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LITHUANIAN UNIVERSITY OF HEALTH
SCIENCES
Department of Psychiatry
MASTER’S
THESIS
Correlation of cognitive impairment and
depressive mood disorder in multiple sclerosis
Systematic review
Thesis supervisor Dr. Aida Kunigėlienė Author
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Table of content
1. SUMMARY ... 3 2. SANTRUKA ... 4 3. ACKNOWLEDGE ... 5 3.1. Conflict of interest ... 54. CLEARANCE ISSUED BY THE ETHICS COMMITTEE ... 6
5. ABBREVIATION ... 7
6. TERMS ... 9
7. INTRODUCTION ... 10
8. AIM AND OBJECTIVES OF THE THESIS ... 12
9. RESEARCH METHODOLOGY AND METHODS ... 13
10. RESULTS AND THEIR DISSCUSION ... 15
10.1. To evaluate epidemiology, socio-demographical factors (gender, age, occupational status) and quality of life in patient with multiple sclerosis. ... 15
10.2. To analyze cognitive impairment for patient with multiple sclerosis. ... 18
10.3. To analyze mood disorder for patient with multiple sclerosis. ... 23
10.4. To analyze depressive mood disorder for patient with multiple disorder.- sclerosis ... 25
11. CONCLUSION ... 30
12. REFERNCES ... 31
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1. SUMMARY
Author: Miki Klaiman
Title: Correlation of cognitive impairment and depressive mood disorder in multiple sclerosis Introduction: Multiple sclerosis (MS) is a potentially disabling disease of the brain and spinal cord (central nervous system). In MS, the immune system attacks the myelin sheath. Most patients with MS have relapsing-remitting disease, which typically presents in a young adult with a clinically isolated syndrome. MS results in motor, cognitive, and
neuropsychiatric symptoms, all of which can occur independently of one another.
Research aim: to evaluate the correlation of cognitive impairment and depressive mood
disorder in multiple sclerosis.
Objectives:
1. Evaluate epidemiology, socio-demographical factors (gender, age, occupational status)
and quality of life in patient with multiple sclerosis. 2. Cognitive impairment for patient with multiple sclerosis.
3. Mood disorder for patient with multiple sclerosis.
4. Depressive mood disorder for patient with multiple disorder.- sclerosis
Methodology: Systematic review that analyzed and compared research work and publication
in the last 20 years in the English language. Using PubMed Medline research engine and including exclusion and inclusion criteria.
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2. SANTRAUKA
Autorios: Miki Klaiman
Pavadinimas: Kognityvinių funkcijų ir nuotaikos sutrikimų sąsajos sergant
išsėtine skleroze
Įžanga: Išsėtinė sklerozė – tai centrinės nervų sistemos liga, potencialiai
sukelianti neįgalumą. Sergant IS imuninių procesų pasekoje pažeidžiamas
mielinas. Dauguma sergančiųjų pasireiškia recidyvuojanti-remituojanti išsėtinės
sklerozės eiga, dažniausiai jauname amžiuje. Išsėtinė sklerozė sukelia
motorinius, kognityvinius, neuropsichiatrinius simptomus, kurie gali pasireikšti
nepriklausomai vienas nuo kito.
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3. ACKNOWLEDGE
I would like to thank my supervisor for her guidance and advice on this review. Her knowledge and experience within the field of psychiatry helped me a great deal in completing this systematic review.
3.1.
Conflict of interest
I declare that there is no conflict of interest.
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4. CLEARANCE ISSUED BY THE ETHICS COMMITTEE
No clearance issued by the Ethics Committee is needed in this study.7
5. ABBREVIATION
ANN - american academy of neurologyBD – bipolar disorder
BDI – Beck Depression Inventory
CBT – Cognitive behavioral therapy
CI – cognitive impairment
CNS – central nervous system
CSF – cerebrospinal fluid
D – Depression
fMRI – functional magnetic resonance imaging
GM – grey matter
IFG - inferior frontal gyrus
IPS – information processing speed
MRI – magnetic resonance imaging
MS – multiple sclerosis
OCD – obsessive compulsive disorder
PPMS – primary progressive multiple sclerosis
PRMS – progressive remitting multiple sclerosis
PwMS – patient with multiple sclerosis
QoL – quality of life
8 SPMS – secondary progressive multiple sclerosis
TNF – tumor necrosis factor
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6. TERMS
EDSS - the Expanded Disability Status Scale is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. It is widely used in clinical trials and in the assessment of people with MS.
Neuroinflammation - defined as the activation of the brain's innate immune system in response to an inflammatory challenge and is characterized by a host of cellular and molecular changes within the brain.
Fluorodeoxyglucose - radionuclide combined with glucose, which is the currency of
metabolism for malignant and benign cells and usually used in the medical imaging modality positron emission tomography.
