Havana Syndrome Mystery Continues to Deepen

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NIH reports no brain injury evidence, but findings may be like comparing “apples with artichokes”

by
Judy George
,
Deputy Managing Editor, MedPage Today

March 18, 2024

Despite persistent symptoms, no significant evidence of brain injury and no abnormalities in most clinical measures were found in U.S. government personnel who experienced anomalous health incidents (AHIs) known as Havana syndrome, NIH researchers said.

After adjusting for multiple comparisons, no differences in MRI measures of brain structure or function emerged between individuals with AHIs and matched controls, reported Carlo Pierpaoli, MD, PhD, of the National Institute of Biomedical Imaging and Bioengineering in Bethesda, Maryland, and co-authors in JAMA.

And in many clinical and biomarker measures — excluding measures of imbalance and symptoms of fatigue, post-traumatic stress, and depression — no differences between people with AHIs and controls were seen, according to Leighton Chan, MD, MPH, of the NIH Clinical Center in Bethesda, and colleagues.

New daily persistent headaches were common in the AHI group. About a quarter of people with AHIs presented with functional neurological disorders.

The studies involved U.S. government staff and family members with AHIs from Cuba, Austria, China, and other locations. The etiologies of AHIs remain unclear.

The findings did not replicate those reported in previous research. “While we did not identify significant differences in participants with AHIs, it’s important to acknowledge that these symptoms are very real, cause significant disruption in the lives of those affected, and can be quite prolonged, disabling, and difficult to treat,” Chan said in a press statement.

“It is possible that individuals with an AHI may be experiencing the results of an event that led to their symptoms, but the injury did not produce the long-term neuroimaging changes that are typically observed after severe trauma or stroke,” Pierpaoli added.

In late 2016, U.S. government personnel in Havana reported sudden neurologic symptoms after experiencing unusual sounds associated with a sensation described as pressure-like or vibratory. The number of reports in Havana grew and similar cases occurred in other locations over the next 5 years.

The two most comprehensive papers on the topic involved the Havana cases, Chan and co-authors noted. In 2018, researchers at the University of Pennsylvania in Philadelphia documented that Havana embassy personnel with AHIs experienced visual and balance problems, headaches, sleep problems, and deficits in working memory, sustained attention, and concentration.

In 2019, the Penn team showed that Havana personnel who had neurologic symptoms also showed differences in whole brain white matter volume, regional gray and white matter volume, cerebellar tissue microstructural integrity, and functional connectivity compared with healthy individuals. The overall picture was one of “concussion without concussion,” said Penn researcher Douglas Smith, MD, who led the Havana clinical studies.

The new NIH research is not a replication study, Smith pointed out in an interview with MedPage Today. Not only was the population different, but the exposures may have been different, too. “It is like trying to compare apples with artichokes,” he said.

“Perhaps one of the most important aspects of our studies was that the study cohort was all from one location with similar descriptions of the character of the exposures,” Smith observed. “Otherwise, any effect of one type of exposure could be diluted by the effects — or lack thereof — of different exposures.”

“The patients who overlapped were seen in NIH after they had rehab, so there is no comparison to their brains when they were seen at Penn, prior to any kind of treatment,” added Ragini Verma, PhD, also of Penn.

Study Details

In the NIH imaging study, Pierpaoli and colleagues studied 81 people with AHIs (mean age 43) and 48 matched controls from June 2018 through November 2022. Scans were performed a median of 80 days after experiencing AHIs. No significant between-group differences in MRI measures of volume, diffusion MRI-derived metrics, or functional connectivity were seen, after adjustment for multiple comparisons.

At an unadjusted threshold (P<0.05), the NIH researchers found that people with AHIs had lower intranetwork connectivity in the salience networks, a larger corpus callosum, and diffusion MRI differences in the corpus callosum, superior longitudinal fasciculus, cingulum, inferior cerebellar peduncle, and amygdala compared with controls. No clear relationships between imaging and clinical variables were seen.

In the NIH clinical study, Chan and co-authors evaluated 86 people with AHIs (mean age 42) and 30 controls from June 2018 through July 2022. Participants with AHIs were evaluated a median of 76 days from the most recent incident. No differences emerged between the AHI group and controls in most tests of auditory, vestibular, cognitive, or visual function, or in blood biomarkers.

However, individuals with AHIs reported significantly more post-traumatic stress, fatigue, and depressive symptoms, and less satisfaction with life compared with controls (all P<0.001). A total of 25 people with AHIs (29%) developed new daily persistent headaches, and eight people were diagnosed with new-onset migraines.

Overall, 24 people with AHIs (28%) presented with functional neurological disorders, including 22 cases of persistent postural-perceptual dizziness (PPPD).

It’s possible that physiologic markers are no longer detectable or can’t be identified with the methodologies and sample sizes used, NIH researchers said.

With few differences between cases and controls in the NIH studies, one might suspect that nothing serious happened to people who reported AHIs, noted David Relman, MD, of Stanford University in California, in an accompanying editorial.

“This would be ill-advised,” Relman suggested. “Two detailed investigations of AHIs (in which I played a role) found the cases with abrupt-onset, location-dependent sensory phenomena to be unlike any disorder reported in the neurological or general medical literature, and potentially caused by an external mechanism.”

Three issues undermine our efforts to understand AHIs, Relman observed: clinical heterogeneity, lack of detailed information about the effects of electromagnetic and acoustic energy on the brain, and difficulties dealing with uncertainty and complexity in “a topic that is politically charged and divisive,” partly because of its implications.

“The experience with AHIs provides valuable lessons for clinicians, the scientific and national security communities, and national and international policymakers,” Relman said. “We ignore them at our own, collective peril.”