1. Bipolar disorder and resembling special psychopathological
manifestations in multiple sclerosis: a review
Apostolos Iacovides and Elias Andreoulakis
3rd Department of Psychiatry, Aristotle University of Purpose of review
Thessaloniki, AHEPA General Hospital, Thessaloniki,
Greece
The higher prevalence of psychiatric disorders in multiple sclerosis (MS) compared with
the general population is well documented, with depression being the leading disorder.
Correspondence to Apostolos Iacovides, PhD, MD,
Professor Psychiatry, Director of 3rd Department of Apart from depression, other psychiatric disorders and symptoms such as bipolar
Psychiatry, Aristotle University of Thessaloniki, AHEPA disorder, pseudobulbar affect, euphoria sclerotica, anxiety and personality changes are
General Hospital, 1, St Kyriakidi Str, Thessaloniki
54636, Greece also reported to be overpresented in MS patients. Psychiatric disorders in MS lead to
Tel: +30 231 0994 626; fax: +30 231 0994 623; significant disruption in patients’ family, work and social life, affecting patients’ quality of
e-mail: apiacov@med.auth.gr
life in general. Moreover, they are reported to be associated with poorer adherence to
Current Opinion in Psychiatry 2011, 24:336–340 MS medication. The literature concerning bipolar disorder and affect disorders in MS is
rather scarce. The purpose of this article is to provide a critical review on the latter
subject.
Recent findings
This review focuses upon the recent findings with regard to the epidemiology and the
comorbidity rates of bipolar and affect disorders in MS, questions raised about the
potential underlying mechanisms that could explain such a high comorbidity, diagnostic
issues and the recent developments in the treatment of those psychiatric disorders in
MS.
Summary
Despite the fact that the higher prevalence of psychiatric disorders in MS is well
established, such disorders still remain underdiagnosed and undertreated. A shift in the
clinical suspicion towards the psychiatric morbidity in MS patients and the optimal
treatment of those disorders is fundamental.
Keywords
affect, bipolar, euphoria, mood, multiple sclerosis, pathological laughing and crying,
pseudobulbar affect
Curr Opin Psychiatry 24:336–340
ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
0951-7367
The neuropsychiatric manifestations in MS fall into two
Introduction broad categories: disorders of mood, affect and behavior
The occurrence of psychopathological symptoms and
on the one hand, and cognitive impairment on the
signs in multiple sclerosis (MS) was underlined and
other, with considerable overlapping between these
systematically described as early as in 1877 by Charcot.
two categories. As far as mood and affect disorders
The psychopathological symptoms mentioned included
are concerned, they are mainly represented by major
pathological laughing and weeping (also variably termed
depression, bipolar disorder, euphoria and PBA.
nowadays ‘pseudobulbar affect’ (PBA), ‘emotional
incontinence’, or – most recently – ‘involuntary The main body of the literature focuses on the comorbid
emotional expression disorder’), euphoria, mania, depres-
depression found in MS, whereas the bibliography
sion and hallucinations.
concerning bipolar disorder, euphoria sclerotica and
PBA remains rather scarce. This disproportion obviously
Psychiatric symptoms are regarded as occurring more reflects the fact that depression is the most frequent
commonly during the evolution of MS. Although among psychiatric disorders seen in MS, with a lifetime
there are a few case studies reporting such symptoms prevalence reaching 50% and a 12-month prevalence of
as the initial manifestations of MS, this phenomenon is 15.7%, the latter being twice as high as in the general
thought to be rather uncommon. According to Fermo population (odds ratio: 2.3) [2].
et al. [1], the frequency of psychiatric symptoms among
the presenting manifestations of MS ranges from 0.2 The purpose of this article is to provide a critical review of
to 2%. the recent findings with regard to the relationship of MS
0951-7367 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/YCO.0b013e328347341d
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

2. Bipolar disorder in multiple sclerosis Iacovides and Andreoulakis 337
with mood and affect disorders beyond depression, Key points
that is, bipolar disorder, euphoria sclerotica and PBA
in the fields of epidemiology, comorbidity, diagnosis, Bipolar disorder and special emotional psycho-
pathological symptoms in multiple sclerosis.
pathophysiology and treatment.
Diagnostic features, prevalence, etiopathological
factors.
Comorbidity.
Bipolar disorder
Treatment.
