Current Literature In Clinical Science
Are Idiopathic Generalized Epilepsies Focal?
Investigation of the Cingulate Cortex in Idiopathic Generalized Epilepsy. Braga AM, Fujisao EK, Verdade RC, Paschoalato RP, Paschoalato RP, Yamashita S, Betting LE. [published online ahead of print September 28, 2015]. Epilepsia 2015;56:1803–1811. doi: 10.1111/epi.13205.
OBJECTIVE: Studies using quantitative neuroimaging have shown subtle abnormalities in patients with idiopathic generalized epilepsy (IGE). These findings have several locations, but the midline parasagittal structures are most commonly implicated. The cingulate cortex is related and may be involved. The objective of the current investigation was to perform a comprehensive analysis of the cingulate cortex using multiple quantitative structural neuroimaging techniques. METHODS: Thirty-two patients (18 women, 30 ± 10 years) and 36 controls (18 women, 32 ± 11 years) were imaged by 3 Tesla magnetic resonance imaging (MRI). A volumetric three-dimensional (3D) sequence was acquired and used for this investigation. Regions-of-interest were selected and voxel-based morphometry (VBM) analyses compared the cingulate cortex of the two groups using Statistical Parametric Mapping (SPM8) and VBM8 software. Cortical analyses of the cingulate gyrus was performed using Freesurfer. Images were submitted to automatic processing using built-in routines and recommendations. Structural parameters were extracted for individual analyses, and comparisons between groups were restricted to the cingulate gyrus. Finally, shape analyses was performed on the anterior rostral, anterior caudal, posterior, and isthmus cingulate using spherical harmonic description (SPHARM). RESULTS: VBM analyses of cingulate gyrus showed areas of gray matter atrophy, mainly in the anterior cingulate gyrus (972 mm3) and the isthmus (168 mm3). Individual analyses of the cingulate cortex were similar between patients with IGE and controls. Surface-based comparisons revealed abnormalities located mainly in the posterior cingulate cortex (718.12 mm2). Shape analyses demonstrated a predominance of anterior and posterior cingulate abnormalities. SIGNIFICANCE: This study suggests that patients with IGE have structural abnormalities in the cingulate gyrus mainly localized at the anterior and posterior portions. This finding is subtle and variable among patients.
Commentary The forefathers of epilepsy gave us the clinical definition of idiopathic generalized epilepsies (IGEs) that, in general terms, includes any combination of absence and generalized seizures, and myoclonus in someone who is cognitively intact. The clinical events are typically associated with generalized (as in occurring or initiated in all areas of the brain) spike and wave discharges (GSWDs) distributed fairly symmetrically with maximum over the bifrontal or paracentral head regions. The origins of the GSWDs remain elusive but definitely involve bilaterally distributed cortical and subcortical networks. Over the years, we have recognized that IGEs are not as benign as we originally thought; many patients exhibit various social, educational, psychologic, and cognitive handicaps. Our forefathers also taught us that IGEs should not be associated with any structural brain abnormalities. But, were they correct in their assumptions? Before we tackle the above question, let’s quickly analyze what we know about the origins of GSWDs. While over the Epilepsy Currents, Vol. 16, No. 4 (July/August) 2016 pp. 242–244 © American Epilepsy Society
242
years several possible explanations have emerged, the unifying “corticoreticular” theory has gained the most traction. It posits that GSWDs in patients with IGEs are assumed to either originate from or involve at some point bilateral cortical and subcortical (thalamocortical neurons and nucleus reticularis thalami) networks (1). In other words, this theory posits that the cortex entrains the thalamus, and the thalamocortical network sustains the discharge/seizure. If so, then we should expect to notice at least subtle changes in the function and possibly the anatomy of the involved structures with possibly different nodes of the epileptic network involved in some of the IGE syndromes, which would then lead to different clinical presentations. One of the first indications of the possible cortical onset of generalized epilepsies in humans was provided by Professor Dieter Janz who documented microdysgenetic changes in the cortex of patients with juvenile myoclonic epilepsy (JME) (2). Later, the early structural MRI studies noticed subtle anatomic differences between patients with IGEs and healthy controls as well as differences between various IGE syndromes. For example, in one study, patients with JME were noticed to have larger medial frontal cortical volumes compared with healthy controls (3), while another study reported bilateral thalamic atrophy and widespread
Are Idiopathic Generalized Epilepsies Focal?
