It was a pure coincidence that thalidomide ever was tried in the treatment of leprosy. Now everybody has jumped on the bandwagon, hailing the advantages of the drug. No moderating voices are to be heard. With one exception; Colin Crawford.
Thalidomide was banned world-wide by WHO (World Health Organisation) in 1962. The ban was lifted in 1985, once again by WHO. Right now the drug is in use in all continents, and makes service in more countries than during the peak of the 1960s catastrophe.
The new chapter in the drug's history began in 1965, only four years after the teratogenic disaster. An Israeli dermatologist, Dr J Sheskin administering the drug to six leprosy patients as a sedative. He discovered by accident that thalidomide was an inhibitor of Erythema Nodosum Leprosum (ENL), a complication of lepromatous (multibacillary) leprosy.
"Thalidomide neuropathy and the production of severe congenital malformations were well known side-effect's by the physicians at that time," says Colin Crawford, a respected leprologist at Imperial College School of Medicine, Department of Neuromuscular Diseases, Division of Neuroscience and Psychological Medicine in London , England ."Yet in reintroducing the drug in 1965 for the management of the lepra reaction, Sheskin ignored this complication."
Imperial College School of Medicine in London.
Leprosy (Hansen's Disease) is a chronic, infectious disease of human beings that primarily affects the skin, mucous membranes, and nerves. The disease is caused by a rod-shaped bacillus; Mycobacterium leprae, which is normally contracted through the respiratory tract and it, is similar to the bacillus that causes tuberculosis. Leprosy is perhaps the least infectious of all the contagious diseases. The germ reproduces very slowly, and the disease develops insidiously for years, infiltrating skin and nerves. If untreated there can be progressive and permanent damage to skin, limbs and eyes, which may lead to paralysis and mutilation. But the visible symptoms may not show themselves for 10, 15 or even 20 years. By that time, lepromatous cases may have more than 7,000 million bacilli in just one gram of skin tissue!
Loss of sensation
The earliest symptom is often anaesthesia (loss of sensation) in a patch of skin. The mucous membranes of the nose, mouth, and throat may be invaded by large numbers of the organism. Because of damage to the nerves, muscles may become paralysed. The loss of sensation that accompanies the destruction of nerves may result in unnoticed injuries. These may result in secondary infections, the replacement of healthy tissue with scar tissue, and the destruction or absorption of bone. The classic disfigurements of leprosy, such as loss of extremities from bone damage or the so-called leonine facies, a lion like appearance with thick nodulous skin, are signs of advanced disease, now preventable with early treatment.
Everybody jumped on the bandwagon
Colin Crawford is the only leprologist that question the wide-spread use of thalidomide in treatment of leprosy. Everybody has jumped on the bandwagon and testify that is impossible to do without the drug in treatment of leprosy. Even Dr Shaik Kahder Noordeen, Director of WHO's Action Programme for the Elimination of Leprosy (LEP) in Geneva , has labelled thalidomide a "wonder-drug" and an "excellent drug".
WHO's Action Programme for the Elimination of Leprosy in Geneva has set a ultimative goal: Total elimination of leprosy before the en of the century.
Despite initial concern by prominent leprologists that there may be a recurrence of the teratogenic disaster which had occurred only a few years previously there been no serious discussion about the pros and cons of the usage of thalidomide in treatment of leprosy. In 1973 a researcher issued a warning about the dangers of side-effects in leprosy patients given the drug, with the recommendation that thalidomide be withdrawn as alternative treatment was available. In the beginning it had been assumed that because of the teratogenic dangers, the drug should only be used for research purposes, a view endorsed by the WHO expert committee on leprosy in 1970 who stated that thalidomide should only be used for: "strictly investigative purposes". Yet by 1973 it was being used in at least 62 centres many of which were in developing countries. By 1974 it had become the drug of choice in males and post-menopausal females for the management of ENL. The drug was obtainable directly from Chemie-Grünenthal.
"But WHO did not set up any advisory body to monitor the side-effects, or even to record how many patients were being treated," says Colin Crawford. "The widespread use in developing countries created a new danger because of the absence of any statutory body to monitor side-effects and because of the frequency with which drugs are stolen and misused."
Radical drop in number of cases
For quite some time has the number of registered leprosy cases in the world has dropped radically. According to the WHO's LEP-unit, the number of registered cases has been lowered by a factor ten in ten years, 1986 the stand was 11 million cases, compared with 1,1 million in 1995.
