Keywords coma - disorders of consciousness - curing coma campaign - research - education
In 2018, the Neurocritical Care Research Network of the Neurocritical Care Society
identified gaps in knowledge about coma and disorders of consciousness (DoC) necessitating
prioritization for neurocritical care research prompting initiation of the Curing
Coma Campaign (CCC), the first global public health initiative to tackle the unifying
concept of coma as a treatable medical entity.[1 ] The CCC was officially launched in 2019 to address these knowledge gaps and improve
care standards for patients with DoC.[2 ] The National Institute of Neurological Disorders and Stroke (NINDS) collaborated
with the CCC to organize two virtual symposia in 2020 and 2021, involving various
stakeholders and experts in coma science. These symposia resulted in the formation
of multiple workgroups, each focused on specific domains related to research in coma
and DoC. The discussions and proceedings of these workgroups have been published,
providing valuable insights and action items to advance the CCC's mission.[3 ]
[4 ] Since its inception, the CCC platform now includes 1,685 members across 85 countries
worldwide, with 15% of members directly working on various specific task-based modules
and workgroups ([Fig. 1 ]). The CCC leadership designed an organizational structure and 10-year roadmap, both
of which are instrumental in aligning priorities among experts in the field ([Fig. 2 ]).[5 ] The CCC recognizes the dedication of its members and their collaboration, which
has facilitated harmonization of research efforts. This article serves as an update
on the CCC, focusing on the identification of key knowledge gaps and the campaign's
ongoing efforts in various areas pertaining to coma and DoC. These efforts are fundamental
components of the 10-year strategic roadmap of the CCC, with the goal of improving
the lives of patients with coma and DoC.
Fig. 1 A world map representing Curing Coma Campaign members. Curing Coma Campaign members
across 85 countries; darker shade represents higher number of participants compared
with lighter shade.
Fig. 2 Curing Coma Campaign: 10-year roadmap. An initial plan developed by Curing Coma Campaign
that established three main pillars to conduct future research. Source: Olson et al.[5 ]
Key Areas of Focus
Advanced neurological assessment tools can offer vital insights into the pathophysiology
of various stages of DoC which could help tailor treatment approaches. However, the
use of these advanced tools (e.g., quantitative electroencephalography (EEG)/connectivity
analysis, functional magnetic resonance imaging, single-photon emission computerized
tomography, positron emission tomography, invasive EEG, and cerebral microdialysis)
remains limited globally, often constrained to a small number of health care systems.
Currently, the diagnoses of persistent coma and DoC primarily rely on clinical assessments,
which do not provide insight into the underlying dynamic pathobiological mechanisms.
The absence of detailed understanding of the underlying pathology has led to a broad,
yet nontargeted, application of therapeutic strategies, notably the use of neurostimulants.
This generalized approach, not tailored to individual pathophysiology, results in
varied and unpredictable treatment outcomes.[6 ] An imprecise diagnosis and inaccurate prognostication can not only result in ineffective
therapeutic approaches but can also potentially lead to premature withdrawal of life-sustaining
interventions. Recognizing these challenges, the CCC members have delineated critical
areas of focus. This deliberate outlining of priorities is intended to guide and shape
the direction of ongoing and future research in the fields of coma and DoC. A summary
of research priorities is listed in [Table 1 ].[7 ]
Table 1
Summary of research priorities in coma and disorders of consciousness
• Understand neurochemical substrates and biology associated with consciousness
• Differentiate clinical subtypes of DoC
• Develop comprehensive brain map using neuroimaging, behavioral assessment tools,
electrophysiology, and computational models to identify structural-functional relationship
• Develop DoC specific common data elements
• Develop a comprehensive database to include imaging and text
• Build a network of organization to readily execute clinical trials
• Identify resources to institute novel statistical, analytical, and methodological
approach to clinical trials design
• Develop prognostic indicators for patients with DoC
• Design an observational coma registry including pediatric population
Abbreviation: DOC, Disorders of Consciousness.
