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LETTERS TO THE EDITOR
Year : 2021  |  Volume : 24  |  Issue : 1  |  Page : 111-115
 

Ketogenic diet for super-refractory status epilepticus: A case series and review of literature


Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission13-Mar-2020
Date of Acceptance13-Apr-2020
Date of Web Publication05-Feb-2021

Correspondence Address:
Dr. Vimal Kumar Paliwal
Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.AIAN_170_20

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How to cite this article:
Anand S, Vibhute AS, Das A, Pandey S, Paliwal VK. Ketogenic diet for super-refractory status epilepticus: A case series and review of literature. Ann Indian Acad Neurol 2021;24:111-5

How to cite this URL:
Anand S, Vibhute AS, Das A, Pandey S, Paliwal VK. Ketogenic diet for super-refractory status epilepticus: A case series and review of literature. Ann Indian Acad Neurol [serial online] 2021 [cited 2021 Apr 12];24:111-5. Available from: https://www.annalsofian.org/text.asp?2021/24/1/111/308707




Sir,

Super-refractory status epilepticus (SRSE) is a life-threatening condition with high mortality (16–23%).[1] There are no clear guidelines for its treatment. Failure of anesthetic agents has prompted the use of immunotherapy, intravenous magnesium, pyridoxine, hypothermia, resective surgery, and ketogenic diet (KD) in SRSE.

We share our experience and discuss the literature regarding use of KD in SRSE.


   Cases Top


Our protocol for KD in SRSE is given in [Figure 1]. Details of MRI, EEG, and KD are given in [Table 1].
Figure 1: Protocol for the use of ketogenic diet in superrefractory status epilepticus

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Table 1: Clinical details, diagnosis, and treatment details of patients treated with ketogenic diet

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Case 1

A 60-years-old lady presented with seizures leading to status epilepticus and left-hemiparesis for 3 days. She had left face/arm clonic seizures spreading to other side every few minutes. She had received lorazepam, loading dose of phenytoin sodium, levetiracetam, sodium valproate, and clobazam. In view of lower lobe pneumonia and sepsis, she was intubated and mechanically ventilated. She did not respond to midazolam (0.3 mg/kg/h). After 2 days of initiating classic KD, ketosis and seizure cessation were achieved. The KD was gradually weaned over 18 days. At 1 month, she was seizure free on phenytoin sodium and clobazam.

Case 2

A 27-year-old man presented with headache, vomiting, and altered behavior for 5 days. On fifth day, he developed generalized tonic–clonic seizures that evolved to status epilepticus. He received diazepam, lorazepam, loading dose of phenytoin, levetiracetam, and lacosamide over next 5 days. He was referred to us on midazolam infusion (0.3 mg/kg/h). On examination, his consciousness was 8/16 (FOUR score), no focal weakness, and extensor planters. His seizure continued despite thiopentone sodium (5 mg/kg bolus followed by 5 mg/kg/h infusion). In view of new-onset refractory status epilepticus and white-mater hyperintensities on MRI, he was given methylprednisolone (1 g/day) for 3 days with no response. On day 14, he was initiated on KD that improved his seizures. Patient remained seizure free on levetiracetam and clobazam. He was successfully weaned from KD over 18 days. Autoantibody panel and repeat cranial MRI were normal.

Case 3

A 24-year-old male, a known case of Lennox–Gastaut syndrome, developed generalized status epilepticus for 1 day after missing his antiepileptic drugs. Midazolam infusion (0.3 mg/kg/h) produced only transient seizure freedom. From day 2 of status epilepticus, patient was given KD (4:1). On day 5, patient had complete cessation of seizures. He is seizure free for 1 month on KD, sodium valproate, levetiracetam, and clobazam.

Case 4

A 7-year-old boy, a known case of postencephalitis sequalae (minimal conscious state and epilepsy) for 6 months, presented with generalized tonic–clonic status epilepticus for 6 days. Before visiting us, he had received lorazepam, levetiracetam, phenytoin sodium, oxcarbazepine, and clobazam. The child was not arousable. The family refused the use of intravenous anesthetic agents. He was started on KD (4:1); ketosis achieved on day 5, seizure cessation from day 7. The child is seizure free on KD, oxcarbazepine, and clobazam for 10 months.


