Effects of fluoxetine on functional outcomes after acute stroke (focus): a pragmatic, double-blind, randomized, controlled trial, by M Dennis (Chair), J Forbes, C Graham, M Hackett, GJ Hankey, A House, S Lewis, E Lundstrom, P Sandercock, G Mead, and the FOCUS Trial Collaboration. Lancet. 2019; 393(10168):265-274.
Background and Purpose: The purpose of this parallel-group, placebo-controlled trial was to evaluate the effect of a 6-month course of 20 mg of fluoxetine on the functional status of individuals with a clinical stroke diagnosis. Results from previous studies indicated that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), may enhance neuroplasticity and promote neurogenesis, thus improving motor recovery. However, to date, evidence supporting the impact of fluoxetine to reduce poststroke disability has not been sufficient to incorporate this treatment into stroke guidelines or fully ascertain if possible adverse effects may offset any benefits.
Methods: This double-blind, randomized controlled trial was carried out across 103 hospitals in the UK and enrolled 3127 participants between 2 and 15 days of intracerebral hemorrhage or ischemic stroke onset. Criteria for enrollment included a persisting focal neurological deficit at the time of randomization, and no current or recent depression treated with an SSRI. Fluoxetine 20 mg or placebo was administered to participants orally once daily for 6 months. The primary outcome was functional status measured with the modified Rankin Scale (mRS) administered by the questionnaire at 6-months follow-up. Secondary outcomes included survival, functional status at 12 months, health status (Stroke Impact Scale), mood (Mental Health Inventory), fatigue (Vitality Subscale of SF-36), and health-related quality of life (EuroQol5).
Results: After excluding participants with no follow-up data and performing an ordinal analysis assuming proportional odds, the primary outcome (ordinal comparison of the distribution of participants across the mRS categories) results were similar in both groups (common odds ratio 0.951 [95% CI 0.839-1.079]; P = 0.439). Dichotomized mRS (0-2 vs 3-6) showed no significant results. Secondary outcomes demonstrated that the fluoxetine group was less likely than the placebo group to be diagnosed with new depression at 6 months (210 [13.43%] participants vs 269 [17.21%]; difference in proportions 3.78% [95% CI 1.26-6.30]; P = 0.0033); and had better mood at the 6-month follow-up (median 76 [IQR 60-88] vs 72 [56-88]; P = 0.0100). An increased risk of bone fractures was seen in participants receiving fluoxetine as compared with those allocated the placebo (45 [2.88%] participants vs 23 [1.47%]; difference in proportions 1.41% [95% CI 0.38-2.43]; P = 0.0070). There were no significant differences in any other secondary outcomes at 6 months. Mood difference between groups was not sustained and the difference in depression diagnoses was no longer significant at the 12-month follow-up. No other significant between-group differences were observed.
Discussion and Conclusions: Findings from this study indicate that administration of fluoxetine 20 mg daily for 6 months after an acute stroke does not significantly improve functional outcomes or survival at 6 and 12 months. Although fluoxetine seemed to reduce the occurrence of depression, adversely this treatment may increase the occurrence of bone fractures at 6 months. The authors suggest that these results do not support the use of fluoxetine for prevention of poststroke depression nor to promote recovery of function. Future research on the use of SSRIs after stroke is underway to confirm generalizability of findings to different patient populations, to clarify potential benefits to possible subgroups, and provide a precise estimate of any harms.
Abstracted by
Josue Rodriquez and Sarah Blanton, PT, DPT, NCS, FNAP
Department of Rehabilitation Medicine, Division of Physical Therapy, Emory University School of Medicine, Atlanta, Georgia
Evidence for differential effects of 2 forms of exercise on prefrontal plasticity during walking in Parkinson's disease, by I Maidan, F Nieuwhof, H Bernad-Elazari, BR Bloem, N Giladi, JM Hausdorff, J Claasen, and A Mirelman. Neurorehabil Neural Repair. 2018;32(3):200-208.
Background and Purpose: Individuals with Parkinson disease (PD) demonstrate decreased automaticity of movement due to dopamine deficiency within the striatum. A proposed mechanism of compensation is the recruitment and activation of prefrontal areas of the brain. Such early activation of cortical activity during simple tasks may predispose system failure under more complex walking conditions such as dual tasking or obstacle negotiation. This may predispose individuals with PD to falls. In a cohort of individuals with PD, this study aimed to evaluate (1) the effects of gait training on prefrontal activation, (2) the effects of simultaneous motor-cognitive training on prefrontal activation versus motor training alone, and (3) the relationship between training effects and fall risk in people with PD. The purpose of this RCT study was to determine whether a treadmill training walking program that is combined with virtual reality (TT + VR) to target motor and cognitive aspects of ambulation would lead to fewer falls when compared to treadmill training (TT) alone. Researchers hypothesized that both training forms will reduce prefrontal activation, reflecting enhanced automaticity, but that TT + VR will reduce activation to a greater extent than the TT, mainly during more complex walking conditions.
