correspondence 2012. Stockholm: European Center for Disease Prevention and Control, 2013 (http://www.ecdc.europa.eu/en/publications/ publications/healthcare-associated-infections-antimicrobial -use-pps.pdf).
3. Vital signs: improving antibiotic use among hospitalized pa-
tients. MMWR Morb Mortal Wkly Rep 2014;63:194-200. DOI: 10.1056/NEJMc1405194
Hyperimmune Globulin to Prevent Congenital CMV Infection To the Editor: Revello et al. (April 3 issue)1 report the results of a randomized, placebo-controlled, phase 2 trial of hyperimmune globulin for the prevention of maternofetal cytomegalovirus (CMV) transmission. This study was based on the findings of a nonrandomized 2005 study by Nigro et al.2 Both studies, as well as the retrospective observational study by Buxmann et al.,3 used monthly administration of hyperimmune globulin, based on the assumption of a terminal elimination half-life of 22.4 days for total IgG antibodies.4 We reassessed the pharmacokinetic characteristics of the CMV-specific antibody response5 in a volunteer pregnant woman with proven CMV primary infection who received intravenous hyperimmune globulin every 4 weeks. We found periodic decreases in CMV-IgG levels with a half-life of about 11 days, along with fluctuations in epitope-specific recombinant CMV IgG avidity and repeated decreases in epithelialcell–specific neutralization capacity. These findings may have an effect on clinical outcome. Therefore, we suggest a reanalysis of the pharmacokinetics of hyperimmune globulin–induced, compartment-specific CMV antibody and CMV neutralization capacity in plasma, amniotic fluid, and cord blood in order to redefine an optimized treatment schedule for the administration of hyperimmune globulin. Klaus Hamprecht, M.D., Ph.D. Karl-Oliver Kagan, M.D., Ph.D. Rangmar Goelz, M.D. University Hospital Tübingen Tübingen, Germany [email protected] Dr. Hamprecht reports serving on a scientific advisory board for the online Initiative for the Prevention of Congenital Cytomegalovirus Infection, which is sponsored by Biotest, and receiving lecture fees from Roche, Abbott, and Siemens. Fees were donated directly to the University Hospital Tuebingen. No other potential conflict of interest relevant to this letter was reported. 1. Revello MG, Lazzarotto T, Guerra B, et al. A randomized
trial of hyperimmune globulin to prevent congenital cytomegalovirus. N Engl J Med 2014;370:1316-26. 2. Nigro G, Adler SP, La Torre R, Best AM. Passive immuniza-
tion during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350-62. 3. Buxmann H, Stackelberg OM, Schlößer RL, et al. Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease: a retrospective analysis. J Perinat Med 2012;40:439-46. 4. Thürmann PA, Sonnenburg-Chatzopoulos C, Lissner R. Pharmacokinetic characteristics and tolerability of a novel intravenous immunoglobulin preparation. Eur J Clin Pharmacol 1995;49:237-42. 5. Hamprecht K, Bissinger AL, Arellano-Galindo J, et al. Intrafamilial transmission of human cytomegalovirus (HCMV): long-term dynamics of epitope-specific antibody response in context of avidity maturation. J Clin Virol 2014;60:119-26. DOI: 10.1056/NEJMc1405377
To the Editor: Revello et al. report that the use of CMV-specific hyperimmune globulin did not significantly alter the course of congenital CMV infection in their study. However, several aspects of the study design could have led to an underestimation of the effect. First, hyperimmune globulin was discontinued when testing of amniotic fluid was positive for CMV. An observational study showed that in women with CMV-positive amniotic fluid, the use of hyperimmune globulin mitigated fetal infection.1 It is unclear whether these pregnancies were terminated. Second, three women delivered a fetus with congenital CMV despite negative results on amniocentesis. Al though an interval of 6 to 8 weeks between the presumed onset of maternal infection and amniocentesis is described for these three women, it is unknown whether the same interval after maternal infection was respected in all patients.2 Third, the statistical power of the study by Revello et al. was based on an absolute reduction of 24 percentage points (a relative reduction of 60%) in clinical infections, as described previously.1 Al though the between-group difference was not significant, the observed absolute reduction in CMV infection among women receiving hyperimmune globulin was 14 percentage points. However, the 95% confidence interval was −3 to 31, which does not exclude a clinically relevant effect. A larger study is needed to draw definite conclusions.
