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Leprosy, Prednisolone, and Low DHEA
- James M. Howard (18 June 2004)
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Nerve damage in Leprosy : Prevent it before its too late !!
- Susheel Oommen John (18 June 2004)
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Few questions
- Shingirai Chiruka (19 June 2004)
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Nerve Damage in Leprosy
- Colin L. Crawford (21 June 2004)
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Ensuring compliance with treatment
- Amir-Reza Mehrkar-Asl (23 June 2004)
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Not by Steroids alone
- Antonio Salafia, Gautam Chauhan (23 June 2004)
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Preventing nerve impairment in leprosy
- Alan W Fowler (2 July 2004)
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James M. Howard, independent biologist 1037 North Woolsey Avenue, Fayetteville, Arkansas 72701-2046, U.S.A.
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It is my hypothesis that dehydroepiandrosterone (DHEA) was selected by evolution because it optimizes replication and transcription of DNA. Therefore, all tissues may be affected by levels of DHEA. I think increases in DHEA produced mammalia (“Hormones in Mammalian Evolution,” Rivista di Biologia / Biology Forum 2001; 94: 177-184). I suggest DHEA positively affects growth in a reciprocal cycle involving “recruitment” of DHEA via cell produced molecules which stimulate DHEA production and absorption of DHEA at cell surfaces. Some molecules are more universal and some are more specific. That is, some molecules stimulate growth in many tissues, such as growth hormone, while others are specific, such as nerve growth factor, among many. Exogenous molecules may also affect DHEA “recruiters” in specific ways that promote growth generally or specifically such as anabolic steroids or cocaine. Growth and addiction may be controlled by the same mechanism. Prednisolone may act in this manner. Since I think all tissues are affected by levels of DHEA, this includes the immune and nervous systems. In 1985, I first suggested low DHEA may result in vulnerability to the AIDS virus. (The term, HIV, did not exist at the time.) The first report of low DHEA in AIDS appeared in 1989 and, while major, national organizations fail to acknowledge this connection, a debate about AIDS and DHEA continues to this day.) Subsequently, I decided that low DHEA may result in vulnerability to other infectious agents; this has been supported in many areas. Therefore, when leprosy attracted my attention, I expected that DHEA would be low. This is supported. “In contrast, adrenal androgen dehydroepiandrosterone sulphate (DHEA-S) plasma levels were significantly lower in leprosy patients than in sex-matched control subjects.” (Parasite Immunol 2003; 25: 457-61). (DHEA-S is the large, reserve source of DHEA.) I suggest low DHEA results in vulnerability to the infectious agent and that continued low DHEA results in the symptoms of the “disease.” I suggested that the symptoms of AIDS actually represent the symptoms of loss of DHEA; since then, others have suggested this. The symptoms of leprosy may also be due to loss of DHEA in a manner characteristic of the infectious agent dissimilar to that caused by the HIV. Now, if prednisolone acts to stimulate a “recruitment” of DHEA, then prednisolone, and other glucocorticoids, may ameliorate symptoms of loss of DHEA. I suggest this is the basis of the effects of glucocorticoids in infants whose lungs are poorly developed and positively stimulated by glucocorticoids. However, it is known that some infants of this type are not helped by this treatment. They may represent infants who developed poorly because of low DHEA in utero and who cannot respond to glucocorticoids at birth because they cannot produce sufficient DHEA upon glucocorticoid stimulation. In the case of Smith, et al., I suggest individuals with leprosy, who did not respond to prednisolone, are unable to mount a DHEA response. Low DHEA in these individuals may result in the both the infection and nerve damage, among other symptoms. When prednisolone causes recruitment of DHEA, the DHEA positively affects the nerves. In those who cannot maintain DHEA levels, the nerve damage continues. Evidentally, nerve damage may indicate when DHEA is too low to respond to prednisolone. (The mechanism involves prolactin, which has been shown to specifically and positively affect DHEA production. It is my hypothesis that melatonin and DHEA reciprocate to produce our circadian rhythms. (When melatonin is high, sleep occurs. When DHEA is high, consciousness occurs.) Melatonin induces sleep by reducing levels of DHEA. This suppression of DHEA causes “recruitment” of DHEA throughout the night in increasingly greater amounts until DHEA responds in sufficient amounts to stimulate consciousness. (This small recruitment of DHEA during sleep maintains brainstem function during sleep. It is known that the first slow wave sleep is the deepest with each subsequent cycle lessening in depth of SW sleep. This is due to the recruitment.) Melatonin induces sleep, or DHEA reduction, by inhibiting prolactin production. Just before morning consciousness, there is a large production of prolactin. Prednisolone is used to inhibit prolactin production. Drugs of abuse affect prolactin production. If prolactin production is inhibited by prolonged, excessive use of glucocorticoids, many tissues are adversely affected. I suggest this occurs because of excessive, prolonged reductions in DHEA.) Competing interests: None declared |
