 March 2023

This is the website for UKRI: our seven research councils, Research England and Innovate UK. Let us know if you have feedback or would like to help improve our online products and services .

Assessment of limb muscle strength in critically ill patients: a systematic review

Affiliation.

• 1 1Department Rehabilitation Sciences, Faculty of Kinesiology and Rehabilitation Sciences, KU Leuven, Leuven, Belgium. 2Department of Intensive Care, University Hospitals Leuven, Leuven, Belgium. 3Medical Intensive Care Unit of the Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
• PMID: 24201180
• DOI: 10.1097/CCM.0000000000000030

Objectives: To determine the reliability of volitional and nonvolitional limb muscle strength assessment in critically ill patients and to provide guidelines for the implementation of limb muscle strength assessment this population.

Data sources: The following computerized bibliographic databases were searched with MeSH terms and keywords or combinations: MEDLINE through PubMed and Embase through Embase.com.

Study selection: Articles were screened by two independent reviewers. Included studies were all performed in humans and were original articles. The research population exists of adult, critically ill patients or ICU survivors of either sex, and those admitted to a medical, surgical, respiratory, or mixed ICU. A study was included if reliability of muscle strength measurements was determined in this population.

Data extraction: Data on baseline characteristics (country, study population, eligibility, age, setting and method, and equipment of limb muscle strength assessment) and reliability scores were obtained by two independent reviewers.

Data synthesis: Data of six observational studies were analyzed. Interrater reliability of the Medical Research Council scale for individual muscle groups varied from "fair" or "substantial" (weighted κ, 0.23-0.64) to "very good" agreement (weighted κ, 0.80-0.96). Interrater reliability of the Medical Research Council-sum score was found to be very good in all four studies (intraclass correlation coefficients, 0.86-0.99 or Pearson product moment correlation coefficient = 0.96). Interrater reliability of handheld dynamometry was comparable between two studies (intraclass correlation coefficients, 0.62-0.96). Interrater reliability of handgrip dynamometry was very good in two studies (intraclass correlation coefficients, 0.89-0.97). Intrarater reliability of handheld dynamometry and handgrip dynamometry was assessed in one study, and results were very good (intraclass correlation coefficients > 0.81). No studies were obtained on reliability of nonvolitional muscle strength assessment.

Conclusions: Voluntary muscle strength measurement has proven reliable in critically ill patients provided that strict guidelines on adequacy and standardized test procedures and positions are followed.

Publication types

• Meta-Analysis
• Systematic Review
• Critical Illness*
• Intensive Care Units*
• Lower Extremity
• Muscle Strength / physiology*
• Muscle Strength Dynamometer
• Muscle Weakness / diagnosis*
• Muscle, Skeletal / physiology
• Observational Studies as Topic
• Observer Variation
• Reproducibility of Results
• Upper Extremity

• Open access
• Published: 10 October 2013

Clinical predictive value of manual muscle strength testing during critical illness: an observational cohort study

• Bronwen A Connolly 1 , 2 , 3 ,
• Gareth D Jones 4 ,
• Alexandra A Curtis 4 ,
• Patrick B Murphy 1 , 3 ,
• Abdel Douiri 2 , 5 ,
• Nicholas S Hopkinson 6 ,
• Michael I Polkey 6 ,
• John Moxham 1 &
• Nicholas Hart 1 , 2 , 3  

Critical Care volume  17 , Article number:  R229 ( 2013 ) Cite this article

6436 Accesses

91 Citations

Metrics details

Introduction

Impaired skeletal muscle function has important clinical outcome implications for survivors of critical illness. Previous studies employing volitional manual muscle testing for diagnosing intensive care unit-acquired weakness (ICU-AW) during the early stages of critical illness have only provided limited data on outcome. This study aimed to determine inter-observer agreement and clinical predictive value of the Medical Research Council sum score (MRC-SS) test in critically ill patients.

Study 1: Inter-observer agreement for ICU-AW between two clinicians in critically ill patients within ICU ( n = 20) was compared with simulated presentations ( n = 20). Study 2: MRC-SS at awakening in an unselected sequential ICU cohort was used to determine the clinical predictive value ( n = 94) for outcomes of ICU and hospital mortality and length of stay.

Although the intra-class correlation coefficient (ICC) for MRC-SS in the ICU was 0.94 (95% CI 0.85–0.98), κ statistic for diagnosis of ICU-AW (MRC-SS <48/60) was only 0.60 (95% CI 0.25–0.95). Agreement for simulated weakness presentations was almost complete (ICC 1.0 (95% CI 0.99–1.0), with a κ statistic of 1.0 (95% CI 1.0–1.0)). There was no association observed between ability to perform the MRC-SS and clinical outcome and no association between ICU-AW and mortality. Although ICU-AW demonstrated limited positive predictive value for ICU (54.2%; 95% CI 39.2–68.6) and hospital (66.7%; 95% CI 51.6–79.6) length of stay, the negative predictive value for ICU length of stay was clinically acceptable (88.2%; 95% CI 63.6–98.5).

Conclusions

These data highlight the limited clinical applicability of volitional muscle strength testing in critically ill patients. Alternative non-volitional strategies are required for assessment and monitoring of muscle function in the early stages of critical illness.

Skeletal muscle weakness is a common complication of critical illness and a major factor influencing both short-term and long-term clinical outcome [ 1 – 5 ]. This has driven, as a priority, the development of the clinical concept of ICU-acquired weakness (ICU-AW). ICU-AW has a reported prevalence of up to 65% [ 6 ], with observational studies showing associations with prolonged weaning, delayed rehabilitation, increased hospital length of stay (LOS) and increased mortality [ 6 – 13 ]. However, such observational cohort studies do not necessarily demonstrate a causal relationship.

Diagnostic criteria for ICU-AW are based on clinical examination [ 14 ]. Whilst further subclassification of critical illness neuromyopathy can be achieved using detailed nonvolitional electrophysiological investigations, this can be technically challenging in the ICU because it requires skilled personnel for both assessment and interpretation [ 15 ]. Simple tests with potentially greater clinical applicability have been proposed. A measure of global peripheral muscle strength, the Medical Research Council sum score (MRC-SS), which ranges from 0 (complete paralysis) to 60 (normal strength) [ 16 ], has been widely used, with scores less than 48 providing the basis for diagnosing ICU-AW [ 14 ]. As with all volitional measures of muscle strength, however, a patient’s inability to perform the test or a low score may occur as a result of nonmuscular factors, such as impaired cognition, reduced consciousness level and poor motivation. Furthermore, the ordinal, nonlinear nature of grading muscle strength results in potential variability between clinicians in both application of testing and interpretation of results [ 17 ]. These caveats have led to contrasting data for diagnosing ICU-AW within the ICU, as well as to variability in interobserver agreement of the MRC-SS in ICU patients with differing levels of weakness [ 18 , 19 ].

There are no published studies to date that have reported the clinical applicability of the MRC-SS in a general ICU population, in particular the clinical usefulness of the MRC-SS in predicting ICU and in-hospital patient outcomes. In the current study, we investigated (1) interobserver agreement regarding ICU-AW in critically ill patients in the ICU and regarding simulated weakness, (2) the clinical predictive value of ability to perform the MRC-SS test at awakening and (3) the clinical predictive value of an MRC-SS less than 48, which is considered diagnostic of ICU-AW [ 20 ].

Materials and methods

Study design and ethical approval.

We conducted a two-part, observational, single-centre study in a 30-bed mixed medical and surgical ICU in a university teaching hospital. In study 1, we determined interobserver agreement regarding MRC-SS in ICU patients and simulated weakness presentations. Local ethical review board approval was granted (London–Westminster Research Ethics Committee 09/H0802/80). Written informed consent was obtained from all participants. In study 2, we investigated the clinical predictive value of ability to perform MRC-SS at awakening and the degree to which MRC-SS is indicative of ICU-AW. The local hospital ICU audit committee considered study 2 an evaluation of clinical service for which specific ethical approval was not required.

Patients 18 years of age and older who had been invasively ventilated for 48 or more hours were eligible for inclusion. Exclusion criteria included neurological weakness, requirement for acute noninvasive ventilation, pregnancy, malignancy, palliation-only orders and those admitted for routine overnight postoperative surgical recovery. Separate patient cohorts were recruited for studies 1 and 2.

Screening for awakening and assessment of peripheral muscle strength

For studies 1 and 2, the consciousness level of patients was determined using the Richmond Agitation Sedation Scale [ 21 ], with a score from −1 to +1 being indicative of wakefulness. Awake patients were then required to demonstrate a positive response to simple one-stage commands [ 6 , 7 , 10 ]. Successful completion of commands was followed by muscle strength assessment using the MRC-SS—a six-point grading scale ranging from 0 (no visible contraction) to 5 (normal power) applied to six upper- and lower-limb muscle groups bilaterally [ 16 ] (Additional file 1 : S2, Table S2a). ICU-AW was defined as an MRC-SS less than 48 out of a possible score of 60 [ 7 – 9 , 13 , 22 ].

Clinical examiners

Clinical examiners for the MRC-SS were two specialist physiotherapists (GJ and AC) with extensive clinical expertise in rehabilitation of critically ill patients, including muscle strength assessment using the MRC-SS. A standardised protocol for performing the MRC-SS was followed at all times during testing (Additional file 1 : S2, Tables S2b and S2c). Given the volitional nature of manual muscle testing, strong verbal encouragement was provided during all strength assessments. Each patient was tested in the same position by the examiners.

