A Case Report from the Ancient Past.

BACKGROUND Standard translations of Hippocratic works are sometimes misleading because the translators knew less about their subject than did the ancient authors. CASE REPORT A new translation and explication of a chapter from a Hippocratic work of the fifth century before the Common Era (BCE), Diseases II, describes patients with pituitary apoplexy and subsequent myxedema, the 2 events separated by as much as 14 years. CONCLUSIONS The association of myxedema with an intracranial event that occurred years earlier predates by 2400 years the causal association of a pituitary adenoma with hormonal deficiency.

Background

Many clinical works attributed to Hippocrates (460–380 BCE), venerated for over 2 thousand years, are now all but forgotten. Popular textual references on clinical content have been to classic translations from the Greek, most notably by Dr. Emile Littre (1801–1881) in France and Dr. Francis Adams (1796–1861) in Scotland [1,2]. Both were trained in medicine and both published in the mid-nineteenth century when scientific truths were beginning to flood the medical world, but their translations retained many elements of medieval interpretation and vocabulary. Some recent translations of Hippocratic passages by medical specialists suggest, however, that ancient Hippocratic physicians were more observant and prescient than were their translators until well into the twentieth century [3-6].

This paper presents a new translation of a single short chapter selected from the Hippocratic treatise, Diseases II, a work that, focusing on internal medicine, contains much that, on cursory reading, seems to elude common sense. Chapter 12 of Diseases II shares that shortcoming, but when parsed more carefully reveals a syndrome associated with pituitary tumors. Validity of the present translation is supported by a recent neurosurgical interpretation of chapters 14 and 15 of Diseases II as representing a credible diagnosis and surgical management of an otitis-related brain abscess [7,8].

Case Report

(As translated by the author from the Greek of the 1538 Froben edition of the works of Hippocrates [see Appendix]).

Diseases that develop from the head

Whenever it becomes full and it happens that it becomes heated from something, hypesthesia grips the head, and the patient must urinate all the time. Otherwise he suffers as if he had strangury. After 9 days of these symptoms, should something like water or dribble drain from the nose or ears he will recover from the disease and the strangury ceases. By day 20 he then will urinate a lot without difficulty and the urine will be pale. And the distress emanating from the head then remits, but should the eyes be looked into, the gleam [of the eyes, glint] is absent and the patient sees faces from only one side. By 40 days he becomes completely healthy.

In many the disease sometimes gradually recurs 7 to 14 years later; the skin of the head is thicker and exhibits edema. Despite little food the skin appears soft and of a good complexion, but auditory acuity is decreased.

Whenever you come across a patient with these problems early in the course of the disease before there is watery drainage down from the nose and/or ears, and if there is the same discomfort [of the head], it is necessary to shave the head and then tie a leather flask filled with water as hot as tolerable to the forehead, refilling the flask when it cools down. But if the patient becomes too weak, leave off for a while but do it to him [continue it] until the tenderness eases. If the patient is constipated, use an enema and hydrate him … [remainder of paragraph irrelevant].

And during that time if there is watery drainage from the nose and the urine is concentrated [viscous] but the discomfort [of the head] is easing, the flask on the head is no longer needed, but [have him] drink the well-washed and warmed diuretic with diluted honey. … [remainder of the paragraph irrelevant].

Should the disease recur, give the patient a vapor bath and in the morning give him some hellebore to drink; and after an interval of whatever you think might be the [right] time, cleansing the head, give a lower medicine [probably a laxative], and scarify the head in 8 places, 2 near the ear, 2 on the forehead, and 2 posteriorly on the head on each side over the occiput, and 2 by the nose near the inner canthus of the eye. Then burn [to seal] the blood vessels near the ears until the pulsations stop; do this with wedged hot irons, to cauterize across the vessels. In doing this the patient becomes healthy.