"The dramatic progress achieved in the global fight against the disease makes us more than ever optimistic that the target of eliminating leprosy as a public health problem before the end of the century will be met," said Shaik Kahder Noordeen in a 1994 WHO press release.
In mid-1996 WHO's LEP-unit, announces that the number of registered cases now stands at 926 259. For the first time since global statistics on leprosy were collected, the number of registered cases in the world had fallen below one million. Close to half a million new cases — a human being every minute — are being detected each year, and these detection rates are particularly high in some countries or in areas within countries. During 1996, about 570 000 new cases were detected according to WHO Weekly Epidemiological Record, No. 23. Leprosy remains a public health problem in 60 countries, or areas, but 16 countries contribute to about 90% of the leprosy problem in the world. India heads the list with 560 000 registered cases, followed by Brazil with 95 564. Then follow Indonesia, Myanmar (Burma), Nigeria, Nepal, Bangladesh, Philippines, Mozambique, Ethiopia, Zaire, Madagascar, Sudan, Tanzania, Guinea and Cambodia. About 535 000 new cases (95%) were detected in these 16 major endemic countries, and 73% of the newly detected cases are living in India alone. Among newly detected cases more than 85 000 (16%) are children.
It is tragic scenes like this that WHO want to eliminate. The picture is taken in India in the 1970s. The country alone has about half of the total number of lepers in the world. The disease is found more frequently in poor areas where hygiene, nutrition and housing are poor. The man on the photo did not get the cure soon enough. The loss of sensation that accompanies the destruction of nerves often results in unnoticed injuries. These may result in secondary infections, which cause in the classic disfigurements of leprosy, such as loss of fingers and toes, i.e. disfigurement is not caused by the germ itself, but is signs of secondary infections. Historically the disease spread from its probable area of origin in the Indus Valley in India to the Mediterranean, then on to African, Europe, South America, the rest of Asia and Pacific islands was affected. The disease is much less common now. It is estimated that less than 5 percent of the world population is susceptible.
Total elimination by year 2000
WHO's declared goal is total elimination of leprosy as a public health problem by the end of the year 2000 — that is, reducing the number of cases in the world (global prevalence) to less than 1 per 10 000 population. In June 1996 WHO gives a global prevalence of 1.67 cases per 10 000 population. However, in the top 16 countries, the prevalence rate is still 4.5 per 10 000, i.e. 5 times higher than the elimination target (below 1 case per 10,000 population), and even WHO admits that it will become increasingly difficult to obtain large reductions in the number of cases over short periods of time.
"We have every reason to believe that victory over this age-old scourge is within reach", said Dr Shaik Kahder Noordeen in a 1994 WHO LEP press release. "This is no time to let our guard down, since we have the know-how, the determination and the necessary network to achieve WHO's ultimate goal. A final effort is needed to reach what will remain in history as one of the major successes in the struggle for health and against disease".
Nice picture
But WHO does a statistical manoeuvre to nice up the picture. WHO does only include potential "curable" cases in the statistics, not "chronics" with permanent damages? In mid 1980s the number of cases was over ten millions. In 1991, when the World Health Assembly fixed the year 2000 as the target for the elimination of the disease, the number of registered cases in the world was about 5,5 million. With one struck of the pen the figures was halved. Prominent Swedish leprologists estimates the number of cases with permanent damages to 4,5 - 5 million. Far more than the official WHO estimation of 1 to 2 million individuals disabled because of leprosy, according to WHO Fact Sheet No 101(Revised) May 1996. Since thalidomide is used as a sedative the large number of chronically cases can not be over-seen as a potential group at risk of teratogenic effects; i.e. also individuals with permanent damages can be prescribed thalidomide, thus risking new cases of thalidomide embryopathy.
Leprosy is considered to have been eliminated as a public health problem when its prevalence rate falls below one per 10,000 populations. WHO is close of full-filling the goal. They set normal pre-cautions aside in order to reach the goal: Total elimination of leprosy.
Treatment started in 1950s
When the leprosy bacillus was identified in 1873 by the Norwegian physician Gerhard Henrik Armauer Hansen, it was the first bacterium to be identified as causing disease in man. For centuries, leprosy control consisted mainly of isolating patients. Genuine treatment started in the 1950s with the introduction of the drug Dapsone. Within 25 years, however, the disease had become resistant to the drug, rendering treatment increasingly ineffective. Leprosy is caused by a rod-shaped bacillus, Mycobacterium leprae, which is similar to the bacillus that causes tuberculosis. The leprosy bacillus was first identified in 1873 by the Norwegian physician G. A. Hansen; it was the first bacterium to be identified as causing disease in man.
