Complications of the Ketogenic Diet

Epilepsia, 39(7):744-748, 1998 Lippincott-Raven Publishers, Philadelphia 0 International League Against Epilepsy Complications of the Ketogenic Diet *f$karen Ballaban-Gil, *fc. Callahan, *fc. O'Dell, SM. Pappo, *f$'s. MoshC, and *?$S. Shinnar "Comprehensive Epilepsy Management Center, and Departments of fneurology, $Pediatrics, $Nutrition, and "Neuroscience, Montefore Medical Center and the Albert Einstein College of Medicine, Bronx, New York, U.S.A. Summary: Purpose: The ketogenic diet has been successfully used in treatment of pediatric epilepsy for >70 years. Few serious complications caused by the diet have been reported. We report complications that have been experienced by children receiving the ketogenic diet. Methods: In a 22-month period, we treated 52 children with the classic ketogenic diet and monitored them in a prospective manner. Results: Five children (10%) experienced serious adverse events (AE) after initiation of the diet. Four patients (80%) were treated with valproate (VPA) in addition to the diet, as compared with 25 (53%) of the other 47 children. Two patients developed severe hypoproteinemia within 4 weeks of initiation of the diet, and 1 of them also developed lipemia and hemolytic anemia. A third child developed Fanconi's renal tubular acidosis within 1 month of diet initiation. Two other children manifested marked increases in liver function tests, 1 during the initiation phase and the other 13 months later. Conclusions: Clinicians who wish to use the ketogenic diet must be aware of the potential of serious AE and possible interactions of the diet with VPA. Key Words: Ketogenic diet-complications-epileps y. The ketogenic diet is a high-fat, low-carbohydrate, low-protein diet used in treatment of pediatric epilepsy since the 1920s (1). Currently, it is used primarily to treat refractory childhood epilepsy (2,3). Few serious complications caused by the classic or modified ketogenic diet have been reported. Short-term complications during the initial hospital stay include.dehydration, hypoglycemia, vomiting, diarrhea, and refusal to eat (2). Long-term complications (1 week to 2 years) include kidney stones (3-5%), recurrent infections (2%), metabolic derangements [hyperuricemia (2%), hypocalcemia (2%), decreased amino acid levels, acidosis (2%)], hypercholesterolemia (29-59%), irritability, lethargy, and refusal to eat (3-9). Very long-term complications (>2 years) have not been reported. In a 22-month period, we treated 52 children aged 1.5-16 years with intractable epilepsy with the classic 4: l-ratio (fats:protein + carbohydrates) ketogenic diet. We report 5 children (10%) who experienced serious adverse events (AE) after initiation of the diet. Accepted February 17, 1998. Address correspondence and reprint requests to Dr. K. Ballaban-Gil at Epilepsy Management Center, Montefiore Medical Center, 11 1 E. 210th St., Bronx, NY 10467-2490, U.S.A. Presented in part at the Annual Meeting of the Child Neurology Society, Minneapolis, Minnesota, September 2628, 1996. MATERIALS AND METHODS From November 1994 to August 1996, the classic ketogenic diet was initiated in 52 children with refractory epilepsy aged 18 months to 16.5 years (mean age 6.63 years). The protocol of the Johns Hopkins Hospital (2) was used, and the children were monitored prospectively. Eight of the children were also enrolled in a multicenter prospective study of the efficacy of the ketogenic diet (10). Caloric intake ranged from 40 to 75 calories (cal)/kg, with older children receiving fewer calories per kilogram. The minimum protein provided for children aged <12 years was 1 g/kg/day. Most patients were started on a diet with a ratio of 4: 1, although children aged <2 years and.adolescents received lower ratios. RESULTS Patient characteristics The characteristics of the entire group in whom the ketogenic diet was initiated as compared with the 5 children who developed serious complications are shown in Table 1. Because of the small number of children with complications, we were not able to make meaningful statistical comparisons beyond the descriptive data shown in Tabre 1. Although a higher percentage of children in the group with complications were receiving 744

