Correspondence
children younger than 1 year who were ultimately diagnosed with NF1 could not be given a diagnosis of NF1 at initial presentation, 97% met diagnostic criteria by age 8 years (average age at diagnosis 6 years).15 Moreover, 99% of children with NF1 will manifest six or more café-au-lait macules of at least 5 mm diameter by age 1 year.16 For these reasons, we start the process of routine anticipatory management in children with five or more café-au-lait macules as though the diagnosis of NF1 has already been formally made. Other clinical features have been nominated as potential additional diagnostic criteria, including short stature, macrocephaly, and the presence of T2 hyperintensities on brain MRI. Although short stature and macrocephaly are relatively common in the general population and are highly affected by genetic factors independent of NF1 status, T2 hyperintensity abnormalities (sometimes called unidentified bright objects) are detected in about 70% of children with NF1.17 Importantly, these lesions typically decrease in number and size or even disappear completely by adulthood. Furthermore, when formally assessed, these criteria have only 74–84% sensitivity.18 Aside from the clear role for NF1 genetic testing in prenatal reproductive decision making,19,20 NF1 genetic testing is also useful to diagnose individuals who present with spinal neurofibromas or to distinguish NF1 from other genetic disorders with clinical overlap, such as Noonan’s syndrome or Legius’ syndrome. However, there is little cost-effective benefit of NF1 genetic testing in a young child with only café-au-lait macules, especially when clinical surveillance is already planned. Although we agree with Milani and colleagues that the NIH diagnostic criteria for NF1 require critical reexamination, we firmly believe that evidence-based data are needed www.thelancet.com/neurology Vol 14 January 2015
to develop accurate methods to establish a diagnosis of NF1 in children. In addition, for physicians caring for children with NF1, the focus should also turn to prognostic factors that predict clinical outcome and progression. The identification of such risk assessment methods will transform current clinical practice into one in which screening and treatments can be more specifically tailored to each individual child.21 As such, we might envision NF1 moving from a diagnostic discipline to a therapeutic subspecialty.
10
11
12
13
14
We declare no competing interests.
Jonathan A Epstein, David A Ingram Jr, Angela C Hirbe,*David H Gutmann [email protected] Department of Cell and Developmental Biology, The Institute for Regenerative Medicine and the Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA (JAE); Departments of Pediatrics and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA (DAI); Department of Medicine (ACH) and Department of Neurology (DHG), Washington University School of Medicine, St Louis, MO 63110, USA 1
2 3 4
5
6
7
8
9
Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 2014; 13: 834–43. Salyer WR, Sayler DC. The vascular lesions of neurofibromatosis. Angiology 1974; 25: 510–19. Zochodne D. Von Recklinghausen’s vasculopathy. Am J Med Sci 1984; 287: 64–65. Feyrter F. Über die Vasculare Neurofibromatose, nach Untersuchungen am menschlichen Magen-Darmschlauch. Virchow Arch Path Anat 1949; 317: 221–65. Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE, McManus B, Korf BR. Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet Med 2002;4:105-11. Xu J, Ismat FA, Wang T, Lu MM, Antonucci N, Epstein JA. Cardiomyocyte-specific loss of neurofibromin promotes cardiac hypertrophy and dysfunction. Circulation Res 2009; 105: 304–11. Norton KK, Xu J, Gutmann DH. Expression of the neurofibromatosis I gene product, neurofibromin, in blood vessel endothelial cells and smooth muscle. Neurobiol Dis 1995; 2: 13–21. Li F, Downing BD, Smiley LC, et al. Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. Circulation 2014; 129: 1213–24. Gitler AD, Zhu Y, Ismat FA, Lu MM, Yamauchi Y, Parada LF, Epstein JA. Nf1 has an essential role in endothelial cells. Nat Genet 2003; 33: 75–79.
