Clinical/Scientific Notes
Fleur Cohen-Aubart, MD, PhD Jean-François Emile, MD, PhD Philippe Maksud, MD* Damien Galanaud, MD, PhD* Ahmed Idbaih, MD Dorian Chauvet, MD Yaël Amar, MD Neila Benameur, PharmD Zahir Amoura, MD, MSc Julien Haroche, MD, PhD
Supplemental data at Neurology.org
1294
MARKED EFFICACY OF VEMURAFENIB IN SUPRASELLAR ERDHEIM-CHESTER DISEASE
Erdheim-Chester disease (ECD) is a rare non– Langerhans cell histiocytosis characterized by the accumulation of foamy CD681CD1a2 histiocytes. Tissue infiltration preferentially affects long bones and retroperitoneal and peri-aortic spaces, but almost any organ or system can be affected.1 Cardiac and neurologic involvements are associated with significantly higher levels of mortality and morbidity.2 Interferon-a is the first-line treatment for ECD, but may be poorly tolerated, particularly at high doses needed for the treatment of CNS involvement.3,4 It has been shown that more than half of all patients with ECD harbor the BRAFV600E mutation.5,6 The mitogenactivated protein kinase has been implicated in the pathophysiology of many cancers, especially melanoma, lung, and colorectal cancers. Under physiologic conditions, the Ras-Raf-MEK-ERK signaling cascade interaction is initiated by ligation of a receptor-linked tyrosine kinase by its corresponding growth factor. BRAFV600E mutation is responsible for a constitutively active kinase. Vemurafenib—a selective low-molecularweight BRAF kinase inhibitor effective for the treatment of metastatic melanoma, including cerebral metastases—has been shown to be highly effective for treating bone, retro-orbital, retroperitoneal, and cardiac lesions in 3 patients with ECD with mutations.7 Vemurafenib selectively suppresses proliferation in tumor cells expressing mutated BRAFV600E proteins. We report the case of a 58-year-old man with ECD with visual loss due to compression of the optic chiasm by a suprasellar lesion who displayed reversal of this vision loss after 1 month of vemurafenib therapy. This is a single observational study without controls (Class IV). Case report. A 58-year-old man was diagnosed with pituitary adenoma in 2012, following a 5-year history of diabetes insipidus. In March 2013, systemic explorations revealed bilateral symmetric femoral and tibial bones, lung, and suprasellar involvement, with no cardiac or retroperitoneal infiltration. ECD was diagnosed with xanthelasma biopsy, which revealed an accumulation of foamy CD681CD1a2 histiocytes with BRAFV600E mutations. Treatment with pegylated interferon-a was initiated in April Neurology 83
September 30, 2014
2013 at a dose of 135 mg/wk for 4 weeks, increased to 180 mg/wk thereafter. In September 2013, the patient complained of marked loss of vision, concordant with a significant increase in the size of the suprasellar lesion (figure 1 and figure e-1 on the Neurology® Web site at Neurology.org). The visual field revealed bitemporal notch and enlargement of the blind spot. Vemurafenib was started on September 29, 2013, after counseling and written informed consent, at a dose of 480 mg twice daily, after dermatologic examination and ECG. On day 10, improvement in visual acuity was noted in both eyes, from 0.7 to 1.0 in the left eye and 0.8 to 1.0 in the right eye. The visual field was normal in both eyes. The patient was reassessed on October 21, 2013, by PET and cerebral MRI. Visual acuity was 1.0 in both eyes. PET showed a subtle residual suprasellar and lung hypermetabolism (figure 1). Cerebral MRI showed a decrease in the size of the suprasellar mass of 24% for the transverse diameter, 21% for the antero-posterior diameter, and 35% for height (figure 1 and figure e-1). At M4, cerebral MRI showed a stability of the size of the suprasellar mass and PET the disappearance of suprasellar and lung hypermetabolism. No side effects occurred during treatment. Discussion. We describe the case of a patient with visual loss due to compression of