Impact of sex on clinical outcome in early Multiple Sclerosis.

BACKGROUND: Previous evidence suggests sex differences in the clinical course of relapsing remitting multiple sclerosis (RRMS), but comprehensive early-stage prospective studies are lacking. We aim to quantify the impact of sex on clinical outcomes in early-stage RRMS. METHODS: Utilizing prospective cohort data, we assessed the impact of biological sex on time-to-relapse, disability progression (Expanded Disability Status Scale [EDSS]), extremity function (Nine-Hole Peg Test, Timed-25-food walk test), cognition (Paced Auditory Serial Addition Test, Symbol Digit Modalities Test), quality-of-life (Hamburg Quality of Life Questionnaire in Multiple Sclerosis, Short-Form-36), fatigue (Fatigue Severity Scale, Fatigue Scale for Motor and Cognitive functions), and depression (Beck Depression Inventory-II) in clinically isolated syndrome (CIS) or RRMS patients. Inclusion was within 12 months of symptom onset. Linear, negative binomial, mixed, and Cox models estimated male vs. female effects at the four-year follow-up including baseline-to-follow-up course. RESULTS: We included 149 patients (65.1 % female). Eighty-five completed four-year follow-up. No sex differences in time-to-relapse emerged (HR = 0.91;95 %CI = 0.53-1.58). Males had no increased risk of EDSS worsening (OR = 0.75;95 %CI = 0.21-2.35) compared to females. Similarly, minor/no sex differences emerged in other outcomes. CONCLUSIONS: Four years after first manifestation, neither disease activity (disability progression and relapse rate) nor patient-reported outcomes showed sex-related disparities in this early-MS-cohort. GOV IDENTIFIER: NCT01371071.

Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial.

BACKGROUND: Exercise may have beneficial effects on both well-being and walking ability in multiple sclerosis (MS). Exercise is shown to be neuroprotective in rodents and may also enhance cognitive function in humans. It may, therefore, be particularly useful for MS patients with pronounced neurodegeneration. OBJECTIVE: To investigate the potential of standardized exercise as a therapeutic intervention for progressive MS, in a randomized-controlled pilot trial. METHODS: Patients with progressive MS and moderate disability (Expanded Disability Status Scale (EDSS) of 4-6) were randomized to one of three exercise interventions (arm ergometry, rowing, bicycle ergometry) for 8-10 weeks or a waitlist control group. We analyzed the drop-out rate as a measure of feasibility. The primary endpoint of the study was aerobic fitness. Secondary endpoints were walking ability, cognitive function as measured by a neuropsychological test battery, depression and fatigue. RESULTS: A total of 42 patients completed the trial (10.6% drop-out rate). Significant improvements were seen in aerobic fitness. In addition, exercise improved walking ability, depressive symptoms, fatigue and several domains of cognitive function. CONCLUSION: This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS. Larger exercise studies are needed to confirm the effect on cognition. TRIAL REGISTRATION: ISRCTN (trial number 76467492) http://isrctn.org.

Comparison of patient-reported outcome measures in multiple sclerosis.

BACKGROUND: Patient-reported outcome measurements (PROMS) have been proposed sensitive outcome parameters in multiple sclerosis (MS). In this study, we assessed a German version of the Multiple Sclerosis Impact Scale (MSIS-29) and a revised version of the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) in comparison with rater- and physician-based tools. METHODS: Consecutive MS patients (n = 117) of the MS outpatient unit were included. In addition to MSIS-29 and HAQUAMS, the following parameters were obtained: Expanded Disability Status Scale (EDSS) and modified Multiple Sclerosis Functional Composite (MSFC) [9-hole peg test (9HPT), 25-foot walk test and symbol digit modalities test]. We investigated validity, internal consistency and test-retest reliability as well as correlation between these measures. RESULTS: Internal consistency (Cronbach's α ≤ 0.96) and test-retest coefficients (ICC ≤ 0.87) of both scales were high and satisfied psychometric standards. Convergent and discriminant validity was supported by direction, magnitude and pattern of correlation with other rater-based measures depending on the functional subdomain. Both MSIS-29 and HAQUAMS correlated with EDSS (ρ = 0.55 vs 0.62), but stronger correlation was found between MSIS-29 and HAQUAMS total score (ρ = 0.90). Both scales distinguished between patient groups of varied disease severity and cognitive impairment. CONCLUSION: Patient-reported outcome measurements as MSIS-29 and HAQUAMS seem to be valid instruments to detect different impairment levels in comparison with traditional rater-based instruments like EDSS or MSFC.

