Faculty Bibliography

PURPOSE/OBJECTIVE:H MRS) offers biomarkers of metabolic damage after mild traumatic brain injury (mTBI), but a lack of replicability studies hampers clinical translation. In a conceptual replication study design, the results reported in four previous publications were used as the hypotheses (H1-H7), specifically: abnormalities in patients are diffuse (H1), confined to white matter (WM) (H2), comprise low N-acetyl-aspartate (NAA) levels and normal choline (Cho), creatine (Cr) and myo-inositol (mI) (H3), and correlate with clinical outcome (H4); additionally, a lack of findings in regional subcortical WM (H5) and deep gray matter (GM) structures (H6), except for higher mI in patients' putamen (H7). METHODS:26 mTBI patients (20 female, age 36.5 ± 12.5 [mean ± standard deviation] years), within two months from injury and 21 age-, sex-, and education-matched healthy controls were scanned at 3 Tesla with 3D echo-planar spectroscopic imaging. To test H1-H3, global analysis using linear regression was used to obtain metabolite levels of GM and WM in each brain lobe. For H4, patients were stratified into non-recovered and recovered subgroups using the Glasgow Outcome Scale Extended. To test H5-H7, regional analysis using spectral averaging estimated metabolite levels in four GM and six WM structures segmented from T1-weighted MRI. The Mann-Whitney U test and weighted least squares analysis of covariance were used to examine mean group differences in metabolite levels between all patients and all controls (H1-H3, H5-H7), and between recovered and non-recovered patients and their respectively matched controls (H4). Replicability was defined as the support or failure to support the null hypotheses in accordance with the content of H1-H7, and was further evaluated using percent differences, coefficients of variation, and effect size (Cohen's d). RESULTS:Patients' occipital lobe WM Cho and Cr levels were 6.0% and 4.6% higher than controls', respectively (Cho, d = 0.37, p = 0.04; Cr, d = 0.63, p = 0.03). The same findings, i.e., higher patients' occipital lobe WM Cho and Cr (both p = 0.01), but with larger percent differences (Cho, 8.6%; Cr, 6.3%) and effect sizes (Cho, d = 0.52; Cr, d = 0.88) were found in the comparison of non-recovered patients to their matched controls. For the lobar WM Cho and Cr comparisons without statistical significance (frontal, parietal, temporal), unidirectional effect sizes were observed (Cho, d = 0.07 - 0.37; Cr, d = 0.27 - 0.63). No differences were found in any metabolite in any lobe in the comparison between recovered patients and their matched controls. In the regional analyses, no differences in metabolite levels were found in any GM or WM region, but all WM regions (posterior, frontal, corona radiata, and the genu, body, and splenium of the corpus callosum) exhibited unidirectional effect sizes for Cho and Cr (Cho, d = 0.03 - 0.34; Cr, d = 0.16 - 0.51). CONCLUSIONS:H MRS biomarkers for mTBI may best be achieved by using high signal-to-noise-ratio single-voxels placed anywhere within WM. The biochemical signature of the injury, however, may differ and therefore absolute levels, rather than ratios may be preferred. Future replication efforts should further test the generalizability of these findings.

OBJECTIVE:To determine the incidence of cognitive dependence in adults who are physically independent at discharge from acute traumatic brain injury (TBI) rehabilitation. DESIGN/METHODS:Analysis of historical clinical and demographic data obtained from inpatient stay. SETTING/METHODS:Inpatient rehabilitation unit in a large, metropolitan university hospital. PARTICIPANTS/METHODS:Adult inpatients with moderate-to-severe TBI (N = 226) who were physically independent at discharge from acute rehabilitation. INTERVENTIONS/METHODS:Not applicable MAIN OUTCOME MEASURES: FIM Motor and Cognitive subscales, discharge destination, and care plan. RESULTS:Approximately 69% (n = 155) of the physically independent inpatients were cognitively dependent at discharge from acute rehabilitation, with the highest proportions of dependence found in the domains of problem solving and memory. Most (82.6%; n =128) of these physically independent, yet cognitively dependent, patients were discharged home. Of those discharged to home, 82% (n = 105) were discharged to the care of family members, and 11% (n = 15) were discharged home alone. Patients from racial-ethnic minority backgrounds were significantly more likely than White patients to be discharged while cognitively dependent. CONCLUSIONS:The majority of physically independent TBI patients were cognitively dependent at the time of discharge from acute inpatient rehabilitation. Further research is needed to understand the impact of cognitive dependence on caregiver stress and strain and the disproportionate burden on racial-ethnic minority patients and families. Given the potential functional and safety limitations imposed by cognitive deficits, healthcare policy and practice should facilitate delivery of cognitive rehabilitation services in acute TBI rehabilitation.

