S U D D E N D E AT H
Spreading depression: Epilepsy’s wave of death Christophe Bernard
CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
Seizures may trigger spreading depression in brainstem nuclei, leading to central cardiorespiratory collapse and sudden unexpected death in epilepsy (Aiba and Noebels, this issue).
As the second most common neurological disorder afer migraine headaches, epilepsy afects 1% of the world’s population, and seizures are resistant to drug treatment in 30% of cases. Even more ominous is the fact that epilepsy patients—in particular, those with generalized tonic-clonic seizures—have a 20-fold increased risk of sudden death as compared with that of the general population (1). Sudden unexpected death in epilepsy (SUDEP) is particularly prominent in young and drugresistant patients, reaching an incidence of 9 per 1000 person-years (1). Because seizures are ofen associated with an abnormal heartbeat (and rapid tachycardia), suspension of breathing (apnea), and bloodoxygen desaturation, two major mechanisms have been proposed to explain SUDEP: cardiac and respiration dysfunction. In this issue of Science Translational Medicine, Aiba and Noebels provide new mechanistic insight into SUDEP. Tis study represents a major breakthrough because it provides a conceptual framework for attempting to prevent SUDEP (2). A recent retrospective study— MORTEMUS—that involved patients who died from SUDEP in epilepsy-monitoring units afer generalized tonic-clonic seizures revealed that terminal apnea preceded terminal asystole (lack of electrical activity in and beating of the heart) (3). Although no precise measurement of respiration parameters was performed in these units, clinical data clearly indicate that SUDEP involves both cardiac and respiratory defects. How can seizures lead to such dysfunctions? Generalized and complex partial seizures can recruit thalamic and subthalamic regions of the brain and cause loss of consciousness (4), which in turn could prevent protective responses such Aix Marseille Université, Inserm, INS UMR_S 1106, 13005 Marseille France. E-mail: [email protected]
as gasping. Another possible mechanism involves post-seizure depression or fattening of the electroencephalogram. If brainstem nuclei, which control cardiorespiraMutation in Na+ or K+ channel genes
* Brainstem nuclei cell
* K+
K+ K+
K+
K+
Membrane depolarization
Cardiorespiratory control lost
Cardiorespiratory collapse (abnormal heartbeat, apnea, blood-oxygen desaturation)
Sudden death
Fig. 1. Can small molecules quell monster waves? Shown are the mechanisms that underlie SUDEP in transgenic mice with a mutation in a K+ channel–encoding gene. Seizures caused a wave of depolarization (purple gradient) in brainstem nuclei, resulting in apnea, bradycardia, asystoles, and death. Electrophysiological recordings in brainstem regions, which contain cardiorespiratory pacemaker cells, revealed a large negative shift in the field potential (a DC shift), which always preceded death. These mechanistic insights may reveal potential points of therapeutic intervention (yellow asterisks) that, in turn, could spur the discovery of drugs that normalize the SD threshold and prevent seizure-related death.
