Introduction

The Amyotrophic Lateral Sclerosis Rating Scale in its revised version (ALSFRS-R) [1] is the most widely used instrument for assessing functional deficits in amyotrophic lateral sclerosis (ALS) [2]. The scale is disease-specific and encompasses 12 prompts-referred to as items-grouped into four domains to assess bulbar symptoms, limb and trunk functionality, respiratory symptoms, and the need for percutaneous endoscopic gastrostomy, non-invasive ventilation, or tracheostomy with invasive ventilation [1]. The precursor scale was initially developed as an outcome measure for clinical trials [3], but over time its revised version became commonly used in both ALS research and clinical practice [4,5,6]. Assessments were originally conducted exclusively through in-person and telephone interviews with healthcare professionals [4, 7], but self-assessments and online questionnaires are now part of standard practice [8, 9].

Functional assessment via the ALSFRS-R is one of the most significant outcomes in clinical ALS trials, both because surrogate parameters such as neurofilaments have only recently become available and because this method is accepted for determining clinically meaningful outcomes [10]. In addition, the scale allows for modeling of individual disease courses [11, 12], can predict survival [13], and supports the staging of ALS as done with Milano-Torino (MiToS) functional staging or the King's system [14]. Although the second is not based on the ALSFRS-R score, it can be deducted from it with 92% concordance [15]. Since cognitive and executive deficits occur within the ALS spectrum and the disease pathophysiologically overlaps with frontotemporal degeneration, functional assessments in studies are often complemented by questionnaire-based cognitive tests, e.g., the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) [16]. The further inclusion of disease-specific quality of life instruments such as the ALS Assessment Questionnaire ALSAQ-40 [17], or more generic tool like the EuroQol 5 Dimension (EQ-5D) [18], contribute to a comprehensive approach to ALS research.

Although the ALSFRS-R is a validated instrument with high inter-rater and intra-rater reliability [4, 9, 19], design inconsistencies have been reported in both the description and classification of items in the ALSFRS-R [20, 21]. Recent observations revealed substantial deviations in consecutive assessments [22] and inconsistent application of the scale, particularly in the area of respiration [23]. Due to a lack of consistent standard operating procedures, the original ALSFRS-R may not adequately represent functional deficits [24]. Close analysis of the scale suggests that the original ALSFRS-R falls short of meeting all the conceptual requirements placed upon it [25, 26]. Furthermore, several variants of the same scale have evolved and circulated over time in Germany, at least. The existence of scale variants may be explained by the absence of a validated German-language version of the ALSFRS-R. As a result, translation of the ALSFRS-R has primarily taken place at the initiative of individual institutions. Alternately, researchers often use a shortened form of the ALSFRS-EX. This extended scale is a version of a self-assessment test, available in German, with three items added [27]. While the ALSFRS-EX mitigates the floor effect associated with the ALSFRS-R score, it falls short of resolving the fundamental issues in need of addressing.

Consequently, there have been calls not only in Germany but around the world to refine, harmonize, and revise the ALSFRS-R in terms of language accuracy [22, 24, 25]. As it is used as an endpoint in clinical trials and plays a crucial role in monitoring disease progression in routine care for individuals with ALS, overcoming the scale’s methodological shortcomings is paramount to its continued use in the future.

Raters who participate in clinical trials typically undergo ALSFRS-R training based on the guidelines of different certifying organizations; namely those of the Northeast ALS Consortium (NEALS) in association with the Barrow Neurological Institute (BNI), or the European Network for the Cure of ALS (ENCALS). However, demand for an internationally consistent ALSFRS-R scale has been tempered by divergent training content and the observation that raters’ skills may decrease over time [22]. Another factor that might further comprise the quality of data assessment is the lack of available ALSFRS-R training in languages other than English. To compensate for any ambiguity surrounding the description of individual items and reply options within the scale, and to reduce training requirements for conducting assessments, explanatory comments have already been added to several version of the scale [19, 27, 28].

Methods

Definition of the terms “version” and “variant”

Over the course of developing an optimized version of the ALSFRS-R, it became evident that the terms “version” and “variant” have to be distinguished. An ALSFRS-R “version” is defined relative to its place in the evolution of the scale. The predecessor of ALSFRS-R, for example, is the ALSFRS version. Subsequent versions of the ALSFRS-R include the ALSFRS-EX and validated translations in various languages [29,30,31,32,33,34,35,36,37] (which raise previously mentioned problems of interpretation). In contrast, “variants” are slight deviations that occur within the original scale. For example, variants may emerge as the result of parallel translations, adaptations by different institutions, or simply through truncation.

