Could a wayward breath mint have caused his symptoms?The young woman was awakened by the screams of her 39-year-old husband. “Please make it stop!” he shouted, leaping from the bed. “It hurts!” He paced back and forth across the room, arms crossed over his chest as if to protect himself. Two days earlier, he had inhaled a breath mint when his wife startled him. He felt it move slowly down his throat as he swallowed repeatedly. His chest had hurt ever since. But not like this.The man squirmed miserably throughout the short drive to the emergency room at Westerly Hospital, near the Rhode Island and Connecticut border. No position was comfortable. Everything hurt. Even breathing was hard. Although the doctors in the E.R. immediately determined that the young man wasn’t having a heart attack, it was clear something was very wrong. His blood pressure was so low that it was hard to measure. A normal blood pressure may be 120/80. On arrival, his was 63/32. With a pressure this low, blood couldn’t get everywhere it was needed — a condition known as shock. His lips, hands and feet had a dusky hue from this lack of well-​oxygenated blood. He was given intravenous fluids to bring up his pressure, and when that didn’t work, he was started on medications for it. Three hours later, he was on two of these medicines and his fourth liter of fluid. Despite that, his pressure remained in the 70s. He had to be put on a breathing machine to help him keep up with his body’s demand for more oxygen.The most common cause of shock is infection. But this man, as sick as he was, had no signs of infection. The medical team started him on antibiotics anyway. Could the painful mint have torn his esophagus? Up to 50 percent of patients with that injury will die. A CT scan showed no evidence of perforation or of fluid in his chest. What else could this be? There was no sign of a clot keeping blood from entering the lungs, another cause of deadly low blood pressure. An ultrasound of the heart showed that he had some fluid in the sac called the pericardium, which contains and protects the heart, but not enough to interfere with how well it was beating. He was tested for Covid and for recreational drugs — both negative.The doctors in the small community hospital began to worry that they wouldn’t figure out what was going on with this young man in time to save his life. They reached out to Yale New Haven Hospital an hour and a half away, which was better equipped to handle tough cases. Dr. Laura Glick, a resident finishing her second year of training at Yale New Haven, heard about this pending transfer and looked him up in the electronic medical record shared by the two hospitals. The patient was getting a CT of his abdomen and pelvis. Could there be a hidden infection there? As she read through his chart, an event note popped up. The patient’s heart had stopped while he was in the scanner. Was he going to die before he even got to Yale?His rapid deterioration — from a previously healthy young man who had walked into the E.R. complaining of severe pain a few hours earlier to someone who had “coded” while being scanned — was terrifying. More notes appeared. CPR was started, and after about seven minutes, the man’s heart began to beat on its own. More notes: He was awake. He was able to answer yes-or-no questions, though the breathing tube kept him from speaking. He was loaded into the transport helicopter and flown to Yale New Haven.Photo illustration by Ina JangThree PossibilitiesGlick estimated she had 20 minutes, maybe a little more, to figure out how to save this dying man. She reached out to the I.C.U. specialist in training, Dr. Stella Savarimuthu. There are only a few things that can kill you this fast, Glick acknowledged, and at Westerly they’d done a good job of ruling out most of them. She listed other possibilities she was considering. One: If the man had a perforated esophagus, he would need to go to the operating room, so she would alert surgery. Two: Maybe he didn’t have enough cortisol, one of the “fight or flight” hormones, which could cause persistent and dangerously low blood pressure. They would need to check that right away. Three: The only abnormality seen at Westerly was the small amount of fluid around his heart. In medicine, when it really matters, the rule is “Trust but verify.” With a patient this sick, things can change rapidly. When he arrived, she would have cardiologists ready to examine his heart.A couple of hours later, Glick stood watching the ultrasound monitor. The pixelated gray-and-white image of the patient’s rapidly beating heart muscle was surrounded by an unnatural black halo, indicating the presence of excess fluid in the pericardial sac. The pump was hard at work, but there wasn’t enough room for blood to even enter his heart. No wonder his blood pressure was so low.The patient was moved to the O.R., and a cardiologist inserted a thick needle into the fluid-filled sac. Just under a cup of pale yellow liquid poured out. On the screen, the halo shrank until it disappeared. His doctors would still need to figure out why he had this fluid in the first place, but now that it was gone, his blood pressure should return to normal.Back in the I.C.U., Glick followed the patient closely. Hours passed, then days, and though his blood pressure was better, it remained too low. Why? Glick sent test tube after test tube to the lab, looking for signs of infection, inflammation, autoimmune disorders — everything she could think of. After the man’s near-death experience, Glick knew that many of his lab results would be abnormal. His liver was damaged, his kidneys, his heart. Her job was to identify which abnormalities were a result of his rapid deterioration and which were the cause.Aberrant results streamed in, but only one surprised the resident. The man’s thyroid wasn’t making its essential hormone. The thyroid is like the carburetor in an old internal-combustion engine. It tells the body when to rev up and when to slow down. Right now the man’s body needed to be fully revved up, but without this hormone, it couldn’t do it. Before giving the man replacement hormones, Savarimuthu reminded Glick they had to recheck his cortisol level. They had checked it when he arrived, and it was high — as expected, given the physiological stress he was under. But administering thyroid hormone to someone who is cortisol-deficient is like jump-starting a car that has no oil in the engine. You could ruin the whole machine. So Glick sent off a second cortisol-level test. This time, the level was undetectable. She checked again: undetectable.The Steroid TestA different test revealed the cause: His adrenal glands, where cortisol is made, weren’t working at all, just like his thyroid gland. She started the man on steroids — an artificial form of cortisol — along with thyroid hormone, and consulted the endocrine team. She then reviewed the records from Westerly, where she saw, buried deep in his chart, that he had been given steroids there. Because he wasn’t deficient when he arrived, and they hadn’t mentioned the steroids in their notes, Glick hadn’t administered them at Yale New Haven. She now turned to the medical literature to figure out just what might have caused these devastating twin hormone deficiencies.It didn’t take long to determine that he must have autoimmune polyglandular syndrome Type 2. In this rare disorder, the immune system suddenly and mistakenly starts to attack parts of the patient’s own body — in this case, the thyroid gland and the adrenal glands. Why this happens is not well understood. A few hours after getting both replacement hormones, the young man was well enough to begin tapering the medications sustaining his blood pressure. A couple of days later, he was well enough to leave the I.C.U. Ten days later, he was able to go home.Once the patient understood what he had and started to feel the benefit of the treatment, he realized he’d been sick long before that mint went down wrong. He will have to take these hormones for the rest of his life, but he feels better than he has for years. No one can be certain exactly when his glands were destroyed; it was probably long ago. “I’m not a guy who goes to the doctor,” he admitted. He thought he was just getting old: “You know what they say — after 30, it’s all downhill.” But not anymore. Not for him, anyway.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is “Diagnosis: Solving the Most Baffling Medical Mysteries.” If you have a solved case to share with Dr. Sanders, write her at Lisa.Sandersmd@gmail.com.

