Rheumatology Helps Discover and Treat Illness

Washington Post – Health & Science
 – June 30
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A woman in Kensington, Md., developed a daily fever that stumped doctors for nearly a year. (Robert Carter for The Washington Post)  

The fever would descend every afternoon around 3, an occurrence so predictable that Carol Maryman could barely remember what normal felt like. Every night Maryman’s 101-degree temperature mysteriously slid back to normal while she slept; in the morning she awoke feeling wrung out.

The 10 months of unexplained fevers, which began in March 2013, had been preceded by night sweats, episodes of breathlessness and bone-crushing fatigue. Maryman, then 59, recalled that it was all she could do to make it through a day as the assistant to the chief executive of Bethesda’s Strathmore Center for the Arts before dragging herself home to Kensington and collapsing into bed. Her once-active life had ground to a halt: She stopped going out to dinner, practicing yoga or seeing friends.

For months doctors searched for the cause of her problems. Maryman underwent test after test: MRI scans, increasingly sophisticated blood assays to rule out malaria and exotic parasites, and a bone marrow biopsy to check for cancers both common and rare. Most tests revealed nothing significant, but several blood values remained stubbornly abnormal: Maryman was anemic, her white blood cell count was too high and there was evidence of inflammation, which suggested a smoldering infection. But no one knew where the problem lay.

Nearly a year after the fever first surfaced, an MRI performed months earlier provided the clue that ultimately led to a definitive diagnosis. The scan had revealed a painless mass in her left ovary that didn’t seem worrisome to doctors – at first. But when it nearly doubled in size in eight months, Maryman underwent surgery to remove both ovaries. A biopsy of her right ovary, which had looked normal, revealed the unusual cause that had long eluded a growing team of specialists.

“If I had not had that surgery,” Maryman said, “they would not have figured out what it was I had.”

Breaking both arms

Carol Maryman endured months of unexplained fevers that began every afternoon and receded while she slept. (Family Photo) 

To Maryman, the fever and malaise were worse than an injury she had suffered in July 2012. While on a lunchtime errand in Rockville, Maryman fell, crashing into a store’s plate-glass door and breaking both arms. She’s not sure how the accident happened, but doesn’t remember tripping. Several days later, Maryman had surgery to place a metal rod in her right arm and a plate in her left wrist. Although she was able to return to work after a few weeks, recovery was long, involving eight months of physical therapy. Her arms remained weak, and she had difficulty lifting anything heavy.

The fevers started in March 2013, soon after she returned from a trip to Arizona. A hike in the red rock canyons that rim Sedona left her unusually winded and tired, feelings that persisted after she returned home. “I just didn’t feel right,” she recalled. After a few weeks of night sweats that did not abate, she consulted her primary-care doctor.

“She did a lot of blood work,” Maryman said, and ordered a chest X-ray to check for pneumonia. The X-ray showed that her lungs were clear, but the doctor thought she detected a heart murmur and sent Maryman to a cardiologist. An echocardiogram found that her heart was normal.

But her blood tests were not: Maryman’s white cell and platelet count, her sedimentation rate and level of C-reactive protein, which indicate inflammation, were markedly elevated. Maryman clearly seemed to have an infection.

Next stop was an infectious-disease specialist: He ran tests for Lyme disease, HIV and tuberculosis, among other ailments; all were negative, and the doctor told her he couldn’t find what was causing her fever or elevated inflammatory markers. He told Maryman that she had a “fever of unknown origin,” a common condition defined as a fever that persists for more than three weeks without an unidentifiable cause. Often the problem simply goes away on its own.

During a scan of her abdomen in May 2013, doctors discovered a five-centimeter mass – roughly the size of a thumb – on her left ovary; the radiologist suspected it was a benign and very common fibroid tumor.

“I really didn’t ask about this because I had so many other things going on,” said Maryman, who had not felt any discomfort from the growth.

No closer to an answer about the cause of her fever, fatigue or anemia, her primary-care physician sent her to an oncologist, who found nothing new. “Everyone knew something was wrong with me, but nobody knew what it was,” Maryman said.

Sometime in early fall, the daily fever receded and Maryman seemed to be slowly getting better. She and her doctors hoped that she was through the worst of it, whatever it was.

But by Thanksgiving her fever came roaring back and blood tests ordered by the oncologist, who had continued to monitor her regularly, showed that her inflammatory markers were again very elevated.

“I was pretty upset,” Maryman recalled, especially “because everyone kept telling me how tired I looked.” No closer to an answer, Maryman made an appointment with an infectious-disease specialist at Johns Hopkins Hospital in Baltimore.