the optic chiasm by a suprasellar mass during ECD, refractory to conventional treatment with interferon-a. Treatment induced a major clinical and metabolic response within 1 month. The patient recovered normal vision, and his cerebral PET after treatment was normal. A decrease in tumor size was also observed on MRI. Although ECD lesions may tend to regress spontaneously, the dramatic improvement is thought to be due to vemurafenib in the present case since the suprasellar mass had been continuously growing in the preceding months. Thus we show efficacy of BRAF inhibition for treating CNS infiltration in ECD. Visual acuity and visual field improved significantly and returned to a normal level rapidly. This response is striking in this case as it allowed us to cancel surgery. The targeted inhibition of mutant BRAF kinase could become the preferred first-line treatment for ECD at life-threatening sites. Although vemurafenib is
Figure 1
Tumor response on MRI and PET scans
(A) Coronal and sagittal T1-weighted gadolinium-enhanced MRI scans. Coronal T2-weighted MRI scan. Baseline (March 2013). MRI shows a nodular suprasellar mass, with homogeneous intense enhancement after the administration of gadolinium-based contrast material, with a low signal on the T2-weighted image. The dimensions of this mass were as follows: transverse diameter 29 mm 3 antero-posterior diameter 28 mm 3 height 22 mm. This mass had a major effect on the optic chiasm, which is barely visible (arrow). (B) Coronal and sagittal T1-weighted gadolinium-enhanced MRI scans. Coronal T2-weighted MRI scan. Follow-up MRI at 6 months (September 2013): the mass is markedly larger: transverse diameter 33 mm 3 antero-posterior diameter 34 mm 3 height 26 mm. The effect of the mass on the optic chiasm has also increased, this structure no longer being visible. (C) Coronal and sagittal T1-weighted gadolinium-enhanced MRI scans. Coronal T2-weighted MRI scan. Follow-up MRI 1 month after the introduction of vemurafenib (October 2013): the mass has considerably decreased in size: transverse diameter 25 mm 3 antero-posterior diameter 27 mm 3 height 17 mm. The mass is no longer affecting the optic chiasm, which is now of normal shape and thickness (arrow). (D) Coronal and sagittal T1-weighted MRI scans. Coronal T2-weighted MRI scan (January 2014): the mass has considerably decreased in size, with no compression of the optic chiasm. (E) 18F-FDG TEP in March 2013 shows intense FDG uptake with a maximum standardized uptake value (SUVmax) of 31 for the suprasellar lesion. A second lesion displaying lower levels of uptake was found in the occipital area (SUVmax 5 9). (F) In September 2013, 18 F-FDG TEP shows a significant increase in SUV, by about 50%, for both the suprasellar (SUVmax 5 46) and occipital (SUVmax 5 14) lesions. (G) In October 2013, 18F-FDG TEP shows a large decrease in SUVmax for the suprasellar and occipital lesions (SUVmax 5 9, not significantly different from the other cerebral areas). (H) In January 2014, 18F-FDG TEP reveals no significant abnormality.
usually well-tolerated, safety concerns should be kept in mind, especially for long-term treatments, such as epidermoid tumors, especially skin squamous cell carcinoma, reported in up to 10%; melanomas; arthralgias; sunlight sensitivity; hepatotoxicity; and QT prolongations. Regular dermatologic and electrocardiographic assessments are mandatory. Acquired resistance to BRAF inhibitors has not been described in ECD, in contrast to melanoma, and the long-term outcome of BRAF inhibitor treatment should be studied. *These authors contributed equally to this work. From AP-HP (F.C.-A., P.M., D.G., A.I., D.C., N.B., Z.A., J.H.), Groupe Hospitalier Pitié-Salpêtrière, Paris; Université Paris VI Pierre et Marie Curie (F.C.-A., P.M., Z.A., D.G., A.I., D.C., J.H.); AP-HP (J.-F.E.), Hôpital Ambroise-Paré, Boulogne; Université de Versailles (J.-F.E.); and AP-HP (Y.A.), Hôpital Cochin, Paris, France.