Consensus building

A seven-step consensus process with the aim of optimizing the ALSFRS-R was carried out between October 2020 and December 2021 (Fig. 1). The initiative was conducted by members of the “German ALS/MND-NET” – a clinical and scientific network of ALS/motor neuron disease centers with 27 sites in Germany, two partners in Switzerland and one partner in Austria. This consensus group encompassed 18 ALS experts, each with long-standing expertise in ALSFRS-R assessments and ALSFRS-R certifications from at least one, and most often two, organizations.

Fig. 1
figure 1

seven-step consensus process to develop the ALSFRS-R-SE

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For linguistic revision and translation into English, a technical editor, a professional translator, and first language editor were brought in, neither of whom have backgrounds in ALS.

Design

A consensus group design [38] was used to develop an optimized version of the ALSFRS-R scale. To assess the existing ALSFRS-R variants in circulation, more than 120 neurologists, researchers, and study nurses within the MND-NET were contacted via e-mail and asked to share the German-language ALSFRS-R forms that they were using at the time.

Preconditions

Optimizing the ALSFRS-R scale to closely adhere to the standard English-language version [1] took the following factors into consideration: (1) Since the assessment process conducted by healthcare professionals and the self-assessments performed by patients and patient caregivers are well established, the ALSFRS-R should be accessible to both healthcare professionals and patients. In order to facilitate this, there should be no ambiguity surrounding the language of the individual diagnostic items. (2) Adding explanatory language to the scale items and reply options may reduce ambiguity as well as the need for ALSFRS-R training. (3) As ALSFRS-R assessments through computers, mobile devices, and other remote digital means are increasingly common, it is important to consider the scale’s use and suitability for these media.

Results

Status quo of German ALSFRS-R variants currently in use and the process towards consensus

Nine German language variants of the ALSFRS-R were collected, three of which already contained instructions for self-assessment. Six variants were individual translations of the original English version for external evaluation. Figure 2 depicts the schematic process of consolidating the pre-existing English scale and nine German variants of the ALSFRS-R. The additional files includes the German and English-language versions of the ALSFRS-R-SE that emerged from the consensus process [see Additional file 1 and Additional file 2].

Fig. 2
figure 2

Overview of origins of ALSFRS-R versions and variants and the collection process. A total of 20-ALS centers responded to the request to provide extant ALSFRS-R versions and variants. Nine different German variants and the original English version by Cedarbaum et al. [1] were collected. Translated variants differed in terms of wording. Two variants were designated for self-assessment. Several ALS centers use a shortened variant of the ALSFRS-EX [27]

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Item structure of the ALSFRS-R and impact of assistive measures

The ALSFRS-R is a functional scale that measures deviations from unrestricted or "normal" motor functioning as caused by ALS. The two major symptoms that present in ALS and limit functionality in specific areas are muscle weakness and stiffness. Muscle weakness is caused predominantly by the loss of the second motor neuron. Muscle stiffness often, but not always, results from spasticity, indicating degeneration of the upper neuron [39]. If possible, complaints that are not related to ALS-such as orthopedic issues that might affect functional areas-should be excluded from the evaluation. There are two ways to do this: Firstly, functionality should always be assessed in relation to the person’s status before the onset of ALS symptoms; and secondly, conditions that are obviously unrelated to ALS should be excluded from the assessment even if they lead to functional impairment.

To ordinally scale the loss of functionality, anchor points grade functionality from 0 to 4 for each item. To determine an ordinal score, the scale considers whether there is an increased need for assistance or assistive devices. The most unambiguous scores are 4, which designates unrestricted functionality, and 0, which designates a complete loss of functionality. Whereas the latter score can be identified by the full-time use of assistive procedures or devices, differentiating between intermediary scores can be difficult. A mild impairment (score 3) should reflect a condition that does not yet require compensatory help. Score 2 is characterized by intermittent use of compensatory measures. Score 1 is given if assistive procedures or devices are needed in all instances, and independence is severely reduced but not entirely lost. These considerations apply to the first nine items and to item 11. With regard to respiratory items 10 and 12 functional compensation (i.e., mechanical ventilation) is implied either at the 0-point level (item 10: dyspnea) or already at the 3-point level (item 12: respiratory insufficiency). This change does not eliminate the structure of those items, but instead shifts the anchor points in a given direction.

The specific moment in which personal assistance, technical support, or other substituting procedures are first used may be influenced by several factors, including the personal convictions of the affected person and the availability of assistive options such as PEG or mechanical ventilation. Since circumstantial considerations do not necessarily reflect an affected person’s functional capacity, they should not overrule the implicit logic of an item.

