Section 3
Clinical Features
SOURCES OF INFORMATION
The clinical investigators presented data to the committee as aggregated summaries of patients’ histories, physical examination findings, and results of laboratory testing and neuroimaging. These data were obtained from well-established methods of clinical assessment (Friedman et al., 2019; Hoffer et al., 2019; Swanson et al., 2018), as well as procedures that were investigative (i.e., experimental) in nature (Balaban et al., 2016; Verma et al., 2019). Experimental procedures included novel interpretations of results derived from well-established procedures (Friedman et al., 2019; Hoffer et al., 2019) and results obtained from newly developed, but not yet standardized, technologies (Balaban et al., 2016; Friedman et al., 2019; Verma et al., 2019). Individual patient-level data were not provided to the committee. DOS and the four clinical teams (Miami, Penn, National Institutes of Health [NIH], and Dalhousie) appropriately cited patient privacy and diplomatic and other security concerns in limiting data shared with the committee to the aggregate summaries only. The NIH team provided detailed multi-disciplinary clinical diagnoses of all patients that they evaluated, though this information, too, was provided to the committee in summary format. This made it impossible to link specific symptom constellations, physical examination results, and laboratory or imaging test findings within and between affected individuals for diagnostic purposes.
The committee was afforded an opportunity to speak directly with eight patients associated with U.S. Embassy Havana or with the U.S. Embassy or Consulates in China.
The CDC Report indicated substantial overlap in the populations of Havana patients included in the Miami, Penn, and NIH summative data. In fact, it was difficult for the committee to determine to what extent some individual patients may have been reported two or more times and whether the patients interviewed were among those included in the summative data from these three clinical sites. Importantly, the evaluations included in the summative data were generally separated from the original case events and from each other by considerable periods of time. Therefore, it was difficult to know whether differences in the reported signs and symptoms were due to changes from time of onset to the time of various evaluations, or because of the different evaluation procedures employed at the different sites, or because different subsets of patients were included in the different summaries.
ASSESSMENT AND FINDINGS
Clinical Features of Personnel Who Spent Time in Havana
The committee compiled signs and symptoms reported by DOS employees that spent time in Havana, based on information provided by the four clinical evaluation sites (Miami, Penn, NIH, Dalhousie) in presentations to the committee or in publications, as well as the signs and symptoms of affected employees interviewed by the committee in person. The committee included the sparse and fragmentary information on the China and Canadian patients here for the sake of a few comments.
The committee finds that the most distinctive and specific clinical features of these individuals occurred acutely at, or soon after the time of onset of their illness. In contrast, the chronic features that persisted for weeks, months, or years after the initial onset (in those individuals who reported an acute distinctive phase) were less specific to these DOS personnel and more common among general populations of patients with a variety of neurological or systemic conditions. The committee reasoned that the acute, more distinctive clinical features would be more informative about the possible cause(s) of the overall illnesses, rather than the chronic, less specific features.
The most common and distinctive features of the initial onset and acute phase of the illness in Havana personnel were the sudden onset of a perceived loud sound, sometimes described as screeching, chirping, clicking, or piercing, a sensation of intense pressure or vibration in the head, and pain in the ear or more diffusely in the head. Most individuals reported that the sound or these other sensations seemed to originate from a particular direction or that they perceived them only in certain physical locations. Individuals interviewed by the committee described alleviation of the symptoms by moving from their initial location to a different one, e.g., into a different room of the building in which they were located. According to data from Miami, 25 of 25 individuals perceived a loud sound, and according to data from Penn, 28 of 35 individuals from Havana, and 12 of 12 from China perceived a loud sound. Of the 35 Havana individuals assessed at Penn, 16 reported a sensation of pressure or vibration in the head and18 described the sound or pressure as directional or as restricted spatially in their immediate environment. Variable numbers of individuals reported the accompanying sudden onset of tinnitus (8 of 25 reported this at Miami and 6 of 21 at Penn), ear pain (7 of 25 at Miami and 7 of 21 at Penn), hearing loss (8 of 25 at Miami and 9 of 21 at Penn), dizziness, unsteady gait (4 of 21 at Penn), and visual disturbances (14 of 21 at Penn).3 Importantly, the committee finds this constellation of acute symptoms with directional and location-specific features to be very unusual, and to the best of its knowledge, unlike any disorder reported in the neurological or general medical literature.