Discussion

The patient proposed by the examiner presents with facial numbness and headache and might have had a purulent sinusitis or otitis media eased by spontaneous drainage of pus. But the problem is more complex. The facial numbness (anesthesia or hypesthesia) suggests cranial nerve V involvement and, because of urinating “very much” and “much and easily,” the patient may have had antidiuretic hormone (ADH) deficiency. Strangury is mentioned, but, in contrast to polyuria, strangury is associated with voiding of small amounts of urine. It is likely that the term “strangury” was used here by the examiner because the patient had a feeling of urgency to urinate caused by frequent bladder distention rather than bladder or urethral irritation associated with the hesitancy, sense of incomplete voiding, and straining at urination that defines strangury. A week or so later such a patient can have a watery trickle from the nose or ear, not descriptions that would suggest purulent drainage. The facial numbness and headache then disappear, but the urine remains plentiful and pale (of low specific gravity), suggesting ongoing diuresis of a hypotonic urine, but urinary urgency has ceased. At this point the patient is developing a cranial nerve palsy, for on looking into the eyes the normal positioning of the corneal light reflex apparently is not seen by the examiner, indicating asymmetry of gaze has now developed. Concurrently the patient has developed a visual field defect. Diagnostic visual field testing was yet to be invented, and the description that such a patient might see only one-half of faces is probably an incorrect interpretation by the examiner. Visual field cuts are common with pituitary tumors. They tend, however, to be bitemporal hemianopias, and a homonymous hemianopia is possible but rare. Central scotomas, however, are frequent. These might have produced an image interpreted as “half a face” [9]. Despite these symptoms the patient was judged healthy a month or so later.

Years later some symptoms described might recur, but now such a patient can have thickened skin of the face that compresses with fingertip pressure. It is proposed that the patient has developed myxedema. Along with the skin changes, his hearing is diminished and there is a decrease in caloric requirements, both often present in advanced hypothyroidism. A “good” complexion is not how modern physicians would describe the advanced hypothyroidism facies, for the skin tends to be dry and some sallow pallor is often present, but in older textbooks the classical description of hypothyroidism can include a “peaches and cream” complexion. Furthermore, pallor may have seemed less obvious in a Mediterranean population. Hypothyroidism is more likely than anasarca to explain the skin changes, for edema is not described as pitting (a distinction made in another Hippocratic work), and dependent edema, ascites, and generalized tissue edema are not described[1]. There is a suggestion of chronicity as weakness developed in the intervening years, a vague symptom, but one consistent with hypothyroidism and not attributed to a new problem. Years later, should the proposed patient have another exacerbation, the recommendation is scarification and cautery of superficial vessels of the head, thus following the usual Hippocratic practice of surgery as a last resort.

The probable cause of such a relatively acute clinical sequence in an adult is pituitary apoplexy. Hormones that might be affected include ADH, oxytocin, and any or all of the anterior pituitary hormones such as thyroid-stimulating hormone and adrenocorticotropic hormone. The role of ADH is postulated as follows: when first seen, the patient’s pituitary tumor was impairing ADH release from the posterior pituitary, which explains the increased urination. Nine days later (after consulting the physician?) a cerebrospinal fluid (CSF) leak occurred, one consequence being a decrease in intracranial pressure either generally or locally, and this, perhaps with a decrease in tumor size from infarction, led to cessation of the headache and a concurrent decrease in pressure on the hypothalamus or posterior pituitary that permitted a correction of the impaired ADH release. Urine output, therefore, could have transiently decreased, presumably for a few days, and been viewed as normalized by day 9. Alternatively, the syndrome of inappropriate ADH secretion (SIADH) or an element of adrenal or thyroid insufficiency might have masked ADH deficiency, thus mimicking an improved ADH status [10]. Once the CSF leak spontaneously ceased, which often occurs, the effect of local pressure on the mechanism of ADH release returned, for 11 days later there is extraocular muscle impairment, a visual field defect, and resumption of diuresis. Although tumor effects reappeared, the discomfort of the head did not.

Hippocratic treatment is given in 3 phases. In phase 1, prior to the nasal drainage, the symptoms of headache, hypesthesia, constipation, and polyuria are treated with local heat, hydration, and laxatives. Application of localized heat to the head may have been prescribed to promote drainage and ease pain, just as hot compresses were thought to do when applied to abscesses. Fortuitously, nasal drainage appeared and some symptoms abated. The alternative of ear drainage is inconsistent here and may have been merely inferred by the examiner from experience with trauma-induced CSF leaks. In phase 2, therefore, hot compresses were discontinued, and mild cathartics started. In phase 3, efforts now shift to scarification and cautery, presumably because it has been decided that no medicinal therapies are effective against the late manifestations of the underlying problem, which, quite remarkably, is still considered to be in the head.

