使用 ACTH 治療嬰兒點頭痙攣後之腦波分析及生長發育的追蹤

EEG Analysis and Developmental Outcome following ACTH Treatment in Infantile Spasms

陳瑩慈(Ying-Tzu Chen)

指導教授 ： 林本元

共同指導教授 ： 闕壯卿(Chuang Chin Chiueh)

臺北醫學大學/藥學院/藥學研究所/碩士(2012年)

摘要

研究背景：
嬰兒點頭痙攣是一種只會發生在嬰孩時期的癲癇，其有三個特徵：(一) 叢發性痙攣、(二) 腦波有高幅亂律波、(三) 發展遲緩。嬰兒點頭痙攣病童大多發展遲緩且死亡率高，目前主要以皮下注射促腎上腺皮質激素或 vigabatrin 為主要治療方法，可以控制部分病童的痙攣及腦波異常情形，但是由於缺乏治療後長期腦波及發展評量之研究，因此未有任何藥物確定對於嬰兒點頭痙攣之長期發展或長期腦波有益。
研究目的：
1. 研究使用ACTH治療嬰兒點頭痙攣前後腦波之變化。
2. 嬰兒點頭病童使用ACTH治療後之長期發展追蹤。
研究方法：
本研究為小型非侵入性包含前瞻與回溯的觀察性案例研究，在署立雙和醫院、市立萬芳醫院及臺北醫學大學附設醫院進行病歷回溯之研究。參與此試驗之嬰兒點頭痙攣病童皆有接受皮下注射促腎上腺皮質激素的治療。療程為前兩週每天連續注射，接著為期六週的劑量漸減期。期間定期觀察其癲癇改善情形，及其腦波變化。病童療程結束後定期回診，並記錄其腦波變化、癲癇情況與發展情形。

研究結果：
共有十一位童有嬰兒點頭痙攣的病童納入本試驗。平均發病年齡介於0.25 至15個月之間。這些病童中大多有明顯腦部損傷，如腦性麻痺、小腦症或平腦症等。使用ACTH治療後痙攣的頻率及強度皆有顯著改善，且腦波的振幅在不同的腦部區域也都有顯著降低。以兒童日常職能發展量表所做的發展評估結果顯示，病童發展的程度為常模的0.4% 至9.9%。進一步分析腦波的頻率，發現治療前在7.8 Hz 處有較高振幅，而使用ACTH 治療後振幅有顯著降低。但只有18% 病童看到接近正常的運動及語言能力之生長。
研究結論：
本研究結果顯示ACTH可降低嬰兒點頭痙攣病童的痙攣頻率及強度，也可降低腦波的振幅。以職能活動量表所做的發展評估結果較差，推測可能是因大多病童在發病前就有已知之腦部損傷。多數病童仍須服用抗癲癇藥物來控制其癲癇症狀。本研究分析腦波頻率發現治療後theta 波7.8 Hz的振幅顯著下降，但與嬰兒點頭痙攣的關係仍需後續研究。

關鍵字

促腎上腺皮質激素、7.8 Hz 腦波頻率、高幅亂律波、發展遲緩、兒童日常職能活動量表, theta wave

並列摘要

Background:
Infantile spasms or West syndrome is an infant-specific epilepsy syndrome characterized by the clinical triad: (i) clusters of spasms, (ii) hypsarrhythmia, and (iii) delay of psychomotor development. Infantile spasms is associated with developmental retardation, high mortality rate, refractory to conventional antiepileptic drugs, and unique responsiveness to ACTH treatment. ACTH and vigabatrin are the current recommended treatments for managing most of the patients with infantile spasms. However, the long-term outcomes of both ACTH and vigabatrin treatments are not promising because 8.4% of the study cases died and the remaining cases progressed to other types of seizure with developmental retardation. Therefore, further studies on infantile spasms cases are warranted.
Objectives:
This study was focused on the EEG changes and developmental outcomes before and after ACTH treatment in patients with infantile spasms.

Methods:
This was a small sampling non-invasive observational case series study including both retro- and pro-spective cases. The study was performed during the period of February, 2012 to June, 2012. Patients from the TMU-affiliated hospitals with the diagnosis of infantile spasms by pediatric neurologists were enrolled in this study. Patients were treated with ACTH 2-3 IU/kg subcutaneously for two weeks following a 6-week tapering-off period. The primary endpoints were to observe symptomatic relief and EEG frequency and voltage change before and after treatment. The secondary endpoints included progression to other types of seizure and long-term developmental outcome. Developmental outcome was assessed by Pediatric Daily Occupation Scale on children’s daily lives prepared by their main caregivers.
Results:
A total of eleven infantile spasms patients were enrolled in this study now. The age of infantile spasms onset ranged from 0.25 to 15 months after birth. Most of them were symptomatic infantile spasms with brain injuries including cerebral palsy, microcephaly, lissencephaly, etc. Both frequency and intensity of spasms along with the voltage of hypsarrhythmia were decreased significantly after ACTH treatment which decreased the voltage of EEG significantly in different brain regions. The Pediatric Daily Occupation Scale was merely 0.4-9.9 % of normal children. Unexpectedly, EEG frequency of 7.8 Hz (theta wave) found in all five IS patients with hypsarrhythmia was significantly inhibited after ACTH treatment; the amplitude of 7.8 Hz was consistently decreased by an average of 81% in all the five available cases tested (p < 0.05). However, only 18% cases (case II and VI) developed near normal motor and language skills.

Discussion and Conclusions:
The present results show that ACTH decreased the frequency and intensity of spasms and hypsarrhythmia significantly. The developmental outcome measured by daily occupation ability after ACTH treatment was not promising in all infantile spasms cases. This may be due to the brain injuries which cannot be cured/rescued by ACTH treatment. All cases still need antiepileptic drugs to control seizures after reducing infantile spasms by ACTH treatment. To the best of our knowledge, this is the first report shows that EEG 7.8 Hz (theta wave) found in hypsarrhythmia of infantile spasms that can be suppressed by ACTH. The exact mechanism underlying the inhibition of hypsarrhythmia especially the amplitude of the theta wave of 7.8 Hz in the EEG of patients with infantile spasms remains to be elucidated in the future.

並列關鍵字

ACTH, developmental retardation, EEG 7.8 Hz, hypsarrhythmia, Pediatric Daily Occupation Scale, theta wave

參考文獻

Appleton RE (2001) West syndrome: long-term prognosis and social aspects. Brain Dev 23: 688-691.

Asano E, Juhasz C, Shah A, Muzik O, Chugani DC, Shah J, Sood S and Chugani HT (2005) Origin and propagation of epileptic spasms delineated on electrocorticography. Epilepsia 46: 1086-1097.

Avanzini G, Panzica F and Franceschetti S (2002) Brain maturational aspects relevant to pathophysiology of infantile spasms. Int Rev Neurobiol 49: 353-365.

Baram TZ and Hatalski CG (1998) Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain. Trends Neurosci 21: 471-476.

Baram TZ, Mitchell WG, Brunson K and Haden E (1999) Infantile spasms: hypothesis-driven therapy and pilot human infant experiments using corticotropin-releasing hormone receptor antagonists. Dev Neurosci 21: 281-289.