centered image

centered image

The Ketogenic Diet For Super-Refractory Status Epilepticus

Discussion in 'General Discussion' started by The Good Doctor, Mar 3, 2021.

  1. The Good Doctor

    The Good Doctor Golden Member

    Aug 12, 2020
    Likes Received:
    Trophy Points:

    The ketogenic diet is emerging as a potential treatment option for all stages of status epilepticus (SE), including refractory and super refractory status epilepticus.

    Super refractory status epilepticus, or SRSE, occurs when status epilepticus persists for at least 24 hours after the initiation of anesthesia. About 15% of people with SE will progress to SRSE. Of those that do, outcomes are quite poor; up to 40% die, and about 3 of every 4 survivors have a poor functional outcome, at least at hospital discharge.

    The causes of SRSE vary with age and population, but include brain trauma (from stroke, hypoxia, or other injury), infectious diseases, immunological disorders, mitochondrial disorders, and genetic disorders, as well as epilepsy and brain tumors. Outcome is generally dependent upon the cause, though complications from the SRSE and the treatment—including hypotension, heart failure, liver or kidney failure, acute hypersensitivity and allergic reactions, bleeding disorders, infection, gastrointestinal disturbance, and neuropathy—also contribute to mortality.


    Due to its emergent and rare nature and the heterogeneity of causes, randomized controlled treatment trials in SRSE are sparse. Only one phase III trial of any therapy has been conducted: A 2017 trial found brexanolone no more effective than placebo (43.9% resolution with brexanolone, versus 42.2% with placebo).

    As with other treatments for SRSE, evidence for the ketogenic diet’s efficacy and safety comes mostly from case studies, case series, and retrospective studies, which carry inherent limitations (no standard treatment protocol, variation in SRSE etiology, varying criteria for determining SRSE resolution). As well, because treating SRSE involves multiple medications and treatments, it is difficult to directly tie SRSE resolution to any individual treatment.

    With these caveats, the small evidence base of outcomes of the ketogenic diet for SRSE is encouraging, say experts. More published evidence exists for children than adults, but reviews of adult case reports, case series, and studies have shown high efficacy rates (see table).

    Multiple mechanisms

    The diet likely has multiple mechanisms, making it an option for most patients in either convulsive or nonconvulsive SRSE. Research has suggested effects on neurotransmitters, mitochondria, gut microbiota, DNA methylation, ion channels, inflammation, and G-protein coupled receptors.

    “Several of these potential mechanisms can occur rapidly and are likely involved in the [anti-seizure] effects of the diet in SRSE,” said Mackenzie Cervenka, director of the Adult Epilepsy Diet Center at Johns Hopkins Hospital. “I think the effects on mitochondria, gut microbiota, and DNA methylation are likely more long-term mechanisms for seizure control, and not as involved acutely.”

    The ketogenic diet has been shown to reduce inflammation, which may partly explain its effectiveness in autoimmune-mediated cases of SE, she said. “Because FIRES is thought to be triggered by an autoimmune response, the ketogenic diet could potentially treat the inflammatory response as well as have antiseizure effects,” said Cervenka. “The same has been shown for patients of all ages with new-onset refractory status epilepticus (NORSE).”

    Cervenka and colleagues are designing a randomized controlled trial of the ketogenic diet for refractory status epilepticus (RSE), introducing it as soon as patients have received anesthetic medication.

    A recent publication in Neurology Clinical Practice provides guidance on how to administer the ketogenic diet in patients experiencing SRSE.

    The publication is meant to meet a need, said Neha Kaul, first author of the publication and senior dietitian at the Royal Melbourne Hospital. “We’re seeing an increase in the number of centers using the diet as a treatment for adults in super refractory status epilepticus,” as well as centers considering the diet earlier in the course of status epilepticus, she said.

    Ketogenic diet by the numbers

    Administering the ketogenic diet for SRSE requires a prescription by a dietitian or neurodietitian. Oral administration of the diet is generally not suitable in cases of SRSE; instead, the diet is administered enterally, through a feeding tube. The diet also has been administered in other ways in some case reports without significant side effects, though close monitoring for hepatotoxicity and pancreatitis is important. As SRSE resolves, patients may transition to an oral ketogenic diet.

