Conceptual work and HRQoL domains mapping.

Data extraction was performed by two reviewers (AG and ED) and verified by a third reviewer (RR) using a bespoke electronic form.

We extracted key HRQoL domains from the MS-specific HRQoL instruments included in the review and mapped them using the HRQoL domains proposed by Leidy et al. [10]. All (sub)domains included in at least one of the tools cited in the selected literature were considered.

For each (sub)domain, we assessed item-related content to ensure alignment with its conceptual framework and to refine its characterization within the theoretical model. The identified (sub)domains were then illustrated in a figure, with revisions made to names and redundant (sub)domains consolidated.

The provisional HRQoL figure was reviewed during a steering committee (SC) meeting and revised based on feedback from the SC members. Subsequently, the figure was discussed with focus group facilitators to develop focus group meeting (FGM) guides and assist participants in understanding the structure of the domains.

Meeting with the ECT for finalizing the FGM guides.

Ten days before the meeting, ECT members received the two FGM guides in order to read and comment on them individually. Both consist of five sections which investigated the impact of MS on HRQOL. Field notes were taken and integrated accordingly to the issues identified to modify the guides.

FGM enrolment procedure and conduct.

Investigators at each participating centre identified potentially eligible PwMS from their database and invited them to participate in the study. Eligible MS HPs were identified by the SC from the participating centres and subsequently invited to join. FGM participants were selected through purposive sampling to ensure a broad range of perspectives and opinions. Participants were drawn from two geographic regions of Italy (North and South) and varied in terms of age, gender, education, and, for PwMS, neurological impairment (based on the Expanded Disability Status Scale, EDSS [56]), and years since MS diagnosis.

PwMS were included if they were at least 18 years of age, fluent in Italian, and provided written informed consent. Exclusion criteria for PwMS included severe cognitive impairment, as assessed by the referring neurologist, and an inability to communicate effectively.

HPs were eligible if they had experience in the care of pwMS (i.e., working in clinical or rehabilitative specialized settings and actively involved in the assistance, care, and support of PwMS), were fluent in Italian, and provided written informed consent.

Each FGM included 6–10 participants and two facilitators (AMG and GDD) and was conducted online via Zoom to enhance accessibility and feasibility for PwMS. Sessions followed a semi-structured guide covering pre-specified topics, were audio-recorded, fully transcribed, and subsequently reviewed by participants for validation.

Analysis.

Content analysis was used to code the FGM transcripts, employing a combination of deductive and inductive approaches. The deductive process, informed by findings from the literature review (existing HRQoL domains), applied category labels consistent with the literature when appropriate. Simultaneously, the inductive approach enabled the identification of novel themes that emerged directly from the data. This dual approach began with a deductive framework to structure the initial analysis while incorporating inductive coding to capture insights not anticipated in the literature, ensuring a more comprehensive and nuanced understanding of the data.

A line-by-line coding method ensured thorough and detailed analysis. A three-step coding scheme was implemented: Two researchers (AMG and GDD) analyzed the transcripts independently during steps 1 and 2, and collaboratively in step 3. In the first step, initial codes were extracted directly from participants’ written responses. The second step involved data aggregation, with each researcher independently generating labels for codes and categories. In the third step, the researchers discussed and refined the independently generated codes and categories [57]. The Consolidated Criteria for Reporting Qualitative Research (COREQ) [58] guided the presentation of findings, leading to the creation of a detailed report. The adherence to the COREQ checklist is documented in the S3 File. The results from this phase were reviewed by the SC and the ECT, which determined the final set of HRQoL domains and updated the HRQoL list accordingly.

Conceptual work and HRQoL domains mapping.

After the SC meeting, a few symptoms (i.e., sensory impairments, balance and coordination, swallowing and spasticity) were added to the ‘physical domain’. The ‘psychological domain’ was slightly revised by splitting cognition and emotion subdomains, and deleting a few redundant subdomains (i.e., general contentment, mood).

