Ketogenic diets (KDs) have emerged as a highly effective treatment for epilepsy, particularly for those who do not respond well to traditional anti-seizure medications. The ketogenic diet is a very high fat, very low carbohydrate, controlled protein diet that has been used since the 1920s to treat epilepsy. The diet is a medical treatment, and is usually only considered when at least two suitable medications have been tried and not worked. It is an established treatment option for children with hard to control epilepsy. However, adults may also benefit from dietary treatments. This dietary therapy induces a state of ketosis through carbohydrate restriction. Ketosis is a metabolic state where cells rely on ketone bodies and fatty acids once glycogen stores have been depleted. Within the brain, ketone bodies modulate neurotransmission and provide additional anti-inflammatory effects. Specifically, ketone bodies increase GABA while simultaneously decreasing glutamate reuptake. Despite the versatility of KDs, they are not completely benign. Therefore, it is important to carefully document complications that result from this type of therapy and what can be done to mitigate these problems.
However, like any medical intervention, KDs can have side effects. While many of these are manageable with careful monitoring, some can be serious and require immediate attention. This article provides a comprehensive overview of the potential side effects associated with ketogenic diets for epilepsy, offering insights into their management and prevention.
The Ketogenic Diet: An Overview
KDs are considered viable for patients who are unresponsive to two or more anti-seizure medications. Some parents prefer to start a KD earlier because they perceive it as a “natural” option and expect it to come with fewer side effects. A KD is a dietary therapy that induces a ketotic state through carbohydrate restriction. Ketosis is a metabolic state where cells rely on ketone bodies and fatty acids once glycogen stores have been depleted. Within the brain, ketone bodies modulate neurotransmission and provide additional anti-inflammatory effects. Specifically, ketone bodies increase GABA while simultaneously decreasing glutamate reuptake. There are four different ketogenic diets that have been used for medical purposes. These include the classical ketogenic diet (cKD), the traditional medium chain triglyceride ketogenic diet (tMCTKD), the modified medium chain triglyceride ketogenic diet (mMCTKD), and the modified Atkins diet (MAD). Additionally, the low glycemic index diet (LGIT) is not a true KD, but it is a carbohydrate restricted diet that is efficacious in epilepsy management. The cKD is predominantly composed of long chain triglycerides (LCTs), and the fat to carbohydrate ratio ranges from 3:1 to 4:1. Carbohydrate restriction is also sometimes combined with additional calorie or protein restrictions. Traditionally, the cKD was started with a medically supervised fast in the hospital to help the patient achieve a baseline level of ketosis. Some patients find it helpful in transitioning to a KD from a behavioral standpoint, but this is no longer deemed necessary. The tMCTKD and mMCTKD were designed as more flexible alternatives to the cKD. Commercial medium chain triglycerides (MCTs) produce more ketone bodies per kilocalorie than LCTs, allowing for a higher carbohydrate intake. The MAD and LGIT diets were designed to allow more dietary freedom. While the previous diets have a 4:1 or 3:1 fat to carbohydrate ratio, the MAD has a ratio of 2:1 to 1:1. On the other hand, the LGIT is not a true KD as it simply aims to prevent large increases in postprandial blood glucose by focusing on low glycemic index foods and limiting total daily carbohydrates.
Common Side Effects During the Initiation Phase
During the initiation phase of the diet, common side effects include vomiting, hypoglycemia, metabolic acidosis and refusal of the diet.
System-Specific Side Effects of the Ketogenic Diet
While on the diet, the side effects involve the following systems: gastrointestinal, hepatic, cardiovascular, renal, dermatological, hematologic and bone.
