Ketogenic diet for adults in super-refractory status epilepticus

Design

Multicenter retrospective case review

N= 10

Objective

To describe a case series of adult patients in the intensive care unit (ICU) in super-refractory status epilepticus (SRSE; refractory status lasting 24 hours or more despite appropriate anesthetic treatment) who received treatment with the ketogenic diet (KD)

Study Groups

Inclusion Criteria

Adult patients (aged > 17 years) in SRSE treated with KD

Exclusion Criteria

Methods

Patient data were compiled via retrospective chart review. Patients were treated at one of the following four medical centers: Johns Hopkins Hospital; Johns Hopkins Bayview Medical Center; Mayo Clinic, Rochester; or Rush University Medical Center. SRSE was defined as SE (convulsive and/or nonconvulsive) continuing ≥ 24 hours after the initiation of general anesthetic medications (i.e., propofol, high-dose barbiturates, high-dose benzodiazepines, and ketamine), or recurred after general anesthetics.

Duration

Patients treated between 2010 and 2013

Outcome Measures

Primary: resolution of SE, ability to wean from anesthetic agents

Baseline Characteristics

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Patient 6

Patient 7

Patient 8

Age, years

Sex

Race

Diagnosis

Admission GCS score

Days SE duration before KD

Number AEDs before KD

Diet initiation

GCS score at KD initiation

Fasting at start of KD

KD ratio

Steroids while on diet

5 

Yes 

4:1 

Yes 

3

Yes 

4:1

Yes 

3 

Yes 

4:1 

Yes 

6 

Yes 

4:1

No 

6 

No

4:1

No 

3

Yes

4:1

No 

6 

Yes

4:1

No

3

No 

3:1

Yes 

11

No

4:1

Yes 

3

Yes

4:1

No 

Abbreviations: Ab, antibody; AED, antiepileptic drug; GCS, Glasgow Coma Scale; LGI1, leucine-rich glioma-inactivated 1; KD, ketogenic diet

Results

Outcomes

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Patient 6

Patient 7

Patient 8

Patient 9

Patient 10

Ketosis achieved

Time to ketosis

Total length of KD

Side effects

Days to anesthetics wean after KD

Total days on anesthetics

Days to EEG seizure resolutions

Days in ICU

Total days hospitalization

Days to solid food after KD

Number AEDs after discharge

GCS score at discharge

mRS score at discharge

Disposition

Nine patients (90%) had resolution of SE within a median of 3 days (interquartile range [IQR] 8) after KD initiation.

Seven patients had clinical and/or electrographic seizure resolution within 1 week of diet initiation and 9 within 1 month.

The median days on anesthetic agents after KD initiation was 5 (IQR 4).

On discharge, 6 patients had a GCS score ≥ 12 (including 4 with known epilepsy taking AEDs before admission).

The median number of AEDs prescribed at discharge was 4 (IQR 2.5).

Adverse Events

Study Author Conclusions

This case series suggests that the KD is safe and feasible in ICU patients and may have a role in refractory cases. It remains to be shown whether early intervention with KD and transition to the MAD improves morbidity and mortality in this critically ill population.

InpharmD Researcher Critique

Due to the retrospective nature of this study, numerous confounding variables could not have been accounted for, and various other interventions may have impacted clinical improvement. Notably, the specific modality of nutrition utilized in these patients to deliver KD was not specified, and delivery of KD may have potentially not been via parenteral nutrition. However, due to the scarcity of available relevant literature in this scenario, the success of a KD in SE patients in the critical care setting may still be notable. 

The Feasibility, Safety and Effectiveness of a Ketogenic Diet for Refractory Status Epilepticus in Adults in the Intensive Care Unit

Design

Retrospective, single-center study

N= 11

Objective

Study Groups

Inclusion Criteria

A convenience sample of adults with RSE who were aged 18–80 years and administered the KD as part of multimodal treatment for RSE

Exclusion Criteria

On propofol within past 24 hours; mean arterial pressure (MAP) < 60 mmHg; glucose < 50 mg/dL; aspartate aminotransferase/alanine transaminase 5x upper limit of normal; total bilirubin > 15 mg/dL; pregnancy; ileus or other limitation to oral feeding; known fatty acid oxidation disorder or pyruvate carboxylase deficiency

Methods

Eligible patients received the same KD protocol using the Ketovie^TM (for more information: info@ketovie.com). The product contained a ratio of 3:1 to 4:1 fat: protein + carbohydrate. Depending on individual patient needs, the Nutrition Team would add medium-chain triglyceride oil and Beneprotein® (Nestle Corporation) on a case-by-case basis. 