Could all this really be a result of a urinary-tract infection?The 75-year-old man lay sprawled on the floor between the kitchen counter and the island, surrounded by a halo of pills. “What happened?” his wife asked as she hurried to his side, although she suspected she already knew.He wasn’t sure, he told her. One minute he was standing at the counter, getting ready to take his morning medications; the next, just like that, he was on the floor. She helped him sit up. When he was able to, he slowly rose to his feet. It was the third time he fainted in the last week and a half. The first spell came when his wife was out of town. He was dozing on the patio and woke up hot and sweaty. As he made his way into the house, he felt unsteady and braced himself on the wall. He made it to a chair but passed out a couple of times just sitting there. And when awake, he was confused. He was trying to read a text from his daughter but couldn’t remember how.The next time, a couple of days later, he woke to go to the bathroom. He got up, then suddenly found himself on the floor. A sharp pain in his forehead told him he’d clipped the bedside table on his way down. His wife helped him up and to the bathroom. He found that he’d been incontinent. He was embarrassed, in front of his wife of 53 years. He called his doctor’s office the next morning and arranged to come in the following day. He hadn’t been feeling well for the past couple of weeks, he told the young physician assistant. He’d woken up drenched with sweat a few times recently, and his wife told him he rattled the bed with his shivering. He felt feverish. Tired. No appetite. No ambition. Foggy. One night he wasn’t even able to remember the prayer he always said before bed. And urinating was strangely uncomfortable.After finishing her exam, the physician assistant sent him to the lab. This was probably a urinary-tract infection, she told him after reviewing his test results. These are not uncommon in older men, because an enlarging prostate can make it hard to urinate. She started him on an antibiotic often used to treat this kind of infection.That was just two days before this most recent episode. The P.A. told him to go to the hospital if he felt any worse. He definitely felt worse.A Highly Motivated ClinicianIn the emergency department of the Yale New Haven Hospital, it was clear that the elderly man was sick. He had a fever of 101, his heart was racing and his blood pressure was abnormally low, even though he hadn’t taken his hypertension medications that morning. Lab results confirmed that first impression. His kidneys were failing — though they were fine just two days earlier. He was given IV fluids and started on broad-spectrum antibiotics. The drug he’d been taking for the past couple of days didn’t seem to be doing the job.On the floor, the first clinician the patient met was Alan Lee, who was in his last year of med school and serving as an intern. Lee was excited to see this patient. Because the hospital was so crowded, thanks in part to the recent resurgence in Covid-19 cases, patients often spent hours, sometimes days, in the E.R. waiting for a bed. By the time they got onto a medical floor, they could already have a doctor assigned. This meant most of the thinking about the patient had been done, and the accepting physician usually just carried out the first doctor’s plan. This Sunday-morning admission came during a lull in the action, so Lee’s team would get the first crack at figuring out what was going on.The doctors in the E.R. were focused on the man’s failing kidneys, but what injured those kidneys? What caused the fever? These were the questions Lee had to answer for himself and for the patient. The young man entered the room accompanied by his supervising resident, Dr. Roger Ying. They introduced themselves, and Lee started asking questions. The patient told the story of his three episodes of fainting, how he felt feverish and sick and how he lost 10 pounds in the past week or so because he felt too sick to eat or drink.Once Lee finished his questions, Ying asked the patient if he had been bitten by a tick recently. Absolutely not, the man answered promptly. He often took his dog to wooded paths down by the Connecticut River, but once he got home, he was careful to check his body for ticks.Dr. Joseph Donroe, the attending physician, joined the trainees at the bedside. Lee acknowledged that a urinary-tract infection could have caused the man’s urinary problems as well as the fever. Those symptoms could make the patient not want to eat or drink, allowing him to become dehydrated. That, in turn, could have caused him to faint and could have even damaged his kidneys. But a 10-pound weight loss was not a common finding in a urinary-tract infection. Neither was night sweats. Could this be a tick-borne illness like Lyme?Photo illustration by Ina JangThe Most Likely DiagnosisDonroe agreed that these symptoms were atypical. It seemed likely the patient now had urosepsis — an infection that started in the urinary tract but then involved the entire body — and that the cause of his symptoms was a urinary infection. But because he was already on antibiotics, they probably wouldn’t see anything in the urine if they tested him now. Lee should call the patient’s primary-​care doctor Monday morning to get the results of the tests done before he had started the antibiotics.The next day, the patient was feeling a lot better. He’d gotten fluids and a good night’s sleep. No fever, no shaking chills. Maybe the antibiotics were working. Still, his kidneys were no better.After rounds, Lee called the patient’s doctor. The urine culture hadn’t grown anything at all. The only abnormality was that the urine contained a lot of blood. Now what? Lee went to the attending with the news. Together Lee and Donroe went over the data one more time. One of the labs ordered suggested that red blood cells were being destroyed somewhere in the body. Suddenly it all made sense.The man had been sick for nearly two weeks with fevers and chills, and he had something destroying his red blood cells. To Donroe that sounded like a tick-borne disease. Not Lyme, but a different disease carried by the same type of tick: a disease called babesiosis. They should order a test for Babesia as well as one for Lyme, ehrlichiosis and anaplasmosis — the most common tick-borne diseases in Connecticut.It was late afternoon when the first result came back. Inside many of the patient’s red blood cells, the lab tech had seen a single tiny dark circle — a parasite. The patient had babesiosis.A Circle or a CrossBabesia is a protozoan, a single-celled parasitic organism, carried by the deer tick. This arachnid picks up the bug while feeding on a white-footed mouse and delivers it to the next mammal it bites. Once the organisms enter the circulation, they invade red blood cells, where they multiply. Under the microscope the organisms look like either a circle or a cross depending on where they are in maturation and reproduction. Then progenitor and offspring burst out of the cell, enter neighboring red blood cells and the process continues.In the Northeast, the deer tick is best known as the carrier of Lyme disease. And in fact, up to 42 percent of ticks that carry Babesia also carry Lyme disease, according to a study from a Connecticut state lab. The following day, the team learned that it was true for the tick that bit this patient as well. He had both Lyme and babesiosis, and so needed to be treated with three medications — two for the Babesia and one for the Borrelia, the bacteria that cause Lyme disease. He would have to take them for about two weeks.The patient could feel the difference the day after he started taking the medications. His appetite was back. So was his energy. Now that he is back home, he is considering how to deal with those ticks. He knows they’re not going anywhere, but neither are he and his wife. He already uses a spray to discourage their bites. Clearly he will just have to look a lot harder after his walks with the dog. He’s not going to let the arachnids win.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is ‘‘Diagnosis: Solving the Most Baffling Medical Mysteries.’’ If you have a solved case to share with Dr. Sanders, write her at Lisa.Sandersmd@gmail.com.

Her eye chart tests showed improvement. It took a radical experiment to find out why her reality wasn’t matching up.The burning started as soon as the 59-year-old woman put the drops into her eye. She blinked to try to rinse away the medication with her tears. She leaned forward to the mirror. Her left eye was red and angry-looking. She’d been using these eye drops for nearly a year to treat her newly diagnosed glaucoma, adding artificial tears for the dry eyes that appeared a few months later. And while she’d had plenty of problems with her eyes since all this started, this fiery pain was new. The vision in her left eye had been bad for a few years by then, but with an operation nearly two years earlier to remove an abnormal membrane on her retina and more recent cataract surgery, she had hoped she would have her old vision back by now. She was a physician-researcher and spent much of her time reading and writing, so her vision was very important to her livelihood. But despite the efforts of her eye doctors — and at this point she had many — she still couldn’t see well. It was when she was getting ready for the cataract surgery that the patient learned she had glaucoma. After her initial exam, her new eye surgeon told her that the pressure inside her left eye was abnormally high, and she was already showing signs of damage from it. He wanted her to see one of his colleagues, Dr. Amanda Bicket, a glaucoma specialist who was then at the Wilmer Eye Institute at Johns Hopkins. A quick phone call later, she had an appointment to see the doctor that day. It was urgent that this be evaluated and treated before her upcoming surgery. Drops, Drops and More DropsWhat we call glaucoma is really a group of diseases in which the optic nerve — the tissue that transmits what the eye sees to the brain — is damaged, usually by increased pressure within the eye. It is the second most common cause of blindness in the world, and surgery can be a trigger in those who are prone to the disease. The good news is that there are effective, sight-sparing treatments. The first are medications that reduce the intraocular pressure (IOP) by either slowing the production of the fluid in the eye or increasing the drainage of that fluid out of the eye. In cases like this patient’s where there is already damage to the nerve, a tiny tube must be inserted into the front of the eye to allow the excess fluid to drain and bring the pressure even lower. Bicket started the patient on the pressure-lowering drops that day, and three days later, she had her cataract extracted and the pressure-reducing tube inserted. The day after these surgeries, she came back to Bicket’s office to have the bandage removed and her vision checked. It was bad: She could just barely make out the E at the top of the eye chart. That put her vision at 20/200, which means that at 20 feet she could see only what normally sighted people saw when they were standing 200 feet away from the chart. For context, if both of her eyes were persistently 20/200, she would be considered legally blind.Photo illustration by Ina JangBicket reassured the worried patient. It’s going to get better, she told her. And it did, slowly. Over the following weeks, her visual acuity was measured at 20/150, then 20/100, 20/80 and finally 20/50. Bicket was pleased. Everything was going as she expected. The patient wasn’t so sure. It was good to hear that her vision was improving on the tests, but she still felt that she couldn’t see worth a darn. Moreover, her eyes were dry, and her eyelids sometimes scratched as if they were dusted with a layer of sand. So in addition to the drops to lower her pressure and the ocular antibiotic and steroids she sometimes had to use, she started using artificial tears for the dryness. With all these medications, she could end up putting drops in her eyes a dozen times a day. Worst of all, she was now intensely sensitive to light. Her computer screen was like an interrogation beam. She turned off all the lights in her office and wore a broad-brimmed hat and post-surgical wraparound sunglasses to shield her eyes from the relentless light, both indoors and out. She had to stop driving; the sunlight on even the cloudiest day forced her to close her eyes. Everyday tasks — at work and at home — became difficult, sometimes impossible. A Risky ExperimentAfter