FEBRUARY 25, 2001; Pg. A01

Routine Symptoms, then a Fatal Medical Mystery

Doctors tested for Viruses, Bacteria and even the Human form of Mad Cow Disease.

By Shankar Vedantam

Evelyn Mahan remembers the last conversation she had with her daughter Carrie before the 29-year-old died. As good-byes go, it wasn't much.

It was a Sunday night. Carrie, who was working two jobs and studying for a second bachelor's degree in accounting, called from her home in Northeast Philadelphia to say she'd been to a party in New York with her boyfriend. She had been tired before she left and she was tired now.

That was it.

On Monday, Carrie told her boyfriend that she didn't feel well. He took her to the emergency room at Albert Einstein Medical Center in Philadelphia. Doctors gave her medicine. She slept poorly that night and was back in the ER the next day.

Hospital staff noted in her chart that her blood pressure was 156 over 98, slightly elevated. Her temperature was 97.1, slightly low. She had just had her period. Her chief complaint was nausea.

Doctors recommended rest and clear liquids such as juice, tea or soda until the nausea subsided and told her to follow up with her family doctor.

The symptoms worsened: Carrie began hearing music in her head. She hallucinated. She felt acutely afraid. Within days, she was admitted to Einstein's psychiatric ward.

In the six weeks that followed, doctors at two hospitals puzzled over Carrie's strange symptoms. As Carrie's family clamored for answers, doctors raced packages of her brain tissue across the country to top scientists.

Among the many explanations they investigated was mad cow disease. Today, a year after Carrie's death on Feb. 24, 2000, doctors have reached a conclusion, but her family remains tormented. Evelyn Mahan is still searching for answers.

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It was around noon on Martin Luther King Day when Carrie's boyfriend went to Evelyn Mahan's home in Stratford, N.J., to tell her that her daughter had been struck with a mysterious illness and had just been transferred to the Hospital of the University of Pennsylvania for psychiatric treatment.

Mahan fainted. When she came to, the mother of six marshaled her family and rushed to Penn, where doctors were puzzling over why a healthy person would suddenly become apparently psychotic. The most obvious explanations were drug abuse, stroke or a brain tumor. All were ruled out.

Besides the hallucinations, Carrie was now rapidly growing confused and disoriented.

Neurologist Grant Liu suggested a spinal tap. A sample of the fluid that bathed Carrie's spinal cord and brain was extracted. It contained an excessive number of disease-fighting white blood cells. Her body was probably fighting a mysterious infection. She was transferred to the neuro-intensive care unit.

Peter Crino, the attending neurologist, remembered going down the list of diseases that could explain the extra white cells. Most likely was the common herpes simplex virus, which can cause encephalitis, an inflammation of the brain.

Carrie's spinal fluids were sent to the microbiology lab to test for herpes, but rather than lose time, doctors started her on antiviral medication. On the chance that a bacterium was the culprit, she was also started on antibiotics. Doctors also ordered brain scans.

Carrie grew lethargic. She sat silently in bed, staring blankly. Her lips twitched.

Crino asked Carrie to hold out her hands, point to the TV, and hold up two fingers. She complied but seemed to Crino on the verge of slipping into a stupor.

Each morning, Crino huddled with other neurologists outside Carrie's door. They went over how she had fared during the night and decided whether to run new tests or add medicines to her growing list of prescriptions. Crino discussed treatment options with the family if she tested positive for an infection.

The viral and bacterial lab tests arrived: all negative.

The brain scans - the magnetic resonance imaging to see whether there were structural changes in Carrie's brain and the electro-encephalograph to look for anything unusual about her brain waves - also came back normal.

It was frustrating.

The accumulated negative results had eliminated all of the most likely causes of Carrie's symptoms.

It was time to step back and ask whether Carrie was suffering from some rare neurological condition that was raging below the radar sweeps of the usual battery of tests.

