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Metabolic and endocrine aspects of the ketogenic diet
Epilepsy Research 37 (1999) 191 – 201 www.elsevier.com/locate/epilepsyres
Metabolic and endocrine aspects of the ketogenic diet Raman Sankar a,*, Marcio Sotero de Menezes b a
Departments of Neurology and Pediatrics, Pediatric Neurology (22 -474 MDCC), UCLA School of Medicine, and Mattel Children’s Hospital at UCLA, Box 951752, Los Angeles, CA 90095 -1752, USA b Departments of Neurology and Pediatrics, Uni6ersity of Washington School of Medicine, and Children’s Hospital and Regional Medical Center, Seattle, WA 98195, USA
Abstract The ketogenic diet (KD) is designed to simulate the biochemical effects of fasting by maintaining a state of ketosis. The complex interplay of endocrine and metabolic factors requires that a continuous ingestion of a diet high in lipid calories is necessary to achieve such a state and yet maintain body weight. The resulting condition provides for much of the cerebral energy requirements in the form of ketone bodies. We review energy metabolism with special emphasis on fatty acid oxidation to provide the readers with a foundation that facilitates identification of patients who will especially benefit from this diet, as well as to assist clinicians in screening candidates who may experience a catastrophic outcome if fasted and placed on this diet. The review includes a discussion of the role of carnitine in mitochondrial fatty acid metabolism, and the criteria for carnitine supplementation. Only limited information is available regarding the interaction of the diet with the commonly used antiepileptic drugs. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Ketogenic diet; Carnitine; Epilepsy; Seizures; Lipid metabolism; Metabolic disease; Energy metabolism; Antiepileptic drugs; Patient selection
1. Introduction The ketogenic diet (KD) has re-emerged as an important alternative approach to the management of pharmaco-resistant, early childhood, epileptic disorders in the 1990s. As pointed out by Nordli and De Vivo (1997) it has always had a place in the therapy of difficult to control seizure disorders. Nevertheless, its application had diminished over the years and only a few centers con* Corresponding author. Tel.: +1-310-7941014; fax: +1310-8255834. E-mail address: [email protected] (R. Sankar)
tinued to practice it to a significant extent. The efforts of the Charlie Foundation in organizing news media coverage and educational programs during the 1990s has stimulated renewed interest in the KD by families of patients and by physicians alike. However, even as the number of patients placed on the KD increases, clinicians remain unsure about the best way to screen patients for entry into the KD and to monitor them from a metabolic perspective to ensure their safety. At the present time, there are insufficient data to formulate rigid guidelines. In this chapter, we shall provide a brief review of the metabolic
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and endocrine bases for potential complications of the diet, including those based on carnitine metabolism, and recommend screening and monitoring strategies that are derived from such an understanding. In the interest of simplicity, details of regulation of lipolysis, gluconeogenesis, etc. will not be discussed; rather, we shall focus on those issues particularly important for the safe deployment of the KD.
2. Outline of energy metabolism Glucose derived from food-based carbohydrate, from hepatic gluconeogenesis, or from glycogenolysis (the latter sources used under conditions when enterally derived carbohydrates are not available) undergoes glycolysis to produce pyruvate (Fig. 1). Pyruvate is converted to acetate in the mitochondria by pyruvate dehydrogenase, an enzyme that depends upon thiamine as a cofactor. Under conditions of starvation when this glucose-derived source of energy is not available, lipolysis is stimulated to mobilize free fatty acids (FFA). The major stimulus for this process is the decreasing insulin to glucagon ratio, a function of insulin reduction in response to decreasing plasma glucose. Also contributing to this switch to lipolysis is a shift in circulating catecholamines in favor of epinephrine over norepinephrine. The process of b-oxidation of FFA, which takes place in the mitochondria, yields acetate. Acetate enters the Krebs cycle for complete oxidation to two molecules of carbon dioxide and water (Fig. 2). The reduced cofactors that result from substrate oxidation enter the electron transport chain, where they are reconverted into their oxidized form with concomitant production of energy. The respiratory chain complexes ultimately provide the link between substrate oxidation, molecular oxygen, and energy production. Amino acids can also contribute; they undergo transamination by pyridoxal-dependent enzymes that convert them to ketoacids (e.g. alanine to pyruvate), which can ultimately enter the Krebs cycle (Fig. 1). As illustrated in Fig. 1, because carbohydrates and protein are minimized, the KD is designed to force the system to derive almost its the energy
needs from lipids, by mitochondrial oxidation of FFAs.
3. Production of ketone bodies and availability of energy substrates for cerebral metabolism In addition to undergoing complete oxidation to CO2 and water, acetate molecules can combine to form acetoacetate (AcAc), which exists in equilibrium with hydroxybutyrate (BHB). The condensation of acetate into these ketone bodies [AcAc = BHB] provides for acetates in a form that can be transported efficiently across the blood–brain barrier (BBB) and into the neuron (Fig. 2). Acetone itself is a minor ketone body and is produced in small quantities by the decarboxylation of AcAc. Acetone becomes detectable in the breath only when the concentration of AcAc is increased, such as in diabetic ketoacidosis. Muscle tissue is also capable of utilizing ketone bodies as a fuel. In a comparison of CSF metabolites between control subjects and patients on the KD, Nordli and De Vivo (1997) found no significant differences in the concentrations of glucose, lactate, or pyruvate; however, BHB and AcAc rose from levels of 15 and 16 mM, respectively, to 432 and 248 mM. The transporter for moving ketone bodies across the BBB is inducible, and the transporter’s expression is stimulated by fasting (Gjedde and Crone, 1975). Indeed, in fasting obese volunteers, it was shown that 52% of oxygen consumption by the brain could be accounted for by BHB extraction, and 8% by AcAc extraction (Cahill et al., 1966), suggesting that these ketones contributed a major fraction of the fuel for energy production in this fasting state.
4. Endocrine regulation of blood glucose and ketone bodies The readily understood reciprocal relationship between blood glucose and insulin is, in fact, just a fragment of a complex and circular feedback relationship among energy substrates, intermediates, and several hormones that include insulin,
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Fig. 1. Schematic of energy metabolism showing carbohydrate and lipid metabolism converging at the level of acetyl-CoA. When there is a block at any level of lipid metabolism either due to delivery of fatty acids to the mitochondria or due to a oxidation defect, the hepatic microsomal system converts fatty acids to dicarboxylic acids by the process of oxidation of the terminal carbon.
glucagon, epinephrine, cortisol, and growth hormone. The major aspects of this relationship pertaining to the pancreatic hormones insulin and glucagon, and epinephrine from the adrenal medulla, are shown schematically in Fig. 3. The initial period of fasting facilitates lowering the insulin to glucagon ratio, stimulating lipolysis and the production of ketone bodies. However, disruption of the ketotic state occurs readily upon ingestion of carbohydrates by increasing the insulin to glucagon ratio. When ketogenesis is halted, the insulin levels produced by carbohydrate ingestion tend to be higher and more sustained — hence ketosis may not be re-achieved for several hours or a day, thus opening a window of vulnerability to breakthrough seizures. In such a circumstance, a brief period (B24 h) of fasting may help reset the insulin to glucagon ratio. The other important point is that the ketone bodies themselves limit further mobilization of FFA from lipid stores (Fig. 3). Hence, the need for the continuous intake of the high proportion of lipid calories in the KD. Under equilibrium conditions, the patient thus does not sustain a loss of body weight, even though the patient is in a continuous state of ketosis, mimicking a state of starvation.
