Fatigue after stroke: a major but neglected issue

Subjective fatigue, defined as a feeling of early exhaustion developing during mental activity, with weariness, lack of energy and aversion to effort, remains virtually unstudied in patients with stroke, bur recent surveys suggest that it is a major, commonly overlooked, stroke sequela. While the few existing series did not show significant correlations between fatigue and stroke severity, lesion location, cognitive and neurological impairment and depression, recent neurobehavioral studies have highlighted an association between fatigue and brainstem and thalamic lesions. This suggests that fatigue may be linked to the interruption of neural networks involved in tonic attention, such as the reticular activating system. In fact, several subtypes of fatigue may develop after stroke, in connection with cognitive sequelae, neurological impairment, psychological factors and sleep disorders. A challenge is to identify and delineate these different subtypes and to distinguish them from mood disorders, which frequently coexist. We emphasize the concept of 'primary' poststroke fatigue, which may develop in the absence of depression or a significant cognitive sequela, and which may be linked to attentional deficits resulting from specific damage to the reticular formation and related structures involved in the subcortical attentional network. In the patients with excellent neurological and neuropsychological recovery, poststroke fatigue may be the only persisting sequela, which may severely limit their return to previous activities. The recognition of poststroke fatigue may be critical during recovery and rehabilitation after stroke.     

Poststroke depression: prevalence, diagnosis, treatment, and disease progression.

In recent years, poststroke depression has attracted worldwide interest. This review focuses on the major research themes that have emerged. Pooled data from studies conducted throughout the world have found prevalence rates for major depression of 19.3% among hospitalized patients and 23.3% among outpatient samples. The diagnosis of poststroke depression is most appropriately based on a structured mental state exam and DSM-IV criteria for depression due to stroke with major depressive-like episode or depressive features. Rarely, poststroke patients may also develop bipolar mood disorder. The treatment of poststroke depression has been examined in several placebo-controlled randomized clinical trials with both nortriptyline and citalopram showing efficacy. The progression of recovery following stroke can be altered by treating depression, which has been shown to improve recovery in activities of daily living and cognitive impairment and to decrease mortality. In addition, two studies have demonstrated that poststroke depression can be prevented using antidepressant medication, which also decreases the frequency of associated physical illness. Furthermore, two studies have shown that premorbid depression can significantly increase the risk of stroke over the subsequent 10-15 years. The mechanisms underlying the association of cerebrovascular diseases and mood disorder are important areas for future investigation.     

A two-year longitudinal study of poststroke mood disorders. In-hospital prognostic factors associated with six-month outcome

In a prospective study of mood disorders in stroke patients, variables obtained during the acute hospitalization were examined for their relationship to outcome at either 3- or 6-month follow-up. Distance of the lesion on computerized axial tomography scan from the frontal pole in patients with left anterior infarcts was significantly associated with severity of depression at 3 and 6 months poststroke. In addition, intellectual and functional physical impairment in-hospital were significantly correlated with severity of depression and social functioning scores at 3 and 6 months poststroke. Thus, patients who develop depression during the first 6 months poststroke may be responding to the severity of their impairment whereas the patients who develop depressions during the acute poststroke period may have a neuroanatomical and neurophysiological basis for their depression. Although other explanations might be proposed, the dynamic nature of the relationship between depression and associated variables during the first 6 months poststroke indicates that etiology of poststroke depression may be different depending upon the time of onset of the depression after brain injury.     