Study 1: Investigation of interobserver agreement in ICU patients and simulated weakness

A pragmatic sample size of 20 patients was chosen for this observational study. Sequential eligible, consenting patients were recruited depending on the working schedules and availability of both examiners over a three-month period. MRC-SS testing was performed by both examiners individually, separated by 30 minutes. Initial testing order between examiners of the first patient was randomly assigned by concealed envelope, and subsequent patient testing orders followed an alternating pattern. The MRC-SS value obtained by the first testing clinician on each occasion was defined as the ‘reference’ score for the simulated presentation. One healthy volunteer, trained comprehensively in the MRC-SS, simulated these 20 reference scores in a random order, and the reference scores were rescored by both clinicians (Additional file 1 : S3). Clinician order of testing was randomised for the first presentation, and an alternating pattern was followed thereafter. At each stage, the clinicians were blinded to each other’s scoring and to the reference score.

Study 2: Investigation of the clinical predictive value of Medical Research Council sum score

Daily screening of ICU patients for eligibility and suitability for MRC-SS testing occurred over a three-month period. MRC-SS at awakening, defined as the first occasion when an MRC-SS could be measured, and at seven days postawakening, were compared against outcomes of ICU and hospital mortality and LOS. Awakening scores were used to determine association with prospective outcomes. Prolonged LOS was defined a priori as longer than 14 days for ICU LOS and longer than 28 days for in-hospital LOS.

Statistical analysis

In study 1, interobserver agreement between clinicians for the MRC-SS in ICU patients and simulated presentations was determined using intraclass correlation coefficients (ICCs), which were calculated using two-way random effects for absolute agreement [ 23 ], and percentage agreement for total MRC-SS (total number of exact MRC-SS measurements divided by total number). Level of agreement for the binary outcome of ICU-AW (MRC-SS <48;≥48) was determined using Cohen’s κ statistic with a grading system from ‘poor’ to ‘complete’ agreement [ 24 ]. Additional details of the analysis of interobserver agreement are provided in Additional file 1 : S4. In study 2, Fisher’s exact test was used to determine associations between MRC-SS outcomes (ability to perform the test and scores less than 48 on a scale of 60) and clinical outcomes (ICU and hospital mortality and LOS). Subsequent analysis of test characteristics (sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)) was then performed with a cutoff of 75% used to define clinically acceptable results. We additionally performed receiver-operator curve (ROC) analysis on MRC-SS measurements at awakening for each clinical outcome to assess sensitivity and specificity at levels of MRC-SS from 0 to 60. Parametric data are presented as means ± SD, nonparametric data are presented as medians (IQR) and appropriate testing was applied. A P value less than 0.05 was considered statistically significant. Data analyses were performed using SPSS Statistics software (SPSS, Inc, Chicago, IL, USA), GraphPad Prism version 5 for Windows software (GraphPad Software, La Jolla, CA USA) and Confidence Interval Analysis (CIA) for Windows software (University of Southampton, UK).

Interobserver agreement regarding Medical Research Council sum scores of ICU patients

The demographic and clinical data from the cohort ( N = 20) are shown in Table  1 . The median (IQR) ICU LOS prior to MRC-SS testing was 24.0 days (6.8 to 43.3). At the time of testing, 45% of patients were receiving invasive mechanical ventilation (MV). All muscle groups were tested on all occasions. The median MRC-SSs for each testing clinician were 48 (IQR: 39 to 51; range: 22 to 57) and 48 (IQR: 38 to 51; range: 22 to 60) (Figure  1 ). Table  2 reports the MRC-SSs obtained during testing by both clinicians. Median time between testing by clinicians was 30 minutes (IQR: 29 to 33). The maximum difference in MRC-SS measurements for any one patient was 7, and the agreement between clinicians’ scores was 15.0%. The ICC was 0.94 (95% confidence interval (CI): 0.85 to 0.98), and the κ statistic for agreement on the diagnosis of ICU-AW was 0.60 (95% CI: 0.25 to 0.95). The results of interobserver agreement for individual muscle group scores, and the comparison between clinicians for the ICU cohort, can be found in Additional file 1 : S5, Tables S5a and S5b.

Medical Research Council sum score for clinician testing of critically ill patients and simulated presentations. a) Medical Research Council sum scores (MRC-SSs) in critically ill patients from each clinician. b) MRC-SSs in simulated presentations from each clinician. Error bars indicate medians and IQRs. Dotted lines indicate cutoff value of 48 on a 60-point scale to indicate diagnosis of ICU-acquired weakness. Abbreviations: MRC-SS = Medical Research Council sum score.

Interobserver agreement for simulated Medical Research Council sum score presentations

The data were analysed in a manner similar to that used previously. MRC-SS measurements by the two clinicians were 47 (IQR: 40 to 51; range: 20 to 60) and 47 (41 to 53; range: 20 to 59) (Figure  1 ). Table  2 reports the MRC-SSs obtained during testing by both clinicians against the simulated reference score. Ten reference MRC-SSs were less than 48, including four that were less than 36. The maximum difference between clinicians’ MRC-SS measurements for any individual presentation was 2 with 45.0% agreement. The ICC for simulated MRC-SS values was 1.0 (95% CI: 0.99 to 1.0). Complete agreement for diagnosis of ICU-AW on the basis of simulated presentations was evident (κ statistic: 1.0 (95% CI: 1.0 to 1.0)). The results for interobserver agreement regarding individual muscle group scores, and for comparisons between clinicians and against the reference score, are reported in Additional file 1 : S6, Tables S6a and S6b; and S7, Tables S7a and S7b.

Predictive value of ability to perform Medical Research Council sum score testing at awakening

Ninety-four patients were eligible for enrolment during the three-month study period (Figure  2 ). The baseline demographic data for the cohort are reported in Table  1 . Eighteen patients died prior to any testing, and eleven patients were consistently unable to perform (UTP) MRC-SS testing throughout their ICU stay because of cognitive impairment. Sixty-five patients were able to undergo MRC-SS at awakening. When the cohort was categorised into able to perform (ATP) and UTP MRC-SS testing at awakening patient groups, significant differences between groups were evident across the parameters of age (ATP 35.3 ± 14.9 years vs. UTP 60.6 ± 20.0 years; P < 0.0001), illness severity at time of ICU admission (Acute Physiological and Chronic Health Evaluation II score) (ATP 18.5 ± 5.1 vs. UTP 14.9 ± 4.6; P = 0.03) and hospital LOS (ATP 33 days (14.5 to 55.5) vs. UTP 15 days (7.0 to 37.0); P = 0.02). Groups were similar for gender, ICU LOS and total MV days. Duration of MV prior to awakening MRC-SS was five days (3 to 9.5) in the ATP group and 0.0 days (0.0 to 6.5) following awakening MRC-SS testing. In the UTP group, the number of attempted MRC-SS assessments was 4.0 (2.0 to 8.0). ICU mortality rates were 12.3% and 0.0% and in-hospital mortality rates were 24.6% and 18.2% for the ATP and UTP groups, respectively. We performed Fisher’s exact testing to examine any association between ability to perform the test at awakening and ICU and in-hospital mortality and LOS. The results of all tests were nonsignificant, and therefore further analysis of test characteristics was not considered appropriate.

Flow diagram of patient enrolment and evaluation throughout the study. MRC-SS: Medical Research Council sum score.

At day 7, 45 of the 65 patients with awakening scores had been discharged from the ICU (8 patients had died, and 37 patients had been transferred to the ward or repatriated), and 6 were unable to perform the test. Fourteen patients had MRC-SSs of 33.5 (22.3 to 44.8). Eleven had ICU-AW (MRC-SSs less than 48). Owing to the small numbers of patients, further analysis of this cohort was not considered appropriate.

Predictive value of a Medical Research Council sum scores less than 48 and 48 or higher at awakening

Of the 65 patients with MRC-SSs at awakening, 33 had scores of 0 to 36 (50.8%), 15 (23.1%) scored 37 to 47 and 17 (26.1%) scored 48 or higher. The prevalence of ICU-AW (MRC-SS less than 48) in the cohort was 73.9% (M:F ratio 35:13). There was no association between MRC-SS and ICU and hospital mortality ( P = 0.67 and P = 0.53, respectively), and therefore further analysis of test characteristics was not performed. However, a significant association was found for ICU and hospital LOS ( P = 0.004 and P = 0.04, respectively). The clinical predictive value of MRC-SS less than 48 at awakening was therefore determined (Table  3 ). Using a cutoff of 75%, high sensitivity was evident for ICU and hospital LOS. Specificity and PPV were poor across both parameters, with a high NPV evident for ICU LOS.

ROC analysis was performed on the 65 awakening MRC-SS measurements for each clinical outcome to assess sensitivity and specificity at levels of MRC-SS from zero to 60. Further data from this analysis can be found in Additional file 1 : S8, Table S8. The greatest sensitivity was observed at an MRC-SS less than 35 (64.3%) with 64.9% specificity (area under the curve (AUC): 0.69 (95% CI: 0.56 to 0.82)) for ICU LOS, and the greatest specificity was observed at an MRC-SS less than 29.5 (70.2%) with 62.5% sensitivity (AUC: 0.63 (95% CI: 0.42 to 0.83)) for ICU mortality, albeit that these ‘cutoffs’ have limited clinical usefulness.

