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Keywords:

  • caloric restriction;
  • dietary restriction;
  • fasting;
  • ketogenic diet;
  • metabolic control theory;
  • seizures

Abstract

  1. Top of page
  2. Abstract
  3. Brain energy metabolism and epilepsy
  4. Historical perspectives on the dietary management of epilepsy
  5. Epilepsy management with fasting
  6. Epilepsy management with the ketogenic diet
  7. Epilepsy management with caloric restriction
  8. Epilepsy management with antiepileptic drugs and vagal nerve stimulation
  9. Metabolic control theory and epilepsy management
  10. Acknowledgements
  11. References

Brain cells are metabolically flexible because they can derive energy from both glucose and ketone bodies (acetoacetate and β-hydroxybutyrate). Metabolic control theory applies principles of bioenergetics and genome flexibility to the management of complex phenotypic traits. Epilepsy is a complex brain disorder involving excessive, synchronous, abnormal electrical firing patterns of neurons. We propose that many epilepsies with varied etiologies may ultimately involve disruptions of brain energy homeostasis and are potentially manageable through principles of metabolic control theory. This control involves moderate shifts in the availability of brain energy metabolites (glucose and ketone bodies) that alter energy metabolism through glycolysis and the tricarboxylic acid cycle, respectively. These shifts produce adjustments in gene-linked metabolic networks that manage or control the seizure disorder despite the continued presence of the inherited or acquired factors responsible for the epilepsy. This hypothesis is supported by information on the management of seizures with diets including fasting, the ketogenic diet and caloric restriction. A better understanding of the compensatory genetic and neurochemical networks of brain energy metabolism may produce novel antiepileptic therapies that are more effective and biologically friendly than those currently available.

Abbreviations used
CR

caloric restriction

KD

ketogenic diet

TCA

tricarboxylic acid

Epilepsy is a group of disorders involving recurrent seizures and is one of the most prevalent human neurological afflictions. The number of people having epilepsy in the USA is estimated at 2.5 million or about 1% of the population (Hauser 1997). Epileptic seizures are the clinical manifestation of epilepsy and result from excessive, synchronous, abnormal electrical firing patterns of neurons (Engel and Pedley 1997). Many epileptics manifest partial or generalized seizures without signs of organic brain disorder, i.e. idiopathic epilepsy (Baumann 1982; Wolf 1994; Engel and Pedley 1997). This contrasts with symptomatic or acquired epilepsy, where seizures arise from brain injury, disease or neurostructural change. While some idiopathic epilepsies are inherited as simple Mendelian traits, most idiopathic epilepsies are multifactorial and involve complex gene–environmental interactions (Berkovic 1998; Todorova et al. 1999).

Despite intensive antiepileptic drug research and development, seizures remain unmanageable in many epileptics (Browne and Holmes 2001). Moreover, many antiepileptic drugs produce adverse side-effects that can include somnolence, nervousness, ataxia, diplopia, constipation, confusion, memory difficulties and weight loss (Porter et al. 1997; Browne and Holmes 2001; Wheless et al. 2001). Clearly, new therapies are needed that can better manage epileptic seizures while permitting a good quality of life.

Metabolic control theory applies principles of bioenergetics and genome flexibility for the control or management of complex phenotypic traits (Veech et al. 2001; Strohman 2002). Since metabolism is a universal process underlying all phenotypes, modification of metabolism can modify phenotype. The theory is based on the idea that compensatory genetic and biochemical networks, operating through flexible biological systems, are capable of modulating the bioenergetics of glycolysis, the tricarboxylic acid (TCA) cycle, electron transport and oxidative phosphorylation (Greenspan 2001; Strohman 2002). Moreover, this dynamic and versatile system can potentially produce a normal phenotype through metabolic adjustments despite the continued presence of the inherited or acquired factors responsible for a complex disease.