Author contributions: All authors were involved in drafting the article or revising it critically for important intellectual content and all authors approved the final version to be published. Dr. Fleur Cohen-Aubart collected and analyzed data and wrote the paper. Pr. Jean-François Emile designed the figures and edited the manuscript. Dr. Maksud collected nuclear imaging data and edited the manuscript. Dr. Galanaud collected MRI data and edited the manuscript. Dr. Idbaih, Dr. Chauvet, Dr. Amar, Dr. Benameur, and Dr. Amoura analyzed data and edited the manuscript. Dr. Haroche designed the research and wrote the paper. Study funding: No targeted funding reported. Disclosure: F. Cohen-Aubart reports no disclosures relevant to the manuscript. J. Emile performed some expertise on BRAF targeted therapies for Roche and GlaxoSmithKline. P. Maksud, D. Galanaud, A. Idbaih, D. Chauvet, Y. Amar, N. Benameur, and Z. Amoura report no disclosures relevant to the manuscript. J. Haroche received honoraria from GlaxoSmithKline for counseling patients with histiocytosis on treatments with targeted therapies. Go to Neurology.org for full disclosures. Received December 7, 2013. Accepted in final form May 14, 2014. Correspondence to Dr. Haroche: [email protected] Neurology 83
September 30, 2014
1295
© 2014 American Academy of Neurology 1.
2.
3.
Haroche J, Arnaud L, Cohen-Aubart F, et al. ErdheimChester disease. Rheum Dis Clin North Am 2013;39: 299–311. Arnaud L, Hervier B, Neel A, et al. CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients. Blood 2011;117:2778–2782. Haroche J, Amoura Z, Trad SG, et al. Variability in the efficacy of interferon-alpha in Erdheim-Chester disease by patient and site of involvement: results in eight patients. Arthritis Rheum 2006;54:3330–3336.
4.
5. 6.
7.
Hervier B, Arnaud L, Charlotte F, et al. Treatment of ErdheimChester disease with long-term high-dose interferon-alpha. Semin Arthritis Rheum 2012;41:907–913. Emile JF, Charlotte F, Amoura Z, Haroche J. BRAF mutations in Erdheim-Chester disease. J Clin Oncol 2013;31:398. Haroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 2012;120: 2700–2703. Haroche J, Cohen-Aubart F, Emile JF, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory ErdheimChester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013;120:2700–2703.
Your Research Recognized: Apply for an AAN Award Have you, or someone you know, been conducting research that may be advancing the field of neurology? Apply—or nominate a colleague—for a prestigious AAN award and your research could be recognized during the 2015 AAN Annual Meeting in Washington, DC, April 18–25, 2015, the world’s largest gathering of neurologists. Awards are available for all career stages and interests. View all 2015 AAN awards and application deadlines at AAN.com/view/15Awards. Application deadline is October 23, 2014.
It’s Time to Plan for ICD-10, and the AAN Can Help All health care providers are required to transition to ICD-10 on October 1, 2015. Claims for services performed on or after this date with an ICD-9 code will not be processed and payments will be delayed. The AAN provides information and resources to help you make this a smooth transition, and has partnered with Complete Practice Resources to provide you with an affordable online project management tool to help walk you through each phase of the necessary preparation to ensure you’re ready. Learn more at AAN.com/view/ICD10 and start your transition today!