Association between cortisol awakening response and memory function in major depression.

BACKGROUND: While impaired memory and altered cortisol secretion are characteristic features of major depression, much less is known regarding the impact of antidepressant medication. We examined whether the cortisol awakening response (CAR) is increased in depressed patients with and without medication compared with healthy controls (HC) and whether CAR is associated with memory function in each group. METHOD: We examined 21 patients with major depression without medication, 20 depressed patients on antidepressant treatment, and 41 age-, sex- and education-matched healthy subjects. We tested verbal (Auditory Verbal Learning Task) and visuospatial (Rey figure) memory and measured CAR on two consecutive days. RESULTS: Patient groups did not differ in severity of depression. We found a significant effect of group (p = 0.03) for CAR. Unmedicated patients exhibited a greater CAR compared with medicated patients (p = 0.04) with no differences between patient groups and HC. We found a significant effect of group for verbal (p = 0.03) and non-verbal memory (p = 0.04). Unmedicated patients performed worse compared with medicated patients and HC in both memory domains. Medicated patients and HC did not differ. Regression analyses revealed a negative association between CAR and memory function in depressed patients, but not in HC. CONCLUSIONS: While in unmedicated depressed patients the magnitude of CAR is associated with impaired memory, medicated patients showed a smaller CAR and unimpaired cognitive function compared with HC. Our findings are compatible with the idea that antidepressants reduce CAR and partially restore memory function even if depressive psychopathology is still present.

[Depression and neurological diseases]. / Depression und neurologische Erkrankungen.

In many neurological diseases a depressive syndrome is a characteristic sign of the primary disease or is an important comorbidity. Post-stroke depression, for example, is a common and relevant complication following ischemic brain infarction. Approximately 4 out of every 10 stroke patients develop depressive disorders in the course of the disease which have a disadvantageous effect on the course and the prognosis. On the other hand depression is also a risk factor for certain neurological diseases as was recently demonstrated in a meta-analysis of prospective cohort studies which revealed a much higher stroke risk for depressive patients. Furthermore, depression plays an important role in other neurological diseases with respect to the course and quality of life, such as Parkinson's disease, multiple sclerosis and epilepsy. This article gives a review of the most important epidemiological, pathophysiological and therapeutic aspects of depressive disorders as a comorbidity of neurological diseases and as a risk factor for neurological diseases.

Behavioral interventions in multiple sclerosis: a biopsychosocial perspective.

Managing uncertainty is a major challenge associated with the diagnosis of multiple sclerosis (MS). In addition to physical symptoms, neuropsychiatric symptoms are highly prevalent in this disease. Depression in particular is more common in MS than in other chronic diseases. While substantial achievements have been made in the therapy of MS and an increasing number of immunomodulatory treatments are now available, the long-term benefits of these are still a matter of debate. Importantly, while the approved therapies show good efficacy on inflammatory lesions and relapse rate, and may slow certain aspects of disease progression, improvements in function have rarely been reported. On the other hand, behavioral interventions have recently been shown to significantly improve fatigue and depression as well as motor function. In addition, recent evidence suggests that group education or face-to-face behavioral interventions may decrease inflammatory disease activity (such as relapse rate or lesion formation measured by MRI). Therefore, behavioral interventions not only ameliorate symptoms but may have the potential to modify the disease process itself.

Correlates of cognitive dysfunction in multiple sclerosis.