tory functions, are switched of by a wave of depression, deregulation of cardiac and respiratory systems might lead to SUDEP. Mutations in several genes have been linked to SUDEP, mostly those that encode K+ or Na+ channels (1). For example, long QT syndrome—characterized by prolongation of the QT interval on electrocardiograms— is a disorder of the heart’s electrical system that augments the duration of the action potential, causes ventricular tachycardia, and is associated with mutations in K+ or Na+ channel–encoding genes, such as KCNQ1, that increase the probability of sudden death. Transgenic mouse models with mutations in KCNQ1 that correspond to those that cause human long QT syndrome show cardiac anomalies and seizures, both of which could lead to SUDEP (5). Dravet syndrome, a dramatic form of epilepsy with a high rate of SUDEP, is most ofen caused by a mutation in the Na+ channel–encoding SCN1A gene, which is expressed in both the heart and brain, and animal models of Dravet show bradycardia (slow heart rate) during seizures, which may lead to SUDEP (6). However, respiratory function was not assessed in these studies, and so it remains unclear whether cardiac or respiratory defects are the primary cause of SUDEP. More importantly, these observations lack an explanation for the moment of death—that is, how and why seizures could unexpectedly result in irreversible cardiorespiratory dysfunction and death. WAVE OF DEATH In the new work, Aiba and Noebels (2) frst studied animals that carried mutations in the gene that encodes the K+ channel Kv1.1. Tese animals exhibited generalized seizures, and half of them died by the end of the third postnatal week. In order to unravel the mechanisms underlying SUDEP in the mice, the authors recorded electrophysiological signals in the cortex and brainstem as well as heart and respiration parameters. Seizures were triggered in anaesthetized mice by applying a convulsant agent at the surface of the cortex resulting in apnea, bradycardia, and asystoles in mutant but not wild-type mice. Electrophysiological recordings performed in direct-current (DC) mode in the dorsal medulla—the brainstem nucleus that contains cardiorespiratory pacemaker cells—revealed that a large negative shif in the feld potential
www.ScienceTranslationalMedicine.org 8 April 2015 Vol 7 Issue 282 282fs14
1
Downloaded from stm.sciencemag.org on April 9, 2015
FOCUS
(a DC shif) always preceded death. Evoked seizures did not generate a DC shif in wild-type animals, and all tested wild-type animals survived seizures (Fig. 1). A negative DC shif results from the net accumulation of positive charges (mostly K+) in the extracellular space of any brain region (7). Te accumulation of extracellular K+ can occur with intense neuronal activity, as happens during seizures. Usually, glial cells restore homeostasis by redistributing the surplus of extracellular K+, and the feld potential returns to baseline levels. However, when the DC shif/extracellular K+ concentration reaches a critical value (>10 mV/10 mM K+), a slow wave (2 to 6 mm/min) of depolarization, known as spreading depolarization (SD), is generated in neuronal networks (7). Te SD wave is a self-generating event that occurs because of the existence of a positive feedback loop that involves a strong depolarization of brain-cell membranes (7). During SD, the neuronal membrane is depolarized in such a way that action potentials can no longer be generated, which leads to a fattening of the electroencephalogram (EEG). Tus, neuronal networks are transiently turned of until they recover from the SD wave. It is important to note that SD corresponds to a type of activity that is “hardwired” in any healthy brain structure, and all normal neuronal networks can be forced into SD via various pathways, in particular afer seizures (8). SD is believed to underlie migraine headaches. Te presence of a strong DC shif just before SUDEP supports the hypothesis that brain networks that control cardiorespiratory functions are switched of before death. Indeed, Aiba and Noebels found that cardiorespiratory failure and EEG fattening happened upon occurrence of the DC shif. Te authors obtained similar results in a second genetic mouse model, one that carries the mutation that gives rise to Dravet syndrome; these complementary fndings suggest that a strong DC shif is the key event that drives death. Te authors then showed causality by triggering a DC shif in the brainstem of Kv1.1 knockout animals by means of direct injection of a K+-containing solution. Tis treatment resulted in bradycardia, apnea, and EEG suppression, even in the absence of a seizure. Death occurred if the DC shif was maintained for more than 10 min. Together, these results support the idea that a wave of SD switches of key brainstem networks that regulate cardiac function and