15
16
17
18
19
20
21
Li F, Munchhof AM, White HA, Mead LE, et al. Neurofibromin is a novel regulator of RASinduced signals in primary vascular smooth muscle cells. Hum Mol Genet 2006; 15: 1921–30. Xu J, Ismat FA, Wang T, Yang J, Epstein JA. NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response. Circulation 2007; 116: 2148–56. Lasater EA, Bessler WK, Mead LE, et al. Nf1+/- mice have increased neointima formation via hyperactivation of a Gleevec sensitive molecular pathway. Hum Mol Genet 2008; 17: 2336–44. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988; 45: 575–78. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997; 278: 51–57. DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 2000; 105: 608–14. Nunley KS, Gao F, Albers AC, Bayliss SJ, Gutmann DH. Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol 2009; 145: 883–87. Lopes Ferraz Filho JR, Munis MP, Soares Souza A, Sanches RA, Goloni-Bertollo EM, Pavarino-Bertelli EC. Unidentified bright objects on brain MRI in children as a diagnostic criterion for neurofibromatosis type 1. Pediatr Radiol 2008; 38: 305–10. DeBella K, Poskitt K, Szudek J, Friedman JM. Use of “unidentified bright objects” on MRI for diagnosis of neurofibromatosis 1 in children. Neurology 2000; 54: 1646–51. Radtke HB, Sebold CD, Allison C, Haidle JL, Schneider G. Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors. J Genet Couns 2007; 16: 387–407. Terzi YK, Oguzkan-Balci S, Anlar B, Aysun S, Guran S, Ayter S. Reproductive decisions after prenatal diagnosis in neurofibromatosis type 1: importance of genetic counseling. Genet Couns 2009; 20: 195–202. Gutmann DH. Eliminating barriers to personalized medicine: learning from neurofibromatosis type 1. Neurology 2014; 83: 463–71.
Site of effect of LY2951742 for migraine prophylaxis In The Lancet Neurology, David Dodick and colleagues1 report an important study of treatment in migraine prophylaxis: parenteral administration of LY2951742, a monoclonal antibody to calcitonin gene-related peptide 31
Correspondence
(CGRP). Mean decrease from baseline in migraine days in 4 weeks was higher in patients given LY2951742 (4·2) than in those given placebo (3·0; p=0·003).1 Results of other trials that use antibodies against CGRP will probably be published soon.2 Apart from the clinical questions such as benefit and tolerability, this new prophylactic treatment raises questions about the pathophysiology of migraine. Most available prophylactic drugs for migraine exert their various effects in the CNS, seemingly supporting the neuronal theory of migraine. In discussing the possible site of action of LY2951742, Dodick and colleagues state that “the site and mechanism of action of CGRP monoclonal antibodies is unclear”, but suggest that blocking neurogenic vasodilation induced by CGRP or inhibition of central trigeminal nociceptive transmission could each be possible mechanisms of action.1 The authors acknowledge that monoclonal antibodies do not readily penetrate the blood–brain barrier, and the results of study, along with other results with CGRP receptor antagonists, seem to suggest a peripheral site of action.1 The authors then argue that the blood–brain barrier might be more permeable during migraines, giving sufficient access to central sites of action. The authors thus suggest that during migraines there is a temporary window, in which opening of the blood–brain barrier allows access of LY2951742 to the CNS and thus inhibiting nociceptive transmission of the central trigeminal nerve, resulting in a prophylactic effect in migraine. In the trial, 32% of patients with migraine were complete responders (no migraine days) in the 3 months versus 17% in the placebo group. If the above hypothesis was correct, then complete responders would not benefit from further treatment with LY2951742 because there is no access to CNS without migraine attacks. Without this 32
access for LY2951742, the migraine attacks would be expected to recur and, after this, a new period with effect of LY2951742 could result. However, this hypothetical sequence of effect alternating with no effect is incompatible with long-term complete response. In addition, it would be a serious drawback for the clinical use of a monoclonal antibody to CGRP in migraine prophylaxis. In conclusion, monoclonal antibodies do not readily cross the blood–brain barrier under normal physiological conditions.3 In 2008, a review of the blood–brain barrier in migraine treatment concluded that no clear proof has been shown of breakdown or leakage of the bloodbrain barrier during migraines.4 In an MRI study of seven patients with migraine with aura and in 14 patients with migraine without aura during migraine attacks, there was no gadolinium enhancement during attacks, compatible with an intact blood-brain barrier.4,5 On the basis of these MRI results and the above argument against a temporary window, a CNS effect of LY2951742 in migraine prophylaxis is, in my view, most unlikely. I declare no competing interests.
