By MOISES VELASQUEZ-MANOFFOCT. 11, 2014
WHEN Andre H. Lagrange, a neurologist at Vanderbilt University in Nashville, saw the ominous white spots on the patient’s brain scan, he considered infection or lymphoma, a type of cancer. But tests ruled out both. Meanwhile, anti-epilepsy drugs failed to halt the man’s seizures. Stumped, Dr. Lagrange turned to something the mother of the 30-year-old man kept repeating. The fits coincided, she insisted, with spells of constipation and diarrhea.
That, along with an odd rash, prompted Dr. Lagrange to think beyond the brain. Antibody tests, followed by an intestinal biopsy, indicated celiac disease, an autoimmune disorder of the gut triggered by the gluten proteins in wheat and other grains. Once on a gluten-free diet, the man’s seizures stopped; those brain lesions gradually disappeared. He made a “nearly complete recovery,” Dr. Lagrange told me.
I began encountering case descriptions like this some years ago as I researched autoimmune disease. The first few seemed like random noise in an already nebulous field. But as I amassed more — describing seizures, hallucinations, psychotic breaks and even, in one published case, what looked like regressive autism, all ultimately associated with celiac disease — they began to seem less like anomalies, and more like a frontier in celiac research.
They tended to follow a similar plot. What looked like neurological or psychiatric symptoms appeared suddenly. The physician ran through a diagnostic checklist without success. Drugs directed at the brain failed. Some clue suggestive of celiac disease was observed. The diagnosis was made. And the patient recovered on a gluten-free diet.
The cases highlighted, in an unusually concrete fashion, the so-called gut-brain axis. The supposed link between the intestinal tract and the central nervous system is much discussed in science journals, often in the context of the microbial community inhabiting the gut. But it’s unclear how, really, we can leverage the link to improve health.
Here, though, was a rather spectacular example: Treating an autoimmune disease of the gut (by avoiding gluten) resolved what looked like a debilitating disorder of the brain. The broader takeaway was that, in some subset of patients, apparent neurological symptoms could signal undiagnosed celiac disease.
These are individual cases, but Celiac disease has long been associated with symptoms beyond the gut, including blistering rashes, burning nerve pain, and a loss of muscle control called ataxia. Historically, scientists often attributed these problems to nutrient deficiencies, which undoubtedly occur in some cases. Gut inflammation can hinder the absorption of critical nutrients, such as copper or B vitamins, prompting neurological dysfunction.
But as antibodies specific to tissues beyond the gut have come to light, some now suspect that the autoimmune firestorm ignited in the gut may descend on other organs, including the brain. This idea, which remains hypothetical, has gained traction during a time of progress in understanding autoimmune diseases of the central nervous system.
At the Mayo Clinic in Rochester, Minn., a center of research on neurological autoimmunity, patients with autoimmune epilepsy, dementia and other recently described autoimmune disorders are frequently “cured” with immunotherapy. That usually involves some combination of steroidal immune-suppressants, intravenous immunoglobulin-G, which consists of antibodies from donors, and plasmapheresis, a procedure that removes antibodies from the blood.
THE Mayo Clinic is on track to run 140,000 tests this year for autoimmune disorders of the brain, about a 20 percent increase over last year. One-tenth of samples usually come back positive for the self-directed antibodies indicative of autoimmunity, said Sean J. Pittock, a neurologist there. Many of these patients have cancers, which can trigger an attack. But a fraction have an autoimmune disease of the brain.
“There are people out there who are very ill and in nursing homes, and their condition is treatable and reversible,” he said. “And they’re being missed.” It’s rare, but he estimates these patients to number in the many thousands.
One such story comes from the journalist Susannah Cahalan whose memoir “Brain on Fire” details her bout with autoimmune encephalitis. Her sudden descent into “madness” resembled a psychotic break. And just a few years earlier, before the condition was understood to be autoimmune, she might have been considered lost to psychosis and institutionalized. But in 2009, Ms. Cahalan, the 217th patient to get the diagnosis of what’s called anti-NMDA receptor encephalitis, was treated for her autoimmune disorder and recovered.
Celiac disease differs from most other autoimmune diseases in one critical respect: The trigger, gluten, is known. And in most cases, removing gluten will turn off the autoimmune destruction in the gut. Around 10 percent of people with celiac disease, and possibly more, are thought to suffer neurological symptoms, ranging from headache and nerve pain, to ataxia and to epilepsy.
