Clinical, Biomarker, and Research Tests Among US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: Since 2015, US government and related personnel have reported dizziness, pain, visual problems, and cognitive dysfunction after experiencing intrusive sounds and head pressure. The US government has labeled these anomalous health incidents (AHIs). Objective: To assess whether participants with AHIs differ significantly from US government control participants with respect to clinical, research, and biomarker assessments. Design, Setting, and Participants: Exploratory study conducted between June 2018 and July 2022 at the National Institutes of Health Clinical Center, involving 86 US government staff and family members with AHIs from Cuba, Austria, China, and other locations as well as 30 US government control participants. Exposures: AHIs. Main Outcomes and Measures: Participants were assessed with extensive clinical, auditory, vestibular, balance, visual, neuropsychological, and blood biomarkers (glial fibrillary acidic protein and neurofilament light) testing. The patients were analyzed based on the risk characteristics of the AHI identifying concerning cases as well as geographic location. Results: Eighty-six participants with AHIs (42 women and 44 men; mean [SD] age, 42.1 [9.1] years) and 30 vocationally matched government control participants (11 women and 19 men; mean [SD] age, 43.8 [10.1] years) were included in the analyses. Participants with AHIs were evaluated a median of 76 days (IQR, 30-537) from the most recent incident. In general, there were no significant differences between participants with AHIs and control participants in most tests of auditory, vestibular, cognitive, or visual function as well as levels of the blood biomarkers. Participants with AHIs had significantly increased fatigue, depression, posttraumatic stress, imbalance, and neurobehavioral symptoms compared with the control participants. There were no differences in these findings based on the risk characteristics of the incident or geographic location of the AHIs. Twenty-four patients (28%) with AHI presented with functional neurological disorders. Conclusions and Relevance: In this exploratory study, there were no significant differences between individuals reporting AHIs and matched control participants with respect to most clinical, research, and biomarker measures, except for objective and self-reported measures of imbalance and symptoms of fatigue, posttraumatic stress, and depression. This study did not replicate the findings of previous studies, although differences in the populations included and the timing of assessments limit direct comparisons.

Neuroimaging Findings in US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: US government personnel stationed internationally have reported anomalous health incidents (AHIs), with some individuals experiencing persistent debilitating symptoms. Objective: To assess the potential presence of magnetic resonance imaging (MRI)-detectable brain lesions in participants with AHIs, with respect to a well-matched control group. Design, Setting, and Participants: This exploratory study was conducted at the National Institutes of Health (NIH) Clinical Center and the NIH MRI Research Facility between June 2018 and November 2022. Eighty-one participants with AHIs and 48 age- and sex-matched control participants, 29 of whom had similar employment as the AHI group, were assessed with clinical, volumetric, and functional MRI. A high-quality diffusion MRI scan and a second volumetric scan were also acquired during a different session. The structural MRI acquisition protocol was optimized to achieve high reproducibility. Forty-nine participants with AHIs had at least 1 additional imaging session approximately 6 to 12 months from the first visit. Exposure: AHIs. Main Outcomes and Measures: Group-level quantitative metrics obtained from multiple modalities: (1) volumetric measurement, voxel-wise and region of interest (ROI)-wise; (2) diffusion MRI-derived metrics, voxel-wise and ROI-wise; and (3) ROI-wise within-network resting-state functional connectivity using functional MRI. Exploratory data analyses used both standard, nonparametric tests and bayesian multilevel modeling. Results: Among the 81 participants with AHIs, the mean (SD) age was 42 (9) years and 49% were female; among the 48 control participants, the mean (SD) age was 43 (11) years and 42% were female. Imaging scans were performed as early as 14 days after experiencing AHIs with a median delay period of 80 (IQR, 36-544) days. After adjustment for multiple comparisons, no significant differences between participants with AHIs and control participants were found for any MRI modality. At an unadjusted threshold (P < .05), compared with control participants, participants with AHIs had lower intranetwork connectivity in the salience networks, a larger corpus callosum, and diffusion MRI differences in the corpus callosum, superior longitudinal fasciculus, cingulum, inferior cerebellar peduncle, and amygdala. The structural MRI measurements were highly reproducible (median coefficient of variation <1% across all global volumetric ROIs and <1.5% for all white matter ROIs for diffusion metrics). Even individuals with large differences from control participants exhibited stable longitudinal results (typically, <±1% across visits), suggesting the absence of evolving lesions. The relationships between the imaging and clinical variables were weak (median Spearman ρ = 0.10). The study did not replicate the results of a previously published investigation of AHIs. Conclusions and Relevance: In this exploratory neuroimaging study, there were no significant differences in imaging measures of brain structure or function between individuals reporting AHIs and matched control participants after adjustment for multiple comparisons.

