- Email: [email protected]
Generalized epilepsy: Don’t look too close
Clinical Neurophysiology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Generalized epilepsy: Don’t look too close See Article, pages xxx–xxx
The concept of ‘generalized’ epilepsy originates from the EEG. No clinician would consider childhood absence seizures as generalized because children typically show focal movements in eyelids, mouth and hands, which we call automatisms. A purely clinical classification would probably group absence seizures with temporal lobe seizures with which they share these features and loss of consciousness. Neither would careful observation allow myoclonic seizures in juvenile myoclonic epilepsy to be called generalized, as they are focal or segmental. People might argue that it is the ‘genetic’ aspect of these ‘generalized’ epilepsies that holds them together. Still, we do not find genetic explanations for the majority of people with generalized epilepsy. So, it is still the EEG that lumps these epilepsies together, with some success, e.g. in the choice of anti-epileptic drugs or prognosis. Showing the EEG of generalized seizures is an educational delight. It becomes clear to anyone that generalized tonic–clonic seizures should be placed next to absence seizures, as their EEGs look identical. Asked how such extremes can share the same electrophysiology, and how ‘interictal generalized paroxysms’ of many seconds may exist without interruption of consciousness, we remain silent. Clinical neurophysiology is mostly phenomenological; we have to take things at face value. Unfortunately, even phenomenology often resists the term ‘generalized’. Several papers by Seneviratne et al. have already appeared on how generalized seizures and generalized EEG findings are often confounded by focal signatures (Seneviratne et al., 2014; Seneviratne et al., 2015a,b) to which one is now added (Seneviratne et al., 2015c). Many things were already known. What these authors provide, however, is a meticulous and systematic approach with regard to EEG with some lessons for clinical neurophysiological practice and teaching. Their original contributions are based on a cohort of 126 patients with established genetic generalized epilepsy who underwent 24-hour EEG recordings and MRI. Analysis of interictal EEG abnormalities show that two-thirds of these patients have focal EEG features, such as atypical spike-wave morphology and asymmetry of amplitude or onset in ‘generalized’ discharges, and independent focal abnormalities (Seneviratne et al., 2015b). Should we see these focal abnormalities as a result of a generalized increase in neuronal excitability or are we actually seeing a generalization of a disease which might primarily focal in its nature? Even if anatomical and functional imaging shows evidence of focal disturbances in grey and white matter in generalized epilepsy
(Seneviratne et al., 2014), this does not prove that the origin of the epilepsy is focal. One could well hypothesize that a general reduction of the threshold to generate seizures affects some parts of the brain more than others and may secondarily result in these focal abnormalities. A scenario of secondary focal epileptogenesis would imply an increase in focal abnormalities along the disease history. This comparison has not been made yet. The evidence for generalized processes is, as described above, the truly generalized appearance of the majority of EEG events and the link to genetics. Also the different responses to anti-epileptic drugs between focal and generalized epilepsies suggests a basically different pathophysiological process going on in the two of them. This does not rule out a focal onset though, as in true focal epilepsies we can also encounter that the focal disease only reveals itself because of a general lowering of the seizure generating threshold. As much as focal epilepsy can be considered a general brain network disorder (Englot et al., 2015), generalized epilepsies encounter some focal characteristics. Instead of the black-and-white division we might want to put epilepsy syndromes more in a gradual distribution between focal and generalized. What should clinicians learn? Faced with an EEG that shows the above atypical characteristics in e.g. a patient suspected of juvenile absence epilepsy (JAE), there are two options. One is to conclude that ‘‘the EEG shows focal features that question the diagnosis of a generalized epilepsy, hence an MRI is advised” or ‘‘the EEG is compatible with a diagnosis of JAE”. We propose the latter. As Seneviratne et al. show us, in JAE and other generalized epilepsy syndromes nothing is more typical than the atypical. Could this avoid many unnecessary MRIs? It probably can, because a reliable diagnosis of genetic (idiopathic) generalized epilepsy has a very low odds of MRI abnormalities that bear consequences (Seneviratne et al., 2015c; King et al., 1998). The essential part, of course, is to obtain a proper history and seizure description by a physician experienced in epilepsy. Only then the EEG can join in an accurate syndrome diagnosis. Other questions arise. Could misclassification occur in a person with generalized epilepsy when the EEG accidentally shows only the focal abnormalities? Translation of these 24-hour – posttreatment-EEGs to 15 min EEGs would yield a 0.3% chance to find only focal events. These odds are probably negligible in diagnostic EEGs before treatment and including stimulation protocols and if needed followed-up by a sleep-deprivation EEG. When should long-term recordings be advised in diagnosis? Both questions are
http://dx.doi.org/10.1016/j.clinph.2015.09.128 1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
2
Editorial / Clinical Neurophysiology xxx (2015) xxx–xxx
better answered by comparing first EEG findings in a cohort with a probable diagnosis of generalized epilepsy based on the clinical presentation. Could these focal features serve as a phenotype for genetic association studies? Do they associate with clinical factors such as seizure frequency, drug response and intractability, age at remission or psychology? Do they indicate a different underlying pathophysiology? Perhaps further studies into the Australian cohort will reveal some answers to that. Acknowledgement Maeike Zijlmans received funding from the Rudolf Magnus Young Talent Fellowship and from ZonMw (Veni 91615149). Conflict of interest: None. References
Seneviratne U, Woo JJ, Boston RC, Cook M, D’Souza W. Focal seizure symptoms in idiopathic generalized epilepsies. Neurology 2015a;85:589–95. Seneviratne U, Hepworth G, Cook M, D’Souza W. Atypical EEG abnormalities in genetic generalized epilepsies. Clin Neurophysiol 2015. http://dx.doi.org/ 10.1016/j.clinph.2015.05.031. Seneviratne U, Cook M, D’Souza W. Consistent topography and amplitude symmetry are more typical than morphology of epileptiform discharges in genetic generalized epilepsy. Clin Neurophysiol 2015. http://dx.doi.org/ 10.1016/j.clinph.2015.08.019.