Explanatory introduction

To illustrate the operation of the ALSFRS-R and to standardize its application, an explanatory introduction was included (see bottom of Table 1). The introduction instructs any individual using the ALSFRS-R-health care professional, family member, or a patient-to carefully review the response options and their corresponding comments and to select the most applicable answer. With regard to pre-existing functional limitations, the recommendation is to score the item as “normal” or "unrestricted" by ALS (4 points). This recommendation should be waived only if ALS symptoms have exacerbated a pre-existing impairment. Once an approach is chosen, it should be followed consistently across all items and in future ALSFRS-R assessments.

Table 1 ALSFRS-R versus ALSFRS-R-SE after consensus process
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Revision of items

Table 1 compares the revised items in the ALSFRS-R-SE to those in the original ALSFRS-R scale. All changes are classified and evaluated. Adjustments made to individual items within the four scoring domains are described in the following sections. The wording of the English and German scales may not be perfectly identical due to linguistic differences.

Bulbar function (Items 1–3)

Item 1 (Speech): In contrast to the frequent use of the word "language" in the German variants, this discrepancy was balanced by consistent use of the term "speech." In the explanatory notes, "speech" was further subdivided into "phonation" and "articulation” in order to cover these both aspects of speech production. Item 2 (Salivation): Adverbs such as "occasionally" or "often" are used to describe the frequency of an occurrence. This also applies to saliva collection and its associated methods, such as use of a tissue. Item 3 (Swallowing): To more precisely describe this item, explanations were augmented to include descriptions such as "more careful swallowing" or "smaller bites." The reference to an "early eating problem" was replaced by the more specific "minor swallowing problem." Differences between various kinds of food consistencies were clarified with examples. Language concerning the use of an enteral feeding tube was explicitly contextualized in terms of dysphagia and explained in general terms.

Fine motor function (Items 4–6)

Item 4 (Handwriting): An explanation appended to this item clarifies that it refers to the dominant (writing) hand in the usual posture. The use of writing aids was included within the criteria for point 2. The ability to write only one’s signature is considered applicable to meet the criteria for score 1. Item 5a (Cutting food and handling utensils, without gastrostomy): The altered use of cutlery in the context of a functional limitation is explained with examples. Adverbs such as “on occasion” or “on most occasions” indicate the degree of impairment or the need for help. For purposes of harmonizing the complete loss of functionality across all items, score 0 was defined as total dependence with regard to all activities in question. This includes elimination of imprecise descriptions, such as the phrase "must to be fed." Item 5b (Cutting food and handling utensils, with gastrostomy): The extent to which a patient is dependent from a caregiver when handling a feeding tube is specified by score points 1 and 2. Item 6 (Dressing and hygiene): The degree to which assistance or accommodations are needed for certain tasks related to dressing and personal hygiene (such as wearing clothes that are easy to put on and remove, or showering while sitting down) are explained in greater detail.

Gross motor functions (Items 7–9)

Item 7 (Turning in bed and adjusting bed clothes): The explanation to this item takes into account the gradual transition from independence without increased effort (score 4) to any need for personal assistance (scores 1 and 0). It is also explained how to assess the effort it takes to perform the activity without help (scores 3 and 2). Item 8 (Walking) Problems with walking are further described to include issues of unsteadiness and stumbling. The use of walking aids is explicated, and the explanation specifically accounts for patients who must hold onto objects for support. The ability to stand (e.g., for transfer) as a targeted leg movement is introduced as an explanatory example (score 1). Item 9 (Climbing stairs) For this item, language is included to account for the necessity of a handrail (score 1) and non-essential use of a handrail (score 2).

Respiratory function (Items 10–12)

Item 10 (Dyspnea): The phrase "dyspnea and shortness of breath" is consistently used to describe symptoms. Score 3 designates the occurrence of these symptoms during normal walking or moderate (physical) activity. Score 2 symptoms, by contrast, are related to low-intensity activities, which now include “talking for longer periods of time.” The actual use of non-invasive ventilation to treat dyspnea and shortness of breath unambiguously lead to score 0. Item 11 (Sleep disturbances due to breathing problems, formerly “orthopnea”): The explanation for this item specifies that if mechanical ventilation is usually provided, but sleep is still possible without it, breathing should be assessed without the use of ventilation. As the term "orthopnea" does not accurately reflect the spectrum of sleep-related symptoms caused by respiratory impairment, we have chosen to revise the title of this item. Moreover, as reflected in the criteria for score 3, patients may be able to tolerate a flat lateral position while being unable to lie on their back. Sleep disturbances due to respiratory impairment have to be considered most severe when mechanical ventilation is indispensable to achieve acceptable sleep quality (score 0). Item 12 (Mechanical ventilation): Continuous positive airway pressure for treatment of obstructive sleep apnea must not be equated with non-invasive ventilation (NIV). Score 0 is assigned when invasive ventilation procedures are in use. Scores 1–3 are calculated via the amount of NIV use during a 24-h period. If a period equals or exceeds the duration of nighttime sleep but is below permanent dependence (22 h), score 2 is assigned.

