Causes of Jane Austen's death

The causes of Jane Austen's death, which occurred on July 18, 1817 at the age of 41, following an undetermined illness that lasted about a year, have been discussed retrospectively by doctors whose conclusions have subsequently been taken up and analyzed by biographers of Jane Austen, one of the most widely read and acclaimed of English writers.

The two main hypotheses are that of Addison's disease, put forward in 1964 by the English surgeon Zachary Cope (1881–1974), and that of Hodgkin's disease, first mentioned concisely the same year by Dr. F. A. Bevan, then developed and argued in 2005 by the Australian Annette Upfal, professor of British literature at the University of Queensland.

The discussion is based primarily on Jane Austen's writings on her own clinical case. It does not rule out the possibility of tuberculosis, which was the usual etiology of Addison's disease in the 19th century.

Case history
The story of Jane Austen's illness has been reconstructed by Annette Upfal, who indicates at the end of her work that she has received the approval of Australian immunologist Ian Frazer.

Jane Austen was born four weeks postterm. In childhood and young adulthood, she suffered from serious infections: typhus, which it has become conventional to claim she "almost died" of at the age of seven, while attending Mrs Ann Cawley's school in Southampton; chronic conjunctivitis; whooping cough, which occurred at the age of 30 and was considered "unusually severe"; and otitis externa (side unspecified), in 1808, treated by applying sweet almond oil to the external auditory canal. In 1813, she repeatedly showed signs of facial neuralgia (attributed by A. Upfal to trigeminal shingles) severe enough to force her to appear in public with "a cushion pressed to her face" ("Jane was a very private person, and the pain must have been intense for her to walk out in public with a cushion pressed to her face"). Towards the end of the winter of 1815, she began to complain of generalized pruritus, without a rash.

The onset of her fatal affliction is generally placed in the early months of 1816, around her fortieth birthday, when it became clear to those around her that she was seriously ill. Her troubles consisted of insidious weakness, asthenia and progressive wasting. She had frequent "bilious attacks" (vomiting) and her face changed color, becoming "black and white". From February 1817, she was subject to regular bouts of high fever, during which she sometimes lost consciousness. She died during one of these attacks.

Symptom analysis
The retrospective diagnosis of the illness that led to the novelist's death is based on the following symptoms and clinical signs, which relate only to the last year of Jane Austen's life. This symptomological inventory is largely based on the work of Cope and Upfal.

General signs
All the authors emphasize the rapid deterioration in the patient's general condition, with weight loss and weakening in the space of a few months. Asthenia was severe, and brief fainting spells occurred regularly. Febrile attacks lasting several days were observed intermittently from February 1817 onwards. On the other hand, frequent "attacks of bile" are mentioned in Jane Austen's letters, and probably refer to nausea and vomiting.

Cutaneous signs
In her letter to Fanny Knight dated March 23, 1817, Jane Austen referred to the color of her skin, which had darkened in places. There is little evidence, however, as to the exact mechanism of this color change, which may correspond either to hyperpigmentation as part of melanoderma, or to spontaneous subcutaneous hemorrhages (petechia or ecchymoses).

Speculative differential diagnosis
All authors agree that sources on Jane Austen's final illness are too limited to allow a diagnosis of certainty. Her doctors left no notes, and her family spoke only reluctantly of her illness. Moreover, her most informative letters were destroyed by her sister Cassandra after her death. Cope asserts that Jane Austen was an accurate observer, and although to the end she downplayed her health problems, her formal statements can be trusted. In addition to Jane Austen's own observations, Cope consulted the recollections of one of the patient's nieces, Caroline Austen, as well as an 1817 letter written by Cassandra Austen and addressed to Fanny Knight.

Addison's disease


This diagnosis was proposed in 1964 by a famous surgeon, Sir Vincent Zachary Cope, in a short two-page article published in the British Medical Journal. The disease referred to a chronic progressive adrenal insufficiency, and was described in 1855 by the Englishman Thomas Addison, who gave it his name, Addison's disease. The cardinal signs included asthenia, low blood pressure, anorexia (with weight loss) and melanoderma, with hyperpigmentation of the skin at friction points and of the mucous membranes. Only the latter sign was specific to the disease, and Zachary Cope underlined the fact that melanoderma was not always uniform, and that "in some cases the dark patches of the skin were mingled with areas showing a lack of pigment – a true black and white appearance". Skin coloration was of particular importance, as it was the only clinical feature distinguishing Addison's disease of the adrenals from another "Addison's disease" (described by the same author six years earlier, in 1849), which corresponded to a hematological condition better known today as pernicious anemia and by its other eponymous name, Biermer's disease. Anemia often causes pallor and, in "Addison's anemia", a discolored appearance of the skin is normally to be expected, i.e. the opposite of the bronzed appearance usually seen in "Addison's adrenal insufficiency". Cope concluded: "There is no disease other than Addison's disease that could present a face that was "black and white" and at the same time give rise to the other symptoms described in her letters."