The complex interplay among the various gastrointestinally-derived peptides and other factors that control this process are beyond the scope of this review.
5. Implications of a KD-induced switch in substrate for energy metabolism From the foregoing, it is obvious that the KD may provide us with an especially effective way to treat patients whose difficulties (including, but not limited to, seizures) are based on the lack of availability of glucose for cerebral energy metabolism, or involve an inborn metabolic error that results in lactic acidosis when glucose is the primary metabolic substrate. Indeed, the KD is considered the ideal treatment (Nordli and De Vivo, 1997) for a syndrome presenting with seizures, developmental delay, and persistent hypoglycorrachia due to deficiency of the glucose transporter in the BBB (De Vivo et al., 1991). Likewise, the KD has been used successfully in patients who presented with inborn errors involving the glycolytic pathway such as phosphofructokinase deficiency (Swoboda et al., 1997), or
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Fig. 2. Schematic showing that hydroxybutyrate (BHB) is a key energy intermediate for the brain since it can be transported by circulation across the blood–brain barrier (via the inducible monocarboxylic acid transporter in the endothelium) for delivery to neural tissue as an alternate to glucose. Free fatty acids themselves cannot be made available to neurons directly.
those who presented with pyruvate dehydrogenase deficiency (Falk et al., 1976; Wijburg et al., 1992; Wexler et al., 1997). In contrast, one would predict that patients with defects in the transport or oxidation of FFA should deteriorate on the KD. The KD was reported to have resulted in coma in a patient with pyruvate carboxylase deficiency (De Vivo et al., 1977). Results from careful evaluation of this patient suggested that pyruvate carboxylase to be important in modulating the fractional distribution of intracellular acetyl-CoA between the Kreb cycle, the b-hydroxy-b-methylglutaryl-CoA cycle (and the synthesis of cholesterol and ketone bodies), and fatty acid synthesis. The entity of ketotic hypoglycemia, apparently peculiar to youngsters between the ages of 1 and 6 years, and disappearing by the age of 10, can also pose challenges during the early phase of instituting the KD. Pathogenesis in these cases is believed to be due to a deficiency of gluconeogenic precursors; these patients respond to an oral alanine challenge with increased blood glucose while even intravenous glucagon does not provide an adequate stimulus to restore euglycemia (De Vivo et al., 1973). It seems likely that patients with either unrecognized carnitine deficiency (primary or secondary — see below), or deficiencies
in the mitochondrial enzymes involved in fatty acid oxidation, may be at risk for complications resulting from the KD. A basic understanding of the oxidation of FFA can be useful in the assessment and screening of patients at risk, as well as in identifying patients whose treatment with the KD may become safer by specific addition (carnitine) or removal (valproic acid) of components.
6. Oxidation of fatty acids–the role of carnitine Long-chain fatty acids have to be esterified by carnitine in order to be transported into the mitochondrion (Figs. 1 and 4). Given its great importance, therefore, in the KD, it is important to understand its role and the consequences of carnitine deficiency. Carnitine is an aliphatic alcohol with a carboxyl end and a quaternary ammonium end that is typically derived (up to 75% of daily requirements) from diet, largely from meat and dairy products. It can also be biosynthesized from precursor amino acids lysine and methionine. It should be recognized that even biosynthesis requires precursors that are derived from the diet. Up to 90% of the body carnitine stores are in muscle, where the concentration of carnitine may
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Fig. 3. The central role of glucagon (from a-pancreatic cells) and insulin (from pancreatic b-cells) in regulating blood glucose and ketone body levels. The major stimulus that controls the ratio of these hormones is blood glucose; other factors also further modulate these interactions. For the sake of simplicity, the role of growth hormone and cortisol in increasing blood glucose are not shown (both epinephrine and cortisol are released by the adrenal gland in response to stress).
be 70 × that in serum. Carnitine is actively reabsorbed in the proximal tubules of the kidneys, and any urinary loss (free carnitine plus carnitine in the form of carnityl esters) has to be replaced by either dietary intake or biosynthesis. While primary carnitine deficiency is extremely rare, a variety of conditions may predispose one to sec-
ondary carnitine deficiency (Coulter, 1995). These include chronic hepatic or renal disease, dialysis, chronic therapy with valproic acid (VPA) (Laub et al., 1986; Riva et al., 1991, 1993; Shapira and Gutman, 1991; Zelnik et al., 1995), therapy with the KD (Rutledge et al., 1989; Chez et al., 1997), diabetes mellitus (DM) (Averbuch-Heller et al.,
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Fig. 4. Schematic of a mitochondrion showing the transport of fatty acids as carnityl esters across the inner mitochondrial membrane (imm). They are converted to the fatty acyl-CoA at the outer mitochondrial membrane (omm) to prepare them for esterification with carnitine by carnitine palmitoyltransferase I (CPT I) at the outer surface of the imm. After translocation by translocase (not shown) carnitine palmitoyltransferase I (CPT I) carnitine palmitoyltransferase II (CPT II) removes the carnityl moiety and the fatty acid is subject to the actions of the enzymes involved with b-oxidation to produce acetyl-CoA. Microsomal oxidation (extramitochondrial) leads to dicarboxylic acids, which are excreted as carnityl conjugates, thus contributing to secondary carnitine deficiency. Circles in lighter gray represent aliphatic chain; darker gray represents the carboxyl end. Circle with ‘C’ represents carnityl moiety.
