Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disorder of the central nervous system and the second most common cause of severe disability and decreased quality of life in young adults.
1 Neuropsychiatric symptoms are well recognized, as MS can present with primarily psychiatric or neuropsychiatric features.
2,3 Patients with MS are more likely to suffer from depression
4 and other mood disorders
5,6 compared with the general population.
7 It is also known that there is an increased risk of psychiatric disorders even before a definite diagnosis of MS is made, with a high odds ratio of 1.4.
8 Mood disorders are also associated with lower treatment compliance, poor outcomes and functional status, and overall decreased quality of life among MS patients.
9 Although symptoms of major depressive disorder (MDD) can occur before the onset of neurological symptoms of MS,
10,11 few studies have focused on the relationship between bipolar disorder (BD) and MS.
Approximately 3.4% of the general population suffers from BD,
7 the disability-adjusted years for which are greater than that for all forms of cancer or other major neurological diseases, including epilepsy and Alzheimer’s disease. This is likely due to the earlier onset and chronic disease course.
7 When misdiagnosed as unipolar depression, BD may contribute to worse quality of life and affect treatment adherence in persons with MS.
12 The initial presentation of BD may include a depressive phase or a manic phase with or without psychotic symptoms. All of these presentations have been temporally associated with MS
13–17 and pharmacological treatments of MS,
18,19 making expeditious and confident diagnosis difficult. It remains unclear whether and/or to what degree BD may, in some cases, be a prodromal feature of MS.
The objectives of this study were to assess the prevalence of BD among patients with MS using standardized psychiatric diagnostic interviews and evaluate quality of life among MS patients with BD. We also investigated whether BD occurred prior to the onset of MS neurological symptoms, as well as the influence of BD on MS diagnosis.
Results
The baseline characteristics of the studied patient population as stratified by the presence of BD are shown in
Table 1. The mean age of study participants was 49 years (median age: 51 years). The median age of participants screening positive versus negative for BD did not differ (43 years versus 52 years, p=0.09). The number of females among the MS patients without BD was 105/142 (73.9%), while 9/10 (90%) had BD (p=0.453). The majority of studied participants had a diagnosis of relapsing remitting MS.
Among the 16 participants who screened positive on the MDQ (10%), 10 participants (6.5%) scored positive for BD via SCID (p<0.001).
Bipolar disorder type 1 was more prevalent than type 2 in the study group (60% versus 30%, p<0.001). Only 50% of the participants with BD were receiving any psychopharmacological treatment (p=0.001). Interestingly, for patients with BD, 50% (5/10) were receiving either a selective serotonin reuptake inhibitor or an anxiolytic, which is not standard of care for BD.
The medical record review revealed that 66/142 (46.45%) of MS patients without the diagnosis of BD were receiving antidepressants or anxiolytics for coexisting depression/anxiety disorders, and 7% of MS patients without BD were on multiple therapies for complex psychiatric comorbidities.
There were no statistically significant differences in the age, sex, race, MS subtype, and MS disease-modifying therapies among MS patients with and without BD. There was no statistically significant association with MS disease duration and diagnosis of BD. There was a significant association between family history of BD and the presence of BD in subjects (p<0.001).
The presence of BD was associated with significantly reduced MSQOL-54 physical and mental composites (p=0.003 and p<0.001, respectively).
Tables 2 and
3 show the MSQOL-54 subgroup scores (PCS-54 and MCS-54) as stratified by the presence of BD. For PCS-54, poor health perception (p=0.011), energy fatigue (p=0.036), physical role limitations (p=0.007), social function (p<0.001), and physical health distress (p=0.003) subscales were noted to drive the differences in the PCS-54 between persons with and without BD. The differences in the MCS-54 scores between persons with and without bipolar disorders are all statistically significant, as each subscale showed p values <0.05.