   Discussion Top


The classic KD uses four-part fat to one-part protein and carbohydrate. The traditional way is to initiate KD after maintaining fasting for 1–3 days. Ketosis is measured by urinary ketones and serum beta-hydroxybutyrate levels.[2] The other diet forms with similar efficacy are modified Atkins diet (allows 20 g of carbohydrate and fat: protein in 60–70%:40–30%), low glycemic index treatment (allows 60 g carbohydrates of < 50% glycemic index), and medium chain fatty acid (MCT) variant of classic KD (uses MCT as fat source).[3] We preferred classic KD due to urgency of achieving ketosis. Contraindications to KD like persistent metabolic derangement, fatty acid oxidation disorders, pancreatitis, and severe dyslipidemia were excluded. Dextrose-free fluid was used and tablets replaced syrups [Figure 1]. We gave one-third of total required calories on first day, escalated to full KD dose by third day.

We compiled studies that used KD for SRSE in [Table 2].[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19] Response rate with KD in SRSE is not known due to lack of controlled trials. KD is postulated to be more effective in children than adults probably due to high levels of ketone-metabolizing enzymes in their brain, resulting in higher uptake of ketone bodies. With cerebral maturation, the number of monocarboxylic acid transporters in brain decreases. However, the ketone-dependent monocarboxylic acid transporters increase in adults in situations like ischemia, trauma, and sepsis. A multicenter study did not find relationship between KD outcome and age, sex, seizure type, or EEG findings.[18]
Table 2: Review of studies reporting the effect of ketogenic diet on refractory/superrefractory and nonconvulsive status epilepticus

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The optimal timing of initiating KD and its duration in SRSE have not been established. KD showed similar efficacy, whether used early or after the seizure became refractory.[19]

A recent review found no significant difference between KD responders and KD nonresponders based on age of seizure-onset, etiology, seizure types, number of previously tried anti-epileptic drugs/anesthetic agents, duration of SRSE before initiating KD, time to ketosis, and KD duration.[17] Specifically, good response to KD was seen in children with febrile infection-related epilepsy syndrome.[9],[17] KD has been successfully used in nonconvulsive status epilepticus.[6],[7],[9] Most people used classic KD. Only few used modified Atkins diet and low glycemic index diet.[6],[9] The time to freedom from status epilepticus ranged from zero to 10th day after initiation of KD. Time to ketosis ranged from 1 to 16 days. Most authors used KD after failure to control status epilepticus with anesthetic agents. The common adverse effects of KD were gastrointestinal disturbances, hypoglycemia, hyponatremia, hypertriglyceridemia, hypoproteinemia, metabolic acidosis, nephrolithiasis, and weight loss.
Figure 2: (a) Cranial MRI diffusion-weighted sequence showing acute right middle cerebral artery infarct, (b) T2 FLAIR-weighted MRI of brain showing bilateral cerebral white-mater hyperintensity, and (c) T2 FLAIR-weighted MRI of brain showing gyral hyperintensities on right cerebral hemisphere

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KD can be used in diabetics by closely monitoring for hypoglycemia and ketoacidosis. It can be rapidly withdrawn in diabetics after the control of status to prevent hyperlipidemia and weight loss/gain.

Use of KD for SRSE is a team effort. A trained dietician should institute and monitor KD. ICU staff should avoid glucose-containing fluids and syrups. KD poses a theoretical risk of renal stones if combined with zonisamide and topiramate. Poor palatability is other concern that can be managed by using 2:1 formulation or other KDs.