n engl j med 370;26 nejm.org june 26, 2014
The New England Journal of Medicine Downloaded from nejm.org on October 31, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2543
The
n e w e ng l a n d j o u r na l
Elisabeth van Leeuwen, M.D., Ph.D. K. Oude Rengerink, M.Sc. Eva Pajkrt, M.D., Ph.D. Academic Medical Center Amsterdam, the Netherlands [email protected]
m e dic i n e
3. Nigro G, Capretti I, Manganello AM, Best AM, Adler SP.
Primary maternal cytomegalovirus infections during pregnancy: association of CMV hyperimmune globulin with gestational age at birth and birth weight. J Matern Fetal Neonatal Med 2014 April 25 (Epub ahead of print).
DOI: 10.1056/NEJMc1405377
No potential conflict of interest relevant to this letter was reported. 1. Nigro G, Adler SP, La Torre R, Best AM. Passive immuniza-
tion during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350-62. 2. Benoist G, Leruez-Ville M, Magny JF, Jacquemard F, Salomon LJ, Ville Y. Management of pregnancies with confirmed cytomegalovirus fetal infection. Fetal Diagn Ther 2013;33:203-14. DOI: 10.1056/NEJMc1405377
To the Editor: In our phase 1 safety and immunogenicity trial, my colleagues and I estimated that the use of hyperimmune globulin may decrease the rate of fetal CMV infection and disease.1 Using our protocol, Revello et al. report an infection rate of 30% for mothers treated with hyperimmune globulin, with a trend toward efficacy, as compared with untreated mothers (P = 0.13). In addition, three infants in the hyperimmune globulin group were infected at birth but had negative results on amniocentesis. Delayed infection occurred in the hyperimmune globulin group and not in the placebo group, so the use of hyperimmune globulin may delay fetal infection. Revello et al. report that neonates whose mothers received hyperimmune globulin had rates of prematurity and growth restriction that were higher than those of neonates whose mothers were untreated. This finding is surprising to us.2 In particular, in a recent study involving 358 pregnant women with primary CMV infection, 164 women who received multiple doses of hyperimmune globulin gave birth to infants with significant increases in birth weight and gestational age at delivery.3 Giovanni Nigro, M.D. University of L’Aquila L’Aquila, Italy [email protected] No potential conflict of interest relevant to this letter was reported. 1. Nigro G, Adler SP, La Torre R, Best AM. Passive immuniza-
tion during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350-62. 2. Moraru M, Carbone J, Alecsandru D, et al. Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells. Am J Reprod Immunol 2012;68:75-84.
2544
of
The authors reply: Hamprecht and colleagues suggest that the administration schedule for CMV-specific hyperimmune globulin should be based on a half-life of 11 days and continuous fluctuation of epitope-specific IgG avidity and epithelial-cell–neutralizing activity, as observed in a volunteer. We agree that this is a potentially important observation if it can be confirmed in a larger cohort. In response to the comments of van Leeuwen et al.: the primary end point of our study was congenital CMV infection, so treatment was discontinued in women with CMV-positive amniotic fluid. Second, an interval of 6 to 8 weeks between the presumed onset of maternal infection and amniocentesis was respected in all patients. On the whole, seven patients (four in the hyperimmune globulin group) terminated their pregnancies after prenatal diagnosis of congenital CMV infection. Finally, as already discussed in our article, the results of our phase 2 study do not exclude a clinically relevant difference (95% confidence interval, −3 to 31), although the mean effect we observed was much lower than expected. In response to Nigro’s comments: false negative results on amniocentesis have been reported previously.1 Therefore, the theory that CMVspecific hyperimmune globulin is responsible for delayed intrauterine transmission is, at the moment, purely speculative. With respect to the higher rate of prematurity that we observed among women who received hyperimmune globulin, this observation must be confirmed or excluded in larger controlled studies. In addition, ongoing histologic and ultrastructural studies of placentas obtained from women enrolled in the Congenital HCMV Infection Prevention (CHIP) study (ClinicalTrials.gov number, NCT00881517) may help to clarify the effects of maternal treatment with hyperimmune globulin on placental morphology and circulation, fetal growth, and length of gestation. As for the use of immune globulin to prevent miscarriage, data from observational and randomized studies2 suggest that maternal treatment with intravenous immune
