抄録
Background: Lumboperitoneal shunt surgery has the potential to alleviate symptoms of normal pressure hydrocephalus but the benefits of such surgery have not been tested in a randomised trial. The aim of this trial was to determine the safety and efficacy of the lumboperitoneal shunt surgery for this disorder. Methods: For the open-label randomised SINPHONI-2 trial, eligible participants (60-85 years of age) with idiopathic normal pressure hydrocephalus, with ventriculomegaly, and tightness of the high-convexity and medial subarachnoid spaces on MRI, were recruited from 20 neurological and neurosurgical centres in Japan. Enrolled participants were randomly assigned in a 1:1 ratio according to a random code generated by the trial statistician, with a permuted block design (using a block size of 4 or 6) within each centre, to receive lumboperitoneal shunt surgery within 1 month after randomisation, or to surgery postponed for 3 months. Patients and assessors were not masked to treatment assignment. The primary endpoint was favourable outcome, defined as an improvement of one point or more on the modified Rankin scale (mRS) at 3 months after randomisation, analysed by intention to treat, and the main secondary endpoint was the same outcome 12 months after surgery, analysed per protocol. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), number UMIN000002730. Findings: Between March 1, 2010, and Oct 19, 2011, 93 patients with idiopathic normal pressure hydrocephalus were enrolled and randomly assigned to the immediate treatment group (n=49) or the postponed treatment group (n=44). More patients in the immediate treatment group than in the postponed treatment group had an improvement of one point or more on the mRS at 3 months: 32 (65%) of 49 in the immediate group vs 2 (5%) of 44 in the postponed group (difference 61% [95% CI 42-68]; p<0·0001). The number of patients who had an improvement of one point or more on the mRS at 12 months after surgery was similar between the two groups: 30 (67%) of 45 patients in the immediate group vs 22 (58%) of 38 in the postponed group (difference 9% [95% CI -14 to 31]; p=0·496). The proportions of patients with serious adverse events did not differ significantly between the groups during the 3 months post-randomisation (7 [15%] of 46 in the immediate group vs 1 [2%] of 42 in the postponed group; p=0·060). During the 12 months after surgery, 19 (22%) of 87 patients had serious adverse events, the most common of which was cerebral infarction (six patients [7%]). Interpretation: Our results suggest that lumboperitoneal shunt surgery might be beneficial for patients with idiopathic normal pressure hydrocephalus and, if these findings are confirmed in larger studies, could be a first-line treatment option for this disease. Funding: Johnson & Johnson and Nihon Medi-Physics.
| 本文言語 | English |
|---|---|
| ページ（範囲） | 585-594 |
| ページ数 | 10 |
| ジャーナル | The Lancet Neurology |
| 巻 | 14 |
| 号 | 6 |
| DOI | |
| 出版ステータス | Published - 6月 1 2015 |
ASJC Scopus subject areas
- 臨床神経学
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「Lumboperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (SINPHONI-2): An open-label randomised trial」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。引用スタイル
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In: The Lancet Neurology, Vol. 14, No. 6, 01.06.2015, p. 585-594.
研究成果 › 査読
}
TY - JOUR
T1 - Lumboperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (SINPHONI-2)
T2 - An open-label randomised trial
AU - for the SINPHONI-2 Investigators
AU - Kazui, Hiroaki
AU - Miyajima, Masakazu
AU - Mori, Etsuro
AU - Ishikawa, Masatsune
AU - Hirai, O.
AU - Kuwana, N.
AU - Hashimoto, M.
AU - Ishii, K.
AU - Hirata, Y.
AU - Miyake, H.
AU - Mori, S.
AU - Kajimoto, Y.
AU - Origasa, H.
AU - Yamamoto, H.
AU - Mori, K.
AU - Nakamura, S.
AU - Miki, T.
AU - Arai, H.
AU - Kajimoto, Y.
AU - Nakayama, T.
AU - Takeda, M.
AU - Chang, C. C.
AU - Date, I.
AU - Atsuchi, M.
AU - Okada, T.
AU - Kita, D.
AU - Watanabe, M.
AU - Kimura, T.
AU - Kaijima, M.
AU - Sunada, S.
