Epilepsy has traditionally been discussed as an electrical disorder of the brain and due to underlying disorders of ion channel function and neurotransmitters, both of which contribute to the imbalance of excitatory and inhibitory neural activity. Consequently, treatments address this by suppressing abnormal electrical discharges or by surgical removal, isolation or modulation. While these techniques work for most affected individuals, epilepsy is often refractory and is sometimes a progressive disorder.
Many different conditions can lead to epileptic seizures. Increasing evidence suggests that comorbidities, in particular mental health disorders, also influence seizure control and quality of life. This raises important questions about shared underlying mechanisms. The increasing prevalence of epilepsy with aging also suggests shared mechanisms, usually ascribed to the known higher prevalence of common age-related brain health issues including stroke, tumor and neurodegeneration.
A key shared mechanism for these issues is mitochondrial dysfunction.Reference Patel1–Reference Andreazza, Kauer-Sant’Anna and Frey3 Thus, the frequently observed co-association of these and other age-associated comorbidities such as cardiovascular disorders (this latter also associated with cerebrovascular disease) may represent the shared impact of mitochondrial dysfunction. Neurons need a steady supply of adenosine triphosphate (ATP) to maintain ion gradients and to balance excitatory and inhibitory neurotransmission. When energy production falters (e.g., due to mitochondrial dysfunction), ATP production drops, reactive oxygen species (ROS) rise and neurons dysfunction, including in the context of epilepsy, becoming hyperexcitable. These metabolic imbalances also trigger neuroinflammatory pathways, amplifying seizure susceptibility. It is insightful mechanistically that a metabolic intervention, the ketogenic diet, a treatment that does not impact electrical aberrations directly but stabilizes neuronal energetics, can reduce epileptic activity in patients who are resistant to conventional ion channel/neurotransmitter agents. Furthermore, when measuring brain energy metabolism in focal epilepsy, epileptogenic tissue demonstrates significantly decreased metabolism and energy consumption, except when a seizure occurs.
We therefore view epilepsy as, in part, a condition of failing energy metabolism, in which an epileptic seizure can also be aggravated by, and contribute to, mitochondrial dysmetabolism.Reference Patel4 Thus, conceivably, the slow progressive deterioration in mitochondrial function seen with aging may underlie the accompanying increased epilepsy risk.
If so, it is appropriate to consider whether strategies that improve mitochondrial function could mitigate both the progressive age-related cerebral deterioration and epilepsy. We recently conducted a literature review of animal studies and human trials examining the role of antioxidants in treating epilepsy. Preclinical results suggest that oxidative stress and mitochondrial dysfunction play important roles in the pathophysiology of epilepsy, contributing to neuronal hyperexcitability and cell death. Additionally, preclinical studies provide evidence that antioxidant therapies can mitigate these pathological processes, reducing seizure activity and protecting neuronal integrity. There are also currently 13 human clinical trials registered on ClinicalTrials.gov evaluating the efficacy and safety of various antioxidant and potentially mitochondrial-protective therapies in epilepsy. Agents being studied include melatonin, vitamin E, zinc, selenium, idebenone, celecoxib, pentoxifylline, N-acetylcysteine and a low-glutamate diet.Reference Ji, Mylvaganam, Ravi Chander, Tarnopolsky, Murphy and Carlen5
Discussion
At a global level, infectious disease, malnutrition and environmental toxins from poverty and under-resourcing likely impose additional burdens on mitochondrial health. Also directly related to poverty, the unavoidable use of older, cheaper anti-seizure medications (ASMs) such as valproic acid and phenytoin has known negative effects on mitochondrial function.
As technologies advance beyond ASMs and surgery, costs of epilepsy care will likely increase, and as the focus evolves to precision medicine, paradoxically, population-based preventative strategies will become increasingly important. While epilepsy prevention has usually been addressed by improving perinatal health, reducing communicable and noncommunicable diseases and reducing brain trauma, alcohol and substance abuse, in practice, these are difficult to do when inadequate resources limit infrastructural improvement. Prevention becomes even more urgent given the progressive aging of the global population, whose growth is now mainly in the developing world.