WriteClick® rapid online correspondence Have a comment on a recent Neurology® article you would like to share? Now it is easier and more convenient. Neurology.org has launched WriteClick on the home page and sidebars of each article to encourage remarks and debate among users. WriteClick is restricted to comments about studies published in Neurology within the last eight weeks. Learn more at Neurology.org/letters
1296
Neurology 83
September 30, 2014
Marked efficacy of vemurafenib in suprasellar Erdheim-Chester disease Fleur Cohen-Aubart, Jean-François Emile, Philippe Maksud, et al. Neurology 2014;83;1294-1296 Published Online before print August 29, 2014 DOI 10.1212/WNL.0000000000000832 This information is current as of August 29, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/14/1294.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/29/WNL.0000000000 000832.DC1.html
References
This article cites 7 articles, 3 of which you can access for free at: http://www.neurology.org/content/83/14/1294.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Optic nerve http://www.neurology.org//cgi/collection/optic_nerve
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Fleur Cohen-Aubart, MD, PhD Jean-François Emile, MD, PhD Philippe Maksud, MD* Damien Galanaud, MD, PhD* Ahmed Idbaih, MD Dorian Chauvet, MD Yaël Amar, MD Neila Benameur, PharmD Zahir Amoura, MD, MSc Julien Haroche, MD, PhD
Supplemental data at Neurology.org
1294
MARKED EFFICACY OF VEMURAFENIB IN SUPRASELLAR ERDHEIM-CHESTER DISEASE
Erdheim-Chester disease (ECD) is a rare non– Langerhans cell histiocytosis characterized by the accumulation of foamy CD681CD1a2 histiocytes. Tissue infiltration preferentially affects long bones and retroperitoneal and peri-aortic spaces, but almost any organ or system can be affected.1 Cardiac and neurologic involvements are associated with significantly higher levels of mortality and morbidity.2 Interferon-a is the first-line treatment for ECD, but may be poorly tolerated, particularly at high doses needed for the treatment of CNS involvement.3,4 It has been shown that more than half of all patients with ECD harbor the BRAFV600E mutation.5,6 The mitogenactivated protein kinase has been implicated in the pathophysiology of many cancers, especially melanoma, lung, and colorectal cancers. Under physiologic conditions, the Ras-Raf-MEK-ERK signaling cascade interaction is initiated by ligation of a receptor-linked tyrosine kinase by its corresponding growth factor. BRAFV600E mutation is responsible for a constitutively active kinase. Vemurafenib—a selective low-molecularweight BRAF kinase inhibitor effective for the treatment of metastatic melanoma, including cerebral metastases—has been shown to be highly effective for treating bone, retro-orbital, retroperitoneal, and cardiac lesions in 3 patients with ECD with mutations.7 Vemurafenib selectively suppresses proliferation in tumor cells expressing mutated BRAFV600E proteins. We report the case of a 58-year-old man with ECD with visual loss due to compression of the optic chiasm by a suprasellar lesion who displayed reversal of this vision loss after 1 month of vemurafenib therapy. This is a single observational study without controls (Class IV). Case report. A 58-year-old man was diagnosed with pituitary adenoma in 2012, following a 5-year history of diabetes insipidus. In March 2013, systemic explorations revealed bilateral symmetric femoral and tibial bones, lung, and suprasellar involvement, with no cardiac or retroperitoneal infiltration. ECD was diagnosed with xanthelasma biopsy, which revealed an accumulation of foamy CD681CD1a2 histiocytes with BRAFV600E mutations. Treatment with pegylated interferon-a was initiated in April Neurology 83
September 30, 2014
2013 at a dose of 135 mg/wk for 4 weeks, increased to 180 mg/wk thereafter. In September 2013, the patient complained of marked loss of vision, concordant with a significant increase in the size of the suprasellar lesion (figure 1 and figure e-1 on the Neurology® Web site at Neurology.org). The visual field revealed bitemporal notch and enlargement of the blind spot. Vemurafenib was started on September 29, 2013, after counseling and written informed consent, at a dose of 480 mg twice daily, after dermatologic examination and ECG. On day 10, improvement in visual acuity was noted in both eyes, from 0.7 to 1.0 in the left eye and 0.8 to 1.0 in the right eye. The visual field was normal in both eyes. The patient was reassessed on October 21, 2013, by PET and cerebral