Faculty Bibliography

Cerebrovascular disease (stroke) is one of the ten leading causes of death in children and adolescents. Multiple etiologies, from arteriopathies to prothrombic states, can cause stroke in youth. In adult stroke, hypertension has been shown to be the single most important modifiable risk factor. Although hypertension has not been strongly identified as a risk factor in childhood stroke to date, there is preliminary evidence that suggests that hypertension may also be associated with stroke in children. In this review, we summarize the literature that may link hypertension to stroke in the young. We have identified a series of barriers and limitations in the fields of pediatric hypertension and pediatric neurology that might explain why hypertension has been overlooked in childhood stroke. We suggest that hypertension may be a relevant risk factor that, alone or in combination with other multiple factors, contributes to the development of stroke in children. Currently, there are no consensus guidelines for the management of post-stroke hypertension in children. Thus, we recommend that blood pressure be assessed carefully in every child presenting with acute stroke in order to better understand the effects of hypertension in the development and the outcome of childhood stroke. We suggest a treatment algorithm to help practitioners manage hypertension after a stroke.

Purpose: African American (AA) patients are at risk for increased rates of rejection after heart transplantation (HT).We compared cell-free DNA (cf-DNA) levels after HT by recipient race.
Method(s): This was a retrospective analysis of 96 HT recipients from the Genomic Research Alliance for Transplantation (GRAFT) Registry, of which 63 patients had cf-DNA values. Cf-DNA values were compared by race withan exponential decay model and Kaplan-Meier (KM) analysis was performed to compare time-to-first rejection.
Result(s): Compared to non-AA patients, AA recipients had a similar prevalence of diabetes and hypertension,proportion of males, and donor characteristics. AA recipients had higher cf-DNA values compared to non-AA recipients for the first five days following transplant (8.3% vs. 3.2% p=0.001 Table 1/figure 1). The stable state cf-DNA values decayed rapidly for AA patients and equalized to non-AA patients over the first 7 days (0.46% vs 0.45%, p=0.8 Table 1). Cellular rejection did not differ by race (HR [CI]=1.4 [0.62,3.2], p=0.4). However AA were at higher risk of antibody mediated rejection (HR [CI]=3.8 [1.3,10.9], p=0.01).
Conclusion(s): African American patients had increased cf-DNA values in the first week following heart transplant. This may be a marker of early injury contributing to increased rates of allograft rejection in AA patients. Further analysisadjusting for confounding variables and determining predictors of clinical outcomes will be included at the time of presentation once follow-up of the GRAFT registry is complete.
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This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H₂O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (C_max > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H₂O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

Large hemispheric infarcts occur in up to 10% of all ischemic strokes and can cause devastating disability. Significant research and clinical efforts have been made in hopes of mitigating the morbidity and mortality of this disease. Areas of interest include identifying predictors of malignant edema, optimizing medical and surgical techniques, selecting the patient population that would benefit most from decompressive hemicraniectomy, and studying the impact on quality of life of those who survive. Decompressive surgery can be a life-saving measure, and here we discuss the most up-to-date literature and provide a review on the surgical management of large hemispheric ischemic strokes.

OBJECTIVE:Patients with traumatic brain injury who fail to obey commands after sedation-washout pose one of the most significant challenges for neurological prognostication. Reducing prognostic uncertainty will lead to more appropriate care decisions and ensure provision of limited rehabilitation resources to those most likely to benefit. Bedside markers of covert residual cognition, including speech comprehension, may reduce this uncertainty. METHODS:We recruited 28 patients with acute traumatic brain injury who were 2 to 7 days sedation-free and failed to obey commands. Patients heard streams of isochronous monosyllabic words that built meaningful phrases and sentences while their brain activity via electroencephalography (EEG) was recorded. In healthy individuals, EEG activity only synchronizes with the rhythm of phrases and sentences when listeners consciously comprehend the speech. This approach therefore provides a measure of residual speech comprehension in unresponsive patients. RESULTS:Seventeen and 16 patients were available for assessment with the Glasgow Outcome Scale Extended (GOSE) at 3 months and 6 months, respectively. Outcome significantly correlated with the strength of patients' acute cortical tracking of phrases and sentences (r > 0.6, p < 0.007), quantified by inter-trial phase coherence. Linear regressions revealed that the strength of this comprehension response (beta = 0.603, p = 0.006) significantly improved the accuracy of prognoses relative to clinical characteristics alone (eg, Glasgow Coma Scale [GCS], computed tomography [CT] grade). INTERPRETATION/CONCLUSIONS:A simple, passive, auditory EEG protocol improves prognostic accuracy in a critical period of clinical decision making. Unlike other approaches to probing covert cognition for prognostication, this approach is entirely passive and therefore less susceptible to cognitive deficits, increasing the number of patients who may benefit. ANN NEUROL 2021.

Fatal familial insomnia (FFI) is a rare inherited prion disease characterized by sleep, autonomic and motor disturbances. Neuro-ophthalmological abnormalities have been reported at the onset of disease, though not further characterized. We analyzed video recordings of eye movements of six FFI patients from three unrelated kindreds, seen within six months from the onset of illness. Excessive saccadic intrusions was the most prominent finding. In patients with severe insomnia, striking saccadic intrusions are an early diagnostic clue for FFI. The fact that the thalamus is the first structure affected in FFI also suggests its role in the control of steady fixation. This article is protected by copyright. All rights reserved.

Direct electrical stimulation can modulate the activity of brain networks for the treatment of several neurological and neuropsychiatric disorders and for restoring lost function. However, precise neuromodulation in an individual requires the accurate modelling and prediction of the effects of stimulation on the activity of their large-scale brain networks. Here, we report the development of dynamic input-output models that predict multiregional dynamics of brain networks in response to temporally varying patterns of ongoing microstimulation. In experiments with two awake rhesus macaques, we show that the activities of brain networks are modulated by changes in both stimulation amplitude and frequency, that they exhibit damping and oscillatory response dynamics, and that variabilities in prediction accuracy and in estimated response strength across brain regions can be explained by an at-rest functional connectivity measure computed without stimulation. Input-output models of brain dynamics may enable precise neuromodulation for the treatment of disease and facilitate the investigation of the functional organization of large-scale brain networks.

Proton (¹H) magnetic resonance spectroscopy provides a non-invasive and quantitative measure of brain metabolites. Traumatic brain injury impacts cerebral metabolism and a number of research groups have successfully used this technique as a biomarker of injury and/or outcome in both pediatric and adult TBI populations. However, this technique is underutilized, with studies being performed primarily at centers with access to MR research support. In this paper we present a technical introduction to the acquisition and analysis of in vivo ¹H magnetic resonance spectroscopy and review ¹H magnetic resonance spectroscopy findings in different injury populations. In addition, we propose a basic ¹H magnetic resonance spectroscopy data acquisition scheme (Supplemental Information) that can be added to any imaging protocol, regardless of clinical magnetic resonance platform. We outline a number of considerations for study design as a way of encouraging the use of ¹H magnetic resonance spectroscopy in the study of traumatic brain injury, as well as recommendations to improve data harmonization across groups already using this technique.