Source: Mainali et al.[7 ]
Current and Emerging Behavioral Assessment Tools
Current and Emerging Behavioral Assessment Tools
Of the various behavioral assessment tools, three tools are most commonly used in
clinical settings, namely, Glasgow Coma Scale, Full Outline of UnResponsiveness Score,
and Coma Recovery Scale-Revised (CRS-R).[8 ] Despite the CRS-R being the most comprehensive behavioral assessment tool for coma
at the bedside, the use of advanced techniques such as stimulus-based functional MRI
(fMRI) and EEG have uncovered evidence of covert command following and higher-order
cortical responses ([Fig. 3 ]).[9 ] Furthermore, although the CRS-R is endorsed by multiple clinical guidelines and
is a part of the NINDS common data elements (CDE), its use is somewhat limited due
to the lengthy administration time. Addressing this, the Coma Recovery Scale Revised
For Accelerated Standardized Testing, an abbreviated version suitable for ICU settings,
was developed; it has shorter administration time (approximately 6 minutes), potentially
enabling its widespread use for early assessments following acute brain injuries.[10 ] Forthcoming initiatives of the CCC are actively incorporating this practical and
efficient tool to enhance its utilization at a global scale.
Fig. 3 Categorization of disorders of consciousness using behavioral and diagnostic tools.
Abbreviations: CMD, cognitive motor dissociation; fMRI, functional MRI; EEG, electroencephalography;
HMD, Higher-order cortex motor dissociation, MCS, Minimally conscious state; VS, vegetative
state. fMRI and EEG results for a healthy patient and patients with different diagnosis
of disorders of consciousness. Source: Edlow et al.[9 ]
Advancing Imaging Modalities and Electrophysiology in Practice
Advancing Imaging Modalities and Electrophysiology in Practice
Incorporating various imaging modalities alongside clinical tools (such as clinical
biomarkers, patient characteristics, and behavioral assessments) can provide a more
comprehensive approach and potentially enhance the accuracy of prognostication. They
include fMRI, quantitative EEG, transcranial magnetic stimulation EEG (TMS-EEG), and
fluorodeoxyglucose positron emission tomography.[11 ] Presently, the correlation between clinical assessment and neuroimaging findings
remains imperfect, highlighting an area ripe for further investigation. This knowledge
could not only refine prognostic precision but also play a crucial role in selecting
patients for acute interventions and possibly optimizing the allocation of health
care resources. Ongoing efforts are being made to increase the sensitivity and specificity
of imaging studies to yield more accurate prognoses. For instance, the measurement
of quantitative whole-brain white matter fractional anisotropy in postcardiac arrest
patients has shown promise with normal values linked to favorable outcomes at 6 months,
suggesting its potential utility in guiding decisions regarding continuation of care.[12 ] Similarly, recent findings suggest that in patients affected by coronavirus disease
2019, quantitative diffusion tensor imaging could be effective in identification of
cortical and hippocampal abnormalities that account for the altered mental states
observed in many individuals.[13 ] The ongoing research in advanced neuroimaging is crucial, not only for enhancing
its value in prognostication, but also as a vital tool for unraveling the complexities
of structural and functional brain networks. This understanding is expected to significantly
aid in the development and advancement of future therapeutic interventions.
EEG is increasingly utilized for assessing consciousness in intensive care units (ICUs).
In ICU settings, EEG can differentiate between the unresponsive wakeful state and
the minimally conscious state (MCS) with high predictive accuracy, albeit with limited
sensitivity.[14 ] However, at times, EEG or fMRI alone may not be sufficient to evaluate for MCS.
A combination of EEG with TMS may enhance diagnostic sensitivity and mitigate common
confounders in ICU environments.[15 ] This approach, which involves directly exciting neurons using TMS and measuring
the brain's response via EEG, allows for quantifiable interpretation. TMS-EEG appears
to offer several advantages: it neither rely on the integrity of the sensory or motor
systems nor on the cognitive function of the patient, and it provides insights into
overall brain dynamics. Presently, the application of TMS-EEG is constrained by a
lack of standardized procedures and interpretation methods. However, future clinical
trials aimed at testing its reliability in ICU patients, along with advancements in
device refinement for clinical use, could broaden its adoption among health care providers.