respiration, leading to death. It is important to note that the authors did not perform SD detection in awake animals, which would require technically difcult, stable recordings over prolonged periods until the moment of death. Hence, it remains to be demonstrated that SD precedes SUDEP during naturally occurring seizures as opposed to evoked seizures in anesthetized animals. WAVE ORIGIN Why do seizures trigger a strong DC shif in mutant but not wild-type mice? Teoretical and experimental work has demonstrated that “normal” electrical brain activity, seizures, and SD correspond to diferent states of activity separated from one another by barriers that must be crossed in order to move from one to another—like three valleys surrounded by mountains with passes through which messages can be communicated; the height of the pass corresponds to a threshold that must be crossed by brain activity (8). In keeping with this hypothesis, Aiba and Noebels (2) demonstrated that both types of mutant mice have lower thresholds for SD transition than do wildtype animals when measured in brainstem slices. Although blocking Kv1.1 channels lowers the threshold for SD in wild-type animals (which would explain the results in Kv1.1 mutant mice), the mechanism that underlies the lower SD threshold in Dravet mice is unclear. What kind of in vivo environment could cause a strong DC shif? Te authors showed that triggering cortical seizures can lead to such shifs with variable time delays (sometimes several minutes). Tis observation is consistent with the concept that seizure genesis and propagation as well as SD are controlled by slow-state variables—biophysical parameters that evolve slowly over time and push brain networks to cross the threshold to seizure or SD (8, 9). Such biophysical parameters include extracellular K+ and O2 (9). In keeping with this scheme, the authors found that ventilation was disrupted during seizures, which could lead to hypoxemia and thus bring the system closer to the SD threshold. Once the threshold is crossed, SD in brainstem structures would worsen hypoxia, thus generating a vicious circle. RIDING THE WAVE TOWARD PREVENTION? Te model proposed by Aiba and Noebels provides a coherent picture that can explain SUDEP. Te authors also dem-
onstrate that the threshold can be raised by genetic changes that decrease neuronal hyperexcitability. Te axonal microtubuleassociated protein tau controls neuronal excitability, and its removal from mouse models of SUDEP decreases seizure frequency and increases survival rate (10). In keeping with these previous fndings, the authors measured an increased SD threshold when they crossed the Kv1.1 mutant mouse with a tau knockout mouse. Te data thus demonstrate that it is possible to raise a low SD threshold, but whether this can be accomplished with pharmacological interventions remains to be investigated. Interestingly, fuoxetine, a selective serotonin reuptake inhibitor, prevents seizure-induced apnea, and cafeine, acting as an antagonist of adenosine receptors, could have similar efects and is known to prevent apnea in highly premature babies (1). It will be particularly interesting to test whether fuoxetine, cafeine, or other treatments can normalize the SD threshold in Kv1.1 mutant and Dravet mice. A major contribution of the current study is the description of a simple in vitro test for assessing the SD threshold quickly and efciently. Tis assay could be used to screen for SD threshold–raising pharmacological agents that can then be tested for their ability to block SUDEP in various animal models. REFERENCES 1. C. A. Massey, L. P. Sowers, B. J. Dlouhy, G. B. Richerson, Mechanisms of sudden unexpected death in epilepsy: The pathway to prevention. Nat. Rev. Neurol. 10, 271– 282 (2014). 2. I. Aiba, J. L. Noebels, Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci. Transl. Med. 7, 282ra46 (2015). 3. P. Ryvlin, L. Nashef, S. D. Lhatoo, L. M. Bateman, J. Bird, A. Bleasel, P. Boon, A. Crespel, B. A. Dworetzky, H. Høgenhaven, H. Lerche, L. Maillard, M. P. Malter, C. Marchal, J. M. Murthy, M. Nitsche, E. Pataraia, T. Rabben, S. Rheims, B. Sadzot, A. Schulze-Bonhage, M. Seyal, E. L. So, M. Spitz, A. Szucs, M. Tan, J. X. Tao, T. Tomson, Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): A retrospective study. Lancet Neurol. 12, 966–977 (2013). 4. M. Arthuis, L. Valton, J. Régis, P. Chauvel, F. Wendling, L. Naccache, C. Bernard, F. Bartolomei, Impaired consciousness during temporal lobe seizures is related to increased long-distance cortical-subcortical synchronization. Brain 132, 2091–2101 (2009). 5. A. M. Goldman, E. Glasscock, J. Yoo, T. T. Chen, T. L. Klassen, J. L. Noebels, Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Sci. Transl. Med. 1, 2ra6 (2009). 6. F. Kalume, R. E. Westenbroek, C. S. Cheah, F. H. Yu, J. C. Oakley, T. Scheuer, W. A. Catterall, Sudden unexpected death in a mouse model of Dravet syndrome. J. Clin. Invest. 123, 1798–1808 (2013).
