Letters
circulation of patients treated with natalizumab, specifically CD34+ and CD19+ cells, as suggested previously.2 There is no evidence basis from which to seriously consider a link between natalizumab treatment itself and the establishment of JCV latency in body tissues. As such, the identification of JCV DNA in baseline samples in 2 patients with multiple sclerosis, and several healthy control individuals, was not surprising. Through its action of triggering the migration and ultimate mobilization of CD 34+ and pre–B cells out of these tissues, natalizumab increases not only the identification of JCV in peripheral circulation, but correspondingly has important ramifications for the predilection to PML. The evidence reported in our article represents the elucidation of a missing link in the pathoetiologic basis of PML (the localization of JCV to endogenous body tissues, such as bone marrow, while also forging a strategic alignment within the cells of B-cell lineage, that are capable of delivering the virus and thereby PML to the central nervous system [in keeping with the Trojan Horse hypothesis]). We, and others, have searched for relevant reservoir compartment(s) from which JCV is responsive to immune dysregulation, thereby precipitating the pathogenically required conversion of archetype to the PML-associated MAD (Madison, Wisconsin) viral genomic disposition of the noncoding control region. Bone marrow, and perhaps other lymphoid tissues, fits the description for such a compartment. While the mechanistic link between natalizumab-treated patients with multiple sclerosis and PML has remained enigmatic, our observations, and those reported in other articles,3,4 have demonstrated that the B-cell transcription factor Spi B is upregulated in patients with multiple sclerosis treated with natalizumab and is temporally associated with the period of greatest predilection to developing PML. We now report evidence on the tissue (bone marrow) of viral origin for JCV, in conjunction with elucidating additional targets as biomarkers for risk assessment, with important implications for both the treatment and prevention of PML. Elliot M. Frohman, MD, PhD Daniel Douek, MD, PhD Eugene O. Major, PhD Author Affiliations: Department of Neurology, University of Texas Southwestern Medical Center at Dallas (Frohman); National Institutes of Health, Bethesda, Maryland (Douek, Major). Corresponding Author: Elliot M. Frohman, MD, PhD, University of Texas Southwestern Medical Center at Dallas, Department of Neurology, 5323 Harry Hines Blvd, Dallas, TX 75390 ([email protected]). Conflict of Interest Disclosures: Dr Frohman has received speaking and consulting fees from Biogen Idec, TEVA Neuroscience, Acorda, Genzyme, and Novartis and has received consulting fees from Abbott Laboratories. No other disclosures were reported. 1. Frohman EM, Monaco MC, Remington G, et al. JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab. JAMA Neurol. 2014;71(5):596-602. 2. Major EO. Reemergence of PML in natalizumab-treated patients: new cases, same concerns. N Engl J Med. 2009;361(11):1041-1043. 3. Meira M, Sievers C, Hoffman F, et al. MiR-126: a novel route for natalizumab action? [published online March 5, 2014]. Mult Scler.
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4. Marshall L, Ferenczy M, Daley E, Jensen P, Ryschkewitsch C, Major EO. Lymphocyte gene expression and JCV noncoding control region sequences are linked with the risk of progressive multifocal leukoencephalopathy. J Virol. 2014;88(9):5177-5183.
Brief Rhythmic Discharges in Electroencephalography on an Interictal to Ictal Continuum To the Editor I read with interest the article by Yoo et al1 on brief potentially ictal rhythmic discharges visualized in continuous electroencephalography recordings of critically ill patients. Periodic patterns, such as atypical triphasic waves, and lateralized epileptiform discharges are not so uncommonly seen in the electroencephalograms of critically ill patients. Current understanding is that they lie on the continuum of interictal-ictal and most experienced electroencephalographers choose not to treat the electroencephalography unless there is some added rhythmicity to these discharges or accompanying subtle clinical correlate such as facial twitching or myoclonic jerks. Brief potentially ictal rhythmic discharges seem to lie in the same category too. Their presence in a record certainly indicates the potential for epileptogenicity but their mere presence should not warrant anticonvulsant treatment. On the other hand, if brief potentially ictal rhythmic discharges coexist with electrographic or electroclinical seizures in the same record, aggressive anticonvulsant treatment is justified. Nitin K. Sethi, MD Author Affiliation: New York–Presbyterian Hospital, Weill Cornell Medical Center, New York, New York. Corresponding Author: Nitin K. Sethi, MD, New York–Presbyterian Hospital, Weill Cornell Medical Center, 525 East 68th St, New York, NY (sethinitinmd @hotmail.com). Conflict of Interest Disclosures: None reported. 1. Yoo JY, Rampal N, Petroff OA, Hirsch LJ, Gaspard N. Brief potentially ictal rhythmic discharges in critically ill adults. JAMA Neurol. 2014;71(4):454-462.
