Enigmatic painful bladders and mysterious “ulcers” in the urinary bladder first appeared in medical publications in the early nineteenth century. Medical textbooks at the time drew a clear distinction between bladder neuralgia and bladder ulcers or lesions. However, by the beginning of the twentieth century, increasing use of the cystoscope may have led surgeons to focus on visible pathology, including ulcers and lesions, to the neglect of bladder neuralgia with invisible causes. Furthermore, Freudian theories prevalent at that period claiming women were “more prone to neurosis and hysteria” would have led to many women with urogenital pain being dismissed as psychosomatic and hysterical. While the original eighteenth to nineteenth century term “neurosis” referred to a neurological disorder, Freud’s version of neurosis inferred a psychological/hysterical disorder as used by Walsh in this book. This has regrettably been a cause of great harm to women and their health, particularly in urogenital fields, and has not entirely disappeared today.

In the nineteenth century, as noted by Walsh, “interstitial cystitis” was a term used to describe a non-specific pathologic condition with inflammation in interstitial tissue caused by many diseases, disorders or trauma. The first mention of this term (found so far) was by Samuel D. Gross in 1876. In Germany, however, Maximilian Nitze was writing about a bladder disorder with frequency, pain and inflammatory ulceration of the mucosa which he described as “cystitis parenchymatosa”, a term which was not to survive, but which was, however, used by Howard Kelly in 1898 to describe “when inflammation extends into the muscular vesical wall”.

The Johns Hopkins Hospital in Baltimore, opened in 1889, was a centre of excellence in the United States. Howard Kelly, head of the new gynaecology and obstetrics department and Guy Hunner’s boss, had a special interest in female urology and this laid the foundation for Guy Hunner’s work with patients with a painful bladder. Howard Kelly, who had travelled extensively in Europe, took the Nitze cystoscope back to the Johns Hopkins Hospital in Baltimore and developed his own air distension version. Kelly had an interest in what he termed the irritable bladder: “A differential diagnosis must be made between cystitis and an irritable bladder or a hyperemia of the trigonum. In an ‘irritable bladder’ there is no inflammation and there is no pus in the urine, and no inflammatory area is seen,” he wrote in 1922. He further noted that “the condition is dependent as a rule upon abnormal sensibility of the nerves of the bladder either at their ending or at some point in their course. With this anatomical basis a number of conditions bring about the disturbance which would not cause it in a healthy adult”. With regard to treatment, he recommended that “where the central nervous system is involved, the treatment should be directed towards this.” This was remarkably forward thinking at the time, bearing in mind that it is only in recent years that researchers have been investigating the “new” concept of central sensitization. Like others, Kelly had already discovered that “such items of diet as tomatoes, fruits, or acids, should be avoided when the patient finds that they aggravate her condition”.

When Guy Hunner joined Howard Kelly’s department, he consequently had every opportunity to study urological as well as gynaecological disorders in women. In 1899, Hunner was given leave by Kelly for a 4-month study visit to Europe to familiarize himself with the latest medical knowledge and insights. Endoscopy was now rapidly becoming all the rage in Europe, with the cystoscope opening up new horizons in urology. Eminent surgeons, including Hurry Fenwick in London, had published papers on perforating ulcers and simple solitary ulcers of unknown cause and this may have caught the interest of Guy Hunner. However, Hunner felt that most of the ulcers he was seeing differed from Fenwick’s simple solitary ulcers. Guy Hunner was the first person to publish a detailed report about painful bladders and to describe what he saw through the cystoscope, case by case. Since by 1930 Hunner wrote that he now had over 200 patients, he was considered the expert in this field in the United States. While he concentrated on ulcer and lesion pathology, Hunner did not forget patients with pain, urgency and frequency in whom the inside of the bladder appeared normal. His papers of 1915 and 1918 were seen as the “guideline” for many decades and consulted extensively. This is probably the reason why the term Hunner’s ulcer was passed down from generation to generation. Hunner reported in 1918 that his colleague Dr. Cullen had suggested the name “elusive ulcer” due to the difficulty in locating the ulcer part of the lesion, but in his own opinion “it fails to describe adequately the widespread character of the chronic inflammatory involvement of the bladder walls.”