cortical thinning, both of which were related to the duration of epilepsy exacerbated by poor seizure control (4). These findings go along with the metabolic abnormalities noted, using MRS, in patients with IGEs (5) and are supplemented by the widespread abnormalities noted using structural and functional connectivity measures (6, 7). Thus, are the generalized epilepsies truly generalized or are we seeing what is a focal cortical discharge with rapid spread via the thalamus to all brain regions? Certainly, clinical, EEG, and neuroimaging studies seem to support the notion of focal cortical onset with later symmetric and generalized involvement of all cortical regions—something considered to be the rapid bilateral synchrony as described by Lombroso and Erba (8). As such, the findings by Braga et al. are not and should not be surprising. These authors examine in detail the anatomy and morphology of the midline parasagittal structures including the cingulate cortex. In multiple confirmatory analyses performed in sizable groups of patients and controls, they document the presence of areas of cortical atrophy in the anterior cingulate and isthmus and of abnormalities in the cortical surface in the posterior cingulate. Thus, in their group morphologic analyses, these authors confirm the presence of subtle structural abnormalities in patients with IGEs. But, what is interesting is the finding that these abnormalities were not represented uniformly in all patients. In fact, individual comparisons between patients and healthy controls reveal the high variability of their findings, indicating that visual inspection or analyses of individual scans may not be fruitful in identifying patient-specific abnormalities as the source or result of their epilepsy. The findings of subtle structural cingulate abnormalities are in agreement with a recent study that documented decreased connectivity changes between the anterior thalamus and the paracingulate cortex but increased connectivity between the posterior thalamus and the paracingulate cortex in patients with IGEs (9). Of course, these and other studies support the presence of abnormalities but do not answer the question of what appears first—abnormalities that cause seizures or seizures that lead to the development of subtle abnormalities. The early data may have indicated that the subtle cortical abnormalities, as described by Janz and others, are present first and that they lead to the development of what we call IGEs (2). But, since then, the presence of such microscopic abnormalities as an etiology of seizures in IGEs has been questioned (10). While studies of structural and functional neuroimaging abnormalities in patients with IGEs abound, very few studies specifically compare treatment-responsive and treatment-resistant groups or, even less frequently, perform longitudinal assessment or evaluate subjects who may be susceptible to but have not yet developed seizures (11, 12). Where such comparisons are performed, treatment-resistance is typically associated with more pronounced anatomic and functional abnormalities, indicating that persistence of seizures may either be associated with the presence of more substantial structural or functional abnormalities or that the persistence of seizures results in more substantial brain injury. The lack of structural differences between healthy controls and patients with epilepsy at the onset of disease, but in whom diverging trajectories of brain development were later observed,
suggests that the observed differences may be related to epilepsy progression. In contrast, the presence of abnormalities in asymptomatic individuals (e.g., unaffected siblings of patients with JME) seems to indicate that the abnormalities precede the onset of seizures and that they may be exacerbated by seizures, by treatments, or by both. We all believe in something. In the case of IGEs, the beliefs are divided between two distinct camps—one that believes the IGEs are of focal and cortical, and another that they are of generalized and widespread onset. As always, the answer lies probably somewhere in between—multiple nodes of the epileptic network can be involved in and generate the GSWDs and seizures, and this is the reason why several cortical and subcortical structures were shown to have subtle anatomic and functional abnormalities. The response to treatment, the presence (or absence) of cognitive and other complications, the presence (or absence) of EEG focal abnormalities along with the GSWDs, and the presence of subtle structural and functional abnormalities may depend on which part of the network is primarily involved in the generation of the clinical events and which part of the network is merely supportive of the spread and maintenance of GSWDs. The answer to the question regarding which came first, the chicken or the egg, will come one day and will be important for the patients who have treatment-resistant IGEs. If the cortical onset of IGEs is proven in patients who are treatmentresistant, the addition of surgical treatment or neurostimulation techniques to the current pharmacotherapy may become an option that will need to be addressed. by Jerzy P. Szaflarski, MD, PhD References 1. 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 Gesamte Physiol Menschen Tiere 2012;463:201–212. 2. Meencke HJ, Janz D. Neuropathological findings in primary generalized epilepsy: A study of eight cases. Epilepsia 1984;25:8–21. 3. Woermann FG, Free SL, Koepp MJ, Sisodiya SM, Duncan JS. Abnormal cerebral structure in juvenile myoclonic epilepsy demonstrated with voxel-based analysis of MRI. Brain 1999;122(pt 11):2101–2108. 4. Bernhardt BC, Rozen DA, Worsley KJ, Evans AC, Bernasconi N, Bernasconi A. Thalamo-cortical network pathology in idiopathic generalized epilepsy: Insights from MRI-based morphometric correlation analysis. Neuroimage 2009;46:373–381. 5. Lin K, Carrete H Jr, Lin J, Peruchi MM, de Araújo Filho GM, Guaranha MS, Guilhoto LM, Sakamoto AC, Yacubian EM. Magnetic resonance spectroscopy reveals an epileptic network in juvenile myoclonic epilepsy. Epilepsia 2009;50:1191–1200. 6. Kay B, Szaflarski JP. EEG/fMRI contributions to our understanding of genetic generalized epilepsies. Epilepsy Behav 2014;34:129–135. 7. O’Muircheartaigh J, Vollmar C, Barker GJ, Kumari V, Symms MR, Thompson P, Duncan JS, Koepp MJ, Richardson MP. Abnormal thalamocortical structural and functional connectivity in juvenile myoclonic epilepsy. Brain 2012;135:3635–3644. 8. Lombroso CT, Erba G. Primary and secondary bilateral synchrony in epilepsy: A clinical and electroencephalographic study. Arch Neurol 1970;22:321–334.