KETOGENIC DIET COMPLICATIONS 745 TABLE 1. Characteristics of total patient group and of 5 who developed complications while receiving the ketogenic diet Total group No complications Complications Parameter (n = 52) (n = 47) (n = 5) Mean age (yr) 6.63 6.82 5.75 Sex distribution (W), n ("/.I 31 (60)/21(40) 27 (57)/20(43) 4 (80)/1 (20) No. receiving AEDs at time of diet initiation (%) No. receiving VPA at diet 50 (98) 45 (96) 5 (loo) initiation (%) No. receiving polypharmacy 29 (56) 25 (53) 4 (80) at diet initiation (%) 29 (56) 25 (53) 4 (80) AEDs, antiepileptic drugs; VPA, valproate. polypharmacy at the time of initiation of the ketogenic diet, there was no difference in the severity of their epilepsy as compared with that of the group without complications. All children, both those with and without complications, had poorly controlled, intractable epilepsy. All had failed treatment with at least three conventional antiepileptic drugs (AEDs), and all but 3 of the children had been treated with polypharmacy previously, although some were no longer receiving polypharmacy at the time of diet initiation. Patient 1 Patient 1, a 2X-year-old boy, had had intractable myoclonic epilepsy since the first week of life, severe global developmental impairment, and spastic quadriparesis. At the time of initiation of the ketogenic diet, he was treated with nitrazepam and felbamate. The diet was initiated at 68 cal/kg/day in a ratio of 4: 1, with 1 g/kg/day protein, through G-tube. Initial laboratory values were as follows: hematocrit level 36%, total serum protein 7.3 g/dl (normal 6.3-8.2 g/dl) and serum albumin 4.9 g/dl (normal 3.9-5.0 g/dl). Within 2 weeks, the boy developed peda! edema. Thirteen days after the diet was started, his total serum protein was 2.6 g/dl and serum albumin was 1.6 g/dl. Dietary protein intake was increased. Twenty-one days after initiation of the diet, he was admitted to the hospital with presacral and periorbital edema. Total serum protein was 2.6 g/dl, serum albumin was 1.4 g/dl, and serum triglycerides were >5,000 mg/dl (normal 50-200 mg/dl). No source of protein loss was identified: The urine did not contain protein, and there was no diarrhea to indicate protein-losing enteropathy. At the same time, he developed hemolytic anemia. The hematocrit level was 19.7%. The peripheral smear demonstrated a high reticulocyte count and spherocytes, consistent with hemolysis. Platelet count was >1 million, and white blood cell count was 25,700 k/mm3, with a left shift. He was treated with blood transfusions. The ketogenic diet was discontinued. He was placed on a high-protein diet, and within 1 week the edema resolved and the abnormal laboratory values returned to normal. Patient 2 Patient 2, a 22-month-old boy with myoclonic encephalopathy, had onset of seizures at 19 days of age, and manifested severe global developmental impairment. At the time of initiation of the ketogenic diet, he was being treated with VPA, 53 mg/kg/day, with a trough VPA level of 118 p,g/ml. The diet was initiated at 76 cal/kg/ day at a ratio of 3.51, with 1.27 g/kg/day protein. Initial laboratory values were total serum protein 6.3 g/dl, serum albumin 4.0 g/dl, and serum potassium 4.6 meq/l (normal 3.5-5.0 meq/l). Fifteen days after initiation of the diet, because he had a weight loss of 0.5 kg, calories were increased to 94 cal/kg/day. Ten days later (25 days after diet initiation), because of his continuing weight loss, caloric intake was again increased to 116 cal/kg/ day, with 1.5 g/kg/day protein. Twenty-eight days after initiation of the diet, his weight had decreased by 0.77 kg. Total serum protein was 4.4 g/dl, serum albumin was 2.8 g/dl, and serum potassium was 2.9-3.1 mjtq/l. The urine did not contain protein, and he had no diarrhea. The diet was continued because seizure control had improved. Daily protein intake was increased to 2.25 g/kg/ day and potassium supplementation 10 meq/day was added. In the next 14 days, his weight gradually increased, serum total protein increased, and serum potassium stabilized at 3.8-4.5 meq/l. Patient 3 Patient 3, a 12-year-old girl, had a history of intractable epilepsy and mild cognitive impairment after receiving intrathecal methotrexate and CNS radiation for leukemia in infancy. For the 3-year period before initiation of the ketogenic diet, she was treated with VPA 41 rn@g/day and phenytoin (PI-IT) 4.3 mg/kg/day, with a trough W A level of 36 p,g/ml. The ketogenic diet was initiated at another institution, with a protocol different from the classic ketogenic diet. Six months after initiation of that diet, because of poor seizure control, we changed the diet to the classic ketogenic diet at 35 c&g/day, at a ratio of 3.5:l with 0.76 g/kg/day protein. Daily fluid allowance was 1,200 ml/day, which is adequate to maintain a normal state of hydration.