    The Neurology Clinical Practice publication suggests starting calorie intake between 25 and 30 kilocalorie per kilogram of body weight (kcal/kg), and then gradually increasing as needed. Excess calorie intake may inhibit ketosis and is associated with poorer outcomes.

    Protein is generally started at 1.0 grams/kilogram of body weight (g/kg) and then increased to between 1.2 g/kg and 2.0 g/kg. This is more protein than most ketogenic diet protocols for epilepsy; the extra protein is meant to protect against muscle mass loss.

    More than 80% of calories should be derived from fat, with up to 30% of total calories from medium-chain triglycerides (MCTs), which are more readily metabolized to ketone bodies. The remaining fat may be long-chain fatty acids.

    There’s no minimum carbohydrate requirement; authors note the importance of considering and minimizing sources of existing carbohydrate, such as from concurrent medications and infusions. Though the classical oral ketogenic diet can include up to 20 g of carbohydrate daily, a prescribed ketogenic diet for SRSE may contain no carbohydrate.

    Adequate micronutrients should be provided, as well as carnitine supplements (10-50 mg/kg/day) in patients receiving valproate or those with elevated serum triglycerides.


    While the diet is an option for most cases of SRSE, there are contraindications, note Kaul and Cervenka. “The main contraindications are metabolic disorders — any disorder related to impaired fatty acid oxidation. And any diets that require someone to have a high carbohydrate intake,” said Kaul.

    Cervenka noted that patients in hepatic or renal failure and those with metabolic acidosis, acute pancreatitis or ileus also should not receive the ketogenic diet for SRSE.

    Drug-diet interactions

    Patients receiving propofol must be switched to an alternative anesthetic agent before the ketogenic diet is started. This eliminates the risk of propofol infusion syndrome, a potentially fatal condition that likely stems from a combination of excess fat provision (from both the propofol preparation and the ketogenic diet) and impaired fatty acid metabolism.

    If the ketogenic diet is initiated in patients taking carbonic anhydrase inhibitors (such as topiramate or zonisamide), the authors suggest also initiating treatment with potassium citrate or sodium bicarbonate, as these medications can exacerbate metabolic acidosis and increase the risk of kidney stones.

    Reviewing medications to minimize intake of glucose, lactate, glycerol, and alcohols is important. Liquid medications often contain high levels of sugar alcohols, which interfere with ketosis. Steroids also may inhibit ketosis.

    The most common side effects of ketogenic diet therapy are gastrointestinal issues, such as nausea, vomiting, or high gastric residual volume.

    There is no guideline on when to stop ketogenic diet therapy in someone with SRSE. The diet can be weaned by slowly introducing carbohydrate and monitoring for seizure recurrence. Continuing therapy long term (through oral administration) also is an option.

    Advantages and the future

    Weaning anesthetics without seizure recurrence is the end goal; the ketogenic diet can help reach that goal, said Joshua Laing, a Melbourne neurologist and epileptologist and co-author of the guidelines.

    “The common property of other treatments for SRSE is sedation,” he said. “The ketogenic diet is non-sedative, which is reassuring … because the therapy can continue while you’re waking a patient up.”

    Using ketogenic diet therapy in people with SRSE requires integrated care among health care professionals, including dietitians and pharmacists. Ketogenic diet therapy potentially has a lower risk burden than high-dose anti-seizure medications and anesthetic agents, but it is not yet known if the diet has a primary therapeutic effect or works synergistically with other treatments.

    After a learning curve, said Kaul, “We now more commonly use the diet to treat these patients, who have a very difficult to treat condition. As a community of dietitians, intensivists, neurologists, we have been communicating with each other to try to find advice to guide treatment.”

    Kaul, Laing and colleagues regularly provide guidance to other centers on managing the ketogenic diet in patients with status epilepticus. They encourage neurologists, dietitians, and intensive care clinicians to contact experienced centers for advice.

    Case study

    The Neurology Clinical Practice article includes a case study of a 65-year-old man with a history of hypertension. He was admitted to the intensive care unit (ICU) following a spontaneous subarachnoid hemorrhage from a ruptured anterior communicating artery aneurysm. He went into non-convulsive SE on day 14. After four anti-seizure medications, two anesthetic infusions, and multiple failed attempts at anesthetic weaning, the ketogenic diet was started on day 25. Four days later, the anesthetic was weaned with no seizure recurrence. The diet was provided for 14 days and then weaned with no seizure recurrence.


    Add Reply

Share This Page