, , , , , , , , , ,

“When you hear hoofbeats, think horses, not zebras.” It is one of medicine’s most enduring aphorisms. Anyone who has ever stalked the wards of a teaching hospital as part of a general medicine team has heard this at one time or another from a wizened senior resident or gray eminence attending. Usually, this proverb is offered when a more junior trainee suggests an unusual diagnosis to a superior. It might be medicine’s equivalent of engineering’s KISS (Keep It Simple, Stupid). Hard as it is to pinpoint the source of such a ubiquitous saying, Wiki credits Dr. Theodore Woodward, a ‘40s-era professor at UMBC (I hope that he used to round while chewing an unlit pipe or cigar). In the American heartland, hoofbeats are usually made by horses. “Zebra” has come to be medical slang for a rare diagnosis. Perhaps Saharan physicians have turned the saying on its head? Like bird watchers crossing species off their lifetime “lists”, many physicians are coveters and collectors of Zebra diagnoses. What is the basis for doctor’s fascination with rare diagnoses? What is it like to make one?

Last week I was working my way through a pretty typical morning clinic at Texas Scottish Rite Hospital for Children, a Masonic charity hospital in Dallas that specializes in caring for children with musculoskeletal and developmental conditions. Arthritis is a common feature of a variety of autoimmune and inflammatory processes. Since Rheumatology is the “ology” of autoimmunity and inflammation, we see children who are referred from across Texas and adjoining states in Scottish Rite’s “Arthritis Clinic”. I had seen a patient with one of the forms of Juvenile Idiopathic Arthritis (the most current name for a family of disorders which cause inflammatory arthritis in children, the “idiopathic” is because the cause remains poorly understood). She was doing well. I refilled her prescription for every-other-week injections of an anti-TNF arthritis drug. One of our fine clinic staff asked me if I was up for seeing a new patient, freshly referred by her pediatrician. I said sure.

The ten year old girl was being referred for high blood pressure. This was a bit strange. Some rheumatology patients do have hypertension as a symptom of their condition, particularly our patients with kidney disease due to lupus (systemic lupus erythematosus). But we usually don’t see high blood pressure all by itself. I made my way through a mercifully thin packet of material sent along by the pediatrician’s office trying to figure out what else there was to the story. In late June, Maria (not her name, but we’ll call her that) went to her pediatrician’s office in a town about 30 miles east of Dallas for a routine well visit. When a nurse took her blood pressure it was 150/70. You can imagine the scene, they probably adjusted the cuff, re-checked it, maybe even had someone else check it again. Why should a perfectly healthy ten year old have such a high blood pressure? Maria’s pediatrician was astute and checked the blood pressure in one of her legs. Sure enough, the systolic pressure (the top number, the pressure during the contraction of the heart’s ventricles) was thirty points lower when the cuff was placed on her leg.

Within a few days, Maria was in the office of a pediatric cardiologist in Dallas. The most straightforward (KISS) explanation for the discrepancy in her arm and leg blood pressures was that she had a narrowing in the caliber of the aorta (the main artery taking blood away from the left ventricle to supply the body). This would be a structural abnormality, present from birth, known as coarctation of the aorta. Congential heart defects are common (0.5 to 1 per 1,000 births) and coarctation makes up a significant portion of this group (5-8%, corresponding to about 1 in 20,000 births). By the standards of pediatric subspecialty care, this is a relatively common condition – right down the middle of the plate for a pediatric cardiologist. And yes, not uncommonly these congenital defects do not cause significant symptoms and are not recognized until later in life, sometimes even into adulthood.

The cardiologist confirmed the blood pressure discrepancy between Maria’s arms and legs. When he palpated her radial (on the wrist at the base of the thumb) and femoral (in the groin) pulses simultaneously, one in each hand, the cardiologist noticed that the radial pulse came first and the femoral one was delayed – a classic physical exam finding  indicated a narrowing of the aorta known as radial-femoral delay. An echocardiogram (done by applying an ultrasound probe to the chest wall) showed that Maria’s heart squeezed normally with each beat. The pulse did not seem as strong as would be expected in the portion of the aorta that courses through the abdomen, further evidence of coarctation. The pitch seemed to be right in the strike zone; everything was consistent with a diagnosis of coarctation of the aorta. The cardiologist referred Maria to have an MRI of her heart performed. This would reveal exactly where the congenital narrowing was located so that a heart surgeon could plan an approach to repair the defect and “cure” Maria’s problem.