The Supine Superior Semicircular Canal Dehiscence Test.

Purpose The purpose of this clinical focus article is to describe a new method for assessment of superior semicircular canal dehiscence by laying the patient supine during Valsalva-induced nystagmus testing. Method The traditional Valsalva-induced nystagmus test is described, followed by a new method for assessment of superior semicircular dehiscence conducted by laying the patient supine during testing. A case study is presented to illustrate this new testing technique known as the Supine Superior Semicircular Canal Dehiscence Test. Results It is hypothesized that during Valsalva-induced nystagmus testing performed in the upright, seated position, the dura mater could potentially seal the superior semicircular canal fistula, thereby concealing a defect in the bony labyrinth and yielding a false-negative test. To circumvent this, the patient should be placed in the supine position during Valsalva-induced nystagmus testing in order to prevent the dura mater from inadvertently sealing itself against the petrous portion of the temporal bone. The Supine Superior Semicircular Canal Dehiscence Test may reveal the defect in the bony labyrinth and improve the sensitivity of the Valsalva-induced nystagmus test. Conclusions The Supine Superior Semicircular Canal Dehiscence Test may be more sensitive for identifying superior semicircular canal dehiscence in patients with traditional symptoms and a negative Valsalva-induced nystagmus test in the seated position. While a case study is presented to illustrate the potential benefits of including the Supine Superior Semicircular Canal Dehiscence Test in the battery of diagnostic tests, further research is needed in larger samples.

Outcomes in Previously Healthy Cryptococcal Meningoencephalitis Patients Treated With Pulse Taper Corticosteroids for Post-infectious Inflammatory Syndrome.

BACKGROUND: Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite antifungal therapy and negative cerebrospinal fluid (CSF) cultures. Data on effective treatment are limited. METHODS: Between March 2015 and March 2020, 15 consecutive previously healthy patients with CM and PIIRS were treated with adjunctive pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky performance scores, magnetic resonance imaging (MRI) brain scanning, ophthalmic and audiologic exams, and CSF parameters including cellular and soluble immune responses were compared at PIIRS diagnosis and after methylprednisolone completion. RESULTS: The median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month (P < .0003), which was accompanied by improvements in CSF glucose, white blood cell (WBC) count, protein, cellular and soluble inflammatory markers 1 week after receiving corticosteroids (CS) (P < .003). All patients with papilledema and visual field deficits also exhibited improvement (P < .0005). Five out of 7 patients who underwent audiological testing demonstrated hearing improvement. Brain MRI showed significant improvement of radiological findings (P = .001). CSF cultures remained negative. CONCLUSIONS: PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting.

Stability of Early Auditory Evoked Potential Components Over Extended Test-Retest Intervals in Young Adults.

