Post-viral effects of COVID-19 in the olfactory system and their implications.

BACKGROUND: The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides a research opportunity to evaluate the natural course of this neurological finding. Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples. Although data from neuropathological specimens are now available, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge. RECENT DEVELOPMENTS: The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. WHERE NEXT?: The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.

Restless Leg Syndrome Is Underdiagnosed in Hereditary Hemorrhagic Telangiectasia-Results of an Online Survey.

BACKGROUND: Recurrent bleeding in patients with hereditary hemorrhagic telangiectasia (HHT) can lead to chronic iron deficiency anemia (CIDA). Existing research points to CIDA as a contributing factor in restless leg syndrome (RLS). The association between HHT-related symptoms and the prevalence of RLS was analyzed. METHODS: An online survey was conducted whereby the standardized RLS-Diagnostic Index questionnaire (RLS-DI) was supplemented with 82 additional questions relating to HHT. RESULTS: A total of 474 persons responded to the survey and completed responses for questions pertaining to RLS (mean age: 56 years, 68% females). Per RLS-DI criteria, 48 patients (48/322, 15%; 95% confidence interval (CI): 11-19%) self-identified as having RLS. An analysis of physician-diagnosed RLS and the RLS-DI revealed a relative frequency of RLS in HHT patients of 22% (95% CI: 18-27%). In fact, 8% (25/322; 95% CI: 5-11%) of the HHT patients had RLS which had not been diagnosed before. This equals 35% of the total amount of patients diagnosed with RLS (25/72; 95% CI: 25-46%). HHT patients with a history of gastrointestinal bleeding (prevalence ratio (PR) = 2.70, 95% CI: 1.53-4.77), blood transfusions (PR = 1.90, 95% CI: 1.27-2.86), or iron intake (PR = 2.05, 95% CI: 0.99-4.26) had an increased prevalence of RLS. CONCLUSIONS: Our data suggest that RLS is underdiagnosed in HHT. In addition, physicians should assess CIDA parameters for possible iron supplementation.

Olfactory Testing Informs the Decision Process to Obtain Advanced Neuroimaging in Traumatic Brain Injury.

The purpose of this article is to examine the usefulness of olfactory testing as a tool for the evaluation or stratification of traumatic brain injury (TBI) patients. Olfactory dysfunction is more likely to be overlooked by both the patient and the provider, especially in the acute setting, in contrast to deficits in other senses like vision or hearing. This is a retrospective clinical analysis (case series) of eight active duty service members referred to ear, nose, and throat clinic at Walter Reed National Military Medical Center during a 2-yr period between March 2014 and March 2016 for subspecialist evaluation of suspected olfactory impairment after an exposure to closed head trauma. Advanced neuroimaging revealed evidence of frontal lobe injury in all eight patients, which was subtle and subcentimeter in half of the cases, best demonstrated with high-resolution imaging in the coronal plane. In this article, we discuss the correlation between olfactory dysfunction and brain pathology in both TBI and non-TBI settings. We then provide our recommendation for an orbit magnetic resonance imaging (MRI) to evaluate the inferior frontal lobes and olfactory bulbs in patients with unexplained anosmia.

Predictors of Neurocognitive Syndromes in Combat Veterans.

Traumatic brain injury, depression and posttraumatic stress disorder (PTSD) are neurocognitive syndromes often associated with impairment of physical and mental health, as well as functional status. These syndromes are also frequent in military service members (SMs) after combat, although their presentation is often delayed until months after their return. The objective of this prospective cohort study was the identification of independent predictors of neurocognitive syndromes upon return from deployment could facilitate early intervention to prevent disability. We completed a comprehensive baseline assessment, followed by serial evaluations at three, six, and 12 months, to assess for new-onset PTSD, depression, or postconcussive syndrome (PCS) in order to identify baseline factors most strongly associated with subsequent neurocognitive syndromes. On serial follow-up, seven participants developed at least one neurocognitive syndrome: five with PTSD, one with depression and PTSD, and one with PCS. On univariate analysis, 60 items were associated with syndrome development at p < 0.15. Decision trees and ensemble tree multivariate models yielded four common independent predictors of PTSD: right superior longitudinal fasciculus tract volume on MRI; resting state connectivity between the right amygdala and left superior temporal gyrus (BA41/42) on functional MRI; and single nucleotide polymorphisms in the genes coding for myelin basic protein as well as brain-derived neurotrophic factor. Our findings require follow-up studies with greater sample size and suggest that neuroimaging and molecular biomarkers may help distinguish those at high risk for post-deployment neurocognitive syndromes.

Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study.