Peer Tfelt-Hansen [email protected] Danish Headache Center, University of Copenhagen, Department of Neurology, Glostrup Hospital, Glostrup 2600, Denmark. 1
2
3
4
5
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014; 13: 885–92. Yu YJ, Watts RJ. Developing therapeutic antibodies for neurodegenerative disease. Neurotheraeutics 2013; 10: 459–72. Reuter U. Anti-CGRP antibodies: a new approach to migraine treatment. Lancet Neurol 2014; 13: 857–59. Edvinsson L, Tfelt-Hansen P. The blood-brain barrier in migraine treatment. Cephalalgia 2008; 28: 1245–58. Sanchez del Rio M, Bakker D, et al. Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia 1999; 19: 701–07.
Authors’ reply We thank Peer Tfelt-Hansen for his interest in our study1 and his important questions about mechanism of action for monoclonal antibodies against CGRP, particularly LY2951742. Tfelt-Hansen argues that since monoclonal antibodies do not cross the blood–brain barrier, their site of action cannot be central because there is no clear proof to suggest that the blood–brain barrier is breeched in patients with migraine, either during or between attacks. He further argues that even if the blood–brain barrier were opened during attacks, then that would not explain the complete resolution of attacks in a significant proportion of subjects after the first dose of study drug. As we noted, the principle site of action of monoclonal CGRP antibodies is not known; a peripheral site of action seems likely, but a central site of action cannot be ruled out. Although antibodies are generally considered not to cross the blood– brain barrier or to reach intracellular targets in sufficient quantity to have a physiological or therapeutic effect, the ability of large protein molecules to cross the blood–brain barrier is well known. For example, insulin and transferrin are believed to enter the brain by receptor-mediated transcytosis through binding to receptors expressed by capillary endothelial cells.2,3 Dual-specific monoclonal antibodies that bind to the transferrin receptor have been used to allow therapeutic monoclonal antibodies to traverse the blood–brain barrier in animal models, including primates.4 Other drugs cross the blood–brain barrier by mimicking an endogenous substrate of a transporter receptor. For example, gabapentin, a water-soluble drug, is active in the CNS because the drug crosses the blood–brain barrier on the large neutral amino-acid transporter.5 Whether monoclonal CGRP antibodies specifically cross the blood–brain barrier is unknown, although the www.thelancet.com/neurology Vol 14 January 2015
children younger than 1 year who were ultimately diagnosed with NF1 could not be given a diagnosis of NF1 at initial presentation, 97% met diagnostic criteria by age 8 years (average age at diagnosis 6 years).15 Moreover, 99% of children with NF1 will manifest six or more café-au-lait macules of at least 5 mm diameter by age 1 year.16 For these reasons, we start the process of routine anticipatory management in children with five or more café-au-lait macules as though the diagnosis of NF1 has already been formally made. Other clinical features have been nominated as potential additional diagnostic criteria, including short stature, macrocephaly, and the presence of T2 hyperintensities on brain MRI. Although short stature and macrocephaly are relatively common in the general population and are highly affected by genetic factors independent of NF1 status, T2 hyperintensity abnormalities (sometimes called unidentified bright objects) are detected in about 70% of children with NF1.17 Importantly, these lesions typically decrease in number and size or even disappear completely by adulthood. Furthermore, when formally assessed, these criteria have only 74–84% sensitivity.18 Aside from the clear role for NF1 genetic testing in prenatal reproductive decision making,19,20 NF1 genetic testing is also useful to diagnose individuals who present with spinal neurofibromas or to distinguish NF1 from other genetic disorders with clinical overlap, such as Noonan’s syndrome or Legius’ syndrome. However, there is little cost-effective benefit of NF1 genetic testing in a young child with only café-au-lait macules, especially when clinical surveillance is already planned. Although we agree with Milani and colleagues that the NIH diagnostic criteria for NF1 require critical reexamination, we firmly believe that evidence-based data are needed www.thelancet.com/neurology Vol 14 January 2015
to develop accurate methods to establish a diagnosis of NF1 in children. In addition, for physicians caring for children with NF1, the focus should also turn to prognostic factors that predict clinical outcome and progression. The identification of such risk assessment methods will transform current clinical practice into one in which screening and treatments can be more specifically tailored to each individual child.21 As such, we might envision NF1 moving from a diagnostic discipline to a therapeutic subspecialty.
10
11
12
13
14
We declare no competing interests.
