Post-stroke fatigue: how it relates to motor fatigability and other modifiable factors in people with chronic stroke.

Post-stroke fatigue (PSF) is a common symptom associated with disability and decreased quality of life. Distinction can be made between perceived fatigue and fatigability. The first aim of this study was to evaluate the prevalence of perceived fatigue and fatigability amongst patients with chronic stroke and to explore how these two parameters relate. The second aim was to study the relationship between modifiable factors (sleep disorders, anxiety, depression and activities of daily living) and fatigue in this population. Sixty-two patients with chronic stroke (> 6 months) were included. Perceived fatigue was evaluated using the Fatigue Severity Scale (FSS). Motor fatigability was assessed with the percent change in meters walked from first to last minute of the 6-min Walk Test and an isometric muscular fatigability test. Subjects also completed self-report questionnaires assessing anxiety and depression (Hospital Anxiety and Depression Scale-HADS), sleep quality (Pittsburgh Sleep Quality Index-PSQI) and activity limitations (ACTIVLIM-stroke). Seventy-one percent of participants presented PSF. There was no correlation between the FSS and motor fatigability. FSS significantly correlated with HADS-Anxiety (ρ = 0.53, P < 0.001), HADS-depression (ρ = 0.63, P < 0.001), PSQI (ρ = 0.51, P < 0.001) and ACTIVLIM (ρ = - 0.30, P < 0.05). A linear regression model showed that the HADS-Depression, the PSQI and the ACTIVLIM explained 46% of the variance of the FSS. A high proportion of chronic stroke patients presents PSF, with no relation between their fatigue and fatigability. Perceived fatigue is associated with potentially modifiable factors: anxious and depressive symptoms, poor sleep quality and activity limitations. Registered at ClinicalTrials.gov (NCT04277234) (21/02/2019).

Impact of series length on statistical precision and sensitivity of autocorrelation assessment in human locomotion.

Long-range autocorrelations (LRA) are a robust feature of rhythmic movements, which may provide important information about neural control and potentially constitute a powerful marker of dysfunction. A clear difficulty associated with the assessment of LRA is that it requires a large number of cycles to generate reliable results. Here we investigate how series length impacts the reliability of LRA assessment. A total of 94 time series extracted from walking or cycling tasks were re-assessed with series length varying from 64 to 512 data points. LRA were assessed using an approach combining the rescaled range analysis or the detrended fluctuation analysis (Hurst exponent, H), along with the shape of the power spectral density (α exponent). The statistical precision was defined as the ability to obtain estimates for H and α that are consistent with their theoretical relationship, irrespective of the series length. The sensitivity consisted of testing whether significant differences between experimental conditions found in the original studies when considering 512 data points persisted with shorter series. We also investigate the use of evenly-spaced diffusion plots as a methodological improvement of original version of methods for short series. Our results show that the reliable assessment of LRA requires 512 data points, or no shorter than 256 data points provided that more robust methods are considered such as the evenly-spaced algorithms. Such series can be reasonably obtained in clinical populations with moderate, or even more severe, gait impairments and open the perspective to extend the use of LRA assessment as a marker of gait stability applicable to a broad range of locomotor disorders.

Reversible and Species-Specific Depigmentation Effects of AZD3293, a BACE Inhibitor for the Treatment of Alzheimer's Disease, Are Related to BACE2 Inhibition and Confined to Epidermis and Hair.

