Psychiatric comorbidities are a major concern in PwMS; they have been associated with fatigue and reduced QoL, and they may also impact on adherence to DMT. Psychiatric comorbidities are more prevalent in PwMS compared with the general population [
10], although the cause and effect are not yet clear. Psychiatric features of MS are a major cause of disability in PwMS, early recognition and a better understanding of how psychiatric comorbidities affect disease progression could help to determine optimal treatment, ensuring better long-term outcomes. For example, psychiatric disturbances in the incipient phase of MS may be predictive of future psychiatric illness in a considerable proportion of PwMS, so their early detection is crucial [
31].
Depression, anxiety, and bipolar disorder (Supplemental Table 2)
Mood dysfunction, including depression, anxiety, and bipolar disorder, is more common among PwMS than in the general population [
10,
32]. Mood disorders are also associated with rapid disease progression and overall decreased QoL among PwMS [
14], and can occur before the onset of neurologic symptoms of MS [
33].
Depression in PwMS is likely to be, in part, a reaction to physical disability, such as problems with balance and walking, [
34,
35] or other defined MS symptoms such as fatigue [
36,
37]. Recent studies indicate that an inflammatory component, involving several pro-inflammatory cytokines, such as interferon gamma and tumor necrosis factor alfa may be associated with mood disorders [
38] and that structural brain alterations may also play a role [
39].
Prevalence studies on psychiatric comorbidities (N = 42) examined patients in Europe (n = 12), the USA and Canada (n = 19), Brazil (n = 1), Australia (n = 3), the Middle East (n = 9) and Taiwan (n = 2). These studies (Supplemental Table 2) were reported using numerous different neurologic and diagnostic tools: Athens Insomnia Scale; Beck Anxiety Inventory; Beck Depression Inventory Fast Screen; Beck Depression Inventories; The Center for Epidemiologic Studies—Depression scale; Diffuse Axonal Injury; Expanded Disability Status Scale; Epworth Sleepiness Scale; Fatigue Scale for Motor and Cognitive Functions; Functional Assessment of Multiple Sclerosis; General Health Questionnaire 12; Godin Leisure-Time Exercise Questionnaire; Hospital Anxiety and Depression Scale for depression and anxiety; International Classification of Diseases; Multiple Sclerosis International Quality of Life questionnaire; Numeric Rating Scale; Patient Health Questionnaires; Perceived Stress Scale; Patient-Reported Outcomes Measurement Information System; State-Trait Anxiety Inventory.
The frequency of mood disorders in PwMS is high and significantly elevated when compared with control groups, but prevalence levels vary substantially according to the studied population and the research methods used. Most of the studies were cohort studies without control subjects and overall, global prevalence rates for depression and anxiety ranged from 21.1–59.4% to 28.1–57.0% for depression and anxiety, respectively. Several studies reported depression at ~ 35% [
40‐
49] and anxiety at ~ 55% in PwMS [
43‐
46,
49‐
52], and exceptionally low rates were observed for studies performed in Abu Dhabi (10.8–17.5% for depression and 4.8–20.0% for anxiety) [
53,
54]. Jun-O'Connell et al. reported an increased prevalence of bipolar disorder in PwMS in a cohort from the US (type 1 was more significantly more prevalent than type 2 in the study group: 60% versus 30%, respectively), although this study lacked a control group. Moreover, the majority of these patients reported mood disorders before MS diagnosis, which may have delayed initial consideration of MS [
32]. Given that the prevalence of psychiatric conditions is profoundly influenced by geographical location [
55], global trends in comorbidity data in PwMS should be interpreted cautiously. For example, anxiety appears to be more common in cultures with European/Anglo roots than others, with the lowest prevalence reported in African cultures, irrespective of MS prevalence [
56].
The relationship between different aspects of depression and anxiety may also change throughout the disease course; for example, Hartoonian et al. found that non-somatic symptoms were more strongly associated with anxiety early in the disease and somatic symptoms were more prominently linked to anxiety later in the disease [
57]. Some researchers have studied the lifetime prevalence, while others have looked at point prevalence in the course of MS. Although often coexisting, depression and anxiety may be associated with distinct aspects of cognitive impairment and functional outcomes [
43,
58]. Point prevalence data lack insight on disease trajectory, which is key to understanding optimal monitoring of PwMS, particularly for those comorbidities that are associated with disability at baseline [
59]. Physicians should ideally follow PwMS—not only in exacerbation of psychiatric symptoms but also those who report recent increases in somatic depressive symptoms—as these conditions may forecast an upcoming clinical exacerbation [
60], which may be crucial when considering MS prognosis.
Epilepsy (Supplemental Table 3)
Epilepsy is more prevalent in PwMS compared with the general population [
21]. Although frequently conceptualized as a white matter disease, MS lesions are also present in gray matter, potentially interrupting neuronal circuits. However, it is not clear whether epilepsy is triggered by the initiation of MS or whether MS is a risk factor for developing epilepsy. Structural abnormalities in PwMS, such as cortical demyelinating lesions appearing in early MS [
61] or edema surrounding the foci, may be involved [
62], but MRI data are non-conclusive [
63].
Studies on the prevalence of epilepsy (Supplemental Table 3,
N = 11) include physician reported, hospital admissions, and administrative health data from Europe (
n = 5), South America (
n = 2), Canada (
n = 1), and Iran (
n = 2). The reported prevalence of epilepsy in PwMS ranged from 1.9% to 7.6% in MS (~ 3% in 4 studies) and this increased to 8.5% in early-onset MS. Epilepsy and disability were robustly associated, reaching a cumulative incidence of 5.3% in patients with MS with an EDSS score 7 [
63], indicating the importance of this comorbidity in relation to prognosis and outlook for PwMS.
It is important to consider that Epilepsy is highest in central Latin America, Chile, North Africa, the Middle East, and Bangladesh, where studies of PwMS and comorbid epilepsy are few or non-existent [
64].
Restless leg syndrome (RLS) (Supplemental Table 4)
RLS is characterized by an irresistible urge to move the legs and often accompanied by unpleasant sensations and nocturnal occurrence. RLS can severely disturb sleep and QoL of PwMS and is more frequent in PwMS than in the general population [
21]. The mechanisms in RLS are not fully understood in PwMS, but may involve aberrant signaling in the dopaminergic system caused by demyelinating or neurodegenerative damage to the diencephalospinal tract [
65,
66].
Several cohort studies, cross-sectional studies, and metanalyses have investigated the epidemiology of RLS in PwMS (Supplemental Table 4,
N = 10). RLS prevalence was found to be elevated in PwMS with an odds ratio of 3–4 in PwMS versus control subjects. In agreement with observations by Minar et al. [
66], RLS prevalence varied widely from study to study, ranging from 12.12 to 57.50% in PwMS and 2.5% to 18.3% in controls, one study reported faster MS progression in those patients with concomitant RLS [
67]. Supporting the concept of dopaminergic involvement in RLS in PwMS, data from two studies showed that the risk of RSL increased in PwMS with spinal cord lesions [
66,
68]. Globally, different regions were well represented across studies, including Europe (
n = 3), Asia (
n = 2), the Middle East (
n = 2), and South America (
n = 1), and notably, RLS was more prevalent in PwMS outside of Asia (27%) than inside Asia (20%) [
65].