Relationship between Medical Research Council sum score at awakening and handgrip strength and physical function

Data detailing the relationship between MRC-SS at awakening and handgrip strength and physical function at ICU discharge are reported in Additional file 1 : S1, Table S1. Patients diagnosed with ICU-AW demonstrated reduced handgrip strength compared to those without ICU-AW. However, only a weak direct relationship between MRC-SS at awakening and handgrip strength at ICU discharge was demonstrated. Furthermore, only a weak correlation was shown between MRC-SS and two common measures of physical function, with no difference in physical function observed between groups with or without a diagnosis of ICU-AW.

We have shown that, despite high interobserver agreement regarding MRC-SSs between two expert clinicians who assessed ICU patients and between their evaluations and simulated presentations of weakness, there was only moderate agreement for the diagnosis of ICU-AW in the ICU cohort. This confirms that interobserver agreement for the diagnosis of ICU-AW is a consequence of patient rather than clinician variability during testing, which wholly limits the clinical value of the test. In addition, almost one-third of ICU patients were unable to perform the MRC-SS test, but there were no relationships observed between the ability to perform the MRC-SS at awakening and mortality and LOS. Furthermore, an MRC-SS less than 48, indicative of ICU-AW, had limited PPV and NPV for a hospital LOS of more than four weeks, albeit that a high NPV was observed for an ICU LOS of more than two weeks. Clinically, this suggests that an MRC-SS less than 48 had poor predictive value but that an MRC-SS greater than 48 predicted a more favourable outcome. These data highlight the limitations and clinical usefulness of the MRC-SS as a marker of ICU-AW in a general ICU population in the early stages of critical illness.

Critique of the method

Determining the ideal protocol for establishing interobserver agreement regarding the MRC-SS in critically ill patients within the ICU and controlling for potentially confounding variables is challenging. We separated patient testing by 30 minutes to minimise the effect of clinical fluctuation and avoid patient exhaustion, albeit that a longer duration may have been required for this purpose. Specifically, we elected not to collect measurements at any intervening time points, as unpredictable fluctuations in the clinical status of patients remains a constant limiting factor in the reliability of MRC-SSs. Furthermore, we adopted a standardised protocol for MRC-SS measurement according to patient position to limit clinician variability, which has not previously been reported. Despite these approaches, we acknowledge that patient-related factors, in particular pain, may have influenced the clinician’s ability to perform the assessment, regardless of the patient’s successfully meeting screening criteria for alertness and cognitive ability on each occasion. A small cohort of patients were unable to complete MRC-SS testing because of persistent inability to understand or follow the necessary instructions, suggesting that screening using simple one-stage commands may be inadequately sensitive to detect cognitive ability sufficient for MRC-SS assessment. More thorough assessment of delirium and complex cognitive ability may have addressed this problem [ 25 ], but we aimed to reflect the common approach employed in previous studies [ 6 , 7 , 10 , 19 ]. We also acknowledge that we did not document sedation dose and opiate requirements, but the absence of this information should not detract from the fact that the inability to perform the test lacked clinical utility in predicting outcome and follows the methodology of previous studies in this area [ 4 , 7 , 10 ]. Indeed, there were no patients within the cohort whose causal ICU admission diagnosis physically precluded them from completing testing, for example, secondary to trauma. Outcomes of mortality and LOS were selected based on findings from previous observational cohort studies in which researchers investigated ICU-AW, diagnosed on the basis of the MRC-SS, and clinical course [ 6 , 7 , 10 ]. However, we recognise that these outcomes are influenced by multiple factors in critically ill patients and that peripheral muscle strength may not represent the most relevant diagnostic tool. We acknowledge that these data need to be interpreted carefully, as only one-fourth of patients with awakening MRC-SS values did not have ICU-AW.

In the current study, awakening was defined as the first occasion on which MRC-SS could be obtained from a patient. In contrast to the original study of De Jonghe et al. [ 10 ], who defined ICU-AW as an MRC-SS less than 48 at seven days postawakening, we found that, owing to high rates of patient discharge from the ICU by this time, scores at day 7 were considerably less useful. Specifically, the majority of patients in the ICU at day 7 postawakening demonstrated ICU-AW, but these patients comprised a small subgroup of the general ICU patient cohort studied (15%), and thus analysis of these data was extremely limited. This reflects the change in clinical ICU practice toward earlier discharge as a result of implementation of structured weaning and reduced-sedation protocols, as well as a growing culture of early mobilisation.

Interobserver agreement

Although interobserver agreement was determined in a relatively small sample of ICU patients recovering from critical illness in our present study, thus limiting the application of these findings to the wider ICU population, our approach allowed testing in a relatively stable group of patients with potentially less clinical fluctuation whilst they were still in the ICU. However, only moderate agreement regarding MRC-SSs less than 48, diagnostic of ICU-AW, was evident. The current subgroup shared clinical characteristics similar to those of a recently published data set that also demonstrated moderate levels of interobserver agreement regarding ICU-AW diagnosis [ 18 ]. Levels of agreement between clinicians were completely matched for MRC-SS and diagnosis of ICU-AW in simulated weakness presentations. Interobserver variability was therefore the result of patient-related variation in ability to perform the volitional MRC-SS rather than variability between clinicians in conducting the assessment. Whilst previously assumed, these results confirm the source of error in determining interobserver agreement of MRC-SS measurement to be patient variability and represent an important and novel aspect of the current research. We focussed on interobserver agreement of the MRC-SS, given that, in routine clinical practice, it is likely that more than one therapist is involved in the management of critically ill patients and that any potentially diagnostic measure requires consistency between clinicians. We therefore attempted to reduce interobserver bias by using experienced raters, but we acknowledge that, in clinical practice, greater variability in scoring may occur when carried out by clinicians with less experience.

Clinical interpretation of Medical Research Council sum score

Although previous data have associated ICU-AW with poor clinical outcome [ 6 – 8 , 10 ], determining the test characteristics of the MRC-SS as an assessment tool has never previously been reported in the literature. The clinical interpretation of these data is important to clarify.

Inability to perform the test did not predict a poor outcome in terms of ICU and in-hospital mortality and LOS. Likewise, there was no relationship observed between preserved peripheral muscle strength (MRC-SS 48 or higher) and ICU-AW (MRC-SS less than 48) and mortality. Despite demonstration of an association between MRC-SS and ICU and hospital LOS, test characteristics revealed that, whilst higher scores predicted a favourable outcome, lower scores did not predict a poor clinical outcome. These observations are in principle similar to those our own group and others have made when using volitional measurements of respiratory muscle strength whereby a high value supports confirmation of preserved muscle strength and a low value is not necessarily representative of muscle weakness, but rather is related to ability to perform the test effectively [ 26 – 29 ]. Further analysis using ROCs to define an MRC-SS cutoff for each of the important clinical outcomes of ICU and in-hospital mortality and LOS failed to identify clinically meaningful values of the MRC-SS with satisfactory sensitivity and specificity. These data highlight the limitations in the robustness of the MRC-SS for use in day-to-day clinical practice for predicting outcome, albeit that the sample size in this study was probably too small to be definitive. These data support the development of alternative outcome measures for monitoring the progression of muscle-wasting and weakness in critically ill patients, which need to be correlated with physical performance. Recent data have demonstrated a reduction in quadriceps rectus femoris cross-sectional area during early critical illness measured using ultrasound [ 30 ], with muscle layer thickness being negatively correlated with LOS [ 31 ]. These simple nonvolitional and effort-independent tests have the potential for further clinical application in the ICU to provide physiologically more accurate and robust data regarding muscle structure and function during critical illness. It is rational to consider that physical function has a relationship with muscle-wasting, although this connection has yet to be proven in the post–critical care population. Such data would provide strong support for targeted exercise therapy and rehabilitation for those patents with significant muscle-wasting with the expectation of enhancing physical function.

Comparison with previous studies

The moderate interobserver agreement regarding the diagnosis of ICU-AW and low PPV of ICU-AW in the current study was not unexpected. Inherent clinical variation and unpredictability during early critical illness highlight the major limitations of employing volitional testing in this population and affect reliability. Although original reports of MRC-SS testing by Kleyweg et al. [ 16 ] demonstrated high levels of interobserver reliability of the MRC-SS, this finding was in a cohort of recovering, stable patients with Guillain-Barré syndrome, albeit that the cohort included bedbound patients still requiring invasive ventilatory support. κ agreement levels of 88% reported by Fan et al. [ 32 ] and 68% by Hermans et al. [ 18 ] for stable recovery patients differ from those of 38% reported by Hough et al. [ 19 ] and 60% in our current study for the diagnosis of ICU-AW in patients assessed whilst in the ICU. Furthermore, similar to Hough et al. [ 19 ], we have demonstrated in the present that a significant proportion of patients were unable to perform MRC-SS testing. The current data challenge the clinical usefulness of the MRC-SS in ICU patients early in the course of critical illness.

Clinicians should understand the limitations of using the MRC-SS to diagnose ICU-AW during the early stages of critical illness. Even when MRC-SS testing is performed by expert clinicians, the fluctuating clinical status of patients can significantly reduce test reliability. Furthermore, patient inability to perform the test and a score indicative of ICU-AW demonstrated limited clinical usefulness in considering outcome. The findings of the current study reflect the limitations of volitional strength testing, and thus alternative nonvolitional techniques are required to objectively assess and monitor patients.