N1 - Funding Information: The results of this randomised controlled trial show that patients with idiopathic normal pressure hydrocephalus can benefit from shunt surgery in terms of their functional status and triad symptoms ( ). Several large studies have previously reported shunt surgery to be effective in idiopathic normal pressure hydrocephalus, panel 4,9,28,29 but they only included patients who had shunt surgery (ie, they had no control group). A more recent non-randomised study reported that patients who received ventriculoperitoneal shunt surgery had a more favourable outcome than those who did not receive the surgery. 30 However, that study might suffer from a selection bias because the non-operated patients might have had reasons for avoiding surgery, such as coexisting disease, old age, or little support from family members, all of which could cause functional deterioration. In our study, at 12 months after surgery, 52 (63%) of the 83 patients showed improvement in their functional status. The proportions of patients with improvement of functional status following lumboperitoneal shunt surgery for idiopathic normal pressure hydrocephalus were reported to be 51% at 4–60 months 31 and 64% at 12 months 6 after shunt surgery in retrospective studies. The participants in the latter study were mostly patients with DESH. Our present results confirm the findings of our previous SINPHONI study 9 that patients with DESH have high shunt responsiveness (in the present study, the percentage of patients with a favourable outcome on mRS at 12 months after shunt surgery was 63%, and similarly it was 69% in SINPHONI)—a result that is also supported by a recent neuroimaging study in which patients had shunt surgery. 32 No significant difference between the two groups was noted in change of mRS at 12 months after surgery, suggesting that a delayed start of surgery had no significant long-term effect on functional outcome. However, one recent non-randomised study indicated that later shunt surgery in patients with idiopathic normal pressure hydrocephalus led to poorer improvement of clinical symptoms. 30 This finding does not necessarily contradict our results, because our study had a shorter waiting time (3 months) than the median waiting time in the previous study (13·2 months), 30 and had low statistical power as our study was not designed to detect the effect of a delayed start of surgery. Based on the results of our present study, we estimate that it would take ten-times more participants (475 patients) in each group to detect the effect of a 3-month delay with a power of 0·8 and an α of 0·05. Almost all the adverse events that were related to lumboperitoneal shunt surgery were caused by shunt malfunction or over-drainage, which were expected on the basis of the results of previous studies. 31,33 The peritoneal catheter is prone to prolapse. However, shunt catheter migration might be avoidable with a recently developed technique, in which the catheter is obliquely passed through the abdominal rectal muscle and anchored to the anterior and posterior rectal muscle sheaths. 34 Although over-drainage symptoms can develop at any point after surgery, symptoms that occurred soon after the procedure were likely to be caused by leakage of CSF, 35 which can resolve spontaneously. However, a third of the serious adverse events were subdural haematomas requiring surgery, which would be due to over-drainage. Clinicians have to pay attention to avoid subdural haematoma. Our study procedure was based on the standard treatment for idiopathic normal pressure hydrocephalus in Japan, which differs from that in European and North American countries. First, lumboperitoneal shunt surgery is the most common shunt surgery for idiopathic normal pressure hydrocephalus in Japan. 6 An advantage of this procedure is that patients and their caregivers are less likely to refuse lumboperitoneal shunt than ventriculoperitoneal shunt surgery, because the lumboperitoneal approach can avoid cranial surgery. Important advantages of ventriculoperitoneal shunt surgery are that it avoids rupture and clogging of the shunt tube, because the shunt tube for the ventriculoperitoneal shunt is thicker than that for the lumboperitoneal shunt. It is also suitable for patients with spinal degeneration. Second, the inclusion criteria in our study were based on the diagnostic criteria in the Japanese idiopathic normal pressure hydrocephalus guidelines, 36 which differ from the diagnostic criteria in the international guidelines. 