Patient-Reported Outcome Measures in Neuromuscular Disorders 

Patient-reported outcomes (PROs) are those reported directly by patients concerning their perception of their health (eg, symptoms such as pain and fatigue), functional status (eg, disability), and quality of life (QoL).¹ Patient-reported outcome measures (PROMs) are instruments that capture and quantify PRO data in a standardized, consistent manner. As such, PRO data can be compared across patient populations and over time, providing valuable insights and holistic assessment of the effects of symptoms on the individual.² PROMs regard patients as experts on their experiences and enable their participation in clinical decision-making.³

PROMs can be used in routine clinical care, clinical trials, and health policy assessments.¹ When used in the clinical setting, PROMs supplement the patient interview and examination, and may save time, allowing the provider to focus on counseling and education.⁴ In short, PROMs improve both provider communication and patient satisfaction by helping providers ask effective, patient-centered questions.^4-6 An ideal PROM must be easy to use and interpret; include relevant, meaningful items; be responsive to change in status; and reflect the patient’s status reliably.⁴

For PROMs used in clinical trials to assess treatment effectiveness, it is necessary to have a detailed understanding of their measurement properties. Both the Food and Drug Administration (FDA) and European Medicines Agency recommend the incorporation of PROMs into clinical trials to support labeling claims and note that PROMs must demonstrate criterion, construct, and discriminant validity; test–retest reliability; and internal consistency.^7,8

PROMs may be generic or disease-specific (ie, condition-specific). Generic PROMs lack sensitivity to disease-specific outcomes, but maximize comparability and have greater applicability across health conditions.^7,9 Neuromuscular diseases are often chronic and progressive and affect various aspects of people’s lives that are not captured by a simple symptom inventory. Disease-specific PROMs capture the unique symptoms and issues faced by people with neuromuscular disease and maximize content validity.^7,9 Disease-specific PROMs are more sensitive to changes in health status than generic PROMs; have greater face validity, credibility, and responsiveness to changes; and are better for determining treatment outcomes.^3,10

A comprehensive review of all PROMs used to assess the impact of neuromuscular disorders is not only impossible, but impractical. In the following, we focus on neuromuscular PROMs that are commonly used in clinical settings and as clinical trial endpoints. The Table includes a more extensive list of PROMs, including their strengths and limitations.

PROMs Used in Amyotrophic Lateral Sclerosis

The Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) is not a true PROM because it is administered by an assessor but is commonly used to assess function in people with amyotrophic lateral sclerosis (ALS). This 12-item scale has 4 subdomains (bulbar, fine motor, gross motor, and respiratory), with each item scored from 0 to 4 points, with a maximum of 48 points possible.¹¹ Used as a primary and secondary outcome across ALS clinical trials and in routine clinical practice, the ALSFRS-R is the gold standard measure of functional disability and disease progression in ALS.¹² The rate of decline on the ALSFRS-R has been used to predict survival and to determine fast vs slow disease progression.¹³ This ordinal, non–linearly weighted scale may not be sensitive to measure meaningful change, and symptomatic treatment may result in improved scores despite clinical progression.^12,14 The ALSFRS-R has limitations as an instrument, and it may not be as helpful as a tool to assess function in people with ALS with severe motor disability, less severe bulbar disability, or less respiratory dysfunction.¹⁵ The self-entry version of the ALSFRS-R (ALSFRS-RSE) is a PROM, and correlates strongly with the ALSFRS-R.^16,17

The Rasch-built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is a 28-question validated, unidimensional, linear PROM assessing overall disability level with high reliability.^18,19 ROADS is free, is in the public domain, has psychometric advantages over the ALSFRS-R and ALSFRS-RSE, and has been demonstrated to perform similarly to the ALSFRS-RSE.¹⁹ ROADS has been used in numerous clinical trials and is being adopted for clinical use due to its ease of administration and clinical meaningfulness. 

The 40-item Amyotrophic Lateral Sclerosis Questionnaire (ALSAQ-40), a disease-specific health-related QoL instrument, is a valid, reliable PROM that tests 5 domains (communication, eating/drinking, physical mobility, activities of daily living independence, and emotional functioning).²⁰ ALSAQ-40 results have been used as a secondary endpoint in many clinical trials. The ALSAQ-5 is a shortened, 5-item version of ALSAQ-40, with each item taken from 1 of the 5 domains, which performs similarly both cross-sectionally and longitudinally to the lengthier 40-item ALSAQ-40.^21-23 A recent review of 15 PROMs used to measure QoL in ALS identified ALSAQ-40 and ALSAQ-5 as both having strong psychometric properties and moderate to high quality of evidence.²⁴