months of this, the woman could feel her life getting smaller and smaller. She wondered if she was going to have to apply for disability. Finally she mentioned this to Bicket. The doctor was shocked. Her vision was so much better, Bicket countered. “Well, my vision may be better, but I still can’t see,” the patient replied. Bicket referred her to a low-vision clinic. The optometrist there recommended glasses with special glare-reducing lenses. They didn’t do much. Then came the day she put in the first of her two glaucoma drops, and her eyes began to burn. She immediately sent an email to Bicket, telling the doctor that she was going to stop that medication and just use the others. Maybe it was this medicine that was causing the photophobia, the eye dryness and now the burning. “I’m fine with any short-term IOP-drop experiment you’d like to run,” Bicket wrote back. But the symptoms the patient was having didn’t match the usual side-effect profile of any of the medications she was using. There was another possibility, Bicket added: Maybe it’s not any single drop, but all of them. They all contain a preservative called benzalkonium chloride (BAK). “If that is what you don’t tolerate,” Bicket wrote, “stopping one agent vs. another won’t help.” The patient decided to stop them all, she wrote to Bicket. It was a risky action, because the drops were important for keeping her pressure down and avoiding further damage. But the pain and light sensitivity were unbearable. The Lag Between Test and RealityThree days later, the patient had her answer. Her eyes felt so much better without the drops. The gritty feeling when she blinked was gone. So was the photophobia. It had to be the BAK. The patient turned to PubMed to read up on it. There was a lot there. Preservatives were essential to prevent the growth of bacteria in bottles of medications that contained more than a single dose, and BAK was the most commonly used preservative in both over-the-counter and prescription eye drops. The patient’s discomfort, she discovered, was not due to an allergy to the preservative but rather was a response to the way BAK works. This compound kills germs by dissolving the layer of lipids that make up their outer protective coat. Here’s the problem: Eyes are kept from drying out by a similar protective coat — of tears. Tears are composed of a thin sheet of liquid from the lacrimal (tear) gland, which is in turn covered by a layer of oil made by the meibomian glands. BAK breaks down this outer protective lipid layer, exposing the salty fluid to the air. In many of those who have dry eyes, the unprotected fluid evaporates, and the patient’s eyes become even dryer. Eye-drop users who make enough tears won’t be affected, but many do not. Aging will also reduce this protective layer, putting older users of medications containing BAK at higher risk of drying eyes. The dryness can eventually lead to permanent damage to the cornea, the clear outermost layer of the eye. The patient immediately switched to single-dose bottles of the drops; these don’t need any preservatives at all. With that change, her eyes began to heal. It has been five years, and she still can’t see well out of the left eye, and she now has glaucoma in the right one as well. But she has figured out how to work with the vision she has, and her glaucoma is well controlled. Bicket, who is now at the University of Michigan, has been fascinated by the difference between the visual acuity measured in the office and patients’ own sense of how well they can see. Research she and colleagues published recently shows that this can lag behind the tested acuity by weeks or sometimes months. The first question anyone facing eye surgery will ask, Bicket told me, is how long will it take for them to recover enough to go back to work, or to read or drive. “The simple answer,” she says, “is we just don’t know.” But Bicket is working hard to find out.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is ‘‘Diagnosis: Solving the Most Baffling Medical Mysteries.’’ If you have a solved case to share with Dr. Sanders, write her at Lisa .Sandersmd@gmail.com.

The obvious place to look isn’t always the right place.“I’ve been coughing up blood,” the 59-year-old man confessed to his wife as they drove toward New York City from their home in Connecticut. It started the night before, he admitted when she asked. After 40 years of marriage, his wife, a nurse, was used to this kind of nonchalance from her husband, though it always carried a kind of punch. Take this exit, she instructed. They were near an urgent-care center in Brewster, N.Y. He needed to get this checked out.It was quiet when the couple walked in to urgent care, so her husband was seen right away. He had a runny nose and a cough for the past couple of days, and a few times he’d seen streaks of blood in what he coughed up, he told the nurse. His chest hurt a little when he took a deep breath, but otherwise he felt just fine. His vital signs, however, told a different story. He didn’t have a fever, but his oxygen level was at 91 percent. Even with the worst cold, his oxygen should have been 98 to 100 percent. Did he feel short of breath? Not particularly, he said. Maybe when he was walking from the car, but sitting here now? Not at all. He needed a CT scan of his chest, the couple was told, and so he was transferred to the emergency department at Northern Westchester Hospital in Mount Kisco, N.Y.The CT didn’t reveal any clots in the arteries of the lungs, so he didn’t have the feared pulmonary embolus, which could have caused his low oxygen and hemoptysis (coughing up blood) without other symptoms. Even so, the images were far from normal. There were patches of a light haze in areas that should be dark in both lungs. Maybe pneumonia? People usually feel sicker than this man when they have pneumonia, but how else could they explain the low oxygen level? He was started on antibiotics and admitted for observation.Crisis in the HarborDr. Tara Shapiro was the doctor assigned to his care that night. She was not at all sure the problem was in the man’s lungs. The CT scan also revealed a heart that was thicker and more muscular-looking than it should be. This kind of hypertrophy, as it’s called, is frequently seen in patients who have high blood pressure, when the heart has to work hard to squeeze its payload into the bloodstream. But this man didn’t have high blood pressure.The patient had a full cardiac work-up a few months earlier that he said was normal. But Shapiro was still worried that it was his heart and not his lungs that was failing him. His oxygen level improved greatly in just the few hours he’d been in the hospital. It was far too early for the antibiotics to have done this. More likely it was from the powerful diuretic he’d already been given in case the haziness in his lungs was fluid rather than an infection. A muscular heart doesn’t pump as well as a normal heart and sometimes can’t keep up. When that happens, fluid can get backed up — right into the lungs.Shapiro reached out to a cardiologist colleague, Dr. Ronald Wallach. He was one of the most knowledgeable doctors she knew. Wallach saw the patient the following day, just before he was discharged. The patient’s wife was reassured by the doctor’s white hair and air of quiet authority. Her husband, something of a hardhead, would certainly listen to this guy.After hearing the man’s story, Wallach asked if he had been short of breath before. Well, maybe it had been going on for a while, the man acknowledged. How long? The man’s wife gave him a sharp look. Certainly for the past several months, at least since the summer, he said. That’s when he’d had some serious trouble breathing.He was out one weekend on his motorboat with his wife and adult daughter. The women were on inner tubes in the cove just behind New Rochelle Harbor, enjoying the sun and calm waters. Then suddenly: “Throw me the rope,” he heard his wife shout. He looked up to see the two women moving rapidly away from his boat, caught in the oceanbound tide. He wrapped one end of a rope around his body and threw the other end out to his wife. It took a couple of tries, but she got it. He struggled to pull wife and daughter back to the side of the boat. As they clambered over the side, it was his wife who noticed his breathing. His face was red and shiny with sweat, and he was panting for breath. Are you OK? she asked. He nodded his head and held up a finger as if to say give me a minute. It took more than a minute — a lot more. It scared her. He was a tough guy, but it might have scared him too, because, though he refused to go to the emergency room then, he did see his primary-care doctor later that week.That doctor immediately sent him to a pulmonologist and then a cardiologist. The lung doctor gave him a diagnosis of asthma. It’s unusual at this age, the doctor said, but it happens. He gave the patient an inhaler to use when he felt short of breath. It didn’t help. The cardiologist ordered a stress test. The patient lasted only a few minutes before he was too out of breath to continue. His EKG was normal throughout the test, so his cardiologist chalked it up to his asthma. He was an elevator mechanic and that meant that most days he had to climb stairs — sometimes lots of stairs — to fix broken machinery. The man noticed the stairs had become a little harder on him over the past year or so, but, he asked Wallach with shrug and a smile, what can you do?Illustration by Ina JangZigzag FibersIt was the EKG done in the emergency department that provided Wallach with the last clue he needed to make his diagnosis. An EKG measures the electricity generated by the heart in order to make the muscles contract effectively. A thick, muscular heart will make an EKG tracing that is bigger, more exaggerated than normal. The more muscle present, the bigger the signal. But this man’s heart generated a signal that was smaller than normal. Less electricity could suggest less muscle. Was this man’s heart enlarged by something other than muscle?There are diseases that can invade cardiac muscles to make them look bigger but be weaker. A disease like that could account for all the man’s symptoms — the thick-looking walls, the overflow into the lungs, the strange EKG, the shortness of breath, even the hemoptysis. “I think you might have something serious,” Wallach told the patient. A cardiac M.R.I. could give them the answer. The patient got that test a few days later. He wasn’t out of the scanner for more than 20 minutes when his phone rang. It was Wallach. The images told the story: The man had a disease known as amyloidosis.Amyloidosis is the final result of many disease processes that ultimately cause zigzag-shaped fibers to accumulate in different parts of the body. Cardiac amyloidosis can be a result of a cancer known as multiple myeloma. In this cancer, a type of white cell called a plasma cell creates abnormal fibers that can break down and form the characteristic saw-toothed fibers of amyloidosis. These jagged fibers can also be a result of aging. In this version of the disease, carrier proteins known as transthyretins break down and take on the abnormal but characteristic irregular folds of amyloidosis. In both diseases, these serrated fibers travel through the body, invading and accumulating in muscle — often the heart muscle.Tests on blood and urine quickly showed that his disease wasn’t due to myeloma. That was a relief; the prognosis for patients with cardiac amyloidosis from multiple myeloma is poor. They often die within a year of getting the diagnosis. A biopsy of the heart muscle proved that it was the form of amyloidosis associated with aging. This type of amyloidosis is also progressive but much more slowly. The patient was referred to a cardiothoracic surgeon at Columbia University. Sooner or later, he was going to need a heart transplant.Three years passed before Wallach heard again from the patient. He wrote to let Wallach know he’d received his heart transplant and was doing well. He was writing to say thank you: “You saved my life.”I asked Wallach how he could make this diagnosis when other doctors had not. He called it the Aunt Tilly Sign. “If I described Aunt Tilly to you and sent you out into a crowd to find her, you’d probably fail. But if you’d ever seen Aunt Tilly” — he snapped his fingers — “no problem. You’d find her in a second. It’s all about recognition.”Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is “Diagnosis: Solving the Most Baffling Medical Mysteries.” If you have a solved case to share with Dr. Sanders, write her at Lisa .Sandersmd@gmail.com.