746 K. BALLABAN-GIL ET AL. At the time of reinitiation of the diet, serum potassium was 3.8 meq/l, serum creatinine was 0.9 mg/dl (normal 0.5-1.5 mg/dl), and serum CO, was 17 meq/l (normal 22-30 meq/l). Twenty-three days later, she developed weakness and palpitations. Laboratory values were remarkable for serum potassium of 3.0 W/L, serum creatinine of 1.7 mg/dl, serum blood urea nitrogen (BUN) of 26 mg/dl, and serum CO, of 10 meq/l. She was orally rehydrated, her fluid allowance was increased, and potassium supplements were initiated. Serum creatinine and BUN levels returned to normal. She remained hypocarbic (serum CO, 9-16 meq/ L). Urinalysis showed trace to 1+ proteinuria. She required 60 meq/day potassium supplementation to maintain serum potassium in the normal range. Approximately 2 months later, she was hospitalized with vomiting and dehydration. Laboratory values at the time of hospital admission were serum CO, c5 meq/l, with an anion gap of 19. Worhp showed Fanconi's renal tubular acidosis, believed to be secondary to VPA treatment (1 1). She was treated with intravenous rehydration and electrolyte replacement and stabilized with polycitra-k" and bicarbonate supplementation; VPA was discontinued. Within l month, while she remained on the diet, the renal tubular acidosis resolved and she was successfully weaned off polycitra-k+ and bicarbonate supplements. Patient 4 Patient 4, a 6-year-old boy, had had global developmental delay and intractable myoclonic epilepsy since age 3% months. At the time of initiation of ketogenic diet, he was being treated with VPA 17 mg/kg/day and lorazepam (LZP) 0.16 mg/kg/day. He had been treated with stable doses of VPA since age 15 months, with a nontrough VPA level of 100 p,g/ml. The ketogenic diet was initiated at another institution and was reinitiated at our institution 7 months later at 59 calkgldayat a ratio of 4:l. Seven months after reinitiation of the diet, he developed viral gastroenteritis and was admitted to the hospital. Serum laboratory values were ammonia 203 p,g/dl (normal 15-45 pg/dl), lactate dehydrogenase (LDH) 6,260 U/L (normal 60-250 U/L), SGOT 8,580 U/L (normal 5-40 U/L), SGPT 10,080 U/L (normal 5-40 U/L), total protein level 5.3 g/dl, albumin level 2.9 g/dl, and glucose level 78 mg/dl. Liver biopsy showed microvascular steatosis in acinar zones 1 and 2 and necrosis in acinar zone 3, consistent with VPA toxicity. Free serum carnitine levels were low. VPA was discontinued. The diet was maintained. Carnitine supplementation was started, and the patient received supportive care. Results of liver function tests were normal within 2 weeks. Patient 5 Patient 5, a 6-year 8-month-old boy, had a history of autism and Lennox-Gastaut syndrome. At the time the ketogenic diet was initiated, he was treated with 64 mg/ kg/day VPA and 0.04 mg/kg/day clonazepam (CZP). He had been treated with VPA for >4 years, with dosage increased in the 4 months before initiation of the diet, which was started at 48 cal/kg/day at a ratio of 4:l. Laboratory values 1 week before initiation of the diet included a platelet count of 150,000 k/p1, serum SGOT 100 U/L and serum SGPT 40 U/L, with a VPA trough level of 158 p,g/ml. During the fasting phase of initiation of the diet, his liver functions increased, with serum SGOT peaking at 283 U/L and serum SGPT peaking at 120 U/L. At the same time, platelet count decreased, with a nadir of 40,000 k/mm3. VPA was discontinued, and in 5-7 days both the liver function tests and the platelet count returned to normal. The patient continued the ketogenic diet, and seizure control improved. DISCUSSION We report 5 children who experienced serious, potentially life-threatening complications while treated with the ketogenic diet. Approximately 10% of the patients in whom the diet was initiated at our center experienced serious complications. Four of the five complications occurred within 1 month after initiation of the diet. The fifth complication occurred 7 months after initiation of the classic ketogenic diet, possibily precipitated by an intercurrent illness. Patient 5 had a brief episode of increase in liver function tests, which is commonly associated with VPA treatment, even in patients receiving a stable dosage of medication. However, because of the temporal relationship between the initiation of the diet and the increase in the liver function tests, as well as the concomitant onset of thrombocytopenia, we believe that this complication was a rekult of the ketogenic diet. The etiology of these AE remains unclear. Patients 