Anosognosia for hemiplegia after stroke is a multifaceted phenomenon: a systematic review of the literature.

Anosognosia is the lack of awareness or the underestimation of a specific deficit in sensory, perceptual, motor, affective or cognitive functioning due to a brain lesion. This self-awareness deficit has been studied mainly in stroke hemiplegic patients, who may report no deficit, overestimate their abilities or deny that they are unable to move a paretic limb. In this review, a detailed search of the literature was conducted to illustrate clinical manifestations, pathogenetic models, diagnostic procedures and unresolved issues in anosognosia for motor impairment after stroke. English and French language papers spanning the period January 1990-January 2007 were selected using PubMed Services and utilizing research words stroke, anosognosia, awareness, denial, unawareness, hemiplegia. Papers reporting sign-based definitions, neurological and neuropsychological data and the results of clinical trials or historical trends in diagnosis were chosen. As a result, a very complex and multifaceted phenomenon emerges, whose variable behavioural manifestations often produce uncertainties in conceptual definitions and diagnostic procedures. Although a number of questionnaires and diagnostic methods have been developed to assess anosognosia following stroke in the last 30 years, they are often limited by insufficient discriminative power or a narrow focus on specific deficits. As a consequence, epidemiological estimates are variable and incidence rates have ranged from 7 to 77% in stroke. In addition, the pathogenesis of anosognosia is widely debated. The most recent neuropsychological models have suggested a defect in the feedforward system, while neuro-anatomical studies have consistently reported on the involvement of the right cerebral hemisphere, particularly the prefrontal and parieto-temporal cortex, as well as insula and thalamus. We highlight the need for a multidimensional assessment procedure and suggest some potentially productive directions for future research about unawareness of illness.

Insight and danger in Alzheimer's disease.

To determine the frequency, and demographic and clinical correlates of dangerous behaviours in Alzheimer's disease (AD). We assessed a consecutive series of 278 patients with AD and 45 age-comparable healthy controls with a comprehensive psychiatric and neuropsychological evaluation. Caregivers rated the frequency of patients' exposure to dangerous situations or commission of dangerous behaviours. The frequency of dangerous behaviours was 16% in the AD group and 2% in the healthy control group. The presence of anosognosia was associated with a threefold increase in the risk of dangerous behaviours, but there was no significant association between dangerous behaviours and patients' age, years of education, diagnosis of major or minor depression and presence of suicide ideation. Sixteen per cent of a consecutive series of patients with AD had dangerous behaviours during the month preceding the clinical evaluation. Anosognosia was the main clinical correlate of dangerous behaviours in this population.

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.

A diagnostic formulation for anosognosia in Alzheimer's disease.

OBJECTIVE: To determine the earliest symptoms of anosognosia in people with Alzheimer's disease and to validate a criteria-guided strategy to diagnose anosognosia in dementia. METHODS: A consecutive series of 750 patients with very mild or probable Alzheimer's disease attending a memory clinic, as well as their respective care givers, was assessed using a comprehensive psychiatric evaluation. RESULTS: The factors of anosognosia for (1) basic activities of daily living (bADL), (2) instrumental activities of daily living (iADL), (3) depression and (4) disinhibition were produced by a principal component analysis on the differential scores (ie, caregiver score minus patient score) on the anosognosia questionnaire for dementia. A discrepancy of two or more points in the anosognosia-iADL factor was found to have a high sensitivity and specificity to identify clinically diagnosed anosognosia in people with Alzheimer's disease. By logistic regression analysis, the severity of dementia and apathy were both shown to be noticeably associated with anosognosia in people with Alzheimer's disease. CONCLUSION: Anosognosia in those with Alzheimer's disease is manifested as poor awareness of deficits in iADL and bADL, depressive changes and behavioural disinhibition. The frequency of anosognosia is found to increase considerably with the severity of dementia. The validity of a specific set of criteria to diagnose anosognosia in people with Alzheimer's disease was shown, which may contribute to the early identification of this condition.

A prospective longitudinal study of apathy in Alzheimer's disease.

