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our rigorous risk management program for natalizumab, we will continue to closely monitor the safety of natalizumab regarding all adverse events, including PCNSL. Biogen Idec, Cambridge, MA References 1. Schweikert A, Marcus KM, Ringel F et al. Primary central nervous system lymphoma in a patient treated with natalizumab. Ann Neurol 2009;66:403– 406. 2. Gulley ML, Tang W. Laboratory assays for Epstein-Barr virus- related disease. J Mol Diagn 2008;10:279 –292. 3. DeAngelis LM. Primary central nervous system lymphoma imi- tates multiple sclerosis. J Neurooncol 1990;9:177–181. 4. Olson JE, Janney CA, Rao RD, et al. The continuing increase in the incidence of primary central nervous system non-Hodgkin lymphoma: a surveillance, epidemiology, and end results analy- sis. Cancer 2002;95:1504 –1510. 5. Pulido JS, Vierkant RA, Olson JE, et al. Racial differences in primary central nervous system lymphoma incidence and survival rates. Neuro Oncol 2009;11:318 –322. DOI: 10.1002/ana.21959 Reply James Woodworth, PhD, Meena Subramanyam, PhD, Mark Rogge, PhD The pharmacokinetics of natalizumab have been determined in several studies (1,000 patients) supporting registration and in- dicate disposition that is consistent with endogenous immuno- globulin (Ig) G 4 . The pharmacokinetic variability is considered low, consistent with the study cited by Dr Focosi. 1 In that study, the coefficient of variation of the AUC inf and maximum concen- tration values for any of the doses tested never exceeded 24.7%. This is consistent with predictable and well-behaved therapeutic antibodies. Data from phase 3 studies show that average predose (trough) concentrations at steady-state range from 23 to 28g/ml (N 500); occasionally predose concentrations can approach 40g/ml (data on file, Biogen Idec). With a 10-to 16-day half- life, the concentration of 10.8g/ml reported by Wenning et al 2 57 days after the last natalizumab dose is well within the expected range. As such, it does not appear that natalizumab exposure in progressive multifocal leukoencephalopathy patients is abnormal. In the reported case of primary central nervous system lymphoma by Schweikert et al, no collections were made to de- termine natalizumab concentration. 3 The patient received 7 courses of plasmapheresis, which would most likely have been quite thorough in clearing natalizumab. No more than 5 courses are typically needed to ensure concentrations fall below 1g/ml; this concentration is well below that producing complete alpha-4 integrin saturation. As an IgG 4 product, natalizumab is also subject to Fab- arm exchange with endogenous human IgG 4 , as suggested by Labrijn et al. 4 Our studies suggest that a “Fab-arm exchanged” natalizumab still retains activity for binding alpha4-integrin, al- beit reduced from intact natalizumab. Thus, despite the possi- bility of an alternate arm binding to another antigen, the like- lihood of this impacting natalizumab’s ability to bind the target VLA-4 antigen is very low. It is also not anticipated that the pharmacokinetics will change. A Fab-arm exchanged form of na- talizumab will still be an IgG 4 , and as such, will retain distribu- tion and clearance characteristics similar to other IgG 4 antibod- ies. Such characteristics are in line with those already noted for natalizumab. Additionally, the Fab-arm exchange occurs quickly, with significant amounts of natalizumab exchanged within 24 hours. 4 Therefore, the reported pharmacokinetics for natali- zumab are primarily those of the exchanged form, and become what is already reported and known. In summary, the pharma- cokinetics of natalizumab are predictable, with relatively low variability, and are reflective of a Fab-arm exchanged form. Biogen Idec, Cambridge, MA References 1. Sheremata WA, Vollmer TL, Stone LA, et al. A safety and phar- macokinetic study of intravenous natalizumab in patients with MS. Neurology 1999;52:1072–1074. 