Assessment of Cognitive Motor Dissociation in Neuroprognostication
Assessment of Cognitive Motor Dissociation in Neuroprognostication
Cognitive motor dissociation (CMD) is characterized by a distinctive state of consciousness
in which cognitive responses are evident in advanced monitoring tools like fMRI or
task-based EEG, while no motor responses are observed during clinical bedside examinations.
One important feature of CMD is the engagement of the associated cortex which is detected
by fMRI or EEG.[16 ] This was first reported in a patient with traumatic brain injury who was unresponsive
behaviorally but evidently showed appropriate neuronal response on fMRI. Diagnosing
CMD presents substantial challenges, primarily stemming from significant gaps in current
scientific knowledge and the limited availability of advanced diagnostic tools, which
are accessible in only a few specialized centers globally. However, recognition of
CMD is crucial, as timely detection has been linked to better functional outcomes
following brain injuries. Despite this, CMD often remains underdiagnosed, underscoring
the urgent need for enhanced scientific understanding, development of refined diagnostic
criteria and future development of simplified and scalable tools. A summary of major
gaps reported by Coma Science Working Group of the CCC is listed in [Table 2 ]. The initial steps toward addressing this gap involve in-depth exploration of the
key brain networks that govern consciousness, along with an evaluation and potential
repurposing of existing tools to efficiently diagnose CMD. Accurate prognostication
based on improved understanding of CMD can lead to better resource allocation, individualized
treatment plans, and setting realistic expectations for recovery. Furthermore, these
advancements are crucial in promoting enhanced involvement and informed decision-making
among caregivers, ensuring that they are more actively engaged in the care process.
Thus, advancement in CMD research holds great potential for significantly impacting
patient care and remains one of the CCC's areas of focus.
Table 2
Major Research Gaps for Patient with Cognitive Motor Dissociation (CMD)
1. Lack of consensus on a term and definition that fully encapsulates the concept
of Cognitive Motor Dissociation (CMD).
2. The lack of comprehensive, multicenter studies investigating the prevalence of
CMD across diverse brain injury populations.
3. Lack of firsthand accounts from patients experiencing CMD to enhance understanding
and care approaches.
4. Insufficient understanding of the perspectives of caregivers, including families
and healthcare professionals, who support CMD patients.
5. Uncertainty surrounding the mechanisms of CMD, necessitating comprehensive, multimodal
analyses of brain structure and function at both the network and cellular levels.
6. Lack of a standardized approach/protocol to identify CMD, considering individual
(age, sex), contextual (injury type, sedation level), and logistical (ICU vs. nursing
home setting) variables.
7. Lack of educational programs and training for healthcare professionals regarding
the implementation of existing methods for detecting CMD.
8. Lack of comprehensive understanding related to the detection of CMD and its implication
on patient-focused outcomes, including quality of life and long-term recovery.
9. Lack of advanced technology such as the brain-computer interface (BCI) to establish
communication with CMD patients.
10. Lack of understanding related to the variability in neural recovery pathways in
CMD patients and implications for rehabilitation to optimize outcomes.
Adapted from Classen et al.[16 ]
Harnessing Computational Modeling in Brain Injury Research
Harnessing Computational Modeling in Brain Injury Research
Utilizing data and algorithms through mathematical and computer science methods is
a powerful tool for researchers studying brain injuries. These techniques enable the
creation of diverse simulations, providing a comprehensive understanding of brain
injury from the cellular to the clinical level. Recently, Luppi et al described two
approaches to modeling: statistical and biophysical models. Descriptive statistical
modeling, a traditional approach, focuses on identifying relationships between disease
predictors.[17 ] It operates either by analyzing individual data points (supervised model) or by
examining data point aggregations (unsupervised model). Generative statistical modeling,
in contrast, infers patterns within data, thus enabling the generation of new data
points. Biophysical models take a different approach, applying biological knowledge
to understand the intricacies of brain injury mechanisms and effects. These models
are subject to rigorous validation to ensure their reliability and reproducibility.