Cognitive impairment is one of the most frequent symptoms in patients with multiple sclerosis (MS) but its underlying mechanisms are poorly understood. A number of pathogenetic correlates have previously been proposed including psychosocial factors (such as depression and fatigue), inflammation, neurodegeneration, and neuroendocrine dysregulation. However, these different systems have never been studied in parallel and their differential contributions to cognitive impairment in MS are unknown. We studied a well-characterized cohort of cognitively impaired (CI, n=25) and cognitively preserved (CP, n=25) MS patients based on a comprehensive neuropsychological testing battery, a test of hypothalamo-pituitary-adrenal axis functioning (dexamethasone-corticotropin-releasing hormone suppression test, Dex-CRH test) as well as peripheral blood and MRI markers of inflammatory activity. CI patients had significantly higher disability. In addition, CI patients showed higher levels of fatigue and depression. Fatigue was more closely associated with measures of attention while depression showed strongest correlations with memory tests. Furthermore, percentage of IFNγ-positive CD4+ and CD8+ T cells showed modest correlations with processing speed and working memory. MRI markers of inflammation or global atrophy were not associated with neuropsychological function. Compared to previous studies, the number of patients exhibiting HPA axis hyperactivity was very low and no correlations were found with neuropsychological function. We conclude that fatigue and depression are the main correlates of cognitive impairment, which show domain-specific associations with measures of attention and memory.

Patient perception of bodily functions in multiple sclerosis: gait and visual function are the most valuable.

Multiple sclerosis is a heterogeneous disease with varying clinical picture. There have been substantial efforts to develop outcome measurements for therapeutic interventions but very few studies have addressed the value of bodily functions from the patient perspective. In a randomly selected cohort of early (<5 years, n=84) and longer lasting disease courses (>15 years, n=82) patients we asked for a weighting of 13 bodily functions and compared results with actual disability as measured by the United Kingdom Disability Scale. Lower limb function was given the highest priority in both patient groups followed by visual functioning and cognition especially in longer lasting MS. Actual disability did not correlate with the given priorities indicating that experienced deficits do not influence the subjective ratings of bodily functions. These results underline that ambulation-focused scales in MS represent a key dimension from the patient perspective. Visual functioning should be taken more into account.

Stress and hypothalamic-pituitary-adrenal axis function in experimental autoimmune encephalomyelitis and multiple sclerosis - a review.

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the CNS with an assumed autoimmune-mediated pathogenesis. Stressful life events have been hypothesized as potential triggers of disease exacerbation. Animal studies using experimental autoimmune encephalomyelitis (EAE), as a model for MS, suggest that decreased hypothalamic-pituitary-adrenal (HPA) function may play a role in the increased susceptibility and severity of the disease. Histopathological studies of the hypothalamus point to disturbances in corticotropin-releasing hormone (CRH) regulation as a result of MS lesions in this area. Functional endocrine tests (e.g., the combined Dexamethasone-CRH test) showed a disturbed negative feedback after steroid application in MS patients. Hyper- and hypoactivity of the HPA axis, have been described to be associated with more severe courses. This paper presents an overview of the evidence for a role of HPA dysfunction in EAE and MS based on stress-experimental studies.

Stress regulation in multiple sclerosis: current issues and concepts.

Since its first description by Charcot, psychological stress has been considered a triggering factor for exacerbations in multiple sclerosis, but until recently the clinical evidence for a causal relation was weak. Over the past years, a growing number of studies have started to elucidate this association and highlight potential mechanisms, including brain-immune communication. On 5 June 2005, a panel of international researchers discussed the current evidence. This article summarizes the observational, animal experimental, as well as human experimental findings on stress regulation in MS, as well as studies on the functioning of the major stress response systems, ie, the hypothalamo-pituitary-adrenal (HPA) axis and the autonomous nervous system (ANS) in MS. Consensus statements from the group to these aspects are given. Research objectives and strategies are delineated, as well as clinical implications.

Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes.

