She had conducted the online search so often it had become a compulsion, even though the result was invariably a dead end. But one weekend in April 2019, Nancy M. Chiancone settled into a Starbucks near her suburban Maryland home, flipped open her laptop, and typed her increasingly desperate question, “Why can’t I get a diagnosis?” into a search engine. To her surprise, something new and actionable popped up.
Chiancone had no way of knowing that the serendipitous result would, months later, lead to the answer that had eluded doctors for more than three years. It would provide an explanation for her alarming deterioration, which had left the Prince George’s County Public Schools instructional specialist who had participated in 5K races with a dragging left foot, an inability to walk without a cane, and a failing memory. More than a year earlier, Chiancone had been told she had amyotrophic lateral sclerosis (ALS), a devastating diagnosis that was subsequently withdrawn.
But the specialists treating her, who had prescribed powerful medications that would later be called into question, were stumped.
That changed when Chiancone’s chance query led her to the Undiagnosed Diseases Program (UDP) at the National Institutes of Health, where an astute neurologist zeroed in on a confluence of factors that had been overlooked. Five weeks after her NIH work-up, Chiancone’s illness was identified and she began treatment that has largely restored her health.
“Our program has the capacity to look at these difficult cases without the pressures of a busy practice,” said Camilo Toro, director of the Adult Undiagnosed Diseases Program who heads the team that treated Chiancone. “I’ve seen hundreds of patients and in the first week of evaluation I’ve been able to diagnose three.” Chiancone was one of them.
Cold numb hands
Chiancone’s difficulties started when she was 46. In 2013, she experienced periodic episodes in which her fingers would become numb and painful and turn white. Her primary care doctor sent her to a rheumatologist who diagnosed Raynaud’s disease, a typically self-limiting condition in which small arteries that supply blood to the skin overreact to stress or cold temperatures.
Because Raynaud’s can accompany certain autoimmune diseases, the rheumatologist ordered a blood test for lupus, which causes joint pain. When the test appeared to be positive, Chiancone began taking the immunosuppressive drug plaquenil (better known by its generic name hydroxychloroquine) but stopped after a second lupus test was normal.
After Chiancone’s hand pain worsened, the rheumatologist ordered blood tests for rheumatoid arthritis (RA), a chronic inflammatory disorder that attacks joints. Although tests for RA were negative, her erythrocyte sedimentation rate and other inflammatory markers were elevated. Inflammation has many causes, including other forms of arthritis, certain bowel diseases, and some cancers. It has also been linked to obesity.
In 2014, the rheumatologist diagnosed possible seronegative rheumatoid arthritis, an uncommon form of the disease. She prescribed medicine for RA and told Chiancone that if her pain improved, that would probably validate the diagnosis, Chiancone recalled.
Chiancone began taking methotrexate, a powerful drug used in chemotherapy and to treat RA that has not responded to other medications. She also began giving herself injections of Enbrel, a medicine used to treat moderate or severe RA. Chiancone was told to take folic acid supplements; methotrexate is known to reduce levels of folate, a vitamin essential to the formation of blood cells among other functions.
The pain in her hands initially improved once she began taking the medications, but then returned.
In 2016, after a lifelong struggle with her weight, Chiancone decided to undergo gastric sleeve surgery, which removed about 80 percent of her stomach. The operation was successful (she has since lost 115 pounds) but six months later the pain in Chiancone’s hands worsened and spread to her hips and legs.
Her rheumatologist suspected that the weight loss surgery had impaired her ability to absorb methotrexate and switched her to an injectable form of the drug. Chiancone didn’t notice much improvement. For months she felt exhausted, achy, and generally ill.
In December 2017, she began having severe cramps in her calves which intensified after the mile-long walks she frequently took with her sister Janet. Chiancone’s family physician sent her for a sonogram, which ruled out a blood clot.
Her rheumatologist then prescribed a muscle relaxant and a steroid; neither helped. A week later, Chiancone was trying to reach something on a shelf in her office when she realized she could no longer stand on tiptoes. “It was just really weird,” she said.
She was referred to a neurologist who quickly ordered blood tests, MRI scans of her brain and spine as well as an electromyography (EMG) test and a nerve conduction study, which assess the functioning of nerves and muscles. Both were abnormal. On Feb. 1, 2018, the neurologist told Chiancone she had ALS, a rare, progressive, and fatal disease that destroys motor neurons in the brain and spinal cord.
“I knew something was wrong but I never expected that,” Chiancone recalled. “I kept thinking, ‘There’s no way I have this.’ But then I’d think that’s probably what other people think when they get this diagnosis.”
The neurologist sent her to a specialized ALS clinic. Chiancone said she was certain the ALS expert would tell her that something less dire was to blame. But he concurred with the diagnosis and scheduled follow-up appointments.
