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Outcome Measures in Myasthenia Gravis

Incorporation Into Clinical Practice

Muppidi, Srikanth MD

Journal of Clinical Neuromuscular Disease: March 2017 - Volume 18 - Issue 3 - p 135–146
doi: 10.1097/CND.0000000000000156
Review Article

The development of validated assessment tools for evaluating disease status and response to interventions in patients with myasthenia gravis (MG) has been driven by clinical studies of emerging MG therapies. However, only a small proportion of MG-focused neurology practices have adopted these assessment tools for routine clinical use. This article reviews the suitability of 5 assessment instruments for incorporation into clinical practice, which should be driven by their ability to contribute to improved patient outcomes, and to be implemented within practice personnel and resource constraints. It is recommended that assessments based on both physician-evaluated and patient-reported outcomes be selected, to adequately evaluate both point-in-time symptom load and functional impact of MG symptoms over time. Provider resource allocation and reimbursement issues may be the most significant roadblocks to successful ongoing use of these tools; to that end, the addition of regular assessments to MG standards of care is recommended.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA.

Reprints: Srikanth Muppidi, MD, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305 (e-mail:

Supported by Alexion Pharmaceuticals, Inc (New Haven, CT). Editorial and writing assistance has been provided to the author by Connexion Healthcare (Newtown, PA). The author meets the criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), and is fully responsible for all content.

S. Muppidi has served on scientific advisory boards for Alexion Pharmaceuticals, Inc and Lundbeck.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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Current approaches to myasthenia gravis (MG) treatment have been largely empirical, guided by clinical observation and retrospective evaluations rather than by controlled clinical studies.1 As with many disease states, the need for controlled studies of existing and emerging MG treatments has driven the development of various outcome measures to characterize patient status and disease severity, and to evaluate the effects of treatment. Such outcome measures are of potential use in everyday clinical practice and as a tool for the ongoing management of patients with MG, in addition to their utility in clinical studies. However, the routine use of outcome measures in clinical practice may be constrained by factors that are less problematic in the setting of clinical studies, such as billing issues, administration time, rater training and expertise, the need for specialized equipment, ease of administration, interrater consistency and reliability, and patient-specific factors such as a lack of effort and variability over time.2–5 Moreover, any outcome measure proposed for routine clinical use should be broadly applicable across MG subtypes defined by symptoms (ie, predominantly or exclusively ocular, bulbar, or limb) or by autoimmune target (AChR, MuSK).

This article reviews the development, attributes, and features of 5 MG-specific outcome measures with respect to their possible utility and applicability for use in everyday clinical practice for the management of patients with MG. These tools were selected based on their frequent use in MG clinical studies, their potential ease of incorporation into clinical practice, and their cross-correlation with one another.

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Physician-Evaluated Outcome Measures

Quantitative MG Test

The original 8-item Quantitative MG (QMG) test was developed and used by Besinger et al in a study of the relationship between autoantibody titers and symptom severity.6,7 The QMG was subsequently modified and expanded to 13 items by Tindall et al for use in clinical studies of the immunosuppressant cyclosporine in MG.7–9 The version by Tindall et al retained the 4-point severity scale for each item (0 = no weakness, 3 = severe weakness). However, in contrast to the version by Besinger et al, in which a predefined subset of items was used for each patient (based on symptoms) throughout the study, with a clinical score calculated by summing the individual item scores and dividing by the number of items, Tindall et al tested each patient using all assessment items. The result was a single overall QMG score generated by the sum of all item scores.6,8

Further modification by Barohn and Herbelin7 established the QMG in its current form (Fig. 1). Its interrater reliability was validated and a threshold for clinical significance was established of at least 2.6 points in response to treatment. Modifications included the substitution of a defined-volume water-swallowing item to assess swallowing earlier in disease progression and the addition of a speech test to assess the presence and time to onset of dysarthria.5,8



In its current form, the QMG includes 13 physician-rated items, each scored from 0 (no symptoms) to 3 (severe symptoms), with a total score ranging from 0 to 39. Test domains include ocular symptoms (2 items), facial/oropharyngeal symptoms (5 items, including the 2 ocular items), and nonfacial symptoms (8 items).5,7 In clinical studies of MG interventions, a threshold of more than 3.5 points has typically been used to define minimal clinically important change, and a recent study suggested that the minimal clinically important change threshold may differ according to baseline score (eg, 2 points for a baseline score of <16, and 3 points for a baseline score of >16).10

