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Can EEG predict outcomes in genetic generalized epilepsies?
Clinical Neurophysiology 125 (2014) 215–216
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Can EEG predict outcomes in genetic generalized epilepsies? See Article, pages 263–269
Several explanations have emerged regarding the possible origins of generalized spike and wave discharges (GSWDs) in patients with genetic generalized epilepsies (GGEs). The ‘‘centrencephalic theory’’ by Penfield and Jasper, later redefined by Buzsaki, proposed the onset of EEG abnormalities to be in the midline and intra-laminar nuclei of the thalamus with later simultaneous projection to both hemispheres to produce symmetric GSWDs (Penfield and Jasper, 1954; Buzsaki, 1991). In contrast, the ‘‘cortical’’ and ‘‘cortical focus’’ theories have posited that GSWDs in GGEs might originate around the cortical somatosensory areas (Meeren et al., 2005). Finally, Gloor proposed the unifying ‘‘corticoreticular’’ theory that the thalamic and brain stem reticular systems are responsible for the genesis of the GSWDs which are the result of abnormal oscillations within the cortico-reticular neurons and of the interactions between them (Gloor, 1968); this theory has recently been disputed (Leresche et al., 2012). Nevertheless, GSWDs in patients with GGEs are assumed to either originate from or involve at some point bilateral subcortical (thalamo-cortical neurons and nucleus reticularis thalami) and cortical networks (Leresche et al., 2012). If there is, in fact, an involvement of the entire network in the generation of GSWDs, the presence or absence of symmetries in the EEGs of patients with GGEs could be of clinical significance. Since the structural imaging in GGEs is usually normal, are there functional abnormalities that lead to the focal abnormalities observed in 10–60% of GGE patients, and can the presence of focal EEG changes predict the treatment outcomes? The answer to these questions, as suggested by Karakis et al. in this issue of Clinical Neurophysiology, is ‘‘no’’; these authors show that focal EEG abnormalities do not predict clinical outcomes (Karakis et al., 2014). Before we accept this contention, let’s review the available evidence. First, let’s consider the incidence and meaning of focal EEG abnormalities in patients with GGEs that has been reported. By various accounts, focal abnormalities exist in a significant portion of GGE patients, but the methods of EEG data interpretation, association with outcome, and reporting of the results are quite variable making the comparisons between studies difficult, if not impossible. For example, in the largest study to date, 98 of 902 patients with available EEGs had focal abnormalities. However, the definition of focal abnormalities was not provided, nor was it stated whether the authors reviewed one or all available EEGs; there was no relationship between EEG variables and achieving 1-year remission (Nicolson et al., 2004). In another study, any focal EEG abnormalities defined as focal slowing, focal epileptiform discharges (including spike fragments), and >30% GSWD amplitude
difference between sides, in any (or all) available EEGs, were associated with decreased odds of achieving intermediate term seizure remission (Szaflarski et al., 2010). In the third study, 96 of 229 patients had asymmetric GSWDs, the presence of which was associated with a lower chance of remission for 1 year (p < 0.05). However, in this study, the definition of the asymmetries was not provided (Wolf and Inoue, 1984). Several smaller studies have found the EEGs of patients with GGEs to be either predictive or not predictive of long-term seizure outcomes. Finally, in a longitudinal study that followed GGE patients for up to 20 years, Lombroso showed that the majority of patients had focal EEG abnormalities in some but not all of their EEGs. These abnormalities consistently occurred in the same location in the individual patient but not necessarily in the same areas across the patients (Lombroso, 1997). The author did not observe any correlation between focal EEG abnormalities and outcomes. He explained these focal abnormalities as resulting either from secondary and focal epileptogenesis (as, for example, observed in patients with combined diagnosis of generalized and focal epilepsies) or from preexisting micro-structural lesions (Gloor, 1979; Meencke and Janz, 1984). While both of these rationales for the presence of focal changes in GGE patients are plausible, perhaps the third explanation – the cortical focus theory – provides the best explanation. This theory posits that GSWDs in GGEs are initiated in one area (cortical focus), followed by rapid synchronization and propagation via the cortico-cortical networks to the thalamo-cortical loops, which serve as oscillators with both structures driving each other and thus producing sustained GSWDs (Meeren et al., 2005). The relatively small (N = 51) study