RSE was defined as continued or repeated seizures that do not respond to appropriate treatment for status epilepticus (SE) (e.g., benzodiazepine) and a second-line pharmacologic agent (e.g., phenytoin). Resolution of RSE was based on both clinical and electrographic evaluations (i.e., the Salzburg Consensus Criteria). Super-refractory status epilepticus (SRSE) was defined as seizures that persist or reemerge in the setting of intravenous anesthetic infusions x 24 hours used for the treatment of SE.

Duration

Treatment: November 2016-May2018

Outcome Measures

Primary: urine ketone body production as a biomarker of feasibility

Secondary: resolution of RSE, progression to SRSE, and KD-related side effects 

Baseline Characteristics

Age/Gender/Ethnicity 

3

AA= African American, ASD= anti-seizure drugs, CA= cardiac arrest, EtOH= ethanol withdrawal, KD= ketogenic diet, NMDA= n-methyl-d-aspartate receptor encephalitis, TBI= traumatic brain injury

Results

Patient

Time to ketosis, days

ASD= anti-seizure drugs, Abd Perf= bowel perforation, CM= comfort measures, withdrawal of life support, HypoGly= hypoglycemia (serum level​ < 60 mg/dL), HypoNa= hyponatremia, ICU= intensive care unit, Infxn= infection, LOS= length of stay, LTACH= long-term acute care hospital, MA= metabolic acidosis (pH​ < 7.4 mmHg or serum bicarbonate < 24 mEq/L), Rehab= rehabilitation, SNF= skilled nursing facility

Median duration to achieve ketosis: 1 day

RSE resolved: 72.7% (n= 8); 27.3% (n= 3) developed SRSE

Adverse Events

Study Author Conclusions

KD may be feasible, safe and effective for treatment of RSE in the ICU. A randomized controlled trial may be indicated to further test the safety and efficacy of KD.

InpharmD Researcher Critique

The study is limited by its small sample size and retrospective design. Without a controlled group, the true extent of the clinical benefits of KD remains uncertain. Results of a specific KD product may not readily apply to other formulations with different fat-protein ratios. Additionally, the product specified in the study appears to be made for enteral nutrition, so the results may not be applicable to KD given parenterally. 

Phase I/II Multicenter Ketogenic Diet Study for Adult Superrefractory Status Epilepticus

Design

Prospective, multicenter, open-label, single-arm study

N= 15

Objective

To investigate the feasibility, safety, and efficacy of a ketogenic diet (KD) for super refractory status epilepticus (SRSE) in adults

Study Groups

All participants (N= 15)

Inclusion Criteria

Exclusion Criteria

Unstable metabolic condition (sodium < 130 mg/dL or > 150 mg/dL, glucose < 50 mg/dL, albumin corrected calcium < 8 mg/dL, pH < 7.2 within 24 hours); hemodynamic or cardiopulmonary instability (mean arterial pressure [MAP] < 60, persistent tachycardia > 120 beats/min within 24 hours); liver failure (aspartate transaminase, alanine transaminase, ammonia > 5 x upper limits of normal, total bilirubin > 15 mg/dL, direct bilirubin > 5 mg/dL within 24 hours); total cholesterol > 300 mg/dL; inability to tolerate enteral feeds, including ileus; pregnancy; received any propofol infusions within 24 hours; known fatty acid oxidation disorder or pyruvate carboxylase deficiency   

Methods

After minimizing carbohydrates in medications, parenteral and intravenous fluids, and obtaining nutrition consultation, eligible patients replaced enteral formula with 4:1 ratio (fat: carbohydrate and protein grams) ketogenic liquid formula at half estimated calorie needs for the first 24 hours before advancing to full calories. Supplements with multivitamins, vitamins, and calcium were allowed based on individual needs. During diet maintenance, laboratory values were monitored periodically while titrating sedating mediations to seizure suppression for 72 hours with no other changes to antiseizure medications unless medically indicated. If patients failed to wean off sedating medications after 72 hours, anesthetic drug can be restarted at 1 week. In case of unsuccessful treatments after 2 weeks of KD, diet was discontinued.

Upon transfer or discharge, patients continued on general 4:1 ratio ketogenic diet, or in those taking oral nutrition, Modified Atkins Diet was initiated (MAD; 20 grams per day net carbohydrates, high fat, goal urine ketones ≥ 40 mg/dL). Urine ketones, weights, seizure control, amylase, lipase, and fasting lipid profile were also assessed.  

