DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE
The ketogenic diet is effective for refractory epilepsy associated
with acquired structural epileptic encephalopathy
MEL MICHEL VILLALUZ
J HELEN CROSS
INGRID E SCHEFFER
1 Epilepsy Research Centre, Austin Health, The University of Melbourne, Heidelberg, Vic., Australia. 2 Neurosciences Unit, Great Ormond Street Hospital, UCL Institute
of Child Health, London; 3 Young Epilepsy, London, UK. 4 Department of Paediatrics, Royal Children’s Hospital, The University of Melbourne, Melbourne, Vic.; 5 Florey
Institute of Neuroscience and Mental Health, Melbourne, Vic., Australia.
Correspondence to Ingrid E. Scheffer at Austin Health, Melbourne Brain Centre, The University of Melbourne, 245 Burgundy Street, Heidelberg, Vic. 3084, Australia.
*These authors contributed equally to this work.
This article is commented on by Auvin on page 644 of this issue.
Accepted for publication 19th December
Published online 16th February 2018.
Ketogenic diet therapies have proven efﬁcacy for refractory epilepsy. There are many
reports of their use in the genetic developmental and epileptic encephalopathies; however,
little attention has been paid as to whether the diet is also effective in individuals with an
acquired structural aetiology. We observed remarkable efﬁcacy of the diet in two patients
with hypoxic-ischaemic encephalopathy. We then analysed our cases with refractory
structural epilepsies of acquired origin to characterize their response to the ketogenic diet.
The classical ketogenic diet was implemented with dietary ratios of 3:1 to 4.4:1.
Seizure frequency at 1 month, 3 months, 6 months, 1 year, and 2 years was ascertained. A
responder was deﬁned as greater than 50% seizure reduction compared to baseline.
Seven of the nine patients were responders at 3 months.
Somewhat surprisingly we found that the ketogenic diet was effective in
patients with a developmental and epileptic encephalopathy due to an acquired structural
aetiology. This cohort may not be routinely considered for the ketogenic diet because of their
structural and acquired, rather than genetic, basis. The ketogenic diet should be considered
early in the management of patients with acquired structural encephalopathies as it can
improve seizure control with the potential to improve developmental outcome.
Patients with severe epilepsy secondary to an acquired
structural aetiology may have refractory seizures that are
not surgically amenable, often in association with bilateral
cortical involvement. Patients with structural brain lesions
acquired in infancy, such as hypoxic-ischemic encephalopa-
thy, intraventricular haemorrhage, infections, or birth
trauma, are at high risk of developing refractory epilepsy.
In these patients, the management of refractory epilepsy
remains extremely challenging despite the availability of
multiple antiepileptic drugs.
The ketogenic diet has been used in the treatment of
refractory childhood epilepsy since the 1920s. It is a medi-
cally initiated high fat, low carbohydrate diet with demon-
strated efﬁcacy in many epilepsy syndromes, including
epilepsy with myoclonic–atonic seizures (described by
Doose), Lennox-Gastaut syndrome, and Dravet syn-
The ketogenic diet is also the treatment of
choice for two rare disorders of brain energy metabolism:
glucose transporter 1 deﬁciency and pyruvate dehydroge-
Most studies of ketogenic diet efﬁcacy
have focused on seizure types or epilepsy syndromes rather
than speciﬁc aetiological subgroups. Two patients with
hypoxic-ischemic encephalopathy from our study of 61
patients on the ketogenic diet were seizure-free at
This led to the hypothesis that patients with
refractory epilepsy associated with an acquired structural
encephalopathy may respond to the ketogenic diet. Here,
we analysed the responder rate in a collaborative cohort of
patients with refractory epilepsy associated with an
acquired structural epileptic encephalopathy.
In this retrospective study, patients were referred to the
ketogenic diet clinics at Austin Health, Melbourne, Aus-
tralia (IES) and Great Ormond Street Hospital for Chil-
dren, London, UK (JHC). Children with a history of
acquired neonatal or infantile structural lesions who devel-
oped refractory epilepsy were included. Refractory epilepsy
was deﬁned as failure to achieve seizure freedom after ade-
quate trials of two or more suitable antiepileptic medica-
A developmental and epileptic encephalopathy was
diagnosed by a paediatric neurologist on the basis of
718 DOI: 10.1111/dmcn.13687 © 2018 Mac Keith Press