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CLINICAL ARTICLEJ Neurosurg 126:2002–2009, 2017
ABBREVIATIONS CSF = cerebrospinal fluid; iNPH = idiopathic
normal-pressure hydrocephalus; INPHGS = iNPH grading scale; mRS =
modified Rankin Scale; RR = rela-tive risk; SINPHONI = study of
iNPH on neurological improvement.SUBMITTED February 15, 2016.
ACCEPTED May 13, 2016.INCLUDE WHEN CITING Published online July 15,
2016; DOI: 10.3171/2016.5.JNS16377.
Disability risk or unimproved symptoms following shunt surgery
in patients with idiopathic normal-pressure hydrocephalus: post hoc
analysis of SINPHONI-2Shigeki Yamada, MD, PhD,1 Teruo Kimura, MD,
PhD,2 Naoto Jingami, MD,3 Masamichi Atsuchi, MD, PhD,4 Osamu Hirai,
MD, PhD,5 Takahiko Tokuda, MD, PhD,6 Masakazu Miyajima, MD, PhD,7
Hiroaki Kazui, MD, PhD,8 Etsuro Mori, MD, PhD,9 Masatsune Ishikawa,
MD, PhD,1 and the SINPHONI-2 Investigators1Normal Pressure
Hydrocephalus Center, Department of Neurosurgery and Stroke Center,
Rakuwakai Otowa Hospital, Kyoto; 2Department of Neurosurgery,
Dohtoh Neurosurgical Hospital, Hokkaido; 3Department of Neurology,
Kyoto University Graduate School of Medicine, Kyoto; 4Department of
Neurosurgery, Atuchi Neurosurgical Hospital, Kagoshima; 5Department
of Neurosurgery, Shinko Hospital, Kobe; 6Department of Molecular
Pathobiology of Brain Diseases (Neurology), Kyoto Prefectural
University of Medicine, Kyoto; 7Department of Neurosurgery,
Juntendo University Graduate School of Medicine, Tokyo; 8Department
of Psychiatry, Osaka University Graduate School of Medicine, Osaka;
and 9Department of Behavioral Neurology and Cognitive Neuroscience,
Tohoku University Graduate School of Medicine, Miyagi, Japan
OBJECTIVE The study aim was to assess the influence of
presurgical clinical symptom severity and disease duration on
outcomes of shunt surgery in patients with idiopathic
normal-pressure hydrocephalus (iNPH). The authors also evalu-ated
the cerebrospinal fluid tap test as a predictor of improvements
following shunt surgery.METHODS Eighty-three patients (45 men and
38 women, mean age 76.4 years) underwent lumboperitoneal shunt
sur-gery, and outcomes were evaluated until 12 months following
surgery. Risks for poor quality of life (Score 3 or 4 on the
modified Rankin Scale [mRS]) and severe gait disturbance were
evaluated at 3 and 12 months following shunt surgery, and the tap
test was also conducted. Age-adjusted and multivariate relative
risks were calculated using Cox proportion-al-hazards
regression.RESULTS Of 83 patients with iNPH, 45 (54%) improved by 1
point on the mRS and 6 patients (7%) improved by ≥ 2 points at 3
months following surgery. At 12 months after surgery, 39 patients
(47%) improved by 1 point on the mRS and 13 patients (16%) improved
by ≥ 2 points. On the gait domain of the iNPH grading scale
(iNPHGS), 36 patients (43%) improved by 1 point and 13 patients
(16%) improved by ≥ 2 points at 3 months following surgery.