BACKGROUND:Early neurorehabilitation improves outcomes in patients with disorders of consciousness (DoC) after brain injury, but its applicability in COVID-19 is unknown. We describe our experience implementing an early neurorehabilitation protocol for patients with COVID-19-associated DoC in the intensive care unit (ICU) and evaluate factors associated with recovery. METHODS:During the initial COVID-19 surge in New York City between March 10 and May 20, 2020, faced with a disproportionately high number of ICU patients with prolonged unresponsiveness, we developed and implemented an early neurorehabilitation protocol, applying standard practices from brain injury rehabilitation care to the ICU setting. Twenty-one patients with delayed recovery of consciousness after severe COVID-19 participated in a pilot early neurorehabilitation program that included serial Coma Recovery Scale-Revised (CRS-R) assessments, multimodal treatment, and access to clinicians specializing in brain injury medicine. We retrospectively compared clinical features of patients who did and did not recover to the minimally conscious state (MCS) or better, defined as a CRS-R total score (TS) ≥ 8, before discharge. We additionally examined factors associated with best CRS-R TS, last CRS-R TS, hospital length of stay, and time on mechanical ventilation. RESULTS:Patients underwent CRS-R assessments a median of six (interquartile range [IQR] 3-10) times before discharge, beginning a median of 48 days (IQR 40-55) from admission. Twelve (57%) patients recovered to MCS after a median of 8 days (IQR 2-14) off continuous sedation; they had lower body mass index (p = 0.009), lower peak serum C-reactive protein levels (p = 0.023), higher minimum arterial partial pressure of oxygen (p = 0.028), and earlier fentanyl discontinuation (p = 0.018). CRS-R scores fluctuated over time, and the best CRS-R TS was significantly higher than the last CRS-R TS (median 8 [IQR 5-23] vs. 5 [IQR 3-18], p = 0.002). Earlier fentanyl (p = 0.001) and neuromuscular blockade (p = 0.015) discontinuation correlated with a higher last CRS-R TS. CONCLUSIONS:More than half of our cohort of patients with prolonged unresponsiveness following severe COVID-19 recovered to MCS or better before hospital discharge, achieving a clinical benchmark known to have relatively favorable long-term prognostic implications in DoC of other etiologies. Hypoxia, systemic inflammation, sedation, and neuromuscular blockade may impact diagnostic assessment and prognosis, and fluctuations in level of consciousness make serial assessments essential. Early neurorehabilitation of these patients in the ICU can be accomplished but is associated with unique challenges. Further research should evaluate factors associated with longer-term neurologic recovery and benefits of early rehabilitation in patients with severe COVID-19.

OBJECTIVES/OBJECTIVE:To assess whether MR fingerprinting (MRF)-based relaxation properties exhibit cross-sectional and prospective correlations with patient outcome and compare the results with those from DTI. METHODS:from MRF were compared in 12 gray and white matter regions with Mann-Whitney tests. Bivariate associations between MR measures and outcome were assessed using the Spearman correlation and logistic regression. RESULTS:, accounted for five of the six MR measures with the highest utility for identification of non-recovered patients at timepoint 2 (AUC > 0.80). CONCLUSION/CONCLUSIONS:, FA, and ADC for predicting 3-month outcome after mTBI. KEY POINTS/CONCLUSIONS:, and FA.

The pathological cascade of tissue damage in mild traumatic brain injury is set forth by a perturbation in ionic homeostasis. However, whether this class of injury can be detected in vivo and serve as a surrogate marker of clinical outcome is unknown. We employ sodium MRI to test the hypotheses that regional and global total sodium concentrations: (i) are higher in patients than in controls and (ii) correlate with clinical presentation and neuropsychological function. Given the novelty of sodium imaging in traumatic brain injury, effect sizes from (i), and correlation types and strength from (ii), were compared to those obtained using standard diffusion imaging metrics. Twenty-seven patients (20 female, age 35.9 ± 12.2 years) within 2 months after injury and 19 controls were scanned with proton and sodium MRI at 3 Tesla. Total sodium concentration, fractional anisotropy and apparent diffusion coefficient were obtained with voxel averaging across 12 grey and white matter regions. Linear regression was used to obtain global grey and white matter total sodium concentrations. Patient outcome was assessed with global functioning, symptom profiles and neuropsychological function assessments. In the regional analysis, there were no statistically significant differences between patients and controls in apparent diffusion coefficient, while differences in sodium concentration and fractional anisotropy were found only in single regions. However, for each of the 12 regions, sodium concentration effect sizes were uni-directional, due to lower mean sodium concentration in patients compared to controls. Consequently, linear regression analysis found statistically significant lower global grey and white matter sodium concentrations in patients compared to controls. The strongest correlation with outcome was between global grey matter sodium concentration and the composite z-score from the neuropsychological testing. In conclusion, both sodium concentration and diffusion showed poor utility in differentiating patients from controls, and weak correlations with clinical presentation, when using a region-based approach. In contrast, sodium linear regression, capitalizing on partial volume correction and high sensitivity to global changes, revealed high effect sizes and associations with patient outcome. This suggests that well-recognized sodium imbalances in traumatic brain injury are (i) detectable non-invasively; (ii) non-focal; (iii) occur even when the antecedent injury is clinically mild. Finally, in contrast to our principle hypothesis, patients' sodium concentrations were lower than controls, indicating that the biological effect of traumatic brain injury on the sodium homeostasis may differ from that in other neurological disorders. Note: This figure has been annotated.

