Prevalence of psychiatric disorders among patients with Multiple Sclerosis: a cross-sectional study.

Background: Multiple Sclerosis is one of the leading autoimmune disorders causing disability among young adults. Various types of mood, affect, and behaviour disorders along with cognitive impairment can be manifested in a course of MS, with affective and anxiety disorders being the most prevalent. Mental health challenges, in addition to the neurological burden of MS, significantly affect quality of life and the course of the underlying disease. Objective: The aim of this work was to determine the prevalence of mental disorders in a sample of MS patients during outpatient treatment in Zabrze, Poland, with a focus on those with mood and anxiety disorders, and to compare the results obtained in these groups with clinical and sociodemographic data. Method: The study was conducted between 2017 and 2018 on 103 MS patients of the Neurological Outpatient Clinic of the Medical University of Silesia Hospital No.1 in Zabrze, Poland. During the study, sociodemographic data were collected, as well as the type and course of the underlying disease, comorbidities, and medicines used. The MINI-international neuropsychiatric interview and a psychiatric examination were utilized to assess the occurrence of mental disorders. Result: 68% of all patients received a psychiatric diagnosis at some point in their life with only 4% having been hospitalized before; 49.5% met the diagnostic criteria for various psychiatric disorders. Measured by the MINI International Neuropsychiatric Interview, 33% of patients reported a past episode of major depression while 8.7% met the criteria for a current episode. The same number of patients admitted ongoing treatment due to recurrent depressive disorder. In regards to anxiety disorders, the most common was generalized anxiety disorder (10.7%), followed by agoraphobia (8.7%), panic disorder (7.8%), and social phobia (4.9%). Most of the patients (94.2%) at the time of the psychiatric evaluation presented a low level of suicide risk, while 1.9% of the patients presented a medium risk, and 3.9% - a high risk. Conclusion(s): The study confirmed a significantly higher prevalence of mental disorders among MS patients; thus, the psychiatric state of patients in this group should be investigated systematically, simultaneously with the assessment of their neurological state. Trial registration: N/A Key words:


Background
Multiple Sclerosis is one of the leading autoimmune disorders, with around 2-3 million people living with this diagnosis across the globe (1). The geographical distribution of MS is not homogenous and varies widely depending on region, with a general rule of increased incidence along with increased distance from the equator, though there are exceptions (2). The reasons for this are widely debated (3). As the majority of affected individuals are in their early adult life, MS has a huge impact on quality of life and is one of the most common causes of a nontraumatic neurological disability in this age group in Europe and Northern America (4). MS is also a heterogenous disease in its course; thus, various degrees of worsening during the progressive phase can be observed, as well as various degrees of activity of pathological processes in the relapsing phase (5) (6). The very moment of receiving the diagnosis is a stressful, life-changing event for the majority of patients and their families. To improve the quality of life of the patients, recognition of this emotional and cognitive burden is crucial in regards to all parties involved (7) (8).
Various types of mood, affect, and behaviour disorders along with cognitive impairment can be manifested in a course of MS, however some of them are understood as direct consequences of the ongoing brain damage resulting from multiple areas of axonal demyelination (9), while others are classi ed as varied psychological reactions to the progressing and disabling course of the disease (10) (11). The pattern of their development is still debated, however clinicians agree that these two categories usually overlap and are not, in any case, exclusive (12) (13). Cases of pure neuropsychiatric manifestations of MS are occasionally reported and show that the symptoms presented by patients are not speci c, therefore, nal diagnosis is often delayed because the diagnostic process is focused rstly on the primary psychiatric condition (14) (15) (16).
Much published research focuses on the prevalence of comorbid psychiatric disorders, in particular mood disorders, with the rst studies conducted in the eld in the 1920s (17). Major depressive disorder is especially common among MS patients. Studies show lifetime prevalence on a level varying between 24% and 50%, which is substantially higher than in the general population and in most other neurological disorders (13) (18) (19) (20) (21). In addition, higher rates of completed suicide are observed in this study group (22). Lifetime prevalence of anxiety disorders was reported on a level between 21-36% (23) (13) (24). Other less frequently reported mental disorders are bipolar affective disorder, psychosis, euphoria, pseudobulbar affect, and personality change (25) (13). Even though neurological and psychiatric manifestations are developed by MS patients with a higher prevalence than in the general population, they are usually overlooked in clinical settings (26) (27).
