The manifestation of affective symptoms in multiple sclerosis and discussion of the currently available diagnostic assessment tools

Introduction In addition to physical and cognitive symptoms, patients with multiple sclerosis (MS) have an increased risk of experiencing mental health problems. Methods This narrative review provides an overview of the appearance and epidemiology of affective symptoms in MS such as depression, anxiety, bipolar disorder, euphoria, and pseudobulbar affect. Furthermore, the association between affective symptoms and quality of life and the currently used diagnostic instruments for assessing these symptoms are considered whereby relevant studies published between 2009 and 2021 were included in the review. Results Patients with mild and moderate disability more frequently reported severe problems with depression and anxiety than severe mobility problems. Apart from the occurrence of depression, little is known about the association of other affective symptoms such as anxiety, bipolar disorder, euphoria, and pseudobulbar affect and subsyndromal symptoms, which fail to meet the diagnostic criteria but are nevertheless a significant source of distress. Although there are a few recommendations in the research to perform routine screenings for diagnosable affective disorders, a standardized diagnostic procedure to assess subsyndromal symptoms is still lacking. As the applied measurements are diverse and show low accuracy to detect these symptoms, patients who experience affective symptoms are less likely to be identified. Discussion In addition to the consideration of definite psychiatric diagnoses, there is an unmet need for a common definition and assessment of disease-related affective symptoms in MS. Future studies should focus on the improvement and standardization of a common diagnostic procedure for subsyndromal affective symptoms in MS to enable integrated and optimal care for patients.


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Background Apart from physical symptoms, most patients with multiple sclerosis (MS) experience cognitive deficits [1] and affective symptoms which may negatively affect their social and family life, thereby contributing to the burden of the disease [2,3]. Significantly, patients are found to experience severe affective symptoms at all levels of disease severity and patients with mild and moderate disability (EDSS 0-6.5) reported severe problems with depression and anxiety even more often than severe mobility problems [3].
The lifetime prevalence of affective disorders such as major depression or anxiety disorders in MS can be as high as 50% [4][5][6] and is thus substantially higher than in the general population [7,8]. Several factors may mediate the occurrence of affective symptoms, including socioeconomic status, age, sex, and the region of residence. Even when these factors are controlled for, there remains a significantly higher annual prevalence risk of affective symptoms in patients with MS when compared to the general population [9]. While the prescription of steroid therapy [10] as well as of some disease modifying treatments is associated with subsequent risks of mood disturbance, such as depressive episodes [11], manic and psychosis [10,12] the etiology and pathogenesis of these comorbidities are still poorly understood.
There are also indications that affective symptoms become apparent at an early stage of the disease, even before the definite diagnosis of MS [13][14][15], and remain stable for at least 3 years [16]. Support for this assumption comes from a recent retrospective cohort study in which an association between stress-related disorders and an increased risk of subsequent autoimmune diseases was shown [17]. The association between autoimmune disease and affective disorders also indicated an immunological contribution to the development of affective symptoms [18] and hence affective symptoms may comprise the first manifestations of MS [15]. From this, it can be inferred that the presence of neuropsychiatric comorbidities indicates a clear need for intervention as early as possible [14,19].
Nevertheless, there is evidence suggesting that affective symptoms are still underdiagnosed and undertreated in the clinical standard care of patients with MS [20,21]. Against this background, in this narrative review, we provide an overview of the incidence and prevalence of affective disorders and symptoms in MS and their impact on quality of life, as well as the current clinical assessment options.

Methods
Included in this narrative review were studies with findings on the appearance and epidemiology of affective symptoms and disorders which include depression, anxiety, bipolar disorder, euphoria, and pseudobulbar affect (pathological laughing and crying) in patients with MS. Furthermore, studies focusing on the association between the mentioned affective symptoms or disorders and quality of life were considered, and the findings from the available diagnostic assessment tools are discussed. The literature search was limited to studies that were published between 2009 and 2021, even though a few selective earlier studies were also included if they showed basic insights concerning the covered domains. Case reports were not included. The articles of interest were identified in the ISI Web of Science, Sci-enceDirect, PubMed, EBSCO Psychology (PsycINFO, PsycARTICLES, PSYNDEXplus), Google Scholar, and Cochrane library.

Results
The 65 analyzed articles for this literature review are displayed in the appendix (Tables 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13), sorted chronologically by year (and alphabetically by author name). The tables contain information about the first author, publication year, investigated symptom or disorder category, total sample size of MS population, age, gender, country of data, included diagnostic assessment tools, main findings, and comments.

