The association of chemotherapy-induced peripheral neuropathy with reduced executive function in chemotherapy-treated cancer survivors: A cross-sectional study.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is common and disabling among cancer survivors. Little is known about the association of CIPN with other measures of the nervous system's integrity, such as executive dysfunction. We compared measures of executive function in older chemotherapy-treated cancer survivors with and without CIPN. MATERIALS AND METHODS: This cross-sectional study enrolled 50 chemotherapy-treated cancer survivors (65.6 ± 11.5 years, 88% female) post-chemotherapy treatment who were previously referred for outpatient rehabilitation at the request of the cancer survivor or a medical provider. Twenty-two participants (44%) had CIPN defined by patient-reported distal paresthesia or numbness, which began with chemotherapy and continued to the time of cognitive testing. Measures of executive function included Trails-B, Stroop, and rapid reaction accuracy (RRA) and were evaluated between cancer survivors with and without CIPN using t-tests. Multivariable models were then used to determine whether CIPN was an independent determinant of the measures of executive function (Trails-B, Stroop Incongruent, and RRA). Models were adjusted for age, sex, history of anxiety, and benzodiazepine use due to their known associations with CIPN and executive function. RESULTS: Cancer survivors with CIPN (CIPN+) had reduced executive function compared to survivors without CIPN (CIPN-) on Trails-B (CIPN+: 84.9 s ± 44.1 s, CIPN-: 59.1 s ± 22.5 s, p = 0.01), Stroop (CIPN+: 100.6 s ± 38.2 s, CIPN-: 82.1 s ± 17.3 s, p = 0.03), and RRA (CIPN+: 60.3% ± 12.9%, CIPN-: 70.6% ± 15.7%, p = 0.01). There were no differences in cancer stage severity or functional status by patient report or sit-to-stand function. The association between CIPN and reduced executive function was found in multivariable models after adjusting for age, sex, anxiety, and benzodiazepine use for Trails-B (ß:17.9, p = 0.046), Stroop (ß:16.9, p = 0.02), and RRA (ß:-0.072, p = 0.03). DISCUSSION: In this population, CIPN is associated with reduced executive function in older cancer survivors treated with chemotherapy. Future research is required to further understand this preliminary association, the causality, and the potential risk factors.

Short-latency reaction time and accuracy are impaired in patients with cirrhosis: An international multicenter retrospective study.

AIM: The inability to quickly react to an external event can lead to an increased risk for accidents (e.g., falls, car crashes) in patients with cirrhosis. The aim of this study was to determine whether a novel clinically feasible measure of simple reaction time (SRT) and reaction accuracy (RA)-a go/no-go task occurring within 400 ms-could differentiate patients with cirrhosis from controls. METHODS: This retrospective study included 160 patients with cirrhosis and 160 controls assessed between January 2010 and October 2022. SRT and RA were evaluated using a ruler drop paradigm and compared using propensity score matching. Factors distinguishing patients with cirrhosis from controls were assessed using logistic regression and receiver operating characteristics curve (ROC) analyses. RESULTS: Propensity score matching identified 112 participants in each group with comparable baseline characteristics. As compared with controls, patients with cirrhosis exhibited significantly prolonged SRT (200 vs. 174 ms; P < 0.001) and diminished total RA (63% vs. 73%; P < 0.001). After adjustment for confounding factors, SRT and RA independently identified patients with cirrhosis. ROC analyses showed that SRT more effectively identified patients with cirrhosis than did the number-connection test/trail-making test-B (area under the curve, 0.87 vs. 0.60; P < 0.001). CONCLUSIONS: Patients with cirrhosis demonstrated impairments in short-latency cognitive function. Given that SRT and RA are associated with balance, falls, and response to perturbation, these parameters may present a task-specific method to identify patients with cirrhosis at high risk of falls and motor vehicle crashes. Geriatr Gerontol Int 2024; 24: 25-31.

Suppressing a Blocked Balance Recovery Step: A Novel Method to Assess an Inhibitory Postural Response.

