Neuropsychiatric Symptoms in Demyelination Disorders

Abstract

Inflammatory demyelinating diseases are defined as being a miscellaneous group of disorders that develop as a consequence of an acute or chronic inflammatory process. The types of demyelinating disease with a high prevalence are multiple sclerosis, neuromyelitis optica and acute-disseminated encephalomyelitis. Patients with multiple sclerosis frequently experience depressive and anxiety symptoms including cognitive impairments. Depression is correlated with an unsatisfatory quality of life, having a conceivably important psychological impact on all the aspects of the patient’s live, including less efficient coping mechanisms and a decreased compliance with disease-modifying drugs. As a general rule among population, depression in multiple sclerosis patients is regularly correlated with anxiety. The clinical importance of neuropsychiatric symptoms should not be neglected because multiple sclerosis patients are more prone to be affected in all the aspects of life, in view of the morbidity that these symptoms bring in patients with neurodegenerative diseases.

1. Introduction

In the history of multiple sclerosis, noted as the first notation of the disease in the title of a neuropathological disorder was made by Charcot in 1868 [1].

In the evolution of multiple sclerosis, related to the diagnosis of the disease, a requirement is the apparition and subsequent demonstration of demyelinating lesions that are dispersed in time and location. In conjunction to the neurologic symptoms, the discovery of lesions through the magnetic resonance imaging are accordant with the diagnostic of multiple sclerosis [2, 3].

Further investigations include the evidence of the presence of oligoclonal bands located in the cerebrospinal fluid [4], and/or the discovery of pathological optical induced potentials (interruption with a conserved wave form) are suggested to acquire a proper diagnosis [5]. A monosymptomatic course of the disease could be existent in patients with multiple sclerosis, as well as an evolution including a classical relapsing remitting course of the disease or even a primary or secondary progressive disease.

The evolution of multiple sclerosis can be characterized by a constant degradation of symptoms from the neurological area, regardless of the lack of presence of new MRI lesions and also a infrequent prevalence of lesions enhanced by contrast. The principal course of the disease for the most patients includes an onset represented by a relapsing remitting form of multiple sclerosis, with a subsequent evolution consisting of secondary progressive disease.

In the primary progressive form of multiple sclerosis, the evolution of the disease includes a continuous progression from since the commencement of the disease. Regarding the pathophysiological mechanism subsidiary to the progression of multiple sclerosis, the disruption of inflammatory nature of the blood–brain barrier is incriminated.

The underlying morphopathologic emblem of multiple sclerosis is the production of inflammation-related demyelinating lesions with variable lesions located at the axonal level, accompanied by deterioration as long as astrocytic gliosis.

In the course of the disease, including both early and late stages of multiple sclerosis, the lesions present in the following locations of the nervous system: neurons and the axonal level of the neurons, also synapses can be affected by the disease, the term used at large scale being represented by neurodegeneration [6, 7].

The axonal injuries and also the subsidiary loss have been proposed to represent a fundament to the extent of perpetual motor impairment in multiple sclerosis [8]. The acute injury with the location in axonal level is most enhanced in the active demyelinating injuries and can be recognized through immunohistochemistry.

Patients with MS commonly encounter through the evolution of the disease: signs and symptoms that are not especially a result of a relapse or the progressive stage, as fatigue, chronic pain, and urogenital dysfunction.

2. Depression in multiple sclerosis

Multiple sclerosis is correlated with a wide spectrum of neuropsychiatric disorders of which depression is the most frequent. Depression is a complex disorder taking into consideration, firstly, the symptom of madness and, secondly, the entire syndrome diagnosis of major depression.

The major depression syndrome was characterized by the American Psychiatric Association being a selection that includes nine signs and symptoms with the nominalization of five or more that are required be positive for minimum 2 weeks as a sequence for the positive diagnosis.