Was there a clue in the dark color of his urine?The 22-year-old man struggled to get out of bed. The E.M.T.s were just outside his door, if he could only get there. The previous day he felt that he was coming down with something. Normally he never took naps, but that afternoon, he returned from class feeling completely wiped out and slept long and hard. Yet when he awoke, he felt even worse. Every muscle was sore. He felt feverish. This must be the flu, he told himself. He had the flu shot before starting school that year, but of course no vaccine is 100 percent effective.He spent the rest of that afternoon in bed, too tired and in too much pain to even get up to join his partner for dinner. When he awoke in the middle of the night to go to the bathroom, he was so weak and sore he could hardly sit up. He maneuvered to the edge of the bed and, using the headboard, pulled himself to his feet, but his partner had to help him get to the bathroom. Once he was there, the urine he produced was startlingly dark — the color of Coca-Cola.The next day he felt no better. His partner wanted to stay home with him, but he hurried her off to work. It’s just the flu, he assured her. But as the morning wore on, he started to worry. He called his parents, who were both nurses. They were worried too; influenza can be bad. When he got the same message from a doctor back home in New York, he started wondering if he should go to the hospital. He’d never been this sick before.It was late morning when fear overcame embarrassment and the young man called 911. And now that the E.M.T.s were here, he was worried that he couldn’t get to them. Just standing had every fiber in his legs on fire. He supported himself by leaning on furniture and slowly made his way to the front door. He was grateful that they had pulled the stretcher to the bottom of the steps leading to his porch.An Off-the-Charts Test ResultHe wasn’t in the emergency department of C.H.A. Cambridge Hospital in Massachusetts for long before the decision to admit him was made. The test for the flu was negative, but the blood tests done were dangerously abnormal. His kidneys were failing, and it looked as if his liver was damaged, too. His white-blood-cell count was twice the normal level, suggesting a severe infection.The patient told the doctor that he had been working out a few days before he got sick, so the doctor sent a blood sample to look for the presence of creatine kinase (C.K.), an enzyme that goes up when muscle tissue is injured. Extreme bouts of exercise can cause this kind of injury, and when C.K. and other muscle components leak into the bloodstream, they can cause all kinds of damage — a condition called rhabdomyolysis. A normal level of creatine kinase is in the 100 to 200 range. This patient’s C.K. was over 40,000. Just how much over was unknown because that was as high as this initial test could measure.Dr. Frances Ue was the third-year resident assigned to care for the young man. He hadn’t been working out that hard, he told her, after she explained the possible link between his exercise and his current pain. He went to the gym three times a week to help him manage the stress of grad school. He had added a couple of new exercises to his regimen, but nothing extreme. The doctor asked if he was using any drugs or supplements to help him build muscle. Absolutely not. Was he using any drugs like cocaine or Adderall, either recreationally or as study aids? These can increase the risk of developing rhabdomyolysis. Again, his answer was no.She asked if anything like this had ever happened to him before. Never. Later he recalled an episode of really dark urine when he was sick as a child. But he never had this kind of muscle pain before.The doctors in the emergency room thought exercise-induced rhabdomyolysis was the most likely cause of his symptoms and lab abnormalities, but not the only possibility. They had already sent off tests to look for infections known to affect the liver and kidneys: hepatitis A, B and C, Epstein-Barr virus, cytomegalovirus. They also ordered a blood test to look for Wilson’s disease, an inherited inability to eliminate copper from the body, which can cause sudden liver failure in young adults. What else? Ue wasn’t sure.Ina JangFlushing Out the KidneysWhatever the cause, she told the anxious young man, his muscles would recover. But his kidneys were in danger. His urine was dark because the oxygen-carrying parts of the muscle known as myoglobin were collecting in the kidneys. Myoglobin is a dark red color; it’s why muscle is red. The most important thing the medical team was doing for him right then was giving him fluids to help his kidneys flush out myoglobin and other components released by the damaged muscle.Ue ordered additional tests to track the patient’s creatine kinase. On admission, his total C.K., initially reported at over 40,000, had actually been 189,000. It peaked the next day at nearly twice that: 364,000. Ue kept the IV fluids going and looked for a reason for the worst case of rhabdo she had ever seen. It wasn’t hepatitis or any of the common viruses they tested for. It wasn’t Wilson’s disease. It wasn’t any of the drugs she checked for.A Fuel Problem?What else? In search of an answer, she turned to the medical literature and found a paper describing two young people who, like her patient, developed severe rhabdo after a moderate workout. The writers listed factors that could predispose a patient to having this kind of muscle injury, and Ue found what she was looking for. There are people born with abnormalities in how their bodies use the fuel provided by the foods they eat. Because of this abnormality, when stressed or working hard these people could quite literally run out of fuel. Could he have one of these rare inherited diseases? To answer that question, after the patient recovered enough to leave the hospital, Ue referred him to a neurologist who specializes in neuromuscular diseases.It was months later when the patient had enough of a break in his schedule to make an appointment to see Dr. Courtney McIlduff, a neurologist at Beth Israel Deaconess Medical Center in Boston. Since his week in the hospital, the man reported, he had two more episodes — though neither as severe as the first. Both happened after he took an easy walk. Hearing that, McIlduff, like Ue, began considering an inherited problem in turning food into fuel. These so-called metabolic myopathies sometimes didn’t reveal themselves until adolescence or even adulthood.McIlduff examined the man carefully, looking for muscle weakness. Many forms of muscle disease can permanently alter how muscles look or work, but most metabolic myopathies don’t. The patient’s muscle exam was completely normal. She sent him to get genetic testing, to look for one of the several inborn errors of metabolism.And indeed, he had one: He was born without the ability to make an enzyme called carnitine palmitoyltransferase type 2. Patients with CPT2 deficiency are missing the necessary biological equipment to turn some dietary fats into energy. Normally the body runs on a type of sugar made from carbohydrates and stored in the liver. When that sugar is used up, the body switches to fat for fuel. Patients with CPT2 deficiency can’t do that, or at least not well. Without the proper fuel, the muscle cells are injured and release their contents, causing the pain and dark urine. Neither of the man’s parents have this disorder, but they both have one copy of the erroneous gene for this enzyme. It takes two copies to get the disease, and so their son got one copy from each of them.There is no cure for CPT2 deficiency. It’s managed with diet and lifestyle changes, as well as a supplement that provides fats that these bodies can break down. It has been a year and a half since this young man’s condition was diagnosed. To learn how to live with it, he has turned to others who have it, too. An online community called What Can You Do Despite CPT Type 2 has provided real-time tips and tales from those who, like him, live with this genetic abnormality. He has figured out how to eat, how to rest and how to exercise with this disorder. He is, he says, determined to learn how to take care of the only body he’ll ever have.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is “Diagnosis: Solving the Most Baffling Medical Mysteries.” If you have a solved case to share with Dr. Sanders, write her at Lisa.Sandersmd@gmail.com.

