Comment
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Van Dongen HP, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003; 26: 117–26. Schmid SM, Hallschmid M, Schultes B. The metabolic burden of sleep loss. Lancet Diabetes Endocrinol 2014; published online March 25. http://dx.doi. org/10.1016/S2213-8587(14)70012-9. National Aeronautics and Space Administration (NASA). Operational ground testing protocol to optimize astronaut sleep medication efficacy and individual effects (Sleep_Meds_Phase_II). July 15, 2014. http://lsda.jsc.nasa. gov/scripts/experiment/exper.aspx?exp_index=2104 (accessed Aug 1, 2014). Mader TH, Gibson CR, Pass AF, et al. Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after longduration space flight. Ophthalmology 2011; 118: 2058–69. Basner M, Dinges DF, Mollicone D, et al. Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing. Proc Natl Acad Sci USA 2013; 110: 2635–40.
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Basner M, Dinges DF, Mollicone DJ, et al. Psychological and behavioral changes during confinement in a 520-day simulated interplanetary mission to mars. PLoS One 2014; 9: e93298. Arendt J. Biological rhythms during residence in polar regions. Chronobiol Int 2012; 29: 379–94. Barger LK, Sullivan JP, Vincent AS, et al. Learning to live on a Mars day: fatigue countermeasures during the Phoenix Mars Lander mission. Sleep 2012; 35: 1423–35. Basner M, Mollicone DJ, Dinges DF. Validity and sensitivity of a brief Psychomotor Vigilance Test (PVT-B) to total and partial sleep deprivation. Acta Astronautica 2011; 69: 949–59. NASA. Psychomotor Vigilance Test (PVT) on ISS (Reaction). July 15, 2014. http://lsda.jsc.nasa.gov/scripts/experiment/exper.aspx?exp_index=1490 (accessed Aug 1, 2014).
Epilepsy: lost in translation Published Online August 11, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70125-5 See Personal View page 949
862
The Personal View by Simonato and colleagues1 was overdue, but it falls short of what is needed. Is epilepsy truly a disorder that can be easily defined? Epilepsy is a brain state characterised by its ability to generate seizures more easily than can a healthy brain.2 Thus, in contrast to many other diseases, epilepsy is characterised by a symptom—the epileptic seizure—which can be viewed as the common denominator for the various types of epilepsy. As such, epilepsy cannot be compared with other neurological disorders that have shown good progress by improvements in translational research, such as multiple sclerosis. Moreover, although seizures and epilepsies in animals can be generated easily and many models of epilepsy exist, their relevance for human epilepsies is open to question. Epilepsy has two facets: first, the seizure symptom; and second, the cause or process leading to epilepsy as a chronic state (the epileptogenicity) of the brain. Epilepsies are treated primarily with anticonvulsive drugs, which are ineffective in about a third of cases. Generally, all the years of translational research have resulted in little progress in terms of efficacy. In focal epilepsies, results of controlled, blinded studies have not shown superiority of monotherapy compared with the old standby carbamazepine.3,4 And when high-quality studies are taken into account for the add-on design, efficacy is lost with the newer anticonvulsive drugs because of an increase in the placebo response.5,6 Disease-modifying therapy (the prevention of an epilepsy after an initial, potentially epileptogenic hit) is an important concept, but with only a small amount
of experimental background and no real measure of whether this type of therapy can be proven to work in humans. The use of experimental post-traumatic epilepsy as a model for a disease-modifying therapy ignores two facts for translation: the complexity of human posttraumatic epilepsy and efforts to reduce its incidence; and Andres Salazar’s experience in Vietnam veterans, who were often uncompliant for preventive therapy but compliant for a therapy after the first seizure.7 The search for biomarkers to predict a developing epilepsy is intense. The MRI screening of all children with febrile convulsions to identify those at risk is not only an economic challenge but also an ethical one, because children need to be anaesthetised for many MRI scans over the years.8 Additionally, power calculations will show the immense logistical effort necessary to establish whether or not one substance is anti-epileptogenic (or disease-modifying). When