Medical Treatment & Research
“The ang moh (Caucasian) doctor used to come every week and wheel me away to ‘cut my flesh’, patch by patch, for research purposes. A few of us went through this, so we were often given supplements and nutrient injections. At the beginning, it happened very frequently. I got cut every week until there were wounds all over my body, but the cuts have now healed and the scars are gone now,” said 94-year-old Fun Ah Har, an inmate of the Sungai Buloh Settlement, before she passed on in April 2017.
She remembered that the “ang moh” doctor was Dr Waters. She believed that it was Dr Waters who cured her and spared her from potential disabilities and deformities, so she had always been grateful for that.
Fun Ah Har was one of the patients who participated in the clinical studies at the Research Unit that was based in the Sungai Buloh Settlement. Between 1950 and 1980, four hospital wards in the settlement were zoned exclusively as the research wards to house selected leprosy patients placed under the clinical studies. The doctor often took living tissues from these patients and inoculated the bacteria into the foot pads of mice, in order to test if the bacteria had developed any resistance to the drugs.
The 66-year-old Sungai Buloh Settlement Research Unit was established since 1950 during the British rule. Before 1976, only doctors appointed by the UK Medical Research Council had led the unit. Dr Lim Kuan Joo, who served as the settlement’s Deputy Director from 1976 to 1985, said that the UK Medical Research Council set up the research lab at the settlement to capitalise on the clinical facilities and resources. The settlement rose to international fame because of the many influential papers published here.
According to A. Joshua-Raghavar’s book, Leprosy in Malaysia: past, present and future, the research unit had published up to 100 academic papers over 14 years between 1967 and 1981, working in collaboration with the Malaysian Ministry of Health and the UK Medical Research Council. Between 1948 and 1949, the Research Unit conducted Malaysia’s first batch of DDS (dapsone) trials. Research on alternative drugs was also one of its aims. The Research Unit made remarkable contributions to the development of Morphological Index in medicine.
Between 1964 and 1965, in the collaboration between the Research Unit and the British Medical Research Institute, Dr R. J. W. Rees and Dr J. H. S. Pettit managed to prove the dapsone resistance, based on the outcome on three Sungai Buloh Settlement’s patients, using the mouse foot pad technique. In 1976, the Research Unit, led by Dr Waters, achieved another breakthrough – the team discovered the first case of primary dapsone resistance, namely drug resistance that was found in new patients not treated with DDS before. This discovery once again thrust the Sungai Buloh Settlement into the limelight of the international medical community.
The world-renowned Sungai Buloh
Dr Lim Kuan Joo was invited twice to the Geneva-based World Health Organisation (WHO). “I went to Geneva in the 1970s and the 1980s. And the moment I said I came from Sungai Buloh, people would look at me with great respect and I could read the expression on their faces, which seemed to say, ‘yeah, I know the name!’ So I benefited from this fame.” The doctor recounted the experiences with a proud smile.
During his service in the settlement, Dr Lim Kuan Joo travelled to Geneva to attend international conferences at the WHO Headquarters and published papers on leprosy control strategies. He was also a committee member of two WHO research programmes: the Epidemiology of Leprosy and the Multidrug Therapy (MDT) programme. The name “Sungai Buloh” was like a business card for Dr Lim Kuan Joo in Geneva – everyone knew of the place and that was how famous it became.
Apart from the discovery of dapsone resistance that spurred the development of MDT, the Sungai Buloh Settlement also had a notable achievement in developing leprosy research techniques. Dr Lim Kuan Joo said: “I think the greatest contribution of the Research Unit, was the development of the Bacteriological Index (BI) and the Morphological Index (MI), which was used to quantify patients’ infectivity. This is also the place where the standards for mouse foot pad injection volumes were set, which was a technical contribution to the studies.”
Amrish Shah Osman, the head of Sungai Buloh Settlement Research Unit, has been working in the unit for 13 years. He added that the Research Unit has also improved the slit-skin smear method in leprosy detection and had introduced it to the world.
Dato Dr Khalid Ibrahim, the director of Sungai Buloh Hospital, and Dr Radhiah Mustafar, the deputy director of the National Leprosy Control Centre, said the Research Unit, including its researchers and the leprosy patients, had all contributed enormously to the research progress.
Dato Dr Khalid Ibrahim said that the Sungai Buloh Settlement pioneered the inoculation of leprosy bacteria in the foot pad of mice for research purposes. This research technique has been widely used around the world upon its introduction. “We should be proud that Malaysia is ahead of the developed countries in the use of this technique in leprosy research.”
Mouse foot pad technique, first of its kind
Dr Radhiah Mustafar explains that the mouse foot pad technique is a famous cultivation and inoculation technique that uses mice to test the reaction of leprosy bacteria to dapsone, rifampicin and clofazimine. First of all, the researchers will cut skin tissues from the patients to obtain Mycobacterium Leprae (M. Leprae) and inject it into the foot pads of a group of mice. Then, they will mix a few types of drugs and include them in the mice feed, distributing different dosages to different groups of mice. After six months, the researchers will kill one of the mice and observe its foot pad with a microscope to check if it still has any M. Leprae left. If it does, that means the drugs have yet to take effect.
