Behavioral Assessment With the Coma Recovery Scale-Revised Is Safe and Feasible in Critically Ill Patients With Disorders of Consciousness.

OBJECTIVES: Accurate classification of disorders of consciousness (DoC) is key in developing rehabilitation plans after brain injury. The Coma Recovery Scale-Revised (CRS-R) is a sensitive measure of consciousness validated in the rehabilitation phase of care. We tested the feasibility, safety, and impact of CRS-R-guided rehabilitation in the ICU for patients with DoC after acute hemorrhagic stroke. DESIGN: Retrospective cohort study. SETTING: This single-center study was conducted in the neurocritical care unit at the University of Maryland Medical Center. PATIENTS: We analyzed records from consecutive patients with subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH), who underwent serial CRS-R assessments during ICU admission from April 1, 2018, to December 31, 2021, where CRS-R less than 8 is vegetative state/unresponsive wakefulness syndrome (VS/UWS); CRS-R greater than or equal to 8 is a minimally conscious state (MCS). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcomes included adverse events during CRS-R evaluations and associations between CRS-R and discharge disposition, therapy-based function, and mobility. We examined the utility of CRS-R compared with other therapist clinical assessment tools in predicting discharge disposition. Seventy-six patients (22 SAH, 54 ICH, median age = 59, 50% female) underwent 276 CRS-R sessions without adverse events. Discharge to acute rehabilitation occurred in 4.4% versus 41.9% of patients with a final CRS-R less than 8 and CRS-R greater than or equal to 8, respectively (odds ratio [OR] 13.4; 95% CI, 2.7-66.1; p < 0.001). Patients with MCS on final CRS-R completed more therapy sessions during hospitalization and had improved mobility and functional performance. Compared with other therapy assessment tools, the CRS-R had the best performance in predicting discharge disposition (area under the curve: 0.83; 95% CI, 0.72-0.94; p < 0.0001). CONCLUSIONS: Early neurorehabilitation guided by CRS-R appears to be feasible and safe in the ICU following hemorrhagic stroke complicated by DoC and may enhance access to inpatient rehabilitation, with the potential for lasting benefit on recovery. Further research is needed to assess generalizability and understand the impact on long-term outcomes.

Dysphagia and Enteral Feeding After Stroke in the Rehabilitation Setting.

Physiatrists play a vital role in post-stroke dysphagia management not only by providing guidance on the risks, benefits, and efficacy of various treatment options but also as advocates for patients' independence and quality of life. While swallow study results are often discussed broadly by acute stroke clinicians as "pass/fail" findings, physiatrists need a more nuanced working knowledge of dysphagia diagnosis and treatment that encompasses swallow pathophysiology, targeted treatment strategies, and prognosis for recovery. To that end, this review summarizes current clinical practice guidelines on dysphagia, nutrition and oral care, risks and benefits of differing enteral access routes, prognostic factors, and approaches to rehabilitation.

Genome-Wide Association Studies of 3 Distinct Recovery Phenotypes in Mild Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Stroke genetic research has made substantial progress in the past decade. Its recovery application, however, remains behind, in part due to its reliance on the modified Rankin Scale (mRS) score as a measure of poststroke outcome. The mRS does not map well to biological processes because numerous psychosocial factors drive much of what the mRS captures. Second, the mRS contains multiple disparate biological events into a single measure further limiting its use for biological discovery. This led us to investigate the effect of distinct stroke recovery phenotypes on genetic variation associations with Genome-Wide Association Studies (GWASs) by repurposing the NIH Stroke Scale (NIHSS) and its subscores. METHODS: In the Vitamin Intervention for Stroke Prevention cohort, we estimated changes in cognition, motor, and global impairments over 2 years using specific measures. We included genotyped participants with a total NIHSS score greater than zero at randomization and excluded those with recurrent stroke during the trial. A GWAS linear mixed-effects model predicted score changes, with participant as a random effect, and included initial score, age, sex, treatment group, and the first 5 ancestry principal components. RESULTS: In total, 1,270 participants (64% male) were included with a median NIHSS score of 2 (interquartile range [IQR] 1-3) and median age 68 (IQR 59-75) years. At randomization, 20% had cognitive deficits (NIHSS Cog-4 score >0) and 70% had ≥1 motor deficits (impairment score >1). At 2 years, these percentages improved to 7.2% with cognitive deficits and 30% with motor deficits. GWAS identified novel suggestive gene-impairment associations (p < 5e-6) for cognition (CAMK2D, EVX2, LINC0143, PTPRM, SGMS1, and SMAD2), motor (ACBD6, KDM4B, MARK4, PTPRS, ROBO1, and ROBO2), and global (MSR1 and ROBO2) impairments. DISCUSSION: Defining domain-specific stroke recovery phenotypes and using longitudinal clinical trial designs can help detect novel genes associated with chronic recovery. These data support the use of granular endpoints to identify genetic associations related to stroke recovery.

