Original research paper
The impact of the modified Atkins diet on lipid profiles in adults with epilepsy Mackenzie C. Cervenka1, Katlyn Patton 1*, Ani Eloyan 2, Bobbie Henry 3, Eric H. Kossoff1,4 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA, 3Institute for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Pro of
1
cor rec t
ed
Objectives: The modified Atkins diet (MAD) is a high fat, low carbohydrate ketogenic diet used to treat intractable seizures in children and adults. The long-term impact on fasting lipid profiles (FLPs) remains unknown. This study was designed to detect significant lipid changes in adults on MAD. Methods: Patients were observed prospectively. A FLP was obtained in all patients at the first visit then serially. Patients were started on a 20 g per day net carbohydrate limit MAD. They were screened for risk for coronary heart disease and counseled to reduce saturated fats by a registered dietitian if deemed at risk. Patients that remained on MAD for 3 or more months with one or more follow-up FLP were included. Results: Thirty-seven patients (14 male), mean age 33 years (SD 13, range 18–59) met study criteria. Median diet duration was 16 months (range 3–41). Total cholesterol and low-density lipoprotein (LDL) increased significantly over the first 3 months of MAD (P = 0.01 and 0.008, respectively), but were not significantly different from baseline after 1 year of treatment (P = 0.2 and P = 0.5, respectively). High-density lipoprotein levels trended upward in the first 3 months (P = 0.05) and triglycerides remained unchanged (P = 0.5). In 12 patients followed for 3 or more years, no cardiovascular or cerebrovascular events were reported. Discussion: Although total cholesterol and LDL increased over the first 3 months of the MAD, these values normalized within a year of treatment, including in patients treated with MAD for more than 3 years. Keywords: Cholesterol, Lipoprotein, Triglycerides, Hyperlipidemia, Ketogenic diet, Modified Atkins diet, Seizure, Epilepsy
Introduction
Un
Ketogenic diets (KDs) such as the classical KD and the modified Atkins diet (MAD) have been shown to be effective treatments for medically resistant seizures in children and are being used increasingly in adults with refractory epilepsy.1–4 KD is typically a 4:1 ratio (fat: carbohydrates and protein grams) diet, resulting in approximately 90% daily caloric intake provided by fat1 and approximately 2% provided by carbohydrates. Elevated total cholesterol and low-density lipoprotein (LDL) levels have been documented in children on KD5–7 but have been shown to improve with long-term treatment in some patients.8,9 Many children are weaned off of KD after several months to years after seizures cease or they transition out of pediatric Correspondence to: Mackenzie C. Cervenka, Department of Neurology, Johns Hopkins Hospital, 600 North Wolfe Street, Meyer 2–147, Baltimore, MD 21287, USA. Email: [email protected] *Institutional affiliations listed are from the time the manuscript was written. Katlyn Patton’s current affiliation is with Villanova University, Villanova, PA 19085, USA.
© W. S. Maney & Son Ltd 2014 DOI 10.1179/1476830514Y.0000000162
diet clinics,10 so long-term consequences may not be fully appreciated. Chronic elevations in LDL and total cholesterol may increase risk for coronary heart disease or cerebrovascular disease in adults using lifelong KD therapy.7,11 The MAD is a less restrictive alternative to the classical KD and limits net carbohydrates (subtracting fiber) to 10–20 g per day while fat intake is encouraged ad libitum.1 This has been shown in adults to result in approximately a 1:1 ratio of fat to carbohydrates and protein or nearly 70% kilocalorie per day fat intake12 and intake of saturated fat is not restricted. The National Institutes of Health Adult Treatment Panel (ATP) III guidelines13 stratify patients for coronary heart disease risk based on gender, age, history of cigarette smoking, hypertension, family history of premature coronary heart disease, presence of clinical atherosclerotic disease, and fasting high-density lipoprotein (HDL) levels, and provide recommendations on goal LDL levels based on risk category. The
Nutritional Neuroscience
2014
VOL.