When I called Alessio Fasano, director of the Center for Celiac Research at Massachusetts General Hospital in Boston, he spoke of his own celiac-related miracle stories. In one, a boy with autism-like symptoms actually had undiagnosed celiac disease, and recovered on a gluten-free diet. Dr. Fasano told me he had seen a few similar cases in his native Italy.
In another, a former professor diagnosed with dementia and institutionalized, recovered on a gluten-free diet. Her doctors knew she had celiac disease, but thought it irrelevant to her degenerative brain disorder.
Some researchers have proposed autoimmune mechanisms to explain these phenomena. The presence of antibodies that bind to an enzyme called transglutaminase 2 is used to help diagnose celiac disease. Among other functions, transglutaminases help seal barriers in the body. Scientists at the Royal Hallamshire Hospital in Sheffield, Britain, have identified an antibody that binds to a version of transglutaminase, called TG6, which occurs primarily in the brain.
This antibody, they argue, may identify celiac patients at risk for neurological complications. When celiac patients with ataxia adopt a gluten-free diet, they showed last year, those brain-directed antibodies decline and their symptoms improved. And injecting the antibodies into the brains of mice prompts ataxia-like symptoms, suggesting that they can cause (rather than result from) disease.
Not everyone buys the idea, however. In a recent study, the neuroimmunologist Andrew McKeon at the Mayo Clinic mostly found copper deficiencies in his celiac patients with neurological problems; others had autoimmune diseases of the central nervous system. A relative minority — six of 33 — saw neurological improvements on a gluten-free diet.
Rather than celiac disease driving autoimmune brain problems, he thinks, distinct autoimmune diseases are likely to cluster in the same individual. Avoiding gluten won’t entirely mend these patients.
The even more controversial idea is that a subset of patients mounts an immune response to gluten without obvious intestinal inflammation, and develops neurological symptoms. Marios Hadjivassiliou, a neurologist at the Royal Hallamshire Hospital, calls one variant of this entity “gluten ataxia”: a gluten-triggered disease whose primary symptoms occur in the brain.
Although the idea remains debated, physicians I queried weren’t ready to dismiss it. That’s partly because some years ago, Armin Alaedini, an immunologist now at Columbia University, found that antibodies directed at gliadin, a gluten protein, could cross-react with proteins in the brain. The finding suggests that, by some coincidence, certain proteins on neurons structurally resemble proteins in wheat. Meaning that, if your immune system attacks gluten, it might also inadvertently pursue brain tissue.
This discovery has helped revive an old idea about schizophrenia. Might an immune reaction to wheat contribute in some cases? In 2011, Johns Hopkins University scientists found that nearly one-quarter of serum samples from some 1,400 schizophrenia patients had anti-gliadin antibodies, compared with just 3 percent of healthy controls. Of the subset with those antibodies, one-fifth also had those antibodies to transglutaminase 6 linked with neurological dysfunction, compared with 6 percent of healthy controls.
It’s unclear if these antibodies contribute to schizophrenia, result from it, or are irrelevant to it. Dr. McKeon considers some of the antibody tests to be poor diagnostic tools. And Dr. Alaedini suspects that, rather than causing problems, they may indicate systemic inflammation and a defect in the intestinal barrier. Numerous immune abnormalities have been described in schizophrenia.
But in a pilot study on two patients with those antibodies, Deanna L. Kelly, a researcher at the University of Maryland in Baltimore, found that a gluten-free diet alleviated some symptoms. Now Dr. Kelly is beginning a larger, gluten-free intervention on that subgroup.
By one recent estimate, meanwhile, one in three Americans dabbles in a gluten-free diet. That vastly outnumbers those thought to have celiac disease — about 1 percent — or the (still unmeasurable) percentage of people with gluten sensitivity, estimated at slightly higher. And yet, the prevalence of celiac disease is indeed rising. Symptoms are increasingly understood to manifest beyond the gut, including occasionally in the brain. Gluten sensitivity may yet prove to be real and measurable.
No one I spoke to recommends going on a gluten-free diet proactively. But when sudden and inexplicable neurological problems arise, it’s not completely far-fetched to raise the gluten question with your doctor. It just might provide an answer.
Moises Velasquez-Manoff is a science writer and the author of “An Epidemic of Absence.”
A version of this op-ed appears in print on October 12, 2014, on page SR6 of the New York edition with the headline: Can Celiac Disease Affect the Brain?