However, important associated signs that do not belong to the classic picture of Addison's disease remain poorly explained, as Claire Tomalin, with the medical endorsement of Dr. Eric Beck, Fellow of the UK Royal College of Physicians, was quick to point out. Cope believed that the presence of fever was due to the rapid progression of the disease, and pointed out that "back pain was noted in Addison's disease by several observers".

The main Jane Austen biographers to support Cope's hypothesis were Jan Fergus, and Deirdre Le Faye. In recent years medical opinion has put forward the theory, based on Jane's own description of her symptoms, that early in 1816 she fell victim to the then unrecognized Addison's Disease. Finally, some academics, such as Australian English literature professor John Wiltshire in his book Jane Austen and the Body (1992), also advocated Addison's Disease.

Hodgkin's disease
Defined histopathologically by the presence of Reed-Sternberg cells in the lymph nodes, it was historically the first human lymphoma to be precisely described, by the English pathologist Thomas Hodgkin (1798–1866). Hodgkin was a contemporary and colleague of Addison's at Guy's Hospital in London.

The possibility of Hodgkin's disease in Jane Austen was first raised by F.A. Bevan, only one month after the publication of Cope's article in the British Medical Journal, in the form of a short 22-line reply in which this general practitioner provides no argument other than the recollection of a personal case in which the disease ("lymphadenoma"), proven by biopsy, had had as its initial manifestation a "pain in the back" without any superficial lymphadenopathies being noted during the course.

The hypothesis that Jane Austen died of Hodgkin's disease was taken up and defended 41 years after Bevan by an Australian academic, Annette Upfal, with the medical support of her compatriot, immunologist Ian Frazer. In her argument, she cites a possible history of infectious mononucleosis ("Glandular fever"), which could have been contracted following kisses that some letters written by Jane in her twenties suggest she might have given to suitors: indeed, this viral disease is known to be sometimes associated with the later development of Hodgkin's disease. Certain clinical manifestations can also be interpreted as heralding this disease, such as the onset of facial neuralgia in 1813, presumably following shingles, and the episode of intense pruritus at the beginning of 1815. But it is above all the cyclic fever characteristic of the terminal period of Jane Austen's illness that receives its best explanation, being assimilated to Pel-Ebstein fever, classic (but of disputed specificity) in the advanced stages of Hodgkin lymphoma. However, A. Upfal was forced to appeal to a rare complication of Hodgkin's disease, thrombocytopenic purpura, to explain such dramatic changes in Jane Austen's skin coloration.

Brill-Zinsser disease
This recurrent form of typhus was described in the 20th century by two Americans, first clinically in 1910 by physician Nathan Brill (1860–1925), then formally linked to its cause in 1934 by bacteriologist Hans Zinsser (1878–1940). Brill-Zinsser disease is usually mild, resembling an attenuated form of epidemic typhus, with circulatory, hepatic, renal and central neurological disorders. The fever episode lasts 7 to 10 days. The rash is very mild, if not completely absent. There are, however, severe forms of Brill-Zinsser disease that can lead to death, and which, according to Linda Robinson Walker, are included in the differential diagnosis of the causes of Jane Austen's death. Arguments in favor of this hypothesis include a history of severe typhus in childhood, digestive disorders ("bile"), skin signs (discoloration) and recurrent febrile attacks interspersed with free intervals. According to L. Robinson Walker, this hypothesis was dismissed by Jane Austen's doctors because, at the time, resurgent forms of typhus were unknown and it was thought that typhus, like typhoid, conferred a definitive immunity on the patient who survived it (an opinion later defended by Charles Nicolle in 1928 in his Nobel Prize acceptance speech).

Tuberculosis
Tuberculosis can affect the adrenals, causing Addison's disease. It commonly causes attacks of intermittent fever, and it can also affect the digestive organs, giving rise to "tabes mesenterica", a hypothesis briefly considered (but ultimately dismissed) by Cope to explain "gastrointestinal attacks". Annette Upfal pointed out that the autopsy demonstrated the association of tuberculosis with Hodgkin's disease in 20% of cases. A diagnosis of tuberculosis in Jane Austen (of which Addison's disease of the adrenals would have been one of the consequences) therefore in no way precludes the coexistence of Hodgkin's disease, and would reconcile Cope's and Upfal's respective points of view. Park Honan's analysis in Jane Austen: A Life (1987) supports this view.

Other hypotheses
In addition to digestive tuberculosis, Cope's work considered various diagnostic hypotheses:


 * pernicious anemia (Addison's) to explain the pallor and asthenia;
 * stomach cancer, to explain the digestive disorders, deteriorating general condition and weight loss;
 * myasthenia to explain the fluctuating fatigue and weakness (but he noted that there were no records of any difficulty in speaking, chewing or swallowing).

These various hypotheses were refuted in the discussion as failing to explain the changes in skin coloration. Cope cited Jane Austen's letter of March 23, 1817 to Fanny Knight, in which she reported some improvement in her condition: as she put it, "I have recovered some of my appearance, which has been rather ugly, black and white and all colors askew".