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For Evelyn Mahan, 60, the swift decline in Carrie's mental state was unbearable.

The twitching around Carrie's mouth had spread to her limbs, and Mahan had to endure watching her daughter writhe like a puppet. Carrie shook and bit her tongue.

Doctors, fearing that she would lose the power to breathe on her own or that she might choke on her own saliva, implanted a tube in her throat that could pump oxygen into her failing body.

As doctors went down one diagnostic blind alley after another, Carrie slipped into a coma. Evelyn Mahan and her family pursued their own answers. Mahan remembered suffering hallucinations herself after someone once slipped a drug in her drink. Could that have happened to Carrie in New York?

"Somebody gave her something," she concluded. "She was perfectly healthy before she left."

As her daughter grew unrecognizable before her eyes, Mahan became increasingly angry. Here they were, at one of medicine's meccas, surrounded by the best technology and the most knowledgeable doctors. Why weren't they saving her Carrie's life?

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Doctors shined flashlights into Carrie's eyes; she did not react. The involuntary twitching continued, which suggested brain damage.

On the last Friday in January, 19 days after Carrie first showed symptoms that something was wrong, Penn surgeons cut into her skull above her right ear and extracted a tiny piece of tissue. Still hopeful that she would recover, they took the sample from the nondominant side of her brain to minimize any adverse effects.

Crino suspected a bizarre encephalitis. He asked Penn neuropathologist Nicholas Gonatas to check for rare viral infections in Carrie's nerve cells.

Technicians sliced the tissue into layers so thin that 40 piled on top of one another would be as thick as a human hair. Gonatas looked at it under a microscope: Amazingly, there was still nothing unusual.

Gonatas ordered the tissue sliced 10 times thinner for viewing under an electron microscope.

When the tissue was ready, Gonatas sat down before the 10-foot-high device. He peered through the lenses. Finally, the devastation in Carrie's brain was apparent.

Blotches of tissue had simply vanished. Photos of her brain looked like the pictures astronomers make of galaxies - except that in this case, each of the stars represented a hole in Carrie's brain. Gonatas immediately knew he was looking at a spongiform encephalopathy - a range of rare disorders that chew holes in the brain. Gonatas paged Crino and gave him the news.

The most likely explanation, the doctors agreed, was sporadic Creutzfeldt-Jakob disease (CJD). Worldwide, it strikes one in 1 million people a year, most of them over 55.

Scientists believe CJD is caused by a deformed protein known as a prion, which seems to appear randomly. Growing like a crystal, it runs amok through the brain. There is no cure. Carrie was going to die.

At a family meeting, Crino told 20 people gathered in a room that Carrie's brain was being eaten away. Doctors were not sure why. They did know that it was fatal.

The room was silent. Finally someone asked a question.

"Does this mean she is going to die?"

"Yes," Crino said.

Evelyn Mahan began to weep.

"This can't be happening," someone said.

"Are you sure there's nothing you can do?" someone else asked.

Crino fielded their questions and finally posed one of his own.

"What would you want to do if her heart stops beating?" he asked. Should doctors bring back her heartbeat?

Crino remembers someone asked, "Bring her back to what?"

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The Penn doctors were not completely satisfied with the diagnosis. The disease was unusual in someone as young as Carrie.

In Britain, an eruption of young people with CJD-like symptoms had led doctors to deduce that they were confronting a new condition - the human form of mad cow disease, technically called new-variant CJD. This illness was not random but was caused by eating beef contaminated with deformed proteins.

Mad cow had another unusual characteristic: Its first symptoms are often psychiatric.

No American had ever been diagnosed with the disease that had claimed dozens of lives in Britain and led to panic across Europe. Crino knew that if Carrie had the disease, the news could cause hysteria in America. It would be exciting to spot the first case, but the ramifications were frightening.

Working against the mad cow hypothesis was the fact that Gonatas' electron microscope slides had not displayed a characteristic feature - little bubbles of plaque.

