Olfactory impairment and traumatic brain injury in blast-injured combat troops

DISCUSSION

When normal transnasal airflow of odorant molecules is present, olfactory dysfunction is routinely subdivided into 2 basic groups: (1) peripheral disorders of sensation—involving direct injury to the intranasal olfactory receptor cells due to toxic inhalational chemical vapors, infectious agents, or fractures involving the anterior skull base; and (2) central disorders of perception—involving disruption of CNS neuronal network circuitry that makes odorant identification possible.

Across all study groups, we observed no neuroradiographic evidence of trauma to the cribriform plate, olfactory bulbs, olfactory tracts, or gyrus recti, as noted within the limits of scanner resolution and trauma protocol sequencing. The radiographic findings support a higher-order CNS etiology for the observed impairment. Furthermore, use of a demographically comparable blast-injured control group of patients, all of whom had normal olfactometric scores, served to discount the concern that any observed impairment was the result of peripheral trauma, from inhalational explosive blast vapors, at the intranasal receptor level.

Olfactory impairment was observed only in troops with concurrent acute traumatic radiographic abnormalities. This finding approximates to previous conclusions from other historical clinical research investigations of consecutive closed head injuries and supports the assertion that impaired olfactory identification is only present in the context of significant intracranial neurotrauma.^16,–,21 However, our data stand in contrast with what is frequently noted or tacitly implied in the specialties of neurology, neurosurgery, or otorhinolaryngology, whereby olfactory impairment resulting from slight or minor blows to the head region—presumably due to partial stretching or sheering of fila olfactoria at the cribriform plate—has long-standing, albeit suppositious, clinical acceptance but no compelling advanced radiographic or histopathologic evidence for substantiation.^{12,13,22,–,27}

Although 6.1% of the blast-injured troops (14/231) exhibited impaired olfactory performance, our data indicate that knowledge of the overall “headline” value for incidence distorts framing of the real risk and is not sufficient to be clinically informative. From our data, we conclude that ultimately it is the radiographic presence and the radiographic locations of the structural brain injuries that define the probability of subsequent olfactory performance degradation and not simply the abstract and unquantifiable risk factor of a “blow or hit to the head region.” In addition, despite the seemingly low sensitivity of olfactometry for detecting abnormal neuroimaging, the absolute specificity and the ability to presage troops with more serious frontal or temporal lobe injuries—those who may require emergent attention and potentially more invasive interventions—has salutary value in both an acute military and civilian trauma setting. This is because structural brain injuries involving the frontal or temporal lobes typically drive the behavioral and cognitive outcome for the patient.²⁸

Our data are also consistent with the historical literature whereby the frontal and temporal regions have been shown to be selectively vulnerable to contusions from closed head trauma, independent of the site of impact. This is due to the kinematics of intrinsic pressure and strain responses within the brain tissue and rapid acceleration of cortical parenchymal surfaces along edges of the floor of the anterior cranial fossa.^28,29 Moreover, damage to these regions, whether from brain trauma, stroke, or through neurodegenerative processes (e.g., premotor Parkinson disease, Alzheimer disease, multiple sclerosis, frontotemporal dementia), has been demonstrated to significantly impair memory and thereby the ability of the brain to correctly match up and link common inhalational odorant molecules to past learning and experience.^30,–,34

Our study differs from previous olfactory investigations in ways that ultimately serve to enhance methodologic precision. First, the intrinsic demographic homogeneity and low intersubject variability, which are present within any military study whereby the cohort is restricted specifically to combat troops (young adult age range, sex, education, physical fitness standards), serves to discount multiple potential sources of bias and confounding, because of minimal individual differences among the participants at baseline.⁶ Second, anterior rhinoscopy and physician administration of the olfactory test by a dedicated otorhinolaryngologist rather than patient self-administration ensured compliance, motivation, consistency, and reliability of responses as well as normal intranasal dynamics and physiology. Specifically, direct physician monitoring of effort and task performance often prevented misattribution of seemingly incorrect responses to olfactory impairment resulting from sociocultural, geographic, and age-related maturational unfamiliarity with certain odorants (i.e., ascertainment bias), patient fatigue, as well as persistent intracohort difficulties with several indistinct and ambiguous odorants endemic to the UPSIT. Third, olfactometric scores were contemporaneously matched to posttraumatic anatomical changes on concurrent neuroimaging. As a practical matter, studies in which neuroimaging is performed with a lengthy latency from date of injury may no longer reveal structural pathology because of interval resolution of abnormal signals. This allows for the real possibility that impairment of the neuronal underpinnings essential to the olfactory processing network may be attributable to residual microstructure damage that exists below the threshold of detection for conventional radiographic resolution. Fourth, this is the only prospective olfactory study for which contemporaneous neuroimaging was available for a demographically comparable comparison control group.