www.ScienceTranslationalMedicine.org 8 April 2015 Vol 7 Issue 282 282fs14
2
Downloaded from stm.sciencemag.org on April 9, 2015
FOCUS
FOCUS Nonlin. Soft Matter Phys. 91, 010701 (2015). 9. V. K. Jirsa, W. C. Stacey, P. P. Quilichini, A. I. Ivanov, C. Bernard, On the nature of seizure dynamics. Brain 137, 2210–2230 (2014). 10. J. K. Holth, V. C. Bomben, J. G. Reed, T. Inoue, L. Younkin, S. G. Younkin, R. G. Pautler, J. Botas, J. L. Noebels, Tau loss attenuates neuronal network hyperexcitability in
mouse and Drosophila genetic models of epilepsy. J. Neurosci. 33, 1651–1659 (2013). 10.1126/scitranslmed.aaa9854 Citation: C. Bernard, Spreading depression: Epilepsy’s wave of death. Sci. Transl. Med. 7, 282fs14 (2015).
Downloaded from stm.sciencemag.org on April 9, 2015
7. D. Pietrobon, M. A. Moskowitz, Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat. Rev. Neurosci. 15, 379–393 (2014). 8. K. El Houssaini, A. I. Ivanov, C. Bernard, V. K. Jirsa, Seizures, refractory status epilepticus, and depolarization block as endogenous brain activities. Phys. Rev. E Stat.
www.ScienceTranslationalMedicine.org 8 April 2015 Vol 7 Issue 282 282fs14
3
Spreading depression: Epilepsy’s wave of death Christophe Bernard
CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
Seizures may trigger spreading depression in brainstem nuclei, leading to central cardiorespiratory collapse and sudden unexpected death in epilepsy (Aiba and Noebels, this issue).
As the second most common neurological disorder afer migraine headaches, epilepsy afects 1% of the world’s population, and seizures are resistant to drug treatment in 30% of cases. Even more ominous is the fact that epilepsy patients—in particular, those with generalized tonic-clonic seizures—have a 20-fold increased risk of sudden death as compared with that of the general population (1). Sudden unexpected death in epilepsy (SUDEP) is particularly prominent in young and drugresistant patients, reaching an incidence of 9 per 1000 person-years (1). Because seizures are ofen associated with an abnormal heartbeat (and rapid tachycardia), suspension of breathing (apnea), and bloodoxygen desaturation, two major mechanisms have been proposed to explain SUDEP: cardiac and respiration dysfunction. In this issue of Science Translational Medicine, Aiba and Noebels provide new mechanistic insight into SUDEP. Tis study represents a major breakthrough because it provides a conceptual framework for attempting to prevent SUDEP (2). A recent retrospective study— MORTEMUS—that involved patients who died from SUDEP in epilepsy-monitoring units afer generalized tonic-clonic seizures revealed that terminal apnea preceded terminal asystole (lack of electrical activity in and beating of the heart) (3). Although no precise measurement of respiration parameters was performed in these units, clinical data clearly indicate that SUDEP involves both cardiac and respiratory defects. How can seizures lead to such dysfunctions? Generalized and complex partial seizures can recruit thalamic and subthalamic regions of the brain and cause loss of consciousness (4), which in turn could prevent protective responses such Aix Marseille Université, Inserm, INS UMR_S 1106, 13005 Marseille France. E-mail: [email protected]
as gasping. Another possible mechanism involves post-seizure depression or fattening of the electroencephalogram. If brainstem nuclei, which control cardiorespiraMutation in Na+ or K+ channel genes
* Brainstem nuclei cell
* K+
K+ K+
K+
K+
Membrane depolarization
Cardiorespiratory control lost
Cardiorespiratory collapse (abnormal heartbeat, apnea, blood-oxygen desaturation)
Sudden death
Fig. 1. Can small molecules quell monster waves? Shown are the mechanisms that underlie SUDEP in transgenic mice with a mutation in a K+ channel–encoding gene. Seizures caused a wave of depolarization (purple gradient) in brainstem nuclei, resulting in apnea, bradycardia, asystoles, and death. Electrophysiological recordings in brainstem regions, which contain cardiorespiratory pacemaker cells, revealed a large negative shift in the field potential (a DC shift), which always preceded death. These mechanistic insights may reveal potential points of therapeutic intervention (yellow asterisks) that, in turn, could spur the discovery of drugs that normalize the SD threshold and prevent seizure-related death.