1 and 2 had precipitous decreases in serum total protein with no evidence of protein loss, while receiving adequate dietary protein. One possible mechanism is an underlying inborn error of metabolism, specifically a disorder of fatty acid metabolism or mitochondria1 dysfunction. If such underlying disorders did exist, the patients would have been unable to metabolize the fatty acids that constitute most of the calories in the diet. In the face of significantly reduced caloric intake (because of the inability to metabolize fats), the body tissues would therefore have to rely on breakdown of body proteins for energy metabolism, which would lead to protein depletion. However, we were not able to demonstrate any such inborn errors of metabolism in our patients. The complications in patients 3-5 may have been due to an adverse interaction between the ketogenic diet and VPA therapy, with the diet in some way potentiating

KETOGENIC DIET COMPLICATIONS 74 7 either the idiosyncratic or the dose-related toxicity of VPA. It is noteworthy that there appeared to be no relationship between the VPA dosage or level and the development of presumed VPA toxicity, although we could not make meaningful statistical comparisons because of the small number of children with complications. The mechanism of interaction between the ketogenic diet and VPA in the development of renal tubular acidosis in patient 3 is not known, but because of the temporal relationship between reinitiation of the diet and onset of symptoms, we believe that the diet in some way precipitated the development of this complication. Neither do we know the mechanism of interaction between the ketogenic diet and VPA in the development of hepatotoxicity in patients 4 and 5, but it may involve either impairment of fatty acid oxidation by VPA and/or the additive effects of VPA and the ketogenic diet in the development of carnitine deficiency. VPA inhibits oxidative phosphorylation (1 2,13). In addition one study demonstrated that liver glycogen content is reduced by 6680% in infant mice treated with VPA (14). The ketogenic diet utilizes high amounts of dietary fats, particularly long-chain fatty acids, and low amounts of protein and carbohydrates. If fatty acid oxidation cannot be accelerated in patients because of inhibition by VPA, reduced glycogen stores (secondary to chronic VPA administration), and insufficient dietary intake of protein and carbohydrates to maintain blood glucose and glycogen stores, a Reye syndrome-like hepatocerebral toxicity may occur. The occurrence of hepatotoxicity in patient 5 during the fasting stage and in patient 4 during an episode of viral gastroenteritis may represent the additive effects of the ketogenic diet and VPA and increased susceptibility to the nutritional deprivation associated with relative starvation. Another possible mechanism for the development of hepatotoxicity in our patients is carnitine deficiency. The role of carnitine deficiency in VPA-induced hepatotoxicity is unclear, but carnitine deficiency has been demonstrated in some patients with VPA-induced hepatotoxicity (15). Patients treated with VPA have been shown to have lower mean serum levels of total and free carnitine (15). Those particularly at risk for low carnitine levels include younger children (age 1-10 years), patients receiving polypharmacy, and patients with multiple disabilities (15). The mechanism of carnitine depletion is not known but may be related to impairment of tissue carnitine uptake and increased renal excretion of carnitine in patients treated with VPA (15). Similarly, carnitine deficiency has been demonstrated in children receiving the ketogenic diet (16,17). Dietary sources that are particularly rich in carnitine include red meat and milk. The intake of red meat is quite restricted on the ketogenic diet, and milk is completely absent. Thus, there may be decreased dietary intake of carnitine. Because the keto- genic diet is high in long-chain fatty acids, utilization of carnitine also may be increased. Therefore, in patients treated with both the ketogenic diet and VPA, there may be an additive effect, resulting in carnitine deficiency significant enough to cause or aggravate hepatotoxicity. In the present study, the percentage of children treated with VPA and polypharmacy was higher in the group with complications than in the group without complications. Because of the small number of children with complications, we could not make meaningful statistical comparisons. 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