Mechanistic insights into the sleep-glymphopathy-cerebral small vessel disease loop: implications for epilepsy pathophysiology and therapy
Epilepsy is the second most common neurological disorder and affects approximately 50 million people worldwide. Despite advances in antiepileptic therapy, about 30% of patients develop refractory epilepsy. Recent studies have shown sleep, glymphatic function, cerebral small vessel disease (CSVD), an...
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Frontiers Media S.A.
2025-03-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2025.1546482/full |
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| author | Zaw Myo Hein Zaid Adnan Subhi Al-Zaghal Mazira Muhammad Ghazali Usman Jaffer Hafizah Abdul Hamid Hafizah Abdul Hamid Muhammad Zulfadli Mehat Muhammad Zulfadli Mehat Muhammad Danial Che Ramli Che Mohd Nasril Che Mohd Nassir |
| author_facet | Zaw Myo Hein Zaid Adnan Subhi Al-Zaghal Mazira Muhammad Ghazali Usman Jaffer Hafizah Abdul Hamid Hafizah Abdul Hamid Muhammad Zulfadli Mehat Muhammad Zulfadli Mehat Muhammad Danial Che Ramli Che Mohd Nasril Che Mohd Nassir |
| author_sort | Zaw Myo Hein |
| collection | DOAJ |
| description | Epilepsy is the second most common neurological disorder and affects approximately 50 million people worldwide. Despite advances in antiepileptic therapy, about 30% of patients develop refractory epilepsy. Recent studies have shown sleep, glymphatic function, cerebral small vessel disease (CSVD), and epilepsy are interrelated by sharing a multidirectional relationship in influencing their severity and progression. Sleep plays a vital role in brain homeostasis and promotes glymphatic clearance responsible for the removal of metabolic wastes and neurotoxic substances from the brain. Disrupted sleep is a common feature in epilepsy and can lead to impairment in glymphatic efficiency or glymphopathy, promoting neuroinflammation and accrual of epileptogenic factors. CSVD, occurring in up to 60% of the aging population, further exacerbates neurovascular compromise and neurodegeneration by increasing seizure susceptibility and worsening epilepsy outcomes. This narrative review aims to discuss the molecular and pathophysiological inter-relationships between these factors, providing a new framework that places glymphopathy and CSVD as contributors to epileptogenesis in conditions of sleep disruption. We propose an integrative model wherein the glymphopathy and vascular insufficiency interact in a positive feedback loop of sleep disruption and increased seizure vulnerability mediated by epileptic activity. Acknowledging these interactions has significant impacts on both research and clinical practice. Targeting sleep modulation, glymphatic function, and cerebrovascular health presents a promising avenue for therapeutic intervention. Future research should focus on developing precision medicine approaches that integrate neuro-glial-vascular mechanisms to optimize epilepsy management. Clinically, addressing sleep disturbances and CSVD in epilepsy patients may improve treatment effectiveness, reduce seizure burden, and improve overall neurological outcomes. This framework highlights the need for interdisciplinary approaches to break the vicious cycle of epilepsy, sleep disturbance, and cerebrovascular pathology, paving the way for innovative treatment paradigms. |
| format | Article |
| id | doaj-art-13fcdeb0b2c64b40b8d85bfa99fed1d0 |
| institution | Kabale University |
| issn | 1662-453X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj-art-13fcdeb0b2c64b40b8d85bfa99fed1d02025-08-20T03:42:03ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2025-03-011910.3389/fnins.2025.15464821546482Mechanistic insights into the sleep-glymphopathy-cerebral small vessel disease loop: implications for epilepsy pathophysiology and therapyZaw Myo Hein0Zaid Adnan Subhi Al-Zaghal1Mazira Muhammad Ghazali2Usman Jaffer3Hafizah Abdul Hamid4Hafizah Abdul Hamid5Muhammad Zulfadli Mehat6Muhammad Zulfadli Mehat7Muhammad Danial Che Ramli8Che Mohd Nasril Che Mohd Nassir9Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman, United Arab EmiratesDepartment of Basic Medical Sciences, College of Medicine, Ajman University, Ajman, United Arab EmiratesDepartment of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu, Kelantan, MalaysiaKulliyyah of Islamic Revealed Knowledge and Human Sciences, International Islamic University Malaysia, Kuala Lumpur, MalaysiaDepartment of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, MalaysiaBrain