- Email: [email protected]
Searching for the mechanisms of consciousness in epilepsy
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Ryan NS, Nicholas JM, Weston PSJ, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol 2016; published online Oct 21. http://dx.doi. org/10.1016/ S1474-4422(16)30193-4. Moulder KL, Snider BJ, Mills SL et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimers Res Ther 2013; 5: 48. Crutch SJ, Schott JM, Rabinovici GD, et al. Shining a light on posterior cortical atrophy. Alzheimers Dement 2013; 9: 463–65. Ossenkoppele R, Pijnenburg YA, Perry DC, et al. The behavioural/ dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features. Brain 2015; 138: 2732–49. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006–14. Barnes J, Dickerson BC, Frost C, Jiskoot LC, Wolk D, van der Flier WM. Alzheimer’s disease first symptoms are age dependent: Evidence from the NACC dataset. Alzheimers Dement 2015; 11: 1349–57. Koedam EL, Lauffer V, van der Vlies AE, van der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset Alzheimer’s disease: more than age alone. J Alzheimers Dis 2010; 19: 1401–08. van der Flier WM, Pijnenburg YA, Fox NC, Scheltens P. Early-onset versus late-onset Alzheimer’s disease: the case of the missing APOE varepsilon4 allele. Lancet Neurol 2011; 10: 280–88.
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McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 263–69. Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 2010; 9: 1118–27. Scheltens P, Blennow K, Breteler MM et al. Alzheimer’s disease. Lancet 2016; 388: 505–17. Miller ZA, Mandelli ML, Rankin KP, et al. Handedness and language learning disability differentially distribute in progressive aphasia variants. Brain 2013; 136: 3461–73. Mandelli ML, Vilaplana E, Brown JA, et al. Healthy brain connectivity predicts atrophy progression in non-fluent variant of primary progressive aphasia. Brain 2016; 139: 2778–91. Mesulam MM. A plasticity-based theory of the pathogenesis of Alzheimer’s disease. Ann N Y Acad Sci 2000; 924: 42–52. Mattsson N, Schott JM, Hardy J, Turner MR, Zetterberg H. Selective vulnerability in neurodegeneration: insights from clinical variants of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2016; 87: 1000–04.
Searching for the mechanisms of consciousness in epilepsy
Alfred Pasieka/Science Photo Library
See Articles page 1336
1298
Defining and understanding consciousness is often assumed to be similar to searching for the Holy Grail. The term consciousness has many ambiguous meanings and often, in medicine, awareness or responsiveness (or lack thereof) are used as surrogate markers. Epileptic seizures provide an opportunity to study these types of changes as part of the consciousness experience. In the Lancet Neurology, Jennifer Guo and colleagues1 report the results of their study aimed at discovering the potential
neuronal underpinnings of impaired consciousness, as depicted by alterations in awareness or responsivity, in presumed typical absence epilepsy using functional MRI (fMRI) and electroencephalography (EEG), and behavioral testing in children and adolescents aged 5–19 years. The investigators propose that the impairments identified are the result of widespread involvement of the brain, implicating suspension of the default mode network in conjunction with reduced sensory perception, and not because of focal changes. They also suggest that the behavioural impairments might happen at the onset of the seizures. To collect an adequate number of patients, the investigators expanded the criteria for absence seizures and probably included patients with different syndromes, as discussed by Panayiotopoulos.2 The International League Against Epilepsy is proposing a classification of seizures and epilepsies3,4 and Guo and colleagues provide new insights that might help classification. Their findings suggest a different way of interpreting how changes in impairment of consciousness occur in absence seizures. It is often assumed that the impairment of consciousness occurs if the seizures last more than 3 s, based on the reaction times tested with EEG monitoring.5 This cutoff was included in the study of the effectiveness of antiseizure medications to define an electroclinical seizure as lasting more than 3 s;6 the medications were considered www.thelancet.com/neurology Vol 15 December 2016
Comment
