Malnutrition and epilepsy share a complex bidirectional relationship, with malnutrition serving as a potential risk factor for epilepsy development, while epilepsy, in turn, often exerts profound effects on nutritional status. Nutritional interventions have emerged as a critical adjunctive approach in epilepsy management.

To explore the multifaceted associations between malnutrition and epilepsy, structured into three primary sections: (1) Elucidating the impact of malnutrition as a risk factor for epilepsy onset; (2) Examining the reciprocal influence of epilepsy on nutritional status, and (3) Evaluating diverse nutritional interventions in the management of epilepsy.

A systematic search was conducted across PubMed, Scopus, and Web of Science databases utilizing defined keywords related to malnutrition, epilepsy, and nutritional interventions. Inclusion criteria encompassed various study types, including clinical trials, animal models, cohort studies, case reports, meta-analyses, systematic reviews, guidelines, editorials, and review articles. Four hundred sixteen pertinent references were identified, with 198 review articles, 153 research studies, 21 case reports, 24 meta-analyses, 14 systematic reviews, 4 guidelines, and 2 editorials meeting the predefined criteria.

The review revealed the intricate interplay between malnutrition and epilepsy, highlighting malnutrition as a potential risk factor in epilepsy development and elucidating how epilepsy often leads to nutritional deficiencies. Findings underscored the importance of nutritional interventions in managing epilepsy, showing their impact on seizure frequency, neuronal function, and overall brain health.

This systematic review emphasizes the bidirectional relationship between malnutrition and epilepsy while emphasizing the critical role of nutritional management in epilepsy treatment. The multifaceted insights underscore the need for a holistic approach to addressing nutritional aspects alongside conventional epilepsy management strategies.

• Epilepsy
• Nutritional management
• Seizure disorders
• Antiepileptic drugs
• Minerals
• L-carnitine
• Vitamins
• Omega-3
• Gut microbiota

• Metabolism
• Mitochondrial dysfunction
• Mitochondrial pyruvate carrier
• Neurological disorders

• Humans
• Nervous System Diseases/metabolism
• Nervous System Diseases/pathology
• Animals
• Mitochondria/metabolism
• Mitochondrial Membrane Transport Proteins/metabolism
• Mitochondrial Membrane Transport Proteins/chemistry
• Monocarboxylic Acid Transporters/metabolism

• Dravet syndrome
• KCNA1
• Kv1.1
• Nav1.1
• SCN1A
• brain energy metabolism

• Humans
• Animals
• Epilepsy/genetics
• Epilepsy/metabolism
• Epilepsy/diet therapy
• Diet, Ketogenic
• NAV1.1 Voltage-Gated Sodium Channel/genetics
• NAV1.1 Voltage-Gated Sodium Channel/metabolism
• Kv1.1 Potassium Channel/genetics
• Kv1.1 Potassium Channel/metabolism
• Mutation/genetics
• Brain/metabolism
• Ion Channels/genetics
• Ion Channels/metabolism

• APP1186025 National Health and Medical Research Council
• National Health and Medical Research Council

• P01 AG073082 NIA NIH HHS
• R01 AG061150 NIA NIH HHS
• R01 AG071697 NIA NIH HHS

• ADP-ribosylation
• Aging-related diseases
• Cellular senescence
• PARPs

• Humans
• Aging/metabolism
• Aging/physiology
• ADP-Ribosylation/physiology
• Animals
• Cellular Senescence/physiology
• Neurodegenerative Diseases/metabolism

• PARP-1
• PARP-1 inhibitors
• cell death
• neuroinflammation
• oxidative stress
• parthanatos

• Humans
• Poly (ADP-Ribose) Polymerase-1/metabolism
• Poly(ADP-ribose) Polymerases/metabolism
• Ribose
• Poly(ADP-ribose) Polymerase Inhibitors
• Parthanatos
• Autism Spectrum Disorder
• Epigenesis, Genetic
• Neurodegenerative Diseases/pathology