Stepping to recover balance is an important way we avoid falling. However, when faced with obstacles in the step path, we must adapt such reactions. Physical obstructions are typically detected through vision, which then cues step modification. The present study describes a novel method to assess visually prompted step inhibition in a reactive balance context. In our task, participants recovered balance by quickly stepping after being released from a supported forward lean. On rare trials, however, an obstacle blocked the stepping path. The timing of vision relative to postural perturbation was controlled using occlusion goggles to regulate task difficulty. Furthermore, we explored step suppression in our balance task related to inhibitory capacity measured at the hand using a clinically feasible handheld device (ReacStick). Our results showed that ReacStick and step outcomes were significantly correlated in terms of successful inhibition (r = 0.57) and overall reaction accuracy (r = 0.76). This study presents a novel method for assessing rapid inhibition in a dynamic postural context, a capacity that appears to be a necessary prerequisite to a subsequent adaptive strategy. Moreover, this capacity is significantly related to ReacStick performance, suggesting a potential clinical translation.

Executive function is associated with balance and falls in older cancer survivors treated with chemotherapy: A cross-sectional study.

INTRODUCTION: Balance decrements and increased fall risk in older cancer survivors have been attributed to chemotherapy-induced peripheral neuropathy (CIPN). Cognition is also affected by chemotherapy and may be an additional contributing factor to poor balance through changes in executive functioning. We examined the association of executive function with balance and falls in older cancer survivors who had been treated with chemotherapy. MATERIALS AND METHODS: Fifty cancer survivors (aged 65.6 ± 11.5 years; 88% female) who were all treated with chemotherapy were included in this cross-sectional study at a tertiary medical center. Executive function was measured by Trails-B, Stroop, and rapid reaction accuracy, a measure emphasizing rapid inhibitory function. Balance was measured by five sit-to-stand time (5STS), repetitions of sit-to-stand in thirty seconds (STS30), and unipedal stance time (UST), which was the primary balance outcome measure. Self-reported falls in the past year were also recorded and was a secondary outcome. Bivariate analyses were conducted between executive function measures and balance variables. Multivariable models were constructed for UST and falls outcomes and included covariates of age and chemotherapy induced peripheral neuropathy status. RESULTS: Pearson correlations demonstrated significant relationships between two executive function measures (rapid reaction accuracy, Trails-B) and all the balance measures assessed (UST, STS30, and 5STS). Rapid reaction accuracy correlations were stronger than Trails-B. The Stroop measure correlated solely with UST. In multivariable models, rapid reaction accuracy was associated with better UST (standardized regression coefficient: 64.1, p < 0.01), decreased any fall (odds ratio = 0.000901, p = 0.04), and decreased recurrent falls (odds ratio = 0.0000044, p = 0.01). The interaction of CIPN with the inhibitory measures in the prediction of balance was not significant. DISCUSSION: Measures of executive function were associated with balance, but among the executive function tests, rapid reaction accuracy had the strongest correlations to balance and was independently associated with falls. The findings suggest that executive function should be considered when assessing fall risk and developing interventions intended to reduce fall risk in older chemotherapy-treated cancer survivors.

The relationship between clinical measures of cognitive function and grip strength in healthy older adults.

BACKGROUND: Handgrip strength is considered a surrogate for musculoskeletal strength, however there is emerging evidence of an association with cognition. The specific neurocognitive attribute which best associates with grip strength is unknown. METHODS: We performed a secondary analysis on baseline data in 49 healthy older adults. Grip strength was corrected for body mass index. Control independent variables included age, Montreal Cognitive Assessment, and Trails B. Experimental variables included a clinical measure of simple reaction time, and clinical and computerized go/no-go tasks. The clinical Go/No-Go measure was determined with ReacStick, a rod-shaped device which - when released by the examiner - requires the participant to decide within 390 ms whether to catch the device or let it fall to the ground. RESULTS: Bivariate analysis demonstrated that age and all cognitive measures other than the computer go/no-go response accuracy related to grip strength. Multivariate analyses showed that following inclusion of the control variables, only ReacStick measures (reaction accuracy/simple reaction time) significantly predicted grip strength, explaining an additional 15.90% variance (p = 0.026). In contrast, computerized Go/No-Go accuracy (p = 0.391), response time variability (p = 0.463), and the control variables (p value range = 0.566-0.942) did not predict grip strength. CONCLUSION: A short latency (< 390 ms) visuomotor Go/No-Go task independently predicted over 15% of grip strength variance, whereas a slower screen-based Go/No-Go task did not. These findings support the notion that declining grip strength likely reflects sub-clinical brain changes as well as musculoskeletal dysfunction, possibly explaining the potent relationships between grip strength, disability, chronic disease, and mortality.