All of the mental disorders reported have a negative impact on disability developing progressively in relation to MS. Signi cantly lower quality of life, higher levels of fatigue, as well as lower levels of adherence to therapy are the main elements connected to psychiatric comorbidity in MS patients (28) (29).
The aim of this work was to determine the prevalence of mental disorders in a sample of MS patients during outpatient treatment in Zabrze, Poland, with a focus on those with mood and anxiety disorders, and to compare the results obtained in these groups with clinical and sociodemographic data.

Materials And Methods
This study involved 103 patients with a previously con rmed diagnosis of MS according to the McDonald criteria (30). These criteria are recommended by the Polish Multiple Sclerosis Society and were revised on a global level in 2017 (31). All patients were recruited while attending a follow-up treatment in an outpatient specialist clinic in the Neurological Department of the Medical University of Silesia Clinical Hospital No1 in Zabrze, Poland between January and December 2017. Inclusion criteria were: literacy, signed, informed consent for participation in the survey, age between 18 and 70 years old, and a formal diagnosis of multiple sclerosis during a treatment process. Exclusion criteria were: illiteracy, withdrawal of consent or refusal to participate in the survey, age outside the set limit, a degree of disability > 8.0 on the Expanded Kurtzke Disability Status Scale (EDSS), and cognitive impairments which would prevent proper understanding of the course and nature of participation in the study including a history of brain injury and stroke.
The study protocol for this cross-sectional research was presented to the Bioethics Committee at the Medical University of Silesia and received a thorough approval (No. KNW/022/KB1/136/16). All patients selected to join the study were shown a comprehensive summary of the aims and goals of the study, tools used by the researchers, and information processing conditions. Written consent was given to the participants to sign and they were informed that it can be withdrawn at any time without consequences to their basic treatment process. Medical history with a focus on sociodemographic data and medications was gathered along with a clinical assessment performed by a neurology specialist to evaluate disability status through the Expanded Kurtzke Disability Status Scale (EDSS) (32). Then, in the next stage, quali ed MS patients were referred to psychiatrists to conduct a full psychiatric evaluation. The main diagnostic tool was the MINI International Neuropsychiatric Interview (version 6.0) that allows clinicians to assess for the 15 most common psychiatric disorders included in the DSM-IV and ICD-10 (33) (34). A separate section of this diagnostic instrument allowed for the evaluation of suicide risk within the studied group. In addition, a clinical psychiatric examination was conducted to supplement the results obtained in the questionnaire.
Statistical analysis was performed using R environment version 3.3.2. Data obtained by measurement were expressed as arithmetical mean ± standard deviation and quartiles, and those obtained by counting were expressed as a percentage. Pearson's χ2 test with Yates's correction for continuity was performed for categorical univariate analysis. Student's t-test was used in comparing patient groups for the score of normal distribution and equal variances, whereas Welch's test was employed when the null hypothesis in Fisher's test for variances was rejected. The Mann-Whitney U test was performed for scores that did not exhibit normal distribution. P < .05 was regarded as signi cant.

