Using MRS to
Predict Emergence from Coma State after Traumatic Brain
by Allen Maniker, MD and Frank Hillary, MD
This research utilizes magnetic resonance spectroscopy (MRS) to measure brain metabolites after traumatic brain injury (TBI). These metabolites have been shown to have predictive value in emergence from coma state. Tracking metabolites offers the potential for advancing the treatment of TBI and providing further understanding of which individuals may or may not make good functional and cognitive recovery after injury. This research will better refine the protocols utilizing MRS to study these metabolites and help to define their predictive value for the treatment of injured patients.
Traumatic brain injury (TBI) has been defined as an injury to the brain resulting from an external mechanical force, which may lead to significant impairment in the individual’s physical, cognitive, and psychosocial functioning. These types of injuries may occur as a result of automobile accidents, falls, sports related incidents, and assaults. Each year one million people are treated and released from hospital emergency rooms, 230,000 of these individuals are hospitalized and survive, and 50,000 fatalities occur because of traumatic brain injury. As a result, a large number of individuals with TBI endure life-long impairment and disability. The impact on our society from healthcare costs and lost wages ranges into the billions of dollars.
During the early moments of hospitalization following TBI the patient is stabilized and the head is scanned using computed tomography (CT). Injury severity is rated using scales such as the Glasgow Coma Scale (GCS) which assesses and combines into a single numeric score eye opening, verbal response and motor response. The scale ranges from 3 to 15, and gives a consistent thumbnail picture of the severity of the injury and what level of survival can be expected. This scale, in combination with a neurological examination and CT scan, is used to make operative and medical intervention decisions in the early period immediately post TBI. Operative evacuation of epidural or subdural hematomas or even of irreversibly damaged, contused brain is frequently undertaken within the first hours of a patient’s arrival in the Emergency Department.
A monitor inserted into the parenchyma of the brain allows the tracking of intracranial pressure (ICP), which, if elevated, may result in damage to potentially salvageable brain tissue. Subsequently, in the immediate post admission phase, control of ICP and another important indicator, cerebral perfusion pressure (CPP), are monitored closely. Maintenance of appropriate blood pressure, electrolyte balance, blood gasses, fluid intake, and seizure prophylaxis are also among the mainstays of the acute care of the TBI patient.
These interventions allow for improved chances of the patients’ survival. However, this care still cannot ensure the patients’ functional or cognitive recovery. The question of who will recover to resume a normal functioning life is much more problematic and variable than the ability to predict survival.
Recovery from TBI has traditionally been monitored by scales that measure gross behavioral changes such as the GCS or the Galveston Orientation and Amnesia Test (GOAT). While the GCS serves a critical function at the time of hospital admission and during early treatment, it remains a more accurate predictor of outcome for patients with scores at the extremes and a weak predictor of outcome for patients who achieve mid-range scores.
Thus, the GCS has limited predictive power for acute recovery and more longterm functional and cognitive outcome. While behavioral measures such as the duration of post-traumatic amnesia (PTA) assessed with the GOAT have shown superiority to the GCS as an indicator of TBI severity, they only provide information ex post facto and, therefore, remain undetermined for days to weeks following injury. Similarly, traditional neuroimaging techniques such as CT or MRI have shown limited correlation with functional and cognitive outcome.
Advances in neuroimaging have provided researchers with an important tool for the correlation of the pathophysiology of brain dysfunction following TBI to the emergence from coma states. One such advanced imaging method is MRS. MRS is based on the same basic physical principles employed in conventional MR sequences; however, its signal is not derived simply from water or lipid as in conventional MR imaging. Signals arising in MRS are produced by hydrogen nuclei in larger macromolecules with distinct local magnetic environments. The MRS signal is typically displayed as a spectrum of waves. Put simply, nuclei with a higher number of electrons subtract from the MR field and result in a lower peak in the spectrum. Thus, each measurement of nuclei maintain discrete orientations when placed within the MR field and can be localized and quantified. The primary signals of interest in MRS arise from N-acetylaspartate (NAA), creatine/phosphocreatine (Cre), choline-containing compounds (Cho), glutamate (Glu), and lactate (Lac), and studies in TBI have primarily examined alterations in NAA and Cho concentrations.