In Reply We appreciate Dr Sethi’s interest in our work. Dr Sethi’s concerns have already been addressed at length in the original article.1 We would like to reemphasize the following points. In neonates with brain injury, brief potentially ictal rhythmic discharges (B[I]RDs) are independently associated with poor outcome to the same extent as fulllength seizures.2,3 We found a similar trend toward worse outcome in patients with B(I)RDs, although this did not reach statistical significance, probably owing to the small size of our cohort. Many careful investigations have documented that nonconvulsive seizures/status epilepticus are responsible for acute adverse metabolic and hemodynamic derangements 4 and are independently associated with worse short- and long-term outcomes. 5,6 Because most (>90%) patients with B(I)RDs will also exhibit full-length seizures, for which treatment is accepted, the decision to treat B(I)RDs or not is moot—they need treatment for their seizures whether you have already documented their existence or not. JAMA Neurology September 2014 Volume 71, Number 9
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The interictal-ictal continuum comprises patterns of variable significance and should not be regarded as a single entity. We are unaware of any study indicating that most experienced electroencephalographers choose not to treat the electroencephalogram unless there is additional evidence suggesting the ictal nature of a discharge. In fact, we would recommend that most or all of these patients be given antiepileptic drugs because they are at high risk for seizures (if not already having them). Given the high prevalence of nonconvulsive seizures in patients with lateralized periodic discharges, lateralized rhythmic delta activity, 7 and B(I)RDs, as well as the potentially deleterious impact of nonconvulsive seizures on the injured brain, we, as well as many other experienced electroencephalographers, usually recommend starting a prophylactic antiseizure medication in these patients and, most importantly, continuing to monitor the electroencephalogram.
(Gaspard, Hirsch); Department of Neurology, Hôpital Erasme, Brussels, Belgium (Gaspard); Department of Neurology, Mount Sinai Hospital, New York, New York (Yoo).
Nicolas Gaspard, MD, PhD Ji Yeoun Yoo, MD Lawrence J. Hirsch, MD
6. Payne ET, Zhao XY, Frndova H, et al. Seizure burden is independently associated with short term outcome in critically ill children. Brain. 2014;137(pt 5):1429-1438.
Author Affiliations: Comprehensive Epilepsy Center, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut
7. Gaspard N, Manganas L, Rampal N, Petroff OAC, Hirsch LJ. Similarity of lateralized rhythmic delta activity to periodic lateralized epileptiform discharges in critically ill patients. JAMA Neurol. 2013;70(10):1288-1295.
Corresponding Author: Nicolas Gaspard, MD, PhD, Department of Neurology, Hôpital Erasme, Route de Lennik 808, 1070 Brussels, Belgium (ngaspard@ulb .ac.be). Conflict of Interest Disclosures: None reported. 1. Yoo JY, Rampal N, Petroff OA, Hirsch LJ, Gaspard N. Brief potentially ictal rhythmic discharges in critically ill adults. JAMA Neurol. 2014;71(4):454-462. 2. Oliveira AJ, Nunes ML, Haertel LM, Reis FM, da Costa JC. Duration of rhythmic EEG patterns in neonates: new evidence for clinical and prognostic significance of brief rhythmic discharges. Clin Neurophysiol. 2000;111(9):16461653. 3. Nagarajan L, Palumbo L, Ghosh S. Brief electroencephalography rhythmic discharges (BERDs) in the neonate with seizures: their significance and prognostic implications. J Child Neurol. 2011;26(12):1529-1533. 4. Claassen J, Perotte A, Albers D, et al. Nonconvulsive seizures after subarachnoid hemorrhage: Multimodal detection and outcomes. Ann Neurol. 2013;74(1):53-64. 5. Wagenman KL, Blake TP, Sanchez SM, et al. Electrographic status epilepticus and long-term outcome in critically ill children. Neurology. 2014;82(5):396-404.