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Gastrointestinal Complications
According to a 2017 meta-analysis, gastrointestinal (GI) complications including constipation, diarrhea, vomiting, and gastroesophageal reflux are the most commonly reported side-effects, with up to 40% of reported side-effects being GI related. However, these problems occurred primarily at the initiation of the diet. A more serious GI complication that may require modification or cessation of the KD is hypoproteinemia, which can be caused by enteropathy secondary to intestinal inflammation or lymphatic leakage of protein. Enteropathy in the context of a KD often occurs when another underlying pathology exists. For example, a case report by Wang et al. describes a three-month-old female with a genetic epileptic syndrome (STXBP1), managed on a 4:1 ketogenic diet, who presented with an intestinal lymphangiectasia and protein-wasting enteropathy. This young female’s enteropathy was alleviated by decreasing her fat to carbohydrate level to a 1:1 ratio, and despite this dietary change, she remained seizure free for at least 20 months. Another possible trigger for KD-induced enteropathy is previously undiscovered intolerances and allergies, but there is only one report of a protein-losing enteropathy during the ketogenic diet, due to a soy allergy. Furthermore, Kang et al. and Suo et al. also found unexplained hypoproteinemia in 12 of 129 patients (9.3%) and 39 of 317 patients (12.3%) respectively, indicating that subclinical enteropathy or other factors may be present in a larger population than what is documented. These reports highlight the importance of carefully considering all of the patient’s medical history in order to craft an individually appropriate KD. Other rare extraluminal GI effects of the KD diet include cholelithiasis, pancreatitis, and hepatitis. Cholelithiasis is most likely triggered by metabolic changes and increased gallbladder activity. Only two cases of this complication have been reported and only one of them needed surgical management. Pancreatitis appears to be a little more common and is thought to be a result of increased serum lipids. Most reports of this side effect occurred in obese or overweight patients embarking on a KD for weight loss purposes, who likely had underlying dyslipidemia. Pediatric patients do not commonly have this problem, but three pediatric cases have been reported. One patient was discussed in a case report and the other two were reported in a retrospective study of 71 patients. Of these, one patient died due to necrotizing pancreatitis; the other two simply stopped the diet and the pancreatitis remitted. The patient who passed away had an EIF2S3 mutation that triggered seizures and pancreatic dysfunction. Hepatitis is a rare complication of the KD, but concomitant use of valproic acid (VPA) has been thought to increase the risk of hepatitis. However, Kang et al. found that there was not a significant increase in the number of hepatitis cases in patients taking VPA and following a KD. Additionally, low carnitine levels in some KD patients may also contribute to liver dysfunction. Hence, screening for familial dyslipidemia and pancreatic dysfunction along with routine monitoring of blood lipids, liver enzymes, and carnitine levels is recommended.
Management of Gastrointestinal Issues
- Constipation: Increase fiber intake through allowed vegetables and consider stool softeners.
- Diarrhea: Adjust fat content and consider lactose intolerance.
- Vomiting: Ensure adequate hydration and adjust the diet to improve tolerance.
- Gastroesophageal Reflux: Elevate the head of the bed and avoid large meals.
- Hypoproteinemia: Monitor protein levels and adjust the diet accordingly.
Cardiac Complications
KD-induced cardiac complications are rare, with the most serious concerns being a prolonged QT interval and cardiomyopathy. In the 2000s, QT prolongation was reported in at least three children whose epilepsy was being managed with a KD. Two of these children suddenly passed away after developing torsade de pointes. Furthermore, the length of the QT interval was inversely related to the bicarbonate concentration and directly correlated to ketone concentrations, suggesting that the cardiac abnormalities were a result of metabolic disturbances. KD-related cardiomyopathy occurs in the context of selenium deficiency, which is typically a rare cause of cardiomyopathy. A 2003 report of 39 epilepsy patients on a KD was triggered by a single patient with no detectable selenium in their blood. This study showed that 9 of the 39 patients had significantly reduced serum selenium. However, only the index case had evidence of cardiomyopathy by echocardiogram. Others have also reported selenium deficiency both with and without cardiomyopathy. In 2015, a prospective study with 61 patients on a KD documented cardiac outcomes for one year. Measures for this study included serum carnitine, serum selenium, electrocardiography, and echocardiographic examinations throughout the study. None of these measures were significantly different between the start and the end of the trial, except for the mitral A wave (0.66 m/s vs. 0.61 m/s, p = 0.05). Others have challenged the presence of selenium deficiency in KD patients, but often these studies last for approximately one year, which may not be enough time to develop this complication. Ultimately, a protein restricted or deficient diet may result in selenium deficiency as animal proteins tend to have the highest concentration of selenium. Therefore, selenium concentration monitoring and selenium supplementation should be considered in patients who are not eating significant amounts of animal products.
Management of Cardiac Issues
- QT Prolongation: Monitor electrolytes and consider bicarbonate supplementation.
- Cardiomyopathy: Monitor selenium levels and supplement as needed.
Lipid Profile Changes
Because KDs are high in fat, there is concern that increased dietary fats could result in dyslipidemia and atherosclerosis. Kapetanakis and colleagues evaluated 26 epileptic children treated with a KD and found decreased carotid distensibility and worsened lipid profiles at 3- and 12-months post KD initiation, but the changes stabilized at 24 months. Another study by Ozedmir and colleagues found that an olive oil-based KD does not appear to change aortic and carotid artery elasticity in pediatric epilepsy patients. However, this type of KD was still associated with an increased concentration of serum lipids, consistent with the work of Kapetanakis. Given the propensity of the KD to increase serum lipid levels, patients who have existing metabolic dysregulations must be monitored carefully.
Management of Lipid Abnormalities
- Regularly monitor lipid profiles.
- Consider dietary modifications, such as increasing polyunsaturated fatty acids.
- In some cases, medication may be necessary to manage dyslipidemia.