When he tried to get up, he realized he couldn’t move. His weakness had a surprising cause — and an even more surprising cause behind the cause. “I can’t move my legs,” the 26-year-old man told his younger brother, who towered above him as he lay sprawled on the floor. He’d been on his computer for hours, he explained, and when he tried to stand up, he couldn’t. His legs looked normal, felt normal, yet they wouldn’t move.At first, he figured his legs must have fallen asleep. He pulled himself up, leaning on his desk, and slowly straightened until he was standing. He could feel the weight on his feet and knees. He let go of the desk and commanded his legs to move. Instead, they buckled, and he landed on the floor with a thud.His brother awkwardly pulled him onto the bed. Then they waited. Surely this weird paralysis would disappear just as suddenly as it came. An hour passed, then two. I’m calling an ambulance, the younger brother announced finally. Reluctantly, the elder agreed. He was embarrassed to be this helpless but worried enough to want help. When the E.M.T.s arrived, they were as confused as the brothers. The medics asked what the young man had been up to. Nothing bad, he assured them. For the past few weeks he had been getting back into shape. He changed his diet, cut out the junk and was drinking a protein concoction that was supposed to help him build muscle. And he was working out hard every day. He’d lost more than 20 pounds, he added proudly. Hearing about this extreme diet and exercise regimen, the E.M.T.s told the man he was probably dehydrated. He needed fluids and some electrolytes. A couple of bottles of Gatorade and he would very likely feel a lot better. And if he didn’t, he could call again.With his brother’s help, the man moved himself to a sitting position. He drank some water and Gatorade and waited to start feeling better. He fell asleep, still waiting. By the following afternoon he was having trouble sitting upright. He was drinking yet another Gatorade when he noticed that the bottle felt heavy. He realized with a start that the weakness had moved into his arms. Call the ambulance, he told his brother. This can’t be dehydration. A new set of E.M.T.s agreed. They hoisted the weakened man onto a stretcher, fastened the straps tightly and headed down the stairs. The man felt himself pitch forward as the stretcher tilted down. Was he going to fall? He imagined himself tumbling down the stairs like a sack of potatoes, completely unable to protect himself. The straps held him on the stretcher, but that feeling of helplessness terrified him. A Quick Test ResultDr. Getaw Worku Hassen was the emergency-medicine doctor on duty that night at Metropolitan Hospital in Upper Manhattan. He asked the patient if anything like this had happened before. No, the patient replied, though recently his thighs had felt tired and weak at times. It never lasted long, and he figured it was from working out so hard. The man asked if he might have had a stroke. Would he ever be able to walk again? Hassen reassured him that his symptoms didn’t look like a stroke. But, the doctor acknowledged, he wasn’t sure what it did look like.On exam, the man’s heart was racing at 110 beats a minute. And his blood pressure was high. He couldn’t lift either leg off the stretcher — not even an inch. His arms were weak as well. But his reflexes, sensation and the rest of his nervous system seemed otherwise normal. Hassen told the man that they would need to wait for the results of his blood work and other tests. He would be back when he knew more. Moments later the doctor was called by the lab. One of the patient’s electrolytes was dangerously low — his potassium. Photo illustration by Ina JangThe Cause Behind the CausePotassium is probably the most important electrolyte we measure routinely. It is essential for every cell in the body, and its movement in and out of cells is key to many of the body’s functions. Hassen immediately ordered potassium to be given both by mouth and intravenously. He wasn’t sure why this young man had such a low level of potassium but knew that if he didn’t get more, he could die. Cells in the heart depend on the flow of potassium to work properly. Either too much or too little of it could cause the heart to develop a life-threatening arrhythmia. The patient was admitted to the intensive-care unit so that his heart could be monitored as the deficit was reduced. The patient says he could feel strength flowing back into his muscles almost as soon as he started getting the replacement electrolyte. By morning he felt strong enough to stand. By midafternoon, he could walk. The doctors gave him potassium tablets to take every day for the next week and told him to stay hydrated if he was going to keep up this fitness regimen. And, of course, he should follow up with his regular doctor. A few days later, when Hassen returned to the hospital for his next shift, he wondered what had happened to the man with the weakened legs. He saw that his potassium had come back to a normal level and that he had been discharged. These days, financial pressures push doctors caring for hospitalized patients to narrow their focus to identifying life-threatening conditions and addressing those enough to stabilize the patient. Patients are then sent back to their primary-care doctors to determine the hows and whys behind the conditions that sent them to the hospital in the first place. Hassen accepted this reality, and yet to him the real pleasure of medicine wasn’t just identifying and addressing the serious symptoms but figuring out the cause behind the cause of the symptom. This man’s weakness was caused by low potassium. But what made his potassium low? A Striking ResemblanceHassen reviewed the notes from the patient’s overnight stay. In the emergency department, he had been weak, his heart racing, his blood pressure high and his potassium low. When electrolytes were repleted, his strength returned and his blood pressure dropped. But his heart continued to race. Heart rates are often high in the E.R.: Patients are scared and sometimes sick, often in pain. But this man’s heart rate stayed high even as everything else got better. That struck Hassen as strange. And so Hassen turned to the internet. He eventually found a case report that bore a striking resemblance to his patient: a young man with weak legs, low potassium and a high heart rate. That patient turned out to have something Hassen had never heard of: thyrotoxic periodic paralysis, muscle weakness where the low potassium was being caused by an excess of thyroid hormone.The thyroid is a gland located in the neck that helps control the body’s metabolic rate. Too much thyroid hormone causes the body to race. Too little, and it slows to a crawl. Unchecked, either state can be fatal. Rarely, in some people — usually young, often male — too much thyroid hormone can make circulating potassium levels drop and cause weakness. Hassen called the lab. He ordered tests to check the level of thyroid hormone in the sample. It was very high. He called the patient and got no answer, and he had no way to leave a message. He called the number a dozen times over the course of the next few weeks. Finally, maybe accidentally, the patient picked up. Hassen explained what he’d discovered. He gave the patient the name of an endocrinologist in the area. It turned out the young man had what is known as Graves’s disease. This is an autoimmune disease in which the patient’s own antibodies induce the thyroid gland to produce too much hormone. It’s often treated with radioactive iodine, which kills off some or most of the hormone-producing cells in the gland. This man, instead, chose to take a medicine that interferes with the gland’s ability to make thyroid hormone.This diagnosis was made almost four years ago. The patient gave up his intensive diet and exercise regimen and is now trying just to stay in shape and eat smarter — and to take his medicine every day. Sometimes when he feels his thighs are tired or weak, he eats a banana or avocado to get the potassium that he thinks his body is craving. He is determined to never relive that kind of helplessness again.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is ‘‘Diagnosis: Solving the Most Baffling Medical Mysteries.’’ If you have a solved case to share with Dr. Sanders, write her at Lisa.Sandersmd@gmail.com.

