The Chalder fatigue scale (CFQ or CFS or FS-14), developed by Butler and refined by Chalder in 1991 (11), is among the most widely used fatigue tools. It contains 14 items measuring physical and mental fatigue and can distinguish fatigued individuals from healthy controls and track fatigue changes in ME/CFS (12). However, Kirke argued that the FS-14 is inadequately captures changes in ME/CFS fatigue. His study found that a two-point reduction in score increases bias toward perceived symptom improvement, whereas a 10-point reduction enhances the accuracy of outcome interpretation (13). To address these limitations, a shortened version, the CFQ-11, was later developed by removing the items “easy start,” “clear thinking,” and “loss of interest,” reducing the total from 14 to 11 items. Items 1–7 assess physical fatigue, and 8–11 assess mental fatigue (14). Structural equation modeling confirmed that the CFQ-11 achieved a better three-factor structure than the FS-14 (15). Although the FS-14 remains widely used in ME/CFS research, the CFQ11 demonstrates improved structural validity and may provide more reliable fatigue assessments.

The fatigue assessment instrument (FAI), developed by Schwartz and Jandorf (16), consists of 29 items assessing the past 2 weeks across four domains: fatigue severity, sensitivity, psychological impact, and the effect on rest or sleep. The scale was designed to measure both the quantitative and qualitative components of fatigue (17), qualitatively to determine whether fatigue is persistent and physiological or transient and physiological in healthy individuals, and quantitatively to evaluate the graded severity of fatigue, with higher total scores indicating more severe symptoms (16). Despite its application in ME/CFS research, psychometric validation remains limited, and further studies are needed to confirm its reliability and validity.

The fatigue severity scale (FSS), developed by Krupp (18) for multiple sclerosis (MS) and systemic lupus erythematosus (SLE), is now widely applied in studies of ME/CFS (19) and cancer-related fatigue (20). It consists of nine items rated on a seven-point Likert scale ranging from 1 (strongly disagree) to 7 (strongly agree), with higher scores indicating greater fatigue severity (21). The FSS primarily reflects the impact of fatigue on daily life rather than the intensity of symptoms (22). Psychometric studies have demonstrated high validity, internal consistency, and test-retest reliability, supporting its use in follow-up assessments and treatment evaluation (23).

The fatigue impact scale (FIS), developed by Fisk in 1994, is a multidimensional instrument designed to evaluate patients' fatigue during the previous month across three domains: cognitive, physical (somatic) and psychological functioning. It primarily reflects the impact of fatigue on patients' ability to perform daily and social activities (24). The FIS comprises 40 items, each rated on a five-point scale from 0 (no fatigue) to 4 (very severe fatigue), with higher scores indicating greater impairment in the respective domain (25). A 21-item modified version (MFIS), retaining the same domains and scoring method, was later adopted by the U.S. National Multiple Sclerosis Society for inclusion in its 1998 Clinical Practice Guidelines as a measure of fatigue impact on daily living (26). The MFIS has since been widely applied in ME/CFS research (19, 27).

The checklist individual strength (CIS), developed by the University Medical Centers of Amsterdam and Rotterdam in 1994, is a multidimensional instrument designed to evaluate self-perceived fatigue over the preceding 1–2 weeks (28). It has been widely applied in studies of ME/CFS (29), cancer (30) and multiple sclerosis (31), as well as in epidemiological studies of healthy working populations. It has also been validated in rheumatoid arthritis (RA) (32) and fibromyalgia (33). The scale comprises 20 items across four domains: fatigue severity, attention, motivation and activity level, each rated on a seven-point Likert scale, with higher scores indicating more severe physical and mental fatigue (34). Psychometric analyses have reported a Cronbach's α of ~0.90, demonstrating high internal consistency, test-retest reliability and sensitivity to change (35), and validated cut-offs for severe fatigue (36). Compared to other scales, the CIS places greater emphasis on cognitive aspects of fatigue in ME/CFS.

