People with Primary Progressive Multiple Sclerosis Have a Lower Number of Central Memory T Cells and HLA-DR+ Tregs.

The importance of circulating immune cells to primary progressive multiple sclerosis (PPMS) pathophysiology is still controversial because most immunotherapies were shown to be ineffective in treating people with PPMS (pwPPMS). Yet, although controversial, data exist describing peripheral immune system alterations in pwPPMS. This study aims to investigate which alterations might be present in pwPPMS free of disease-modifying drugs (DMD) in comparison to age- and sex-matched healthy controls. A multicentric cross-sectional study was performed using 23 pwPPMS and 23 healthy controls. The phenotype of conventional CD4+ and CD8+ T cells, regulatory T cells (Tregs), B cells, natural killer (NK) T cells and NK cells was assessed. Lower numbers of central memory CD4+ and CD8+ T cells and activated HLA-DR+ Tregs were observed in pwPPMS. Regarding NK and NKT cells, pwPPMS presented higher percentages of CD56dimCD57+ NK cells expressing NKp46 and of NKT cells expressing KIR2DL2/3 and NKp30. Higher disease severity scores and an increasing time since diagnosis was correlated with lower numbers of inhibitory NK cells subsets. Our findings contribute to reinforcing the hypotheses that alterations in peripheral immune cells are present in pwPPMS and that changes in NK cell populations are the strongest correlate of disease severity.

Cost-effectiveness Analysis of Ocrelizumab for the Treatment of Relapsing and Primary Progressive Multiple Sclerosis in Portugal.

OBJECTIVES: Ocrelizumab demonstrated significant clinical benefit for the treatment of relapsing (RMS) and primary progressive (PPMS) multiple sclerosis (MS), an incurable disease characterized by disability progression. This study evaluated the clinical and economic impact of ocrelizumab relative to current clinical practice, including other disease-modifying therapies (DMT), available in Portugal. METHODS: Markov models for MS were adapted to estimate the impact of ocrelizumab across three patient populations: treatment-naïve RMS, previously treated RMS, and PPMS. Health states were defined according to the Expanded Disability Status Scale. For RMS, the model further captured the occurrence of relapses and progression to secondary progressive multiple sclerosis (SPMS). A lifetime time-horizon and Portuguese societal perspective were adopted. RESULTS: For RMS patients, ocrelizumab was estimated to maximize the expected time (years) without progression to SPMS (10.50) relative to natalizumab (10.10), dimethyl fumarate (8.64), teriflunomide (8.39), fingolimod (8.38), interferon ß-1a (8.33) and glatiramer acetate (8.18). As the most effective option, with quality-adjusted life year (QALY) gains between 0.3 and 1.2, ocrelizumab was found to be cost-saving relative to natalizumab and fingolimod, and presented incremental cost-effectiveness ratios (ICER) below €16,720/QALY relative to the remaining DMT. For PPMS patients, the ICER of ocrelizumab versus best supportive care was estimated at €78,858/QALY. CONCLUSIONS: Ocrelizumab provides important health benefits for RMS and PPMS patients, comparing favourably with other widely used therapies. In RMS, ocrelizumab was revealed to be either cost-saving or have costs-per-QALY likely below commonly accepted cost-effectiveness thresholds. In PPMS, ocrelizumab fills a clear clinical gap in the current clinical practice. Overall, ocrelizumab is expected to provide good value for money in addressing the need of MS patients.

Deep Learning-Based Energy Expenditure Estimation in Assisted and Non-Assisted Gait Using Inertial, EMG, and Heart Rate Wearable Sensors.