BACKGROUND: AZD3293 (also known as LY3314814) is a novel, potent, non-selective BACE1/BACE2 inhibitor currently in Phase 3 clinical development for the treatment of Alzheimer's disease. OBJECTIVES: The purpose of these studies was to characterize the effects, putative mechanism, and reversibility of hypopigmentation following treatment with AZD3293 in pigmented Long-Evans rats, Beagle dogs, human cell cultures, and humans. DESIGN: Nonclinical studies were conducted in Long-Evans pigmented rats, and both young and older Beagle dogs using a variety of oral dose levels of AZD3293 or AZD3839 (BACE inhibition reference compound; used in older dogs only) for dosing durations of 13 to 26 weeks. In vitro studies of normal human epidermal melanocytes and reconstituted human epidermis were also conducted. Skin biopsy data from a multiple-dose Phase 1 clinical study of AZD3293 (NCT01795339) are also reported. SETTING: Nonclinical in vivo and in vitro studies were conducted in laboratory settings in the US, Canada, and France; the multiple dose clinical study was conducted in a specialized inpatient setting in the US. PARTICIPANTS: Beagle dogs: 13-week study N=36 young (8-10 mo) animals; 39-week study N=64 young animals; and a second 13-week study N=32 older (30-32 mo) animals. Long-Evans rats: N=68 animals. Multiple-dose clinical study: only data for subjects enrolled in Part 2 of this study are included in this report (N=16). INTERVENTIONS: AZD3293 was the primary intervention used in these studies. AZD3839, a relatively BACE1-selective reference inhibitor compound was used in one group in the 13 week study in older Beagle dogs and one in vitro assessment. Finally, AZ1340, another relatively BACE1-selective reference inhibitor compound was used only in one in vitro assessment. MEASUREMENTS: Measurements for the nonclinical studies in dogs and rats included macroscopic observation and assessment of skin biopsies via histopathology, immunochemistry, and electron microscopy. Measurements for the in vitro studies included melanocyte premelanosome protein (PMEL) processing, cytotoxicity, melanin synthesis, Pmel17 labeling, and melanocyte dendricity. Measurements in the clinical study included scoring of melanin content in skin biopsies taken before and after dosing with AZD3293 over 14 days at dose levels up to 150 mg. RESULTS: Depigmentation in rats and dogs was limited to skin, hair, and mucosa with no effects on other pigmented tissues. At a cellular level depigmentation was observed within a week of treatment, whereas the appearance of depigmentation in skin and hair did not become apparent until, at earliest, 4 weeks of treatment. The depigmentation effects were reversible, not associated with degenerative or inflammatory changes, and were dose- and species-dependent in severity. Full recovery of melanization was observed at the microscopic (cellular) level and at least partial recovery was seen in the macroscopic appearance of animals by the end of the 12-week recovery period in both rats and dogs. Interestingly, no changes in melanin production or melanocyte morphology were seen in human primary melanocytes or reconstituted human epidermis in vitro. Finally, there were no changes in melanization level in skin biopsies following 12 days of daily AZD3293 treatment at doses of AZD3293 up to 150 mg/day in human subjects. CONCLUSIONS: AZD3293, a novel, potent, non-selective BACE1/BACE2 inhibitor is in development as a potentially disease-modifying treatment for Alzheimer's disease. Chronic nonclinical studies in Beagle dogs and pigmented rats showed macroscopic and microscopic hypopigmentation effects of AZD3293 that were limited to skin, hair, and mucosa. These effects were shown to be reversible in both species. Analysis of data from nonclinical and in vitro studies suggests that hypopigmentation is caused by BACE2 inhibition resulting in accumulation of a premelanosome protein fragment, which interrupts the normal production of melanin. No macroscopic or microscopic reports of hypopigmentation were observed in a Phase 1 clinical study following 13 doses of AZD3293 over 14 days at dose levels up to 150 mg/day. These data suggest that hypopigmentation is species-specific and humans appear to be least sensitive to the depigmentation effect caused by BACE2 inhibition.

In vivo optical spectroscopy monitoring in a new model of muscular compartment syndrome.

BACKGROUND: Muscular compartment syndrome (MCS) is a rare but serious postoperative complication. In vivo optical spectroscopy (INVOS) monitors continuously and non-invasively regional oxygen saturation (rSO(2)), and could predict the development of MCS. METHODS: In 10 healthy volunteers, we inflated a tourniquet to the mean arterial pressure to produce slight venous congestion and arterial hypoperfusion. Comparisons were made between the relative reduction in rSO(2) with baseline (deltaINVOS) and the time to observe motor nerve block (with non-invasive electromyography). Neurological symptoms, pain, and invasive intracompartmental pressure (ICP) were assessed. RESULTS: In the eight volunteers completing the protocol, we observed a profound motor nerve conduction block, immediately reversible. Baseline values were: [mean (sd)] INVOS: 73.3 (8.9)% and ICP: 16.9 (8.6) mm Hg. At the time of the block, values were: INVOS: 46.4 (10.9)%, deltaINVOS: 28.7 (10.6)%, and ICP: 70.0 (5.5) mm Hg. The time to reach the block was 33.0 (10.9) min, and to a deltaINVOS>10%: 27.4 (10.4) min. Receiver-operating characteristic curves demonstrated a similar accuracy of ICP and INVOS to predict the occurrence of the block. Twenty minutes with a deltaINVOS>10% or ICP>30 mm Hg were associated with a sensitivity and a specificity of 95% and 70%; or 91% and 65%, respectively. CONCLUSIONS: We have developed a model of acute immediately reversible MCS. Monitoring using the INVOS technology is as accurate as measurement of ICP, and could be a useful tool to prevent development of intraoperative MCS.