Treatment of cognitive impairment after poststroke depression : a double-blind treatment trial

BACKGROUND AND PURPOSE: Patients with poststroke major depression have a greater severity of cognitive impairment than nondepressed patients even when matched for size and location of stroke lesion. Prior treatment studies have consistently failed to show an improvement in cognitive function even when poststroke mood disorders responded to antidepressant therapy. We examined the response of cognitive function to treatment with nortriptyline or placebo in a double-blind trial. METHODS: Patients with major (n=33) or minor (n=14) depression participated in a double-blind treatment study with nortriptyline or placebo. They were examined for change in depressive mood, measured by the Hamilton Rating Scale for Depression (HAM-D), and change in cognitive impairment, assessed by the Mini-Mental State Examination (MMSE), after treatment with nortriptyline or placebo. Cognitive treatment response, as measured by the MMSE, was compared between patients whose depression did and did not respond to treatment. RESULTS: Patients whose poststroke depression remitted (predominantly associated with nortriptyline treatment) had significantly greater recovery in cognitive function over the course of the treatment study than patients whose mood disorder did not remit (predominantly associated with placebo treatment). CONCLUSIONS: Our findings support the contention that poststroke major depression leads to a "dementia of depression." Prior studies failed to show an effect of treatment because the effect size was too small. Successful treatment of depression may constitute one of the major methods of promoting cognitive recovery in victims of stroke.     

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines

Although poststroke depression is unlikely to represent a single disorder and numerous etiologies for different kinds of poststroke depression will likely emerge as the result of future research, we believe that a number of poststroke depressive disorders are likely to be the result of specific changes in brain pathology and neurophysiology. Nevertheless, there are relatively few hypotheses about the pathophysiology of poststroke depression. This paper, therefore, proposes a new hypothesis for poststroke depression involving increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas linked to the pathogenesis of mood disorders. This paper reviews the evidence supporting the hypothesis that proinflammatory cytokines are involved in the occurrence of stroke as well as mood disorders linked to the brain damage. The increased production of proinflammatory cytokines such as IL-1beta, TNF-alpha or IL-18 resulting from stroke may lead to an amplification of the inflammatory process, particularly in limbic areas, and widespread activation of indoleamine 2,3-dioxygenase (IDO) and subsequently to depletion of serotonin in paralimbic regions such as the ventral lateral frontal cortex, polar temporal cortex and basal ganglia. The resultant physiological dysfunction may lead to poststroke depression. Future investigations may explore this hypothesis through more extensive studies on the role of proinflammatory cytokines, such as IL-1beta, TNF-alpha or even IL-18, in patients with poststroke depression.     

Electrophysiological changes in poststroke subjects with depressed mood: A quantitative EEG study

Background

We aimed to explore the electrophysiological changes in poststroke subjects with depressed mood.

Methods

Resting‐state electroencephalogram (EEG) signals of 16 electrodes in 35 poststroke depressed, 24 poststroke nondepressed, and 35 age‐matched healthy control subjects were analyzed by means of spectral power analysis, a quantitative EEG measurement of different frequency bands. The relationship among depressed mood, functional status, lesion side, and poststroke time was assessed by using variance and Spearman correlation analysis. Multiple analysis of variance was used to compare the differences among the 3 groups. Binary logistic regression analysis was used to establish a regression model to predict depressed mood in stroke subjects and to explore the association between depression and EEG band power. Receiver operating characteristic curves were used to estimate the ability of spectral power selected by binary logistic regression to indicate depressed mood in stroke subjects.

Results

We found that the hemisphere in which the lesion was located and the time since stroke onset had no effect on depressed mood. Only the patient's functional status was related to emotional symptoms. Quantitative EEG analysis revealed increased delta, theta, and beta2 power in stroke subjects with depressed mood, particularly in temporal regions. The theta and beta2 power in the right temporal area were shown to be highly sensitive to depressed mood, and these parameters showed good discriminatory ability for depressed subjects following stroke.

Conclusion

Depressed mood after stroke is associated with functional status. Quantitative EEG parameters may be a useful tool in timely screening for depressed mood after stroke.     