The symptomatology contains depressed disposition during the majority of the day, a disappearance of enthusiasm or enjoyment concerning occupations that consisted as pleasant previously, modifications in appetite related to weight loss or weight gain, insomnia or hypersomnia, a reduction or an increase in psychomotricity, agitation or lag, fatigue, impressions of uselessness or improper and exaggerated culpability, a decrease in the ability to concentrate, and persisting thoughts related to death.

For the medical health personal that is in relation with MS patients, the presented description can represent a possible issue taking into consideration the particularity of the symptoms that represent the base of depression’s diagnosis that can further be induced by multiple sclerosis. The most occurring coincidental symptoms are those of fatigue, decreased concentration, and impairments related to sleep.

3. Quality of life

Depression prevalence in MS patients is correlated with a decrease in the quality of life regardless of the neurological or related to function deficits in correlation with MS [9]. In a study by Carta et al. [10] was concluded that patients with MS and a subsequent chronic affection mood disorder present significantly decreased results on the SF-12 (an assessing instrument of quality of life) in comparison with MS patients wich do not present a history of mood impairments. In a study by Wang et al. [11] in which was assessed the MSQOL-54 score in multiple sclerosis patients, the participants that presented depression in antecedents, regardless of the state of their mood in the examination, provided significantly decreased MSQOL-54 averages in relation to energy, mental health, cognitive capacity and general quality of life.

4. Depression and cognition

In relation with the cognitive status, generally 40–70% of MS patients will present impairments in correlation with the disease type. Studies in the literature have concluded that clinically significant depression could conduce to a even more visible impairment in a patient’s cognitive capacities. Studies by Arnett et al. [12, 13, 14], revealed that depression can affect in a negative way the working memory, especially the executive component. The conclusions exposed before suggest the probability that compensating the emotional disorders as depression have the possibility of influencing in a beneficial way the cognitive capacity in a multiple sclerosis patient, this theory was not demonstrated yet.

5. Adherence to disease-modifying drugs

Studies from literature have found a connection between the decreases in compliance for multiple sclerosis patients regarding to disease-modifying drugs [15, 16, 17]. In a study by Bruce et al. was demonstrated that MS patients which present an existing emotional disorder or anxiety disorder are approximately five times less probable to comply with disease-modifying therapy in comparison with MS patients that do not present psychiatric diagnosis positive [15]. A more favorable adheration in disease-modifying drugs was reported in patients with multiple sclerosis and secondary depression which received antidepressant therapy.

6. Suicidal risks

A third proportion of the MS patients experience suicidal ideation [18]. The predisposal factors are represented by: major depression episode, the level of severity of the depression, social detachment, and usage of alcohol and substances [19]. Suicidal thoughts and ideation represent risk cause for a suicide pursue. Studies related to patients with MS from the scandinavian region conclude that the mentioned patients are twice as inclined to attempt suicide compared to healthy subjects in the population [20, 21, 22].

Pujol et al. [23] studied the correlation between the depressive symptoms and cerebral dysfunction and concluded that hyperintense lesions with the location of left arcuate fasciculus were associated with Beck Depression Inventory scores. Other studies on the matter pointed out that lesion volume was associated with depressive symptoms but also stated that gray matter atrophy could represent a more powerful prognosticator of depression than lesion volume [24].

Feinstein et al. [25] used structural MRI on patients with multiple sclerosis and subsequent depression in comparison with patients which only presented multiple sclerosis who were equal in terms of age, and duration of the disease’s course, general disability and cognitive functioning. The conclusions were that MS patients with depression showed more hyperintense and hypointense lesions in the left medial lower frontal regions, as well as decreasing gray matter volume in the anterior left. Further analysis showed that these two factors predicted 42% of the probability variance to be diagnosed with depression [25].

Taking into account the presence of anomalies in the structure and also the dysfunctions that are constituents of; in patients with depression without neurological disease and their associated patterns of depression, the question arises as to the extent to which imaging results from patients with MDD bring us information about our understanding and determination of depression in MS.

