By Howard Bell
A Mayo Clinic investigator helps solve a neurological mystery.
Mysteries often start with a note slipped under a door. For Daniel Lachance, M.D., one started last year with an email.
In September 2007, Lachance was one of four Mayo Clinic neurologists to receive a message from a colleague in Austin, Minnesota—family physician Richard Schindler, M.D. Schindler described six patients with a mysterious neurologic illness who had been seen at the Austin Medical Center since November 2006. “There are several disturbing facts involved,” he wrote. The patients all worked at Quality Pork Processing (QPP), a meat-processing plant in Austin; all worked in the “kill” section; none had been exposed to chemicals; and at least three had worked with the brains and spinal cords of pigs.
Intrigued by the note, Lachance, who had been doing neurology consults in Austin, reviewed the patients’ records. All had similar neuromuscular symptoms of an inflammatory nature: fatigue, pain, weakness, numbness, and tingling in the legs and feet. The leg pain worsened when they bent over or stood for prolonged periods. Weak legs felt weaker when walking or playing sports. Some of the patients had similar achiness and weakness in their hands and arms. Most were young adult Spanish-speaking men and women. All were previously healthy.
Some of the patients developed symptoms within three to four weeks after starting work at the plant. But others, for unknown reasons, started experiencing them several years after they’d begun working there. That kind of variation in onset made it difficult to pin down the cause, Lachance thought. In all cases, the patients’ conditions had deteriorated to the point where they were no longer able to work.
“Sounds like this needs more investigation,” Schindler wrote in the email. “Suggestions on how to proceed with this?”
Lachance began to consider the facts. He knew that the incidence of inflammatory disorders of the nervous system was very low in the general population. He knew that all of the patients had worked in the same place and none had gotten sick until after they started working there. “I suspected we had something different on our hands, and we better set up a consistent way to refer and examine future patients with these symptoms,” he recalls. Lachance responded to the email within hours, thus casting him into the role of Mayo’s lead detective in a medical mystery that would draw national attention before it was solved.
Case of a Lifetime
Lachance knew the case was special. “In neurology, we see puzzling symptoms every day in individual patients,” he says. “This was different because it was a cluster of patients with the same symptoms from the same geographic area.” As he pondered the mystery of the patients and their symptoms, Lachance recalled seeing a female patient from QPP with similar symptoms back in 2004. After examining her and seeing her electromyography (EMG) results, he thought she was suffering from something other than carpal tunnel syndrome, a condition common among meat-processing workers—perhaps an inherited neuropathy or an inflammatory neuropathy. But her symptoms and the test results were not consistent with any easily identifiable neurological disorder. Before Lachance could do a spinal fluid examination and other tests, the patient returned to Mexico.
Then Lachance recalled another QPP worker who had been hospitalized at Mayo for two weeks in December 2006 with significant lower body weakness. Tests showed marked spinal cord inflammation. “No one could figure out what caused it,” Lachance remembered. It didn’t occur to anyone at the time that the problem might be related to the patient’s occupation. Steroids helped alleviate the inflammation and by spring of 2007, the patient returned to work. Within weeks, however, he developed leg pain, weakness, and numbness and became unable to work again. By the fall of 2007, he had recovered and returned to his job at QPP. The symptoms soon reappeared. Between September and November of 2007, Lachance saw six more patients from the pork-processing plant, bringing the total to 12. All had the same symptoms, which began after they started working there. Something was causing serious nerve damage in some QPP employees, but no one knew what.
To guide his decision making, Lachance asked himself, “What all should I be doing to take advantage of this unique opportunity?” Lachance, who describes himself as a problem solver, brought in help. He consulted P. James B. Dyck, M.D., a peripheral neuropathy expert at Mayo, and enlisted Vanda Lennon, M.D., Ph.D., and Sean Pittock, M.D., colleagues from the Neuro-Immunology Laboratory.
Each patient underwent the same battery of tests—first to establish what their problem wasn’t. And it wasn’t carpal tunnel syndrome, bovine spongiform encephalopathy (mad cow—or, in this case, mad pig—disease), trichinosis, Lyme disease, HIV, rheumatoid arthritis, Lupus, sarcoidosis, a malignancy, diabetes, or any of several viruses, bacteria, or parasites tested for. “The exams were about as comprehensive as you can get,” Lachance says.
He and his partners agreed the cause had to be one of three things: an infection; a post-infection inflammation response, in which an infectious agent triggers symptoms not directly caused by that organism; or an autoimmune response. Infection seemed unlikely. “The pattern of its appearance among affected individuals was not consistent with infection,” Lachance explains. “It didn’t affect people who ate pork, and it didn’t spread from person to person. No family members of employees were affected.”