selecting and using epilepsy models, one must ask for which group of epilepsy patients do we want to provide better treatment? The answer should be those who are pharmacoresistant. This group, comprising about a third of patients with epilepsy, is badly characterised. In many cases, we do not know the phenotype (ie, the epilepsy is of unknown cause or cryptogenic), nor do we know the degree of pharmacoresistance (which might be slight or amount to no response at all). How can we create models when the epilepsy type with which we are dealing is an unknown? Glauser’s study on childhood absence epilepsy has shown that identification of the epilepsy phenotype can provide answers in treatment trials and www.thelancet.com/neurology Vol 13 September 2014
Comment
can help to clearly differentiate between anticonvulsive drugs.9 Research has shown that translation in epilepsy is a difficult enterprise with possibly only limited success. Why not attempt a top-down approach by first solving problems on the clinical side? There are many problems to address. Restriction of studies to a specific phenotype might show higher efficacies for certain anticonvulsive drugs than do the present results. The use of surgical candidates for testing of pharmacoresistance before and after surgery to investigate the cause of the pharmacoresistance in the resected brain tissue might be another way in which to provide a basis for translation. Nothing, however, will lead to clinically relevant information until we have solved the major problem: the documentation of epileptic seizures by patients. Results of studies done during inpatient recordings, and of studies undertaken on an outpatient basis, have shown that objective and subjective data differ at a dimension that should be deemed intolerable for use in serious scientific studies.10,11 If objective seizure documentation is not possible, then new study designs must be developed. It was time to balance the challenges and promises of translational research in epilepsy, and this has been done by Simonato and colleagues.1 However, in my opinion, epilepsy is momentarily lost in translation. The coming years will show whether or not the many challenges—not least the complexity of epilepsy—can be overcome. Simonato and colleagues summarise important recommendations for epilepsy therapy development in animal models, but new concepts in
translational research are urgently needed to meet the needs of people with epilepsy. Christian E Elger Department of Epileptology, University of Bonn Medical Centre, Sigmund-Freud-Str. 25, 53105 Bonn, Germany [email protected] I declare no competing interests. I have received speakers’ honoraria from Bial, Eisai, Novartis, Pfizer, Desitin, and UCB. 1
2 3
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6
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Simonato M, Brooks-Kayal AR, Engel J Jr, et al. The challenge and promise of epilepsy therapy development in animal models. Lancet Neurology 2014; published online Augst 11. http://dx.doi.org/10.1016/ S14744422(14)70076-6 Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55: 47–82. Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ, for the Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007; 68: 402–08. Baulac M, Brodie MJ, Patten A, Segieth J, Giorgi L. Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol 2012; 11: 579–88. Costa J, Fareleira F, Ascencão R, Borges M, Sampaio C, Vaz-Carneiro A. Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis. Epilepsia 2011; 52: 1280–91. Glauser T, Ben-Menachem E, Bourgeois B, et al, for the ILAE Subcommission on AED Guidelines. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2014; 54: 551–63. Salazar AM, Jabbari B, Vance SC, Grafman J, Amin D, Dillon JD. Epilepsy after penetrating head injury. I. Clinical correlates: a report of the Vietnam Head Injury Study. Neurology 1985; 35: 1406–14. Lewis DV, Shinnar S, Hesdorffer DC, et al, for the FEBSTAT Study Team. Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study. Ann Neurol 2014; 75: 178–85. Glauser TA, Cnaan A, Shinnar S, et al, Childhood Absence Epilepsy Study Group. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 2010; 362: 790–99. Hoppe C, Poepel A, Elger CE. Epilepsy: accuracy of patient seizure counts. Arch Neurol 2007; 64: 1595–99. Cook MJ, O‘Brien TJ, Berkovic SF, et al. Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drugresistant epilepsy: a first-in-man study. Lancet Neurol 2013; 12: 563–71.