A common variable of the existing work on depression is the hyperactivity of the limbic-prefrontal circuits that influences attention to negative stimuli, which when correlated with dysfunctional prefrontal regions involved in the executive control, can result in a prejudice of negative emotions or environmental stimuli without the necessary means to resolve or rethink the situation. The problem presented above is in connection with cognitive patterns of depression insisting on the role of dysfunctional cognitive schemes.

Considering the amount of atrophy that may be underlying MS, it is likely that localized atrophy in the prefrontal white and gray matter will help maintain depression through its negative role on emotional regulation. Although considering the fact that a small number of studies on the quantification of depression in MS through neuroimaging revealed localized atrophy primarily in gray and white prefrontal substances that partially overlaps with those areas found to be atrophied and/or have low activation of emotional stimuli.

Furthermore, there has been ample evidence that patients with MS have dysfunction in the course of their disease. Prefrontal activation as a response to cognitive control tasks such as working memory tasks. In this way, it is quite likely that decreases in prefrontal volume have a negative effect on the regulation of emotional emotions and the use of cognitive reassessments in MS patients [26, 27].

Moreover, monitoring the poor evolution of these networks, along with the evolution of the disease, as well as monitoring changes in the brain to the diversity of depressive symptoms, especially on responsibility for variable situations and poor emotional regulation, will be useful to successfully describe this neuropsychological presentation of a disease with a complex clinical evolution.

Summing up, it is shown that functional neural networks related to depression in the general psychiatric population have partially the same brain location as current findings of neuroimaging in MS. However, future investigations are needed to find clearer connections between depressive symptoms and specific structural abnormalities are essential, especially given the heterogeneity of atrophy and lesions in MS.

7. Anxiety and multiple sclerosis

In accordance with the standards defined by the American Psychological Association, anxiety represents “an emotion characterized by feelings of tension, worried thoughts, and physical changes like increased blood pressure” presenting as originator the anticipation of forthcoming warning or a motivational disagreement [28]. Anxiety is defined as a sentimental condition represented by unconcerned rational – implying thoughts of concerned predictions, physiological- implying corporeal invigorating, and behavioral elements [29].

The differentiation among anxiety and fear, as the latter represents the emotional feed-back in case of prompt warning, even though fear and anxiety are closely connected [30]. Furthermore, fear and anxiety are able to be differentiated using the support of duration, transitory center of attraction, warning particularity, and stimulated course: Taking into consideration that the sense of fear is experienced acute, emphasized in the present tense, and aimed to a particular warning, with the purpose of avoidance, anxiety is present in an extended period beyond particular warnings.

Subsequent to danger, fear and anxiety stimulate a concatenation of flexible practice with the scope of decreasing the disagreeable corporeal reaction in order to subdue the factual warning or settle the latent disagreement. Physiological type of anxiety and fear are extensively adaptive, as their effect is the acquisition of reserves with the scope of coping with a factual warning. Furthermore, extending anxiety is deliberately defective, and depending of its presentations, it might be a specific component of clinical diseases, as it has the effect of endangering the physiology and quality of life of the individual. Furthermore, pathological anxiety levels, in addition to the latter, materializes in the form of symptomatology as taking part of psychiatric diseases, specific to clinical depression.

Anxiety affections evolve in a matter of possessing a quantity of biological and social determinants being partly responsible of the apparition and evolution of the symptomatology. On this matter, malfunctional anxiety can be acquired from the social or familial habitat, in the existence of a biological inclination [30], or it can be the consequence of adverse life circumstance being acquired trauma. In the study of Bruce et al. [15], on the theme of connections related to worry and anxiety in MS patients has revealed the fact that nevertheless, the significant correlance with anxiety, worry can be revealed as a unique and independent element.

Even though anxiety related diseases are frequently diagnosed in multiple sclerosis patients, this pathology is in some cases neglected and investigated more superficial in comparison with other representatives of neuropsychiatric disorders such as depression. However, the occurrence of anxiety disorders in patients with MS is statistically more important in comparison with the general population. In a study by Korostil et al. [31], was demonstrated that lifetime rates of anxiety in patients with multiple sclerosis are more increased in comparison with the rates of anxiety in chronic medical illnesses. Accordingly, a more wide investigation on the theme of anxiety disorders in multiple sclerosis pathology is recommended.