They are instrumental in producing simulations that facilitate the testing of specific
treatments, potentially influencing clinical outcomes.
Integration of clinical, biological, and imaging data can lead to the development
of a neuro-recovery process model, considering various outcomes at different time
points. This computational modeling approach is promising for deepening our understanding
of DoC and enhancing treatment methodologies and remains a ripe area of growth for
the CCC.
Study Design Considerations in Disorders of Consciousness Research
Study Design Considerations in Disorders of Consciousness Research
Studies focusing on DoC face several challenges, including their observational nature,
limited generalizability, methodological heterogeneity, and a dearth of long-term
outcome data. These limitations were thoughtfully reviewed and discussed by Cho et
al, who also provided insights into the optimal design of clinical trials for DoC.[18 ] Clinical trials involving patients with DoC present unique challenges, particularly
in terms of definitively defining endotypes, often necessitating a reliance on phenotypic
characteristics. Additionally, there is a substantial challenge concerning resource
allocation in both inpatient and outpatient settings, including the provision of expert
DoC care and ensuring continuity of care, which may influence the overall study design.
Traditional comparative effectiveness study designs may not be the most efficient
approach in DoC research due to the potential presence of numerous confounders, such
as patient and treatment heterogeneity, limited sample sizes, and protracted study
durations. Alternatively, platform trials emerge as an appealing design choice, as
they allow for the evaluation of multiple interventions within shorter timeframes
and across various settings, provided that there are no significant interactions among
the interventions. This innovative approach may help address some of the complexities
associated with studying DoC and expedite advancements in our understanding and treatment
of these conditions.
The importance of standardization through the utilization of CDEs has been widely
acknowledged by research funding agencies as a crucial support mechanism for research
endeavors. These efforts facilitate sharing and consolidation of datasets, particularly
those generated from clinical trials. As a testament to this commitment, the CCC has
commenced the publication of manuscripts describing CDEs for coma and DoC, including
case report forms.[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ]
[26 ]
[27 ] The development of these CDEs followed a meticulous process, commencing with a comprehensive
review of existing CDEs from the NINDS CDE catalog. These were then supplemented with
newly crafted CDEs tailored specifically to enable standardized data collection for
DoC. The final selection of CDEs resulted from a consensus-driven approach, which
involved evaluating and discussing factors such as availability, feasibility, reliability,
and the strength of supporting evidence. On average, the timeline for the final development
of these CDEs spanned approximately 2 years. The overarching goal of this initiative
is to establish a standardized approach to data collection and reporting while fostering
collaborations on a global scale. Notably, this effort represents one of the inaugural
undertakings by the CCC, making it the first organization in this field to achieve
this pivotal milestone. The CDE recommendations offer standardization for data collected
on various fronts, including behavioral phenotyping, goals-of-care, family/surrogate
decision-making, neuroimaging, electrophysiology, physiology, big data, hospital course/confounders,
biospecimens, outcomes and endpoints, and therapeutic interventions. For researchers'
convenience, case report forms are accessible on the Zenodo website (https://zenodo.org/records/8172359 ) and can be readily downloaded.[28 ]
Current Research Initiatives Endorsed by the Curing Coma Campaign
Current Research Initiatives Endorsed by the Curing Coma Campaign
Six research studies, endorsed by the CCC, have received funding and are currently
in progress. These studies include:
Curing Coma Campaign Acute Coma Prospective Pilot Observational Study (COMPOSE): Supported
by the NeuroCritical Care Foundation, COMPOSE is a prospective, multicenter study
designed to characterize the natural history of coma recovery across various etiologies
in a diverse population. The ultimate goal is to identify biomarkers that define coma
endotypes for targeted intervention.
Covert Volitional Eye Response Test (COVERT): Funded by the National Institute of
Health (NIH), this multicenter study investigates whether covert tracking during ICU
stays can predict recovery in brain injury patients.