The new specialist “ordered a huge battery of blood tests and cultures,” Maryman said. The results were largely the same, except for a TB test that was deemed inconclusive. A new possibility emerged: Maybe Maryman had contracted some form of tuberculosis.

But Maryman had a more pressing concern: The ovarian mass, which had been thought to be a benign fibroid tumor, had grown substantially in just a few months, according to a new abdominal MRI. Maryman consulted two gynecologic oncologists, who each gave her the same advice: She needed a complete hysterectomy, or at least the removal of her ovaries so that the mass could be biopsied and the ovaries inspected. Ovarian cancer was a distinct possibility. Maryman told the surgeon she chose that she wanted a hysterectomy only if invasive cancer was found.

A surprise
On Jan. 23, Maryman underwent laparoscopic surgery at Holy Cross Hospital in Silver Spring. Doctors found no sign of invasive cancer; the mass in her ovary turned out to be a Stage 1, noninvasive, low-grade form of cancer that had not spread outside the ovary. “Her prognosis should be quite good,” the surgeon wrote in her medical record, and no further treatment was required at this point.

But the real surprise lay in her right ovary. Doctors found evidence of a rare autoimmune disorder that appeared to be giant cell arteritis. Also called temporal arteritis, it is a vascular condition in which the linings of the body’s large arteries, including those leading to the heart, become inflamed, causing them to thicken and narrow, resulting in decreased blood flow. The cause is unknown, and most people who develop it suffer severe headaches or double vision. Fever can be a symptom, as can anemia, but signs of the disorder rarely show up in the reproductive tract.

Maryman was referred to yet another specialist: rheumatologist Alan Matsumoto, who practices in Montgomery County.

“This is a case rheumatologists actually love,” said Matsumoto, who first saw Maryman on Feb. 21. “There’s a lot of Monday morning quarterbacking, but it is an aha! moment” because rheumatic diseases can mimic many other problems.

Matsumoto said he suspected that, based on her symptoms and extensive testing, Maryman did not have giant cell arteritis, but rather a much rarer disease: Takayasu’s arteritis, which affects 1 in about 200,000 people, usually those younger than 40. Ninety percent are female.

Chronic inflammation is present in both forms of arteritis, but the giant cell type affects the head and neck arteries, often causing ferocious headaches – and Maryman didn’t have headaches. Takayasu’s arteritis affects the aortic arch, and large arteries branching out of the heart, including those that supply blood to the arms. One of Maryman’s recurring symptoms was arm pain, which had been attributed to the fractures from her fall.

“I asked her if she had any pain when she performed a repetitive motion like vacuuming,” Matsumoto recalled, as had a previous Takayasu’s patient he treated. Maryman replied that the action was so painful that she couldn’t vacuum or lift her arms above her head.

The rheumatologist was convinced he was correct when he tried to take her pulse and blood pressure. “I couldn’t get it on either arm, ” he recalled. This impaired blood flow resulted in an old nickname for Takayasu’s: the pulseless disease. Matsumoto prescribed prednisone, a potent steroid that reduces inflammation, and ordered MRA scans, which provide pictures of the interior of blood vessels, to determine which form of arteritis Maryman had.

A suprise

The tests confirmed his hypothesis. Maryman’s head scan found nothing abnormal, while the one of her chest showed thickening of the arteries emanating from her heart and narrowing consistent with Takayasu’s.

Getting a diagnosis, Maryman said, was a relief. “I had been so scared that I had some horrible disease but nobody knew what it was.”

The prednisone, which Maryman continues to take – although at a diminishing dose – knocked out the fever and restored much of her energy. But her arms remain affected – she still can’t vacuum – and it is unclear whether some of the damage is permanent.

Matsumoto wonders whether her disease could have been caught earlier and whether her pulses had been adequately checked; the fact that they were undetectable was a red flag as well as a key clue.

But, he added, “this is a case where people did the right thing and kept following up. No one said, ‘We don’t know what’s wrong’ and that was the end of it. It was a bit of a serendipitous diagnosis. Had they not taken that right ovary out, it might never have crossed anyone’s mind . . . until later.” Untreated Tayakasu’s can cause kidney failure, stroke or a heart attack.

Maryman said she is getting better – the fatigue and night sweats are gone – and she is grateful for the care her many doctors provided as they struggled to make a diagnosis. “I was starting to feel hopeless, like nobody would ever figure it out,” she said.

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