OBJECTIVES: Synaptic damage from noise exposures can occur even in the absence of changes in hearing sensitivity in animal models. There is an unmet clinical need for measurements sensitive to such damage to the human auditory system that can augment the pure-tone audiogram. Early components (i.e., <10 msec) of the auditory evoked potential (AEP) may be useful noninvasive indicators of synaptic integrity. Wave I is a measure of synchronous neural activity at the level of the synapse between cochlear inner hair cells and the auditory nerve and may be of particular clinical utility. This amplitude measure has historically been classified as too variable in humans to be used for clinical waveform interpretation, though several recent reliability studies have challenged this view. The focus of the present study is to examine across-session stability of early AEP amplitude measures. DESIGN: In this study, amplitudes of early components (wave I, wave V, summating potential [SP]) of the AEP were measured in a cohort of 38 young adults aged 19 to 33 years (21 female). Stability of these amplitude measures was examined in a subset of 12 young adults (8 female), at time intervals ranging from 15 hr to 328 days between tests. Eligibility criteria included normal pure-tone hearing sensitivity, normal tympanometry, and intact acoustic reflexes. Participants were tested at up to four time points. Each evaluation included pure-tone thresholds, tympanometry, speech-in-noise testing, distortion-product otoacoustic emissions (DPOAE), and early AEPs. AEPs were collected in response to click and tone burst stimuli, with both ear canal and mastoid electrode montages. RESULTS: No clinical changes in pure-tone hearing were found between baseline and follow-up visits. Intraclass correlation coefficients (ICCs) indicated good to excellent reliability for wave I and wave V peak-to-trough amplitudes within individuals across time, with greatest reliability (0.92, 95% confidence interval [0.81 to 0.96]) and largest amplitudes for wave I when measured from the ear canal in response to a click stimulus. Other measures such as amplitude ratios of waves V/I and the SP and action potential (AP) showed lower ICC values when measured from the ear canal, with SP/AP ratio demonstrating the lowest reliability. CONCLUSIONS: The results of this study suggest that, when recorded under certain conditions, wave I amplitude can be a stable measure in humans. These findings are consistent with previous work and may inform the development of clinical protocols that utilize wave I amplitude to infer inner ear integrity.

Audiologic and Otologic Complications of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Patients.

OBJECTIVE: To identify audiologic and otologic outcomes in previously healthy non-HIV patients with cryptococcal meningoencephalitis (CM). STUDY DESIGN: Retrospective case review of a subset of patients recruited in a prospective observational study following previously healthy individuals who developed CM. SETTING: Tertiary referral center, National Institutes of Health Clinical Center. PATIENTS: Previously healthy adult patients with CM without immune suppressive therapy before disease onset. INTERVENTIONS: Diagnostic evaluations included audiometry, acoustic immittance, otoacoustic emissions, and auditory brainstem response studies, in addition to neurotologic assessment. RESULTS: Twenty-nine patients (58 years) underwent audiologic evaluation between 6 months and 3.5 years after CM diagnosis; 21 patients were seen for longitudinal assessment with an average duration of follow up of 20.3 months. Nearly three-quarters (73%) of the cohort presented with hearing loss, most commonly (90%) sensorineural in origin. The most frequent degree of loss was mild and then moderate, although some patients had severe or profound impairment. Hearing loss improved (43%) or remained stable (38%) in most cases. Ears with internal auditory canal enhancement on magnetic resonance imaging (MRI) had significantly more hearing loss than those without enhancement, although a similar finding was not observed with gyral enhancement or the presence of ependymitis or ventricular volume expansion. Hearing loss was not associated with reduced cerebrospinal fluid (CSF) glucose, CSF total protein, cryptococcal antigen, or total cell count. CONCLUSIONS: Hearing loss is a common manifestation of cryptococcal meningitis in previously healthy patients and may involve a cochlear or neural site of lesion, or both. Routine surveillance of hearing in patients is recommended, regardless of symptomatology, to ensure early and appropriate intervention and care.

Audiologic Natural History of Small Volume Cochleovestibular Schwannomas in Neurofibromatosis Type 2.

OBJECTIVE: To characterize the audiometric natural progression in patient-ears with small volume (<1,000 mm), treatment-naïve cochleovestibular schwannomas (CVSs) in Neurofibromatosis Type 2 (NF2). STUDY DESIGN: Prospective, longitudinal cohort study. SETTING: Quaternary medical research institute. PATIENTS: One hundred eleven ears in 71 NF2 patients with small, treatment-naïve CVSs observed from July 2006 to July 2016. INTERVENTION: Serial audiometric testing, including pure tone audiometry, speech audiometry, and magnetic resonance imaging (MRI). OUTCOME MEASURES: Four-frequency pure tone average (4f-PTA) of 0.5, 1, 2, and 4 kHz and word recognition score (WRS) were recorded. Their changes were compared with MRI changes in CVS volume over time. Times to significant hearing loss (10 dB loss in 4f-PTA) and WRS based on 95% critical difference were measured. RESULTS: Linear regression analysis showed a significant correlation with baseline hearing level (4f-PTA) and internal auditory canal (IAC) tumor volume to annual hearing decrease rate (AHDR) (p = 0.003, p = 0.0004). Hearing level at baseline and tumor volume correlate with AHDR while tumor volume growth rate does not. Two-way analysis of variance found significant differences in AHDR, risk of significant hearing loss, and risk of critical difference in WRS based on baseline hearing level (abnormal or normal) and IAC tumor volume (greater or less than 200 mm). CONCLUSION: Subjects with normal baseline hearing and small IAC tumor component had a low AHDR and low risk of significant hearing loss and may warrant conservative management while the presence of baseline hearing loss and large IAC volume resulted in higher ADHR and greater risk for further hearing loss and may benefit from early treatment interventions.

