**1. Introduction**

Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is post-viral or post-infectious fatigue syndrome or systemic exertional intolerance disease (SEID) that affects the functioning ability of a person and reduces the energy below the level that is considered the average. It is a complex and multifactorial disease that not only dysregulates the central nervous system, immune system and cellular energy metabolism, but also influences physical and cognitive state [1].

Nowadays there are several terms that are being used in the literature to describe ME/CFS. Historically CSF and ME were used separately, as different nosologic entities, but when Federal Health Agencies in the United States of America combined them together in 2016, ME/CFS has been used as an umbrella term to identify multi-systemic, chronic disease that causes physical, cognitive, or emotional exertion [2]. SEID is a relatively new term that has been proposed by the Institute of Medicine (IOM) in 2015 [3] and introduced based on the characteristic, central elements of the disease. No matter which diagnostic

**Citation:** Krumina, A.; Vecvagare, K.; Svirskis, S.; Gravelsina, S.; Nora-Krukle, Z.; Gintere, S.; Murovska, M. Clinical Profile and Aspects of Differential Diagnosis in Patients with ME/CFS from Latvia. *Medicina* **2021**, *57*, 958. https:// doi.org/10.3390/medicina57090958

Academic Editor: Tibor Hortobágy<sup>i</sup>

Received: 16 July 2021 Accepted: 6 September 2021 Published: 11 September 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

criteria are being used, the recent publications aim to declare that post-exertional malaise (PEM) is one of the key symptoms [4]. In this report the term ME/CFS will be used.

As to the statistics of ME/CFS, the numbers vary and depend on the country and research. The prevalence is from 0.42% to 2.54% worldwide [5] and there are from one million to over five million people suffering from ME/CFS in Europe [4].

Several aetiological scenarios are discussed in terms of ME/CFS, but it is still considered multifactorial spectrum of illness with controversial, complex and unknown aetiology that is triggered by different factors and happens to develop in people with predisposition. There have been investigations in terms of neurological, immunological, endocrine, genetic and infectious causes, but none of these are considered the leading one [6].

As regards the diagnostics of ME/CFS, there is no single golden standard that is accepted worldwide, but several criteria systems have been used depending on the country or healthcare centre. In general, the diagnosis is based on the patient's subjective symptoms and differential diagnostics to exclude other pathologies, because there are no biomarkers or other tests that could serve to objectify this process.

In the last 30 to 40 years approximately 20 different diagnostic criteria systems have been proposed. One of the most commonly used is the Fukuda criteria (FC) [7], more recently the Canadian Consensus Criteria (CCC) [8] have been proposed, as well as the International Consensus Criteria (ICC) [1], the Oxford criteria (OC) [9] and the criteria released by the IOM in 2015 [10], the latter having received international recognition [4]. FC (1994) commonly serves as a diagnostic tool in research purposes. As to the recent suggestion from the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) expert consensus, PEM should also be included in the core symptoms of the Fukuda criteria, to decrease the risk of hyperdiagnostics [4].

To better asses ME/CFS symptoms and to objectify them, several questionnaires and functional tests are being used: "UK ME/CFS Participant Questionnaire" [11]; "De-Paul Symptom Questionnaire" (DSQ) [5,12]; "The RAND-36 Item Health Survey" [13,14]. There are certain strengths for each of the questionnaires, but they all have been used in both clinical and research purposes [15]. To evaluate the functioning ability, the most commonly used scales are: "Work and Social Adjustment Scale (WSAS) [16,17], "Energy Index Point Score" [18], "The Lawton Instrument Activities of Daily Living Scale" [19], VAS [20], "SF-36" [21,22], EQ-5D [23,24] and others. To evaluate sleep disturbances: "Sleep Assessment Questionnaire" [25], "Pittsburg Sleep Quality Index" [26], "PROMIS Sleep questionnaire" [27], as well as The Epworth Sleepiness Scale to detect daytime sleepiness [4] are being used.

To decrease the risk of hyperdiagnostics, several differential diagnosis should be excluded. Besides that, there are certain diseases that usually manifest together with ME/CFS and do not rule out the diagnosis of ME/CFS. Some of the overlap syndromes are: allergies, fibromyalgia, irritable bowel syndrome, postural orthostatic tachycardia syndrome, hypotension, hypogonadism and premature menopause, sleep disorders, hypersensitivities, hypoglycaemia, mitral valve prolapse, metabolic syndrome, vitamin B12 deficiency, endometriosis and others [28].

Although ME/CFS is a disabling disease with an impact on functional status and quality of life, no specific treatment or cure for ME/CFS exist, it tends to be individualised and usually vary from case to case. Nevertheless, both - pharmacological and non-pharmacological methods, as well as alternative medicine are used to reduce the symptoms and improve the quality of life and well-being [12]. But it should be noted that results of the research have been controversial, leading to reduction of the symptoms, aggravation of the symptoms, being ineffective or causing side effects. That is why these measurements should be done under control and the choice of treatment should be based according to the national guidelines.