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7. INTRODUCTION
Multiple sclerosis (MS) is a progressive disease of the CNS and is characterized by the production of widespread lesions, or plaques, in the brain and spinal cord. These lesions and plaques affect the myelin sheath, thus causing inhibition of axonal transmission.
Inflammatory demyelination has been seen as the main disease process in MS; however, axonal damage or loss is increasingly being documented to occur early in the disease and result in permanent disability.
There are four clinical types of MS that can be categorized based on disease progression: Relapsing-remitting MS (RRMS) which is characterized by clearly defined relapses with full recovery or sequel and residual defects. During periods between relapses the disease does not progress clinically. In case this phenotype of the disease is followed by a progression with or without occasional relapses minor remissions and plateaus it is classified as secondary progressive MS (SPMS). In contrast, primary progressive MS (PPMS) takes a progressive course from the beginning with plateaus and temporary minor improvements. The fourth type is progressive-relapsing MS (PRMS), which is progressive from the onset with acute relapses(1).
Because of the widespread development of the plaques, MS results in a broad range of symptoms, which include motor, cognitive, and neuropsychiatric problems, depending on the extent and location of damage in the CNS. The most commonly reported symptoms at the time of diagnosis are blurred vision, tingling and/or numbness, and loss of coordination. As the disease progresses, usually with a series of acute immune attacks and a late-stage steady progression of function loss, patients with MS commonly experience fatigue, spasticity, difficulty walking, and cognitive impairment (CI). Treatments are designed to reduce the frequency of clinical exacerbations in MS.
CI is when a person has trouble remembering, learning new things, concentrating, or making decisions that affect their everyday life. Cognitive impairment ranges from mild to severe. With mild impairment, people may begin to notice changes in cognitive functions, but still be able to do their everyday activities. Severe levels of impairment can lead to losing the ability to understand the meaning or importance of something and the ability to talk or write, resulting in the inability to live independently. Studies have revealed that CI is present in 40– 65% of individuals with clinically definite MS on neuropsychological testing. CI has been
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identified at all stages and affects all subtypes of MS. Studies have shown cognitive deficits, in particular, deficits in information processing speed (IPS), concentration and working memory, to be present in the early stages of MS. Therefore the presence of CI may provide a measure of diffuse brain pathology early in the course of MS.
Depression is classified as mood disorder that involves a persistent feeling of sadness and loss of interest that interfere with a person’s everyday activities. It may feature sadness, difficulty in thinking and concentration and a significant increase or decrease in appetite and time spent sleeping. The increase in the prevalence of depression in patients with multiple sclerosis (PwMS) in comparison with the general population has been exhaustively reported. The depressive status represents one of the main determinants of PwMS quality of life (QoL). Structural brain alterations and immune-inflammatory, genetic and psychosocial factors have been reported in depressed PwMS, suggesting that depression might not only be an affective disorder associated with MS, but a complication of it, as well as a biologically based symptom.
Rates of depression and cognitive dysfunction are higher among patients with MS than the general population. Depression and CI are reported in up to 50% and 40% of MS cases. These two symptoms frequently co-occur, particularly in patients with moderate-to-severe depression. A few studies found that depressed PwMS were more cognitively impaired compared to PwMS who were not depressed.
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8. AIM AND OBJECTIVES OF THE THESIS
Research aim: to evaluate the correlation of cognitive impairment and depressive mood disorder in multiple sclerosis.
Objectives:
1. Epidemiology, socio-demographical factors (gender, age, occupational status) and quality of life in patient with multiple sclerosis.
2. Cognitive impairment for patient with multiple sclerosis.
3. Mood disorder for patient with multiple sclerosis.
4. Depressive mood disorder for patient with multiple disorder.
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9. RESEARCH METHODOLOGY AND METHODS
Data collection and search strategy:
In this systematic review PRISMA 2009 statement and check list were used as the main resource for research methodology. The main search engine was MEDLINE PubMed that yielded about 2256 research works. Randomized clinical trials, retrospective studies,
systematic and literature reviews were used. Inclusion and exclusion criteria navigated which works should or shouldn’t be used.
Information source:
MEDLINE PubMed online research engine
Inclusion criteria:
Terms used: multiple sclerosis, cognitive impairment, depressive disorder, mood disorder, quality of life, epidemiology, gender, age, occupation.
Sentences used:
- Pathophysiology of cognitive impairment in multiple sclerosis
- Cognitive impairment in multiple sclerosis
- Assessment of cognitive impairment in multiple sclerosis.