Thus, improving and preserving mitochondrial health may be a cheaper global strategy for broad-based trajectory-altering epilepsy prevention and care. Most forms of epilepsy in under-resourced environments are focal and acquired. While addressing established risk factors must continue as part of any preventative strategy, broad-based treatments that can be used by all persons with epilepsy (PWE) would provide an important additional mechanism to address large epilepsy treatment gaps in these settings.
Recent studies have also reported significant alterations in the gut microbiome of both epilepsy patients and aging individuals.Reference Zachos, Gamboa, Dewji, Lee, Brijbassi and Andreazza6 Modifying the gut microbiome in animal models as well as in PWE has been shown to reduce seizure burden. Preclinical work has shown evidence of mitochondria-microbiome bidirectional crosstalk.Reference Zachos, Gamboa, Dewji, Lee, Brijbassi and Andreazza6 Hence, improving gut health could have significant positive impacts on mitochondrial function and might mitigate the subsequent development of multiple age-related comorbidities. The deleterious impact of ultra-processed foods on mitochondrial health and the growing consumption of such foods in the developing world also brings into focus the need for paying close attention to healthy diets and the gut microbiome as part of broader preventative strategies. Indeed, poverty itself, through multiple mechanisms including inadequate diet, chronic infections and stress, may be a pathway to gut dysbiosis and subsequent negative impacts on mitochondrial health.
Thus, mitochondrial health interventions should begin at least in the early-middle years of life, not only with lifestyle preventative strategies such as exercise and good diet but also with direct strategies to improve mitochondrial health. Therapeutic options include a wide range of antioxidants, nutritional supplements including creatine and L-carnitine, energy metabolism modulators such as magnesium and biogenesis activators such as resveratrol and berberine. We have previously shown that adding oral magnesium (which has both effects of depressing neuronal excitability directly and also metabolic and antioxidant properties) to the treatment of intractable epilepsy patients was associated with marked anti-seizure efficacy in some patients.Reference Abdelmalik, Politzer and Carlen7 As these strategies in general have low risk and are mostly naturally derived and not costly, the likelihood of patient acceptability and patient safety is high. This is very important, given the marked variability in regulatory protection in many under-resourced environments.
Conclusion
Current mitochondrial therapies may have their biggest impact as a preventative strategy for treating epilepsy and are cheap enough to be used by millions, especially when locally available, unlike the usual scenario of new ASMs being only affordable and accessible to a very few. These therapies, including the ketogenic diet, which has been successfully implemented in many lower- and middle-income countries (LMICs), by simultaneously addressing multiple comorbidities and aging, are therefore potentially of significant impact when measured in terms of quality of life, disability adjusted life years and cost.
With the increasing global burden of epilepsy, particularly in resource-limited settings, action is required to explore and implement mitochondrial-targeted therapies as both preventative and therapeutic strategies, particularly in the rapidly expanding aging population. Urgently needed are large-scale clinical trials to assess the long-term efficacy and safety of mitochondrial-targeted interventions, including antioxidants, metabolic modulators and gut microbiome therapies. Collaborations between neuroscientists, mitochondrial researchers and public health experts should be prioritized to develop evidence-based protocols.
From the perspective of public health and policy, as evidence builds of their efficacy and safety, governments and global health organizations could cooperate to integrate mitochondrial health strategies into national epilepsy prevention programs, especially in low-resource settings where conventional epilepsy care remains inaccessible, perpetuating long-standing treatment gaps. Global health disparities often revolve around a paucity of financial and human resources, reluctance to take conventional ASMs, side effects of older ASMs, cost of diagnosis and treatment and the economic impacts, direct and indirect, of living with a highly stigmatized condition. Indeed, the acceptability of natural products is usually much better than that of synthetic medicines in LMICs. In addition, using indigenous natural products that are shown to be supportive of mitochondrial function may make such culturally customized strategies more acceptable, cost-effective and therefore, locally sustainable.
