Pauline Anderson

December 04, 2017

WASHINGTON, DC — The ketogenic diet (KD) appears to be just as effective as corpus callosotomy (CC) and vagal nerve stimulation (VNS) in reducing seizures and improving behavior and quality of life in children with drug-resistant epilepsy, new research shows.

In patients not responding to antiepileptic drugs (AEDs), "clinicians tend to just keep pouring on more medicines" instead of considering palliative techniques, study investigator Dave F. Clarke, MD, director, Clinical Epilepsy, Texas Children's Hospital, and Baylor College of Medicine, Houston, told Medscape Medical News.

"We suggest that once a patient is deemed pharmaco-resistant, so having failed two to three medicines, then you should start thinking outside the box."

The findings, along with results of other research on the KD, were presented here at the American Epilepsy Society (AES) 71st Annual Meeting 2017.

High-Fat, Low-Carb Diet

The KD is a high-fat, low-carbohydrate diet — typically at a ratio of 4 to 1 — that pushes patients into a state of ketosis. It's believed that this state helps control seizures.

The study included 210 patients with pharmaco-resistant epilepsy who had 292 treatments. A total of 150 had received VNS, 44 had received CC (a surgical procedure that cuts the corpus callosum and interrupts the spread of seizures from the two hemispheres), and 98 were on a KD between January 2010 and November 2015.

Some children in the study had tried more than one of the treatment approaches.

The patient sample was 60% male and ranged in age from 8 months to 20 years.

The patients' parents participated in a phone interview. They used a nine-item questionnaire to rate seizure control, cognitive and behavioral factors, quality of life, and treatment satisfaction.

Improvement across four cognitive and behavioral domains ranged from 33.3% to 49.3% for VNS, 40.9% to 59.1% for CC, and 34.7% to 57.1% for KD.

At least a 50% reduction in atonic and/or other generalized seizures occurred in 51.7% of the VNS group, 53.5% of the CC group, and 62.5% of the KD group. Focal seizures decreased by at least 50% in 52.9%, 55.8%, and 56% of the groups, respectively.

Improved quality of life was reported by 43.9% of the VNS group, 62.5% of the CC group, and 48.4% of the KD group.

Injury reduction of at least 50% was observed in over half of all the groups. For patients who are prone to falls and injuries during a seizure, CC might be the best option, commented Dr Clarke.

"If someone is falling seven, eight, or nine times a day, you may want to move toward corpus callosotomy, but if the patient has frequent uncontrolled seizures and is not in danger of falls, I would suggest the diet first because it's less invasive."

Tolerability Issues

But not all children with epilepsy can tolerate the ketogenic diet, and it may be too restrictive for a young child who doesn't understand why he can't have candy like his friends, said Dr Clarke.

As for treatment satisfaction, parents reported this in 80% of the VNS, 75% of the CC, and 79.6% of the KD groups.

Despite the large number of study patients, the results were all "trends" and not statistically significant, said Dr Clarke.

It's important for clinicians to know that these approaches not only help control seizures but also improve quality of life, he said.

Some physicians, for example, believe that CC reduces seizures but has a negative effect on quality of life.

"This study proves to them that it's the inverse; it actually can improve quality of life. It's assuring them that the benefits outweigh the risks."

In the past, children stayed on the KD for only about 2 years, but today, patients are closely monitored with regard to levels of calcium, vitamin D, and various minerals and bone health, and as a result they can continue on the diet for longer, said Dr Clarke.

In some patients, the diet might create a "reset," so even if they go off the diet, seizure control is maintained, said Dr Clarke.

Commenting on the findings for Medscape Medical News, J. Helen Cross, professor, Developmental Neurosciences Programme, UCL Institute of Child Health, London, United Kingdom, who is studying the KD in infants, described the study as "perhaps a little one-sided" because VNS and CC are surgical procedures.

"One might suggest that a ketogenic diet should always be considered as treatment prior to consideration of such palliative surgical procedures. So perhaps all the better to know that effectiveness may be slightly in favor of the KD."

Slow Initiation Best Approach

Another study presented at the meeting highlighted the benefit of slow initiation of the KD on an outpatient basis.

The usual practice in many centers is to initiate the classic KD on an inpatient basis.

"Although this provides an opportunity to rapidly titrate the diet ratio up, acute metabolic fluctuations — for example, hypoglycemia and acidosis — can be high, and because the diet is so restrictive, it can be very challenging for families to maintain," study author Rajesh RamachandranNair, MD, a pediatric neurologist and epileptologist at McMaster Children's Hospital, Hamilton, Ontario, Canada, told Medscape Medical News.

"Our results indicated that slow outpatient initiation of the classic ketogenic diet allowed many patients to achieve good seizure control, including seizure freedom, at low ratios."

The study included 40 patients aged 5 months to 17 years with medically refractory epilepsy who initiated the KD as outpatients between January 2010 and October 2016.

To begin with, the ratio was very low (0.6 to1:1) and, depending on the tolerability and desired seizure control, was gradually increased every 2 to 3 weeks.

Researchers defined "good seizure outcome" as greater than 50% reduction in seizure frequency and "excellent seizure outcome" as greater than 90% reduction in seizure frequency.  

Results showed that overall, seizure frequency decreased from a median of 90 per month to a median of 25 per month at 6 months. Almost half the patients had good seizure control at 6 months, including 13 (32. 5%) who had excellent seizure control and 7 (17.5%) who were seizure free.

Almost two thirds (62%) of the patients with good seizure control were on a low ratio at 6 months.

"This study demonstrated that many patients who are arbitrarily put on higher ratios by a rapid inpatient or outpatient titration method might have had good seizure control at lower ratios had there been a slower titration of the ratio," said Dr RamachandranNair.

"The findings might encourage centers to opt for a low ratio and gradual initiation of the classic KD."

Commenting on this research for Medscape Medical News, Dr Cross said it's "interesting" because it highlights how success can be achieved through a slow introduction of the diet.

"In times when resources are low, and admission to hospital may provide a greater inconvenience to families, it's useful to know that a slow introduction, and even lower ratios, may be effective."

However, Dr Cross pointed out that outpatient introduction of the diet "is not new to other healthcare systems around the world."

Modified Atkins

In yet another study, Johns Hopkins researchers investigated lipid levels and other measurements in adult patients with epilepsy who followed the modified Atkins diet (MAD), another diet high in fat and low in carbohydrates, but with a fat-to- carbohydrates ratio that is much lower than that in the ketogenic diet.

Researchers compared 20 adult patients who followed the MAD for more than a year to 21 who were not on the diet.

They found no significant differences between MAD followers and controls in levels of total cholesterol, high-density lipoprotein, low-density lipoprotein (LDL), or total number of LDL particles.

However, compared with controls, patients on the MAD had significantly higher serum levels of small LDL particles (P = .023) and were significantly more likely to have LDL pattern B, in which small LDL particles predominate (P = .025). Small LDL particles are associated with increased cardiovascular disease (CVD) risk and atherogenesis because they cross the arterial wall more readily and are more easily oxidized.

Small, dense LDL particles could be a potential marker of CVD risk, the authors note. This, they add, should be more closely monitored in patients following the diet long term.

Dr Clarke has spoken on behalf of LevaNova (a pioneer of VNS therapy). The other investigators and commentators have disclosed no relevant financial relationships.

American Epilepsy Society (AES) 71st Annual Meeting 2017. Abstracts  3.178, 3.332m and 3.329 . Presented December 4, 2017.

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