Key messages

Volitional manual muscle strength testing has limited clinical applicability in critically ill patients.

There was high interobserver agreement between two expert clinicians regarding MRC-SSs used to assess ICU patients, as well as with regard to simulated weakness presentations, but only moderate agreement regarding the diagnosis of ICU-AW.

There was no relationship between MRC-SS and mortality.

MRC-SSs less than 48, diagnostic of ICU-AW, have limited clinical value for predicting LOS.

Nonvolitional techniques are required for the assessment and monitoring of muscle-wasting in the early stages of critically illness.

Abbreviations

Able to perform

Area under the curve

Intraclass correlation coefficient

ICU-acquired weakness

Interquartile range

Length of stay

Medical Research Council sum score

Negative predictive value

Positive predictive value

Receiver-operator curve

Unable to perform.

Cheung AM, Tansey CM, Tomlinson G, Diaz-Granados N, Matté A, Barr A, Mehta S, Mazer CD, Guest CB, Stewart TE, Al-Saidi F, Cooper AB, Cook D, Slutsky AS, Herridge MS: Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome. Am J Respir Crit Care Med 2006, 174: 538-544. 10.1164/rccm.200505-693OC

Article   PubMed   Google Scholar  

Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados N, Al-Saidi F, Cooper AB, Guest CB, Mazer CD, Mehta S, Stewart TE, Barr A, Cook D, Slutsky AS, Canadian Critical Care Trials Group: One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003, 348: 683-693. 10.1056/NEJMoa022450

Herridge MS, Tansey CM, Matté A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, Kudlow P, Cook D, Slutsky AS, Cheung AM, Canadian Critical Care Trials Group: Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011, 364: 1293-1304. 10.1056/NEJMoa1011802

Article   CAS   PubMed   Google Scholar  

Hough C, Herridge M: Long-term outcome after acute lung injury. Curr Opin Crit Care 2012, 18: 8-15. 10.1097/MCC.0b013e32834f186d

Hurel D, Loirat P, Saulnier F, Nicolas F, Brivet F: Quality of life 6 months after intensive care: results of a prospective multicenter study using a generic health status scale and a satisfaction scale. Intensive Care Med 1997, 23: 331-337. 10.1007/s001340050336

Sharshar T, Bastuji-Garin S, Stevens RD, Durand MC, Malissin I, Rodriguez P, Cerf C, Outin H, De Jonghe B, Groupe de Réflexion et d’Etude des Neuromyopathies en Réanimation (GRENER): Presence and severity of intensive care unit-acquired paresis at time of awakening are associated with increased intensive care unit and hospital mortality. Crit Care Med 2009, 37: 3047-3053. 10.1097/CCM.0b013e3181b027e9

Ali NA, O’Brien JM Jr, Hoffmann SP, Phillips G, Garland A, Finley JC, Almoosa K, Hejal R, Wolf KM, Lemeshow S, Connors AF Jr, Marsh CB, Midwest Critical Care Consortium: Acquired weakness, handgrip strength, and mortality in critically ill patients. Am J Respir Crit Care Med 2008, 178: 261-268. 10.1164/rccm.200712-1829OC

De Jonghe B, Bastuji-Garin S, Durand MC, Malissin I, Rodrigues P, Cerf C, Outin H, Sharshar T, Groupe de Réflexion et d’Etude des Neuromyopathies en Réanimation: Respiratory weakness is associated with limb weakness and delayed weaning in critical illness. Crit Care Med 2007, 35: 2007-2015. 10.1097/01.ccm.0000281450.01881.d8

De Jonghe B, Bastuji-Garin S, Sharshar T, Outin H, Brochard L: Does ICU-acquired paresis lengthen weaning from mechanical ventilation? Intensive Care Med 2004, 30: 1117-1121. 10.1007/s00134-004-2174-z

De Jonghe B, Sharshar T, Lefaucheur JP, Authier FJ, Durand-Zaleski I, Boussarsar M, Cerf C, Renaud E, Mesrati F, Carlet J, Raphaël JC, Outin H, Bastuji-Garin S, Groupe de Réflexion et d’Etude des Neuromyopathies en Réanimation: Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002, 288: 2859-2867. 10.1001/jama.288.22.2859

de Letter MA, Schmitz PI, Visser LH, Verheul FA, Schellens RL, Op de Coul DA, van der Meché FG: Risk factors for the development of polyneuropathy and myopathy in critically ill patients. Crit Care Med 2001, 29: 2281-2286. 10.1097/00003246-200112000-00008

Leijten F, Harinck-de Weerd J, Poortvliet D, de Weerd A: The role of polyneuropathy in motor convalescence after prolonged mechanical ventilation. JAMA 1995, 274: 1221-1225. 10.1001/jama.1995.03530150045032

Nanas S, Kritikos K, Angelopoulos E, Siafaka A, Tsikriki S, Poriazi M, Kanaloupiti D, Kontogeorgi M, Pratikaki M, Zervakis D, Routsi C, Roussos C: Predisposing factors for critical illness polyneuromyopathy in a multidisciplinary intensive care unit. Acta Neurol Scand 2008, 118: 175-181. 10.1111/j.1600-0404.2008.00996.x

Stevens RD, Marshall SA, Cornblath DR, Hoke A, Needham DM, de Jonghe B, Ali NA, Sharshar T: A framework for diagnosing and classifying intensive care unit-acquired weakness. Crit Care Med 2009, 37(10 Suppl): S299-S308.

Article   Google Scholar  

Schweickert WD, Hall J: ICU-acquired weakness. Chest 2007, 131: 1541-1549. 10.1378/chest.06-2065

Kleyweg RP, van der Meché FG, Schmitz PI: Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome. Muscle Nerve 1991, 14: 1103-1109. 10.1002/mus.880141111

Dvir Z: Grade 4 in manual muscle testing: the problem with submaximal strength assessment. Clin Rehabil 1997, 11: 36-41. 10.1177/026921559701100106

Hermans G, Clerckx B, Vanhullebusch T, Segers J, Vanpee G, Robbeets C, Casaer MP, Wouters P, Gosselink R, Van Den Berghe G: Interobserver agreement of Medical Research Council sum-score and handgrip strength in the intensive care unit. Muscle Nerve 2012, 45: 18-25. 10.1002/mus.22219

Hough CL, Lieu BK, Caldwell ES: Manual muscle strength testing of critically ill patients: feasibility and interobserver agreement. Crit Care 2011, 15: R43. 10.1186/cc10005

Article   PubMed Central   PubMed   Google Scholar  

Connolly B, Jones G, Curtis A, Murphy P, Moxham J, Hart N: Predicting clinical outcome in critically ill patients using the medical research council sum-score [abstract]. Am J Respir Crit Care Med 2012, 185(Abstract issue): A3649.

Google Scholar  

Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal PV, Keane KA, Tesoro EP, Elswick RK: The Richmond Agitation–Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002, 166: 1338-1344. 10.1164/rccm.2107138

Guarneri B, Bertolini G, Latronico N: Long-term outcome in patients with critical illness myopathy or neuropathy: the Italian multicentre CRIMYNE study. J Neurol Neurosurg Psychiatry 2008, 79: 838-841. 10.1136/jnnp.2007.142430

Shrout PE, Fleiss JL: Intraclass correlations: uses in assessing rater reliability. Psychol Bull 1979, 86: 420-428.

Guggenmoos-Holzmann I: The meaning of κ: probabilistic concepts of reliability and validity revisited. J Clin Epidemiol 1996, 49: 775-782. 10.1016/0895-4356(96)00011-X

Ely EW, Margolin R, Francis J, May LR, Truman BR, Dittus RM, Speroff T, Gautam S, Bernard G, Inouye SK: Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001, 29: 1370-1379. 10.1097/00003246-200107000-00012

Hart N, Polkey MI, Sharshar T, Falaize L, Fauroux B, Raphaël JC, Lofaso F: Limitations of sniff nasal pressure in patients with severe neuromuscular weakness. J Neurol Neurosurg Psychiatry 2003, 74: 1685-1687. 10.1136/jnnp.74.12.1685

Article   PubMed Central   CAS   PubMed   Google Scholar  

Héritier F, Perret C, Fitting JW: Maximal sniff mouth pressure compared with maximal inspiratory pressure in acute respiratory failure. Chest 1991, 100: 175-178. 10.1378/chest.100.1.175

Iandelli I, Gorini M, Misuri G, Gigliotti F, Rosi E, Duranti R, Scano G: Assessing inspiratory muscle strength in patients with neurologic and neuromuscular diseases: comparative evaluation of two noninvasive techniques. Chest 2001, 119: 1108-1113. 10.1378/chest.119.4.1108

Uldry C, Fitting JW: Maximal values of sniff nasal inspiratory pressure in healthy subjects. Thorax 1995, 50: 371-375. 10.1136/thx.50.4.371

Puthucheary Z, Rawal J, Connolly B, McPhail M, Ratnayake G, Sidhu P, Shrikrishnapalasuriyar D, Hopkins P, Hopkinson NS, Polkey MI, Rennie M, Rowlerson A, Moxham J, Harridge S, Montgomery H, Hart N: Serial muscle ultrasound can detect acute muscle loss in multi-organ failure (abstract). Am J Respir Crit Care Med 2011, 183(Abstract issue): A2376.