1994), and a variety of inborn errors of metabolism that result in increased urinary excretion of carnityl esters (Pons and De Vivo, 1995). The clinical presentation of primary carnitine deficiency syndromes has been classified as myopathic or systemic (De Vivo and Tein, 1990; Pons and De Vivo, 1995). In the former, there is progressive limb weakness with normal serum carnitine levels but decreased muscle carnitine and a lipid storage myopathy. This pathology is presumed to be due to a muscle transporter defect, and the response to supplemental carnitine is variable. Systemic carnitine deficiency presents in early life with cardiomyopathy and hypotonia and/or weakness, failure to thrive, hypoketotic hypoglycemia, and, at times, coma. Patients with this condition may show a dramatic response to therapy with carnitine. The secondary syndromes may have variable manifestations including weakness, hypotonia, hypoglycemia, acidosis, coma, dicarboxylic aciduria. Serum carnitine is generally
low, muscle carnitine is variable, and there may be increased excretion of esterified carnitine (reflected by increased ratio of esterified to free carnitine \ 0.4). While there have been reports in abstract form suggesting that the KD itself may be associated with carnitine deficiency (Rutledge et al., 1989; Chez et al., 1997), systematic studies are lacking. It has been suggested that carnitine supplementation be instituted for patients on the KD only after a clear demonstration of deficiency (Nordli and De Vivo, 1997). Plasma free carnitine levels B 20 M/l or an esterified to free carnitine ratio \ 0.4 are considered to be abnormal and warrant supplementation. The long-chain FFAs are transported across the outer mitochondrial membrane as fatty acylCoAs. On the outer leaf of the inner mitochondrial membrane (imm), the fatty acyl-CoA is converted to carnityl fatty acid by the enzyme carnitine palmitoyltransferase I (CPT I). This ester is carried across the imm by translocase. At
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the inner leaf of the imm, carnitine palmitoyltransferase II (CPT II) removes the carnityl moiety and delivers the long-chain FFA as an acyl-CoA to the mitochondrial matrix (schematically shown in Fig. 4). The cleaved carnitine is transported back to the outer leaf of the imm by translocase. This whole process constitutes the carnitine cycle. Medium chain FFAs do not require carnitine to be delivered to the mitochondrial matrix. Any deficiency of carnitine, CPT I, II or translocase can impair entry of long chain fatty acids into the mitochondrion. In CPT II deficiency or translocase deficiency, carnityl esters of long chain FFAs may be excreted. In carnitine deficiency or CPT I deficiency, the long chain FFAs are diverted to the hepatic microsomal system (Figs. 1 and 4). Here, they undergo oxidation, resulting in the formation of dicarboxylic acids (DCAs), which are excreted in the urine as carnityl esters. Thus, in carnitine deficiency, this process results in further depletion of carnitine. CPT I deficiency presents in infancy with recurrent attacks of hypoketotic hypoglycemia in the fasting state, marked hepatomegaly, and steatosis. There is hypertriglyceridemia and normal or elevated serum carnitine levels. Administration of medium chain triglycerides (MCT) may ameliorate the situation. A patient with CPT I deficiency is likely to tolerate the MCT oil based KD better than the cream-based KD. To our knowledge there has only been a single case of translocase deficiency reported (Stanley et al., 1992). CPT II deficiency usually presents in the second decade or later with exercise-induced myalgia and myoglobinuria. This recessively inherited condition should be differentiated from McArdle disease (myophosphorylase deficiency) and Tarui disease (phophofructokinase deficiency).
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catastrophe if fasted or placed on the KD. A brief review of the oxidation scheme is being provided to aid in the understanding of these disorders and to place them in perspective. The oxidation of fatty acids occurs in stages, whereby two carbons are removed in each stage to form acetyl-CoA, which can enter the Krebs cycle for further oxidation to CO2 and H2O. In the first step of each stage (Fig. 5), an acyl-CoA dehydrogenase (CAD) oxidizes the fatty acyl-CoA to an a,b-unsaturated fatty acyl-CoA. There are short, medium, and long chain acyl-CoA dehydrogenases, with some overlap in substrate selectivity among them. In the next step, the a,b-unsaturated fatty acyl-CoA is hydrated to a 3or b-hydroxy compound by enoyl-CoA hydratase. The hydroxyl group is then oxidized to a b-keto moiety by a chain length-selective hydroxy-CoA dehydrogenase (CHAD). Acyl-CoA thiolase cleaves the b-keto acyl-CoA to acetyl-CoA and a
7. b-Oxidation of fatty acids b-Oxidation provides the energy supply for children on the KD. A variety of syndromes involving deficiency of the enzymes that participate in catalyzing the b-oxidation sequence of reactions have been described. Patients with any of these metabolic disorders will be at risk to sustain a
Fig. 5. b-Oxidation of fatty acids to yield acetyl-CoA. S, short; M, medium; L, long chain; CAD, acyl-CoA dehydrogenase; CHAD, 3-hydroxyacyl-CoA dehydrogenase.
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fatty acyl-CoA with two fewer carbon atoms than the one we started with, which can undergo the same set of reactions again and again, until the final remnant is acetyl- or propanoyl-CoA. Extensive references to specific disorders involving fatty acid oxidation may be found in a volume on the neurology of hereditary metabolic diseases by Lyon et al. (1996). The most common defect in b-oxidation is medium chain acyl-CoA dehydrogenase (MCAD) deficiency. The onset of symptoms occurs between 5 months and 2 years of age, consisting of fasting intolerance with vomiting, episodic lethargy, coma, hypoglycemia (hypoketotic), and hepatic steatosis. Laboratory tests reveal low serum carnitine, increased acyl carnitine excretion, and medium chain dicarboxylic aciduria. Treatment involves adequate caloric intake with a low fat diet, carnitine, and avoidance of fasting. Clearly patients with this disorder should not be placed on the KD. Less common, but earlier and more severe in presentation, is long chain acyl-CoA dehydrogenase deficiency (LCAD) deficiency. In this condition, long chain dicarboxylic aciduria is seen, with secondary carnitine deficiency. Even rarer is short-chain acetylCoA dehydrogenase deficiency (SCAD) deficiency, an often lethal syndrome in early infancy with metabolic acidosis, hyperammonemia, and hypoglycemia. Other described syndromes include long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and the much rarer medium chain 3-hydroxyacyl-CoA dehydrogenase (MCHAD) deficiency. The presentation of LCHAD deficiency is usually in early infancy and can resemble Reye syndrome. Tyni et al. (1997) reported on the clinical findings of 13 patients with LCHAD deficiency. At presentation these patients had hypoglycemia, cardiomyopathy, hypotonia, and hepatomegaly during the first 2 years of life. Seven patients had recurrent metabolic crises, and six patients had a steadily progressive course. Dicarboxylic aciduria was detected in nine of 10 patients, and most patients had lactic acidosis, increased serum creatine kinase activities, and low serum carnitine concentration. The discovery of an abnormal dicarboxylic acid excretion profile in urine organic acid screening may serve as an important warning sign that
the patient is very likely not to be a candidate for the KD. A severe syndrome involving multiple acyl-CoA dehydrogenases is glutaric aciduria, type II. This syndrome is so distinctive with multiple congenital malformations in a very sick infant with a characteristic odor of sweaty feet (resembling isovaleric aciduria) that it is unlikely that such a patient would be considered for the KD.