At the end of October 2007, Lachance decided it was time to notify the Minnesota Department of Health. He asked his colleague, infectious disease expert Robert Orenstein, D.O., to make the contact because Orenstein had worked with the Department of Health before and knew how to do it in an official manner. After learning about the situation, health officials immediately launched their own epidemiological investigation. Although Mayo has the resources to conduct epidemiological studies, the Department of Health had the authority to go to QPP and investigate, which they did. Department of Health staff tested for an extensive number of infections that could come from humans or pigs. None could be found. This ruled out infection as the cause of the symptoms.
And since they knew it wasn’t an infection, it couldn’t be a post-infection response. That left an autoimmune condition—one never seen before. “We had a new disease here in Minnesota,” Lachance says, “one that had never been reported anywhere else in the world.”
Lachance had his hands full. On top of seeing his other patients, he had become Mayo’s point man for a mysterious new illness. It’s not unusual for the medical world to turn to Mayo for answers to questions that stump others. That’s what happened during the post-9/11 anthrax-in-the-envelopes scare, when Mayo was tapped to develop a rapid test for anthrax exposure. But in this case, Lachance was dealing with an entirely new illness. Those who worked with him believed he was the right man for the job. “Dan Lachance is extremely methodical and looks at every detail before jumping to conclusions,” Schindler says.
Lachance, along with colleague James Dyck, examined, interviewed, and oversaw testing of the 12 patients coming in from Austin. (By April of 2008, he would see a total of 21 patients.) And he continued to tap the expertise of a growing number of people at Mayo and the Minnesota Department of Health. The CDC got involved at the Department of Health’s request to conduct a nationwide search for patients from other pork-processing plants with similar symptoms. They found several such individuals in Indiana and one in Nebraska.
After touring the QPP plant on November 28, state epidemiologist Ruth Lynfield, M.D., narrowed the source of the problem to the “head table,” the spot where workers did a grizzly job referred to as “blowing brains.” All of the patients had worked at or near the head table, where someone would insert a metal hose into the skull through the opening for the spinal cord and shoot blasts of compressed air, turning the brain into a slurry that could drain back out the same hole. Often, brain tissue would splatter the hose operator and nearby workers. Lynfield saw workers swallowing or inhaling aerosolized brain tissue. That same day, QPP stopped blowing brains and issued face shields to all head table workers.
On December 3, Department of Health officials held a press conference to announce the initial results of their investigation: They called the condition progressive inflammatory neuropathy (PIN). They noted that of the 25 swine-processing plants in the United States, only two besides QPP blew brains with compressed air—one in Nebraska, which reported one case of a worker who was sick with symptoms similar to those affecting the Austin workers, and another in Indiana, which reported three cases. Lachance and Dyck examined three of the patients from Indiana and confirmed that they had the same set of symptoms and physical findings. All had worked at or near the head table.
The three plants stopped blowing brains with compressed air. Since then, no new cases of the mysterious neuropathy have developed in Austin or anywhere else.
The case generated global media attention, which in turn prompted the Department of Health and Mayo Clinic to hold a teleconference, during which they agreed to carefully coordinate all press reports to make sure both organizations were giving out the same information. Lachance remembers the date of the December 10 teleconference because it came one day after his son was born. “The timing wasn’t the best,” he says with a smile. “But at least I was there for the birth—and mom and baby were fine.”
It had taken the Department of Health only one month to crack the case epidemiologically. But important questions remained unanswered: Why did exposure to hog brains cause illness? How did exposure cause illness? And why did these cases appear only recently, even though compressed air had been used to blow brains at QPP since 1998?
Lachance learned the answer to the last question from the patients themselves. In lengthy interviews through Spanish-speaking interpreters, nearly every patient told Lachance the same thing: The assembly line had been sped up in 2007, the same time the illness started appearing. Workers said they didn’t have enough time to properly orient the head before blowing the brains. Consequently, more aerosolized brain tissue escaped into the surrounding air. Speeding up the line also caused the skull to fracture more frequently, which allowed more brain tissue to escape.
The Seven Crucial Clues
As for figuring out how and why aerosolized hog brain caused the condition, seven tests proved crucial to bringing Lachance closer to an answer. First, 18 of 21 patients tested had elevated protein levels in their cerebral spinal fluid. “This helped confirm we were dealing with inflammation of the nervous system,” Lachance says.
Second, EMG results showed inflammation at two separate points along the nerves: proximally, just after the nerve leaves the spinal cord, and distally in motor and sensory nerve terminals. “Other inflammatory neuropathies have a more diffuse pattern of inflammation along the nerve,” Lachance explains. “This helped confirm we were dealing with something we hadn’t seen before.”
The meningeal stretch test revealed a third clue. A common test for meningitis, the test involves the patient either bending their leg up while sitting or moving their head forward while lying down. Having these patients bend their legs while they sat caused shooting pain down their legs. Flexing the head forward while they were lying down caused pain in the lower and middle back and sometimes in the legs. “It was striking to see the back and leg pain they all felt when they did this,” Lachance says. “This helped us confirm meningeal inflammation.”