BACKGROUND: Apathy and depression are the most frequent behavioural and psychiatric disorders in Alzheimer's disease, and may both have a negative impact on the progression of the illness. OBJECTIVES: To examine the clinical correlates of apathy in Alzheimer's disease (AD), and to determine whether apathy is a significant predictor of more rapid cognitive, functional and emotional decline. METHODS: Using a structured psychiatric evaluation, we examined a consecutive series of 354 subjects meeting clinical criteria for AD. Apathy was assessed by the Apathy Scale, and diagnosed using standardised criteria. Additional measurements included scales for depression, functional impairment, and global cognitive functions. A follow up evaluation was carried out in 247 patients (70% of the total sample) between 1 and 4 years after the baseline evaluation. RESULTS: Apathy was significantly associated with older age (p = 0.009), and a higher frequency of minor and major depression (p < 0.0001). Apathy at baseline was a significant predictor of depression at follow up (p = 0.01), and was associated with a faster cognitive (p = 0.0007) and functional decline (p = 0.006). CONCLUSIONS: Apathy in AD is a behavioural marker of a more aggressive dementia, characterised by a faster progression of cognitive, functional, and emotional impairment.

Erosions and urinary retention following polypropylene synthetic sling: Australasian survey.

INTRODUCTION: There are few published reports on the incidence and management of urethral and vaginal erosions following the use of polypropylene synthetic slings. Moreover, there is very little Australasian data on their use for management of female urinary incontinence or on their associated complications. METHODS: A 1-page survey was mailed to the Australian and New Zealand members of the Urological Society of Australasia (N=326). The survey included questions on the use of polypropylene synthetic sling and the incidence and management of post-operative vaginal and urethral erosions and urinary retention. RESULTS: 198 surveys were returned (response rate: 61%). Polypropylene synthetic sling procedure is practiced by 39% of the respondents with a total of 1459 cases (TVT: 993, SPARC: 466). The incidence of vaginal erosions, urethral erosions and urinary retention was 1.2%, 0.6% and 6.5%, respectively. Thirty five percent of vaginal erosions were asymptomatic and only identified on routine post-operative vaginal examination. One third of urethral erosions presented more than 1 year after surgery and 89% of these were symptomatic. Thirty four percent of patients with urinary retention required surgical intervention to correct the retention. CONCLUSIONS: The incidence of urethral and vaginal erosions following polypropylene synthetic sling procedures is lower than that with other synthetic slings. However, a high index of suspicion and long-term follow-up are required to identify and manage these complications of this relatively new procedure.

A reappraisal of poststroke depression, intra- and inter-hemispheric lesion location using meta-analysis.

A recent publication based on a meta-analysis concluded that there was no association between poststroke depression (PSD) and lesion location. This study, therefore, was undertaken to reappraise the hypothesis using meta-analysis of the correlation between severity of depression following stroke and proximity of the lesion to the frontal pole, an issue that was not examined in the prior meta-analysis. Results showed there was a significant inverse correlation between severity of depression and distance of the lesion from the frontal pole among 163 patients with left hemisphere stroke but not among 106 patients with right hemisphere stroke. This study supports the hypothesis that risk of poststroke depression is related to the location of brain injury.

Improved executive functioning following repetitive transcranial magnetic stimulation.

The cognitive effects of active and sham repetitive transcranial magnetic stimulation (rTMS) were examined in 19 middle-aged and elderly patients with refractory depression. Patients received either active (n = 9) or sham (n = 10) rTMS targeted at the anterior portion of the left middle frontal gyrus. Patients in the active rTMS group improved significantly on a test of cognitive flexibility and conceptual tracking (Trail Making Test-B).

Suicidal ideation among patients with acute life-threatening physical illness: patients with stroke, traumatic brain injury, myocardial infarction, and spinal cord injury.

