Neurophysiologie Clinique/Clinical Neurophysiology
Original article/Article originalIron depletion induced by bloodletting and followed by rhEPO administration as a therapeutic strategy in progressive multiple sclerosis: A pilot, open-label study with neurophysiological measurementsDéplétion en fer induite par saignées suivie par l’administration d’EPO comme stratégie thérapeutique dans la sclérose en plaques progressive : étude pilote, ouverte avec évaluations neurophysiologiques
Introduction
The current concept of the natural history of multiple sclerosis (MS) refers to a combination of two phenomena underlying the two phases of MS that are an inflammatory process in the remitting phase and a neurodegenerative process in the progressive phase. The secondary progressive phase of MS is caused by axonal degeneration that follows demyelination. To date, no disease modifying drugs have been shown to have an impact on the natural course of the progressive phase.
Demyelination and oxidative stress induce morphological and physiological changes in axonal membrane properties and action potential propagation. One of the major consequences of demyelination is the intra-axonal Na+ overload associated with action potential initiation along the demyelinated axons. In turn, this leads to a constraint of additional energy and ATP production in the mitochondria to allow the Na+/K+ pumps to extrude the Na+ ions from axons and maintain transmembrane concentration gradients of Na+. Such additional energy may be lacking owing to concomitant oxidative stress. In case of significant energetic resource failure, Na+ extrusion requires an involvement of the Na+/Ca2+ exchanger in a reverse mode. By this way, an excessive Ca2+ influx takes place and may activate neuronal degeneration [33].
Oxydative stress is associated with iron metabolism dysregulation in MS patients [1], in whom iron deposits have been observed in the brain [13]. Iron in excess may have several deleterious consequences for axons, including iron-catalyzed production of free radicals able to cause oxidative tissue injury. Iron accumulation may also alter oligodendrocyte activities [22]. However, iron chelation did not provide beneficial therapeutic changes in MS patients [27], although promising effects were found in animal model of MS [29].
Originally known as a hematopoietic growth factor, erythropoietin (EPO) has been shown to have neuroprotective properties [10], [15] and to promote neurite outgrowth, axonal repair, neurogenesis, and angiogenesis [3], [37]. It also has anti-apoptotic and anti-oxidative properties [14], [21], [32], [39]. These properties are potentially beneficial in various traumatic, degenerative, or inflammatory pathological conditions, such as in experimental autoimmune encephalitis [2], [4], [17], [25]. A few open therapeutic trials using recombinant human EPO (rhEPO) have been conducted in patients with stroke [12], critically illness [9], or multiple sclerosis [11]. Maximal walking capacities were shown to improve following administration of high dosage of rhEPO. However, the use of rhEPO is limited by the increased risk of thromboembolic events [5], and cannot be recommended in patients without anemia (i.e. hemoglobin plasma concentration > 12.5 g/dL).
This pilot study was designed to evaluate the concept that iron depletion (ID) induced by bloodletting could reduce hemoglobin concentration and allow to administer rhEPO in patients with MS, while avoiding the risk of thrombosis. The combination of ID and rhEPO administration may have therapeutic value in MS patients by improving neuronal function in the brain. This study also aimed to show that such functional changes could be highlighted by neurophysiological investigation based on cortical excitability study using transcranial magnetic stimulation (TMS) techniques.
Section snippets
Patients
We have included four patients that fulfilled the diagnosis of secondary progressive MS [26], [30]. This pilot study was conducted after taking advice from the local ethics committee (CCP-IdF-IX). All patients gave their written informed consent.
Treatment
Bloodlettings (200 to 250 mL per session) were performed each week for six weeks and then according to biological changes and clinical tolerance, until ID was reached, as defined as defined by iron plasma concentration below 10 μg/L and ferritin plasma
Patients
Clinical features are reported in Table 1. All patients had entered the progressive phase of MS for more than three years.
Treatment
Bloodlettings were well tolerated, except for muscle cramps in the legs in two patients. However, some fatigue, especially during physical effort (exercise-induced fatigability) was observed when ID was achieved. ID was obtained after repeated bloodlettings for 16 weeks (patient 2) to 28 weeks (patient 4). No patient experienced ischemic complications. During this phase of
Discussion
This pilot study showed for the first time that a combined therapeutic strategy based on ID induced by repeated bloodlettings followed by rhEPO administration was feasible in patients with secondary progressive MS. As already mentioned, the use of rhEPO is limited by the increased risk of thromboembolic events [5], and is not recommended in patients without anemia (i.e. hemoglobin plasma concentration > 12.5 g/dL), especially in patients with cancer or kidney disease [38]. In our series, one
Disclosure of interest
AC: Expert testimony and grants pending from for Bayer-Schering Pharma, Biogen Idec, Sanofi-Aventis, Merck-Serono, Teva, Novartis. JPL, MOB, FG: no conflict of interest related to this study.
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These authors equally contributed.