Renal Complications
Renal calculi have been reported in 3-7% of children on a ketogenic diet, consisting of both uric acid and calcium. In addition, three studies of over 200 children on a KD, showed that potassium citrate led to a reduced incidence of renal calculi. There is also a theoretical increased risk of renal calculi in patients on a KD and anti-epileptic drugs (AEDs) with carbonic anhydrase inhibitor activity such as zonisamide and topiramate. However, one study showed that regardless of the patient’s medication status, urolithiasis is associated with the presence of metabolic derangements including metabolic acidosis, concentrated urine, acidic urine, hypercalciuria and hypocitraturia. Finally, in rare instances, hematuria without the presence of a stone has also been reported. Therefore, a risk-benefit analysis of initiating a KD in patients with preexisting kidney abnormalities, such as Alport syndrome, polycystic kidney disease or nephropathic cystinosis, must be done. A renal ultrasound may also be recommended before the initiation of a KD and at six months to one year after starting a KD, to diagnose asymptomatic renal stones.
Management of Renal Issues
- Ensure adequate hydration.
- Administer potassium citrate to reduce the risk of renal calculi.
- Monitor urine pH and electrolytes.
Hematological Complications
Hematological complications of the KD include neutropenia, increased hemoglobin, and decreased platelet function. In a retrospective study by Munro and colleagues, 27 of 89 children developed neutropenia, which was associated with increased urinary ketones and longer duration of the KD. Despite the presence of neutropenia, there were no clinically significant infections. Interestingly, other studies that investigated complete blood counts showed a normal neutrophil count. Finally, platelet dysfunction and bruising have also been reported in some patients on the KD. Further study of six patients revealed increased bleeding time and diminished platelet reactivity to aggregating factors, suggesting altered membrane dynamics secondary to lipid changes. However, a more recent study of 162 children on a KD for epilepsy found no differences in platelet counts or function after one year on the KD. In this study, it was also shown that desmopressin was able to stimulate clotting in vitro, suggesting a possible treatment for patients with concerning bruising.
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Management of Hematological Issues
- Monitor complete blood counts regularly.
- Manage neutropenia with careful observation and potential diet adjustments.
- Address platelet dysfunction with desmopressin if necessary.
Neurological Complications
The KD is generally thought to be a neuroprotective treatment, and only one major negative neurological outcome has been reported. In 2003, Erickson and colleagues reported on a child with cryptogenic epileptic encephalopathy who developed chorea and ataxia corresponding with putaminal lesions on MRI three weeks after starting a classical KD. A subsequent MR spectroscopy study showed a lactate peak in the basal ganglia, suggesting a failure of mitochondrial energy metabolism. Both the MRI and MRS abnormalities resolved after discontinuing the KD, while her new onset movement disorder did not. Since this case report, no other neurological sequelae have been reported in the use of KD for epilepsy. The authors of this report also suggested that a secondary mitochondrial condition such as familial striatal necrosis could be the culprit.
Management of Neurological Issues
- Monitor for any new neurological symptoms.
- Consider MRI and MR spectroscopy if symptoms arise.
- Discontinue the KD if significant neurological complications develop.
Dermatological Complications
Prurigo pigmentosa is a papular, pruritic rash that appears rapidly after the commencement of a KD, and it responds well to increased carbohydrate intake or tetracyclines. Originally, this rash was thought to be specific to East Asian populations, but later it was reported in two Middle Eastern patients on strict diets with prolonged fasting. Furthermore, a recent literature review identified 19 case reports of prurigo pigmentosa in patients following ketogenic diets. The highest proportion of reports were among Asian (32%), Middle Eastern (32%), and Caucasian (11%) patients.
Management of Dermatological Issues
- Increase carbohydrate intake slightly.
- Consider tetracycline treatment.
Monitoring and Prevention Strategies
Many of the common side effects can be tackled easily with careful monitoring including blood counts, liver enzymes, renal function tests, urinalysis, vitamin levels, mineral levels, lipid profiles, and serum carnitine levels. Some rare and serious side effects reported in the literature include pancreatitis, protein-losing enteropathy, prolonged QT interval, cardiomyopathy and changes in the basal ganglia. These serious complications may need more advanced work-up and immediate cessation of the diet.
Regular Monitoring
- Blood Counts: Monitor for neutropenia and other hematological abnormalities.
- Liver Enzymes: Assess liver function and detect potential hepatitis.
- Renal Function Tests: Evaluate kidney function and detect renal calculi.
- Urinalysis: Monitor for metabolic derangements.
- Vitamin and Mineral Levels: Ensure adequate nutrient intake and identify deficiencies.
- Lipid Profiles: Track cholesterol and triglyceride levels.
- Serum Carnitine Levels: Assess carnitine deficiency, which can contribute to liver dysfunction.
Preventative Measures
- Hydration: Encourage adequate fluid intake to prevent renal calculi and constipation.
- Supplementation: Provide appropriate vitamin and mineral supplements to address deficiencies.
- Dietary Adjustments: Modify the diet as needed to improve tolerance and address specific side effects.
- Regular Follow-Ups: Schedule regular appointments with a multidisciplinary team, including a dietitian and neurologist, to monitor progress and address any concerns.
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