Of the 14 patients, 5 were diagnosed with infantile spasms, 4 with the Lennox–Gastaut syndrome, 1 with the Landau–Kleffner syndrome, 1 with nonspecific generalized seizure disorder, and 3 with a partial seizure disorder. Patients experienced their first seizure at a mean (± SD) age of 22 ± 21.6 months. Nonepileptic-associated neurological disabilities included mental retardation in all patients, hypotonia in five patients, cerebral palsy in seven patients, behavioral problems in four patients, and peripheral neuropathy in one patient. Nine patients had Complex I defects, one had a Complex II defect, three had Complex IV defects, and one had combined Complex I and IV defects. Of the three patients with Complex IV defects, two (patients 13 and 14) showed clinical progression compatible with the Leigh disease. The detailed clinical profiles and the results of stepwise investigations for diagnosing RC complex defects are summarized in Tables 1 and 2.
Table 1. Clinical profiles of 14 patients with intractable childhood epilepsy and mitochondrial respiratory chain defects
|Age of seizure onset||1 year 10 months|
| ||(±SD, ±21.6 months)|
|Type of respiratory chain defects|| |
| I|| 9|
| II|| 1|
| III|| 0|
| IV|| 3|
| I and IV|| 1|
|Epileptic diagnoses|| |
| Infantile spasms|| 5|
| Lennox–Gastaut syndrome|| 4|
| Landau–Kleffner syndrome|| 1|
| Partial seizure disorder|| 3|
| Generalized seizure disorder|| 1|
|Associated neurologic symptoms|| |
| Mental retardation||14|
| Behavioral problems|| 4|
| Cerebral palsy|| 7|
| Hypotonia|| 5|
| Peripheral neuropathy|| 1|
Table 2. The results of diagnostic workups for assessing the mitochondrial respiratory chain complexes enzyme defects in 14 patients
|Pt 1||F/5.6||I (30.3)||Increaseb (increasec)||Increased||+e||−||ND||ND|
|Pt 2||M/11.8||I (9.7)||Normal (normal)||ND||−||−||+f||−|
|Pt 3||M/1.0||I (11.7)||Normal (normal)||Normal||−||−||+||−|
|Pt 4||F/8.7||I (12.9)||Increase (increase)||ND||+||+g||−||−|
|Pt 5||F/8.5||I (11.1)||Increase (increase)||Normal||−||−||+||−|
|Pt 6||F/2.1||I (9.3)||Increase (increase)||ND||+||−||+||+h|
|Pt 7||M/6.3||I (12.2)||Increase (increase)||ND||+||−||+||−|
|Pt 8||F/2.5||I (10.8)||Increase (increase)||ND||ND||ND||+||−|
|Pt 9||F/0.9||I (10.7)||Normal (normal)||ND||+||−||+||−|
|Pt 10||M/8.8||I (5.9), IV (2.9)||Increase (increase)||ND||+||−||ND||+|
|Pt 11||F/4.0||II (10.8)||Increase (increase)||Normal||+||ND||ND||−|
|Pt 12||F/11.8||IV (8.5)||Increase (increase)||ND||ND||ND||ND||ND|
|Pt 13||M/1.7||IV (8.6)||Increase (increase)||Increase||+||−||+||+|
|Pt 14||F/5.1||IV (10.1)||Increase (increase)||Normal||−||−||+||−|
KD efficacy and safety
The mean (± SD) age of patients at the commencement of the KD was 45 (± 36) months, and the mean (± SD) duration of the KD was 18 (± 15) months. Seven patients became seizure-free after commencing the KD. Three of those patients (patients 1, 7, and 12) successfully completed the diet regime without a relapse, whereas three maintained the diet for 13 (patient 6), 15 (patient 8), and 36 (patient 11) months. One patient (patient 10), who had combined Complex I and IV defects and who was seizure-free for over 4 years while on the KD, experienced an acute episode of status epilepticus combined with pneumonia. The status epilepticus was controlled, but the pneumonia progressed to acute respiratory distress syndrome, and the patient later died due to respiratory and multiorgan failure. Three patients who experienced 50–90% seizure reductions while on the diet maintained the diet for 6 (patient 3), 19 (patient 4), and 8 (patient 14) months. One patient (patient 9), who did not experience seizure reduction while on the KD, died due to aspiration pneumonia and respiratory failure after 3 months on the diet.