The reasons why stroke patients expend so much energy to walk slowly.

BACKGROUND: The energy consumed per covered distance (C) is increased in hemiparetic stroke adults during walking. OBJECTIVE: To ascertain if increased C in stroke patients is a result of increased mechanical work, of decreased efficiency of work production by muscles or of slow walking speed. METHODS: C and mechanical work were computed in 20 patients walking on a force measuring treadmill at speeds ranging from 1 km h(-1) to their own maximum speed (WS(MAX)). Works done by healthy and pathological limbs were computed separately. RESULTS: For hemiparetic patients, C was around 1.7 times greater than normal. When these patients had a slower WS(MAX), they had greater C and mechanical work (r=-0.44 and -0.57, respectively). The increased C was related to the external work performed to lift the center of body mass when the healthy limb was supporting the body weight (r=0.77). CONCLUSIONS: The increase of C in stroke patients is more pronounced when WS(MAX) is slow. Moreover, this increase is related to increased mechanical work done by muscles and is not related to slow walking speed or decreased efficiency. As in healthy subjects, C and external work presented optimum speeds, indicating a preserved pendular mechanism of walking.

Effects of age and walking speed on long-range autocorrelations and fluctuation magnitude of stride duration.

Stride duration variability is considered a marker of gait balance and can be investigated in at least two different ways. Fluctuation magnitude can be addressed by classical mathematical methods, whereas fluctuation dynamics between strides can be characterized using the autocorrelation function. Although each approach has revealed changes of these parameters in different age-groups, most studies have focused on spontaneous walking speeds, which vary across groups and is described as a possible confounder in the assessment of stride duration variability. In the present study, the influence of speed on stride duration fluctuations was first analyzed in six young adults walking at six different speeds on a treadmill. Second, the results of 18 subjects from three different age-groups (≈5, 25, and 75 years old) were compared to assess the effect of age on the same variables at three different speeds. Fluctuation dynamics was evaluated, thanks to combined mathematical methods recently validated in the context of physiological time series, to increase the level of confidence in the results. Fluctuation magnitude was assessed by coefficients of variation (CV) on the same and large number of 512 gait strides, to enhance the validity of comparisons between both parameters. Long-range autocorrelations were highlighted in all time series, and characteristics were not influenced by gait speed and age of the participants. This suggests that the dynamics of variability is efficient for comparing subjects presenting with different spontaneous speed, and supports the hypothesis that long-range variability of human gait reflects a centrally controlled behavior. In contrast, CV was inversely related to walking speed and the age of the subjects. Slower speeds increased CV values, and fluctuation magnitude was also significantly larger for children compared with young and old adults. This confirms that fluctuation magnitude and dynamics could be complementary tools for more complete gait characterization.

Towards a "gold-standard" approach to address the presence of long-range auto-correlation in physiological time series.

Series of motor outputs generated by cyclic movements are typically complex, suggesting that the correlation function of the time series spans over a large number of consecutive samples. Famous examples include inter-stride intervals, heartbeat variability, spontaneous neural firing patterns or motor synchronization with external pacing. Long-range correlations are potentially important for fundamental research, as the neural and biomechanical mechanisms generating these correlations remain unknown, and for clinical applications, given that the loss of long-range correlation may be a marker of disease. However, no systematic approach or robust analysis methods have yet been used to support the study of correlation functions in physiological series. This study investigates four selected methods (the Hurst exponent, the power spectral density analysis, the rate of moment convergence and the multiscale entropy methods). We present the result of each analysis performed on artificial computer-generated series in which the auto-correlation function is known, and then on time series extracted from gait and upper limb rhythmic movements. Our results suggest that combined analysis using the Hurst exponent and the power spectral density is suitable for rather short series (512 points). The rate of moment convergence directly supports the power spectral density analysis, and the multiscale entropy further confirms the presence of long-range correlation, although this method seems more appropriate for longer series. The proposed methodology increases the level of confidence in the hypothesis that physiological series are long-memory processes, which is of prime importance for future fundamental and clinical research.

Effect of speed on kinematic, kinetic, electromyographic and energetic reference values during treadmill walking.