Prevention and treatment of poststroke depression with mirtazapine in patients with acute stroke

BACKGROUND AND OBJECTIVE: Poststroke depression is one of the most frequent complications of stroke, affecting approximately 20% to 40% of all patients. In spite of the importance of this neuropsychiatric disorder, little attention has been given to the prevention of poststroke depression. The purpose of this study was to examine whether prophylactic treatment with the antidepressant mirtazapine in patients with acute stroke given from day 1 after the incidence prevents poststroke depression. METHOD: Patients with ischemic stroke received either 30 mg mirtazapine or no antidepressant medication from day 1 after the stroke in an open, randomized study design. Data were collected from August 2001 to December 2002. Seventy patients were enrolled in the study and were reexamined on days 7, 44, 90, 180, 270, and 360 using neurologic, functional, and depression rating scales. Those poststroke patients who developed depression (DSM-IV criteria) but had been randomly assigned to the nontreatment group were given the antidepressant mirtazapine after the diagnosis of depression had been established. RESULTS: Forty percent (14/35) of the nontreated patients and only 5.7% (2/35) of the patients who were treated with mirtazapine developed poststroke depression. Altogether, 16 patients developed poststroke depression, 15 of whom remitted after initiation of treatment with mirtazapine. CONCLUSION: Mirtazapine significantly reduced the rate of poststroke depression in patients with acute stroke. The study also demonstrated that this antidepressant was highly effective in treating poststroke depression.     

Does Cognitive Impairment Cause Poststroke Depression?

Studies have demonstrated that poststroke depression is associated with cognitive impairment, but have failed to show improvement in cognitive function when mood improves. A consecutive series of patients with (n=41) or without (n=135) major depression were evaluated for cognitive functioning during acute hospitalization and either 3 or 6 months later. Patients with poststroke major depression whose mood improved at follow-up had significantly greater recovery in cognitive functioning than patients whose mood did not improve. Furthermore, patients whose cognitive functioning improved at follow-up had significantly greater improvement in mood than comparable patients whose cognitive function did not improve, suggesting that poststroke major depression leads to cognitive impairment and not vice versa. The failure of previous treatment studies to show cognitive improvement in poststroke patients with depression was probably due to the inclusion of patients with minor depression (not associated with cognitive impairment) or the failure of patients with major depression to respond to treatment.     

Activation of the Kynurenine Pathway in the Acute Phase of Stroke and its Role in Fatigue and Depression Following Stroke

Many stroke survivors suffer from poststroke fatigue (PSF) and poststroke depression (PSD), indicating the importance of increasing the base of knowledge about the mechanisms underlying these sequelae. The primary aim of this study was to determine whether activation of the kynurenine (KYN) pathway predicts subsequent fatigue or depression in acute ischemic stroke (AIS) patients. Acute serum levels of 5-hydroxytryptamine (5-HT), tryptophan (TRP) catabolites (TRYCATs), and competing amino acids, as well as subsequent fatigue and depression, were measured in 45 stroke patients. TRP index [=100 × TRP?/?(tyrosine + valine + phenylalanine + leucine + isoleucine)] was significantly lower in patients with a Fatigue Severity Scale (FSS) score of ≥4 at 12 months than in those with an FSS score of <4 (p?=?0.039). Furthermore, the serum level of kynurenic acid in the acute stroke phase was significantly higher in patients with an FSS of score ≥4 at 18 months than in those with an FSS score of <4 (p?=?0.026). These findings indicate that stroke patients with PSF have a lower bioavailability of TRP for 5-HT synthesis in the brain in the acute stroke phase. However, they also appear to have greater neuroprotective potential in that phase. In contrast to PSF, no predictors of PSD were found. These findings together with those of previous studies suggest that the immune response and indoleamine 2,3-dioxygenase activation that follows AIS can predict PSF but not PSD.     

Inflammation and the Silent Sequelae of Stroke

Depression and fatigue are common after stroke and negatively impact the quality of life of stroke survivors. The biological bases of these symptoms are unknown, but an abundance of data point to a role for inflammation. This review highlights evidence supporting the contribution of inflammation to poststroke depression and poststroke fatigue. Potential treatments for poststroke depression and poststroke fatigue are explored, with a special emphasis on those that modulate the immune response.     

