When a 55-year-old man presented to the neurology clinic at a hospital in Israel, researchers knew his symptoms weren’t typical for full-blown Parkinson’s disease.
He did have some midline signs, blepharospasm, and slurred speech, but he didn’t have a prominent tremor and he did have a change in handwriting — “something you can see in Parkinson’s disease, but it’s much more common in heavy metal poisoning,” Roy Dayan, MD, of Hadassah Hebrew University Medical Center in Jerusalem, told MedPage Today.
An MRI from a referring neurology clinic didn’t show anything unusual, Dayan said, but his team conducted a revised MRI with new instructions, and what they saw was rare and intriguing.
“He had this bright glow in the globus pallidus, a T1 hyperintensity,” said Dayan, who along with his mentor, David Arkadir, MD, PhD, also of Hadassah Hebrew University Medical Center, published the finding under the “images in clinical medicine” banner in the New England Journal of Medicine.
The globus pallidus is part of the basal ganglia, which is involved in higher control of movement, Dayan said. It’s one of the areas often affected in Parkinson’s disease, but this was “unlike typical Parkinson’s in which the initial pathophysiological problem is in the substantia nigra,” he said.
About a year prior, Arkadir had published a case report about another patient who had a similar clinical and radiological picture, and ultimately was found to have a genetic mutation impacting manganese metabolism.
Manganese moves through the dopamine transporters in the basal ganglia, which is why it tends to accumulate in this brain region, Dayan said.
A language barrier initially made it difficult to get the current patient’s full history, but a family member ultimately was able to translate Russian to Hebrew. That’s when Arkadir and Dayan learned that in his 30s, the patient worked as a welder, without any personal protective equipment.
One of the biggest risk factors for manganese accumulation in the brain is welding without protective equipment, Dayan said. For a certain type of welding, manganese is often used in the welding rod that binds the two pieces of metal together, according to a review of welding and parkinsonism. While manganese toxicity among American steel workers is rare, welding rods used outside the U.S. tend to have higher concentrations of manganese in rod coverings, the review stated.
With suspicion high once again for manganese toxicity, Arkadir and Dayan ordered a series of lab tests, as well as whole-exome sequencing.
All told, the diagnosis took about a month to put together, Dayan said. Labs came back normal, and the patient had no inherited errors in manganese metabolism. So ultimately, Arkadir and Dayan concluded that the patient had manganese toxicity related to welding.
They started him on a course of intravenous ethylenediaminetetraacetic acid (EDTA), which is also referred to as “chelation,” lasting 6 months. Their protocol was “based on the idea that manganese has also accumulated in the bones, and it can still be actively released in the blood,” Dayan said. They also gave him zinc supplements as EDTA also chelates zinc, to prevent a zinc deficiency, he added.
A follow-up MRI showed the manganese buildup had cleared, and most of the patient’s symptoms had abated. He “reported that he felt much better and his speech was much clearer,” Dayan said.
He noted that the key to solving the case was using the T1 MRI sequence. “It’s frequent that we do MRI for patients with atypical parkinsonism, but usually we would go to the flare [a manipulation of the T2 sequence] or to the other sequences because we’re looking for other things,” he explained. “T1 is usually innocent, but there are some things you can find.”
Ray Dorsey, MD, of the University of Rochester Medical Center in New York, who wasn’t involved in the report, said manganese exposure “has long been linked to parkinsonism, and welding has been known to carry a heightened risk of parkinsonism. This is a perfect illustration of that, and of environmental factors contributing to parkinsonism.”
“The nose is the front door of the brain,” Dorsey told MedPage Today. “It’s not protected by the blood-brain barrier. It’s not protected by the liver, which does a good job of detoxifying things we ingest. Manganese is a really small molecule, and like other small molecules that can be inhaled, like dry-cleaning chemicals and pesticides, they can damage the dopamine-producing nerve cells in the brain.”
Dorsey, who has co-authored a book called Ending Parkinson’s Disease, believes inhaled toxicants play a significant role in the development of Parkinson’s disease and other brain diseases, including Alzheimer’s disease, noting a recent study linking wildfire smoke with dementia.
“You have a wide range of environmental toxicants that can be inhaled and damage different nerve cells in the brain,” he said.
As for the current case, he said it shows that some parkinsonism can be reversible, but also that people can protect themselves from environmental toxicants and prevent parkinsonism, and possibly other brain diseases. While EDTA is a serious treatment, “the resulting image and symptoms as reported are certainly convincing.”
EDTA has been used for similar applications, he said, “but chelating agents in the brain should not be used lightly.”
New England Journal of Medicine
Source Reference: Dayan R, Arkadir D “Manganese accumulation in the brain” N Engl J Med 2023; DOI: 10.1056/NEJMicm2301805.