Limitations of our study also warrant consideration. First, our testing strategies did not completely assay the olfactory system across its full spectrum of function. Additional features such as smell threshold and discrimination ability were not assessed. In patients with head trauma, intact sensation detection of an odorant is often present despite impaired perceptual capability (i.e., the ability to interpret, identify, and remember odors).^20,35 Of note, these investigational tests are less widely used and employ methodology that currently lacks strict measures of both reliability and validity. Second, the level of generalizability of the criteria for assessing potential brain trauma occurring within the context of an explosion, in contrast to sports-related concussions or other civilian blunt force incidents, remains a topic of active investigation by the military. In explosion-related whole-body polytrauma, the unwitnessed event as well as the multimodal and “invisible” nature of component blast-injuring mechanisms (e.g., overpressure) has made it exceedingly difficult to identify the essential deterministic attributes necessary to construct discriminative inclusion criteria which can selectively identify—at the primary interface with patients—those troops within the spectrum of “sound-exposed” to “blast-exposed” to “blast-injured” that truly represent a potential neurologic head trauma case. The resultant usage of an overly broad and undifferentiated target population (i.e., inclusion of all troops involved in any manner with an explosive event) diminishes the predictive value of the follow-on, nonspecific, symptoms-based diagnostic rubric, with resultant ambiguity which favors correlation over causation. Current development of helmet-mounted quantitative dosimeters and accelerometers for both the military and the National Football League will facilitate movement toward causation and, ultimately, a more secure concussion diagnosis.

Third, once a potential closed head trauma case has been identified, lack of a reliable and valid methodology for incontrovertibly diagnosing a radiographically normal closed head injury also remains a critical gap in both military and civilian neurotraumatology. At this time, there is neither a universally applied case definition nor signature confirmatory tests for characterizing the phenomenon of “a transitory change in brain function” called mild TBI (concussion), particularly in patients with acute polytrauma. A lack of both a common standard of care and a defined scope of practice among the various types of caregivers who diagnose this condition have impeded meaningful comparisons and progress. Of note, this limitation permeates all clinical research studies dealing with concussions and forces all clinicians to continuously accept an immoderate level of uncertainty with the exactness of this amorphous and widely variegated diagnosis and, for the purposes of this study, its causal relationship with olfactory performance.^6,36 The Glasgow Coma Scale has important disqualifying limitations and is not used to stratify the severity of a closed head injury in the military TBI program, or, for that matter, in athletic environments.³⁷ Moreover, the most current recommendations state that the derived total Glasgow Coma Scale score should only be used to characterize groups rather than individual patients.³⁸ In military polytrauma, the concussion diagnosis is ultimately based on a background level of awareness of a blast-related bodily injury, an autobiographical or observed report of immediate postincident changes from baseline neuro-status (loss of consciousness or an “apparent state of alteration in consciousness”), and depth of knowledge and breadth of experience of an advanced-level caregiver in managing neurotrauma.³⁶ Despite advances in radiology and the arduous search for confirmatory neurodiagnostics, the diagnosis remains clinical and is reliant on each individual caregiver's retrospective assessment, interpretation, and judgment of both “scale” and concurrency of immediate postincident signs, symptoms, or deficits, believed to be pathognomonic and axiomatic for a clinically significant alteration in brain function.³⁹ In lieu of these limitations, shortcomings in both the inclusion criteria and the case definition were partially offset by utilizing TBI evaluations that were performed by a dedicated team of psychologists with unrestricted access to intratheater medical records, superimposing the results of all available contemporaneous neuroimaging on 92.6% (214/231) of the troops, and use of an exceptionally homogeneous cohort consisting of the most critical blast-injured survivors with the highest ISS—whereby the presence of concurrent occult (i.e., radiographically normal) blast neurotrauma would be most likely.

The underlying olfactory impairment neuropathologic mechanisms remain unknown. Possibilities may include abrupt ionic shifts, altered metabolism, changes in neurotransmission due to cellular or interstitial edema, or impaired connectivity that ensue after objective trauma to the brain. However, at the functional level, the inability to specifically identify and verbally label odorants ultimately reflects posttraumatic impairment of memory-based cognitive networks in the CNS.⁴⁰ Until more advanced structural and validated functional neuroimaging or postmortem pathologic evidence becomes available, the mechanism of injury will remain purely speculative. Future studies focusing on additional memory testing may also help to localize the affected circuitry.

The presence of measurable abnormalities with central olfactory dysfunction provides added value to the practicing physician for preclinical detection of intracranial injury and, accordingly, subsequent disease-modifying early interventions. While the level of sensitivity for screening purposes is insufficient to exclude all types of posttraumatic neuropathology, the absolute specificity and the association with frontal or temporal lobe injury enhance its value in clinical practice.