A very conspicuous pathognomonic sign of early states of Duchenne muscular dystrophy (DMD) is the disproportion between size and strength of the skeletal muscles, being most prominent in the enlarged calves. Duchenne himself addressed this sign in all his descriptions of the disease in the decade of 1860-1870, and finally decided to name the disease "paralysie musculaire pseudo-hypertrophique
). Today, 150 years later, the reason and origin of this enlargement is still a matter of debate. Previously a muscle oedema that could contribute to the enlargement was reported (2
). Etiologically it was widely attributed to an interstitial inflammation.
Our own group became interested in this problem after we had identified an increased sodium and water content in chronically weak muscles of patients having hypokalemic periodic paralysis (HypoPP) (3
). In our search for oedemas we used Magnetic Resonance Imaging (MRI) with a Short-Tau Inversion Recovery (STIR) 1H MR sequence. We also had tackled the question as to whether these oedemas were of an interstitial or an intracellular kind by equipping our set-up with a 23
Na MRI Inversion Recovery sequence (Na-IR) which partially suppresses the signal raised by free sodium in the extracellular fluid and thus mainly represents cytoplasmic sodium (4
). In the HypoPP patients the nature of the oedema turned out to be cytotoxic.
With our experience in Paramyotonia and HypoPP patients we applied the same MRI techniques to Duchenne patients in order to unravel the question of pseudo-hypertrophy in this disease. A pilot study on 11 DMD patients suggested that also in this disease muscular sodium and water content is increased, thus causing an osmotic oedema (5
The main aim of the present study was to find a drug for the treatment of the oedema in DMD. Again, we were guided by our findings with periodic paralysis patients: chronic weakness of HypoPP patients was improved by acetazolamide (3
) while episodic weakness of HyperPP patients was relieved by both hydrochlorothiazide and acetazolamide (6
Acetazolamide repolarised electrically depolarised muscle fibres and this in vitro
effect was considered to be responsible for the in vivo
effects on MRI and on muscle strength (3
). Since acetazolamide is a carbonic anhydrase inhibitor, it exerts acidifying effects resulting in respiratory depression. Therefore carbonic anhydrase inhibitors might be contraindicated in DMD. Similarly inappropriate might be hydrochlorothiazide because of its K+
wasting effects which would contribute to muscle weakness.
Therefore we were searching for another diuretic agent. Guided by the experience that spironolactone has favourable effects on episodic (7
) and chronic weakness (3
) in HypoPP, an aldosterone antagonist was taken into consideration. As eplerenone has a higher affinity to the mineralocorticoid receptor and a lower to sexual hormone receptors than spironolactone, it was taken for further testing. Before administering eplerenone to a patient we first tested the repolarizing drug on a cellular DMD model. Since the results with the model were very promising, we treated the marked oedema of a female, wheelchair-bound DMD patient who never had corticosteroid medication.