Energy expenditure is a key rehabilitation outcome and is starting to be used in robotics-based rehabilitation through human-in-the-loop control to tailor robot assistance towards reducing patients' energy effort. However, it is usually assessed by indirect calorimetry which entails a certain degree of invasiveness and provides delayed data, which is not suitable for controlling robotic devices. This work proposes a deep learning-based tool for steady-state energy expenditure estimation based on more ergonomic sensors than indirect calorimetry. The study innovates by estimating the energy expenditure in assisted and non-assisted conditions and in slow gait speeds similarly to impaired subjects. This work explores and benchmarks the long short-term memory (LSTM) and convolutional neural network (CNN) as deep learning regressors. As inputs, we fused inertial data, electromyography, and heart rate signals measured by on-body sensors from eight healthy volunteers walking with and without assistance from an ankle-foot exoskeleton at 0.22, 0.33, and 0.44 m/s. LSTM and CNN were compared against indirect calorimetry using a leave-one-subject-out cross-validation technique. Results showed the suitability of this tool, especially CNN, that demonstrated root-mean-squared errors of 0.36 W/kg and high correlation (ρ > 0.85) between target and estimation (R¯2 = 0.79). CNN was able to discriminate the energy expenditure between assisted and non-assisted gait, basal, and walking energy expenditure, throughout three slow gait speeds. CNN regressor driven by kinematic and physiological data was shown to be a more ergonomic technique for estimating the energy expenditure, contributing to the clinical assessment in slow and robotic-assisted gait and future research concerning human-in-the-loop control.

Low Memory T Cells Blood Counts and High Naïve Regulatory T Cells Percentage at Relapsing Remitting Multiple Sclerosis Diagnosis.

Objective: The aim of this study is to assess the peripheral immune system of newly diagnosed patients with relapsing remitting multiple sclerosis (RRMS) and compare it to healthy controls (HC). Methods: This cross-sectional study involves 30 treatment-naïve newly diagnosed patients with RRMS and 33 sex- and age-matched HC. Peripheral blood mononuclear cells were analyzed regarding: i) thymic function surrogates [T cell receptor excision circles (TRECs) and recent thymic emigrants (RTEs)]; ii) naïve and memory CD4+ and CD8+ T cells subsets; iii) T helper (Th) phenotype and chemokine receptors expression on CD8+ T cells subsets; iv) regulatory T cell (Tregs) phenotype; and exclude expression of activating/inhibitory receptors by natural killer (NK) and NKT cells. Analyses were controlled for age, sex, and human cytomegalovirus (HCMV) IgG seroprevalence. Results: Newly diagnosed patients with RRMS and HC have equivalent thymic function as determined by similar numbers of RTEs and levels of sjTRECs, DJßTRECs, and sj/DJßTREC ratio. In the CD8+ T cells compartment, patients with RRMS have a higher naive to memory ratio and lower memory cell counts in blood, specifically of effector memory and TemRA CD8+ T cells. Interestingly, higher numbers and percentages of central memory CD8+ T cells are associated with increasing time from the relapse. Among CD4+ T cells, lower blood counts of effector memory cells are found in patients upon controlling for sex, age, and anti-HCMV IgG seroprevalence. Higher numbers of CD4+ T cells (both naïve and memory) and of Th2 cells are associated with increasing time from the relapse; lower numbers of Th17 cells are associated with higher MS severity scores (MSSS). Patients with RRMS have a higher percentage of naïve Tregs compared with HC, and lower percentages of these cells are associated with higher MSSS. Percentages of immature CD56bright NK cells expressing the inhibitory receptor KLRG1 and of mature CD56dimCD57+ NK cells expressing NKp30 are higher in patients. No major alterations are observed on NKT cells. Conclusion: Characterization of the peripheral immune system of treatment-naïve newly diagnosed patients with RRMS unveiled immune features present at clinical onset including lower memory T cells blood counts, particularly among CD8+ T cells, higher percentage of naïve Tregs and altered percentages of NK cells subsets expressing inhibitory or activating receptors. These findings might set the basis to better understand disease pathogenesis.

Lipocalin-2 does not influence EAE clinical score but it increases inflammation in central nervous system.

The contribution of lipocalin-2 (LCN2) to multiple sclerosis (MS) is controversial. Herein, we induced experimental autoimmune encephalomyelitis (EAE) in LCN2-null and wild-type (Wt) mice. While we did not find differences between genotypes regarding clinical score, LCN2-null EAE mice presented decreased expression of interferon gamma and diminished demyelination in the cerebellum. Both genotypes presented similar alterations in the thymocyte and splenocyte populations. In MS patients, higher LCN2 CSF levels at diagnosis could be associated with faster disease progression, however further studies are needed to confirm these results, since this association was lost after controlling for the patients age, presence of oligoclonal bands and gender. Overall, our results support a harmful role for LCN2 in the disease context.

Multiple Sclerosis Patient Management During the COVID-19 Pandemic: Practical Recommendations From the Portuguese Multiple Sclerosis Study Group (GEEM).