The MRI images were as unexpected as they were dramatic. Instead of showing one area of narrowing in the aorta, the MRI showed that Maria’s aorta had balloon-like areas of dilation separated by multiple regions of significant narrowing. Remarkably, the abnormalities were not confined to the aorta. Areas of dilation and narrowing were present on all of the large and medium arteries visualized by the study.  The radiologist noticed that the walls of the vessels seemed thicker than usual and obtained additional specialized images that suggested that the thickening was due to inflammation. The perfect strike was turning into a late-breaking curveball. The pediatric cardiologist called up our clinic that day and made a referral.

The description of the cardiac MRI spoke volumes. Could this be a case of Takayasu arteritis? I closed the chart, donned my stethoscope (which, unlike in most of my patient encounters, I would actually need to use), and knocked on the door of the exam room. Maria’s parents sat side-by-side, diminutive in stature and closer to middle age, their faces open but impassive. Maria smiled, scissoring her legs playfully over the edge of the exam table. She looked truly well, the picture of health. After my friendly “Helloooo!” and a few words of introduction, Maria’s parents’ body language made it clear that I would need to break out at least a little bit of Spanish. I speak with reasonable fluency but with the vocabulary of a 2nd grader with a precocious interest in TV medical dramas.

Asking a few questions of Maria’s parents, I confirmed the key point of “the history”: basically, that there was none. She was perfectly healthy and active. No fever, rashes, pain… the answer to the laundry list of symptoms was “no”. They took Maria to the pediatrician and her blood pressure was high. I turned my attention to Maria (relieved to be switching back to English). “Hey, let me ask you this. Do you ever get pain in your legs when you’ve been walking a lot or running?” Maria had noticed that some, she said it was a “soreness” kind of pain. I finished my history taking. Maria was healthy in the past, nothing unusual in the family’s medical history, nothing to suggest that she might have been exposed to tuberculosis infection.

A few moments later, I stood in front of Maria holding the bell (the business end) of my stethoscope up against the side of her neck. I don’t usually do this when examining a kid in the clinic or the hospital. I asked Maria to hold her breath for a moment. Instead of a concentrated thumping noise with each beat of her pulse, I heard a prolonged sound with an irregular, tumbling quality. I heard a similar sound, even more unmistakable, when I listened over her abdomen. The pulses at her wrists were strong and even. I performed a maneuver known as the Allen test to assess the amount of time required for blood to flow back into Maria’s hands after her repeated opening and closing of her fist with my fingers clamped over her radial and ulnar arteries. Her right hand blushed up after about 2 seconds. The left hand stayed pale-white for 7 seconds. The radial-femoral delay was the most pronounced I have seen. Cramping calf pain with exertion (claudication), bruits (turbulent sounds made by blood rushing through the narrowed areas of the carotid artery and the abdominal aorta), the asymmetric Allen test, the radial-femoral delay, all were rare findings consistent with the diagnosis. I was now convinced.

A review published last fall in the journal Rheumatology called “Takayasu arteritis in children and adolescents” pushes off with “Takayasu arteritis is the most common, granulomatous inflammation of large arteritis; it is potentially life threatening.” To say that Takayasu arteritis (TA) is the most common anything is laughable. The incidence of TA in adults is around one in a million depending on the study and the population sampled. There is no good data in kids and the one in a million incidence estimate is extrapolated from the adult studies. The attempt to determine incidence figures for rare diseases is at best an inexact science. The challenge is figuring out the right denominator to go below the numerator of “1”.  There are about 7 million Texans under the age of 18. We certainly do not see 7 new diagnoses of Takayasu arteritis in a year at our state-wide referral center. I doubt that we would come up with that many patients if we compared notes with our colleagues in Austin and Houston.

Takayasu arteritis is a rare type of vasculitis, a group of unusual and mysterious conditions where abnormal activity of the immune system results in inflammation in the walls of blood vessels. A biopsy of involved blood vessels and the help of a pathologist if often needed to make the diagnosis. The different forms of vasculitis have different patterns of immune cell infiltration into the vessel walls. The inflammation in some forms of vasculitis is exacerbated by auto-antibodies, produced when immune regulatory mechanisms fail and the body’s own proteins are recognized as foreign substances. Vasculitis can run the full gamut of typically (but not always) benign conditions that pediatricians diagnose purely based on symptoms and where reassurance and monitoring are sufficient treatment (Henoch Schonlein Purpura or HSP) to the life threatening (like TA and ANCA-associated vasculitis). How do people get vasculitis? As with so many of our diseases, the most current thinking is that people with a very specific (but unknown) genetic susceptibility encounter the wrong environmental trigger (usually infections) at the wrong time. Rather than having a normal, regulated, inflammatory response to the trigger, these people have an exaggerated reaction that not only resolves the inciting cause but also causes collateral tissue damage. Kind of like a park ranger investigating the source of a forest fire, the rheumatologist can’t find evidence for the cigarette negligently flicked into dry brush by a camper or a lightening strike. Like smoke jumpers putting out the flames, the rheumatologist uses the tools at hand (steroids and other immunosuppressive drugs) to try to extinguish the inflammation.