OBJECTIVE: To determine whether a structured and quantitative assessment of differential olfactory performance-recognized between a blast-injured traumatic brain injury (TBI) group and a demographically comparable blast-injured control group-can serve as a reliable antecedent marker for preclinical detection of intracranial neurotrauma. METHODS: We prospectively and consecutively enrolled 231 polytrauma inpatients, acutely injured from explosions during combat operations in either Afghanistan or Iraq and requiring immediate stateside evacuation and sequential admission to our tertiary care medical center over a 2½-year period. This study correlates olfactometric scores with both contemporaneous neuroimaging findings as well as the clinical diagnosis of TBI, tabulates population-specific incidence data, and investigates return of olfactory function. RESULTS: Olfactometric score predicted abnormal neuroimaging significantly better than chance alone (area under the curve = 0.78, 95% confidence interval [CI] 0.70-0.87). Normosmia was present in all troops with mild TBI (i.e., concussion) and all control subjects. Troops with radiographic evidence of frontal lobe injuries were 3 times more likely to have olfactory impairment than troops with injuries to other brain regions (relative risk 3.0, 95% CI 0.98-9.14). Normalization of scores occurred in all anosmic troops available for follow-up testing. CONCLUSION: Quantitative identification olfactometry has limited sensitivity but high specificity as a marker for detecting acute structural neuropathology from trauma. When considering whether to order advanced neuroimaging, a functional disturbance with central olfactory impairment should be regarded as an important tool to inform the decision process. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that central olfactory dysfunction identifies patients with TBI who have intracranial radiographic abnormalities with a sensitivity of 35% (95% CI 20.6%-51.7%) and specificity of 100% (95% CI 97.7%-100.0%).

Epidemiologic aspects of traumatic brain injury in acute combat casualties at a major military medical center: a cohort study.

OBJECTIVE: From the ongoing military conflicts in Iraq and Afghanistan, an understanding of the neuroepidemiology of traumatic brain injury (TBI) has emerged as requisite for further advancements in neurocombat casualty care. This study reports population-specific incidence data and investigates TBI identification and grading criteria with emphasis on the role of loss of consciousness (LOC) in the diagnostic rubric. METHODS: This is a cohort study of all consecutive troops acutely injured during combat operations-sustaining body-wide injuries sufficient to require immediate stateside evacuation-and admitted sequentially to our medical center during a 2-year period. A prospective exploration of the TBI identification and grading system was performed in a homogeneous population of blast-injured polytrauma inpatients. RESULTS: TBI incidence was 54.3%. Structural neuroimaging abnormalities were identified in 14.0%. Higher Injury Severity Score (ISS) was associated with abnormal neuroimaging, longer length of stay (LOS), and elevated TBI status-primarily based on autobiographical LOC. Mild TBI patients had normal neuroimaging, higher ISS, and comparable LOS to TBI-negative patients. Patients who reported LOC had a lower incidence of abnormal neuroimaging. INTERPRETATION: This study demonstrates that the methodology used to assign the diagnosis of a mild TBI in troops with complex combat-related injuries is crucial to an accurate accounting. The detection of incipient mild TBI, based on an identification system that utilizes LOC as the principal diagnostic criterion to discern among patients with outcomes of interest, misclassifies patients whose LOC may not reflect actual brain injury. Attempts to identify high-risk battlefield casualties within the current point-of-injury mild TBI case definition, which favors high sensitivity, will be at the expense of specificity.

Analysis of battlefield head and neck injuries in Iraq and Afghanistan.

OBJECTIVE: At the time of this study, the 1st place that an injured or ill American soldier in Iraq or Afghanistan would have been evaluated by an ENT-head and neck surgeon was at a tertiary care medical center as a result of air evacuation out of theater: Landstuhl Regional Medical Center (LRMC), Ramstein, Germany. By examining the ENT-related diagnoses of all air evacuations from downrange, we were able to match the patients classified as having battle injuries to determine the percentage with head and neck trauma. STUDY DESIGN: A prospective review of 11,287 soldiers air-evacuated from Afghanistan and Iraq, representing the 1st year of combat operations. A new, computerized patient-tracking system was created by our team to merge several disparate databases to generate and compile our data. RESULTS: The ENT-head and neck surgery department evaluated and primarily managed 8.7% of all patients evacuated out of theater by air to Germany. Other medical and surgical services managed 7.3% of all patients evacuated out of theater with overlapping ENT diagnoses. The number of potential ENT patients increased to 16% when one looked at all head and neck pathology instances seen by all medical and surgical departments hospitalwide. Of all patients air-evacuated and classified as having battle injuries, 21% presented with at least 1 head and neck trauma code. CONCLUSIONS: This is the 1st paper focusing on the role of the ENT-head and neck surgeon in treating a combat population and also the patterns of illness and head and neck injuries in a deployed force in our modern military. Improved soldier body armor has resulted in distinctly new patterns of combat injuries. Unprotected areas of the body account for the majority of injuries. SIGNIFICANCE: These findings should be used to improve the planning and delivery of combat medical care.