Headaches, forgetfulness, and then a burning sensation

The first symptoms Velasquez-Manoff experienced were painful headaches, followed by darkness at the edge of his vision and a "dementia-like loss of vocabulary," he writes.

Since his headaches were accompanied by mucus in his throat, he suspected something was wrong with his sinuses. He saw an ear, nose, and throat doctor who inserted a long, flexible rubber scope into his nose. The doctor suggested Velasquez-Manoff may have reflux, as she could see "damage" in his pharynx.

However, Velasquez-Manoff writes the doctor didn't appear too concerned. She prescribed a series of antibiotics to clear whatever may be causing the pain.

But over the course of several weeks, Velasquez-Manoff writes he began to feel a "faint sensation of heat under my sternum" that grew stronger "until it felt as if some part of me had caught fire." He adjusted his diet, getting rid of food and drink said to aggravate reflux, but Velasquez-Manoff only got worse, eventually eating less and losing weight.

Velasquez-Manoff then visited a gastroenterology clinic where he received an endoscopy — a procedure that involves a thin tube with a small camera at the end being pushed down the throat. Velasquez-Manoff's endoscopy revealed his esophagus had strange rings over its entire length, which his gastroenterologist suggested could be indicative of a rare allergic condition called eosinophilic esophagitis (EoE).

Eosinophils are white blood cells that can help repel intestinal parasites and bacteria, and can play a role in a number of allergic diseases like asthma and eczema, Velasquez-Manoff writes. Velasquez-Manoff's biopsies showed elevated numbers of eosinophils, but not high enough to be diagnosed with EoE. However, Velasquez-Manoff had started taking Prilosec to treat his reflux, meaning it was possible the medication was obscuring an allergic condition, or that Velasquez-Manoff had an unusual case of gastroesophageal reflux disease (GERD).

Velasquez-Manoff's doctor noted that a definitive diagnosis wasn't relevant, as both EoE and GERD are treated with Prilosec and other similar drugs called proton pump inhibitors (PPIs). The doctor recommended that Velasquez-Manoff quadruple his dosage.

The symptoms worsen

While most people can take PPIs without an issue, Velasquez-Manoff writes that he experienced "horrendous" side effects. He was unable to see straight or read well, he couldn't concentrate, and was experiencing "bone-crushing fatigue."

Ultimately, Velasquez-Manoff was unable to work and couldn't tolerate food with strong flavors. As his symptoms got worse, Velasquez-Manoff also started feeling like he couldn't breathe. While he did have asthma as a child, the condition hadn't bothered him in adulthood. But now, Velasquez-Manoff writes his breathing became more labored, and inhalers didn't help.

By July 2021, Velasquez-Manoff started experiencing gasping attacks where an "acute feeling of suffocation" would overwhelm him, leaving him hot, panicked, and sweaty. Velasquez-Manoff found the best way to stop them was to sit in front of an air-conditioning unit at full blast and hold his breath for as long as he could.

Velasquez-Manoff then found a new gastroenterologist, one who worked at Stanford Health Care and was a specialist in EoE. This doctor told Velasquez-Manoff that all the acid-suppressing medications he was taking meant his stomach likely wasn't making any acid and he wasn't still suffering from severe reflux. A series of tests confirmed that everything seemed normal, and that Velasquez-Manoff had no acid reflux.

The gastroenterologist theorized the pain Velasquez-Manoff was feeling was a result of a hypersensitivity syndrome, where the nerves that convey pain become overactive and start firing off at the slightest provocation, meaning things you typically wouldn't notice cause extreme pain. The doctor described it as "a headache of the esophagus" that could be treated with neuromodulating drugs first created to treat depression.

A definitive diagnosis

Velasquez-Manoff started taking duloxetine, an antidepressant that increases brain levels of serotonin and norepinephrine, which can help modulate pain signals. However, these didn't help at first, as Velasquez-Manoff writes he became dizzy and nauseated, and any food with a soft texture led to a sense of revulsion.

But after a few weeks, those side effects faded, and Velasquez-Manoff found he could tolerate more foods. Eventually, his doctor recommended he double his duloxetine dose, and Velasquez-Manoff writes that his improvements accelerated.

After six months of taking PPIs, Velasquez-Manoff's gastroenterologist allowed him to stop taking them. In early 2022, Velasquez-Manoff underwent another endoscopy and acidity study that conclusively determined he had EoE. Most likely, his esophagus was being chronically inflamed by an allergic reaction to something he was eating.

However, it's difficult to determine exactly what food causes the reaction, as skin-prick and blood tests often used to determine allergies don't work well for EoE patients, Velasquez-Manoff writes. The only way to determine what's causing the allergic reaction is to eliminate certain food groups, then undergo an endoscopy to see if the inflammation improved, and continue to repeat until the culprit is found.

By autumn of 2021, Velasquez-Manoff noticed the duloxetine he was taking was causing night sweats and sleepiness, ultimately leading him to lose "all drive to do much of anything." After seeing a psychiatrist, Velasquez-Manoff was prescribed bupropion, which affects the dopamine pathways in the brain. This medication "ended up being miraculous," Velasquez-Manoff writes, helping him to focus and care about things again.

Given there are no FDA-approved treatments for EoE, Velasquez-Manoff started taking liquid steroids meant to be inhaled as an asthma treatment, mixing them with honey to help stick to his esophageal wall. A later endoscopy found this helped control inflammation.

In June 2022, Velasquez-Manoff wanted to stop taking duloxetine, but after cutting it out, Velasquez-Manoff started experiencing withdrawal symptoms, including a "zapping" sensation like an electric shock. However, after two weeks, those symptoms subsided and Velasquez-Manoff began to feel better while the burning pain remained subdued.

But seven months after stopping duloxetine, Velasquez-Manoff started experiencing the burning pain again, leading him to resume duloxetine, but at a lower dosage.

What was causing the pain?

Once he had a diagnosis, Velasquez-Manoff realized different episodes from his past had been hinting at the problem for years. He had a lump in his throat in his 20s that he attributed to stress, and he occasionally felt breathless, which he attributed to allergies.

The long time between the onset of symptoms and diagnosis isn't unusual, according to Evan Dellon, of the University of North Carolina's medical school. Dellon said the lag time for diagnosing EoE typically ranges between five to eight years, and patients with the condition often have problems swallowing food years before they know what's causing it.

The burning pain was also unsurprising, Dellon said, noting that animal experiments have found that an allergic reaction over time can lead to a pain syndrome. "That's what I see relatively commonly in patients," he said. Things may look normal, but the patients will complain of constant pain.

"Any disease in which the body overreacts (allergy) or turns against itself (autoimmunity) is bound to inspire a unique kind of desperation," Velasquez-Manoff writes. "Those of us in this club we never asked to join have bodies that are, in ways both literal and figurative, self-lacerating. Our magnificent and complicated bodily defenses, our immune systems, instead torment us. What we yearn for is a single treatment that can, once and for all, correct this wayward tendency toward self-destruction." (Velasquez-Manoff, New York Times Magazine, 10/4)

While most people don't anticipate becoming a "medical mystery," the path to an accurate diagnosis can be "surprisingly complex, strewn with cognitive land mines, logistical roadblocks and red herrings." Writing for the Washington Post, Sandra Boodman offers five tips for patients on how to avoid becoming a medical mystery.