Case Closed? Study Rules Out Mystery Neurologic Syndrome

What has been described as a mysterious neurologic syndrome of unknown cause (NSUC) in the Canadian province of New Brunswick is a “perfect storm” of “misdiagnosis, misdocumentation, and misinformation,” according to the senior author Anthony Lang, MD, professor and past director of neurology at the University of Toronto, Toronto, of a cross-sectional study of 25 of the cases.

The study, which was published on May 7 in JAMA Neurology, found “no support for the existence of an undiagnosed mystery disease” in a cross-section of 222 cases reported to Public Health New Brunswick (PHNB). Instead, the authors suggested that all patients had “other diagnosable neurological conditions that could benefit from multidisciplinary treatment and other resources.”

“When you start to see the evidence, as we did, you realize that it’s a house of cards,” Lang told Medscape Medical News.

“The consequences of this are immense,” he continued. “Being told you have a mystery disease that could be fatal…a progressive, fatal disease with rapidly progressive dementia, is very harmful…and we really feel that patients who have received this diagnosis need to avail themselves of a proper second opinion by experts and then have the appropriate treatment when it’s possible.”

Low Uptake

To be eligible for the study, New Brunswick patients had to have a provisional diagnosis of NSUC, atypical prion disease, neurotoxic syndrome, or rapidly progressive dementia (RPD). Eligible patients were invited to undergo additional testing and clinical evaluation by an independent expert.

But because of the controversy around the issue, which has created political heat and public mistrust since the first cases were reported in 2019, many patients either refused (n = 52) or did not respond (n = 42) to the invitation.

Among 105 patients originally assessed by Alier Marrero, MD, at the Moncton Interdisciplinary Neurodegenerative Diseases (MIND) clinic, Moncton, New Brunswick, which was set up to handle the problem, consent (or waiver of consent) was obtained for only 25 cases: 14 living and 11 deceased.

The median age at symptom onset in the cohort was 55 years, ranging from 16 to 81 years. Data from patients’ initial consultations and follow-ups were analyzed along with the results of a second, independent clinical evaluation by a movement disorders specialist or a behavioral neurologist.

Additional testing included electrophysiology evaluation for movement disorders, complete neurocognitive assessment, EEG, Dopamine Transporter Scan, and [¹⁸F]fludeoxyglucose–positron emission tomography.

For the deceased patients, autopsies included pathology evaluation as part of the Canadian Creutzfeldt-Jakob Disease Surveillance System with extensive tissue sampling and immunohistochemical analysis for prion diseases and other dementias.

Other Diagnoses

All 25 patients had “definable and diagnosable neurological disorders that really refuted the concept of a mysterious brain disease of unknown cause or an NSIC,” said Lang. Diagnoses included Alzheimer’s disease, Parkinson’s disease, progressive supranuclear palsy, other neurodegenerative conditions, functional neurologic disorder, traumatic brain injury, and persisting postconcussion symptoms, he said.

“Diagnostic inaccuracies stemmed from incorrect interpretation of histories (eg, overdiagnosis of RPD), inaccurate physical examination interpretation (eg, myoclonus, ataxia), and overreliance on or misinterpretation of ancillary testing such as EEG and SPECT [single-photon emission computed tomography],” wrote the study authors.

“The records were not accurate,” said Lang. “They said the patient had hallucinations, or the patient had such and such. When we asked the patient who came back for a second opinion, they said, ‘No, I never had that.’ Or there was documentation of myoclonus, of ataxia, of dementia, and then we found no myoclonus, no ataxia, no dementia on clinical examination.”

The researchers also used statistical modeling to calculate the probability of NSUC in the other cases not included in the study. “We said, well, what about the other 200-some patients that had been documented in public health? What are the chances of any of them having a mysterious, undiagnosed neurological disease? And the statistics said that it was less than a one-in-a-million chance of any of those remaining patients having a mystery disease,” he said. “So, we feel very confident that even though we have the small numbers, they are very, very convincing.”

But Marrero disputed the JAMA findings. He first raised concerns with provincial health authorities in 2020 about a growing number of atypical RPD cases in the province, including several cases of Creutzfeldt-Jakob disease.