The visual analog scale for fatigue (VAS-F), developed by Lee et al. (37), was adapted from general visual analog scales (VAS) previously used to quantify subjective emotional or affective states, and designed as a rapid, quantitative measure of fatigue. It was demonstrated to be a valid and reliable unidimensional measure, and has since been applied in studies of inflammatory bowel disease (38), ME/CFS (27), MS (39), and primary Sjögren's syndrome (pSS) (40). The VAS-F consists of a 100 mm (10 cm) horizontal line, with one end labeled “no tiredness” and the other “maximum tiredness” or “extreme fatigue.” Participants mark a point along the line corresponding to their perceived fatigue intensity at that moment. The distance from the left anchor represents the fatigue score, with larger distances indicating greater fatigue severity. Although the VAS-F provides a simple and efficient measure of fatigue intensity, it cannot differentiate fatigue subcomponents (e.g., emotional, physical, or functional impact), and may be influenced by response bias and scoring variability, limiting its use for diagnostic purposes.

Additional instruments applied in ME/CFS research include the multidimensional fatigue inventory (MFI) (41), the PedsQL multidimensional fatigue scale (PedsQL-MFS) (42), the functional assessment of chronic illness therapy-fatigue scale (FACIT-F) (43), and the fatigue scale for motor and cognitive functioning (FSMC) (44). Each has distinct structural or dimensional characteristics but is used relatively infrequently, as their target populations or original design contexts differ from those of ME/CFS. The psychometric validity and reliability of these instruments in ME/CFS populations remain to be further established.

Table 1 summarizes the major fatigue-related scales, while detailed characteristics and supporting references for these additional scales are provided in Supplementary Table S1.

The DSQ-PEM is a subscale of the DePaul symptom questionnaire, developed by Leonard Jason's group at DePaul University to specifically assess PEM in ME/CFS cohorts (52). It typically includes five core items evaluating the frequency, severity, and duration of post-exertional symptoms such as fatigue relapse, cognitive decline, and flu-like malaise, each rated on a Likert scale from 0 to 4 for both frequency and severity. A symptom is considered positive if it is rated at least “moderate” in severity and occurs at least “half the time” during the past 6 months (53). DSQ-PEM has been validated across multiple languages and applied in post-COVID populations (54, 55). Its main advantages are standardized administration and broad applicability in epidemiological surveys and case definitions (56). However, as a self-report tool, it remains subjective and susceptible to recall bias.

The 2-day CPET is an objective physiological test considered the most objective and reproducible measure of PEM (57). It measures cardiopulmonary performance (VO₂max, workload, anaerobic threshold) on two consecutive days (58). Unlike healthy individuals, ME/CFS patients typically show a reduction of ≥8%−15% in VO₂max or workload on the second day, reflecting impaired recovery and abnormal post-exertional physiology (59). This reproducible finding has been consistently validated in ME/CFS and replicated in long-COVID patients (51, 60). The strengths of 2-day CPET are its objectivity and strong empirical reproducibility, making it a valuable endpoint in clinical research (61). However, it is resource-intensive, requires specialized equipment and trained staff, and imposes a substantial burden on patients, which may limit its feasibility in routine clinical practice (58).

The FUNCAP is a recently developed, patient-informed questionnaire designed to assess post-exertional functional decline in ME/CFS (50). It comprises a concise set of items evaluating activity reduction, physical exhaustion, and recovery delay, each scored on a 0–10 scale. Higher scores reflect greater functional impairment. As a newly introduced tool, FUNCAP has shown promise for capturing PEM with minimal patient burden, offering advantages in brevity, rapid administration, and potential scalability for large-cohort studies. However, current evidence is limited to its initial development and validation study, and further psychometric testing across diverse populations is required to establish diagnostic thresholds and comparability for research applications (50).

Table 2 summarizes the key assessment tools for PEM in ME/CFS, while detailed methodological and psychometric information is provided in Supplementary Table S2.

The VAS is one of the most commonly used unidimensional instruments for assessing pain intensity. It consists of a 100-mm horizontal line anchored by “no pain” at one end and “severe pain” at the other, where patients indicate their perceived pain level by marking a point along the line (132, 133). Kempke et al. (134) used the VAS to evaluate pain severity in a study examining the association between self-critical or maladaptive perfectionism and ME/CFS. The VAS is simple, quick, sensitive, and relatively objective, making it suitable for assessing pain intensity and comparing pre- and post-treatment effects. However, its use requires a certain level of abstract reasoning, and scores are not directly comparable across individuals (135).