2. Wenning W, Haghikia A, Laubenberger J, et al. Treatment of progressive multifocal leukoencephalopathy associated with na- talizumab. N Engl J Med 2009;361:1075–1080. 3. Schweikert A, Kremer M, Ringel F, et al. Primary central nervous system lymphoma in a patient treated with natalizumab. Ann Neurol 2009;66:403– 406. 4. Labrijn AF, Buijsse AO, van den Bremer ET, et al. Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo. Nat Biotechnol 2009;27:767–771. DOI: 10.1002/ana.21960 Childhood Absence Epilepsy As a Manifestation of GLUT1 Deficiency Michael Rotstein, MD and Darryl C. De Vivo, MD Suls et al emphasize childhood absence epilepsy as a manifesta- tion of GLUT1 deficiency syndrome (DS). 1 We agree and re- mind the authors that the first 2 patients described by us in 1991 had staring spells, 2,3 as have 18% of 132 patients studied by us since that first report (unpublished observations). The au- thors describe normal cerebrospinal fluid (CSF)/blood glucose ratios as part of the expanding phenotype described in GLUT1 DS. All patients with GLUT1 DS who had a lumbar puncture have a low CSF glucose value. 4 Most have a value 40mg/dl. Milder phenotypes with intermittent symptoms may have CSF glucose values in the 41 to 52 range. We are not aware of any GLUT1 DS patients with normal CSF glucose values. We con- sider the ratio of CSF to blood glucose a less reliable biomarker, as this ratio is determined by the glucose concentration in 2 compartments. A low ratio can result from a low CSF glucose, or a high blood glucose as may be the case if the blood is drawn after the lumbar puncture or postprandially. Even so, the recent reports describing milder GLUT1 DS phenotypes report ratios ranging from 0.47 to 0.59, low compared with controls. 5 The lumbar puncture is still an essential diagnostic test when searching for the cause of patients’ neurological symptoms. It is clear that GLUT1 DS patients have fixed and intermittent neuro- ANNALS of Neurology 272 Volume 67, No. 2
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our rigorous risk management program for natalizumab, we willcontinue to closely monitor the safety of natalizumab regardingall adverse events, including PCNSL.
Biogen Idec, Cambridge, MA
References1. Schweikert A, Marcus KM, Ringel F et al. Primary central nervous
system lymphoma in a patient treated with natalizumab. AnnNeurol 2009;66:403–406.
2. Gulley ML, Tang W. Laboratory assays for Epstein-Barr virus-related disease. J Mol Diagn 2008;10:279–292.
3. DeAngelis LM. Primary central nervous system lymphoma imi-tates multiple sclerosis. J Neurooncol 1990;9:177–181.
4. Olson JE, Janney CA, Rao RD, et al. The continuing increase inthe incidence of primary central nervous system non-Hodgkinlymphoma: a surveillance, epidemiology, and end results analy-sis. Cancer 2002;95:1504–1510.
5. Pulido JS, Vierkant RA, Olson JE, et al. Racial differences inprimary central nervous system lymphoma incidence and survivalrates. Neuro Oncol 2009;11:318–322.
DOI: 10.1002/ana.21959
ReplyJames Woodworth, PhD, Meena Subramanyam, PhD,Mark Rogge, PhD
The pharmacokinetics of natalizumab have been determined inseveral studies (�1,000 patients) supporting registration and in-dicate disposition that is consistent with endogenous immuno-globulin (Ig) G4. The pharmacokinetic variability is consideredlow, consistent with the study cited by Dr Focosi.1 In that study,the coefficient of variation of the AUCinf and maximum concen-tration values for any of the doses tested never exceeded 24.7%.This is consistent with predictable and well-behaved therapeuticantibodies. Data from phase 3 studies show that average predose(trough) concentrations at steady-state range from 23 to 28�g/ml(N � 500); occasionally predose concentrations can approach40�g/ml (data on file, Biogen Idec). With a 10-to 16-day half-life, the concentration of 10.8�g/ml reported by Wenning et al2
57 days after the last natalizumab dose is well within the expectedrange. As such, it does not appear that natalizumab exposure inprogressive multifocal leukoencephalopathy patients is abnormal.
