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It typically starts with uncharacteristic irritability, anxiety and depression. Then comes pain, along with insomnia, and a constellation of other devastating symptoms, including terrifying hallucinations, a loss of balance and co-ordination, and in a few cases, Capgras delusion – the irrational belief that family members or other familiar people have been replaced by imposters.

By now, Dr. Alier Marrero knows what a mysterious brain illness that has sickened dozens of New Brunswickers looks like.

But what he can’t tell you is how to best help these patients – or how to prevent others from suffering the same fate. Because before Dr. Marrero can tackle these questions, he must find the answer to another, more basic one: What has made all these people in his province ill in the first place?

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Without knowing the cause, “it’s very difficult to go out there and shoot in the dark,” said Dr. Marrero, a neurologist at Dr. Georges-L.-Dumont University Hospital Centre in Moncton, explaining the best he and his team can do for the patients is to treat their symptoms. “But still, the puzzle is not solved.”

Dr. Marrero is leading an investigation into this unknown brain disease that has affected residents mostly in the Moncton area and the Acadian Peninsula, and has attracted the attention of scientists around the world. As of Friday, there have been 47 cases, including six patients who have died, and more possible cases are being investigated.

New Brunswick health officials track cluster of patients with mysterious brain disease

Health officials report sixth death linked to mysterious brain syndrome in New Brunswick

Working in the shadow of a global pandemic, he and his colleagues are looking for clues in a hunt that leads down multiple potential paths. One line of pursuit suggests what they’re seeing may be akin to Creutzfeldt-Jakob disease, the human form of mad cow disease. Another hints at a possible environmental toxin, similar to a 1987 outbreak that sickened more than 100 Canadians who ate contaminated Atlantic shellfish. And yet another suggests answers may be found by revisiting a mysterious neurological disease that was detected in the Pacific island of Guam in the 1940s.

“In many ways, it’s the worst thing that could happen, to have this happen in the middle of COVID-19, because what you need are boots on the ground,” said Michael Strong, professor of neurology at Western University and president of the Canadian Institutes of Health Research.

Dr. Strong, an expert in neurodegenerative diseases, explained investigating potential environmental toxins would require going into communities and individual households to look for commonalities between cases, including examining things such as water supply, fishing and hunting habits. It also requires taking soil and water samples, and studying them back in the lab.

“If the worse-case scenario is that this is something new that we haven’t seen before, then truly bringing the whole of the government response that’s working on this now and bringing the academic community to bear on this ... it’s what we’ve got to do,” he said.

Since the first case in 2015, the illness has shown up in more individuals over the past three years, ranging in age from 18 to 86. And researchers say they are a long way from solving the mystery.

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As more patients have been identified, the list of unusual symptoms has grown, Dr. Marrero said. Many experience muscle aches, pain in their limbs, and spasms – symptoms that do not appear to come from the limbs themselves, but from the brain structures that control pain. The majority eventually develop severe insomnia – and some do not sleep for days, even with sleep medication, he said. A few sleep too much, and it is not easy to wake them.

Patients have problems with memory and aphasia, or trouble finding words to express themselves. Some develop stuttering and more than one patient has developed echolalia, where they repeatedly echo what someone else says and are unable to stop. They sometimes become disoriented in familiar places.

All have visual disturbances – most commonly blurry vision – but also problems with depth perception, which causes dizziness. A majority have visual hallucinations, which can be “terrifying or frightening,” he said. Other types of hallucinations have emerged as well – phantom noises or voices, and tactile hallucinations, such as the sensation of crawling insects.

Involuntary muscle jerks persist even in the late stages of the disease when patients are unconscious. Minor stimuli, such as lights or sound, can provoke something similar to a whole-body startle response.

Patients also develop tremors, have trouble walking without falling, and they lose weight, mainly owing to muscle atrophy.

Many have dry hair and skin, leading them scratch so much that they sometimes cause wounds and develop infection. Some also experience hyper-salivation, or drooling.

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In later stages of illness, patients have akinetic mutism, where they no longer have the ability to speak or move.

“It’s very sad to see for the families, and obviously for us, as physicians,” Dr. Marrero said.

Initially, doctors suspected the illness might be a novel human prion disease similar to Creutzfeldt-Jakob disease (CJD), the human form of mad cow disease, which can be contracted by eating the nervous tissue of infected animals. As an adviser to the Public Health Agency of Canada’s Creutzfeldt-Jakob surveillance system, Neil Cashman, a professor at University of British Columbia’s department of medicine, said he was contacted in October to contribute to the investigation.

In prion diseases, prion proteins in the brain are misfolded and they accumulate, Dr. Cashman said, explaining these misfolded proteins can be detected by a technique called immunohistochemistry.

But in autopsies, none of three brains that have been studied to date have shown an accumulation of misfolded prion proteins, he said. And though they haven’t ruled it out completely, the researchers have found no evidence to suggest the illness is a prion disease.

“So we’re doubling back and going back to first principles and trying to figure out if this is an environmental toxin or something else,” Dr. Cashman said.

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If it is indeed an environmental toxin, it wouldn’t be the first such occurrence in the country. Peter Spencer, a professor of neurology and occupational health sciences at Oregon Health and Science University, noted a neurotoxin called domoic acid, produced by algae, caused a major outbreak in Canada in 1987. That outbreak, which killed three people, was eventually traced to contaminated mussels from Prince Edward Island. The symptoms, which included vomiting, abdominal cramps and diarrhea, don’t match those of the new mystery illness. But since the latter has emerged in a coastal province, Dr. Spencer, who is not involved with the investigation, suggested a first step would be to look for algal toxins in mussels and other bivalves.

“That’s where I would start,” he said.

Among the list of potential toxins the research team is investigating is one called beta-methylamino-L-alanine (BMAA), which some believe may be behind a mysterious neurological illness identified in Guam at the end of the Second World War.

Susan Murch, a chemistry professor at the University of British Columbia-Okanagan who studies BMAA, explained this toxin is produced by cyanobacteria (also known as blue-green algae), and is thought to have sickened Indigenous people in Guam by entering their diets through cycad plants and the animals that eat various parts of those plants.

Dr. Murch cautioned this hypothesis is still much debated. But she noted cyanobacteria can be found everywhere in the world, normally existing at fairly low levels.

“What is happening more recently with climate change is we’re seeing much larger blooms and more prevalent blooms,” she said.

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Meanwhile, communities in New Brunswick are hoping for answers.

“We’re trying to live normally, but everybody has that in the back of their mind,” said Kevin Haché, mayor of Caraquet in the Acadian Peninsula. “If we compare it to COVID, they say wash your hands and put a mask on. But for that illness, we have no idea [what to do] because nobody knows where it’s coming from.”

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