- Mood disorders in multiple sclerosis
- Quality of life in multiple sclerosis patient
- Socio-economic factors in multiple sclerosis patient
- Age related to multiple sclerosis
- Gender related to multiple sclerosis
- Epidemiology of multiple sclerosis
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Exclusion criteria
- Research work that wasn’t published in the last 20 years.
- Works written not in the English language
- Not relevant title or abstract
Data collection process:
The initial search in PubMed yielded 2256 results, which were reduced to 321 after using filters such as published in the last ten years and only English language. Using the best match function in PubMed helped review the title and abstract of each work and select the most appropriate once which were 150 overall. After full review of the text 26 research works were included into this systematic review
Figure 1. Inclusion and exclusion flow chart that describes the data collection process
436 Records identified through database
searching
238 titles and abstract were reviewed
85 full text reviews was done
26 studies were included in this systematic review
59 studies were excluded based on bias inappropriate statistical analysis and duplication of information
198 records excluded based on exclusion criteria (language, older than 20 years)
153 works were excluded based on title and abstract review
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10. RESULTS AND THEIR DISSCUSION
10.1. Assessment of epidemiology, socio-demographical factors (gender,
age, occupational status) and quality of life in patient with multiple
sclerosis.
Multiple sclerosis is a common demyelinating disease. Most of the cases appear in high-income countries, and has a variable prevalence span in all over the world: highest in North America (140/100,000 population) and Europe (108/100,000), and lowest in East Asia (2.2/100,000 population) and sub-Saharan Africa
(2.1/100,000). The median prevalence of MS in the world has increased from 30/100,000 in 2008 to 33/100,000 in 2013(2). The evaluation of the distribution and frequency of MS which done by estimates of prevalence and incidence seem to suggest a north to south gradient in the northern hemisphere. We can see it in Europe specially, areas of high MS prevalence (for example the Scandinavian countries and United Kingdom) and areas of low MS prevalence (Italy, Greece, Spain).
Concerning the increase in prevalence in the northern area may be due to the increase in life expectancy, in addition several studies also include the level of vitamin D exposure as a risk factor and the explanation of the differences in the prevalence and incidence according geographical latitude.
Mortality among the MS patient investigated by 40 researches reveal that 70– 88% of patients are survived 25 years after clinical onset. The midpoint from onset to death is from 24 years to more than 45 years.however, it was shown that patient with MS had lower life expectancy by 6-7 years compared with general population
matched for age, gender and follow-up duration. 50–70% of the death cases
considered MS related, are by being in severe progressive disability that can lead to risk of infection or cardiovascular diseases(2).
The cause of MS is multifactorial and it can be developed due to both genetic and environmental risk factors. according environmental, it found three evidences associate with MS with no bias: 1. immunoglobulin G (IgG) seropositivity to Epstein-Barr virus (EBV) nuclear antigen (the risk to developing MS is 15 times higher in children with EBV and 30 times higher in adolescence or later in life with EBV), 2. Infectious mononucleosis and 3. Smoking. From a genetic point of view, there is
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association between HLA-DRB1*15:01 and a high risk of MS. immunogenetic markers have been identified with correlation to MS (IL2RA, IL7RA) and more than 100 genetic variants have been reported. Most of these are involved in the immune response and often associated with other autoimmune diseases.
According to data around the world, women are affected more commonly than men, with ratio of 1.5:1 and 2.5:1(3). In the past it was considered as a male
predominant disease but later articles from many different countries shows an evidence of female excess. The influence of the growing female preponderance is unclear yet, but as the risk factors of MS is environmental and epigenetic also in females it can explain the fast changes as modification of HLA-DRB1*1501 in genetically factors or in the environmental changes related to the life style of female mostly in the western world which can indicate that women may be more sensitive to hypothesizedenvironmental changes than man due to possible biological gender differences. Examples of this are cigarette smoking, changes in dietary habits, obesity, early age of menarche, oral contraceptive use, hormone replacement therapy, later and fever child-births, and changes in type of occupation.Another explanation for the ratio changes could be that more benign cases of MS is found in women, which are identified more quickly by use of MRI and new diagnostic criteria(2). In some cases reported pediatric MS females mostly after the age 10 suggesting that the
environmental factors may play a role in the pre-puberty. According to types of MS, it found that for women there are increasing incidences in RRMS Compare to males clinically females have an earlier onset, fewer of them have PPMS and less disability developed(4).
The incidence of MS onset age rapidly increasing after adolescence, reaching a peak between 25 and 35 years, and then slowly declining. Has similar pattern across different regions, with incidence low in childhood (3). According to research in Slovakia using Multiple Sclerosis Severity Score (MSSS) The faster was a disability progression assessed by MSSS score, the higher was the MS onset age. Relapsing-remitting MS patients older at clinical onset have a higher risk of unfavorable
prognosis. In others studies using EDSS and investigate how long it take to reach the score 6.0 it found that the younger onset age predicted a slower progression and rapid disability progression found in MS patients with onset at later age(5).