The spread of the COVID-19 pandemic has imposed significant challenges on healthcare provision, requiring changes in the conventional patient management, particularly in chronic diseases like multiple sclerosis (MS). To increase patient safety and reduce the risk of infection, while ensuring an appropriate and regular follow-up, tele-medicine gained prominence as a valid alternative to face-to-face appointments. However, the urgency of the implementation and the lack of experience in most MS centers led to "ad hoc" and extremely diverse approaches, which now merit to be standardized and refined. Indeed, while tele-consultation cannot fully replace face-to-face visits, it certainly can, and will, be incorporated as part of the routine care of MS patients in the near future. Bearing this in mind, the Portuguese Multiple Sclerosis Study Group (GEEM) has developed a set of recommendations for the usage of tele-medicine in the management of MS patients, both during the pandemic and in the future. The consensus was obtained through a two-step modified Delphi methodology, resulting in 15 recommendations, which are detailed in the manuscript.

Stigmatizing Attitudes Toward Patients With Psychiatric Disorders Among Medical Students and Professionals.

INTRODUCTION: Stigma attached to mental health encompasses discrimination and exclusion of psychiatric patients and hinders their opportunities to have more productive and fulfilling lives. Moreover, stigma also exists among health professionals, and therefore, it hampers the provision of treatment and care and the promotion of mental well-being. This manuscript intends to assess and compare the levels of stigmatization toward patients with mental illness between medical students and doctors from different specialties. METHODS: The Portuguese version of Attribution Questionnaire (AQ-27) was used to assess the attitudes of medical students (n = 203), non-psychiatry doctors (n = 121), and psychiatry specialists (n = 29) from the University of Minho and three hospitals in the region of Braga, Portugal (Hospital de Braga, Hospital Senhora da Oliveira, and Hospital de Fafe). RESULTS: Psychiatrists were the group that displayed lower levels of stigmatizing attitudes in all the items of the AQ-27, followed by the students. The regression analyses revealed that professional group and presence of a relative with mental illness were the factors that have a significant impact on the levels of stigmatization. CONCLUSIONS: Mental illness stigma is widely spread in community and reaches not only general population but also health professionals. Psychiatrists presented lower levels of stigma compared with non-psychiatry physicians and medical students. We found that stigma is related with age and the presence of relatives with psychiatric disorders. These findings highlight the critical relevance of raising awareness on this topic and, therefore, break stereotypes to reduce the negative consequences of stigma.

A Resting-State Functional MR Imaging and Spectroscopy Study of the Dorsal Hippocampus in the Chronic Unpredictable Stress Rat Model.

Exposure to chronic stress leads to an array of anatomical, functional, and metabolic changes in the brain that play a key role in triggering psychiatric disorders such as depression. The hippocampus is particularly well known as a target of maladaptive responses to stress. To capture stress-induced changes in metabolic and functional connectivity in the hippocampus, stress-resistant (low-responders) or -susceptible (high-responders) rats exposed to a chronic unpredictable stress paradigm (categorized according to their hormonal and behavioral responses) were assessed by multimodal neuroimaging; the latter was achieved by using localized 1H MR spectroscopy and resting-state functional MRI (fMRI) at 11,7T data from stressed (n = 25) but also control (n = 15) male Wistar rats.Susceptible animals displayed increased GABA-glutamine (+19%) and glutamate-glutamine (+17%) ratios and decreased levels of macromolecules (-11%); these changes were positively correlated with plasma corticosterone levels. In addition, the neurotransmitter levels showed differential associations with functional connectivity between the hippocampus and the amygdala, the piriform cortex and thalamus between stress-resistant and -susceptible animals. Our observations are consistent with previously reported stress-induced metabolomic changes that suggest overall neurotransmitter dysfunction in the hippocampus. Their association with the fMRI data in this study reveals how local adjustments in neurochemistry relate to changes in the neurocircuitry of the hippocampus, with implications for its stress-associated dysfunctions.SIGNIFICANCE STATEMENT Chronic stress disrupts brain homeostasis, which may increase the vulnerability of susceptible individuals to neuropsychiatric disorders such as depression. Characterization of the differences between stress-resistant and -susceptible individuals on the basis of noninvasive imaging tools, such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), contributes to improved understanding of the mechanisms underpinning individual differences in vulnerability and can facilitate the design of new diagnostic and intervention strategies. Using a combined functional MRI/MRS approach, our results demonstrate that susceptible- and non-susceptible subjects show differential alterations in hippocampal GABA and glutamate metabolism that, in turn, associate with changes in functional connectivity.