Corrections Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale at 40 years: standing the test of time. Lancet Neurol 2014; 13: 844–54—In this Personal View, the acknowledgment to “Alan Clark (Chandler Trauma and Acute Care Surgery, AZ,USA)” should have read “Alan Cook (Chandler Trauma and Acute Care Surgery, AZ, USA)”. This correction has been made to the online version as of August 18.
www.thelancet.com/neurology Vol 13 September 2014
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Van Dongen HP, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003; 26: 117–26. Schmid SM, Hallschmid M, Schultes B. The metabolic burden of sleep loss. Lancet Diabetes Endocrinol 2014; published online March 25. http://dx.doi. org/10.1016/S2213-8587(14)70012-9. National Aeronautics and Space Administration (NASA). Operational ground testing protocol to optimize astronaut sleep medication efficacy and individual effects (Sleep_Meds_Phase_II). July 15, 2014. http://lsda.jsc.nasa. gov/scripts/experiment/exper.aspx?exp_index=2104 (accessed Aug 1, 2014). Mader TH, Gibson CR, Pass AF, et al. Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after longduration space flight. Ophthalmology 2011; 118: 2058–69. Basner M, Dinges DF, Mollicone D, et al. Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing. Proc Natl Acad Sci USA 2013; 110: 2635–40.
7
8 9
10
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Basner M, Dinges DF, Mollicone DJ, et al. Psychological and behavioral changes during confinement in a 520-day simulated interplanetary mission to mars. PLoS One 2014; 9: e93298. Arendt J. Biological rhythms during residence in polar regions. Chronobiol Int 2012; 29: 379–94. Barger LK, Sullivan JP, Vincent AS, et al. Learning to live on a Mars day: fatigue countermeasures during the Phoenix Mars Lander mission. Sleep 2012; 35: 1423–35. Basner M, Mollicone DJ, Dinges DF. Validity and sensitivity of a brief Psychomotor Vigilance Test (PVT-B) to total and partial sleep deprivation. Acta Astronautica 2011; 69: 949–59. NASA. Psychomotor Vigilance Test (PVT) on ISS (Reaction). July 15, 2014. http://lsda.jsc.nasa.gov/scripts/experiment/exper.aspx?exp_index=1490 (accessed Aug 1, 2014).
Epilepsy: lost in translation Published Online August 11, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70125-5 See Personal View page 949
862
The Personal View by Simonato and colleagues1 was overdue, but it falls short of what is needed. Is epilepsy truly a disorder that can be easily defined? Epilepsy is a brain state characterised by its ability to generate seizures more easily than can a healthy brain.2 Thus, in contrast to many other diseases, epilepsy is characterised by a symptom—the epileptic seizure—which can be viewed as the common denominator for the various types of epilepsy. As such, epilepsy cannot be compared with other neurological disorders that have shown good progress by improvements in translational research, such as multiple sclerosis. Moreover, although seizures and epilepsies in animals can be generated easily and many models of epilepsy exist, their relevance for human epilepsies is open to question. Epilepsy has two facets: first, the seizure symptom; and second, the cause or process leading to epilepsy as a chronic state (the epileptogenicity) of the brain. Epilepsies are treated primarily with anticonvulsive drugs, which are ineffective in about a third of cases. Generally, all the years of translational research have resulted in little progress in terms of efficacy. In focal epilepsies, results of controlled, blinded studies have not shown superiority of monotherapy compared with the old standby carbamazepine.3,4 And when high-quality studies are taken into account for the add-on design, efficacy is lost with the newer anticonvulsive drugs because of an increase in the placebo response.5,6 Disease-modifying therapy (the prevention of an epilepsy after an initial, potentially epileptogenic hit) is an important concept, but with only a small amount
of experimental background and no real measure of whether this type of therapy can be proven to work in humans. The use of experimental post-traumatic epilepsy as a model for a disease-modifying therapy ignores two facts for translation: the complexity of human posttraumatic epilepsy and efforts to reduce its incidence; and Andres Salazar’s experience in Vietnam veterans, who were often uncompliant for preventive therapy but compliant for a therapy after the first seizure.7 The search for biomarkers to predict a developing epilepsy is intense. The MRI screening of all children with febrile convulsions to identify those at risk is not only an economic challenge but also an ethical one, because children need to be anaesthetised for many MRI scans over the years.8 Additionally, power calculations will show the immense logistical effort necessary to establish whether or not one substance is anti-epileptogenic (or disease-modifying). When selecting and using epilepsy models, one must ask for which group of epilepsy patients do we want to provide better treatment? The answer should be those who are pharmacoresistant. This group, comprising about a third of patients with epilepsy, is badly characterised. In many cases, we do not know the phenotype (ie, the epilepsy is of unknown cause or cryptogenic), nor do we know the degree of pharmacoresistance (which might be slight or amount to no response at all). How can we create models when the epilepsy type with which we are dealing is an unknown? Glauser’s study on childhood absence epilepsy has shown that identification of the epilepsy phenotype can provide answers in treatment trials and www.thelancet.com/neurology Vol 13 September 2014
Comment
can help to clearly differentiate between anticonvulsive drugs.9 Research has shown that translation in epilepsy is a difficult enterprise with possibly only limited success. Why not attempt a top-down approach by first solving problems on the clinical side? There are many problems to address. Restriction of studies to a specific phenotype might show higher efficacies for certain anticonvulsive drugs than do the present results. The use of surgical candidates for testing of pharmacoresistance before and after surgery to investigate the cause of the pharmacoresistance in the resected brain tissue might be another way in which to provide a basis for translation. Nothing, however, will lead to clinically relevant information until we have solved the major problem: the documentation of epileptic seizures by patients. Results of studies done during inpatient recordings, and of studies undertaken on an outpatient basis, have shown that objective and subjective data differ at a dimension that should be deemed intolerable for use in serious scientific studies.10,11 If objective seizure documentation is not possible, then new study designs must be developed. It was time to balance the challenges and promises of translational research in epilepsy, and this has been done by Simonato and colleagues.1 However, in my opinion, epilepsy is momentarily lost in translation. The coming years will show whether or not the many challenges—not least the complexity of epilepsy—can be overcome. Simonato and colleagues summarise important recommendations for epilepsy therapy development in animal models, but new concepts in
translational research are urgently needed to meet the needs of people with epilepsy. Christian E Elger Department of Epileptology, University of Bonn Medical Centre, Sigmund-Freud-Str. 25, 53105 Bonn, Germany [email protected] I declare no competing interests. I have received speakers’ honoraria from Bial, Eisai, Novartis, Pfizer, Desitin, and UCB. 1
2 3
4
5
6
7
8
9
10 11
Simonato M, Brooks-Kayal AR, Engel J Jr, et al. The challenge and promise of epilepsy therapy development in animal models. Lancet Neurology 2014; published online Augst 11. http://dx.doi.org/10.1016/ S14744422(14)70076-6 Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55: 47–82. Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ, for the Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007; 68: 402–08. Baulac M, Brodie MJ, Patten A, Segieth J, Giorgi L. Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol 2012; 11: 579–88. Costa J, Fareleira F, Ascencão R, Borges M, Sampaio C, Vaz-Carneiro A. Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis. Epilepsia 2011; 52: 1280–91. Glauser T, Ben-Menachem E, Bourgeois B, et al, for the ILAE Subcommission on AED Guidelines. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2014; 54: 551–63. Salazar AM, Jabbari B, Vance SC, Grafman J, Amin D, Dillon JD. Epilepsy after penetrating head injury. I. Clinical correlates: a report of the Vietnam Head Injury Study. Neurology 1985; 35: 1406–14. Lewis DV, Shinnar S, Hesdorffer DC, et al, for the FEBSTAT Study Team. Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study. Ann Neurol 2014; 75: 178–85. Glauser TA, Cnaan A, Shinnar S, et al, Childhood Absence Epilepsy Study Group. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 2010; 362: 790–99. Hoppe C, Poepel A, Elger CE. Epilepsy: accuracy of patient seizure counts. Arch Neurol 2007; 64: 1595–99. Cook MJ, O‘Brien TJ, Berkovic SF, et al. Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drugresistant epilepsy: a first-in-man study. Lancet Neurol 2013; 12: 563–71.
Corrections Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale at 40 years: standing the test of time. Lancet Neurol 2014; 13: 844–54—In this Personal View, the acknowledgment to “Alan Clark (Chandler Trauma and Acute Care Surgery, AZ,USA)” should have read “Alan Cook (Chandler Trauma and Acute Care Surgery, AZ, USA)”. This correction has been made to the online version as of August 18.
www.thelancet.com/neurology Vol 13 September 2014
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