Antiepileptogenesis in Humans: Ways to Move Forward
Antiepileptogenesis in Humans: Ways to Move Forward
It is widely acknowledged that there is an unmet need for antiepileptogenic and disease-modifying drugs. Scientists should avoid the rather nihilistic view that our methodologies are invalid and they cannot identify antiepileptogenic drugs in the future, or more than that, even if we discover an antiepileptogenic drug, seizure prevention trials would be not feasible to perform. Conversely, the scientific community, comprising basic and clinical scientists, should strive to initiate and foster collaborative actions to improve preclinical methodology, validation of biomarkers, and design new antiepileptogenic trials in humans.
Specific antiepileptogenic drugs are needed. Our current approach uses three pathways: kindling models, status epilepticus induced recurrent seizures, and genetic rodent models of epileptogenesis. However, our current animal models of epileptogenesis might not be relevant in humans, in particular kindling, but also status epilepticus that only occurs in a minority of first epileptic events. It may be an oversimplification to conceptualize epileptogenesis as a similarly linear process across all epilepsy syndromes. The epileptogenic process is likely to differ according to cause and also between individuals with the same type of brain insult and epilepsy syndrome. This target-driven approach has already led to remarkable successes in translational research. The mammalian mTOR signalling pathway has been identified to play a crucial role, not only in seizures associated with tuberous sclerosis but also with focal cortical dysplasia. Currently, the clinical use of rapamycin and its analogue everolimus, both mTOR inhibitors, for preventing epilepsy in patients with tuberous sclerosis are being evaluated with promising success. Other promising antiepileptogenic targets include cation–chloride co-transporters and inflammatory pathways, for which there is mounting evidence that they play a key role in epileptogenesis (for review see), but again translation into the clinical field remains far from easy, as the premature arrest of an investigational trial using VX-765, an interleukin conversion enzyme inhibitor has taught us. To succeed sustainably in this field, key features for a preclinical antiepileptogenesis monotherapy trial in adult rodents have been developed, and should be put in place soon to identify potential antiepileptogenic drugs earlier. Finally, a syndrome and cause-specific approach is needed to better tackle the diversity of causes involved in epileptogenesis.
Prevention trials are more complex, lengthy, and thus more expensive than usual drug trials in the epilepsy field. Irrespective at which point of epileptogenesis the trial aims to interfere (Fig. 2), the conceptual challenges are as high as the logistic demands to fulfil such a trial. As elegantly pointed out by Schmidt, 'any trial designated to evaluate treatments that could prevent epileptogenesis have to meet two essential requirements. First, the design should include a randomised treatment phase versus a control, usually placebo, to assess antiseizure effects, […] and second, very importantly, a study of antiepileptogenic effect after washout.' Otherwise, it would not be possible to disentangle the antiseizure effect of a drug from its antiepileptogenic effect. In addition, it has to be acknowledged that prevention trials are more complex, lengthy, and thus more expensive than usual drug trials in the epilepsy field. Mani et al. as well as Schmidt [16] suggested elements of optimal trial design for successful antiepileptogenic treatment. The key points are as follows: selection of the population, preferably enriched by the use of validated powerful biomarkers; careful examination of competing risk factors for the development of epilepsy in the target population; allowance for rapid informed consent, surrogate informed consent and waiver for informed consent (the latter only applicable outside of Europe); careful choice of the investigational agent, considering also routes of administration in the emergency setting, the timing of initiation of treatment (therapeutic window), multiple arms (including placebo), long observation period after epileptogenesis intervention phase has ended (ideally 5 years or more), adequate sample size and powering; and careful selection of the outcome parameters, with additional outcomes selected to assess an anticomorbidity effect of the investigational drug (for details see). Finally, an improvement in trial design, with studies aimed to specifically assess epileptic syndromes and cause, is warranted, as well as specific biomarkers to identify persons at risk after an insult or in genetic epilepsies.
(Enlarge Image)
Figure 2.
Schematic diagram representing opportunities for antiepileptogenic treatments in different causes. ICH, intracerebral haemorrhage; TBI, traumatic brain injury. Modified with permission [3].
In face of the long trial duration and the large number of patients needed to include in an antiepileptogenesis trial, development and validation of powerful biomarkers are needed. They should be able to predict the development of epilepsy after a brain insult or within a genetic epilepsy syndrome (epileptogenesis), but should also be able to reliably predict the seizure propensity, severity, and associated comorbidities. Powerful biomarkers would allow enrichment of the study population, and could therefore dramatically reduce the costs of an antiepileptogenesis trial. The spectrum of biomarkers for epilepsy is currently wide and ranges from neurophysiological markers such as interictal spikes, high frequency oscillations, and transcranial magnetic stimulation measures to neuroimaging parameters such as diffusion tensor imaging, functional MRI, MRI spectroscopy, PET, or single-photon emission computed tomography with various markers such as fluorodesoxyglucose, alpha-methyl-tryptophan, or translocator protein (for review see). However, the development of biomarkers is a painstaking process that encompasses three phases: Phase I (discovery) with proof-of-concept-studies using in-vivo models, Phase II (validation) in humans to reliably stratify patient groups, and finally Phase III (translation) including the definition of minimal requirements for an experiment that is needed to translate the biomarker from preclinical to clinical use in humans.
Thus, there is a promising outlook that a joint effort between clinical and basic scientists, as well as academia and industry, will be able to succeed in the quest for a truly antiepileptogenic drug in the near future.