At its most reductive, these cellular energy concerns are strongly reminiscent of the well-understood and better-known global concern about energy shortage and its impact on human viability as a species. Perhaps the time has also come for the fundamental issue of cellular energy (ATP) supply and toxic waste (ROS) accumulation to be viewed with similar existential urgency.
There will inevitably be challenges in implementing mitochondrial-targeted interventions on a large scale. While there are several ways to generate patentable intellectual property, natural products are often difficult to monetize, providing lower incentives for the supply chain and distributors. Unlike ASMs, which may stop seizures quite quickly, mitochondrial therapies will be more gradual in effect, requiring sustained use to obtain maximal benefits. Longitudinal cost-benefit analyses will have to be done by each jurisdiction.
Cost-effectiveness of a new range of therapies as proposed must be considered not only against the cost of existing treatments in each jurisdiction but also the cost to external multilateral funding agencies at a regional and global level, as well as the favorable medium- and long-term economic impact of disease modification vs essentially symptomatic conventional treatments. Similarly, it is the remit of key stakeholders, including regulatory agencies and policymakers at national and global levels including institutions such as the World Health Organization, to objectively review preclinical and clinical data as well as post-release real-world data generated in this new area of deployment, brain health, despite many already having been safely used in other indications. For example, the antioxidant Coenzyme Q-10, which may reduce seizure duration in specific animal models, has been used for decades for improving cardiovascular health.Reference Ji, Mylvaganam, Ravi Chander, Tarnopolsky, Murphy and Carlen5
At a national level, practical policy solutions could eventually include the placement of mitochondrial therapies on essential medicines lists, allowing governments to assist patients through subsidies, having pilot programs of subsidized mitochondrial therapies for epilepsy care before more broad-based availability, supporting local manufacture and distribution for cost-containment, and increasing supply-chain reliability.
As some agencies retreat from long-standing roles of supporting healthcare in under-resourced environments, countries like Canada, with strong biomedical research infrastructures, should take the lead in fostering partnerships for natural product research, equitable drug discovery and knowledge-sharing with developing nations. The integration of AI and biomarker-driven diagnostics to stratify patients based on mitochondrial function could lead to more personalized and efficient epilepsy management. Indeed, investments in precision mitochondrial medicine may not only improve epilepsy outcomes but could also revolutionize broader neurodegenerative disease prevention.
At the very least, mitochondrial dysfunction appears to be a compounding factor in the often progressive nature of epilepsy and other neurological disorders. Intervening early could modify this trajectory, to the benefit of untold millions with few options. It may also further improve epilepsy outcomes and quality of life for patients fortunate enough to be able to access the full range of conventional therapies in the developed world. To be clear, mitochondrial therapies would not, on present evidence, be used instead of ASMs for epilepsy but, like the ketogenic diet when used with ASMs in refractory epilepsies, would be better deployed as adjunctive agents, slowing progression and ameliorating the epilepsy syndrome. The same principle applies to the treatment of mental health comorbidities like depression, which also require the use of established first-line agents, including ASMs such as lamotrigine.
In modifying the aging process and comorbidities such as depression, which share pathophysiological mechanisms of oxidative stress, energy deficit and neuroinflammation, mitochondrial therapies would synergistically and simultaneously have multiple beneficial neuroprotective effects. Large-scale randomized controlled trials of mitochondrial therapies will be necessary before these agents can become first-line treatments. This rigor is particularly essential if global deployment is intended in areas where oversight and supportive resources may be lacking.
Addressing mitochondrial dysfunction could be a transformative, low-cost and globally scalable strategy to improve brain health and quality of life. Future research, policy and clinical implementation should now align if mitochondrial therapies are to become an evidence-driven part of epilepsy prevention and care, worldwide.
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Epilepsy has traditionally been discussed as an electrical disorder of the brain and due to underlying disorders of ion channel function and neurotransmitters, both of which contribute to the imbalance of excitatory and inhibitory neural activity. Consequently, treatments address this by suppressing abnormal electrical discharges or by surgical removal, isolation or modulation. While these techniques work for most affected individuals, epilepsy is often refractory and is sometimes a progressive disorder.