Jonathan A Epstein, David A Ingram Jr, Angela C Hirbe,*David H Gutmann [email protected] Department of Cell and Developmental Biology, The Institute for Regenerative Medicine and the Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA (JAE); Departments of Pediatrics and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA (DAI); Department of Medicine (ACH) and Department of Neurology (DHG), Washington University School of Medicine, St Louis, MO 63110, USA 1
2 3 4
5
6
7
8
9
Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 2014; 13: 834–43. Salyer WR, Sayler DC. The vascular lesions of neurofibromatosis. Angiology 1974; 25: 510–19. Zochodne D. Von Recklinghausen’s vasculopathy. Am J Med Sci 1984; 287: 64–65. Feyrter F. Über die Vasculare Neurofibromatose, nach Untersuchungen am menschlichen Magen-Darmschlauch. Virchow Arch Path Anat 1949; 317: 221–65. Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE, McManus B, Korf BR. Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet Med 2002;4:105-11. Xu J, Ismat FA, Wang T, Lu MM, Antonucci N, Epstein JA. Cardiomyocyte-specific loss of neurofibromin promotes cardiac hypertrophy and dysfunction. Circulation Res 2009; 105: 304–11. Norton KK, Xu J, Gutmann DH. Expression of the neurofibromatosis I gene product, neurofibromin, in blood vessel endothelial cells and smooth muscle. Neurobiol Dis 1995; 2: 13–21. Li F, Downing BD, Smiley LC, et al. Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. Circulation 2014; 129: 1213–24. Gitler AD, Zhu Y, Ismat FA, Lu MM, Yamauchi Y, Parada LF, Epstein JA. Nf1 has an essential role in endothelial cells. Nat Genet 2003; 33: 75–79.
15
16
17
18
19
20
21
Li F, Munchhof AM, White HA, Mead LE, et al. Neurofibromin is a novel regulator of RASinduced signals in primary vascular smooth muscle cells. Hum Mol Genet 2006; 15: 1921–30. Xu J, Ismat FA, Wang T, Yang J, Epstein JA. NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response. Circulation 2007; 116: 2148–56. Lasater EA, Bessler WK, Mead LE, et al. Nf1+/- mice have increased neointima formation via hyperactivation of a Gleevec sensitive molecular pathway. Hum Mol Genet 2008; 17: 2336–44. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988; 45: 575–78. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997; 278: 51–57. DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 2000; 105: 608–14. Nunley KS, Gao F, Albers AC, Bayliss SJ, Gutmann DH. Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol 2009; 145: 883–87. Lopes Ferraz Filho JR, Munis MP, Soares Souza A, Sanches RA, Goloni-Bertollo EM, Pavarino-Bertelli EC. Unidentified bright objects on brain MRI in children as a diagnostic criterion for neurofibromatosis type 1. Pediatr Radiol 2008; 38: 305–10. DeBella K, Poskitt K, Szudek J, Friedman JM. Use of “unidentified bright objects” on MRI for diagnosis of neurofibromatosis 1 in children. Neurology 2000; 54: 1646–51. Radtke HB, Sebold CD, Allison C, Haidle JL, Schneider G. Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors. J Genet Couns 2007; 16: 387–407. Terzi YK, Oguzkan-Balci S, Anlar B, Aysun S, Guran S, Ayter S. Reproductive decisions after prenatal diagnosis in neurofibromatosis type 1: importance of genetic counseling. Genet Couns 2009; 20: 195–202. Gutmann DH. Eliminating barriers to personalized medicine: learning from neurofibromatosis type 1. Neurology 2014; 83: 463–71.