We propose here that epilepsy ultimately involves a disruption of brain energy homeostasis and is potentially manageable through principles of metabolic control theory. This control involves moderate shifts in the availability of brain energy metabolites (glucose and ketone bodies) that alter brain energy metabolism through glycolysis and the TCA cycle, respectively. These shifts produce adjustments in gene-linked metabolic networks that manage or control the seizure disorder. It is important to emphasize that this metabolic control is achievable within the normal physiological ranges of blood glucose and ketone levels thus avoiding the pathological extremes of starvation-associated hypoglycemia or ketoacidosis.

Brain energy metabolism and epilepsy

  1. Top of page
  2. Abstract
  3. Brain energy metabolism and epilepsy
  4. Historical perspectives on the dietary management of epilepsy
  5. Epilepsy management with fasting
  6. Epilepsy management with the ketogenic diet
  7. Epilepsy management with caloric restriction
  8. Epilepsy management with antiepileptic drugs and vagal nerve stimulation
  9. Metabolic control theory and epilepsy management
  10. Acknowledgements
  11. References

Under normal physiological conditions, the brain derives almost all of its energy from the aerobic oxidation of glucose. An abundance of glucose transporters (GLUT-1) is enriched in the brain capillary endothelial cells and mediates the facilitated diffusion of glucose through the blood–brain barrier (Janigro 1999; Dwyer et al. 2002). Most of the glucose is metabolized to pyruvate, which enters the mitochondria of neurons and glia and is converted to acetyl-CoA before entering the TCA cycle. Only about 13% of glycolytic pyruvate is converted to lactate under normal conditions (Clarke and Sokoloff 1999).

Brain glycolysis is regulated mainly by phosphofructokinase, which is activated by neuronal activity and is inhibited by citrate and ATP synthesized through the TCA cycle and oxidative phosphorylation. Although more ATP is produced through respiration than through glycolysis (36 vs. 2, respectively), the rate of ATP production is significantly faster through glycolysis than through the oxidative steps of the Krebs cycle and the electron transport chain (McIlwain 1969). Metabolic control in the brain is similar to that in other tissues in that energy homeostasis is maintained through glycolysis, the TCA cycle, electron transport and oxidative phosphorylation (Clarke and Sokoloff 1999; Strohman 2002). Energy metabolism in brain tissue, however, is more complex than that in other tissues due to metabolic (neurotransmitter synthesis) and cellular (neurons and glia) compartmentation (Pellerin et al. 1998b; McKenna et al. 2000; Waagepetersen et al. 2001).

Glucose uptake and metabolism increase more during epileptic seizures than during any other brain activity (McIlwain 1969; Meldrum and Chapman 1999; Cornford et al. 2002). Blood glucose also positively correlates with flurothyl-induced seizures in rats and high glucose may exacerbate human seizure disorders (Schwechter et al. 2003). Brain lactate levels also increase significantly during seizure activity (During et al. 1994; Meldrum and Chapman 1999; Cornford et al. 2002). The seizure-associated lactate increase reflects the rapid increase in glycolytic rate over the cerebral metabolic rate of oxygen with the maximally activated pyruvate dehydrogenase being the rate-limiting step (Meldrum and Chapman 1999). The pyruvate dehydrogenase fails to metabolize pyruvate to acetyl-CoA at the same rate as pyruvate production. Hence, lactate dehydrogenase converts pyruvate to lactate during periods of oxygen deprivation and rapid glucose metabolism as would occur during epilepsy.

