# Bladder dysfunction caused by tuberculosis: A historical review

Etienne Cuénant, Philip van Kerrebroeck

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Etienne Cuénant, Philip van Kerrebroeck. Bladder dysfunction caused by tuberculosis: A historical review. Continence Reports, 2024, 11, pp.100052. 10.1016/j.contre.2024.100052. hal-05073354

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# Bladder dysfunction caused by tuberculosis: A historical review

Etienne Cuénant<sup>a</sup>, Philip Van Kerrebroeck<sup>b,*</sup>

<figure><img src="image_2.png" /></figure>

## ARTICLE INFO

**Keywords:**

Tuberculosis

Bladder dysfunction

History

## ABSTRACT

Tuberculosis has become an infrequent disease in Western society, hence has tuberculosis of the bladder. However, when tuberculosis was prevalent, urogenital tuberculosis and tuberculosis of the bladder could be the consequence if untreated, and were responsible for severe bladder dysfunction. Before antibiotic treatment became available, chronic bladder tuberculosis caused irreversible damage and often necessitated bladder reconstruction or even cystectomy. The specific antibiotic treatment of tuberculosis eradicated bladder dysfunction caused by tuberculosis. We aim to review the history of urogenital tuberculosis and the consequent dysfunction of the bladder based on existing literature.

## 1. Introduction

Tuberculosis (TB) has been present and known to mankind since ancient times. The earliest evidence of TB in humans is provided by fossilized bones. The oldest examples of a patient with spinal TB dates back to about 8000 BC, and was found in Egypt. A bone from the Neolithic period (ca. 5000 BC), found in the region of Heidelberg, likewise shows evidence of tuberculosis changes. There have been references to TB in India around 2000 BC and indications of lung scarring identical to that of modern day TB sufferers were found in several mummies. These findings clearly suggest that TB has been prevalent in many civilizations for thousands of years. Around 460 BC, Hippocrates (460–370 BC) identified phthisis (from the ancient Greek, meaning consumption) as the most widespread disease of those times. Hippocrates first observed tubercles (“phymata”) in the tissues of cattle, sheep, and pigs. However, analogous findings in man were not described, since human autopsies were not performed in the ancient Greek world. The Hippocratic School considered pulmonary phthisis a hereditary, rather than infectious disease. They also failed to recognize a common entity between tubercles and consumption [1].

## 2. History of tuberculosis

Due to the variety of symptoms, TB was not identified as a unified disease until the 1820s and was not named as tuberculosis until 1834 by Johann Lucas Schönlein (1793–1864) of Würzburg. He used the term “tuberculosis” to describe an affliction with tubercles. In 1855, Herman Brehmer (1826–1889) presented his thesis: *Tuberculosis primis in stadiis semper curabilis (Tuberculosis, in primary stadium, always a curable disease)*. He opened the first ‘sanatorium’ for patients with TB in

Görbersdorf (Lower Silesia) in the belief that the disease could be cured with ‘fresh air’. This example was followed by several sanatoriums all over Europe, and although the patients recovered surprisingly well during their stay in a sanatorium, the long-term results were fairly poor [1]. In 1882, Robert Koch (1843–1910) isolated the tubercle bacillus and in 1883 *Mycobacterium tuberculosis*, an acid-fast aerobic bacillus, was identified in samples of urine and sputum. Koch’s discovery revolutionized the diagnosis of urinary tuberculosis and allowed the natural history of the condition to be accurately followed [1].

In the early days, the management of patients with pulmonary TB consisted largely of rest, a high-calorie diet, and symptomatic pharmacological therapy. Attempts were made to treat the patients with stimulus therapy, tuberculin injections, and light. Eventually these methods were gradually abandoned in favor of surgical treatment. Attempts to vaccinate against TB date back to well before the discovery of antibacterial drugs. The BCG (Bacilli Calmette-Guérin) immunization was first carried out in Paris in 1921, particularly in children at high risk of infection, and soon became popular throughout Europe. The surgical therapy of pulmonary TB patients consisted of immobilization of one lung or of each lung successively. Also, pneumothorax techniques were performed in many variations over the course of 40 years. The new era in the treatment of TB began in 1944 with the introduction of streptomycin.

In 1942, Prof. Selman Abraham Waksman (1888–1973) isolated many antibiotics including streptomycin, which was the first antibiotic effective against tuberculosis. A rapid succession of anti-TB drugs appeared in the following years. These were important because with streptomycin monotherapy, resistant mutants began to appear within a few months, endangering the success of antibiotic therapy. However, it

<footnote><sup>a</sup>Department of Urology, Faculty of Medicine, Montpellier University, Montpellier, France</footnote>

<footnote><sup>b</sup>Department of Urology, Maastricht University, Maastricht, The Netherlands</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: urolmaas@hotmail.com (P. Van Kerrebroeck).</footnote>
was soon demonstrated that this problem could be overcome by using combinations of two or three drugs. The next generations of anti-TB drugs included p-aminosalicylic acid (1946), isoniazid (1952), pyrazinamide (1954), cycloserine (1955), ethambutol (1962), and rifampin (rifampicin; 1963).

### 3. History of genito-urinary tuberculosis

Genitourinary tuberculosis (GUTB) involving the kidneys, prostate, and testis was well described by G. L. Bayle in 1810. In 1823, Howship emphasized the importance of bladder symptoms in renal tuberculosis, and Rayer described in 1839 miliary tuberculosis, TB abscess, ulcerocavernous lesions and the accompanying changes in the renal pelvis, ureter, and bladder, as well as the spread to the prostate and seminal vesicles. At that time, TB was difficult to distinguish from other urinary tract infections and diagnoses made on clinical impressions were not always accurate [2].

Hans Wildbolz (1873–1940) was the first person to use the term ‘genitourinary tuberculosis’ in 1937. GUTB is one of the most common late manifestations of an earlier symptomatic or asymptomatic pulmonary TB infection, and is usually caused by metastatic spread of organism through the blood stream during the initial infection. This active disease results from the primary infection or a reactivation of the initial infection, but a latency period ranging from five to 40 years between the time of the initial infection and the expression of genitourinary TB frequently occurs. Extrapulmonary sites account for 10% of TB cases, and GUTB, responsible for 30% to 40% of all extrapulmonary cases, is second only to lymph-node involvement. In developed countries GUTB occurs in two to 10% of cases of pulmonary TB, but in developing countries these figures rise to 15 to 20%. GUTB affects more men than women (2:1) with a mean age of 40.7 (range 5–90), but seldom children [3].

The presentation of genitourinary tuberculosis (GUTB) is often vague and physicians must have a high degree of awareness to make the diagnosis. Patient history is key in the evaluation of GUTB, and a significant differential diagnostic overlap requires maintaining a high index of suspicion for GUTB in both men and women. Diagnosis of GUTB is often delayed owing to the nonspecific nature of its presentation. Therefore, a high degree of suspicion should be kept in mind and a systematic approach should be the rule during investigation [4].

### 4. History of tuberculous cystitis

Bladder TB is secondary to renal TB and usually starts at the ureteral orifice. It initially manifests as superficial inflammation with bullous edema and granulation (Fig. 1). Fibrosis of the ureteral orifice can lead to stricture formation with hydronephrosis or scarification (ie, golf-hole appearance) with vesico-ureteral reflux. Severe cases involve the entire bladder wall, where deep layers of muscle are eventually replaced by fibrous tissue, thus producing a thick fibrous bladder. Tubercles however are rare in the bladder, and if present, they usually appear at the ureteral orifice [5].

When studying the history of tuberculous cystitis we have to distinguish 3 historic time episodes:

- A first period that extends from the origins to the discovery of the eponymous bacillus responsible for the disease by Robert Koch in 1882. This period has been studied extensively and the results have been published previously [2].

- The second period, goes from the discovery of bacillus to the development of streptomycin by Waksman (in reality, this antibiotic was isolated by his student Albert Schatz). The widespread use of streptomycine as a treatment for tuberculosis started in the early 1950s.

- The current period consists of the actual time. While tuberculosis has become very rare in Western Europe and has an incidence of about 7/100,000 individuals, mainly affecting the immunocompromised and people in precarious situations. The anti-tuberculosis drugs

have radically changed the profile of the disease in developed countries, although we have to deal nowadays with growing multi-resistance to antibiotics. Nevertheless, tuberculosis still kills 1.3 million people worldwide [6].

If one were to ask a student or a young doctor today what was the first symptom that led to the consultation of a patient with renal tuberculosis between the two world wars of the twentieth century, it is not certain that the answer would be: cystitis. And if the next question was what the first treatment for this cystitis would be, the answer probably would not be nephrectomy of the affected kidney, although that would be the correct answer.

The second period in the history of tuberculosis is particularly interesting. The causative agent had been isolated, and the different phases of tuberculosis disease were well established. The confirmation of the diagnosis was possible with the culture of BK in the urine, and its inoculation to the guinea pig (if the cultures were negative). Imaging for therapeutic indications had become an essential diagnostic technique to localize the affected kidney(s) by intravenous urography (Fig. 2) and endoscopic retrograde ureteropyelography (Figs. 3–4). This radiological techniques also made it possible to evaluate the status of the bladder. Meanwhile nephrectomy as a treatment for the affected kidney was established and several well documented series with good results were published.

Interesting contemporary documentation on this second period, can be found the book "Renal tuberculosis from the angle of therapeutics." (530 pages), published by Jean Cibert from Lyon in 1945 with the publisher Masson [7]. Our article is also a tribute to this remarkable

<figure><img src="image_3.png" /><figcaption>Fig. 1. Cystoscopic images of bladder tuberculosis. "< Endoscopia Urinaria "> by A. Puigvert Gorro, 1939.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Intravenous pyelography of a patient with urinary tuberculosis, Julián Guimón Rezola (1898–1980) collection, Bilbao, 1940s.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 3.** Bilateral retrograde pyelography of a patient with left kidney tuberculosis, Julián Guimón Rezola (1898–1980) collection, Bilbao, 1930s.</figcaption></figure>

personality of French Urology. Jean Cibert (1900–1988) was President of the French Association of Urology from 1963 to 1969 and of the 51st Congress in 1957. A hard worker, he was in charge of Pavilion V of the Edouard Herriot Hospital in Paris (France). His personal series of urinary tuberculosis consists of 1000 patients treated of which 626 underwent a nephrectomy. The main major series of nephrectomies of the time were that of Hans Wilboz of Heidelberg (500 patients) and

<figure><img src="image_6.png" /><figcaption>**Fig. 4.** Retrograde pyelography of a patient with right mastic kidney, Julián Guimón Rezola (1898–1980) collection, Bilbao, 1930s.</figcaption></figure>

that of Judd and Scholl of the Mayo Clinic (863 patients). They are all quite comparable in results.

During this period, urinary tuberculosis was the dominant condition in urology. This is the first time that surgeons have been confronted with a severe, chronic pathology with unpredictable delayed expression. UGTB still had a major impact on patients even if the life expectancy between the two wars was about 55 years.

## 5. Pathology and diagnosis of tuberculous cystitis

The different phases of tuberculosis have initially been described by Karl Ernest Ranke (1870–1926), a German physician who developed the (now outdated) hypothesis on the pathology of pulmonary tuberculosis, which became known as “Ranke’s stages of tuberculosis” [1].

According to the Ranke a TB infection occurs in 3 phases:

- Primary tuberculosis infection: Koch's bacillus enters the body, most often through the respiratory route, creating an inoculation chancre and satellite mediastinal lymphadenopathy.

- Bacillemia phase: the disease can spread, and eventually the kidney(s) can get contaminated.

- The third phase: in his phase, known as ulcerative tuberculosis, kidney damage is seen in up to 7% of patients (Fig. 5).

Before the advent of antibiotics, a TB patient remained a TB patient for life, even if he or she appears to have been cured. This is evidenced, for example, by very late epididymal recurrences despite the absence of detectable BK and symptoms in people who are presumed to have recovered.

In general, the course of TB remained unpredictable and a bit mysterious, but the general rule was aggravation, although some patients presented with a remission or even spontaneous recovery. Tuberculous cystitis or renal tuberculosis can be considered as quite similar from a pathophysiological point of view. The bladder is contaminated from the kidney, but obviously the cystitis component was more obvious with various symptoms such as diurnal and nocturnal frequent micturition, pain at micturition, pyuria, eventually episodes of haematuria. When not treated, tuberculous cystitis causes a chronic inflammation and result in a small, sclerotic bladder, often with severe
incontinence. Ureterohydronephrosis may develop as a consequence of bladder fibrosis and can endanger renal function [8].

Diagnostics were mainly clinical. The confirmation of the diagnosis consisted of the presence of BK in the urine, BK culture and inoculation in guinea pigs. The radiological diagnosis consisted of endoscopic ureteral catheterization to localize the inflammation and eventual strictures of the excretory tract. This allowed also to assess the bladder condition. Intravenous urography quickly became an indispensable supply, gradually replacing catheterization.

Cibert describes that tuberculous cystitis is a quite characteristic sign of urinary tuberculosis and is easy to diagnose. The big question was whether the underlying renal tuberculosis was unilateral or bilateral, and if it was bilateral, which kidney was most affected. Most of the time, urography was giving the answer, but did not indicate the severity of the involvement. Therefore, retrograde uretero-pyelography still had an important role as in case of unilateral involvement of the kidney the treatment was different and easier.

## 6. Treatment of tuberculous cystitis

So, what was the optimal treatment in those days? Cibert describes various combinations of different treatments such as diet, climatic cure, and heliotherapy. These general measures were combined with local treatment such as the instillation of antiseptics (methylene blue, sulforamides). The existing medical treatment of that time was following Cibert 'not capable of appreciably interfering with the natural course of the disease'. At that time vaccination therapy was trialled and started with tuberculin (Vaudremer vaccine).

The pain and frequency of micturition in case of bladder tuberculosis were major problems in former days. In the literature of that time treatments included, beside what Cibert mentioned, a variety of bladder instillations, irradiation of the vesical mucosa, and other methods that included hydrostatic dilatation and the application of silver nitrate or other cautery, such as: boric acid, corrosive sublimate, iodoform in liquid paraffin, guaiacol in oil, picric acid, and carbolic acid. Also used, was the insufflation of iodine vapor into the bladder by means of a catheter administered together with ultraviolet light.

Cibert discusses extensively the surgical therapy of UGTB, as he was a master in urological surgery. He was a big advocate of a nephrectomy of the affected kidney and desirably as soon as possible, before the cystitis worsened (Fig. 5). However, he also mentions that nephrectomy, apart from the mortality of the procedure (estimated at 3 to 6%, more related to the failure of the remaining kidney than to the operative procedure itself), can also lead to a fatal generalization of the disease in 2 to 3% of patients because of intra-operative manipulation. Nevertheless, he also indicates that a nephrectomy provides a cure for tuberculous cystitis in about 70% of patients. With time and experience, some urologists tended to postpone the nephrectomy since (rare) incidents of spontaneous healing were recorded. However, the opponents of the wait and see policy indicated that the 10% patients with favorable results had to be balanced by 90% of patients with inevitable deterioration of their condition.

Cibert discusses also the situation of therapy resistant cystitis. Most often persistence of tuberculosis of the bladder after unilateral nephrectomy was the consequences of unnoted or non-diagnosed tuberculosis of the contralateral kidney. In case of chronic tuberculous cystitis a small sclerotic bladder was the consequence and often resulted in hydronephrosis with kidney insufficiency. In general persistence of cystitis after nephrectomy had a very poor prognosis, as it often indicated tuberculous involvement of the remaining kidney.

In case of chronic tuberculous cystitis Cibert also proposes some palliative measures:

- The treatment of bladder pain: among the proposals described, the following are noteworthy:

* Smooth sphincter sphincterotomy (perineal or endoscopic).

<figure><img src="image_7.png" /><figcaption>Fig. 5. Chomolitograph of tuberculous kidney specimen after nephrectomy. Same case as Fig. 4.</figcaption></figure>

* Bladder denervation procedures: Of particular note is: simultaneous section of the erector and hypogastric nerves (Richer's operation). This intervention eventually decreased bladder wall contracture and could improve bladder capacity.

- Bladder exclusion

* Procedures on the bladder:

* Cystostomy: despite its relative ease, this technique did not give good results in chronic tuberculous cystitis and was abandoned

* Bladder enlargement by intestinal plasty. Considered by Cibert as a nascent operation, but promising if the bladder was not completely retracted

* Procedures on the kidneys: this consisted mainly of a bypass nephrostomy leaving the kidney in place and combined with ureteral ligature. This intervention was rarely used as the nephrostomy was difficult to maintain.

* Surgery on the ureter

* Cutaneous ureterostomy of the remaining kidney by iliac approach: this provided some comfort but could fail due to the progression of fibrosis of the remaining kidney

* Internal urinary diversion: especially Coffey's operation was often used with good functional results. However, meanwhile long-term follow up indicated a risk for intestinal malignancy.

## 7. Conclusions

Urogenital tuberculosis including tuberculous cystitis was always secondary to military tuberculosis, and never cured spontaneously if not treated. The affection of the kidney(s) was the main cause of severe cystitis, and before the advent of antibiotics, was a serious problem, fatal in more than 50% of patients in the medium term. If the patient survived the chronic cystitis had a major impact of bladder function. The advent of antibiotics especially streptomycine, radically changed the prognosis, but it took many more years to deal with patients that suffered from the sequelae. It were the functional consequences of chronic tuberculous cystitis due to small bladder capacity that led to the development of the different techniques of bladder replacement.
**Declaration of competing interest**

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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[8] LJT. Murphy, The History of Urology, Springfield, Illinois, USA, 1972, pp. 219–223,