effective if there were no seizures or EEG discharges longer than 3 s.6 Other researchers have considered 6 s,7 whereas Stefan8 suggests that changes in eye movements can predict the alteration in consciousness. Guo and colleagues’ data suggest that brief absence seizures (ie, 3.8 s [SD 3]) are more likely to spare consciousness than more prolonged ones, and suggest that absence seizures that impair consciousness do so at their electrographic onset. Browne and colleagues9 have reported that almost half of patients with absence seizures have impaired auditory reaction times within 0.5 s of the spike-wave discharge onset. The study by Guo and colleagues does not necessarily identify neuronal underpinnings, it only provides evidence for changes in the intensity of the measured signals. The suggestion that the impairment of consciousness happens early in association with the spike-wave discharge raises the question of what comes first: the predisposition to impaired consciousness or the onset of the EEG absence seizure discharge. Guo and colleagues propose the emergence of a susceptible state, manifested by the early appearing abnormal fMRI signals followed by increased power, hypersynchronous EEG activities, that lead to the impairment of consciousness—ie, absence seizures with altered consciousness are not provoked by but rather predispose to prolonged spike-wave discharges. The caveat is that surface EEG cannot localise changes that might have occurred in deep structures, and therefore the possibility that early deep electrographic seizure discharges contributed to the altered fMRI signal cannot be excluded. Because the impairment of consciousness did not happen with every spikewave discharge, these data might suggest another mechanism different to the spike-wave discharge. The investigators suggest that the impairment is related to the intensity of the response as measured by the fMRI and power in the EEG, but this intensity might be an epiphenomenon. Additionally, the data do not necessarily exclude the possibility that the impairment of consciousness is greater in those seizures that last longer. The morphology of the recorded seizures is different between the seizures with impairments in consciousness versus those in which consciousness was spared, suggesting that the EEG discharge might contain information that needs to be further explored,
www.thelancet.com/neurology Vol 15 December 2016
including the actual frequency of the discharge and its evolution. Concerns exist about whether data obtained in an fMRI scanner and EEG are directly related, especially in view of the finding that not all the seizures in each patient had alterations in consciousness. However, because of the artifacts produced by the fMRI during the EEG collection, it was not possible to do the analysis simultaneously. As our ability to use more sophisticated methods improves, the investigation of why responses are not uniform from seizure to seizure will be a step to further understand the substrates of consciousness. This compelling study creates a new set of questions. The clinical considerations are that not all brief spikewave discharge bursts might be silent and that use of functional tests will be paramount in establishing whether spike-wave discharges impair responsiveness. *Solomon L Moshé, Aristea S Galanopoulou Saul R Korey Department of Neurology and Dominick P Purpura Department Neuroscience (SLM, ASG), Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Kennedy Center, New York 10461, USA (SLM) [email protected] SLM is the Charles Frost Chair in Neurosurgery and Neurology. He reports grants NINDS 20253, NINDS-NS43209, NINDS-NS45911, NINDS-1U54NS100064 and a grant from the US Department of Defense (W81XWH-13-1-0180), CURE Infantile Spasms Initiative grant and donations from the Heffer Family and the Segal Family Foundations and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. ASG reports grants from NINDS-NS91170, NINDS-1U54NS100064, US Department of Defense (W81XWH-13-1-0180), CURE Infantile Spasms Initiative grant, and donations from the Heffer Family and the Segal Family Foundations and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. 1 2
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Guo J, Kim R, Chen Y, et al. Mechanism of impaired consciousness in absence seizures: a crosssectional study. Lancet Neurol 2016; 15: 1336–45. Panayiotopoulos CP. Typical absence seizures and related epileptic syndromes: assessment of current state and directions for future research. Epilepsia 2008; 49: 2131–39. Fisher RS. Commentary: Operational Definition of Epilepsy survey. Epilepsia 2014; 55: 1688. Scheffer IE, French J, Hirsch E, et al. Classification of the epilepsies: new concepts for discussion and debate—Special report of the ILAE Classification Task Force of the Commission for Classification and Terminology. Epilepsia Open 2016; 1: 37–44. Goode DJ, Penry JK, Dreifuss FE. Effects of paroxysmal spike-wave on continuous visual-motor performance. Epilepsia 1970; 11: 241–54. Glauser TA, Cnaan A, Shinnar S, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia 2013; 54: 141–55. Camfield CS, Camfield PR. Absence seizures. In: Panayiotopoulos CP, ed. Atlas of epilepsies. London: Springer-Verlag, 381–83. Stefan H, Lopes da Silva FH. Epileptic neuronal networks: methods of identification and clinical relevance. Front Neurol 2013; 4: 8. Browne TR, Penry JK, Proter RJ, Dreifuss FE. Responsiveness before, during, and after spike-wave paroxysms. Neurology 1974; 24: 659–65.