MRI. Visual acuity was 1.0 in both eyes. PET showed a subtle residual suprasellar and lung hypermetabolism (figure 1). Cerebral MRI showed a decrease in the size of the suprasellar mass of 24% for the transverse diameter, 21% for the antero-posterior diameter, and 35% for height (figure 1 and figure e-1). At M4, cerebral MRI showed a stability of the size of the suprasellar mass and PET the disappearance of suprasellar and lung hypermetabolism. No side effects occurred during treatment. Discussion. We describe the case of a patient with visual loss due to compression of the optic chiasm by a suprasellar mass during ECD, refractory to conventional treatment with interferon-a. Treatment induced a major clinical and metabolic response within 1 month. The patient recovered normal vision, and his cerebral PET after treatment was normal. A decrease in tumor size was also observed on MRI. Although ECD lesions may tend to regress spontaneously, the dramatic improvement is thought to be due to vemurafenib in the present case since the suprasellar mass had been continuously growing in the preceding months. Thus we show efficacy of BRAF inhibition for treating CNS infiltration in ECD. Visual acuity and visual field improved significantly and returned to a normal level rapidly. This response is striking in this case as it allowed us to cancel surgery. The targeted inhibition of mutant BRAF kinase could become the preferred first-line treatment for ECD at life-threatening sites. Although vemurafenib is
Figure 1
Tumor response on MRI and PET scans
(A) Coronal and sagittal T1-weighted gadolinium-enhanced MRI scans. Coronal T2-weighted MRI scan. Baseline (March 2013). MRI shows a nodular suprasellar mass, with homogeneous intense enhancement after the administration of gadolinium-based contrast material, with a low signal on the T2-weighted image. The dimensions of this mass were as follows: transverse diameter 29 mm 3 antero-posterior diameter 28 mm 3 height 22 mm. This mass had a major effect on the optic chiasm, which is barely visible (arrow). (B) Coronal and sagittal T1-weighted gadolinium-enhanced MRI scans. Coronal T2-weighted MRI scan. Follow-up MRI at 6 months (September 2013): the mass is markedly larger: transverse diameter 33 mm 3 antero-posterior diameter 34 mm 3 height 26 mm. The effect of the mass on the optic chiasm has also increased, this structure no longer being visible. (C) Coronal and sagittal T1-weighted gadolinium-enhanced MRI scans. Coronal T2-weighted MRI scan. Follow-up MRI 1 month after the introduction of vemurafenib (October 2013): the mass has considerably decreased in size: transverse diameter 25 mm 3 antero-posterior diameter 27 mm 3 height 17 mm. The mass is no longer affecting the optic chiasm, which is now of normal shape and thickness (arrow). (D) Coronal and sagittal T1-weighted MRI scans. Coronal T2-weighted MRI scan (January 2014): the mass has considerably decreased in size, with no compression of the optic chiasm. (E) 18F-FDG TEP in March 2013 shows intense FDG uptake with a maximum standardized uptake value (SUVmax) of 31 for the suprasellar lesion. A second lesion displaying lower levels of uptake was found in the occipital area (SUVmax 5 9). (F) In September 2013, 18 F-FDG TEP shows a significant increase in SUV, by about 50%, for both the suprasellar (SUVmax 5 46) and occipital (SUVmax 5 14) lesions. (G) In October 2013, 18F-FDG TEP shows a large decrease in SUVmax for the suprasellar and occipital lesions (SUVmax 5 9, not significantly different from the other cerebral areas). (H) In January 2014, 18F-FDG TEP reveals no significant abnormality.
usually well-tolerated, safety concerns should be kept in mind, especially for long-term treatments, such as epidermoid tumors, especially skin squamous cell carcinoma, reported in up to 10%; melanomas; arthralgias; sunlight sensitivity; hepatotoxicity; and QT prolongations. Regular dermatologic and electrocardiographic assessments are mandatory. Acquired resistance to BRAF inhibitors has not been described in ECD, in contrast to melanoma, and the long-term outcome of BRAF inhibitor treatment should be studied. *These authors contributed equally to this work. From AP-HP (F.C.-A., P.M., D.G., A.I., D.C., N.B., Z.A., J.H.), Groupe Hospitalier Pitié-Salpêtrière, Paris; Université Paris VI Pierre et Marie Curie (F.C.-A., P.M., Z.A., D.G., A.I., D.C., J.H.); AP-HP (J.-F.E.), Hôpital Ambroise-Paré, Boulogne; Université de Versailles (J.-F.E.); and AP-HP (Y.A.), Hôpital Cochin, Paris, France.
