Lessons learned from medical mysteries: Uncovering the cause requires tenacity and toil

David Fajgenbaum, an immunologist at the University of Pennsylvania, knows what it’s like to be a medical mystery.

A decade ago when he was a third-year medical student, Fajgenbaum, then 25, was repeatedly brought to the brink of death by an unidentified illness that inexplicably shut down his organs.

For nearly three months, Fajgenbaum and his father, an orthopedic surgeon, had beseeched teams of specialists at two hospitals to perform a lymph node biopsy, which could help identify the cause of his sudden, catastrophic collapse. Doctors eventually performed the biopsy, which resulted in the diagnosis of a form of Castleman disease, a rare, aggressive and difficult to treat disorder of the lymphatic system.

Fajgenbaum was able to harness his exceptional skills and access to resources into a crowdsourced effort that led to the discovery of a treatment that drove his disease into remission and has so far saved his life. For several years he has taken a daily dose of a widely available drug approved 30 years ago for kidney transplant patients.

» READ MORE: The Penn doctor who wrote the book on fighting his own rare disease

While few of the 150 people I’ve profiled in more than a decade writing the Medical Mysteries column have stories that are so dramatic, their cases and Fajgenbaum’s illuminate some of the logistical obstacles, red herrings, and wrong turns that underpin unsolved cases.

Diagnostic errors — estimated to affect at least 5% of American adults annually — along with the relentless time pressures and financial incentives under which many doctors operate contribute to the creation of mystery cases. So do patient reticence and inexperience contending with systems of care that are often daunting, highly fragmented and difficult to navigate.

But patients are not powerless. Here are some suggestions culled from the experiences of Fajgenbaum and others whose cases were ultimately solved about ways to minimize the chance of becoming a medical mystery.

Many people, even those who are getting worse, worry that if they seek a second opinion they will alienate the doctor treating them.

But a second opinion, or third, can be lifesaving. It’s one reason many insurance companies encourage or even require such consultations before surgery.

A 2017 study by researchers at the Mayo Clinic found that 88% of 286 people who sought a second opinion there received a distinctly different diagnosis or a more accurate one.

Albuquerque neurologist David Smith has a word of advice for those whose doctors are miffed by a second opinion: run.

“Many times such a doctor is trying to intimidate the patient due to the physician’s lack of knowledge,” said Smith, who spotted the repeatedly overlooked cause of his lawyer’s harrowing eight-year ordeal during a careful review of his medical records.

Jeff Sipos wishes he’d gotten another opinion long before he did.

The California elementary school principal, an endurance athlete in exceptional condition, was diagnosed with anemia at age 31, a concerning finding in a man that should have prompted further investigation. Instead, Sipos was told to take over-the-counter iron supplements.

Over the next 17 years, he suffered from worsening pain in his hands and feet that made the weight of his bedsheets feel like lead. Sipos’ pain grew so severe he relied on opioids to get through the day.

In 2017, a hematologist told him he had a precancerous condition that did not require treatment. Even as he deteriorated, Sipos did not seek another opinion because the specialist seemed authoritative and he didn’t want to offend her.

After 18 months, Sipos, at his wife’s urging, made an appointment with a cancer specialist at another hospital. The doctor asked him why he wasn’t receiving urgently needed treatment for his slow-growing malignancy. Stunned, he replied that his hematologist had insisted he didn’t have cancer.

Sipos sought a third opinion. She agreed with the second doctor, telling Sipos he would die unless he received prompt chemotherapy.

Sipos began a grueling chemo regimen overseen by the second specialist that in 2019 drove his cancer into remission. Unfortunately the excruciating nerve damage to his hands and feet caused by the years his cancer went undiagnosed is permanent.

As recently as 15 years ago, getting your records could be a major hassle. But the widespread use of electronic medical records has made the process easier, although obstacles remain.

Even so, studies have found that many patients don’t access their records. That’s a mistake because they serve as a blueprint for treatment and may contain vital, and sometimes ignored, nuggets that can lead to the correct diagnosis or treatment.