Some of the acute signs and symptoms persisted or recurred and became chronic in some individuals, including dizziness (23 of 25 at the time they were examined at Miami and 13 of 21 at Penn), fatigue (10 of 21 at Penn), impaired balance (numbers not available), headache (6 of 25 at Miami and 16 of 21 at Penn), impaired concentration (5 of 8 at Miami and 8 of 21 at Penn) and memory (5 of 8 at Miami and 11 of 21 at Penn), depression (numbers not available), and insomnia (18 of 21 at Penn). These latter symptoms alone do not inform a specific etiologic diagnosis and can be due to a wide variety of common disorders (including viral and other inflammatory conditions, persistent postural-perceptual dizziness, chronic fatigue syndrome, traumatic brain injury, posttraumatic stress disorder, depression, and others). Most of the eight individuals that the committee interviewed described both early, acute onset and chronic clinical features, and continued to be debilitated.
The summary descriptions available to the committee of cases involving Canadian Embassy personnel from Havana failed to mention the perception of a loud sound, sensation of intense pressure or vibration, or ear pain, but did include impaired balance, headache, vertigo, tinnitus, and some of the same chronic clinical features as the U.S. Embassy personnel. The committee did not have sufficient information about U.S. Embassy personnel from China to be able to assess overall similarities or dissimilarities with cases from Havana.
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3 These numbers were extracted by the committee from publications and presentations by the clinical investigators, and not from the patient clinical records or from direct examination of the patients by the committee.
One problem with all of the data presented was that it lacked an appropriate control group (i.e., individuals who were present in the same environment as the U.S. Embassy employees who reported the acute phase of the illness, but were not exposed to whatever caused those distinctive signs and symptoms). It is noteworthy that the Canadian Embassy employees shared much of the environment of the U.S. Embassy employees, but generally lacked the acute signs and symptoms. Hence, it is possible that other exposures (viral illness, toxic chemicals, etc.) may have caused the chronic signs and symptoms shared by both the U.S. and Canadian personnel, while the acute signs and symptoms limited to the U.S. Embassy employees may have had a different cause.
The committee notes that the CDC Report also identified a biphasic onset of symptoms, with a set of early, sudden-onset symptoms and a set of later, more chronic, and less specific symptoms. The CDC Report defined a “presumptive” case as having components of each set.4 Out of 95 records that CDC reviewed, they found 15 who met their case definition, along with 31 other “possible” cases. Out of the 15, over 2 years after the initial symptoms, six were still undergoing therapy with four unable to work and two needing modifications to work. Unlike CDC, the committee did not have the ability to link disparate findings from different clinical sites and times to the same individual. However, it is the committee’s impression that only a subset of individuals who suffered from the early set of signs and symptoms, also suffered from the later set of signs and symptoms. Conversely, only a subset of individuals who reported suffering from the late set of generally more common signs and symptoms, also described the more distinctive early set and in particular, the sudden onset of a directional or location-specific loud noise, pressure or pain. Because of these various aspects of case heterogeneity, the committee found it difficult to know with certainty that all cases were due to the same cause(s), and in particular, whether the individuals with only the chronic set of signs and symptoms suffered from the same cause(s) and etiologic mechanisms as those who reported the initial, sudden onset set of signs and symptoms.
Laboratory Test Results and Physical Examination Findings Reported for Embassy Personnel
DOS personnel underwent physical examinations and different tests at different study sites, at different times during the course of their illness. The committee did not have access to primary reports or complete data. Nonetheless, it sought to identify and summarize pertinent test results and exam findings for which available data were adequate.
Vestibular and Balance Assessments
Patient questionnaires, physical examinations, office-based tests of balance performance, and vestibular and oculomotor laboratory tests were used to evaluate patients. The clinical teams from Miami and Penn selected tests based on each patient’s symptoms. Thus, patients did not undergo a consistent set of diagnostic evaluations at either site. Clinicians at NIH appeared to use a more consistent approach and set of test procedures.
Self-report questionnaires (e.g., Dizziness Handicap Inventory) and tests of balance performance (e.g., dynamic posturography) showed high rates of impairment and poor performance. The clinicians involved in these assessments interpreted these data as evidence of inner ear or brain injury (Swanson et al., 2018). However, self-report questionnaires and tests of
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4 The CDC case definition for a presumptive case required at least one of following in the initial phase (head pressure, disorientation, nausea, headache, vestibular disturbances, auditory symptoms, vision changes) and at least one of the following in a separate secondary phase (vestibular disturbances, cognitive deficits).
balance performance cannot be used properly to make specific diagnoses, as abnormal results may arise from structural, functional, or psychiatric disorders alone or in combination. Thus, these data indicate a high level of impairment in many patients at the time of testing, but do not provide any information about potential causative agents or specific mechanisms of injury.