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In MS patient there are forms which characterized by a progressive disability that reflected by neurological dysfunction which lead to decrease in independence that can affect occupational performance and activities of daily living. Those can affect the perception of their quality of life. The onset age in MS patient is between the ages of 20 - 50 years, when the patients are active and productive, and frequently leads to the loss of gainful employment for many patients. Specifically, 40–80% of individuals with MS are unemployed (6). In latest research using the methods of the outcome measures used were the Canadian Occupational Performance Measure (COPM), the Modified Fatigue Impact Scale (MFIS) and the Multiple Sclerosis Quality of Life 54 (MSQoL-54) were found that the greater the perceived satisfaction of their
performance, quality of life and its associated physical factors predispose individuals towards a greater satisfaction in perceived occupational performance (7). Other research found that the unemployment rate increase over time in patients with MS. Some risk factor identified for unemployment in MS are low education level, advanced age, extent of disability, progressive subtype and personality as well as cognitive impairment that bring negative impact. Within 10 years of diagnosis, about 50% of people with MS become unemployed. The severe effect of MS on
unemployment patient results in extensive personal, social and financial costs.In aspect of depression, unemployed patients had a higher score on the BDI. 25% of men showed moderate to severe depression, as well as 36.9% of women (8). According to some research it found that the SDMT was the most significant predictor of
unemployment and the brief international cognitive assessment for MS (BICAMS) is a better predictor of work productivity. The CVLT-II has also predicted reduced employment status in a longitudinal study. Recent work has also suggested that patient-reported perceptions of cognitive difficulties may be predictive of
unemployment status independent of mood and objective memory performance (9).
The symptoms of MS can be heterogeneous: paresthesia, visual impairment, muscle weakness, depression, speech disorders, cognitive impairment, balancing disorders, chronic fatigue, limited mobility and even disability in more severe cases. All these lead to worse QoL in MS patient than healthy people (10). Severity and progression of disease, disease duration, decreased cerebral integrity on MRI and decreased ability to do everyday activities also related to poor QoL in MS patient. There is also a lower QoL during periods of relapse compared with periods of
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remission (6). QoL, which includes: biological, economic, social and psychological needs comprises objective and subjective elements of social welfare based on
individual perception and community culture experience. QoL includes the individual expectation and the achievement of personal and family goals. In study that was made in Poland found out that compared to patients with relapsing-remitting MS, primary-progressive type of the disease are characterized with worse QoL. They score lower in physical health, psychosocial health and social health scale and environmental health domain. Health and social health scales as well as in the environmental health
domain. However, research that was made in Mexico try to define the QoL in MS they found that economically active individuals and students showed better scores on the MSQOL-54 scale and its dimensions (OvQOL, PHCS, and MHCS) (8). Another factor that may affect the perception that MS patients have about their QoL is sexual dysfunction, which can occur at any stage of the disease.
10.2. Evaluation of cognitive impairment for patient with multiple
sclerosis.
MS is a progressive disease of the CNS. Inflammatory demyelination
considering the main disease process in MS. Some of the characteristics of the disease are damage to axonal or axon loss result in permanent disability along with formation of plaques in the brain and spinal cord results in a broad range of symptoms, which include motor, cognitive, and neuropsychiatric problems.There is also association between the symptoms for example depression in PwMS with high level of
neurological disability and with poor cognition, especially processing speed, working memory and executive function(11).
Prevalence rates of cognitive impairment in PwMS ranging from 43% to 70% all over the stages of the disease. According Rahn’s study, Race plays a role in disease pathogenesis and severity. For example, Caucasians have delayed symptom onset compared to Latin-American and African-American patients. It is possible that because clinical manifestations are more severe in African-American patients, the cognitive findings may be part of what is overall a more aggressive disease course. Race also affects MS impact on cognition: Adult African-American patients with MS
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develop cognitive deficits earlier in the disease course compared to adult Caucasian patients(12).
The main cognitive domains in MS that most likely to be impair are:
Memory (prevalence of 33-65%), mostly long term memory, the ability to learn new information and to recall that information at a later time point. The disability in learning new information results in bad decision-making abilities and affect
prospective memory abilities. Also, latest studies shows that dysfunction of encoding and information storing processes leads to memory deficits. In the early stage of MS, verbal episodic memory deficits seem to affect mainly information retrieval; with the progression of disability they are probably connected with encoding. Recent study from 2015 demonstrated that there is an association between verbal memory and left hippocampal atrophy(13). Tests that evaluate this domain include both auditory-verbal as the Selective Reminding Test (SRT) and California Verbal Learning Test and for visuo-spatial information the Spatial Recall Test (SPART)(14).