Establishing a Clinical Care Pathway to Expedite Rehabilitation Transitions for Stroke Patients With Dysphagia and Enteral Feeding Needs.

OBJECTIVE: The aim of the study is to evaluate the safety and efficacy of a physiatrist-led clinical pathway to expedite rehabilitation transitions for stroke patients with dysphagia requiring nasogastric tube or percutaneous endoscopic gastrostomy. DESIGN: This is a retrospective single-center observational study in 426 adults with stroke and dysphagia admitted to the acute hospital. Physican Medicine and Rehabilitation (PM&R) was consulted to determine dysphagia prognosis and candidacy for rehabilitation admission with nasogastric tube or percutaneous endoscopic gastrostomy. The proportion of patients accepted with nasogastric tube versus percutaneous endoscopic gastrostomy, progression to total oral diet during rehabilitation, and lengths of stay were tracked. RESULTS: The rate of recovery to total oral diet for patients accepted with nasogastric tube was 38/44 = 86.3% versus 29/75 = 38.6% with percutaneous endoscopic gastrostomy. There was a significant difference in mean time to total oral diet with nasogastric tube (20.37 days) versus percutaneous endoscopic gastrostomy (34.46 days): t (43) = 4.49, P < 0.001. The acute hospital length of stay was significantly shorter with nasogastric tube (12.9 days) versus percutaneous endoscopic gastrostomy (20.4 days): t (117) = 4.16, P < 0.001. Rehabilitation length of stay did not differ significantly between groups (26.9 vs. 32.0 days). CONCLUSION: Physiatrist-led initiatives to evaluate stroke patients with dysphagia can expedite rehabilitation transitions, prevent unnecessary invasive procedures, and reduce acute hospital length of stay.

Single Nucleotide Polymorphisms Associated With Motor Recovery in Patients With Nondisabling Stroke: GWAS Study.

BACKGROUND AND OBJECTIVES: Despite notable advances in genetic understanding of stroke recovery, most studies focus only on candidate genes. To date, only 2 genome-wide association studies (GWAS) have focused on stroke outcomes, but they were limited to the modified Rankin Scale (mRS). The mRS maps poorly to biological processes. Therefore, we performed a GWAS to discover single nucleotide polymorphisms (SNPs) associated with motor recovery poststroke. METHODS: We used the Vitamin Intervention for Stroke Prevention (VISP) data set of 2,100 genotyped participants with nondisabling stroke. We included only participants who had motor impairment at randomization. Participants with a recurrent stroke during the trial were excluded. Genotyped data underwent strict quality control and imputation. The GWAS used logistic regression models with generalized estimating equations to leverage the repeated NIH Stroke Scale motor score measurements spanning 6 time points over 24 months. The primary outcome was a decrease in the motor drift score of ≥1 vs <1 at each time point. Our model estimated the odds ratio (OR) of motor improvement for each SNP after adjusting for age, sex, race, days from stroke to visit, initial motor score, VISP treatment arm, and principal components. RESULTS: A total of 488 (64%) participants with a mean (SD) age of 66 ± 11 years were included in the GWAS. Although no associations reached genome-wide significance (p < 5 × 10-8), our analysis detected 115 suggestive associations (p < 5 × 10-6). Notably, we found multiple SNP clusters near genes with plausible neuronal repair biology mechanisms. The CLDN23 gene had the most convincing association with rs1268196-T as its most significant SNP (OR 0.32; 95% CI 0.21-0.48; p value 6.19 × 10-7). CLDN23 affects blood-brain barrier integrity, neurodevelopment, and immune cell transmigration. DISCUSSION: We identified novel suggestive genetic associations with the first-ever motor-specific poststroke recovery GWAS. The results seem to describe a distinct stroke recovery phenotype compared with prior genetic stroke outcome studies that use outcome measures, such as the mRS. Replication and further mechanistic investigation are warranted. In addition, this study demonstrated a proof-of-principle approach to optimize statistical efficiency with longitudinal data sets for genetic discovery.