Vestibular laboratory tests such as the video head impulse test, caloric test, vestibular evoked myogenic potentials, rotary chair test, and oculomotor examinations can provide information on the structural integrity of peripheral (inner ear) and central (brain) vestibular and oculomotor pathways. Test procedures vary across laboratories and several tests require cooperation and volitional effort on the part of patients to yield meaningful and consistent results. Consequently, findings from one center may not be directly comparable to findings from another center in the absence of descriptions of test procedures employed and thresholds for reporting normal versus abnormal results. Data published (Balaban et al., 2020; Hoffer et al., 2019) and presented by the clinical team at Miami were derived from a small number of established laboratory tests plus a battery of new assessment tools (i.e., experimental tests) developed by that group (Balaban et al., 2016). Data published (Swanson et al., 2018) and presented by the clinical team at Penn were derived predominantly from office-based tests. Only a portion of patients were evaluated with standard vestibular laboratory tests and only a portion of those results were published or presented. The Dalhousie team also used a small number of established vestibular tests (Friedman et al., 2019) but only examined Canadian patients. The NIH team employed an extensive battery of established tests, though their assessments were generally conducted later, from months to over a year, in the course of patients’ illnesses and thus were less informative about potential early deficits. Some results were inconsistent across centers, although perhaps in part because they studied different individuals. For example, the Miami group reported high rates of absent or reduced-amplitude vestibular evoked myogenic potentials (Hoffer et al., 2019), whereas the Dalhousie group reported higher than normal mean amplitudes on those tests (Friedman et al., 2019).
The committee concluded that the aggregate data derived from the subset of well-established clinical laboratory diagnostic tests presented by the four clinical groups performed weeks, months, or years after the initial onset did not identify a common pattern of structural injuries to the labyrinths or brains of patients that could explain the reported vestibular symptoms. In the absence of patient-level data, the committee could not determine with certainty if any reported abnormalities coincided with key aspects of clinical histories for individual patients.
Neuropsychological and Psychological Assessments
Patients underwent neuropsychological testing at Penn and NIH in various cases, weeks, months, or years after symptom onset. The Penn team presented aggregate results in a nonstandard manner (i.e., the total number of patients with abnormal scores on each subtest of the test battery that they administered). The NIH team presented results in a more standardized clinical fashion, though still in aggregate. Neurobehavioral and cognitive evaluations in these situations are quite challenging. Standard assumptions and fact-finding methods used in normal clinical settings may be misleading, raising validity concerns (Lees-Haley, 1995). The committee concluded that no distinct pattern of clinically diagnosable cognitive deficits could be discerned from these data. A more comprehensive and uniform assessment approach to the entire group of patients earlier in the course of illness may have provided a better opportunity with regard to diagnosis and treatment issues.
The NIH team also presented aggregate data from psychological testing. The results showed psychological distress in some patients in a pattern that may be seen in those suffering from a variety of chronic medical conditions or somatic symptom disorders. These results indicated an increased burden of illness in patients with chronic symptoms but offered no insights into an initial cause.
Imaging Studies
The committee reviewed the radiological studies from Penn and Dalhousie. The Penn group found essentially normal conventional structural magnetic resonance imaging (MRI) results months to years after initial symptoms. They subsequently reported that among 40 Havana patients compared to 48 healthy controls, there were small group differences in the average brain volumes in specific lobes, a decrease in mean diffusivity in the midline inferior cerebellum, and differences in functional connectivity in auditory and visuospatial networks (Verma et al., 2019). Difficulties in replicating results are common in studies of small patient groups using MR measures with low signal to noise ratios, and which involve a number of computational steps and algorithms that are known to perform imperfectly (based on frequent failures to replicate) (De Santis et al., 2014; Jonathan et al., 2007; Landman et al., 2007). Generally, studies of this type require a replication cohort (which was not available) to determine if the findings are reliable. The committee was not provided the results of efforts to correlate imaging findings to clinical findings, and most subjects examined did not show the pattern of imaging findings reported in the average, which further diminish the clinical value of the reported findings. Investigators at the NIH performed imaging on a small number of the Havana cohort at even later dates (i.e. years in some cases and did not find any differences from normal subjects, but their studies are ongoing).
