The intensive care unit was full of the usual hubbub on that brilliantly sunny July day, but Karen Kincaid’s cubicle at the far end was as dark and silent as a tomb. As our team of infectious-disease consultants knocked at her door and filed inside, Karen’s mother turned around from the window where she was trying to block out light seeping through a broken venetian blind. She quickly raised a finger to her lips, signaling us to be quiet. She’s very bad this time, very bad, Karen’s father mouthed from the bedside, tears forming in his eyes.
Karen was only 22 years old, but in the last year she and her parents had become regulars at the hospital where I work. The strange thing was that, unlike almost all the other young people whose lives and families we get to know, Karen had none of the standard reasons for frequent visits to the hospital--no sickle-cell disease, no cystic fibrosis, no AIDS, no diabetes, none of the usual genetic or infectious or metabolic tragedies that land young adults on our wards. Karen was a healthy young woman without a thing wrong with her, except every once in a while.
Every once in a while--three times, to be exact, in the previous eight months--Karen would suddenly become terribly, and inexplicably, sick. She would develop meningitis, an inflammation of the membranes enveloping the brain. Even in this age of powerful antibiotics and sophisticated medical technology, meningitis is among the most feared of diseases. It has one of the lowest cure rates--and highest complication rates--of any disease we know.
Karen’s episodes always began as a little headache, just a little pressure behind the eyes, usually late in the day. Then, suddenly, the pain seemed to explode. Her head began to throb, and any light or noise became unbearable. Each time she ran a high fever, and her neck became stiff and painful. At first she was very sleepy, then barely arousable. She would be rushed to the emergency room, seemingly on the verge of coma. When all the routine tests pointed to a severe infection, she would be moved to intensive care and started on potent antibiotics. But the next morning she would always be better, and after ten days of antibiotics in the hospital she would be home, back to work during the day, attending community college classes at night, completely well. Until the next time.
Each incident had been a little more severe, a little more frightening than the last. This time Karen really looked as if she might not make it through the afternoon. She moaned and tossed in her darkened room, a sheen of sweat on her upper lip. Her temperature was almost 105 degrees, her pulse rapid and faint. She answered no questions, responded to no commands. Her neck was as stiff as a piece of pipe, and there was a faint, blotchy red rash on her chest. Her heart, lungs, and abdomen were all normal. As we left Karen’s room, her parents returned to her bedside and sat, one on either side, holding her hands.
Out in the corridor we reviewed Karen’s old charts to sort through the details of her previous admissions. Each time, Karen had come to the hospital with a markedly elevated white blood cell count, a sign of an infection or an inflammatory process somewhere in the body. Her spinal fluid always had the high protein content and hundreds of white blood cells characteristic of acute meningitis. Yet no evidence of infection could be found elsewhere.
Of the many causes of meningitis, the most common are the same bacteria that frequently cause infections of the lungs, urinary tract, ears, and sinuses. Bacteria are easy for a hospital microbiology laboratory to culture on petri dishes, and their presence in cultures of blood or spinal fluid from a person with meningitis routinely confirms a diagnosis of bacterial meningitis. If bacterial cultures in a case of meningitis are negative, we begin to suspect other, less common causes of the disease: parasites, viruses, or other organisms that aren’t routinely cultured in a hospital laboratory. We also consider reactions to certain medications, tumors, or noninfectious systemic diseases that may cause inflammation around the brain.
In Karen’s case we could immediately exclude most of these alternatives. She had no good reason to develop repeated episodes of meningitis. No bacteria had ever grown from the specimens of her blood or spinal fluid that were sent to the lab. She took no medicines, had no pets, had traveled to no exotic parts of the world. She had bathed in no stagnant freshwater ponds that might be infested with Naegleria fowleri, a rare, meningitis-causing amoeba. She did not wear contact lenses, let alone wash them in contaminated solutions that sometimes harbor other disease-causing organisms. She had sustained no injuries to her brain, skull, or spine where latent infection might hide. She showed no evidence of any chronic infections that might lead to meningitis, such as tuberculosis, syphilis, or Lyme disease. Her HIV test was negative. She had no complaints of arthritis or shortness of breath hinting at other conditions that sometimes involve the brain.
All she had was an illness that kept recurring. Something was very wrong with Karen, but exactly what was a complete puzzle.
I don’t know what she’s got, but she’s got it again, I muttered as we began to make plans for Karen. The residents and medical student on the team, poring over her chart, looked as discouraged as I felt. All the questions we could think of had already been asked, and all the answers were no. What chance did we have of figuring out Karen’s puzzle when, twice before, teams of infectious-disease experts had been asked to see Karen, both times drawing a blank? To review a case for the third time, probing what has already been probed, testing what has already been tested, is a thankless and frustrating task. But that was exactly what we had to do.
The first thing on our list, of course, was to make sure Karen got better. No matter what the underlying problem was, all diagnostic tests had to wait until she was out of danger. We recommended that she immediately get large doses of an array of antibiotics. Even if we were pretty sure she didn’t have a simple bacterial infection, we couldn’t risk being mistaken. Before I went home that night, I passed by Karen’s room to make sure she had received the first doses of her antibiotics. She still lay feverish in the darkened cubicle, her parents sitting motionless at her side.
By the next afternoon, though, the usual miracle had occurred. Karen was sitting up, eating lunch, and wondering when she could wash her hair. Her head still hurt, but her fever had broken and her neck felt better. She remembered almost nothing of the previous day. Her parents were happy but exhausted and still shaken. Please, her mother said, following us out into the corridor, find out what is the matter with her. Do any tests you have to do. We can’t go through this anymore.