0
NO.
0
1
The impact of the modified Atkins diet on lipid profiles in adults with epilepsy
guidelines define therapeutic lifestyle changes that reduce cardiovascular risk to include 17 years) that attended the Adult Epilepsy Diet Center between August 2010 and August 2013 who were beginning the MAD for the first time and had not tried a KD therapy previously. Written consent was obtained from all participants or their legally authorized representative to participate in the study and the study was approved by the Johns Hopkins Institutional Review Board. All participants were started on a 20 g per day net carbohydrate limit MAD. Patients were asked to keep a record of their seizures daily, urine ketone levels biweekly (as a biomarker of dietary compliance), and weights weekly. Increased fat intake was encouraged with the goal of achieving consistent (biweekly) moderate (40 mg/dl) to large (80–160 mg/dl) urinary ketosis. Clinic follow-up took place at 1–3 months, 4–9 months, and 1–2 years, determined by clinical circumstances and level of adherence with MAD. Those patients that remained on MAD for a minimum of 3 months and attended regular follow-up visits were included in the study. Demographic and clinical data included age, gender, age at the time of seizure onset, seizure type, number of anti-epileptic drugs tried, weight, height, history of cigarette smoking, hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, and family history of premature coronary heart disease. Coronary heart disease risk factors were calculated for each patient at the time of diet initiation using current ATP III Cholesterol Guidelines and at subsequent visits. Baseline fasting LDL, HDL, total
cholesterol, and triglyceride values were obtained at baseline and repeated at subsequent visits whenever possible. ATP III Cholesterol Guidelines were followed in addressing elevated FLP by providing patients who met criteria for increased coronary artery risk with additional counseling regarding using ‘Heart Healthy’ fats, emphasizing unsaturated rather than saturated fats (Fig. 1). Free and total serum carnitine levels were also checked and repleted if a carnitine deficiency was detected. A random effects model with a spline term was used to examine changes in lipid composition from baseline to 1, 3, 6, 12, and 24 months after starting the MAD to determine whether there was a significant change at each time interval and the same model was used to examine changes in seizure frequency over time (P < 0.05) after correcting for covariates age, sex, and body mass index (BMI). In addition, subject specific intercepts and slopes were used to account for within subject variability. Assuming Yij = total cholesterol level for subject i at visit j, the number of months the patient has been on the diet before visit j + + is defined as tj . If t+ j = (tj − 3) , i.e. tj = 0, if tj ≤ 3 + and tj = (tj − 3), if tj > 3, then Yij = β0 + β1 tj + β2 t+ j + β3 Xij + ui + εij , where ui is the random effect term for subject i, εij are the error terms, and Xij is the vector of covariates for subject i at visit j. This model is based on the hypothesis that the trends in the total cholesterol, LDL, HDL, and triglyceride levels may change after being on the diet for 3 months.
Pro of
Cervenka et al.
2
Nutritional Neuroscience
2014
VOL.
0
NO.
0
Results Thirty-seven patients started the MAD for a minimum of 3 months with baseline and one or more follow-up FLPs obtained (Table 1). Of note, the group included two patients that elected to try MAD instead of starting a first anti-seizure drug and two patients that tried MAD instead of beginning a second ASD, therefore, not all patients were considered drug resistant at the time of diet initiation. At the time of data analysis, 33 patients (89%) had been on MAD for 6 or more months, 27 (73%) for 1 or more years, and 12 (32%) for 2 or more years. Seven patients (19%) had elected to stop the diet and four (11%) were lost to follow-up after 3 or more months, while the remainder continued the diet. Fifty additional patients initially consented to be followed and of these, 17 never started MAD, 18 remained on MAD for fewer than 3 months, and 15 for more than 3 months but never received recommended lipid testing. Therefore, these patients were excluded from the analysis. Mean total cholesterol, LDL, HDL, and triglyceride levels at baseline, 1, 3, 6, 12, and 24 months are shown in Table 2. Of note, only a subset of patients received labs within each described time interval.