tory functions, are switched of by a wave of depression, deregulation of cardiac and respiratory systems might lead to SUDEP. Mutations in several genes have been linked to SUDEP, mostly those that encode K+ or Na+ channels (1). For example, long QT syndrome—characterized by prolongation of the QT interval on electrocardiograms— is a disorder of the heart’s electrical system that augments the duration of the action potential, causes ventricular tachycardia, and is associated with mutations in K+ or Na+ channel–encoding genes, such as KCNQ1, that increase the probability of sudden death. Transgenic mouse models with mutations in KCNQ1 that correspond to those that cause human long QT syndrome show cardiac anomalies and seizures, both of which could lead to SUDEP (5). Dravet syndrome, a dramatic form of epilepsy with a high rate of SUDEP, is most ofen caused by a mutation in the Na+ channel–encoding SCN1A gene, which is expressed in both the heart and brain, and animal models of Dravet show bradycardia (slow heart rate) during seizures, which may lead to SUDEP (6). However, respiratory function was not assessed in these studies, and so it remains unclear whether cardiac or respiratory defects are the primary cause of SUDEP. More importantly, these observations lack an explanation for the moment of death—that is, how and why seizures could unexpectedly result in irreversible cardiorespiratory dysfunction and death. WAVE OF DEATH In the new work, Aiba and Noebels (2) frst studied animals that carried mutations in the gene that encodes the K+ channel Kv1.1. Tese animals exhibited generalized seizures, and half of them died by the end of the third postnatal week. In order to unravel the mechanisms underlying SUDEP in the mice, the authors recorded electrophysiological signals in the cortex and brainstem as well as heart and respiration parameters. Seizures were triggered in anaesthetized mice by applying a convulsant agent at the surface of the cortex resulting in apnea, bradycardia, and asystoles in mutant but not wild-type mice. Electrophysiological recordings performed in direct-current (DC) mode in the dorsal medulla—the brainstem nucleus that contains cardiorespiratory pacemaker cells—revealed that a large negative shif in the feld potential
www.ScienceTranslationalMedicine.org 8 April 2015 Vol 7 Issue 282 282fs14
1
Downloaded from stm.sciencemag.org on April 9, 2015
FOCUS
(a DC shif) always preceded death. Evoked seizures did not generate a DC shif in wild-type animals, and all tested wild-type animals survived seizures (Fig. 1). A negative DC shif results from the net accumulation of positive charges (mostly K+) in the extracellular space of any brain region (7). Te accumulation of extracellular K+ can occur with intense neuronal activity, as happens during seizures. Usually, glial cells restore homeostasis by redistributing the surplus of extracellular K+, and the feld potential returns to baseline levels. However, when the DC shif/extracellular K+ concentration reaches a critical value (>10 mV/10 mM K+), a slow wave (2 to 6 mm/min) of depolarization, known as spreading depolarization (SD), is generated in neuronal networks (7). Te SD wave is a self-generating event that occurs because of the existence of a positive feedback loop that involves a strong depolarization of brain-cell membranes (7). During SD, the neuronal membrane is depolarized in such a way that action potentials can no longer be generated, which leads to a fattening of the electroencephalogram (EEG). Tus, neuronal networks are transiently turned of until they recover from the SD wave. It is important to note that SD corresponds to