n engl j med 370;26 nejm.org june 26, 2014
The New England Journal of Medicine Downloaded from nejm.org on October 31, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
globulin did not confer any benefit in terms of reproductive success among women who had undergone abortion. On this basis, the Royal College of Obstetricians and Gynaecologists and the American Society for Reproductive Medicine3 have issued recommendations against the use of intravenous immune globulin for women with multiple reproductive failures. Finally, since the use of intravenous immune globulin is a known risk factor for thrombosis,4 such use in pregnancy should be carefully evaluated. Arsenio Spinillo, M.D. Giuseppe Gerna, M.D. Fondazione IRCCS Policlinico San Matteo Pavia, Italy [email protected]
Since publication of their article, the authors report no further potential conflict of interest. 1. Revello MG, Fabbri E, Furione M, et al. Role of prenatal di-
agnosis and counseling in the management of 735 pregnancies complicated by primary human cytomegalovirus infection: a 20year experience. J Clin Virol 2011;50:303-7. 2. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 2006;117:Suppl:S525-S553. [Erratum, J Allergy Clin Immunol 2006;117:1483.] 3. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012;98:1103-11. 4. Menis M, Sridhar G, Selvam N, et al. Hyperimmune globulins and same-day thrombotic adverse events as recorded in a large healthcare database during 2008-2011. Am J Hematol 2013; 88:1035-40. DOI: 10.1056/NEJMc1405377
Case 8-2014: A Man with Headache, Vomiting, and Diplopia To the Editor: In the Case Record by Cho et al. (March 13 issue)1 about glioblastoma involving the leptomeninges, primary leptomeningeal gliomatosis was diagnosed because there was no evidence of glioblastoma in the underlying brain parenchyma. However, magnetic resonance imaging (MRI) of the brain on the patient’s first admission showed that the left Sylvian fissure appeared to be located more posteriorly than the right one (Fig. 1C in the article), suggesting the possibility that a mass lesion was already present in the left frontal lobe. The authors point out diffuse leptomeningeal enhancement but not the finding of left Sylvian fissure on these MRI scans. On an MRI obtained on the patient’s second admission (about 2 months after the first MRI), a 3.6-cm mass was apparent in the left inferior frontal lobe (Fig. 2 of the article). I believe that the necrosis of the tumor and the promoted vascularization around this tumor are a more likely explanation for visualization of a glioblastoma on MRI, rather than the rapid growth of a previously invisible tumor for 2 months. Kazuhiro Takahashi, M.D., Ph.D. Tohoku University Graduate School of Medicine Sendai, Japan [email protected] No potential conflict of interest relevant to this letter was reported.
The discussants reply: Although some malignant gliomas may initially lack clinically significant enhancement,1 most will manifest with an abnormal T2-weighted signal on MRI. Multiple axial, coronal, and sagittal images (not included in our article because of space limitations) showed no abnormal T2 signal and no important asymmetry or sulcal effacement to suggest an underlying mass in the left frontal region. Although the change in the mass over a 6-week period seemed unusually rapid, glioblastomas have been reported to grow substantially over days to weeks, especially in younger patients.2 Tracey A. Cho, M.D. Andrew S. Chi, M.D., Ph.D. Pamela W. Schaefer, M.D. Massachusetts General Hospital Boston, MA [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Scott JN, Brasher PM, Sevick RJ, Rewcastle NB, Forsyth PA.
How often are nonenhancing supratentorial gliomas malignant? A population study. Neurology 2002;59:947-9. 2. Khalatbari MR, Hamidi M, Moharamzad Y. Glioblastoma multiforme with very rapid growth and long-term survival in children: report of two cases and review of the literature. Childs Nerv Syst 2011;27:1347-52. DOI: 10.1056/NEJMc1404375
1. Case Records of the Massachusetts General Hospital (Case
8-2014). N Engl J Med 2014;370:1049-59.