Suicide is one of the leading causes of death in the community. The risk of suicide is greater among patients with physical illnesses than among the general population. This study was undertaken to evaluate the clinical characteristics and correlates of suicidal ideation in patients with acute life-threatening physical illnesses and to assess the duration of suicidal ideation. The study included a consecutive series of patients admitted with stroke, traumatic brain injury, myocardial infarction, or spinal cord injury (n=496). Study participants were administered a semistructured psychiatric interview as well as a series of standardized quantitative scales of mood, cognitive function, physical impairment, social ties, and social functioning. Follow-up evaluations of up to 24 months were also carried out. This study found that 36 (7.3%) patients with acute medical illness had clinically significant suicidal ideation. The suicidal ideation occurred mostly among patients with major depression and sometimes in those with minor depression. About 25% of patients with major depression and acute physical illnesses developed suicidal ideation. After the improvement of depressive disorders, suicidal ideations were ameliorated. These findings suggest that the detection and treatment of depressive disorders is the most important factor in preventing suicide among this patient population.

Suicidal ideation among patients during the rehabilitation period after life-threatening physical illness.

A total of 496 patients were examined for suicidal ideation during the acute hospital period and at 3, 6, 12, and 24 months' follow-up after suffering either stroke, traumatic brain injury, myocardial infarction, or spinal cord injury. A total of 7.3% of patients had suicidal ideation during the in-hospital evaluation (acute-onset suicidal ideation), and 11.3% developed it during the chronic 3 to 24 month rehabilitation period (delayed-onset suicidal ideation). Compared with delayed-onset suicidal patients, acute-onset suicidal patients had more predisposing risk factors (i.e., personal psychiatric history and alcohol abuse/dependence) and less social support (i.e., lower frequency of being married). Both acute and delayed-onset suicidal ideation, however, were strongly associated with the existence of major depression and impaired social functioning. These findings suggest that the detection and appropriate treatment of depressive disorders and social isolation may be the most important factor in preventing suicide both during the acute and chronic period following life-threatening physical illnesses.

The effect of remission of poststroke depression on activities of daily living in a double-blind randomized treatment study.

Poststroke depression has been associated with impaired recovery of activities of daily living (ADL) during the first 2 years after stroke. This study examined the effect of remission of poststroke depression on recovery in ADL in a double-blind randomized treatment study. Based on a semistructured psychiatric exam and DSM-IV diagnostic criteria, a consecutive series of 23 patients who met criteria for major depression (N = 16) or minor depression (N = 7) were selected and randomly assigned to either active treatment (nortriptyline) or placebo. Functional physical (i.e., ADL) impairment was assessed using the Johns Hopkins Functioning Inventory (JHFI). Patients whose depressive disorder remitted at follow-up had significantly greater recovery in ADL functions compared with patients whose depression did not remit. There were no differences in demographic variables, lesion characteristics, and neurological symptoms between the two groups, which would explain the significantly greater improvement among the remitted patients. Because both major and minor depression patients who remitted showed greater improvement in ADL than nonremitted patients some of whom were treated with active and some with placebo medication, nonpharmacotherapeutic mechanisms related to recovery from depression appear to mediate this enhanced recovery.

A controlled study of repetitive transcranial magnetic stimulation as a treatment of depression in the elderly.

Rapid transcranial magnetic stimulation (rTMS) applied to the left dorsal lateral frontal cortex has been shown to produce antidepressant effects. Older depressed patients, however, in one study showed a lower response rate than younger patients. The current study examined treatment response in 20 depressed, treatment-refractory patients (mean age 60.7 +/- 9.8 years) given five sessions of rTMS at 20 Hz for 2 seconds over 20 trains at 80% of motor threshold or identical placebo stimulation, after patients had been withdrawn from their antidepressants. There were no significant differences in Hamilton Depression Scale scores either before or after treatment at 7 days' follow-up. There were three responders to active treatment and three to sham treatment and responders had significantly greater frontal lobe volume than nonresponders (p = .03). These findings suggest that the stimulation parameters used in this study were probably insufficient to produce treatment response and that frontal atrophy may interfere with the effectiveness of rTMS.

Gender differences in depression associated with neurologic illness: clinical correlates and pharmacologic response.

Functional depression (i.e., depression without neuropathology) occurs approximately twice as often in women as in men. A review of the literature from the period 1966-1999 on the prevalence, clinical correlates, and treatment of depression in neurologic disease revealed a female preponderance of depression in diffuse neurologic disease, including Alzheimer's disease. In focal neurologic disease, the data were consistent for men and women, with a 1:1 ratio. Treatment data on depression in neurologic disease are scant, with the exception of poststroke depression. Although gender-based outcome data on the treatment of functional depression reveal better tolerability and response to serotonin reuptake inhibitors in women than in men, this phenomenon cannot be generalized to depression in neurologic disease. Men seem to consistently respond better than premenopausal women to tricyclic antidepressants in both functional and neurologic disease. Understanding how gender influences depression in neurologic illness and its response to treatment is a necessary step to improve the specificity of psychiatric treatment for depression.