Symptomatic and recurrent hypoglycemia (below 40 mg% blood sugar) occurred in two patients (patients 2 and 3). One of those patients (patient 2) was taken off the diet after 3 months, while the persistent hypoglycemia in the other patient (patient 3) was successfully controlled with a low dose of prednisolone.
Of the two patients diagnosed with the Leigh disease caused by Complex IV defects, one (patient 13) was advised to cease the diet after 3 months due to unfavorable outcomes and persistent metabolic acidosis, while the second (patient 14) maintained the diet for 8 months despite intermittent, recurrent seizures.
All patients showed high blood ketosis (>3.0 mmol/L) within 2–3 days of diet commencement, and these levels were maintained throughout the KD treatment.
Most patients had enzyme activities ranging between 8% and 13% of those of matched controls. Patient 10 had 5.9% of Complex I activity and 2.9% of Complex IV activity compared to controls. Of the eight patients who showed a >90% reduction in seizure frequency while on the KD, five (patients 1, 5, 7, 8, and 11) had >10% enzyme activity, and three (patients 6, 10, and 12) had <10% activity compared to controls. The six patients who did not have favorable outcomes while on the KD had enzyme activities of approximately 10% that of controls.
Of the eight patients (patients 1–8) with Complex I defects, five (patients 1, 5, 6, 7, and 8) experienced a >90% reduction in seizure frequency while on the KD, and three (patients 2, 3, and 4) experienced a >50% reduction. Of the three patients who had Complex IV defects, two diagnosed with the Leigh disease (patients 13 and 14) did not experience favorable seizure outcomes, whereas the third (patient 12) showed a dramatic improvement and completed the KD. One patient with combined Complex I/IV defects (patient 9) and one with a Complex II defect (patient 10) remained seizure-free during KD treatment.
Routine scalp EEG was performed at least once in all but two patients (patients 9 and 13) 3 to 6 months after commencement of the diet. One patient (patient 1), who had an electrographic status epilepticus of slow-wave sleep, and two (patients 8 and 11) who had hypsarrhythmias, showed normal EEG features after becoming seizure-free. Of the four patients who showed EEG features characteristic of the Lennox–Gastaut syndrome, two (patients 5 and 12) who were seizure-free while on the KD showed normal background activities in an awake state, and their pre-KD generalized epileptiform discharges were no longer detectable while on the KD.
Four patients (patients 1, 7, 11, and 12) who responded favorably to the KD in terms of seizures were subsequently able to discontinue antiepileptic drug treatment, and another four patients (patients 5, 6, 8, and 10) were able to decrease the frequency and/or dose of drug administration.
Eight patients showed improvements in cognitive and behavioral functions following KD commencement. This was particularly obvious in patient 1, who initially could not be assessed using the Korean Version of the Wechsler Intelligence Scale for Children (K-WISC) prior to commencing the KD due to complete unresponsiveness, but showed an above average score in a K-WISC assessment 15 months after KD commencement. As expected, EEG findings, the number of medications, and neurobehavioral functions correlated with the seizure frequency.
Of the 14 patients, patient 10 with combined Complex I and IV defects was one who clearly showed a dramatic benefit from the KD but died during the diet. The patient history showed that other than slightly delayed speech development, this patient developed well until reaching 4 years and 4 months of age, at which time frequent partial seizures with secondary generalization began to occur, which were accompanied by an abrupt onset of progressive cognitive deterioration and an episodic ataxia. A brain stem auditory-evoked potential study, stimulating both ears individually with 70 dB and recording from both ear lobes, showed delayed latency of waves I, III, and V. A visual-evoked potential study, stimulating both eyes individually using a goggle stimulator and recording from the scalp, showed a delayed latency on both sides. Brain MRI showed diffuse brain atrophy that included the cerebellum. The patient had an increased level of serum lactate, an increased ratio of lactate/pyruvate, and lactic aciduria accompanied by an elevation in Kreb's cycle metabolites. Muscle histology suggested a mitochondrial myopathy, although there were no ragged-red fibers. KD was commenced 6 months after the first seizure and was maintained for 4 years, during which time the patient responded remarkably and remained seizure-free. Tapering of the KD was unsuccessful. After 4 years, the patient experienced an acute episode of status epilepticus and pneumonia. The pneumonia progressed into acute respiratory distress syndrome from which the patient did not recover.
