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Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
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Section 4

Plausible Mechanisms

Multiple kinds of mechanisms might contribute to the observed phenomena in the Department of State (DOS) personnel. The committee narrowed the investigation to four, based on their previous appearance in analogous outbreaks of paroxysmal symptoms, their presence in similar localized settings, information available from other investigators, and most notably the known constellation of medical effects (centering on neurologic findings of acute onset). As discussed in Section 3, the acute symptoms with directional dependence are highly unusual, and unlike any disorder reported in the neurological or general medical literature including those with known infectious, inflammatory, or toxic mechanism. The committee felt that these acute symptoms were more consistent with a directed radio frequency (RF) energy attack, and explored possible related mechanisms. At the same time, the chronic symptoms that were reported are often seen in patients after head trauma, as a result of chemical exposure, infectious diseases, or stress in a hostile environment. There did not appear to be any evidence for usual forms of traumatic injury, but the committee did evaluate possible chemical and infectious causes as well as psychosocial causes, for the chronic symptoms.

DIRECTED RADIO FREQUENCY ENERGY

Sources of Information

The committee relied on open source data from published literature as well as firsthand reports from clinicians, researchers, and affected DOS personnel shared in person at its December and February meetings, to evaluate the plausibility of directed RF energy exposure as a cause of both the acute and chronic clinical signs and symptoms discussed in Section 3 (Clinical Findings). While the committee did review the significant body of scientific literature on the potential therapeutic and palliative applications of electromagnetic energy (e.g., medical radiotherapies) (Citrin, 2017; Mohan et al., 2019; Saitz et al., 2019; Suh et al., 2020; Tsao et al., 2018) and the health risks of microwave radiation (e.g., cell phone emissions) (FDA, 2020; NTP, 2018a,b), this subsection primarily restricts its focus to RF biological effects that are consistent with the clinical and personal (by DOS patients) observations.

Observations from clinicians (including published summaries of symptoms and experiences) and DOS personnel were considered with respect to known biological effects of a wide variety of RF exposures (defined as 30KHz-300GHz, including microwave radiation as 300MHz-300GHz). The committee used these personal and clinician observations to identify known RF biological effects that should be either included or excluded from consideration in explaining the signs and symptoms in DOS personnel.

Assessment and Findings

Low-level RF exposures typically deposit energy below the threshold for significant heating (often called “nonthermal” effects), while high-level RF exposures can provide enough energy for significant heating (“thermal” effects) or even burns, and for stimulation of nervous and muscle tissues (“shock” effects) (IEEE, 2019). While much of the general public discussion

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

on RF biological effects has focused on cancer, there is a growing amount of data demonstrating a variety of non-cancer effects as well, in addition to those associated with thermal heating.

Based on a review of these information sources, the committee finds that many of the acute, early phase symptoms and observations reported by DOS employees are consistent with RF effects, including a perceived clicking sound within the head even when the ears were covered, a perceived force/pressure sensation within the head and on the face, perceived spatial localization and directionality of these perceived phenomena and other loud sounds, hearing loss, tinnitus, impaired gait and loss of balance, as well as the absence of heating sensation and absence of observed disruption of electronic devices in the immediate environment. In addition, many of the chronic, nonspecific symptoms are also consistent with known RF effects, such as dizziness, headache, fatigue, nausea, anxiety, cognitive deficits, and memory loss.

The absence of certain observed phenomena can also help to constrain potential RF source characteristics. For example, the absence of reporting of a heating sensation or internal thermal damage may exclude certain types of high-level RF energy.

There are multiple possible mechanisms for non-thermal RF biological effects, including apoptosis and cell oxidative stress (Barnes and Greenebaum, 2018; Ilhan et al., 2004; Salford et al., 2003; Steiner and Ulrich, 1989; Zhao et al., 2007). RF-induced, non-thermal cell membrane dysfunction (Ramundo-Orlando, 2010) can occur from coherent excitation (Fröhlich, 1988) above 1 GHz due to a variety of effects including electroporation, metabolic changes, pressure fluctuations, and voltage gated calcium channel disruption (Pall, 2013, 2016). However, many of the cognitive, vestibular, and auditory effects observed in DOS personnel are most consistent with modulated, or pulsed, RF biological effects.

There was significant research in Russia/USSR into the effects of pulsed, rather than continuous wave (CW) RF exposures because the reactions to pulsed and CW RF energy at equal time-averaged intensities yielded substantially different results (Pakhomov and Murphy, 2000). According to Pakhomov and Murphy, the Russian-language studies “indicated that pulsing may be an important (or even the most important) factor that determines the biological effects of low-intensity RF emissions” (Pakhomov and Murphy, 2000, p. 2). Military personnel (in Eurasian communist countries) exposed to non-thermal microwave radiation were said to have experienced headache, fatigue, dizziness, irritability, sleeplessness, depression, anxiety, forgetfulness, and lack of concentration, as well as internal sound perception for frequencies between 2.05-2.50 GHz (Adams and Williams, 1976). The review by Pakhomov and Murphy noted that many of the studies from the former Soviet Union were flawed in one or more ways, but that some were well done, replicated, and credible.

Pulsed RF effects on the nervous system can include changes to cognitive (D’Andrea, 1999; Lai, 1994; Tan et al., 2017), behavioral (D’Andrea and Cobb, 1987), vestibular (Lebovitz, 1973), EEG during sleep (Lustenberger et al., 2013), and auditory (Elder and Chou, 2003) function in animals and humans, though many RF exposure characteristics (carrier frequency, pulse repetition frequency, orientation, power densities, duration of exposure) complicate direct comparisons of different experiments (D’Andrea et al., 2003). Some animal studies have shown conflicting results, however, even when using the same exposure system. For example, researchers using the Transformer Energized Megavolt Pulsed Output (TEMPO) microwave pulse apparatus with high peak power RF energy but low specific absorption rate (SAR) values observed a negative effect on cognitive function in rats (time perception and discrimination tasks) (Raslear et al., 1993), but other researchers found no observable behavioral changes in rhesus monkeys (D’Andrea et al., 1989; Ziriax et al., 1999). It should be noted that the low SAR

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

values for both animal models were lower than whole-body SAR thresholds known to disrupt behavioral performance (D’Andrea, 1991; D’Andrea and de Lorge, 1990; de Lorge, 1984).

In 1961, Alan Frey identified a new, RF-induced auditory phenomenon in both normal and deaf humans that became known as the “Frey effect” (Frey, 1961) (see Appendix C). The areas near the ear were most sensitive to these RF exposures; modulating the RF energy could produce a variety of effects including the perception of “buffeting of the head” or pressure on the face/head without dizziness or nausea, a “pins and needles sensation,” and a sound described as a “buzz, clicking, hiss, or knocking” within the head for RF frequencies between 0.4-3 GHz, depending on pulse width, pulse-repetition frequency (PRF), and peak power density (Frey, 1962). These reported symptoms are consistent with some of the first-person accounts provided to the committee. Frey reported these symptoms with an RF source transmitting at 1.3 GHz (which provides the greatest absorption depth into cortical tissue) with a PRF of 244 Hz, 6 µs pulse width, peak power density of 267 mW/cm2, and average power density of 0.4 mW/cm2 (Frey, 1962). Others have demonstrated that GHz range, pulsed RF energy (~14µs pulse width) interacting with common materials can produce external sounds that are audible to nearby humans (Sharp et al., 1974). This is also consistent with potential smartphone microphone excitation from RF energy that would lead to an external, audible clicking sound from the phone. The ability for a pulsed RF source to create internal and external auditory stimuli simultaneously agrees with published and personal reports. Importantly, the Frey effect may be induced without causing identifiable structural injury to neural or labyrinthine tissues.