Gruther W, Benesch T, Zorn C, Paternostro-Sluga T, Quittan M, Fialka-Moser V, Spiss C, Kainberger F, Crevenna R: Muscle wasting in intensive care patients: ultrasound observation of the M. quadriceps femoris muscle layer. J Rehabil Med 2008, 40: 185-189. 10.2340/16501977-0139

Fan E, Ciesla ND, Truong AD, Bhoopathi V, Zeger SL, Needham DM: Inter-rater reliability of manual muscle strength testing in ICU survivors and simulated patients. Intensive Care Med 2010, 36: 1038-1043. 10.1007/s00134-010-1796-6

Download references

Acknowledgements

The authors thank Juliet Hilton, physiotherapy student at King’s College London, UK, for her assistance as the healthy volunteer trained to demonstrate simulated presentations of the MRC-SS. The authors (BC and NH) acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. Additional acknowledgement is given to Guy’s & St Thomas’ Charity for a New Services and Innovation in Healthcare grant (S091112). MIP’s salary is part funded by the NIHR Respiratory Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust & Imperial College London.

Author information

Authors and affiliations.

Department of Asthma, Allergy & Respiratory Science, Division of Asthma, Allergy and Lung Biology, King’s College London, Great Maze Pond, London, SE1 9RT, UK

Bronwen A Connolly, Patrick B Murphy, John Moxham & Nicholas Hart

Guy’s & St Thomas’ NHS Foundation Trust and King’s College London,, National Institute of Health Research Biomedical Research Centre, Great Maze Pond, London, SE1 9RT, UK

Bronwen A Connolly, Abdel Douiri & Nicholas Hart

Lane Fox Clinical Respiratory Physiology Research Unit,Guy’s & St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK

Bronwen A Connolly, Patrick B Murphy & Nicholas Hart

Physiotherapy Department,Guy’s & St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK

Gareth D Jones & Alexandra A Curtis

Department of Public Health Sciences, King’s College London, 42 Weston Street, London, SE1 3QD, UK

Abdel Douiri

National Heart and Lung Institute, National Institute of Health Research Respiratory Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, Imperial College London, Sydney Street, London, SW3 6NP, UK

Nicholas S Hopkinson & Michael I Polkey

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Nicholas Hart .

Additional information

Competing interests.

The authors declare that they have no conflicts of interest.

Authors’ contributions

BC contributed to the design of the study, was responsible for data analysis and interpretation, and drafted, revised and agreed on the final manuscript version for submission. GJ and AC contributed to the study design, were responsible for data acquisition and contributed to manuscript revision. PM, NSH, MIP and JM contributed to data interpretation and manuscript revision. AD assisted with statistical analysis. NH contributed to the study design and data interpretation, was responsible for manuscript revision and agreed on the final version for submission. NH acts as the guarantor for the intellectual integrity of the work. All authors read and approved the final manuscript.

Electronic supplementary material

Additional file 1: supplemental digital content. (docx 61 kb), authors’ original submitted files for images.

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2, rights and permissions.

Reprints and permissions

About this article

Cite this article.

Connolly, B.A., Jones, G.D., Curtis, A.A. et al. Clinical predictive value of manual muscle strength testing during critical illness: an observational cohort study. Crit Care 17 , R229 (2013). https://doi.org/10.1186/cc13052

Download citation

Received : 18 June 2013

Accepted : 13 August 2013

Published : 10 October 2013

DOI : https://doi.org/10.1186/cc13052

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Positive Predictive Value
• Critical Illness
• Interobserver Agreement
• Handgrip Strength
• Richmond Agitation Sedation Scale

Critical Care

ISSN: 1364-8535

• Submission enquiries: [email protected]

Listen on the go

Share this activity.

We’d love to hear your feedback on this activity. It helps us to continually improve our products.

Thank you for your feedback.

• Account Settings  
• Subscriptions & Interests  
• Saved Activities  
• Education  
• Conference Hub  
• Learning Zone  
• Latest issue  
• Archive  
• Journal Information  
• Editorial board  
• Submit your article  
• COVID-19  
• Alzheimer’s Disease & Dementia  
• Brain Trauma  
• Epilepsy  
• Headache Disorders  
• Movement Disorders  
• View All Specialities »  
• COVID-19 Hub  

Optimizing the Use of Outcome Measures in Chronic Inflammatory Demyelinating Polyneuropathy

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

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

A study of 113 clinically stable patients (83 with Guillain-Barré syndrome [GBS]; 22 with CIDP; 8 with a gammopathy-related polyneuropathy) compared the overall (arm plus leg) ODSS with 2 other measures of disability (Hughes’ functional scale [f score] and Rankin scale), and 3 impairment measures (Medical Research Council sum score [MRC-SS]; sensory sum score; grip strength using the vigorimeter). The authors concluded that the ODSS was simple to use and demonstrated high validity, reliability, and responsiveness in CIDP, providing a better evaluation of impairment leading to disability than the other measures. 10 In another study, the ODSS was compared with other disability scales in 20 consecutive patients with recently diagnosed GBS (n=7) or CIDP (n=13). The ODSS showed higher correlation with short form-36 (SF-36) domains and patients’ own perception of their clinical condition than other disability scales. 11 The authors concluded that the ODSS was a useful primary outcome measure for clinical trials investigating CIDP therapies, 11 an opinion that is shared by many neurologists. 4

One limitation of the ODSS is its failure to measure difficulties with climbing stairs and running. Therefore, a modified peripheral neuropathy measure, the ONLS, was devised. 12 Specifically, the ODSS item “Does the patient have difficulty walking?” was changed to “Does the patient have difficulty walking, running or climbing stairs?” The remaining scoring criteria are not different from the ODSS. This small difference makes it more difficult to improve from 1 to 0, reducing the ceiling effect of the ODSS. In turn, this modification may reduce the responsiveness of the ONLS. In a study of patients with GBS (n=12), CIDP (n=42), chronic idiopathic axonal polyneuropathy (n=11), paraprotein-associated demyelinating neuropathy (n=13), Charcot-Marie- Tooth disease (n=9), and other neuropathies (n=13), the 2 scales correlated strongly with each other. They also correlated with the Role Limitation Physical Subscale of the Medical Outcome Study SF-36 health status scale (a quality of life [QoL] measure) in patients with GBS and CIDP, but not in patients with other forms of peripheral neuropathy. This may reflect the more acute progression of deficits in patients with GBS and CIDP resulting in greater functional limitation, but no firm conclusions can be drawn from such small subgroups. 12

The ODSS and ONLS are among the best measures of disability as an outcome measure in clinical trials and are useful in a routine clinical environment. Like the INCAT disability score, the outcomes can be obtained rapidly and thus are feasible for routine clinical care. They are ordinal measures and cannot be represented linearly like the INCAT disability score. Furthermore, they have not been used to assess outcomes in large cohorts of patients with CIDP.

The Rasch-built overall disability scale The INCAT scales are based on classic test theory, i.e., multi-item measures that assume all components have equal weight and therefore equal relevance. 13 Physicians often incorrectly interpret a 1-point response change for an item (e.g., from 0 to 1 as equivalent to a 1-point change from 2 to 3). However, since the response options are ordinal based, the true distance between the response categories is not known and may be unequal. The Rasch statistical methodology overcomes these shortcomings. Rasch is a mathematical model that aims to give a true reflection of disease impact based on the probability that a person will be able to complete an item, dependent on the item difficulty and the person’s level of ability. 14 For example, it is logical to assume that walking up a flight of stairs will be a much more difficult task to accomplish than washing one’s face. The Rasch-built overall disability scale (R-ODS) for immune-mediated peripheral neuropathies is a patient-based, linearly weighted scale that captures activity and social participation limitations in patients with CIDP, GBS, and polyneuropathy associated with a monoclonal gammopathy of undetermined significance (MGUSP). 14 The assessment includes 24 questions that address upper and lower limb disability. These range in difficulty from ability to read a book, eat, or brush teeth to dance, stand for hours, and run. Participants are asked to indicate if they can easily perform the task, perform it with difficulty, or are unable to perform it at all. Both the ability of the patient and the perceived difficulty of a task are tallied for a raw R-ODS score that ranges between 0 (complete disability) and 48 (no disability). The resulting raw R-ODS score can then be transformed to a final R-ODS score ranging from 0 to 100. Of note, R-ODS scale developed for multifocal motor neuropathy (MMN) is tailored to that condition and should not be confused with the RODS disability score for CIDP, GBS, and MGUS neuropathy. 15

A preliminary study assessed R-ODS in 294 patients who had experienced GBS in the past (n=174) or had stable CIDP (n=80) or MGUSP (n=40), and reported good reliability and validity. 14 Another advantage of R-ODS (now referred to as I-RODS or inflammatory-RODS) is the ability to better capture clinically meaningful changes over time compared with the INCAT-ONLS in patients with GBS (n=55) and CIDP (n=59). 16 The I-RODS offers a more sensitive outcome measure than INCAT-ODDS or OLNS, and it has been proposed as the primary measure of disability in future clinical trials involving patients with GBS and CIDP. 17