Neuronal excitability and epileptic seizures are directly related to rapid glucose utilization and glycolysis (McIlwain 1969; Ackermann and Lear 1989; Meric et al. 1994; Clarke and Sokoloff 1999; Meldrum and Chapman 1999; Cornford et al. 2000; Knowlton et al. 2002; Ikemoto et al. 2003; Schwechter et al. 2003). It is not clear, however, to what extent enhanced glycolysis is related to the cause or effects of seizure activity. Hypermetabolism is often detected in brain epileptic foci upon seizure initiation and then spreads to other brain regions during seizure generalization (Kuhl et al. 1980; Chugani and Chugani 1999). Although hypermetabolic during the ictal event, epileptic foci are often hypometabolic between seizures suggesting abnormalities in energy homeostasis (Kuhl et al. 1980; Chugani and Chugani 1999; Janigro 1999; Meldrum and Chapman 1999; Vielhaber et al. 2003). Repeated seizures may also damage neurons both within and outside the epileptic focus and may contribute to the disease progression according to Gowers' dictum that ‘seizures beget seizures’ (Todorova et al. 1999). Based on these and other observations (Ting and Degani 1993; Li et al. 2000; Knowlton et al. 2002; Vielhaber et al. 2003), we suggest that most epilepsies, regardless of etiology, ultimately involve altered brain energy homeostasis.

Historical perspectives on the dietary management of epilepsy

  1. Top of page
  2. Abstract
  3. Brain energy metabolism and epilepsy
  4. Historical perspectives on the dietary management of epilepsy
  5. Epilepsy management with fasting
  6. Epilepsy management with the ketogenic diet
  7. Epilepsy management with caloric restriction
  8. Epilepsy management with antiepileptic drugs and vagal nerve stimulation
  9. Metabolic control theory and epilepsy management
  10. Acknowledgements
  11. References

Diet therapies for epilepsy management are as old as the disease itself and have evolved over the ages to accommodate changes in the ideas about the origins of epilepsy (Eadie and Bladin 2001). Many of the antiepileptic diets used during the Greek, Roman and Renaissance periods were designed to rid the brain of toxic agents thought to underlie the epileptic seizures. A strict diet regimen was recognized as a key process in the cure for epileptic seizures. These early antiepileptic diets, however, usually comprised vile concoctions of raw animal organs and extracts that induced nausea or vomiting and were often administered together with purgatives and enemas (Eadie and Bladin 2001). It is noteworthy that restricted food intake over days or weeks would be a consequence of such dietary therapies. This would tend to produce physiological conditions of fasting where circulating glucose levels are reduced and levels of ketone bodies are increased. Hence, changes in brain energy homeostasis would be expected following antiepileptic dietary therapies that affect circulating levels of glucose and ketone bodies.

Epilepsy management with fasting

  1. Top of page
  2. Abstract
  3. Brain energy metabolism and epilepsy
  4. Historical perspectives on the dietary management of epilepsy
  5. Epilepsy management with fasting
  6. Epilepsy management with the ketogenic diet
  7. Epilepsy management with caloric restriction
  8. Epilepsy management with antiepileptic drugs and vagal nerve stimulation
  9. Metabolic control theory and epilepsy management
  10. Acknowledgements
  11. References

Fasting has long been recognized as an effective antiepileptic therapy for a broad range of seizure disorders. Using the water only diet of Conklin, Lennox and coworkers demonstrated an impressive management of epilepsy in patients having as many as five seizures per day (Lennox and Cobb 1928; Lennox 1960; Freeman et al. 2000). Fasting-induced seizure control was associated with reduced blood glucose and increased blood ketone levels (Lennox 1960). When the fast was broken through food or glucose intake, however, seizure protection dissipated in association with rising blood glucose levels and falling blood ketone levels (Lennox and Cobb 1928; Lennox 1960).

While glucose is the preferred energy substrate, the brain will metabolize ketone bodies for energy when blood glucose levels decrease as occurs during fasting. Ketone bodies, consisting of acetoacetate and β-hydroxybutyrate are derived from fat catabolism in liver mitochondria and their concentration in blood is inversely related to that of glucose (Clarke and Sokoloff 1999; Greene et al. 2001; Bhagavan 2002). β-hydroxybutyrate is the predominant blood ketone body and is oxidized to acetoacetate in the mitochondria before entering the TCA cycle. Acetone is a non-enzymatic by-product of ketone body synthesis and is largely excreted in the urine or exhaled from the lungs (Veech et al. 2001; Bhagavan 2002). The transport of ketones into the brain occurs through the blood–brain barrier monocarboxylic transporter (MCT-1), whose expression is regulated in part by circulating ketone and glucose levels (Koehler-Stec et al. 1998; Pellerin et al. 1998a; Leino et al. 2001).