The potential for RF sources to stimulate the vestibular end organs via thermoelastic pressure waves (see Appendix C) or to excite central nervous system pathways via transduction akin to the Frey effect is not known. However, if these effects exist, this unusual form of vestibular stimulation could lead to very confusing perceptions, as central vestibular pathways do their best to resolve the non-physiological pattern of end organ stimulation resulting in perceptions of physically impossible motions, unexpected reflexive postural responses to them, and faulty inferences about external forces causing them. Affected individuals could report different sensations in response to the same external stimulus; thus, it is consistent with this scenario that the early phase reports of the perceptions of affected individuals varied from one individual to another, and may have been difficult for the individuals to describe. With regard to vestibular and balance systems, the functional vestibular disorder of persistent postural-perceptual dizziness (PPPD) may be triggered by any condition that causes symptoms of vertigo, unsteadiness, or dizziness, or disrupts balance function, even if transiently and without causing structural injury (Staab et al. 2017). The NIH team diagnosed PPPD in one-quarter of patients that they evaluated. Patients with PPPD commonly report problems with cognition and fatigue in addition to core symptoms of unsteadiness, dizziness and susceptibility to motion stimuli (Stone, 2016).

If a Frey-like effect can be induced on central nervous system tissue responsible for space and motion information processing, it likely would induce similarly idiosyncratic responses. More general neuropsychiatric effects from electromagnetic stimuli are well-known and are being used increasingly to treat psychiatric and neurologic disorders. In 2008, the Food and Drug Administration (FDA) approved transcranial magnetic stimulation (TMS) to treat major depression in adults who do not respond to antidepressant medications (Cook, 2018). Ten years later, the FDA approved office-based TMS as a treatment for obsessive compulsive disorder (OCD) (FDA, 2018) and portable TMS to treat migraine (Jeffrey, 2013).

The benefits derived from purposeful short-term exposures to therapeutic neuromodulation contrast with the adverse neurologic and neuropsychiatric symptoms described

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

by individuals exposed to electromagnetic fields (e.g., high tension electrical transmission cables) over longer periods of time (Pall, 2016) as summarized by Stein and Udasin (2020).

Summary

The committee finds that many of the acute, sudden-onset, early phase signs, symptoms and observations reported by DOS employees are consistent with RF effects. In addition, many of the chronic, nonspecific symptoms are also consistent with known RF effects, such as dizziness, headache, fatigue, nausea, anxiety, cognitive deficits, and memory loss. It is not necessary for RF energy sources to produce gross structural damage to cause symptoms. Rather, as with the Frey effect or potential thermoelastic pressure waves, RF sources may trigger symptoms by transiently inducing alterations in brain functioning.

There are several types of data that would be helpful and could improve both the findings and their level of certainty. While there are several studies on the health effects of continuous wave and pulsed RF sources, there are insufficient data in the open literature on potential RF exposure/dosage characteristics and biological effects possible for DOS scenarios. Specific experiments would be needed with RF exposure and dosage characteristics (frequency, pulse repetition frequency, pulse width, incident angle between potential source and subject, duration of exposure, number of repeated exposures, etc.) to quantify the biological effects, but would be ethically difficult to justify. In the absence of such data, it is difficult to align specific biophysical effects within the potential RF exposure regime that could explain specific medical symptoms reported by DOS personnel and the variability in specific experiences and timelines of individuals. Patient clinical heterogeneity could be due to variability of exposure dosage conditions, differences in interpretation of non-physiological vestibular stimuli, and anatomical differences that could influence individual exposure and/or response.

CHEMICALS

Sources of Information

DOS asked the committee to consider the plausibility of organophosphate (OP) or pyrethroid insecticide exposure as a cause of the clinical signs/symptoms observed in U.S. Embassy personnel in Havana. This possible cause was raised by Canadian investigators who reported decreased cholinesterase activity, temephos (an OP), and pyrethroid metabolites in blood samples collected from some Canadian Embassy personnel and Canadian tourists who were in Havana during the same period as the affected U.S. Embassy personnel. Additionally, the timing of some cases in U.S. Embassy personnel coincided with widespread spraying of OP and pyrethroid insecticides in Cuba in 2016 to mitigate spread of Zika virus by mosquitos.

To address the plausibility of the OP/pyrethroid insecticide hypothesis, the committee examined five sources of information: (1) the Research Report, “Havana Syndrome: Neuroanatomical and Neurofunctional Assessment in Acquired Brain Injury Due to Unknown Etiology” (Friedman et al., 2019); (2) formal presentations to the committee by Claire Huson (DOS Office of Safety, Health, and Environmental Management), Cynthia Calkin and Alon Friedman (Dalhousie University Faculty of Medicine), Marion Ehrich (Virginia-Maryland College of Veterinary Medicine), and Nick Buckley (University of Sydney); (3) feedback provided during a question and answer session with DOS Bureau of Medical Services staff; (4) the National Toxicology Program publication, “Systematic review of long-term neurological effects following acute exposure to the organophosphorus nerve agent sarin,” (NTP, 2019); and (5) peer-reviewed scientific literature.

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

The committee considered three general issues: (1) What is the strength of the evidence that affected individuals were exposed to OP or pyrethroid insecticides?; (2) Were exposures at levels that might be expected to cause toxic effects?; and (3) How similar are the signs and symptoms of acute, subacute, or chronic exposures to OP or pyrethroid insecticides to the distinctive acute signs and symptoms and the less specific chronic signs and symptoms associated with cases from Havana?

Assessment and Findings

With respect to the question of exposure, information presented by Claire Huson regarding the DOS Integrated Pest Management (IPM) program indicated that pyrethroids (lambda cyhalothrin, cyfluthrin, permethrin, and cypermethrin) were used in U.S. Embassy offices and residences in Havana; thus, the potential for exposure of U.S. Embassy personnel to these insecticides was quite high. OPs were not included in the IPM program and it is DOS IPM policy not to allow outside contractors to apply pesticides in U.S. Embassy offices or residences. Consistent with this information, the committee heard in a question and answer session with DOS medical staff that OPs were not detected in environmental samples collected from the residences of U.S. Embassy personnel some months after the incidence of unexplained illnesses. However, this information does not rule out the possibility that U.S. Embassy personnel were exposed to OPs in their residences proximal to the onset of symptoms because OPs are relatively short-lived in the environment (half-life of several days in the outdoor environment and weeks to months in the indoor environment depending on dust levels, light, and humidity). Moreover, information provided by presenters from Dalhousie University indicated widespread heavy spraying of OPs (including the OP chlorpyrifos) and pyrethroids throughout Cuba to prevent the spread of Zika virus by mosquitos. If the images of pesticide spraying shown in the formal presentations to the committee were reflective of actual conditions in Havana, it is highly likely that U.S. Embassy personnel were exposed to OPs either when they were in public spaces or via overspray that drifted from public spaces into U.S. Embassy offices and residences. As an aside, targeted exposures of individuals to OPs are also possible, as illustrated by the assassination of Kim Jong-nam, half-brother of North Korean leader Kim Jong-un, who died after two women allegedly applied OP nerve agent to his skin in the Kuala Lumpur airport on February 13, 2017, and by the attempted assassination of a former Russian spy and his daughter in Great Britain in 2018. However, these individuals showed acute symptoms of cholinergic poisoning associated with their exposure to OPs.