Feasibility is both an advantage and potential limitation of the I-RODS. Although the scale can be completed quickly with minimal training, the resulting raw RODS score is not designed to be interpreted directly but rather items should be transformed to the linear weighted final R-ODS score using a conversion table. 14 Even then, intra-patient I-RODS minimal clinically important differences are difficult to interpret. 16 Another potential disadvantage is the observation that in different geographical regions, item bias was observed in 6 of the 24 (25%) items, which suggests that the scale requires further cross-cultural exploration. 17

Gait assessments The traditional scales used to analyze gait parameters in clinical conditions are carried out by specialists who observe the quality of a patient’s gait by making him/her walk. This is sometimes followed by a survey in which the patient is asked to self-evaluate the quality of his/her gait. The disadvantage of these methods is that they are subjective, raising concerns of accuracy and precision as well as reproducibility. Newer gait analysis devices and techniques allow a more objective evaluation of gait, resulting in more meaningful and reliable data. This reduces the error margin caused by subjective techniques. 18

Gait (GAITrite®) GAITrite® (CIR Systems Inc., New Jersey, US) is an electronic walkway with embedded pressure sensors. Its value in CIDP was demonstrated in a prospective evaluation of 9 newly diagnosed patients. The findings suggested that the GAITrite walkway detects changes following treatment that correlate with changes in the MRC score. 19 Further, a prospective evaluation of 20 patients with CIDP, following a 3-month course of IVIG treatment, indicated that gait parameters, as measured by GAITrite, may provide a sensitive clinical tool. 20 Increases in velocity, cadence, and swing phase percentage and reductions in double support time and stance phase percentage were noted after treatment. Changes in these specific parameters suggest a pattern of objective gait recovery that may reflect improvement in strength, proprioception, and coordination following treatment.

The GAITrite system has the advantage of being portable and easy to store and use, as well as being relatively inexpensive. In a preliminary evaluation, its validity compared with other methods was good, and it was capable of measuring both temporal and spatial parameters of gait at a variety of speeds. 21 A study of 25 healthy adults showed good validity and retest reliability, although the repeatability was more variable at slow speeds. 22 The use of the GAITrite has also been validated in children. 23

Wearable sensors Wearable sensor systems make it possible to analyze gait during a person’s routine daily activity. Sensors are placed on various parts of the patient’s body, such as the feet, knees, or hips, and measure various characteristics of gait. A number of different sensors are available, including force sensors, accelerometers, gyroscopes, extensometers, inclinometers, goniometers, active markers, and electromyography, but none have been validated in studies of patients with CIDP. 18

Timed up and go test The Timed Up and Go (TUG) test involves a patient standing up from a seated position, walking a short distance, turning around, returning, and sitting down again. 24 In a study of 60 elderly patients (mean age 79.5 years) it was found to be reliable (inter-rater and intra-rater) and correlated well with log-transformed scores on the Berg Balance Scale, gait speed, and Barthel Index. It also seemed to predict the ability to walk outside alone safely. The test is quick and requires no special equipment or training, and can be used in routine evaluation. 25 It also includes getting up from a chair, walking, and turning, which incorporates a number of aspects of lower leg function. The limitation of the TUG test is the absence of validity and sensitivity to change data in patients with inflammatory neuropathy.

10-Meter walk test The 10-Meter Walk Test (10MWT) assesses walking speed. In a study of 43 healthy adults (mean age 84.3±6.9 years) the 10MWT was compared with the 4-Meter Walk Test (4MWT). Although both gait speed assessments had excellent test retest reliability with similar standard error of measurement across measurement methods and minimal detectable change values, the 4MWT did not give a high enough degree of concurrent validity, and the discrepancy was large enough to potentially mask meaningful changes in gait speed over time if both methods were used interchangeably. 26 The 4MWT has not been tested in patients with CIDP. In a study of 12 patients with CIDP, the 10MWT was used alongside a performance-based body function test, a self-reported activity test, and a self-reported functioning test. While the 10MWT was considered useful in assessing gait in patients with CIDP, a clear relationship between body activities and functioning was not found, highlighting the importance of assessing multiple parameters in investigating inflammatory neuropathies. 27 In addition, some patients with CIDP and MMN performed the 10MWT with ease as they experienced difficulties only with walking long distances. This suggests that an extended walking test should also be performed.

The 6-minute walking test is another established and validated assessment of walking ability. It has been found to correlate with established outcome measures in spinal muscular atrophy, and is sensitive to fatigue-related changes but has not been assessed in patients with CIDP. 28

In summary, objective gait analysis is a potentially important outcome measure in CIDP. Currently available measures, in particular TUG and 10MWT, may be both reliable and feasible in the routine clinical care setting, but their validity in CIDP has not yet been established. When using gait as a measure of outcome in CIDP it is important to keep in mind that simply assessing the ability to walk is an inadequate representation of a patient’s overall function. 29 As such, quantifying gait impairment with reliable and valid assessments is needed, as is combining gait impairment with other validated clinical outcome tools in patients with relatively preserved gait but substantial disability in other areas.

Grip strength Grip strength has largely superseded older methods of assessment of muscle strength, such as the MRC-SS. 30,31 Grip strength can be assessed using various devices such as the Jamar® hand-held dynamometer (Lafayette Instrument, Indiana, US) and the Martin vigorimeter (Martin, Tuttlingen, Germany) 6 (see Figure 1) . Both provide a quantitative objective measure of grip strength and an instant measure of strength impairment. 32 The dynamometer is used more commonly in the US and the vigorimeter in Europe. A study comparing the vigorimeter versus Jamar dynamometer in immune-mediated neuropathies, including CIDP, revealed that significantly more patients preferred the vigorimeter, largely based on hand comfort during testing. 33 Validity, reliability, and responsiveness were similar between the two tools.

The advantages of testing grip strength are many. It is a quantifiable outcome measure that can be collected quickly and easily, is relatively objective, and is less susceptible to bias than other outcome measures. In a systematic analysis of data from patients with CIDP in the ICE study, both vigorimeter-measured grip strength and the INCAT disability scale showed significant improvement at week 6. Dominant hand grip strength, however, showed a statistically significant improvement earlier than INCAT, at day 16 and at day 21 (p=0.018 and p=0.021) and also captured deterioration earlier.34 Although some have raised concerns that in routine clinical practice a patient’s grip strength may be poorly representative of lower limb or proximal predominant weakness 35 in a randomized controlled trial, grip strength was shown to provide objective documentation of global neurologic status in patients with CIDP, not limited to the upper limb or exclusively motor function. 34 Disadvantages include the expense of purchasing special equipment, the need to supervise the measure to assure standardized technique, and limited utility in patients with severe hand weakness (<5 kg).

Manual muscle strength testing and isokinetic strength testing The MRC developed the manual muscle test (MMT) to assess muscle weakness in daily clinical practice, The MMT is straightforward to perform, allows for muscle strength sampling in proximal and distal upper and lower limb areas, and does not entail the use of expensive instruments. A drawback of this test is its lack of sensitivity for the detection of mild to moderate weakness of large muscle groups when symmetrical weakness is present. 36 Examples of such muscle groups include the ankle plantar flexors, knee extensors, and hip flexors. In addition, the MMT is highly dependent on the skills and experience of the assessors, which means that the inter-rater reliability can be low. 36 By contrast, isokinetic testing is a quantitative measurement of muscular contraction that allows objective, valid, and reliable measurement of the force produced by a skeletal muscle during exercise at constant velocity and when accommodating resistance. 37,38 Isokinetic testing may be better suited to detect small changes in muscle strength over time compared with MMT. In addition, isokinetic testing may be better suited to quantitate how much resistance muscles take when graded 4/5. Isokinetic testing protocols, described by Harbo et al. 39 have been used as an outcome measure in studies exploring the safety and efficacy of subcutaneous administration of immumoglobulins in CIDP. 40-42 Cost and space constraints limit the utility of isokinetic dynamometry in the routine clinical care setting. The assessment also can be timely to perform and requires expertise on the part of the evaluator to become familiar with the testing protocols. Some muscles, in particular muscles that are very weak or very distal, may not be appropriately assessed with isokinetic dynamometry.

Fatigue severity scale Fatigue is a complex entity that is sometimes a debilitating symptom in patients with immune-mediated polyneuropathies. In a noninterventional study, changes in depression and fatigue dynamics are being assessed in patients with CIDP. 43 Early results suggest that fatigue imparts a high burden on patients with CIDP and should be considered a relatively independent and potentially disabling symptom in patients with CIDP. 44

The fatigue severity scale (FSS) is one available tool to measure fatigue. 44 FSS is a patient self-assessment questionnaire that measures fatigue severity and impact on activities and lifestyle by asking participants to respond to 9 separate items. Responses are scored on a 7-point scale (1 = strongly disagree, 7 = strongly agree; total score range 9–63, where a higher score indicates more fatigue). The FSS has been validated in a large patient cohort and was considered simple to use and showed excellent internal consistency and reliability. 45 In a cohort of 133 patients with immune-mediated polyneuropathies (22 with CIDP), “severe” fatigue (FSS scores ≥95th percentile values in controls) was present in 80% of patients. Variables such as age, disease duration, and INCAT sensory sum score were not significantly associated with fatigue. One limitation of the 9-item FSS is its ordinal scale. A newer, 7-item linearly weighted Rasch-built scale, with 4 response categories for each item, has been developed and assessed in 192 patients with immune-mediated neuropathies. It showed good reliability and validity for patients with CIDP, but further validation of this scale is needed. 46

Although fatigue is an important factor in determining QoL in CIDP, experts generally agree that fatigue as an isolated outcome is not an appropriate measure for assessing treatment response. Fatigue can be present in CIDP patients with normal general strength and sensation 44 and, like fatigue in GBS, 47 might persist as a residual deficit even in those with inactive disease. Furthermore, fatigue may be influenced by other, non-CIDP-related factors such as age, medications, comorbid disease, and general conditioning. In summary, FSSs represent a valid and sensitive measure of assessment, but represent only one component of a multifaceted disease.