After the meeting with FGM facilitators, subdomains overlapping the ‘psychological’ and the ‘social’ domains were slightly revised. Specifically, social well-being was considered redundant and, as such, was included in social support and social relationships, while self-perception in social settings was better specified.

All these revisions were integrated into the domain mapping (S5 File), resulting in the graphical representation shown in Fig 1.

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Fig 1. Key HRQoL (sub)domains extracted from the MS-specific HRQoL instruments included in the review.

https://doi.org/10.1371/journal.pone.0349034.g001

The definitions of the ‘physical’, ‘psychological’, and ‘social’ domains were prepared and included in the FGM guides, each accompanied by a list of three representative items.

Meeting with the ECT for finalizing the FGM guides.

On February 2, 2025, a 2-hour online meeting was conducted with six PwMS (median age 35 years [range 31–64], 67% women, 84% single, all with college education and full-time employment, 67% with relapsing-remitting MS, median EDSS 2.0 [range 1.0–6.5], median years since MS diagnosis 11.5 [range 2–19]), and four researchers. The FGM guide was generally considered clear. Key modifications focused on rephrasing questions to better capture the impact of MS on HRQoL, particularly by refining how treatment and daily functioning were framed. Notable changes included adding ‘rehabilitation’ to the definition of MS treatment and clarifying the distinction between activities of daily living (ADL) and instrumental activities of daily living (IADL). Participants appreciated the inclusion of questions addressing both negative and positive influences on HRQoL. The HPs guide was adapted from the patient version. The revised guides are detailed in the S2 File.

FGMs participants and setting.

Between January 1, 2025 and March 31, 2025 we enrolled 18 PwMS and 20 HPs, across all study centers. Four online FGMs were conducted in April 2025, two with PwMS and two with HPs. The average duration of the FGMs was 144 minutes (SD 9.9) with PwMS, and 132 minutes (SD 14.1) with HPs. Among those enrolled, five PwMS and two HPs were unable to participate due to medical or logistical reasons.

PwMS (7 women, 7 men) had a median age of 52.5 years (range 36–64). EDSS scores ranged from 1.5 to 9.0 (median 4.0), and disease duration ranged from 5 months to 42 years (median 17). Half had a relapsing-remitting course and half a progressive form. Participants were recruited from Milano, Cagliari, and Genova, attending FGM 2 (n = 9) or FGM 3 (n = 5).

HPs (15 women, 3 men) had a median age of 50 years (range 30–65) and 3–35 years of experience in MS care (mean 19.6). They had followed a median of 100 PwMS in the past six months (range 12–600) and were employed across MS centres, rehabilitation centres, and AISM facilities, representing roles such as neurologists, nurses, physiotherapists, psychologists, and social workers. HPs participated in FGM 1 (n = 10) and FGM 4 (n = 8).

FGMs findings.

Qualitative data on HRQoL domains were collected during the four FGMs and organized into three themes: 1.1 Physical Domain; 1.2 Psychological Domain; 1.3 Social Domain.

This section presents each theme along with its main categories and illustrative quotes. The quotes include participants’ IDs in brackets: (ID: number, ‘P’ or ‘H’), where ‘P’ represents PwMS and ‘H’ denotes HPs. A complete list of categories, subcategories, and quotes is available in the audit trail (see S6 File).

HRQoL domains.

Table 1 highlights the key determinants of HRQoL across three domains, incorporating perspectives from both PwMS and HPs: Physical, Psychological, and Social. The FGM results confirmed all domains identified in the existing literature, but offered greater detail in terms of categories and subcategories within each domain.

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Table 1. List of HRQoL Domains (only main categories).

https://doi.org/10.1371/journal.pone.0349034.t001

Physical Domain – The Physical Domain includes symptoms (10 subcategories), ADL/IADL (two subcategories), and the impact of disease-modifying therapies (DMTs). For the full list of categories, subcategories, and quotes see S6 File: tables S3, S3.1 and S3.1.1.