Author contributions: All authors were involved in drafting the article or revising it critically for important intellectual content and all authors approved the final version to be published. Dr. Fleur Cohen-Aubart collected and analyzed data and wrote the paper. Pr. Jean-François Emile designed the figures and edited the manuscript. Dr. Maksud collected nuclear imaging data and edited the manuscript. Dr. Galanaud collected MRI data and edited the manuscript. Dr. Idbaih, Dr. Chauvet, Dr. Amar, Dr. Benameur, and Dr. Amoura analyzed data and edited the manuscript. Dr. Haroche designed the research and wrote the paper. Study funding: No targeted funding reported. Disclosure: F. Cohen-Aubart reports no disclosures relevant to the manuscript. J. Emile performed some expertise on BRAF targeted therapies for Roche and GlaxoSmithKline. P. Maksud, D. Galanaud, A. Idbaih, D. Chauvet, Y. Amar, N. Benameur, and Z. Amoura report no disclosures relevant to the manuscript. J. Haroche received honoraria from GlaxoSmithKline for counseling patients with histiocytosis on treatments with targeted therapies. Go to Neurology.org for full disclosures. Received December 7, 2013. Accepted in final form May 14, 2014. Correspondence to Dr. Haroche: [email protected] Neurology 83
September 30, 2014
1295
© 2014 American Academy of Neurology 1.
2.
3.
Haroche J, Arnaud L, Cohen-Aubart F, et al. ErdheimChester disease. Rheum Dis Clin North Am 2013;39: 299–311. Arnaud L, Hervier B, Neel A, et al. CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients. Blood 2011;117:2778–2782. Haroche J, Amoura Z, Trad SG, et al. Variability in the efficacy of interferon-alpha in Erdheim-Chester disease by patient and site of involvement: results in eight patients. Arthritis Rheum 2006;54:3330–3336.
4.
5. 6.
7.
Hervier B, Arnaud L, Charlotte F, et al. Treatment of ErdheimChester disease with long-term high-dose interferon-alpha. Semin Arthritis Rheum 2012;41:907–913. Emile JF, Charlotte F, Amoura Z, Haroche J. BRAF mutations in Erdheim-Chester disease. J Clin Oncol 2013;31:398. Haroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 2012;120: 2700–2703. Haroche J, Cohen-Aubart F, Emile JF, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory ErdheimChester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013;120:2700–2703.
Your Research Recognized: Apply for an AAN Award Have you, or someone you know, been conducting research that may be advancing the field of neurology? Apply—or nominate a colleague—for a prestigious AAN award and your research could be recognized during the 2015 AAN Annual Meeting in Washington, DC, April 18–25, 2015, the world’s largest gathering of neurologists. Awards are available for all career stages and interests. View all 2015 AAN awards and application deadlines at AAN.com/view/15Awards. Application deadline is October 23, 2014.
It’s Time to Plan for ICD-10, and the AAN Can Help All health care providers are required to transition to ICD-10 on October 1, 2015. Claims for services performed on or after this date with an ICD-9 code will not be processed and payments will be delayed. The AAN provides information and resources to help you make this a smooth transition, and has partnered with Complete Practice Resources to provide you with an affordable online project management tool to help walk you through each phase of the necessary preparation to ensure you’re ready. Learn more at AAN.com/view/ICD10 and start your transition today!
WriteClick® rapid online correspondence Have a comment on a recent Neurology® article you would like to share? Now it is easier and more convenient. Neurology.org has launched WriteClick on the home page and sidebars of each article to encourage remarks and debate among users. WriteClick is restricted to comments about studies published in Neurology within the last eight weeks. Learn more at Neurology.org/letters
1296
Neurology 83
September 30, 2014
Marked efficacy of vemurafenib in suprasellar Erdheim-Chester disease Fleur Cohen-Aubart, Jean-François Emile, Philippe Maksud, et al. Neurology 2014;83;1294-1296 Published Online before print August 29, 2014 DOI 10.1212/WNL.0000000000000832 This information is current as of August 29, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/14/1294.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/29/WNL.0000000000 000832.DC1.html
References
This article cites 7 articles, 3 of which you can access for free at: http://www.neurology.org/content/83/14/1294.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Optic nerve http://www.neurology.org//cgi/collection/optic_nerve
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