8. Screening of patients at risk and long term monitoring It is clear that a statement suggesting that one should avoid placing a child with seizures on the KD if the child also demonstrates hypotonia and developmental delay, with metabolic acidosis and abnormalities of organic/amino acids, is too general to provide adequate guidance. As it was mentioned earlier, such a child could have pyruvate dehydrogenase deficiency, and hence may stand to benefit significantly from the KD; on the other hand, a child with a primary or acquired carnitine deficiency or a defect in b-oxidation, will sustain significant morbidity if fasted or placed on the KD. If a patient has undergone a muscle biopsy earlier in the work up for hypotonia and weakness, a biopsy showing a few ragged red fibers may not be a contraindication to the diet, but the appearance of a lipid myopathy is. Increased serum pyruvate and lactate along with alaninuria may not be a problem, but increased dicarboxylic acid excretion may hint at a potential for trouble. Patients with a variety of branchedchain amino aciduria and organic aciduria may also have secondary carnitine deficiency. Children who present with a history of seizures, and a history of intermittent encephalopathy with minor infections should be carefully evaluated for the nature of their metabolic abnormality before consideration of the KD. We agree with Demeritte et al. (1996) that organic acid screening should be done prior to and after the initiation of the KD. However, we do not recommend supplementing all patients on the KD routinely with carnitine. We agree with the recommendations from a recent roundtable on the role of L-carnitine supplementation in children
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with epilepsy (De Vivo et al., 1998) that suggests supplementation when a deficiency can be demonstrated. We also suggest that the type of dicarboxylic aciduria be carefully analyzed and interpreted when abnormal organic acid screens are encountered. Evolving dicarboxylic aciduria with emerging carnitine deficiency may occur in a patient who is on both valproic acid (VPA) and the KD. Even though most centers offering the KD have patients who are also on the VPA, a recent study has hinted at the added risk for complications in concomitant therapy with VPA (Ballaban-Gil et al., 1998). The issue of nephrolithiasis is also recognized as a potential complication associated with the KD, but the importance of fluid restriction in patients on the KD is unclear since liberalization of fluids will be expected to lower the risk for this painful complication. Nordli and De Vivo (1997) point out the theoretical possibility of dehydration diminishing tissue perfusion and generating lactate and pyruvate which may compete for the monocarboxylic transport system. In their patients on the KD, the arterial lactate and pyruvate were actually slightly lowered when compared to the control subjects and they recommend adequate hydration. They found that CSF glucose, lactate, and pyruvate were similar in the KD and control groups.
9. Metabolic interactions between anticonvulsants and the KD Since the KD is most commonly used in conjunction with antiepileptic drugs (AED), it is important to identify interactions that may cause adverse reactions, as well as combinations that are particularly efficacious. Concern regarding the combination of topiramate (TPM) with the KD has been expressed because of the recognition that a small percent of patients on TPM (mainly adults) have experienced nephrolithiasis (believed to be secondary to TPMs weak inhibition of carbonic anhydrase). Some centers have discouraged the use of concomitant therapy involving VPA and the KD (see above). The majority of our patients who
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enter the KD present with highly refractory secondary generalized epilepsies, and tend to be on VPA, TPM, or lamotrigine (LTG). It is neither practical nor advisable that their drug therapy be discontinued before a certain measure of seizure control is achieved on the KD. We have not experienced significant complications at our centers with patients who are on concomitant therapy involving KD and VPA even though a theoretical case can be made that VPA interferes with b-oxidation (Kossak et al., 1993; Toksoy et al., 1995). The effect of VPA on carnitine was stated earlier. Carnitine supplementation could be a beneficial strategy when VPA effects on carnitine are of concern. We do not consider the theoretical risk of increasing the likelihood of nephrolithiasis to be an absolute contraindication for those patients who have benefited from this drug at the time of entering the KD. Such theoretical reservations regarding the combined use of TPM and the KD must be considered in light of the demonstrated increased risk posed by the joint use of the KD with either VPA (Ballaban-Gil et al., 1998) or LTG. Most patients with secondary generalized epilepsy that enter the KD are quite young (under the age of ten) and the use of LTG (and felbamate (FBM)) in this group is restricted by the ‘black box warning’ developed by the manufacturers of these drugs and the FDA. Given these conditions, combined use of the KD with either VPA or LTG (or FBM) is unlikely to occur in most practices, leaving TPM as a significant remaining possibility. There are no data available at present on particularly efficacious combinations of the KD with particular AEDs. While our discussions thus far have focused on the aspects of the KD that pertain to energy metabolism, the possibility exists that the structural relationship between BHB, the excitatory neurotransmitter glutamate, and the inhibitory neurotransmitter GABA, would permit a direct effect of BHB on neuronal excitability. Current investigations focus on hypotheses that suggest that BHB antagonizes glutamatergic transmission, or that BHB
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augments GABAergic mechanisms. Any discovery of specific effects of BHB on the functioning of ion channels linked to neurotransmitter receptors would aid in our ability to consider rational combinations of AEDs with the KD. Much more commonly recognized is the derangement in bone mineral metabolism, described in detail by Hahn et al. (1979) that mandates the use of vitamin D and calcium supplements in patients on the KD. Continued practice of the KD with careful clinical observations guided by biochemical and metabolic insights can be expected to improve the efficacy as well safety of this time-honored approach.
10. Summary A basic understanding of the reciprocal relationships of endocrine hormones with energy substrates and intermediates should allow us to implement the KD with a maximum chance for success. Knowledge of some details of energy metabolism provides a rational basis for why the KD is especially effective in certain patients, while it assists us in identifying other patients who may be at risk to sustain a catastrophe. Safety of the patient can be enhanced by an understanding of the possibility of secondary carnitine deficiency while on the KD, especially if the patient is both on the KD and VPA. We have shown why appropriate laboratory testing for diagnosing this complication may include an assessment of carnitine levels as well as urinary excretion patterns of organic acids, with special attention to dicarboxylic aciduria. Only limited information is available at the present time to assist us in making specific recommendations regarding combinations of AEDs with the KD.
Acknowledgements R. Sankar was supported by a Clinical Investigator Development Award, NS 01792 from NINDS, NIH. The authors acknowledge Dr Jong Rho for assistance with some of the illustrations, and for his critical reading of the manuscript.