by Karakis et al. adds to the existing debate about the use of EEG as a predictor of long-term outcomes. Unfortunately, the neuroimaging literature comes short of solving the focal vs. generalized conundrum or clarifying the use of EEG for predicting seizure control and long-term outcomes in patents with GGEs. Although visual inspection of the neuroimaging scans in GGEs should, by definition, not reveal any abnormalities, some studies have identified areas of focal cortical microdisgenesis or gray matter abnormality (Meencke and Janz, 1984; Woermann et al., 1998). Since then, EEG/fMRI studies have provided evidence in support of either central or cortical onset of GGEs (Moeller et al., 2008; Bai et al., 2010), with at least one study showing clear medial frontal fMRI signal differences in GGE patients who have not achieved remission (Szaflarski et al., 2013). While adding evidence on whether EEG focalities could be used for outcome prediction, the study by Karakis et al. does not definitively answer this question. This well-designed study in patients
1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.08.026
216
Editorial / Clinical Neurophysiology 125 (2014) 215–216
with a mixed group of new onset GGEs uses very strict visual and automated criteria to show that there are no associations between EEG asymmetries and outcomes. However, as the authors acknowledge, this study has several limitations, including a relatively small sample size (N = 51), very strict inclusion/exclusion criteria including what constitutes EEG asymmetry, lack of adjustment for medications used, and a relatively high rate of pharmacoresistance. Thus, subsequent longitudinal studies that include sufficient numbers of new onset GGE patients and use precise and consensus-based definitions of asymmetries and outcomes are needed. Until further evidence emerges, it is still the clinician’s guess whether the observed EEG changes are or are not symmetric and whether these changes could be used for predicting outcomes in GGE patients. However, what is encouraging for the GGE patients is the fact that in the vast majority of them the seizures will become controlled with the currently available AEDs whether they do or do not have EEG asymmetries. References Bai X, Vestal M, Berman R, Negishi M, Spann M, Vega C, et al. Dynamic time course of typical childhood absence seizures: EEG, behavior, and functional magnetic resonance imaging. J Neurosci 2010;30:5884–93. Buzsaki G. The thalamic clock: emergent network properties. Neuroscience 1991;41:351–64. Gloor P. Generalized cortico-reticular epilepsies. Some considerations on the pathophysiology of generalized bilaterally synchronous spike and wave discharge. Epilepsia 1968;9:249–63. Gloor P. Generalized epilepsy with spike-and-wave discharge: a reinterpretation of its electrographic and clinical manifestations. The 1977 William G. Lennox Lecture, American Epilepsy Society. Epilepsia 1979;20:571–88. Karakis I, Pathmanathan J, Chang R, Cook EF, Cash SS, Cole AJ. Prognostic value of EEG asymmetries for development of drug-resistance in drug-naïve patients with genetic generalized epilepsies. Clin Neurophysiol 2014;125:263–9.
Leresche N, Lambert RC, Errington AC, Crunelli V. From sleep spindles of natural sleep to spike and wave discharges of typical absence seizures: is the hypothesis still valid? Pflugers Arch 2012;463:201–12. Lombroso CT. Consistent EEG focalities detected in subjects with primary generalized epilepsies monitored for two decades. Epilepsia 1997;38:797–812. Meencke HJ, Janz D. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia 1984;25:8–21. Meeren H, van Luijtelaar G, Lopes da Silva F, Coenen A. Evolving concepts on the pathophysiology of absence seizures: the cortical focus theory. Arch Neurol 2005;62:371–6. Moeller F, Siebner HR, Wolff S, Muhle H, Granert O, Jansen O, et al. Simultaneous EEG-fMRI in drug-naive children with newly diagnosed absence epilepsy. Epilepsia 2008;49:1510–9. Nicolson A, Appleton RE, Chadwick DW, Smith DF. The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalised epilepsies. J Neurol Neurosurg Psychiatry 2004;75:75–9. Penfield W, Jasper H. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little Brown; 1954. Szaflarski JP, Kay B, Gotman J, Privitera MD, Holland SK. The relationship between the localization of the generalized spike and wave discharge generators and the response to valproate. Epilepsia 2013;54:471–80. Szaflarski JP, Lindsell CJ, Zakaria T, Banks C, Privitera MD. Seizure control in patients with idiopathic generalized epilepsies: EEG determinants of medication response. Epilepsy Behav 2010;17:525–30. Woermann FG, Sisodiya SM, Free SL, Duncan JS. Quantitative MRI in patients with idiopathic generalized epilepsy. Evidence of widespread cerebral structural changes. Brain 1998;121:1661–7. Wolf P, Inoue Y. Therapeutic response of absence seizures in patients of an epilepsy clinic for adolescents and adults. J Neurol 1984;231:225–9.