Marrero was initially hired as one of the clinicians who followed the patients at MIND but was fired in 2022 for performance reasons and moved to the Dr Georges-L.-Dumont University Hospital Centre in Moncton. His patients were given the option to follow him or be assigned a new MIND clinician.

An initial public health review and separate epidemiologic investigation of the first 48 cases concluded that the patients shared no common symptoms or syndrome. “Although some of the cases have presentations with unusual symptomology, they do not appear to have a common illness with an unknown etiology, and there is no evidence of a cluster of a neurological syndrome of unknown cause,” it concluded, according to a provincial government website established to update the public.

The investigation was closed, but after a provincial election in October 2024, the newly elected government reopened the investigation. Although public health authorities have officially recorded 222 cases, Marrero, who was disciplined for improper paperwork and reporting, told Medscape Medical News that he has now evaluated more than 500 patients in this cluster.

“I am appalled that a parallel investigation with a small number of patients has apparently been conducted for a long time without our knowledge or our patients’ and families’ knowledge,” he said. “I am in profound disagreement with the study conclusions and have many questions regarding the methods and the content.”

Not Convinced

New Brunswick’s Chief Medical Officer of Health, Yves Leger, MD, emphasized in a statement that the JAMA findings “do not change my office’s intention to complete its own investigation into cases of undiagnosed neurological illness in New Brunswick. Work has been underway on this matter since early 2023 with support from the Public Health Agency of Canada (PHAC).”

“There are too many unanswered questions for us to stop the work that Public Health is doing to be able to provide patients — and potentially future patients — with the information they need about what’s causing these illnesses,” New Brunswick Premier Susan Holt told reporters in reaction to the JAMA findings.

“On request from PHNB, PHAC has also agreed to conduct a scientific review of the investigation findings once PHNB has completed its analysis and interpretation,” said a spokesperson for PHAC.

“I trust that the current process of independent multidisciplinary scientific investigation and extensive file analysis that is underway by our public health authorities could provide appropriate answers to our communities,” said Marrero. “We are hopeful that this process would include not only comprehensive additional patient testing but also testing for water, food, soil, and air samples in the affected areas, as well as additional patient support and effective prevention and treatment measures.”

But Connie Marras, MD, PhD, a University of Toronto neurologist and movement disorder specialist with an expertise in epidemiology, questioned the need for further investigation.

“It is premature to start looking at any environmental agents that might be responsible for this before we have evidence that there is indeed a cluster, and both the investigations that have been done so far don’t support that,” Marras, who was not involved in any of the investigations, told Medscape Medical News. “The evidence that has been pulled together to date strongly suggests that there is not a unifying, underlying diagnosis for these individuals.”

If the current evidence is insufficient to convince public health and the public, then an ideal next step, from an epidemiologic point of view, would be to test a larger, random sample of patients, she said. The limitations of the JAMA study included small numbers and the potential for selection bias.

“If the purportedly affected people are willing to submit to further evaluation, their engagement in this is critical, for the sake of everybody.”

The study “underscores the critical importance of systematic data collection and objective evaluation (seeing) in cases of neurological syndromes with unknown causes,” wrote Michael Okun, MD, professor of neurology and director of the Norman Fixel Institute for Neurological Diseases at the University of Florida Health in Gainesville, Florida, in a post on X.

“I completely agree with the authors that these types of unknown ‘neuro’ cases are ‘complex neurological disorders [that will] benefit from a second, independent and/or subspecialist evaluation and require multidisciplinary support throughout the diagnostic journey.’ Always ask yourself, ‘Do you see what you want to see? Are you being rigorous and as unbiased as possible? Are you open to revising your initial impressions? Can a second look enhance diagnostic accuracy and outcomes?’…These authors are sharing hard data to help us to understand a phenomenon. We must always seek clarity.”

No funding source for the study was reported. Lang reported receiving personal fees from AbbVie, AFFiRis, Alector, Amylyx Pharmaceuticals, APRINOIA Therapeutics, Biogen, BioAdvance, Biohaven, BioVie, BlueRock, Bristol Myers Squibb, Cavion, CoA Therapeutics, Denali, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Lilly, Novartis, Paladin, Pharma Two B Ltd., PsychoGenics, Roche, Sun Pharma, and UCB outside the submitted work and litigation related to paraquat and Parkinson’s disease (for the plaintiffs). Marrero and Marras reported having no relevant financial relationships.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.