Commentary
Fatigue, Exercise Intolerance, and Weakness
Lessons on Herding Zebras
Physicians often need to look beyond the obvious diagnosis.
By Philip R. Fischer, M.D., Jonathan N. Johnson, M.D., and Chad K. Brands, M.D.
In real life, their obvious stripes make zebras easily distinguishable from horses. The animals behave differently, too. When excited, horses rear up on their hind legs. Agitated zebras, on the other hand, plant their front legs and kick their hind legs backwards. How do we distinguish zebras from horses in medicine? Sometimes it’s by how patients look, and sometimes it’s by how they act. Often, though, our diagnostic acumen is clouded by our myopic view of our own patient populations. We overconsider the conditions to which we’re most accustomed, fail to consider a longer menu of disease processes in broader categories, and come to premature closure on a patient’s case by reverting to a list of problems we’ve seen frequently or recently.
When Mayo Clinic’s Pediatric Diagnostic and Referral (PDR) Clinic opened eight years ago (see next page), we expected to see lots of “zebras.” To some degree, our expectation was realized, as we’ve seen a variety of fascinating patients, some with named syndromes such as Turner, San Filippo, and Hashimoto and others with conditions known by clever acronyms such as TRAPS, HIDS, and ALPS. At the same time, though, we’ve seen our fair share of common conditions such as chronic fatigue syndrome. When Minnesota Medicine put out a call for papers on “zebras,” we thought of what we have learned from our years of trying to identify our patients’ uncommon zebra-like stripes. We decided to share three recent cases, (These cases are based on real patients. Information has been modified to protect their identity and that of referring physicians. In addition, some of the case details have been simplified for illustrative purposes.) all adolescent patients experiencing similar symptoms—fatigue and weakness—to illustrate lessons we have learned from dealing with unusual diagnostic possibilities. These cases show how patients with common symptoms can end up with very different, sometimes unusual, diagnoses.
Girl with Chronic Fatigue
A 15-year-old girl from Minnesota presented to our clinic after experiencing fatigue for more than a year and a half. She was a popular, straight-A student who was active in dance and volleyball when, 20 months prior, she developed a fever, sore throat, and fatigue. Her exhaustion never resolved. An initial Strep swab result was negative, and a subsequent heterophile antibody test was positive. She had negative tests for liver, kidney, adrenal, thyroid, hematologic, and rheumatologic conditions. As she grew increasingly discouraged with the fatigue, which limited her ability to participate in sports and school activities, she was started on an antidepressant—without noticeable effect. Despite being tired, it took hours for her to fall asleep at night. Her menstrual periods became heavy and painful but were being managed with cycling hormone pills. She experienced dizziness when she stood up, was often nauseated (but maintained her normal weight), and had near-constant headaches. By the time she came to Mayo, she was taking classes at home and found leaving the house difficult.
We conducted a physical exam that revealed dilated pupils, hyperextensible joints, and a postural heart rate change of 42 beats per minute. When standing still for a few minutes, her hands and feet got dusky, and she complained of dizziness and nausea. The physical exam was otherwise normal, as were most screening tests. An autonomic reflex screen confirmed postural tachycardia without hypotension and without other evidence of autonomic failure. Unlike many other adolescents with chronic fatigue, she had normal ferritin and vitamin D levels.
Mayo Clinic's Pediatric Diagnostic and Referral Clinic
In the late 1990s, patients who were referred to Mayo Clinic for complicated problems that didn’t fit within a single organ system or specialty area were seen primarily by subspecialists. Understanding that generalists might be better suited to provide feedback about multiple organ systems and coordinate care and knowing that subspecialists need to concentrate on patients within their own areas, the department of pediatric and adolescent medicine asked several recently hired pediatric generalists to start a general pediatric referral practice. Now eight years old, the Pediatric Diagnostic and Referral (PDR) Clinic has become one of the nation’s largest general pediatric referral clinics. Currently, four general pediatricians staff the clinic, which sees hundreds of patients each year who have proved to be challenging for a single primary care provider. About
35 percent of those patients come from Minnesota and the surrounding states; others come from throughout the United States and from other countries.
Patients arrive at the clinic early in the week—Monday or Tuesday—for evaluation by one of the pediatricians. That pediatrician then arranges and coordinates the diagnostic evaluation, including necessary tests and subspecialty consultations. The physician meets again with the patient and family at the end of the week for a wrap-up visit to review diagnostic impressions and discuss a comprehensive management plan formulated by an interdisciplinary Mayo team.
