Alexander the Great, who ruled much of the ancient world until his death in 323 B.C., was conquered at age 32 not by an enemy, but possibly by a tiny intestinal bug.

In an analysis based on available historical records, physicians at the University of Maryland Medical Center believe that Alexander was the victim of typhoid fever.

Their analysis, titled, "A Mysterious Death," is published in the June 11 issue of the New England Journal of Medicine. The most popular theories among historians previously have been that Alexander was poisoned or had died of malaria.

In the week before he died, historical accounts say Alexander the Great had chills, sweats, exhaustion and high fever, all of which are typical symptoms of certain infectious diseases, including typhoid fever.

"He was also described as having severe abdominal pain, causing him to cry out in agony," says David W. Oldach, an infectious disease expert at the University of Maryland Medical Center and lead author of the article.

"That was an important clue, because untreated typhoid fever can lead to perforation of the bowel and may have been the reason for his abdominal pain," according to Dr. Oldach, who is also an assistant professor of medicine at the University of Maryland School of Medicine.

"My discussions with Dr. Oldach and his colleagues caused me to change my mind about what caused the death of Alexander the Great," says Eugene N. Borza. Ph.D., professor emeritus of ancient history who taught for 31 years at Penn State University. Dr. Borza, who is also an author of the New England Journal article, previously thought that malaria caused Alexander's demise.

A curious symptom described in ancient accounts is that Alexander's body did not begin to decay for at least several days after his death. Dr. Oldach says while that defies reason, those around him may have gotten that impression because of another complication of typhoid fever, called ascending paralysis. It is a neurological problem that starts with the feet and moves up the body, paralyzing muscles and slowing down breathing. It can make a person look dead, even if he is not. Alexander may have been in that state for a few days before he died.

Accounts of the death were not consistent with poisoning, although Dr. Borza says that has been a popular belief. "It was an ancient conspiracy theory. People have often suspected a conspiracy when a famous young person dies unexpectedly." Dr. Borza says ancient Greeks who didn't succumb to disease as a child or a battlefield wound often lived into their 70's, because of a healthy diet and constant physical activity.

The New England Journal of Medicine article is believed to be the first collaboration between medical scientists and an historian to answer an ancient question about what caused a famous historical figure to die. Dr. Borza says the earliest surviving accounts about Alexander's death available today were written three centuries after he died, so there was not a lot of information to go on.

"Even so, we found out that much of the scant information we do have is credible, because it makes sense to the medical community. It is important for us to be able to validate the evidence and set the record straight. As historians, that's what we try to do," says Dr. Borza.

For his analysis, Dr. Oldach also had to rely on historical medical accounts of what happens when typhoid fever goes untreated with antibiotics, which did not become available until the 1950's. U.S. physicians today rarely witness untreated patients in the late stages of typhoid fever.

Typhoid fever comes from salmonella typhi, an organism that lives only in humans and can be spread by contaminated water or because of poor hygiene.

The analysis of Alexander's death began as part of a regular meeting of University of Maryland Medical Center physicians, called the Clinical Pathologic Conference. It is an exercise in which a complex case is presented, and physicians discuss how they would make a diagnosis and determine the course of treatment.

"This was an effort to provoke thought and be a good teaching exercise," says R. Michael Benitez, M.D., a University of Maryland Medical Center cardiologist and assistant professor of medicine who is also a co-author of the article.

"This was a fun exercise designed to come up with a diagnosis that explains all the symptoms that were written by ancient historians. "We will never know for sure if this diagnosis is correct," says Dr. Oldach, who adds with a smile, "But I challenge someone to prove me wrong."