Stroke recovery phenotyping through network trajectory approaches and graph neural networks.

Stroke is a leading cause of neurological injury characterized by impairments in multiple neurological domains including cognition, language, sensory and motor functions. Clinical recovery in these domains is tracked using a wide range of measures that may be continuous, ordinal, interval or categorical in nature, which can present challenges for multivariate regression approaches. This has hindered stroke researchers' ability to achieve an integrated picture of the complex time-evolving interactions among symptoms. Here, we use tools from network science and machine learning that are particularly well-suited to extracting underlying patterns in such data, and may assist in prediction of recovery patterns. To demonstrate the utility of this approach, we analyzed data from the NINDS tPA trial using the Trajectory Profile Clustering (TPC) method to identify distinct stroke recovery patterns for 11 different neurological domains at 5 discrete time points. Our analysis identified 3 distinct stroke trajectory profiles that align with clinically relevant stroke syndromes, characterized both by distinct clusters of symptoms, as well as differing degrees of symptom severity. We then validated our approach using graph neural networks to determine how well our model performed predictively for stratifying patients into these trajectory profiles at early vs. later time points post-stroke. We demonstrate that trajectory profile clustering is an effective method for identifying clinically relevant recovery subtypes in multidimensional longitudinal datasets, and for early prediction of symptom progression subtypes in individual patients. This paper is the first work introducing network trajectory approaches for stroke recovery phenotyping, and is aimed at enhancing the translation of such novel computational approaches for practical clinical application.

International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery.

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.

Accurate Prediction of Persistent Upper Extremity Impairment in Patients With Ischemic Stroke.

OBJECTIVE: To develop a simple and effective risk score for predicting which stroke patients will have persistent impairment of upper extremity motor function at 90 days. DESIGN: Post hoc analysis of clinical trial patients hospitalized with acute ischemic stroke who were followed for 90 days to determine functional outcome. SETTING: Patient were hospitalized at facilities across the United States. PARTICIPANTS: We created a harmonized cohort of individual patients (N=1653) from the NINDS tPA, ALIAS part 2, IMS-III, DEFUSE 3, and FAST-MAG trials. We split the cohort into balanced derivation and validation samples. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome was persistent arm impairment, defined as a National Institutes of Health Stroke Scale (NIHSS) arm domain score of 2 to 4 at 90 days in patients who had a 24-hour NIHSS arm score of 1 or more. We used least absolute shrinkage and selection operator regression to determine the elements of the persistent upper extremity impairment (PUPPI) index, which we validated as a predictive tool. RESULTS: We included 1653 patients (827 derivation, 826 validation), of whom 803 (48.6%) had persistent arm impairment. The PUPPI index gives 1 point each for age 55 years or older and NIHSS values of worse arm (4), worse leg (>2), facial palsy (3), and total NIHSS (≥10). The optimal cutpoint for the PUPPI index was 3 or greater, at which the area under the curve was greater than 0.75 for the derivation and validation cohorts and when using NIHSS values from either 24 hours or in a subacute or discharge time window. Results were similar across different levels of stroke severity. CONCLUSION: The PUPPI index uses readily available information to accurately predict persistent upper extremity motor impairment at 90 days poststroke. The PUPPI index can be administered in minutes and could be used as inclusion criterion in recovery-related clinical trials or, with additional development, as a prognostic tool for patients, caregivers, and clinicians.

Intensive In-Bed Sensorimotor Rehabilitation of Early Subacute Stroke Survivors With Severe Hemiplegia Using a Wearable Robot.

Rehabilitation for stroke survivors with severe motor impairment remains challenging. Early motor rehabilitation is critical for improving mobility function post stroke, but it is often delayed due to limited resources in clinical practice. The objectives of this study were to investigate the feasibility and effectiveness of early in-bed sensorimotor rehabilitation on acute stroke survivors with severe hemiplegia using a wearable ankle robot. Eighteen patients (9 in the study group and 9 in the control group) with severe hemiplegia and no active ankle movement were enrolled in acute/subacute phase post stroke. During a typical 3-week hospital stay, patients in the study group received ankle robot-guided in-bed training (50 minutes/session, 5 sessions/week), including motor relearning under real-time visual feedback of re-emerging motor output, strong passive stretching under intelligent control, and game-based active movement training with robotic assistance. Whereas the control group received passive ankle movement in the mid-range of motion and attempted active ankle movement without robotic assistance. After multi-session training, the study group achieved significantly greater improvements in Fugl-Meyer Lower Extremity motor score (p = 0.007), plantarflexor strength (p = 0.009), and active range of motion (p = 0.011) than controls. The study group showed earlier motor recovery for plantarflexion and dorsiflexion than the control group (p < 0.05). This study showed that in-bed sensorimotor rehabilitation guided by a wearable ankle robot through combining motor relearning in real-time feedback, strong passive stretching, and active movement training facilitated early motor recovery for stroke survivors with severe hemiplegia in the acute/subacute phase.