a type of activity that is “hardwired” in any healthy brain structure, and all normal neuronal networks can be forced into SD via various pathways, in particular afer seizures (8). SD is believed to underlie migraine headaches. Te presence of a strong DC shif just before SUDEP supports the hypothesis that brain networks that control cardiorespiratory functions are switched of before death. Indeed, Aiba and Noebels found that cardiorespiratory failure and EEG fattening happened upon occurrence of the DC shif. Te authors obtained similar results in a second genetic mouse model, one that carries the mutation that gives rise to Dravet syndrome; these complementary fndings suggest that a strong DC shif is the key event that drives death. Te authors then showed causality by triggering a DC shif in the brainstem of Kv1.1 knockout animals by means of direct injection of a K+-containing solution. Tis treatment resulted in bradycardia, apnea, and EEG suppression, even in the absence of a seizure. Death occurred if the DC shif was maintained for more than 10 min. Together, these results support the idea that a wave of SD switches of key brainstem networks that regulate cardiac function and
respiration, leading to death. It is important to note that the authors did not perform SD detection in awake animals, which would require technically difcult, stable recordings over prolonged periods until the moment of death. Hence, it remains to be demonstrated that SD precedes SUDEP during naturally occurring seizures as opposed to evoked seizures in anesthetized animals. WAVE ORIGIN Why do seizures trigger a strong DC shif in mutant but not wild-type mice? Teoretical and experimental work has demonstrated that “normal” electrical brain activity, seizures, and SD correspond to diferent states of activity separated from one another by barriers that must be crossed in order to move from one to another—like three valleys surrounded by mountains with passes through which messages can be communicated; the height of the pass corresponds to a threshold that must be crossed by brain activity (8). In keeping with this hypothesis, Aiba and Noebels (2) demonstrated that both types of mutant mice have lower thresholds for SD transition than do wildtype animals when measured in brainstem slices. Although blocking Kv1.1 channels lowers the threshold for SD in wild-type animals (which would explain the results in Kv1.1 mutant mice), the mechanism that underlies the lower SD threshold in Dravet mice is unclear. What kind of in vivo environment could cause a strong DC shif? Te authors showed that triggering cortical seizures can lead to such shifs with variable time delays (sometimes several minutes). Tis observation is consistent with the concept that seizure genesis and propagation as well as SD are controlled by slow-state variables—biophysical parameters that evolve slowly over time and push brain networks to cross the threshold to seizure or SD (8, 9). Such biophysical parameters include extracellular K+ and O2 (9). In keeping with this scheme, the authors found that ventilation was disrupted during seizures, which could lead to hypoxemia and thus bring the system closer to the SD threshold. Once the threshold is crossed, SD in brainstem structures would worsen hypoxia, thus generating a vicious circle. RIDING THE WAVE TOWARD PREVENTION? Te model proposed by Aiba and Noebels provides a coherent picture that can explain SUDEP. Te authors also dem-