Duration

Follow-up: 6 months 

Outcome Measures

Primary: significant ketosis (defined as urine acetoacetate ≥ 40 mg/dL and/or serum β-hydroxybutyrate ≥ 2 mmol/L)

Secondary: resolution of SRSE, Glasgow Coma Scale (GCS) and modified Rankin Scale (mRS) scores at discharge, and disposition; long-term (6 months) outcome measures, including seizure frequency and continuation of KD therapy (either KD or MAD)

Baseline Characteristics

Age (y)/Sex/Race

Diagnosis

Epilepsy before admission 

Duration of status before KD, d

ASD = antiseizure drugs; LGS = Lennox-Gastaut syndrome with inadequate seizure control; NORSE = new-onset refractory status epilepticus of unknown etiology 

Results

Endpoint

Ketoacidosis 

Seizure-free 

Adverse Events

Study Author Conclusions

InpharmD Researcher Critique

The study findings from a phase I/II trial merely remain exploratory. Additionally, variations in baseline etiologies may limit the generalizability of study results to a target patient population. Of note, KD was admistered enterally and thus the results of this study may not be applicable to parenteral administration. 

Intravenous Initiation and Maintenance of Ketogenic Diet: Proof of Concept in Super-Refractory Status Epilepticus

Design

Case presentation

A 14-year-old patient who first presented with myoclonus and generalized tonic-clonic seizures had no seizure remission achieved over the next 7 years regardless of various combinations of anticonvulsant drugs or treatment with vagus nerve stimulation. Following a rapid progression of disturbance in gait (ataxia) and cognitive decline, a mutation in the EPM2A gene was detected, and thus patient was diagnosed with Lafora disease. At the age of 21 years, the patient got admitted for a generalized, convulsive status epilepticus (SE) and received initial treatment with valproate 780 mg/d, levetiracetam 4,000 mg/d, topiramate 250 mg/d, clonazepam 9 mg/d. While the treatment of SE required generalized anesthesia with propofol (200 mg/h), it was discontinued due to °II atrioventricular block. As use of midazolam (100 mg/h) failed to generate adequate sedation, thiopental (500 mg/h) anesthesia was established for 48 h. Despite adjustments of the anticonvulsive regimen and additional steroids and magnesium, on hospital day 16, patient experienced a second generalized, convulsive SE. Again, thiopental (500 mg/h) anesthesia was established for 48 h due to lack of response to midazolam up to 250 mg/h.

After discontinuing parenteral nutrition and fasting for six hours, patients received emergency induction of a ketogenic diet (KD). Given the intolerance of tube feeds and persistent reflux, a KD (1,000 kcal during the first 24 hours and 2,500 kcal/day on the following days) was infused continuously over 16 hours and was stopped for eight hours at nighttime. Saline (glucose-free solution) was also required to be given. The KD had a 4:1 ketogenic ratio and was composed of commercially available fat emulsion with medium-chain triglycerides (Lipofundin 20% with MCT), amino acid (Aminoplasmal 10%), and carbohydrate (Glucose 5%) solutions for intravenous application. Urine ketones were present after 3.5 days, and ketone bodies were confirmed in the plasma with a b-hydroxybutyrate level of 3,627 mmol/L and acetoacetate of 1,705 mmol/L. KD was continued until hospital day 27 and then switched to an enteral preparation administered via a gastrostomy tube. The commercially available KetoCal 4:1 LQ Multi Fibre 237 mL (Nutricia GmbH, Heilbronn, Germany) was given 5 times per day resulting in a total daily intake of 1,780 kcal. The patient and electroencephalogram improved, and her mental status recovered to baseline. She had daily myoclonus, and generalized tonic-clonic seizures every three to four days. However, on hospital day 47, the patient was discharged and did not report any further episodes of status epilepticus during the four-month follow-up.

Study Author Conclusions

The patient case was treated with a total parenteral KD and ketosis in super-refractory SE. Initiation of KD resolved the SE, compared to the use of multiple anticonvulsants, anesthetics, steroids, and magnesium. Administration of KD was safe and could be made with commercially available solutions. The relationship between the KD and resolution of SE is not absolutely certain due to the considerable amount of confounding factors. 