OP exposure is also monitored by measuring AChE activity in blood samples because OP insecticides inhibit AChE. AChE activity was not measured in blood from U.S. Embassy personnel. The Dalhousie University research team presented data they believed demonstrated significantly decreased AChE activity in at least a subset of Canadian Embassy personnel and Canadian tourists who were in Havana during the same time as affected U.S. Embassy personnel. Based on these data and targeted analysis of OPs and pyrethroid metabolites in serum samples that identified the OP temephos and the pyrethroid metabolite 3-PBA in blood from a subset of individuals (although the overlap between individuals with AChE inhibition and detectable OPs/pyrethroids is not clear), the Dalhousie University group developed a working hypothesis that neurological effects were due to chronic low level cholinesterase inhibitor toxicity. These data cannot, however, be considered supportive of this hypothesis. One reason, based on information presented to the committee, is that the Dalhousie group measured AChE activity in serum/plasma samples. However, AChE is a membrane-bound molecule found in blood only on erythrocytes; thus, whole blood samples, not serum or plasma, are required for accurate

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

determination of AChE activity in blood. Another concern with the Dalhousie measurements is that AChE levels should always be compared to the established reference values of the clinical laboratory in which the measurements are performed, rather than to the values of a specific and limited set of experimental controls, because laboratory reference values are generally based on many more samples and reflect a more realistic range of normal activities. The Dalhousie study relied instead on experimental controls. A second reason is that the number of Canadian personnel with detectable levels of temephos or 3-PBA was much smaller than the number of individuals with symptoms. A third reason is that Canadian personnel were not sampled at the time of initial signs and symptoms.

Absent data regarding the concentration of OPs or pyrethroids in relevant environmental samples collected proximal to the onset of symptoms or in samples from affected U.S. Embassy personnel at the time of initial signs and symptoms, it is not possible to determine whether exposures were at levels that might reasonably cause toxic effects, particularly in vulnerable individuals. This issue is complicated by the fact that there is growing evidence that at least some of the neurotoxic effects of OPs are mediated by mechanism(s) other than or in addition to AChE inhibition (Anger et al., 2020; Costa, 2006; Naughton and Terry, 2018; Pope, 1999).

With regards to the overlap of symptoms between chemical exposures and the Havana cases, epidemiologic and clinical studies have linked occupational or environmental chemical (including OP and pyrethroid insecticide) exposures to a subset of the distinctive early phase symptoms and many of the nonspecific chronic problems suffered by some of the U.S. Embassy Havana cases (see Appendix D).

Acute OP poisoning manifests as a clinical toxic syndrome known as cholinergic crisis, which includes parasympathomimetic symptoms (sweating, tears, rhinorrhea, salivation, urination, diarrhea, increased bronchial secretions and bronchoconstriction, and bradycardia), muscle fasciculation followed by flaccid paralysis, loss of consciousness and seizures (Eddleston et al., 2008; Hulse et al., 2014). Subacute and chronic OP exposures involving doses that do not cause significant AChE inhibition, do not cause cholinergic signs but can be associated with neurotoxic effects not only in individuals with occupational exposures, but also in the general public. OP-associated neurotoxic effects, which may or may not be associated with AChE inhibition in affected individuals, include hearing loss, tinnitus, dizziness, headache, fatigue, motor incoordination, nausea, insomnia, anxiety, memory deficits and inability to concentrate (Anger et al., 2020; Ashok Murthy and Visweswara Reddy, 2014; Choochouy et al., 2019; Crawford et al., 2008; Dassanayake et al., 2007, 2008, 2009; Dundar et al., 2016; Edwards and Tchounwou, 2005; London et al., 1998; Richter et al., 1992; Roldan-Tapia et al., 2006; Ross et al., 2013; Teixeira et al., 2002). Some of these effects were reported among affected DOS employees stationed in Havana.

There are significantly less epidemiologic and clinical data available regarding the neurotoxic effects of pyrethroids than there are for OPs, but published studies report associations between acute, subacute, and chronic pyrethroid exposures and hearing loss, visual disturbance, tinnitus, dizziness, headache, nausea, fatigue, and deficits in memory and concentration in occupational cohorts and in the general public (Campos et al., 2016; Chen et al., 1991; Lessenger, 1992; Müller-Mohnssen, 1999; Richardson et al., 2019; Teixeira et al., 2002; Xu et al., 2020; Zeigelboim et al., 2019). High dose acute pyrethroid exposures are also associated with tremors and seizures (Bal-Price et al., 2015).

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

Summary

In summary, the committee concludes that it is not likely that acute high-level exposure to OPs and/or pyrethroids contributed to the unexplained illnesses observed in the Havana cases because there is no convincing evidence of acute high-level exposures and the clinical history of affected U.S. Embassy personnel is not consistent with acute OP poisoning. It is also unlikely that subacute or chronic OP or pyrethroid exposures precipitated the onset of the distinctive acute symptoms associated with the Havana cases. However, given experimental data indicating that interactions between pesticides (particularly OPs) and psychosocial or physical stressors, the latter including noise and non-ionizing radiation, can increase risk and/or severity of adverse outcomes, the committee could not rule out the possibility, although slight, that exposure to insecticides, particularly OPs, increased susceptibility to the triggering factor(s) that caused the Embassy personnel cases. Alternatively, differential exposure to insecticides amongst affected individuals may have contributed to the clinical heterogeneity of the acute symptoms noted in Havana cases, since OP and pyrethroid exposures are associated with a subset of these acute symptoms (see Appendix D). The committee also finds it plausible that subacute or chronic OP and/or pyrethroid exposures contributed to the nonspecific chronic symptoms observed in affected U.S. Embassy personnel.

INFECTIOUS AGENTS

Sources of Information

The committee reviewed published medical and public health literature, including results of searches of PubMed for infectious diseases, Cuba, and neurological features.

Assessment and Findings

The committee considered endemic and epidemic infectious diseases known to have been present in Cuba during 2016-2018 and focused on those with known neurological manifestations. Some of these diseases could be excluded based on their dissimilar clinical features relative to the signs and symptoms reported by U.S. Embassy personnel in Havana, such as rabies or Guillain-Barré syndrome as a post-infectious complication of campylobacteriosis. Several mosquito-borne infections received further attention because of their prevalence and association with relevant, albeit rare, clinical features. These included dengue, chikungunya, and Zika virus infections. All three have been associated with encephalitis, Guillain-Barré syndrome, transverse myelitis, and neuro-ocular disease (Mehta et al., 2018). All of these complications are rare. For example, it has been estimated that approximately 0.1 percent of all chikungunya infections develop neurological disease (Economopoulou et al., 2009). Risk factors include underlying comorbidities, and the extremes of age. However, nearly all of these chikungunya cases with neurological complications also presented with typical acute systemic manifestations (i.e., fever, rash, arthralgia, and conjunctivitis). Although dengue has been the most commonly reported arboviral infection in Cuba (Guanche Garcell et al., 2020), the epidemiology and incidence of Zika in Cuba is particularly relevant to the timing of the DOS personnel health events.

Travel surveillance and genomic epidemiology revealed a large, unreported, and delayed Zika outbreak in Cuba that followed Zika outbreaks elsewhere in the Caribbean by about one year (Grubaugh et al., 2019). Zika disease began in Cuba in the latter half of 2016 and peaked in fall 2017. Genomic surveillance confirmed dengue disease in Cuba in 2014 and 2015 and a chikungunya outbreak in 2014, but little or none of these two diseases in 2016 and 2017. It is believed that implementation of an intensive mosquito control program based on insecticide use

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

beginning in February 2016 may have delayed the establishment of Zika virus and subsequent disease in Cuba until 2016-2017. (The committee considered the possible role of organophosphate and pyrethroid insecticide exposure in the DOS personnel illnesses—see Section 4, Chemicals.) Thus, the timing and relative prevalence of Zika in Cuba justify further comment on this infection as a possible cause of the DOS personnel cases.