Walsh is of the opinion that Hunner’s use of the term “ulcer” led people to think that the disease might be focal. However, Hunner himself did not think it was focal but widespread, as we have seen above. Hunner also made a clear distinction in his publications between lesions and ulcers. Since his study of more than 200 of these patients took place over a period of at least 20 years, during which time cystoscopes would have been continually improving, it is debatable whether his belief that he was seeing true ulcers was entirely due to poor vision from the cystoscope. However, any meaningful comparison between Hunner’s time and the situation today is always going to be problematic since he worked in an era when disease, infection and trauma were rife, antibiotics had not yet been invented, and women were very prudish and would probably have waited a very long time before plucking up the courage to consult a physician and may have concealed some of the more embarrassing details.

Hand presented a grading system for lesions, subdivided into three grades. There was, however, no mention of “ulcers” and no reference to non-lesion painful bladders. He noted that some of their patients had now been treated with antibacterial sulfonamides introduced in the 1930s and that the new pioneering antibiotic penicillin had been tried on three patients.

When performing cystoscopy, Hand recommended that the bladder should be distended, emptied and distended a second time in order to avoid overlooking the early lesions of interstitial cystitis. He noted that on distention small discrete submucosal hemorrhages and dotlike bleeding points could be observed.

While numerous theories had been put forward concerning etiology, Hand was inclined to believe that interstitial cystitis is caused by a neurogenic factor. The proliferation of nerve tissue mentioned by Hand also caught the attention of Walsh.

Hand drew attention to comorbidities in these patients, noting that “allergies were more common among the patients with interstitial cystitis than among those from the general admission.” He also reported that Fister drew attention to the striking similarity of some features of interstitial cystitis and Lupus erythematosus.

Like others before him, Hand noted that there is a large element of individual variation in these patients.

Interstitial cystitis received a huge boost in awareness when Anthony Walsh was invited to write Chap. 19 on Interstitial Cystitis for the 1978 edition of Campbell’s Urology where he famously described “an irritable bladder in an irritable patient”. Here too he notes that “the synonym ‘Hunner’s Ulcer’ has led many less experienced physicians to expect to see an ulcer at cystoscopy, and when no ulcer could be found, they erroneously failed to diagnose many genuine cases.” True ulceration is rarely seen, noted Walsh. In recent years, lesion expert Magnus Fall has described the Hunner’s Ulcer as a “vulnus” or wound seen only upon distension.

The tiny, punctate red dots seen after distension are “an experience that we describe as glomerulation”. However, he emphasized that glomerulation is not absolutely pathognomonic, since it has been seen after distension in patients with dyskinesia.

Despite Walsh’s warnings, the term Hunner’s ulcer continued to be used and to mislead, while glomerulation was adopted as a hallmark of interstitial cystitis and incorporated into criteria.

Until this point, patients with no lesions were considered to have an early stage of the lesion disease. However, in 1978 Messing and Stamey pointed out that “we have no direct evidence that the classic disease will eventually develop in patients in the early group”.

This was further reinforced in 1987 when Fall et al., describing interstitial cystitis as a heterogeneous syndrome, reported that they had observed clear differences between lesion and non-lesion disease which they considered to be two separate conditions and which, they emphasized, should be studied separately in clinical studies. This advice was unfortunately also largely ignored with a mixed bag of patients still participating in clinical studies and drug trials, rendering all results very questionable for years to come.

A major impulse was the founding of the Interstitial Cystitis Association (ICA) in 1984 in the United States by Dr. Vicki Ratner, an IC patient and orthopaedic surgeon. The ICA’s success in sparking the interest of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) led to more coordinated research, an attempt to define the disease and the creation of strict diagnostic criteria for research purposes in 1987 at a workshop and later published in 1988. However, it was soon clear that the criteria needed to be modified since there was a risk of 20–40% of patients diagnosed with IC now being excluded. The revised criteria were published in the 1990 first edition of this book but not in a journal, resulting in many physicians being unaware of them. The 1987 criteria therefore continued to be used extensively worldwide including for clinical diagnosis which had never been the intention.