Chemotherapy-induced peripheral neuropathy onset is associated with early risk of depression and anxiety in breast cancer survivors.

OBJECTIVE: The objective was to assess for an association between chemotherapy-induced peripheral neuropathy (CIPN) onset and development of depression and anxiety in breast cancer (BrCa) survivors. METHODS: A retrospective observational cohort was used and identified from Optum's De-identified Clinformatics® Data Mart Database years 2012-2015. Three groups of women were derived based on BrCa and CIPN status: BrCa+/CIPN+ (n = 244), BrCa+/CIPN- (n = 8870), and BrCa-/CIPN- (n = 1,125,711). The ratio of the prevalence ratios (RPR) determined if the change in risk of depression and anxiety from the 12-month preindex period to postindex period I (0-6 months) and II (7-12 months) was different for BrCa+/CIPN+ compared to BrCa+/CIPN- and BrCa-/CIPN-. RESULTS: The adjusted RPR for depression was significantly elevated for BrCa+/CIPN+ compared to BrCa+/CIPN- and BrCa-/CIPN- for postindex periods I (RPR = 1.35 [1.10,1.65] and 1.33 [1.08,1.63], respectively) and II (RPR = 1.53 [1.21,1.94] and 1.50 [1.17,1.93], respectively). The RPR for anxiety was significantly elevated for BrCa+/CIPN+ compared to BrCa+/CIPN- and BrCa-/CIPN- for postindex periods I (RPR = 1.37 [1.12,1.67] and 1.31 [1.06,1.61], respectively) and II (RPR = 1.41 [1.13,1.76] and 1.28 [1.02,1.62], respectively). CONCLUSIONS: Among BrCa survivors, CIPN onset is associated with a subsequent increased 12-month risk of depression and anxiety. Depression and anxiety screening should be considered in BrCa+/CIPN+ survivors, particularly given their known impact on fall risk. The observed association between CIPN and an increased risk of depression and anxiety should be further studied in prospective studies.

Rapid Inhibition Accuracy and Leg Strength Are Required for Community-Dwelling Older People to Recover Balance From Induced Trips and Slips: An Experimental Prospective Study.

BACKGROUND AND PURPOSE: Falls can result in bone fractures and disability, presenting a serious threat to quality of life and independence in older adults. The majority of falls in community-living older adults occur while walking and are often caused by trips and slips. The study aimed to identify the specific sensorimotor and psychological factors required for older adults to recover balance from trips and slips. METHODS: Forty-one older adults aged 65 to 87 years were assessed on sensorimotor (knee extension strength, proprioception, postural sway, and edge contrast sensitivity), reaction (simple reaction time, stepping, and catching reaction inhibition), and psychological (general anxiety and concern about falling) measures. Using a harness system, participants walked at 90% of their usual pace on a 10-m walkway that could induce trips and slips in concealed and changeable locations. Post-perturbation responses resulting in more than 30% of body weight being recorded by the harness system were defined as falls. Poisson regressions were used to test associations between the sensorimotor, reaction, and psychological measures and number of falls. RESULTS: Fifty-one falls occurred in 25 of 41 participants. Poisson regression revealed body mass index, lower-limb proprioception, knee extension strength, rapid inhibition accuracy, concern about falling, and anxiety were significantly associated with the rate of falls. Other measures including postural sway were not statistically significant. Using stepwise Poisson regression analyses, normalized knee extension strength (rate ratio [RR]: 0.68, 95% confidence interval [CI]: 0.47-0.98), and rapid inhibition accuracy (RR: 0.64, 95% CI: 0.46-0.87) were independently associated with falls. CONCLUSION: Our findings suggest rapid inhibition accuracy and adequate leg strength are required for older adults to recover balance from trips and slips. The mechanisms for balance recovery during daily life activities are likely different from those for static balance, suggesting the need for task-specific assessments and interventions for fall prevention in older adults.

Chemotherapy-induced peripheral neuropathy increases nontraumatic fracture risk in breast cancer survivors.