243
Are Idiopathic Generalized Epilepsies Focal?
9. Kay BP, Holland SK, Privitera MD, Szaflarski JP. Differences in paracingulate connectivity associated with epileptiform discharges and uncontrolled seizures in genetic generalized epilepsy. Epilepsia 2014;55:256–263. 10. Opeskin K, Kalnins RM, Halliday G, Cartwright H, Berkovic SF. Idiopathic generalized epilepsy: Lack of significant microdysgenesis. Neurology 2000;55:1101–1106.
244
11. Pulsipher DT, Dabbs K, Tuchsherer V, Sheth RD, Koehn MA, Hermann BP, Seidenberg M. Thalamofrontal neurodevelopment in new-onset pediatric idiopathic generalized epilepsy. Neurology 2011;76:28–33. 12. Wandschneider B, Kopp UA, Kliegel M, Stephani U, Kurlemann G, Janz D, Schmitz B. Prospective memory in patients with juvenile myoclonic epilepsy and their healthy siblings. Neurology 2010;75:2161–2167.
Are Idiopathic Generalized Epilepsies Focal?
Investigation of the Cingulate Cortex in Idiopathic Generalized Epilepsy. Braga AM, Fujisao EK, Verdade RC, Paschoalato RP, Paschoalato RP, Yamashita S, Betting LE. [published online ahead of print September 28, 2015]. Epilepsia 2015;56:1803–1811. doi: 10.1111/epi.13205.
OBJECTIVE: Studies using quantitative neuroimaging have shown subtle abnormalities in patients with idiopathic generalized epilepsy (IGE). These findings have several locations, but the midline parasagittal structures are most commonly implicated. The cingulate cortex is related and may be involved. The objective of the current investigation was to perform a comprehensive analysis of the cingulate cortex using multiple quantitative structural neuroimaging techniques. METHODS: Thirty-two patients (18 women, 30 ± 10 years) and 36 controls (18 women, 32 ± 11 years) were imaged by 3 Tesla magnetic resonance imaging (MRI). A volumetric three-dimensional (3D) sequence was acquired and used for this investigation. Regions-of-interest were selected and voxel-based morphometry (VBM) analyses compared the cingulate cortex of the two groups using Statistical Parametric Mapping (SPM8) and VBM8 software. Cortical analyses of the cingulate gyrus was performed using Freesurfer. Images were submitted to automatic processing using built-in routines and recommendations. Structural parameters were extracted for individual analyses, and comparisons between groups were restricted to the cingulate gyrus. Finally, shape analyses was performed on the anterior rostral, anterior caudal, posterior, and isthmus cingulate using spherical harmonic description (SPHARM). RESULTS: VBM analyses of cingulate gyrus showed areas of gray matter atrophy, mainly in the anterior cingulate gyrus (972 mm3) and the isthmus (168 mm3). Individual analyses of the cingulate cortex were similar between patients with IGE and controls. Surface-based comparisons revealed abnormalities located mainly in the posterior cingulate cortex (718.12 mm2). Shape analyses demonstrated a predominance of anterior and posterior cingulate abnormalities. SIGNIFICANCE: This study suggests that patients with IGE have structural abnormalities in the cingulate gyrus mainly localized at the anterior and posterior portions. This finding is subtle and variable among patients.