We assured her that we would leave no test unordered. We made a list of all the possible reasons Karen might have recurrent meningitis, and all the tests we needed to reevaluate these possibilities. She had already had most of them once or twice, but there was always the chance that something might have changed. We planned to repeat her tests for tuberculosis, syphilis, HIV, and Lyme disease. We would also run blood tests for autoimmune diseases such as systemic lupus erythematosus, in which the body reacts to its own cells and proteins, sometimes causing meningitis. We wanted a new MRI scan of her brain and skull so we could look for hidden anatomic abnormalities. We wanted the laboratory to examine Karen’s blood proteins and white blood cells for the rare abnormalities associated with recurrent episodes of severe infection. We wanted consulting otolaryngologists to examine her ears and sinuses carefully, since infection deep in the skull sometimes leads to meningitis. We wanted special viral cultures sent of her throat, urine, and stool.
And last, we wanted to sit down and talk to Karen and her parents, asking them yet one more time every one of the questions our predecessors had already asked. Pets, travel, accidents, medications, contact lenses--all these subjects had to be carefully and methodically reviewed. That’s your job, I told Bob, a fourth-year medical student and the junior member of our team. He rolled his eyes, made a face, and walked back down the corridor toward Karen’s room.
When our team met for rounds the next afternoon, I could sense that something was up. The residents, and Bob in particular, looked like they’d just stumbled onto a winning lottery ticket. You’ll never guess, they chorused. They were right.
It turned out that Bob, dutiful if unenthusiastic, had talked to Karen for half an hour the day before but turned up nothing new. Then he had wandered over to the library to read a little about recurrent meningitis. Something he read had given him an idea. At nine that night he raced back to the hospital and woke Karen from a deep sleep, sat her up, and turned on the light.
Look, he said, you don’t take any medicines, right?
Right, she yawned. No medicines.
No medications at all, right?
Right. She was sleepy and annoyed. I told you already. I don’t have a doctor. I don’t take medications. None.
But do you ever take pills? You know, from the drugstore.
Oh, those. Well, I take vitamins. And I used to take Tylenol for headaches. But when they stopped working, I started taking Advil.
And that was it.
Bob had remembered what the rest of us had forgotten. For many people, pills you can get without the elaborate and expensive ritual of doctors and prescriptions aren’t really medicines. Medicines are powerful chemicals, dangerous and mysterious (and usually time-consuming to obtain). The pills in the friendly, colorful, reasonably priced boxes in the drugstore are just pills--safe, cheap, good for little problems, and certainly nowhere near as potent and significant as medicines.
In fact, though, despite the stringent review a medication must pass before it can be sold without a prescription, over-the-counter drugs are exactly like any other drug. They are compounds with good effects and bad effects. They are safe enough to be sold freely, but even when they are taken absolutely as directed not a single one of them is always safe for everybody.
Ibuprofen--the active ingredient in Motrin, Advil, Nuprin, Medipren, and other brand-name painkillers--is by any reasonable standard an impressively safe and effective drug. Millions of doses have been taken with no more ill effect than the occasional stomachache. Against this background, the few reported cases of people with an odd allergy to ibuprofen that causes them to develop meningitis after exposure to the drug are, statistically, quite insignificant.
Of course, if you’re the rare person with ibuprofen-induced meningitis, the statistics take on more significance. Over the last 15 years, reactions exactly like Karen’s have been reported in about 35 men and women of all ages. Many have had autoimmune diseases, such as lupus, that may predispose them to develop idiosyncratic reactions to drugs, but others have been, like Karen, completely healthy. What they all share is an inability to tolerate the ibuprofen molecule--a response that is poorly understood but probably involves an immune reaction. No one has died from a reaction to ibuprofen, although one patient experienced weakness on one side of his body that persisted for months. Several of the patients, aware of their allergy to Motrin, have steered clear of that drug only to take nonprescription Advil for a backache or muscle cramp and find themselves back in the hospital.
Ibuprofen is far from the only nonprescription drug to cause this kind of serious reaction. A single aspirin tablet may result in a life- threatening asthma attack in a sensitive person. Pseudoephedrine hydrochloride, a decongestant found in dozens of cold and sinus preparations, caused a devastating syndrome, similar to toxic shock, in a young woman with a cold. Vitamin B6 supplements have caused numbness in the legs and difficulty walking; vitamin C has caused kidney stones; and niacin has caused sudden and severe liver failure. All these substances were taken in the usual therapeutic doses by people who just happened to be configured slightly differently from the norm.
Karen and her parents weren’t entirely sure they believed the news we gave them. It was true that Karen had taken an Advil for a little headache each time she had gotten so sick, but so, her mother pointed out, did she herself and everyone else in the family, with no problem at all. Karen and her parents were reluctant to cancel any further evaluation of Karen’s problem. So we compromised: instead of embarking on a lavish array of tests, we agreed on an experiment.
When a drug is suspected of causing an adverse but not life- threatening condition, the simplest way to get an answer is to rechallenge the patient with the drug under controlled conditions. We were all but certain of what was causing Karen’s meningitis, and should she become very sick again, all the resources of the hospital could be summoned to treat her. At eight the next morning, instead of going home, Karen took a 200- milligram ibuprofen tablet obtained from the hospital pharmacy. Within two hours she had a 104-degree fever, a raging headache, a stiff neck, and, in fact, all the symptoms that had brought her into the hospital in the first place. This time we gave her no antibiotics. We simply put her to bed and made her comfortable. Sure enough, the next morning she was almost completely recovered.
We sent Karen home armed with a list of all the prescription and over-the-counter preparations we could think of that contained ibuprofen. We also gave her strict instructions to read the ingredients of any drugstore purchase she planned to put in her mouth. And we devoutly hoped not to see her for a long time to come.