Information processing efficiency and speed (prevalence of 20-50%) – include maintain and manipulate information in the brain for a short time period (working memory) and IPS. Impairments in working memory found in the earliest stage of MS and along the disease courses.It is frequent cognitive alteration in MS and one of the first cognitive symptoms that can be detected(14). Moreover, deficit in IPS is
correlated with decrease of cerebellum grey matter in posterior lobules(13). Recent large sample studies have shown that people with MS present with more deficits in speed of processing than in working memory, especially in secondary-progressive course. The paced auditory serial addition test (PASAT), a test of working memory with influence on processing speed, is a sensitive measure of cognitive impairment in MS and has a sensitivity and specificity of 74% and 65%, respectively. Symbol Digit Modalities Test (SDMT) considered the measure of choice in assessing cognitive processing speed in MS(14).
Attention (prevalence of 12-25%) - links different processes such as alertness and vigilance. According to the latest study findings, the thalamus appears to be important grey matter structure for attention performance in MS. The form of
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by progressive MS subtypes, rather than this there is also sustained attention that commonly impaired, disturbances in selective attention in MS patients were
demonstrated in 2015. But it is very difficult to assess attention impairment due to the fact that it strongly connected with other cognitive domains such as IPS and working memory(6).
Executive functions (prevalence of 17-19%) - the deficit in abstract and conceptual reasoning, fluency, planning, and organization. Changes within the networks involved with the prefrontal cortex which associated with the integration and coordination of endogenous and exogenous processes, to allow the facilitation of context appropriate and adaptive behavior have been demonstrated in MS(15). deficits in both phonemic and semantic fluency was found, as well perseverative errors (e.g., errors that are repeated despite evidence that they are incorrect) have been repeatedly seen in patients with MS. Assessment executive functioning is not easy due depression in patients with MS considered in the interpretation of poor
performance on executive tasks.
Visual perceptual functions (prevalence of up to 25%) - recognition of a visual stimulus, the ability to evaluate that stimulus accurately. Abnormality in primary visual processing (e.g., from optic neuritis) in MS can affect the higher-order visual functions. New publish article reveals a strong relationship between latent sensorial temporal limitation of the visual system and processing speed deficits in MS.
All domains assess by tests and batteries define Impairment as performance below a chosen threshold. It found that Brief International Cognitive Assessment for MS (BICAMS) is a central importance battery because of its numerous advantages and validation in monitoring MS, including Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), and Selective Reminding Test or California Verbal Learning Test–II (CVLT-II) are the most sensitive tasks(16).
Factors as age found associated to a decline of neuropsychological performance, while few evidence suggests that male sex is a risk factor for progression of CI(17). The result of the tests on verbal and nonverbal memory,
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Sorting Test, demonstrate vulnerability of especially male patients to cognitive deficits that supported on study conducted in 2014, which investigated the extent and severity of white matter damage in MS with respect to sex differences both
parameters were higher in male patients(13).
In addition, progressive MS generally results in more severe cognitive impairment than does relapse-remitting MS. This interesting finding can be due to specific neuroanatomical changes. This is supported by the latest study using the MRI technique that was performed in 2015, that caudate volume in PPMS patients was significantly lower than in RRMS individuals(13). Significantly greater cognitive dysfunction was seen in the secondary-progressive MS group. Few studies have examined the characteristics of cognitive decline in MS over time, for exampleby tests of working memory and processing speed, and found that 27–44% of patients showed a decline over time(6).
Other factor such as smoking increase susceptibility for MS and can predict the disease progression. Moreover, it has been link to increased lesion volumes and brain atrophy in MS and CI in one study(17).
Depression as emotional symptom found link to CI in many people with neurological disorders. Depression is common in MS and is thought to interfere considerably with cognitive and non-cognitive activities. Depression affects domains of cognitive functioning in MS, including working memory processing speed,
learning and memory functions, abstract reasoning and executive functioning. The association of cognitive dysfunction and depression leads to worse results in different neuropsychological tests than those without a depressive symptomatology(14). In one study was found that the occurrence of depression and cognitive impairment in MS patients is characterized by profoundly different patterns of involvement of cortical and subcortical GM structures, but also found that there was an interaction between depression and cognitive impairment for atrophy of the right temporal pole and IFG: in these two regions, no thinning (or moderate thinning) was found in non-depression CI MS patients, whereas severe cortical thinning was detected in depression CI MS patients. Therefore, it seems that thinning of these regions might result in depression when cognitive impairment is present(18).
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According to fatigue, it affects approximately 90% of PwMS, both physical activities and cognition, motor and cognitive fatigue can be distinguished. Cognitive fatigue has been shown to be stronger correlated with depression than motor fatigue. However, according to the latest study, there is no independent correlation between cognitive fatigue and CI.
