Proceedings of the First Pediatric Coma and Disorders of Consciousness Symposium by the Curing Coma Campaign, Pediatric Neurocritical Care Research Group, and NINDS: Gearing for Success in Coma Advancements for Children and Neonates

Abstract

This proceedings article presents the scope of pediatric coma and disorders of consciousness based on presentations and discussions at the First Pediatric Disorders of Consciousness Care and Research symposium held on September 14th, 2021. Herein we review the current state of pediatric coma care and research opportunities as well as shared experiences from seasoned researchers and clinicians. Salient current challenges and opportunities in pediatric and neonatal coma care and research were identified through the contributions of the presenters, who were Jose I. Suarez, MD, Nina F. Schor, MD, PhD, Beth S. Slomine, PhD Erika Molteni, PhD, and Jan-Marino Ramirez, PhD, and moderated by Varina L. Boerwinkle, MD, with overview by Mark Wainwright, MD, and subsequent audience discussion. The program, executively planned by Varina L. Boerwinkle, MD, Mark Wainwright, MD, and Michelle Elena Schober, MD, drove the identification and development of priorities for the pediatric neurocritical care community.

Keywords: Coma; Covert consciousness; Disorders of consciousness; Neonatal; Neurocritical care; Pediatric; Resting state fMRI; Withdrawal of care.

Fig. 1

Multidimensional assessment of consciousness with pediatric consideration. Patients in coma are evaluated for overt cognition and motor function using the Coma Recovery Scale—Pediatrics (CRS-P), among other available measures, which classifies the patient’s DoC. In those who emerge from a minimally conscious state with language (MCS+) to a confusional state, the Confusion Assessment Protocol differentiates between a confusional state, cognitive dysfunction, and full recovery in adults and older children. When there is no behavioral evidence of language function (MCS-), task-functional MRI (fMRI) or EEG evidence of command-following indicates cognitive motor dissociation, fMRI or EEG responses within an association cortex during passive stimuli indicate covert cortical processing, and an absence of fMRI or EEG responses indicates a true negative fMRI/EEG classification. In pediatrics, the feasibility hurdles of task-fMRI/EEG (requirement of current awake state, developmental level of adequate cognition for test instruction comprehension, trained bedside technician, and extra equipment) may be overcome by resting state fMRI-based identification of DoC, possibly covert cognition, treatable pathological networks, and stratification of both recovery and epilepsy potential [–25]. Patients with behavioral evidence of language or higher cognition are classified as false negatives if there are no fMRI or EEG responses, and as true positives if there are fMRI and EEG responses. CLIS, complete locked-in syndrome; LIS, locked-in syndrome; MCS–, minimally conscious state without language; VS/UWS, vegetative state/unresponsive wakefulness syndrome. *Patients with LIS are identified by the presence of consistent purposeful movements, typically vertical eye movements, and a reliable movement-based communication system. Patients with LIS who demonstrate inconsistent movements would not be distinguishable by behavioral measures from patients with CLIS, cognitive dysfunction, confusional state or MCS. Some patients with LIS are able to communicate via assistive communication devices. Adapted with permission from Edlow et al. [6]

Fig. 2

Organizational structure of the Curing Coma Campaign. Reprinted with permission [73]

Fig. 3

Distribution of active grants (July 2021) awarded by NINDS by topical area [81], Results of a search using the keyword “Consciousness” (n = 886)

Fig. 4

Results of a search using the intersection of the keywords “Consciousness” and “Children” (n = 100)

Fig. 5

Functional Object Use (FOU) and Functional Communication (FC) on the Coma Recovery Scale – Pediatrics (CRS-P) in a Typically Developing Sample of Young Children. A Percent of sample meeting criteria for FOU and FC by age on CRP-S. Twenty-nine (88%) of the 33 participants displayed at least one of the two behaviors that signal emergence into a conscious state using either the original or modified CRS-P criteria. All 29 exhibited FOU, while 13 (45%) also showed FC. There were no cases in which FC occurred in the absence of FOU. Two of the participants who demonstrated FC were < 3 years of age (29 and 32 months). The remainder of the sample were at least 3 years old. B Percent meeting criteria for FOU by age on the original Coma Recovery Scale- Revised and CRS-P. FOU, defined by CRS-R as movements generally compatible with a specific function of object, was observed in all children over 12 months of age. A total of four (13%) of the 29 children who did not exhibit FOU based on the original CRS-R scoring instructions met the modified criteria for FOU. C Percent meeting criteria for FC by age on the original Coma Recovery Scale- Revised and CRS-P. Thirteen children, all at least 29 months of age, demonstrated functional communication (defined in the CRS-R as clearly discernible and accurate verbal or gestural “yes” or “no” responses to six consecutive visual or aurally based situational orientation questions or by the modified CRS-P criteria, which require clearly discernible and accurate verbal or gestural “yes” or “no” responses to six consecutive questions about images in a picture book). Among these 13 children, two participants (ages 32 and 37 months) who did not display FC utilizing the original CRS-R met criteria using the picture book question set.

Fig. 6

Example of typological analysis with four classes clustering based on the Functional Independence Measurement (FIM) scale. The method separated between four endotypes: high-start fast (red), low-start fast (green), slow (orange) and nonresponders (blue). “adm” and “disch” indicate first admission and discharge, respectively, followed by yearly assessments (Color figure online). Adapted from Molteni et al. [112], with permission from the authors. Of note, “nonresponder” status is conditional to the assessment tool used

Fig. 7

Intermittent hypoxia multiple effects on network interactions controlling cardiorespiratory coupling. Among these networks is an intrinsically active network that is critical for the generation of the respiratory rhythm: the Pre-Bötzinger complex (panel A, C) [135]. This microcircuit is located within the ventrolateral medulla, in close vicinity to the Nucleus Ambiguus which includes the cardiovagal neurons that inhibit the heart (panel C) [139]. Exposure to intermittent hypoxia affects not only the central nervous system but leads also to the activation of the carotid body, a chemosensory organ that is critical for cardiorespiratory coupling. Activation of the carotid body by intermittent hypoxia leads to a system-wide upregulation of Hypoxia-Inducible Factor 1-alpha, a prooxidant gene regulator that activates a cascade of prooxidant genes [133, 134]. Neurons in the Central Nervous System are also affected by intermittent hypoxia produce hydrogen peroxide and reactive oxygen species (ROS). The effect of chronic intermittent hypoxia on that tissue is reflected in an increased lipid peroxidation. Chronic intermittent hypoxia also affects the pre-Bötzinger complex, as neurons in the respiratory network lose excitability resulting in desynchronization and disturbances in rhythmogenesis [140, 141]. The preBötzinger complex neurons activate the hypoglossal nucleus (panel A) and due to such synchronization failure in the rhythmogenic networks, hypoglossus-mediated apnea occurs, causing an obstruction and pharyngeal collapse (panel C). The pre-Bötzinger complex inhibits the cardiovagal neurons located in the Nucleus ambiguous (panel A). Thus, disturbances in the interactions between the Pre-Bötzinger complex and the cardiovagal neurons lead to a decrease in heart-rate variability. Interestingly, these desynchronizations are driven not by the hypoxia, but by the reactive oxygen species. By applying reactive oxygen species scavengers, the rhythmic activity can be restored, including activation of the hypoglossus [137]