and Mental Health Research Advancement and Innovation Networks (PUTRA BRAIN), Universiti Putra Malaysia, UPM Serdang, Selangor, MalaysiaDepartment of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, MalaysiaBrain and Mental Health Research Advancement and Innovation Networks (PUTRA BRAIN), Universiti Putra Malaysia, UPM Serdang, Selangor, MalaysiaFaculty of Health and Life Sciences, Management and Science University, Shah Alam, Selangor, MalaysiaDepartment of Anatomy and Physiology, School of Basic Medical Sciences, Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu, Terengganu, MalaysiaEpilepsy is the second most common neurological disorder and affects approximately 50 million people worldwide. Despite advances in antiepileptic therapy, about 30% of patients develop refractory epilepsy. Recent studies have shown sleep, glymphatic function, cerebral small vessel disease (CSVD), and epilepsy are interrelated by sharing a multidirectional relationship in influencing their severity and progression. Sleep plays a vital role in brain homeostasis and promotes glymphatic clearance responsible for the removal of metabolic wastes and neurotoxic substances from the brain. Disrupted sleep is a common feature in epilepsy and can lead to impairment in glymphatic efficiency or glymphopathy, promoting neuroinflammation and accrual of epileptogenic factors. CSVD, occurring in up to 60% of the aging population, further exacerbates neurovascular compromise and neurodegeneration by increasing seizure susceptibility and worsening epilepsy outcomes. This narrative review aims to discuss the molecular and pathophysiological inter-relationships between these factors, providing a new framework that places glymphopathy and CSVD as contributors to epileptogenesis in conditions of sleep disruption. We propose an integrative model wherein the glymphopathy and vascular insufficiency interact in a positive feedback loop of sleep disruption and increased seizure vulnerability mediated by epileptic activity. Acknowledging these interactions has significant impacts on both research and clinical practice. Targeting sleep modulation, glymphatic function, and cerebrovascular health presents a promising avenue for therapeutic intervention. Future research should focus on developing precision medicine approaches that integrate neuro-glial-vascular mechanisms to optimize epilepsy management. Clinically, addressing sleep disturbances and CSVD in epilepsy patients may improve treatment effectiveness, reduce seizure burden, and improve overall neurological outcomes. This framework highlights the need for interdisciplinary approaches to break the vicious cycle of epilepsy, sleep disturbance, and cerebrovascular pathology, paving the way for innovative treatment paradigms.https://www.frontiersin.org/articles/10.3389/fnins.2025.1546482/fullsleepglymphatic systemcerebral small vessel diseaseepilepsytherapy |
| spellingShingle | Zaw Myo Hein Zaid Adnan Subhi Al-Zaghal Mazira Muhammad Ghazali Usman Jaffer Hafizah Abdul Hamid Hafizah Abdul Hamid Muhammad Zulfadli Mehat Muhammad Zulfadli Mehat Muhammad Danial Che Ramli Che Mohd Nasril Che Mohd Nassir Mechanistic insights into the sleep-glymphopathy-cerebral small vessel disease loop: implications for epilepsy pathophysiology and therapy Frontiers in Neuroscience sleep glymphatic system cerebral small vessel disease epilepsy therapy |
| title | Mechanistic insights into the sleep-glymphopathy-cerebral small vessel disease loop: implications for epilepsy pathophysiology and therapy |
| title_full | Mechanistic insights into the sleep-glymphopathy-cerebral small vessel disease loop: implications for epilepsy pathophysiology and therapy |
| title_fullStr | Mechanistic insights into the sleep-glymphopathy-cerebral small vessel disease loop: implications for epilepsy pathophysiology and therapy |
| title_full_unstemmed | Mechanistic insights into the sleep-glymphopathy-cerebral small vessel disease loop: implications for epilepsy pathophysiology and therapy |
| title_short | Mechanistic insights into the sleep-glymphopathy-cerebral small vessel disease loop: implications for epilepsy pathophysiology and therapy |
| title_sort | mechanistic insights into the sleep glymphopathy cerebral small vessel disease loop implications for epilepsy pathophysiology and therapy |
| topic | sleep glymphatic system cerebral small vessel disease epilepsy therapy |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2025.1546482/full |
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