The impact of the modified Atkins diet on lipid profiles in adults with epilepsy
ed
Pro of
Cervenka et al.
cor rec t
Figure 1 ‘Heart-healthy’ recommendations provided to patients in the Adult Epilepsy Diet Center whose cholesterol panel suggests an increased risk of coronary artery disease based on National Institutes of Health Adult Treatment Panel III guidelines. Table 1 Participant demographics (n = 37) Female gender Age at first seizure (years) Age at start of diet (years) Anti-seizure drugs tried Generalized seizure disorder Focal or multifocal seizure disorder Other seizure disorder Coronary heart disease risk factors
23 (62%) 11 (0–57) 28 (18–59) 6 (0–13) 8 (21.6%) 28 (75.7%) 1 (2.7%) 0 (0–2)
Un
Values are expressed as median (range) or number (percentage of n participants enrolled).
Thirty-three of 37 patients provided reports of ketone levels biweekly and of these, 27 (82%) achieved at least moderate (40 mg/dl or higher) urinary ketosis during treatment, indicating dietary compliance. Within the first month on MAD, total cholesterol level increased by an average of 28.5 mg/dl. Within
the first 3 months of diet initiation, cholesterol levels increased by an average of 8.9 mg/dl per month (P = 0.01) for patients with the same age, gender, and BMI. The estimate for the average rate of change per month of cholesterol level within 1 month after the 3-month visit based on this model was computed as −10.9 mg/dl per month (P = 0.008). None of the covariates were significantly associated with total cholesterol levels. Assuming a linear trend in cholesterol level over the initial 12-month period, a multiple regression model with random effects revealed that total cholesterol levels did not change significantly from baseline by 12 months (P = 0.2). Similar findings were seen for LDL levels which increased on average by 7.9 mg/dl (P = 0.008) per month during the first 3 months of diet initiation while correcting for age, sex, and BMI. The estimated
Table 2 Baseline and follow-up lipid levels at 1 month, 3 months, 6 months, 12 months, and 24 months in adults on the MAD (mean (standard deviation)) Plasma level (mg/dl)
Baseline (n = 37)
1 month (n = 8)
3 months (n = 30)
6 months (n = 13)
12 months (n = 9)
24 months (n = 5)
Total cholesterol LDL HDL TG
190 (55) 117 (40) 57 (25) 86 (42)
204 (43) 130 (40) 60 (25) 61 (20)
205 (55) 130 (46) 62 (22) 77 (34)
200 (35) 131 (35) 56 (15) 85 (47)
188 (42) 115 (38) 59 (19) 68 (31)
166 (22) 97 (28) 57 (13) 60 (30)
n = number of patients for whom fasting lipid panels were obtained at each follow-up time point.
Nutritional Neuroscience
2014
VOL.
0
NO.
0
3
The impact of the modified Atkins diet on lipid profiles in adults with epilepsy
levels decreased overall but no changes were statistically significant (P = 0.482 and P = 0.5719 for before and after 3 months of diet initiation, respectively). Fig. 2 indicates the estimated changes over time for each patient studied including a line fitted to these changes based on the model for each cholesterol value. During the course of treatment, eight patients qualified for recommended therapeutic lifestyle changes based on ATP III guidelines and received hearthealthy counseling (Fig. 1). One of these patients was found to have a carnitine deficiency which was repleted and LDL normalized. In three patients, LDL normalized after following these recommendations. Three patients stopped the diet for reasons unrelated to lipid levels without any additional follow-up. One patient was on statin therapy (20 mg of simvastatin) before beginning MAD with elevated LDL (164 mg/dl) and total cholesterol (264 mg/dl) at baseline and was immediately provided with heart-healthy
Un
cor rec t
ed
average rate of change of LDL within 1 month before and after the 3-month visit based on this model can be computed as −9.768 mg/dl per month (P = 0.007) per month. None of the covariates in the model were significantly associated with changes in LDL. A multiple regression model with random effects revealed that assuming a linear trend in LDL level over the initial 12-month period of treatment, LDL levels did not change significantly from baseline by 12 months (P = 0.5). Before 3 months, the HDL increased marginally by 2.2 mg/dl monthly (P = 0.048). However, unlike total cholesterol and LDL, the trend did not change significantly after 3 months; the estimated change in the trend was a decrease by −0.204 mg/dl monthly. We also found significant differences in the HDL based on patient’s gender after correcting for the other covariates. HDL in male patients was on average 18.395 mg/dl (P = 0.006) lower compared to female patients at all time points. The trend in the triglyceride
Pro of
Cervenka et al.