AIMS/HYPOTHESIS: There is evidence that type 2 diabetes mellitus is associated with cognitive impairment. Most studies investigating this association have evaluated elderly individuals, after many years of diabetes, who generally have poor glycaemic control and significant vascular disease. The aim of the current study was to investigate the early cognitive consequences and associated brain correlates of type 2 diabetes. MATERIALS AND METHODS: With regard to cognition and brain measures, we compared 23 age-, sex- and education-matched control subjects with 23 mostly middle-aged individuals with relatively well-controlled diabetes of less than 10 years from the time of diagnosis. RESULTS: We found deficits in hippocampal-based memory performance and preservation of other cognitive domains. Relative to control subjects, individuals with diabetes had reductions in brain volumes that were restricted to the hippocampus. There was an inverse relationship between glycaemic control and hippocampal volume; in multivariate regression analysis, HbA(1c) was the only significant predictor of hippocampal volume, accounting for 33% of the observed variance. Other variables commonly associated with type 2 diabetes, such as elevated BMI, hypertension or dyslipidaemia, did not independently contribute to the variance in hippocampal volume. CONCLUSIONS/INTERPRETATION: These results suggest that the medial temporal lobe may be the first brain site affected by type 2 diabetes and that individuals in poorer metabolic control may be affected to a greater extent.

Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour?

BACKGROUND: Fatigue is a major complaint of multiple sclerosis (MS) patients. However, little is known about its pathophysiological mechanisms. Evidence from chronic fatigue syndrome and studies on sickness behaviour suggest that immune and neuroendocrine factors may play a causative role in the development of fatigue. METHODS: We compared whole blood stimulatory capacity for pro- (TNFalpha, IFNgamma) and anti-inflammatory cytokines (IL-10) as well as hypothalamo-pituitary-adrenal (HPA) axis function in 15 MS patients with marked fatigue and 15 patients without fatigue as determined by the Fatigue Severity Scale (FSS). RESULTS: Proinflammatory cytokines were significantly higher (TNFalpha: 478.9 v 228.2 pg/ml, p = 0.01; IFNgamma: 57.6 v 27.8 pg/ml; p = 0.01) in MS patients with fatigue. Furthermore, TNFalpha values significantly correlated with daytime sleepiness as measured by the Epworth Sleepiness Scale (r = 0.64, p = 0.001). Controlling for disease activity (as measured by the Cambridge Multiple Sclerosis Basic Score), disease duration, Expanded Disability Status Scale, and depression further increased the correlation of cytokine production and fatigue. HPA axis activity was not related to fatigue but was modestly correlated with cognitive impairment. CONCLUSION: Our data suggest that fatigue in MS is at least partially mediated through activation of proinflammatory cytokines. In line with earlier findings, HPA axis dysfunction seems not to be relevant in MS fatigue pathogenesis but appears to be linked to cognitive impairment. Our findings suggest that increased levels of inflammatory cytokines may be involved in MS fatigue. Investigation of cytokine profiles may increase the understanding of fatigue pathogenesis in MS.

Characterization of basal and re-inflammation-associated long-term alteration in pain responsivity following short-lasting neonatal local inflammatory insult.

Recently, several studies have suggested that neonatal noxious insult could alter future responses to painful stimuli. However, the manifestations, mechanisms, and even developmental nature of these alterations remain a matter of controversy. In part, this is due to the lack of detailed information on the neonatal sensitive period(s) during which noxious stimulation influences future nociception, and the time-course and distribution of the resultant abnormalities. The present paper describes these parameters in a rat model of short-lasting ( approximately 24 h) neonatal local inflammation of a hindpaw produced by injection of 0.25% carrageenan (1 microl/g). Examinations of paw withdrawal responses to thermal and mechanical stimulations in adult animals, which as neonates were subjected to this insult, showed that the previously-reported long-term hypoalgesia and hyperalgesia are not mutually exclusive outcomes of early noxious experience. Long-term hypoalgesia was apparent at the basal conditions and was equally strong in the previously injured and uninjured paws, which suggests a globally-driven deficit. In contrast, long-term excessive hyperalgesia had the strongest manifestation in the neonatally-injured paw after re-inflammation, indicating significant segmental involvement in its generation. The differences between mechanisms underlying the observed hypoalgesia and hyperalgesia are further underscored by the finding that, while the former is detectable only after animals reach the second month of life, the latter is elicitable immediately upon cessation of the initial neonatal inflammation. Nevertheless, we detected a significant overlap in the neonatal sensitive periods for generation of these effects (both occurring within the first postnatal week). Also, neither the basal hypoalgesia nor excessive re-inflammation-associated hyperalgesia subsided with age and were detectable in 120-125-day-old rats. These finding provide a framework within which the entire complex of long-term effects of early noxious experience can be understood and examined.