A population-based observational study of Zika infection in the French West Indies in 2016 provides a valuable description of the neurologic complications of this disease (Lannuzel et al., 2019), and a reference against which the clinical features reported in DOS personnel (see Section 3) can be compared. In 2016, 66,600 persons in Guadeloupe and Martinique sought medical attention with manifestations of Zika infection. Of these, 87 presented to the major referral centers on the two islands with neurologic manifestations. Of the 87, 54 (62 percent) had peripheral nervous system (PNS) involvement, and of those 54, 40 were diagnosed with Guillain-Barré syndrome. Among the other 14 with PNS disease, 8 had cranial nerve palsies; in all 8, the facial nerve was involved, and in 4 of them, there was involvement of the vestibulocochlear nerve. Of the 87, 19 had central nervous system (CNS) involvement, with encephalitis the most common diagnosis. Of the 87, 14 had both PNS and CNS disease. Of 76 patients available for follow-up, 19 had residual disease at a median of 14 months after presentation.

Thus, the overall rate of Zika neurological complications seen in the main clinical referral centers during this epidemic year in the French West Indies was approximately 0.1-0.2 percent of those with known Zika infection (Lannuzel et al., 2019). This is similar to the rate for chikungunya on Reunion Island in 2005-2006. Approximately 5 percent of this small subpopulation with Zika neurologic complications shared a feature with the illnesses reported in the DOS Cuba patient cohort (i.e., vestibular disease, manifest as dizziness, nystagmus, and/or vertigo). A smaller number had hearing loss, memory difficulties, and visual loss. Thus, Zika virus can cause a few of the acute and chronic clinical features reported in the DOS Cuba patient cohort, but these features are quite rare with Zika and would not be expected to occur at all in a population of less than 1,000 people with Zika. None of the patients in the DOS Cuba cohort are said to have suffered from the much more common manifestations of Zika: rash, fever, arthralgia, myalgia, and conjunctivitis.

Summary

In summary, the committee considered possible infectious etiologies that might explain the clinical features reported in DOS employees and focused on those infectious agents known to be prevalent in Cuba and capable of causing neurological manifestations. Among those agents, Zika infection received attention from the committee because it was epidemic in Cuba in 2016-2017 and is known to be able to produce relevant neurological findings. However, after reviewing the medical and public health literature, the committee found it highly unlikely that Zika was the cause of the constellation of signs and symptoms reported among DOS personnel, especially the acute, sudden onset, initial phase clinical features, for two major reasons. First, Zika is not known to cause an abrupt onset illness nor an illness with the collection of findings reported in the initial phase of the DOS employee illnesses—especially in the absence of rash, fever, arthralgia, myalgia and conjunctivitis. Second, the relevant neurological features of Zika are exceedingly rare and statistically would not be expected to occur in any DOS employee in Havana, and certainly not more than one.

The committee could not rule out the possibility that some employees were infected by Zika, and that it contributed in some fashion together with other causative factors to the chronic

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

clinical findings, especially during 2017. The committee is not aware of serological testing for Zika or any other infectious agents among DOS Embassy Havana affected personnel.

PSYCHOLOGICAL AND SOCIAL FACTORS

Sources of Information

As noted in Section 3, clinical investigators presented data to the committee as aggregated summaries of patients’ histories, physical examination findings, and results of laboratory testing including neuropsychological assessments. Individual patient-level data were not provided to the committee, other than what the committee learned from direct interviews with a small number of affected DOS personnel.

Assessment and Findings

Acute Symptoms

The committee carefully considered three possible roles for psychological and social factors in the morbidity experienced by DOS employees: (1) psychiatric disorders as primary causes of symptoms; (2) psychiatric disorders as secondary sequelae of other causes of illness; and (3) psychological and social factors co-existing with other causes of illness. As with all other potential causes and mechanisms reviewed by the committee, evidence was sought for and against specific associations between psychological and social factors and patients’ symptoms. The committee did not regard psychological and social factors to be default explanations for enigmatic symptoms but endeavored to make a positive identification of their potential contributions to morbidity. These efforts were constrained by the limits of data collected and presented by the clinical teams from Miami, Penn, Dalhousie, and NIH, which offered an incomplete picture of the range of acute and chronic symptoms over space and time, and in particular about the course of illness of individual patients. Nevertheless, it appeared that a biphasic distribution of acute and chronic symptoms (see Section 2) offered coherence to the patterns of neuropsychiatric symptoms reported by the clinical teams and patients themselves.

In general, psychological factors may cause or contribute to emotional symptoms (sadness, frustration, irritability, anxiety, and anhedonia), vegetative symptoms (sleep, energy, and appetite changes), and cognitive symptoms (attention, concentration, and memory problems), as well as enigmatic somatic symptoms. At the milder end of the spectrum, these may fall short of fully diagnosable psychiatric disorders (i.e., transient and self-limited responses to life circumstances) or may represent adjustment disorders (i.e., periods of poor adjustment to stressors, including other illnesses). More severe or persistent symptoms may constitute major depressive or anxiety disorders, either as primary, secondary, or co-existing illnesses. In cases where individuals are exposed to potential threats to life or limb, acute and posttraumatic stress disorders may develop, manifesting with symptoms of re-experiencing, avoidance, hyperarousal, and negative mood and cognitions regarding the triggering event. The development of acute and posttraumatic stress disorders rests on the perception of threat by affected individuals. As such, reactions may vary considerably among exposed persons.

Potential threats attributed to human causes are more likely to trigger traumatic stress symptoms than threats attributed to natural causes, especially when the threat is thought to arise from the concerted efforts of an adversarial group (e.g., warfare) rather than isolated actions of individuals (e.g., unprovoked assaults) (Bromet et al., 2017; Staab et al., 1999). Environments that include incomplete, inconsistent, or erroneous information about potential threats may

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

exacerbate and perpetuate symptoms. After reviewing the nature of these disorders, the committee concluded that such reactions could not cause the initial sudden-onset distinct and unusual audio-vestibular symptoms and signs described in Section 3 or by CDC, but that psychological or psychiatric disorders could conceivably contribute to some of the other acute and chronic symptoms in some patients.

The committee then considered the possibility that acute auditory and vestibular symptoms described by DOS patients were hallucinations or delusions. Psychotic disorders may cause hallucinations involving any sensory modality. Auditory hallucinations are common, whereas vestibular and balance hallucinations are uncommon. However, auditory hallucinations caused by primary psychotic disorders usually take the form of human voices or other human sounds, less often other natural or mechanical sounds. Importantly, the committee received no evidence that any patients had psychiatric symptoms indicative of primary, secondary, or coexisting schizophrenic spectrum disorders, brief reactive psychoses, mood disorders with psychosis, psychoses related to substances of abuse, or psychoses associated with major cognitive disorders. Therefore, the committee found it very unlikely that any of the acute or chronic symptoms experienced by patients were caused by these conditions.

Patients with delusional disorders may describe a variety of sensory experiences that they relate to plausible (i.e., non-bizarre) but not factual causes. The most common delusions are paranoid in nature. Affected individuals are otherwise normal from a psychiatric perspective. Delusional disorders do not cause other emotional, vegetative, or cognitive symptoms. Infrequently, delusions may be shared by a few individuals close to the index case. The committee did not receive information about the psychiatric or psychological status of individual patients; therefore, it could not make a determination about the presence or absence of delusional disorder as a cause for the distinct acute symptoms in any affected persons. However, the committee did conclude that delusional disorders could not explain the full range of symptoms reported by the entire group of patients.