That’s what Lynda Holland, a retired administrative assistant who lives in Maryland, learned in her six-year search for the cause of intractable hip pain. Her internist and two orthopedists she consulted had diagnosed bursitis, osteoarthritis, and sciatica.

But in 2017 after Holland tripped over a dog and landed on her affected hip, the pain suddenly vanished. When an X-ray revealed a mass the size of a robin’s egg, a third orthopedist told her it might be malignant. Holland, a breast cancer survivor, was terrified.

A few weeks later an orthopedic oncologist in Maryland diagnosed synovial chondromatosis, a benign disorder caused by small nodules of cartilage that become unmoored and can result in severe disability. Holland’s fall had dislodged a large calcified body that was pressing on her sciatic nerve. She subsequently underwent successful surgery to remove the nodules and the egg-sized body.

Buried in records Holland took to the fourth specialist was an MRI report from 2013 that noted the presence of “calcified/ossified bodies,” also spotted on an earlier CT scan, that the radiologist said were “suspicious for an underlying synovitis.”

Sipos had a similar experience. Among the records he obtained from the oncologist who erroneously told him he didn’t need treatment was an old pathology report that had mentioned his unusual cancer as the possible cause of his symptoms.

Some people are reluctant to seek treatment at an academic medical center sometimes called a major teaching hospital fearing it is too big or impersonal or that their problem isn’t serious enough to warrant it.

But anyone who’s not improving, isn’t sure what’s wrong, or wants a second opinion should consider a visit.

Large teaching hospitals are referral centers with expertise treating people with uncommon or unusual diagnoses that community physicians may never see. And teaching hospitals employ teams of experts in multiple specialties.

While not a requirement, it may be faster and more efficient if a doctor makes a referral.

“When patients call a referral center now they are asked ‘What’s your diagnosis?’ and ‘What specialty do you want to see?’ " Fajgenbaum said. People whose diagnosis is unclear or incorrect may be stymied.

“We like to group people into whether you should see rheumatology or immunology or oncology. But it’s clear more and more that the old silos really don’t work” well, he added. Diagnosis and treatment can involve multiple specialties.

That was the case for Pennsylvania software engineer Ram Gajavelli, who spent 18 months seeing various community physicians outside Philadelphia for unexplained stress fractures that were so painful he had to sleep sitting up.

Frustrated by the lack of a diagnosis, Gajavelli arranged to see specialists in India during a brief visit to relatives. An MRI was suggestive of an advanced cancer or rare bone disease. Upon his return Gajavelli sought treatment at Penn, where an oncologist sent him to a specialized endocrinologist. She diagnosed a bone-weakening disease so rare that only 1,000 cases have been reported worldwide; Gajavelli’s was her second.

In the weeks after his diagnosis, the endocrinologist consulted experts at the National Institutes of Health about his treatment, while radiologists pored over images of the fractures that stretched from his jaw to his feet in search of the tiny benign tumor that was causing them. In August 2019, an orthopedist who specializes in bone tumors performed a tricky 9 ½ hour operation to remove the mass, without having to replace Gajavelli’s hip.

Managing an illness — particularly if the diagnosis is uncertain — requires assertiveness, organizational skills, and a willingness to ask questions.

Primary care doctors can make referrals and offer guidance, but few have the time to provide the detailed coordination and follow-up necessary, Fajgenbaum said. They are not reimbursed for being “quarterbacks,” he added, which is what people searching for a diagnosis or treatment need. That role typically falls to the patient or a relative.

“I advise people to treat it like a job, or that you’re the project manager for this diagnosis,” Fajgenbaum said. Some people keep a notebook with a running log, recording visits with doctors and other pertinent documents.

Fajgenbaum, who has amassed more than 7,000 pages of medical records, distilled the most relevant information and sent spreadsheets and other documents to his doctors.

“You are probably going to have to get your information in a central place and make sure everyone has it,” he said, adding that early in the course of his illness doctors in three states were involved in treating him.

“You have to be proactive,” he said, “and you may need to push.”

People grappling with a medical mystery often experience “a realization that ‘I’m going to have to be part of making this diagnosis happen,’ ” Fajgenbaum said. “The important thing to know is that you have some agency, even if it’s an agency you don’t really want. It’s a major mind shift.”