An end's beginning
More than half of all elderly hospitalized patients suffer severe confusion. Many ultimately decline into dementia. Are there common triggers to both?
I'm dead. Are you dead, too?"
Larry Carsman's mother had always been solidly grounded. But four years ago, as she emerged groggily from surgery, she blurted out those chilling words.
Her delirium -- likely from some combination of the surgery, anesthesia, and painkillers -- lifted within a day, he said. But his mother, then 81, began a slide into dementia.
"The assumption was that she would come out of it," said Carsman, of Wellesley. "But she never really did."
Before, she was sharp enough to drive 25 miles a day to a part-time job and care for herself. After, she forgot to buy food. She couldn't keep track of her medications. Bills went unpaid. She lost her job. And within a few months, the family moved her to supported housing and later, assisted living.
Her deterioration provides a stark example of the new connections doctors are drawing between two illnesses that wreak havoc on millions of older patients.
Doctors used to believe that delirium was a short-lived problem for older, hospitalized patients. But research now suggests that delirium -- a sudden, serious mental confusion -- can linger for months and can increase the likelihood of more serious mental decline, including dementia.
And the harmful effects may go both ways. Patients with dementia are at least five times more likely to experience delirium while hospitalized than patients with sound minds, according to Dr. Sharon Inouye , director of the Aging Brain Center at Hebrew SeniorLife, based in Boston.
The connection between these illnesses is still a mystery. But new studies suggest a genetic link and a possible tie-in with the most commonly used general anesthesia agent. If the connection can be solidly established, researchers say it could provide a new way to fight dementia.
"If we could prevent delirium -- and we know we can -- then we might prevent dementia from developing or getting worse" in many cases, said Inouye, who is leading a group of local scientists examining the connections.
Delirium causes severe confusion that is often accompanied by hallucinations and agitation but may also bring withdrawal or extreme sleepiness. Research shows that delirium affects more than half of all elderly patients who are hospitalized or undergo surgery. It is also extremely common in patients of all ages treated in intensive care units. Studies show delirium itself can lengthen hospitalization and hasten death.
For many patients, the delirium is caused by a combination of factors including medical and surgical procedures, infections, medications, malnutrition, immobility, noise, and sleep disruption. For the sickest, it can be triggered by something as simple as one sleeping pill, Inouye said.
Several studies have found a connection with dementia, a range of conditions including Alzheimer's that -- over many years -- destroys memory, organized thinking, and eventually everyday functioning. One particularly striking study found that 60 percent of hospitalized patients with delirium were diagnosed with dementia over the next three years, compared with 18 percent of those without, according to a review of the research by James C. Jackson , a neuropsychologist at Vanderbilt University in Nashville.
"It's a very big public health problem flying under the radar screen," he said.
A paper by Jackson and colleagues, published last month in Critical Care Medicine , found the first genetic link between the two brain disorders. In a small group of ICU patients, those with a genetic variation called APOE4 were more likely to have longer-lasting delirium. APOE4 also increases the risk of getting Alzheimer's disease.
"We're beginning to think that genetic factors may predispose people to delirium," Jackson said. "Those could be the same factors that predispose them to dementia."
Inouye helped convene a symposium last year to look for connections between delirium and dementia and coordinated publication of a group of research papers last month in the Journal of Gerontology: Medical Sciences .
One of those papers studied the effect of isoflurane , the drug most commonly used to induce general anesthesia. Because of the high rate of post operative delirium, earlier research suggested that anesthesia might be a risk factor, but the evidence is not conclusive.
When isoflurane was "given" to cultured brain cells in the lab, it triggered the death of some cells. That, in turn, caused a build up of a protein called beta-amyloid that crowds the brains of people with Alzheimer's. The anesthetic also increased the harmful clumping of beta-amyloid and that accumulation caused more cell death.
"Isoflurane can cause the pathology underlying dementia," said Dr. Zhongcong Xie , an anesthesiologist at Massachusetts General Hospital who led the research, which was also published last week in the Journal of Neuroscience . "It can also cause a delirium. We suggest that they share a similar pathology -- one agent causes both, but one illness happens quickly, and one happens over a long time."
Xie, assistant professor of anesthesia at Harvard Medical School, called the finding "alarming" but warned against panic because of the long history of safe use of isoflurane and because results in cells don't always hold up in real people. Xie and colleagues have begun testing the effects of isoflurane in mice and in people.
"It's too early to take isoflurane out of the operating room," said Rudy Tanzi , director of genetics and aging research at Mass. General and a co-author of the paper. "And for healthy people, it may not be a problem."
However, Tanzi said he asked doctors to give his elderly mother another anesthetic instead of isoflurane when she had knee replacement surgery last summer. In the past, after surgeries, his mother was often delirious for days, he said. This time, she woke up and asked whether the Red Sox were on television. "I've got to see my Big Papi," she told Tanzi.
Larry Carsman said no one focused on anesthesia as a possible cause of his mother's delirium. Instead, they looked to the painkiller Demerol , which he said had made her delirious in the past and was given to her by hospital doctors unaware of that history.
Before the delirium, Carsman's mother was occasionally forgetful, but showed no signs of dementia, he said. Highly educated with a doctorate in gerontology, she even directed her own medical care. Yet, a year after the delirium, she was diagnosed with dementia.
"I would love for my mother's dementia not to have gotten this big shot" in the arm from the delirium, he said. "She was so independent. Had she not taken this downturn, she could have stayed in her house longer."
Alice Dembner can be reached at Dembner@globe.com.