Site of effect of LY2951742 for migraine prophylaxis In The Lancet Neurology, David Dodick and colleagues1 report an important study of treatment in migraine prophylaxis: parenteral administration of LY2951742, a monoclonal antibody to calcitonin gene-related peptide 31
Correspondence
(CGRP). Mean decrease from baseline in migraine days in 4 weeks was higher in patients given LY2951742 (4·2) than in those given placebo (3·0; p=0·003).1 Results of other trials that use antibodies against CGRP will probably be published soon.2 Apart from the clinical questions such as benefit and tolerability, this new prophylactic treatment raises questions about the pathophysiology of migraine. Most available prophylactic drugs for migraine exert their various effects in the CNS, seemingly supporting the neuronal theory of migraine. In discussing the possible site of action of LY2951742, Dodick and colleagues state that “the site and mechanism of action of CGRP monoclonal antibodies is unclear”, but suggest that blocking neurogenic vasodilation induced by CGRP or inhibition of central trigeminal nociceptive transmission could each be possible mechanisms of action.1 The authors acknowledge that monoclonal antibodies do not readily penetrate the blood–brain barrier, and the results of study, along with other results with CGRP receptor antagonists, seem to suggest a peripheral site of action.1 The authors then argue that the blood–brain barrier might be more permeable during migraines, giving sufficient access to central sites of action. The authors thus suggest that during migraines there is a temporary window, in which opening of the blood–brain barrier allows access of LY2951742 to the CNS and thus inhibiting nociceptive transmission of the central trigeminal nerve, resulting in a prophylactic effect in migraine. In the trial, 32% of patients with migraine were complete responders (no migraine days) in the 3 months versus 17% in the placebo group. If the above hypothesis was correct, then complete responders would not benefit from further treatment with LY2951742 because there is no access to CNS without migraine attacks. Without this 32
access for LY2951742, the migraine attacks would be expected to recur and, after this, a new period with effect of LY2951742 could result. However, this hypothetical sequence of effect alternating with no effect is incompatible with long-term complete response. In addition, it would be a serious drawback for the clinical use of a monoclonal antibody to CGRP in migraine prophylaxis. In conclusion, monoclonal antibodies do not readily cross the blood–brain barrier under normal physiological conditions.3 In 2008, a review of the blood–brain barrier in migraine treatment concluded that no clear proof has been shown of breakdown or leakage of the bloodbrain barrier during migraines.4 In an MRI study of seven patients with migraine with aura and in 14 patients with migraine without aura during migraine attacks, there was no gadolinium enhancement during attacks, compatible with an intact blood-brain barrier.4,5 On the basis of these MRI results and the above argument against a temporary window, a CNS effect of LY2951742 in migraine prophylaxis is, in my view, most unlikely. I declare no competing interests.
Peer Tfelt-Hansen [email protected] Danish Headache Center, University of Copenhagen, Department of Neurology, Glostrup Hospital, Glostrup 2600, Denmark. 1
2
3
4
5
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014; 13: 885–92. Yu YJ, Watts RJ. Developing therapeutic antibodies for neurodegenerative disease. Neurotheraeutics 2013; 10: 459–72. Reuter U. Anti-CGRP antibodies: a new approach to migraine treatment. Lancet Neurol 2014; 13: 857–59. Edvinsson L, Tfelt-Hansen P. The blood-brain barrier in migraine treatment. Cephalalgia 2008; 28: 1245–58. Sanchez del Rio M, Bakker D, et al. Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia 1999; 19: 701–07.
Authors’ reply We thank Peer Tfelt-Hansen for his interest in our study1 and his important questions about mechanism of action for monoclonal antibodies against CGRP, particularly LY2951742. Tfelt-Hansen argues that since monoclonal antibodies do not cross the blood–brain barrier, their site of action cannot be central because there is no clear proof to suggest that the blood–brain barrier is breeched in patients with migraine, either during or between attacks. He further argues that even if the blood–brain barrier were opened during attacks, then that would not explain the complete resolution of attacks in a significant proportion of subjects after the first dose of study drug. As we noted, the principle site of action of monoclonal CGRP antibodies is not known; a peripheral site of action seems likely, but a central site of action cannot be ruled out. Although antibodies are generally considered not to cross the blood– brain barrier or to reach intracellular targets in sufficient quantity to have a physiological or therapeutic effect, the ability of large protein molecules to cross the blood–brain barrier is well known. For example, insulin and transferrin are believed to enter the brain by receptor-mediated transcytosis through binding to receptors expressed by capillary endothelial cells.2,3 Dual-specific monoclonal antibodies that bind to the transferrin receptor have been used to allow therapeutic monoclonal antibodies to traverse the blood–brain barrier in animal models, including primates.4 Other drugs cross the blood–brain barrier by mimicking an endogenous substrate of a transporter receptor. For example, gabapentin, a water-soluble drug, is active in the CNS because the drug crosses the blood–brain barrier on the large neutral amino-acid transporter.5 Whether monoclonal CGRP antibodies specifically cross the blood–brain barrier is unknown, although the www.thelancet.com/neurology Vol 14 January 2015