37 The Japanese guidelines include an age of onset older than 60 years and any one of the triad of symptoms, whereas the international guidelines include an age of onset over 40 years and mandatory gait or balance disturbance plus one of the other two symptoms of the triad. However, the mean ages of patients in previous studies from high-income countries 4,28–30 was also around 70 years and older, and 88 of 93 patients in this study had gait disturbance, suggesting that the differences in age and symptoms of patients with idiopathic normal pressure hydrocephalus between Japan versus other high-income countries were irrelevant. However, Japanese guidelines also emphasise the role of brain imaging features of DESH, whereas international guidelines consider brain imaging no more than a supportive feature without operational criteria. Third, Japan has many neurological and neurosurgical hospitals, most of which are smaller and have smaller referral areas than typical European hospitals. In this study, 87 patients with idiopathic normal pressure hydrocephalus received shunt surgery in 20 centres (about four patients per centre) and in a 2011 survey of patients with the same disorder in Japan, 1608 patients received shunt surgery in 289 facilities (about six patients per centre). 6 This might mean neurosurgeons in Japan have less experience in shunt surgery than do those in Europe. In a European multicentre study, 142 patients with idiopathic normal pressure hydrocephalus were recruited from 13 centres in 1 year (about 11 patients per centre). 29 In North America, 151 patients were examined for 11 years in one centre (about 14 patients per year and per centre). 28 However, the percentages of patients with favourable outcomes in studies done in Japan, 6,9 including the present study, are similar to those in studies done in Europe and North America, 4,28–30 suggesting that the small number of patients per centre in Japan did not have a large effect on our results. Our study has several limitations. First, the patients, their caregivers, and the raters were not masked to the type of treatment that the patients received, which might have biased their detection and assessment of symptoms. Second, this study was small to disclose adverse effects and to detect the effect of a 3-month delay on shunt surgery. Third, the extent to which the patients followed the recommended exercise programme was not verified. Fourth, we did not analyse the effect of lumboperitoneal shunt surgery on the health-related quality of life of the patients, which needs to be addressed in further studies. However, despite these limitations, the results of this study suggest that lumboperitoneal shunt surgery might be beneficial in patients with idiopathic normal pressure hydrocephalus. If these findings are confirmed in larger studies, in our view lumboperitoneal shunt surgery has the potential to become a first-line treatment for idiopathic normal pressure hydrocephalus. Contributors MI and EM conceived the study, coordinated the study, and chaired the steering committee. MI, EM, MM, and HK were members of the steering committee and designed and wrote the study protocol with input from all listed members of the study advisory board. HO is the study statistician who prepared the analysis for the report. All listed investigators contributed to enrolment of patients. The steering committee and independent data and safety monitoring committee monitored the study. HK wrote the first draft. All authors were involved in interpretation or presentation of the data, reviewed and revised the initial draft and subsequent versions of the report, and approved the submitted version. SINPHONI-2 investigators Principal investigators : M Ishikawa (Rakuwakai Otowa Hospital, Kyoto, Japan) and E Mori (Tohoku University Graduate School of Medicine, Sendai, Japan). Steering committee : M Ishikawa (Rakuwakai Otowa Hospital, Kyoto, Japan), E Mori, M Miyajima (Juntendo University Graduate School of Medicine, Tokyo, Japan), and H Kazui (Osaka University Graduate School of Medicine, Suita, Japan). Writing committee : H Kazui (Osaka University Graduate School of Medicine, Suita, Japan), M Miyajima, E Mori, and M Ishikawa. Study advisory board : O Hirai (Shinko Hospital, Kobe, Japan), N Kuwana (Tokyo Kyosai Hospital, Tokyo, Japan), M Hashimoto (Noto General Hospital, Nanao, Japan), K Ishii (Kinki University Faculty of Medicine, Osakasayama, Japan), Y Hirata (Kumamoto Takumadai Rehabilitation Hospital, Kumamoto, Japan), H Miyake (Nishinomiya Kyoritsu Neurosurgical Hospital, Nishinomiya, Japan), S Mori (University of Shiga Prefecture, Hikone, Japan), and Y Kajimoto (Osaka Medical College, Takatsuki, Japan). Study statistician : H Origasa (Department of Biostatistics and Clinical Epidemiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan). Independent data and safety monitoring committee : H Yamamoto (Department of Advanced Medical Technology Development, National Cerebral and Cardiovascular Center Hospital, Suita, Japan), K Mori (Kochi Medical School, Kochi, Japan), S Nakamura (Rakuwakai Kyoto Clinical Trial Center, Kyoto, Japan), and T Miki (Department of Neurosurgery, Tokyo Medical University, Tokyo, Japan). Study investigators and centres M Ishikawa (Rakuwakai Otowa Hospital, Kyoto, Japan); E Mori (Tohoku University Graduate School of Medicine, Sendai, Japan); H Arai and M Miyajima (Juntendo University Graduate School of Medicine, Tokyo, Japan); M Hashimoto (Noto General Hospital, Nanao, Japan); Y Kajimoto (Osaka Medical Collage, Takatsuki, Japan); H Miyake (Nishinomiya Kyoritsu Neurosurgical Hospital, Nishinomiya, Japan); T Nakayama (Hamamatsu Medical Centre, Hamamatsu, Japan); O Hirai (Shinko Hospital, Kobe, Japan); H Kazui and M Takeda (Osaka University Graduate School of Medicine, Suita, Japan); N Kuwana (Tokyo Kyosai Hospital, Tokyo, Japan); C-C Chang (Yokohama Minami Kyosai Hospital, Yokohama, Japan); I Date (Okayama University Graduate School of Medicine, Okayama, Japan); Y Hirata (Kumamoto Takumadai Rehabilitation Hospital, Kumamoto, Japan); M Atsuchi (Atsuchi Neurosurgical Hospital, Kagoshima, Japan); T Okada (Tama-Hokubu Medical Centre, Higashimurayama, Japan); D Kita (Kanazawa University Graduate School of Medicine, Kanazawa, Japan); M Watanabe (Tama-Nanbu Regional Hospital, Tama, Japan); T Kimura (Dohtoh Neurosurgical Hospital, Kitami, Japan); M Kaijima (Megumino Hospital, Eniwa, Japan); S Sunada (Tsudanuma Central General Hospital, Narashino, Japan). Declaration of interests This investigator-initiated study was supported in part by Johnson & Johnson and Nihon Medi-Physics. We have not been paid to write this article by a pharmaceutical company or other agency. HK has received donations for the 15th Japan Congress of Normal Pressure Hydrocephalus from Johnson & Johnson, Nihon Medi-Physics, Medtronic, Ono Pharmaceutical, Pfizer, and Eisai; research grants from Eisai, Daiichi-Sankyo, and MSD; and speaker's honoraria from Johnson & Johnson, Nihon Medi-Physics, Medtronic, Ono Pharmaceutical, Pfizer, Eisai, Daiichi-Sankyo, Novartis, Janssen, and Takeda. MM has received donations for the 14th Japan Congress of Normal Pressure Hydrocephalus from Johnson & Johnson, Nihon Medi-Physics, Medtronic, and Novartis; and speaker's honoraria from Johnson & Johnson, Nihon Medi-Physics, Medtronic, Eisai, and Daiichi-Sankyo. EM has received research grants from Eisai and Fuji Film; consulting fees from Lundbeck; and speaker's honoraria from Johnson & Johnson, Nihon Medi-Physics, Medtronic, Eisai, Daiichi-Sankyo, Janssen, Novartis, and Ono Pharmaceutical. MI has received speaker's honoraria from Johnson & Johnson and Medtronic. Acknowledgments This study was a project of the Japanese Society of Normal Pressure Hydrocephalus. We thank the patients for their participation, and we also thank the health professionals involved in patients' management and examination, including the neurosurgeons, neurologists, psychiatrists, neuropsychologists, and physical therapists. Publisher Copyright: © 2015 Elsevier Ltd.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - Background: Lumboperitoneal shunt surgery has the potential to alleviate symptoms of normal pressure hydrocephalus but the benefits of such surgery have not been tested in a randomised trial. The aim of this trial was to determine the safety and efficacy of the lumboperitoneal shunt surgery for this disorder. Methods: For the open-label randomised SINPHONI-2 trial, eligible participants (60-85 years of age) with idiopathic normal pressure hydrocephalus, with ventriculomegaly, and tightness of the high-convexity and medial subarachnoid spaces on MRI, were recruited from 20 neurological and neurosurgical centres in Japan. Enrolled participants were randomly assigned in a 1:1 ratio according to a random code generated by the trial statistician, with a permuted block design (using a block size of 4 or 6) within each centre, to receive lumboperitoneal shunt surgery within 1 month after randomisation, or to surgery postponed for 3 months. Patients and assessors were not masked to treatment assignment. The primary endpoint was favourable outcome, defined as an improvement of one point or more on the modified Rankin scale (mRS) at 3 months after randomisation, analysed by intention to treat, and the main secondary endpoint was the same outcome 12 months after surgery, analysed per protocol. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), number UMIN000002730. Findings: Between March 1, 2010, and Oct 19, 2011, 93 patients with idiopathic normal pressure hydrocephalus were enrolled and randomly assigned to the immediate treatment group (n=49) or the postponed treatment group (n=44). More patients in the immediate treatment group than in the postponed treatment group had an improvement of one point or more on the mRS at 3 months: 32 (65%) of 49 in the immediate group vs 2 (5%) of 44 in the postponed group (difference 61% [95% CI 42-68]; p<0·0001). The number of patients who had an improvement of one point or more on the mRS at 12 months after surgery was similar between the two groups: 30 (67%) of 45 patients in the immediate group vs 22 (58%) of 38 in the postponed group (difference 9% [95% CI -14 to 31]; p=0·496). The proportions of patients with serious adverse events did not differ significantly between the groups during the 3 months post-randomisation (7 [15%] of 46 in the immediate group vs 1 [2%] of 42 in the postponed group; p=0·060). During the 12 months after surgery, 19 (22%) of 87 patients had serious adverse events, the most common of which was cerebral infarction (six patients [7%]). Interpretation: Our results suggest that lumboperitoneal shunt surgery might be beneficial for patients with idiopathic normal pressure hydrocephalus and, if these findings are confirmed in larger studies, could be a first-line treatment option for this disease. Funding: Johnson & Johnson and Nihon Medi-Physics.
AB - Background: Lumboperitoneal shunt surgery has the potential to alleviate symptoms of normal pressure hydrocephalus but the benefits of such surgery have not been tested in a randomised trial. The aim of this trial was to determine the safety and efficacy of the lumboperitoneal shunt surgery for this disorder. Methods: For the open-label randomised SINPHONI-2 trial, eligible participants (60-85 years of age) with idiopathic normal pressure hydrocephalus, with ventriculomegaly, and tightness of the high-convexity and medial subarachnoid spaces on MRI, were recruited from 20 neurological and neurosurgical centres in Japan. Enrolled participants were randomly assigned in a 1:1 ratio according to a random code generated by the trial statistician, with a permuted block design (using a block size of 4 or 6) within each centre, to receive lumboperitoneal shunt surgery within 1 month after randomisation, or to surgery postponed for 3 months. Patients and assessors were not masked to treatment assignment. The primary endpoint was favourable outcome, defined as an improvement of one point or more on the modified Rankin scale (mRS) at 3 months after randomisation, analysed by intention to treat, and the main secondary endpoint was the same outcome 12 months after surgery, analysed per protocol. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), number UMIN000002730. Findings: Between March 1, 2010, and Oct 19, 2011, 93 patients with idiopathic normal pressure hydrocephalus were enrolled and randomly assigned to the immediate treatment group (n=49) or the postponed treatment group (n=44). More patients in the immediate treatment group than in the postponed treatment group had an improvement of one point or more on the mRS at 3 months: 32 (65%) of 49 in the immediate group vs 2 (5%) of 44 in the postponed group (difference 61% [95% CI 42-68]; p<0·0001). The number of patients who had an improvement of one point or more on the mRS at 12 months after surgery was similar between the two groups: 30 (67%) of 45 patients in the immediate group vs 22 (58%) of 38 in the postponed group (difference 9% [95% CI -14 to 31]; p=0·496). The proportions of patients with serious adverse events did not differ significantly between the groups during the 3 months post-randomisation (7 [15%] of 46 in the immediate group vs 1 [2%] of 42 in the postponed group; p=0·060). During the 12 months after surgery, 19 (22%) of 87 patients had serious adverse events, the most common of which was cerebral infarction (six patients [7%]). Interpretation: Our results suggest that lumboperitoneal shunt surgery might be beneficial for patients with idiopathic normal pressure hydrocephalus and, if these findings are confirmed in larger studies, could be a first-line treatment option for this disease. Funding: Johnson & Johnson and Nihon Medi-Physics.
UR - http://www.scopus.com/inward/record.url?scp=84929504858&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929504858&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(15)00046-0
DO - 10.1016/S1474-4422(15)00046-0
M3 - Article
C2 - 25934242
AN - SCOPUS:84929504858
SN - 1474-4422
VL - 14
SP - 585
EP - 594
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 6
ER -