Quality of life Experts have emphasized the importance of QoL measures in the assessment of inflammatory neuropathies. Factors such as low motivation, fatigue, pain, and depression can affect patients’ confidence to focus on the challenges of recovery. 17 A neuropathy-targeted healthrelated QoL measure based on the RAND-36 Health Survey was described in 2000. 48 This measure demonstrated acceptable validity, reliability, and responsiveness in patients with diabetes-related neuropathies and was considered appropriate for patients with CIDP, 48 although it has not been widely adopted.

The SF-36 is one of the most widely used generic QoL measures but does not address specific QoL issues in CIDP or other neuropathies. In addition, patient responses may be influenced by unrelated health issues. In a 2002 study, the SF-36, together with 3 other measures (MRC-SS; sensory sum score; Hughes functional scale) was shown to complement traditional outcome measures in 144 patients with immunemediated polyneuropathies, including 23 patients with CIDP. 49 The SF- 36 demonstrated acceptable validity and internal consistency values and moderate to good standardized response. Patients who were more disabled had lower scores on the physical measures compared with the less disabled. In general, patients alter their functional expectations over time and learn to cope with their limitations as mental health and subjective well-being were the least affected parameters. 48 The SF-36, therefore, complements the traditional assessment of symptoms, signs, and laboratory studies in these conditions and facilitates the evaluation of not only physical but also mental functioning. Neurospecific QoL measures, such as the NeuroQoL, have been validated in other neurologic conditions but have not been widely adopted and have not been used in CIDP. 50 A new disease-specific, health-related QoL scale has recently been validated in patients with CIDP, MMN, and monoclonal Ab-associated polyneuropathy, termed the Chronic Acquired Polyneuropathy Patientreported Index (CAP-PRI). The CAP-PRI assesses various life domains, including physical and social functioning, pain, and emotional well-being and appears to cover the various degrees of disease severity. Although not yet used in clinical trials of CIDP, the CAP-PRI is quick, easy to use and interpret, and available in the public domain and thus may be well suited for assessing QoL in clinical practice. 51

A comprehensive examination of the relationships between impairments, activity levels, participation restriction, and reduction in QoL has been reported using the data from the ICE trial. 52 This analysis suggested that changes in strength, sensation, and some neurophysiologic measures are associated with a restriction on daily activities and social participation and a reduction in QoL. Up to two-thirds of disability was accounted for by impairment measures and half of the variance of QoL component measures was explained by a combination of impairment and activity measures. Future studies are needed to further explore the impact of CIDP on disability and QoL changes. Practical application of outcome measures There are no evidence-based data to guide the timing of outcome assessment in those with CIDP. Based on a large interventional trial in CIDP, it is advisable to assess CIDP outcomes at month 3 after starting treatment as most who respond to treatment should do so within the first 3 months. 7 Periodic assessments thereafter are highly influenced by individual disease severity and response to immunotherapy. Repeat clinical assessments are encouraged before and after dosing changes. It may also be preferable to arrange assessments immediately prior to IVIG to capture patients at their theoretically worst CIDP status.

Patient-related outcome measures (PROMs) are emerging as a valuable means of assessing response to IVIG therapy, and are increasingly administered in the home setting. 53 The use of PROMs is particularly appropriate in conditions such as CIDP, where disease manifestations are readily evident to the patient and may vary with daily activities. 54 The utility of home evaluation of I-RODS has been previously discussed. 16 A small study found strong correlations between clinic and home evaluations of I-RODS and INCAT scores in leg function, although INCAT scores for arm function showed significant differences, with home evaluations typically scoring 1 point less. 55 In some clinical practices, frequent patient-reported grip strength collection at home with electronic communication to the physician is utilized to complement outcomes collected during routine clinical visits. The feasibility and reliability of at-home grip strength collection has not been reported in large groups of CIDP patients. Important advantages of at-home collection include frequency of data entry, the ability to monitor remotely, and the collection of data at clinically critical time points (e.g., end-of-cycle IVIG deterioration, after-treatment assessment of response, or for relapse after therapy discontinuation).

Summary and concluding remarks The applicability of an outcome measure is dependent on its validity, reliability, and capacity to detect meaningful clinical changes over time (“responsiveness”). 56 Ease of implementation in clinical practice is also important. To be useful in a clinical setting, outcome measures need to navigate constraints in time, equipment, and expertise while also providing accurate data that inform therapeutic decisions. It is important to be aware of the possibility of misinterpretation. Uniform assessment and clinical judgment are necessary when interpreting results.

This article has highlighted advantages and disadvantages of several outcome measures for CIDP. While some have potential application during routine clinical care, several challenges remain. Although a sustained disease remission with complete or near-complete clinical recovery is achievable in some patients with CIDP, this is not the case for all. Residual irreversible deficits are not uncommon in patients with both immunologic active and inactive disease. One challenge that often arises during CIDP treatment is separating stable immunologically inactive deficits from an ongoing or active inflammatory process. For patients with well-defined active disease another challenge is optimization of therapy, thereby avoiding the potential toxicities or accumulating disability that can come with over- and undertreatment. At present, there is no single assessment that can differentiate between active and inactive disease, or that can identify optimal treatment response. However, a combination of these assessments over time along with clinical and electrodiagnostic findings may provide a better idea of whether weakness and function have the potential for recovery. The tools that have traditionally been used during routine clinical care to guide treatment decisions are inadequate. Gathering a better understanding of a patients’ disability and strength impairment over time, along with subjective patient experience and neurologic examination, can assist the clinician in dosing adjustment decision-making and, in general, optimizing treatment plan. This is especially true if those assessments of disability and strength impairment are valid and disease-specific. I-RODS and grip strength collection appear poised to fill the gaps in routine clinical monitoring of patients with CIDP. When further combined with measures of gait and fatigue, the potential to understand CIDP disease activity status and to make informed treatment decisions is enhanced. Even so, the emphasis placed on any one assessment, no matter how objective, is uncertain. There is an unmet need for a CIDP biomarker, CIDP specific immunologic signature, or composite clinical measure that can broadly assess disease activity, functional status, and the effect of therapy at different stages of the inflammatory process.

We strongly endorse the use of objective outcome measures in clinical practice. Strength impairment testing with a handheld dynamometer is a validated measure that can be collected quickly. Although the Jamar and vigorimeter devices require purchase (available online from $200–400), the cost is similar to other devices routinely used as part of the bedside neurologic examination. I-RODS, INCAT, and/or ONLS are available at no cost and take little time during a visit. Even though not validated in CIDP, a gait assessment with TUG or 10MWT can potentially provide useful data. Fatigue and pain scales can also be recorded to complement one of the above objective measures.

Additional studies are needed to develop and validate reliable outcomes measure for routine clinical assessments in CIDP. We contend that the development of a weighted composite measure, incorporating multiple assessments including patient- and physician-reported outcomes, potentially available as a mobile app and based on gaming technology is one future possibility and addresses an essential unmet need in the care of patients with CIDP.

Please see Important Safety Information about GAMUNEX-C on the following pages and refer to the brief summary of full Prescribing Information57 in the Appendix.

Important safety information GAMUNEX®-C (immune globulin injection [human], 10% caprylate/ chromatography purified) is indicated for the treatment of primary humoral immunodeficiency disease (PIDD) in patients 2 years of age and older, idiopathic thrombocytopenic purpura (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP).

GAMUNEX-C is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. It is contraindicated in IgA-deficient patients with antibodies against IgA and history of hypersensitivity.

Severe hypersensitivity reactions may occur with IVIG products, including GAMUNEX-C. In case of hypersensitivity, discontinue GAMUNEX-C infusion immediately and institute appropriate treatment.

Monitor renal function, including blood urea nitrogen (BUN), serum creatinine, and urine output in patients at risk of developing acute renal failure.

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IVIG treatment, including GAMUNEX-C.

There have been reports of noncardiogenic pulmonary edema (transfusionrelated acute lung injury [TRALI]), hemolytic anemia, and aseptic meningitis in patients administered with IVIG, including GAMUNEX-C.

The high-dose regimen (1g/kg x 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern.

Because GAMUNEX-C is made from human blood, it may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

Do not administer GAMUNEX-C subcutaneously in patients with ITP because of the risk of hematoma formation.

Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of GAMUNEX-C and at appropriate intervals thereafter.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/ markedly high triacylglycerols (triglycerides), or monoclonal gammopathies, because of the potentially increased risk of thrombosis.

If signs and/or symptoms of hemolysis are present after an infusion of GAMUNEX-C, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and patient’s serum.

After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation.