1960s, dapsone resistance has increased and considered to be in part due to low doses of the drug. Hence it has been mandatory to give full doses of dapsone for lepromatous leprosy and also for those patients with ENL. According to Crawford there is conflicting evidence about the relation between low doses and dapsone resistance. It has been found that 8% of patients given low dose sulphones as sulphetrone (solapsone) developed resistance compared to 2% given sulphones in larger doses as dapsone. In Karamui , New Guinea , long-acting sulphones were given by injection of acedapsone at 225 mg every 75 days which is equivalent to giving only 17 mg weekly of dapsone, whereas the recommended dose to prevent resistance is 700 mg weekly. Moreover, sulphone blood levels in patients given acedapsone were only half those given sulphetrone. Twenty eight lepromatous patients were followed for up to six years using mouse foot pad tests to detect resistance, but none was found.
MDT introduced 1981
The use of a combination of anti-leprosy drugs, known as multidrug therapy (MDT) — a treatment by the "cocktail" of three powerful antileprosy drugs which ensures that the bacillus M. leprae cannot develop drug resistance — was introduced on the recommendation of a WHO Study Group in 1981.The introduction of MDT revolutionized leprosy control with some countries experiencing a tenfold decrease in disease prevalence within five years. The average cost of MDT per patient is US$ 15. Although this is relatively expensive, the treatment periods are comparatively short. In some cases, Dapsone was used over a patient's entire lifetime. Over the past ten years, the leprosy problem has been reduced by 83% worldwide, according to LEP.
This is Moriamnessa with her seven children pictured in 1996. Underneath you see a picture of Moriamnessa taken in 1994 whilst she was suffering from severe lepromatous leprosy. Her whole body was disfigured by large nodules. She got access to multidrug therapy (MDT-treatment) via The Leprosy Mission's DBLM Center in North East Bangladesh, and took all seven children to the clinic for a check up. Five were found to have leprosy and immediately put on MDT-treatment before any disability or disfigurement could occur. Now Moriamnessa and her children have finished treatment. As you can see from the photo above, her appearance is almost back to normal and her children are completely healthy again.
WHO LEP-unit reported that well over 97% of known cases are being treated with MDT in 1997 compares with only 55% who had access to MDT in 1994, and states proudly that MDT has now successfully cured more than 8.4 million sufferers from the disease since 1981. The number of countries showing prevalence rates above 1 case per 10,000 populations has fallen from 122 in 1985 to 55 at the beginning of 1997. Besides the 8.4 million patients who have been cured, LEP claims that more than one million individuals have been saved by multidrug therapy from becoming disabled.
"The global strategy to eliminate the disease, which is based on MDT, is working extremely well," proclaims WHO in a 1996 press release. "The increased coverage is a result of the efficacy and acceptability to patients of this treatment, which is now fully standardized and of fixed duration".
Side-effects and relapses are extremely low
According to LEP more than 15 years of experience with MDT show that side-effects and relapses are extremely low, and there is no evidence of resistance developing to the combination of drugs. The treatment has proved itself both safe and efficacious.
"Drug resistance to MDT has never been reported. The number of treatment failures or relapses remains also very low," writes LEP in a WHO press release from June 1997.
Against these encouraging figures must be set the fact that, in a few high-endemic countries, substantial numbers of patients do not have easy access to diagnosis and treatment. Many live in poor areas, or in such remote districts that they may not even be aware that leprosy is a curable disease.
Cocktail of three drugs
MDT-treatment is a "cocktail" of three drugs. The drugs used in WHO-MDT are a combination of rifampicin and dapsone during six months for patients with the milder form of leprosy (Paucibacillary leprosy).
Patients with the more severe type; lepromatous leprosy, is recommended in 1994 a standardized 24-month WHO-MDT treat combination rifampicin, clofazimine and dapsone. Rifampicin: 600 mg once a month. Dapsone: 100 mg daily. Clofazimine: 300 mg once a month and 50 mg daily.