The NRS is a numerical adaptation of the VAS that asks patients to rate their pain intensity on an 11-point scale from 0 to 10, where 0 indicates no pain, 1–3 mild pain, 4–6 moderate pain, and 7–10 severe pain, with 10 representing the most intense pain (136). Thompson et al. (137) used the NRS to evaluate pain severity in ME/CFS patients when examining the association between activity pacing and symptom fluctuation. The NRS is simple, intuitive, and widely used, showing strong concordance with the VAS. However, it requires adequate verbal comprehension and understanding of numerical concepts, and may be influenced by linguistic or cognitive factors, leading to slightly lower sensitivity and accuracy (138, 139).

The MPQ, developed by Melzack (140), is a classic multidimensional instrument for assessing pain across three domains: sensory, affective, and evaluative. It includes 78 descriptors grouped into four categories and 20 subclasses, each arranged in order of increasing intensity. Participants select the words that best describe their pain; if none apply, they may skip the group (141). The MPQ yields three indices: the pain rating index (PRI, calculated from the ordinal values of chosen descriptors), the number of words chosen (NWC), and the present pain intensity (PPI, rated from 0 = no pain to 5 = excruciating pain). Mckay et al. (142) used the MPQ in a quasi-experimental study exploring the relationship between ME/CFS and fibromyalgia to assess pain frequency and intensity. The MPQ is sensitive to treatment-related changes and useful for distinguishing nociceptive and neuropathic pain (143). However, it is lengthy, literacy-dependent, time-consuming, and influenced by demographic factors such as gender and race.

In addition to the instruments described above, several other tools have been used to evaluate pain in ME/CFS, including the brief pain inventory (BPI) (144) and the pain catastrophizing scale (PCS) (145).

Table 7 summarizes the pain-related assessment tools, while Supplementary Table S7 provides detailed information on their psychometric properties, validation evidence, and clinical applicability.

The HADS, developed by Zigmond and Snaith (152), is a reliable and valid instrument designed to assess symptoms of anxiety and depression in general medical populations. It consists of two subscales, the anxiety scale (HADS-A) and the depression scale (HADS-D), comprising a total of 14 items, with seven items for each domain. Each item is rated on a four-point Likert scale from 0 to 3, yielding a total score ranging from 0 to 42. A score of 9 or above is generally considered indicative of anxiety or depression (153). Loades and colleagues used the HADS as an outcome measure in a cross-sectional epidemiological study of adolescents with ME/CFS presenting with comorbid anxiety and depression (154). The HADS is independent of somatic symptoms and demonstrates strong discriminative validity for psychological distress in ME/CFS (155). However, its ability to differentiate clearly between anxiety and depression constructs remains uncertain, and psychometric validation specific to ME/CFS populations is still limited, suggesting that reliability may vary across settings.

The HAMA and HAMD, both developed by Hamilton (156, 157), are widely used examiner-rating instruments for evaluating anxiety and depression. The HAMA consists of 14 items that assess psychological and somatic symptoms of anxiety (158), and demonstrates good reliability and validity in reflecting both symptom severity and treatment (159). The 17-item version of the HAMD (HAMD-17) is the most widely used in ME/CFS studies and covers anxiety (psychological and somatic), somatic symptoms (gastrointestinal and general), depression, and insight (160). Both scales use a 0–4 scoring system, with higher scores indicating greater symptom severity and a threshold score of eight suggesting clinical significance (161).

Tingting et al. (162) used the HAMA to assess anxiety and the SDS to evaluate depression in a study on spaced ginger moxibustion for ME/CFS. Although some items overlap, including depressive mood, somatic anxiety, gastrointestinal symptoms, and insomnia, which may blur the distinction between anxiety and depression (163). However, factor analyses support the ability of both scales to detect symptom changes and treatment effects. Owing to their long history of clinical use and demonstrated psychometric robustness, the HAMA and HAMD remain among the most established tools for assessing psychological status in ME/CFS (164).