It felt like the itch was coming from somehow under her skin. The cause ended up being even deeper.It was dark by the time the 41-year-old woman was able to start the long drive from her father’s apartment in Washington, D.C., to her home in Westchester County, N.Y. She was eager to get back to her husband and three children. Somewhere after she crossed the border into Maryland, the woman suddenly developed a terrible itch all over her body. She’d been a little itchy for the past couple of weeks but attributed that to dry skin from her now-faded summertime tan. This seemed very different: much stronger, much deeper. And absolutely everywhere, all at the same time.The sensation was so intense it was hard for the woman to pay attention to the road. She found herself driving with one hand on the steering wheel and the other working to respond to her skin’s new need. There was no rash — or at least nothing she could feel — just the terrible itch, so deep inside her skin that she felt as if she couldn’t scratch hard enough to really get to it. By the light of the Baltimore Harbor Tunnel she saw that her nails and fingers were dark with blood. That scared her, and she tried to stop scratching, but she couldn’t. It felt as if a million ants were crawling all over her body. Not on her skin, but somehow under it.The woman had gone to Washington to help her elderly father move. His place was a mess. Many of his belongings hadn’t been touched in years. She figured that she was having a reaction to all the dust and dirt and who knows what else she encountered while cleaning. As soon as she got home, she took a long shower; the cool water soothed her excoriated skin. She lathered herself with moisturizer and sank gratefully into her bed. But the reprieve didn’t last, and from that night on she was tormented by an itch that no scratching could satisfy.A Year of Unrelenting AgonyAfter two weeks, she went to an urgent-care center. There didn’t seem to be a rash or bites, the doctor told her, but her skin was so red and scratched up that he might not be able to see if there was an allergic reaction or bites from bedbugs or fleas beneath it all. He started her on a two-week course of prednisone; that should calm your itch, he told her, no matter the cause. She took it faithfully. It didn’t help.She cleaned every inch of her house and hired an exterminator to search for bedbugs. She took her dog and two cats to the vet to have them treated for fleas. She bought new mattresses. None of it helped.She saw a dermatologist, who thought it was eczema and recommended a moisturizer. Useless. She went to her internist, who wondered if this could be a symptom of a disease beyond her skin. He asked her if she had noticed any other symptoms. No, she felt fine — except for this itch. He ordered some blood tests, but the only abnormality found, he told her when he called with the results, was a mild iron-deficiency anemia. That can cause pruritus — the medical term for itch — though not usually this severe. She was prescribed an iron supplement and waited for a relief that never came.An allergist found a reaction to dust mites and a chemical preservative used in some cosmetics and cleaning products called methylisothiazolinone (MIT). The patient bought an air purifier, put allergy covers on her (new) mattresses and pillows and searched labels for any MIT-containing products and replaced them. She took antihistamines. The itch continued.A second dermatologist took biopsies from the skin on her thigh and arm. They were unrevealing. He started her on a steroid cream to treat what he thought might be eczema. It had no effect. When a third dermatologist, recommended by a close friend, also suggested that she had eczema, the patient burst into tears. She’d been suffering for over a year. Was she going to feel like this for the rest of her life? That doctor prescribed gabapentin, which can be used to treat pain and itching caused by injured nerves. The drug helped — she was able to get to sleep at night, when the itch was its worst. And it helped a little during the day. But even so, she was still horribly itchy.A New Round of QuestionsThe patient’s husband started doing some research of his own. He found a couple of specialists he thought might help. One was in London, but another, Dr. Melissa Iammatteo, a specialist in allergy and immunology, was quite close. By the time he made this discovery, though, Covid-19 was rampaging through Westchester. His wife scheduled an appointment for the early summer, crossing her fingers that by then it would be safe for her to see the doctor.It was a bright, cool day when the woman finally met Iammatteo. On exam, the patient’s arms and legs were covered with blotches of inflamed red skin, shiny in places and covered with marks from scratching. The patient repeated the story she’d already told a half dozen times: She felt fine except for this terrible itch that drove her nuts.Iammatteo pressed: Did she really feel fine? Like the patient’s internist the year before, she was worried about problems that went beyond the skin. Iammatteo asked her specific questions, which helped the patient realize that she did not actually feel healthy. Yes, the patient acknowledged, she was tired. Yes, she had recently lost a little weight. And, come to think of it, yes, she did sometimes feel feverish, though, no, she didn’t have night sweats.When dealing with patients who have already had an extensive work-up and seen many providers, it’s important to focus on the less likely causes of a symptom. Iammatteo forced herself to think broadly through all the different types of diseases that can cause itching. Diseases of the kidneys and liver are common causes of pruritus — but repeated testing was normal. Infection with parasites or viruses can cause itching; she would order tests for some of the more common of these, including toxocara, a type of parasite carried by cats and dogs, and for H.I.V. It was also important to check for cancer: Nearly 10 percent of patients with persistent unexplained pruritus are found to have cancer. She would order a chest X-ray to look for enlarged lymph nodes. And she would refer the patient to a cancer specialist just in case she’d missed anything.She reviewed the plan with the patient, who needed to go to the lab and the radiology department before she left the building. Iammatteo would call her with the results, she said; it would probably take a few days.Photo illustration by Ina JangA Flurry of Tests, Scans and BiopsiesThe patient hadn’t been home for long when Iammatteo called. She had some results. It wasn’t an answer, but a clue. The X-ray revealed a mass the size of a softball in her chest. Iammatteo wasn’t sure exactly what it was but had sent the image to the cancer specialist. And she had moved up the patient’s appointment with the specialist to that week. Iammatteo was sure he would be able to tell them exactly what was going on.The next few days were a flurry of blood tests, scans and biopsies. Although this was scary, the patient was eager to finally have an answer — even if it meant she had cancer. And that is what it meant. She had Hodgkin lymphoma, an unusual cancer of a type of white blood cell known as lymphocytes. This cancer usually starts in the chest or neck and spreads through the lymph nodes. H.L. is often diagnosed when patients develop enlarged lymph nodes in the neck or under the arms. This patient never had that. Up to 30 percent of patients with H.L. report having pruritus for months or occasionally years before a diagnosis is made. Why this occurs is not well understood.Treatment for this disease can be tough, but the prognosis is good. The patient would need months of chemotherapy. She was eager to start. “I would have done anything to get rid of this itch,” she told me. The itch subsided significantly after the first round of chemo. After six weeks it was gone completely. And it hasn’t come back.As the patient neared the end of her treatment, she tracked down Iammatteo, who now only sees patients with severe drug allergies, to thank her for helping to beat that all-consuming itch.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is “Diagnosis: Solving the Most Baffling Medical Mysteries.” If you have a solved case to share with Dr. Sanders, write her at Lisa .Sandersmd@gmail.com.

A visit to the dentist unexpectedly led to a resolution.The dental hygienist greeted her longtime patient enthusiastically. Unexpectedly, the 68-year-old woman burst into tears. “I feel so bad,” she said, her voice cracking with emotion. “I’m worried I might be dying.” She was always tired, as if all her energy had been sucked out. And she felt a strange dread that something awful was happening to her. And if that weren’t enough, for the past couple of weeks she had lost much of her hearing in her right ear. She was sure she had a brain tumor — though none of her doctors thought so. After offering sympathy, the dental assistant realized she had something more to offer: “We have a dental CT scanner. Should we get a CT of your head?” The patient was amazed. Yes — she would very much like a CT scan of her head. It would cost her $150, the technician told her. At that point, it seemed like a bargain. And, just like that, it was done. And there was a mass. It wasn’t on the right side, where she thought her trouble lay. It was on the left. And it wasn’t in her ear, but in the sinus behind her cheek. That was confusing. She thanked the tech for the scan. She had an ENT and would send the images to him to see what he thought. A History of Ear IssuesThat right ear had been giving the patient trouble for more than 20 years, she reminded her ear, nose and throat doctor in Prescott, Ariz., when she spoke with him. In her 40s she developed terrible vertigo. She was living in Atlanta then and saw an ENT there who told her she probably had Ménière’s disease, a disorder induced by increased pressure in the inner ear. The cause is unknown, though in some cases it appears to run in families. And it’s characterized by intermittent episodes of vertigo usually accompanied by a sensation of fullness in the ear, as well as tinnitus and hearing loss. These symptoms can be present from the start, but often develop over time. There’s no definitive test for the disease, though evidence of the increased pressure is sometimes visible on an M.R.I. Medications like antihistamines and steroids can mitigate the symptoms, but there is no treatment for the disease itself. The patient was encouraged when her vertigo went away after a few months, and she tried to forget about it, but her body wouldn’t let her. Two years later she developed a problem with her balance. It wasn’t the sense of motion she had felt with the vertigo. Instead, there were times when the simple action of walking seemed strangely unnatural; times when she found it difficult to walk in a straight line. It could last for weeks, then disappear for months. And she couldn’t predict its coming or going. It got so bad that she started using a hiking stick whenever she walked farther than her front yard.She went to a neurologist, who ordered an M.R.I. of her brain. The images showed a little patch of something on the right side of her skull, near her inner ear. But both he and the radiologist thought it wasn’t significant. Besides, it was in the wrong place to be causing her symptoms. Instead, her doctor sent her to physical therapy to treat a disorder known as benign paroxysmal positional vertigo (B.P.P.V.), the most common cause of vertigo, usually triggered by head movements. The inner ear has fluid-filled tubes called semicircular canals. The sensation of the fluid moving in these canals tells your brain the position of your body in the world and helps you keep your balance. B.P.P.V. occurs when small pieces of bone (otoliths) are dislodged and roll around on the sensitive surface of the semicircular canals, sending confusing signals to the brain about the body’s position in the world.Physical therapy is normally effective in the treatment of B.P.P.V., though it didn’t do much for this patient. Throughout all this, even though all her doctors agreed that her right ear was the source of her intermittent loss of balance and vertigo, she never had a problem with the ear itself. She never had earaches. Her hearing was perfect. And then one day, it wasn’t. Photo illustration by Ina JangBuzzing That Would Not StopTwo years earlier, when she was 66, she was awakened one morning by a loud buzz. It took her a minute to locate the sound. It was coming from inside her right ear. It sounded like a fluorescent light on its last legs. Tinnitus is what her ENT at the time called it. It was, he told her, just