• epilepsy
• hypoxia
• migraine
• patent foramen ovale

• National Natural Science Foundation of China
• Science and Technology Department of Sichuan Province

• astrocytes
• epilepsy
• hippocampus
• neurons
• progesterone receptor membrane component 2

• FDG-PET
• glucose utilization
• glycogen
• interictal epileptic hyperactivity

• Humans
• Fluorodeoxyglucose F18
• Glycogen
• Electroencephalography
• Epilepsy
• Positron-Emission Tomography
• Seizures
• Glucose/metabolism

• National Health and Medical Research Council

• Nuclear magnetic resonance (NMR)-based metabolomics
• Pentylenetetrazole
• Seizures

• Animals
• Rats
• Alanine
• Anticonvulsants/therapeutic use
• Asparagine
• Citrates
• Creatine/therapeutic use
• Creatinine
• Disease Models, Animal
• Epilepsy/drug therapy
• Glucose
• Glutamates
• Isoleucine
• Ketone Bodies
• Lactates
• Leucine
• Pentylenetetrazole/toxicity
• Pyruvates
• Seizures/drug therapy
• Succinates
• Valine

• adipose tissue
• heart
• liver
• mitochondrion
• pyruvate

• Anion Transport Proteins/metabolism
• Humans
• Mitochondria/metabolism
• Mitochondrial Membrane Transport Proteins/genetics
• Mitochondrial Membrane Transport Proteins/metabolism
• Monocarboxylic Acid Transporters/genetics
• Pyruvic Acid/metabolism

• T32 HL134635 NHLBI NIH HHS
• P30 DK020579 NIDDK NIH HHS
• R01 DK104735 NIDDK NIH HHS
• P30 DK056341 NIDDK NIH HHS
• R01 DK117657 NIDDK NIH HHS
• HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

• Alzheimer’s disease
• NADPH oxidase
• acquired epilepsy
• glucose hypometabolism
• ketogenic diet
• oxidative stress

A predominant trigger and driver of sporadic Alzheimer’s disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences have remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind Aβ_1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that Aβ_1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.

Anton Malkov, Irina Popova et al. demonstrate that beta-amyloid application induces oxidative stress and reduces glucose consumption in the mouse brain, leading to network hyperactivity and behavioral changes—pathologies similar to those observed early on in Alzheimer’s disease patients. Inhibition of NADPH oxidase 2 (NOX2) rescued these phenotypes, suggesting that NOX2 may represent an important therapeutic target for Alzheimer’s disease.

• Drug
• EEG
• epilepsy
• epileptiform
• mouse
• rat
• transgenic

Epilepsy is characterized by an imbalance in neurotransmitter activity; an increased excitatory to an inhibitory activity. Acetylcholine (ACh), serotonin, and norepinephrine (NE) may modulate neural activity via several mechanisms, mainly through its receptors/transporter activity and alterations in the extracellular potassium (K⁺) concentration via K⁺ ion channels. Seizures may disrupt the regulation of inwardly rectifying K⁺ (Kir) channels and alter the receptor/transporter activity. However, there are limited data present on the immunoreactivity pattern of these neurotransmitter receptors/transporters and K⁺ channels in chronic models of epilepsy, which therefore was the aim of this study. Changes in the immunoreactivity of epileptogenesis-related neurotransmitter receptors/transporters (M2, 5-HT2B, and NE transporter) as well as Kir channels (Kir3.1 and Kir6.2) were determined in the cortex, hippocampus and medulla of adult Wistar rats by utilizing a Pentylenetetrazol (PTZ)-kindling chronic epilepsy model. Increased immunoreactivity of the NE transporter, M2, and 5-HT2B receptors was witnessed in the cortex and medulla. While the immunoreactivity of the 5-HT2B receptor was found increased in the cortex and medulla, it was decreased in the hippocampus, with no changes observed in the M2 receptor in this region. Kir3.1 and Kir6.2 staining showed increase immunoreactivity in the cerebral cortex, but channel contrasting findings in the hippocampus and medulla. Our results suggest that seizure kindling may result in significant changes in the neurotransmitter system which may contribute or propagate to future epileptogenesis, brain damage and potentially towards sudden unexpected death in epilepsy (SUDEP). Further studies on the pathogenic role of these changes in neurotransmitter receptors/transporters and K⁺ channel immunoreactivity may identify newer possible targets to treat seizures or prevent epilepsy-related comorbidities.

