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To the Editors:

West syndrome (WS; we prefer this term instead of infantile spasms) is a catastrophic devastating neurologic disorder preferentially affecting infants within a narrow age range. It has been (and still is) a most attractive target of investigation for pediatric neurologists in Japan (as in other countries) for the last five decades. Therefore, Japanese colleagues heartily welcome a nice review by Pellock and his colleagues (Pellock et al., 2010), based upon their intensive discussions as well as an extensive literature review, which beautifully summarizes the current status of our understanding of various aspects of WS. Japanese colleagues would share the majority of views expressed in this review. A particular thanks should be addressed to the American contributors for their work in establishing, over the past few years, several experimental models of WS, a goal that we have all be anxious to achieve.

Regarding treatment protocols, we note a few discrepancies between Japanese and U.S. consensus. First, the dosage of ACTH is strikingly different. In Japan, natural adrenocorticotropic hormone (ACTH) preparation in a long-acting form (ACTHAR-Z) was used from 1958–1970, at which time a synthetic ACTH-Z preparation, called Cortrosyn-Z (tetracosactide acetate with zinc suspended in emulsion) (Organon Co, Oss, The Netherlands), was first marketed to replace ACTHAR-Z. Cortrosyn Z seems to be identical to Cosyntropin in the United States, with a generic name of tetracosactide (synthetic ACTH 1–24 segment). According to the Miami Children’s Brain Institute (MCBI) website, Cortrosyn Z (or Cosyntropin) 1 mg corresponds approximately to 100 IU of ACTH (as defined in the 3rd International Working Standard). According to Japan Pharmaceutical Information Center (JAPIC), however, Cortrosyn Z 1 mg is considered as biologically equivalent to 40 IU of ACTH. The reason for the conversion difference between MCBI Web/Wiki and JAPIC is unclear. In Japan, the standard protocol before 1970 consisted of ACTHAR-Z, 10 units, i.m., daily for 2 weeks and tapering for infants younger than 12 months old; from 1971 to the present, the usual treatment protocol has been Cortrosyn-Z 0.0125 mg/kg, i.m., daily for 2 weeks and tapering. The efficacy in seizure control and electroencephalography (EEG) normalization was the same for the period before 1970 as for the period after 1970 (Fukuyama, 1968; Ito et al., 2000; Ito, 2001, 2006).

The preceding treatment protocol reflects a significantly lower dosage of ACTH in Japan in comparison to the U.S. standard of 150 IU/m2/day of natural ACTH preparation (Yanagaki et al., 1999). For example, for a 6-month-old male infant with an 8 kg body weight and a 0.4 m2 body surface, the daily dose of ACTH to be given in the U.S. versus that given in Japan would be 60 IU/day (=0.6 mg/day) versus 0.1 mg/day, respectively. Despite this large difference in dosage, the rate of seizure disappearance and EEG amelioration appears to be similar. Since the introduction of this low dosage scheme in Japan, it has been rare in our daily practice to observe serious side effects of ACTH [e.g., obesity, hypertension, hypertrichosis, electrolyte imbalance, manifest immunodepression, cardiac dilation, or brain shrinkage on computed tomography/magnetic resonance imaging (CT/MRI)].

Duration of ACTH administration was also assessed by a recent multicenter collaborative study in Japan (Ozasa et al., 2009), in which subjects were divided into two groups: one involving a shorter tapering period of less than 2 weeks (8 days on average) and the other involving a longer than 3-week tapering period (32 days 0n average). There was no statistically significant difference in seizure recurrence/EEG aggravation rates between the two groups. In the group with the shorter tapering period, there were numerous cases in which ACTH was never given after the initial 2 weeks of daily administration, thus reducing the total ACTH dose as well as side effects and, eventually, the hospitalization period.

From the perspective of our current scheme in Japan, the standard dosage in United States seems too large. Multiple factors might be involved in this great difference. It is important, therefore, to exchange information and share experiences between these two countries. A unified collaborative research project is highly recommended.

Another difference between practice in the United States and Japan involves a therapeutic evaluation of vitamin B6 in WS. In Japan, massive doses of vitamin B6 (PAL-P or pyridoxal phosphate; 20–40 mg/kg/day) are strongly advocated by Ohtahara and Yamatogi (2010), and the majority of pediatric seizure clinics follow the practice of giving B6 as the first-line agent to newly diagnosed WS patients (Tsuji et al., 2007; Suzuki, 2009). Because the efficacy of B6 usually becomes apparent during the first week of treatment, massive B6 therapy can be tried during the first week of admission when the workup for underlying diseases is routinely carried out. Ohtahara and Yamatogi (2010) observed a complete seizure remission in 8of 25 idiopathic WS cases (32%), and in 22 of 191 symptomatic cases (11.5%) with this treatment, with hypsarhythmia disappearing concomitantly. Success rate at other clinics has been more moderate (5–10%). However, such cases with favorable effects should be respected, since most responders taking B6 monotherapy can be seizure-free for life.

It is important to note that, unfortunately, vigabatrin is not yet commercially available in Japan.

Acknowledgment

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  2. Acknowledgment
  3. Disclosure
  4. References

I thank my Japanese colleagues for useful discussions on this topic.

Disclosure

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  2. Acknowledgment
  3. Disclosure
  4. References

I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. I have no conflicts of interest to disclose relevant to this publication.

References

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  2. Acknowledgment
  3. Disclosure
  4. References
  • Fukuyama Y. (1968) Diagnosis and treatment of epilepsies in childhood. Nihon Shonika Gakkai Zasshi 72:14621483.
  • Ito M, Seki T, Takuma Y. (2000) Current therapy for West syndrome in Japan. J Child Neurol 15:423428.
  • Ito M. (2001) Extremely low-dose ACTH therapy for West syndrome in Japan. Brain Dev 23:635641.
  • Ito M, with the Guideline Committee, Japan Epilepsy Society (Chair: Fujiwara T). (2006) Guideline for diagnosis and treatment of West syndrome – a report of the Guideline Committee, Japan Epilepsy Society. Tenkan Kenkyu 24:6875.
  • Ohtahara S, Yamatogi Y. (2010) Clinical evaluation of pyridoxine treatment of intractable seizures. Program and Abstracts, International Symposium on Epilepsy in Neurometabolic Disease, Taipei, March 26–28, 2010: pA34.
  • Ozasa S, Nomura K, Kosuge H, Mitsui K, Kimura S, Okumura A. (2009) Seizure recurrence rates during/after tapering period in West syndrome patients which were freed from seizures through initial ACTH daily stage of two weeks. No To Hattatsu 41:S117.
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  • Yanagaki S, Oguni H, Hayashi K, Imai K, Funatsuka M, Tanaka T, Yanagaki M, Osawa M. (1999) A comparative study of high-dose and low-dose ACTH therapy for West syndrome. Brain Dev 21:461467.