Among the MDT-drugs rifampicin is the most important antileprosy drug and therefore is included in the treatment of both types of leprosy. No toxic effects have been reported in the case of monthly administration of rifampicin. LEP gives the information that clofazimine is well tolerated and virtually non-toxic in the dosage used for MDT. The drug causes brownish black discoloration and dryness of skin. However, this is said to disappear within few months after stopping treatment. The drug dapsone is claimed by LEP to very safe in the dosage used in MDT and side effects are rare. The main side effect is allergic reaction, causing itchy skinrashes and exfoliates dermatitis. Patients known to be allergic to any of the sulpha drugs should not be given dapsone.
The main novelty with MDT is the mix of three different antileprosy drugs, with a simultaneous increase of dosage. WHO LEP-unit warns in WHO Fact Sheet No 101 that treatment of leprosy with only one antileprosy drug always will result in development of drug resistance to that drug. Treatment with dapsone or any other antileprosy drug used as immunotherapy should be avoided.
According to Crawford it was Sheskin who first introduced high dosages when he gave patients 700 mg of dapsone weekly. Other leprologists recommended lowering the dapsone-dose to only 20 mg weekly. Management with low doses of 10-25 mg weekly was also the rule in northern Nigeria in the 1960s where ENL could be successfully managed, although not completely suppressed, with the addition of 5-10 mg prednisone (a corticosteroid) daily.
MDT theraphy for one year
Recently, the Seventh Expert Committee on Leprosy, which met at WHO headquarters in June 1997, has agreed that, based on the information currently available on MDT- success, "it is possible that the duration of the current MDT regimen for lepromatous leprosy could be shortened from 24 to 12 months without increasing the risk of developing rifampicin-resistance."
Welcoming these moves, Dr Shaik Kahder Noordeen commented in a WHO press release: "The conclusions and recommendations of the Expert Committee, particularly as regards simplifying the chemotherapy, will bring tremendous benefits to the patients, and to the health services which are currently burdened with treating patients over long periods. The simplified treatment is expected to be introduced in the countries concerned in stages, according to the capacity and needs of the national leprosy programmes."
Cleaver enough the decision taken by the Seventh Expert Committee on Leprosy will create further positive statistical revenues for the LEP-mission. If a patient is on MDT-treatment for 12 month period, he will be a figure in the statistics during one single year; thus lowering the total number of cases and at the very same time increasing the chance of WHO reaching it's illusory goal.
Leprosy side effects
The "cocktail" of potent drugs often results in complications labelled under the name of "lepra reactions". ENL (Erythema Nodosum Leprosum) is one of them. It only occurs in lepromatous leprosy and characteristically starts about six months after the commencement of MDT when the percentage of viable M. leprae has fallen to zero, but where there are still masses of dead bacteria. ENL is readily recognised clinically and is exactly the same in appearance as erythema nodosum in other diseases except that it is generalised and is not confined to the legs. According to Crawford it is also chronic and recurrent and lasts for as long as MDT-treatment is being given.
WHO takes a negligent approach on ENL
WHO leprologists gives a completely other view when they claim that the frequency of ENL is reduced during the later stage of treatment, and that "the experience with MDT shows that the frequency of ENL-reaction decrease in patients taking MDT." Clearly WHO takes a negligent approach towards the ENL-problem and what actions are to be taken? The cause of ENL still is uncertain; it may be the failure of the body to clear away dead bacteria which is an important contributory factor in the chronic nature of the syndrome.
The leprosy bacillus was identified in 1873 by the Norwegian physician G. A. Hansen. Yet ENL was hardly mentioned in Hansen's account and it was not until 1913 that this complication was described in detail and concluded that it was "generally benign". "It is interesting and significant that as late as 1958 "lepra reaction" or, ENL, was not regarded as a serious complication and had been regarded as a good sign that the treatment was efficient," says Colin Crawford.
Although ENL was originally regarded as a benign condition it has generally been regarded much more seriously since the introduction of MDT.
Colin Crawford comments: "Undoubtedly, the frequency of ENL has increased markedly since the introduction of chemotherapy and now leprologists considers ENL as it is life-threatening; hence the use of thalidomide is justifiable".
Before the introduction of thalidomide the main treatment for ENL was corticosteroids. If ENL was defined to be "life threatening," then it was necessary to suppress it completely necessitating the use of very high doses of corticosteroids. In fact leprologists have used 160 mg of prednisone/day. At this stage serious side-effects is inevitable, and thalidomide was a welcome alternative.
Is ENL serious?