⇑
Jerzy P. Szaflarski, MD, PhD University of Alabama at Birmingham (UAB) and the UAB Epilepsy Center, Civitan International Research Center, Birmingham, AL, USA ⇑ Tel.: +1 205 9343866; fax: +1 205 975 6255 E-mail address: szafl[email protected] Available online 10 October 2013
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Can EEG predict outcomes in genetic generalized epilepsies? See Article, pages 263–269
Several explanations have emerged regarding the possible origins of generalized spike and wave discharges (GSWDs) in patients with genetic generalized epilepsies (GGEs). The ‘‘centrencephalic theory’’ by Penfield and Jasper, later redefined by Buzsaki, proposed the onset of EEG abnormalities to be in the midline and intra-laminar nuclei of the thalamus with later simultaneous projection to both hemispheres to produce symmetric GSWDs (Penfield and Jasper, 1954; Buzsaki, 1991). In contrast, the ‘‘cortical’’ and ‘‘cortical focus’’ theories have posited that GSWDs in GGEs might originate around the cortical somatosensory areas (Meeren et al., 2005). Finally, Gloor proposed the unifying ‘‘corticoreticular’’ theory that the thalamic and brain stem reticular systems are responsible for the genesis of the GSWDs which are the result of abnormal oscillations within the cortico-reticular neurons and of the interactions between them (Gloor, 1968); this theory has recently been disputed (Leresche et al., 2012). Nevertheless, GSWDs in patients with GGEs are assumed to either originate from or involve at some point bilateral subcortical (thalamo-cortical neurons and nucleus reticularis thalami) and cortical networks (Leresche et al., 2012). If there is, in fact, an involvement of the entire network in the generation of GSWDs, the presence or absence of symmetries in the EEGs of patients with GGEs could be of clinical significance. Since the structural imaging in GGEs is usually normal, are there functional abnormalities that lead to the focal abnormalities observed in 10–60% of GGE patients, and can the presence of focal EEG changes predict the treatment outcomes? The answer to these questions, as suggested by Karakis et al. in this issue of Clinical Neurophysiology, is ‘‘no’’; these authors show that focal EEG abnormalities do not predict clinical outcomes (Karakis et al., 2014). Before we accept this contention, let’s review the available evidence. First, let’s consider the incidence and meaning of focal EEG abnormalities in patients with GGEs that has been reported. By various accounts, focal abnormalities exist in a significant portion of GGE patients, but the methods of EEG data interpretation, association with outcome, and reporting of the results are quite variable making the comparisons between studies difficult, if not impossible. For example, in the largest study to date, 98 of 902 patients with available EEGs had focal abnormalities. However, the definition of focal abnormalities was not provided, nor was it stated whether the authors reviewed one or all available EEGs; there was no relationship between EEG variables and achieving 1-year remission (Nicolson et al., 2004). In another study, any focal EEG abnormalities defined as focal slowing, focal epileptiform discharges (including spike fragments), and >30% GSWD amplitude
difference between sides, in any (or all) available EEGs, were associated with decreased odds of achieving intermediate term seizure remission (Szaflarski et al., 2010). In the third study, 96 of 229 patients had asymmetric GSWDs, the presence of which was associated with a lower chance of remission for 1 year (p < 0.05). However, in this study, the definition of the asymmetries was not provided (Wolf and Inoue, 1984). Several smaller studies have found the EEGs of patients with GGEs to be either predictive or not predictive of long-term seizure outcomes. Finally, in a longitudinal study that followed GGE patients for up to 20 years, Lombroso showed that the majority of patients had focal EEG abnormalities in some but not all of their EEGs. These abnormalities consistently occurred in the same location in the individual patient but not necessarily in the same areas across the patients (Lombroso, 1997). The author did not observe any correlation between focal EEG abnormalities and outcomes. He explained these focal abnormalities as resulting either from secondary and focal epileptogenesis (as, for example, observed in patients with combined diagnosis of generalized and focal epilepsies) or from preexisting micro-structural lesions (Gloor, 1979; Meencke and Janz, 1984). While both of these rationales for the presence of focal changes in GGE patients are plausible, perhaps the third explanation – the cortical focus theory – provides the best explanation. This theory posits that GSWDs in GGEs are initiated in one area (cortical focus), followed by rapid synchronization and propagation via the cortico-cortical networks to the thalamo-cortical loops, which serve as oscillators with both structures driving each other and thus producing sustained GSWDs (Meeren et al., 2005). The relatively small (N = 51) study by Karakis et al. adds to the existing debate about the use of EEG as a