DOI: 10.1056/NEJMc1404375
n engl j med 370;26 nejm.org june 26, 2014
The New England Journal of Medicine Downloaded from nejm.org on October 31, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2545
3. Vital signs: improving antibiotic use among hospitalized pa-
tients. MMWR Morb Mortal Wkly Rep 2014;63:194-200. DOI: 10.1056/NEJMc1405194
Hyperimmune Globulin to Prevent Congenital CMV Infection To the Editor: Revello et al. (April 3 issue)1 report the results of a randomized, placebo-controlled, phase 2 trial of hyperimmune globulin for the prevention of maternofetal cytomegalovirus (CMV) transmission. This study was based on the findings of a nonrandomized 2005 study by Nigro et al.2 Both studies, as well as the retrospective observational study by Buxmann et al.,3 used monthly administration of hyperimmune globulin, based on the assumption of a terminal elimination half-life of 22.4 days for total IgG antibodies.4 We reassessed the pharmacokinetic characteristics of the CMV-specific antibody response5 in a volunteer pregnant woman with proven CMV primary infection who received intravenous hyperimmune globulin every 4 weeks. We found periodic decreases in CMV-IgG levels with a half-life of about 11 days, along with fluctuations in epitope-specific recombinant CMV IgG avidity and repeated decreases in epithelialcell–specific neutralization capacity. These findings may have an effect on clinical outcome. Therefore, we suggest a reanalysis of the pharmacokinetics of hyperimmune globulin–induced, compartment-specific CMV antibody and CMV neutralization capacity in plasma, amniotic fluid, and cord blood in order to redefine an optimized treatment schedule for the administration of hyperimmune globulin. Klaus Hamprecht, M.D., Ph.D. Karl-Oliver Kagan, M.D., Ph.D. Rangmar Goelz, M.D. University Hospital Tübingen Tübingen, Germany [email protected] Dr. Hamprecht reports serving on a scientific advisory board for the online Initiative for the Prevention of Congenital Cytomegalovirus Infection, which is sponsored by Biotest, and receiving lecture fees from Roche, Abbott, and Siemens. Fees were donated directly to the University Hospital Tuebingen. No other potential conflict of interest relevant to this letter was reported. 1. Revello MG, Lazzarotto T, Guerra B, et al. A randomized
trial of hyperimmune globulin to prevent congenital cytomegalovirus. N Engl J Med 2014;370:1316-26. 2. Nigro G, Adler SP, La Torre R, Best AM. Passive immuniza-
tion during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350-62. 3. Buxmann H, Stackelberg OM, Schlößer RL, et al. Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease: a retrospective analysis. J Perinat Med 2012;40:439-46. 4. Thürmann PA, Sonnenburg-Chatzopoulos C, Lissner R. Pharmacokinetic characteristics and tolerability of a novel intravenous immunoglobulin preparation. Eur J Clin Pharmacol 1995;49:237-42. 5. Hamprecht K, Bissinger AL, Arellano-Galindo J, et al. Intrafamilial transmission of human cytomegalovirus (HCMV): long-term dynamics of epitope-specific antibody response in context of avidity maturation. J Clin Virol 2014;60:119-26. DOI: 10.1056/NEJMc1405377
To the Editor: Revello et al. report that the use of CMV-specific hyperimmune globulin did not significantly alter the course of congenital CMV infection in their study. However, several aspects of the study design could have led to an underestimation of the effect. First, hyperimmune globulin was discontinued when testing of amniotic fluid was positive for CMV. An observational study showed that in women with CMV-positive amniotic fluid, the use of hyperimmune globulin mitigated fetal infection.1 It is unclear whether these pregnancies were terminated. Second, three women delivered a fetus with congenital CMV despite negative results on amniocentesis. Al though an interval of 6 to 8 weeks between the presumed onset of maternal infection and amniocentesis is described for these three women, it is unknown whether the same interval after maternal infection was respected in all patients.2 Third, the statistical power of the study by Revello et al. was based on an absolute reduction of 24 percentage points (a relative reduction of 60%) in clinical infections, as described previously.1 Al though the between-group difference was not significant, the observed absolute reduction in CMV infection among women receiving hyperimmune globulin was 14 percentage points. However, the 95% confidence interval was −3 to 31, which does not exclude a clinically relevant effect. A larger study is needed to draw definite conclusions.