JAMA Neurology September 2014 Volume 71, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Florida International University Medical Library User on 05/25/2015
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circulation of patients treated with natalizumab, specifically CD34+ and CD19+ cells, as suggested previously.2 There is no evidence basis from which to seriously consider a link between natalizumab treatment itself and the establishment of JCV latency in body tissues. As such, the identification of JCV DNA in baseline samples in 2 patients with multiple sclerosis, and several healthy control individuals, was not surprising. Through its action of triggering the migration and ultimate mobilization of CD 34+ and pre–B cells out of these tissues, natalizumab increases not only the identification of JCV in peripheral circulation, but correspondingly has important ramifications for the predilection to PML. The evidence reported in our article represents the elucidation of a missing link in the pathoetiologic basis of PML (the localization of JCV to endogenous body tissues, such as bone marrow, while also forging a strategic alignment within the cells of B-cell lineage, that are capable of delivering the virus and thereby PML to the central nervous system [in keeping with the Trojan Horse hypothesis]). We, and others, have searched for relevant reservoir compartment(s) from which JCV is responsive to immune dysregulation, thereby precipitating the pathogenically required conversion of archetype to the PML-associated MAD (Madison, Wisconsin) viral genomic disposition of the noncoding control region. Bone marrow, and perhaps other lymphoid tissues, fits the description for such a compartment. While the mechanistic link between natalizumab-treated patients with multiple sclerosis and PML has remained enigmatic, our observations, and those reported in other articles,3,4 have demonstrated that the B-cell transcription factor Spi B is upregulated in patients with multiple sclerosis treated with natalizumab and is temporally associated with the period of greatest predilection to developing PML. We now report evidence on the tissue (bone marrow) of viral origin for JCV, in conjunction with elucidating additional targets as biomarkers for risk assessment, with important implications for both the treatment and prevention of PML. Elliot M. Frohman, MD, PhD Daniel Douek, MD, PhD Eugene O. Major, PhD Author Affiliations: Department of Neurology, University of Texas Southwestern Medical Center at Dallas (Frohman); National Institutes of Health, Bethesda, Maryland (Douek, Major). Corresponding Author: Elliot M. Frohman, MD, PhD, University of Texas Southwestern Medical Center at Dallas, Department of Neurology, 5323 Harry Hines Blvd, Dallas, TX 75390 ([email protected]). Conflict of Interest Disclosures: Dr Frohman has received speaking and consulting fees from Biogen Idec, TEVA Neuroscience, Acorda, Genzyme, and Novartis and has received consulting fees from Abbott Laboratories. No other disclosures were reported. 1. Frohman EM, Monaco MC, Remington G, et al. JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab. JAMA Neurol. 2014;71(5):596-602. 2. Major EO. Reemergence of PML in natalizumab-treated patients: new cases, same concerns. N Engl J Med. 2009;361(11):1041-1043. 3. Meira M, Sievers C, Hoffman F, et al. MiR-126: a novel route for natalizumab action? [published online March 5, 2014]. Mult Scler.
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4. Marshall L, Ferenczy M, Daley E, Jensen P, Ryschkewitsch C, Major EO. Lymphocyte gene expression and JCV noncoding control region sequences are linked with the risk of progressive multifocal leukoencephalopathy. J Virol. 2014;88(9):5177-5183.
Brief Rhythmic Discharges in Electroencephalography on an Interictal to Ictal Continuum To the Editor I read with interest the article by Yoo et al1 on brief potentially ictal rhythmic discharges visualized in continuous electroencephalography recordings of critically ill patients. Periodic patterns, such as atypical triphasic waves, and lateralized epileptiform discharges are not so uncommonly seen in the electroencephalograms of critically ill patients. Current understanding is that they lie on the continuum of interictal-ictal and most experienced electroencephalographers choose not to treat the electroencephalography unless there is some added rhythmicity to these discharges or accompanying subtle clinical correlate such as facial twitching or myoclonic jerks. Brief potentially ictal rhythmic discharges seem to lie in the same category too. Their presence in a record certainly indicates the potential for epileptogenicity but their mere presence should not warrant anticonvulsant treatment. On the other hand, if brief potentially ictal rhythmic discharges coexist with electrographic or electroclinical seizures in the same record, aggressive anticonvulsant treatment is justified. Nitin K. Sethi, MD Author Affiliation: New York–Presbyterian Hospital, Weill Cornell Medical Center, New York, New York. Corresponding Author: Nitin K. Sethi, MD, New York–Presbyterian Hospital, Weill Cornell Medical Center, 525 East 68th St, New York, NY (sethinitinmd @hotmail.com). Conflict of Interest Disclosures: None reported. 1. Yoo JY, Rampal N, Petroff OA, Hirsch LJ, Gaspard N. Brief potentially ictal rhythmic discharges in critically ill adults. JAMA Neurol. 2014;71(4):454-462.