Depression
According to cross-national data, major depression represents one of the most common affective disorders with a lifetime prevalence of 20% in the general population [22]. In patients with MS, depression seems to occur more often [23][24][25][26][27] and there is evidence suggesting that patients with MS show a risk of up to 50% of developing major depression in their lifetime [28]. In comparison to the general population, patients with MS have been found to show an elevated point prevalence in depression by 9.3% [8] up to 23.7% [5]. Adjusting for age and sex, the incidence of depression was found to be 71% higher in a group of patients with MS than in a matched healthy control sample [6]. When considering self-reports only, depression rates were even higher. For example, 54% of the patients with MS in the United Kingdom were found to experience depression at some point in their life [29].
In the general population, depressive symptoms are reported to be more frequent in females (12.4%) than in males (6.1%) [8]. However, Théaudin and colleagues [30] did not find any evidence of sex differences concerning depression in MS patients.
Furthermore, compared to patients experiencing depressive symptoms without underlying medical illness, patients with MS showed a comparable clinical presentation of depressive symptomatology. The observed differences between depressive patients and patients with MS were found in specified symptoms: fatigue and irritability were pronounced in patients with MS, while anhedonia and loss of interest were pronounced in patients with a Major Depression [24,31].

Anxiety
Compared to the lifetime prevalence rates for depression, the reported prevalence rates of an anxiety disorder or anxiety symptoms in MS (general anxiety disorder, social anxiety, agoraphobia, etc.) are more homogeneous, ranging from 20 to 44.5% [32][33][34][35][36]. According to the World Health Organisation (WHO), 8.5% of people in the normal population experience a general anxiety disorder. In contrast, Poder and colleagues (2009) showed that 30.6% of patients with MS were diagnosed with social anxiety disorder, while half of these patients were also diagnosed with general anxiety [37]. Compared to the general population, patients with MS were found to show a higher point prevalence in generalized anxiety disorder by 2.2% [8]. The systematic review by Marrie and colleagues in 2015 also revealed an elevated average point prevalence for anxiety of 21.9% in the MS population [5]. An increased risk of anxiety was found in the pre-and post-diagnostic period of MS, compared to control groups [7,38]. Female patients with MS and patients with a relapsing-remitting disease course and a worse degree of functional disability showed higher symptoms of anxiety [29,30].
After adjusting for age and sex, the incidence of an anxiety disorder was still 42% higher in patients with MS than in a matched healthy control sample [6]. In a recent meta-analysis, Boeschoten and colleagues (2017) demonstrated that 22.1% of patients with MS were affected by anxiety [35]. As is the case for depression, when considering self-reports only, anxiety rates were higher as 46.9% of patients with MS in the United Kingdom indicated experiencing anxiety at some point in their life [29].

Interaction of depression and anxiety
With respect to the interaction between depression and anxiety in patients with MS, the results are inconsistent. Some studies indicate that depression and anxiety may be interdependent [33,39] while more recent findings show that nonsomatic symptoms of depression (excessive worry, fear of losing control, inability to relax, etc.) and employment status were risk factors for higher levels of anxiety symptoms in MS [40]. Askari et al. (2014) concluded that depression and the disability level are independent predictors of anxiety [32]. Other studies revealed that the relationship between different aspects of depression and anxiety might change over the course of MS, such that patients may report a stronger link between somatic symptoms of depression with symptoms of anxiety at later disease stages than at earlier stages [40]. Kehler and Hadjistavropoulos (2009) showed that patients with MS and depression had higher levels of health anxiety, the fear or worry about health, compared to an age-matched control group [41]. Nevertheless, although there are no clear correlations between anxious and depressive symptoms in patients with MS the suffering of pressure in the medical history of the affected patients is indisputable.

Bipolar disorder
A further manifestation of affective disorder that should be considered in patients with MS is a bipolar spectrum disorder. Although findings vary from country to country, a large cross-sectional survey across 11 countries found the overall lifetime prevalence of bipolar spectrum disorder to be 2.4% in the general population [42]. There are currently only a few findings concerning the epidemiology, prevalence, and incidence of bipolar disorder in MS patients or correlations between MS and bipolar disorder [12]. Relative to age-and sex-matched controls, Carta and colleagues (2013) reported an odds ratio of 44.4 for experiencing a bipolar disorder together with MS [43].  reported a lifetime prevalence of up to 16.2% in patients with MS. An increased lifetime prevalence of bipolar spectrum disorder (bipolar disorders type I and II and cyclothymic disorders) has also been reported for patients with MS when compared to age-and sex-matched controls [5]. After adjusting for age and sex, the incidence of bipolar disorder was 99% higher in MS patients than in the matched healthy population [7].