OBJECTIVE: Evaluation of normal and pathological gait on the level ground has drawbacks that could be overcome by walking on a treadmill. The present work was designed to assess the feasibility of extended gait analysis on a treadmill allowing multiple steps recording at a constant speed in young healthy subjects. It also aimed to provide speed-specific kinematic, kinetic, electromyographic and energetic reference values. METHOD: Twelve healthy volunteers (23 +/- two years) walked on a force measuring treadmill at six speeds (1-6 k mh(-1)). Kinematics and kinetics were analysed at the hip, knee and ankle. Electromyographic muscle activity timing of quadriceps femoris, biceps femoris, tibialis anterior and lateral gastrocnemius was recorded. The energy cost was computed from oxygen consumption measurement. RESULTS: All variables were speed-dependent. Kinematics and kinetics peaks amplitude increased and occurred earlier during the walking cycle with increasing walking speed. Muscle activity timing also changed with speed, although the number of bursts remained constant. The energetic cost presented a U-shaped curve, with minimal values around 4 km h(-1). Data were compared to overground walking data obtained by several authors: all results, except kinetic ones, were similar, turning down the thought that biomechanics of treadmill and overground walking could be different. CONCLUSION: This study provides reference values for normal and pathological walking on treadmill and allows speed-dependent comparison between subjects.

Assessment of the Chignon dynamic ankle-foot orthosis using instrumented gait analysis in hemiparetic adults.

OBJECTIVE: In the hemiplegic adult, gait is frequently perturbed by lack of ankle dorsiflexion at toe-off and may prompt prescription of an ankle-foot orthosis (AFO). Our objective was to evaluate the effect on gait of a dynamic AFO (the Chignon orthosis) in comparison with a prefabricated AFO (PAFO). METHOD: Ten chronic hemiplegic patients performed a 10 m gait test and then underwent an instrumented treadmill gait test under three different sets of conditions (without an orthosis, with a PAFO and with a Chignon orthosis). The energy cost was calculated by measuring the oxygen consumption during gait. RESULTS: The patients' free-walking speed was higher with the Chignon orthosis (0.81+/-0.25 ms(-1)) than without it (0.64+/-0.25 ms(-1); p<0.001). The ankle's segmental kinematics were better with the Chignon orthosis than without an orthosis, notably in terms of ankle position at heel strike (-0.8 degrees +/-4.6 versus -7.9 degrees +/-8.3; p=0.009) and ankle dorsiflexion at toe-off (1.7 degrees +/-4.6 versus -5.5 degrees +/-7.2; p=0.006). External mechanical work was lower with both the PAFO (0.61+/-0.2 J kg(-1)m(-1)) and the Chignon orthosis (0.61+/-0.23 J kg(-1)m(-1)), relative to gait without an orthosis (0.73+/-0.25 J kg(-1)m(-1); p=0.003). Total mechanical work was also lower with the PAFO (0.9+/-0.25 J kg(-1)m(-1)) and the Chignon orthosis (0.87+/-0.25 J kg(-1)m(-1)), relative to gait without an orthosis (1.09+/-0.37 J kg(-1)m(-1); p=0.001), whereas the reduction in energy cost with orthosis use was borderline-significant (p=0.06). CONCLUSION: Mechanical work was similarly improved by the two orthoses. The Chignon orthosis improved the free-walking speed and the ankle's segmental kinematics.

Severe necrotizing encephalitis in a Yorkshire terrier: topographic and immunohistochemical study.

Necrotizing encephalitis of the Yorkshire terrier is a chronic non-suppurative encephalitis that was reported in approximately 15 cases worldwide. We report the case of a 10-year-old female Yorkshire terrier with gross evidence of severe cortical degeneration and necrosis. Microscopically, affected areas were mainly located in the cortical white matter and in the mesencephalon without implication of the cerebellum. Cavitation necrosis, demyelination, gemistocytic astrocytosis, marked perivascular lymphocytic cuffing with a diffuse lymphocytic/histiocytic/gitter cell infiltration characterized the lesions. Immunohistochemical analysis identified the major infiltration of T lymphocytes and macrophages with implication of some cytotoxic lymphocytes and IgG-producing plasma cells; depositions of IgG in the affected white matter were also observed. Specific stains did not reveal fungal, protozoal or bacterial organisms and reverse transcriptase-polymerase chain reaction analysis for distemper virus was also negative. The lympho-histiocytic inflammation suggests a T-cell-mediated and a delayed-type immune reaction as a possible pathogenic mechanism for this brain disorder.