Chemotherapy is a common treatment for breast cancer (BrCa) and can cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN contributes to falls, and is thus a potential risk factor for nontraumatic fractures (NTFx); yet, the effect of CIPN on NTFx risk has not been examined for BrCa survivors. We therefore investigated the association between CIPN and NTFx in BrCa survivors. Data were extracted from Optum's Deidentified Clinformatics® Data Mart Database years 2010-2015 in this retrospective cohort study. Among women, three groups were derived based on BrCa and CIPN status: BrCa+/CIPN+ (primary group of interest), BrCa+/CIPN- (first comparison group), and BrCa-/CIPN- (second comparison group). After propensity score matching the comparison groups to BrCa+/CIPN+ at a ratio of 1:11 (BrCa:control) for demographics, osteoporosis, glucocorticoid medication, comorbidities, and cancer-related variables for BrCa+/CIPN-, 1-year incidence rate (IR) of NTFx was determined for each group. The incident rate ratio (IRR) determined if the IR for NTFx was different for BrCa+/CIPN+ compared to BrCa+/CIPN- and BrCa-/CIPN-. Cox proportional hazards regression models estimated the hazard ratios (HRs) after adjusting for covariates that were unable to be matched for. The crude IR (95% confidence interval [CI]) of NTFx was 4.54 (2.32-6.77) for BrCa+/CIPN+ (n = 359), 2.53 (2.03-3.04) for BrCa+/CIPN- (n = 3949), and 1.76 (1.35-2.18) for BrCa-/CIPN- (n = 3949). The crude IRR of NTFx was significantly elevated for BrCa+/CIPN+ as compared to BrCa+/CIPN- (IRR = 1.80; 95% CI, 1.06-3.05) and BrCa-/CIPN- (IRR = 2.58; 95% CI, 1.50-4.44). The elevated rate of NTFx for BrCa+/CIPN+ remained unchanged after adjusting for aromatase inhibitors compared to BrCa+/CIPN- (HR = 1.79; 95% CI, 1.06-3.04). Female BrCa survivors have an increased 1-year IR of NTFx after the onset of CIPN, suggesting that CIPN is an additive burden on NTFx risk among BrCa survivors. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Characterization and clinical implications of ankle impedance during walking in chronic stroke.

Individuals post-stroke experience persisting gait deficits due to altered joint mechanics, known clinically as spasticity, hypertonia, and paresis. In engineering, these concepts are described as stiffness and damping, or collectively as joint mechanical impedance, when considered with limb inertia. Typical clinical assessments of these properties are obtained while the patient is at rest using qualitative measures, and the link between the assessments and functional outcomes and mobility is unclear. In this study we quantify ankle mechanical impedance dynamically during walking in individuals post-stroke and in age-speed matched control subjects, and examine the relationships between mechanical impedance and clinical measures of mobility and impairment. Perturbations were applied to the ankle joint during the stance phase of walking, and least-squares system identification techniques were used to estimate mechanical impedance. Stiffness of the paretic ankle was decreased during mid-stance when compared to the non-paretic side; a change independent of muscle activity. Inter-limb differences in ankle joint damping, but not joint stiffness or passive clinical assessments, strongly predicted walking speed and distance. This work provides the first insights into how stroke alters joint mechanical impedance during walking, as well as how these changes relate to existing outcome measures. Our results inform clinical care, suggesting a focus on correcting stance phase mechanics could potentially improve mobility of chronic stroke survivors.

Short-latency inhibition mitigates the relationship between conscious movement processing and overly cautious gait.

