“Time to Feed the Baby”: Should There Be a Paradigm Change in the Treatment of Infantile Epileptic Spasms Syndrome?

Commentary

Infantile epileptic spasms syndrome (IESS) is a severe developmental and epileptic encephalopathy syndrome with a typical onset in infancy, first described by William James West, a British physician, in his own son, James West, in The Lancet in 1841. The syndrome is characterized by a prototypic seizure type, epileptic spasms, which is strongly associated with developmental stagnation or regression and commonly, but not always, with a hypsarrhythmia pattern on the electroencephalogram (EEG). Etiologies of IESS are varied, including, but not limited to, genetic alterations, metabolic disorders, structural brain abnormalities, or CNS infection. IESS frequently evolves to other epilepsy types or syndromes, especially Lennox-Gastaut syndrome (LGS), or other drug-resistant epilepsies later in childhood.

IESS generally poses a treatment challenge to the treating physician because it tends to be a difficult-to-treat epilepsy with a high prevalence of therapy resistance and seizure relapse. The goal of treatment is not only to achieve cessation of seizures/spasms but also a normalization of the EEG or, at least, that the EEG should no longer show the hypsarrhythmia pattern (electroclinical response/cessation). Traditionally, hormonal therapy, with adrenocorticotropic hormone (ACTH) or oral corticosteroid, and vigabatrin (VGB) are recommended first-tier therapies, with the exception of IESS associated with tuberous sclerosis complex. The efficacy of first-tier therapies has been shown in multiple studies and randomized controlled trials. Electroclinical cessation is achieved in ∼37% to 76% with hormonal therapy, 30% to 52% with VGB, and 72% with combined hormonal therapy and VGB.^1–3 However, it is not uncommon to encounter treatment-related adverse effects, such as hypertension, cushingoid appearance, irritability, and susceptibility to infection with hormonal therapy, or changes in muscle tone, white matter signal change, and irreversible visual field restriction with VGB.

Alternatively, non-pharmacological treatments such as epilepsy surgery and dietary therapy have also been employed for the treatment of IESS, especially in those patients whose seizures have failed to respond to first-tier therapy or relapsed after initial remission. Resective epilepsy surgery has shown great results in some selected cases of IESS associated with focal structural abnormality or malformation of cortical development. Dietary treatment with ketogenic diet therapy (KDT) has also been used with high efficacy and good tolerability. A prospective study by Hong et al ⁴ reported that 37% of patients with IESS in whom first-tier therapy failed showed electroclinical cessation at 3 months on KDT. Similar findings were also found in a systematic review by Prezioso et al, ⁵ with 34.6% achieving electroclinical cessation. However, to date, there have been only a few studies on the KDT as a first-line treatment of IESS.

In this study, Mahesan et al ⁶ performed a head-to-head comparison of ACTH and KDT in treatment-naïve patients with IESS, focusing primarily on electroclinical spasms response/cessation. Remarkably, the study found no significant differences in either electroclinical response or cessation rate between the ACTH and KDT arms (P = .39 and P = .83, respectively). Interestingly, KDT outperformed ACTH in relapse rate, which was 38.9% in the ACTH and 0% in the KDT arm (P = .004). Treatment-related adverse effects were also much more prevalent in the ACTH (95.1%) than the KDT arm (59.5%), with two treatment-related deaths from sepsis and pneumonia occurring in the ACTH treatment group. The authors, however, did not elaborate in detail on the neurodevelopmental outcomes of patients at the last follow-up. This may be because the study had a relatively short follow-up time (only 6 months), preventing a clear conclusion in this area.

This study, to date, is the largest randomized controlled trial comparing KDT and ACTH as first-line therapy in patients with IESS without prior exposure to other treatments. The results are aligned with those of a prior study by Kossoff et al, ⁷ which found comparable efficacy in spasms control between KDT and ACTH when used as first-line treatment, with a lower relapse rate (12.5% vs 33%) and lower adverse effects with KDT. Interestingly, in the study by Kossoff et al, ACTH was more likely to lead to EEG normalization faster than KDT. However, in this study by Mahesan et al, the lead times to EEG normalization were similar in both groups. These findings were also seen in another randomized controlled trial by Dressler et al, ⁸ which reported that electroclinical cessation of spasms was achieved at similar time points for both KDT and ACTH (mean of 14 and 16 days, respectively).

Although the pathogenesis of IESS is complex and not well-elucidated, it is postulated to involve various mechanisms, including abnormal excitatory ionic channels, dysfunction of GABAergic interneurons, increased activity of the mammalian target of rapamycin (mTOR) pathway, insulin-like growth factor 1, and T-cell dysregulation. ⁹ KDT, a metabolism-based therapy, exerts anti-seizure and anti-epileptogenic properties through multiple pathways, including increasing the intracerebral level of GABA, attenuating activity of the mTOR pathway, reducing neuronal excitation by inhibiting vesicular glutamate transporters (VGLUTs) and AMPA receptors, promoting mitochondrial function and biogenesis, which leads to potential neuroprotection, decreasing the inflammasome, and altering the gut microbiome. KDT, therefore, may be a suitable treatment option for a disorder with various pathomechanisms such as IESS.

Moreover, KDT may also have added benefits for patients with IESS. Because of a relatively lower side effect profile and better tolerability in comparison to hormonal therapy and VGB, the diet can be used as a long-term treatment, especially in patients with a high likelihood to develop other types of seizure or epilepsy after IESS, such as those with monogenic epilepsies or structural brain abnormalities. Moreover, You et al ¹⁰ evaluated the incidence of IESS evolving to LGS in patients who received different modalities of treatment and found that 44% of patients treated with hormonal therapy alone later developed LGS, whereas only 30% of the KDT group did.

In summary, KDT has been shown in multiple studies to be a safe, effective, and well-tolerated therapy for patients with IESS. Several studies to date have also demonstrated comparable efficacy of KDT with hormonal therapy in both seizure control and normalization of the EEG, but with significantly lower seizure relapse rate and adverse effects. KDT may also have added benefits as it can be employed as a long-term treatment for patients who have etiologically high likelihoods to develop other types of seizures, besides potentially providing long-term neuroprotection and anti-epileptogenesis. It may, therefore, be time to carefully reconsider the treatment paradigm in IESS and possibly allow the ketogenic diet its rightful place among the first-tier therapies. This would potentially broaden our treatment options and selections to offer more individualized and personalized therapy for our patients and families.

Future researchers may want to systematically evaluate long-term neurodevelopmental outcomes in patients with IESS who receive KDT as a first-line treatment. Studies of response to KDT in patients with different etiologies of IESS may also help us tailor our therapy selection more precisely. Finally, parental perceptions of treatment-related benefits and adverse effects of current first-tier therapy compared to KDT would also be an interesting topic worth addressing.