Even though a significant number of studies investigated anxiety in MS, a large proportion of the literature on the subject is counterfeit by assorted constraints, being the absence of clinical interviews, which are essential toward to systematize a clinical interpretation. Certainly, even if educational, the preponderance of the studies on the theme of emotional impairments in MS specially commit on self-report measurement instruments as questionnaires and scales for the determination of clinically significant anxiety with some exceptions.

In a study by Galeazzi et al. [32], was concluded that the prevalence of anxiety consisted of 36% of a quantity of 50 patients with MS with the usage of the instrument: the Structured Clinical Interview for DSM-IV disorders (SCID-IV). Furthermore, as in the study of Galeazzi et al. [32], in a study by Shabani et al. [33], the conclusions revealed that MS patients were more suitable for the diagnostic of obsessive–compulsive disorder than anxiety. Also, in a study by Korostil et al. [31], using the scales: Structured Clinical Interview for DSM-IV disorders and Hamilton Anxiety Depression Scale, was concluded a lifetime prevalence of anxiety disorders of 35.7% in the sample of the MS patients. Among of the conclusions of the studies, was also revealed that anxiety disorders were widely underdiagnosed between multiple sclerosis patiens, hence limiting the opportunity of providing the essential treatment in the targeted disease.

Various elements should be considered in the case of referring to the clinical manifestations of anxiety in MS. Regarding this matter, a constant problem in the clinical objectivation of psychiatric impairments, being anxiety and depression is represented by the symptom projection along with somatic symptomatology of MS. As it is the case, various somatic elements of symptomatology related to anxiety being restlessness, vertigo, episodes of loss of consciousness, and leg unsteadiness that can be often prevalent amidst the corporeal symptomatology of MS. In the matter of the investigations of the issue of depression, the literature conduced on the theme of symptom overlaying among anxiety and MS is insufficient [34].

The overlaying of the symptomatology among anxiety and MS was further investigated and emphasized in a retrospective study by Carmonsino et al. [35]. In the same study, the conclusions revealed the presence of psychiatric diagnoses in 63 MS patients in which the primary objective clinical investigation implied the presence of a primary psychiatric etiology for the patients’ symptomatology. In the same study, a major preponderance of 92% of MS patients completed the diagnostic criteria for one or more psychiatric diseases containing personality, somatic, and anxiety impairments. Therefore, clinicians are advised to present large amounts of deliberation in the attempts of determination of psychiatric disorders generating neurological-like and also nonspecific symptomatology - likely anxiety, and also, special caution regarding the evaluation of anxiety only using the screening instruments, as this symptom overlie might increase the scale records and demand additional investigation using a clinical consult.

In the study of Korostil et al. [31], investigated the occurrence of certain anxiety disorders using as instrument a clinical consult based on the interview method concluded that generalized anxiety disorder is the most frequent in the cohort of MS patients. Generalized anxiety disorder is represented by unmanageable concern followed by various physical symptomatology including: cephalalgia, vomiting sensation, muscle tightness, and swallowing impairments.

The presence of generalized concern and health related anxiety in MS patients has been emphasized in several studies, and and this fact is not surpring, considering the nature of the complex demyelinating disease [36, 37, 38].

In a study by Janssens et al. [39], a correlation was made among the understanding of evolution risk and anxiety in the case of patients with multiple sclerosis. On this matter, the patients who considered that they would use a wheelchair in the further 2 years experienced more elevated levels of anxiety and depression. Interestingly, patients had the tendance to exaggerate in estimation their short-term risk of using wheelchair.

In a study performed by Jopson et al. [40], was revealed the correlation among multiple sclerosis features and anxiety, explained with the evidence that the patient’s inclination to consider inconstant and unclassifiable symptoms as cephalalgia and aching to MS might cause anxiety among the patients in the cases they consider the mentioned symptomatology as causative for progression in multiple sclerosis.