predictor of long-term outcomes. Unfortunately, the neuroimaging literature comes short of solving the focal vs. generalized conundrum or clarifying the use of EEG for predicting seizure control and long-term outcomes in patents with GGEs. Although visual inspection of the neuroimaging scans in GGEs should, by definition, not reveal any abnormalities, some studies have identified areas of focal cortical microdisgenesis or gray matter abnormality (Meencke and Janz, 1984; Woermann et al., 1998). Since then, EEG/fMRI studies have provided evidence in support of either central or cortical onset of GGEs (Moeller et al., 2008; Bai et al., 2010), with at least one study showing clear medial frontal fMRI signal differences in GGE patients who have not achieved remission (Szaflarski et al., 2013). While adding evidence on whether EEG focalities could be used for outcome prediction, the study by Karakis et al. does not definitively answer this question. This well-designed study in patients
1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.08.026
216
Editorial / Clinical Neurophysiology 125 (2014) 215–216
with a mixed group of new onset GGEs uses very strict visual and automated criteria to show that there are no associations between EEG asymmetries and outcomes. However, as the authors acknowledge, this study has several limitations, including a relatively small sample size (N = 51), very strict inclusion/exclusion criteria including what constitutes EEG asymmetry, lack of adjustment for medications used, and a relatively high rate of pharmacoresistance. Thus, subsequent longitudinal studies that include sufficient numbers of new onset GGE patients and use precise and consensus-based definitions of asymmetries and outcomes are needed. Until further evidence emerges, it is still the clinician’s guess whether the observed EEG changes are or are not symmetric and whether these changes could be used for predicting outcomes in GGE patients. However, what is encouraging for the GGE patients is the fact that in the vast majority of them the seizures will become controlled with the currently available AEDs whether they do or do not have EEG asymmetries. References Bai X, Vestal M, Berman R, Negishi M, Spann M, Vega C, et al. Dynamic time course of typical childhood absence seizures: EEG, behavior, and functional magnetic resonance imaging. J Neurosci 2010;30:5884–93. Buzsaki G. The thalamic clock: emergent network properties. Neuroscience 1991;41:351–64. Gloor P. Generalized cortico-reticular epilepsies. Some considerations on the pathophysiology of generalized bilaterally synchronous spike and wave discharge. Epilepsia 1968;9:249–63. Gloor P. Generalized epilepsy with spike-and-wave discharge: a reinterpretation of its electrographic and clinical manifestations. The 1977 William G. Lennox Lecture, American Epilepsy Society. Epilepsia 1979;20:571–88. Karakis I, Pathmanathan J, Chang R, Cook EF, Cash SS, Cole AJ. Prognostic value of EEG asymmetries for development of drug-resistance in drug-naïve patients with genetic generalized epilepsies. Clin Neurophysiol 2014;125:263–9.
Leresche N, Lambert RC, Errington AC, Crunelli V. From sleep spindles of natural sleep to spike and wave discharges of typical absence seizures: is the hypothesis still valid? Pflugers Arch 2012;463:201–12. Lombroso CT. Consistent EEG focalities detected in subjects with primary generalized epilepsies monitored for two decades. Epilepsia 1997;38:797–812. Meencke HJ, Janz D. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia 1984;25:8–21. Meeren H, van Luijtelaar G, Lopes da Silva F, Coenen A. Evolving concepts on the pathophysiology of absence seizures: the cortical focus theory. Arch Neurol 2005;62:371–6. Moeller F, Siebner HR, Wolff S, Muhle H, Granert O, Jansen O, et al. Simultaneous EEG-fMRI in drug-naive children with newly diagnosed absence epilepsy. Epilepsia 2008;49:1510–9. Nicolson A, Appleton RE, Chadwick DW, Smith DF. The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalised epilepsies. J Neurol Neurosurg Psychiatry 2004;75:75–9. Penfield W, Jasper H. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little Brown; 1954. Szaflarski JP, Kay B, Gotman J, Privitera MD, Holland SK. The relationship between the localization of the generalized spike and wave discharge generators and the response to valproate. Epilepsia 2013;54:471–80. Szaflarski JP, Lindsell CJ, Zakaria T, Banks C, Privitera MD. Seizure control in patients with idiopathic generalized epilepsies: EEG determinants of medication response. Epilepsy Behav 2010;17:525–30. Woermann FG, Sisodiya SM, Free SL, Duncan JS. Quantitative MRI in patients with idiopathic generalized epilepsy. Evidence of widespread cerebral structural changes. Brain 1998;121:1661–7. Wolf P, Inoue Y. Therapeutic response of absence seizures in patients of an epilepsy clinic for adolescents and adults. J Neurol 1984;231:225–9.
⇑
Jerzy P. Szaflarski, MD, PhD University of Alabama at Birmingham (UAB) and the UAB Epilepsy Center, Civitan International Research Center, Birmingham, AL, USA ⇑ Tel.: +1 205 9343866; fax: +1 205 975 6255 E-mail address: szafl[email protected] Available online 10 October 2013