one more thing she would have to put up with. Those were not words the patient wanted to hear. It was so loud that at times it was hard to hear what people were saying. The buzz — or, sometimes, a siren — was so intense it could wake her up from a dead sleep. Sometimes it would quiet down, but it never went away. Never.When her own doctors had nothing to offer, the woman looked elsewhere. She saw chiropractors, naturopaths and doctors specializing in alternative medicine. She was treated with antibiotics, antivirals and lots and lots of supplements. Nothing helped. Then, just weeks before she went to her dentist, she woke up and could hardly hear at all out of that ear. Everything was muffled, as if that ear was underwater. Her current ENT prescribed prednisone to reduce any inflammation.But when he saw the dental CT, he immediately ordered a conventional CT of her head. The dental scan was developed to give a three-dimensional image of the jaw and teeth, so it can’t be expected to show the entire skull. The full CT confirmed that there was a small mass in the left sinus. Based on its appearance, her doctor suspected it was a remnant of an infection from years before. But on the right side there was something else: A mass about the size of a strawberry had destroyed much of the mastoid bone just behind her ear. It was in the same place as the much smaller abnormality seen in the first M.R.I. years earlier. Now it was large enough to compress one of the vessels leading to the jugular vein. The radiologist said it looked like an infection. Or possibly a rare kind of bone cancer. Stray Cells in the BrainWith cancer a possibility, the patient decided she needed a second opinion. She reached out to the Arizona branch of the Mayo Clinic, in Phoenix, and was scheduled to see Dr. Peter Weisskopf two weeks later. Weisskopf listened as the patient described the vertigo, tinnitus and loss of hearing, along with the debilitating fatigue and terrifying sense of impending doom. “I’m not sure this mass could cause all that,” he told her, but he agreed that an M.R.I. would provide important diagnostic information. He suspected that she had something known as a cholesteatoma. These are benign growths of cells that get trapped inside the ear — or, rarely, as in this patient’s case, inside the brain — and start to grow. Sometimes these cells are imported into the ear after a chronic infection, but most of the time they get left there during fetal development. Weisskopf reviewed the M.R.I. The brain tissue showed up, as expected, as stripes of light and dark gray surrounded by fluid, which appears black. But just behind this patient’s ear, nestled into the lower edge of the mastoid bone of the skull, was a big bright cloud of white. Based on that appearance, Weisskopf knew what she had. It was a cholesteatoma. Although this is not a cancer, these sorts of tumors have to be removed. Left in place, they continue to enlarge until they cause real trouble. The patient was eager to have the thing removed. She felt certain that it had to be behind the symptoms she had been living with these past few years. Removing the large mass took two operations, the second one late last spring. But it was worth it, the patient told me. The worst symptoms are completely gone. Her fatigue and sense of oppression and doom disappeared after the first surgery. But even after the second, she still has the tinnitus, which is very loud at times. She still has trouble with her balance. Her hearing is not as good as it used to be. Weisskopf doesn’t believe the mass caused the patient’s symptoms. The patient respectfully disagrees; where it really mattered, with her mood, her sense of well-being, she feels back to something like her old self. And even though her doctor can’t see the link, she’s certain it all came from that growth, which, she thinks, maybe wasn’t quite as benign as her doctors and the textbooks say.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is “Diagnosis: Solving the Most Baffling Medical Mysteries.” If you have a solved case to share with Dr. Sanders, write her at Lisa .Sandersmd@gmail.com.

The clock was ticking. An M.R.I., a spinal tap and blood tests weren’t revealing the culprit. Could it be psychological? The 35-year-old man rose abruptly from the plastic chair in the waiting room at the Health Sciences Center Emergency Department in Winnipeg, Manitoba. He lurched toward the door, arms held stiffly before him as if warding off something only he could see. “I gotta get out of here,” he muttered. His eyes looked unfocused as he glanced at the family he didn’t seem to recognize. His mother hurried to his side. “It’s OK, Sean,” she murmured in his ear. “We’re here with you.” She took him over to his seat. And then, just as suddenly, he was back to normal, back to the man his family knew and loved. This was why Sean was in the E.D. that day. He had been completely healthy until the day before, when his brother-in-law found him wandering through the house, confused. He didn’t seem to know where he was, or even who he was. But by the time the ambulance reached the community hospital near their home, the confusion had cleared, and he seemed fine. The doctors in the E.D. ordered a few tests and, when they were unrevealing, sent him home. Only a few hours later, it happened again. That’s when they brought him here, to the biggest hospital in the city. By the time they arrived, the bizarre episode had subsided. A second attack in the waiting room lasted only a few minutes, so when the E.D. doctors saw him, he was fine. These doctors also wanted to send him home, but the mother was adamant. Her 30-year-old daughter, Andrea, was admitted to another hospital in the city just three months earlier. Andrea had episodes of confusion, too. And she died in that hospital 12 days later. No one understood what her daughter had or why she died, the mother told the doctors. She wasn’t about to let the same thing happen to her son. Re-enacting His Sister’s Symptoms?And so Sean was admitted for observation. Over the next two days, he had many of these strange episodes. He would try to leave the unit. He wouldn’t answer questions; he didn’t even seem to hear them. He looked afraid. And then it would be over. He was seen by specialists in internal medicine and neurology. He had an M.R.I., a spinal tap and many blood tests. When none of those tests provided an answer, the doctors worried that he had been so emotionally traumatized by his sister’s sudden death that he developed psychological symptoms, something known as conversion disorder. He was transferred to the psychiatric unit for further evaluation. What struck Dr. Kenneth Zimmer, the psychiatrist caring for Sean, was how normal he seemed between these episodes of confusion and fear. Zimmer reviewed the results of the tests done so far. The blood tests and spinal-tap results were unremarkable. Two head CTs were normal. The M.R.I. was hard to read because the patient moved in the scanner and blurred the images, but the radiologist said there wasn’t anything obviously abnormal. His EEG was interrupted when he sat up after the technician startled him. (It’s part of the study.) But what they got before that interruption seemed fine. With every normal test, the likelihood that this was a psychiatric disorder increased. And yet Zimmer was worried by Andrea’s similar illness and her sudden unexplained death. Zimmer had his resident reach out to the hospital where the sister died. What did they know about the cause of her death? Very little. An autopsy revealed the cause of death was swelling in her brain. The cause of the swelling was still unclear. Zimmer suspected this wasn’t a psychiatric disease and felt certain that the medicine and neurology teams would figure it out. Sean’s parents did not share that confidence. Andrea’s doctors had looked at all the usual suspects, they had been told. Sean’s doctors needed to look further, but it wasn’t clear that they would or even could. They sent a letter to the hospital’s patient advocate asking that their son be transferred to a facility capable of providing appropriate testing and expertise. A neurology resident recently assigned to the man’s case shared their concern. Andrea had been hospitalized for only 12 days. Sean had been in this hospital for four, and they were no closer to an answer than when he arrived. The resident tacked up a calendar in the neurology team’s work room. She figured they couldn’t count on his having more days than his sister. Photo illustration by Ina JangSomething Genetic?The patient had another EEG. He moved too much for the team to see a lot, but what could be seen was clearly abnormal. A second M.R.I. was even more revealing, showing a subtle abnormality in a region called the pons that was just like one noted in Andrea’s imaging. To the resident it was obvious that this was not psychiatric. But what was it? She had never seen or read about anything like this. Neither had the attending physician on the case. At the end of each day, the neurology team would meet to take stock of where they were and what more they could do as they crossed off one more day. It was the resident’s third or fourth day without an answer when someone on the team suggested consulting the metabolism service. Metabolic diseases are disorders that interrupt the processes that turn food into energy at the cellular level. Most of these disorders are inherited — caused by genetic mutations that alter the structure or function of one of the body’s tools needed to metabolize carbohydrates, fats, proteins and other nutrients. And while most of these diseases are rare, there are many of them. It is estimated that metabolic diseases affect up to one in 1,000 people. Still, most show up in infancy or childhood, not at age 35. The neurology resident called a friend on the metabolism service, Dr. Tyler Peikes, who immediately went to see Sean. He reviewed the records, examined the patient and got the story from Sean and his family. It didn’t sound like any of the metabolic diseases he knew. The rapid course of the sister’s illness was uncharacteristic. He ordered tests to look for those diseases that usually appear intermittently. The neurology resident continued to look for answers. And slowly the results trickled in. It wasn’t an exposure to a metal like arsenic or mercury. It wasn’t an autoimmune disease. It wasn’t an infection. At the end of each day, the resident made another X on her calendar and went home worried. The only hopeful sign was that the patient’s episodes were becoming less frequent. She wasn’t sure why but hoped it meant they would have enough time.Ordering the Right TestFinally, on Day 11, one of the tests that Peikes ordered came back positive. The patient had a rare form of a rare disorder called maple syrup urine disease (M.S.U.D.). Patients with M.S.U.D. are born with abnormalities in the machinery used to break down certain amino acids, the building blocks of proteins. This causes the accumulation of unmetabolized protein components, which can damage the body. Untreated, the disease can result in significant, often fatal swelling of the brain. The name comes from the smell of maple syrup in urine and sweat sometimes caused by the buildup of amino acids during episodes of protein overload. The patient never experienced this. The frequency of a patient’s attacks, and the age at which they begin, depend on how badly the machinery is broken. In intermittent M.S.U.D. — the version this patient had — the body can handle low levels of amino acids, but a high-protein meal or severe physiological stress can overwhelm the system and allow toxic components to build up. A simple blood test provided the answer. Eventually genetic testing revealed the specific defect. A subsequent test on Andrea’s tissue revealed the same abnormality. Patients with M.S.U.D. must maintain a low-protein diet. That’s the only way to prevent these crises. It has been more than two years since Sean got his diagnosis. He says he misses the occasional steak or burger, but the memory of what happened to him and his sister is enough to keep him away. It was Sean’s family that brought this story to my attention. His mother hoped that by sharing her children’s story she could help doctors and families consider the possibility of these rare metabolic diseases when patients present with a psychiatric or neurological disease that no one can figure out. “It’s not a hard test,” the mother said. “You just have to think of it.” Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is “Diagnosis: Solving the Most Baffling Medical Mysteries.” If you have a solved case to share with Dr. Sanders, write her at Lisa .Sandersmd@gmail.com.