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Susheel Oommen John, Consultant Research Resource Centre, The Leprosy Mission, New Delhi 110001
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The TRIPOD study has established beyond doubt that "blanket treatment with corticosteroids" is not the answer to tackling the problem of nerve damage in Leprosy. The currently used field methods to detect nerve function impairment using the sensory testing on hands and feet and the Voluntary Muscle Testing, although sensitive enough to detect nerve damage,detects the "deficits"!. As the neural tissue has very little capacity to regenerate,the current modality of using corticosteroids once the damage has been established may perhaps be the reason for not being able to reverse the damage completely. A significant number of nerve fasicles need to be damaged before the VMT/ST to detect nerve damage, sadly this may be too late ! The whole problem of leprosy being a dreaded disease is the deformities that it causes, and the associated stigma. If the stigma associated with Leprosy has to be reduced, we need to have solutions to problems that lead to it. When we say Leprosy is curable, we need to ensure that we have methods in place to ensure that no one with WHO grade 0 deformity at diagnosis, worsens in thier grading at stopping of treatment or beyond it. The mere killing of Mycobacterium Lepra does not amount to cure, at least not to someone who develops nerve damage despite early diagnosis and regular treatment with Multi Drug Therapy. We need to have methods to detect early nerve damage, early enough so that as many nerve fasicles could be saved, and these methods have to be sensitive as well as cost effective to be used in the field. We also need treatments beyond just steroids and immunomodulators, we need to answer why nerve damage in Leprosy is so peculiar ?. But with the emphasis on reducing prevalence , research funding for basic sciences research in leprosy seems to be reducing faster than the prevalence itself. Competing interests: None declared |
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Shingirai Chiruka, SHO Neurology B15 2TH
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Was the choice of 4 months treatment empirical, based on prior clinical experience or studies? In the results section the authours state that at four months there was a significant reduction in the primary outcome, quoting a figure of 75% but no calculated p - value, the same applies to the results at twelve months; a 31% reduction however may sound significant. I found Table 1 difficult to understand, does it relate to all the patients or to patients in one particular arm? With respect to pre-existing nerve damage, were the severity of nerve damage in the two arms comparable? Competing interests: None declared |
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Colin L. Crawford, Retired 23 Grafton Rd, London W3 6PB
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Sensory loss in leprosy leads to mutilation of the digits, trophic ulcers and Charcot's joints. In Smith et al's study of nerve impairment (1), both in the control and prednisone treated groups, none of these complications appear to have occurred. This is not surprising because, as Lockwood and Kumar point out (2), peripheral nerve damage is immune mediated, whereas in multibacillary leprosy there is a defect in the immune system. Smith et al's assessment appears to be based on impairment of individual peripheral nerves such as the ulnar, median and tibial nerves, but it is well known that mononeuritis multiplex lesions do not give rise to mutilation of the digits. In leprosy, a purely sensory polyneuritis could be responsible for the mutilation of the digits, trophic ulcers and Charcot's joints (3). Furthermore, this polyneuritis is acute, leading to sensory loss in all four limbs, but occurring in the paucobacillary and not the multibacillary form of the disease. Motor loss can occur through nerve compression because of the intense oedema in this acute phase. This information was published in the British Medical Journal (BMJ) in 1991 (4). Lockwood and Kumar claim that erythema nodosum leprosum (ENL) occurs in 20% of lepromatous cases (2), but were not reported in any of Smith et al's patients. Lockwood and Kumar (2) omit to mention that thalidomide causes a neuropathy which can be serious and irreversible. It is worth emphasising that the first report of this neuropathy was printed in the BMJ in 1960, by a general practitioner in a letter to the editor (5). As nerve damage is the main reason why leprosy is a serious disease, it would appear logical that neurologists would be the most competent to become familiar with this disease, instead of dermatologists as Lockwood and Kumar maintain. 1. Smith WCS, Anderson AM, Withington SG, Van Brakel WH, Croft RP, Nicholls PG, Richardus JH. Steroid prophylaxis for prevention of nerve function impairment in leprosy: randomised placebo controlled trial (TRIPOD). BMJ 2004; 328: 1459-62. 2. Lockwood DNJ and Kumar B. Treatment of leprosy. BMJ 2004; 328: 1447-8. 3. Monrad-Krohn GH. The neurological aspect of leprosy. Christiania: Jacob Dybwad, 1923. 4. Crawford CL. Leprosy in reaction. BMJ. 1991; 303: 647. 5. Florence AL. Is thalidomide to blame? BMJ 1960: 2: 1954. Competing interests: None declared |
