I love these historical analyses of disease–real, or fictional. One historical event that has been the subject of much speculation over the decades has been the Plague of Athens, a mysterious outbreak that is thought to have changed the direction of the Peloponnesian War, and for which the cause still remains uncertain:
 As a rule, however, there was no ostensible cause; but people in good health were all of a sudden attacked by violent heats in the head, and redness and inflammation in the eyes, the inward parts, such as the throat or tongue, becoming bloody and emitting an unnatural and fetid breath.
 These symptoms were followed by sneezing and hoarseness, after which the pain soon reached the chest, and produced a hard cough. When it fixed in the stomach, it upset it; and discharges of bile of every kind named by physicians ensued, accompanied by very great distress.
 In most cases also an ineffectual retching followed, producing violent spasms, which in some cases ceased soon after, in others much later.
 Externally the body was not very hot to the touch, nor pale in its appearance, but reddish, livid, and breaking out into small pustules and ulcers. But internally it burned so that the patient could not bear to have on him clothing or linen even of the very lightest description; or indeed to be otherwise than stark naked. What they would have liked best would have been to throw themselves into cold water; as indeed was done by some of the neglected sick, who plunged into the rain-tanks in their agonies of unquenchable thirst; though it made no difference whether they drank little or much.
 Besides this, the miserable feeling of not being able to rest or sleep never ceased to torment them. The body meanwhile did not waste away so long as the distemper was at its height, but held out to a marvel against its ravages; so that when they succumbed, as in most cases, on the seventh or eighth day to the internal inflammation, they had still some strength in them. But if they passed this stage, and the disease descended further into the bowels, inducing a violent ulceration there accompanied by severe diarrhea, this brought on a weakness which was generally fatal.
 For the disorder first settled in the head, ran its course from thence through the whole of the body, and even where it did not prove mortal, it still left its mark on the extremities;
 for it settled in the privy parts, the fingers and the toes, and many escaped with the loss of these, some too with that of their eyes. Others again were seized with an entire loss of memory on their first recovery, and did not know either themselves or their friends.
This plague has been attributed to bubonic plague, toxic shock syndrome and/or necrotizing fasciitis due to Streptococcus pyogenes or Staphylococcus aureus, Salmonella, yellow fever, malaria, Ebola, influenza, and smallpox, to name just a few. Typhus seems to fit the description best, but it’s likely that a cause will never be known with certainty.
In the summer of 1485, a rapidly fatal infectious fever struck England: “A newe Kynde of sickness came through the whole region, which was so sore, so peynfull, and sharp, that the lyke was never harde of to any mannes rememberance before that tyme.”
Sudor Anglicus, later known as the English sweating sickness, was characterized by sudden headaches, myalgia, fever, profuse sweating, and dyspnea. Four additional epidemics were reported in the summers of 1508, 1517, 1528, and 1551, after which the disease abruptly disappeared. Contemporary observers distinguished the condition from plague, malaria, and typhus. Later suggestions included influenza, food poisoning, an arbovirus, and an enterovirus as possible causes.
(For the record, the authors suggest a rodent-borne virus, such as a hantavirus, as a potential causal agent.)
Historical diagnoses aren’t limited to epidemics; historical figures are also fair game. Those of you familiar with the story of how Jeffrey Taubenberger eventually came to sequence the 1918 influenza virus probably know that it all began with an investigation of chemist John Dalton’s eyeballs. Dalton was color-blind, and left instructions that, upon his death, his eyes be preserved and examined to figure out why he saw the world differently than everyone else. A 1995 Science paper found that Dalton was a deuteranope; that is, he had trouble discriminating small differences in hues in the red, orange, yellow, green region of the spectrum. And while Dalton may have wanted to know what ailed him, it’s likely that Shakespeare never expected the suggestion made in this paper published almost 400 years after his death that the Bard had syphilis.
And don’t think fictional characters and epidemics are off the hook just because, y’know, they’re not real or somethin’. A 1989 Journal of the American Medical Association paper concluded that porphyria was the disease that caused the fall of Edgar Allan Poe’s house of Usher. And a few years ago, a paper in Emerging Infectious Diseases explored the idea that Poe may have been inspired by Ebola or another hemorrhagic fever for his short story, “The Masque of Red Death.”
Now, in the current issue of Clinical Infectious Diseases, Norton et al. suggest that Macbeth may be an account of an early prion disease.
Macbeth’s descent into madness often elicits psychological interpretations, but he experienced neurologic and cognitive deterioration as well. This brings into question whether a psychiatric disorder alone could fully account for his condition. Any patient today, particularly one from Scotland, presenting with a similar rapid decline in neurologic, psychiatric, and cognitive function, accompanied (as in Macbeth’s case) by involuntary movements, hallucinations, and insomnia, would require an evaluation for variant Creutzfeldt-Jakob disease.
They even have a whole table dissecting the passage, sign or symptom described, and prion diseases that share these symptoms. Does it get any better than this?
Although we contend that Macbeth’s presentation is compatible with a spongiform encephalopathy, no evidence corroborates that this is what Shakespeare intended. Nevertheless, Shakespeare showed an uncannily prescient understanding of prion disease transmission via exposure to neural tissues: “[Once], when the brains were out, the man would die / And there an end; but now they rise again / With twenty mortal murders on their crowns” (3.4.78-80). Conceivably, Macbeth was exposed to infectious prions during an early encounter with the weird sisters, whose necromantic brews contained a variety of human and animal organs. Proclaiming, “Round about the cauldron go / In the poison’d entrails throw,” (4.1. 4-5), they added, for example, a human nose and liver tissues that are capable of carrying infectious prions. It is not clear that anyone consumed the witches’ brews, but if Macbeth had, that could explain the exposure. Furthermore, Shakespeare foreshadowed current culinary controversies in prion disease epidemiology by warning his audiences to “eat our meal in fear” (3.2.17) until the time when “we may again / Give to our tables meat” (3.6.33-34). (A character in Twelfth Night declares “I am a great eater of beef, and I believe that does harm to my wit” [1.3.85-86]).
Just another reason to study those classics…you never know what you might glean from them.