To conclude, it is clearly seen that ME/CFS remains a challenge for medical specialists. As this disease has unclear aetiology, symptomatic variability and there are no common grounds for unified diagnostic criteria, it is challenging to find the best treatment option. However, a wide range of research is being conducted in pharmacological, non-pharmacological, as well as alternative medicine fields, therefore new strategies and potential improvements are still to come to improve the work of the clinicians and to raise the quality of life of the patients.

#### **2. Materials and Methods**

#### *2.1. Patient Selection and Eligibility Criteria*

This prospective observational study includes a Latvian population of 65 Caucasian participants (43 females, 22 males) undergoing outpatient treatment in R¯ıga Stradin, š University ambulance in Riga, Latvia from April 2020 to May 2021. Age ranged from 23–78 years in females and 21–72 years in males. The average age ± SD for both genders was 47.4 ± 14.92 years (47.40 ± 14.66 in females and 47.41 ± 15.78 in males).

The inclusion criteria were as follows:


The exclusion criteria were as follows:


Patient selection was made by a qualified physician (infectologist, neurologist or general practitioner), specialised in ME/CFS diagnostics, who determined patient's suitability depending on one's clinical expertise. The selection was based on the new-onset fatigue symptoms, previously reported fatigue symptoms registered in medical histories, as well as a previous diagnosis of ME/CFS. All patients were observed by the physician, who reported demographic, medical, occupational and additional information.

#### *2.2. Symptom Registration*

Data were collected as part of care at an ambulatory outpatient health care facility. First, the participants were informed about the research, its purposes, their participation and then an informed consent was signed. Second, if the patients agreed, we asked to fill in questionnaires in the waiting room by hand. Of the 65 patients all 65 individuals returned the questionnaire. After completion, the patients were asked to share their questions and comments with a certified specialist, they were consulted and a VAS score was measured.

All patients were interviewed with questionnaires to evaluate various categories. To examine the symptom pattern in ME/CFS patients, we used adapted semi-structured interview questions created by Minnock et.al [29]. The questions were structured in six sections: causes and triggers of fatigue; character of fatigue; current symptoms; comorbidities; solutions for fatigue; and its influence on work disability. Multiple choice answers were provided for each question.

Regarding sleep disturbances, we included a self-reported questionnaire—Athens Insomnia Scale 8 [30]—to assess insomnia symptoms, which included the evaluation in various sleep-related questions: sleep induction, awakenings during the night, final awakening, sleep quality, well-being during the day, functioning capacity during the day and sleepiness during the day. We used the cut-off value of ≥ six points for the confirmation of sleep disturbances.

VAS, ranging from zero to ten was also measured for all patients to assess the diseaserelated pain intensity.

To better evaluate the differences in terms of symptoms, first, we divided the respondents into three groups—patients without ME/CFS presenting with symptoms of fatigue (*n =* 10), patients diagnosed with ME/CFS according to the Fukuda et.al criteria (*n* = 19) and patients diagnosed with ME/CFS according to the Fukuda et.al criteria, who have at least one comorbidity, which might be affecting the symptom severity and pattern of fatigue (*n* = 36). In some situations, we combined the two groups with the diagnosis of ME/CFS (*n* = 55) to better emphasise the differences between ME/CFS and non-ME/CFS patients. Second, based on the patient's self-reported answers to the questionnaires, the answers were graded by our specialists according to the severity and a total score calculated, so that the correlation analysis and comparison regarding different patterns of fatigue could be made.

#### *2.3. Statystical Analysis*

Descriptive and advanced statistical analysis, as well as graphing were done using GraphPad Prism V.9.1 for macOS (GraphPad Software, Inc., San Diego, CA, USA). The normality of the distribution of the studied data was checked by D'Agostino and Pearson, Anderson–Darling and Shapiro–Wilk normality tests. The homogeneity of variances was tested using F-test or Brown–Forsythe and Bartlett's tests. To determine and assess the correlative associations between indicators of fatigue in predefined groups, the Spearman's rank correlation test was performed. Between-group comparisons of summarised fatigue scores expressed in percentage were done by unpaired t-test or Brown-Forsythe and Welch ANOVA tests with Dunnett's T3 multiple comparison test as post-hoc procedure.

As characteristic of central tendency, arithmetic mean with ± standard deviation (SD) was applied. A *p* value < 0.05 was considered statistically significant for all tests.

#### *2.4. Ethical Consideration*

All of the participants received the information regarding research ethical considerations, description of the research, including the aim, the design and potential results of the inquiry, as well as an informed consent prior to study inclusion. Confidentiality was guaranteed and research subjects were informed about withdrawing from participation without any consequences.