Auditory and otologic profile of Alström syndrome: Comprehensive single center data on 38 patients.

Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by mutations in the ALMS1 gene. Hallmark characteristics include childhood onset of severe retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, and cardiomyopathy. Here we comprehensively characterize the auditory and otologic manifestations in a prospective case series of 38 individuals, aged 1.7-37.9 years, with genetically confirmed AS. Hearing loss was preceded by retinal dystrophy in all cases, and had an average age of detection of 7.45 years (range 1.5-15). Audiometric assessments showed mean pure tone averages (0.5, 1, 2, 4 kHz) of 48.6 and 47.5 dB HL in the right and left ears, respectively. Hearing was within normal limits for only 8/74 ears (11%). For the 66 ears with hearing loss, the degree was mild (12%), moderate (54%), or severe (8%). Type of hearing loss was predominantly sensorineural (77%), while three ears had mixed loss, no ears had conductive loss, and type of hearing loss was indeterminate for the remaining 12 ears. Serial audiograms available for 33 patients showed hearing loss progression of approximately 10-15 dB/decade. Our data show that hearing loss associated with AS begins in childhood and is a predominantly symmetric, sensory hearing loss that may progress to a severe degree. Absent otoacoustic emissions, intact speech discrimination, and disproportionately normal auditory brainstem responses suggest an outer hair cell site of lesion. These findings indicate that individuals with AS would benefit from sound amplification and if necessary, cochlear implantation.

Vestibular Dysfunction in Patients with Enlarged Vestibular Aqueduct.

OBJECTIVE: Enlarged vestibular aqueduct (EVA) is the most common inner ear malformation. While a strong correlative relationship between EVA and hearing loss is well established, its association with vestibular dysfunction is less well understood. In this study, we examine the effects of EVA on the vestibular system in patients with EVA. STUDY DESIGN: Prospective, cross-sectional study of a cohort ascertained between 1999 and 2013. SETTING: National Institutes of Health Clinical Center, a federal biomedical research facility. SUBJECTS AND METHODS: In total, 106 patients with unilateral or bilateral EVA, defined as a midpoint diameter greater than 1.5 mm, were referred or self-referred to participate in a study of the clinical and molecular aspects of EVA. Clinical history was ascertained with respect to the presence or absence of various vestibular signs and symptoms and history of head trauma. Videonystagmography (VNG), cervical vestibular evoked myogenic potential (cVEMP), and rotational vestibular testing (RVT) were performed to assess the vestibular function. RESULTS: Of the patients with EVA, 45% had vestibular signs and symptoms, and 44% of tested patients had abnormal VNG test results. An increased number of vestibular signs and symptoms was correlated with the presence of bilateral EVA (P = .008) and a history of head injury (P < .001). Abnormal VNG results also correlated with a history of head injury (P = .018). CONCLUSION: Vestibular dysfunction is common in patients with EVA. However, not all patients with vestibular signs and symptoms have abnormal vestibular test results. Clinicians should be aware of the high prevalence of vestibular dysfunction in patients with EVA.

Mechanisms of hearing loss in neurofibromatosis type 2.