Reports in the medical literature (Bartholomew and Baloh, 2020) and mass media (Borger and Jaekl, 2017; Hurley, 2019) have opined that mass psychogenic illness (also known as mass hysteria or epidemic hysteria) was the cause of patients’ symptoms. These reports cited the challenging political and security circumstances surrounding the diplomatic missions in Cuba and China, the frequent harassment experienced by DOS employees in their homes, the lack of evidence for a clear external cause for patients’ symptoms, and the absence of a definitive pattern of structural deficits on medical examinations in support of this conclusion. The committee considered this possibility, while keeping in mind that the likelihood of mass psychogenic illness as an explanation for patients’ symptoms had to be established from sufficient evidence. It could not be inferred merely by the absence of other causal mechanisms or the lack of definitive structural injuries.

Studies of mass psychogenic illnesses have found that social and environmental variables are important in triggering these events. Thereafter, social connections or exposure to developing cases either in person or vicariously through word of mouth or media, including social media, are necessary to sustain them (Bartholomew et al., 2012; Boss, 1997; Cole et al., 1990; Knight et al., 1965). However, adverse social circumstances are not required preconditions. Well-documented cases of mass psychogenic illnesses have occurred in groups that were under no identifiable external stress or internal strain at the onset of events (Bartholomew et al., 2012). Most individuals affected by mass psychogenic illnesses do not have pre-existing psychiatric disorders. Rather, in most events, index cases developed their initial symptoms in response to idiosyncratic interpersonal circumstances or after exposures to perceived or actual but benign

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

environmental stimuli (Bartholomew et al., 2012; Boss, 1997; Cole et al., 1990; Knight et al., 1965). However, it is important to recognize that mass psychogenic illness may follow index cases afflicted with serious medical conditions or exposed to harmful environmental agents, especially when potential causes of illnesses affecting index cases are unclear or misattributed to agents, actual or perceived, that may affect the larger group (Bartholomew et al., 2012). The term “mass” may be mistaken to imply that large numbers of individuals must be involved over a short period of time in these events. However, the medical literature shows that one-third of incidents since the 1970s involved fewer than 30 individuals and approximately 20 percent of events lasted longer than 30 days (Cole et al., 1990). For communities under chronic stress, resolution may take months (Bartholomew et al., 2012). Nonspecific dizziness, lightheadedness, and fatigue have been described commonly in mass psychogenic illnesses, but complaints similar to the directional audio-vestibular symptoms reported by affected individuals from Cuba have not (Bartholomew et al., 2012; Cole et al., 1990). Events of mass psychogenic illness end when the potential for social contagion is reduced (not necessarily eliminated) by separation of unaffected individuals from sources of contagion and when the majority of unaffected or previously affected individuals reach the conclusion that the inciting event was physically benign or no longer poses a risk (Bartholomew et al., 2012).

These key characteristics of mass psychogenic illness have strong parallels with outbreaks of infectious diseases and have been investigated successfully using similar rigorous epidemiologic methods since the 1960s (Knight et al., 1965), including detailed examinations of index cases and subsequently affected individuals, contact tracing, and careful investigation of the environments in which the events occurred (Bartholomew et al., 2012; Boss, 1997; Cole et al., 1990; Knight et al., 1965). As described in Section 3, the committee noted two constellations of signs and symptoms, one of them acute, occurring at the onset of some cases with more distinct and unusual features, and the other chronic, occurring later in the course of these cases or with subacute onset in other cases. However, in the absence of patient-level data, the committee could not identify index versus subsequent cases. Furthermore, the committee received no epidemiological evidence about patterns of social contacts that would permit a determination about possible social contagion. Without access to these data, a retrospective diagnosis of mass psychogenic illness is considered to be speculative at best and subject to necessary criticism (Jacobsen and Ebbehøj, 2016, 2017; Jansen et al., 2016). Thus, the committee was not able to reach a conclusion about mass psychogenic illness as a possible cause of the events in Cuba or elsewhere.

Chronic Symptoms

Despite extensive clinical evaluations, definitive causes of chronic symptoms have not been identified in most DOS personnel with ongoing morbidity. However, approximately one quarter of patients examined by the clinical team at NIH were diagnosed with persistent postural-perceptual dizziness (PPPD) and at least one patient received that diagnosis after a series of clinical examinations conducted elsewhere. PPPD is a functional (not psychiatric) vestibular disorder that may be triggered by vestibular, neurologic, other medical, and psychological conditions (Staab et al., 2017). Thus, its presence provides no information regarding the initial causality of patients’ symptoms. On the other hand, its presence may inform treatment as there are data from uncontrolled and small controlled investigations to support the use of vestibular (including visual) habituation exercises, cognitive behavioral therapy, and serotonergic antidepressants (selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors) for treating this condition (Popkirov et al., 2018; Staab, 2020). When symptoms of

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

PPPD occur in the setting of additional morbidity such as cognitive symptoms and psychological distress, expert opinion and clinical experience suggest that a broader array of treatments, including cognitive rehabilitation and third-wave psychotherapies (e.g., Mindfulness, Acceptance and Commitment Therapy) may be helpful.

Summary

As stated previously, the committee sought positive evidence that psychological and social factors may have caused or contributed to symptoms reported by DOS personnel. The acute initial, sudden-onset, distinct and unusual symptoms and signs described in some affected DOS personnel (see Section 3 and CDC Report) cannot be ascribed to psychological and social factors in the absence of patient-level data. The significant variability and clinical heterogeneity of the illnesses affecting DOS personnel leave open the possibility of multiple causal factors over time and place, both for individual cases and for the population. Like other mechanisms reviewed by the committee, psychological and social factors could exacerbate other forms of pathology and have to be considered as contributors to morbidity in some of the cases, especially for individuals with chronic symptoms.

The chronic vestibular symptoms experienced by some DOS personnel are consistent with persistent postural-perceptual dizziness. This functional vestibular disorder may be triggered by vestibular, neurologic, other medical, and psychological conditions, and offers a potential avenue for rehabilitative interventions.

REFERENCES

Adams, R. L., and R. A. Williams. 1976. Biological effects of electromagnetic radiation (radiowaves and microwaves)—Eurasian communist countries. Defense Intelligence Agency.

Anger, W. K., F. M. Farahat, P. J. Lein, M. R. Lasarev, J. R. Olson, T. M. Farahat, and D. S. Rohlman. 2020. Magnitude of behavioral deficits varies with job-related chlorpyrifos exposure levels among egyptian pesticide workers. Neurotoxicology 77:216-230.

Ashok Murthy, V., and Y. J. Visweswara Reddy. 2014. Audiological assessment in organophosphorus compound poisoning. Indian Journal of Otolaryngology and Head and Neck Surgery 66(1):22-25.

Bal-Price, A., K. M. Crofton, M. Sachana, T. J. Shafer, M. Behl, A. Forsby, A. Hargreaves, B. Landesmann, P. J. Lein, J. Louisse, F. Monnet-Tschudi, A. Paini, A. Rolaki, A. Schrattenholz, C. Sunol, C. van Thriel, M. Whelan, and E. Fritsche. 2015. Putative adverse outcome pathways relevant to neurotoxicity. Critical Reviews in Toxicology 45(1):83-91.

Barnes, F., and B. Greenebaum. 2018. Role of radical pairs and feedback in weak radio frequency field effects on biological systems. Environmental Research 163:165-170.

Bartholomew, R. E., and R. W. Baloh. 2020. Challenging the diagnosis of ‘Havana syndrome’ as a novel clinical entity. Journal of the Royal Society of Medicine 113(1):7-11.

Bartholomew, R. E., S. Wessely, and G. J. Rubin. 2012. Mass psychogenic illness and the social network: Is it changing the pattern of outbreaks? Journal of the Royal Society of Medicine 105:509-512.