• 5-HT2B
• M2
• PTZ
• chronic epilepsy
• norepinephrine

• Alzhiemer's disease
• animal studies
• circuit dysfunction
• clinical trials
• deep brain stimulation
• neuromodulation

Epileptic nonconvulsive spike-wave discharges (SWDs) are commonly seen in amyloid plaque bearing transgenic mice but only rarely in their wild-type littermates. To shed light on their possible treatment options, we assessed the effect of drugs with variable and known mechanisms of action on the occurrence of SWDs in aged APPswe/PS1dE9 mice. The treatments included prototypic antiepileptic drugs (ethosuximide and levetiracetam), donepezil as the typical Alzheimer drug and atropine as an antagonistic effect, GABA_B antagonist CGP-35348, and alternate energy substrates beta-hydroxybutyrate (BHB), pyruvate and lactate on the occurrence of SWDs in aged APPswe/PS1dE9 mice. All agents were administered by single intraperitoneal injections at doses earlier documented to be effective and response was assessed by recording 3 h of video-EEG. Atropine at 25 mg/kg significantly decreased SWD occurrence in all behavioral states, and also resulted in altered frequency composition of SWDs and general EEG slowing during sleep. Ethosuximide at 200 mg/kg and levetiracetam at 75 mg/kg effectively suppressed SWDs only during a period of mixed behavioral states, but levetiracetam also increased SWDs in sleep. BHB at 1 g/kg decreased SWDs in sleep, while both pyruvate and lactate at the same dose tended to increase SWD number and total duration. Unexpectantly, donepezil at 0.3 mg/kg CGP-35348 at 100 mg/kg had no effect on SWDs. These findings call for re-evaluation of some prevailing theories on neural circuit alternations that underlie SWD generation and show the utility of APP/PS1 mice for testing potential new treatments for nonconvulsive epileptic activity related to Alzheimer pathology.

• NMDA receptors
• astrocytes
• calcium signaling
• excitotoxicity
• neurodegenerative diseases
• oxidative stress

• Animals
• Cell Proliferation/drug effects
• Cell Proliferation/genetics
• Cells, Cultured
• Cytokines/metabolism
• Down-Regulation/drug effects
• Down-Regulation/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• HeLa Cells
• Hep G2 Cells
• Histones/genetics
• Histones/metabolism
• Humans
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NAD/metabolism
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Nicotinamide Phosphoribosyltransferase/metabolism
• Pyruvic Acid/pharmacology
• Sirtuin 1/metabolism
• Xenograft Model Antitumor Assays

• R35 GM118068 NIGMS NIH HHS

• Warburg effect
• excitotoxicity
• mitochondrial pyruvate carrier (MPC)
• neuroprotection
• neurotoxicity

Epilepsy is a common neurological disorder of which seizures are a core symptom. Approximately one third of epileptic patients are resistant to antiepileptic drugs and therefore require alternative therapeutic options. Dietary and nutritional supplements can in some cases replace drugs, but with the exception of ketogenic diets, there are no officially recommended dietary considerations for patients with epilepsy. In this review we summarize a selection of nutritional suggestions that have proved beneficial in treating different types of epilepsy. We describe the types of seizures and epilepsy and follow this with an introduction to basic molecular mechanisms. We then examine several functional nutrients for which there is clinical evidence of therapeutic efficacy in reducing seizures or epilepsy-associated sudden death. We also discuss experimental results that demonstrate possible molecular mechanisms elicited by the administration of various nutrients. The availability of multiple dietary and nutritional candidates that show favorable outcomes in animals implies that assessing the clinical potential of these substances will improve translational medicine, ultimately benefitting epilepsy patients.