Although the levels of glucose and ketones in brain are proportional to their levels in blood, the adult brain does not usually burn ketones for energy under normal conditions unless blood glucose levels are reduced (Owen et al. 1967; Redies et al. 1989; Clarke and Sokoloff 1999; Laterra et al. 1999; Guzman and Blazquez 2001; Bhagavan 2002; Schwechter et al. 2003). Reduced blood glucose and increased blood ketone levels may be needed to induce the activity of succinyl-CoA-acetoacetate-CoA transferase, a key enzyme required for ketone body metabolism (Fredericks and Ramsey 1978; Bhagavan 2002). The MCT-1 transporter is also up-regulated during fasting in adults (Pan et al. 2001) and during milk feeding in neonates (Cremer et al. 1976, 1979; Pellerin et al. 1998a). Gjedde and Crone (1975) found that the fasting brain takes up ketone bodies from the blood, while Pan et al. (2002) recently reported that neurons are capable of metabolizing ketones. Hence, neurons and glia will metabolize ketones for energy under fasting-induced reductions of blood glucose.

In contrast to glucose, ketone bodies by-pass cytoplasmic glycolysis and directly enter mitochondria where they are oxidized in the TCA cycle as acetyl-CoA (Nehlig and Pereira de Vasconcelos 1993; Sato et al. 1995; Veech et al. 2001). This causes significant increases in the TCA cycle metabolites (from citrate to α-ketoglutarate) and improves metabolic efficiency through an increase in the energy of ATP hydrolysis (Sato et al. 1995; Veech et al. 2001). While providing sufficient energy for normal brain activities, we recently proposed that ketones, unlike glucose, may be unable to deliver the immediate and large amount of energy necessary to initiate or sustain seizure activity (Greene et al. 2001).

The metabolism of ketones also produces multiple changes in the content and distribution of brain neurotransmitters. Ketones stimulate glutamic acid decarboxylase activity that can potentially elevate GABA content in synaptosomes (Erecinska et al. 1996; Daikhin and Yudkoff 1998; Yudkoff et al. 2001). Ketone-induced alterations in TCA cycle metabolites (oxaloacetate, citrate, succinyl-CoA and α-ketoglutarate) will favor the formation of glutamate over aspartate and thereby reduce brain aspartate, an excitatory neurotransmitter implicated in epilepsy (Flavin et al. 1991; Flavin and Seyfried 1994; Veech et al. 2001; Yudkoff et al. 2001). Reductions in excitatory neurotransmitters (glutamate and aspartate) together with elevations in GABA could decrease neuronal excitation and increase inhibition.

In addition to neurotransmitter alterations, increased ketone body metabolism could also increase the activity of the sodium pump in both neurons and glia. Acute food restriction in rats produces significant reductions in blood glucose and brain monoamine oxidase activity and significant elevations in brain membrane Na+,K+-ATPase activity (Kaur and Kaur 1990; Veech et al. 2001). Whether the fasting-induced elevations in sodium pump activity result from altered neurotransmitter metabolism or from altered membrane lipid composition is not clear. Nevertheless, increased pump activity in neurons could increase the membrane potential thereby decreasing neuronal excitability (McIlwain 1969; Silver and Erecinska 1997; Schwartzkroin 1999; Veech et al. 2001). Increased pump activity in astroglia, on the other hand, could facilitate glutamate uptake following synaptic release since glutamate uptake is coupled to the activity of the sodium pump (Pellerin and Magistretti 1994; Meldrum and Chapman 1999). This could reduce the duration or spread of seizure activity. We propose that moderate shifts in energy metabolism from glucose to ketones would produce global changes in brain excitability that could potentially manage seizure activity.