Pilot Trial of a Web/Mobile/Tablet-Based Communication and Goals-of-Care Decision
Aid: Supported by the NIH, this study focuses on a digital aid and communication (DA + C)
tool for clinicians and families of patients with moderate to severe traumatic brain
injury, large hemispheric acute ischemic stroke, and intracerebral hemorrhage, aiming
to facilitate informed, shared decision-making.
Precision Care in Cardiac Arrest- Influence of Cooling Duration on Efficacy in Cardiac
Arrest Patients (ICECAP): Also funded by the NIH, this study is part of the ICECAP
trial, applying machine learning to identify biomarkers predicting responses to therapeutic
hypothermia and functional recovery.[29 ]
Electroencephalographic Biomarkers of Covert Conscious Processing During Pediatric
Coma: This research assesses covert consciousness in pediatric acute brain injury
using event-related potentials in EEG.
Knowledge Translation Strategies for Provider Adoption of American Academy of Neurology
-American Congress of Rehabilitation Medicine-National Institute on Disability, Independent
Living and Rehabilitation Research Guidelines: Targeting clinicians across various
care settings, this survey-based study evaluates the understanding and implementation
of DoC guidelines set by the American Academy of Neurology, American Congress of Rehabilitation
Medicine, and the National Institute on Disability, Independent Living, and Rehabilitation
Research.
Establishment of a Coma Care Registry
Establishment of a Coma Care Registry
The CCC is also working on developing a coma care registry, modeled off other disease-specific
registries like the American Heart Association's Get With the Guidelines—Stroke registry.
The primary objective of this registry is to offer real-time feedback to participating
entities and enhance the quality of care provided. Presently, the registry is in a
pilot phase, concentrating on the prospective collection of data, thorough analysis,
and sharing of data among participating institutions. The aggregated data from this
registry will serve as an invaluable asset for monitoring, comparing current medical
practices, and analyzing patient outcomes. This initiative is expected to empower
clinicians and scientists with actionable insights, thereby facilitating more informed
decision-making and overall enhancement of patient care. The registry will include
comprehensive patient-level information, encompassing demographics, treatments, and
outcomes.
Efforts Related to Coma and Disorders of Consciousness Education
Efforts Related to Coma and Disorders of Consciousness Education
In addition to ongoing efforts to promote DoC research, the CCC is working on promoting
knowledge about the care of individuals with DoC. The Curing Coma Campaign International
Survey on Coma Epidemiology, Evaluation, and Therapy study, an international epidemiological
endeavor by the CCC, provided crucial insights into the care of patients with DoC.[6 ] Although the survey found significant agreement among health care professionals
on the definition of coma, there was poor consensus on its cardinal features ([Table 3 ]). It also highlighted the limited use of advanced neurological assessment tools
([Fig. 4 ]) and the need for more definitive neuroprognostication determinants. Additionally,
86% of respondents demonstrated interest in future collaborative research. Recognizing
the outcomes of the COMETOGETHER survey, which highlighted the lack of consensus among
health care professionals and inconsistent practices in coma care worldwide, the CCC
launched an Education Module. This module is designed for health care professionals
involved in patient care across various stages, spanning from prehospital to hospital
and posthospital rehabilitation care. It aims to cover an extensive range of topics
crucial for a multidisciplinary care team, including the diagnosis, treatment, and
prognosis of coma and DoC across all age groups. It also sheds light on the future
prospects of the field, particularly focusing on ongoing research and advancements
not yet integrated into routine clinical practice. This module ensures that global
health care professionals receive standardized training and ongoing education. It
aims to establish a consistent comprehension of coma and DoC management strategies,
encourage the adoption of evidence-based guidelines, promote the utilization of advanced
coma and DoC assessment techniques, and facilitate interdisciplinary collaboration
and coordinated follow-up care. By educating the health care workforce on coma and
DoC care, the module contributes to the efficiency of health care systems and may
reduce costs associated with ineffective or inconsistent care. Furthermore, the CCC's
Education Module will work collaboratively with the Community of Collaborators Module
and together play a vital role in enhancing communication with patients and families,
thereby improving public awareness and understanding of coma and DoC and related conditions
and helping to dispel misconceptions and reduce stigma. Community of Collaborators
Module serves as a communication channel between CCC and patients, families, and advocacy
groups. Overall, this initiative will hopefully benefit patients by improving outcomes
and quality of life and positively influence society by fostering understanding, reducing
stigma, and optimizing health care resource allocation. The education efforts of the
CCC mark a substantial step forward in enhancing the medical community's comprehension
of coma and DoC care and equipping clinicians and scientists with essential knowledge
for effective patient care coordination and the development of practical clinical
trials.