The lifetime prevalence of bipolar disorder in the general
population is often estimated to be around 1%. However,
Perala et al. [3] in a recent population study reported found to be reversed when chronic corticosteroid
a 0.24% life-prevalence, 0.31% for men and 0.18% therapy is concerned, with depression being the leading
for women, with a difference in sexes which was not mood disorder. These drug-induced hypomanic or manic
statistically significant. Moreover, the lifetime prevalence symptoms are dose dependent, often occur during the
of bipolar disorder showed no significant difference first few weeks of the therapy and are reversible with
among age groups, being 0.22, 0.36, 0.23, 0.14% in dose reduction or treatment discontinuation. A preven-
age groups of 30–44, 45–54, 55–64 and over 65 years, tive benefit of lithium and phenytoin against the steroid-
respectively. With regard to the prevalence and induced mood disturbances has been reported. However,
comorbidity rates of bipolar disorder in MS in particular, Jefferies [10] points out the lack of sufficient clinical trials
they have been reported to range from 0.3 to 32% [4–7]. investigating the effective treatment of manic episodes
The great variability in the sample sizes, the prospective in MS patients in particular.
or retrospective planning and the evaluation methods
used in each study could account for such a diversity Concerning neuroimaging findings, corticosteroid use
in the reported rates. However, the particularly high rates has been associated with changes in the temporal lobe
reported in earlier studies are no longer supported in [11].
recent population studies and have declined to 0.3–2.4%
[8,9]. Most recently, Marrie et al. [9] in a large population Interferon (INF) has been another medication implicated
study (8983 patients with MS) reported a prevalence rate in side effects concerning mood. Depression is regarded
of 2.4% for bipolar disorder in MS . Conclusively, bipolar as a potential side effect of the use of INF (particularly
disorder seems to be two to three times more frequent in INF-a, but also INF-b), especially, though not necess-
MS than in the general population. arily, in patients with a previous history of depression.
The mechanism of the action of INF-b in inducing
The relationship of bipolar disorder and MS, though depression has not been thoroughly investigated yet.
well established, remains complex. The cause of such Fragoso et al. [12] reported 11 cases of severe depression
a high comorbidity is regarded as being multifactorial. It with suicidal ideation in patients under INF-b therapy.
is attributed to a variety of factors, such as the medication In some of the cases, depression was accompanied by
used in MS, the demyelination brain lesions, genetics, psychotic or manic behavior, leading them to suggest
or, finally, the psychological reactions and adjustment that there might be a psychiatric syndrome associated
difficulties – associated with premorbid personality with INF-b therapy that goes beyond depression.
vulnerabilities – to the chronic, severe and progressive
character of the disease (the latter particularly concerning With regard to the investigation of a potential causal
the appearance of depression in MS). association between demyelinating lesions due to MS
and the appearance of bipolar disorder, there are
Among medication used in MS implicated in inducing some studies that investigated the morphological findings
hypomanic or manic episodes are the corticosteroids, in MRI patients who exhibited bipolar disorder or
baclofen, dantrolene, tizanidine and illicit drugs [10]. similar symptoms. Plaques in bilateral temporal horn
However, the medication side effects alone cannot fully areas [13] and ubiquitous white matter changes [14]
account for the higher comorbidity between mania or were reported. According to Fazzito et al. [15], the
hypomania and MS. psychiatric disorders shown in MS patients are thought
to be secondary to temporal lobe demyelinating
As far as the corticosteroids are concerned, mood disturb- lesions, though the physiopathology still remains not
ances are reported to be the most common psychiatric fully known.
side effects associated with them. Brown [11], in the most
recent study on the subject, stated that hypomania and Concerning two newer medications applied in MS,
mania have been reported as the most common mood mitoxantrone and natalizumab, there is not sufficient
changes during acute corticosteroid therapy, whereas evidence regarding their potential psychiatric side effects
depression comes in second place. This relation has been to date.