The SAS and SDS, both developed by Zung in 1971, are 20-item, four-point self-report instruments with similar structures and scoring methods (165). The SAS assesses anxiety symptoms aligned with major U.S. psychiatric diagnostic criteria and includes 15 negatively and five positively worded items (166). Although primarily designed for anxiety, it also reflects depressive tendencies due to overlapping affective components (167). The SDS, comprising 10 negative and 10 positive items, focuses primarily on emotional and somatic symptoms of depression (168, 169).

Meng et al. (170) employed both the SAS and the SDS as secondary outcome measures to evaluate the efficacy of different pressure cupping interventions for ME/CFS, alongside fatigue and sleep scales. When used together, these two instruments provide a rapid, reliable, and comprehensive evaluation of anxiety and depression symptoms, as well as their severity and temporal changes in ME/CFS. When combined with the fatigue assessment tools, they can help differentiate ME/CFS from primary anxiety or depressive disorders, although their accuracy may be limited in individuals with lower literacy or cognitive ability.

In addition to the aforementioned scales, various tools have been employed in ME/CFS studies to assess psychological status, including the BDI, the symptom checklist-90 (SCL-90), the center for epidemiologic studies depression scale (CES-D), and the general health questionnaire (GHQ), among others. Recognizing the inherent subjectivity and time sensitivity of psychometric measures, both clinical and research protocols often combine multiple instruments or integrate self-report with examiner-rated assessments to minimize bias and enhance accuracy.

Table 8 summarizes the psychological state assessment scales, while Supplementary Table S8 provides details on their psychometric properties, validation evidence, and clinical applicability.

The SF-36 evolved from the earlier medical outcomes study short form (MOS SF) questionnaires first described by Stewart et al. (199), with the finalized 36-item version later developed by Ware and Sherbourne (200). It is one of the most widely used self-report instruments for evaluating health-related QoL across diverse populations. The SF-36 assesses physical, psychological, and social functioning, as well as overall health status, with total scores ranging from 0 to 100, where lower scores indicate poorer health (201). Kim et al. (202) reported that 30.9% of randomized controlled trials (RCTs) on ME/CFS employed the SF-36 to examine QoL outcomes. However, certain items may be overly sensitive and fail to distinguish moderate-to-severe ME/CFS cases, while the instrument's length may limit its practicality in large-scale surveys (203).

The EQ-5D, developed by the EuroQol Group in 2001, is a standardized instrument for measuring health status in clinical and population studies (204). Several versions exist, including EQ-5D-3L, EQ-5D-5L, and the youth version, EQ-5D-Y (205). The EQ-5D-3L comprises the descriptive system and the visual analog scale (EQ-VAS), with the descriptive system assessing five key dimensions, namely mobility, self-care, usual activities, pain or discomfort, and anxiety or depression, each rated at three levels: no problems, some problems, and extreme problems (206). The EQ-VAS records self-rated health on a 0–100 vertical scale, where 0 represents the worst and 100 the best imaginable health (207). To improve sensitivity and reduce ceiling effects, the EuroQol group developed the EQ-5D-5L, which expands each dimension to five response levels (208). Mapping studies have shown that the EQ-5D-5L provides greater reliability across different ages and genders (209). In ME/CFS research, Salonen et al. (27) applied the EQ-5D-3L to assess changes in health-related QoL after fecal microbiota transplantation, whereas Orji et al. (210) used the EQ-5D-5L in a cross-sectional study of Australian patients.

The WHOQOL-BREF (211), developed by the WHOQOL group as an abbreviated version of WHOQOL-100, is a cross-cultural instrument designed to assess QoL across diverse populations. It consists of 26 items covering four domains: physical health, psychological health, social relationships, and environment. Each item is rated on a five-point Likert scale ranging from “not at all” to “extremely,” and domain scores are calculated by averaging item values and multiplying by four. The weighted sum of domain scores provides the overall QoL score, with higher scores indicating better quality of life (212). Brittain et al. (213) applied WHOQOL-BREF to evaluate QoL among individuals with ME/CFS and their family members. Although it lacks the detailed assessment of 24 specific QoL facets included in the WHOQOL-100, its brevity and ease of administration make it suitable for clinical research and trials where time constraints or participant burden limit the use of longer instruments.

