INTRODUCTION

Concussion is a functional syndrome typically consisting of neurological, behavioral, and cognitive manifestations following blunt head trauma. Though historically considered an acute, unpredictable, and transient process, we can now appreciate concussion and mild traumatic brain injury (mTBI) as a recognized disease state associated with a constellation of manifestations and the potential for persistent clinical effects. Despite increased understanding of the pathophysiology and morbidities associated with concussion, the degree to which this altered neurological state may affect outcome following anesthesia is poorly understood. This review will summarize the most current understanding of the pathophysiology and impact of concussion in the perianesthetic period, and present opportunities for future investigations.

KEY POINTS Concussion is associated with alterations in brain homeostasis and these changes can persist despite resolution of signs and symptoms of concussion. Anesthesia may be required in patients with concussion to facilitate procedures with the greatest rate of utilization likely occurring soon following concussion. There are efforts to develop objective tests that can be used to quantify severity and recovery, and stratify prognosis, following concussion. Significant knowledge gaps exist regarding the perianesthetic management of patients with concussion and those with suspected chronic traumatic encephalopathy. There is currently no guidance in the literature to indicate how long an elective case should be delayed following a concussion. It seems reasonable to delay elective procedures requiring anesthesia until the clinical manifestations of the concussion have resolved. At the current time, patients should be informed that the impact of anesthesia on recovery from concussion, including cognitive recovery, is unknown. CURRENT EVIDENCE Definitions and Epidemiology

The terms “mTBI” (defined as Glasgow Coma Scale score ≥13 after blunt head injury) and “concussion” are often used interchangeably as there are currently no criteria that are used to distinguish concussion from mTBI.

Traumatic brain injury (TBI) is common, with ∼1.5 million injuries occurring annually in the United States, of which 75% to 95% are mTBI.1 Thus, ∼1.2% of the population suffers from a concussion each year.2 This translates to more than 800,000 outpatient visits each year for mTBI in the United States, with a likelihood that this grossly underestimates the true burden of disease because of under reporting.3

The likelihood that an anesthesiologist may care for an individual with a recent concussion has not been described until recently. At a single institution, Abcejo et al4 retrospectively identified patients with concussion who received anesthesia. During a 10-year period, 7699 patients suffered from a clinically diagnosed concussion, 13.8% of whom underwent a subsequent anesthetic for a diagnostic or procedural intervention within 1 year of the index injury. Motor vehicle accidents, falls, and sport-related injuries accounted for 36%, 31%, and 13% of concussions, respectively. In this cohort, 44% of patients received an anesthetic within 1-month of injury with 30% having an anesthetic within a week of concussion. Notably, 7% of patients who received an anesthetic within 1 week of a concussion did not have a formal diagnosis of concussion in their medical record at the time of anesthesia; in this cohort, the diagnosis of concussion was made at some point after the patient received anesthesia. Fifteen percent of anesthetics performed after concussion were administered to facilitate elective procedures; one-third of these were unrelated to the initial concussive injury (eg, elective third molar extractions with general anesthesia). Taken collectively, patients frequently receive anesthesia to facilitate diagnostic or therapeutic procedures following concussion, with the greatest utilization occurring soon after concussion at the time when the brain may be most vulnerable to injury from secondary insults. The cohort analyzed by Abcejo et al4 was limited to a single center, and the generalizability of these findings to other populations requires further confirmation. A cohort of interest for further study would consist of members of the military where concussion is more frequent.

Cellular and Global Neurophysiological Derangements after Concussion

Concussion has significant effects on brain homeostasis (Table 1). Following even mTBI, multiple cellular neurometabolic pathways are disturbed; these neurophysiological perturbations contribute to the clinical manifestations of concussion. After concussive injury, disruptions in neurometabolic pathways can be generalized in 2 different patterns: a neuronal state of energy crisis and a proinflammatory state.5 In an effort to repair dysfunctional pathways, support neuroinflammation, and produce neurotrophic factors for neuronal repair, cells rapidly become depleted of energy. This energy crisis is exacerbated by a diminished ability to produce adenosine trisphosphate. At the same time, energy-dependent cellular pathways to activate microglia, the primary immune cells of the brain, are upregulated soon following injury.6