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3. 338 Medical comorbidity
Another hypothesis stated is that of a genetic relationship
between MS and bipolar disorder – reflecting a potential Pseudobulbar affect
common genetic susceptibility – based on findings from This terminology points out the importance of bulbar
familial bipolar disorder and MS studies, in which high nuclei in the brain stem thought to be implicated in
similarity concerning the human leukocyte antigen controlling emotional expression, whereas the alternative
(HLA) system genes, particularly of class II (DR, DQ), terms used – mentioned in the introduction section –
was found [16–18]. mainly focus on the phenomenology of this entity. PBA is
an affective disinhibition syndrome, a condition in which
Finally, concerning the treatment of bipolar disorder in mood (emotional experience) and affect (emotional
MS, bipolar disorder is usually treated with lithium or expression) are not in concordance. It is characterized
anticonvulsants [19]. However, no sufficient data are by spontaneous, involuntary and uncontrollable outbursts
available regarding the effect of mood stabilizers such of contextually inappropriate crying or laughing that
as carvamazepine or valproic acid, because there are no are inconsistent with the patient’s underlying mood,
controlled trials of their use in treating manic symptoms disproportionate or incongruent to the patient’s
in MS in particular. underlying feelings or to external triggers. Uncontrollable
crying seems to be more common than laughing. Never-
Apart from bipolar depression, individual symptoms theless, the patient’s insight is spared. This emotional
of euphoria and PBA have also been reported in MS incontinence is perceived as ego-dystonic by the patient,
patients. causes significant social embarrassment and urges the
patient to voluntarily control it, though inadequately.
What makes it superficially similar to bipolar disorder
Euphoria is that such an emotional lability (though the latter
Euphoria can be defined as ‘a fixed state of well being, tends to be regarded as a distinct entity) could be
despite the presence of considerable physical morbidity’. misinterpreted as being a manifestation of a mixed mood
This definition points out the lack of insight regarding episode or even a rapid-cycling bipolar disorder.
the severity of the illness, which results in an elevated However, what mainly distinguishes the two entities is
affect and an overoptimistic attitude. Compared with the disassociation of the affect and the underlying mood,
hypomania or mania, euphoria looks similar concerning resulting in emotional expression incongruent or dispro-
the presence of elevated affect but is distinguished by the portionate to the underlying emotional experience or to
lack of hyperactivity, pressured speech, racing thoughts, the external stimuli, the shorter duration of such episodes
grandiosity ideas and so on. compared with a more sustained underlying emotional
state in mood episodes and, finally, the fact that such an
There are no studies investigating the prevalence rate of outburst is ego-dystonic and causes significant distress to
this entity in the general population. The estimates of the patient, who feels unable to control it. Moreover, PBA
euphoria’s prevalence in MS are declining throughout can also be distinguished from a bipolar disorder mood
time. Initially, in the 1920s, euphoria had been episode by the lack of specific symptoms and signs such
overestimated – reported to be found in over two-thirds as hyperactivity, poor sleep, pressured speech and so on.
of MS patients and regarded as the specific psychopatho- However, although distinct entities, PBA and a mood
logical trait of MS. In 1990, Rabins [20] summarized the disorder – particularly depression – could also coexist, at
mean prevalence rate of euphoria in MS to 25% among a rate as high as 50% [24].
the studies they investigated. Later on, Diaz-Olavarieta
et al. [7] reported that euphoria was present in 13% of There are no studies concerning the prevalence rate of
44 MS patients studied compared with 0% of 25 control PBA in the general population. PBA is not exclusively
individuals [7]. found in MS but can also be found in other neurological
disorders such as amyotrophic lateral sclerosis, the
Regarding the stage of the illness, euphoria seems to cerebellar type of multiple system atrophy, cerebro-
occur in the later stages of MS [21]. It is reported to be vascular disease, Parkinson’s disease, traumatic brain
associated with significant cognitive impairment, heavy injury, dementia, migraine, progressive supranuclear
total load of brain demyelinating lesions, especially in the palsy and mass lesions, particularly in the cerebellopon-
frontal lobe, significant cerebral atrophy and ventricular tine junction [25]. Haussleiter et al. [26] summarized
enlargement [20,22] and reduced global gray matter PBA prevalence rate in MS to a mean of 10%. However,
volume [23]. most recently, Strowd et al. [27] reported a prevalence
rate ranging from 7 to 52% and a mean occurrence of one
Euphoria mainly remains untreated, as it does not such episode every 2 days (3.6 days per week) [27]. PBA
cause any distress to patients that would make them in MS is generally regarded to occur in the chronic–
seek help. progressive type of MS and seems to be associated with
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4. Bipolar disorder in multiple sclerosis Iacovides and Andreoulakis 339
severe disability, cognitive impairment and longer depression, suggests that PBA and depression are distinct
disease duration, whereas no correlation has been found entities, although they often co-occur in MS patients [46].