Additionally, 32 patients (38%) improved by 1 point and 14 patients
(17%) by ≥ 2 points at 12 months following surgery. In contrast, 3
patients (4%) and 2 patients (2%) had worse symptoms according to
the mRS or the gait domain of the iNPHGS, respectively, at 3 months
following surgery, and 5 patients (6%) and 3 patients (4%) had
worse mRS scores and gait domain scores, re-spectively, at 12
months after surgery. Patients with severe preoperative mRS scores
had a 4.7 times higher multivariate relative risk (RR) for severe
mRS scores at 12 months following surgery. Moreover, patients with
severe gait disturbance prior to shunt surgery had a 46.5 times
greater multivariate RR for severe gait disturbance at the 12-month
follow-up. Pa-tients without improved gait following the tap test
had multivariate RRs for unimproved gait disturbance of 7.54 and
11.2 at 3 and 12 months following surgery, respectively. Disease
duration from onset to shunt surgery was not significantly
associated with postoperative symptom severity or unimproved
symptoms.CONCLUSIONS Patients with iNPH should receive treatment
before their symptoms become severe in order to achieve an improved
quality of life. However, the progression of symptoms varies
between patients so specific timeframes are
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Shunting in early-stage iNPH
J Neurosurg Volume 126 • June 2017 2003
IdIopathIc normal-pressure hydrocephalus (iNPH) is an
established syndrome with gait disturbance, cog-nitive impairments,
and urinary incontinence. Typi-cal presentation occurs in elderly
patients with ventricu-lar dilation, and iNPH can be treated with
cerebrospinal fluid (CSF) shunt surgery. Increasing elderly
populations in developed countries are expected to result in more
pa-tients with iNPH who may require surgical treatment; however,
the ideal patient characteristics for CSF shunt surgery have not
been elucidated. Some neurosurgeons assert that surgery should only
be performed in patients with mild iNPH symptoms once those
symptoms become more severe because the benefits of surgery would
then be greater than its risks. The clinical outcomes of CSF shunt
surgery are affected by patient age, preoperative symptom severity,
comorbidities, radiological findings, duration of time from initial
symptoms until shunt sur-gery, response to the CSF tap test, and
factors related to the devices and procedures specific to the shunt
sur-gery.2,3,6,7,9–14,16–23 Our previous multicenter prospective
cohort study of iNPH on neurological improvement (SINPHONI)
demonstrated great improvement in symp-toms after
ventriculoperitoneal shunt surgery in the pa-tients with iNPH.4,5
The second study of iNPH on neu-rological improvement (SINPHONI-2),
an open-label randomized controlled trial, demonstrated the
efficacy of lumboperitoneal shunt surgery in elderly patients with
iNPH.8 Furthermore, we recently reported that the rates of both
improvements and side effects for lumboperito-neal shunts in
patients with iNPH are similar to those for ventriculoperitoneal
shunts.15
The aim of the present study was to systematically as-sess the
influence of iNPH symptom severity and disease duration on the
efficacy of shunt surgery by using the data collected for
SINPHONI-2.
MethodsParticipants
The institutional review boards at each study site ap-proved the
study protocol of SINPHONI-2 (University Hospital Medical
Information Network [UMIN] Clini-cal Trials no. UMIN000002730),
which was designed by all of the SINPHONI-2 investigators
(Appendix) includ-ing the biostatistician and Independent Data and
Safety Monitoring Committee members, in conformity with the
Guidelines for Good Clinical Practice and the Declaration of
Helsinki of the World Medical Association. All patients or their
representatives gave written informed consent. All clinical and
radiological data were prospectively re-corded in an independent
protocol compliance center via a Web-based case report system.
Participant details, vari-able definitions of iNPH, and protocol
compliance, as well
as details of data collection, including data acquisition and
management, have been described elsewhere.8,15 In brief, 102
patients diagnosed with possible iNPH were recruited from 20
Japanese institutes and hospitals between March 2010 and October
2011. The inclusion criteria for this study were as follows: age
60–85 years at study enrollment, pre-sentation with the clinical
triad of symptoms (gait distur-bance, cognitive impairment, and
urinary incontinence), ventriculomegaly with an Evans index >
0.3, and dispro-portionately enlarged subarachnoid space
hydrocephalus (DESH) observed on CT or MRI. Patients with
compli-cations such as severe disuse muscle atrophy, psychiatric
disorders, or other neurological diseases were excluded from the
study. Therefore, 93 patients were enrolled and were randomly
assigned to an immediate surgery group (49 patients) or a postponed
(3 months) surgery group (44 patients). After randomization, all
participants underwent the CSF tap test and lumboperitoneal shunt
surgery using a Codman Hakim programmable valve with SiphonGuard
(Codman Neuro, DePuy Synthes). Responses to the CSF tap test did
not influence randomization or patient man-agement. Eighty-three
patients (45 men and 38 women, mean age 76.4 years) complied with
randomization and were assessed at 3 and 12 months after shunt
surgery (the per protocol population). In patients suspected to
have shunt malfunction, the patency of the shunt system was checked
according to the CSF aspiration via shunt valve and shuntgram at
the follow-up points.