onstrate that the threshold can be raised by genetic changes that decrease neuronal hyperexcitability. Te axonal microtubuleassociated protein tau controls neuronal excitability, and its removal from mouse models of SUDEP decreases seizure frequency and increases survival rate (10). In keeping with these previous fndings, the authors measured an increased SD threshold when they crossed the Kv1.1 mutant mouse with a tau knockout mouse. Te data thus demonstrate that it is possible to raise a low SD threshold, but whether this can be accomplished with pharmacological interventions remains to be investigated. Interestingly, fuoxetine, a selective serotonin reuptake inhibitor, prevents seizure-induced apnea, and cafeine, acting as an antagonist of adenosine receptors, could have similar efects and is known to prevent apnea in highly premature babies (1). It will be particularly interesting to test whether fuoxetine, cafeine, or other treatments can normalize the SD threshold in Kv1.1 mutant and Dravet mice. A major contribution of the current study is the description of a simple in vitro test for assessing the SD threshold quickly and efciently. Tis assay could be used to screen for SD threshold–raising pharmacological agents that can then be tested for their ability to block SUDEP in various animal models. REFERENCES 1. C. A. Massey, L. P. Sowers, B. J. Dlouhy, G. B. Richerson, Mechanisms of sudden unexpected death in epilepsy: The pathway to prevention. Nat. Rev. Neurol. 10, 271– 282 (2014). 2. I. Aiba, J. L. Noebels, Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci. Transl. Med. 7, 282ra46 (2015). 3. P. Ryvlin, L. Nashef, S. D. Lhatoo, L. M. Bateman, J. Bird, A. Bleasel, P. Boon, A. Crespel, B. A. Dworetzky, H. Høgenhaven, H. Lerche, L. Maillard, M. P. Malter, C. Marchal, J. M. Murthy, M. Nitsche, E. Pataraia, T. Rabben, S. Rheims, B. Sadzot, A. Schulze-Bonhage, M. Seyal, E. L. So, M. Spitz, A. Szucs, M. Tan, J. X. Tao, T. Tomson, Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): A retrospective study. Lancet Neurol. 12, 966–977 (2013). 4. M. Arthuis, L. Valton, J. Régis, P. Chauvel, F. Wendling, L. Naccache, C. Bernard, F. Bartolomei, Impaired consciousness during temporal lobe seizures is related to increased long-distance cortical-subcortical synchronization. Brain 132, 2091–2101 (2009). 5. A. M. Goldman, E. Glasscock, J. Yoo, T. T. Chen, T. L. Klassen, J. L. Noebels, Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Sci. Transl. Med. 1, 2ra6 (2009). 6. F. Kalume, R. E. Westenbroek, C. S. Cheah, F. H. Yu, J. C. Oakley, T. Scheuer, W. A. Catterall, Sudden unexpected death in a mouse model of Dravet syndrome. J. Clin. Invest. 123, 1798–1808 (2013).
www.ScienceTranslationalMedicine.org 8 April 2015 Vol 7 Issue 282 282fs14
2
Downloaded from stm.sciencemag.org on April 9, 2015
FOCUS
FOCUS Nonlin. Soft Matter Phys. 91, 010701 (2015). 9. V. K. Jirsa, W. C. Stacey, P. P. Quilichini, A. I. Ivanov, C. Bernard, On the nature of seizure dynamics. Brain 137, 2210–2230 (2014). 10. J. K. Holth, V. C. Bomben, J. G. Reed, T. Inoue, L. Younkin, S. G. Younkin, R. G. Pautler, J. Botas, J. L. Noebels, Tau loss attenuates neuronal network hyperexcitability in
mouse and Drosophila genetic models of epilepsy. J. Neurosci. 33, 1651–1659 (2013). 10.1126/scitranslmed.aaa9854 Citation: C. Bernard, Spreading depression: Epilepsy’s wave of death. Sci. Transl. Med. 7, 282fs14 (2015).
Downloaded from stm.sciencemag.org on April 9, 2015
7. D. Pietrobon, M. A. Moskowitz, Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat. Rev. Neurosci. 15, 379–393 (2014). 8. K. El Houssaini, A. I. Ivanov, C. Bernard, V. K. Jirsa, Seizures, refractory status epilepticus, and depolarization block as endogenous brain activities. Phys. Rev. E Stat.
www.ScienceTranslationalMedicine.org 8 April 2015 Vol 7 Issue 282 282fs14
3
