Original article/Article original
Iron 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

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Summary

Objectives

To evaluate the concept that iron depletion (ID) induced by bloodletting and followed by recombinant human erythropoietin (rhEPO) administration could be a therapeutic strategy in progressive multiple sclerosis (PMS) and that it could be assessed by neurophysiological measurements.

Patients and methods

In four patients with PMS, bloodletting was performed until ID was induced, and then rhEPO was administered (300 UI/kg/week). The changes induced by the treatment were assessed by clinical scores, biological tests, and neurophysiological study of cortical excitability using transcranial magnetic stimulation techniques.

Results

The treatment was well tolerated except for muscle cramps and one popliteal vein thrombosis in a patient confined to chair. ID was obtained within 28 weeks and was associated with endogenous production of EPO. No bloodletting was further required during a six-month period after introduction of rhEPO. At the end of the follow-up (up to one year), fatigue and walking capacities tended to improve in two patients. Neurophysiological changes were characterized by an increased cortical excitability, including a decrease of motor thresholds and an enhancement of intracortical facilitation and cerebellothalamocortical inhibition.

Conclusions

The combined ID-rhEPO therapy could authorize a prolonged administration of rhEPO in PMS patients, able to modify cortical excitability of the glutamatergic and gabaergic circuits. These preliminary data are encouraging to design a larger, controlled therapeutical trial to assess the value of such a strategy to improve functional symptoms in PMS patients, and maybe to prevent axonal degeneration. Neurophysiological measurements based on cortical excitability studies could provide sensitive parameters to evaluate treatment-induced changes in this context.

Résumé

Objectifs

Évaluer le concept que la déplétion en fer (DF) induite par des saignées répétées et suivie par l’administration d’érythropoïétine recombinante humaine (EPO-rh) pourrait être une stratégie thérapeutique dans la sclérose en plaques progressive (SEP-P) et que ceci peut être évalué par des mesures neurophysiologiques.

Patients et méthodes

Chez quatre patients atteints de SEP-P, des saignées ont été effectuées jusqu’à ce qu’une DF soit induite, puis l’EPO-rh a été administrée (300 UI/kg par semaine). Les changements induits par le traitement ont été évalués par des scores cliniques, des tests biologiques et l’étude neurophysiologique de l’excitabilité corticale à l’aide des techniques de stimulation magnétique transcrânienne.

Résultats

Le traitement fut bien toléré en dehors de crampes et de la thrombose d’une veine poplitée chez un patient confiné au fauteuil. La DF a été obtenue dans un délai de 28 semaines maximum et fut associée à la production endogène d’EPO. Aucune saignée ne fut nécessaire dans les six mois suivant l’introduction de l’EPO-rh. A la fin du suivi (jusqu’à un an), la fatigue et les capacités de marche tendaient à être améliorées chez deux patients. Les changements neurophysiologiques étaient caractérisés par une augmentation de l’excitabilité corticale, incluant une diminution des seuils moteurs et une amélioration de la facilitation intracorticale et de l’inhibition cérebello-thalamocorticale.

Conclusions

L’association thérapeutique DF-EPO-rh pourrait permettre une administration prolongée d’EPO-rh chez les patients SEP-P, capables de modifier l’excitabilité corticale des circuits glutamatergiques et gabaergiques. Ces données préliminaires sont encourageantes pour concevoir un essai thérapeutique contrôlé de plus grande ampleur, afin d’évaluer la valeur d’une telle stratégie pour améliorer les symptômes fonctionnels de patients atteints de SEP-P et peut-être de prévenir la dégénérescence axonale. Les mesures neurophysiologiques basées sur l’étude de l’excitabilité corticale pourraient fournir des paramètres sensibles pour évaluer les changements induits par le traitement dans ce contexte.

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.

References (42)

  • C. Adembri et al.

    Carbamylated erythropoietin is neuroprotective in an experimental model of traumatic brain injury

    Crit Care Med

    (2008)
  • R. Bianchi et al.

    Erythropoietin both protects from and reverses experimental diabetic neuropathy

    Proc Natl Acad Sci U S A

    (2004)
  • S. Boesch et al.

    Neurological effects of recombinant human erythropoietin in Friedreich's ataxia: a clinical pilot trial

    Mov Disord

    (2008)
  • C. Brugnara et al.

    Membrane properties of erythrocytes in subjects undergoing multiple blood donations with or without recombinant erythropoietin

    Br J Haematol

    (1993)
  • A.R. Cohen

    New Advances in Iron Chelation Therapy

    Hematology

    (2006)
  • H.L. Corwin et al.

    Efficacy and safety of epoetin alfa in critically ill patients

    N Engl J Med

    (2007)
  • H. Ehrenreich et al.

    Erythropoietin: novel approaches to neuroprotection in human brain disease

    Metabolic brain disease

    (2004)
  • H. Ehrenreich et al.

    Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis

    Brain

    (2007)
  • H. Ehrenreich et al.

    Erythropoietin therapy for acute stroke is both safe and beneficial

    Mol Med

    (2002)
  • K. Genc et al.

    Erythropoietin decreases cytotoxicity and nitric oxide formation induced by inflammatory stimuli in rat oligodendrocytes

    Physiological research/Academia Scientiarum Bohemoslovaca

    (2006)
  • J.J. Geurts et al.

    Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis

    Brain

    (2003)
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