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AVAglio trial, as well as an additional measure of symptom burden and three tests of neurocognitive function. These measures were shown to provide important outcomes information in an earlier phase 3 clinical trial involving patients with brain tumors.1 Unlike the AVAglio trial, in which the primary quality-of-life analyses were based on time to either deterioration in qualityof-life measures or tumor progression, our analyses evaluated longitudinal changes in the EORTC QLQ-C30/BN20 in patients without disease progression. Similar findings across all assessment measures in our trial provided confirmation that the results reflected the experience of the patients and that the differences between the two study groups were real. Further analyses comparing the quality-of-life outcomes of the RTOG 0825 and AVAglio trials could be of value but may be limited by specific differences in data collection between the two studies. Mark R. Gilbert, M.D. Erik P. Sulman, M.D., Ph.D. University of Texas M.D. Anderson Cancer Center Houston, TX [email protected]

Minesh P. Mehta, M.D. University of Maryland Baltimore, MD Since publication of their article, the authors report no further potential conflict of interest. 1. Armstrong TS, Wefel JS, Wang M, et al. Net clinical benefit

analysis of Radiation Therapy Oncology Group 0525: a phase III trial comparing conventional adjuvant temozolomide with doseintensive temozolomide in patients with newly diagnosed glioblastoma. J Clin Oncol 2013;31:4076-84. DOI: 10.1056/NEJMc1403303

Dr. Chinot and Colleagues Reply: Although no other drugs evaluated since 2005 for use in

patients with glioblastoma have shown activity, bevacizumab, as compared with placebo, was associated with a 4.4-month increase in median progression-free survival (from 6.2 to 10.6 months, an increase of 71%) in the AVAglio trial. These findings, which were confirmed by an independent review, were similar to those observed in RTOG 0825. These results should not be regarded as subjective, but rather as a positive outcome reinforced by clinical measures with value for patients.1 We did not claim that bevacizumab, as compared with placebo, improved quality of life, but rather that good quality of life was maintained for a longer time. The reasons for the discrepancy between our quality-of-life findings and the negative effect of bevacizumab on some quality-of-life domains reported at specific time points in RTOG 0825 remain a major challenge. To address these important discrepancies, we and the sponsor fully support an independent review of both quality-of-life and magnetic resonance imaging data. Indeed, these data may be linked, given the difference in tumor assessment criteria used in the two studies. Olivier L. Chinot, M.D. Aix-Marseille University Marseille, France [email protected]

Wolfgang Wick, M.D. University Hospital of Heidelberg Heidelberg, Germany

Timothy Cloughesy, M.D. University of California, Los Angeles Los Angeles, CA Since publication of their article, the authors report no further potential conflict of interest. 1. Fine HA. Bevacizumab in glioblastoma — still much to learn.

N Engl J Med 2014;370:764-5.

DOI: 10.1056/NEJMc1403303

Pregabalin versus Pramipexole for Restless Legs Syndrome To the Editor: Allen et al. (Feb. 13 issue)1 provide very useful clinical information about pregabalin for restless legs syndrome (RLS). The careful differentiation of augmentation from loss of efficacy is especially remarkable. In this context, one may wonder how frequent the latter occurred in this trial, because pregabalin has been associated with the potential for abuse in some specific populations2 and might therefore lead to

loss of efficacy. With regard to the outcome of the trial, we would like to ask the authors how they dealt with the potential confounders of depressive and anxiety disorders, which are frequent coexisting conditions in patients with RLS.3 One could assume that pregabalin at least partially reduced symptoms of anxiety,4 whereas pramipexole might have had a positive effect on depression.5 If these potential effects are not

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ruled out, the specificity of the results is not unequivocal. Ion Anghelescu, M.D. Clinic Dr. Kurt Fontheim Liebenburg, Germany