Results
In total, 103 patients quali ed for the study over the course of a year, with none of them withdrawing consent once given. The studied sample consisted of 70 (67.96%) female and 33 (32.03%) male patients. The age ranged from 18 to 66 years, with a mean of 43 (SD = 12.05). The duration of MS treatment ranged from below one year to 30 years, with a mean of 5.9 (SD = 5.64). The duration of MS symptoms ranged from below one year to 40 years, with a mean of 10.85 (SD = 8.75). The degree of disability ranged from 0.5 to 8.0, with a mean of 3.2 (SD = 1.61). The most common form of this disease, relapsing-remitting form, was found in 89 (86.40%) MS patients, while primary progressive form was found in 3 (2.91%), and secondary progressive in 11 (10.67%). The majority of patients, 97 (94.17%), had more than 20 areas of demyelination detected in an MRI scan. The number of neurological hospitalizations within the group ranged from 1 to 50, with a mean of 4.74 (SD = 7.53). 56 (54.36%) patients were being treated additionally due to other somatic illness. 5 (4.85%) patients reported an elementary level of education (8 years), 21 (20.38%) patients nished vocational school (12 years), 37 (35.92%) graduated from secondary school (12 years), and 40 (38.83%) people had a higher education (up to 18 years). 55 (53.39%) patients reported being professionally active at the time of the study (Table 1). Regarding the frequency of psychiatric disorders within the group as measured by the MINI International Neuropsychiatric Interview, the most common were diagnoses from the groups of mood and anxiety disorders. As regards the rst group, mood disorders, 33% of patients reported a past episode of major depression while 8.7% met the criteria for a current episode. The same number of patients admitted ongoing treatment due to recurrent depressive disorder. A past manic/hypomanic episode was reported by 3.9% of patients, and bipolar disorder by 2.9%. None of the patients met the criteria for a current manic/hypomanic episode or reported past mood disorders with psychotic features. In regards to anxiety disorders, the most common was generalized anxiety disorder (10.7%), followed by agoraphobia (8.7%), panic disorder (7.8%), social phobia (4.9%), obsessive-compulsive disorder (2.9%), and posttraumatic stress disorder (1.9%). For other mental disorders, we had 3 patients reporting past psychotic disorders, current psychotic disorder, and harmful use of alcohol, while 2 other patients from the group were diagnosed and treated due to bulimia nervosa. Among those in the studied group, alcohol addiction, psychoactive substance addiction/harmful use, anorexia nervosa, antisocial personality, and intellectual disability were not detected ( Table 2). In regards to suicide risk, most of the patients (94.2%) at the time of the psychiatric evaluation presented a low level of suicide risk, while 1.9% of patients presented a medium risk and 3.9% -a high risk. In comparison, in the clinical psychiatric examination, the most frequent psychiatric disorders diagnosed according to the International Statistical Classi cation of Diseases and Related Health Problems (ICD-10) were depressive episodes (F32) and organic mood disorders (F06.3) (24.3%), followed by anxiety disorders (F41) (11.7%), and adjustment disorders (F43.2) (10.7%). In addition, mild cognitive disorder (F06.7) (7.8%), bipolar affective disorder (F31) (2.9%), and schizophrenia (F20.0) (1.9%) were present (Fig. 1).  Intellectual disability 0 0.0 In the study, the general demographics and clinical characteristics of patients experiencing current and past affective disorders and affective disorders with coexisting anxiety disorders (from the group of diagnoses F33 and F40-43) were examined and compared. The results showed no statistical signi cance in terms of gender. Also, the acquired data showed no signi cance in regards to age, duration of the disease, and scoring obtained on the EDSS scale (Graph 1, 2, 3).

Discussion
Most of the published studies assessing the prevalence of psychiatric disorders in multiple sclerosis patients were conducted in the countries of the northern hemisphere (Europe and the USA being the leading centres of research in the eld) with a variety of limitations resulting also from the different tools used for analysis of psychiatric diagnosis (validated and non-validated questionnaires, structured . In regards to anxiety disorders, the most common was generalized anxiety disorder (GAD) diagnosed in 16.7% of respondents, while the second most common was panic disorder (PD) detected in 3.3%. Other disorders from the anxiety axis were absent (22). Our study, by using a very similar study protocol and tools, also con rmed that the mood and anxiety disorders are the most prevalent among MS patients, however we noted a higher percentage of depressive episodes throughout life, a lower percentage of bipolar disorders, as well as a more diverse spectrum of anxiety disorders in comparison to Cerquiera et al. Attention should be paid to the 54% of patients with MS who were simultaneously treated for additional somatic diseases, which could affect the severity and increase the incidence of mental disorders (36).