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MG Manual Muscle Test

The MG Manual Muscle Test (MG-MMT) was developed and introduced by Sanders et al11 in 2003. The MG-MMT (Fig. 2) assesses the strength or function of 30 muscle groups typically affected by MG and includes a total of 18 items, with 12 assessed bilaterally, and 6 assessed as single items (lid closure, cheek puff, tongue protrusion, jaw closure, neck flexion, and neck extension).11 Each item is scored on a 5-point severity scale, based on the severity of muscle weakness [0 = no weakness, 1 = weak/mild (25%) impairment, 2 = weak/moderate (50%) impairment, 3 = weak/severe (75%) impairment, 4 = paralyzed/unable to perform]. Bilateral scores are summed for a total item score, and all item scores are summed for a total MG-MMT score. MG-MMT scores range from 0 to 120; domains include ocular (3 items, including eyelid closure), facial/oropharyngeal (3 items), axial strength (neck flexion/extension; 2 items), and limb strength (10 items).11



Completely physician-performed, and requiring no special training beyond typical neurologist training, the MG-MMT demonstrates good interrater reliability and (based on 1655 clinic visits) correlates strongly with the QMG.11 Although both MG-MMT and QMG scores were broadly correlated with a 5-level assignment of qualitative disease severity (by a senior physician), significant scatter was observed within each severity category for both measures. Therefore, the authors concluded that the MG-MMT and QMG are better suited for assessing change in symptom severity over time (in clinical studies) than for assigning disease severity at a single time point.11

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Patient-Reported Outcome Measures

MG Activities of Daily Living Scale

The MG Activities of Daily Living (MG-ADL) Scale in Figure 3 was developed and introduced as an easily administered, 8-item questionnaire by Wolfe et al in 1999.14 As with the QMG, each item is graded on a 4-point symptom severity scale (0 = normal, 3 = most severe), with the total score ranging from 0 to 24.14 Test items emphasize the functional impact of muscle weakness (eg, the ability to comb one's hair or brush one's teeth instead of hand grip or outstretched arm strength tests) rather than its quantitation.11,14 The MG-ADL requires no special equipment or training and can be administered in 10 minutes.14



The MG-ADL test domains include ocular (2 items), oropharyngeal (3 items), respiratory (1 item), and extremity/limb (2 items).14 Based on concurrent administration of the QMG and the MG-ADL in 254 consecutive encounters in 156 patients with MG, MG-ADL scores correlated well with QMG scores.14

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MG Quality of Life Questionnaires

The original 60-item version of the MG Quality of Life (MG-QOL) Questionnaire was developed and introduced by Mullins et al in 2008.15 The goal was to develop an MG-specific QOL measure that, in contrast to more generalized QOL measures [eg, Short Form 36 (SF-36)], incorporated items on which MG had a specific impact and eliminated items having no relevance to patients with MG.15 In estimates of disease severity and impact, the MG-QOL correlated well with other validated MG severity measures (including the QMG and MG-MMT), and with the SF-36.15 When used in an MG clinical study of mycophenolate mofetil, changes in MG-QOL correlated with changes in QMG and MG-ADL, but not with changes in MG-MMT.15

The potential unwieldiness of a 60-item assessment in clinical trials and everyday clinical use led to the development of an abbreviated 15-item version, the MG-QOL15, by Burns et al12 in 2008 (Fig. 4). These 15 items were derived from the mobility (9 items), symptoms (3 items), general contentment (1 item), and emotional well-being (2 items) domains of the 60-item version.12,15 Each of the items/statements (eg, “I have limited my social activity because of my condition”) is scored by patients on a 5-point scale ranging from 0 (“not at all”) to 4 (“very much”) based on their experience over the previous 4 weeks; the item scores are summed to generate a total score ranging from 0 to 60.12



In a clinical study of mycophenolate mofetil, the MG-QOL15 correlated strongly with the SF-36, and the correlation between the MG-QOL15 and the QMG (primary outcome measure) was much stronger than that between the SF-36 and the QMG.12

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Mixed Outcome Measures

MG Composite Scale

The MG Composite (MGC) Scale, which was developed and introduced by Burns et al13 in 2008, is considered a mixed outcome measure that incorporates both physician-evaluated and patient-reported outcome items. In creating this composite scale, the developers sought to minimize the number of items (and thus administration time), to maximize the sensitivity and clinical relevance of each item, and to weight items (as recommended by the Myasthenia Gravis Foundation of America MGFA task force) commensurate with their impact on functional status, QOL, overall health status, and prognosis.13