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Ryan NS, Nicholas JM, Weston PSJ, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol 2016; published online Oct 21. http://dx.doi. org/10.1016/ S1474-4422(16)30193-4. Moulder KL, Snider BJ, Mills SL et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimers Res Ther 2013; 5: 48. Crutch SJ, Schott JM, Rabinovici GD, et al. Shining a light on posterior cortical atrophy. Alzheimers Dement 2013; 9: 463–65. Ossenkoppele R, Pijnenburg YA, Perry DC, et al. The behavioural/ dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features. Brain 2015; 138: 2732–49. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006–14. Barnes J, Dickerson BC, Frost C, Jiskoot LC, Wolk D, van der Flier WM. Alzheimer’s disease first symptoms are age dependent: Evidence from the NACC dataset. Alzheimers Dement 2015; 11: 1349–57. Koedam EL, Lauffer V, van der Vlies AE, van der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset Alzheimer’s disease: more than age alone. J Alzheimers Dis 2010; 19: 1401–08. van der Flier WM, Pijnenburg YA, Fox NC, Scheltens P. Early-onset versus late-onset Alzheimer’s disease: the case of the missing APOE varepsilon4 allele. Lancet Neurol 2011; 10: 280–88.
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McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 263–69. Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 2010; 9: 1118–27. Scheltens P, Blennow K, Breteler MM et al. Alzheimer’s disease. Lancet 2016; 388: 505–17. Miller ZA, Mandelli ML, Rankin KP, et al. Handedness and language learning disability differentially distribute in progressive aphasia variants. Brain 2013; 136: 3461–73. Mandelli ML, Vilaplana E, Brown JA, et al. Healthy brain connectivity predicts atrophy progression in non-fluent variant of primary progressive aphasia. Brain 2016; 139: 2778–91. Mesulam MM. A plasticity-based theory of the pathogenesis of Alzheimer’s disease. Ann N Y Acad Sci 2000; 924: 42–52. Mattsson N, Schott JM, Hardy J, Turner MR, Zetterberg H. Selective vulnerability in neurodegeneration: insights from clinical variants of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2016; 87: 1000–04.
Searching for the mechanisms of consciousness in epilepsy
Alfred Pasieka/Science Photo Library
See Articles page 1336
1298
Defining and understanding consciousness is often assumed to be similar to searching for the Holy Grail. The term consciousness has many ambiguous meanings and often, in medicine, awareness or responsiveness (or lack thereof) are used as surrogate markers. Epileptic seizures provide an opportunity to study these types of changes as part of the consciousness experience. In the Lancet Neurology, Jennifer Guo and colleagues1 report the results of their study aimed at discovering the potential
neuronal underpinnings of impaired consciousness, as depicted by alterations in awareness or responsivity, in presumed typical absence epilepsy using functional MRI (fMRI) and electroencephalography (EEG), and behavioral testing in children and adolescents aged 5–19 years. The investigators propose that the impairments identified are the result of widespread involvement of the brain, implicating suspension of the default mode network in conjunction with reduced sensory perception, and not because of focal changes. They also suggest that the behavioural impairments might happen at the onset of the seizures. To collect an adequate number of patients, the investigators expanded the criteria for absence seizures and probably included patients with different syndromes, as discussed by Panayiotopoulos.2 The International League Against Epilepsy is proposing a classification of seizures and epilepsies3,4 and Guo and colleagues provide new insights that might help classification. Their findings suggest a different way of interpreting how changes in impairment of consciousness occur in absence seizures. It is often assumed that the impairment of consciousness occurs if the seizures last more than 3 s, based on the reaction times tested with EEG monitoring.5 This cutoff was included in the study of the effectiveness of antiseizure medications to define an electroclinical seizure as lasting more than 3 s;6 the medications were considered www.thelancet.com/neurology Vol 15 December 2016
Comment