Actually, what then is the evidence for ENL being a serious complication? Thalidomide is said to have a specific action in suppressing ENL and in reducing the associated temperature but is of questionable value in treating other complications arising during chemotherapy. In view of it's well-known side-effects its use should have been strictly confined to patients with ENL. Unfortunately, in several studies describing it's use, it is not clearly stated whether attacks of ENL did actually occur. Also, many patients have been designated merely as having "lepra reaction", where complications other than ENL have been included and the term has even been used to describe reactions in non-lepromatous leprosy where ENL does not occur.
Wide disparity in ENL frequency
Because ENL has not been strictly defined its reported frequency is found to vary widely between 3% and 50% of lepromatous cases.
Another reason for the wide disparity is that the higher figure is based only on a concentrated group of institutional cases, whereas the low figure includes lepromatous cases treated as out-patients.
The lowest figure of 3% lepromatous cases was calculated in an area where the prevalence of all types of leprosy, determined by population survey, was 0.2% and this agreed very closely with the figure found by out-patient attendance and population as determined from the census. A similar frequency of ENL of 5% lepromatous cases was found in the coastal region of Tanzania by Crawford in a personal observation. Other leprologists gives a figure of 5.9% lepromatous cases from Nepal that supports the Tanzanian findings.
Most patients, however, are treated on an out-patient basis. Therefore, the percentage of patients really in need of thalidomide is more likely to be close to 10 percent of the total number of lepromatous cases in the area, then 50%.
Despite the above evidence, ENL has been assumed to be much more common than it really is, and hence a large number of patients have received thalidomide unnecessarily.
Leprologists often claims that recurrent bouts of ENL have led to amyloidosis; justifying the need for thalidomide, and also the need to suppress the attacks completely using high doses of corticosteroids.
"Lepromatous leprosy patients given dapsone immunotherapy have been shown to have a normal life expectancy, which is the main argument against ENL being a life-threatening condition", says Colin Crawford. "The other complications such as arthritis, iritic or orchitis were not seen in my patients and although proteinuria can occur as a result of amyloidosis this is a complication of untreated disease. Besides, if these complications were common and serious there should be sufficient patients to conduct a therapeutic trial, comparing for example, the effect of thalidomide with corticosteroids but no such trial has been carried out."
WHO says nothing about ENL nor thalidomide
Finally, the WHO official information does not include anything about ENL, and obviously not a single word about thalidomide. In a statement from the 1997-meeting of the Seventh Expert Committee on Leprosy this is the only information given under headline "Management of reactions:"
"The crucial elements in the management of leprosy reactions and, thereby, the prevention of disabilities are early diagnosis of reactions together with prompt and adequate treatment. Most reactions, and neuritis, can be treated successfully under field conditions by a standard 12-week course of prednisolone. If patients do not respond to corticosteroid therapy in the field, they should be sent to an appropriate referral centre."
High thalidomide doses
Back to thalidomide: Leprosy patients have received 400 mg daily, which is well over twice the daily dose when used as a sedative. After a few weeks, WHO leprologists claim, that the dosage can be lowered to 50 - 100 mg/day (The equal of the dose recommended in the 1960s). The main advantage of thalidomide is that the drug is said to mitigate the MDT-allergic reaction of itchy skinrashes and act as a mild traqulizer. Naturally WHO claims that every action in its power is been taken to prevent fertile woman to be exposed to thalidomide.
"Even if it would be possible to avoid the teratogenic effects, it would be impossible to avoid the neuropathic side-effects which were observed in adults of both sexes when thalidomide was used as a sedative," say Colin Crawford. "It should be emphasised that everyone who takes the drug is at risk as there is no evidence that the neuropathy is due to hypersensitivity and is related to the dose and total amount of the drug taken. Also, there is no minimum dosage below which it is safe to give the drug. Thalidomide neuropathy can not be over-ruled in treatment in leprosy patients."
Nicotine and alcohol is well-known to be toxic to be foetus. It is about time that leprologists should recognise thalidomide as a teratogen, with both embryopathy and neuropathy effects that should be avoided.
The nature of the thalidomide neuropathy shows that it primarily affects the axon rather than the myelin sheath and is initially sensory. Burning pain in the feet was a common feature together with cramping pain in the calves. Although all modalities of sensation could be affected the sensory loss was sometimes confined to pain and temperature sensation, leaving joint and position sense and vibration intact, an important point when considering the differentiation of thalidomide neuropathy from leprous neuropathy.