In clinical studies, the most common adverse reactions with GAMUNEX-C were headache, fever, chills, hypertension, rash, nausea, and asthenia (in CIDP); headache, cough, injection-site reaction, nausea, pharyngitis, and urticaria with intravenous use (in PIDD) and infusion-site reactions, headache, influenza, fatigue, arthralgia, and pyrexia with subcutaneous use (in PIDD); and headache, vomiting, fever, nausea, back pain, and rash (in ITP).

The most serious adverse reactions in clinical studies were pulmonary embolism (PE) in 1 subject with a history of PE (in CIDP), an exacerbation of autoimmune pure red cell aplasia in 1 subject (in PIDD), and myocarditis in 1 subject that occurred 50 days post-study drug infusion and was not considered drug related (in ITP).

Article Information:

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.

Authorship All 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.

Correspondence

Jeffrey A Allen, Department of Neurology, 12–150 Phillips Wangensteen Building, 516 Delaware Street SE, Minneapolis, MN 55455. E: [email protected]

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

2016-12-19T00:00:00

Further Resources

• View eJournal
• Get Permission

Share this Article

Related content in neuromuscular diseases.

Updates in the Use of Vamorolone and Steroids in the Treatment of Duchenne Muscular Dystrophy

touchREVIEWS in Neurology. 2023;19(2):7-9

Duchenne muscular dystrophy (DMD) is an X-linked recessive, progressive and universally fatal disease in the spectrum of dystrophinopathies,1 with an incidence of 21.4 patients in 100,000 live male births worldwide.2,3 Historically, patients with DMD would lose ambulation by the age of 10 due to muscle weakness and die by the age of 20 from respiratory failure […]

LGMDR1 with Prominent Limb–Joint Contractures and Inflammatory Changes Misdiagnosed as Scleromyositis with a Novel CAPN3 Mutation: A Case Report

touchREVIEWS in Neurology. 2023;19(1): DOI: https://doi.org/10.17925/USN.2023.19.1.46

Highlights Limb–joint contractures may represent an important clinical clue of muscle dystrophies, as they limit the spectrum of the diagnosis assumptions. Limb–girdle muscular dystrophies phenotype can rarely be a clinical presentation of retractile myopathies, except for non-specific Achilles tendon tightness. Anti-PM/Scl antibody screening using line-blot assays and commercial antibody–panel testing is likely to detect false-positive antibodies. Dysferlinopathies, calpainopathy and facioscapulohumeral muscular dystrophy are the conditions most frequently confused […]

Hirayama Disease: Review on Pathophysiology, Clinical Features, Diagnosis and Treatment

touchREVIEWS in Neurology. 2022;18(2):109–16 DOI: https://doi.org/10.17925/USN.2022.18.2.109

Hirayama disease (HD) is a lower motor neurologic disorder that manifests in young males in their early 20s, manifesting with gradually progressive weakness and wasting of C7-T1 innervated muscles. Dynamic magnetic resonance imaging (MRI) clinches the diagnosis, and treatment is mainly supportive using a cervical brace, and in refractory cases, surgical. This review aims to […]

Trending In Neuromuscular Diseases:

Journal articles and more to your inbox.

Get the latest clinical insights from touchNEUROLOGY

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Rev Bras Ter Intensiva
• v.27(3); Jul-Sep 2015

A guided approach to diagnose severe muscle weakness in the intensive care unit

Abordagem dirigida para o diagnóstico de fraqueza muscular grave na unidade de terapia intensiva, nicola latronico.

1 Department of Anesthesia, Critical Care Medicine and Emergency, Spedali Civili University Hospital - Brescia, Italy.

2 Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia - Brescia, Italy.

Rik Gosselink

3 Department of Rehabilitation Sciences, Katholieke Universiteit Leuven - Leuven, Belgium.

Intensive care unit (ICU) acquired muscle weakness (ICUAW) is a clinically detected condition characterized by diffuse, symmetric weakness involving the limbs and respiratory muscles. ( 1 ) Patients have different degrees of limb muscle weakness and are dependent on a ventilator, while the facial muscles are spared. Diagnosis of ICUAW requires that no plausible etiology other than critical illness be identified, and thus, other causes of acute muscle weakness are excluded. One major diagnostic criterion is that ICUAW is detected after the onset of critical illness; therefore, it is important to differentiate ICUAW from Guillain-Barrè syndrome or other acute neuromuscular disorders that may cause respiratory failure and ICU admission ( Figure 1 ). ( 1 ) The use of neuromuscular blocking agents for long periods of time, the use of some antibiotics and electrolyte abnormalities, such as hypermagnesemia, hypokalemia, hypercalcemia, and hypophosphatemia, and prolonged immobilization are common in the ICU and should be appropriately treated before a diagnosis of ICUAW is posed. ( 2 )

Diagnostic algorithm for intensive care unit acquired muscle weakness (ICUAW).

Modified from: Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011;10(10):931-41. ( 1 ) Cut-off handgrip strength values were below 7kg for female and below 11Kg for males. DD - differential diagnosis; NCS - nerve conduction study; EMG - electromyography; NM - neuromuscular; CIP - critical illness polyneuropathy; CIM - critical illness myopathy; MRC - Medical Research Council; CMAP - compound muscle action potential.

A diagnosis of ICUAW is achieved by manually testing the muscle strength using the Medical Research Council (MRC) scale or by measuring handgrip strength using a dynamometer.

MRC muscle strength is assessed in 12 muscle groups ( Figure 2 ): a summed score below 48/60 designates ICUAW or significant weakness, and an MRC score below 36/48 indicates severe weakness. ( 3 ) Recently, a simplified version of the scale with only four categories and improved clinimetric properties was proposed ( Figure 2 ). ( 4 ) To date, this version has been validated in a small cohort of 60 critically ill patients with excellent inter-rater reliability and high sensitivity and specificity in diagnosing ICUAW compared to complete full MRC. ( 5 )

Original and simplified Medical Research Council (MRC) scales.

Both scales are bilaterally applied to six muscle groups of the upper and lower limbs in order to obtain a summed score ranging from 0 to 60 for the classic MRC scale and from 0 to 36 for the simplified version: (1) abduction of the arm; (2) flexion of the forearm; (3) extension of the wrist; (4) flexion of the leg or hip flexion; (5) extension of the knee; and (6) dorsal flexion of the foot.

Handgrip dynamometry measures isometric muscle strength and can be used as a quick diagnostic test. Cut-off scores of less than 11kg (IQR 10 - 40) in males and less than 7kg (IQR 0 - 7.3) in females are considered to be indicative of ICUAW ( Figure 1 ). ( 5 ) Both MRC and handgrip dynamometry are volitional tests and require the patients to be alert, cooperative, and motivated. Sedation, delirium and coma often interfere with the early evaluation of muscle strength in the ICU. However, voluntary muscle strength using the MRC sum score or handgrip dynamometry can be reliably assessed if adequate clinical experience is gained with manual muscle testing in ICU patients and strict guidelines and the use of standardized test procedures and positions are followed to accurately select patients. ( 6 )

Common causes of ICUAW include critical illness polyneuropathy (CIP) and myopathy (CIM), which are revealed by appropriate nerve conduction studies and electromyography. ( 1 , 7 ) Because these electrophysiological studies are time-consuming and require specialized personnel, simplified tests have been proposed to be used as screening tests. ( 8 ) Unilateral peroneal and sural nerve conduction studies can accurately screen for CIP and CIM in ICU patients. ( 9 ) A single nerve test (the peroneal nerve test) has been validated in two multicenter studies as a 100% sensitivity test compared to a complete nerve conduction study and electromyography in the diagnosis of CIP/CIM, ( 10 ) and it can be performed in 10 minutes. ( 11 ) A reduced amplitude of the muscle action potential obtained after direct muscle stimulation can identify muscle membrane excitability and CIM in non-cooperative patients and can be useful in differentiating CIM from CIP in the ICU. Prolonged duration of the compound muscle action potential amplitude, which is obtained during a conventional nerve conduction study, can also suggest CIM ( Figure 1 ). ( 1 ) Differential diagnosis between CIP and CIM is important because prognosis can be better for CIM than for CIP. ( 12 , 13 )

ICUAW is a clinically relevant complication during the acute stage of disease and after discharge from the acute-care hospital. In the ICU, severe muscle weakness is independently associated with prolonged mechanical ventilation, ICU stay, hospital stay and increased mortality. ( 1 ) Patients developing weakness during the ICU stay have reduced quality of life and increased mortality 1 year after ICU discharge. ( 14 ) In survivors of acute lung injury, ICUAW resolves within several weeks to months in most patients, but it can persist longer in other patients. ( 15 , 16 ) In a recent Brazilian cohort study, physical activity, muscle strength and exercise capacity were significantly reduced in survivors of severe sepsis and septic shock. ( 17 ) Physical dysfunction, either measured using objective physical function tests, such as the 6-minute walking distance test, or subjectively perceived by the patients as weakness, persists longer than muscle weakness and can be a major problem affecting the quality of life even in patients who regain their full muscle strength. There can be several reasons for this, not least that the outcome is affected by a myriad of factors. ( 18 )

In conclusion, muscle weakness acquired during the ICU stay is a clinically relevant complication with an impact on early and late outcome. Timely diagnosis is much deserved for patients, and pragmatic diagnostic flow-charts, as proposed here, may be of help in daily practice.

Conflicts of interest: None.

Editor responsável: Jorge Ibrain Figueira Salluh