F.S.S. Leijten Brain Center Rudolf Magnus, Dept. of Clinical Neurophysiology, University Medical Center Utrecht, Utrecht, The Netherlands E-mail address: [email protected]
⇑
M. Zijlmans Brain Center Rudolf Magnus, Dept. of Clinical Neurophysiology, University Medical Center Utrecht, Utrecht, The Netherlands Stichting Epilepsie Instellingen Nederland, The Netherlands
Englot DJ, Hinkley LB, Kort NS, Imber BS, Mizuiri D, Honma SM, et al. Global and regional functional connectivity maps of neural oscillations in focal epilepsy. Brain 2015;138:2249–62. King MA, Newton MR, Jackson GD, Fitt GJ, Mitchell LA, Silvapulle MJ, et al. Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients. Lancet 1998;352:1007–11. Seneviratne U, Cook M, D’Souza W. Focal abnormalities in idiopathic generalized epilepsy: a critical review of the literature. Epilepsia 2014;55:1157–69.
⇑ Address: University Medical Center Utrecht, Heidelberglaan 100, 3584
CX Utrecht, The Netherlands. E-mail address: [email protected]
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Generalized epilepsy: Don’t look too close See Article, pages xxx–xxx
The concept of ‘generalized’ epilepsy originates from the EEG. No clinician would consider childhood absence seizures as generalized because children typically show focal movements in eyelids, mouth and hands, which we call automatisms. A purely clinical classification would probably group absence seizures with temporal lobe seizures with which they share these features and loss of consciousness. Neither would careful observation allow myoclonic seizures in juvenile myoclonic epilepsy to be called generalized, as they are focal or segmental. People might argue that it is the ‘genetic’ aspect of these ‘generalized’ epilepsies that holds them together. Still, we do not find genetic explanations for the majority of people with generalized epilepsy. So, it is still the EEG that lumps these epilepsies together, with some success, e.g. in the choice of anti-epileptic drugs or prognosis. Showing the EEG of generalized seizures is an educational delight. It becomes clear to anyone that generalized tonic–clonic seizures should be placed next to absence seizures, as their EEGs look identical. Asked how such extremes can share the same electrophysiology, and how ‘interictal generalized paroxysms’ of many seconds may exist without interruption of consciousness, we remain silent. Clinical neurophysiology is mostly phenomenological; we have to take things at face value. Unfortunately, even phenomenology often resists the term ‘generalized’. Several papers by Seneviratne et al. have already appeared on how generalized seizures and generalized EEG findings are often confounded by focal signatures (Seneviratne et al., 2014; Seneviratne et al., 2015a,b) to which one is now added (Seneviratne et al., 2015c). Many things were already known. What these authors provide, however, is a meticulous and systematic approach with regard to EEG with some lessons for clinical neurophysiological practice and teaching. Their original contributions are based on a cohort of 126 patients with established genetic generalized epilepsy who underwent 24-hour EEG recordings and MRI. Analysis of interictal EEG abnormalities show that two-thirds of these patients have focal EEG features, such as atypical spike-wave morphology and asymmetry of amplitude or onset in ‘generalized’ discharges, and independent focal abnormalities (Seneviratne et al., 2015b). Should we see these focal abnormalities as a result of a generalized increase in neuronal excitability or are we actually seeing a generalization of a disease which might primarily focal in its nature? Even if anatomical and functional imaging shows evidence of focal disturbances in grey and white matter in generalized epilepsy