Effects of antidepressant drugs on emotion

Until recently, scant attention has been paid to the effect of antidepressant drugs on emotion, and we have little knowledge about the way antidepressant drugs modulate neural processing of emotional and affective information, or their relationship to mood changes. Numerous behavioral studies have examined the impact of depression on the recognition of facial expressions. Although conflicting results have been obtained, depressive patients seem to attribute a different emotional valence to these stimuli than do control subjects. Recent studies have shown that a single dose of an antidepressant can increase the processing of positively versus negatively valenced material in nondepressed volunteers. Such psychopharmacological effects may ameliorate the negative biases that characterize mood disorders. Antidepressants may therefore work in a manner comparable with that of psychologic treatments that aim to redress negative biases in information processing. Studies with functional neuroimaging also show that emotional processes are dependent upon a variety of structures; most which form part of the limbic system and are altered in depression. Other studies have demonstrated changes in these structures during antidepressant treatment, mainly in the amygdala. Future research should attempt to explain, for example, the implications of changes in early emotional processing on mood and remission of depression, and the differences between acute and chronic treatment.     

Clinical and psychological correlates of poststroke fatigue. Preliminary results

BACKGROUND AND PURPOSE: Although poststroke fatigue concerns almost 60% of patients, still little is known about its pathogenesis and contributing factors. Therefore, the purpose of this study was to evaluate the severity of fatigue in terms of its impact on physical, psychological and social functioning as well as to determine the relation between fatigue and clinical, demographic and psychological factors. MATERIAL AND METHODS: Patients (n = 50) with acute first-ever stroke admitted to the neurological department were interviewed at 3 months after discharge. Poststroke fatigue was assessed using the Polish version of the Fatigue Impact Scale. Neurological status was examined with the Scandinavian Stroke Scale, functional status with the Barthel Index, and emotional status with the Beck Depression Inventory. Styles of coping with stress were identified using the Coping Inventory for Stressful Situations. Sex, age, type of stroke and lesion location were documented as well. RESULTS: Ninety percent of patients demonstrated high level of fatigue in physical functioning, 16% in the psychological domain, and 18% in the social domain. In the univariate analyses, impact of fatigue on patients functioning significantly correlated with age, lower mood, neurological and functional status, as well as with styles of coping. Emotion-oriented coping was associated with lower level of fatigue, whereas the reverse was found regarding task-oriented coping. In the multivariate analyses the emotion-oriented style of coping was the most important correlate of fatigue. CONCLUSIONS: The causes of poststroke fatigue appear to be multifactorial. Psychological factors, especially coping strategies, might be an important area for future interventions.     

A two year longitudinal study of poststroke mood disorders: prognostic factors related to one and two year outcome

In a prospective study of mood disorders in 103 stroke patients, we examined the predictive value of affective, cognitive, social and neurologic variables obtained in-hospital and at six months poststroke in terms of outcome as determined by the same measures at one and two years follow-up. The following factors were found to have prognostic significance: 1) Lesion Location: proximity of the lesion on CT scan to the frontal pole in patients with left anterior infarcts showed a strong positive relationship with severity of depression at one year but not at two years poststroke. 2) Affective Status: depression (in-hospital and at 6 months) strongly predicted depression at one year but not at two years poststroke. Additionally, in-hospital depression significantly correlated with physical impairment at two years, while depression at six months bore a moderate relationship to physical impairment at one year. 3) Physical Impairment: impairment in activities of daily living in-hospital bore a modest relationship to depression at one year while such impairment at six months correlated strongly with depression at both one and two years. These findings may reflect the natural course of major depression which remits between one and two years poststroke. Although stroke lesion location is the strongest predictor of subsequent depression, there appears to be a reciprocal relationship between physical impairment and depression (i.e., depression predicts impairment and impairment predicts depression). Since poststroke depressions are amenable to therapeutic intervention, these prognostic factors may have implications for the treatment and rehabilitation of stroke patients.     