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nase deficiency with arthrogryposis: clinical benefit of a ketogenic diet. J. Pediatr. 131, 932 – 934. Toksoy, H.B., Tanzer, F.N., Atalay, A., 1995. Serum carnitine, b-hydroxybutyrate and ammonia levels during valproic acid therapy. Turk. J. Pediatr. 37, 25 – 29. Tyni, T., Palotie, A., Viinikka, L., Valanne, L., Salo, M.K., von Dobeln, U., Jackson, S., Wanders, R., Venizelos, N., Pihko, H., 1997. Long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G 1528C mutation: clinical presentation of 13 patients. J. Pediatr. 130, 67 – 76. Wexler, I.D., Hemalatha, S.G., McConnell, J., Buist, N.R., Dahl, H.H., Berry, S.A., Cederbaum, S.D., Patel, M.S., Kerr, D.S., 1997. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology 49, 1655 – 1661. Wijburg, F.A., Barth, P.G., Bindoff, L.A., Birch-Machin, M.A., van der Blij, J.F., Ruitenbeek, W., Turnbull, D.M., Schutgens, R.B., 1992. Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: results of treatment with a ketogenic diet. Neuropediatrics 23, 147 – 152. Zelnik, N., Fridkis, I., Gruener, N., 1995. Reduced carnitine and antiepileptic drugs: cause relationship or co-existence? Acta Paediatr. 84, 93 – 95.
Metabolic and endocrine aspects of the ketogenic diet Raman Sankar a,*, Marcio Sotero de Menezes b a
Departments of Neurology and Pediatrics, Pediatric Neurology (22 -474 MDCC), UCLA School of Medicine, and Mattel Children’s Hospital at UCLA, Box 951752, Los Angeles, CA 90095 -1752, USA b Departments of Neurology and Pediatrics, Uni6ersity of Washington School of Medicine, and Children’s Hospital and Regional Medical Center, Seattle, WA 98195, USA
Abstract The ketogenic diet (KD) is designed to simulate the biochemical effects of fasting by maintaining a state of ketosis. The complex interplay of endocrine and metabolic factors requires that a continuous ingestion of a diet high in lipid calories is necessary to achieve such a state and yet maintain body weight. The resulting condition provides for much of the cerebral energy requirements in the form of ketone bodies. We review energy metabolism with special emphasis on fatty acid oxidation to provide the readers with a foundation that facilitates identification of patients who will especially benefit from this diet, as well as to assist clinicians in screening candidates who may experience a catastrophic outcome if fasted and placed on this diet. The review includes a discussion of the role of carnitine in mitochondrial fatty acid metabolism, and the criteria for carnitine supplementation. Only limited information is available regarding the interaction of the diet with the commonly used antiepileptic drugs. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Ketogenic diet; Carnitine; Epilepsy; Seizures; Lipid metabolism; Metabolic disease; Energy metabolism; Antiepileptic drugs; Patient selection
1. Introduction The ketogenic diet (KD) has re-emerged as an important alternative approach to the management of pharmaco-resistant, early childhood, epileptic disorders in the 1990s. As pointed out by Nordli and De Vivo (1997) it has always had a place in the therapy of difficult to control seizure disorders. Nevertheless, its application had diminished over the years and only a few centers con* Corresponding author. Tel.: +1-310-7941014; fax: +1310-8255834. E-mail address: [email protected] (R. Sankar)
tinued to practice it to a significant extent. The efforts of the Charlie Foundation in organizing news media coverage and educational programs during the 1990s has stimulated renewed interest in the KD by families of patients and by physicians alike. However, even as the number of patients placed on the KD increases, clinicians remain unsure about the best way to screen patients for entry into the KD and to monitor them from a metabolic perspective to ensure their safety. At the present time, there are insufficient data to formulate rigid guidelines. In this chapter, we shall provide a brief review of the metabolic
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and endocrine bases for potential complications of the diet, including those based on carnitine metabolism, and recommend screening and monitoring strategies that are derived from such an understanding. In the interest of simplicity, details of regulation of lipolysis, gluconeogenesis, etc. will not be discussed; rather, we shall focus on those issues particularly important for the safe deployment of the KD.
2. Outline of energy metabolism Glucose derived from food-based carbohydrate, from hepatic gluconeogenesis, or from glycogenolysis (the latter sources used under conditions when enterally derived carbohydrates are not available) undergoes glycolysis to produce pyruvate (Fig. 1). Pyruvate is converted to acetate in the mitochondria by pyruvate dehydrogenase, an enzyme that depends upon thiamine as a cofactor. Under conditions of starvation when this glucose-derived source of energy is not available, lipolysis is stimulated to mobilize free fatty acids (FFA). The major stimulus for this process is the decreasing insulin to glucagon ratio, a function of insulin reduction in response to decreasing plasma glucose. Also contributing to this switch to lipolysis is a shift in circulating catecholamines in favor of epinephrine over norepinephrine. The process of b-oxidation of FFA, which takes place in the mitochondria, yields acetate. Acetate enters the Krebs cycle for complete oxidation to two molecules of carbon dioxide and water (Fig. 2). The reduced cofactors that result from substrate oxidation enter the electron transport chain, where they are reconverted into their oxidized form with concomitant production of energy. The respiratory chain complexes ultimately provide the link between substrate oxidation, molecular oxygen, and energy production. Amino acids can also contribute; they undergo transamination by pyridoxal-dependent enzymes that convert them to ketoacids (e.g. alanine to pyruvate), which can ultimately enter the Krebs cycle (Fig. 1). As illustrated in Fig. 1, because carbohydrates and protein are minimized, the KD is designed to force the system to derive almost its the energy
needs from lipids, by mitochondrial oxidation of FFAs.
3. Production of ketone bodies and availability of energy substrates for cerebral metabolism In addition to undergoing complete oxidation to CO2 and water, acetate molecules can combine to form acetoacetate (AcAc), which exists in equilibrium with hydroxybutyrate (BHB). The condensation of acetate into these ketone bodies [AcAc = BHB] provides for acetates in a form that can be transported efficiently across the blood–brain barrier (BBB) and into the neuron (Fig. 2). Acetone itself is a minor ketone body and is produced in small quantities by the decarboxylation of AcAc. Acetone becomes detectable in the breath only when the concentration of AcAc is increased, such as in diabetic ketoacidosis. Muscle tissue is also capable of utilizing ketone bodies as a fuel. In a comparison of CSF metabolites between control subjects and patients on the KD, Nordli and De Vivo (1997) found no significant differences in the concentrations of glucose, lactate, or pyruvate; however, BHB and AcAc rose from levels of 15 and 16 mM, respectively, to 432 and 248 mM. The transporter for moving ketone bodies across the BBB is inducible, and the transporter’s expression is stimulated by fasting (Gjedde and Crone, 1975). Indeed, in fasting obese volunteers, it was shown that 52% of oxygen consumption by the brain could be accounted for by BHB extraction, and 8% by AcAc extraction (Cahill et al., 1966), suggesting that these ketones contributed a major fraction of the fuel for energy production in this fasting state.