The Ketogenic Diet in Treatment of Two Adults with Prolonged Nonconvulsive Status Epilepticus

Design

Case presentation 1

A 29-year-old women with Parry Romberg (diagnosed at age 12 after progressive left hemifacial atrophy, stabilizing by age 20) and Rasmussen's syndromes presented in simple partial status epilepticus (SE), which manifested as aphasia. The patient's first seizure started at age 14, complex partial seizures began at age 21 which increased in frequency until age 25, when they occurred 1-2 times per week, with secondary generalization and recurrent SE. Despite multiple antiepileptic drugs (carbamazepine, gabapentin, lamotrigine, levetiracetam, zonisamide, topiramate, pregabalin, and clobazam), her seizure control was poor. Electroencephalography (EEG) showed frequent left hemispheric seizures without discrete clinical signs and serial magnetic resonance imaging (MRI) studies showed multifocal left-sided signal abnormalities and progressive atrophy of the left hemisphere. A left anterior lobectomy (including amygdalohippocampectomy) was performed at age 26; after surgery, overall language mildly worsened, there was a right superior temporal quadrantanopia, and subtle right upper extremity weakness. Despite treatment with intravenous immunoglobulin (IVIG) and steroids, there continued to be a decline in language, concentration, and memory; Rasmussen's encephalitis was diagnosed on the basis of focal intractable seizures, progressive cognitive decline, inflammatory infiltrates on biopsy, and unilateral cerebral atrophy on imaging.

The patient presented in prolonged simple partial SE, manifested by mutism. EEG on admission showed nearly continuous seizures arising from the left central parietal region; after failure of first-line medications that would preserve consciousness, pentobarbital was started; the infusion rate was titrated to 5.75 mg/kg/hr, with highest serum level of 19.1 mcg/mL which induced burst suppression, but was unable to decrease sedation as any attempt was followed by nearly continuous seizures on EEG. SE remained refractory to: IV phenytoin (levels 15-20 mg/L), levetiracetam (1,500 mg IV BID), phenobarbital (highest level 118.6 mg/L, midazolam, and valproic acid (highest level 71 mg/L); enteral topiramate (500 mg BID, highest level 14.4 mg/L), pregabalin, felbamate (max dose 900 mg q6h, highest level 47 mcg/mL); general anesthesia with desflurane; ten sessions of electroconvulsive therapy (ECT); IVIG, two courses of plasmapheresis, IV SoluMedrol, and transcranial magnetic stimulation. The patient required tracheostomy and gastrostomy for enteric nutrition as a result of medication effects and impairment from seizures. 

On hospital day 101, the ketogenic diet (KD) was introduced as a formula via gastrostomy tube (KetoCal 4:1, Nutricia, North America). Within four days, seizure frequency decrease to one discrete seizure per 3-4 days; by 11 days after initiation, seizures stopped completely. The patient was consistently ketotic 10 days after initiation of the diet (serum beta-hydroxybutyrate levels of 1.6–5.27 mm/L; levels monitored weekly and daily urinalysis checked for ketones. Oral bicarbonate supplementation was titrated to maintain serum bicarbonate levels > 18 mEq/L. The patient's mental status improved by hospital discharge, with a moderate expressive aphasia (beyond her previous baseline; but improved from mutism during SE). She was discharged on phenobarbital, phenytoin, pregabalin, topiramate, and the KD. One year later, she remained on a 3:1 ratio KD using food. She has returned to living at home with her husband, requiring minimal assistance with activities of daily living. 

Case presentation 2

A previously healthy, 34-year-old man presented to the trauma bay after driving into a wall; he was witnessed to be staring blankly prior to impact and convulsing immediately after. In the weeks prior, he had intermittent fevers, malaise, vomiting, and diarrhea. Patient had further generalized tonic-clonic seizures after admission, which progressed to SE; he was intubated and sedated with continuous EEG monitoring showing multiple bilateral independent seizures with rapid secondary generalization. Serum and cerebrospinal fluid (CSF) analysis were unremarkable for infectious and autoimmune sources (except for CSF white blood cell count from 3-11 with lymphocytic predominance). Serial brain MRI showed T2 hyperintensities in both temporal lobes (consistent with ongoing seizures); the presumptive diagnosis was viral or postinfectious encephalitis. SE was refractory to lorazepam, levetiracetam (2,000 mg BID), phenytoin (highest level 23.6 mg/L), topiramate (highest level 16.8 mg/L), phenobarbital (highest level 68.5 mg/L), pentobarbital (titrated to burst suppression), and valproic acid (highest level 68 mg/L). High-dose midazolam (> 20 mg/h) infusion induced burst-suppression on EEG; each time it was weaned, there was return of electrographic seizures. Patient was receiving all nutrition via gastric tube. 