Although PROMs are used routinely in ALS clinical trials, they can be incorporated successfully into routine clinical practice and correlate with the ALSFRS-R. A recent study demonstrated that the generic Patient-Reported Outcomes Measurement Information System (PROMIS), the PROMIS-10, and the Quality of Life in Neurological Disorders (Neuro-QoL)–fatigue subscale can be used to measure physical, mental, and social health status.²⁵

PROMs Used in Neuropathies

Diabetic Neuropathy

The neuropathy-specific Neuro-QoL is a 27-question tool for assessing the impact of diabetic peripheral neuropathy and foot ulcers on QoL.^26-29 This instrument features 7 subscales: painful symptoms, paresthesia, reduction or loss of ability to feel temperature or objects with the feet, unsteadiness, daily activity limitations, interpersonal problems, and emotional distress. The questionnaire includes 6 QoL questions and 2 on the overall impact of neuropathy. 

The Norfolk Quality of Life–Diabetic Neuropathy (Norfolk QoL-DN) is an instrument that captures symptoms related to small, large, and autonomic fiber involvement in diabetic neuropathy.³⁰ The Norfolk QoL-DN has been validated in large multicenter studies and correlates with the Total Neuropathy Score (a composite score that combines information based on symptoms, clinical signs, nerve conduction studies, and quantitative sensory tests).^31,32 The Norfolk QoL-DN questionnaire has 47 items, is self-administered, and explores the relationship between diabetic neuropathy symptoms and QoL. It is more commonly used in clinical trials due to the length of the questionnarie. This instrument has been validated for use in transthyretin familial amyloid polyneuropathy, and subsequently used in several large phase 3 trials.^33-35

The Diabetic Peripheral Neuropathic Pain Impact measure (DPNPI) is a valid, reliable PROM that measures the impact of diabetic peripheral neuropathy pain on 3 domains: physical functioning, sleep, and daily activities.³⁶ This 18-item questionnaire takes ~10 minutes to complete, with a lower score indicating better health. However, the DPNPI does not evaluate psychological or social aspects of pain related to diabetic peripheral neuropathy. This instrument may be used to capture the efficacy of treatment.

Chemotherapy-Induced Polyneuropathy 

The Functional Assessment of Cancer Therapy (FACT) group collaborated with the Gynecologic Oncology Group (GOG) to develop FACT/GOG-neurotoxicity (FACT/GOG-Ntx), a key tool that evaluates the severity and effects of chemotherapy-induced polyneuropathy (CIPN) on patient’s lives in relation to sensory, motor, and auditory challenges.³⁷ An 11-item neurotoxicity section was added to the core QoL FACT-GOG questionnaire. Each question is rated on a 5-point scale in which higher scores (range, 0 to 52) reflect better outcomes.³⁸ The FACT/GOG-Ntx has been translated into multiple languages, but studies validating its effectiveness across cultures are lacking. Strengths include a comprehensive examination of functional consequences of CIPN, strong psychometric properties, and a focus on immediate outcomes. However, the FACT/GOG-Ntx tool has drawbacks, such as limited ability to identify subtle differences and failure to recognize important long-term effects (eg, sleep issues, balance problems, and decreased physical activity). Furthermore, the FACT/GOG-Ntx tool may not address secondary effects of neurotoxicity on daily functioning and QoL.³⁹

The Quality of Life Questionnaire–chemotherapy-induced peripheral neuropathy (QLQ-CIPN20) is a 20-item tool that enhances the European Organization for Research and Treatment of Cancer core QoL questionnaire and serves as a primary outcome measure for CIPN in research. This tool focuses on sensory, motor, and autonomic factors, with higher scores (range, 0 to 100) indicating worse CIPN.⁴⁰ Individuals rate symptom severity over the past 7 days on a 4-point scale. Advantages of this tool include feasibility for multicultural use, with translations and psychometric evaluations available for Arabic, Korean, and Chinese populations; however, cross-cultural validity is unassessed. The QLQ-CIPN20 reliably detects subtle changes in proximal CIPN symptoms. Disadvantages of this tool include failing to capture sleep disturbances, balance impairment, or reduced physical activity, which are substantial distal CIPN outcomes.³⁹ These exclusions may disregard important neurotoxicity effects on daily functioning and QoL.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy

The Inflammatory Neuropathy Cause and Treatment (INCAT) disability scoring system is used to assess activity limitations in people with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).^41,42 The questionnaire assesses both upper and lower extremities on a scale (range, 0 to 5) based on how affected the limb is during activity. The INCAT tool is easily administered in under 2 minutes. A limitation of this questionnaire is that it does not evaluate fatigue or proximal arm weakness. Several recent prospective controlled trials of immunotherapies in people with CIDP have used change in the INCAT disability score (a measure of activity limitation) as the primary endpoint.^43,44