Euphoria
Pathological euphoria as one component of the affective symptoms in MS was first described in the nineteenth century, whereby approximately 10% of the patients were diagnosed to be affected by the pathological expression of euphoria [44]. Given that there was no guidance for a common operationalization of euphoria in patients with MS, different subsequent definitions must be considered. Cottrell and Wilson (1926) provided a classical description of euphoria in which three associated but independent types of euphoria are distinguished [45,46]: (1) "euphoria sclerotica": a mental state or mood of cheerfulness and happiness; (2) "eutoniasclerotica": a feeling of being physically well despite physical deficits; patients in this state are convinced that they can do anything and they are oblivious of their actual physical disability; and (3) "spessclerotica": 1 3 a great optimism concerning the future and the prospects of complete recovery from the symptoms [46]. Based on this definition of "euphoria sclerotica," Paparrigopoulos et al. (2010) described euphoria as a fixed mental state of unusual cheerfulness and optimism about the future despite the presence of a neurological disability. The authors suggested that euphoria should be regarded as a personality change that should be considered distinct from hypomania despite having superficial similarities with it [26]. Duncan et al. (2015) put forward a contemporary definition of euphoria as an "overly optimistic" or "unrealistic optimism" [45]. Using the classical euphoria definition and interviewing method developed by Cottrell and Wilson (1926), Duncan et al. (2016) found high proportions of Cottrell and Wilson's three types of euphoria (between 63 and 70%, depending on the type of euphoria) in patients with MS. In contrast, using a more contemporary definition and measurement instrument (questions of the Neuropsychiatric Inventory by Cummings (1997) [47]), only 11% of patients with MS were diagnosed as having symptoms of euphoria. The proportions of Cottrell and Wilson's three types of euphoria in the control group varied between 86 and 94% and thus were significantly higher than the proportions found in the MS group. In contrast, when the Neuropsychiatric Inventory was used, the proportion of persons diagnosed with euphoria in the control group was 4% and thus was lower than the proportion found in the group of patients with MS although the relevant statistical test narrowly missed the conventional criterion of statistical significance [48]. Nevertheless, there are some clear correlations, and patients with symptoms of euphoria were more likely to suffer from a progressive disease form and showed more significant structural pathology [45].

Pseudobulbar affect
A particular type of affective symptom that occurs in patients with MS is pseudobulbar affect. This affective disinhibition syndrome is also known as pathological laughing and crying and is characterized by spontaneous, involuntary, and uncontrollable outbursts of contextually inappropriate laughing or crying that are inconsistent with the patient's underlying feelings or incongruent with external triggers [49]. Uncontrollable crying seems to be more common than laughing and this mood disturbance has been described in 10% of the MS patients [50]. There are no studies on the prevalence rate of pseudobulbar affect in the general population [49]. A recent study suggests that there may be a relationship between the occurrence of pseudobulbar affect and cognitive impairment in patients with MS. Specifically, deficits in processing speed, visuospatial memory, verbal learning, and fluency in patients with MS have been reported to be associated with pseudobulbar affect [51]. Although more scientific evidence is needed in this area, based on previous indications attention should also be given to pseudobulbar affect in the care of patients with MS.

Association between affective symptoms and quality of life
Affective symptoms such as depression, anxiety, and bipolar disorder are associated with decreased adherence to MS treatment [52], more unfortunate disease progression, cognitive deficits [33], higher suicide risk [53], and reduced quality of life [3,20,27]. Depressive symptoms were found to covary with fatigue and reduced cognitive performance, especially concerning information processing speed, attention, working memory, and executive function [54]. Both symptoms of fatigue and reduced cognitive performance may severely affect patients' quality of life.
Higher levels of health anxiety are associated with greater emotional preoccupation, more use of social support, and reduced use of adaptive coping strategies to manage disabilities in MS [41]. Recent findings show an association between emotional dysregulation and lower health-related quality of life. Maladaptive strategies and difficulties in regulating emotions mediated the associations of depression and anxiety with the quality of life in patients with a progressive course of MS [55].
There seem to be no studies on the possible interactions of euphoria or pseudobulbar affect with important aspects of quality of life such as physical disability or cognitive impairment. The most elaborated studies on quality of life in patients with MS with affective symptoms are available for depression.
Early studies seemed to indicate that greater disease severity and shorter disease duration may be associated with a clinically significant level of depressive symptoms in patients with MS [56]. However, there are also controversial findings concerning the correlation between depression and physical limitations in patients with MS: previous findings provided no evidence of a direct relationship between depression and the Expanded Disability Status Scale [57] as a measure of physical disability in MS [58]. More recent findings showed that patients with MS and comorbid depression had a significantly increased risk of worsening disability [59]. The presence of depression, anxiety, or bipolar disorder was associated with a higher EDSS score in female patients with MS (adjusted for disease duration and progression, age, sex, socioeconomic status, physical comorbidity count, and disease-modifying therapy exposure) [60]. Furthermore, Honarmand et al. (2011) reported a strong association between unemployment and the severity of depression in MS. This work highlighted the need to consider more than physical functioning for the prediction of the employment status as an essential aspect of quality of life [61].