Protective factor found as better cognitive performance associated with higher cognitive reserve strongly associated with individual features such as variation in cell number, dendritic density and other neuronal factors that mediate increased activation of usual or alternative neural networks. Greater intellectual enrichment and larger maximal lifetime brain growth are thought to protect individuals from developing cognitive decline in MS. More factor with positive effects is estrogen therapy on cognitive performance, one of the proposed mechanisms is that estradiol may enhance performance by increasing cholinergic activity in the hippocampus and cerebral cortex(17).
As related to QoL, individual with deficits in cognitive functioning correlates with a poor QoL. Reduce in various domains of cognitive impairment have been related to the difficulty in maintaining employment, particularly information processing efficiency, memory performance, and executive dysfunction.
Neuroimaging analyses CI in MS patients in various methods. MRI, most common, can fined for example brain atrophy, cortical atrophy and lesion volume. Studies have shown that patients with greater lesion burden have significantly more cognitive dysfunction than those with less lesion burden. Grey matter and white matter atrophy could result in specific functional and cognitive skills deficits.
Research in 2015 used MRI for measure the total lesion volume, third ventricle width, corpus callosum and thalamic atrophy. The study concluded that thalamic atrophy could be useful in predicting cognitive decline in the RRMS patients group(13). In other researchcognitive impairment exhibited widespread fronto-parietal cortical and subcortical GM atrophy.Thinning of the right precuneus and high T2 lesion volume found to be the best predicted for cognitive impairment(18). UsingDiffusion tensor imaging, it has recently been indicated that the volume of cerebrospinal fluid located in subarachnoid space is related to CI in MS patients. A clinically relevant
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relationship was indicated between CI in MS and changes in the regional cerebral metabolic rate of glucose in brain grey matter in the positron emission tomography-fluorodeoxyglucose technique. fMRI findings were correlated with cognitive domains investigation. In 2006 was shown that fMRI localized in brain regions functionally linked with these domains deficit and could be seen before clinical symptoms. In 2014 found that fMRI is a viable method to monitor disease progression and treatment effects in future studies(13).
According CI in PwMS management the evidence in this field including pharmacologic interventions, cognitive rehabilitation and exercise training is still not sufficient to establish unified guidelines. It still require for high-quality studies concerning current as well as new approaches of cognitive rehabilitation and exercise training in the future.
10.3. Evaluation of mood disorder for patient with multiple sclerosis.
MS is a chronic neurological disease that characterized with different degrees of neurological disability, in addition MS have low QoL and high prevalence of neuropsychiatric symptoms (depression, irritability).MS patients have an increased risk of presenting with psychiatric disorders, especially mood disorders. At least one psychiatric symptom reported in 80% among PwMS. Mood disorder, if not identified and treated, can worsen patient functioning and QoL, reduce treatment adherence and increase the risk of suicide.
The prevalence in PwMS of major depression throughout life is between 36-54%, BD 13%, and anxiety disorders 35.7%(19). Research in turkey found that the prevalence rates of any mood disorder and any anxiety disorder were 40.5 and 45.9%, respectively. Major depression (33.8%), generalized anxiety disorder (18.9%),
specific phobia (18.9%), OCD (14.9%), dysthymic disorder (13.5%) and social phobia (13.5%)(20). other research identified major depression in 46%, BD in 6%, and anxiety disorders in 37% of the patients(19). Major depression and bipolar in MS patients considerably higher than that in the general population. The results of study
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in Brazil according demographic and clinical characteristics are similar to those described in the literature, mood disorders involving mainly young female patients, and the most frequent clinical form the relapsing-remitting MS.
According study in turkey, exacerbation phase were more likely to meet the criteria for at least one mood and anxiety disorder. Specifically, these patients had significantly higher frequencies of major depression, panic disorder and OCD. Pro-inflammatory cytokines such as TNF-a may play a role in the development of mood and anxiety disorders by affecting the central monoamine turnover in some subjects during exacerbation of MS. However, because there may be a reciprocal relationship between mood or anxiety disorders and phases of MS, it is difficult to conclude that the exacerbation phase of MS leads to these mental disorders.
In other study etiology try to be define also by neuroinflammation that can contribute to the pathogenesis of mood disorders as indicated by Positron Emission Tomography and post-mortem identification of inflammatory biomarkers(21).
Assessment of mood disorders ascertained by means of the Structured Clinical Interview for DSM-IV (SCID-I). SCID-I is a standardized diagnostic instrument performed by an interviewer experienced in psychiatric disturbances to determine Axis I psychiatric diagnoses according to DSM-IV criteria. Another test is
standardized Mood Disorder Questionnaire (MDQ) screened for BD, has been well utilized in the MS population. The Beck Fast screen is seven questions and has been validated for use for define depression in patients with MS(19).