Borger, J., and P. Jaekl. 2017. Mass hysteria may explain ‘sonic attacks’ in Cuba, say top neurologists. The Guardian. https://www.theguardian.com/world/2017/oct/12/cuba-mass-hysteria-sonic-attacks-neurologists (accessed July 18, 2020).

Boss, L. P. 1997. Epidemic hysteria: A review of the published literature. Epidemiologic Reviews 19(2):243-253.

Bromet, E. J., L. Atwoli, N. Kawakami, F. Navarro-Mateu, P. Piotrowski, A. J. King, S. Aguilar-Gaxiola, J. Alonso, B. Bunting, K. Demyttenaere, S. Florescu, G. de Girolamo, S. Gluzman, J. M. Haro, P. de Jonge, E. G. Karam, S. Lee, V. Kovess-Masfety, M. E. Medina-Mora, Z. Mneimneh, B. E. Pennell, J. Posada-Villa, D. Salmerón, T. Takeshima, and R. C. Kessler. 2017. Post-traumatic

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

stress disorder associated with natural and human-made disasters in the world mental health surveys. Psychological Medicine 47(2):227-241.

Campos, Y., V. Dos Santos Pinto da Silva, M. Sarpa Campos de Mello, and U. Barros Otero. 2016. Exposure to pesticides and mental disorders in a rural population of southern Brazil. Neurotoxicology 56:7-16.

Chen, S. Y., Z. W. Zhang, F. S. He, P. P. Yao, Y. Q. Wu, J. X. Sun, L. H. Liu, and Q. G. Li. 1991. An epidemiological study on occupational acute pyrethroid poisoning in cotton farmers. British Journal of Industrial Medicine 48(2):77-81.

Choochouy, N., P. Kongtip, S. Chantanakul, N. Nankongnab, D. Sujirarat, and S. R. Woskie. 2019. Hearing loss in agricultural workers exposed to pesticides and noise. Annals of Work Exposure and Health 63(7):707-718.

Citrin, D. E. 2017. Recent developments in radiotherapy. New England Journal of Medicine 377(22):2200-2201.

Cole, T. B., T. L. Chorba, and J. Hora. 1990. Patterns of transmission of epidemic hysteria in a school. Epidemiology 1:212-218.

Cook, I. A. 2018. Current FDA-cleared TMS systems and future innovations in TMS therapy. In Transcranial magnetic stimulation: Clinical applications for psychiatric practice, edited by R. A. Bermudes, K. Lanocha, and P. G. Janicak. Washington, DC: American Psychiatric Association Publishing. Pp. 173-198.

Costa, L. G. 2006. Current issues in organophosphate toxicology. Clinica Chimica Acta 366(1-2):1-13.

Crawford, J. M., J. A. Hoppin, M. C. Alavanja, A. Blair, D. P. Sandler, and F. Kamel. 2008. Hearing loss among licensed pesticide applicators in the agricultural health study. Journal of Occupational and Environmental Medicine 50(7):817-826.

D’Andrea. J. A. 1991. MW radiation absorption: Behavioral effects. Health Physics 61:29-40.

D’Andrea, J. A. 1999. Behavioral evaluation of microwave irradiation. Bioelectromagnetics Suppl 4:64-74.

D’Andrea, J. A,. and B. L. Cobb. 1987. High-peak-power microwave pulses at 1. 3. GHz: Effects on fixed-interval and reaction-time performance in rats. Naval Aerospace Medical Research Laboratory Report #1337.

D’Andrea, J. A., and J. O. de Lorge. 1990. Behavioral effects of electromagnetic fields. In Biological Effects and Medical Applications of Electromagnetic Energy, edited by O. P. Gandhi. Englewood Cliffs, NJ: Prentice Hall. Pp. 319-338.

D’Andrea, J. A., B. L. Cobb, and J. O. de Lorge. 1989. Lack of behavioral effects in the rhesus monkey: High peak microwave pulses at 1.3 ghz. Bioelectromagnetics 10(1):65-76.

D’Andrea, J. A., C. K. Chou, S. A. Johnston, and E. R. Adair. 2003. Microwave effects on the nervous system. Bioelectromagnetics Suppl 6:S107-S147.

Dassanayake, T., V. Weerasinghe, U. Dangahadeniya, K. Kularatne, A. Dawson, L. Karalliedde, and N. Senanayake. 2007. Cognitive processing of visual stimuli in patients with organophosphate insecticide poisoning. Neurology 68(23):2027-2030.

Dassanayake, T., V. Weerasinghe, U. Dangahadeniya, K. Kularatne, A. Dawson, L. Karalliedde, and N. Senanayake. 2008. Long-term event-related potential changes following organophosphorus insecticide poisoning. Clinical Neurophysiology 119(1):144-150.

Dassanayake, T., I. B. Gawarammana, V. Weerasinghe, P. S. Dissanayake, S. Pragaash, A. Dawson, and N. Senanayake. 2009. Auditory event-related potential changes in chronic occupational exposure to organophosphate pesticides. Clinical Neurophysiology 120(9):1693-1698.

de Lorge, J. O. 1984. Operant behavior and colonic temperature of Macaca mulatta exposed to radiofrequency fields at and above resonant frequencies. Bioelectromagnetics 5:233-246.

Dundar, M. A., S. Derin, M. Aricigil, and M. A. Eryilmaz. 2016. Sudden bilateral hearing loss after organophosphate inhalation. Turkish Journal of Emergency Medicine 16(4):171-172.

Economopoulou, A., M. Dominguez, B. Helynck, D. Sissoko, O. Wichmann, P. Quenel, P. Germonneau, and I. Quatresous. 2009. Atypical chikungunya virus infections: Clinical manifestations, mortality

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

and risk factors for severe disease during the 2005-2006 outbreak on reunion. Epidemiology & Infection 137(4):534-541.

Eddleston, M., N. A. Buckley, P. Eyer, and A. H. Dawson. 2008. Management of acute organophosphorus pesticide poisoning. Lancet 371(9612):597-607.

Edwards, F. L., and P. B. Tchounwou. 2005. Environmental toxicology and health effects associated with methyl parathion exposure--a scientific review. International Journal of Environmental Research and Public Health 2(3-4):430-441.

Elder, J. A., and C. K. Chou. 2003. Auditory response to pulsed radiofrequency energy. Bioelectromagnetics Suppl 6:S162-S173.

FDA (Food and Drug Administration). 2018. FDA permits marketing of transcranial magnetic stimulation for treatment of obsessive compulsive disorder. https://www.fda.gov/news-events/press-announcements/fda-permits-marketing-transcranial-magnetic-stimulation-treatment-obsessive-compulsive-disorder (accessed July 16, 2020).

FDA. 2020. Review of published literature between 2008 and 2018 of relevance to radiofrequency radiation and cancer. https://www.fda.gov/media/135043/download (accessed July 18, 2020).

Frey, A. H. 1961. Auditory system response to radio frequency energy. Technical note. Aerospace Medicine 32:1140-1142.

Frey, A. H. 1962. Human auditory system response to modulated electromagnetic energy. Journal of Applied Physiology 17:689-692.

Friedman, A., C. Calkin, and C. Bowen. 2019. Havana syndrome: Neuroanatomical and neurofunctional assessment in acquired brain injury due to unknown etiology.. https://www.scribd.com/document/426438895/Etude-du-Centre-de-traitement-des-lesions-cerebrales-de-l-Universite-de-Dalhousie#download (accessed July 7, 2020).

Fröhlich, H. 1988. Theoretical physics and biology. In Biological coherence and response to external stimuli, edited by H. Fröhlich. Berlin, Germany: Springer-Verlag. Pp. 1-24.

