4. Jeune M, Tommasi M, Freycon F, Nivelon JL. Syndrome familial associant ataxie, surdite et oligophrenie.

Sclerose myocardique devolution fatale chez lun des enfants. Pediatrie

1963;18:984 987.
5. Berman W, Haslam RH. A new familial syndrome with ataxia,
hearing loss, and mental retardation. Report of three brothers.
Arch Neurol 1973;29:258 261.
6. Harbord MG, Harden A, Harding B, Brett EM, Baraister M.
Megaloencephaly with dysmyelination, spasticity, ataxia, seizures and distinctive neurophysiological findings in two siblings. Neuropediatrics 1990;21:164 168.

Cardiac complications
in pediatric patients
on the ketogenic diet

7. Van der Knaap MS, Barth PG, Stroink H, et al. Leukoencephalopathy with swelling and a discrepantly mild clinical course
in eight children. Ann Neurol 1995;37:324 334.
8. Hanefeld F, Holzbach U, Kruse B, Wilichowski, Christen H-J,
Frahm J. Diffuse white matter disease in three children: an
encephalopathy with unique features on magnetic resonance
imaging and proton magnetic resonance spectroscopy. Neuropediatrics 1993;24:244 248.
9. Schiffmann R, Moller JR, Trapp BD, et al. Childhood ataxia
with diffuse central nervous system hypomyelination. Ann
Neurol 1994;35:331340.

Article abstractCardiac complications of the ketogenic diet, in the absence of selenium deficiency, have not been reported. Twenty patients on the
ketogenic diet at one institution were investigated. Prolonged QT interval
(QTc) was found in 3 patients (15%). There was a significant correlation
between prolonged QTc and both low serum bicarbonate and high betahydroxybutyrate. In addition, three patients had evidence of cardiac chamber
enlargement. One patient with severe dilated cardiomyopathy and prolonged
QTc normalized when the diet was discontinued. Key words: Cardiac complicationsPediatric patientsKetogenic diet.
NEUROLOGY 2000;54:23282330

T.H. Best, MD; D.N. Franz, MD; D.L. Gilbert, MD; D.P. Nelson, MD, PhD; and M.R. Epstein, MD

The ketogenic diet (KD) is a high-fat, adequateprotein, low-carbohydrate intake designed to mimic
the biochemical changes of starvation. Many adverse
effects of KD have been reported.1,2 Cardiac abnormalities have not been described except when associated with selenium deficiency.3 Cardiovascular
deterioration of a child on KD prompted an investigation of this potential adverse effect in other children receiving this treatment.
Case report. A previously healthy boy presented at age
4 with partial seizures, exhibiting secondary generalization and status epilepticus. MRI scan revealed multifocal
areas of increased T2-weighted signal within the white
matter, which was believed to represent gliosis from a
remote insult. EEG demonstrated moderate background
slowing and right central epileptiform discharges. CSF,
serum, and urine metabolic screening was normal. After
failing phenytoin, high dose valproate, carbamazepine,
clonazepam, topiramate, ethosuximide, and lamotrigine,
KD was started. He tolerated this well and was weaned off
anticonvulsants. The initial fat to nonfat calorie ratio of
4:1 was eventually reduced to 3:1. Multivitamins, minerals, selenium, and carnitine supplements were given. Serum beta-hydroxybutyrate (BHB) levels of 4.4 to 6.9
mmol/L were achieved. He experienced a marked decrease

From the Departments of Pediatrics, Cardiology (Drs. Best, Nelson, and

Epstein), and Neurology (Drs. Franz and Gilbert), University of Cincinnati
College of Medicine, OH.
Received November 11, 1999. Accepted in final form March 17, 2000.
Address correspondence and reprint requests to Dr. David Neal Franz,
Department of Neurology/OSB-5, Childrens Hospital Medical Center, 3333
Burnet Avenue, Cincinnati, OH 45229-3039; e-mail: d.franz@chmcc.org
2328

