Leprosy Mailing List – June 11, 2015
Ref.: (LML) Bolus treatment and the prevention of nerve damage in Erythema Nodosum Leprosum ENL
From: Ben Naafs, Munnekesburen, the Netherlands
Dear Pieter,
May I refer to my previous letter to LML, May 28, 2015: Treatment and prevention of reversal reaction (T1R) and nerve damage in leprosy. This present letter concerns: Bolus treatment and the prevention of nerve damage in Erythema Nodosum Leprosum ENL.
Oral, parenteral and surgical treatment and prevention of nerve damage in multibacillary patients.
Most of the damage in multibacillary patients occurs during reactions which are frequently type 2 leprosy reactions (T2R).
Erythema Nodosum Leprosum (ENL) reaction or T2R, is an event in the course of a leprosy infection that may occur in mid borderline, borderline lepromatous and lepromatous (BB, BL and LL) patients treated or untreated with anti-leprosy treatment. But even before during and after the T2R episodes nerve damage may occur.
Nerve damage not directly ENL related.
The early nerve damage (mostly demyelination) may be the result of entrance of M.leprae into the Schwann cell or by complement activation leading to the membrane attack by MAC of the Schwann cell activated by the lipoarabinomannan (LAM) of the cell wall of M.leprae (innate immunity). The prevention of these occurrences like in T1R is anti-leprosy treatment. The earlier the better.
Some of the damage may be due to the adaptive immunity when a patient downgrades in the spectrum. Due to the inflammation as result from this CMI reactivity (the host tries to upgrade in some) there is nerve damage. This damage can be prevented with steroids or sometimes with NSAID’s while giving MDT in the meantime. The risk of treatment is that the patient goes in a frank T2R (due to the dying bacilli there is an increase in M.leprae antigenic determinants), which than has to be treated. But despite this phenomenon anti-M.leprae treatment stays the mainstay of treatment of leprosy reactions .
Erythema Nodosum leprosum
When a patient goes into ENL there is an antigen-antibody reaction leading to complement activation and the recruitment of eosinophils accompanied with inflammatory oedema and tissue damage. This may happens in the whole body except the CNS. But it happens in peripheral nerves too. A good thing is that usually an ENL reaction is self-limiting, lasting only 1-4 weeks. But when it becomes chronic, (I think, that is due to wrong treatment with steroids) usually it may cause a lot of damage, not only to the nerve but to other organs as well.
Treatment and prevention of ENL.
From clofazimine it is known that it diminishes the number of ENL attacks; it thus prevents. In higher dose (100-300 mg/day) it can be used as treatment and prevention of new attacks. The treatment works slowly and the dose should be diminished again after some time to prevent gastro-intestinal problems. Whether it really works as treatment or mainly as prevention for the next attack has to be investigated, since T2R (ENL) is self-limiting. Many treatments therefor have been claimed to be effective, when the improvement is actual the natural course.
When a mild ENL occurs, treatment may consist out of NSAID’s making the patient more comfortable and possibly decreasing the inflammatory oedema in the nerve. Whether it is actual stopping the T2R has to be seen. When there is arthritis too, antimalarials are considered effective.
More severe ENL is treated with steroids. Since ENL is episodic and complement mediated the steroid treatment needs to be high. At least 60-120 mg at start. Since the ENL activity weans by itself the steroids can go down too (within 2-4 weeks). But when the tapering goes to quickly the ENL may flair up again and the dosage should go up to at least double the given dose. Low dose steroid maintenance treatment does not really prevent new ENL reactions but may lead to steroid dependence.
When people have severe ENL a 3 days bolus dose with 100-150 mg hydrocortisone IV daily may be helpful to curtail the immunological events leading to T2R more quickly than oral treatment does. These interventions have been done with other diseases as well, with great effect. In non-double blind trials in leprosy it seemed effective.
Another effective treatment is thalidomide, 100-300 mg start, tapering off within 2-4 weeks to a maintenance dose of 50-100 mg daily. Thalidomide is nearly the only drug for which a preventive action is shown. Low dose thalidomide should not be given with low dose steroids together, because they seem to counteract each other. Disadvantages are the well-known teratogenicity and the peripheral sensory loss; the latter is better known for other diseases .This is underestimated in leprosy were the loss of sensation is usually attributed to the leprosy itself.
Alternative treatments
A drug which seems to suppress and heal T2R is methotrexate (MTX). In my experience MTX on the long-run prevents ENL. It can be used to wean patients of steroids. It may diminish the activity of the antibody producing B and plasma cells. A biological that suppresses these cells like the anti CD20 rituximab is as far as I know not yet tried.
A drug claimed to be effective in ENL is pentoxyfilline being a TNF-alpha inhibitor. It surely has an effect on the concomitant peripheral oedema, but according to me the ENL takes it normal course and heals spontaneous. The anti-TNF alpha biologicals have been claimed to be effective, but since I doubt this is the crucial molecule in ENL I wonder whether it really shortens the natural course of ENL.
Colchicine is used in treatment by some. Apart from inhibiting mitosis, colchicine also inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect. It has a narrow therapeutic index, with no clear-cut distinction between nontoxic, toxic, and lethal doses.
Azathioprine has been used with little effect, what could be expected since it is mainly used as an anti-Cell Mediated Immunity drug.
Promising may be the use of anti IL5 antibodies which diminish the action of eosinophils. But a problem is like all biologicals they are prohibitive expensive.
Not so expensive and in trials really preventing in many (but not all) patients a T2R is vaccination, with non-tuberculous mycobacteria NTM’s like M.vaccae or M.w.
When patients have a continuing damage of the nerve due to oedematous compression not reacting on medical treatment, a nerve release operation should be considered.
When patients continue to suffer from ENL it is worthwhile to look in the triggering factors. These can be varied ranging from stress to intestinal parasites (some think this the major factor), diabetes, anaemia, infections (Foot ulcers, TB), vaccinations and many more. These should be treated.
Mark: for all nerve damage it is important to assess the nerve function regularly to guide your attempts to treatment
Ben
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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