Exaggerated anxiety and concern regarding health develops in more necessity for medical attendance [41] and greater corporeal impairments [42]. Kehler et al. [38], discovered that MS patients which present increased anxiety related to health are inclined to a lowed degree to practice issue-focused coping methods, favoring emotional concentration and familial assistance as principal coping method. The cases of patients in cause also revealed that increased standards of health related anxiety propose and encounter higher disability and also generalized anxiety disorder. The former conclusions are emphasized with the ideas revealed from the study supervised by Feinstein et al. [43], in which was revealed that the presence of anxiety and depression in patients with MS culminate in greater corporeal health related concerns and familial and group malfunctions. Among the conclusions of the study was also the theory that the liabilities of self-harm and suicidal judgment in patients with MS are the consequence of existence of both anxiety and depression and not isolated depression.

Studies on the matter of the consequences of exacerbations on the emotional state showed that the aggravation in the evolution of the disease, heightens the level of emotional distress when assessed with the remission phase [44, 45, 46].

Interestingly, MS patients often state that in the extent prior to the commencement of the symptomatology, subsequent diagnosed as being the onset of MS, or anteriorly to the exacerbations, significant disturbing circumstances have occurred. In some cases, between the reports of the patients were encountered bizarre, abnormal subjective sensations and perceptions prior to the relapse symptomatology.

Methodical conclusions of several studies have revealed that aggravating occurrences are correlated with a higher frequency of exacerbation, not taking into consideration the infectious etiologies and psychosocial elements as unfavorable familiar and social circumstances in relation with anxiety which are correlated with MS commencement [47, 48, 49, 50, 51].

The possible existence of anxiety, including another emotional related symptomatology, with psychological impairments in multiple sclerosis drew attention to the concern of different investigators. Dysfunction of various cognitive activities modifies an important part of the evolution of MS patients and it is accordingly appropriate to analyze all the potential causes.

Anxiety stages and anxiety related diseases are more prevalent in MS patients compared with the general population; with an undesirable elevation in anxiety which is described in the literature as being more prevalent compared with depression, in the papers that examined the same sample of patients.

In the study by Carta et al. [10], was concluded that multiple sclerosis is correlated with a unsatisfactory quality of life in comparison with psychiatric diagnosis of bipolar disorders, major depression, or eating disorder or to various neurological diseases being Wilson’s disease. In one study that used as sample patients with MS, the quality of life was more affected in the cases of comorbidity consisting of bipolar disorders, compared with the comorbid represented by major depressive disorders [10].

Respecting the pattern prevalent in the general population, depression in MS patients is frequently correlated with anxiety. The clinical significance of this type of morbidity should be taken into consideration because MS patients that experience twain anxiety and depression are more prevalent to present a high frequency of thoughts related to self-harm, more important somatic discontents, and be even more socially impaired in comparison with MS patients with depression or anxiety singularly [43, 52].

Regarding the symptomatology the frequency is higher in anxiety than depression as a solitary symptom, and the occurrence of generalized anxiety, panic disorders, obsessive–compulsive disorder, and social phobia are significantly more frequently encountered in MS patients compared to the general population [53].

In a study that included 115,071 adult Canadians, the 12-month prevalence of depression in MS subjects was increased twain in healthy individuals and in individual that presented chronic medical diseases [54]. The most significant prevalence of depression was reported in individuals with the age between 18 and 45 years.

Other studies revealed the high prevalence of depression and anxiety among the multiple sclerosis patients with the presence of furthermore debilitating symptomatology [55, 56, 57]. A study using administrative data from Canada revealed that the risk of psychiatric disorders such as: depression, anxiety, and bipolar disorders is more prevalent in multiple sclerosis patients in comparison with the general population.

There has not been established a correlation between the diagnosis of depression and the characteristics of the disease, furthermore, the correlation with physical disability is uncertain [54, 58]. The ambiguity is presented in relation with the disease duration [59].