Temporal relationship of onset of BD symptoms and development of neurological symptoms of MS after post-SCID telephone survey are summarized in
Table 4. Among the 10 BD patients that were interviewed via telephone, eight patients reported onset of mood symptoms prior to the onset of neurological symptoms of MS, and one patient reported concurrent mood and neurological symptoms. Three participants believed the presence of mood symptoms delayed their diagnosis of MS (
Table 4). Interestingly, physician interpretation of chart documentation showed that eight participants with BD had complained to their treating physician that the presence of their mood disorder might have delayed their MS diagnosis. The remaining chart review on two participants did not document any delay in diagnosis of MS by the presence of mood disorder.
Discussion
Our study shows a BD prevalence of 6.5% among MS patients, which is higher than what is reported in the general population (3.4%).
27 This is consistent with another report of a higher prevalence of BD in MS in Swedish
5 and Canadian
28 cohorts. Specifically, the known prevalence of BD in MS includes 0%−16.2%,
29 and a recent large population-based Canadian cohort study showed a higher BD prevalence of 4.7% compared with 2.3% in the general population.
28 That study also showed that comorbid psychiatric conditions, such as BD, MDD, anxiety, and schizophrenia, are more common in MS.
28 Similar to the prior work, our study also showed a significant association between family history of BD and BD diagnosis among MS patients.
27It has been previously shown that there is a strong association between depression and bipolar disorder type 2, as well as a poorer quality of life in MS.
12 Our study is unique in that after screening BD via MDQ, the diagnosis of BD was confirmed via gold standard diagnostication utilizing SCID administered by physicians with psychiatric training. Furthermore, the study used a more extensive assessment of quality of life by the MSQOL-54 that combines both generic and MS-specific items into a single instrument. Not only does our study show the strong association between BD and poorer quality of life in MS, but also that both physical and mental quality of life are negatively affected.
The study further analyzed the effects of subscale MSQOL-54 components in BD, and it has shown that health perception, energy fatigue, physical role limitations, social function, and physical health distress are negatively affected by the presence of BD (p<0.05). Although the subscale scores in physical function, pain, and sexual function were lower in patients with BD, it was not statistically significant. It is speculated that they can be affected by other disease mechanisms and multiple neuroanatomical pathway involvements in MS.
This suggests that multidisciplinary coordination and effective treatment of BD may potentially improve the overall quality of life in MS patients. Only 50% (N=5) of our subjects who had a diagnosis of BD were receiving any psychopharmacological treatments (p<0.001). This is an important observation because lack of psychopharmacological treatments can worsen psychiatric symptoms and adversely affect outcome,
30–33 including leading to suicidality,
34,35 lost productivity,
36 and even additional MS exacerbations.
37 This is particularly relevant to quality of life evaluations in MS, as comorbid psychiatric conditions are seemingly more prevalent, underdiagnosed, and undertreated in persons of low socioeconomic status.
9The strong association between family history of BD and BD in MS are known.
38,39 It remains uncertain whether psychiatric features of MS are part of the underlying neurobiology of the disease, comorbidities of chronic illness, or adverse reactions of treatment.
30Delays in MS diagnosis and greater disability at time of diagnosis are associated with psychiatric and medical comorbidity among MS patients.
7 Low mood among MS patients has also been associated with structural and functional brain abnormalities, suggesting that depression in MS may arise directly from the demyelination process and be of a different etiology than depression in non-MS patients.
40,41 For example, a diffusion tensor imaging study demonstrated reduced fractional anisotropy—a measure of white-matter pathology—in frontal and temporal lobes of depressed patients with MS compared with nondepressed patients with MS.
42 In addition, a recent whole-brain structural connectivity analysis demonstrated altered patterns of white-matter connectivity, specifically the right hippocampus and right amygdala, which differentiated MS patients with depression from nondepressed patients.
43A potential etiological relationship between MS and BD also has been suggested,
5 and neuroinflammation may contribute to the pathogenesis of mood disorders as indicated by positron emission tomography
44 and postmortem identification of inflammatory biomarkers.
45 It has also been suggested that there is a possible genetic association between MS and BD.
38,46,47 It has been hypothesized that MS-related inflammation relates to the mood symptoms of BD. Alternatively, mood symptoms could be exacerbated by MS treatments (e.g., interferon beta and steroids). In our study, there was no significant difference between the MS treatment agents and presence of BD diagnosis.