n engl j med 370;26 nejm.org june 26, 2014
The New England Journal of Medicine Downloaded from nejm.org on October 31, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2543
The
n e w e ng l a n d j o u r na l
Elisabeth van Leeuwen, M.D., Ph.D. K. Oude Rengerink, M.Sc. Eva Pajkrt, M.D., Ph.D. Academic Medical Center Amsterdam, the Netherlands [email protected]
m e dic i n e
3. Nigro G, Capretti I, Manganello AM, Best AM, Adler SP.
Primary maternal cytomegalovirus infections during pregnancy: association of CMV hyperimmune globulin with gestational age at birth and birth weight. J Matern Fetal Neonatal Med 2014 April 25 (Epub ahead of print).
DOI: 10.1056/NEJMc1405377
No potential conflict of interest relevant to this letter was reported. 1. Nigro G, Adler SP, La Torre R, Best AM. Passive immuniza-
tion during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350-62. 2. Benoist G, Leruez-Ville M, Magny JF, Jacquemard F, Salomon LJ, Ville Y. Management of pregnancies with confirmed cytomegalovirus fetal infection. Fetal Diagn Ther 2013;33:203-14. DOI: 10.1056/NEJMc1405377
To the Editor: In our phase 1 safety and immunogenicity trial, my colleagues and I estimated that the use of hyperimmune globulin may decrease the rate of fetal CMV infection and disease.1 Using our protocol, Revello et al. report an infection rate of 30% for mothers treated with hyperimmune globulin, with a trend toward efficacy, as compared with untreated mothers (P = 0.13). In addition, three infants in the hyperimmune globulin group were infected at birth but had negative results on amniocentesis. Delayed infection occurred in the hyperimmune globulin group and not in the placebo group, so the use of hyperimmune globulin may delay fetal infection. Revello et al. report that neonates whose mothers received hyperimmune globulin had rates of prematurity and growth restriction that were higher than those of neonates whose mothers were untreated. This finding is surprising to us.2 In particular, in a recent study involving 358 pregnant women with primary CMV infection, 164 women who received multiple doses of hyperimmune globulin gave birth to infants with significant increases in birth weight and gestational age at delivery.3 Giovanni Nigro, M.D. University of L’Aquila L’Aquila, Italy [email protected] No potential conflict of interest relevant to this letter was reported. 1. Nigro G, Adler SP, La Torre R, Best AM. Passive immuniza-
tion during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350-62. 2. Moraru M, Carbone J, Alecsandru D, et al. Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells. Am J Reprod Immunol 2012;68:75-84.
2544
of
The authors reply: Hamprecht and colleagues suggest that the administration schedule for CMV-specific hyperimmune globulin should be based on a half-life of 11 days and continuous fluctuation of epitope-specific IgG avidity and epithelial-cell–neutralizing activity, as observed in a volunteer. We agree that this is a potentially important observation if it can be confirmed in a larger cohort. In response to the comments of van Leeuwen et al.: the primary end point of our study was congenital CMV infection, so treatment was discontinued in women with CMV-positive amniotic fluid. Second, an interval of 6 to 8 weeks between the presumed onset of maternal infection and amniocentesis was respected in all patients. On the whole, seven patients (four in the hyperimmune globulin group) terminated their pregnancies after prenatal diagnosis of congenital CMV infection. Finally, as already discussed in our article, the results of our phase 2 study do not exclude a clinically relevant difference (95% confidence interval, −3 to 31), although the mean effect we observed was much lower than expected. In response to Nigro’s comments: false negative results on amniocentesis have been reported previously.1 Therefore, the theory that CMVspecific hyperimmune globulin is responsible for delayed intrauterine transmission is, at the moment, purely speculative. With respect to the higher rate of prematurity that we observed among women who received hyperimmune globulin, this observation must be confirmed or excluded in larger controlled studies. In addition, ongoing histologic and ultrastructural studies of placentas obtained from women enrolled in the Congenital HCMV Infection Prevention (CHIP) study (ClinicalTrials.gov number, NCT00881517) may help to clarify the effects of maternal treatment with hyperimmune globulin on placental morphology and circulation, fetal growth, and length of gestation. As for the use of immune globulin to prevent miscarriage, data from observational and randomized studies2 suggest that maternal treatment with intravenous immune