In the Physical Domain, determinants of HRQoL for PwMS reveal significant challenges. Key symptoms include mobility impairments, with many reporting progressive difficulties: ‘The illness makes itself felt, even though from the outside it’s not so noticeable’ (ID: 8P). Pain, particularly neuropathic pain, is frequently overlooked but severely impacts daily life: ‘Pain is often very disabling for PwMS’ (ID: 11H). Incontinence issues further complicate daily experiences, with one participant stating, ‘I stopped going out because I couldn’t control the situation’ (ID: 4P). Symptoms often limit ADL and IADL: ‘I can only manage to do one thing a day’ (ID: 6P). The impact of DMTs can also influence physical function, with one HP stated, ‘The type of drug absolutely changes daily life’ (ID: 14H).

Psychological Domain – Central factors affecting HRQoL in PwMS in the Psychological Domain include cognitive function, health perception (five subcategories), emotional well-being (seven subcategories), and stress related to MS. For the full list of categories, subcategories, and quotes see S6 File: tables S3, S3.2; S3.2.1). Participants reported feeling mentally slower and less sharp. One PwMS expressed this concern: ‘Mentally, I feel much slower, even in terms of attention. That, for me, is what the disease has affected the most.’ (ID: 10P). HPs also noted that cognitive impairment can significantly impact a person’s life: ‘Sometimes, even when physical limitations are relatively minor, the person might struggle with concentration, and that can have a major impact’ (ID: 8H). Another participant reflected on initial misconceptions related to illness representation and its impact on QoL: ‘Not knowing much about the disease, I immediately thought of a diagnosis leading to a wheelchair. And that was difficult to shake off as an impact, let’s say’ (ID: 4P).

Finally, a recently diagnosed PwMS pointed out how MS can act as stressor: ‘Certainly, [MS] is a source of stress because it is unpredictable—you don’t know how things will be today or a year from now. You can read all you want and hear all sorts of things, but no one can tell you how it will progress.’ (ID: 1P). Participants also highlighted that the ongoing management of the disease—including therapies, diagnostic tests, and regular medical appointments—can itself generate psychological strain: ‘One aspect that hasn’t been mentioned is the impact—not just physical, but also the effects of therapies and the planning of the entire diagnostic process on daily life… individuals suddenly feel they are in need of support from others and require assistance from healthcare professionals.’ (ID: 6H). These concerns were further emphasized by HPs when describing the emotional impact of receiving the diagnosis: ‘The impact [of the diagnosis] is quite profound, as we know, because MS […] is one of those conditions that elicits fear and is frequently mentioned in news reports, alongside other incurable diseases. […] Thus, it is grouped with other major fears, such as cancer. Consequently, when a diagnosis is made, it signifies that ‘from this moment on, my life will be forever different, and I am, in fact, among the most unfortunate people in the world’ (ID: 17H).

Social Domain – The Social Domain includes Support (two subcategories), Social Connectedness (six subcategories), Self-Perception in Social Settings (three subcategories), Social Life (four subcategories), Work (four subcategories) and Finances (two subcategories). For the full list of categories, subcategories, and quotes see S6 File: tables S3, S3.3 and S3.3.1.

Support covers the assistance patients receive and the challenges they face in supporting others, especially in parenting and relationships. The psychological burden from MS can hinder empathy and limit the ability to seek help. One participant emphasized the importance of family, expressing concerns about not being able to engage in activities with their young child as they once could, saying, ‘I worry about how much I can physically give him… it’s different now’ (ID: 14P).

Social Connectedness reveals the impact of invisible symptoms like fatigue and incontinence on interactions. Medical care demands, fear of disclosure, and sexual dysfunction further isolate PwMS. One participant shared: ‘Fatigue limits opportunities for social interactions… I might manage to go out once a week at best’ (ID: 11P).

Self-Perception addresses stigma and feelings of vulnerability. One participant noted: ‘What bothers me more is how others perceive my situation… I’m less concerned about my experience than about judgment from others’ (ID: 14P).