Variability of the Modified Rankin Scale Score Between Day 90 and 1 Year After Ischemic Stroke.

OBJECTIVE: Studies indicate that the functional outcome evolves in the year after ischemic stroke onset. However, the traditional outcome measure in stroke trials is the modified Rankin Scale (mRS) at 90 days from onset. To determine mRS fluctuations in the first year after stroke, we examined data from 3 major stroke trials. METHODS: In a secondary analysis, we evaluated intrapatient mRS between 90 days and 1 year from stroke onset, the mRS shift (∆mRS = 1 year-day 90), and the trials' primary outcome at day 90 and 1 year. RESULTS: We included 624 patients from the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study, 587 from Albumin Treatment for Acute Ischaemic Stroke, and 611 from Interventional Management of Stroke III, for which the proportion of patients with a ∆mRS change between day 90 and 1 year was 36.5%, 41.7%, and 36.0%. However, the trials' primary outcomes did not differ at 1 year vs 90 days. Similar findings were seen in a second cohort where we pooled the trials and excluded patients with recurrent stroke or death during the follow-up. In those 1,314 patients, 544 (41.4%) had a ∆mRS change, of which 379 (28.9%) had improvement and 165 (12.5%) had worsening, apart from death. CONCLUSION: We describe the patient-level spectrum of mRS change from day 90 to 1 year after ischemic stroke in 3 high-quality randomized trials. The patient-level shifts consisted of a sufficiently counterbalanced number of mRS improvements and declines, which masked clinical evolution occurring in over one-third of patients. These results may have important implications, both for clinical trial design and outcome adjudication in stroke research and duration of rehabilitative therapy.

Domain-Specific Outcomes for Stroke Clinical Trials: What the Modified Rankin Isn't Ranking.

Global outcome measures that are widely used in stroke clinical trials, such as the modified Rankin Scale (mRS), lack sufficient detail to detect changes within specific domains (e.g., sensory, motor, visual, linguistic, or cognitive function). Yet such data are vital for understanding stroke recovery and its mechanisms. Poststroke deficits in specific domains differ in their rate and degree of recovery and in their effects on overall independence and quality of life. For example, even in a patient with complete recovery of strength, persistent deficits in the nonmotor domains such as language and cognition may make a return to independent living impossible. In such cases, global measures based solely on the patient's degree of independence would overlook a complete recovery in the motor domain. Capturing these important aspects of recovery demands a domain-specific approach. If stroke outcomes trials are to incorporate finer-grained recovery metrics-which can require substantial time, effort, and expertise to implement-efficiency must be a priority. In this article, we discuss how commonly collected clinical data from the NIH Stroke Scale can guide the judicious selection of relevant recovery domains for more detailed testing. Our overarching goal is to make the implementation of domain-specific testing more feasible for large-scale clinical trials on stroke recovery.

Motor Recovery: How Rehabilitation Techniques and Technologies Can Enhance Recovery and Neuroplasticity.

There are now a large number of technological and methodological approaches to the rehabilitation of motor function after stroke. It is important to employ these approaches in a manner that is tailored to specific patient impairments and desired functional outcomes, while avoiding the hype of overly broad or unsubstantiated claims for efficacy. Here we review the evidence for poststroke plasticity, including therapy-related plasticity and functional imaging data. Early demonstrations of remapping in somatomotor and somatosensory representations have been succeeded by findings of white matter plasticity and a focus on activity-dependent changes in neuronal properties and connections. The methods employed in neurorehabilitation have their roots in early understanding of neuronal circuitry and plasticity, and therapies involving large numbers of repetitions, such as robotic therapy and constraint-induced movement therapy (CIMT), change measurable nervous systems properties. Other methods that involve stimulation of brain and peripheral excitable structures have the potential to harness neuroplastic mechanisms, but remain experimental. Gaps in our understanding of the neural substrates targeted by neurorehabilitation technology and techniques remain, preventing their prescriptive application in individual patients as well as their general refinement. However, with ongoing research-facilitated in part by technologies that can capture quantitative information about motor performance-this gap is narrowing. These research approaches can improve efforts to attain the shared goal of better functional recovery after stroke.

