Leprosy Mailing List – May 28, 2015
Ref.: (LML) Treatment and prevention of reversal reaction (T1R) and nerve damage in leprosy
From: Ben Naafs, Munnekesburen, the Netherlands
Dear Editor,
Challenged by dr Muherman Harun from Jakarta, I would like to write my thoughts about treatment and possible prevention of Reactions and nerve damage in leprosy.
I will start with the Reversal or Type 1 leprosy reaction.
Treatment and prevention of reversal reaction (T1R) and nerve damage in leprosy
Introduction
Although most of the nerve damage in leprosy takes place during episodes of exacerbation of the disease called “reactions”, there is damage that occurs before, even during and after reactions that cannot be accounted for by the reaction. In this paper we deal with treatment and prevention of nerve damage, keeping the theoretical pathophysiologic mechanisms in mind.
Contact and complement mediated demyelination
The nerve damage start most likely by M.leprae making contact with the nerve and its entrance into the Schwann cell with demyelination as consequence.
This contact mediated demyelination can be prevented by anti-leprosy treatment (MDT).
At the same time complement activation occurs which leads to Schwann cell death and in this way to demyelination too. For the complement activation probably lipoarabinomannan (LAM), a cell wall component of M.leprae, is responsible. LAM is degraded only slowly after the bacillus is dead. Treatment, killing M.leprae, is therefore only effective in the long run when the LAM is degraded. Thus the damage may occur over a long time.
High dose steroids may diminish complement activation in general. A lower dose may stop only the T-cell mediated complement activation. A new drug eculizamab may stop the action of Complement factor 5 (C5), and thus the formation of the final Membrane Attack Complex (MAC), responsible for the dead of the Schwann cell. This has, as far as I know, not been tried. Action of heparin, antimalarials, promethazine and chlorpromazine against complement activation has been proposed but not researched in this condition.
Damage due to Cell Mediated Immunity
Most of the damage is due to a T cell mediated action ( this seems to be against antigenic epitopes of M.leprae either on remnants of bacteria or on/in host own cells as an autoimmunity), the T1R, which can be stopped, in my experience, with relative low dose (30- 40 mg) prednisolone in BB-LLs and usually higher dose (40- 60) mg in BT. The difference in starting dose is determined by the strength of the CMI and thus the place in the spectrum. These dosages can be tapered off to 0,25 mg/kg (15-20 mg) within 2-3 months, stay at that level 2-10 months and stopped when no further improvement occurs within 1-2 months. The progresses of improvement and deterioration of the nerve function should be monitored, at least monthly, in the initial period preferably twice a month. This can be done by VMT, ST, electro-neurophysiology or imaging by echo-Doppler duplex. When these parameters deteriorate due to tapering down the anti-reaction treatment, the treatment has to be increased to the previous dose till a next trial of renewed tapering off. Be aware that a T1R may last months!
Mechanical compression of the axon
The inflammatory oedema within the osteo-fibrous passages and within epi- and particular endoneurium may lead to compression and thus demyelination and axonal dead. If the axon does not die directly from the demyelination the compression compromises the flow in the axon too, the peripheral part of the axon does not receive nutrients anymore from the cell body and dies. Even when the immunological inflammation weans, a venostatic oedema, due to a compression of the draining veins within the perineurium, may remain and thus the compression within the endoneurium continues. This compression will contribute to further damage. The fact that the blood flow is diminished by the compression of the veins will contribute to a bad nutrient supply of the endoneurium , depriving the remaining Schwann cells and axons from oxygen and nutrients.
Bolus dose of steroids
As we just theorized, some of the early damage in a T1R may be due to inflammatory oedema in the nerve. A bolus dose of 100-150 mg hydrocortisone IV can be considered for 1-3 days where after the usual prednisolone dose can be given. Some authors advocate to take away the compression be surgery. For T1R reactions I have only experience with a higher dose of oral steroids not with a IV bolus and not with initial surgery. I would not advice surgical intervention at start but may be very useful later on.
Alternative treatments for T1R
After an initial treatment with steroids of about 1 week (important against the compressing oedema in the nerve), cyclosporine can be given instead of the steroids to diminish the CMI.
I have only little experience with azathioprine, but I think it is not very effective. Some use it for enabling them to lower the steroid dosage.
From the biologicals TNF-alpha inhibiters may be of help. I used it once with effect. But it should be given during the whole T1R which lasts between 4 and 18 months. All biologicals and biosimilars are very expensive and not yet investigated in T1R.
It has been noticed that dapsone prevents the development of a T1R in “active” patients and it even can be used in some patients for treatment but due to the high dosage needed, side effects (haemolyse) are common often independent of the G6PD status.
When with medical treatment in one or two nerves no improvement occurs when other nerves improve in one to two month time, a nerve release operation should be considered, the inflammatory oedema has than changed to a venostatic one. In my experience this is very effective.
In my hands clofazimine does not improve T1R, neither does thalidomide.
It is clear that all types of nerve damage will benefit from decreased antigen and bacterial load. For the present time MDT seems most appropriate.
In summary
Present anti-reactional treatment restores nerve function and prevents further deterioration of nerve function. It is effective in the majority of the patients, but it does not lead to full recovery in an estimated quarter of the victims. It is therefore essential that the search for alternative treatments continues.
But for all nerve damage it is adamant to diminish the antigens. For the present MDT seems most appropriate, but its duration is disputable.
The mechanism behind chronic neuritis and pain with or without continued deterioration of nerve function (after release from treatment, with no signs of reaction or relapse) is not known and stays an enigma and again deserves investigation.
These treatments can be given to outpatients. Only for severe reactions and bolus treatment patients have to be attended to in the clinic and for surgery they have to be admitted too.
Acknowledgment:
I thank Salvatore and Pieter for their careful reading and comments.
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