Stronger endocrine responses after brief psychological stress in women at familial risk of breast cancer.

Recent research has linked exposure to chronic stress to altered acute stress responses and suggests a sensitizing effect of chronic stress leading to a stronger endocrine and cardiovascular response to acute stressors. Substantial evidence indicates that familial breast cancer risk is a chronic life stressor with higher levels of self reported distress. In this study, we investigated whether the endocrine response to a brief psychological stressor was stronger for women at familial risk for breast cancer. Thirty-six women at normal risk of breast cancer (FR- Stress Group) and 17 women at familial risk (FR+ Stress Group) underwent a brief psychological laboratory stress test (speech task and mental arithmetic) over a 15 min period. Thirty women at normal risk not subjected to the stressful task served as controls (FR- Control Group). Plasma epinephrine, norepinephrine and cortisol were measured at baseline, directly after the stress test (15 min) and at 30 min and 45 min post baseline. Heart rate data confirmed the effectiveness of the stress regimen. While there were no significant baseline group differences in the endocrine parameters, the response curves for the familial risk group revealed stronger epinephrine and cortisol reactivity to the stress test, as confirmed by significant group by time interactions. Norepinephrine levels showed a similar pattern, but results did not reach significance. These findings are in line with previous research documenting the facilitating effects of chronic stressors on acute stress response in animals and humans and provide the first evidence in the literature of a heightened endocrine reactivity to acute psychological stress in women at familial risk of breast cancer. The heightened endocrine reactivity to the experimental tasks seen here suggests that these women may experience stronger responses to stressors in their daily lives. According to the recently proposed concept of allostatic load, repeated overly strong stress responses may cumulatively have negative health implications.

Delivering the diagnosis of MS--results of a survey among patients and neurologists.

OBJECTIVES: The need for an early disclosure of the diagnosis of multiple sclerosis (MS) has become more pressing with the publication of two recent randomized trials which have indicated that very early treatment may favourably alter the disease course. We assessed the current status of diagnostic and therapeutic information on MS from the point of view of patients and neurologists. METHODS: A standardized questionnaire was sent out through the patients' self-help organization in Hamburg, Germany and to all neurologists. RESULTS: A total of 434 of 1300 patients and 80 of 250 neurologists replied. Neurologists gave 90% of the diagnoses but only 50% of patients reported them as the major aid helping to understand the disease. Fifty per cent of patients were not informed about any form of therapy at the time of diagnosis regardless of whether their MS diagnosis was disclosed within the last 5 years or earlier. In contrast to physicians, patients voted for information about a possible MS even if the diagnosis may not yet be clear. CONCLUSION: From the patients' perspective, information about the diagnosis of MS should be more straightforward, and more information about therapies should be provided.

Disease specific quality of life instruments in multiple sclerosis: validation of the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS).

Quality of life (QoL) is discussed as an additional outcome measure in multiple sclerosis (MS). However, few questionnaires assessing disease specific QoL in MS have been published. On the basis of the literature and interviews with clinicians and MS patients, we have developed a disease specific QoL instrument and validated it in a broad range of patients with MS. In this study, a heterogeneous sample of n = 237 MS patients completed the newly developed Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS, in German language) and a battery of already validated questionnaires. They further underwent neurological scoring and objective tests. By these means, we investigated its validity, appropriateness, internal consistency, and retest reliability. Internal consistency and retest coefficients were high and satisfied psychometric standards. Convergent and discriminant validity was supported by direction, magnitude and pattern of correlations with other health measures. HAQUAMS subscales and its total score distinguished between patient groups of varied disease severity, cognitive impairment, and affective symptomatology. No floor or ceiling effects were found in either of the HAQUAMS subscales. The HAQUAMS is a reliable, valid and appropriate instrument for QoL assessment in multiple sclerosis. Data of responsiveness are currently being obtained.

Cerebral blood flow and personality: a positron emission tomography study.