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Amir-Reza Mehrkar-Asl, Student Doctor School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2SP, UK
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I was interested in finding out how compliance with the (steroid) treatment was ensured by the researchers. Did the researchers incorporate a particular method in the study design to monitor compliance? If so, was there any concern over how robust this was? Competing interests: None declared |
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Antonio Salafia, Chief of Reconstructive Surgery Vimala Centre, Bombay 400053, Gautam Chauhan
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The authors of the article are aware of the fact that in 1997 dr.Chauhan and I published a book on "Treatment of Neuritis in Leprosy. Medical and Surgical." In the book, among other things, we stressed the point that Steroids alone are not an effective way to tackle neuritis, at least in a good number of patients: surgery should be considered as an adjuvant in many cases, and in those cases where there is clinical evidence of mechanical compression, surgery should be the first line of treatment. Steroids should be used in high dosages to be effective: we suggested as 'rule of the thumb' 1 mg.of Prednisolone or its equivalent /Kg/Day(pg.76). In severe cases, and in hospital set up, we use - and suggested too - I.V. drip of 1 pint of normal saline with 8 mg.or more or Betamethasone(pg.78). Again in the book it is said that in children neuritis can cause extensive and rapid-onset damage, and hence surgery should be considered without delay(pg.125). Nerve damage is more severe in those who have had a previous episode of neuritis,as compaired to those who have a first-time neuritis(pg.126). We quoted a research worker who maintains that steroids diminish the rate of axon regeneration and hence are potentially harmful, at least as far as nerve function is concerned(pg.82). Lastly; in case of neuritis we advice first and foremost medical treatment with steroids in high dosages, anti-inflammatory and anti-edema drugs; further we insist on rest to the limb and when 2-3 weeks of medical care do not benefit the patients, we go in for surgery. Mechanical compression is more common that so far noted, and we have listed (and demonstrated with photos) all the types of mechanical compression. It is evident that no drug can relieve a mechanical compression. Our statements are based on 15 years experience; we have examined and treated medically more than 10 thousand cases of neuritis (ours is a referral centre) and have operated upon more than 2500 nerves. Competing interests: None declared |
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Alan W Fowler, Retired Home CF31 iQJ
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Dear Sir, Preventing nerve impairment in leprosy The study by Cairns Smith et al highlights the ongoing problem of late nerve damage in treated leprosy. Just when we think we have conquered the infection we are defeated by reaction. I am convinced that, until we find an effective drug regime, we need to adopt a radically different approach to the problem- a solution based on the pathogenesis of the nerve damage It is surely no coincidence that the sites of permanent nerve damage in the limbs are where nerves pass through tunnels and where even normal nerves are liable to become compressed. Fig 1 shows the grossly swollen ulnar nerve on the inner side of the elbow after opening the cubital tunnel of a patient with reactive leprosy causing complete paralysis of the hand. This nerve could not avoid being severely compressed in a normal cubital tunnel.* The concept of ischaemia from tunnel compression as the cause of permanent nerve damage is consistent with the authors’ findings that later nerve damage is more likely if some damage has already occurred. Those with narrower tunnels are clearly more likely to suffer from long term compression leading to permanent damage. Paul Brand showed how the loss of nerve function leads to loss of tissue but he surmised that the selective damage to the ulnar, median and posterior tibial nerves was because they were subject to cooling at points where they become superficial. But, like so many others, he did not recognise that the real problem is that at these superficial sites the nerves are lying in protective tunnels. I am not suggesting nerve decompressions for all lepers, but in view of our current failure to prevent late onset reactive nerve damage, leprologists should be ready to advise decompression in carefully selected cases. Carpal, cubital and tarsal tunnel decompressions can all be done under sedation and local anaesthesia. They are minor procedures compared with the major disability of loss of nerve function. But bad surgery could make matters worse and training is vital. For example, ulnar decompression must extend below the elbow and beneath the arcuate ligament (which gives rise to fibres of the flexor carpi ulnaris). Because of the severe nerve swelling, the carpal tunnel should be opened under direct vision and operations should be performed in a bloodless field. Alan W Fowler * Original photograph can be supplied Competing interests: None declared |
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