Although primarily a peripheral dying-back neuropathy with the maximal involvement of the longest nerve fibres and with loss of ankle and knee reflexes, other patients showed evidence of pyramidal tract damage with increased reflexes and extensor-plantar responses.
If thalidomide was continued then motor involvement occurred affecting the proximal muscles of the lower limbs.
Surely nerve biopsies in patients with neuropathy showed a loss of mainly larger myelinated fibres and teased fibres confirming that the changes were those of axonal degeneration, without segmental demyelisation. Unmyelinated fibres did not appear to be affected. Nerve conduction studies, both motor and sensory, were normal but sensory action potentials were reduced.
In patients who stopped taking the drug the motor and pyramidal signs recovered but sensory loss was permanent, even years after stopping the drug in over half the patients.
Up to20% with neuropathy
The frequency of this neuropathy was originally uncertain, with estimates ranging from 0,5% to 5-20 %.
"Recently, more reliable assessments are available because the drug has been used in a variety of non-leprous disorders and the frequency has been found to be very high," says Colin Crawford.
At least 21% if electrophysiological studies, especially the recording of sural nerve action potentials, are carried out. Leprologists continue to maintain — that although the frequency of neuropathy in non-leprous disorders is over 20% — not a single case of neuropathy has been detected in a leprosy patient given thalidomide, even though the drug has been in use for 25 years!
"Unfortunately, the current classification is based on the cutaneous manifestations and does not include any information about the presence or absence of nerve damage in the peripheral nervous system", says Colin Crawford.
A spectrum of disease is defined; with at one end the presence of well defined skin lesions, at the other end of the spectrum is the lepromatous form.
"Paradoxically, although there are masses of bacteria in this lepromatous form, nerve damage is slight and late in appearance. This point is not emphasized in the current classification, and perhaps it is necessary to go back to Hansen's description of the disease."
Must define sensory loss
As thalidomide is used to treat a complication which only occurs in the lepromatous form it is necessary to evaluate if sensory loss due to the disease may, or may not, be present.
Colin Crawford comments: "In my own survey a symmetrical loss of sensation was present in four out of 14 patients who had the complication for which thalidomide is being used. In any event, it is imperative that a detailed sensory examination of the peripheral nervous system must be carried out and recorded before starting treatment with thalidomide."
Any deterioration in function while thalidomide is being administered must be assumed to be due to the drug, the more so as we know from Hansen's observation that sensory loss in this form of the disease is insidious and if the treatment is successful, deterioration due to the disease should not occur.
Similarity in sensory loss
Another problem is that the nature of the sensory loss in the disease and due to the drug may be remarkably similar in that both pain and temperature sensation may be selectively involved with preservation of "deep sensation", as described in leprosy patients over 70 years ago. Of course if evidence occurs that deep modalities of sensation become impaired during thalidomide administration then this is due to the drug, and not the disease. There are other symptoms which are distinctive of thalidomide neuropathy but do not occur in leprosy such as burning pains in the legs and cramps in the calf.
Colin Crawford: "The fact that a drug causing a peripheral neuropathy was being used in a disorder where damage to the peripheral nerves was occurring might lead to difficulties in detection of toxic effects did not appear to occur to leprologists advocating its use."
Although neuropathy as a side-effect of thalidomide was recognized by German neurologists soon after the drug was introduced in 1958, this side-effect was not mentioned in Sheskin's initial publications. In 1969 Sheskin were criticized for not mentioning the neuropathic side effects in his publications and an accompanying editorial reference was made in the Lancet (a very well-known medical journal) editorial on thalidomide.
On the contrary, this infamous Sheshin showed no sign of regret. In 1968 a paper appeared jointly by Sheskin, Sagher, Dorfmann and Von Schrader-Beielstein (The last named was an employee of Chemie-Grünenthal, yet this fact was not recorded). In this study, dapsone was withheld and thalidomide was given on its own to test if it had any chemotherapeutic effect.
"Thalidomide is obviously not a cure for leprosy, since it has no effect on M. leprae. Not surprisingly, several patients in Sheskin‘s study deteriorated. It was not necessary to conduct this trial when thalidomide could have been tested for its chemotherapeutic action against M. leprae in the footpads of mice."