Of the more than 70 works listed under the sobriquet of “Hippocrates,” most were written between 450–350 BCE. Many are notable for their brevity and sparse commentary, more like quick clinical notes than prolix sophism of the philosophers. In the words of Dr. W. H. S. Jones, translator of the first 4 volumes of the Loeb Classical Library series on the works of Hippocrates, “Not a word is thrown away” [11]. There is no unanimity of opinion that a medical personage now hailed as Hippocrates ever existed, and scholars are convinced that the Hippocratic works are the product of many authors. The clinical case presently under discussion nonetheless inhabits a niche in history to which its credibility can be appended, namely, confidence in the approximate dates of its production, mid-fifth century BCE, and confidence that its authors were clinicians that as a group can be designated “Hippocratic.”

The final diagnosis of the present case report is postulated to have been a nonfunctioning pituitary tumor with infarction or hemorrhage, still quaintly termed “pituitary apoplexy,” and subsequent hypothyroidism. But the correctness of the diagnosis is of less interest than the implication that the same patient, or perhaps 2 or 3 patients from whom the clinical sequence was put together, was under medical observation for as long as 14 years, thus allowing what likely was advanced hypothyroidism to be postulated as a consequence of the much earlier event affecting the head. If true, the continued personal involvement of one or more local physicians with one or more patients over such a long time suggests a stability of Hippocratic medical practice, a continuity of care, and a method of data collection/preservation that would seem without parallel in ancient times. Support for this inference is provided by other Hippocratic works describing situations where acute events and later, seemingly unrelated, phenomena were considered one illness, such as diphtheria and its paralytic effects, relapsing spirochetal fevers, and the association of “critical days” with physiological responses to pathogens [12].

Seemingly healthy after a month and a half, the patient was assessed as “cured,” just as he was following cautery and scarification. Yet when reassessed 7 years later, primary hypothyroidism was developing. It does underscore the fact that many of the patients identified in Hippocratic clinical works who are claimed to have been “cured” were, in fact, not cured. Their later consequences may not have been known to the initial physician because of the peripatetic nature of his practice or because the patient died or moved from the region prior to the arrival of a subsequent physician who would be unaware of the ultimate outcome. In the present case, continuity of care appears to have covered as much as 14 years, although one might suppose that the physician who scarified and cauterized the patient’s head promptly left town after pronouncing the patient as cured.

The question remains, how could the course of such a protracted illness be described in terms that suggest similar illnesses had been seen by Hippocratic physicians, thus allowing for a filling in, over time, of clinical events covering 14 years? The prevalence of “clinically relevant” pituitary tumors in Belgium has been reported to be 1 per 1000 persons[2] [13,14]. About one-half were nonfunctioning. If an ancient Greek city-state contained 10 000 persons who might have been visited by Hippocratic physicians (excluding slaves and foreigners who would not have been their patients), several nonfunctioning pituitary adenomas might have been present at any given time if the epidemiology of pituitary disease were similar to the present day, and, as there was no effective treatment, that number, because of case accumulation, may have been even higher. The prevalence of pituitary apoplexy in a defined population in southern England was about 6 cases per 100 000 population, or somewhat less than 1 patient per year at any given time in the proposed city-state [15,16]. If classical pituitary apoplexy and hypothyroidism are both to be included, the situation is even more uncommon. On the other hand, if mild forms of pituitary apoplexy are included, such cases would be more common, although it is uncertain as to what degree [17]. Assuming a standardized incidence ratio approaching 2 patients with pituitary apoplexy per 100 000 population per year, of whom half become hypothyroid, this would equate to a case of hypothyroidism following pituitary apoplexy every 10 years. Given this statistical background, if a small group of medical professionals, perhaps 4 or 5 practitioners, periodically pooled their knowledge and experience over a generation, the assertions of Chapter 12 of Diseases II could claim epidemiological plausibility. Furthermore, it has been proposed that Hippocratic physicians could communicate with one another even though geographically dispersed [18].

Conclusions

While of clinical interest in itself, the 2 remarkable features of the physician’s report are 1) the association of clinical evidence of pituitary apoplexy and subsequent myxedema as manifestations of a single underlying disease process despite many years between the 2 events, and 2) the ability of early Hippocratic clinicians to maintain a written or oral record of one or perhaps several patients’ clinical history over those years that allowed them to make such an audacious assumption, one that would not be confirmed for 2400 years [19].