Immune Thymic Profile of the MOG-Induced Experimental Autoimmune Encephalomyelitis Mouse Model.

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease that affects the neurons of the central nervous system. Activated T cells, specific for myelin epitopes, cross the brain barriers, and react against the myelin sheath, leading to demyelination. Since T cells are generated within the thymus, here we explored, in mice, the alterations occurring in this organ throughout the different phases of the disease. We induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 females and sacrifice them at the onset (day 16) and chronic phases of disease (day 23), along with non-induced controls. We observed thymic atrophy in EAE mice at the onset that remained until the chronic phase of disease. This atrophy was associated with a preferential loss of the CD4+CD8+ double positive thymocytes, an intermediate population between the more immature CD4-CD8- double negative and the most mature single positive thymocytes. This was accompanied by an increase in the thymic medullary/cortical ratio and by an altered expression levels of genes important for T cell survival. During the chronic phase, the thymi remained atrophic, but reacquired the normal proportion of the main four thymocyte populations and the normal medullary/cortical ratio. Importantly, at the onset phase, and accompanying these thymic alterations, EAE animals presented an increased percentage of demyelinating lesion area in the cerebellum, and an increased expression of interferon gamma (Ifng), interleukin (Il) 12a, and Il17a. This study suggests dynamic thymic alterations occurring in response to EAE, from the induction to the chronic phase, that might help to elucidate the MS pathophysiology.

Depression in medical students: insights from a longitudinal study.

BACKGROUND: Factors associated with depression of medical students are poorly understood. The purpose of this study is to determine the prevalence of depression in medical students, its change during the course, if depression persists for affected students, what are the factors associated with depression and how these factors change over time. METHODS: A prospective, longitudinal observational study was conducted at the Medical School of the University of Minho, Portugal, between academic years 2009-2010 to 2012-2013. We included students who maintained their participation by annually completing a questionnaire including Beck Depression Inventory (BDI). Anxiety and burnout were assessed using the State Trait Anxiety Inventory and Maslach Burnout Inventory. Surveys on socio-demographic variables were applied to evaluate potential predictors, personal and academic characteristics and perceived difficulties. ANOVA with multiple comparisons were used to compare means of BDI score. The medical students were organized into subgroups by K-means cluster analyses. ANOVA mixed-design repeated measurement was performed to assess a possible interaction between variables associated with depression. RESULTS: The response rate was 84, 92, 88 and 81% for academic years 2009-2010, 2010-2011,2011-2012 and 2012/2013, respectively. Two hundred thirty-eight medical students were evaluated longitudinally. For depression the prevalence ranged from 21.5 to 12.7% (academic years 2009/2010 and 2012/2013). BDI scores decreased during medical school. 19.7% of students recorded sustained high BDI over time. These students had high levels of trait-anxiety and choose medicine for anticipated income and prestige, reported more relationship issues, cynicism, and decreased satisfaction with social activities. Students with high BDI scores at initial evaluation with low levels of trait-anxiety and a primary interest in medicine as a career tended to improve their mood and reported reduced burnout, low perceived learning problems and increased satisfaction with social activities at last evaluation. No difference was detected between men and women in the median BDI score over time. CONCLUSIONS: Our findings suggest that personal factors (anxiety traits, medicine choice factors, relationship patterns and academic burnout) are relevant for persistence of high levels of BDI during medical training. Medical schools need to identity students who experience depression and support then, as early as possible, particularly when depression has been present over time.

Using endogenous saccades to characterize fatigue in multiple sclerosis.