Michael Dettling, M.D. Charité–University Medicine Berlin Berlin, Germany No potential conflict of interest relevant to this letter was reported. 1. Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of

pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014;370:621-31. 2. Grosshans M, Lemenager T, Vollmert C, et al. Pregabalin abuse among opiate addicted patients. Eur J Clin Pharmacol 2013;69:2021-5. 3. Lee HB, Hening WA, Allen RP, et al. Restless legs syndrome is associated with DSM-IV major depressive disorder and panic disorder in the community. J Neuropsychiatry Clin Neurosci 2008;20:101-5. 4. Kasper S, Brasser M, Schweizer E, Lyndon G, Prieto R. How well do randomized controlled trial data generalize to ‘real-world’ clinical practice settings? A comparison of two generalized anxiety disorder studies. Eur Neuropsychopharmacol 2014;24:125-32. 5. Cusin C, Iovieno N, Iosifescu DV, et al. A randomized, doubleblind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder. J Clin Psychiatry 2013;74(7):e636-e641. DOI: 10.1056/NEJMc1402987

To the Editor: Allen and colleagues report on the relative merits of pregabalin and pramipexole in the management of RLS. Allen recently reviewed the putative contribution of iron in the pathophysiology of RLS.1 Several case reports and studies involving both children and adults have provided support for the use of oral iron therapy, parenteral iron therapy, or both in the treatment of RLS.2-4 In the study by Allen et al., it would be interesting to know the iron status of the study participants and whether they had received prior iron therapy. The adverse effects — worsening augmentation, in particular — associated with dopaminergic drugs and pregabalin are problematic. However, augmentation does not occur with parenteral iron preparations. Modern parenteral iron preparations are safe, cheap, widely available, easy to administer as a single dose, associated with high rates of adherence, and effective in a considerable proportion of patients with RLS. There is little to be lost, and perhaps a great deal to be gained, by making iron status the initial priority in the management of RLS. Patrick Coleman, M.B. Manly Hospital Sydney, NSW, Australia [email protected]

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Dr. Coleman reports receiving lecture fees from Vifor. No other potential conflict of interest relevant to this letter was reported. 1. Allen RP. Pathophysiology: the biology of restless legs syn-

drome (Willis-Ekbom disease). In: Chokroverty S, Allen RP, Walters AS, Montagna P, eds. Sleep and movement disorders. 2nd ed. New York: Oxford University Press, 2013:585-97. 2. Tilma J, Tilma K, Norregaard O, Ostergaard JR. Early childhood-onset restless legs syndrome: symptoms and effect of oral iron treatment. Acta Paediatrica 2013;102(5):e221-e226. 3. Picchietti DL, Wang VC, Picchietti MA. Intravenous iron given prior to pregnancy for restless legs syndrome is associated with remission of symptoms. J Clin Sleep Med 2012;8:585-6. 4. Cho YW, Allen RP, Earley CJ. Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep Med 2013; 14:274-7. DOI: 10.1056/NEJMc1402987

The Author Replies: Depression occurs commonly with RLS, but treatments that are effective for reducing depression generally increase, not decrease, RLS symptoms.1 Thus, treating depression seems unlikely to significantly reduce RLS symptoms, although the reverse may not be true. At least the International RLS (IRLS) Study Group Rating Scale indicates that mood improves when other RLS symptoms are reduced. Anxiety also commonly co-occurs with RLS. Data from blinded, controlled studies on the use of anxiolytic agents in patients with RLS are limited, but a small controlled study of clonazepam was negative.2 I see no indication in the literature that the treatment of anxiety or depression significantly affects RLS symptoms, and thus there has been no effort to control for these conditions. My colleagues and I did not carefully evaluate loss of efficacy, but we did report on patients who discontinued treatment owing to an insufficient response (see Fig. S1 in the Supplementary Appendix, available with the full text of our article at NEJM.org). The patients who received treatment for the entire 52 weeks from the start of treatment and had an insufficient response include 13 of 180 patients who received pramipexole at a dose of 0.5 mg per day, 18 of 178 patients who received pramipexole at a dose of 0.25 mg per day, and 5 of 182 patients who received pregabalin. There is certainly no indication of an appreciable loss of efficacy of pregabalin. The continuing very good IRLS scores shown in Figure 1 of our article (available at NEJM.org) also do not indicate a significant loss of efficacy of pregabalin, since that would have reduced the IRLS score with continued treatment. I agree with Coleman that iron status should be a first consideration in the treatment of patients