Social Participation highlights restrictions in family activities, social life, and leisure. A nurse commented, ‘Treatments impact social life and energy levels… after a rehab session, they often need to rest, which cuts into their social time’ (ID: 16H).

Work captures the challenges PwMS face in maintaining employment and navigating professional roles. Key issues include difficulties caused by MS symptoms (e.g., cognitive fatigue), changes in work activities, the burden of medical leave, and discrimination. One participant shared: “Yes, definitely [MS cognitive symptoms affect QoL], both in my work and personal life. Sometimes I forget things that were said to me, and I struggle to follow conversations until the end. I lose track and realize I’ve missed part of the dialogue. I don’t know, I was a bit absent at times.” (ID: 7P).

A paediatric nurse reflected on the professional consequences of treatment: “My job is very important to me… When I started interferon therapy about 15 years ago, I had to give up my previous duties for lighter tasks. It wasn’t a choice; it was something I had to endure.” (ID: 12P).

An HP added insight into structural challenges in the workplace: “Patients often struggle to justify their medical needs, like physiotherapy or hospital visits, due to inadequate workplace accommodations. This need to constantly explain their condition disrupts their work-life balance and is a major challenge.” (ID: 15H).

Financial concerns relate to both direct disease-management costs and the economic burden of work limitations. Participants described the financial strain of accessing ongoing rehabilitation, often requiring private services. One HP noted: “Often, to receive continuous rehabilitation care, one must resort to private services, which can be quite costly. This financial burden is a significant concern.” (ID: 2H). A PwMS reflected on the personal cost of self-employment with MS: “I am self-employed, so when I take time off, I don’t receive payment. This concern has been present since the day I was hospitalized. With two children to support, I inquired about the length of my hospital stay because I knew these days would be counted as sick leave. Whenever I feel unwell, I make every effort to continue working because the financial impact is significant and a constant worry.” (ID: 1P).

Physical domain.

As detailed in Table 2, most instruments provided broad coverage of physical HRQoL, particularly regarding symptoms, mobility (lower and upper limb), fatigue, pain, and activity limitations. However, fine-grained distinctions emerging from the qualitative analysis—such as the separation between acute and chronic pain, or between lower- vs. upper-limb mobility impairments—were often not reflected in instrument items, which were frequently non-specific or mapped simultaneously to multiple subcategories. The category of Sexual Impairment was captured by only two instruments (MSQoL-54 and PRIMUS), and mainly at a general functional level, without addressing the broader experience described qualitatively. Overall, physical HRQoL constructs were represented, but item specificity remained limited.

Psychological domain.

Coverage in the Psychological Domain (Table 3) was substantial but uneven. Cognitive function, emotional well-being, and health perceptions were commonly represented across instruments. Nevertheless, several key psychological constructs derived from the qualitative study—including illness-as-threat, emotional responses to assistive devices, perceived fragility, and MS-related stressors—were either captured only indirectly or not addressed at all. Items overlapped across categories, especially for emotional well-being and health perceptions, reflecting limited conceptual differentiation. Some subcategories, such as the emotional impact of sexual impairment or disease-modifying therapies, were present but measured through generic or non-specific items. Overall, while core psychological constructs were included, granularity and contextualization were frequently lacking in the main MS-specific HRQOL questionnaires.

Social domain.

The most pronounced gaps emerged in the Social Domain (Table 4). Although several instruments partially covered support, social connectedness, social participation, and work-related issues, many subcategories identified qualitatively—such as limitations in providing or seeking support, the social consequences of invisible symptoms, stigma, romantic and intimate relationship challenges, and the financial impact of MS—were entirely absent from current instruments. When present, items typically reflected high-level constructs (e.g., general social participation), without addressing the specific mechanisms described by PwMS and HPs. Work- and finance-related categories were among the least represented. This domain therefore exhibited the greatest discrepancy between the qualitative findings and existing measurement tools.