BACKGROUND: Overly cautious gait is common in older adults. This is characterised by excessively slow gait, shortened steps, broadened base of support and increased double limb support. The current study sought to (1) evaluate if overly cautious gait is associated with attempts to consciously process walking movements, and (2) explore whether an individual's ability to rapidly inhibit a dominant motor response serves to mitigate this relationship. METHODS: A total of 50 older adults walked at a self-selected pace on an instrumented walkway containing two raised wooden obstacles (height = 23 cm). Trait conscious movement processing was measured with the Movement-Specific Reinvestment Scale. Short-latency inhibitory function was assessed using a validated electronic go/no-go ruler catch protocol. We used linear regressions to explore the relationship between these variables and gait parameters indicative of overly cautious gait. RESULTS: When controlling for general cognitive function (MoCA), and functional balance (Berg Balance Scale), the interaction between trait conscious movement processing and short-latency inhibition capacity significantly predicted gait velocity, step length and double limb support. Specifically, older adults with higher trait conscious movement processing and poorer inhibition were more likely to exhibit gait characteristics indicative of cautious gait (i.e. reduced velocity, shorter step lengths and increased double limb support). Neither conscious movement processing nor inhibition independently predicted gait performance. CONCLUSION: The combination of excessive movement processing tendencies and poor short-latency inhibitory capacity was associated with dysfunctional or 'overly cautious' gait. It is therefore plausible that improvement in either factor may lead to improved gait and reduced fall risk.

Primary cancer location predicts predominant level of brachial plexopathy.

BACKGROUND: Changes in radiation therapy practice and cancer incidence bring into question prior evidence suggesting that radiation therapy predominantly injures the brachial plexus upper trunk, while tumor invasion typically injures the lower trunk. METHODS: We reviewed electrodiagnostic brachial plexopathy reports in cancer survivors for predominant trunk involvement, injury mechanism (tumor invasion vs radiation), and primary cancer location. RESULTS: Fifty-six cases of cancer-associated brachial plexopathy were identified. There was no relationship between injury mechanism and brachial plexus injury level. However, primary cancer location superior/inferior to the clavicle increased the odds of predominantly upper/lower trunk involvement by a factor of 60.0 (95% confidence interval: 7.9, 1401, respectively). CONCLUSIONS: Cancers superior/inferior to the clavicle increase the likelihood of predominantly upper/lower trunk plexopathy, respectively, regardless plexus injury mechanism. These findings contrast with older work, possibly due to more precise radiation therapy techniques and increased incidence of radiosensitive head and neck cancers.

A clinical method of evaluating simple reaction time and reaction accuracy is sensitive to a single dose of lorazepam.

RATIONALE: Benzodiazepines are useful and commonly prescribed. Unfortunately, they are associated with subtle but functionally significant neurocognitive side effects that increase the risk of motor vehicle accidents and falls. OBJECTIVE: The objective of this study was to determine whether clinically feasible measures of simple reaction time and reaction accuracy are sensitive to a single dose of lorazepam. METHODS: Using a randomized, double-blind, crossover design, 26 healthy adults (13 women; age = 26.9 ± 8.2 yr) were given 1.0 mg lorazepam or placebo 90 minutes prior to two data collection sessions. Participants completed simple and reaction accuracy tasks using a standardized "ruler drop" testing paradigm during each session. Outcomes were mean and variability of simple reaction time and reaction accuracy, which evaluates a participant's ability to catch the device solely on the random 50% of trials that lights affixed to it illuminate on release. Reaction accuracy requires a go/no-go decision within 420 ms before the falling device strikes the floor. RESULTS: As compared with placebo, lorazepam increased simple reaction time variability (range = 43 ± 18 vs. 60 ± 23 ms, respectively; p = 0.004 and standard deviation = 14.6 ± 5.7 vs. 19.7 ± 7.3 ms, respectively; = 0.006) and decreased reaction accuracy (90 ± 7% vs. 84 ± 11%, respectively; p = 0.010). CONCLUSION: Given prior work demonstrating associations between simple reaction time and reaction accuracy and functional outcomes such as self-protection, response to perturbations, and fall risk, these clinically available measures may have a role in identifying subtle, functionally significant cognitive changes related to short-term benzodiazepine use.

Neurocognitive and Muscular Capacities Are Associated with Frailty in Adults with Cirrhosis.