effective if there were no seizures or EEG discharges longer than 3 s.6 Other researchers have considered 6 s,7 whereas Stefan8 suggests that changes in eye movements can predict the alteration in consciousness. Guo and colleagues’ data suggest that brief absence seizures (ie, 3.8 s [SD 3]) are more likely to spare consciousness than more prolonged ones, and suggest that absence seizures that impair consciousness do so at their electrographic onset. Browne and colleagues9 have reported that almost half of patients with absence seizures have impaired auditory reaction times within 0.5 s of the spike-wave discharge onset. The study by Guo and colleagues does not necessarily identify neuronal underpinnings, it only provides evidence for changes in the intensity of the measured signals. The suggestion that the impairment of consciousness happens early in association with the spike-wave discharge raises the question of what comes first: the predisposition to impaired consciousness or the onset of the EEG absence seizure discharge. Guo and colleagues propose the emergence of a susceptible state, manifested by the early appearing abnormal fMRI signals followed by increased power, hypersynchronous EEG activities, that lead to the impairment of consciousness—ie, absence seizures with altered consciousness are not provoked by but rather predispose to prolonged spike-wave discharges. The caveat is that surface EEG cannot localise changes that might have occurred in deep structures, and therefore the possibility that early deep electrographic seizure discharges contributed to the altered fMRI signal cannot be excluded. Because the impairment of consciousness did not happen with every spikewave discharge, these data might suggest another mechanism different to the spike-wave discharge. The investigators suggest that the impairment is related to the intensity of the response as measured by the fMRI and power in the EEG, but this intensity might be an epiphenomenon. Additionally, the data do not necessarily exclude the possibility that the impairment of consciousness is greater in those seizures that last longer. The morphology of the recorded seizures is different between the seizures with impairments in consciousness versus those in which consciousness was spared, suggesting that the EEG discharge might contain information that needs to be further explored,
www.thelancet.com/neurology Vol 15 December 2016
including the actual frequency of the discharge and its evolution. Concerns exist about whether data obtained in an fMRI scanner and EEG are directly related, especially in view of the finding that not all the seizures in each patient had alterations in consciousness. However, because of the artifacts produced by the fMRI during the EEG collection, it was not possible to do the analysis simultaneously. As our ability to use more sophisticated methods improves, the investigation of why responses are not uniform from seizure to seizure will be a step to further understand the substrates of consciousness. This compelling study creates a new set of questions. The clinical considerations are that not all brief spikewave discharge bursts might be silent and that use of functional tests will be paramount in establishing whether spike-wave discharges impair responsiveness. *Solomon L Moshé, Aristea S Galanopoulou Saul R Korey Department of Neurology and Dominick P Purpura Department Neuroscience (SLM, ASG), Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Kennedy Center, New York 10461, USA (SLM) [email protected] SLM is the Charles Frost Chair in Neurosurgery and Neurology. He reports grants NINDS 20253, NINDS-NS43209, NINDS-NS45911, NINDS-1U54NS100064 and a grant from the US Department of Defense (W81XWH-13-1-0180), CURE Infantile Spasms Initiative grant and donations from the Heffer Family and the Segal Family Foundations and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. ASG reports grants from NINDS-NS91170, NINDS-1U54NS100064, US Department of Defense (W81XWH-13-1-0180), CURE Infantile Spasms Initiative grant, and donations from the Heffer Family and the Segal Family Foundations and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. 1 2
3 4
5 6
7 8 9
Guo J, Kim R, Chen Y, et al. Mechanism of impaired consciousness in absence seizures: a crosssectional study. Lancet Neurol 2016; 15: 1336–45. Panayiotopoulos CP. Typical absence seizures and related epileptic syndromes: assessment of current state and directions for future research. Epilepsia 2008; 49: 2131–39. Fisher RS. Commentary: Operational Definition of Epilepsy survey. Epilepsia 2014; 55: 1688. Scheffer IE, French J, Hirsch E, et al. Classification of the epilepsies: new concepts for discussion and debate—Special report of the ILAE Classification Task Force of the Commission for Classification and Terminology. Epilepsia Open 2016; 1: 37–44. Goode DJ, Penry JK, Dreifuss FE. Effects of paroxysmal spike-wave on continuous visual-motor performance. Epilepsia 1970; 11: 241–54. Glauser TA, Cnaan A, Shinnar S, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia 2013; 54: 141–55. Camfield CS, Camfield PR. Absence seizures. In: Panayiotopoulos CP, ed. Atlas of epilepsies. London: Springer-Verlag, 381–83. Stefan H, Lopes da Silva FH. Epileptic neuronal networks: methods of identification and clinical relevance. Front Neurol 2013; 4: 8. Browne TR, Penry JK, Proter RJ, Dreifuss FE. Responsiveness before, during, and after spike-wave paroxysms. Neurology 1974; 24: 659–65.
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