Copyright 2000 by the American Academy of Neurology

in seizure activity with subjective improvement in mental

status and alertness.
After being stable on the KD for 1 year and 8 months, a
follow-up visit revealed elevation of serum transaminases
(SGOT 234 IU/L [normal 15 to 60], SGPT 183 IU/L
[10 to 35], GGT 39 IU/L [10 to 30]), with normal bilirubin and negative hepatitis serology. Transaminase elevation consequent to KD was suspected. Tachypnea, exercise
intolerance, and a progressive increase in weight subsequently developed. Chest roentgenogram revealed cardiomegaly and pulmonary edema. Electrocardiogram (ECG)
showed diminished QRS voltage and marked prolongation
of corrected QT interval (QTc) to 543. ECG before initiation of KD was normal (figure 1). Echocardiography demonstrated severe left ventricular dilation and dysfunction
(shortening fraction 19%, normal 35%).
On admission, BHB was 11.7 mmol/L, higher than previously observed. Serum bicarbonate (HCO3) was 12
mmol/L. Selenium and calcium levels were normal. Repeat
metabolic testing was normal. Endomyocardial biopsy was
negative for viral myocarditis by light microscopy and
PCR. Treatment with IV inotropes, diuresis, and afterload
reduction was initiated. Although QTc was prolonged, no
ventricular ectopy or T wave alternans was observed. Because other explanations for his cardiomyopathy were not
identified, KD was discontinued and tiagabine and clonazepam started. Transaminase levels returned to normal and
his cardiac status improved. QTc normalized over 1 month,
ventricular function over 2.5 months, and left ventricular
size over 4.5 months. Off the diet, frequency of recurrent
generalized tonic clonic attacks increased, but overall seizure severity was less than before KD was begun.

Figure 2. Scattergram of corrected QT interval (QTc)

and serum beta-hydroxybutyrate (BHB) demonstrates a
correlation between elevated BHB and prolonged QTc
(r 0.572, p 0.026).

Figure 1. Electrocardiograms obtained before the initiation of the ketogenic diet (A), at the time of presentation
with congestive heart failure (B), and 1 month after the
ketogenic diet was discontinued (C), showing a QTc of
401, 542, and 404, respectively. The development of
marked reduction in QRS voltage on the ketogenic diet (B)
is also seen.

8.4 months) had a QTc 450, two of which were 500.

Pre-KD ECGs were available on two of the patients and
indicated development of prolonged QTc (LQT) while on
the diet. Two patients with markedly LQT had left atrial
and left ventricular enlargement. The index case had severe ventricular dilation and dysfunction. An additional
patient without LQT had mild left atrial and left ventricular dilation with normal systolic function. Echocardiogram
of the remaining patient with LQT was normal. The KD
was discontinued in one patient (index case) with resolution of LQT and dilated cardiomyopathy. Normal calcium
levels were documented in patients with LQT and ambulatory rhythm monitoring was normal. A correlation was
found between QTc and BHB (r 0.572, p 0.026) (figure
2) and between QTc and HCO3 (r 0.765, p 0.002)
(figure 3).

Discussion. Although few serious side effects have

been reported with KD, emerging evidence suggests
diets associated with a starvation-like state may
create metabolic derangement conducive to cardiac
conduction abnormalities and/or myocardial dysfunction. Severe malnutrition can cause bradycardia, di-

Methods. Patients currently on KD at Childrens Hospital Medical Center underwent screening ECGs, echocardiograms, and blood chemistries including BHB. Prior studies
were retrospectively reviewed. QT intervals were corrected
for rate by Bazetts formula (QTc QT/R R).4 Normal
QTc was defined as 450 for infants and 440 for children
and adolescents. Patients with ECG abnormalities underwent 24 to 48 hour ambulatory rhythm monitoring.
Nonparametric analysis of serum HCO3 and BHB versus QTc was performed using Spearman correlation coefficient. Correlation analysis included only blood levels and
ECGs obtained on the same day (n 9 patients, n 15
QTc, n 15 BHB, n 13 HCO3). A p value 0.05 was
considered significant.
Results. Twenty-one of 26 patients on KD were evaluated (mean age 9.8 4.7 years; range 1.0 to 19 years). One
patient was excluded because of tricyclic antidepressant
treatment. Three of 20 patients (15%, diet duration 13

Figure 3. Scattergram of corrected QT interval (QTc) and

serum bicarbonate (HCO3) demonstrates a correlation between low HCO3 and prolonged QTc (r 0.765, p
0.002).
June (2 of 2) 2000

