Nearly two centuries after King George III famously mistook a large tree for a Prussian king, peed red- and blue-tinged urine, and died blind, deaf, and mad, scientists are still finalizing his diagnosis.
In 1969, a mother-and-son team of psychiatrists with a penchant for diagnosing deranged, dead celebrities suggested that the king suffered from a hereditary disorder called porphyria. The diagnosis stuck, and the British king's legacy brought fame to the rare metabolic disease -- though it remained hotly contested.
Other possibilities have been floated over the years, too: the king who sat on the throne when the United States earned its independence could have had manic-depressive psychosis, or even pent-up sexual frustration -- the theory is that after being forced to marry an ugly German princess, the king, as a ''God-fearing man, had to remain faithful . . . and that put him over the edge," said Martin Warren, a biochemist at Queen Mary, University of London.
Now, using modern forensic techniques on a two-inch lock of the king's hair and retracing the royal family tree, Warren and his colleagues have uncovered further evidence that the king likely suffered from porphyria, which even today is frequently mistaken for mental illness -- and a possible explanation for his unusually long, severe episodes of madness. Their analysis, published late last month in the British medical journal, The Lancet, implicates arsenic -- a heavy metal known to aggravate and even trigger episodes of the disease.
The arsenic, researchers wrote, was probably a contaminant in his medications, meaning that as the royal physicians attempted to cure the king of his porphyria -- they may have been making him much worse.
''Of course, postulates such as this one are of the armchair variety," and not provable, but the paper is ''provocative," said Dr. Peter Tishler, a professor at Harvard Medical School, and a member of the advisory board of the American Porphyria Foundation. He has long been skeptical of King George's diagnosis.
Porphyria is a complicated diagnosis: Even today, the disease is nicknamed ''the little imitator" because it looks like dozens of other diseases on first examination. The genetic disorder interferes with metabolism, causing acute abdominal pain, muscle weakness, confusion, and red-tinged urine, which seems to have affected several of the king's offspring and relatives.
To support their diagnosis, researchers drew on the royal physicians' reports from the 1780s until the king's death in 1820: They were giving the king medications that -- unbeknownst to them -- commonly contained arsenic.
''His Majesty's medicine was given him by force at seven o'clock and this has certainly contributed to his irritation and irascibility which has prevailed ever since," one note from 1811 reads.
Nonetheless, controversy continues. Wilfred Niels Arnold, a biochemistry professor at the University of Kansas Medical Center who has written several papers suggesting that the impressionist painter Vincent Van Gogh had porphyria, said he is skeptical of the new claims. He believes the arsenic found in the hair may have been an external preservative and that several of the king's medications could have triggered episodes of porphyria. In an e-mail, he called the paper ''one of the worst so far in this field," because many of the king's medicines contained different compounds that could have triggered attacks of porphyria.
Like other subjects of ''pathography," a field of science that reconstructs illness long after a person has died (posthumous medical diagnoses have been offered in books whose titles include ''The Health of Presidents," ''The Madness of Kings," and ''Medical Biographies: The Ailments of Thirty-three Famous Persons") King George III has long excited both medical and historical curiosity -- although researchers cheerfully agree that such medical mysteries are ultimately unsolvable.
The king's madness often overshadows his most important achievements and his great failure: the expansion of the British empire, the defeat of Napoleonic France, mastery of the oceans, and the loss of the American colonies. Despite efforts to put one of the king's sons in power during a particularly debilitating episode of madness in 1788, King George was able to recover from the early episodes of derangement, and was one of Britain's longest serving monarchs. His oldest son, later King George IV, served as regent during his father's last nine years on the throne.
Disagreements over what felled long-dead celebrities may seem pointless, since such belated diagnoses aren't likely to illuminate much about how diseases work, and the dead can't campaign on behalf of their illness as Michael J. Fox has done for Parkinson's disease and Lance Armstrong for cancer. But their influence on modern medicine can't be discounted.
''It's interesting and instructive, and perhaps it explains something of where we're from," Tishler said, who sees patients who suffer the same fate as King George: given a wrong treatment that actually triggers a debilitating attack. ''Like a lot of history, we'd rather not repeat the mistakes of yesterday."
Carolyn Y. Johnson can be reached at firstname.lastname@example.org.