The Inflammatory Rasch-built Overall Disability Scale (I-RODS) was developed using the Rasch measurement model to assess disability in people with CIDP. The Rasch-built Overall Disability Scale (RODS) was introduced and validated in 2011.⁴⁵ I-RODS demonstrates reliability and sensitivity in measuring disability across various domains, including motor and sensory function. This development marked a considerable step in creating a more precise tool for monitoring disease progression and assessing treatment outcomes in CIDP. The I-RODS has also been shown to have greater responsiveness compared with the Rasch-transformed Medical Research Council sum score and the Rasch-transformed modified INCAT sensory scale for both CIDP and Guillain-Barré syndrome.⁴⁶ I-RODS was found to have significant correlation with grip strength as a linear objective measure.⁴⁷

The Chronic Acquired Polyneuropathy Patient-Reported Index (CAPPRI) is a PROM developed to assess the effects of CIDP, which focuses on symptoms often underrepresented in traditional clinical evaluations (eg, pain, fatigue, and QoL).⁴⁸ CAPPRI provides a more comprehensive view of the effects of the disease by capturing the multidimensional burden on patients. CAPPRI was validated through psychometric testing, ensuring its reliability and sensitivity in tracking symptom changes over time.⁴⁹

Multifocal Motor Neuropathy

The RODS for Multifocal Motor Neuropathy (MMN-RODS) is a 25-item questionnaire designed to evaluate disability across various activities.⁵⁰ Multifocal motor neuropathy often presents asymmetrically and distally, and this scale is specifically intended to capture these unique features of the disease. 

Charcot-Marie-Tooth Disease

Because of the multiple subtypes of Charcot-Marie-Tooth disease (CMT), symptoms and associated disabilities in individuals with CMT can vary widely. The Charcot-Marie-Tooth Health Index (CMTHI) was developed to capture the impact of various disease subtypes.⁵¹ Comprising 127 questions, the CMTHI addresses the symptoms and functional domains most affected by CMT and demonstrates high internal consistency and test–retest reliability. The CMTHI can discriminate between levels of disability measured with the CMT Examination Score and the Mobility–Disability Severity Index. The Accelerate Clinical Trials in Charcot-Marie-Tooth Disease study used the CMTHI as a PROM.⁵²

PROMs in Myasthenia Gravis

The Myasthenia Gravis Activities of Daily Living (MG-ADL) scale evaluates 8 symptoms across 4 domains (bulbar, respiratory, limb weakness, and ocular), each with 4 response options scored from 0 to 3.⁵³ Total scores range from 0 (no impact) to 24 (severe impact), indicating effects of myasthenia gravis (MG) on daily living. Limitations include equal weighting of symptoms, which may not represent patient experiences. However, the MG-ADL provides valuable insights into MG symptoms, and is commonly used in clinical practice and clinical trials to assess symptoms and treatment responses.⁵⁴

The Myasthenia Gravis Symptoms Patient-Reported Outcome (MG Symptoms PRO) is used as a primary or secondary endpoint tool that captures core MG symptoms in clinical trials as a measure of treatment efficacy and in clinical practice to monitor symptom severity.⁵⁵ This instrument uses a modular approach and includes 5 scales that track the severity of muscle weakness: fatigability, physical fatigue, bulbar weakness, ocular weakness, and respiratory weakness. MG Symptoms PRO is the only MG-specific measure assessing physical fatigue. Items are graded on a 4-point scale for severity or a 5-point scale for frequency based on symptoms from the past 7 days. Higher scores indicate more severe symptoms. These scales help define accurate clinical trial endpoints, demonstrating treatment efficacy on specific symptoms, and potentially guiding inclusion criteria without excluding participants with focal weakness. Although useful in clinical practice for highlighting symptoms of interest, the 42-item questionnaire is too lengthy for routine clinical use.⁵⁶

PROMs in Muscle Disease

Myositis

Myositis encompasses dermatomyositis, polymyositis, inclusion body myositis, and overlap myositis. Because of the variability of these conditions, the PROMs used in clinical trials and clinical practice are diverse. A recent review of 20 different dermatomyositis trials found that PROMs are underused.⁵⁷ The Myositis Working Group identified 5 patient-prioritized domains that should be considered for measurement in clinical trials and cohort studies: fatigue, pain, level of physical activity, physical function, and muscle symptoms.⁵⁸

The PROMIS, developed by the National Institutes of Health, is unique in that it captures disease impact across a range of physical, emotional, and social health domains.⁵⁹ The PROMIS comprises physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles, pain interference, and pain intensity. The PROMIS Pain Interference, Fatigue, and Physical Function instruments have recently been demonstrated to have excellent test–retest reliability and construct validity in a large cohort of participants with idiopathic inflammatory myopathies.⁶⁰ The 20-item PROMIS Physical Function short form (PF-20) demonstrated good correlation with previously accepted PROMs and showed high compliance and feasibility in people who self-administered the tool remotely using smartphone- or web-based technology.⁶¹ Each of the 20 items is scored on a 5-point scale. A single center study demonstrated that the PF-20 was valid, reliable, and responsive to clinical change in myositis.⁶² However, content validity was not fully studied. The PF-20 can easily be used clinically and as a clinical trial endpoint.

