The short-term efficacy of combined hormone therapy in West syndrome

A single center retrospective comparative observational study was used as it closely resembling routine clinical practice. The study population comprised 131 children aged between 2 and 18 months, followed at the Novosibirsk City Center for Epilepsy and the Novosibirsk City Neurology Center “Sibneiromed” between 1999 and 2009. Observation period in the study was approximately 45 days, with the majority of patients continuing follow up at the same facility for up to 10 years.

Study inclusion criteria:1.

2–18 months of age.

IS were characterized as brief severe axial muscles contractions (flexors, extensor, or mixed), lasting fractions of a second, in clusters (5 to 50 per cluster), with multiple clusters daily, often upon awakening. IS were either symmetric or asymmetric, with head and eye deviation, or only in one side of the body. In rare scenarios we observed only a brief upward eye deviation with typical for IS ictal EEG pattern (Engel, 2001).

Hypsarrhythmia was defined as “…random high-voltage slow waves and spikes. These spikes vary from moment to moment, both in location and duration. At times they appear to be focal, and a few seconds later they seem to originate from multiple foci. Occasionally, the spike discharge becomes generalized, but it never appears as a rhythmically repetitive and highly organized pattern that could be confused with a discharge of the petit mal variant type. … The abnormality is almost continual…” (Gibbs and Gibbs, 1952). Hypsarrhythmia was either classical or modified, the latter of several types: synchronized, asymmetrical, with sustained regional pattern, high amplitude asynchronous, or with suppression-burst pattern. Hypsarrhythmia was diagnosed by EEG during wakefulness and sleep. We recorded bioelectrical brain activity and ECG simultaneously, using Neurotravel and Encephalan-131-01 encephalographs. EEG results were evaluated by us.

According to the ILAE the classic triad of WS is rare. Due to early diagnosis and treatment, classical hypsarrhythmia is practically never found. Nowadays modified hypsarrhythmia or multiregional epileptiform discharges are more often registered. There are also some difficulties in defining regression in children who have developmental delay and early debut IS. Taking into consideration the fact mentioned above, when describing the syndrome, it is currently recommended to use the term “infantile spasms”. The name “West syndrome” is used only in rare cases (Pavone et al., 2015; Howell et al., 2016). However, due to the retrospective nature of the study, we continue to use the historical term “West syndrome”.

Exclusion criteria:1.

Atypical infantile spasms (IS with developmental retardation or regression without hypsarrhythmia, or hypsarrhythmia with developmental retardation without IS).

97 out of 131 patients matched all inclusion and exclusion criteria. 34 patients were not included.

None of the patients had previously received therapy. At the start of therapy, the majority of patients received a combination of oral sodium valproate and intramuscular injections of tetracosactide, while a minority of patients received a combination of oral sodium valproate and intramuscular injections of dexamethasone. 79 infants (Group 1), 53 males and 26 females, received synthetic ACTH, while 18 infants (Group 2), 13 males and 5 females, received dexamethasone. The hormone therapy choices were dictated by drug availability in the healthcare system.

All patients received standard doses. Sodium valproate (Depakene syrup, Sanofi, France) was administered at a daily dose of 30–40 mg/kg/d. The initial dose was 10 mg/kg/d, with a 10 mg/kg dose increase every second day according to H. Siemes treatment protocol. Tetracosactide (Synacthen Depot, Novartis, USA) therapy at a daily dose of 0.03–0.05 mg/kg or dexamethasone (Dexasone, Polfa, Poland) therapy at a daily dose of 0.3–0.5 mg/kg were administered intramuscularly, according to the following schedule: one injection daily for 10 days, followed by 5 alternate-day injections, followed by 5 injections every third day. Patients were concurrently administered diuretics on the days of hormone injections and received potassium, calcium and vitamin D daily. Other AEDs were not used.

All the patients were hospitalized for the whole period of hormone therapy and were under twenty-four hour observation. Counting of seizures was carried out by parents and medical staff.

Primary endpoints were:1.

Percentage of patients with IS cessation by day 5.

Secondary endpoints were:1.

Percentage of patients with IS cessation at hormone therapy completion.

Safety was assessed by recording spontaneously reported adverse events throughout the study. Additionally, hematology, blood chemistry panel, and ECG were performed every 10^th days during the first month of therapy. The presence of side effects was assessed according to records in patient clinical chart.

Student’s t-test for alternate groups and χ² test were used to determine statistical differences between the groups.

The major limitation was concurrent administering of valproate and hormones, because at the start of the study in 1999 this type of formula was common. However, the titration rate and the maximum valproate therapeutic dose of 30–40 mg/kg were identical in both study groups. We believe that it made it possible to assess the efficacy of tetracosactide versus dexamethasone. With concurrent administering of therapies, the difficulty lies in determining adverse effects. Definitely, video EEG monitoring is ideal for determining the number of seizures, as there may be hidden IS. Unfortunately, we did not have such a possibility at that time. Another design limitation was unequal numbers of patients in the groups due to the retrospective nature of the study. Also in this study it was possible to estimate only the short-term efficacy of this protocol.

Voluntary informed consent, approved by the Local Ethics Committee, was received for each patient.

Overall, we provided initial treatment to 97 children with WS. The follow-up period lasted from one month to ten years. In the course of the study, patients were divided into 2 groups based on the type of hormone therapy.

Demographic data and medical history data are shown in Table 1.

The onset of IS in Group 1 occurred at the age range of 2–14 months, however, in the majority of cases onset occurring at 5–6 months; the onset of IS in Group 2 occurred at the same age range of 2–14 months, however, in the majority of cases onset occured at 7 months (Figure 1).

Figure 1.

The description of epileptic syndrome by study group is shown in Table 2.

Tables 1 and 2 demonstrate that despite the unequal numbers of patients in Group 1 and 2, the demographic data (age, gender) and the descriptions of epileptic syndrome (age at onset, types and frequency of IS, and hypsarrhythmia types) were similar in both groups.

The results of hormone therapy are shown in Table 3. Thus, it can be seen from Table 3 that in most cases IS ceased during the first 5 days of hormone therapy. The protocol that included tetracosactide proved to be more effective for IS cessation. Also the disappearance of hypsarrhythmia is achieved in most cases during the first 10 days of hormone treatment. And herein the protocol included tetracosactide showed its greater efficacy. Epileptiform discharges on EEG (multiregional, focal and hypsarrhythmia) remained more often in patients of Group 2.

The data on adverse effects are summarized in Table 4. Appetite increase and weight gain are predictable and unpreventable adverse effects of hormone therapy, and were not taken into account in comparing tetracosactide versus dexamethasone. Treatment had no adverse effects in 32/79 (40.5%) of patients on tetracosactide, and in more than 50% of patients on dexamethasone: 10/18 (55.6%).

Most adverse effects were mild, occurring on the second week of hormone therapy, and did not require suspension or cessation of therapy.