Evaluation of amino acid-based linkers in potent macrocyclic inhibitors of farnesyl-protein transferase.

A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.

Diaryl ether inhibitors of farnesyl-protein transferase.

Imidazolemethyl diaryl ethers are potent inhibitors of farnesyl-protein transferase. The SNAr displacement reaction used to prepare these diaryl ethers was amenable to rapid parallel synthesis of FPTase inhibitors. The use of a broad range of commercially available phenols quickly identified compounds which proved active in cells.

Sexual dysfunction following stroke.

This study was undertaken to examine the prevalence of sexual dysfunction among 100 patients (75 men and 25 women) following stroke and its relationship to neuropsychiatric impairments or stroke characteristics. Forty-four men (58.6%) and 11 women (44.0%) reported dissatisfaction with their sexual functioning after stroke, as compared with only 16 men (21.3%) and five women (20.0%) before stroke. Twenty men (26.6%) and six women (24.0%) reported diminished libido after stroke as compared with eight men (10.6%) and seven women (28.0%) before stroke. Patients with sexual dysfunction had significantly more depressive symptoms among both males (P =.007) and females (P =.0005) and more impaired activities of daily living (ADL) in males (P =.0009). Based on logistic regression, the independent predictors of poststroke sexual dysfunction were Hamilton Rating Scale for Depression (HAM-D) score (odds ratio [OR] 1.55; 95% confidence interval [CI], 1.20 to 2.01), left hemisphere lesion (OR, 16.51; 95% CI, 2.34 to 116.25), and poststroke depression (OR, 8.09; 95% CI, 1.28 to 51.38). These data suggest that treatment of depression may have a significant beneficial effect on patients with sexual dysfunction. Our findings also suggest that left hemisphere lesions, for unknown reasons, play an important role in poststroke sexual dysfunction.

Aryloxy substituted N-arylpiperazinones as dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I.

A series of aryloxy substituted piperazinones with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to have potent inhibitory activity in vitro and are promising agents for the inhibition of Ki-Ras signaling.

2-Arylindole-3-acetamides: FPP-competitive inhibitors of farnesyl protein transferase.

A series of 2-arylindole-3-acetamide farnesyl protein transferase inhibitors has been identified. The compounds inhibit the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed.

Anions modulate the potency of geranylgeranyl-protein transferase I inhibitors.

We have identified and characterized potent and specific inhibitors of geranylgeranyl-protein transferase type I (GGPTase I), as well as dual inhibitors of GGPTase I and farnesyl-protein transferase. Many of these inhibitors require the presence of phosphate anions for maximum activity against GGPTase I in vitro. Inhibitors with a strong anion dependence were competitive with geranylgeranyl pyrophosphate (GGPP), rather than with the peptide substrate, which had served as the original template for inhibitor design. One of the most effective anions was ATP, which at low millimolar concentrations increased the potency of GGPTase I inhibitors up to several hundred-fold. In the case of clinical candidate l-778,123, this increase in potency was shown to result from two major interactions: competitive binding of inhibitor and GGPP, and competitive binding of ATP and GGPP. At 5 mm, ATP caused an increase in the apparent K(d) for the GGPP-GGPTase I interaction from 20 pm to 4 nm, resulting in correspondingly tighter inhibitor binding. A subset of very potent GGPP-competitive inhibitors displayed slow tight binding to GGPTase I with apparent on and off rates on the order of 10(6) m(-)1 s(-)1 and 10(-)3 s(-)1, respectively. Slow binding and the anion requirement suggest that these inhibitors may act as transition state analogs. After accounting for anion requirement, slow binding, and mechanism of competition, the structure-activity relationship determined in vitro correlated well with the inhibition of processing of GGPTase I substrate Rap1a in vivo.