Many different conditions can lead to epileptic seizures. Increasing evidence suggests that comorbidities, in particular mental health disorders, also influence seizure control and quality of life. This raises important questions about shared underlying mechanisms. The increasing prevalence of epilepsy with aging also suggests shared mechanisms, usually ascribed to the known higher prevalence of common age-related brain health issues including stroke, tumor and neurodegeneration.
A key shared mechanism for these issues is mitochondrial dysfunction.Reference Patel1–Reference Andreazza, Kauer-Sant’Anna and Frey3 Thus, the frequently observed co-association of these and other age-associated comorbidities such as cardiovascular disorders (this latter also associated with cerebrovascular disease) may represent the shared impact of mitochondrial dysfunction. Neurons need a steady supply of adenosine triphosphate (ATP) to maintain ion gradients and to balance excitatory and inhibitory neurotransmission. When energy production falters (e.g., due to mitochondrial dysfunction), ATP production drops, reactive oxygen species (ROS) rise and neurons dysfunction, including in the context of epilepsy, becoming hyperexcitable. These metabolic imbalances also trigger neuroinflammatory pathways, amplifying seizure susceptibility. It is insightful mechanistically that a metabolic intervention, the ketogenic diet, a treatment that does not impact electrical aberrations directly but stabilizes neuronal energetics, can reduce epileptic activity in patients who are resistant to conventional ion channel/neurotransmitter agents. Furthermore, when measuring brain energy metabolism in focal epilepsy, epileptogenic tissue demonstrates significantly decreased metabolism and energy consumption, except when a seizure occurs.
We therefore view epilepsy as, in part, a condition of failing energy metabolism, in which an epileptic seizure can also be aggravated by, and contribute to, mitochondrial dysmetabolism.Reference Patel4 Thus, conceivably, the slow progressive deterioration in mitochondrial function seen with aging may underlie the accompanying increased epilepsy risk.
If so, it is appropriate to consider whether strategies that improve mitochondrial function could mitigate both the progressive age-related cerebral deterioration and epilepsy. We recently conducted a literature review of animal studies and human trials examining the role of antioxidants in treating epilepsy. Preclinical results suggest that oxidative stress and mitochondrial dysfunction play important roles in the pathophysiology of epilepsy, contributing to neuronal hyperexcitability and cell death. Additionally, preclinical studies provide evidence that antioxidant therapies can mitigate these pathological processes, reducing seizure activity and protecting neuronal integrity. There are also currently 13 human clinical trials registered on ClinicalTrials.gov evaluating the efficacy and safety of various antioxidant and potentially mitochondrial-protective therapies in epilepsy. Agents being studied include melatonin, vitamin E, zinc, selenium, idebenone, celecoxib, pentoxifylline, N-acetylcysteine and a low-glutamate diet.Reference Ji, Mylvaganam, Ravi Chander, Tarnopolsky, Murphy and Carlen5
Discussion
At a global level, infectious disease, malnutrition and environmental toxins from poverty and under-resourcing likely impose additional burdens on mitochondrial health. Also directly related to poverty, the unavoidable use of older, cheaper anti-seizure medications (ASMs) such as valproic acid and phenytoin has known negative effects on mitochondrial function.
As technologies advance beyond ASMs and surgery, costs of epilepsy care will likely increase, and as the focus evolves to precision medicine, paradoxically, population-based preventative strategies will become increasingly important. While epilepsy prevention has usually been addressed by improving perinatal health, reducing communicable and noncommunicable diseases and reducing brain trauma, alcohol and substance abuse, in practice, these are difficult to do when inadequate resources limit infrastructural improvement. Prevention becomes even more urgent given the progressive aging of the global population, whose growth is now mainly in the developing world.