Little evidence for different phenomenology in poststroke depression

Cumming TB, Churilov L, Skoog I, Blomstrand C, Linden T. Little evidence for different phenomenology in poststroke depression. Objective: It remains unclear whether mood depressive disorders after stroke have a distinct phenomenology. We evaluated the symptom profile of poststroke depression (PSD) and assessed whether somatic symptoms were reported disproportionately by stroke patients. Method: The sample was 149 stroke patients at 18 months poststroke and 745 age‐ and sex‐matched general population controls. A comprehensive psychiatric interview was undertaken and depression was diagnosed according to DSM‐III‐R criteria. Results: Depressed controls reported more ‘inability to feel’ (P = 0.002) and ‘disturbed sleep’ (P = 0.008) than depressed stroke patients. Factor analysis of the 10 depressive symptoms identified two main factors, which appeared to represent somatic and psychological symptoms. There was no difference in scores on these two factors between stroke patients and controls. Conclusion: Phenomenology of depression at 18 months poststroke is broadly similar but not the same as that described by controls. Somatic symptoms of depression were not over‐reported by stroke patients.     

Do Stroke Patients have an Increased Risk of Developing Suicidal Ideation or Dying by Suicide? An Overview of the Current Literature

Stroke is a leading cause of death that affects 15 million people worldwide each year. Increasing evidence suggests that stroke confers substantial risk for suicide and following a stroke, patients frequently develop poststroke depression, which is a well‐established risk factor for suicide. In this overview of the current literature, we examined the association between suffering a stroke and subsequent risk for suicide and suicidal ideation. We performed a careful MedLine, Excerpta Medica, PsycLit, PsycInfo, and Index Medicus search to identify all articles and book chapters in English. We initially selected 31 articles published between 1990 and 2011; however, only 16 studies were included in this review. All articles identified stroke as a significant risk factor for suicide, especially among depressed patients, providing further support for poststroke depression and suicidality. The results also indicated that there were differences between patients who developed acute‐onset suicidal plans and those who reported delayed‐onset plans, which occurred more frequently. Many of the stroke patients who died by suicide suffered from depression prior to their death, suggesting that being diagnosed with a mood disorder contributes to an increased risk of suicide in this population. Suffering from a stroke increases the risk of dying by suicide and developing suicidal ideation, particularly in young adults and women. The factors found to confer the most risk for suicidality were depression, previous mood disorder, prior history of stroke, and cognitive impairment.     

The Effect of Poststroke Depression on Recovery from Stroke

Background : Stroke is a major health problem and poststroke depression is known to be one of the frequent and severe psychiatric complications following stroke.
Methods : Based on the results of structured psychiatric mental state exams and DSM diagnostic criteria, the prevalence of poststroke depression has been examined in numerous study populations throughout the world. Longitudinal examinations have documented the effect of poststroke depression on recovery from stroke.
Results : The mean prevalence of poststroke major depression was 21.1 % and minor depression was 17.1% among hospitalized or outpatient samples. Community samples showed a slightly lower rate of 14.1% and 9.1%, respectively. Furthermore, the existence of poststroke depression leads to poorer physical recovery, greater cognitive impairment, and worse recovery in activities of daily living compared with non-depressed patients. Several studies have also found that poststroke depression is associated with increased mortality compared with non-depressed patients who had comparable strokes and similar premorbid risk factors. Finally, several studies have found that successful treatment of poststroke depression improves both cognitive and physical recovery and decreases mortality.
Conclusion : The current review documents the beneficial effect of identifying and treating poststroke depression on both recovery and survival following stroke.     

Emotions, behaviours and mood changes in stroke.