A low profile
During the years since the thalidomide disaster in the 1960s has Chemie-Grünenthal kept a low profile. But in a paper from 1974 Chemie-Grünenthal was mentioned in the study where thalidomide even was given to women of reproductive age without contraception. New derivatives obtained from Chemie-Grünenthal were tested in countries such as Tanzania and Ethiopia , presumably without the detailed and expensive procedure which is mandatory in developed countries. In 1976, according to information from David Owen, then the Minister of Health to Jack Ashley MP, some 12 derivatives of thalidomide were in the process of being investigated but it is not clear how many of these drugs were given to leprosy patients or what safety tests were carried out.
Neuropathy ignored
All this time the neuropathic side-effects were being ignored and in the WHO expert committee on leprosy in 1977, there is no mention of neuropathy as a side-effect. Severe neurological disturbances did occur after administration of thalidomide but were considered to be of "uncertain causation", or ascribed to Guillain-Barré polyneuritis (a rare disease and not nearly as common as thalidomide neuropathy). One particular patient developed muscular paralysis involving muscles around the hip, consistent with the pattern of thalidomide nerve damage of considerable severity as muscle paralysis only follows sensory loss, but this was diagnosed as a rare form of dimorphous leprosy.
Another warning about the dangers of thalidomide neuropathy was issued in 1978, but was ignored. In the 1980s the drug was now being used for a variety of non-leprous disorders. In 1987, thalidomide ernbryopathy was detected by ultrasound and an abortion carried out at 17 weeks to a Brazilian woman who had leprosy and had been given thalidomide.
The WHO expert committee on leprosy in 1988 again did not mention that thalidomide could cause a neuropathy, but while emphasizing that thalidomide should only be given to men and post-menopausal women, this group stated that the: "treatment of choice for ENL is thalidomide, and the importance of making this drug available cannot be overstressed."
"Inevitably, this recommendation must have increased the risk of the drug being given to a pregnant woman by mistake," says Colin Crawford.
Severe nerve damage
The 19th edition of Martindae, The Extra Pharmacopeia published in 1989 stated that the nerve damage produced by thalidomide could be: "severe and irreversible". In the same issue claims were made that the nerve damage resulting from thalidomide was a rare complication and could be: "reversed by stopping treatment or reducing dosage", a view repeated in 1992.
Even later well-known leprologists tend to ridicule the threat of thalidomide side-effects. Yet, even if clinical evidence of sensory loss is to be seen in lepromatous leprosy, most patients already have some thickening of the peripheral nerves which would predispose to nerve damage from thalidomide so they claim that "the nerves of lepromatous patients are relatively insusceptible to thalidomide-induced nerve damage."
Crawford’s conclusion
Colin Crawford sums up his investigations in a conclusion. Thalidomide has very serious side-effects, yet it has not been excluded in leprosy patients given the drug. By failing to take this side-effect seriously leprologists have recommended the widespread use of the drug especially in developing countries resulting in a teratogenic tragedy, like the one recently revealed in Brazil.
Thalidomide suppresses ENL, but this complication of lepromatous leprosy is not serious and its frequency has been exaggerated. Treatment with thalidomide can be avoided as alternative methods of management are available. These include low dose dapsone together with low doses of corticosteroids or clofazimine. The view that low dose dapsone leads to resistance is challenged. Chemotherapy in lepromatous leprosy complicated by ENL should not be prolonged indefinitely. By ceasing chemotherapy, the attacks of ENL may be greatly diminished.
Thalidomide should not be used
In view of the evidence presented here, thalidomide should not be used any longer for the management of ENL. But thalidomide is easy to produce at a very low cost. This is the main reason why it is proclaimed "the drug-of-choice" in the management of ENL. In the past sufferers from leprosy was gathered in leprosy-colonies, where medication could be easily monitored. At present, the favourable method in treating the patients is on an out-going basis in their own residential area.
The difficulties of multi-dose treatment for lepramatous leprosy are considerable. Getting patients to comply with "doctor's orders" is a problem in any country. The primary health care workers has to persuade each person to return to the health centre, for continues treatments over a period of a full year so the can supervise the taking of the treatment. Often a big volume of thalidomide is in circulation, due to the ambitious plans of national health programmes. In many developing countries the monitoring, and surveillance systems is not working properly; thus resulting in severe congenital malformations.
WHO LEP is shockingly silent
In this very moment, new babies are being born with thalidomide embropathy in countries such as Argentina, China, Peru, Cuba, Nigeria, as-well in other African countries.