with MS relapses [28]. Treatment with anticonvulsants such as lamotrigine
has also been reported [47]. A novel treatment [dextro-
Concerning the pathophysiology of PBA, a three- methorphan–quinidine (DMQ)] with a combination
structured model was originally proposed: the cortex of dextromethorphan (DM), a s-1 receptor agonist inhi-
being the controller, the bulbar nuclei as the physiologi- biting glutaminergic signaling and quinidine (Q), used
cal effector and the hypothalamus in an integrating role as a CYP2D6 inhibitor in order to increase plasma levels
[29]. The role of the prefrontal cortex in PBA pathophy- of dextromethorphan, which is vulnerable to extensive
siology has been pointed out, based on the poorer metabolism by CYP2D6, has also been pointed out as
performance of the MS patients group in specific tasks beneficial recently [34]. According to Wortzel et al. [36],
which are regarded as being mediated by this region and the SSRIs are the recommended first-line pharma-
the fact that this region is regarded as taking part in cotherapy for PBA. When SSRIs turn out to be not well
keeping emotional expression compatible with social tolerated or ineffective, alternative treatments such as
contexts [30]. Findings concerning not only the interrup- those mentioned above should be considered. However,
tion of cortical inhibition of postulated laughing and Strowd et al. [27], based on the lack of large well con-
crying centers in the upper brainstem but also the trolled clinical trials concerning the treatment of PBA,
dysfunction resulting from lesions in the cerebro- posed the issue that antidepressants might be helpful
ponto-cerebellar pathways, which are thought to be in treating coexisting depression, but not sufficient in
involved in appropriate adjustment to social and treating PBA, raising implications for a better tailored
cognitive context, provided a further link of PBA to pharmacological treatment of PBA.
the cerebellum [31]. Moreover, the case of a 46-year-
old woman, suffering from idiopathic Parkinson’s disease,
who exhibited pseudobulbar crying induced by stimu- Conclusion
lation in the region of the subthalamic nucleus was Despite the fact that the coexistence of psychopatho-
reported [32]. Recent studies implicate widely dispersed logical symptoms in MS is well established, most of
lesions including bilateral medial inferior frontal, bilateral the affected patients are still underdiagnosed and under-
inferior parietal and brainstem regions and also basal treated. A shift concerning the clinical suspicion and
ganglia [33,34]. Summarizing, Parvizi et al. [35] in the the treatment of psychiatric disorders in MS seems
most recent and thorough review on the subject con- fundamental, as they can have a considerable impact
cluded that basis pontis is the only identified anatomical on the patients’ quality of life and also on the MS
site in which a discrete lesion can cause PBA. Other treatment adherence.
anatomical sites also implicated in the pathophysiology of
PBA are the prefrontal cortex and anterior cingulate, the In the reverse direction, because psychopathological
internal capsula, the thalamus and subthalamic nucleus, symptoms and signs might represent, though not very
the cerebral peduncles and the cerebellum [35]. often, the first clinical manifestations of MS – even in the
absence of neurological clinical findings, or in the pre-
Regarding the neurochemistry of PBA, neurotransmitters sence of ‘mild’ ones – MS should be also be considered
such as serotonin, dopamine, noradrenaline and gluta- in the differential diagnosis in some people presenting
mate appear to be implicated in the pathophysiology of with such symptoms as euphoria, pseudobulbar affect or
PBA. However, although the role of serotonergic systems even a manic episode with atypical features, cognitive
seems better established, the role of nonserotonergic impairment, peripheral physical findings or a lack of
systems still remains speculative [36]. response to the standard bipolar disorder treatment.
Regarding the treatment of PBA, several types of
Acknowledgements
psychotropic drugs have been applied. Amantadine and The authors have no conflicts of interest to declare.
levodopa [37], tricyclic antidepressants (TCAs) such as
amitriptyline [38] and nortriptyline [24], selective sero-
tonin reuptake inhibitors (SSRIs) such as fluoxetine [39], References and recommended reading
citalopram [40] and sertraline [41], serotonin–norepi- Papers of particular interest, published within the annual period of review, have
been highlighted as:
nephrine reuptake inhibitors (SNRIs) such as duloxetine of special interest
[42], venlafaxine [43] and revoxetine [44] and other of outstanding interest
Additional references related to this topic can also be found in the Current
antidepressants such as mirtazapine [45]. The response World Literature section in this issue (p. 363).
to the treatment with antidepressants has been reported
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