Every patient had an MRI—most of them more than one type. “With a few exceptions, most of the patients had a striking pattern of enlargement and enhancement of lumbar and cervical nerves, both where the nerves emerge from the spinal cord and in the portion of the nerves called the sensory ganglia,” Lachance says. In both locations, the nerves appeared thickened and bright when given contrast agents—a sign that the blood-nerve barrier had been breached. “Overall, the nerve injury pattern we were seeing in the EMGs and on MRI studies was consistent with some form of demyelination that appeared to be caused by inflammation,” he says. “Proximal and distal areas of nerves are where the blood-nerve barrier is deficient or nonexistent, which makes them more vulnerable to nervous system injury.”
A fifth test—quantitative sensory testing—measures the threshold for detecting various sensations and confirmed the presence of both large- and small-fiber neuropathy. A sixth test—a thermoregulatory sweat test, which measures loss of sweating ability over various areas of the body—showed two abnormal patterns: one consistent with a polyradiculopathy or polyganglionopathy and the other consistent with distal small fiber neuropathy. Those results helped confirm the nature of some of the patients’ symptoms and the patterns of abnormality seen in EMG and MRI.
The most important clue was revealed in a seventh test, called a paraneoplastic autoantibody profile, a package of antibody tests developed by Lachance’s senior colleague, neuroimmunologist Vanda Lennon. Mayo, which does about 35,000 of these profiles a year, is the only facility in Minnesota and one of the few in the world to do them. The profile is a blood test usually used to find antibody evidence of autoimmune responses to malignancies. Such autoimmune responses, according to Lachance, can sometimes cause devastating neurological disorders and are triggered by a cancer that has not yet been diagnosed. Lachance and Dyck used the test to determine whether any of their mystery patients developed an autoimmune response specifically targeting the nervous system. Here’s how it works. A patient’s blood is applied to mouse tissues, then washed off. If the blood contains IgG antibody with an affinity to an antigen in the mouse tissue, the human IgG will remain bound to the antigen. Then a second human IgG antibody is added, which binds to those antibodies still bound to the mouse tissue. When that second antibody is tagged with a fluorescene label and the tissue is viewed under a fluorescene microscope, you see patterns of antibody-antigen reactivity that show up as visual patterns that are usually unique for a particular antibody response in the patient. “What we saw in all these patients was a consistent pattern of reactivity against the mouse nervous system tissues,” Lachance says. “We’d never seen anything like it before. When we put together the results from these antibody tests and all the other tests, we knew we were seeing a consistent pattern of abnormality, an autoimmune response that didn’t match up with anything we’d seen before. It was kind of exciting.”
To date, the working hypothesis is that aerosolized hog brain triggered the production of antibodies to defend the body against antigens in the brain tissue. But the antibodies also attacked the patient’s own nervous system. “Hogs and humans share a significant overlap of antigens in our nervous systems,” Lachance says.
Mayo is calling the condition sensory predominant polyradiculoneuropathy, shying away from the “PIN” label because, as Lachance points out, “It’s not progressive. Patients plateau, then improve over time with steroids, immunoglobulin, and avoidance of the aerosolized trigger.”
Sensory predominant polyradiculoneuropathy somewhat resembles paraneoplastic neurologic disorders triggered by autoimmune responses in cancer patients, Lachance explains. These disorders occur when the body’s immune system, in the process of trying to suppress a cancer, attacks both the cancer and the nervous system at the same time. “This new disease gives us a unique glimpse into how autoimmune reactions might trigger neurologic disorders,” he says.
Researchers from Mayo and the Department of Health will soon submit companion papers about the disease to a major medical journal.
Telling the Story
Meanwhile, Lachance says it’s been an exciting and gratifying several months. Now that the investigation is winding down, he’s being asked to tell the story. In April 2008, he gave his first presentation to peers at the American Academy of Neurology’s annual meeting. He’s scheduled to speak at grand rounds at the University of Wisconsin-Madison, Johns Hopkins in Baltimore, and Mt. Sinai in New York City. This past September, he spoke at the annual meeting of the American Academy of Neuromuscular and Electrodiagnostic Medicine in Providence, Rhode Island, a dozen miles from where he grew up and where he almost became an ironworker like his father, grandfather, brother, and many uncles. “I tried that for one summer, and one summer was enough.” He went on to Dartmouth College, Dartmouth Medical School, Mayo Clinic for residency, and Duke University for a neuro-oncology fellowship.
Lachance says he doesn’t recall the specifics of his Myers-Briggs profile, but he remembers the results reflect his problem-solving style: Gather all available resources, consider that most problems are best solved in stages, build consensus, and think outside the box. That approach has paid off.
For all the sleuthing it took to crack the case, sensory predominant polyradiculoneuropathy may be short-lived, as long as pork plants discontinue processing heads with compressed air. For that reason, colleagues have encouraged Lachance to replicate the condition in the lab for further study. “That might happen some day,” he says. “But for now, I suspect things will settle down to the way they were before I got that email.” MM
Howard Bell is a medical writer in Onalaska, Wisconsin.