Among mood disorders in PwMS few studies have focused on the relationship between BD and MS. The initial presentation of BD may include a depressive phase, or a manic-phase with or without psychotic symptoms, these presentations have been temporally associated with MS. According to the etiology there is a possible genetic association between MS and BD. In addition, there is the hypothesis of 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)(21).
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10.4. Evaluation of depressive mood disorder for patient with multiple
disorder.- sclerosis
Depressive disorders are common in patients with MS and affect their QoL. Depressive disorders are more frequent with the progression of the disease and in the secondary progressive form of MS. Depression in PwMS typically associate with fatigue, pain and CI. The pathogenesis of MS-related depression remains partially unclear, even though in PwMS genetic, immune-inflammatory and psychosocial factors might be seen to play a role in the etiology of depression. In addition, brain structural alterations documented by MRI studies can show correlation between depression and MS.
A review of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) reveals three diagnoses that capture the spectrum of mood disorders associated with MS: adjustment disorder, depressive disorder due to a medical condition, and major depressive disorder. The DSM-5 marks that a patient must have at least five of nine clearly defined symptoms, some including fatigue, altered sleep patterns, changes in appetite, poor concentration and impaired memory(22).
Among the studies the prevalence of depressive disorders and symptoms varied widely, ranging from 4.27 to 59.6%(23). Women and patients younger than 45 years of age found to be more susceptible for depressive disorders. Patients with secondary progressive MS presented with depressive symptoms more frequently than patients with RR-MS or with primary progressive MS, independently from disease duration and physical disability.
Regarding PwMS, assessment method to define depressive disorders often contains a number of questions related to physical symptoms such as fatigue, sleep problems and pain. Scales produce ordinal scores expressing the severity of
depressive symptoms. Several scales have been used to score depressive symptoms in PwMS: Beck Depression Inventory (BDI), Beck Depression Inventory II (BDI-II) and Beck Depression Inventory – fast screen (BDI-FS), Hospital Anxiety and Depression Scale (HADS), Center for Epidemiologic Studies Depression Scale
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(CESD), Patient Health Questionnaire-9 (PHQ-9) and Patient Health Questionnaire-2 (PHQ-2), Hopkins Symptom Checklist-25 (HSCL-25), Montgomery Asberg
Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HDRS), Inventory of Depressive Symptomatology (IDS-SR) and Depression Anxiety Stress Scale (DASS-21). According to the evidence-based guidelines of the American Academy of Neurology (AAN), the BDI scale is recommended for assessing
depression in PwMS. As considering to interview semi-structured interviews represent the main type of evaluations available for depression, the most used were the CIDI and SCID. According to some reviews the use of two screening questions has been proposed for detecting major depressive disorder in the context of MS(24).
Unfortunately depression are frequently underdiagnosed and undertreated. In a cross-sectional community study of patients with MS by Cetin, 59% of the patients who had significant symptoms of depression were not taking medication, possibly due to missed diagnosis, denial of symptoms, or false reporting, whereas the rest 41% received inadequate treatment(24). Most of them were from low socioeconomic status according to findings from a North American study(22).
It has been hypothesized that genetic, immune-inflammatory and psychosocial factors and the presence of MS-related structural brain alterations might be the
potential causes of MS-related depression. Genetically, some studies did not found correlation between MS-related depression and a family history of depression. In the other hand some studies suggested a possible correlation, they found higher
prevalence of depression in female PwMS with a family history of depression. According Immune-Inflammatory factors, proinflammatory cytokines might act as main role in the genesis of MS-related depression (mostly depression in relapsing– remitting MS than in progressive MS) for example proinflammatory cytokines presumed to affect serotonin synthesis and reuptake in the central nervous system as well as constitute the trigger for the increased secretion of adrenal corticosteroids through the activation of the hypothalamic-pituitary-adrenal axis. In various research Immunofluorescence determination of T cells demonstrated a higher rate of T4-helper/inducer cells in the peripheral blood in depressed PwMS. In a longer periods studies, depression correlated to a lower CD8+ percentage and a higher CD4/CD8 ratio, with greater CD4 percentages when subjects were in a more severe depressive
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state. In study on patients with RR-MS, higher depression rating scores were
correlated with a higher lymphocyte count in the CSF and with gadolinium-enhancing lesions on MRI. Correlation between BDI scale and the increase of whole blood TNF and interferon mRNA has been demonstrated during relapses, as well as increase in IL-6 and decrease in IL-4 and albumin levels in the peripheral blood(23).