The conclusions presented could have the explanation of the ambiguity as a result of the ambiguity of the disease, with multiple different presentations. In the acceptation of the facts stated before is the fact that patients which present the similar disease duration can possess a definitively contrasting relapse rate or disease evolution. Furthermore, the stage of of physical impairment could be decided by a combination of cerebral and spinal affection, twain presenting a conceivably distinctive mood related consequence.

The presence of depression is correlated with a deficient quality of life, significant cognitive impairment, a high rate of suicidal thoughts, and a decreased compliance with disease-modifying drugs.

8. Bipolar disorders in multiple sclerosis

Bipolar disorders and broadly mood related disorders were considered as being a primordial symptom of MS [60], as the performing of mood symptomatology was reported to be initiated previously of the manifestation of the neurological features [61].

Appealing and adjacent connections that associate energy metabolism, inflammation, and demyelination were prevalent in multiple sclerosis. Furthermore, the results of oxidative stress at the oligodendrocyte level can be located between down manifestation of oligodendrocyte genes – as noticed in psychiatric diseases and in bipolar disorders specifically – to cell destruction and brain impairments emblematic of MS [62].

The susceptibility for bipolar disorders might appear as a result of the dysfunction of the brain courses controlling emotions, motor behavior, and pleasure [63, 64].

9. Euphoria in multiple sclerosis

The definition of euphoria includes the description of a constant extreme happiness and happiness, an inadequate animation, or a absence of interest in the concerns of repercussion of the disease. This disorder arises as a sequence of personality related disorders and it is not defined as a disposition related disorder. Euphoria represents a distinct disorder compared with mania. This disorder is correlated with the apparition of the following features: infantilism, spontaneousness, emotional impairments, anger attacks, and absence of sympathy. In recent studies from literature, the occurrence of euphoria was reported to be approximately 15% in patients with multiple sclerosis.

In a study by Diaz-Olavarietta et al. [65], which included 44 patients as MS group and 25 healthy patients as control group, the prevalence of euphoria was reported to be present in 13% of the patients presenting multiple sclerosis, meanwhile the control group was euphoria-free.

In a study conducted by Fishman et al. [66], which included 75 patients with multiple sclerosis, was reported a presence of euphoria in 7% of the multiple sclerosis patients, compared with the healthy subjects which did not present any of the symptoms associated with euphoria.

Euphoria is neuroimagistically correlated with the rigor of the amount T2 lesions and the degeneration of gray and white matter [67].

10. Conclusions

There is conclusive data relating depression manifested clinically in a consequential manner in MS patients to a variety of unfavorable results in relation with occupations of daily living. Due to the particularly wide and varied implications of multiple sclerosis, it is important that the disciplinary team of physicians treating patients with this condition be alert to any changes in symptoms and aware of the increased prevalence of neuro-psychological disorders in the course of the disease.

This point is reinforced by studies showing the effectiveness of treatments for patients with multiple sclerosis and depression. Successful treatment will not only decrease MS-related morbidity; but it also has the potential to reduce suicide-related mortality.

Related to the presence of associated symptoms, depression is the most common psychiatric complaint in patients with multiple sclerosis, and this conceives 25 to 50% of patients during the course of the disease, which is from two to five times higher compared to the prevalence rate in the general population. The cause of such a frequent occurrence of depression in patients with MS becomes more evident in the light of pathophysiology brain changes, and psychosocial changes are likely to be important in the course of the disease.

Psychiatric disorders have a significant frequency in multiple sclerosis cohort of patients. The risk of suicide is specifically considerable in the initially part of the disease’s evolution. Anxiety is prevalent in multiple sclerosis and is the most influential prognosticator of the manifestation of depression. Major depressive disorder is inadequately diagnosed and treated. Behavioral impairments are more prevalent in comparison with severe psychiatric diseases and appear apparently subsequent to cognitive dysfunction. Addictions might be not diagnosed appropriately.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

None.

Appendices and nomenclature

MS

multiple sclerosis.

MRI

magnetic resonance imaging.