Measurement of Clinical SymptomsA CSF tap test consisted of
removing ≥ 30 ml of CSF
via lumbar tap. Clinical symptoms before and after the tap test
and at the postsurgical follow-up points (3 and 12 months
postsurgery) were evaluated by neurologists, psy-chiatrists,
neuropsychologists, and/or physical therapists who were independent
of the neurosurgeons performing the lumboperitoneal shunt
surgeries. Gait improvement was assessed 24 hours and cognitive
improvement was assessed within 7 days after the CSF tap test.5 The
gait domain of the iNPH grading scale (iNPHGS) was scored using the
following 5-point grading scale: 0 = normal, 1 = dizziness or drift
and dysbasia without objective gait dis-turbance, 2 = unstable but
independent gait, 3 = walking possible with support, or 4 = walking
not possible. Simi-larly, the cognitive domain was scored as 0 =
normal, 1 = only complaints of amnesia or inattention but no
objective memory and attentional impairment, 2 = minimal
atten-tional or memory deficits, 3 = disorientation of time and
place, or 4 = meaningful conversation impossible. The uri-nary
domain was scored as 0 = normal, 1 = pollakiuria or urinary
urgency, 2 = occasional incontinence, 3 = frequent incontinence, or
4 = uncontrollable incontinence. Gait
not meaningful. The authors also found that tap test scores
accurately predicted shunt efficacy. Therefore, indications for
shunt surgery should be carefully assessed in each patient with
iNPH, considering the relative risks and benefits for that person,
including healthy life
expectancy.https://thejns.org/doi/abs/10.3171/2016.5.JNS16377KEY
WORDS idiopathic normal pressure hydrocephalus; gait disturbance;
improvement rate; lumboperitoneal shunt
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S. Yamada et al.
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was also quantitatively evaluated using the timed 3-m up-and-go
test (TUG) and the 3-m reciprocating walking test (RWT). Cognition
was evaluated using the Mini-Mental State Examination (MMSE) and
the frontal assessment battery (FAB).
Statistical AnalysesThe number of patients with favorable
outcomes on
the modified Rankin Scale (mRS) and the total iNPHGS at 12
months after lumboperitoneal shunt surgery were not significantly
different between the immediate and postponed surgery groups.
Therefore, we pooled the data from both groups. Mean values for age
at study enroll-ment and other continuous variables were analyzed
using 1-way ANOVA. Age-adjusted relative risks and 95% con-fidence
intervals were calculated using Cox proportional-hazards
regression. We assessed the risk for poor quality of life (Grade 3
or 4 on the mRS) and the risk for contin-ued severe gait
disturbance (Grade 3 or 4 on the gait do-main of the iNPHGS) at 3
and 12 months following shunt surgery. We also assessed the risk
for unimproved symp-toms, which we defined as unchanged or higher
scores on the mRS and the iNPHGS at 3 and 12 months following
surgery. To assess interactions or the effects of modify-ing other
potential risk factors, multivariate analyses were conducted after
adjustments for age, body mass index, Evans index, duration of time
from symptom onset until shunt surgery, immediate surgery or
postponed surgery, preoperative disability, and response to the CSF
tap test. In the postponed surgery group, disease duration was
cal-culated based on the onset of initial symptoms until study
enrollment plus 3 months. Responses to the CSF tap test were
defined as an increase of 1 or more points on either the mRS or
each domain of the iNPHGS. All missing data were treated as deficit
data and therefore did not affect other variables. A p value <
0.05 indicated statistical sig-nificance. All statistical analyses
were performed using R software (version 3.0.1, R Foundation for
Statistical Com-puting, http://www.R-project.org).
ResultsBaseline Characteristics
Characteristics of the study population prior to shunt surgery
are presented in Table 1. The mean age at study enrollment
increased concurrently with mRS grades. Sim-ilarly, scores on each
of the 3 domains on the iNPHGS, as well as for the quantitative
examinations of gait and cogni-tion, gradually worsened as mRS
grades increased. Figure 1 presents box-and-whisker plots of the
time from initial presentation to shunt surgery against mRS scores
and gait domains of the iNPHGS before shunt surgery. There was no
significant relationship between disease duration and preoperative
symptom severity.