TABLE 1 - Neurophysiological Changes Following Concussion Parameter Sequelae Observed Following Concussion Cerebral energy homeostasis Significant energy demand occurs to support a state of cellular repair and neuroinflammation Normal energy production is altered in response to disruption of metabolic pathways Cerebral blood flow Persistent, inappropriate changes in CBF that may continue despite resolution of clinical symptoms Autoregulation of CBF Cerebrovascular responsiveness to changes in systemic BP may be attenuated CBF response to neuronal Exaggerated increase in CBF in response to neural activity Cerebral metabolism Altered cerebral metabolism Decreased adenosine triphosphate in the brain CO2 reactivity Exaggerated increase in CBF in response to hypercapnia White matter tract integrity May be disrupted as measured by diffusion tension MRI Neuroinflammation Microglial activation These neuroinflammatory cells can remain upregulated for some time following injury

BP indicates blood pressure; CBF, cerebral blood flow; CO2, carbon dioxide; MRI, magnetic resonance imaging.

Brain movement within the cranial vault at the time of injury can cause axonal stretch of white matter tracts which can manifest as abnormalities in magnetic resonance diffusion tensor imaging.7 These water diffusion abnormalities are evident soon after injury and can persist for months.8 Other changes include relative cerebral hyperperfusion and altered cerebrovascular responsiveness to changes in systemic blood pressure, arterial carbon dioxide tension, and neuronal activity.9–13 Changes in cerebral blood flow (CBF) can persist for months to years after the index event despite resolution of clinical manifestations. For example, in athletes after concussion, Churchill et al14 found an increase in CBF immediately after injury followed by persistent changes in CBF even 1 year following return to sport, despite athletes being clinically cleared to “return to play” play based on resolution of symptoms. It is currently not known how long other pathophysiological changes are sustained in the brain following concussion. Thus, clinical signs and symptoms of concussion may not be a reliable marker for the return to normal cerebral physiology.

Concussion Diagnosis and Biomarker Updates

Common clinical manifestations of concussion are summarized in Table 2. Traditionally, the diagnosis of concussion was made based on clinical testing that generally relied on the Glasgow coma scale score, the presence of classic signs and symptoms of concussion, and the ability of the patient to perform executive tasks. However, relying on patients to report symptoms imparts a degree of subjectivity to this clinical-based diagnostic strategy. For example, athletes may deny symptoms of concussion to minimize restrictions on returning to sport following concussion.

TABLE 2 - Prevalence of Symptoms After Concussion in High School Athletes 2008 to 2009 Symptom Prevalence of symptoms (%) Headache 93 Unsteadiness 75 Difficulty concentrating 67 Confusion 46 Sensitivity to light 38 Nausea 29 Drowsiness 27 Amnesia 24 Sensitivity to noise 19 Tinnitus 11 Irritability 9 Hyperexcitability 2 Adapted from Meehan et al15 with permission from SAGE Publications. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

For definitive noninvasive diagnoses, alternative modalities have been explored. Electroencephalographic slowing can occur following concussion but it is currently unclear whether electroencephalography can be used to diagnose concussion or provide prognostic information.16 Alternatively, functional near infrared spectroscopy may also play a role in diagnosing concussion, quantifying physiological derangements in the brain after concussion, and providing prognostic information17,18; with its relative low-cost and portability, this technique may be a feasible clinical adjunct to concussion diagnosis. Lastly, magnetic resonance spectroscopy has been shown to detect neurodegeneration after concussion that may be associated with postconcussive cognitive dysfunction.19

Serum biomarkers have gained attention in the past decade as a potential means to diagnose concussion and predict recovery patterns. Changes in serum S100 calcium binding protein B (S100B) concentrations have been studied extensively in patients with TBI. Elevated S100B has been shown to: (1) correspond to TBI severity stratified by Glasgow coma scale score20,21; (2) linearly correlate with ongoing physiological derangements such as hypoxia and hypotension,22,23 and; (3) in concussion, identify athletes who suffered repeated subclinical head injuries.24 Tau protein is a neuronal microtubule structural protein. Following TBI and concussion, serum concentrations of tau protein can increase and subsequent decreases in serum tau protein concentration may help predict return to play status in athletes following concussion.25,26 Both S100B and tau levels have been shown to correlate with irregularities in CBF and reduced global neuronal connectivity on functional magnetic resonance imaging.27

In 2018, the United States Food and Drug Administration approved the first blood test for TBI based on glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1.28 This test is most reliable when administered within hours after injury.29 Interpretation of the test may not be reliable in those with normal brain imaging following concussion.