OBJECTIVE: This study sought to describe brain regions associated with the personality dimension of introversion/extraversion. METHOD: Measures of cerebral blood flow (CBF) were obtained from 18 healthy subjects by means of [150]H20 positron emission tomography. Correlations of regional CBF with introversion/extraversion were calculated, and a three-dimensional map of those correlations was generated. RESULTS: Overall, introversion was associated with increased blood flow in the frontal lobes and in the anterior thalamus. Regions in the anterior cingulate gyrus, the temporal lobes, and the posterior thalamus were found to be correlated with extraversion. CONCLUSIONS: The findings of the study lend support to the notion that introversion is associated with increased activity in frontal lobe regions. Moreover, the study suggests that individual differences in introversion and extraversion are related to differences in a fronto-striato-thalamic circuit.

Small wire external fixation of high energy tibial plateau fractures.

Open plate osteosynthesis for high energy tibial plateau fractures with dissociation between the metaphysis and diaphysis has been plagued with frequent soft tissue complications. The Harbor-University of California at Los Angeles Medical Center's experience with small wire external fixation supplemented by limited internal fixation is examined. This alternative method of adequate stable fixation offers the advantage of minimal soft tissue compromise. Twenty-four patients with Schatzker Type VI tibial fractures were treated with small wire external fixation. Supplementary limited internal fixation was used with percutaneous screws in 10 patients and with open reduction in one patient. Sixteen patients had isolated fractures, and eight others suffered multiple injuries. Minimum followup was 12 months. All fractures healed. Complications included one septic knee, two infections at screw sites, and one 10 degrees knee flexion contracture. One knee had Grade 3 radiographic arthrosis, five had Grade 2, 10 had Grade 1, and eight showed no arthrosis. The outcomes (Knee Society clinical rating system) of this study compare favorably with outcomes described in reports published previously for this type of fracture, despite inclusion of eight multiply injured patients. This technique preserves the goals of early range of motion and stable fixation for these devastating injuries, while decreasing the observed major wound complications and nonunion rates. However, longer followup may reveal higher arthrosis rates, specifically in those fractures that were not anatomically reduced.

Role of middle meatus aspiration culture in the diagnosis of chronic sinusitis.

Although empiric antibiotic therapy is often used for sinusitis, the emergence of antibiotic resistance has increased the failure rate of this approach. Culture-directed therapy usually increases treatment success, but traditional antral puncture is often accompanied by poor patient and physician acceptance. Endoscopically directed middle meatal aspiration culture is increasingly used in this setting, but studies have not convincingly demonstrated the validity of this technique. Both endoscopic middle meatal and direct antral cultures were performed during endoscopic sinus surgery. Cytologic examination was performed to confirm the presence of inflammatory cells. When culture results were compared in 21 specimen pairs, exact correlation was found in 18 (85.7%). Based on this study, endoscopically directed middle meatus aspiration culture appears to be a valuable alternative to antral puncture for guiding organism-specific antibiotic therapy in sinusitis.

Blunt laryngotracheal trauma in children.

OBJECTIVES: To demonstrate the diverse causes and manifestations of blunt laryngotracheal trauma in children, and to recommend an appropriate treatment protocol for these patients. DESIGN: A retrospective review of the medical records of patients treated at a tertiary care children's hospital for blunt laryngotracheal trauma during the 12 years before March 1, 1995 was performed. Clinical signs and symptoms, mechanisms of injury, and the results of laryngoscopy were included. PATIENTS: The study included 23 patients ranging from 2 1/2 to 18 1/2 years of age. The medical records of patients who had sustained an injury as a result of penetrating trauma, intubation, or foreign body were excluded. RESULTS: Four patients urgently required tracheotomies; 2 of these patients required subsequent reconstructive airway procedures. One child required a microlaryngoscopy with relocation of the arytenoid cartilage. The remaining 18 patients were treated conservatively with continuous pulse oximetry, cool mist room air, and serial flexible fiberoptic laryngoscopy. The 18 patients were discharged from the hospital after 24 to 48 hours of observation without sequelae. CONCLUSIONS: The signs and symptoms of blunt laryngotracheal trauma in children are not always specific to the extent or type of injury. A prompt diagnosis and treatment plan are needed to prevent potentially catastrophic complications. Patients with obvious airway compromise require immediate intervention. Those without acute airway symptoms often can be treated conservatively, provided that flexible fiberoptic laryngoscopy confirms a safe airway.