Clinical OutcomesFigure 2 shows changes in mRS scores and each
of the 3
domains of the iNPHGS before surgery, as well as at 3 and 12
months afterward. Forty-five patients (54%) improved by 1 point on
the mRS and 6 patients (7%) improved by ≥
2 points at 3 months following surgery. Furthermore, 39 patients
(47%) improved by 1 point and 13 patients (16%) improved by ≥ 2
points at 12 months after surgery. On the gait domain of the
iNPHGS, 36 patients (43%) im-proved by 1 point and 13 (16%)
improved by ≥ 2 points at 3 months following surgery. Thirty-two
patients (38%) improved by 1 point and 14 (17%) improved by ≥ 2
points at 12 months following surgery. On the cognitive domain of
the iNPHGS, 33 patients (40%) improved by 1 point and 8 patients
(10%) improved by ≥ 2 points at 12 months following surgery.
Finally, 25 patients (30%) improved by 1 point on the urinary
domain of the iNPHGS and 18 pa-tients (22%) had a ≥ 2-point
increase at 12 months follow-ing surgery.
In contrast, 3 patients (4%) had mRS scores and 2 pa-tients (2%)
had gait domain scores indicating worsening symptoms at the 3-month
follow-up, and 5 patients (6%) had worse mRS scores and 3 patients
(4%) had worse gait domain scores at 12 months following shunt
surgery. Reduced daily activity in the 5 patients with worse mRS
scores at 12 months following surgery was influenced by brainstem
infarction (2 patients), advanced dementia (1 patient), death from
lung cancer 10 months after surgery (1 patient), and suicide 6
months after surgery (1 patient). Additionally, severe adverse
events related to the shunt surgery included shunt malfunction
requiring reoperation (6 patients), chronic subdural hematoma (3
patients), and compressed vertebral fracture (3 patients). The
severe ad-verse events did not contribute to reduced daily
activity.
TABLE 1. Preoperative patient characteristics
Parameter TotalPreop mRS Score p
Value*1 2 3 4
No. of patients 83 1 30 30 22 No. of females 38 0 11 15 12 Mean
age (yrs) 76.4 68 74.2 77.5 78.3
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Risk for Severe Disability Following Shunt SurgeryTables 2 and 3
present the age-adjusted and multivariate
relative risks for disability or poor quality of life related to
the triad of symptoms at 3 and 12 months following shunt surgery.
The age-adjusted relative risk (RR) for a severe
score (Score 3 or 4) on the mRS at 3 months following sur-gery
was 6.7 (95% CI 1.96–22.6) for iNPH patients who had had a severe
preoperative status on the mRS com-pared with patients who had had
a mild mRS score. Addi-tionally, patients with a severe grade
(Grade 3 or 4) on the gait domain of the iNPHGS before operation
had an 18.6 times higher risk for continued severe gait disturbance
at 3 months following surgery. These statistically significant
associations between preoperative and postoperative se-verities
were also observed at 12 months following shunt surgery. After
adjustment for the multivariate covariates, patients with a severe
preoperative mRS score had a 4.7 times higher risk for a severe mRS
score at 12 months following surgery. Moreover, patients with a
severe gait disturbance prior to surgery had a 46.5 times greater
risk for severe gait disturbance at the 12-month follow-up.
Prediction of Responses to Shunt Surgery by the CSF Tap Test
Patients with unimproved mRS scores at the CSF tap test had
significantly greater risks for unimproved mRS scores at the
12-month follow-up (multivariate RR 5.5, 95% CI 1.26–24.0).
Unimproved gait at the CSF tap test was also a significant
predictive factor for unimproved gait following CSF shunt surgery
(Tables 4 and 5). The multi-variate RRs for 3 and 12 months
following surgery were 7.5 (2.2–25.6) and 11.2 (3.3–38.3),
respectively. In contrast, on the cognitive and urinary domains of
the iNPHGS, re-sponses to the CSF tap test were not significantly
associ-ated with responses to shunt surgery. Finally, the duration
of time from symptom onset until shunt surgery was not
significantly associated with postoperative symptom se-verity or
unimproved symptoms.