Also under investigation are salivary biomarkers. Changes in the concentration of various inflammatory biomarkers in saliva have been associated with concussion in teenage athletes.30 MicroRNAs are small nucleic acid fragments that regulate protein synthesis in response to physiological changes. Changes in the concentration of specific microRNAs in saliva have been correlated with concussion, and these changes show promise in predicting recovery of the clinical manifestations of concussion.31

Chronic Traumatic Encephalopathy

First described in the brains of 2 American football players postmortem, chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder that can occur in individuals who have sustained multiple concussions.32,33 Significant findings included brain atrophy and widespread deposition of hyperphosphorylated tau protein and β-amyloid in the brain, similar to the microneuropathologic findings in the brains of those with Alzheimer dementia. To better understand CTE, the Concussion Legacy Foundation created a Global Brain Bank, and, in 2017, Mez et al34 reported on findings from brains donated from American football players. Pathologic changes consistent with CTE, including widespread hyperphosphorylated tau protein (that often spares the cerebellum and brainstem), was found in 99% of the brains donated by American football players. Increased deposition of β-amyloid and α-synuclein, the protein that comprises Lewy bodies, was also found in those with CTE. Cognitive impairment, mood and behavioral problems, and substance abuse disorders were common among those diagnosed with CTE, and greater deposition of hyperphosphorylated tau protein was found among those who also suffered from ataxia, discoordination, and tremor. Further research is necessary to characterize the epidemiology of anesthesia utilization in patients with suspected CTE and the impact that anesthesia may have on the perianesthetic course in his cohort.

KNOWLEDGE GAPS

A concussive injury likely coincides with a window of neurological vulnerability that may or may not correlate with the clinical manifestations of concussion. The risk, if any, that the perioperative period impacts neurological recovery after concussion remains unclear. D’Souza et al35 performed a post hoc, retrospective matched cohort study of patients with and without concussion who received anesthesia within 90 days of their injury. Despite no periprocedural factors or adverse outcomes being independently associated with concussion, anesthesia following concussion was likely not completely benign. Concussion was associated with higher postoperative pain scores, higher rates of postoperative headache, and greater degrees of sedation in the recovery room. Investigation of these and other variables would benefit from larger studies or prospective trials. There is also insufficient evidence to determine how long, if at all, anesthesia for elective procedures should be delayed following concussion. If anesthesia is required following concussion, it would be necessary to identify how periprocedural physiological and pharmacologic parameters can be optimized to improve outcomes.

Prognosis and recovery following concussion can vary significantly among patients. Currently, defining a predictable pattern of physiological recovery after concussion is not possible.36 Variables that affect recovery include age, sex, and individual comorbidities. For instance, the period of impaired cerebral metabolism may endure longer with increasing age in animal models, while human teenagers, especially young girls, may be more vulnerable to persistent symptoms.37 Similarly, a majority of larger scale studies report female sex as an independent risk factor for persistence of concussive symptoms longer than a month after injury.38 Persistence of symptoms is also associated with prior mental health disorders, including attention-deficit/hyperactivity disorder and learning disabilities.37 The individual impact of these variables and recovery from recent concussion after anesthesia has yet to be elucidated. Moreover, comorbid states of malperfusion and maloxygenation (ie, chronic heart, pulmonary or kidney disease) and their impact on concussion severity or recovery has yet to be determined.

Identifying vulnerable patients with at-risk head injury is critical to preventing secondary injury. Clinical screening for concussion symptoms has been shown to be easy, quick, and applicable to many levels of clinical training.39 Serum biomarkers may show significant promise in predicting concussion after head injury and predict pathophysiological changes associated with subclinical concussion. Lastly, the influence of CTE and persistent concussion syndromes on perioperative physiology behavior and recovery has not been described at all. Furthermore, identifying these patients without relying on postmortem histology has been inconsistent, and difficult at best, specifically with magnetic resonance and computed tomography imaging.40

CONCLUSIONS

Despite significant advances in our understanding of the pathophysiology of concussion and CTE, we are currently only left to hypothesize on how to appropriately manage patients with recent or repeated concussion in the perianesthetic period. Given the high prevalence of concussion in the general population, and the common need for anesthesia in those with concussion, significant effort is required to better understand how to minimize risk to the potentially vulnerable brain in those with concussion or suspected CTE.

Currently, the literature does not provide sufficient guidance on how long anesthesia for elective procedures should be delayed following a concussion. While urgent or emergent procedures likely should not be delayed, we believe that it is reasonable to wait until the clinical manifestations of a concussion have resolved before proceeding with elective procedures requiring anesthesia. At the current time, patients should be informed that the impact of anesthesia on recovery from concussion, including cognitive recovery, is unknown.

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