BACKGROUND: Frailty is common in cirrhosis and associated with mortality, hospitalization, and reduced quality of life. Interventions aimed at forestalling frailty are limited by a lack of understanding of underlying physiologic deficits. AIMS: This study's aim was to examine contributions of discrete sensorimotor and neurocognitive capacities to conventional frailty measures of unipedal stance time, chair stands, and grip strength. METHODS: This cross-sectional study enrolled 119 outpatients with cirrhosis (50% female, aged 62.9 ± 7.3 years). Capacities included sensory (lower limb sensation and visual contrast), neurocognitive (Number Connection Tests A and B, simple and recognition reaction time), and muscular (hip/core strength determined by lateral plank time (LPT)). Bivariate analyses and linear regression models were performed to identify significant contributors to each frailty measure. RESULTS: The average performance was 9.8 ± 3.9 chair stands, 12.7 s ±9.9 unipedal stance time, and 60.3 ± 25.6 lb grip strength. In multivariate models, factors explained 40% of variance in unipedal stance and 43% of variance in chair stands. The LPT was most strongly associated with unipedal stance and chair stands. Grip strength was associated with LPT, but did not have physiologic predictors. CONCLUSIONS: Clinically useful measures of frailty in adults with cirrhosis can be explained by disease severity but also deficits in strength and neurocognitive function. Recognition reaction time, a novel measure in cirrhosis, had a significant contribution to frailty. These findings have implications for frailty assessment and suggest that the optimal rehabilitation approach to frailty targets neurocognitive function in addition to strengthening.

Electrophysiological Changes After Human Muscle Tear: A Potential Confounder.

The goal of this prospective electrophysiologic study is to describe the chronological electromyographic findings observed in a human gastrocnemius muscle after a traumatic tear. A 30-yr-old man sustained a tear of the medial gastrocnemius. Needle electromyography was performed serially at 5, 15, and 26 wks after injury, with the contralateral gastrocnemius muscle serving as a control. Audiovisual recordings of the studies were analyzed in a blinded manner. Five weeks after injury, the affected gastrocnemius displayed increased insertional activity on electromyography. By 15-wk postinjury, insertional activity had diminished. However, motor unit action potentials showed chronic neurogenic morphological changes not previously observed. These changes persisted 26 wks after injury. The study findings reveal a chronological trajectory of increased insertional activity followed by reinnervation changes in a human muscle after local trauma, paralleling a course previously observed in a rat model. Electrodiagnosticians unaware of this phenomenon are at risk for making erroneous interpretations when examining patients with a history of muscle trauma.

Motor amplitudes may predict electromyography-confirmed radiculopathy in patients referred for radiating limb pain.

INTRODUCTION: Radiculopathy is diagnosed by needle electromyography, with nerve conduction studies excluding alternative diagnoses. METHODS: In patients referred for electrodiagnostic evaluation of radiating limb pain, we compared ulnar motor amplitudes between those with and without electromyographically confirmed C8 radiculopathy, as well as fibular motor amplitudes between those with and without electromyographically confirmed L5 radiculopathy. RESULTS: Patients with electromyographically confirmed C8 or L5 radiculopathy demonstrated decreased ulnar or fibular motor amplitudes, respectively, as compared to patients without radiculopathy. Receiver operating characteristic curves demonstrated good diagnostic accuracy, with areas under the curve of 0.85 and 0.82, respectively. Optimal cut-offs for electromyographically confirmed C8 and L5 radiculopathies were 10.2 mV and 3.6 mV, respectively, with associated sensitivities/specificities of 0.86/0.74 and 0.92/0.60. DISCUSSION: Ulnar and fibular motor amplitudes may have clinical utility in assessing the likelihood of patients demonstrating electromyographically confirmed C8 and L5 radiculopathies with active denervation. The findings may be particularly useful in patients intolerant of needle electromyography. Muscle Nerve 59:561-561, 2019.

Why Do Individuals with Cirrhosis Fall? A Mechanistic Model for Fall Assessment, Treatment, and Research.

Falls are prevalent for people with cirrhosis and commonly lead to loss of independence, reduced quality of life, and mortality. Despite a critical need for fall prevention in this population, cirrhosis-specific fall-related mechanisms are not well understood. We posit that most falls in this patient population are due to a coalescence of discrete subclinical impairments that are not typically detected at the point of care. The combined effect of these subtle age- and disease-related neurocognitive and muscular impairments leads to the inability to respond successfully to a postural perturbation within the available 300 to 400 ms. This article provides a conceptual model of physiological resilience to avoid a fall that focuses on attributes that underlie the ability to withstand a postural perturbation and their clinical evaluation. Evidence supporting this model in cirrhosis and other high fall risk conditions will be synthesized and suggestions for fall assessment and treatment will be discussed.