Thus, improving and preserving mitochondrial health may be a cheaper global strategy for broad-based trajectory-altering epilepsy prevention and care. Most forms of epilepsy in under-resourced environments are focal and acquired. While addressing established risk factors must continue as part of any preventative strategy, broad-based treatments that can be used by all persons with epilepsy (PWE) would provide an important additional mechanism to address large epilepsy treatment gaps in these settings.
Recent studies have also reported significant alterations in the gut microbiome of both epilepsy patients and aging individuals.Reference Zachos, Gamboa, Dewji, Lee, Brijbassi and Andreazza6 Modifying the gut microbiome in animal models as well as in PWE has been shown to reduce seizure burden. Preclinical work has shown evidence of mitochondria-microbiome bidirectional crosstalk.Reference Zachos, Gamboa, Dewji, Lee, Brijbassi and Andreazza6 Hence, improving gut health could have significant positive impacts on mitochondrial function and might mitigate the subsequent development of multiple age-related comorbidities. The deleterious impact of ultra-processed foods on mitochondrial health and the growing consumption of such foods in the developing world also brings into focus the need for paying close attention to healthy diets and the gut microbiome as part of broader preventative strategies. Indeed, poverty itself, through multiple mechanisms including inadequate diet, chronic infections and stress, may be a pathway to gut dysbiosis and subsequent negative impacts on mitochondrial health.
Thus, mitochondrial health interventions should begin at least in the early-middle years of life, not only with lifestyle preventative strategies such as exercise and good diet but also with direct strategies to improve mitochondrial health. Therapeutic options include a wide range of antioxidants, nutritional supplements including creatine and L-carnitine, energy metabolism modulators such as magnesium and biogenesis activators such as resveratrol and berberine. We have previously shown that adding oral magnesium (which has both effects of depressing neuronal excitability directly and also metabolic and antioxidant properties) to the treatment of intractable epilepsy patients was associated with marked anti-seizure efficacy in some patients.Reference Abdelmalik, Politzer and Carlen7 As these strategies in general have low risk and are mostly naturally derived and not costly, the likelihood of patient acceptability and patient safety is high. This is very important, given the marked variability in regulatory protection in many under-resourced environments.
Conclusion
Current mitochondrial therapies may have their biggest impact as a preventative strategy for treating epilepsy and are cheap enough to be used by millions, especially when locally available, unlike the usual scenario of new ASMs being only affordable and accessible to a very few. These therapies, including the ketogenic diet, which has been successfully implemented in many lower- and middle-income countries (LMICs), by simultaneously addressing multiple comorbidities and aging, are therefore potentially of significant impact when measured in terms of quality of life, disability adjusted life years and cost.
With the increasing global burden of epilepsy, particularly in resource-limited settings, action is required to explore and implement mitochondrial-targeted therapies as both preventative and therapeutic strategies, particularly in the rapidly expanding aging population. Urgently needed are large-scale clinical trials to assess the long-term efficacy and safety of mitochondrial-targeted interventions, including antioxidants, metabolic modulators and gut microbiome therapies. Collaborations between neuroscientists, mitochondrial researchers and public health experts should be prioritized to develop evidence-based protocols.
From the perspective of public health and policy, as evidence builds of their efficacy and safety, governments and global health organizations could cooperate to integrate mitochondrial health strategies into national epilepsy prevention programs, especially in low-resource settings where conventional epilepsy care remains inaccessible, perpetuating long-standing treatment gaps. Global health disparities often revolve around a paucity of financial and human resources, reluctance to take conventional ASMs, side effects of older ASMs, cost of diagnosis and treatment and the economic impacts, direct and indirect, of living with a highly stigmatized condition. Indeed, the acceptability of natural products is usually much better than that of synthetic medicines in LMICs. In addition, using indigenous natural products that are shown to be supportive of mitochondrial function may make such culturally customized strategies more acceptable, cost-effective and therefore, locally sustainable.
At its most reductive, these cellular energy concerns are strongly reminiscent of the well-understood and better-known global concern about energy shortage and its impact on human viability as a species. Perhaps the time has also come for the fundamental issue of cellular energy (ATP) supply and toxic waste (ROS) accumulation to be viewed with similar existential urgency.