Diagnostic assessment tools
Although there are a few recommendations in the research to perform routine screenings for diagnosable affective disorder in MS, clinicians generally collect information about affect symptoms through unstructured and semi-structured interviews [62][63][64], and a clear diagnostic procedure is still lacking [21,35].
Specifically, affective symptoms deserve more attention in patients with MS given that they have a substantial impact on disease progression and quality of life [27]. Mood disturbances may reduce the ability to cope with disabilities in MS [39,41], cognitive performance [33,54], and adherence to therapy [52]. However, it is important to note that despite the apparent plausibility, causal interpretations of the typically correlational findings in this domain are not warranted.
An overview of the diagnostic methods used for diagnosing affective disorders and symptoms in MS is provided in Table 1. In clinical contexts, a semi-structured interview is applied to identify DSM-IV diagnoses (SCID) including anxiety and depression [65]. However, this method is time-consuming and thus is seldom used in clinical practice for the care of patients with MS. Typically, self-reporting measures are used instead and a systematic review revealed the need to assess the utility of these measures [66]. The following screening measures for depression were frequently reported: the Beck Depression Inventory-II (BDI-II) [67], the Center for Epidemiologic Studies Depression rating scale (CES-D) [68], and the Chicago Multiscale Depression Inventory (CMDI) [69]. Regarding screening measures for anxiety, the following self-reporting measures are partially validated and usually used in MS: the Beck Anxiety Inventory (BAI) [32], and the Anxiety 7-item and Generalized Anxiety Disorder Scale (GAD-7) [70]. Some measures assessing both depression and anxiety that are used include the 9-item Patient Health Questionnaire (PHQ-9) [71], the Hospital Anxiety and Depression Scale (HADS) [68,72], and the Patient-Reported Outcome Measurement Information System (PROMIS) [66]. A systematic review confirmed the need for early intervention and treatment of anxiety throughout the course of MS [73]. Therefore, research has already addressed the need for improvement in diagnosing depression [74,75] and anxiety [70,72,75] in MS. The Hospital Anxiety and Depression Scale has become a widely used screening instrument in patients with MS and it can be considered a valid instrument for assessing symptoms of both depression and anxiety [76].
A more specialized instrument for manic and hypomanic symptoms is the Mood Disorder Questionnaire, which is a standardized screening questionnaire [77]. It is the most widely studied screening instrument for bipolar disorder [77] and has been applied in patients with MS [78]. Unfortunately, both the sensitivity and specificity of this instrument are low [77]. To detect and measure the severity of a pseudobulbar affect, the self-reporting method known as the Center for Neurologic Study-Liability Scale (CNS-LS) includes two subscales measuring labile laughter and tearfulness [12]. However, the CNS-LS was not developed for use in MS and a disease-related diagnostic procedure for euphoria does not seem to exist.
A considerable number of studies have revealed that the instruments to measure diagnosable affective symptoms which have been validated in patients with MS show similar characteristics and correlate with each other [65,79] whereby there was no clear superiority of one instrument over the others. The instruments shared high negative predictive values; therefore, clinicians could exclude the presence of a definite diagnosis of depression or generalized anxiety disorder, although the diagnostic accuracy was low. Consequently, individuals with scores that are elevated but still below the cut-off points may experience subsyndromal symptoms, which are not discovered but also warrant clinical attention. Furthermore, a recent study in this context showed that less obvious symptoms such as social and emotional health problems can be more relevant in identifying mood disturbances in patients with MS than anxiety and depression [80]. This underpins the role of subsyndromal affective symptoms and the need for the identification of individuals with symptoms below the cut-off points of definite diagnostic criteria in the context of MS.