Figure 2 Total cholesterol (A), LDL (B), HDL (C), and triglyceride (D) levels plotted over time on the MAD using a random effects model with two linear spline terms. Points represent values (mg/dl) for all patients plotted over 0–24 months. Light gray lines represent cholesterol trends over time. Dark gray lines show the average of these values.
4
Nutritional Neuroscience
2014
VOL.
0
NO.
0
not maintained (levels decreased below 40 mg/dl at least once) during the entire treatment despite report of continued diet adherence. Loss of ketosis did not correspond with changes in FLPs in these patients.
Discussion The MAD is a promising therapy for adults with medically and surgically refractory epilepsy.4,12,16 However, little is known regarding potential long-term consequences of this high fat diet in the adult population with a potential increased risk of hyperlipidemia resulting in cardiovascular and cerebrovascular complications. In this prospective study of 37 adults started on a 20 g per day net carbohydrate limit MAD, LDL and total cholesterol increased significantly in the first 3 months on the diet. However, in those patients that elected to continue the diet for 12 or more months, values normalized. HDL initially trended upward and triglycerides trended downward but not significantly. No cardio- or cerebrovascular events were reported. Current National Institutes of Health ATP III guidelines13 recommend intake of
The impact of the modified Atkins diet on lipid profiles in adults with epilepsy Mackenzie C. Cervenka1, Katlyn Patton 1*, Ani Eloyan 2, Bobbie Henry 3, Eric H. Kossoff1,4 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA, 3Institute for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Pro of
1
cor rec t
ed
Objectives: The modified Atkins diet (MAD) is a high fat, low carbohydrate ketogenic diet used to treat intractable seizures in children and adults. The long-term impact on fasting lipid profiles (FLPs) remains unknown. This study was designed to detect significant lipid changes in adults on MAD. Methods: Patients were observed prospectively. A FLP was obtained in all patients at the first visit then serially. Patients were started on a 20 g per day net carbohydrate limit MAD. They were screened for risk for coronary heart disease and counseled to reduce saturated fats by a registered dietitian if deemed at risk. Patients that remained on MAD for 3 or more months with one or more follow-up FLP were included. Results: Thirty-seven patients (14 male), mean age 33 years (SD 13, range 18–59) met study criteria. Median diet duration was 16 months (range 3–41). Total cholesterol and low-density lipoprotein (LDL) increased significantly over the first 3 months of MAD (P = 0.01 and 0.008, respectively), but were not significantly different from baseline after 1 year of treatment (P = 0.2 and P = 0.5, respectively). High-density lipoprotein levels trended upward in the first 3 months (P = 0.05) and triglycerides remained unchanged (P = 0.5). In 12 patients followed for 3 or more years, no cardiovascular or cerebrovascular events were reported. Discussion: Although total cholesterol and LDL increased over the first 3 months of the MAD, these values normalized within a year of treatment, including in patients treated with MAD for more than 3 years. Keywords: Cholesterol, Lipoprotein, Triglycerides, Hyperlipidemia, Ketogenic diet, Modified Atkins diet, Seizure, Epilepsy
Introduction
Un
Ketogenic diets (KDs) such as the classical KD and the modified Atkins diet (MAD) have been shown to be effective treatments for medically resistant seizures in children and are being used increasingly in adults with refractory epilepsy.1–4 KD is typically a 4:1 ratio (fat: carbohydrates and protein grams) diet, resulting in approximately 90% daily caloric intake provided by fat1 and approximately 2% provided by carbohydrates. Elevated total cholesterol and low-density lipoprotein (LDL) levels have been documented in children on KD5–7 but have been shown to improve with long-term treatment in some patients.8,9 Many children are weaned off of KD after several months to years after seizures cease or they transition out of pediatric Correspondence to: Mackenzie C. Cervenka, Department of Neurology, Johns Hopkins Hospital, 600 North Wolfe Street, Meyer 2–147, Baltimore, MD 21287, USA. Email: [email protected] *Institutional affiliations listed are from the time the manuscript was written. Katlyn Patton’s current affiliation is with Villanova University, Villanova, PA 19085, USA.