Effects of the BDNF Val66Met polymorphism on functional status and disability in young stroke patients.

BACKGROUND AND PURPOSE: The preponderance of evidence from recent studies in human subjects supports a negative effect of the BDNF Val66Met polymorphism on motor outcomes and motor recovery. However prior studies have generally reported the effect of the Met allele in older stroke patients, while potential effects in younger stroke patients have remained essentially unexamined. The lack of research in younger patients is significant since aging effects on CNS repair and functional recovery after stroke are known to interact with the effects of genetic polymorphisms. Here we present a study of first-ever ischemic stroke patients aged 15-49 years that examines the effect of Met carrier status on functional disability. METHODS: 829 patients with a first ischemic stroke (Average age = 41.4 years, SD = 6.9) were recruited from the Baltimore-Washington region. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. Our sample contained 165 Met carriers and 664 non-Met carriers. Modified Rankin scores as recorded at discharge were obtained from the hospital records by study personnel blinded to genotype, and binarized into "Good" versus "Poor" outcomes (mRS 0-2 vs. 3+), with mRS scores 3+ reflecting a degree of disability that causes loss of independence. RESULTS: Our analysis showed that the Met allele conveyed a proportionally greater risk for poor outcomes and disability-related loss of independence with mRS scores 3+ (adjusted OR 1.73, 95% CI 1.13-2.64, p = 0.01). CONCLUSIONS: The BDNF Val66Met polymorphism was negatively associated with functional outcomes at discharge in our sample of 829 young stroke patients. This finding stands in contrast to what would be predicted under the tenets of the resource modulation hypothesis (i.e. that younger patients would be spared from the negative effect of the Met allele on recovery since it is posited to arise as a manifestation of age-related decline in physiologic resources).

Gene therapy for inherited muscle diseases: where genetics meets rehabilitation medicine.

The development of clinical vectors to correct genetic mutations that cause inherited myopathies and related disorders of skeletal muscle is advancing at an impressive rate. Adeno-associated virus vectors are attractive for clinical use because (1) adeno-associated viruses do not cause human disease and (2) these vectors are able to persist for years. New vectors are now becoming available as gene therapy delivery tools, and recent preclinical experiments have demonstrated the feasibility, safety, and efficacy of gene therapy with adeno-associated virus for long-term correction of muscle pathology and weakness in myotubularin-deficient canine and murine disease models. In this review, recent advances in the application of gene therapies to treat inherited muscle disorders are presented, including Duchenne muscular dystrophy and x-linked myotubular myopathy. Potential areas for therapeutic synergies between rehabilitation medicine and genetics are also discussed.

Kinematic analysis of motor recovery with human adult bone marrow-derived somatic cell therapy in a rat model of stroke.

BACKGROUND: The extent to which pharmaceutical and behavioral therapies following central nervous system injury may either deter or encourage the development of compensatory movement patterns is a topic of considerable interest in neurorehabilitation. However, functional outcome measures alone are relatively insensitive to compensatory changes in movement patterns per se. OBJECTIVE: This study used both functional outcome measures and kinematic analysis of forelimb movements to examine the effects of human adult bone marrow-derived somatic cells (hABM-SCs) on motor recovery in a rat model of stroke. METHODS: Adult male Long-Evans black-hooded rats (n = 12) were trained in a forelimb reaching task and then underwent surgical middle cerebral artery occlusion, producing a stroke that impaired the trained paw. One week poststroke, animals were randomly assigned to either a hABM-SC injection or control injection group. Reaching behaviors were then compared at baseline and at 10 weeks poststroke. RESULTS: Both groups improved their outcome scores during the 10-week recovery period. However, the hABM-SC group recovered significantly more function than controls in terms of the number of pellets retrieved. Furthermore, the control group appeared to improve their functional performance by using compensatory strategies that involved an increased number of trajectory adjustments, whereas the hABM-SC group's kinematics more closely resembled prestroke movement patterns. CONCLUSIONS: This study demonstrates that kinematic measures established in stroke research on humans are also sensitive to performance differences prestroke versus poststroke in the rat model, reinforcing the utility of this method to evaluate treatments that may ultimately translate to patient populations.