My attending rheumatologist became wide-eyed when I told her Maria’s story, related the results of my exam, and my working diagnosis. We formulated a plan to treat Maria with high doses of daily oral steroids. Steroids are indispensable in controlling many inflammatory diseases but are a terribly blunt tool. Virtually every patient exposed to chronic high-dose steroids develop adverse effects ranging from the cosmetic (hair growth, acne) to the serious (weight gain, metabolic abnormalities, osteoporosis…). We decided to start a second immunomodulatory drug called methotrexate (a workhorse in pediatric rheumatology) with the hope that this would allow us to decrease and hopefully stop the steroids sooner.  Turning to look at me while placing her stethoscope over Maria’s carotid artery, she silently mouthed “Wow!”. I explained the diagnosis as best as I could in both languages to Maria and her family. Yes, she would be able to play and do everything that she wanted to do. I told them that in historical studies up to 60% of patients had complete resolution of the disease with steroid therapy alone. In that old literature, mortality in children was reported to be as high as 35%. With the treatment tools and imaging modalities available, and with the fact that she is so well, we have every reason to be hopeful.

I admit, for me, Maria’s clinic visit was exhilarating. After all, I chose rheumatology, a field where the diseases range from unusual to exceedingly rare. Even our bread and butter, Juvenile Idiopathic Arthritis (the first patient I saw that day), only occurs in about 1 in 10,000 children (similar to coarctation of the aorta). The principle attraction for me was the fact that the etiology of our diseases are unknown, mysterious, and as a result, fascinating for a physician-scientist. Since meeting Maria, I’ve been thinking about what draws me, and so many other physicians, to the pursuit of Zebras. Of course, there is the appeal of being able to see enough patients with a rare condition to gain sufficient experience to help doctors who haven’t. As hard as it is to tell a child and her family that she has a life-threatening disease, being able to rely on some experience and to interpret the medical literature in a very specialized area, puts one in a position to be helpful. The details of what exactly happened comprise a patient’s story and create narrative drama. The more unusual the story is, the greater the dramatic effect. Like everyone else, physicians collect and trade stories. Ours happen to be about patients.

But I think that there is even more to the Zebra phenomenon.

A few minutes on the weather channel or ESPN will illustrate that we are intrigued by rare occurrences, be it consecutive days of over 100 degree heat in North Texas or a ballplayer’s 3,000th career hit (boo Yankees). Rare events, more precisely, the awareness that one is witnessing a rare event (often the event itself has little interest – just another absurdly hot day in Dallas), have an aesthetic appeal. The onlooker has a sense of awe that discharges reflexively, like a jolt of adrenaline. Through the millennia, this innate part of our psyche has made us well equipped to perceive miracles. Even if the rare event is not a good one, such as a life-changing diagnosis, the shock of awe is irrepressible.

The existence of Zebra diagnoses is oddly reassuring to doctors. The fact that there is a little girl in Texas who has peculiar inflammation in her blood vessels that matches relatively specific descriptions in textbook chapters and review articles makes us more convinced that the foundation underlying our medical edifice holds firm. That one could read a textbook and then go and put a stethoscope on that girl’s neck and hear a particular sound almost seems like predicting the future. Although dramatically abnormal, the pattern of findings has been seen before. Takayasu was an ophthalmologist who reported a curious case of a patient with inflammation of the arteries located at the back of the retina at a 1908 meeting in Japan. Two other cases were reported that week, patients whose pulses were absent due to some problem in the large arteries. With more patients and more descriptions, the pattern of abnormalities took shape over time and began to define a disease. Being able to make sense of the seeming randomness of nature with logical first principles is the mission of science. The closest physicians come to this is fitting a constellation of symptoms, findings, and abnormal test results into a recognizable pattern – this is making a diagnosis. We carry around in our minds (and sometimes our smart phones) a large matrix which matches diagnoses with clinical findings. Being able to find a pattern in the labyrinthine matrix of diagnoses that matches an unusual patient story makes us feel that we understand disease and the workings of the body. It gives us just enough confidence to take a shot at knowing what to do.