• epilepsy
• nutrients
• omega-3 fatty acid
• seizure
• vitamin B6
• vitamin D3
• vitamin E

Epilepsy is characterized by the regular occurrence of seizures, which follow a stereotypical sequence of alterations in the electroencephalogram. Seizures are typically a self limiting phenomenon, concluding finally in the cessation of hypersynchronous activity and followed by a state of decreased neuronal excitability which might underlie the cognitive and psychological symptoms the patients experience in the wake of seizures. Many efforts have been devoted to understand how seizures spontaneously stop in hope to exploit this knowledge in anticonvulsant or neuroprotective therapies. Besides the alterations in ion-channels, transmitters and neuromodulators, the successive build up of disturbances in energy metabolism have been suggested as a mechanism for seizure termination. Energy metabolism and substrate supply of the brain are tightly regulated by different mechanisms called neurometabolic and neurovascular coupling. Here we summarize the current knowledge whether these mechanisms are sufficient to cover the energy demand of hypersynchronous activity and whether a mismatch between energy need and supply could contribute to seizure control.

• adenosine
• lactate
• neurometabolic coupling
• neurovascular coupling
• pericyte
• seizure

• Optimization
• Pyruvic acid (PA) production
• Waste glycerol from biodiesel production process
• Yarrowia lipolytica

• Biofuels
• Glycerol/metabolism
• Pyruvic Acid
• Saccharomyces cerevisiae
• Yarrowia

• anaplerosis
• glucose metabolism
• medium chain fatty acids
• pilocarpine
• temporal lobe epilepsy

• Amyotrophic lateral sclerosis
• Energy metabolism
• Metabolic dysfunction
• Metabolic treatment
• Mitochondria
• Neuron-glia metabolic coupling

• Amyotrophic Lateral Sclerosis/metabolism
• Amyotrophic Lateral Sclerosis/therapy
• Animals
• Energy Metabolism
• Humans

• KU Leuven
• Vlaams Instituut voor Biotechnologie
• Fund for Scientific Research Flanders
• Belgian government
• Fondation Thierry Latran
• Association Belge contre les Maladies neuro-Musculaires
• ALS Liga Belgium (“A Cure for ALS”)

• mitochondrial function
• neuroprotection
• oxidative stress
• pilocarpine
• triheptanoin

Epilepsy afflicts up to 1.6% of the population and the mechanisms underlying the appearance of seizures are still not understood. In past years, many efforts have been spent trying to understand the mechanisms underlying the excessive and synchronous firing of neurons. Traditionally, attention was pointed towards synaptic (dys)function and extracellular ionic species (dys)regulation. Recently, novel clinical and preclinical studies explored the role of brain metabolism (i.e., glucose utilization) of seizures pathophysiology revealing (in most cases) reduced metabolism in the inter-ictal period and increased metabolism in the seconds preceding and during the appearance of seizures. In the present review, we summarize the clinical and preclinical observations showing metabolic dysregulation during epileptogenesis, seizure initiation, and termination, and in the inter-ictal period. Recent preclinical studies have shown that 2-Deoxyglucose (2-DG, a glycolysis blocker) is a novel therapeutic approach to reduce seizures. Furthermore, we present initial evidence for the effectiveness of 2-DG in arresting 4-Aminopyridine induced neocortical seizures in vivo in the mouse.

• 2 deoxyglucose
• beta hydroxybutyrate
• epilepsy
• metabolism
• seizures

• Animals
• Disease Models, Animal
• Energy Metabolism
• Humans
• Neurons/metabolism
• Seizures/etiology
• Seizures/metabolism
• Seizures/physiopathology