© W. S. Maney & Son Ltd 2014 DOI 10.1179/1476830514Y.0000000162
diet clinics,10 so long-term consequences may not be fully appreciated. Chronic elevations in LDL and total cholesterol may increase risk for coronary heart disease or cerebrovascular disease in adults using lifelong KD therapy.7,11 The MAD is a less restrictive alternative to the classical KD and limits net carbohydrates (subtracting fiber) to 10–20 g per day while fat intake is encouraged ad libitum.1 This has been shown in adults to result in approximately a 1:1 ratio of fat to carbohydrates and protein or nearly 70% kilocalorie per day fat intake12 and intake of saturated fat is not restricted. The National Institutes of Health Adult Treatment Panel (ATP) III guidelines13 stratify patients for coronary heart disease risk based on gender, age, history of cigarette smoking, hypertension, family history of premature coronary heart disease, presence of clinical atherosclerotic disease, and fasting high-density lipoprotein (HDL) levels, and provide recommendations on goal LDL levels based on risk category. The
Nutritional Neuroscience
2014
VOL.
0
NO.
0
1
The impact of the modified Atkins diet on lipid profiles in adults with epilepsy
guidelines define therapeutic lifestyle changes that reduce cardiovascular risk to include 17 years) that attended the Adult Epilepsy Diet Center between August 2010 and August 2013 who were beginning the MAD for the first time and had not tried a KD therapy previously. Written consent was obtained from all participants or their legally authorized representative to participate in the study and the study was approved by the Johns Hopkins Institutional Review Board. All participants were started on a 20 g per day net carbohydrate limit MAD. Patients were asked to keep a record of their seizures daily, urine ketone levels biweekly (as a biomarker of dietary compliance), and weights weekly. Increased fat intake was encouraged with the goal of achieving consistent (biweekly) moderate (40 mg/dl) to large (80–160 mg/dl) urinary ketosis. Clinic follow-up took place at 1–3 months, 4–9 months, and 1–2 years, determined by clinical circumstances and level of adherence with MAD. Those patients that remained on MAD for a minimum of 3 months and attended regular follow-up visits were included in the study. Demographic and clinical data included age, gender, age at the time of seizure onset, seizure type, number of anti-epileptic drugs tried, weight, height, history of cigarette smoking, hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, and family history of premature coronary heart disease. Coronary heart disease risk factors were calculated for each patient at the time of diet initiation using current ATP III Cholesterol Guidelines and at subsequent visits. Baseline fasting LDL, HDL, total
cholesterol, and triglyceride values were obtained at baseline and repeated at subsequent visits whenever possible. ATP III Cholesterol Guidelines were followed in addressing elevated FLP by providing patients who met criteria for increased coronary artery risk with additional counseling regarding using ‘Heart Healthy’ fats, emphasizing unsaturated rather than saturated fats (Fig. 1). Free and total serum carnitine levels were also checked and repleted if a carnitine deficiency was detected. A random effects model with a spline term was used to examine changes in lipid composition from baseline to 1, 3, 6, 12, and 24 months after starting the MAD to determine whether there was a significant change at each time interval and the same model was used to examine changes in seizure frequency over time (P < 0.05) after correcting for covariates age, sex, and body mass index (BMI). In addition, subject specific intercepts and slopes were used to account for within subject variability. Assuming Yij = total cholesterol level for subject i at visit j, the number of months the patient has been on the diet before visit j + + is defined as tj . If t+ j = (tj − 3) , i.e. tj = 0, if tj ≤ 3 + and tj = (tj − 3), if tj > 3, then Yij = β0 + β1 tj + β2 t+ j + β3 Xij + ui + εij , where ui is the random effect term for subject i, εij are the error terms, and Xij is the vector of covariates for subject i at visit j. This model is based on the hypothesis that the trends in the total cholesterol, LDL, HDL, and triglyceride levels may change after being on the diet for 3 months.