Commentary The forefathers of epilepsy gave us the clinical definition of idiopathic generalized epilepsies (IGEs) that, in general terms, includes any combination of absence and generalized seizures, and myoclonus in someone who is cognitively intact. The clinical events are typically associated with generalized (as in occurring or initiated in all areas of the brain) spike and wave discharges (GSWDs) distributed fairly symmetrically with maximum over the bifrontal or paracentral head regions. The origins of the GSWDs remain elusive but definitely involve bilaterally distributed cortical and subcortical networks. Over the years, we have recognized that IGEs are not as benign as we originally thought; many patients exhibit various social, educational, psychologic, and cognitive handicaps. Our forefathers also taught us that IGEs should not be associated with any structural brain abnormalities. But, were they correct in their assumptions? Before we tackle the above question, let’s quickly analyze what we know about the origins of GSWDs. While over the Epilepsy Currents, Vol. 16, No. 4 (July/August) 2016 pp. 242–244 © American Epilepsy Society
242
years several possible explanations have emerged, the unifying “corticoreticular” theory has gained the most traction. It posits that GSWDs in patients with IGEs are assumed to either originate from or involve at some point bilateral cortical and subcortical (thalamocortical neurons and nucleus reticularis thalami) networks (1). In other words, this theory posits that the cortex entrains the thalamus, and the thalamocortical network sustains the discharge/seizure. If so, then we should expect to notice at least subtle changes in the function and possibly the anatomy of the involved structures with possibly different nodes of the epileptic network involved in some of the IGE syndromes, which would then lead to different clinical presentations. One of the first indications of the possible cortical onset of generalized epilepsies in humans was provided by Professor Dieter Janz who documented microdysgenetic changes in the cortex of patients with juvenile myoclonic epilepsy (JME) (2). Later, the early structural MRI studies noticed subtle anatomic differences between patients with IGEs and healthy controls as well as differences between various IGE syndromes. For example, in one study, patients with JME were noticed to have larger medial frontal cortical volumes compared with healthy controls (3), while another study reported bilateral thalamic atrophy and widespread
Are Idiopathic Generalized Epilepsies Focal?
cortical thinning, both of which were related to the duration of epilepsy exacerbated by poor seizure control (4). These findings go along with the metabolic abnormalities noted, using MRS, in patients with IGEs (5) and are supplemented by the widespread abnormalities noted using structural and functional connectivity measures (6, 7). Thus, are the generalized epilepsies truly generalized or are we seeing what is a focal cortical discharge with rapid spread via the thalamus to all brain regions? Certainly, clinical, EEG, and neuroimaging studies seem to support the notion of focal cortical onset with later symmetric and generalized involvement of all cortical regions—something considered to be the rapid bilateral synchrony as described by Lombroso and Erba (8). As such, the findings by Braga et al. are not and should not be surprising. These authors examine in detail the anatomy and morphology of the midline parasagittal structures including the cingulate cortex. In multiple confirmatory analyses performed in sizable groups of patients and controls, they document the presence of areas of cortical atrophy in the anterior cingulate and isthmus and of abnormalities in the cortical surface in the posterior cingulate. Thus, in their group morphologic analyses, these authors confirm the presence of subtle structural abnormalities in patients with IGEs. But, what is interesting is the finding that these abnormalities were not represented uniformly in all patients. In fact, individual comparisons between patients and healthy controls reveal the high variability of their findings, indicating that visual inspection or analyses of individual scans may not be fruitful in identifying patient-specific abnormalities as the source or result of their epilepsy. The findings of subtle structural cingulate abnormalities are in agreement with a recent study that documented decreased connectivity changes between the anterior thalamus and the paracingulate cortex but increased connectivity between the posterior thalamus and the paracingulate cortex in patients with IGEs (9). Of course, these and other studies support the presence of abnormalities but do not answer the question of what appears first—abnormalities that cause seizures or seizures that lead to the development of subtle abnormalities. The early data may have indicated that the subtle cortical abnormalities, as described by Janz and others, are present first and that they lead to