A number of participants reported mood symptoms preceding neurological features of MS. This is a notable observation and warrants further investigation. “Diagnostic overshadowing” is a form of bias in which somatic symptoms or complaints may be misattributed to pre-existing neuropsychiatric pathology and presumably led to delays in accurate diagnosis. It has been previously reported in children with neurological conditions, such as intellectual disability
48 and autism spectrum conditions,
49 and in psychiatric patients presenting to emergency departments.
50,51 To date, and to our knowledge, there have been no well-powered longitudinal epidemiological studies clarifying the role of diagnostic overshadowing or demonstrating symptoms of BD consistently predating MS.
In our cohort, three patients reported a delay in MS diagnosis due to their coexisting neuropsychiatric symptoms of BD during the structured telephone interview. A physician chart review documented that eight out of 10 patients with BD had reported previously delayed MS diagnosis, which was attributed to the presence of their comorbid psychiatric issues. The telephone interview may reflect a recall bias, and physician chart review may also involve bias of the physician interpreting the available chart data. It is possible that the discrepancy between the chart review and the telephone survey may be related to the inherent methodological differences in obtaining this information. Alternatively, this discrepancy may be contributed to cognitive impairment, which is relatively common among persons with comorbid MS with BD, as supported by the literature.
52 However, this possibility remains untested and unproven in this study, since we did not directly assess study participants for cognitive impairments.
Interestingly, a substantial subset of patients was prescribed antidepressants and anxiolytics. Their prescription suggests the possible presence of additional psychiatric comorbidities in the studied cohort, consistent with prior reports of such in similar cohorts of persons with MS.
4–7,12,28 However, our study was not designed to directly determine the presence of depression or anxiety disorders in our MS cohort, and the true prevalence of these conditions in this cohort therefore remains uncertain. Retrospectively evaluating the primary etiology in diagnostic delay is intrinsically difficult. To date, population based studies in Croatia,
53 Canada,
54 Denmark,
55 Spain,
56 and the United States
23,57 have documented referral and diagnostic delays in persons with MS, attributable to availability of subspecialty services, age, and nature of initial presentation. Marrie et al.,
57 in particular, have written at length about diagnostic delay in MS, citing a mean delay of 7.03 years, confirming association with age at onset and noting increased risk of delay with comorbid mental (and nonpsychiatric) confounders, which also seem to increase disability at presentation. This raises the concern that better and more thorough screening, detection, assessment, and treatment need to be done to improve patient care.
There are several limitations to this study, including the cross-sectional design, absence of a study-specific comparison cohort without MS, and relatively small size of the current study population. As the study population was drawn from a tertiary care center, it may not be representative of the general MS population, and ascertainment bias may have potentially overestimated the prevalence of BD compared with community-based samples. Moreover, given the design of the study, participant recall and misclassification bias may be present. As noted above, coexisting psychiatric diagnoses and cognitive status also were not studied, and the absence of data addressing these issues limits the scope of the findings to the comorbidity of MS and BD alone.
The SCID could not be completed for all 152 patients, and thus the sensitivity of the MDQ as a predictor of BD in this population of MS patients could not be assessed. However, despite the possible false negative rate of MDQ, our study shows higher than expected prevalence of BD in patients with MS and also particularly demonstrated the negative impact of BD on quality of life in MS. As the Expanded Disability Status Scale and MS functional composite scores were not analyzed in this study, we cannot comment on the degree of baseline functional disability in our cohort. Including these measures, as well as measures of cognitive impairment, in future studies may further improve our understanding of neuropsychiatric association between MS and BD.
It is possible that this study underestimates the prevalence of BD in persons with MS, given the utilization of the MDQ as a screening measure. The MDQ only has moderate sensitivity for the detection of BD, with the known overall sensitivity and specificity for detecting BD being 0.58 and 0.67, respectively for persons already diagnosed with BD.
58 Furthermore, MDQ is known to have even lower sensitivity of 0.281 but high specificity of 0.972 in detecting BD in the general population.
24 If these prior reports are consistent in this population, BD may have an even higher prevalence in MS than previously recognized.