4. Endocrine regulation of blood glucose and ketone bodies The readily understood reciprocal relationship between blood glucose and insulin is, in fact, just a fragment of a complex and circular feedback relationship among energy substrates, intermediates, and several hormones that include insulin,
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Fig. 1. Schematic of energy metabolism showing carbohydrate and lipid metabolism converging at the level of acetyl-CoA. When there is a block at any level of lipid metabolism either due to delivery of fatty acids to the mitochondria or due to a oxidation defect, the hepatic microsomal system converts fatty acids to dicarboxylic acids by the process of oxidation of the terminal carbon.
glucagon, epinephrine, cortisol, and growth hormone. The major aspects of this relationship pertaining to the pancreatic hormones insulin and glucagon, and epinephrine from the adrenal medulla, are shown schematically in Fig. 3. The initial period of fasting facilitates lowering the insulin to glucagon ratio, stimulating lipolysis and the production of ketone bodies. However, disruption of the ketotic state occurs readily upon ingestion of carbohydrates by increasing the insulin to glucagon ratio. When ketogenesis is halted, the insulin levels produced by carbohydrate ingestion tend to be higher and more sustained — hence ketosis may not be re-achieved for several hours or a day, thus opening a window of vulnerability to breakthrough seizures. In such a circumstance, a brief period (B24 h) of fasting may help reset the insulin to glucagon ratio. The other important point is that the ketone bodies themselves limit further mobilization of FFA from lipid stores (Fig. 3). Hence, the need for the continuous intake of the high proportion of lipid calories in the KD. Under equilibrium conditions, the patient thus does not sustain a loss of body weight, even though the patient is in a continuous state of ketosis, mimicking a state of starvation.
The complex interplay among the various gastrointestinally-derived peptides and other factors that control this process are beyond the scope of this review.
5. Implications of a KD-induced switch in substrate for energy metabolism From the foregoing, it is obvious that the KD may provide us with an especially effective way to treat patients whose difficulties (including, but not limited to, seizures) are based on the lack of availability of glucose for cerebral energy metabolism, or involve an inborn metabolic error that results in lactic acidosis when glucose is the primary metabolic substrate. Indeed, the KD is considered the ideal treatment (Nordli and De Vivo, 1997) for a syndrome presenting with seizures, developmental delay, and persistent hypoglycorrachia due to deficiency of the glucose transporter in the BBB (De Vivo et al., 1991). Likewise, the KD has been used successfully in patients who presented with inborn errors involving the glycolytic pathway such as phosphofructokinase deficiency (Swoboda et al., 1997), or
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Fig. 2. Schematic showing that hydroxybutyrate (BHB) is a key energy intermediate for the brain since it can be transported by circulation across the blood–brain barrier (via the inducible monocarboxylic acid transporter in the endothelium) for delivery to neural tissue as an alternate to glucose. Free fatty acids themselves cannot be made available to neurons directly.
those who presented with pyruvate dehydrogenase deficiency (Falk et al., 1976; Wijburg et al., 1992; Wexler et al., 1997). In contrast, one would predict that patients with defects in the transport or oxidation of FFA should deteriorate on the KD. The KD was reported to have resulted in coma in a patient with pyruvate carboxylase deficiency (De Vivo et al., 1977). Results from careful evaluation of this patient suggested that pyruvate carboxylase to be important in modulating the fractional distribution of intracellular acetyl-CoA between the Kreb cycle, the b-hydroxy-b-methylglutaryl-CoA cycle (and the synthesis of cholesterol and ketone bodies), and fatty acid synthesis. The entity of ketotic hypoglycemia, apparently peculiar to youngsters between the ages of 1 and 6 years, and disappearing by the age of 10, can also pose challenges during the early phase of instituting the KD. Pathogenesis in these cases is believed to be due to a deficiency of gluconeogenic precursors; these patients respond to an oral alanine challenge with increased blood glucose while even intravenous glucagon does not provide an adequate stimulus to restore euglycemia (De Vivo et al., 1973). It seems likely that patients with either unrecognized carnitine deficiency (primary or secondary — see below), or deficiencies
in the mitochondrial enzymes involved in fatty acid oxidation, may be at risk for complications resulting from the KD. A basic understanding of the oxidation of FFA can be useful in the assessment and screening of patients at risk, as well as in identifying patients whose treatment with the KD may become safer by specific addition (carnitine) or removal (valproic acid) of components.
6. Oxidation of fatty acids–the role of carnitine Long-chain fatty acids have to be esterified by carnitine in order to be transported into the mitochondrion (Figs. 1 and 4). Given its great importance, therefore, in the KD, it is important to understand its role and the consequences of carnitine deficiency. Carnitine is an aliphatic alcohol with a carboxyl end and a quaternary ammonium end that is typically derived (up to 75% of daily requirements) from diet, largely from meat and dairy products. It can also be biosynthesized from precursor amino acids lysine and methionine. It should be recognized that even biosynthesis requires precursors that are derived from the diet. Up to 90% of the body carnitine stores are in muscle, where the concentration of carnitine may
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Fig. 3. The central role of glucagon (from a-pancreatic cells) and insulin (from pancreatic b-cells) in regulating blood glucose and ketone body levels. The major stimulus that controls the ratio of these hormones is blood glucose; other factors also further modulate these interactions. For the sake of simplicity, the role of growth hormone and cortisol in increasing blood glucose are not shown (both epinephrine and cortisol are released by the adrenal gland in response to stress).
be 70 × that in serum. Carnitine is actively reabsorbed in the proximal tubules of the kidneys, and any urinary loss (free carnitine plus carnitine in the form of carnityl esters) has to be replaced by either dietary intake or biosynthesis. While primary carnitine deficiency is extremely rare, a variety of conditions may predispose one to sec-
ondary carnitine deficiency (Coulter, 1995). These include chronic hepatic or renal disease, dialysis, chronic therapy with valproic acid (VPA) (Laub et al., 1986; Riva et al., 1991, 1993; Shapira and Gutman, 1991; Zelnik et al., 1995), therapy with the KD (Rutledge et al., 1989; Chez et al., 1997), diabetes mellitus (DM) (Averbuch-Heller et al.,
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Fig. 4. Schematic of a mitochondrion showing the transport of fatty acids as carnityl esters across the inner mitochondrial membrane (imm). They are converted to the fatty acyl-CoA at the outer mitochondrial membrane (omm) to prepare them for esterification with carnitine by carnitine palmitoyltransferase I (CPT I) at the outer surface of the imm. After translocation by translocase (not shown) carnitine palmitoyltransferase I (CPT I) carnitine palmitoyltransferase II (CPT II) removes the carnityl moiety and the fatty acid is subject to the actions of the enzymes involved with b-oxidation to produce acetyl-CoA. Microsomal oxidation (extramitochondrial) leads to dicarboxylic acids, which are excreted as carnityl conjugates, thus contributing to secondary carnitine deficiency. Circles in lighter gray represent aliphatic chain; darker gray represents the carboxyl end. Circle with ‘C’ represents carnityl moiety.