WHO LEP-unit remains shockingly silent. Dr Shaik Kahder Noordeen has on several occasions been informed by Thalidomide's about this ongoing tragedy. Dr Nordeen is reluctant to discuss the subject of thalidomide side-effects. In a recent book review he instead has advocated the use of thalidomide (Manson's Tropical Diseases 1996, p 1016).
When he was confronted with photos of numerous Brazilian babies with thalidomide embryopathy by the British First Tuesday-team from Yorkshire Television he commented that this is not a substantial problem, since only a minimum of cases has been presented in scientific literature.
"One is entitled to ask whether this teratogenic disaster could have been avoided if misleading information about the neuropathic side-effects of thalidomide had not been published and if more serious efforts had been taken to detect it in leprosy patients. The realization that the drug was to toxic to use could then have averted this tragedy," says Colin Crawford.
Colin Crawford is the solely leprologists who has the guts to question the widespread misuse of thalidomide in the treatment of leprosy. All experts are blind for the side-effects of thalidomide in the holy war against leprosy; which must be won before the year 2000. Leprologists legitimate thalidomide of truly false premises. What is a few thousands babies afflicted with thalidomide birth-defects compared with hundreds of thousands successfully cured from leprosy?
The publication of an article on the Brazilian woman with an foetus showing thalidomide embryopathy in 1988 — and showing that the control of thalidomide in Brazil was extremely lax — as confirmed by the 1993 Yorkshire Television film: "Thalidomide: The drug that came back." These two independent sources revealed that horrifying events had been taking place over many years, which were not disclosed by the leprologists using the drug. Now with such clear evidence Thalidomide's, and concerned individuals as Colin Crawford, thought that action should be taken by WHO-LEP. After all, Dr Shaik Kahder Noordeen had said in front of the television camera that WHO would give this alarming situation a full penetration, and that analyse then would point-out anappropriate line-of-action.
Nothing has happened
Since the 1993-film disclosing the tragedy in Brazil was shown, nothing has been done to rectify the situation. Despite the assurance of WHO, given in the film that the use of thalidomide would be reviewed nothing has been done to prevent a recurrence of this tragedy. Although the tragedy in Brazil was revealed several years ago none of the leprosy journals has even mentioned this disaster. During a 1996 Leprosy Congress in Orlando, Florida a Indian speaker only briefly talked about "rumours of thalidomide embryopathy" and when Colin Crawford confronted the Brazilian delegates they first denied the existence of Brazilian women having babies with thalidomide embryopathy and first after picking up a video-cassette with a copy of the British film from his brief-case they had to agree. Colin Crawford asked the organizers of the conference for a special session so he could show the film to the thousands of delegates; thus creating a climate for a sincere discussion, but the organizing committee refused.
"It was only after I threatened to notify the press that time was allowed late one evening. Only 40 persons attended, no conclusions where drawn. Dr Noordeen was present but did not comment, and left before the end of the meeting", says Colin Crawford.
Withdrawal of thalidomide
In view of the arguments advanced here the right solution should be to withdraw thalidomide for use in leprosy and substitute it with alternative treatment regimens. Crawford has showed in his work that there is a substitute for thalidomide. It is an outrage that the cost per pill is the only crucial parameter taken in account by leprologists; thus sentencing numerous thalidomide-affected children to a life in poverty in developing countries.
"Children with thalidomide-induced birth-effects are still being born. And as no leprosy organisations, nor WHO, are prepared to monitor the number of cases, it is left to Thalidomide Associations to draw the attention to this continuing tragedy," Colin Crawford says open-heartily.
WHO-LEP is cynically overlooking the existence of the 2nd generation Thalidomide's as the battle against leprosy is coming close to the finishing-line in the year 2000. What is a few thousands babies afflicted with thalidomide birth-defects compared with hundreds of thousands successfully cured from leprosy?
References:
Crawford CL. Use of thalidomide in leprosy. Adverse Drug Reset. Toxicol. Rev.1994,13(4) 177-192 (Click on this hyper-text if you want to read Mr Crawford's article in fulltext)
WHO Press Release 42, 20 May 1994
Fact Sheet No 101(Revised) May 1996
WHO Press Release 39, 21 May 1996
WHO Press Release 45, 3 June 1997
WHO WEEKLY EPIDEMIOLOGICAL RECORD, No. 23, 6 JUNE 1997
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