Rationale for treating edema in Duchenne muscular dystrophy with eplerenone

Rationale for treating oedema in Duchenne muscular dystrophy with eplerenone

May 2012

FRANK LEHMANN-HORN, MARC-ANDRÉ WEBER,¹ ARMIN M. NAGEL,² HANS-MICHAEL MEINCK,³ SIMON BREITENBACH, JOHANNES SCHARRER, and KARIN JURKAT-ROTT

Abstract

Key words: Duchenne muscular dystrophy, eplerenone, cytotoxic oedema

Recently we reported a cytoplasmic sodium overload to cause a severe osmotic oedema in Duchenne muscular dystrophy (DMD). Our results suggested that this dual overload of sodium ions and water precedes the dystrophic process and persists until fatty muscle degeneration is complete. The present paper addresses the questions as to whether these overloads are important for the pathogenesis of the disease, and if so, whether they can be treated. As a first step, we investigated the effects of various diuretic drugs on a cell model of DMD, i.e. rat diaphragm strips previously exposed to amphotericin B. We found that both carbonic anhydrase inhibitors and aldosterone antagonists were able to repolarise depolarised muscle fibres. Since carbonic anhydrase inhibitors are known to have acidifying effects and this might be detrimental to the ventilation of DMD patients, we mainly concentrated on the modern spironolactone derivative, eplerenone. This drug had a very high repolarizing power, the parameter considered by us as being most relevant for a beneficial effect. In a pilot study we administered this drug to a 22-yr-old female DMD patient who was bound to an electric wheelchair and has had no corticosteroid therapy before. Eplerenone decreased both cytoplasmic sodium and water overload and increased muscle strength and mobility. We conclude that eplerenone has beneficial effects on DMD muscle. In our opinion the cytoplasmic oedema is cytotoxic and should be treated before fatty degeneration takes place.

Full Text Article

Differentiation of cytotoxic and vasogenic edema in a patient with reversible posterior leukoencephalopathy syndrome using diffusion-weighted MRI.

Differentiation of cytotoxic and vasogenic edema in a patient with reversible posterior leukoencephalopathy syndrome using diffusion-weighted MRI.

Doelken M, Lanz S, Rennert J, Alibek S, Richter G, Doerfler A.
From the Departments of Neuroradiology, University of Erlangen-Nuremberg, Erlangen, Germany.

In recent years reversible posterior leukoencephalopathy syndrome (RPLS) has become increasingly recognized. It represents an uncommon entity related to multiple pathologies, the most common being hypertensive crisis. The underlying pathophysiological mechanism is proposed to be one of vasogenic edema, without infarction; however, differentiation from cytotoxic edema can be crucial for therapeutic and clinical outcome. Diffusion-weighted magnetic resonance imaging (DWI), including calculation of the apparent diffusion coefficient (ADC), may be helpful for differentiation. We present a case of a healthy young woman in the 40th week of gestation, with no prior complications, who suddenly developed RPLS with vasogenic edema, which was differentiated with DWI and quantification of ADC. Follow-up cranial MRI showed complete remission. Pre-eclampsia could not be proven according to pathognomonic laboratory findings.

Diagnostic and Interventional Radiology

Aquaporin-4 and brain edema.

Aquaporin-4 and brain edema.

Pediatr Nephrol. 2007 Mar 9

Departments of Medicine and Physiology, University of California, San Francisco, CA, 94143-0521, USA.

Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess.

In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability.

These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury.

Keywords: AQP4 - Brain swelling - Water channel - Hydrocephalus - Hyponatremia

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