Discussion

We hereby present the ALSFRS-R-SE, a self-explanatory revised scale that has been optimized for use by health care professionals, patients, and caregivers. By adhering as closely as possible to the well-established standardized English version, and by supplementing certain items with explanatory comments and linguistic adaptations, we have attempted to reduce a number of ambiguities which have either developed with several German translations of the ALSFRS-R or are already immanent to the original version of the scale. This multistep process was carried out by a group of experts from 13 German ALS centers, who worked together to both harmonize and sharpen the wording of the ALSFRS-R translation. Through additional specifications, explanations, and examples, it was attempted to reduce the room for interpretation within the original ALS-FRS-R. Professionals from outside the medical field reviewed the ALSFRS-R-SE for comprehensibility and consistency.

With its straightforward language, this self-explanatory version of the ALSFRS-R can be used in a wide range of settings, including in a clinical context with healthcare professionals, or by patients either in a medical venue or remotely.

Only necessary and mostly minor adjustments were made to the original English scale.

Adapting the ALSFRS-R-based remote assessment process requires optimizing both the scale itself and the relevant standard operating procedure [40]. Recent observations by medical professionals indicate that digital platforms and mobile applications have gained substantial acceptance by people with ALS and that their use continues to broaden [6, 41, 42]. However, in order to collect high-quality data via remote digital tools, it is necessary to clearly present and differentiate the questions within the scale.

The suitability as a remote assessment of the ALSFRS-R scale as a primary endpoint in clinical trials (or one of various secondary outcome parameters) would be based on patient-friendliness and scrutinizing the self-explanatory language of the scale. Furthermore, digital instruments-whether computer or smartphone-based-fertilize the ground for remote use of the ALSFRS-R-SE, potentially leading to more frequent assessments and a higher density of ALSFRS-R data [9].

The basis for developing this scale was the fact that the ALSFRS-R has been increasingly used by nurses in the context of regular care as well as by patients themselves, even though the scale was originally devised for health care professionals involved in clinical trials. The expanded use of the scale outside of its original context led to compromises and a reduction of data quality, both issues that have been addressed via the proposed self-explanatory version of ALSFRS-R. We anticipate that this scale will offer additional advantages within clinical trials, as its self-explanatory design reduces the need for rater training.

Despite its clear benefits, the ALSFRS-R has some fundamental limitations that have not been resolved by the current modification and should be highlighted. Sensitivity to disease progression is limited by both the granularity of the items and the frequency of assessment. This limits the ability to depict very rapid and very slow disease progression [43]. While digital self-assessment may increase data density by allowing for more frequent capture [44,45,46] and while the ALSFRS-R-SE unifies the structure of individual items, there will still be functional changes not covered by the score. Depending on progression rate and phenotype, the sub-scores of the ALSFRS-R will have a different impact on the total score and prognostic models, prompting the suggestion to focus statistical analysis on these sub-scores rather than the total score [26, 47]. Another factor constraining the validity of a self-reported score can be cognitive deficits or affective changes. Identifying such factors is thus essential. However, the ALSFRS-R-SE used by caregivers can be a possible solution to this issue if cognitive deficits are known and recorded.

A clear limitation of the proposed ALSFRS-R-SE is the temporary constraint on the comparability of data gathered from the ALS-FRS-R-SE with those collected using the established English version of the ALSFRS-R. Thus, further studies are needed which apply both versions of the scale in a larger German patient cohort, including evaluation of the ALSFRS-R-SE with regard to its suitability for digital capture and utilization in a mobile application [44, 48]. Despite the uncertainty regarding data comparability, we are convinced that it is justified, and even necessary, to deviate from traditional scoring in order to improve data quality.

Conclusions

A German consensus group developed an annotated version of the ALSFRS-R scale that is self-explanatory and unambiguous. Given the lack of a standardized German ALSFRS-R, the focus was on creating a German version, but shortcomings of the scale were improved and a qualified English translation was made. The resulting ALSFRS-R-SE can thus be used by healthcare professionals, patients, and their relatives, and is also readily available in a remote setting.