NEUROLOGY 54

2329

minished QRS voltage, and LQT.5 Prolongation of

the QT interval is of particular interest due to the
increased risk for ventricular dysrhythmia and sudden death. Acquired LQT has been demonstrated
with anorexia nervosa and starvation diets for obesity. In both instances, LQT has been observed to
precede ventricular tachycardia and sudden death.6,7
There are no prior reports of LQT associated with
KD, although reports of cardiomyopathy in KD patients have been attributed to concurrent selenium
deficiency.3,8
LQT was identified in 3 of 20 KD patients, 2 of
whom were documented to develop the abnormality
after initiating the diet. One presented with severe
dilated cardiomyopathy and the other demonstrated
left atrial and ventricular chamber enlargement
without systolic dysfunction. The third case had a
minimally prolonged QTc and a normal echocardiogram. In the index patient, both LQT and severe
cardiomyopathy resolved with discontinuation of the
diet. The other two patients chose to continue the
diet because of its efficacy and no additional treatments were initiated. Patients in this study were
known to have normal selenium levels. None of these
patients had a family history suggestive of congenital long QT syndrome.
Significant correlation was found between QTc
and both HCO3 and BHB, suggesting the level of
acidosis or ketosis may be important factors. Our
index case exhibited both LQT and congestive heart
failure with excessive elevation of BHB. Age may
also play a role, as younger children can have higher
BHBs. Some patients may have abnormal transcellular membrane ion channels resulting in a predisposition to develop conduction abnormalities as seen in
those who develop LQT on cisapride, tricyclics, or
class I and III antiarrhythmics.
Patients with intractable epilepsy may be subject
to sudden unexplained death (SUDEP) as a consequence of their underlying disease.9 Significant QT
prolongation during ictal versus interictal epileptiform discharges has been reported in patients who
later had SUDEP.10 Sudden unexplained death in a
child on KD would likely be attributed to SUDEP,
rather than a malignant cardiac arrhythmia, particularly in the absence of documented ECG abnormalities.

2330 NEUROLOGY 54

June (2 of 2) 2000

Several factors may confound identification of cardiac dysfunction caused by KD. Seizure patients may
be less active than unaffected children or have cognitive impairment precluding assessment of exercise
tolerance. As demonstrated in the reported case,
transaminase elevation (often presumed to reflect
hepatic dysfunction associated with KD) may represent cardiac dysfunction and passive congestion of
the liver.
Biochemical alterations associated with KD may
cause important cardiac conduction changes in certain vulnerable children. Experience with other diets
creating a starvation-like state suggests that these
patients may be at increased risk for ventricular dysrhythmias and sudden death. Patients on KD should
be assessed before and during therapy with ECGs
and echocardiograms. It may also be useful to minimize excessive elevation of serum BHB and metabolic acidosis. A prospective investigation will be
necessary to further define the nature of this potentially serious side effect.

References
1. Freeman JM, Vining EP, Pillas DJ, et al. The efficacy of the
ketogenic diet 1998: a prospective evaluation of intervention
in 150 children. Pediatrics 1998;102:1358 1363.
2. Ballaban-Gil K, Callahan C, ODell C, et al. Complications of
the ketogenic diet. Epilepsia 1998;39:744 748.
3. Chee CM, Lutchka L, Brown L, Bergqvist C. Ketogenic diet:
unrecognized selenium deficiency. Epilepsia 1998;39(suppl 6):
228. Abstract.
4. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920;7:353370.
5. Ellis LB. Electrocardiographic abnormalities in severe malnutrition. Br Heart J 1946;8:53 61.
6. Pringle TH, Scobie IN, Murray RG, Kesson CM, Maccuish AC.
Prolongation of the QT interval during therapeutic starvation:
a substrate for malignant arrhythmias. Int J Obesity 1983;7:
253261.
7. Isner JM, Roberts WC, Heymsfield SB, Yager J. Anorexia
nervosa and sudden death. Ann Intern Med 1985;102:49 52.
8. Neve J. Selenium as a risk factor for cardiovascular diseases.
J Cardiovasc Risk 1996;3:42 47.
9. Nilsson L, Farahmand BY, Persson PG, Thiblin I, Tonson T.
Risk factors for sudden unexplained death in epilepsy: a casecontrol study. Lancet 1999;353:888 893.
10. Tavernor SJ, Brown SW, Tavernor RM, Gifford C. Electrocardiograph QT lengthening associated with epileptiform EEG
dischargesa role in sudden unexplained death in epilepsy?
Seizure 1996;5:79 83.