INTRODUCTION: Patients with neurofibromatosis type 2 (NF2) develop bilateral cochleovestibular schwannomas (CVSs) that cause binaural deafness in most individuals. Hearing loss occurs in an unpredictable manner and the underlying mechanisms are not known. To gain insight into the pathophysiologic basis for hearing loss in NF2, we performed a prospective cross-sectional study of untreated ears in NF2 patients. METHODS: One hundred consecutive NF2 patients in a prospective natural history study were included. Clinical and audiometric data were analyzed for treatment naïve ears. In addition to standard MR-imaging sequences, alterations in intralabyrinthine protein content were determined utilizing high resolution FLAIR, the presence of cochlear aperture obstruction was determined by examining 3D T2 sequences, and endolymphatic hydrops was identified on delayed post-contrast FLAIR sequences. RESULTS: Eighty-nine ears harboring 84 untreated CVSs in 56 consecutive NF2 patients (age 30 ± 16 years) were analyzed. Thirty-four (38%) ears had varying degrees of hearing loss. Elevated intralabyrinthine protein was identified in 70 (75%) ears by FLAIR MR-imaging and was strongly associated with the presence of hearing loss (32/34 hearing loss ears; 94%)(Fisher's exact test; P= .005). Elevated intralabyrinthine protein was associated with the presence of CVS-associated cochlear aperture obstruction (64 of 67 ears with elevated protein; 96%)(Fisher's exact test; P<0.0001) in both normal and hearing loss ears. Elevated intralabyrinthine protein was not identified in ears without CVS (5 ears). While larger tumor size was associated with hearing loss (P=0.006), 16 hearing loss ears (47%) harbored CVSs less than 0.5 cm(3), including 14 ears (88%) with block of the cochlear aperture and elevated protein. DISCUSSION: These findings are consistent with a model in which hearing loss develops as a result of cochlear aperture obstruction and accumulation of intralabyrinthine protein. MRI based identification of elevated intralabyrinthine protein may help identify the ear at-risk for developing hearing loss.

XPC initiation codon mutation in xeroderma pigmentosum patients with and without neurological symptoms.

Two unrelated xeroderma pigmentosum (XP) patients, with and without neurological abnormalities, respectively, had identical defects in the XPC DNA nucleotide excision repair (NER) gene. Patient XP21BE, a 27-year-old woman, had developmental delay and early onset of sensorineural hearing loss. In contrast, patient XP329BE, a 13-year-old boy, had a normal neurological examination. Both patients had marked lentiginous hyperpigmentation and multiple skin cancers at an early age. Their cultured fibroblasts showed similar hypersensitivity to killing by UV and reduced repair of DNA photoproducts. Cells from both patients had a homozygous c.2T>G mutation in the XPC gene which changed the ATG initiation codon to arginine (AGG). Both had low levels of XPC message and no detectable XPC protein on Western blotting. There was no functional XPC activity in both as revealed by the failure of localization of XPC and other NER proteins at the sites of UV-induced DNA damage in a sensitive in vivo immunofluorescence assay. XPC cDNA containing the initiation codon mutation was functionally inactive in a post-UV host cell reactivation (HCR) assay. Microsatellite markers flanking the XPC gene showed only a small region of identity ( approximately 30kBP), indicating that the patients were not closely related. Thus, the initiation codon mutation resulted in DNA repair deficiency in cells from both patients and greatly increased cancer susceptibility. The neurological abnormalities in patient XP21BE may be related to close consanguinity and simultaneous inheritance of other recessive genes or other gene modifying effects rather than the influence of XPC gene itself.

Investigation of the role of congenital cytomegalovirus infection in the etiology of enlarged vestibular aqueducts.

OBJECTIVE: To determine whether congenital cytomegalovirus (CMV) infection is an etiologic factor in the pathogenesis of enlarged vestibular aqueducts (EVA). DESIGN: Two different cohort studies. Subjects The study population comprised 19 subjects with a history of congenital CMV infection and sensorineural hearing loss (cohort 1); 39 subjects with nonsyndromic EVA and their unaffected mothers (cohort 2); and 16 control subjects with EVA associated with Pendred syndrome and bi-allelic mutations of the SLC26A4 gene and their unaffected mothers. RESULTS: In cohort 1, we detected EVA in 0 of 19 subjects with congenital CMV infection and sensorineural hearing loss. In cohort 2, anti-CMV serologic profiles were consistent with possible congenital CMV infection in 10 (26%) of 39 subjects with nonsyndromic EVA and 6 (38%) of 16 control subjects with Pendred syndrome (P = .52). These seroprevalence rates are similar to those expected in the general population (40%). CONCLUSION: In spite of their auditory phenotypic similarities, congenital CMV infection is not a significant factor in the etiology of EVA.