A reduction in the cerebral metabolic rate of glucose is another effect of prolonged fasting (Redies et al. 1989). It generally requires about 3–4 days for cerebral energy metabolism to shift from glucose to ketone utilization in humans (Bhagavan 2002). This period closely parallels that required for seizure control through fasting (Lennox 1960). No change is seen in the brain glucose transfer coefficient during long-term fasting in humans (Gjedde and Crone 1975; Redies et al. 1989). We suggest that, as blood glucose levels gradually decline, brain glycolytic energy is gradually reduced. However, an increase in ketone body metabolism will compensate for the reduced glycolytic energy (Haymond et al. 1983). The shift from glucose to ketone metabolism will increase brain ATP and citrate levels that will inhibit the phosphofructokinase and further reduce glycolytic energy (Redies et al. 1989). Since glycolysis is associated with seizure activity, a shift in bioavailable energy substrate from glucose to ketone bodies could reduce glycolytic energy and seizure susceptibility (Greene et al. 2001).

Epilepsy management with the ketogenic diet

  1. Top of page
  2. Abstract
  3. Brain energy metabolism and epilepsy
  4. Historical perspectives on the dietary management of epilepsy
  5. Epilepsy management with fasting
  6. Epilepsy management with the ketogenic diet
  7. Epilepsy management with caloric restriction
  8. Epilepsy management with antiepileptic drugs and vagal nerve stimulation
  9. Metabolic control theory and epilepsy management
  10. Acknowledgements
  11. References

Since prolonged fasting is of limited therapeutic value in epilepsy management, the high fat, low carbohydrate ketogenic diet (KD) was developed to mimic the physiological effects of fasting without starvation (Wilder 1921; Peterman 1925, 1928; Lennox 1960). The KD is remarkably effective in managing intractable seizures in children and may also be effective therapy for seizure disorders in adults (Nordli and De Vivo 1997; Vining 1997; Sirven et al. 1999; Freeman et al. 2000). In addition to altering the distribution of excitatory and inhibitory neurotransmitter levels, according to the studies of Yudkoff et al. (1997, 2001), the KD could also inhibit seizure susceptibility through effects on brain energy metabolism (DeVivo et al. 1978; Schwartzkroin 1999).

It was generally thought that ketone bodies were anticonvulsant and largely responsible for the antiepileptogenic effects of the KD. However, several studies in humans and animal models have failed to show a direct association between seizure inhibition and ketonemia (Appleton and DeVivo 1974; Bough et al. 1999a; Likhodii et al. 2000; Todorova et al. 2000). Also, ketone bodies do not directly alter excitatory or inhibitory synaptic transmission in hippocampal slices (Thio et al. 2000). These findings indicate that elevated ketone bodies alone are unable to account for the anticonvulsant effects of the KD.

The efficacy of the KD for managing epilepsy is best when the diet is administered following a fast or when total calories are restricted (Freeman et al. 2000). Some patients lose weight on the KD due to adverse side-effects, including diarrhea and vomiting, or to the unpalatability of the diet. Adverse effects, however, are greater with the medium chain triglyceride form of the diet than with the classical lard form of the diet (Freeman et al. 2000). Restricted food intake with consequent reduced blood glucose would be a consequence of these adverse effects. It is interesting that the anticonvulsant effects of the KD can dissipate rapidly in patients who experience a rise in blood glucose levels, i.e. those who gain weight on the diet or who consume carbohydrates (Peterman 1928; Lennox 1960; Freeman et al. 2000). We suggest that the seizure protective effects of the KD are largely dependent on the maintenance of reduced blood glucose levels that are also associated with reduced body weight (Livingston 1972; Greene et al. 2001). Reduced blood glucose levels would force the brain to burn ketones for energy. Ketone metabolism would gradually reduce neuronal excitability through effects on neurotransmitter levels and membrane potential. Thus, a restriction of caloric energy intake should enhance the antiepileptic effects of the KD.