BACKGROUND:While the cognitive sequelae of traumatic brain injury (TBI) are well known, emotional impairments after TBI are suboptimally characterized. Lack of awareness of emotional difficulties can make self-report unreliable. However, individuals with TBI demonstrate involuntary changes in heart rate variability which may enable objective quantification of emotional dysfunction. METHODS:Sixteen subjects with chronic TBI and 10 age-matched controls were tested on an emotional function battery during which they watched a series of film clips normed to elicit specific positively and negatively valenced emotions: amusement, sexual amusement, sadness, fear and disgust. Subjective responses to the emotional stimuli were also obtained. Additionally, surface electrodes measured cardiac and respiratory signals to compute heart rate variability (HRV), from which measures of parasympathetic activity, the respiratory frequency area (RFA) and sympathetic activity, the low frequency area (LFA), of the HRV frequency spectrum were derived. The Neurobehavioral Rating Scale-Revised (NRS-R) and the King-Devick (KD) test were administered to assess neurobehavioral dysfunction. RESULTS:The two groups showed no differences in subjective ratings of emotional intensity. Subjects with TBI showed significantly decreased sympathetic activity when viewing amusing stimuli and significantly increased sympathetic activity when viewing sad stimuli compared to controls. Most of the subjects did not show agitation, anxiety, depression, blunted affect, emotional withdrawal, decreased motivation or mental fatiguability on the NRS-R. However, 13/16 subjects with TBI demonstrated attention difficulty on the NRS-R which was positively correlated with the increased sympathetic activity during sad stimuli. Both attention difficulty and abnormal autonomic responses to sad stimuli were correlated with the timing on the KD test, which reflected difficulty with visual attention shifting. CONCLUSIONS:The HRV spectrum may be useful to identify subclinical emotional dysfunction in individuals with TBI. Attention difficulites, specifically impairment in visual attention shifting, may contribute to abnormal reactivity to sad stimuli that may be detected and potentially treated to improve emotional function.

Introduction/Rational A 66 year old female with history of Fuchs' dystrophy presented to an outpatient traumatic brain injury (TBI) office visit one year after sustaining a concussion during a fall. Her complaints at the visit included fatigue, decreased attention, decreased workplace productivity and feeling overwhelmed with basic activities of daily living (ADL). Method/Approach The patient complained of persistent fatigue, neurocognitive deficits and neurological fatigue, at which time she was trialed on twice daily dosing of amantadine and instructed to follow up in the outpatient setting in one month. Shortly after initiating amantadine, the patient developed acute left eye blindness. She saw her ophthalmologist who instructed her that amantadine has been shown to aggravate Fuchs' dystrophy, causing corneal edema. Amantadine was discontinued and steroid eye drops were prescribed with rapid improvement in her vision upon cessation of the medication. Results/Effects The patient reported an overall improvement in her cognitive functioning and fatigue while taking amantadine. However, while amantadine has demonstrated positive outcomes in persistent executive functioning deficits following TBI, several case reports have reported acute visual loss and exacerbation of ocular symptoms in the setting of Fuchs' dystrophy. Fuchs' Dystrophy, also known as Fuchs' corneal endothelial dystrophy (FCED) is an autosomal dominant, slowly progressing degenerative disease leading to corneal edema and vision loss, eventually requiring corneal transplant. The mechanism of action by which amantadine causes corneal edema is currently unknown. Conclusions/Limitations Persistent deficits in higher executive functioning and workplace performance are common following concussion. However, although improvements in these domains are noted following initiation of neurostimulants such as amantadine, this case outlines the importance of weighing the risks and benefits of symptomatic management in TBI