Pro of
Cervenka et al.
2
Nutritional Neuroscience
2014
VOL.
0
NO.
0
Results Thirty-seven patients started the MAD for a minimum of 3 months with baseline and one or more follow-up FLPs obtained (Table 1). Of note, the group included two patients that elected to try MAD instead of starting a first anti-seizure drug and two patients that tried MAD instead of beginning a second ASD, therefore, not all patients were considered drug resistant at the time of diet initiation. At the time of data analysis, 33 patients (89%) had been on MAD for 6 or more months, 27 (73%) for 1 or more years, and 12 (32%) for 2 or more years. Seven patients (19%) had elected to stop the diet and four (11%) were lost to follow-up after 3 or more months, while the remainder continued the diet. Fifty additional patients initially consented to be followed and of these, 17 never started MAD, 18 remained on MAD for fewer than 3 months, and 15 for more than 3 months but never received recommended lipid testing. Therefore, these patients were excluded from the analysis. Mean total cholesterol, LDL, HDL, and triglyceride levels at baseline, 1, 3, 6, 12, and 24 months are shown in Table 2. Of note, only a subset of patients received labs within each described time interval.
The impact of the modified Atkins diet on lipid profiles in adults with epilepsy
ed
Pro of
Cervenka et al.
cor rec t
Figure 1 ‘Heart-healthy’ recommendations provided to patients in the Adult Epilepsy Diet Center whose cholesterol panel suggests an increased risk of coronary artery disease based on National Institutes of Health Adult Treatment Panel III guidelines. Table 1 Participant demographics (n = 37) Female gender Age at first seizure (years) Age at start of diet (years) Anti-seizure drugs tried Generalized seizure disorder Focal or multifocal seizure disorder Other seizure disorder Coronary heart disease risk factors
23 (62%) 11 (0–57) 28 (18–59) 6 (0–13) 8 (21.6%) 28 (75.7%) 1 (2.7%) 0 (0–2)
Un
Values are expressed as median (range) or number (percentage of n participants enrolled).
Thirty-three of 37 patients provided reports of ketone levels biweekly and of these, 27 (82%) achieved at least moderate (40 mg/dl or higher) urinary ketosis during treatment, indicating dietary compliance. Within the first month on MAD, total cholesterol level increased by an average of 28.5 mg/dl. Within
the first 3 months of diet initiation, cholesterol levels increased by an average of 8.9 mg/dl per month (P = 0.01) for patients with the same age, gender, and BMI. The estimate for the average rate of change per month of cholesterol level within 1 month after the 3-month visit based on this model was computed as −10.9 mg/dl per month (P = 0.008). None of the covariates were significantly associated with total cholesterol levels. Assuming a linear trend in cholesterol level over the initial 12-month period, a multiple regression model with random effects revealed that total cholesterol levels did not change significantly from baseline by 12 months (P = 0.2). Similar findings were seen for LDL levels which increased on average by 7.9 mg/dl (P = 0.008) per month during the first 3 months of diet initiation while correcting for age, sex, and BMI. The estimated
Table 2 Baseline and follow-up lipid levels at 1 month, 3 months, 6 months, 12 months, and 24 months in adults on the MAD (mean (standard deviation)) Plasma level (mg/dl)
Baseline (n = 37)
1 month (n = 8)
3 months (n = 30)
6 months (n = 13)
12 months (n = 9)
24 months (n = 5)
Total cholesterol LDL HDL TG
190 (55) 117 (40) 57 (25) 86 (42)
204 (43) 130 (40) 60 (25) 61 (20)
205 (55) 130 (46) 62 (22) 77 (34)
200 (35) 131 (35) 56 (15) 85 (47)
188 (42) 115 (38) 59 (19) 68 (31)
166 (22) 97 (28) 57 (13) 60 (30)
n = number of patients for whom fasting lipid panels were obtained at each follow-up time point.