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We were able to identify this girl’s condition because her presentation was similar to that of many patients who have come through our diagnostic clinic. At first, we had been confounded by these cases. After discussing the symptoms with colleagues and searching for explanations in the literature, we learned of a condition called postural orthostatic tachycardia syndrome (POTS). First described in adults in 1993,
1 and recognized in teenagers a few years later, this form of autonomic dysfunction presents with fatigue, dizziness, nausea, and, often, pain. POTS probably accounts for the majority of cases of chronic fatigue during adolescence.
What is the lesson from this case? When we see patients with symptoms we don’t understand, we should look for patterns, consult colleagues, and search the recent literature. Because much of the initial work on the syndrome had been done on adult populations,2-6 our group is now involved in clinical research that seeks to understand this condition in adolescents. We also participate in efforts to educate patients and their families about POTS and its treatment.
We have found that patients and their families are encouraged when they hear there is an explanation for this chronic condition, and they get excited when they find out that the prognosis is good. Most adolescents eventually return to full activity. But we caution that recovery takes time and that patients will need to combine rest with increased fluid and salt intake, regular aerobic exercise, and prescription medications including beta-blockers to blunt the tachycardia response. Exercising when extremely fatigued can be facilitated by a life coach or psychologist. Participating in a comprehensive, multidisciplinary pain rehabilitation program can be effective for those patients who have chronic pain. Our group is attempting to decipher the presence and degree of deconditioning within the orthostatic intolerance syndromes, hoping that we can influence management of these conditions in the future.
Boy with Exercise Intolerance
A 14-year-old boy from a western state presented with exercise intolerance. He was an A and B student who loved sports. During the current year, however, he had begun to tire easily. He seemed to be moving progressively slower and became winded and pale with prolonged exertion. At times, he was overwhelmed by weakness, palpitations, and headaches and needed to stop exercising. He’d seen several physicians and undergone lots of tests, all with normal results, and did not have a diagnosis. His exam with us was normal, except that he seemed somewhat nervous and had a systolic blood pressure of 150 to 160 and a postural heart rate change of 55 beats per minute. (During our review of his prior records, we discovered he had previous blood pressures of 120 to 140/80 to 90.)
Because of the significant postural tachycardia coupled with fatigue, headache, and palpitations, it was tempting to consider a diagnosis of POTS. But the hypertension was not consistent with what we had read in the literature or observed in other patients who had the syndrome.
During the diagnostic evaluation over the next couple of days, the boy had even higher blood pressure readings, some of which were associated with sudden onset of pallor and sweating. Screening blood tests were normal. A renal ultrasound revealed kidneys that appeared normal and had good blood flow; it also showed huge masses near the kidneys. A CT scan confirmed the presence of large, bilateral adrenal masses, and serum normetanephrine levels were markedly elevated.
The patient was treated with alpha blockade and, subsequently, beta blockade in preparation for surgical excision of his pheochromocytomas. His tumors were completely excised, and he has done well postoperatively. Approximately 40% of adolescents with pheochromocytoma have a genetic predisposition to this and/or other endocrinopathies.7,8 This boy’s evaluation was notable for having a von Hippel-Lindau mutation. With the help of an endocrinologist, a geneticist, a surgeon, and a cardiologist, the boy is improving.
What did we learn from this case? We must be careful to follow up on subtle clues when seeing complicated patients. Even a seemingly minor piece of the puzzle, in this case a few elevated blood pressure readings, might turn out to be important. Also, we must be careful not to jump over contradictory evidence to reach diagnostic conclusions too soon. Finally, it takes an interdisciplinary team to solve complex cases and treat complicated patients. For this boy, the general pediatrician noted the hypertension, arranged for imaging and biochemical studies, coordinated care, and maintained communication with the family. The endocrinologist managed medical therapy. The surgeon provided corrective therapy. The cardiologist ruled out secondary complications of the boy’s hypertension. And the geneticist helped plan a search for associated mutations that might identify a risk of other subsequent health problems. Yes, it takes a team to treat complicated patients.
A Boy with Weakness
A 14-year-old boy from the Midwest presented to the PDR Clinic with a three-month history of fatigue and weakness. He had shortness of breath and had been treated repeatedly for pneumonia without resolution. The fatigue worsened, and he lost weight. An inpatient evaluation revealed a sedimentation rate of 37, mildly elevated liver enzymes, scattered areas of consolidation in both lungs with a lower lobe nodule, and nonspecific infiltrates on a muscle biopsy. Brain and spine MRIs, EMGs, spinal fluid analysis, blood tests for infection and sarcoidosis, and muscle enzyme levels were all normal.