Grubaugh, N. D., S. Saraf, K. Gangavarapu, A. Watts, A. L. Tan, R. J. Oidtman, J. T. Ladner, G. Oliveira, N. L. Matteson, M. U. G. Kraemer, C. B. F. Vogels, A. Hentoff, D. Bhatia, D. Stanek, B. Scott, V. Landis, I. Stryker, M. R. Cone, E. W. T. Kopp, A. C. Cannons, L. Heberlein-Larson, S. White, L. D. Gillis, M. J. Ricciardi, J. Kwal, P. K. Lichtenberger, D. M. Magnani, D. I. Watkins, G. Palacios, D. H. Hamer, G. S. Network, L. M. Gardner, T. A. Perkins, G. Baele, K. Khan, A. Morrison, S. Isern, S. F. Michael, and K. G. Andersen. 2019. Travel surveillance and genomics uncover a hidden Zika outbreak during the waning epidemic. Cell 178(5):1057-1072.

Guanche Garcell, H., F. Gutiérrez García, M. Ramirez Nodal, A. Ruiz Lozano, C. R. Pérez Díaz, A. González Valdés, and L. Gonzalez Alvarez. 2020. Clinical relevance of Zika symptoms in the context of a Zika dengue epidemic. Journal of Infection and Public Health 13(2):173-176.

Hulse, E. J., J. O. Davies, A. J. Simpson, A. M. Sciuto, and M. Eddleston. 2014. Respiratory complications of organophosphorus nerve agent and insecticide poisoning. Implications for respiratory and critical care. American Journal of Respiratory and Critical Care Medicine 190(12):1342-1354.

Hurley, D. 2019. Was it an invisible attack on U.S. Diplomats, or something stranger? The New York Times Magazine. https://www.nytimes.com/interactive/2019/05/15/magazine/diplomatdisorder.html (accessed July 18, 2020).

IEEE (Institute of Electrical and Electronics Engineers). 2019. IEEE standard for safety levels with respect to human exposure to electric, magnetic, and electromagnetic fields, 0 hz to 300 ghz. IEEE Std C95.1-2019 (Revision of IEEE Std C95.1-2005/Incorporates IEEE Std C95.1-2019/Cor 1-2019) 1-312.

Ilhan, A., A. Gurel, F. Armutcu, S. Kamisli, M. Iraz, O. Akyol, and S. Ozen. 2004. Ginkgo biloba prevents mobile phone-induced oxidative stress in rat brain. Clinica Chimica Acta 340(1-2):153-162.

Jacobsen P., and N. E. Ebbehøj. 2016. Outbreak of mysterious illness in a hospital poisoning or iatrogenic induced mass psychogenic illness. Journal of Emergency Medicine 50:e47-e52.

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

Jacobsen, P., and N. E. Ebbehøj. 2017. Reply to Jansen et al. Journal of Emergency Medicine 52(4):581-583.

Jansen, T., E. C. Jenson, U. B. Haastrup, K. Esperson. 2016. Comments on “Outbreak of mysterious illness in a hospital poisoning or iatrogenic induced mass psychogenic illness.” Journal of Emergency Medicine 52(4):581-583.

Jeffrey, S. 2013. FDA approves first device to treat migraine pain. Medscape Medical News. https://www.medscape.com/viewarticle/817831#:~:text=The%20US%20Food%20and%20Drug,by%20migraine%20headache%20with%20aura (accessed July 18, 2020).

Knight, J., T. Friedman, and J. Sulianti. 1965. Epidemic hysteria: A field study. American Journal of Public Health 55(6):858-865.

Lai, H. 1994. Neurological effects of radio frequency electromagnetic radiation. In Electromagnetic Fields in Living Systems, Vol. 1, edited by J. C. Lin. New York: Plenum Press.

Lannuzel, A., J. L. Fergé, Q. Lobjois, A. Signate, B. Rozé, B. Tressières, Y. Madec, P. Poullain, C. Herrmann, F. Najioullah, E. McGovern, A. C. Savidan, R. Valentino, S. Breurec, R. Césaire, E. Hirsch, P. M. Lledo, G. Thiery, A. Cabié, F. Lazarini, and E. Roze. 2019. Long-term outcome in neurozika: When biological diagnosis matters. Neurology 92(21):e2406-e2420.

Lebovitz, R. M. 1973. Caloric vestibular stimulation via uhf-microwave irradiation. IEEE Transactions on Biomedical Engineering 20(2):119-126.

Lessenger, J. E. 1992. Five office workers inadvertently exposed to cypermethrin. Journal of Toxicology and Environmental Health 35(4):261-267.

London, L., V. Nell, M. L. Thompson, and J. E. Myers. 1998. Effects of long-term organophosphate exposures on neurological symptoms, vibration sense and tremor among South African farm workers. Scandanavian Journal on Work, Environironment, & Health 24(1):18-29.

Lustenberger, C., M. Murbach, R. Durr, M. R. Schmid, N. Kuster, P. Achermann, and R. Huber. 2013. Stimulation of the brain with radiofrequency electromagnetic field pulses affects sleep-dependent performance improvement. Brain Stimulation 6:805–811.

Mehta, R., P. Gerardin, C. A. A. de Brito, C. N. Soares, M. L. B. Ferreira, and T. Solomon. 2018. The neurological complications of chikungunya virus: A systematic review. Reviews in Medica Virology 28(3):e1978.

Mohan, G., T. P. Ayisha Hamna, A. J. Jijo, K. M. Saradha Devi, A. Narayanasamy, and B. Vellingiri. 2019. Recent advances in radiotherapy and its associated side effects in cancer—a review. The Journal of Basic and Applied Zoology 80(1):14.

Müller-Mohnssen, H. 1999. Chronic sequelae and irreversible injuries following acute pyrethroid intoxication. Toxicology Letters 107(1-3):161-176.

Naughton, S. X., and A. V. Terry, Jr. 2018. Neurotoxicity in acute and repeated organophosphate exposure. Toxicology 408:101-112.

NTP (National Toxicology Program). 2018a. Toxicology and carcinogenesis studies in B6C3F1/N mice exposed to whole-body radio frequency radiation at a frequency (1,900 mhz) and modulation (GSM and CDMA) used by cell phones. National Institutes of Health. https://ntp.niehs.nih.gov/ntp/about_ntp/trpanel/2018/march/tr596peerdraft.pdf (accessed July 27, 2020).

NTP. 2018b. Toxicology and carcinogenesis studies in HSD: Sprague Dawley SD rats exposed to whole-body radio frequency radiation at a frequncy (900 mhz) and modulations (GSM and CDMA) used by cell phones. National Institutes of Health. https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr595_508.pdf?utm_source=direct&utm_medium=prod&utm_campaign=ntpgolinks&utm_term=tr595 (accessed July 27, 2020).

NTP. 2019. Systematic review of long-term neurological effects following acute exposure to the organophosphorus nerve agent sarin. National Institutes of Health. https://ntp.niehs.nih.gov/ntp/ohat/sarin/sarin_prepublication20190600_508.pdf (accessed July 27, 2020).

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

Pakhomov, A. G., and M. R. Murphy. 2000. A comprehensive review of the research on biological effects of pulsed radiofrequency radiation in Russia and the former Soviet Union. In Electromagnetic Fields in Living Systems, Vol. 3, edited by J. C. Lin. New York: Kluwer Academic/Plenum Publishers. Pp. 265-290.

Pall, M. L. 2013. Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects. Journal of Cellular and Molecular Medicine 17(8):958-965.

Pall, M. L. 2016. Microwave frequency electromagnetic fields (EMFs) produce widespread neuropsychiatric effects including depression. Journal of Chemical Neuroanatomy 75(Pt B):43-51.