Of the 14 patients, patient 13 with a Complex IV defect and the Leigh disease was one who clearly showed no benefit from the KD. This patient's levels of pyruvate dehydrogenase and other RC enzyme complexes were within normal ranges. The patient was born at gestational age 37 weeks to a healthy mother without any fetal or perinatal problems. However, a neurological examination showed decreased spontaneous movement from the newborn period and frequent focal seizures. Postural tremors began at 4 months. Repeated brain MRI showed a progressive signal change in the deep gray nuclei and brain stem. MR spectroscopy showed a definite lactate peak and a significant decrease in the N-acetyl-aspartate to creatinine ratio. The serum lactate and lactate/pyruvate ratio, cerebrospinal fluid lactate, and urine organic acid results were compatible with an RC complex defect. Although the seizures were not frequent, the KD was cautiously introduced to improve the clinical progress of the Leigh disease. However, seizure outcomes and hypotonia did not significantly improve. Rather, a persistent metabolic acidosis below 12 mmol/l bicarbonate persisted during the 3 months KD duration. The KD was ceased, and the patient was then treated with supplementary mitochondrial cocktail therapy only.
The detailed experiences of all 14 patients are summarized in Table 3.
Table 3. The experiences of the ketogenic diet in 14 patients with mitochondrial respiratory chain complexes enzyme defects
|Pt 1||LKS/(−)||7.5/2.6||100||100||100||100||Completion||ESES (I)||4 (Disc)|| |
|Pt 2||LGS/Atonic||9.0/0.3|| 50|| ||Stop d/t complication||sl && dis, GPFA, GSSW (NI)||5||Hypoglycemia|
|Pt 3||IS/Spasms||0.5/0.6|| 50|| 50|| ||Maintain||Hyp (MI)||4||Hypoglycemia|
|Pt 4||LGS/Atonic||7.0/1.7|| 75|| 50|| 50|| ||Maintain||sl && dis, GPFA, GSSW (NI)||4|| |
|Pt 5||LGS/TC||8.0/0.6||100||100|| ||Maintain||sl && dis, GPFA, GSSW (I)||3 (Dec)|| |
|Pt 6||IS/Spasms||1.0/1.1||100|| 90|| 90|| ||Maintain||Hyp (I)||3 (Dec)|| |
|Pt 7||PS/TC||5.0/2.0|| 90||100||100||100||Completion||sl && dis, focal SW (MI)||3 (Disc)|| |
|Pt 8||IS/Spasms||1.3/1.3||100||100||100|| ||Maintain||Hyp (I)||3 (Dec)|| |
|Pt 9||IS/Spasms||0.7/0.3|| 0|| ||Expire||Hyp (−)||3||Asp. pneumonia|
|Pt 10||PS/C||5.0/4.8|| 90||100||100||100||Expire||sl && dis, focal SW (I)||3 (Dec)||Pneumonia|
|Pt 11||IS/Spasms||1.0/3.0||100||100||100||100||Maintain||Hyp (I)||5 (Disc)|| |
|Pt 12||LGS/Atonic||3.5/2.5||100|| 90||100||100||Completion||sl && dis, GPFA, GSSW (I)||3 (Disc)|| |
|Pt 13||PS/C||0.8/0.2|| 50|| 25|| 25|| ||Stop d/t complication||sl && dis, focal SW (NI)||3||Persistent MA|
|Pt 14||GS/TC||4.8/0.8|| 50|| 25|| ||Maintain||GPSW (NI)||3||Asp. pneumonia|