Discussion and conclusion
This narrative review shows a large range of prevalence and incidence rates of affective symptoms in MS such as depression, anxiety, bipolar disorder, euphoria, and pseudobulbar affect. Focusing on individual studies could thus easily lead to an underestimation of the rates at which these affective symptoms occur [21].
One reason for the wide range in prevalence and incidence rates of affective symptoms in MS may be the use of widely varying diagnostic methods. However, even the lower ends of the reported prevalence and incidence rates suggest that a substantial proportion of patients with MS experience affective disorders and symptoms. Affective symptoms may even be the first manifestation of the disease [14,15,19]. Although pathological mood expressions such as euphoria and pseudobulbar affect were already identified in the first description of MS [44], investigations concerning symptoms that do not meet the criteria for a diagnosable disorder are still rare.
In addition to a few recommendations to screen patients with MS for definite psychiatric disorders [62][63][64]81], there are no recommendations concerning how to proceed if symptoms fail to meet diagnostic criteria but are nevertheless a significant source of distress [63]. Such subsyndromal affective symptoms are reported spontaneously by individuals or collected in response to the demand of the clinicians (through interviews, questionnaires, checklists, or severity rating scales) but do not meet the diagnostic criteria (e.g., duration, intensity, and impact of functioning) of definite psychiatric diagnoses [63]. Most of the assessments used focused on single symptoms, which have been partially validated for use in MS patients but not specifically developed for this purpose. A first indication of how relevant subsyndromal symptoms are in dealing with emotional states was derived from a recent study which showed that symptoms such as social and emotional health problems in MS that are less obvious than anxiety and depression are important for the mental health of patients with MS [77]. Neglecting these symptoms would be problematic given that they are negatively associated with the quality of life of MS patients [18,25,78]. These deficiencies point to the need for an MSrelated assessment tool to also detect subsyndromal affective symptoms in the clinical care of patients with MS.
The lack of a common procedure and sensitive assessment tool for less obvious or subsyndromal affective symptoms can partly explain the reason why the occurrence of affective symptoms is still underestimated and as a result, often remain untreated [21,65]. Future studies are needed to facilitate better insights into the interaction of these symptoms and the underlying pathophysiology [50]. The elaboration of a common definition of relevant MS-related affective symptoms and mood disturbances, including relevant subsyndromal symptoms, should be focused on in future investigations as a deeper understanding of these issues could improve the care of MS patients. Translating these findings into a definition of a standardized diagnostic procedure is necessary for integrated treatment methods, including essentially the aspects of mental health. Tables 2,3,4,5,6,7,8,9,10,11,12,13.      Quality of life,

SF-12
Short-Form-Health Survey, SPMS Secondary progressive MS, ZSRDS Zung Self-Report Depression Scale    ICD-9/-10 The annual incidence of depression per 100,000 persons with MS was 979 while the incidence of anxiety was 638 of bipolar disorder was 328, and of schizophrenia was 60. The incidence and prevalence estimates of all conditions were higher in the MS population than in the matched population. Although the incidence of depression was higher among women than men in both populations, the disparity in the incidence rates between the sexes was lower in the MS population than in the matched population. Incidence rates were stable over time while prevalence increased slightly     The MS group demonstrated high frequencies of euphoria using the classical measure but low frequencies using the contemporary measure and definition. The matched control group demonstrated significantly higher rates than the MS group using the classical measure and lower rates than the MS group using the contemporary measure.
The discrepancies in incidence rates of euphoria noted in the literature do not reflect a change in the incidence of euphoria in MS, but rather in the definition and operationalization of "euphoria"  Table 9 (continued) Author, year  has not been well studied, but available data on detection and treatment align with general principles of depression management While the validity of standard measurement scales has often been questioned, available evidence suggests that standard scales provide valid ratings    Funding Open access funding provided by University of Bern. This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest Melanie Filser has no conflict of interest. Axel
Buchner has no conflict of interest. Gereon R. Fink has no conflict of interest. Stefan M. Gold: Honoraria/speaker fees from Mylan, Almirall, and Celgene. Research grants from Biogen and kind support from the GAIA Group. Iris-Katharina Penner: Honoraria/speaker fees from Adamas Pharma, Almirall, Bayer Pharma, Biogen, BMS, Celgene, Desitin, Genzyme, Janssen, Merck, Roche, Novartis, and Teva. Research support from the German MS Society, Celgene, Teva, Roche, and Novartis. All listed potential conflicts of interest are outside the context of this article's research, authorship, and publication.
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