In Reply We appreciate Dr Sethi’s interest in our work. Dr Sethi’s concerns have already been addressed at length in the original article.1 We would like to reemphasize the following points. In neonates with brain injury, brief potentially ictal rhythmic discharges (B[I]RDs) are independently associated with poor outcome to the same extent as fulllength seizures.2,3 We found a similar trend toward worse outcome in patients with B(I)RDs, although this did not reach statistical significance, probably owing to the small size of our cohort. Many careful investigations have documented that nonconvulsive seizures/status epilepticus are responsible for acute adverse metabolic and hemodynamic derangements 4 and are independently associated with worse short- and long-term outcomes. 5,6 Because most (>90%) patients with B(I)RDs will also exhibit full-length seizures, for which treatment is accepted, the decision to treat B(I)RDs or not is moot—they need treatment for their seizures whether you have already documented their existence or not. JAMA Neurology September 2014 Volume 71, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Florida International University Medical Library User on 05/25/2015
1193
Letters
1194
The interictal-ictal continuum comprises patterns of variable significance and should not be regarded as a single entity. We are unaware of any study indicating that most experienced electroencephalographers choose not to treat the electroencephalogram unless there is additional evidence suggesting the ictal nature of a discharge. In fact, we would recommend that most or all of these patients be given antiepileptic drugs because they are at high risk for seizures (if not already having them). Given the high prevalence of nonconvulsive seizures in patients with lateralized periodic discharges, lateralized rhythmic delta activity, 7 and B(I)RDs, as well as the potentially deleterious impact of nonconvulsive seizures on the injured brain, we, as well as many other experienced electroencephalographers, usually recommend starting a prophylactic antiseizure medication in these patients and, most importantly, continuing to monitor the electroencephalogram.
(Gaspard, Hirsch); Department of Neurology, Hôpital Erasme, Brussels, Belgium (Gaspard); Department of Neurology, Mount Sinai Hospital, New York, New York (Yoo).
Nicolas Gaspard, MD, PhD Ji Yeoun Yoo, MD Lawrence J. Hirsch, MD
6. Payne ET, Zhao XY, Frndova H, et al. Seizure burden is independently associated with short term outcome in critically ill children. Brain. 2014;137(pt 5):1429-1438.
Author Affiliations: Comprehensive Epilepsy Center, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut
7. Gaspard N, Manganas L, Rampal N, Petroff OAC, Hirsch LJ. Similarity of lateralized rhythmic delta activity to periodic lateralized epileptiform discharges in critically ill patients. JAMA Neurol. 2013;70(10):1288-1295.
Corresponding Author: Nicolas Gaspard, MD, PhD, Department of Neurology, Hôpital Erasme, Route de Lennik 808, 1070 Brussels, Belgium (ngaspard@ulb .ac.be). Conflict of Interest Disclosures: None reported. 1. Yoo JY, Rampal N, Petroff OA, Hirsch LJ, Gaspard N. Brief potentially ictal rhythmic discharges in critically ill adults. JAMA Neurol. 2014;71(4):454-462. 2. Oliveira AJ, Nunes ML, Haertel LM, Reis FM, da Costa JC. Duration of rhythmic EEG patterns in neonates: new evidence for clinical and prognostic significance of brief rhythmic discharges. Clin Neurophysiol. 2000;111(9):16461653. 3. Nagarajan L, Palumbo L, Ghosh S. Brief electroencephalography rhythmic discharges (BERDs) in the neonate with seizures: their significance and prognostic implications. J Child Neurol. 2011;26(12):1529-1533. 4. Claassen J, Perotte A, Albers D, et al. Nonconvulsive seizures after subarachnoid hemorrhage: Multimodal detection and outcomes. Ann Neurol. 2013;74(1):53-64. 5. Wagenman KL, Blake TP, Sanchez SM, et al. Electrographic status epilepticus and long-term outcome in critically ill children. Neurology. 2014;82(5):396-404.
JAMA Neurology September 2014 Volume 71, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Florida International University Medical Library User on 05/25/2015
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