Chiancone decided that if her life was going to be drastically cut short, she wanted to maximize the time she had left. She borrowed $10,000 from her retirement account to make extra mortgage payments and travel with her sister to Mexico to look at art.
But after six months, the ALS specialist expressed doubts: Chiancone’s condition had not worsened as expected. A few months later the clinic discharged her, suggesting that she might have an unspecified muscle disorder. A subsequent muscle biopsy was essentially normal.
No closer to an answer after more than two years, Chiancone’s joint pain had been eclipsed by exhaustion, immobility, and unpredictable falls. She broke a bone in her foot after falling on stairs in her home and wiped out in front of a crowd in the middle of Dulles International Airport.
And her memory was faltering. “There were long conversations [about students] that I couldn’t remember having even if they had happened the week before,” she said. “I felt very much on my own and that no one could help me.”
Defying long odds
Chiancone’s discovery of the NIH program made her feel hopeful for the first time in months. Earlier in her life, she had spent the better part of a year crushed by severe postpartum depression until, with her mother’s help, she found effective treatment. That ordeal “definitely influenced my persistence in finding someone who could help me,” she said.
The NIH program, launched in 2008, is the original site of the pioneering Undiagnosed Diseases Network, which now operates at 12 medical centers around the country. Since its inception, about 4,500 people have applied to the UDP and 1,500 have been accepted. Care is free and patients spend a week at the NIH Clinical Center undergoing a meticulous work-up conducted by experts from multiple specialties. Approximately 22% receive a diagnosis, sometimes years later.
The program, which has identified 25 new diseases, attempts to tease out possible genetic underpinnings of patients’ illnesses and to provide useful advice to those who do not receive a diagnosis.
Two months after submitting her application, medical records, and a letter from her neurologist, Chiancone was accepted. She spent the last week of January 2020 at NIH. “It was amazing,” she said.
Toro said his interest was piqued by Chiancone’s unusual presentation: a nerve conduction study that he said was “very suggestive” of ALS; extensive white matter brain lesions that are common in neurodegenerative diseases such as multiple sclerosis but not ALS; and her weight loss surgery. People who undergo such operations are warned of the dangers caused by malabsorption and related problems and told they must take replacement supplements of vitamins and minerals for the rest of their lives.
Toro said he wondered whether the combination of weight loss surgery and methotrexate, which is known to deplete folate, had blocked the transport of the essential vitamin across the blood brain barrier, preventing it from reaching the central nervous system.
The result can be cerebral folate deficiency, which can cause nerve damage, muscle weakness, dementia-like memory loss, and white matter lesions. (In children, cerebral folate deficiency is caused by a genetic mutation.)
Cerebral folate deficiency is detected through a specialized test for 5-methyltetrahydrofolate, which requires a spinal tap. Chiancone underwent the test, which confirmed Toro’s hunch: the level of folate in her spinal fluid was virtually undetectable, even though the level in her blood was normal.
After ruling out other neurological diseases, a rare cancer, various errors of metabolism, and genetic mutations, Toro and his team concluded that Chiancone probably had severe adult-onset cerebral folate deficiency caused by weight loss surgery and methotrexate.
“My feeling is that surgery alone or the medication alone would not have [caused] it,” Toro said. Her case, he added, is a reminder that surgery and medication can have unintended consequences: “In Nancy’s case, they converged to magnify the side effects of each other.” An unidentified genetic susceptibility may have played a role, Toro said.
A revelatory conclusion
Early in March 2020, less than two weeks before the pandemic descended, Chiancone and her sister met with Toro. “Not only did they tell me they’d figured it out, but that they could fix it,” Chiancone said. “I was in shock.”
She was advised to immediately stop taking methotrexate and Enbrel and begin high doses of folinic acid, which counters the effects of methotrexate. It took weeks, but her symptoms slowly receded. Chiancone was able to walk without a cane, the pain in her calves and joints diminished, then disappeared, her severe fatigue lifted and her memory returned.
Testing conducted six months later at NIH showed that the level of folate in her spinal fluid was normal. Her EMG remains abnormal but stable, and the white matter lesions in her brain are largely unchanged. “There could be further improvement but we don’t know if she’ll get all the way better,” Toro said.
Adult onset folate deficiency is better known in other parts of the world, including Canada, according to Toro, but remains underrecognized in the United States. “I suspect this disorder is much more common than we know,” he added.
The irony, in Chiancone’s view, is that she doubts that she actually had rheumatoid arthritis, the reason she was prescribed methotrexate for nearly six years. She has not taken RA medication for more than two years, with no ill effects.
“It could have just been Raynaud’s and osteoarthritis all along,” Chiancone said, referring to the most common form of arthritis which is caused by “wear and tear” on joints and typically treated with over-the-counter pain relievers.
Chiancone wonders what would have happened to her had she not stumbled upon the NIH program. “I feel very lucky that it was something they could find and something they had a solution to,” she said. “It makes me wonder how many people out there are struggling with this.”