In addition to the above instruments, the Nottingham health profile (NHP) and the sickness impact profile (SIP) have also been used in ME/CFS research. QoL scales are generally broad and nonspecific, mainly used for overall health assessment in clinical and research contexts. Few QoL tools are included in ME/CFS studies, and most capture symptoms that partly overlap with psychological, sleep, or functional domains. When selecting multidimensional health measures, it is important to consider not only overall health status but also the ability to reflect other relevant symptoms for a more comprehensive evaluation.

Table 11 summarizes the commonly used multi-dimensional health scales, while Supplementary Table S11 provides details on their psychometric properties, validation evidence, and clinical applicability.

Physiological and psychological characteristics that vary across age groups and populations can lead to distinct manifestations and assessment outcomes of ME/CFS symptoms. Children and older adults often present different symptom patterns and coping mechanisms, indicating that instruments designed for adults may not be fully applicable to these groups. For instance, children tend to exhibit greater emotional and behavioral disturbances, whereas older adults experience more pronounced physical decline (220). Furthermore, patients with post-COVID ME/CFS share many core symptoms with traditional ME/CFS but may present with more complex or overlapping mechanisms involving autonomic, inflammatory, and neurocognitive domains (221). These differences highlight the importance of using assessment tools with higher sensitivity and specificity to detect subtle variations across populations. Therefore, the development and validation of population-adapted or age-specific instruments are essential to ensure accurate symptom characterization and enhance the clinical and research applicability of ME/CFS assessments.

Selecting appropriate assessment tools is essential for the long-term management of ME/CFS. Validated instruments enable clinicians to accurately evaluate symptom severity and functional status, forming the basis for individualized treatment planning. Standardized tools also facilitate monitoring of symptom changes, allowing timely adjustment of therapeutic strategies and improvement of patients' overall health and functioning. In research, consistent use of validated measures supports reliable data collection and enhances comparability across clinical trials (222).

Although many existing scales demonstrate acceptable reliability and validity, most remain subjective and prone to observer or recall bias. Some studies rely solely on fatigue-related tools, which may increase measurement error. Combining multiple instruments and integrating subjective questionnaires with objective indicators, such as physiological or digital measures, can improve accuracy and reduce bias. Furthermore, factors such as test duration and patients' health status should be considered when selecting instruments to ensure feasibility, reproducibility, and clinical relevance.

As understanding of ME/CFS continues to advance, the limitations of existing instruments have become increasingly evident, especially in the context of post-COVID ME/CFS and other post-infectious syndromes. Developing novel assessment approaches is therefore essential to address unmet clinical and research needs. Future instruments should integrate recent clinical and neurobiological findings and adopt flexible, multidimensional frameworks capable of capturing both subjective experiences and objective indicators. For example, tools combining biomarker analysis with patient-reported outcomes may allow a more comprehensive evaluation of disease status. In addition, the growing use of digital health technologies, including mobile applications and wearable monitoring systems, provides opportunities for real-time assessment and longitudinal tracking of symptoms (223, 224). The development and validation of such innovative instruments will enhance diagnostic precision and support more individualized management strategies for patients with ME/CFS.

The standardization and normalization of ME/CFS symptom assessment are crucial for improving diagnostic accuracy and enhancing treatment outcomes. Establishing unified assessment standards and procedures can ensure consistency and comparability of results across healthcare and research settings, thereby facilitating longitudinal monitoring and inter-institutional collaboration. International cooperation and multicenter studies are particularly important, as they allow integration of data from diverse regions and populations to refine, validate, and update assessment tools (225). In parallel, advances in artificial intelligence and big data analytics offer opportunities to develop adaptive and personalized assessment systems capable of real-time evaluation and feedback based on individual symptom profiles. The integration of these technologies within standardized frameworks will further promote the objectivity, reproducibility, and clinical applicability of ME/CFS assessments, ultimately supporting precision diagnosis and evidence-based management.

To facilitate the selection of appropriate instruments for clinical and research applications, Table 12 summarizes recommended and less recommended scales by symptom domain, considering their psychometric evidence, sensitivity, and applicability across populations.