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with RLS. In our study, we excluded all patients with a serum ferritin level of less than 15 μg per liter (see the protocol, available at NEJM.org). Unfortunately, intravenous iron treatments have not been adequately evaluated to establish them as a standard treatment for RLS. Data from a small controlled positive study of ferric carboxymaltose3 and from two negative studies of iron sucrose4,5 are available. The differences here may reflect effects of different formulations of iron or random variation around a small treatment benefit. Data are lacking from controlled clinical studies of intravenous iron treatment for RLS to support the recommendation of this approach. Richard P. Allen, Ph.D. Johns Hopkins University Baltimore, MD [email protected]

Since publication of his article, the author reports no further potential conflict of interest. 1. Rottach KG, Schaner BM, Kirch MH, et al. Restless legs syn-

drome as side effect of second generation antidepressants. J Psychiatr Res 2008;43:70-5. 2. Boghen D, Lamothe L, Elie R, Godbout R, Montplaisir J. The treatment of the restless legs syndrome with clonazepam: a prospective controlled study. Can J Neurol Sci 1986;13:2457. 3. Allen RP, Adler CH, Du W, Butcher A, Bregman DB, Earley CJ. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centered, placebo-controlled preliminary clinical trial. Sleep Med 2011;12:906-13. 4. Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord 2009;24:1445-52. 5. Earley CJ, Horská A, Mohamed MA, Barker PB, Beard JL, Allen RP. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med 2009;10:206-11. DOI: 10.1056/NEJMc1402987

Multiple Phenotypes in Phosphoglucomutase 1 Deficiency To the Editor: Tegtmeyer et al. (Feb. 6 issue)1 state that patients with phosphoglucomutase 1 deficiency are susceptible to malignant hyperthermia along with multiple other clinical manifestations, including myopathy, rhabdomyolysis, and dilated cardiomyopathy. Might the authors clarify their diagnostic criterion for malignant hyperthermia in the two patients in whom “severe rhabdomyolysis” developed after general anesthesia was administered? Pronounced rhabdomyolysis distinct from malignant hyperthermia may develop in patients with myopathies such as Duchenne’s muscular dystrophy when they are exposed to volatile anesthetic gases. Virgil M. Airola, M.D.

formed at 1.5 years of age. Halothane was used for anesthesia. Because unexplained acidosis with an increased partial pressure of carbon dioxide, a base excess of −9 mmol per liter, and fever developed in the patient, we assessed the plasma creatine kinase level, which increased from 700 U per liter 2 hours after surgery to more than 10,000 U per liter a few hours later. The serum myoglobin level was 178 μg per liter. The clinical grading scale to predict malignant hyperthermia (on a scale from 0 to 88, with scores higher than 50 indicating malignant hyperthermia) showed a raw score of 68 and the highest rank of 6,1 indicating an almost certain likelihood of malignant hyperthermia. When the patient was 4 years of age and again at 18 years of age, “trigger-free” Children’s Hospital Central California Madera, CA anesthesia (without drugs known to induce maNo potential conflict of interest relevant to this letter was re- lignant hyperthermia) with propofol and remifenported. tanil used together led to minor increases in the 1. Tegtmeyer LC, Rust S, van Scherpenzeel M, et al. Multiple creatine kinase level without fever. No depolarphenotypes in phosphoglucomutase 1 deficiency. N Engl J Med izing muscle relaxants had been used. We are 2014;370:533-42. aware of the ongoing discussion regarding whethDOI: 10.1056/NEJMc1403446 er or not rhabdomyolysis in disorders such as Duchenne’s muscular dystrophy is similar to The Authors Reply: In phosphoglucomutase 1 de- malignant hyperthermia.2,3 ficiency, general anesthesia has been shown to Thorsten Marquardt, M.D. induce rhabdomyolysis and high fever. In our University Children’s Hospital Münster first patient, surgery for cleft palate was per- Münster, Germany

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Pregabalin versus pramipexole for restless legs syndrome.

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