Epilepsy management with caloric restriction

  1. Top of page
  2. Abstract
  3. Brain energy metabolism and epilepsy
  4. Historical perspectives on the dietary management of epilepsy
  5. Epilepsy management with fasting
  6. Epilepsy management with the ketogenic diet
  7. Epilepsy management with caloric restriction
  8. Epilepsy management with antiepileptic drugs and vagal nerve stimulation
  9. Metabolic control theory and epilepsy management
  10. Acknowledgements
  11. References

Caloric restriction (CR) is a natural dietary therapy that improves health, extends longevity and reduces the effects of neuroinflammatory diseases in rodents and humans (Weindruch and Walford 1988; Mattson et al. 2001; Mukherjee et al. 2002; Duan et al. 2003; Koubova and Guarente 2003). It is produced from a total dietary restriction and differs from acute fasting or starvation in that CR reduces total energy intake without causing anorexia or deficiencies of any specific nutrients. In contrast to starvation, CR reduces glucose levels without producing clinical hypoglycemia and elevates ketone body levels without producing clinical ketoacidosis. Hence, CR prolongs the health benefits of fasting while avoiding the pathological conditions of starvation.

We recently showed that mild to moderate CR alone could significantly reduce seizure susceptibility in the EL mouse, a genetic model of idiopathic epilepsy (Greene et al. 2001). Caloric restriction was effective in reducing seizure susceptibility at both juvenile and adult ages and was more effective in reducing seizure susceptibility in the juvenile mice than the KD. Also, no adverse effects occurred in EL mice receiving either a mild 15% CR diet (at juvenile ages) or a moderate 30% CR diet (at adult ages). It is important to mention that juvenile mice and children are more sensitive to the effects of CR than adults. The rate of body weight gain then becomes a critical factor in implementation of CR at younger ages (Greene et al. 2001). Mice maintained on CR are healthier and more physically active than mice maintained on the same diet fed ad libitum or unrestricted. Bough et al. (1999b) also reported that mild CR enhanced the anticonvulsant effects of the KD toward pentylenetetrazol-induced seizures and significantly elevated the pentylenetetrazol seizure threshold in rats fed a standard diet. Considered together, these findings suggest that CR may have anticonvulsant efficacy against a range of seizure disorders at either juvenile or adult ages.

The anticonvulsant effects of CR mice are directly correlated with reductions in blood glucose levels and with elevations in blood ketones in epileptic EL mice (Greene et al. 2001). The association between elevated blood ketone levels and reduced seizure susceptibility is observed, however, only when glucose levels and body weights are also reduced (Todorova et al. 2000; Greene et al. 2001). Furthermore, seizure susceptibility remains high if glucose levels are not reduced despite reductions in food intake. The association between blood glucose levels and seizure susceptibility is less clear in epileptic humans than in animal models of epilepsy. This may be due to the capricious nature of glucose measurements in humans and the broad range of glucose levels in ‘normal’ individuals (60–120 mg/dL) (Livingston 1972; Sacks 2001). A normal glucose level for one person could be hypoglycemic or hyperglycemic in another person. Indeed, some children can function normally with blood glucose levels as low as 20 mg/dL (Livingston 1972). Hence, normal variations in blood glucose levels must be considered when evaluating correlations among seizure susceptibility, glucose and ketone levels in epileptic humans.

In contrast to the KD, where dietary fat elevates blood ketone levels, CR elevates blood ketone levels as a natural physiological response to reduced glucose levels. Caloric restriction also elevates circulating glucocorticoids that would further reduce cerebral glucose utilization and glycolysis (Kadekaro et al. 1988; Birt et al. 1999). The brain will metabolize ketones for energy more effectively under reduced glucose than under high glucose conditions since reduced glucose stimulates ketone body metabolism in liver (Owen et al. 1967; Haymond et al. 1983; Clarke and Sokoloff 1999; Bhagavan 2002). We suggest that CR may underlie the anticonvulsant effects of the KD, since the KD manages epilepsy best when it is administered with restricted food or caloric intake (Freeman et al. 2000). We propose that a simultaneous reduction in brain glucose metabolism and increase in brain ketone metabolism is essential to the process by which CR, the restricted KD and fasting inhibit seizure susceptibility.