n engl j med 370;26 nejm.org june 26, 2014
The New England Journal of Medicine Downloaded from nejm.org on October 31, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
globulin did not confer any benefit in terms of reproductive success among women who had undergone abortion. On this basis, the Royal College of Obstetricians and Gynaecologists and the American Society for Reproductive Medicine3 have issued recommendations against the use of intravenous immune globulin for women with multiple reproductive failures. Finally, since the use of intravenous immune globulin is a known risk factor for thrombosis,4 such use in pregnancy should be carefully evaluated. Arsenio Spinillo, M.D. Giuseppe Gerna, M.D. Fondazione IRCCS Policlinico San Matteo Pavia, Italy [email protected]
Since publication of their article, the authors report no further potential conflict of interest. 1. Revello MG, Fabbri E, Furione M, et al. Role of prenatal di-
agnosis and counseling in the management of 735 pregnancies complicated by primary human cytomegalovirus infection: a 20year experience. J Clin Virol 2011;50:303-7. 2. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 2006;117:Suppl:S525-S553. [Erratum, J Allergy Clin Immunol 2006;117:1483.] 3. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012;98:1103-11. 4. Menis M, Sridhar G, Selvam N, et al. Hyperimmune globulins and same-day thrombotic adverse events as recorded in a large healthcare database during 2008-2011. Am J Hematol 2013; 88:1035-40. DOI: 10.1056/NEJMc1405377
Case 8-2014: A Man with Headache, Vomiting, and Diplopia To the Editor: In the Case Record by Cho et al. (March 13 issue)1 about glioblastoma involving the leptomeninges, primary leptomeningeal gliomatosis was diagnosed because there was no evidence of glioblastoma in the underlying brain parenchyma. However, magnetic resonance imaging (MRI) of the brain on the patient’s first admission showed that the left Sylvian fissure appeared to be located more posteriorly than the right one (Fig. 1C in the article), suggesting the possibility that a mass lesion was already present in the left frontal lobe. The authors point out diffuse leptomeningeal enhancement but not the finding of left Sylvian fissure on these MRI scans. On an MRI obtained on the patient’s second admission (about 2 months after the first MRI), a 3.6-cm mass was apparent in the left inferior frontal lobe (Fig. 2 of the article). I believe that the necrosis of the tumor and the promoted vascularization around this tumor are a more likely explanation for visualization of a glioblastoma on MRI, rather than the rapid growth of a previously invisible tumor for 2 months. Kazuhiro Takahashi, M.D., Ph.D. Tohoku University Graduate School of Medicine Sendai, Japan [email protected] No potential conflict of interest relevant to this letter was reported.
The discussants reply: Although some malignant gliomas may initially lack clinically significant enhancement,1 most will manifest with an abnormal T2-weighted signal on MRI. Multiple axial, coronal, and sagittal images (not included in our article because of space limitations) showed no abnormal T2 signal and no important asymmetry or sulcal effacement to suggest an underlying mass in the left frontal region. Although the change in the mass over a 6-week period seemed unusually rapid, glioblastomas have been reported to grow substantially over days to weeks, especially in younger patients.2 Tracey A. Cho, M.D. Andrew S. Chi, M.D., Ph.D. Pamela W. Schaefer, M.D. Massachusetts General Hospital Boston, MA [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Scott JN, Brasher PM, Sevick RJ, Rewcastle NB, Forsyth PA.
How often are nonenhancing supratentorial gliomas malignant? A population study. Neurology 2002;59:947-9. 2. Khalatbari MR, Hamidi M, Moharamzad Y. Glioblastoma multiforme with very rapid growth and long-term survival in children: report of two cases and review of the literature. Childs Nerv Syst 2011;27:1347-52. DOI: 10.1056/NEJMc1404375
1. Case Records of the Massachusetts General Hospital (Case
8-2014). N Engl J Med 2014;370:1049-59.
DOI: 10.1056/NEJMc1404375
n engl j med 370;26 nejm.org june 26, 2014
The New England Journal of Medicine Downloaded from nejm.org on October 31, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2545