The MGC Scale is composed of individual items from outcome measures (including the QMG, the MG-ADL, and the MG-MMT) used in clinical studies of mycophenolate mofetil as an add-on to prednisone; these items were evaluated with respect to responsiveness, concordance with global measures, score distributions, and correlations with the MG-QOL15.13 The developers explicitly rejected an approach based on the modification of existing scales in favor of selecting the “best” items from a range of scales.13 Items were then weighted based on feedback from worldwide MG specialists, based on their perception of each item's impact on function/QOL impact, overall health risk, and prognosis.13 This process led to the selection of 10 items (Fig. 5) encompassing domains, including ocular (3 items), bulbar (3 items), respiratory (1 item), neck strength (1 item), and limb strength (2 items); the MGC Scale contains a total of 6 physician-evaluated items and 4 patient-reported items.13,18 Items are scored using a 4-level severity assessment (normal/no symptoms to severe symptoms), with weighted point scores for each item summed to generate a total MGC score ranging from 0 (no symptoms) to 50 (maximum severity).13



In 2012, a task force, originally established in 1997 by the Medical Scientific Advisory Board of the MGFA, recommended that the MGC be used as an efficacy evaluation for all prospective studies of potential MG therapies, with a change of ≥3 points indicative of a clinically significant treatment effect.2 This recommendation supplanted the initial one by the task force in 2000 on the use of the QMG in clinical research, and reflected the belief that the MGC provides a better measure of overall disease severity than the QMG because of item weighting and inclusion of patient-reported items.2,16

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Table 1 summarizes the key features of the MG outcome assessment instruments described in this review.5,7,11–14 All the outcome measures included herein demonstrate interrater and test–retest reliability and, as noted in their descriptions, have been cross-correlated with other existing measures. Establishing a regular assessment schedule for each patient with MG is important to tracking patient progress and therapeutic response, and supported by integration of these tools into everyday clinical practice. Understandably, the ease of this clinical procedural change will vary depending on which outcome measure is selected and what resources are available within the practice.





One of most important reasons to incorporate one or more of these assessment instruments into routine clinical care is to improve the quality of care (and presumably, outcomes) at the individual patient level. The use of outcome assessments provides a benchmark that encapsulates disease severity and functional impact at diagnosis or initial consultation, and when applied consistently and regularly to each patient, provides important information on trends in patient symptom load and functional impact on the patient.19

Validated assessment instruments can also measure the impact of medical or surgical interventions on symptom severity and functional status of individuals or groups of patients, providing the clinician with important guidance on the success or failure of a specific clinical approach, and can help signal the need to change tactics.19 Given the use of such instruments in clinical studies (along with the cross-correlations between individual instruments), these instruments enable the clinician to “benchmark” the status of patients and their responses to interventions based on longitudinal studies of MG natural history and clinical studies of those interventions.19 Care of patients with MG has been quite varied even among very senior and experienced neuromuscular specialists, failure to use a consistent measure of clinical response prevents treating physician from objectively evaluating clinical benefit from the therapeutic interventions.

Newly developed or existing scales are being successfully incorporated into clinical practice in other areas of neurology. For example, Bethoux and Bennett address the most appropriate assessment instruments of walking function in multiple sclerosis for use in the clinic. These authors used multiple criteria and concluded that the combination of the Timed 25-Foot Walk (provider-evaluated) and the patient-reported 12-item Multiple Sclerosis Walking Scale provide the most informative assessments along with the ability to be readily adopted for clinical use.17 Similarly, Polman and Rudick compare the multiple sclerosis functional composite with the traditional “gold standard” assessment in MS clinical studies, the Expanded Disability Status Scale. Although primarily directed at the use of these scales in clinical trials, the authors note the ability of the multiple sclerosis functional composite to be administered by a trained technician instead of a neurologist, representing a significant cost savings that might drive additional routine use in the clinic.20

One tool used to evaluate the ability of multi-item assessments to generate an optimally informative single composite score is Rasch analysis.21,22 Rasch analysis has been applied to the MGC, QMG, MG-QOL15, MG-MMT, and MG-ADL.4,21,22 The MGC, MG-QOL15, MG-MMT, and MG-ADL have all been found to have a substantial “floor effect” that prevents accurate discrimination between patients with little or no symptom burden.23 In comparing these assessments, the MG-QOL15 was found to have the greatest ability to distinguish differing levels of symptom burden and was more reliable and stable than the MG-ADL.23