There will inevitably be challenges in implementing mitochondrial-targeted interventions on a large scale. While there are several ways to generate patentable intellectual property, natural products are often difficult to monetize, providing lower incentives for the supply chain and distributors. Unlike ASMs, which may stop seizures quite quickly, mitochondrial therapies will be more gradual in effect, requiring sustained use to obtain maximal benefits. Longitudinal cost-benefit analyses will have to be done by each jurisdiction.
Cost-effectiveness of a new range of therapies as proposed must be considered not only against the cost of existing treatments in each jurisdiction but also the cost to external multilateral funding agencies at a regional and global level, as well as the favorable medium- and long-term economic impact of disease modification vs essentially symptomatic conventional treatments. Similarly, it is the remit of key stakeholders, including regulatory agencies and policymakers at national and global levels including institutions such as the World Health Organization, to objectively review preclinical and clinical data as well as post-release real-world data generated in this new area of deployment, brain health, despite many already having been safely used in other indications. For example, the antioxidant Coenzyme Q-10, which may reduce seizure duration in specific animal models, has been used for decades for improving cardiovascular health.Reference Ji, Mylvaganam, Ravi Chander, Tarnopolsky, Murphy and Carlen5
At a national level, practical policy solutions could eventually include the placement of mitochondrial therapies on essential medicines lists, allowing governments to assist patients through subsidies, having pilot programs of subsidized mitochondrial therapies for epilepsy care before more broad-based availability, supporting local manufacture and distribution for cost-containment, and increasing supply-chain reliability.
As some agencies retreat from long-standing roles of supporting healthcare in under-resourced environments, countries like Canada, with strong biomedical research infrastructures, should take the lead in fostering partnerships for natural product research, equitable drug discovery and knowledge-sharing with developing nations. The integration of AI and biomarker-driven diagnostics to stratify patients based on mitochondrial function could lead to more personalized and efficient epilepsy management. Indeed, investments in precision mitochondrial medicine may not only improve epilepsy outcomes but could also revolutionize broader neurodegenerative disease prevention.
At the very least, mitochondrial dysfunction appears to be a compounding factor in the often progressive nature of epilepsy and other neurological disorders. Intervening early could modify this trajectory, to the benefit of untold millions with few options. It may also further improve epilepsy outcomes and quality of life for patients fortunate enough to be able to access the full range of conventional therapies in the developed world. To be clear, mitochondrial therapies would not, on present evidence, be used instead of ASMs for epilepsy but, like the ketogenic diet when used with ASMs in refractory epilepsies, would be better deployed as adjunctive agents, slowing progression and ameliorating the epilepsy syndrome. The same principle applies to the treatment of mental health comorbidities like depression, which also require the use of established first-line agents, including ASMs such as lamotrigine.
In modifying the aging process and comorbidities such as depression, which share pathophysiological mechanisms of oxidative stress, energy deficit and neuroinflammation, mitochondrial therapies would synergistically and simultaneously have multiple beneficial neuroprotective effects. Large-scale randomized controlled trials of mitochondrial therapies will be necessary before these agents can become first-line treatments. This rigor is particularly essential if global deployment is intended in areas where oversight and supportive resources may be lacking.
Addressing mitochondrial dysfunction could be a transformative, low-cost and globally scalable strategy to improve brain health and quality of life. Future research, policy and clinical implementation should now align if mitochondrial therapies are to become an evidence-driven part of epilepsy prevention and care, worldwide.
Author contributions
AA: Commentary conception, initial manuscript preparation, review and finalization.
PC: Conception, manuscript review, critique, edits.
Ana A: Manuscript review, critique, edits, discussion content.
Funding statement
This commentary article required no funding support.
Competing interests
Amza Ali has no conflict of interest to disclose. Peter Carlen has no conflict of interest to disclose. Ana Andreazza has no conflict of interest to disclose.