We conclude that KD is effective in controlling the SRSE irrespective of the age of the patient, etiology, duration of status epilepticus, and prior use anesthetic agents/antiepileptic drugs.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Vasquez A, Farias-Moeller R, Tatum W. Pediatric refractory and super-refractory status epilepticus. Seizure 2019;68:62-71.  Back to cited text no. 1
    
2.
Cervenka IMC, Kossoff EH. Dietary treatment of intractable epilepsy. Continuum (Minneap Minn). 2013;19:756-66.  Back to cited text no. 2
    
3.
François LL, Manel V, Rousselle C, David M. Ketogenic regime as anti-epileptic treatment: Its use in 29 epileptic children. Arch Pediatr 2003;10:300-6.  Back to cited text no. 3
    
4.
Bodenant M, Moreau C, Sejourné C, Auvin S, Delval A, Cuisset JM, et al. [Interest of the ketogenic diet in a refractory status epilepticus in adults]. Rev Neurol 2008;164:194-9.  Back to cited text no. 4
    
5.
Nabbout R, Mazzuca M, Hubert P, Peudennier S, Allaire C, Flurin V, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010;51:2033-7.  Back to cited text no. 5
    
6.
Kumada T, Miyajima T, Kimura N, Saito K, Shimomura H, Oda N, et al. Modified Atkins diet for the treatment of nonconvulsive status epilepticus in children. J Child Neurol 2010;25:485-9.  Back to cited text no. 6
    
7.
Wusthoff CJ, Kranick SM, Morley JF, Christina Bergqvist AG. The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus. Epilepsia 2010;51:1083-5.  Back to cited text no. 7
    
8.
Nam SH, Lee BL, Lee CG, Yu HJ, Joo EY, Lee J, et al. The role of ketogenic diet in the treatment of refractory status epilepticus. Epilepsia 2011;52:e181-4.  Back to cited text no. 8
    
9.
Martikainen MH, Paivarinta M, Jaaskelainen S, Majamaa K. Successful treatment of POLG-related mitochondrial epilepsy. Epileptic Disord 2012;14:438-41.  Back to cited text no. 9
    
10.
Strzelczyk A, Reif PS, Bauer S, Belke M, Oertel WH, Knake S, et al. Intravenous initiation and maintenance of ketogenic diet: Proof of concept in super-refractory status epilepticus. Seizure 2013;22:581-3.  Back to cited text no. 10
    
11.
Thakur KT, Probasco JC, Hocker SE, Roehl K, Henry B, Kossoff EH, et al. Ketogenic diet for adults in super-refractory status epilepticus. Neurology 2014;82:665-70.  Back to cited text no. 11
    
12.
Lin JJ, Lin KL, Chan OW, Hsia SH, Wang HS; CHEESE Study Group. Intravenous ketogenic diet therapy for treatment of the acute stage of super-refractory status epilepticus in a pediatric patient. J Child Neurol 2015;30:259-66.  Back to cited text no. 12
    
13.
Fung EL, Chang SK, Yam KK, Yau PY. Ketogenic diet as a therapeutic option in super-refractory status epilepticus. Pediatr Neonatol 2015;56:429-31.  Back to cited text no. 13
    
14.
Cobo NH, Sankar R, Murata KK, Sewak SL, Kezele MA, Matsumoto JH. The ketogenic diet as broad-spectrum treatment for super-refractory pediatric status epilepticus: Challenges in implementation in the pediatric and neonatal intensive care units. J Child Neurol 2015;30:259-66.  Back to cited text no. 14
    
15.
Amer S, Shah P, Kommineni V. Refractory status epilepticus from NMDA receptor encephalitis successfully treated with an adjunctive ketogenic diet. Ann Indian Acad Neurol 2015;18:256-7.  Back to cited text no. 15
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16.
Cervenka MC, Hocker SE, Koenig M, Bar B, Henry-Barron B, Kossoff EH, et al. Phase I/II multicenter ketogenic diet study for adult super-refractory status epilepticus. Neurology 2017;88:938-43.  Back to cited text no. 16
    
17.
Park EG, Lee J, Lee J. The ketogenic diet for super-refractory status epilepticus patients in intensive care units. Brain Dev 2019;41:420-7.  Back to cited text no. 17
    
18.
Vining EPG, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, et al. A multi-center study of the efficacy of the ketogenic diet. Arch Neurol 1998;55:1433-7.  Back to cited text no. 18
    
19.
Rubenstein JE, Kossoff EH, Pyzik PL, Vining EP, McGrogan JR, Freeman JM. Experience in the use of the ketogenic diet as early therapy. J Child Neurol 2005;20:31-4.  Back to cited text no. 19
    


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