On hospital day 18, fasting was initiated to induce ketosis; IV fluids provided hydration and electrolytes but no dextrose. On day 20, KD was started via gastric tube (KetoCal 4:1, Nutricia North America) and stable ketosis was achieved within 8 days, with serum beta-hydroxybutyrate levels > 3 mmol/mL; levels were checked weekly and daily urinalysis for ketones done for remainder of hospitalization. Oral bicarbonate supplementation was titrated to maintain serum bicarbonate levels > 18 mEq/L. Starting on hospital day 26, midazolam was weaned without return of seizures and with significant mental status improvement. Upon discharge, the patient had mild cognitive difficulty and critical illness myopathy; he was discharged on phenobarbital, topiramate, levetiracetam, and a low ratio KD, with the gastrostomy tube reversed. At one year after discharge, he had one breakthrough seizure (self-limited), lives at home, and returned to his prior profession.

Study Author Conclusions

 These cases suggest that the KD can be successfully implemented and benefit critically-ill adults in SE. Our patients had distinct underlying pathologies, suggesting that the diet may be useful in some of the diverse processes that cause SE. Further research is needed. 

Super-refractory Status Epilepticus and Ketogenic Diet in Intensive Care: A Series Report

Design

Case presentation 1

A 20-year-old male patient was admitted to the intensive care unit (ICU) due to isolated head trauma, with imaging showing hemorrhagic foci. On the 7th day of admission, the patient suffered a tonic-clonic seizure with no neurological recovery and was admitted to the ICU for 24 hours burst suppression (BS) cycle. The patient remained in super-refractory status epilepticus (SRSE) for the duration of the first 13 days of ICU hospitalization despite adequate BS cycles. On day 5 of ICU admission, a fasting regimen was started to induce ketose state, but was suspended at 36 hours due to hypoglycemic episodes. Fasting regimen was reinitiated, and ketonuria was achieved in 28 hours. A ketogenic diet (KD) enteric formula composed of a 4:1 ratio (4 g of fat to every 1 g of protein) supplemented with minerals, essential fatty acids, and vitamins was then started, and a full dose was attained in 48 hours. The patient maintained a KD with no further complications and was discharged 45 days later with no major neurological sequelae. At 3-month follow-up, patient was on unrestricted diet. 

Case presentation 2

A 38-year-old female presented with 3-day episode of myalgia and fever, resulting in tonic-clonic seizures and posterior admission to emergency department while in a stuporous state. Computed tomography and magnetic resonance imaging (MRI) were normal. Despite BS, the patient remained in a nonconvulsive SE in each BS stop evaluation for 9 days. A fasting regimen was initiated to induce ketosis state; after 4 days of this, ketonuria was still absent, however, and thus a KD with a 4:1 ratio supplemented with vitamins and minerals was initiated. Ketonuria was achieved in 8 days. On day 14, enteric feeding resulted in major gastric stasis and diarrhea, prompting switch to parenteral nutrition and manipulating to a ketogenic profile. The patient gradually improved, and at week 4, was transitioned to modified Atkins diet. Carbohydrates were progressively introduced, and the patient was given a nutritional plan for carbohydrate dose progression upon discharge. 

Case presentation 3

A 20-year-old female patient with no previous medical history presented to the emergency department after a 4-day episode of fever, vomiting, and diarrhea. She presented with a tonic-clonic seizure with no neurological recovery, leading to intubation and ICU admission. The patient was induced 4 BS cycles with seizures after each pause of sedation. A fasting regimen was started to achieve ketosis; KD at a 4:1 ratio was initiated after 48 hours. However, progression to full dose was not achieved due to severe ileus, leading to exchange to parenteral formulation on day 12 of hospitalization. Due to clinical deterioration at day 19 of ICU admission involving severe hypertriglyceridemia and de novo septic shock, parenteral nutrition was suspended. The patient progressed into refractory shock and died on day 21 of hospitalization. 

Study Author Conclusions

To our knowledge, the majority of KD administrations in adults are by the enteral route. The feasibility and safety of parenteral KD in adults has yet to be assessed. There are reports of parenteral KD in pediatric populations with some interesting results, but there are very limited reports of its feasibility and safety in adult populations and, to our knowledge, none in the presence of SRSE. We decided to initiate parenteral KD in two of our cases due to severe gastric stasis, a common feature during KD. Clinical improvement was seen in both cases; however, in one case, this strategy was abandoned because of de novo septic shock.

Regarding nondietary complications, we reported severe hypocalcemia in two patients treated with phenytoin that led to its discontinuation. Hypocalcemia can deteriorate seizure control due to vitamin D deficiency, and close monitoring is required. We opted to supplement our patients with mineral, vitamin, and calcium supplements, mainly those that are not synthesized by the human body.