Epilepsy management with antiepileptic drugs and vagal nerve stimulation

  1. Top of page
  2. Abstract
  3. Brain energy metabolism and epilepsy
  4. Historical perspectives on the dietary management of epilepsy
  5. Epilepsy management with fasting
  6. Epilepsy management with the ketogenic diet
  7. Epilepsy management with caloric restriction
  8. Epilepsy management with antiepileptic drugs and vagal nerve stimulation
  9. Metabolic control theory and epilepsy management
  10. Acknowledgements
  11. References

Antiepileptic drugs are thought to manage epileptic seizures through a variety of effects on ion channels and GABA receptors (Macdonald 1997). Some commonly used antiepileptic drugs also reduce the cerebral metabolic rate of glucose, e.g. phenobarbital, primidone, phenytoin, carbamazepine, vigabratin and valporate (Theodore et al. 1986a,b, 1989; Leiderman et al. 1991; Spanaki et al. 1999). The combination of carbamazepine and valproate causes an even greater reduction in the cerebral metabolic rate of glucose than when either drug is used alone. Decreased nutrient intake and body weight loss are associated with the antiepileptic action of topiramate (Ormrod and McClellan 2001; Brown et al. 2002), suggesting mechanisms involving alterations in energy metabolism. The inclusion of active body weight controls in animal studies and clinical trials could test this hypothesis.

Recent studies have also shown that certain diuretics, e.g. furosemide, have significant anticonvulsant potential (Hesdorffer et al. 2001). While the antiepileptic effects of furosemide involve alterations of extracellular potassium and chloride (Hochman et al. 1995, 1999), other antiepileptic mechanisms may also be involved. For example, furosemide and similar diuretics also inhibit glucose uptake and glycolysis and could thus alter brain energy homeostasis as would occur with CR (Dimitriadis et al. 1993). Although no detailed studies are available on the effects of antiepileptic drugs on blood ketone levels, alterations in cerebral glucose metabolism associated with antiepileptic drugs suggest that some of these drugs may manage epilepsy, in part, by influencing brain energy homeostasis.

Vagal nerve stimulation is a novel therapy that significantly reduces seizure frequency in patients with refractory seizures (Wheless et al. 2001). Afferent fibers of the vagus nerve have access to the brainstem reticular formation, hypothalamus, thalamus, amygdala, hippocampus and insular cortex (Rutecki 1990). The vagus nerve is also known to affect eating behavior and vagal nerve stimulation has been used to treat morbid obesity (Roslin and Kurian 2001). Since a major biological role of the vagus nerve is systemic energy regulation (Szekely 2000), we suggest that vagal nerve stimulation may manage epilepsy, in part, through effects on brain energy metabolism. Studies are needed to determine if epilepsy management with vagal nerve stimulation is associated with changes in body weight or plasma levels of glucose and ketone bodies.

Metabolic control theory and epilepsy management

  1. Top of page
  2. Abstract
  3. Brain energy metabolism and epilepsy
  4. Historical perspectives on the dietary management of epilepsy
  5. Epilepsy management with fasting
  6. Epilepsy management with the ketogenic diet
  7. Epilepsy management with caloric restriction
  8. Epilepsy management with antiepileptic drugs and vagal nerve stimulation
  9. Metabolic control theory and epilepsy management
  10. Acknowledgements
  11. References

Neural metabolic systems are flexible in having multiple non-identical elements (gene network or metabolic interactions) capable of change in response to the nutritional environment (Greenspan 2001). Under normal nutritional conditions, inherited or acquired neural defects may produce pathology by altering metabolic pathway output. Shifts from normally high caloric diets to diets that reduce glucose and elevate ketones would modify multiple gene network interactions in the brain. Such modifications involve reductions in glycolytic gene expression, elevations in respiratory gene expression and changes in glucose and ketone transporter gene expression in the blood–brain barrier (Pellerin and Magistretti 1994; Pellerin et al. 1998a; Lee et al. 2000; Dhahbi et al. 2001; Leino et al. 2001; Cullingford et al. 2002; Lin et al. 2002; Koubova and Guarente 2003). Besides producing multiple changes in gene-linked metabolic networks, diets that reduce energy intake could also influence stress, inflammatory and neuroendocrine network responses (Duan et al. 2003; Koubova and Guarente 2003; Mattson et al. 2003).