Thereafter, the researchers will kill one mouse in each dosage group every month, for the next 12 months. After a year, if M. Leprae is still detected in the foot pad of the mice, the researchers will make a conclusion based on the types of drugs and the dosage administered. If a particular mouse has consumed high-dose rifampicin and M. Leprae still survived in its body, it shows that the M. Leprae from that particular patient has developed resistance to rifampicin and thus must replace the patient’s current prescription with other drugs. Dr Radhiah says that such experiment is still being carried out to date in the detection of drug resistance in patients.
Since 2008, the Sungai Buloh Settlement Research Unit has been placed under the purview of the National Public Health Laboratory. Amrish says that the key functions of the Research Unit are to provide diagnostic service to patients, monitor drug resistance using the mouse foot pad technique, conduct training and handle quality control for skin smear science. The first step of the diagnostic procedures is a smear test. If the patient tests positive, the researchers will conduct a drug sensitivity test, which is to grow the bacteria and test it with antibiotics to identify possible drug resistance.
He says that another diagnostic method is to test the polymerase chain reaction (PCR). It is expected that this modern molecular method would replace the mouse foot pad method in the future, which has been in use for half a decade in the Research Unit.
He says that other than providing diagnostic tests for patients, another objective of this study is to monitor the leprosy resistance pattern in Malaysia. The Research Unit in the Valley of Hope is the only leprosy research centre in Malaysia. Usually, after carrying out smear tests, hospitals in Peninsular Malaysia will pass the test results to the Research Unit for a second examination, whereas hospitals in East Malaysia will send their smear test results to the Kota Kinabalu’s general hospital for crosschecking. However, the hospital in Kota Kinabalu is only responsible to test them as part of quality control and is not involved in the leprosy research.
Acknowledgement of Patients’ contributions
Before dapsone was developed in 1948, leprosy was a much dreaded, incurable disease. There was no modern drug or treatment before the introduction of dapsone. Dr Radhiah said the Sungai Buloh Settlement discovered the first dapsone resistant case in 1964. What makes the discovery a major breakthrough, is that it prompted the medical community to seek alternative drugs in place of dapsone and made the anti-leprosy treatment even more effective and accurate.
“This discovery drew doctors’ attention to the need of finding alternative drugs that would kill leprosy bacteria. WHO called for further studies and search for other drugs and eventually found three effective types of antibiotics. In 1982, WHO decided to treat leprosy with MDT.”
Before the modern drugs were made available, leprosy treatment was basically an experimental process fraught with uncertainties. The patients must receive hydnocarpus oil injections twice a week and the injection was extremely painful, even causing serious side effects and wound inflammation. Thanks to the cooperation of patients’ in the long-term clinical studies, the researchers managed to develop effective drugs to neutralise the threat posed by leprosy bacteria and spare generations to come from the horrors of leprosy.
That is why Dr Lim Kuan Joo, Dato Dr Khalid Ibrahim, and Dr Radhiah Mustafar all acknowledged the patients for the sacrifices they have made. “I think the credit should go to the leprosy patients, for they have contributed to medicine, not just in Malaysia but also around the world,” said Dato Dr Khalid.
WHO stated that there are two systems for classifying the disease, one based on clinical features and the other, on skin smear results. Based on the skin smear results, leprosy is classified into paucibacillary (PB) leprosy and multibacillary (MB) leprosy. Dr Radhiah says that if the patient’s immune system is strong and starts responding at the early stage of bacterial invasion, the body will have a lower level of bacterial infection and would only require six months of medication to heal. If the body is weak, there are more bacteria present in the body, meaning a higher level of infection, which can lead to serious disabilities and even death.
In medicine, leprosy is also classified into five types based on clinical symptoms: lepromatous, borderline lepromatous, tuberculoid, indeterminate and intermediate.
According to Dr Radhiah, if the patient has only one lesion that is flat and numb, it should be tuberculoid leprosy. If there are more than six lesions, it should be indeterminate leprosy. Intermediate leprosy on the other hand, shows features that are a cross between the indeterminate and lepromatous type. If there are many lesions with raised bumps, it is a borderline lepromatous leprosy. Should the lesions develop into large number of bumps, then it is the most serious type – lepromatous leprosy. For ease of treatment, NLCC is currently classifying leprosy patients into only two groups, tuberculoid and lepromatous.
If the skin smear test came out to be negative but doctors strongly believe that the clinical examination points to a leprosy lesion, a biopsy will be conducted. If the patient is diagnosed with tuberculoid leprosy, the treatment will be six months of MDT without clofazimine for PB leprosy. If the skin-smear is positive, meaning leprosy bacteria are identified in the patient, it will be classified as lepromatous leprosy. The doctor will administer, upon diagnosis, medication for MB leprosy, which contains clofazimine.
