What Killed Alexander the Great?

In 323 BCE, Alexander the Great died suddenly at the very young age of 32.  This month, more than 2,300 years later, Dr Katherine Hall of the University of Otaga in New Zealand gives a very strong argument that he died of nerve damage from Guillain-Barré Syndrome (The Ancient History Bulletin, 2018;32(3):106-128).  
Alexander never lost a battle and was one of the most successful military commanders of all time. He was born in 356 BCE and was tutored by Aristotle until he was 16. By age 18, he led large armies in battle. At 20, he became king of Macedon, a state in ancient northern Greece, after the assassination of his father, Phillip II. At 22, Alexander's forces crossed into Asia. By age 30, he had reached the edge of the known world (modern India), to form an empire that stretched from today's Albania to eastern Pakistan, the largest empire of the ancient world. He founded Alexandria in ancient Egypt and more than 20 other cities that were named after him, bringing successful commerce to the entire region. 
How Did He Die?
Alexander had been quite healthy up to age 32, when he hosted a feast in memoriam for the death of a close personal friend.  That evening, after a day of drinking 12 pints of wine, his muscles started to hurt, his stomach started to cramp and he felt exhausted. Over the next few days, his belly felt better but hurt when it was touched.  Then he developed severe chills, sweating and high fever, and was exhausted, lost his appetite and developed diarrhea. On the eighth day of illness, he had an extremely high fever, was unable to speak, was paralyzed and could move only his eyes and hands. His doctors noted that he was sweating heavily and responded to questions only with slight movements of his eyes and hands. On the 11th day of his illness, he started to breathe shallowly, passed out and died. 

Ruling Out Causes of Death
Alexander's contemporaries thought he might have been poisoned, and many other theories on his death have been offered over the years.  I have reviewed the descriptions of his symptoms from the multiple reports on his death written by his contemporaries.  Based on our modern medical knowledge, he did not die from: 
Alcohol Poisoning or Alcoholic Liver Failure: Alcohol poisoning almost always causes continuous vomiting, but I could find no mention anywhere of nausea or vomiting. His illness started after drinking a huge amount of alcohol, but he did not die of liver failure caused by alcohol because that would not explain his fever, belly pain or diarrhea, which point to an infection in his intestines. 
Pancreatitis: One medical article suggested that he died of pancreatitis because of his many years of heavy drinking (J Clin Gastroenterol, 2007;24 (4): 294-296), but that would not explain the acute onset of paralysis.
Typhoid fever: A likely diagnosis was that he was infected with a bacteria that causes diarrhea. The one diarrhea germ that classically causes very high fever and a slow pulse rate is typhoid fever. Typhoid bacteria can punch holes in the intestines to allow fluid to pour from inside the intestines outside into his belly, which would cause severe belly pain, particularly when the abdomen is touched and released. Doctors call this “rebound tenderness”. Typhoid fever also can cause paralysis of the arms and legs (Guillain Barre syndrome), but typhoid fever usually occurs in epidemics, not in isolated cases, because it is usually transmitted by contaminated water. There is no evidence anywhere to suggest an epidemic of  typhoid fever in the region where he died.
West Nile Encephalitis:  When Alexander entered Babylon, ravens fell dead from the sky, and historians said that was an omen to predict that Alexander himself would die. More recently, researchers reported that the ravens could have died from West Nile encephalitis (Emerg Infect Dis, Jul, 2004;10(7):1328–1333), a virus that is spread by mosquitoes and could also have infected Alexander.  However, he was rational right up to the time he died, so it is extremely unlikely that he died from a virus infecting his brain.
Malaria: This disease is caused by a parasite that is transmitted by mosquitoes, but it spreads in tropical jungle areas, not in desert regions such as Babylon (modern central Iraq) where Alexander died.
Poisoning by a rival: A known poison such as strychnine could have killed him, but there was no evidence of any conspiracy to overthrow him in his very successful army. 

Clues for a Correct Diagnosis
Infection in his belly: He had terrible belly pain, so severe that he would not let anyone touch his belly, and very high fever and diarrhea. He was thirsty, had all of the symptoms of a high fever, and became delirious.  The fluid inside his intestines was probably loaded with bacteria that spread with the intestinal contents into his entire abdomen, then into his bloodstream, causing his blood pressure to drop to zero, shock and death.
Guillain-Barré Syndrome: He developed a progressive, equal-on-both-sides, ascending paralysis, with no signs of brain damage such as confusion or unconsciousness.  Although he could still move his head and arms, he could not talk, and eventually he became very short of breath. The diffuse nerve damage of Guillain-Barré syndrome is an auto-immune disease that is neither contagious nor inherited.  His immune system would produce huge amounts of cells and chemicals to kill the germ that invaded his intestines.  As the infection progressed, his immunity would lose its ability to tell the difference between his own nerves and the germ, so these same cells and chemicals attacked and destroyed the nerves located outside his brain and spinal cord. Usually the patient recovers, but in Alexander's case, his immune system probably destroyed the nerves that control breathing and he smothered to death. 
The recent article on Alexander's death proposes that Campylobacter pylori was the germ most likely to have caused him to suffer from  Guillain-Barre syndrome (The Ancient History Bulletin, 2018;32(3):106-128).  Since he was rational and coherent right up to the time of his death, this infectious agent was not likely to have affected his brain.  Infection with Campylobacter pylori is an intestinal germ, spread by eating contaminated food, that would explain his symptoms of belly pain and diarrhea.  This infection is still very common today. Alexander the Great could not have been saved then, but could be saved today with an antibiotic (NEJM, June 1998;338 (24):1764-1769).
Why Didn't Alexander's Body Decay?
His body was reported not to have decayed for six days after he died, and the ancient Greeks thought that this proved that Alexander was a god.  A more likely explanation is that his doctors thought he died up to a week before he actually died.  At that time doctors did not understand how the heart circulates blood through the body.  Furthermore, they had no machines to help them take a person's pulse to measure heart rate, so they checked whether a person was still alive by counting the rate that a person breathes and diagnosed death when a person stops breathing.  Guillain Barre syndrome can reduce a person's need for oxygen to slow breathing considerably.  It also can damage the nerves that stimulate the breathing muscles including the diaphragm to help you breathe.  Most likely he would breathe at a very low rate or periodically not breathe at all.  The doctors at that time interpret his irregular breathing as a sign that he was dead.  They did not check his pulse to show that he was still alive.  They also did not know that he was not yet dead because his pupils were not fixed and dilated.

Then and Now
If Alexander the Great suffered from a Campylobacter infection today, he could probably have been cured by taking the appropriate antibiotic.  However, today we still have no effective treatment for Guillain-Barre syndrome.
Alexander III of Macedon
July 21, 356 BCE - June 11, 323 BCE

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