The brain mediates and integrates all cognitive activities, emotional experiences and finally behaviours. Stroke is undoubtedly a privileged disease for human behavioural studies, because of its high incidence. Recent advances in high-resolution magnetic resonance imaging techniques and functional neuroimaging allow both the precise localization of lesions and on-line visualization of the activity of cerebral areas and networks. Nevertheless, the neuropsychiatry of stroke remains uncertain in its relationship with brain dysfunction. Clinical studies on registry populations, single case studies, and functional neuroimaging data provide interesting findings, but differences in methods and great individual intervariability still prevent a complete understanding of emotional perception and behavioural responses in stroke. We adopted an anatomical-functional model as an operational framework in order to systematize the recent literature on emotional, behavioural and mood changes after stroke. The dysfunction of the areas subserving fundamental and executive functions induces behavioural and affective changes (such as depression, anxiety, apathy) that reflect the dysfunction of the whole system. Conversely, lesions in the system of instrumental functions induce signature syndromes (aphasia, anosognosia). At any delay from stroke, the diagnosis and treatment of mood and behavioural changes are a priority for clinicians and healthcare professionals to improve the quality of life of patients.     

Acute basal ganglia infarcts in poststroke fatigue: an MRI study

Lesions located in the basal ganglia (BG) are thought to be involved in the fatigue observed in neurological disorders. However, the significance of the location of infarcts in poststroke fatigue (PSF) is unknown. This study examined the association between BG infarcts and PSF. A total of 334 Chinese patients with acute ischemic stroke consecutively admitted to the acute stroke unit of a university-affiliated regional hospital in Hong Kong participated in the study. At admission, a host of demographic and clinical characteristics was collected and the number and location of acute infarcts were evaluated with MRI. All participants were assessed for PSF with the fatigue severity scale (FSS) 3 months after their index stroke. PSF was defined as a mean FSS score of 4.0 or more. Depressive symptoms were measured by the geriatric depression scale (GDS). Seventy-eight (23.4%) patients had PSF. In the univariate analysis, the PSF group included more females, had higher GDS scores, and a higher number of acute infarcts, and the PSF patients were more likely to have acute infarcts at the BG. Acute BG infarct remained an independent predictor of PSF in the multivariate analysis. In conclusion, these results suggest that BG infarcts may play a role in the development of PSF.     

Depression and stroke: cause or consequence?

Depression after stroke is common. Although different opinions exist about the definition, diagnosis, and measurement of outcomes related to depression after stroke, there is little debate about the prevalence of depression symptoms and their impact on stroke survivors and their families. Depression after stroke has long been recognized as a common condition with many negative effects in the poststroke period, but more recently depression has also been identified as an independent stroke risk factor. Given that there are at least 500,000 new ischemic strokes yearly in the United States, a conservative estimate is that 150,000 U.S. stroke survivors develop poststroke depression each year. Because effective treatments exist but are likely underutilized for depression, this is an important example of an evidence-practice gap to which increased efforts to improve care should be made. Such efforts would likely improve not only patient symptoms but may also decrease stroke risk, influence stroke functional recovery, decrease mortality, and reduce poststroke health care utilization. This article provides an overview of depression diagnosis in stroke, reviews the epidemiology of poststroke depression and its associated morbidity and mortality, and reviews existing evidence on the treatment and prevention of poststroke depression.     

Research into the specificity of depression after stroke: a review on an unresolved issue

Iwo decades of research have failed to generate consistent insight into the specificity of poststroke depression (PSD). This is, at least in part, caused by methodological difficulties. Differences in symptom profile between PSD and depression with no or another medical cause were described, but no specific and unequivocal clinical picture has been established so far. Prevalence rates of PSD varied largely between studies. In community based studies using standardised diagnostic instruments for depression, relatively low prevalence rates were reported compared to inpatient or rehabilitation studies. PSD occurs most frequently in the first few months after stroke, while a new incidence peak may occur 2-3 years after stroke. Two systematic reviews on the relation between lesion location and depression did not support the claim that left hemisphere lesions are a risk factor for PSD. A new concept of vascular depression has been proposed, which relates depression in the elderly to acute or chronic damage to the cerebral vascular system. Future efforts should aim at increasing the uniformity of study designs, assessment tools should be further improved for use in cognitively impaired patients and appropriate control groups should be defined to study the characteristic features of PSD.