In the reported case of primary central nervous systemlymphoma by Schweikert et al, no collections were made to de-termine natalizumab concentration.3 The patient received 7courses of plasmapheresis, which would most likely have beenquite thorough in clearing natalizumab. No more than 5 coursesare typically needed to ensure concentrations fall below 1�g/ml;this concentration is well below that producing completealpha-4 integrin saturation.
As an IgG4 product, natalizumab is also subject to Fab-arm exchange with endogenous human IgG4, as suggested byLabrijn et al.4 Our studies suggest that a “Fab-arm exchanged”natalizumab still retains activity for binding alpha4-integrin, al-beit reduced from intact natalizumab. Thus, despite the possi-bility of an alternate arm binding to another antigen, the like-
lihood of this impacting natalizumab’s ability to bind the targetVLA-4 antigen is very low. It is also not anticipated that thepharmacokinetics will change. A Fab-arm exchanged form of na-talizumab will still be an IgG4, and as such, will retain distribu-tion and clearance characteristics similar to other IgG4 antibod-ies. Such characteristics are in line with those already noted fornatalizumab. Additionally, the Fab-arm exchange occurs quickly,with significant amounts of natalizumab exchanged within 24hours.4 Therefore, the reported pharmacokinetics for natali-zumab are primarily those of the exchanged form, and becomewhat is already reported and known. In summary, the pharma-cokinetics of natalizumab are predictable, with relatively lowvariability, and are reflective of a Fab-arm exchanged form.
Biogen Idec, Cambridge, MA
References1. Sheremata WA, Vollmer TL, Stone LA, et al. A safety and phar-
macokinetic study of intravenous natalizumab in patients withMS. Neurology 1999;52:1072–1074.
2. Wenning W, Haghikia A, Laubenberger J, et al. Treatment ofprogressive multifocal leukoencephalopathy associated with na-talizumab. N Engl J Med 2009;361:1075–1080.
3. Schweikert A, Kremer M, Ringel F, et al. Primary central nervoussystem lymphoma in a patient treated with natalizumab. AnnNeurol 2009;66:403–406.
4. Labrijn AF, Buijsse AO, van den Bremer ET, et al. TherapeuticIgG4 antibodies engage in Fab-arm exchange with endogenoushuman IgG4 in vivo. Nat Biotechnol 2009;27:767–771.
DOI: 10.1002/ana.21960
Childhood Absence Epilepsy As a Manifestation ofGLUT1 DeficiencyMichael Rotstein, MD and Darryl C. De Vivo, MD
Suls et al emphasize childhood absence epilepsy as a manifesta-tion of GLUT1 deficiency syndrome (DS).1 We agree and re-mind the authors that the first 2 patients described by us in1991 had staring spells,2,3 as have 18% of 132 patients studiedby us since that first report (unpublished observations). The au-thors describe normal cerebrospinal fluid (CSF)/blood glucoseratios as part of the expanding phenotype described in GLUT1DS. All patients with GLUT1 DS who had a lumbar puncturehave a low CSF glucose value.4 Most have a value �40mg/dl.Milder phenotypes with intermittent symptoms may have CSFglucose values in the 41 to 52 range. We are not aware of anyGLUT1 DS patients with normal CSF glucose values. We con-sider the ratio of CSF to blood glucose a less reliable biomarker,as this ratio is determined by the glucose concentration in 2compartments. A low ratio can result from a low CSF glucose,or a high blood glucose as may be the case if the blood is drawnafter the lumbar puncture or postprandially. Even so, the recentreports describing milder GLUT1 DS phenotypes report ratiosranging from 0.47 to 0.59, low compared with controls.5
The lumbar puncture is still an essential diagnostic test whensearching for the cause of patients’ neurological symptoms. It isclear that GLUT1 DS patients have fixed and intermittent neuro-
ANNALS of Neurology
272 Volume 67, No. 2
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