Outcome assessments that use exclusively physician-evaluated items (eg, QMG) may be perceived as more “objective” and typically provide quantitative results for each item. Therefore, these assessments may be especially useful in generating trend data on specific items, as well as on overall scores.19 However, the importance of outcome assessments based on patient-reported items (MG-ADL, MG-QOL15) should not be underestimated. Although traditionally considered “softer” or less objective than physician-evaluated assessments, patient-reported measures are increasingly used and accepted as similarly informative in clinical studies.24 Patient-reported items assess the functional impact of MG symptoms over time, in contrast to physician-measured items, which by necessity provide only a point-in-time “snapshot” of symptom severity. This temporal feature is especially important given the fluctuating and fatigable nature of MG symptoms.4,24

The use of patient-reported assessments may also increase the interest and ability of patients with MG to become active stakeholders in the management of their disease and tracking its progression. Moreover, the brevity and nature of patient-reported assessments could facilitate their regular use through phone or e-mail outreach, potentially making data collection more frequent than through clinic use alone.25,26 Although patient-reported assessments may not be sufficiently informative to be the sole outcome measures used in clinical management, their combination with more objective measures provides a more comprehensive picture of patient status compared with either type of measure alone.19,24,27

One approach to outcome assessment would be the use of a composite measure (MGC) comprising both physician-evaluated and patient-reported items. An alternative approach that may provide a complete picture of patient progression would be to combine one measure comprising patient-reported outcomes (MG-QOL15, MG-ADL) with one measure dependent on provider evaluations (QMG, MG-MMT).24 Based on resource considerations, the more “objective” measure might be used for a given patient on a semiannual or an annual basis (or at defined time points after a change in therapy), with the patient-reported measure applied more frequently (eg, quarterly), possibly using phone, electronic, or mail outreach; significant short-term deterioration in the patient-reported outcome measure could then flag the need for a more comprehensive assessment using a physician-evaluated measure.28

Perhaps the most important roadblock to the regular use of validated outcome assessments in clinical practice, aside from administration time, is the lack of a mechanism to cover administration costs through standard billing procedures.3 In the absence of a specific billing code, the physician/practice is forced to cover outcome assessment administration within the constraints of an already-brief (25–30 minutes) consultation, and to determine the most appropriate use of human resources for administration. Thus, a premium is placed on assessment instruments that can be rapidly administered by a clinical associate (eg, a nurse practitioner or physician's assistant), such as the MG-ADL, MG-QOL15, or the MGC; these tools also have the advantages of not requiring specialized equipment or extensive evaluator training to administer properly. At the same time, it would be important to seek help from local electronic medical record systems to incorporate these measures to make sure they are easy to use and discrete and descriptive data are easy available to review when required at subsequent visits.

One long-term approach to overcoming the challenges inherent in incorporating regular assessment into clinical practice would be to make it a component of MG standards of care. This goal could be pursued by the incorporation of regular assessment into consensus-based MG diagnostic and treatment guidelines, and by establishing standards for clinical practices specializing in MG care. The establishment of standards for clinical practices might be modeled on the Certified Treatment Centers of Excellence program of the amyotrophic lateral sclerosis association or on the accredited Care Centers program of the Cystic Fibrosis Foundation, both of which promote the goal of these patient-centered organizations to ensure high-quality evidence-based care.29,30

Given that many (or most) neurology practices have yet to incorporate validated outcome measures into routine clinical care of patients with MG, the most important point is to select and begin using the measure(s) that the clinician considers most relevant and most easily used within his or her practice.24 The seamless integration and adoption of these assessments will ensure that a physician has data to benchmark a patient, and therefore measure disease progression and response to treatment, which may result in improved patient care.

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Physicians treating patients with MG are fortunate to have at their disposal several validated measures of disease severity that cross-correlate well and can be adopted for routine clinical use. The combination of physician-evaluated and patient-reported outcome measures (or the use of a composite measure) is likely to provide a more discerning picture of patient status and response to various interventions than either type alone, an important consideration given the fluctuating nature of MG symptoms. The (current) lack of an explicit billing mechanism for administration of these instruments argues strongly for choosing those assessments that can be administered rapidly, ideally by clinical associates rather than by the treating clinician; over time, the incorporation of regular assessment into MG standards of care should facilitate improved reimbursement structures. Although there is no “right or wrong” assessment to use in clinical practice, judicious use of these tools and measures can provide the clinician with critical patient-specific information that can help guide the therapeutic approach, signal the need for a change in direction, and potentially improve the care and outcomes for patients with MG.

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outcome measures; myasthenia gravis; clinical evaluation

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