1994), and a variety of inborn errors of metabolism that result in increased urinary excretion of carnityl esters (Pons and De Vivo, 1995). The clinical presentation of primary carnitine deficiency syndromes has been classified as myopathic or systemic (De Vivo and Tein, 1990; Pons and De Vivo, 1995). In the former, there is progressive limb weakness with normal serum carnitine levels but decreased muscle carnitine and a lipid storage myopathy. This pathology is presumed to be due to a muscle transporter defect, and the response to supplemental carnitine is variable. Systemic carnitine deficiency presents in early life with cardiomyopathy and hypotonia and/or weakness, failure to thrive, hypoketotic hypoglycemia, and, at times, coma. Patients with this condition may show a dramatic response to therapy with carnitine. The secondary syndromes may have variable manifestations including weakness, hypotonia, hypoglycemia, acidosis, coma, dicarboxylic aciduria. Serum carnitine is generally
low, muscle carnitine is variable, and there may be increased excretion of esterified carnitine (reflected by increased ratio of esterified to free carnitine \ 0.4). While there have been reports in abstract form suggesting that the KD itself may be associated with carnitine deficiency (Rutledge et al., 1989; Chez et al., 1997), systematic studies are lacking. It has been suggested that carnitine supplementation be instituted for patients on the KD only after a clear demonstration of deficiency (Nordli and De Vivo, 1997). Plasma free carnitine levels B 20 M/l or an esterified to free carnitine ratio \ 0.4 are considered to be abnormal and warrant supplementation. The long-chain FFAs are transported across the outer mitochondrial membrane as fatty acylCoAs. On the outer leaf of the inner mitochondrial membrane (imm), the fatty acyl-CoA is converted to carnityl fatty acid by the enzyme carnitine palmitoyltransferase I (CPT I). This ester is carried across the imm by translocase. At
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the inner leaf of the imm, carnitine palmitoyltransferase II (CPT II) removes the carnityl moiety and delivers the long-chain FFA as an acyl-CoA to the mitochondrial matrix (schematically shown in Fig. 4). The cleaved carnitine is transported back to the outer leaf of the imm by translocase. This whole process constitutes the carnitine cycle. Medium chain FFAs do not require carnitine to be delivered to the mitochondrial matrix. Any deficiency of carnitine, CPT I, II or translocase can impair entry of long chain fatty acids into the mitochondrion. In CPT II deficiency or translocase deficiency, carnityl esters of long chain FFAs may be excreted. In carnitine deficiency or CPT I deficiency, the long chain FFAs are diverted to the hepatic microsomal system (Figs. 1 and 4). Here, they undergo oxidation, resulting in the formation of dicarboxylic acids (DCAs), which are excreted in the urine as carnityl esters. Thus, in carnitine deficiency, this process results in further depletion of carnitine. CPT I deficiency presents in infancy with recurrent attacks of hypoketotic hypoglycemia in the fasting state, marked hepatomegaly, and steatosis. There is hypertriglyceridemia and normal or elevated serum carnitine levels. Administration of medium chain triglycerides (MCT) may ameliorate the situation. A patient with CPT I deficiency is likely to tolerate the MCT oil based KD better than the cream-based KD. To our knowledge there has only been a single case of translocase deficiency reported (Stanley et al., 1992). CPT II deficiency usually presents in the second decade or later with exercise-induced myalgia and myoglobinuria. This recessively inherited condition should be differentiated from McArdle disease (myophosphorylase deficiency) and Tarui disease (phophofructokinase deficiency).
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catastrophe if fasted or placed on the KD. A brief review of the oxidation scheme is being provided to aid in the understanding of these disorders and to place them in perspective. The oxidation of fatty acids occurs in stages, whereby two carbons are removed in each stage to form acetyl-CoA, which can enter the Krebs cycle for further oxidation to CO2 and H2O. In the first step of each stage (Fig. 5), an acyl-CoA dehydrogenase (CAD) oxidizes the fatty acyl-CoA to an a,b-unsaturated fatty acyl-CoA. There are short, medium, and long chain acyl-CoA dehydrogenases, with some overlap in substrate selectivity among them. In the next step, the a,b-unsaturated fatty acyl-CoA is hydrated to a 3or b-hydroxy compound by enoyl-CoA hydratase. The hydroxyl group is then oxidized to a b-keto moiety by a chain length-selective hydroxy-CoA dehydrogenase (CHAD). Acyl-CoA thiolase cleaves the b-keto acyl-CoA to acetyl-CoA and a
7. b-Oxidation of fatty acids b-Oxidation provides the energy supply for children on the KD. A variety of syndromes involving deficiency of the enzymes that participate in catalyzing the b-oxidation sequence of reactions have been described. Patients with any of these metabolic disorders will be at risk to sustain a
Fig. 5. b-Oxidation of fatty acids to yield acetyl-CoA. S, short; M, medium; L, long chain; CAD, acyl-CoA dehydrogenase; CHAD, 3-hydroxyacyl-CoA dehydrogenase.
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fatty acyl-CoA with two fewer carbon atoms than the one we started with, which can undergo the same set of reactions again and again, until the final remnant is acetyl- or propanoyl-CoA. Extensive references to specific disorders involving fatty acid oxidation may be found in a volume on the neurology of hereditary metabolic diseases by Lyon et al. (1996). The most common defect in b-oxidation is medium chain acyl-CoA dehydrogenase (MCAD) deficiency. The onset of symptoms occurs between 5 months and 2 years of age, consisting of fasting intolerance with vomiting, episodic lethargy, coma, hypoglycemia (hypoketotic), and hepatic steatosis. Laboratory tests reveal low serum carnitine, increased acyl carnitine excretion, and medium chain dicarboxylic aciduria. Treatment involves adequate caloric intake with a low fat diet, carnitine, and avoidance of fasting. Clearly patients with this disorder should not be placed on the KD. Less common, but earlier and more severe in presentation, is long chain acyl-CoA dehydrogenase deficiency (LCAD) deficiency. In this condition, long chain dicarboxylic aciduria is seen, with secondary carnitine deficiency. Even rarer is short-chain acetylCoA dehydrogenase deficiency (SCAD) deficiency, an often lethal syndrome in early infancy with metabolic acidosis, hyperammonemia, and hypoglycemia. Other described syndromes include long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and the much rarer medium chain 3-hydroxyacyl-CoA dehydrogenase (MCHAD) deficiency. The presentation of LCHAD deficiency is usually in early infancy and can resemble Reye syndrome. Tyni et al. (1997) reported on the clinical findings of 13 patients with LCHAD deficiency. At presentation these patients had hypoglycemia, cardiomyopathy, hypotonia, and hepatomegaly during the first 2 years of life. Seven patients had recurrent metabolic crises, and six patients had a steadily progressive course. Dicarboxylic aciduria was detected in nine of 10 patients, and most patients had lactic acidosis, increased serum creatine kinase activities, and low serum carnitine concentration. The discovery of an abnormal dicarboxylic acid excretion profile in urine organic acid screening may serve as an important warning sign that
the patient is very likely not to be a candidate for the KD. A severe syndrome involving multiple acyl-CoA dehydrogenases is glutaric aciduria, type II. This syndrome is so distinctive with multiple congenital malformations in a very sick infant with a characteristic odor of sweaty feet (resembling isovaleric aciduria) that it is unlikely that such a patient would be considered for the KD.