MRS has received considerable attention in the study of TBI for both humans and animals during the past three to four years. Studies in animals have revealed both an acute decline in NAA concentration and increases in concentration of choline. In fact, NAA decline has been noted within an hour of injury and this change has been noted to maintain “high sensitivity” to physiological changes that accompany diffuse axonal injury.
Following traumatic brain injury, neuronal damage has traditionally been described in terms of primary injury (e.g.,contusion or axonal shearing) and of secondary injury (e.g., hyperglycolysis, acidosis). Prevention of hyperglycolysis has been a focus of study in both animal and human models of brain injury. Hyperglycolysis occurs when Glu or other excitatory neurochemicals are released into the intercellular space, resulting in excessive neuroexcitation in the absence of functional oxygen metabolism. Following TBI, hyperglycolysis may occur within hours of the injury, resulting in acidosis and cell death and, in animal models, acute elevations in Glu have been shown to last for seven to nine days following TBI. Therefore, Glu, an excitatory amino acid, has been implicated in exacerbating primary TBI and its effect may last for more than one week following the injury. MRS can track the changes in Glu concentration and its influence on brain injury severity. In addition to the study of Glu, reductions in NAA have been correlated with brain injury in both animals and humans. NAA is found only in the central nervous system and is the second most abundant compound in the brain (only Glu is more abundant). Because NAA is thought to be related to catabolic activity and axonal repair, its relationship to brain injury has been widely studied. Animal studies have shown NAA reductions following TBI as early as one hour post injury and examination of metabolism in humans has revealed that NAA depression may continue for months prior to metabolic rebound. The Cho peak has also been shown to be elevated in cases of local tissue breakdown or repair or in the case of tissue inflammation for weeks following injury. Thus, decline in NAA and elevations in Cho are considered reliable markers at the level of the brain substrate representative of TBI. Therefore measuring NAA, Cho, and Glu following TBI provides investigators with the unique opportunity to monitor acute changes at the brain level that coincide with behavioral changes observed during recovery.
Figure reveals MRS values for a patient with very severe head trauma at two separate time points (Day 9 and Day 25). Note diminished NAA concentrations and elevated Cho indicating significant brain damage. In addition, lactate is the highest peak at Day 9, with reductions by Day 25. Lactate elevations coincided with reductions in ICP, which may be indicative of an ischemic process.
While MRS has shown great promise in predicting brain injury severity and patient outcome, the exact protocols for using MRS with TBI remain undetermined. The purpose of this research is to examine three critical areas: 1.) when in the post-injury time period MRS data should be acquired (e.g., within one week of injury, within one month of injury) for gathering optimal predictive data; 2.) how metabolites should be measured (i.e., absolute concentrations or changes in concentration over time); and 3.) brain locations best suited for MRS data acquisition (i.e., acquisition near lesion sites or acquisition at sites remote from probable brain lesion). In humans, MRS has now been applied to the study of both acute and chronic TBI and there is evidence of significant correlation with injury severity and cognitive outcome. This research will provide further insight into the uses of MRS and the treatment of traumatic brain injury.
Allen H. Maniker, MD, is an associate professor of neurological surgery at Rutgers- New Jersey Medical School. He is also the director of neurotrauma at University Hospital. Dr. Maniker attended medical school at Wayne State University in Detroit, Michigan and completed his residency training in neurological surgery at UMDNJ. He completed his fellowship training in neurotrauma at the Medical College of Virginia.
Frank G. Hillary, PhD, is a research scientist and coordinator of Functional Imaging Research at Kessler Medical Rehabilitation Research and Education Corporation. He received a BA in psychology from the University of Michigan and a PhD in clinical neuropsychology from Drexel University. Dr. Hillary completed a post-doctoral fellowship in neuropsychology at the Kessler Medical Rehabilitation Research and Education Corporation.