AdvertisementContinue reading the main storySupported byContinue reading the main storyDiagnosisHer Eyelid Drooped and She Kept Getting Weaker. What Was Going On?Dozens of tests turned up nothing. Then a specialist had a theory.Credit…Photo illustration by Ina JangMarch 4, 2021, 5:00 a.m. ETThe voice on the phone was kind but firm: “You need to go to the emergency room. Now.” Her morning was going to be busy, replied the 68-year-old woman, and she didn’t feel well. Could she go later today or maybe tomorrow? No, said Dr. Benison Keung, her neurologist. She needed to go now; it was important. As she hung up the phone, tears blurred the woman’s already bad vision. She’d been worried for a while; now she was terrified. She was always healthy, until about four months earlier. It was a Saturday morning when she noticed that something seemed wrong with her right eye. She hurried to the bathroom mirror, where she saw that her right eyelid was drooping, covering the top half of the brown of her iris. On Monday morning, when she met her eye doctor, she was seeing double. Since then she’d had tests — so many tests — but received no answers. The woman walked to the bedroom where her 17-year-old granddaughter was still asleep. She woke her and asked for help getting dressed. Her hands were too weak for her to button her own clothes or tie her shoes. When she was completely dressed, she sent the girl to get her mother. She would need a ride to the hospital. She hadn’t been able to drive since she started seeing double. Dozens of TestsThe events of the past few months had left the woman exhausted. First, she had seen her eye doctor. He took one look at her and told her that she had what’s called a third-nerve palsy. The muscles of the face and neck, he explained, are controlled by nerves that line up at the top of the spine. The nerve that controlled the eyelid, called the oculomotor nerve, was the third in this column. But he didn’t know what was affecting it or how to fix the problem. She needed to see a neuro-ophthalmologist, a doctor who specialized in the nerves that control the eyes. That specialist saw her right away, but he couldn’t tell her what had caused her double vision either. And since then, she had seen many specialists and had dozens of tests: blood tests, CT scans, M.R.I.s, biopsies. No one could tell her what she had, but she now knew a long list of terrible diseases that she didn’t have. It wasn’t a brain tumor or an aneurysm. She hadn’t had a stroke. There was no sign of a vasculitis. All that testing was draining. She felt so weak, so tired. She was a salesperson in a department store and often had to move items on the floor. It wasn’t a strenuous job, but lately it was a lot harder. Her hands seemed to lack strength; she bought a brace for her wrist, but it didn’t help much. It got so bad that it was hard to even open a door. When she told Dr. Alissa Chen, her primary-care doctor, about it, Chen got worried. She was still in training, but the patient trusted her. Chen examined her hands and arms closely. Her muscles were very weak. That’s when she ended up in the hospital the first time. Chen sent her straight from her office to the emergency room. She spent three days in the hospital. There she met Keung, a specialist in diseases of the nerves and muscles. He ordered more blood tests, another M.R.I. and a spinal tap. By the time she went home, he had only added to the list of diseases that had been ruled out. It wasn’t multiple sclerosis or Guillain-Barré syndrome. It probably wasn’t sarcoidosis. It probably wasn’t cancer, though she was supposed to go see an oncologist to make sure. Credit…Photo illustration by Ina Jang400 in a MillionWhen she got home from the hospital, Chen called her. She had a theory about what the patient might have. Had she ever heard of a disease called myasthenia gravis (M.G.)? In this rare disorder, the body’s immune system attacks what’s called the neuromuscular junction, the point where the nerves connect to the muscles to tell them what to do. It often starts in the eyes — with a droopy eyelid and double vision. But then it usually spreads to other parts of the body. Patients with myasthenia have muscles that tire out much more quickly than normal. There are fewer than 400 cases per million people, and Chen had never seen a case; still, she thought there was a strong chance the patient had it. A simple blood test could give them an answer. She had ordered it already, and she urged the patient to go to the lab and get it. Three weeks later when she went back to see her doctor, the patient still hadn’t gotten the test. And now she had a new problem: Her mouth felt weak. Talking was hard; her voice was different. By the end of even a short conversation, her words were reduced to whispers. She couldn’t smile, and she couldn’t swallow. Sometimes when she was drinking water, it would come out of her nose rather than go down her throat. It was strange. And scary. Chen wasn’t there, so she saw a colleague, Dr. Abhirami Janani Raveendran, who was also a trainee. Raveendran had never seen M.G. either but knew that it could affect the muscles of the mouth and throat. She urged the patient to get the blood test, and she sent Keung a note updating him about the patient’s disturbing new symptoms and the possible diagnosis. When Keung saw the message, he was alarmed. He agreed that these symptoms made myasthenia gravis a likely diagnosis. And a dangerous one: Patients with M.G. can lose strength in the muscles of the throat and the diaphragm and become too fatigued to take a breath. He called the patient. Her voice, he noticed, was nasal and thin — signs of muscle weakness. She said she wasn’t having any trouble breathing, but Keung knew that could change. That’s why he told her to go to the hospital right away. He scared her. He meant to.A Series of Small ShocksAfter the patient got Keung’s urgent call, her daughter drove her to the emergency department at Yale New Haven Hospital, and she was admitted to the step-down unit. This is the section for patients who are not quite sick enough to need the I.C.U. but might get to that point before long. Every few hours a technician came in to measure the strength of her breathing. If it got too low, she would have to go to the I.C.U. and maybe end up on a breathing machine.Keung wasn’t certain that the patient had myasthenia. Her eyelid was always droopy, her vision always double. With M.G., he would expect those symptoms to worsen after using the muscle and improve after resting. And M.G. usually affected the muscles closest to the body. He would expect her shoulders to be weak, not her hands. Despite his uncertainty, he decided to start the treatment for M.G. He didn’t want to risk having her become even weaker. She was given high-dose steroids and intravenous immunoglobulins to suppress the parts of the immune system attacking the connection between her nerves and her muscles. The next day Keung performed a test that would show whether the patient had M.G. In the repetitive-nerve-stimulation test, a tiny electrode is placed over the muscle, in this case the abductor digiti minimi, the muscle that moves the pinkie finger. A series of small (and uncomfortable) shocks is delivered in rapid sequence, each causing the muscle to contract. In someone with normal nerves and muscles, each identical shock will produce an identical muscle contraction. In this patient, though, the first shocks produced weak contractions and then they became even weaker. That drop-off is characteristic of M.G. The blood test that Chen had been urging her to get was done in the hospital. It was positive. She had myasthenia gravis.The patient stayed in the hospital for nearly two weeks. That first night her breathing was so bad she almost ended up in the I.C.U. And there were days when her arms were so weak she couldn’t even feed herself. Her daughters and granddaughters took turns coming to see her in the hospital to help her eat and care for herself. But slowly her strength began to return. Her voice came back, and she was able to swallow. She graduated from puréed foods to chopped and ultimately back to a normal diet. And finally she went home. That was four months ago. She will probably need to take immune-suppressing medications for the rest of her life. And she still has double vision in bright light. But, she told me when I saw her recently, she can smile again. That’s important, too.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is ‘‘Diagnosis: Solving the Most Baffling Medical Mysteries.’’ If you have a solved case to share with Dr. Sanders, write her at Lisa .Sandersmd@gmail.com.AdvertisementContinue reading the main story