Gonatas shipped a section of Carrie's tissue from the brain biopsy overnight to a lab run by one of his former Penn colleagues, Pierluigi Gambetti at Case Western Reserve University in Cleveland. The federal government had designated Gambetti's lab the national center to screen tissue samples for the human form of mad cow disease.

The doctors also asked Evelyn Mahan whether Carrie ate beef.

"Yes," she told them, "but she ate the best food because she could afford it."

Did Carrie eat pork?

"I'm sure she had pork chops for dinner quite a few times."

What kind of makeup did Carrie use?

"Max Factor," she said.

Contaminated beef had been linked to mad cow disease in Europe, but no one knew whether other meats or meat products in cosmetics were also responsible.

Although the doctors were only groping for clues, to the family, the questions suggested that mad cow disease was a tangible explanation for Carrie's tragedy.

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On the morning of Feb. 24, Evelyn Mahan, who was spending night and day with Carrie, leaned over the bed and kissed her daughter.

Carrie appeared to be sleeping peacefully. Mahan told her she would be back soon. She left the room but something drew her back. She kissed Carrie again.

"I don't want to leave you," she whispered. "Mommy will be back."

When she walked into her apartment, the phone was ringing. It was the hospital. Carrie had died.

"Don't move her. I'll be right there."

Mahan reluctantly agreed to an autopsy. She hated the idea of doctors' cutting up Carrie's brain, but it offered a chance to get a proper explanation.

When it was over, Carrie's body was moved to a funeral home. Whispers of what might have killed her preceded her body.

"The undertaker thought CJD was a disease that was catching," Mahan said. "They were afraid. My niece did her hair - they made her put rubber gloves on and a gown."

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As the family organized a funeral, Gonatas received a letter from the Cleveland lab. It was dated Feb. 22, two days before Carrie died.

There was no evidence of the prions for CJD or mad cow disease in the brain sample that Gonatas had sent Gambetti.

"However," Gambetti wrote, "we have to keep in mind that the tissue examined was very small and therefore may not be representative."

Gonatas sent more samples from the autopsy.

Another letter arrived in mid-March. Still no CJD. Genetic tests also ruled out mad cow disease.

The mad cow finding did not surprise Gonatas, but he was shocked that the lab could not confirm CJD.

On March 20, Gambetti sent a third letter to Penn. Tests on different parts of Carrie's brain further confirmed their negative findings.

Nonetheless, Gonatas was convinced that Carrie died of CJD. He had seen about 20 cases in his several decades as a pathologist and had theories why the lab hadn't found it.

"In a small minority of cases, the biochemistry does not prove it," he said. Another possibility was a CJD prion that the tests do not recognize. Or maybe an unknown toxin had caused the disease.

Crino and Gonatas tried to communicate this complicated conclusion to Carrie's family.

"We know she had spongiform encephalopathy," Crino said. "It was relentless and caused her death. She did not have [mad cow disease]. . . . If anything, she had an atypical CJD."

"I felt pain telling the family this diagnosis," Crino said recently. "There is something unsettling about not knowing the exact cause of death. It's very important for the living to heal and move on."

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Evelyn Mahan's apartment is today a shrine to her daughter. There are pictures of Carrie on every wall, taped to every door: Carrie in high school, Carrie with her family, Carrie at a Christmas party. There is even Carrie's birth certificate, framed on the living room wall.

Mahan cries easily and often when she remembers Carrie's final weeks. In the absence of a definitive diagnosis, the family still theorizes about the illness.

Allen Mahan, Carrie's brother, has come to believe that Carrie died of mad cow disease, even though the tests disproved that.

Evelyn Mahan prefers to think that someone slipped a drug into Carrie's drink.

Both are incredulous that scientists don't have a definitive answer.

Mahan talked about it recently, sitting at her kitchen table. With tears running down her cheeks, she said, "I can't rest. I can't let this go until somebody tells me the truth."

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