Methods: Subjects with PD (n = 65; Hoehn and Yahr stage II-III, mean age 70 +/- 4 years) were randomized into TT alone (n = 34) versus TT combined with VR (n = 30). TT + VR required subjects to negotiate virtual obstacles presented on a screen in front of the treadmill. Prefrontal activation during usual, dual-task (serial 3's), and obstacle negotiation walking was assessed before and after 6 weeks of training, using a functional near-infrared spectroscopy system (fNIRS). Quantitative gait parameters (step/stride length, gait velocity) were also collected via a gait mat. Incidents of falls were documented. Intervention sessions of either TT alone or TT + VR included 45-minute sessions, 3 times per week for 6 weeks.
Results: The effects of exercise on prefrontal activation showed that treadmill training with and without virtual reality reduced prefrontal activation during usual and complex walking (P < 0.001). Differences were also shown between groups, between cortex hemispheres, and between walking conditions: subjects in the TT + VR group had a larger decrease than those in the TT group alone (P = 0.010); left prefrontal cortex demonstrated larger decreases than right prefrontal cortex (P = 0.05); complex walking conditions demonstrated higher activation than usual walking (P = 0.001). Those subjects who trained with treadmill alone showed increased prefrontal activation during dual-task walking and obstacle negotiation after training, while those in the combined training arm (TT + VR) had decreased activation. Following training, subjects in both groups showed improvements in gait speed and stride length across walking conditions. Additionally, the number of falls at 6 months was reduced and executive function scores increased. Lower number of falls after training was associated with reduced left prefrontal activation in both groups.
Discussion and Conclusions: Motor-cognitive training may reduce the excessive demands placed on the prefrontal cortex in those with PD, reflecting more efficient activation patterns during usual and complex walking conditions. The addition of a cognitive training component via VR to a treadmill exercise program modifies the effects on the magnitude and lateralization of prefrontal activation and on falls, offering insight into the compensatory mechanisms used by the brain and potential ways to remediate it.
Abstracted by
Jeffrey M. Hoder, PT, DPT, NCS
Doctor of Physical Therapy Division, Duke University, Durham, North Carolina
Serum albumin predicts long-term neurological outcomes after acute spinal cord injury, by B Tong, CR Jutzeler, JJ Cragg, et al. Neurorehabil Neural Repair. 2018;32(1):7-17.
Background and Purpose: Prediction of neurological recovery after spinal cord injury (SCI) is currently limited. The International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI), which measures sensory and motor function, and the associated American Spinal Injury Association Impairment Scale (AIS) levels are the measures most typically used. Improved prediction of long-term recovery after SCI would advance clinical care and allow more accurate evaluation of treatment effects in clinical trials. Serum albumin concentration has been correlated with outcomes in other neurological populations. The purpose of this study was to investigate whether serum albumin levels can be used to predict long-term outcomes after traumatic SCI.
Methods: This study was a secondary analysis of data from a phase III randomized, controlled, multicenter trial investigating the efficacy of GM-1 ganglioside therapy in people with SCI. This study examined the data from 591 participants with acute traumatic SCI (AIS A, n = 381; AIS B, n = 98; AIS C/D, n = 112). Measures included serum albumin concentration at baseline, 1, 2, and 4 weeks and ISNCSCI measures at baseline, 1, 26, and 52 weeks. Primary outcomes were (1) "marked recovery at 26 weeks" defined as an improvement from AIS A/B to AIS C/D or an improvement from AIS C/D to limited or unlimited walking function and (2) ISNCSCI lower extremity motor scores (LEMS) at 52 weeks. Data were analyzed with multivariable linear and logistical regressions to adjust for potential confounders, including age, sex, treatment group (placebo vs GM-1 ganglioside therapy), AIS level, and presence of polytrauma (ie, 3 or more associated injuries).
Results: Participants with higher serum albumin levels were more likely to have better long-term motor recovery (ie, marked recovery at 26 weeks and higher LEMS at 52 weeks). The strength of association between serum albumin level and LEMS at 52 weeks increased over time, with a stronger correlation at 4 weeks than at baseline. In addition, AIS level at baseline combined with serum albumin level at 4 weeks had a stronger association (P < 0.001) with LEMS at 52 weeks (r2 = 0.720) than baseline AIS level alone (r2 = 0.706).
Discussion and Conclusions: Accurate prediction of neurological recovery, which heavily influences functional outcomes such as walking ability after SCI, is critical to physical therapy evaluation and treatment planning. This study provides evidence that serum albumin concentration, which is included in a standard blood chemistry workup, may be useful for the prediction of neurological recovery after traumatic SCI. Current hypotheses are that serum albumin levels may reflect either a general measure of health or a measure of systemic inflammation. Serum albumin measures are most likely to be useful in combination with ISNCSCI scores, which are already used in clinical and research environments to classify injury severity and to predict long-term recovery. While the results of this study are promising, the data were originally collected for a study that was published 19 years ago and was impacted by the standard of care for acute SCI at the time. Further research in people with recent SCI is indicated.
Abstracted by
Rachel Tappan, PT, DPT
Department of Physical Therapy and Human Movement Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois