Dimitrios Zambakis’ Scientific Hypothesis on the Transmission of Leprosy

Introduction

Dimitrios Zambakis Pasha, born May 6, 1832, was a celebrated physician in Neochori, Constantinople, Turkey (now modern-day Yenikoy, Istanbul, Turkey). He published nearly 60 scientific publications, the majority of which were on leprosy. He was honored with many awards for his work including the Cholera Medal of Honour in 1854, Château-Villard Prize from the Faculty of Medicine in Paris in 1898, the Montyon Prize, and the honorary title of Pasha, which is a name given to men of high rank in Turkey. ¹

Zambakis graduated from E ´cole de medecine de Paris (Paris School of Medicine). He then interned and received a doctorate degree from Hôpitaux de Paris (Hospitals of Paris) in 1851. ¹ In 1856, at Hôpitaux de Paris, he wrote a thesis titled “De la gangrène spontanée produite par perturbation nerveuse” (On spontaneous gangrene produced by nervous disturbance). ¹ Zambakis’ interest in syphilis arose once he became an assistant to Dr Philippe Ricord in 1857, a French specialist in venereology and syphilography. ¹

After graduating, Zambakis continued to practice medicine in Paris and was named chief of the medical clinic of the Faculty of Medicine in Paris in 1861. ¹ He returned to Constantinople in 1872 after being recruited by the Ottoman government to help reform medical practice in the Empire. ¹ Throughout his career, Zambakis engaged in various topics of study including leprosy, syphilis, morphinomania, hemorrhoids though it was his work and publications on leprosy were his most acclaimed achievements.

Leprosy

Leprosy, also referred to as Hansen's Disease, is known to be caused by a bacterial infection affecting the nervous system, skin, eyes, and nasal mucosa. The identified pathogen, which can be either Mycobacterium leprae or Mycobacterium lepromatosis, causes a slow-growing inflammatory reaction resulting in sensory loss, thickened dermis, and subcutaneous swellings. The infection progresses slowly and may take up to 20 years to significantly impact a patient's life; however, most cases become apparent within five years of presumed transmission. Early signs of leprosy include discolored patches on the skin and loss of sensation. If the infection is allowed to continue without appropriate treatment, permanent disability and further nerve damage eventually causing muscle paresis and paralysis may occur. Modern antimicrobial treatment consists of three drugs (usually of rifampicin, dapsone, and clofazimine) taken for six to 12 months. After successful treatment, nerves remain permanently damaged and do not demonstrate significant functional improvement. ²

The bacterial infection is attributed to direct contact and droplet contact, primarily via a respiratory tract route. However, the transmission rate is very low, and 95% of individuals will not contract the disease despite direct contact. Identified risk factors include those associated with secondary immunodeficiency such as poor nutrition, living conditions, and hygiene. ²

The incredibly low transmission rate contributed to confusion amongst early physicians regarding the etiology of leprosy. Although the earliest written description of leprosy was possibly 600 BC in India, ³ at the time of Zambakis’ studies, there was still much debate about the causes and appropriate precautions regarding leprosy.

Leprosy and the Ottoman Empire

Under the Ottoman Empire, there was a stigma among those infected by leprosy, largely based on ancient myths. ² As a societal norm, conversation about leprosy was frightening, and those who were afflicted with the disease were expelled from Istanbul and left to die. If they were wrongly accused of having leprosy, they must attain documentation with a witness that cleared them. ⁴ Article 64 of Ottoman Law stated to “expel the lepers from the city, do not let them to stay in the city”. ⁴ The term ‘leper’ was considered offensive to people with the disease. ²

Zambakis on leprosy

Recognized as the “first leprologist of the Orient” by his professional colleagues for his dedication to the subject of leprosy, Zambakis observed leprosy for 25 years in mainly The Middle East and The Mediterranean. ¹ Zambakis’ (translated) description of leprosy is as follows.

“The bulla ruptures, and despite all precautions, local applications of all kinds and the most varied internal treatments, the little ulcer invades more and more of the surrounding tissues and becomes several centimeters in diameter. In the variety with deep ulceration the tissues are more and more disorganized, tendons arc exposed, and in some cases, fortunately rare, the destructive process extends to a joint and in spite of all attempts to stop it, attacks the ligaments one by one, detaching the extremity”. ⁵

Zambakis suggested that the disease was difficult to diagnose because of the lack of symptoms other than cutaneous signs. ⁵ There were 85 reported causes of leprosy in the United Kingdom in 1898, however, Zambakis firmly believed that this count was a gross understatement of actual cases. ³ Additionally, in Zambakis’ publication “L'heredite de la lepre” (Leprosy Hereditary), he proposed that leprosy was hereditary, not contagious. ⁶ He thought he found cases of leprosy that appeared to be from atavistic (or hereditary) transmission because he observed cases in parents and children without having contact with any other subjects with leprosy.

However, many physicians disagreed with this claim. Dr Gerhard Armauer Hansen (1841–1912), a Norwegian physician, disagreed with Zambakis’ theories. Hansen claimed that if leprosy were truly hereditary, evidence would be found in the ovum or spermatozoon, which Dr Hansen had not observed. ⁶ Hansen also observed 119 Norwegian patients who collectively had around 318 children. In this sample he did not observe any children with the disease or any other pattern suggestive of hereditary origin of the disease. To further assert his theory of infectious etiology, Hansen made note of environmental differences such as the abundance of soap and water between the living situation of those in the asylum and their children. ⁶ Hansen alleged that Zambakis did not know the history of his patients well enough, and that Zambakis’ evidence did not prove that there was no contact amongst his patients. ⁶ Hansen was recognized in 1909 at the International Leprosy Congress for his distinguished work on leprosy.

In his book, Les Lépreux Ambulants De Constantinople (Paris 1897), Zambakis continued to argue against the theory of contagiousness through close contact. ⁴ In Zambakis’ study of 300 patients with leprosy in Istanbul, half lived ‘free’, and half lived in confined spaces. No cases of leprosy were reported among the children of those infected. Not one instance of leprosy spread from husband (with leprosy) to wife. ⁷ This observation served as evidence to support Zambakis’ theory that the disease was not contagious.

Zambakis also observed there were more severe cases among pregnant women. He noted that the complications from the bacterial infection were remarkably bad when associated with pregnancy: “… the influence of pregnancy is disastrous for women with leprosy. The disease reveals itself for the first time and progresses rapidly. The birth of the baby in turn affects the development of the illness, in all comparable to the development of tuberculosis in the same circumstances”. ⁸ Zambakis observed four women who developed leprosy in association with pregnancy. Three of these women developed the disease immediately postpartum, and the remaining woman developed the disease during the third trimester. In two of the three postpartum patients, Zambakis noted a reaction in the skin. With the third patient, he observed signs and symptoms of peripheral nerve involvement developing acutely following the pregnancy. In 1897, Zambakis reported several abortions linked to leprosy in the mother. Mycobacterium leprae causes an infection in the placenta, which leads to fetal infection and subsequently, abortion. However, Zambakis reports that these abortions were not diagnosed with the cause of leprosy because the fetus and placenta were discarded without proper examination. ⁸ Zambakis observed that many children born to mothers with leprosy died as newborns from athrepsia (disturbance of nutrition): “children of leprous women, born like little old men, did not develop normally but died of athrepsie without showing in their body any sign of leprosy. This foetal cachexia which leads to death in utero or shortly after birth, without the lesions of leprosy is certainly due to leprosy and maybe described under the name of para leprosy”. ⁸

Leprosy transmission

Leprosy was long thought to be hereditary as suggested by Zambakis. In was not until Gerhard Armauer Hansen disproved the hypothesis as mentioned above. Hansen worked under Dr Daniel Cornelius Danielssen, who studied clinical and pathological aspects of leprosy. Danielssen had originally regarded leprosy as hereditary, but Hansen suspected that the disease was contagious. In Hansen's first work, published in 1871, he noted the appearance of leprous changes in lymphoid tissue, but he remained inconclusive about what his discovery meant for the transmission of leprosy. ⁹ Hansen then received a grant to further his research, where he began to look for bacteria in infected patients. He first examined blood, but when that yielded no significant findings, he looked at skin nodules. Examination of the skin nodules revealed rod-like bodies that he thought resembled bacteria. ⁹ However, Hansen was hesitant to claim that the rod-like bodies he found were identical to bacteria. ⁹

As a results of his discovery, Hansen was appointed the Chief Medical Officer for Leprosy in Norway in 1875. He implemented a law that required all those with leprosy to be isolated. Resistance to this effort arose since the concept that the disease was contagious was not entirely accepted yet and that the push for isolation was considered inhumane. However, when the presence of leprosy began to decline in the Norway after such measures were taken, resistance to the law declined, and other countries began to adopt similar measures. ⁹ Gerhard Armauer Hansen was the first to identify bacteria to be the cause of a human disease, which paved the way for further findings and research in immunology and bacteriology.

Conclusion

Today, we know that leprosy is in fact contagious, just not easily transmitted. The Centre for Disease Control and Prevention states that for leprosy to be transmitted from person to person, there needs to be “prolonged, close contact with someone with untreated leprosy over many months”. ¹⁰ The CDC also states that leprosy cannot be transmitted by shaking hands, hugging, sexual contact, or sitting next to each other. Because we now know the relative difficulty of leprosy transmission and the slow-growing nature of the bacteria, leading to a delay in its signs, it is more easily understood why Zambakis argued against the fact that the disease was contagious. It is logical to assume that he did not study his subjects in-depth or for as long as needed to conclude that the disease was contagious.

Zambakis’ theory was studied and broken down by others, such as the team of physicians of Hansen and Danielssen as mentioned previously. Although Zambakis’ hypothesis about the transmission of leprosy was later proven invalid, he brought the disease into the wider conversation, encouraging further investigation.