By the time he came to our clinic, he had lost 13 kg, had some generalized weakness that was most evident in the deltoid muscles and neck, and had a normal respiratory rate (16 per minute) and lung exam. The boy had no rash, but we did find periungual telangiectasias. He had mild microcytic anemia (Hb 9.3 g/dL, MCV 78) with elevated ALT (73 with the upper limit of normal being 45) and an FEV1 of 50% predicted. A variety of serological tests and a tuberculosis skin test showed no evidence of an active infection. Computed tomography of the chest showed diffuse nodular infiltrates throughout both lungs.
Finding ourselves at the hospital on a long holiday weekend, the general pediatrician coordinating the boy’s care at the PDR Clinic pulled together an impromptu case conference with specialists in infectious diseases, oncology, neuromuscular diseases, and surgery. The group agreed that a histologic evaluation would be needed. The following day, a lung biopsy showed bronchiolitis obliterans organizing pneumonia with chronic bronchiolitis and lymphoid hyperplasia, and a muscle biopsy revealed endomysial and perimysial inflammatory exudate supporting a diagnosis of an inflammatory myopathy.
This boy’s weakness was the result of previously undiagnosed dermatomyositis and secondary bronchiolitis obliterans organizing pneumonia (BOOP). He felt stronger and tolerated activity better within days of starting steroids. Dermatomyositis has previously been associated with BOOP, but only 21% of adult patients present with both conditions simultaneously, as our patient did.9 Anti-Jo-1 antibodies have been associated with some cases, and cyclosporin A has been used for patients who do not respond well to steroids. In at least one case, the patient did not have an elevated creatine kinase level despite the presence of dermatomyositis.10
What does this patient’s case illustrate? First, uncommon diseases can present in association with other uncommon diseases in unusual ways. In such cases, collaboration and teamwork during the diagnostic evaluation are essential. Sometimes, the issue is tissue, and invasive sampling is needed. But equally important clues in this case were the cutaneous telangiectasias and proximal weakness. This case reminds us that a thoughtful and thorough physical exam can sometimes reveal otherwise hidden diagnoses.
Distinguishing Stripes
Sometimes in our PDR Clinic, we feel as if we’re wandering through a herd of zebras. Not all the “stripes” on the animals are the same, and not every animal in the herd is actually a zebra. Navigating through clinical complexities is difficult, and we’re still learning how to best diagnose and manage our patients. We do know that we must attentively listen to patients, paying attention to all potentially relevant historical information. We must be meticulously careful not to neglect any physical exam findings, even those signs that may be only subtly abnormal. Just as proceduralists pause prior to initiating invasive interventions, we must pause to consider diagnostic possibilities before jumping to conclusions based on incomplete information. We must seek regular input from colleagues and scour the medical literature. And, we need to develop good doctor-patient relationships grounded in trust and compassion that enable our patients to engage with us in the diagnostic evaluation and management planning. MM
Philip Fischer is a professor of pediatrics, Jonathan Johnson is an instructor in pediatrics, and Chad Brands is chair of the division of general pediatric and adolescent medicine at Mayo Clinic. They share patients in the Pediatric Diagnostic and Referral Clinic.
References
1. Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 1993;43(1):132-7.
2. Karas B, Grubb BP, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a potentially treatable cause of chronic fatigue, exercise intolerance, and cognitive impairment in adolescents. Pacing Clin Electrophysiol. 2000;23(3):344-51.
3. Stewart JM. Chronic orthostatic intolerance and the postural tachycardia syndrome (POTS). J Pediatr. 2004;145(6):725-30.
4. Medow MS, Stewart JM. The postural tachycardia syndrome. Cardiol Rev. 2007;15(2):67-75.
5. Thieben MJ, Sandroni P, Sletten DM, et al. Postural orthostatic tachycardia syndrome: the Mayo Clinic experience. Mayo Clin Proc. 2007;82(3):308-13.
6. Antiel RM, Risma JM, Grothe RM, Brands CK, Fischer PR. Orthostatic intolerance and gastrointestinal motility in adolescents with nausea and abdominal pain. J Pediatr Gastroenterol Nutr. 2008;46(3):285-8.
7. Armstrong R, Sridhar M, Greenhalgh KL, et al. Phaeochromocytoma in children. Arch Dis Child. 2008;93(10):899-904.
8. Havekes B, Romijn JA, Eisenhofer G, Adams K, Pacak K. Update on pediatric pheochromocytoma. Pediatr Nephrol. 2008; in press.
9. Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositis-dermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med. 2001;164(7):1182-5.
10. Lee YH, Choi SJ, Ji JD, et al. Dermatomyositis without elevation of creatine kinase presented as bronchiolitis obliterans organizing pneumonia. Korean J Intern Med. 2000;15(1):85-8.