DiscussionPatients with severe preoperative iNPH symptoms
did
not experience sufficient improvement following shunt sur-gery
compared with patients with mild preoperative symp-toms. In
particular, the multivariate RRs for severe gait dis-turbance at 3
and 12 months following shunt surgery were 20.5 and 46.5,
respectively, for iNPH patients who could not walk independently
prior to surgery. Approximately half of these patients improved by
only 1 point on the mRS or 1 point on the gait domain of the
iNPHGS. It was un-common for these patients to experience
improvements of ≥ 2 points. Therefore, complete symptom reversal
should not be expected following shunt surgery, indicating that the
timing of the surgery during the course of iNPH pro-gression is
critical. At our 12-month follow-up time point, 3 patients had
worse symptoms than at the preoperation time point and 2 patients
had died of conditions unrelated to iNPH or the shunt surgery. In
addition to this finding that not all patients experienced symptom
improvement following shunt surgery, we previously demonstrated
that 16% of patients in the postponed surgery group had worse
iNPHGS gait domain scores by the end of the waiting pe-riod,
although scores did not change for 79% of patients.8 These results
suggest that there is variability in symptom progression rates
between individuals. We confirmed that there was no significant
association between disease du-
FIG. 1. Box-and-whisker plots of disease duration (mos),
classified by mRS scores (upper) and grades for the gait domain of
the iNPHGS (lower) prior to shunt surgery.
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ration and preoperative symptom severity in the present study.
Andrén et al. also reported variability in symptom progression
during a surgery waiting period, ranging from slight improvement to
marked declines in functional abilities.1 These authors recommended
performing shunt surgery soon after diagnosis to maximize the shunt
ben-efits given findings that symptom deterioration is partially
reversed by shunt surgery. However, we suggest caution when
considering surgery in elderly patients with mild symptoms.
In the present study we also revealed that the CSF tap test is a
useful clinical tool when considering shunt sur-
gery. Poor responses to the CSF tap test may accurately predict
insufficient improvement following shunt surgery. Although the
possibility of false-negative responses to the tap test cannot be
eliminated, we found that an poor re-sponse to the CSF tap test
contraindicates shunt surgery, especially for elderly patients or
for patients with several severe comorbidities. We recently
reported that the CSF tap test has a shorter time window for
improved symp-toms than shunt surgery.24 Therefore, we recommend
the CSF tap test as soon as possible before considering shunt
surgery. Conversely, in patients diagnosed with possible iNPH whose
symptoms have been present for > 1 year af-
FIG. 2. Number of patients with preoperative and postoperative
mRS scores and grades for the 3 domains of the iNPHGS.
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TABLE 2. Risk of disability 3 months following shunt surgery
Preop Score or Grade Postop Score or Grade (no. of patients)
AA–RR 95% CI p Value* M–RR 95% CI p Value*1 or 2 3 or 4
mRS score 1 or 2 28 3 Ref Ref 3 or 4 23 29 6.66 1.96–22.6
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ter the initial presentation and who have no response to the CSF
tap test, shunt surgery should be considered to focus on symptom
progression and MRI findings.
In this study, we evaluated patients who underwent
lumboperitoneal shunt implantation. However, the ro-bust results
did not differ substantially from those in the SINPHONI cohort,
which was treated with ventriculo-peritoneal shunt
implantation.
ConclusionsPatients undergoing CSF shunt surgery may expect
complete symptom improvement; however, those with se-vere gait
disturbance prior to shunt surgery have a 46.5 times higher risk
for continued gait disturbance than pa-tients without severe
preoperative gait symptoms. There-fore, we suggest that patients
diagnosed with iNPH should undergo shunt surgery before symptoms
become severe so as to maximize activities of daily living.
However, im-mediate surgery is not necessarily the preferred
strategy because there is considerable variability in symptom
pro-gression rates between patients. Additionally, the CSF tap test
is indicated as a useful tool for predicting shunt effi-cacy.
Therefore, decisions regarding shunt surgery should be
individualized to each patient, considering the relative risks and
benefits for that person, including healthy life expectancy.