8. Screening of patients at risk and long term monitoring It is clear that a statement suggesting that one should avoid placing a child with seizures on the KD if the child also demonstrates hypotonia and developmental delay, with metabolic acidosis and abnormalities of organic/amino acids, is too general to provide adequate guidance. As it was mentioned earlier, such a child could have pyruvate dehydrogenase deficiency, and hence may stand to benefit significantly from the KD; on the other hand, a child with a primary or acquired carnitine deficiency or a defect in b-oxidation, will sustain significant morbidity if fasted or placed on the KD. If a patient has undergone a muscle biopsy earlier in the work up for hypotonia and weakness, a biopsy showing a few ragged red fibers may not be a contraindication to the diet, but the appearance of a lipid myopathy is. Increased serum pyruvate and lactate along with alaninuria may not be a problem, but increased dicarboxylic acid excretion may hint at a potential for trouble. Patients with a variety of branchedchain amino aciduria and organic aciduria may also have secondary carnitine deficiency. Children who present with a history of seizures, and a history of intermittent encephalopathy with minor infections should be carefully evaluated for the nature of their metabolic abnormality before consideration of the KD. We agree with Demeritte et al. (1996) that organic acid screening should be done prior to and after the initiation of the KD. However, we do not recommend supplementing all patients on the KD routinely with carnitine. We agree with the recommendations from a recent roundtable on the role of L-carnitine supplementation in children
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with epilepsy (De Vivo et al., 1998) that suggests supplementation when a deficiency can be demonstrated. We also suggest that the type of dicarboxylic aciduria be carefully analyzed and interpreted when abnormal organic acid screens are encountered. Evolving dicarboxylic aciduria with emerging carnitine deficiency may occur in a patient who is on both valproic acid (VPA) and the KD. Even though most centers offering the KD have patients who are also on the VPA, a recent study has hinted at the added risk for complications in concomitant therapy with VPA (Ballaban-Gil et al., 1998). The issue of nephrolithiasis is also recognized as a potential complication associated with the KD, but the importance of fluid restriction in patients on the KD is unclear since liberalization of fluids will be expected to lower the risk for this painful complication. Nordli and De Vivo (1997) point out the theoretical possibility of dehydration diminishing tissue perfusion and generating lactate and pyruvate which may compete for the monocarboxylic transport system. In their patients on the KD, the arterial lactate and pyruvate were actually slightly lowered when compared to the control subjects and they recommend adequate hydration. They found that CSF glucose, lactate, and pyruvate were similar in the KD and control groups.
9. Metabolic interactions between anticonvulsants and the KD Since the KD is most commonly used in conjunction with antiepileptic drugs (AED), it is important to identify interactions that may cause adverse reactions, as well as combinations that are particularly efficacious. Concern regarding the combination of topiramate (TPM) with the KD has been expressed because of the recognition that a small percent of patients on TPM (mainly adults) have experienced nephrolithiasis (believed to be secondary to TPMs weak inhibition of carbonic anhydrase). Some centers have discouraged the use of concomitant therapy involving VPA and the KD (see above). The majority of our patients who
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enter the KD present with highly refractory secondary generalized epilepsies, and tend to be on VPA, TPM, or lamotrigine (LTG). It is neither practical nor advisable that their drug therapy be discontinued before a certain measure of seizure control is achieved on the KD. We have not experienced significant complications at our centers with patients who are on concomitant therapy involving KD and VPA even though a theoretical case can be made that VPA interferes with b-oxidation (Kossak et al., 1993; Toksoy et al., 1995). The effect of VPA on carnitine was stated earlier. Carnitine supplementation could be a beneficial strategy when VPA effects on carnitine are of concern. We do not consider the theoretical risk of increasing the likelihood of nephrolithiasis to be an absolute contraindication for those patients who have benefited from this drug at the time of entering the KD. Such theoretical reservations regarding the combined use of TPM and the KD must be considered in light of the demonstrated increased risk posed by the joint use of the KD with either VPA (Ballaban-Gil et al., 1998) or LTG. Most patients with secondary generalized epilepsy that enter the KD are quite young (under the age of ten) and the use of LTG (and felbamate (FBM)) in this group is restricted by the ‘black box warning’ developed by the manufacturers of these drugs and the FDA. Given these conditions, combined use of the KD with either VPA or LTG (or FBM) is unlikely to occur in most practices, leaving TPM as a significant remaining possibility. There are no data available at present on particularly efficacious combinations of the KD with particular AEDs. While our discussions thus far have focused on the aspects of the KD that pertain to energy metabolism, the possibility exists that the structural relationship between BHB, the excitatory neurotransmitter glutamate, and the inhibitory neurotransmitter GABA, would permit a direct effect of BHB on neuronal excitability. Current investigations focus on hypotheses that suggest that BHB antagonizes glutamatergic transmission, or that BHB
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augments GABAergic mechanisms. Any discovery of specific effects of BHB on the functioning of ion channels linked to neurotransmitter receptors would aid in our ability to consider rational combinations of AEDs with the KD. Much more commonly recognized is the derangement in bone mineral metabolism, described in detail by Hahn et al. (1979) that mandates the use of vitamin D and calcium supplements in patients on the KD. Continued practice of the KD with careful clinical observations guided by biochemical and metabolic insights can be expected to improve the efficacy as well safety of this time-honored approach.
10. Summary A basic understanding of the reciprocal relationships of endocrine hormones with energy substrates and intermediates should allow us to implement the KD with a maximum chance for success. Knowledge of some details of energy metabolism provides a rational basis for why the KD is especially effective in certain patients, while it assists us in identifying other patients who may be at risk to sustain a catastrophe. Safety of the patient can be enhanced by an understanding of the possibility of secondary carnitine deficiency while on the KD, especially if the patient is both on the KD and VPA. We have shown why appropriate laboratory testing for diagnosing this complication may include an assessment of carnitine levels as well as urinary excretion patterns of organic acids, with special attention to dicarboxylic aciduria. Only limited information is available at the present time to assist us in making specific recommendations regarding combinations of AEDs with the KD.
Acknowledgements R. Sankar was supported by a Clinical Investigator Development Award, NS 01792 from NINDS, NIH. The authors acknowledge Dr Jong Rho for assistance with some of the illustrations, and for his critical reading of the manuscript.
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