Pope, C. N. 1999. Organophosphorus pesticides: Do they all have the same mechanism of toxicity? Journal of Toxicology and Environmental Health Part B: Critical Reviews 2(2):161-181.

Popkirov, S., J. Stone, and D. Holle-Lee. 2018. Treatment of persistent postural-perceptual dizziness (PPPD) and related disorders. Current Treatment Options in Neurology 20(12):50.

Ramundo-Orlando, A. 2010. Effects of millimeter waves radiation on cell membrane—a brief review. Journal of Infrared, Millimeter, and Terahertz Waves 31(12):1400-1411.

Raslear, T. G.,Y. Akyel, F. Bates, M. Belt, and S. T. Lu. 1993. Temporal bisection in rats: The effects of high-peak-power pulsed microwave irradiation. Bioelectromagnetics 14:459-478.

Richardson, J. R., V. Fitsanakis, R. H. S. Westerink, and A. G. Kanthasamy. 2019. Neurotoxicity of pesticides. Acta Neuropathology 138(3):343-362.

Richter, E. D., P. Chuwers, Y. Levy, M. Gordon, F. Grauer, J. Marzouk, S. Levy, S. Barron, and N. Gruener. 1992. Health effects from exposure to organophosphate pesticides in workers and residents in Israel. Israel Journal of Medical Sciences 28(8-9):584-598.

Roldan-Tapia, L., F. A. Nieto-Escamez, E. M. del Aguila, F. Laynez, T. Parron, and F. Sanchez-Santed. 2006. Neuropsychological sequelae from acute poisoning and long-term exposure to carbamate and organophosphate pesticides. Neurotoxicology and Teratology 28(6):694-703.

Ross, S. M., I. C. McManus, V. Harrison, and O. Mason. 2013. Neurobehavioral problems following low-level exposure to organophosphate pesticides: A systematic and meta-analytic review. Critical Reviews in Toxicology 43(1):21-44.

Saitz, T. R., M. J. Conlin, C. D. Tessier, and T. R. Hatch. 2019. The safety and efficacy of transurethral microwave therapy in high-risk catheter-dependent men. Turkish Journal of Urology 45(1):27-30.

Salford, L. G., A. E. Brun, J. L. Eberhardt, L. Malmgren, and B. R. Persson. 2003. Nerve cell damage in mammalian brain after exposure to microwaves from GSM mobile phones. Environmental Health Perspectives 111(7):881-883; discussion A408.

Sharp, J. C., H. M. Grove, and O. P. Ghandi. 1974. Generation of acoustic signals by pulsed microwave energy (letters). IEEE Transactions on Microwave Theory and Techniques 22:583-584.

Staab, J. P. 2020. Persistent postural-perceptual dizziness. Seminars in Neurology 40(1):130-137.

Staab, J. P., C. S. Fullerton, R. Ursano. 1999. A critical look at PTSD: Constructs, concepts, epidemiology, and implications. In Response to Disaster: Psychosocial, Community, and Ecological Approaches edited by R.Gist, and B. Lubin B.. Philadelphia, PA: Brunner/Mazel. Pp. 101-128.

Staab, J. P., A. Eckhardt-Henn, A. Horii, R. Jacob, M. Strupp, T. Brandt, and A. Bronstein. 2017. Diagnostic criteria for persistent postural-perceptual dizziness (PPPD): Consensus document of the committee for the classification of vestibular disorders of the barany society. Journal of Vestibular Research 27(4):191-208.

Stein, Y., and I. G. Udasin. 2020. Electromagnetic hypersensitivity (EHS, microwave syndrome)—review of mechanisms. Environmental Research 186:109445.

Stone, J. 2016. Persistent posturo-perceptual dizziness (PPPD) (Functional Dizziness). https://www.neurosymptoms.org/download/i/mark_dl/u/4013612269/4634740784/Dizziness%20%20PPPD%20%20information%20sheet.pdf (accessed July 16, 2020).

Steiner, U. E., and T. Ulrich. 1989. Magnetic field effects in chemical kinetics and related phenomena. Chemical Reviews 89(1):51-147.

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×

Suh, J. H., R. Kotecha, S. T. Chao, M. S. Ahluwalia, A. Sahgal, and E. L. Chang. 2020. Current approaches to the management of brain metastases. Nature Reviews Clinical Oncology 17(5):279-299.

Tan, S., H. Wang, X. Xu, L. Zhao, J. Zhang, J. Dong, B. Yao, H. Wang, H. Zhou, Y. Gao, and R. Peng. 2017. Study on dose-dependent, frequency-dependent, and accumulative effects of 1.5 ghz and 2.856 ghz microwave on cognitive functions in wistar rats. Scientific Reports 7(1):10781.

Teixeira, C. F., L. Giraldo Da Silva Augusto, and T. C. Morata. 2002. Occupational exposure to insecticides and their effects on the auditory system. Noise Health 4(14):31-39.

Tsao, M. N., W. Xu, R. K. Wong, N. Lloyd, N. Laperriere, A. Sahgal, E. Rakovitch, and E. Chow. 2018. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database of Systematic Reviews 1:CD003869.

Xu, H., Y. Mao, and B. Xu. 2020. Association between pyrethroid pesticide exposure and hearing loss in adolescents. Environmental Research 187:109640.

Zeigelboim, B. S., J. S. Malisky, M. R. D. Rosa, A. B. M. Lacerda, P. S. Alcaraz, and V. R. Fonseca. 2019. The importance of otoneurological evaluation in Brazilian workers exposed to pesticides: A preliminary study. International Archives of Otorhinolaryngology 23(4):e389-e395.

Zhao, T. Y., S. P. Zou, and P. E. Knapp. 2007. Exposure to cell phone radiation up-regulates apoptosis genes in primary cultures of neurons and astrocytes. Neuroscience Letters 412(1):34-38.

Ziriax, J. M., D. Hatcher, M. E. Belt, J. Roe, A. Thomas, P. Henry, M. Tovias, and J. A. D’Andrea. 1999. High peak power, low SAR effects on memory task performance in rhesus monkeys. In Electricity and Magnetism in Biology and Medicine, edited by F. Bersani. New York: Springer Science+Business Media. Pp. 621-624.

Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
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Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
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Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
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Page19
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page20
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page21
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page22
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page23
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page24
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page25
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page26
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page27
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page28
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page29
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page30
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page31
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page32
Suggested Citation:"Section 4: Plausible Mechanisms." National Academies of Sciences, Engineering, and Medicine. 2020. An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies. Washington, DC: The National Academies Press. doi: 10.17226/25889.
×
Page33
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In late 2016, U.S. Embassy personnel in Havana, Cuba, began to report the development of an unusual set of symptoms and clinical signs. For some of these patients, their case began with the sudden onset of a loud noise, perceived to have directional features, and accompanied by pain in one or both ears or across a broad region of the head, and in some cases, a sensation of head pressure or vibration, dizziness, followed in some cases by tinnitus, visual problems, vertigo, and cognitive difficulties. Other personnel attached to the U.S. Consulate in Guangzhou, China, reported similar symptoms and signs to varying degrees, beginning in the following year. As of June 2020, many of these personnel continue to suffer from these and/or other health problems. Multiple hypotheses and mechanisms have been proposed to explain these clinical cases, but evidence has been lacking, no hypothesis has been proven, and the circumstances remain unclear.

The Department of State asked the National Academies to review the cases, their clinical features and management, epidemiologic investigations, and scientific evidence in support of possible causes, and advise on approaches for the investigation of potential future cases. In An Assessment of Illness in U.S. Government Employees and Their Families at Overseas Embassies, the committee identifies distinctive clinical features, considers possible causes, evaluates plausible mechanisms and rehabilitation efforts, and offers recommendations for future planning and responses.

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