Medical Mysteries: Patient was at grave risk after tests ruled out fatal disease

By Sandra G. Boodman
Special to The Washington Post
Tuesday, June 15, 2010; HE01

The distinguished senior doctors, most clad in long white coats, settled into padded ochre chairs in a conference room at Johns Hopkins Medical Institutions early one morning last September as a junior specialist began to present the case of a patient who had stumped their colleagues for weeks.

"This is kind of a depressing case," infectious-disease fellow Justin Bailey said by way of introduction. "But it has a happy ending."

Bailey summarized the 55-year-old accountant's symptoms, which had resulted in four admissions to Hopkins in 2009: night sweats, crushing fatigue, headache, shuffling gait and progressive confusion. Bailey ticked off the tests that had been performed. He described how the usual causes of unusual infections -- an exotic organism picked up during travel, a new pet, close contact with someone just returned from overseas -- had all been ruled out.

So why had the patient, whom Bailey did not name, deteriorated so spectacularly in a matter of months? And what was wrong with him when test after test showed nothing that would account for his condition?

Months later, Bailey recalled with satisfaction that the eminent experts in the room that day had not seen a case like it. And most of the diagnoses they offered before Bailey revealed the correct answer were the same ones doctors treating the patient had proposed, then discarded.

* * *

Beginning in the summer of 2008, Eileen Holden noticed that something seemed to be wrong with her husband, Dennis. He had lost about 25 pounds without trying, and seemed stressed and increasingly forgetful, which began to annoy her. Sometimes he would ask her where one of their four children was. She would tell him, and then he'd ask the same question five minutes later, "like he hadn't been listening," she recalled.

Dennis Holden had recently been promoted to a more demanding job as comptroller of the Indian Head Naval Surface Warfare Center. Eileen, a schoolteacher, recalled one Sunday when he called their Charles County home, nearly 10 hours after he had gone to his office to catch up on work that seemed to be piling up at an alarming rate.

"He said he hadn't done anything and it was 4 p.m.," she said, recalling that her husband was uncharacteristically near tears. "He would set a paper down and then not remember where he had just put it."

Dennis had also begun sleeping a lot. He would sit down in the living room and then just drop off, like an old man. Although she repeatedly urged her husband to call the doctor, he did not. But Holden was increasingly aware something was wrong and felt perpetually exhausted. "It was all I could do to drag myself to work and back home," he recalled.

A troubling incident

In February 2009, he went to see his internist. She sent him to a cardiologist for further testing, which revealed nothing out of the ordinary.

A month later, while attending their son's Friday night high school lacrosse game, Eileen noticed Dennis was walking strangely and had trouble navigating the bleachers. He told her he had hurt his back, wasn't feeling well and would meet her at home.

A few minutes later, her cellphone rang. Dennis was calling from the parking lot; he couldn't find his car. "I said, 'Stay there. I'll come find you,' " she recalled. She discovered her husband standing nearly in front of the car he did not recognize as his, speaking gibberish.

Unnerved, she drove him straight to the emergency room of a nearby community hospital. A head CT scan revealed an excess of brain fluid, which could account for his confusion and difficulty walking. Holden was transferred to Hopkins by ambulance.

Doctors there thought he might be suffering from normal pressure hydrocephalus, an accumulation of cerebrospinal fluid on the brain. After a few days they ruled that out and ordered a barrage of tests: spinal taps, blood draws and all kinds of imaging. They ruled out lymphoma and several other cancers; HIV; lupus; Lyme disease; West Nile virus; tuberculosis; and toxoplasmosis, an infection caused by a parasite.

Holden's spinal tap did show an elevated white blood cell count indicating a possible infection, and his chest scan revealed enlarged lymph nodes. But nothing seemed to add up.

He was discharged in early April in somewhat better shape; doctors told Eileen Holden they weren't really sure what was wrong. One suggested meningitis, but no one knew what might be causing it. Two tests for cryptococcus, a fungus that can cause a form of meningitis, were negative. That hadn't seemed likely anyway; "crypto" is an opportunistic infection caused by pigeon droppings and is most often seen in AIDS patients with damaged immune systems. Holden's immune system seemed intact, and his HIV test was negative.

Holden went back to the office, barely able to function. By mid-May he was back at Hopkins. Doctors biopsied the enlarged lymph nodes in his chest. That seemed to reveal the cause of his many problems: neurosarcoidosis, an uncommon, chronic inflammatory disorder of unknown origin that results in abnormal cell deposits in the brain, spinal cord or other parts of the body. The disease can cause headaches, confusion and meningitis.

Doctors prescribed a high dose of prednisone, a steroid that reduces inflammation. Holden said he remembers "calling a bunch of people and telling them, 'Yay, they know what this is.' "

But after a week, Eileen Holden recalled, her husband seemed even worse. One morning he told her he felt like he was having a nervous breakdown. He had such trouble walking he was using a cane and had to attend their daughter's high school graduation in a wheelchair. Mentally he seemed vacant: He put a banana peel in the dishwasher. The couple learned later that his co-workers were deeply concerned, but no one wanted to say anything because he was their boss.

By late June he returned to the hospital. Doctors prescribed an antidepressant along with the prednisone and performed another spinal tap before discharging him.

Two nights later Eileen Holden got an urgent call from a doctor at Hopkins. The latest spinal tap showed unmistakable signs of cryptococcus, the potentially lethal fungal infection that had previously been ruled out after tests were negative. The fungus can attack the spinal cord and brain, causing dementia-like symptoms. And it is virtually unknown in otherwise healthy patients.

Without treatment, cryptococcal meningitis is "invariably fatal," according to an article published last year in the online medical textbook emedicine; death can occur up to several years after the onset of symptoms.

Holden was told he needed to return to Hopkins immediately, so doctors could wean him off steroids and begin treatment with a powerful antifungal drug that must be closely monitored because it can cause kidney damage.

Why the mystery?

So why had previous tests been negative for cryptococcus? The answer, Bailey and other physicians later determined, lay in Holden's healthy immune system. The prednisone had suppressed his immune system and allowed the cryptococcal infection, which had been there all along but held at bay, to blossom and show up on the spinal tap.

"For some reason, these tests aren't as sensitive in people who don't have AIDS," Bailey said. Within a few days of starting the medicine, which he took for months, Holden began to show dramatic improvement. He was less confused, his headaches subsided and his ability to walk improved.

Because of his serious deterioration, he needed two months of specialized occupational, physical and cognitive therapy to regain his balance and relearn executive skills. Last September, Holden returned to work. He said he feels almost entirely back to normal.

"It was a life-changing experience," said Holden, whose memory of his illness is patchy. "I don't know if I'd be here if it wasn't for Eileen."

Bailey, who began treating Holden last summer after his correct diagnosis, said he searched the medical literature for cases of healthy patients who developed cryptococcal meningitis; he unearthed only a handful, although the fungus is ubiquitous in soil and present in pigeon droppings. Holden is not a gardener, nor does he handle birds.

"I have no idea how he got it, and I doubt we'll ever know," said Bailey, adding that he suspects the infection might have been festering for nearly a year. "I've never see anyone with such profound mental status changes get so much better. His progress is amazing."

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