Patients stopping medications out of fear of discrimination
Clofazimine, which the patients call, “black pills”, has a side effect of causing the skin to darken. However, the skin tone of a patient’s body will return to normal after they stop the medication. Fun Ah Har, an ex-patient who had been admitted since the 1960s, said, “Your whole body will turn black after taking the black pills, even your sweat will be black. Your skin will look like an Indian’s, if not darker than the Indians. My whole body became very dark after taking the black pills. I would cover my head with a scarf – like how we dressed for work – and go home like that. People back then was terrified of leprosy, they would spit at you when they saw or walked past you on the street. So mean.”
Dr Radhiah says that M. leprae can be killed with just two weeks of medication. WHO also made a conclusion, based on studies, that continued MDT would keep the disease under control in less than three years. However, some patients would rather stop taking their medications, as they were worried that people might find out that they have the disease. Dr Radhiah, who works at the Central clinic twice a week, said that she had a Chinese patient whose skin became darker and darker after taking the medicine. The unusual skin tone sparked curiosity and questions from relatives and friends, so the patient decided to stop the medication.
She says although leprosy is now curable, many patients still try to hide their medical conditions because they are concerned of what others may think.
Malaysia has implemented the National Leprosy Control Programme since 1969 and people can now go to any government hospitals for leprosy treatment. However, some patients still choose to get their treatment in the Valley of Hope.
“I had a patient who came from somewhere outside of Sungai Buloh. I asked him why he came all the way here for treatment. He said he did not want to see a doctor near his place because he was worried that his neighbours may ask him questions. If he bumps into some neighbours at the skin clinic, they will ask him: ‘what’s wrong with you’ and ‘why are you here?’ So the patients will still try to hide their disease from relatives and neighbours.”
Dr Radhiah says that leprosy therapy is administered based on the bacterial density index. If the density is too high (greater than 4.0), the patient needs to be on medication for two years. If it the index is less than 4.0, then the patient only has to be on medication for a year. After that, the patient must also undergo yearly health examinations for 15 years. Skin-smear is required for the first five years and only clinical examinations are needed from the sixth year onwards. Then, the patient is considered to be fully recovered after 15 years.
A few hundred new cases still detected each year
Similar to Tuberculosis (TB), leprosy is transmitted through air droplets and the risk of infection is almost just as high as TB. Dr Lim Kuan Joo says that it is important to note that there are several types of leprosy and the infectivity varies from one type to another, so we should not consider all types of leprosy to be mildly infectious. What is safe to say is that leprosy patients are no longer contagious after two weeks of modern treatment.
It is noteworthy that there is a trend of relapses in recovered leprosy patients who had been discharged a long time ago in the early years. Dr Radhiah said that there were two relapse cases in 2011, four cases in 2012, one case in 2013, nine cases in 2014, and another nine in 2015. The settlement tracked down long-discharged patients in 2015 and detected 18 relapses. Currently, eight of the relapsed patients are receiving long-term retreatment in the Central Clinic while the other 10 patients have been admitted for in-patient care. As of June 2016, there were another five relapse cases.
Currently, researchers are still unable to tell whether the relapses in recovered patients are caused by new infections or a reactivation of old infections. Dr Radhiah says NLCC has been working with the Dermatology Department of Kuala Lumpur Hospital beginning this year to find out whether the relapse trend is caused by the single therapy administered previously or some other factors. The work includes an investigation into whether or not the bacteria will reactivate later in elderly patients.
Amrish stated that Malaysia recorded 320 new leprosy cases in 2015 and more than 400 cases in 2014, where 70 percent of the new cases were detected in Sabah. The Research Unit is currently conducting a long-term monitoring study to find out whether the bacteria have developed any resistance against the existing drugs.
Leprosy control is a constant battle for the wellness of all mankind. All this while, countless doctors and researchers have contributed their valuable knowledge and precious time to the fight against M. leprae. Now, although the disease has been brought under control with the availability of effective treatments, the medical community is still working just as hard as before, outside of the limelight, to keep things in check.
Dr Lim Kuan Joo’s paper, which was published in Geneva, introduced 4 A’s in leprosy control – awareness, availability of health services, accessibility and acceptability (patients’ willingness to receive treatment), all of which are still applicable today.
He said that the public must have a proper understanding of the leprosy symptoms and seek treatment immediately upon recognition of the disease. Doctors, on the other hand, must also understand about leprosy so that they can take the right actions when they chance upon leprosy patients. In the meantime, sufficient and accessible leprosy treatment and medical services are important to ensure easy access to the nearest health facilities. Certainly, it is also the patients’ responsibility to take their medication as instructed, in order to ensure the effectiveness of the treatment and to prevent a transmission of the disease.
Interviewed by Chan Wei See & Wong San San
Written by Chan Wei See
Translated by Zoe Chan Yi En
Edited by Low Sue San