Low mood among MS patients has 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 in Non-MS patients(21). Recent studies also showed a relation between depression and
demyelination in some brain regions, as cortex and subcortical region, appearing to contribute to depression more than other areas(6). MS related depression is associated also with loss of grey matter volume in frontal and temporal lobes. Weighted lesion load found higher in depressed PwMS especially in the temporal lobe and in the arcuate fasciculus. Patients with brain lesions are more likely to experience depression compared to patients with spinal cord lesions(12).
According to atrophy in the brain it was demonstrate that total temporal brain volume, right hemisphere brain volume and disability have been correlated with the severity of MS related depression. Study of Rocca found that grey matter loss in the right middle cingulate and middle frontal gyrus at baseline predicted the increase of depressive symptoms(18). Amongst depressed PwMS, diffusion tensor imaging studies revealed fractional anisotropy changes within the limbic system (cingulate cortex, hippocampus and left hypothalamus). In addition to that another study using the same technic and tractography demonstrated an abnormal communication between limbic circuits(23).
Rocca studies found out that depressive symptoms have been correlated with the disruption of the default mode network, while Bonavita studies demonstrated an imbalance in the functional connectivity of the salience network, executive control network and default mode network in cognitively preserved depressed PwMS(25).
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In psychosocial factors aspects, feeling helplessness, reduced social activities and the enjoyment of them, maladaptive and stress coping styles have been correlated with depression in PwMS. In addition, the onset of MS in young people who are often trying to establish interpersonal relations and careers could result in stressors that might contribute to the development of depressive symptoms. Some studies concluded that MS-derived disability might be a predictor of depression, especially in the first year after diagnosis. Voss study described that the inability to socialize and participate in activities due to fatigue or physical disability negatively influenced mood health of PwMS(23).
Variables factors as social support, coping strategies, stress, self-knowledge and perception of the disease, all of which would influence modulating the onset of depression. Patients affected with MS and CI and with major depressive
symptomatology adapt high degree of avoidance strategies or negative coping(14).
According to other factors that correlate with depressive MS patient it found that 30% of PwMS experience nociceptive or neuropathic pain and about 65% experience a clinically significant fatigue. It is demonstrated that a successful treatment of depression can decrease fatigue. Depressed PwMS experience lower performances in various cognitive domains, such as working memory or IPS. In a research that was done by cognitive tests as the Selective Reminding Test and the PASAT. The results showed that the significantly depressed MS patients were more impaired than the mildly depressed patients on both tests(26). As we understand, lesions in the temporal lobe related to depression. Temporal lobe lesions could be the linking part between depression and CI, as brain structures involved in learning and memory function, such as the amygdala and the hippocampus, are located in the temporal lobes(12).
Regarding treatment plan for depression, it should include pharmacotherapy, psychotherapy or CBT in specific or combination therapy (but, both CBT and MBI cannot be used by persons with significant CI). Screening for suicidal intent is important due to the high risk for suicide. In the aspect of pharmacological therapies, treating depression has been found to improve related cognitive disturbances, fatigue, QoL, and possibly disease course, by decreasing production of cytokine. There is
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some evidence regarding the neuroprotective effects of antidepressants such as fluoxetine and phenelzine(24). However, the AAN has reported that there is inadequate evidence on the use of antidepressants in MS-related depression.
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11. CONCLUSION
In this systematic review I analyzed and compared different research works done in the last ten year in order to present the most updated information about the correlation of cognitive impairment and depressive mood disorder in multiple sclerosis. Several conclusions could be drawn from the research has be done:
● Contrarily to the assumption that MS is incidencly increasing in the north pole, Migration might mitigate that increasing, as migrants have come almost exclusively from low-risk MS areas. QoL in individuals with PPMS is lower than in other types of this condition. According to age, there is no significant effect on QoL in MS. early identification of deficits in MS as cognitive impairment allows identify patients who are at risk of employment difficulties, which may give a support to be put in place that enables them to continue in their current employment with accommodations.
● The aim is to seek to increase understanding of cognitive deficits and their effect on other abilities (QoL, employment status, psychological status). The investigation of efforts to improve cognitive status in MS is still in its infancy. New clinical
meaningful ways as a measurement criteria should be done in available technologies and new technologies to understand further the association between brain structure and function—as well as their effect on cognition.
● Prevalence of mood and anxiety disorders are in patients with a diagnosis of
relapsing-remitting MS attending a MS clinic are higher than estimated in the general population, and patients in exacerbation phase are more likely to meet the diagnostic criteria for these disorders. Clinicians should be aware that the ramifications of low mood in the MS patient are extensive and disabling.
● Multi factorial etiology for depression in MS can be valuable as increasing evidence demonstrating cerebral damage in association with MS-related depression may lead to a better understanding of the relationship between depression and neurodegeneration, as the correlation between cognitive impairment and depression in MS.
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