Experience with external pump trial prior to implantation for intrathecal baclofen in ambulatory patients with spastic cerebral palsy.

OBJECTIVES: To evaluate effectiveness and safety of intrathecal baclofen administration (ITB) testing with continuous infusion via an external pump before the implantation of an internal one in ambulatory spastic patients with cerebral palsy (CP). PATIENTS AND METHODS: Seven CP patients (3 diplegic, 4 quadriplegic - 18.4+/-7.0 years) with a progressive decrease in walking ability were included. Assessments included: Ashworth's scale, Observational Gait Scale (OGS), and GMFM-66. RESULTS: During the ITB test (45-150 microg/24h), spasticity decreased by more than two points on Ashworth's scale (p<0.001) and walking ability improved (median OGS increased from 7 to 9, p

[Multiple diabetic muscular infarctions after liver and kidney transplantation: a case report]. / Multiples infarctus musculaires diabétiques après transplantation hépatique et rénale.

INTRODUCTION: Several neuromuscular diseases may complicate diabetes mellitus and transplantation, including chronic sensorimotor length dependent polyneuropathy. OBJECTIVE: Description of muscular infarction, a rare complication of diabetes mellitus, which occurred after liver and kidney transplantation. CASE REPORT: A 57-year-old patient presented with long-term diabetes mellitus and multiple complications. End-stage renal and hepatic disease led to kidney and liver transplantation. Twenty-seven days after transplantation, swelling and induration appeared in the left shoulder and forearm. Forty-three days after transplantation, the same symptoms appeared in both lower limbs. Markedly reduced range of motion led to severe disability. Bone scans showed multiple spots following muscle anatomy. Computed tomography gave negative results. Magnetic resonance imaging (MRI) confirmed muscular infarction by a high T1 signal (muscular necrosis) and soft-tissue infiltration. DISCUSSION AND CONCLUSION: Muscular infarction is a rare and unknown complication of diabetes mellitus. It is characterised by sudden painful muscular induration and swelling affecting one muscle at a time with recurrence. Our patient presented with simultaneous multiple muscular infarctions in 3 limbs. Diagnosis was based on clinical investigation and MRI. The treatment is conservative and the condition generally resolved by itself. However, the long-term prognosis of muscular infarction is not good because of the cardiovascular-associated complications of diabetes mellitus.

Efficiency of work production by spastic muscles.

The present study compared the muscular efficiency in spastic and healthy lower limbs producing the same mechanical work. Sixteen chronic post-stroke hemiparetic and spastic patients and 14 age-matched healthy subjects were submitted to a submaximal stepwise exercise testing on a bicycle ergometer, pedalling with only one lower limb. Net energetic expenditure was computed from oxygen consumption above resting values. Electrical activity of antagonistic muscles in the thigh and in the shank was recorded and co-contraction was defined as the percentage of the pedalling cycle when antagonistic muscles were activated simultaneously. The efficiency was calculated as the ratio between the mechanical work done on the ergometer and the net energetic expenditure. Spasticity was quantitatively evaluated by measuring passive ankle plantar flexor muscle stiffness. The working capacity of the patients' paretic lower limb was very low (<40W). The energy expenditure increased linearly as a function of work intensity, without statistical difference between the patients paretic lower limb (PPL), the patients healthy lower limb (PHL) and the healthy subjects lower limb (HSL). Shank co-contraction was 2.9 times greater in PPL (p<0.05) and 2.3 times greater in PHL (p<0.05) than in HSL. Thigh co-contraction was also 1.8 times greater in PPL than in HSL (p<0.05). The ankle plantar flexor muscle stiffness was statistically greater in PPL than in PHL and HSL (p<0.05). The efficiency was not statistically different between the three groups (p=0.155). In conclusion, the efficiency of work production by paretic and spastic lower limb muscles was normal ( congruent with 20%) despite significant neurological impairments.

Energy cost, mechanical work, and efficiency of hemiparetic walking.

The energy cost of walking (C) in nine chronic hemiparetic patients was calculated by measuring the total mechanical work (Wtot) done by the muscles and the efficiency of this work production (eta). The energy cost was twice normal in slow walkers and 1.3 times greater in fast walkers. The increase in C was proportional to the increase in Wtot and eta was normal at around 20%, despite an increase in muscle tone and muscle co-contractions. This type of approach gives a greater understanding into how segmental impairments increase Wtot and C and contribute to a patient's disability.