Nutritional Neuroscience
2014
VOL.
0
NO.
0
3
The impact of the modified Atkins diet on lipid profiles in adults with epilepsy
levels decreased overall but no changes were statistically significant (P = 0.482 and P = 0.5719 for before and after 3 months of diet initiation, respectively). Fig. 2 indicates the estimated changes over time for each patient studied including a line fitted to these changes based on the model for each cholesterol value. During the course of treatment, eight patients qualified for recommended therapeutic lifestyle changes based on ATP III guidelines and received hearthealthy counseling (Fig. 1). One of these patients was found to have a carnitine deficiency which was repleted and LDL normalized. In three patients, LDL normalized after following these recommendations. Three patients stopped the diet for reasons unrelated to lipid levels without any additional follow-up. One patient was on statin therapy (20 mg of simvastatin) before beginning MAD with elevated LDL (164 mg/dl) and total cholesterol (264 mg/dl) at baseline and was immediately provided with heart-healthy
Un
cor rec t
ed
average rate of change of LDL within 1 month before and after the 3-month visit based on this model can be computed as −9.768 mg/dl per month (P = 0.007) per month. None of the covariates in the model were significantly associated with changes in LDL. A multiple regression model with random effects revealed that assuming a linear trend in LDL level over the initial 12-month period of treatment, LDL levels did not change significantly from baseline by 12 months (P = 0.5). Before 3 months, the HDL increased marginally by 2.2 mg/dl monthly (P = 0.048). However, unlike total cholesterol and LDL, the trend did not change significantly after 3 months; the estimated change in the trend was a decrease by −0.204 mg/dl monthly. We also found significant differences in the HDL based on patient’s gender after correcting for the other covariates. HDL in male patients was on average 18.395 mg/dl (P = 0.006) lower compared to female patients at all time points. The trend in the triglyceride
Pro of
Cervenka et al.
Figure 2 Total cholesterol (A), LDL (B), HDL (C), and triglyceride (D) levels plotted over time on the MAD using a random effects model with two linear spline terms. Points represent values (mg/dl) for all patients plotted over 0–24 months. Light gray lines represent cholesterol trends over time. Dark gray lines show the average of these values.
4
Nutritional Neuroscience
2014
VOL.
0
NO.
0
not maintained (levels decreased below 40 mg/dl at least once) during the entire treatment despite report of continued diet adherence. Loss of ketosis did not correspond with changes in FLPs in these patients.
Discussion The MAD is a promising therapy for adults with medically and surgically refractory epilepsy.4,12,16 However, little is known regarding potential long-term consequences of this high fat diet in the adult population with a potential increased risk of hyperlipidemia resulting in cardiovascular and cerebrovascular complications. In this prospective study of 37 adults started on a 20 g per day net carbohydrate limit MAD, LDL and total cholesterol increased significantly in the first 3 months on the diet. However, in those patients that elected to continue the diet for 12 or more months, values normalized. HDL initially trended upward and triglycerides trended downward but not significantly. No cardio- or cerebrovascular events were reported. Current National Institutes of Health ATP III guidelines13 recommend intake of