In general, many antiepileptic drugs are administered under conventional (well fed) nutritional conditions. While such drugs may manage the seizure phenotype, this management often comes at a biological price involving global impairments of neurophysiological function. Under new nutritional conditions, e.g. fasting, the KD or CR, gene network adjustments can produce a normal phenotype through new or compensatory interactions. These adjustments could simply neutralize or by-pass the original pathological defect to reduce seizures while sparing or even enhancing systems neurophysiology. It is the flexibility of these gene–metabolic network interactions in response to alterations in the nutritional environment that underlie metabolic control theory.

We propose that epilepsy involves disruptions of brain energy homeostasis and is potentially manageable through metabolic control where a gradual shift from glucose to ketone body metabolism controls the seizure disorder. Furthermore, these shifts in glucose and ketone levels occur within physiological ranges that maximize metabolic homeostasis. This is important since shifts that are too extreme can produce the pathological complications associated with hypoglycemia or ketoacidosis. Indeed, hypoglycemia alone can produce convulsive seizures. Since the metabolism of ketone bodies is thermodynamically more efficient than the metabolism of glucose (Sato et al. 1995; Veech et al. 2001; Strohman 2002), a shift in brain energy metabolism from glucose to ketones will produce a homeostatic state that is capable of restoring the physiological balance of excitation and inhibition. Moreover, the restoration of a non-epileptic (normal) phenotype can occur despite the continued presence of the idiopathic (genetic) or symptomatic (acquired) defects responsible for the disease. New experimental approaches involving biological system state analyses will be necessary to evaluate the mechanisms by which these gene and metabolic networks interact to manage epilepsy.

In summary, we propose that the metabolic management of epilepsy occurs through two main processes. The first involves a reduction in circulating glucose levels. The second involves an elevation in circulating ketone bodies that replaces the lost energy from glucose. This would shift neurotransmitter pools and modulate membrane excitability thus restoring the physiological balance of excitation and inhibition. The restoration is based on the inherent flexibility of genetic and metabolic systems that reorganize and adapt to changes in the availability brain energy metabolites. Hence, a better understanding of the compensatory genetic and neurochemical networks of brain energy metabolism may produce novel antiepileptic therapies that are more effective and biologically friendly than those currently available.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Brain energy metabolism and epilepsy
  4. Historical perspectives on the dietary management of epilepsy
  5. Epilepsy management with fasting
  6. Epilepsy management with the ketogenic diet
  7. Epilepsy management with caloric restriction
  8. Epilepsy management with antiepileptic drugs and vagal nerve stimulation
  9. Metabolic control theory and epilepsy management
  10. Acknowledgements
  11. References

This research was supported by the Boston College Research Fund, NIH grant (HD39722) and grants from the National Tay-Sachs and Allied Disease (NTSAD) Association and the American Institute of Cancer Research. The authors would like to thank Julie Kasperzyk and John Mantis for technical help and Richard Veech and Russell J. Buono for comments.

References

  1. Top of page
  2. Abstract
  3. Brain energy metabolism and epilepsy
  4. Historical perspectives on the dietary management of epilepsy
  5. Epilepsy management with fasting
  6. Epilepsy management with the ketogenic diet
  7. Epilepsy management with caloric restriction
  8. Epilepsy management with antiepileptic drugs and vagal nerve stimulation
  9. Metabolic control theory and epilepsy management
  10. Acknowledgements
  11. References