PURPOSE: Multiple Sclerosis (MS) is likely to cause dysfunction of neural circuits between brain regions increasing brain working load or a subjective overestimation of such working load leading to fatigue symptoms. The aim of this study was to investigate if saccades can reveal the effect of fatigue in patients with MS. METHODS: Patients diagnosed with MS (EDSS<=3) and age matched controls were recruited. Eye movements were monitored using an infrared eyetracker. Each participant performed 40 trials in an endogenous generated saccade paradigm (valid and invalid trials). The fatigue severity scale (FSS) was used to assess the severity of fatigue. FSS scores were used to define two subgroups, the MS fatigue group (score above normal range) and the MS non-fatigue. Differences between groups were tested using linear mixed models. RESULTS: Thirty-one MS patients and equal number of controls participated in this study. FSS scores were above the normal range in 11 patients. Differences in saccade latency were found according to group (p<0.001) and trial validity (p=0.023). Differences were 16.9ms, between MS fatigue and MS non-fatigue, 15.5ms between MS fatigue and control. The mean difference between valid and invalid trials was 7.5ms. Differences in saccade peak velocity were found according to group (p<0.001), the difference between MS fatigue and control was 22.3°/s and between MS fatigue and non-fatigue was 12.3°/s. Group was a statistically significant predictor for amplitude (p<0.001). FSS scores were correlated with peak velocity (p=0.028) and amplitude (p=0.019). CONCLUSION: Consistent with the initial hypothesis, our study revealed altered saccade latency, peak velocity and amplitude in patients with fatigue symptoms. Eye movement testing can complement the standard inventories when investigating fatigue because they do not share similar limitations. Our findings contribute to the understanding of functional changes induced by MS and might be useful for clinical trials and treatment decisions.

Patterns of Theta Activity in Limbic Anxiety Circuit Preceding Exploratory Behavior in Approach-Avoidance Conflict.

Theta oscillations within the hippocampus-amygdala-medial prefrontal cortex (HPC-AMY-mPFC) circuit have been consistently implicated in the regulation of anxiety behaviors, including risk-assessment. To study if theta activity during risk-assessment was correlated with exploratory behavior in an approach/avoidance paradigm we recorded simultaneous local field potentials from this circuit in rats exploring the elevated-plus maze (EPM). Opposing patterns of power variations in the ventral hippocampus (vHPC), basolateral amygdala (BLA), and prelimbic (PrL) mPFC, but not in the dorsal hippocampus (dHPC), during exploratory risk-assessment of the open arms preceded further exploration of the open arms or retreat back to the safer closed arms. The same patterns of theta power variations in the HPC-BLA-mPFC(PrL) circuit were also displayed by animals submitted to chronic unpredictable stress protocol known to induce an anxious state. Diverging patterns of vHPC-mPFC(PrL) theta coherence were also significantly correlated with forthcoming approach or avoidance behavior in the conflict situation in both controls and stressed animals; interestingly, vHPC-BLA, and BLA-mPFC(PrL) theta coherence correlated with future behavior only in stressed animals, underlying the pivotal role of the amygdala on the stress response.

Glucose intolerance after chronic stress is related with downregulated PPAR-γ in adipose tissue.

BACKGROUND: Chronic stress is associated with increased risk of glucose intolerance and cardiovascular diseases, albeit through undefined mechanisms. With the aim of gaining insights into the latter, this study examined the metabolic profile of young adult male rats that were exposed to chronic unpredictable stress. METHODS: Young adult male rats were submitted to 4 weeks of chronic unpredictable stress and allowed to recover for 5 weeks. An extensive analysis including of morphologic, biochemical and molecular parameters was carried out both after chronic unpredictable stress and after recovery from stress. RESULTS: After 28 days of chronic unpredictable stress (CUS) the animals submitted to this protocol displayed less weight gain than control animals. After 5 weeks of recovery the weight gain rebounded to similar values of controls. In addition, following CUS, fasting insulin levels were increased and were accompanied by signs of impaired glucose tolerance and elevated serum corticosteroid levels. This biochemical profile persisted into the post-stress recovery period, despite the restoration of baseline corticosteroid levels. The mRNA expression levels of peroxisome proliferator-activated receptor (PPAR)-γ and lipocalin-2 in white adipose tissue were, respectively, down- and up-regulated. CONCLUSIONS: Reduction of PPAR-γ expression and generation of a pro-inflammatory environment by increased lipocalin-2 expression in white adipose tissue may contribute to stress-induced glucose intolerance.

Central autonomic nervous system response to autonomic challenges is altered in patients with a previous episode of Takotsubo cardiomyopathy.