the development of what we call IGEs (2). But, since then, the presence of such microscopic abnormalities as an etiology of seizures in IGEs has been questioned (10). While studies of structural and functional neuroimaging abnormalities in patients with IGEs abound, very few studies specifically compare treatment-responsive and treatment-resistant groups or, even less frequently, perform longitudinal assessment or evaluate subjects who may be susceptible to but have not yet developed seizures (11, 12). Where such comparisons are performed, treatment-resistance is typically associated with more pronounced anatomic and functional abnormalities, indicating that persistence of seizures may either be associated with the presence of more substantial structural or functional abnormalities or that the persistence of seizures results in more substantial brain injury. The lack of structural differences between healthy controls and patients with epilepsy at the onset of disease, but in whom diverging trajectories of brain development were later observed,
suggests that the observed differences may be related to epilepsy progression. In contrast, the presence of abnormalities in asymptomatic individuals (e.g., unaffected siblings of patients with JME) seems to indicate that the abnormalities precede the onset of seizures and that they may be exacerbated by seizures, by treatments, or by both. We all believe in something. In the case of IGEs, the beliefs are divided between two distinct camps—one that believes the IGEs are of focal and cortical, and another that they are of generalized and widespread onset. As always, the answer lies probably somewhere in between—multiple nodes of the epileptic network can be involved in and generate the GSWDs and seizures, and this is the reason why several cortical and subcortical structures were shown to have subtle anatomic and functional abnormalities. The response to treatment, the presence (or absence) of cognitive and other complications, the presence (or absence) of EEG focal abnormalities along with the GSWDs, and the presence of subtle structural and functional abnormalities may depend on which part of the network is primarily involved in the generation of the clinical events and which part of the network is merely supportive of the spread and maintenance of GSWDs. The answer to the question regarding which came first, the chicken or the egg, will come one day and will be important for the patients who have treatment-resistant IGEs. If the cortical onset of IGEs is proven in patients who are treatmentresistant, the addition of surgical treatment or neurostimulation techniques to the current pharmacotherapy may become an option that will need to be addressed. by Jerzy P. Szaflarski, MD, PhD References 1. 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 Gesamte Physiol Menschen Tiere 2012;463:201–212. 2. Meencke HJ, Janz D. Neuropathological findings in primary generalized epilepsy: A study of eight cases. Epilepsia 1984;25:8–21. 3. Woermann FG, Free SL, Koepp MJ, Sisodiya SM, Duncan JS. Abnormal cerebral structure in juvenile myoclonic epilepsy demonstrated with voxel-based analysis of MRI. Brain 1999;122(pt 11):2101–2108. 4. Bernhardt BC, Rozen DA, Worsley KJ, Evans AC, Bernasconi N, Bernasconi A. Thalamo-cortical network pathology in idiopathic generalized epilepsy: Insights from MRI-based morphometric correlation analysis. Neuroimage 2009;46:373–381. 5. Lin K, Carrete H Jr, Lin J, Peruchi MM, de Araújo Filho GM, Guaranha MS, Guilhoto LM, Sakamoto AC, Yacubian EM. Magnetic resonance spectroscopy reveals an epileptic network in juvenile myoclonic epilepsy. Epilepsia 2009;50:1191–1200. 6. Kay B, Szaflarski JP. EEG/fMRI contributions to our understanding of genetic generalized epilepsies. Epilepsy Behav 2014;34:129–135. 7. O’Muircheartaigh J, Vollmar C, Barker GJ, Kumari V, Symms MR, Thompson P, Duncan JS, Koepp MJ, Richardson MP. Abnormal thalamocortical structural and functional connectivity in juvenile myoclonic epilepsy. Brain 2012;135:3635–3644. 8. Lombroso CT, Erba G. Primary and secondary bilateral synchrony in epilepsy: A clinical and electroencephalographic study. Arch Neurol 1970;22:321–334.
243
Are Idiopathic Generalized Epilepsies Focal?
9. Kay BP, Holland SK, Privitera MD, Szaflarski JP. Differences in paracingulate connectivity associated with epileptiform discharges and uncontrolled seizures in genetic generalized epilepsy. Epilepsia 2014;55:256–263. 10. Opeskin K, Kalnins RM, Halliday G, Cartwright H, Berkovic SF. Idiopathic generalized epilepsy: Lack of significant microdysgenesis. Neurology 2000;55:1101–1106.
244
11. Pulsipher DT, Dabbs K, Tuchsherer V, Sheth RD, Koehn MA, Hermann BP, Seidenberg M. Thalamofrontal neurodevelopment in new-onset pediatric idiopathic generalized epilepsy. Neurology 2011;76:28–33. 12. Wandschneider B, Kopp UA, Kliegel M, Stephani U, Kurlemann G, Janz D, Schmitz B. Prospective memory in patients with juvenile myoclonic epilepsy and their healthy siblings. Neurology 2010;75:2161–2167.