(Seneviratne et al., 2014), this does not prove that the origin of the epilepsy is focal. One could well hypothesize that a general reduction of the threshold to generate seizures affects some parts of the brain more than others and may secondarily result in these focal abnormalities. A scenario of secondary focal epileptogenesis would imply an increase in focal abnormalities along the disease history. This comparison has not been made yet. The evidence for generalized processes is, as described above, the truly generalized appearance of the majority of EEG events and the link to genetics. Also the different responses to anti-epileptic drugs between focal and generalized epilepsies suggests a basically different pathophysiological process going on in the two of them. This does not rule out a focal onset though, as in true focal epilepsies we can also encounter that the focal disease only reveals itself because of a general lowering of the seizure generating threshold. As much as focal epilepsy can be considered a general brain network disorder (Englot et al., 2015), generalized epilepsies encounter some focal characteristics. Instead of the black-and-white division we might want to put epilepsy syndromes more in a gradual distribution between focal and generalized. What should clinicians learn? Faced with an EEG that shows the above atypical characteristics in e.g. a patient suspected of juvenile absence epilepsy (JAE), there are two options. One is to conclude that ‘‘the EEG shows focal features that question the diagnosis of a generalized epilepsy, hence an MRI is advised” or ‘‘the EEG is compatible with a diagnosis of JAE”. We propose the latter. As Seneviratne et al. show us, in JAE and other generalized epilepsy syndromes nothing is more typical than the atypical. Could this avoid many unnecessary MRIs? It probably can, because a reliable diagnosis of genetic (idiopathic) generalized epilepsy has a very low odds of MRI abnormalities that bear consequences (Seneviratne et al., 2015c; King et al., 1998). The essential part, of course, is to obtain a proper history and seizure description by a physician experienced in epilepsy. Only then the EEG can join in an accurate syndrome diagnosis. Other questions arise. Could misclassification occur in a person with generalized epilepsy when the EEG accidentally shows only the focal abnormalities? Translation of these 24-hour – posttreatment-EEGs to 15 min EEGs would yield a 0.3% chance to find only focal events. These odds are probably negligible in diagnostic EEGs before treatment and including stimulation protocols and if needed followed-up by a sleep-deprivation EEG. When should long-term recordings be advised in diagnosis? Both questions are
http://dx.doi.org/10.1016/j.clinph.2015.09.128 1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
2
Editorial / Clinical Neurophysiology xxx (2015) xxx–xxx
better answered by comparing first EEG findings in a cohort with a probable diagnosis of generalized epilepsy based on the clinical presentation. Could these focal features serve as a phenotype for genetic association studies? Do they associate with clinical factors such as seizure frequency, drug response and intractability, age at remission or psychology? Do they indicate a different underlying pathophysiology? Perhaps further studies into the Australian cohort will reveal some answers to that. Acknowledgement Maeike Zijlmans received funding from the Rudolf Magnus Young Talent Fellowship and from ZonMw (Veni 91615149). Conflict of interest: None. References
Seneviratne U, Woo JJ, Boston RC, Cook M, D’Souza W. Focal seizure symptoms in idiopathic generalized epilepsies. Neurology 2015a;85:589–95. Seneviratne U, Hepworth G, Cook M, D’Souza W. Atypical EEG abnormalities in genetic generalized epilepsies. Clin Neurophysiol 2015. http://dx.doi.org/ 10.1016/j.clinph.2015.05.031. Seneviratne U, Cook M, D’Souza W. Consistent topography and amplitude symmetry are more typical than morphology of epileptiform discharges in genetic generalized epilepsy. Clin Neurophysiol 2015. http://dx.doi.org/ 10.1016/j.clinph.2015.08.019.
F.S.S. Leijten Brain Center Rudolf Magnus, Dept. of Clinical Neurophysiology, University Medical Center Utrecht, Utrecht, The Netherlands E-mail address: [email protected]
⇑
M. Zijlmans Brain Center Rudolf Magnus, Dept. of Clinical Neurophysiology, University Medical Center Utrecht, Utrecht, The Netherlands Stichting Epilepsie Instellingen Nederland, The Netherlands
Englot DJ, Hinkley LB, Kort NS, Imber BS, Mizuiri D, Honma SM, et al. Global and regional functional connectivity maps of neural oscillations in focal epilepsy. Brain 2015;138:2249–62. King MA, Newton MR, Jackson GD, Fitt GJ, Mitchell LA, Silvapulle MJ, et al. Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients. Lancet 1998;352:1007–11. Seneviratne U, Cook M, D’Souza W. Focal abnormalities in idiopathic generalized epilepsy: a critical review of the literature. Epilepsia 2014;55:1157–69.
⇑ Address: University Medical Center Utrecht, Heidelberglaan 100, 3584
CX Utrecht, The Netherlands. E-mail address: [email protected]