AIMS: Takotsubo cardiomyopathy is an intriguing disease characterized by acute transient left ventricular dysfunction usually triggered by an episode of severe stress. The excessive levels of catecholamines and the overactivation of the sympathetic system are believed to be the main pathophysiologic mechanisms of Takotsubo cardiomyopathy, but it is unclear whether there is a structural or functional signature of the disease. In this sense, our aim was to characterize the central autonomic system response to autonomic challenges in patients with a previous episode of Takotsubo cardiomyopathy when compared with a control group of healthy volunteers. METHODS AND RESULTS: Functional magnetic resonance imaging (fMRI) was performed in four patients with a previous episode of Takotsubo cardiomyopathy (average age of 67 ± 12 years) and in eight healthy volunteers (average age of 66 ± 5 years) while being submitted to different autonomic challenges (cold exposure and Valsalva manoeuvre). The fMRI analysis revealed a significant variation of the blood oxygen level dependent signal triggered by the Valsalva manoeuvre in specific areas of the brain involved in the cortical control of the autonomic system and significant differences in the pattern of activation of the insular cortex, amygdala and the right hippocampus between patients with Takotsubo cardiomyopathy and controls, even though these regions did not present significant volumetric changes. CONCLUSION: The central autonomic response to autonomic challenges is altered in patients with Takotsubo cardiomyopathy, thus suggesting a dysregulation of the central autonomic nervous system network. Subsequent studies are needed to unveil whether these alterations are causal or predisposing factors to Takotsubo cardiomyopathy.

Stress induced risk-aversion is reverted by D2/D3 agonist in the rat.

Stress exposure triggers cognitive and behavioral impairments that influence decision-making processes. Decisions under a context of uncertainty require complex reward-prediction processes that are known to be mediated by the mesocorticolimbic dopamine (DA) system in brain areas sensitive to the deleterious effects of chronic stress, in particular the orbitofrontal cortex (OFC). Using a decision-making task, we show that chronic stress biases risk-based decision-making to safer behaviors. This decision-making pattern is associated with an increased activation of the lateral part of the OFC and with morphological changes in pyramidal neurons specifically recruited by this task. Additionally, stress exposure induces a hypodopaminergic status accompanied by increased mRNA levels of the dopamine receptor type 2 (Drd2) in the OFC; importantly, treatment with a D2/D3 agonist quinpirole reverts the shift to safer behaviors induced by stress on risky decision-making. These results suggest that the brain mechanisms related to risk-based decision-making are altered after chronic stress, but can be modulated by manipulation of dopaminergic transmission.

Age effects on EEG correlates of the Wisconsin Card Sorting Test.

Body and brain undergo several changes with aging. One of the domains in which these changes are more remarkable relates with cognitive performance. In the present work, electroencephalogram (EEG) markers (power spectral density and spectral coherence) of age-related cognitive decline were sought whilst the subjects performed the Wisconsin Card Sorting Test (WCST). Considering the expected age-related cognitive deficits, WCST was applied to young, mid-age and elderly participants, and the theta and alpha frequency bands were analyzed. From the results herein presented, higher theta and alpha power were found to be associated with a good performance in the WCST of younger subjects. Additionally, higher theta and alpha coherence were also associated with good performance and were shown to decline with age and a decrease in alpha peak frequency seems to be associated with aging. Additionally, inter-hemispheric long-range coherences and parietal theta power were identified as age-independent EEG correlates of cognitive performance. In summary, these data reveals age-dependent as well as age-independent EEG correlates of cognitive performance that contribute to the understanding of brain aging and related cognitive deficits.

Cotard Syndrome without Depressive Symptoms in a Schizophrenic Patient.

Introduction. Cotard syndrome is a rare condition characterized by nihilistic delusions concerning body or life that can be found in several neuropsychiatry conditions. It is typically associated with depressive symptoms. Method. We present a case of Cotard syndrome without depressive symptoms in the context of known paranoid schizophrenia. A literature review of Cotard syndrome in schizophrenia was performed. Results. Although there are few descriptions of this syndrome in schizophrenia, patients usually present depressive mood and psychomotor retardation, features not seen in our patient. Loss of the sense of the inner self, present in schizophrenia, could explain patient's symptomatology but neurobiological bases of this syndrome remain unclear. Conclusion. Despite not being considered in actual classifications, Cotard syndrome is still relevant and psychiatric evaluation is critical to diagnosing and treating this condition in psychiatric patients.