AppendixCo-Investigators of SINPHONI-2
Masaaki Hashimoto, MD, PhD (Noto General Hospital, Advi-sory
Committee); Hideki Origasa, MD, PhD (University of Toya-ma, study
statistician); Haruko Yamamoto, MD, PhD (National Cerebral and
Cardiovascular Center, Independent Data and Safety Monitoring
Committee); Hajime Arai, MD, PhD (Juntendo Uni-versity, Advisory
Committee); Koreaki Mori, MD, PhD (Kochi Medical School,
Independent Data and Safety Monitoring Com-mittee); Shigenobu
Nakamura, MD, PhD (Rakuwakai Kyoto Clinical Research Center,
Independent Data and Safety Monitoring Committee); Tamotsu Miki,
MD, PhD (Tokyo Medical University, Independent Data and Safety
Monitoring Committee); Kazunari
Ishii, MD, PhD (Kinki University School of Medicine, director of
Imaging Committee), Hiroji Miyake, MD, PhD (Nishinomiya Kyoritsu
Neurosurgical Hospital, Advisory Committee); Nobu-masa Kuwana, MD,
PhD (Tokyo Kyosai Hospital, site investiga-tor); Naoyuki Samejima,
MD, PhD (Tokyo Kyosai Hospital, site investigator); Daisuke Kita,
MD, PhD (Noto General Hospital, site investigator); Takahiko
Tokuda, MD, PhD (Kyoto Prefectural University of Medicine, site
investigator); Madoka Nakajima, MD, PhD (Juntendo University, site
investigator); Mitsuhito Mase (Nagoya City University Graduate
School of Medical Sciences, site investigator); Satoru Mori, MD,
PhD (University of Shiga Prefecture, Advisory Committee); Yoshinaga
Kajimoto, MD, PhD (Osaka Medical Collage, site investigator); Teiji
Nakayama, MD, PhD (Hamamatsu Medical Centre, site investigator);
Osamu Hirai, MD, PhD (Shinko Hospital, Advisory Committee);
Masa-toshi Takeda, MD, PhD (Osaka University Graduate School of
Medicine, Advisory Committee); Chia-Cheng Chang, MD, PhD (Yokohama
Minami Kyosai Hospital, site investigator); Isao Date, MD, PhD
(Okayama University Graduate School of Medicine, site
investigator); Masahiro Kameda, MD, PhD (Okayama University
Graduate School of Medicine, site investigator); Takaharu Okada,
MD, PhD (Tama-Hokubu Medical Center, site investigator); Junichiro
Hamada, MD, PhD (Kanazawa University Graduate School of Medicine,
site investigator); Mitsuya Watanabe, MD, PhD (Tama-Nanbu Regional
Hospital, site investigator); Mitsu-nobu Kaijima, MD, PhD (Megumino
Hospital, site investigator); Souichi Sunada, MD, PhD (Tsudanuma
Central General Hospital, site investigator); Yoshihumi Hirata, MD,
PhD (Kumamoto Taku-madai Hospital, Advisory Committee).
AcknowledgmentsThe study is a Japanese Society of Normal
Pressure Hydro-
cephalus project. We thank the patients for their participation.
We also thank the study contributors.
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DisclosuresThis investigator-initiated study was supported in
part by Johnson & Johnson K.K. and Nihon Medi-Physics Co., Ltd.
The funding sources for the study had no role in the design and
conduct of the study; in the collection, analysis, and
interpretation of the data; or in the preparation, review, or
approval of the manuscript. The authors were never paid by a
pharmaceutical company or another agency to write this article.
Drs. Kazui, Mori, Ishikawa, and Mi yajima have received honoraria
from the companies that manu-factured the devices discussed in this
article, including Johnson & Johnson K.K. (Japan), and Dr.
Kazui has received honoraria from Nihon Medi-Physics Co., Ltd.
(Japan).
Author ContributionsConception and design: all authors.
Acquisition of data: Kimura, Atsuchi, Hirai, Miyajima, Kazui, Mori,
Ishikawa. Analysis and interpretation of data: all authors.
Drafting the article: all authors. Approved the final version of
the manuscript on behalf of all authors: Yamada. Statistical
analysis: Yamada, Ishikawa. Admin-istrative/technical/material
support: all authors. Study supervi-sion: Kimura, Jingami, Tokuda,
Miyajima, Kazui, Mori, Ishikawa.
CorrespondenceShigeki Yamada, Normal Pressure Hydrocephalus
Center, Department of Neurosurgery and Stroke Center, Rakuwakai
Otowa Hospital, Otowachinji-cho 2, Yamashina-ku, Kyoto 607-8602,
Japan. email: [email protected].
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