Table 3
Definition of coma developed by expert consensus
Coma is defined by the absence of sustained spontaneous or stimulus-induced arousal/wakefulness.
The following criteria must be met on clinical examination to establish the diagnosis
of coma:
1. No command following, and,
2. No intelligible speech or recognizable gesture, and
3. No volitional movement (reflexive movement such as extensor or flexor posturing,
withdrawal from pain, triple flexion may occur), and
4. No visual pursuit, fixation, saccade to stimuli, or eye opening or closing to command,
and
5. The above criteria are not due to use of paralytic agent, active use of sedatives,
another neurologic or psychiatric disorder (e.g., locked-in syndrome, neuromuscular
disorder, catatonia, akinetic mute, abulia, conversion disorder), and
6. The patient does not have evidence of cognitive motor dissociation (i.e., the covert
ability to follow commands) based on electrophysiological or functional imaging, if
such testing is available.
Source: Helbok et al.[6 ]
Fig. 4 Diagnostic tools used for the evaluation of disorders of consciousness. Source: Helbok
et al.[6 ]
World Coma Day: Raising Awareness and Fostering Global Collaboration
World Coma Day: Raising Awareness and Fostering Global Collaboration
World Coma Day, organized under the auspices of the CCC, has emerged as an effective
platform for raising awareness about coma and DoC research and facilitating networking
opportunities. Celebrated annually on March 22nd since 2021, World Coma Day brings
together a diverse group of stakeholders, including clinicians, scientists, patients,
caregivers, and the general public. The day is dedicated to celebrating patient recovery
milestones, acknowledging the perseverance of families, and highlighting the efforts
of medical professionals in advancing the field of coma and DoC.
Since its inception, World Coma Day has seen remarkable growth and participation,
attracting over 1,000 participants from more than 80 countries in 2023. The event
features a range of activities, including presentations, discussion sessions, educational
material showcases, scientific updates, inspirational recovery stories, and support
messages from advocates dedicated to coma and DoC research. A particularly moving
segment is the “Stories of Hope,” where patients and their families share their journeys,
which is subsequently archived on the curing coma webpage (www.curingomca.org ) for public viewing. These narratives are powerful reminders of the importance of
continuing research and treatment in the field of DoC.
Looking forward, plans are underway to restructure the event to reach an even broader
audience by expanding online video access and featuring contributions from various
stakeholders. Information about past and upcoming World Coma Day events is available
on the Curing Coma website (https://www.curingcoma.org/ ), providing a comprehensive view of the initiatives and progress in this vital area
of medical research and patient care.
Future of the Curing Coma Campaign
Future of the Curing Coma Campaign
In summary, the quest to deepen our understanding and improve care for those with
coma and DoC is ongoing and marked by considerable knowledge gaps. The CCC plays a
crucial role in this journey, establishing key infrastructure and encouraging collaboration
among medical professionals worldwide. The CCC focuses on identifying vital research
areas and educational opportunities, supporting ongoing studies and initiatives, striving
for standardization in data collection and management strategies, and fostering necessary
clinical collaborations. These efforts are instrumental in gathering timely, patient-centered
data and creating a platform for gaining valuable insights into coma and DoC care.
The field of coma and DoC research holds immense potential, and the CCC is committed
to exploring this domain. The goal of the CCC is to enhance the recovery process through
early and continuous interventions. As the CCC mission moves forward, its global collaborative
and dedicated approach offers hope for advancements in understanding and treating
coma and DoC, benefiting affected individuals and their families. More information
and updates on the CCC's efforts and research initiatives are available on the CCC's
official website (https://www.curingcoma.org/ ).