Conclusion
It is widely acknowledged that there is an unmet need for antiepileptogenic and disease-modifying drugs. Scientists should avoid the rather nihilistic view that our methodologies are invalid and they cannot identify antiepileptogenic drugs in the future, or more than that, even if we discover an antiepileptogenic drug, seizure prevention trials would be not feasible to perform. Conversely, the scientific community, comprising basic and clinical scientists, should strive to initiate and foster collaborative actions to improve preclinical methodology, validation of biomarkers, and design new antiepileptogenic trials in humans.
Specific antiepileptogenic drugs are needed. Our current approach uses three pathways: kindling models, status epilepticus induced recurrent seizures, and genetic rodent models of epileptogenesis. However, our current animal models of epileptogenesis might not be relevant in humans, in particular kindling, but also status epilepticus that only occurs in a minority of first epileptic events. It may be an oversimplification to conceptualize epileptogenesis as a similarly linear process across all epilepsy syndromes. The epileptogenic process is likely to differ according to cause and also between individuals with the same type of brain insult and epilepsy syndrome. This target-driven approach has already led to remarkable successes in translational research. The mammalian mTOR signalling pathway has been identified to play a crucial role, not only in seizures associated with tuberous sclerosis but also with focal cortical dysplasia. Currently, the clinical use of rapamycin and its analogue everolimus, both mTOR inhibitors, for preventing epilepsy in patients with tuberous sclerosis are being evaluated with promising success. Other promising antiepileptogenic targets include cation–chloride co-transporters and inflammatory pathways, for which there is mounting evidence that they play a key role in epileptogenesis (for review see), but again translation into the clinical field remains far from easy, as the premature arrest of an investigational trial using VX-765, an interleukin conversion enzyme inhibitor has taught us. To succeed sustainably in this field, key features for a preclinical antiepileptogenesis monotherapy trial in adult rodents have been developed, and should be put in place soon to identify potential antiepileptogenic drugs earlier. Finally, a syndrome and cause-specific approach is needed to better tackle the diversity of causes involved in epileptogenesis.
Specific Antiepileptogenic Trials are Needed
Prevention trials are more complex, lengthy, and thus more expensive than usual drug trials in the epilepsy field. Irrespective at which point of epileptogenesis the trial aims to interfere (Fig. 2), the conceptual challenges are as high as the logistic demands to fulfil such a trial. As elegantly pointed out by Schmidt, 'any trial designated to evaluate treatments that could prevent epileptogenesis have to meet two essential requirements. First, the design should include a randomised treatment phase versus a control, usually placebo, to assess antiseizure effects, […] and second, very importantly, a study of antiepileptogenic effect after washout.' Otherwise, it would not be possible to disentangle the antiseizure effect of a drug from its antiepileptogenic effect. In addition, it has to be acknowledged that prevention trials are more complex, lengthy, and thus more expensive than usual drug trials in the epilepsy field. Mani et al. as well as Schmidt [16] suggested elements of optimal trial design for successful antiepileptogenic treatment. The key points are as follows: selection of the population, preferably enriched by the use of validated powerful biomarkers; careful examination of competing risk factors for the development of epilepsy in the target population; allowance for rapid informed consent, surrogate informed consent and waiver for informed consent (the latter only applicable outside of Europe); careful choice of the investigational agent, considering also routes of administration in the emergency setting, the timing of initiation of treatment (therapeutic window), multiple arms (including placebo), long observation period after epileptogenesis intervention phase has ended (ideally 5 years or more), adequate sample size and powering; and careful selection of the outcome parameters, with additional outcomes selected to assess an anticomorbidity effect of the investigational drug (for details see). Finally, an improvement in trial design, with studies aimed to specifically assess epileptic syndromes and cause, is warranted, as well as specific biomarkers to identify persons at risk after an insult or in genetic epilepsies.
(Enlarge Image)
Figure 2.
Schematic diagram representing opportunities for antiepileptogenic treatments in different causes. ICH, intracerebral haemorrhage; TBI, traumatic brain injury. Modified with permission [3].
Specific Biomarkers are Needed
In face of the long trial duration and the large number of patients needed to include in an antiepileptogenesis trial, development and validation of powerful biomarkers are needed. They should be able to predict the development of epilepsy after a brain insult or within a genetic epilepsy syndrome (epileptogenesis), but should also be able to reliably predict the seizure propensity, severity, and associated comorbidities. Powerful biomarkers would allow enrichment of the study population, and could therefore dramatically reduce the costs of an antiepileptogenesis trial. The spectrum of biomarkers for epilepsy is currently wide and ranges from neurophysiological markers such as interictal spikes, high frequency oscillations, and transcranial magnetic stimulation measures to neuroimaging parameters such as diffusion tensor imaging, functional MRI, MRI spectroscopy, PET, or single-photon emission computed tomography with various markers such as fluorodesoxyglucose, alpha-methyl-tryptophan, or translocator protein (for review see). However, the development of biomarkers is a painstaking process that encompasses three phases: Phase I (discovery) with proof-of-concept-studies using in-vivo models, Phase II (validation) in humans to reliably stratify patient groups, and finally Phase III (translation) including the definition of minimal requirements for an experiment that is needed to translate the biomarker from preclinical to clinical use in humans.
Thus, there is a promising outlook that a joint effort between clinical and basic scientists, as well as academia and industry, will be able to succeed in the quest for a truly antiepileptogenic drug in the near future.
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