Because the study concerned patients with changes in the structure of the CNS, the questionnaire method was supplemented by a psychiatric examination, which allowed for the diagnosis of clinical psychopathological symptoms characteristic of organic changes and mood disorders that did not meet the criteria for diagnosis in the MINI questionnaire. Almost the entire study group was diagnosed with demyelinating lesions in the CNS which were revealed through the MRI examination. This is a very important etiological factor that can initiate, exacerbate or sustain the existence of mental disorders (most often cognitive disorders) (37). Other causes of comorbidity of mental disorders include adaptation di culties related to limitations, symptoms and social problems associated with MS, genetic susceptibility, structural brain abnormalities, the association between depression and immunological and in ammatory changes, drug therapies causing psychiatric disorders, and personality traits that predispose an individual to the occurrence of mental disorders and diseases (38) (13). However, Gasim et al. presented in their work that there is no correlation between MS treatment and an increased risk of psychiatric symptoms caused by disease-modifying therapies (DMT) (39). The conducted psychiatric examinations of the discussed group revealed the occurrence of depressive disorders, detailing depressive episodes or organic mood disorders in 24% of MS patients, anxiety disorders in 11.9%, depressive disorders related to stress in 10.7%, and cognitive disorders in 7.8%. In other studies and reports, cognitive impairment affects 43-70% of the group. The small number of respondents who were found to have cognitive impairment in a psychiatric examination may be associated with the failure to use additional tools and tests to detect cognitive impairment, beyond interview and medical examination; this is one of the important limitations of this work. Reports analyzing the occurrence of mental disorders in MS only on the basis of a medical examination are few and the results obtained correspond to the results of the current work (40).
Galeazzi et al. evaluated 50 patients with relapsing-remitting MS in Italy using the SCID-I to diagnose lifetime and current Axis I psychiatric disorders. In regards to affective disorders, the results showed that 46% of respondents had depression over the course of their life, 6% had bipolar disorders, and 10% had dysthymic disorders. In regards to anxiety disorders, 36% of respondents had any of the anxiety disorders, with simple phobia being the most common (12%) (41 depressive disorder was found in 3.0% of the population; it was signi cantly more frequent in women (4.0%) than in men (1.9%). Prevalence in men was not age-related, while in women major depressive disorder occurred signi cantly more frequently after the age of 50 (5.5%) than in women aged 18-29 (2.7%) and 30-39 (3.3%). Lifetime generalised anxiety disorder was found in 1.1% of the studied population, signi cantly more often in women (1.5%) than in men (0.6%) (54). This shows that the prevalence of mood and anxiety disorders is signi cantly higher in Poland than in the general population.
The most important limitations of this work are the small group of respondents with different forms of MS as well as a lack of accurate assessment of the severity of depressive disorders and cognitive impairment. The study did not exclude patients in the condition of exacerbation of the underlying MS disease, which could have in uenced the number of patients meeting the criteria for the diagnosis of a speci c mental disorder. We also recognize the limitations of this study resulting from data obtained through the MINI while the ICD10 is the most-used classi cation method in the country and medical records of the patients, along with the clinical psychiatric examination performed, are provided on the basis of the latter. In addition, we are aware of the multilateral model of mental health condition of the MS patients and the need of the more holistic assessment. (55) Conclusion Page 10/15 The study con rmed a signi cantly higher prevalence of mental disorders among MS patients; thus, the psychiatric state of patients in this group should be investigated systematically, simultaneously with the assessment of their neurological state. Literature analysis and the current work con rm the need for a detailed diagnosis of co-occurring problems of MS patients in order to determine the optimal, personalized therapy plan.

Declarations
Ethics approval and consent to participate The study protocol for this cross-sectional research was presented to the Bioethics Committee at the Medical University of Silesia and received a thorough approval (No. KNW/022/KB1/136/16). All patients selected to join the study were shown a comprehensive summary of the aims and goals of the study, tools used by the researchers, and information processing conditions. Written consent was given to the participants to sign and they were informed that it can be withdrawn at any time without consequences to their basic treatment process.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests. Authors' contributions MB: research leader, design of the study, literature searches and analyses, statistical analyses, interpretation of data, manuscript writing