The Dalhousie group also reported normal structural MRI findings, and reported changes in diffusion tensor imaging of the white matter tracts in the posterior part of the corpus callosum and the adjacent part of the fornix (Friedman et al., 2019). These types of changes are subject to the same caveats as the Penn findings (and a lack of congruity between the two studies is noted). However, the Dalhousie patients may not have had the same clinical disorder as DOS employees, as noted above.
In summary, the committee felt that none of the imaging studies performed so far were sufficient to serve as a basis for a case definition or for management of individual subjects.
General Comments About the Patient Evaluations
The committee finds that as a routine, general approach to cases with neurological manifestations, patient evaluations should be performed as soon as possible after onset and should include a complete neurological examination, followed by a standard whole brain MR scan, with and without contrast, preferably performed at 3T, with diffusion weighted imaging and a T2* sensitive sequence (susceptibility weighted imaging is preferred) to detect microbleeds. If the case involves auditory or vestibular symptoms, fine cuts might be added through the inner ear; for visual symptoms, fine cuts through the orbit; and for cases with somatosensory or motor phenomena, fine cuts through the cervical and thoracic spinal cord. Functional MRI is not well-suited to single subject studies. Similarly, diffusion tensor imaging for tractography is not reliable as an indicator of abnormalities in individuals.
In neuro-otology, there is no consensus about a standard test battery for auditory or vestibular symptoms. Evoked potentials are fairly simple, objective measures of slowing of
conduction in these sensory systems, due to a variety of causes, but are not uniformly accepted as a standard for evaluation.
Additional testing should be undertaken as clinically indicated. Blood should be collected as soon as possible after the onset of symptoms, and both plasma and whole blood frozen and stored for future toxicological, infectious, and other appropriate evaluations. All of these evaluations are routinely available in any modern large hospital, but may require plans in advance for referring Embassy personnel to such a facility as soon as possible after onset.
SUMMARY
The most distinctive clinical aspects of the illnesses described in DOS Havana personnel are the nature of the onset and the initial features: the sudden onset of a perceived loud sound, a sensation of intense pressure or vibration in the head, and pain in the ear or more diffusely in the head. Most individuals reported that the sound or these other sensations seemed to originate from a particular direction and that they were perceived only when the individual was in a specific physical location. Different numbers of individuals also reported sudden onset of tinnitus, hearing loss, dizziness, unsteady gait and visual disturbances.
From a neurologic standpoint, this combination of distinctive, acute auditory-vestibular symptoms suggests an effect localized to the labyrinth or VIII cranial nerve or its brainstem connections. The committee found this constellation of acute symptoms with directional and location-specific features to be very unusual and, to the best of the committee’s knowledge, unlike those associated with any disorder reported in the neurological or general medical literature. The sudden onset and immediate amelioration with change in location makes an infectious or toxic cause less likely, while the repeated testimony that the symptoms were experienced only in specific physical locations near windows or as originating or emanating from a particular direction raised the possibility that they were due to some physical force that could penetrate windows but not walls. As such, we considered in detail the possibility that these acute symptoms may have been caused by directed RF energy, as well as toxic, infectious, and psychological processes.
The more chronic (later phase) problems suffered by Havana personnel included mainly vestibular processing and cognitive problems as well as insomnia and headache. From a neurologic standpoint, these cognitive symptoms and insomnia are more consistent with diffuse involvement of forebrain structures and function, such as cerebral cortex or limbic structures. While these chronic symptoms are common complaints, it is quite possible that in those personnel with the dramatic initial phase auditory and vestibular symptoms, these subsequent, more persistent symptoms were caused by sequelae of the same initial insult or that they occurred secondarily as an accommodative response. In those personnel without reports of an acute initial phase, these chronic symptoms could suggest an exposure or cause distinct from those with an initial phase, or a similar exposure that resulted more exclusively in forebrain dysfunction.
A key problem in the committee’s assessment was the lack of information collected in a systematic fashion from every affected individual from the initial onset of the first case, as well as from control individuals. By relying on routine clinical evaluation and management of these individuals within the U.S. commercial health care system, significant information was lost due to delays, differences in insurance coverage and consequent differences in clinical work-up of each case, and lack of a standardized approach. The information was also firewalled in distinct silos by Health Insurance Portability and Accountability (HIPAA) regulations, making it almost
impossible to put together a coherent picture. CDC is currently the only organization that has the ability to penetrate these firewalls, but they were not involved until many months after the primary investigations by Miami, Penn, and NIH. A plan that solves this issue would be of great benefit to DOS and its employees. Baseline visual, auditory, and vestibular data from each individual would have helped as well, given that deficits in these systems can often occur with aging.
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