The Health Assessment Questionnaire–Disability Index (HAQ-DI) is a generic disability PROM used frequently to evaluate myositis functionality.^59,63 The HAQ-DI consists of 8 categories: dressing and grooming, rising, eating, walking, hygiene, reach, grip, and common daily activities. The HAQ-DI was used in one of the largest myositis randomized controlled trials: Rituximab for the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis (NCT00106184).⁶⁴

The Myositis Activities Profile (MAP) was developed to better understand myositis disease activity and limitations of daily living.^59,65 The MAP assesses 31 activities divided into 4 subscales and 4 single questions. When initially validated in individuals from the United States with dermatomyositis or polymyositis, the MAP showed a moderately strong correlation with the HAQ in evaluating the effects of the diseases on well-being.⁶⁶

The Inclusion Body Myositis Functional Rating Scale (IBM-FRS) is a brief, 10-item functional rating scale. The IBM-FRS was developed specifically for inclusion body myositis using the ALSFRS-R as a precursor.⁶⁷ The IBM-FRS shows comparative correlation with physical examination testing, including voluntary isometric contraction, manual muscle testing, and handgrip dynamometry. 

Muscular Dystrophies

Limb-Girdle Muscular Dystrophy. The Limb Girdle Muscular Dystrophy Health Index (LGMD-HI) aims to capture the physical, emotional, and social challenges faced by individuals with limb-girdle muscular dystrophy (LGMD) and serves as a tool for monitoring disease progression, evaluating treatment outcomes, and guiding personalized care strategies.⁶⁸ The LGMD-HI includes 15 subscales and 97 items. Given its length, it is not used frequently in clinical practice.

Generic PROMs have also been used in the evaluation of individuals with LGMD, including the Individualized Neuromuscular Quality of Life (INQoL) scale.⁶⁹ This measure has been used for various muscular dystrophies. The INQoL scale consists of 45 questions divided into 10 sections to evaluate muscle disease symptoms and their impact on activities of daily living. In people with LGMD, a significant correlation was observed between the INQoL Activities of Daily Living subcategory and the 6-minute walk test. INQoL total scores also showed significant correlations with ankle dorsiflexion and total manual muscle testing scores.

Myotonic Dystrophy. The Myotonic Dystrophy Health Index (MDHI) is a disease-specific PROM which estimates overall disease burden and the impact of key symptomatic themes in people with myotonic dystrophy type 1.⁷⁰ Multiple physical function assessments showed correlations with both the motor and nonmotor subscales of the MDHI when compared with clinical measures.⁷¹

Facioscapulohumeral Muscular Dystrophy. The Facioscapulohumeral Muscular Dystrophy–RODS (FSHD-RODS) includes 32 items that focus on the activity and limitations experienced by individuals with facioscapulohumeral muscular dystrophy (FSHD).⁷² The instrument has demonstrated strong reliability and validity in testing with patients worldwide.⁷³ However, the FSHD-RODS may have limitations (eg, need for additional cross-cultural validation, further definition of responsiveness) when used to repeatedly assess symptomatic aspects.

The Facioscapulohumeral Muscular Dystrophy Health Index (FSHD-HI) was developed to assess symptomatic burden and to demonstrate treatment response.⁷⁴ This valid, reliable instrument contains 14 subscales that measure physical, mental, and social health. Unlike many other PROMs, the FSHD-HI is designed to assess disease impact across a range of symptomatic areas, including those related to extraskeletal manifestations of FSHD (eg, emotional health, body image, pain). In addition, the FSHD-HI has been used as a secondary outcome measure in several clinical trials.^75,76

Conclusion

PROMs are used routinely in assessment of people with neuromuscular disorders, both clinically and in clinical trials. Regardless of the instrument selected, using a PROM enables individuals to self-report on the impact of their condition on function and QoL, as well as their overall perception of disease status. From the time of their development in the 1990s and early 2000s, PROMs have been routinely used for the assessment of neuromuscular disorders, and their use will continue to grow and evolve.