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Longitudinal morphological
changes during recovery from brain
deformation due to idiopathic
normal pressure hydrocephalus
after ventriculoperitoneal shunt
surgery
Shigeki Yamada
1,2,3*, Masatsune Ishikawa2,4, Makoto Yamaguchi2 & Kazuo Yamamoto2
The present study aimed to examine time-dependent change in cerebrospinal uid distribution and
various radiological indices for evaluating shunt eectiveness in patients with idiopathic normal
pressure hydrocephalus (iNPH). This study included 54 patients with iNPH who underwent MRI before
and after ventriculoperitoneal shunt surgery. The volume of the total ventricles and subarachnoid
spaces decreased within 1 month after shunting. However, more than 1 year after shunting, the volume
of the total ventricles decreased, whereas that of the total subarachnoid spaces increased. Although
cerebrospinal uid distribution changed considerably throughout the follow-up period, the brain
parenchyma expanded only 2% from the baseline brain volume within 1 month after shunting and
remained unchanged thereafter. The volume of the convexity subarachnoid space markedly increased.
The changing rate of convexity subarachnoid space per ventricle ratio (CVR) was greater than that
of any two-dimensional index. The brain per ventricle ratio (BVR), callosal angle and z-Evans index
continued gradually changing, whereas Evans index did not change throughout the follow-up period.
Both decreased ventricular volume and increased convexity subarachnoid space volume were important
for evaluating shunt eectiveness. Therefore, we recommend CVR and BVR as useful indices for the
diagnosis and evaluation of treatment response in patients with iNPH.
Normal pressure hydrocephalus (NPH) was rst proposed by Hakim and Adams as a surgically treatable cause
of dementia in 19651. With the development of imaging predictors of shunt eectiveness, the prevalence of idi-
opathic NPH (iNPH) has been increasing rapidly in developed countries characterized by a higher proportion
of the elderly population1–8. Additionally, recent developed devices, such as adjustable valves with anti-siphon
mechanisms, preoperative virtual simulators, and several intraoperative guiding tools, have improved the out-
come of shunt surgery; approximately 70% of patients improve their symptoms to some extent9–13, and 10% of
patients need shunt revision10,11,14. However, the symptoms of 30% of patients with iNPH who undergo shunt
surgery are not improved for various reasons, including underdrainage, shunt malfunction, and comorbidi-
ties. If a patient’s symptoms do not improve or even worsen aer shunt surgery, neurosurgeons must investigate
the cause by computed tomography (CT) or magnetic resonance imaging (MRI). However, it is unknown how
iNPH-specic indices change following shunt surgery.
According to Hakim’s hypothesis15, brain shrinkage due to compression from enlarged ventricles in NPH
can be reverted by cerebrospinal uid (CSF) volume subtraction. Indeed, in typical patients with secondary or
congenital NPH, the brain parenchyma obviously expands as ventricular size decreases aer CSF shunt surgery
1Department of Neurosurgery, Shiga University of Medical Science, Shiga, Japan. 2Department of Neurosurgery
and Normal Pressure Hydrocephalus Center, Rakuwakai Otowa Hospital, Kyoto, Japan. 3Interfaculty Initiative in
Information Studies/Institute of Industrial Science, The University of Tokyo, Tokyo, Japan. 4Rakuwa Villa Ilios, Kyoto,
Japan. *email: shigekiyamada39@gmail.com
OPEN
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(Fig.1A–D)16,17. However, the ventricular size measured by the Evans index remains oen unchanged in elderly
patients with iNPH (Fig.1E,F), even if their symptoms are improved aer shunting18–21. e key features of iNPH
are compressed high-convexity sulci concurrent with enlarged Sylvian ssure and basal cistern, i.e., dispropor-
tionately enlarged subarachnoid space hydrocephalus (DESH)4,22–24. We recently showed that the pathophys-
iological mechanism of DESH in iNPH mainly involves the compensatory direct pathway of CSF between the
inferior horn of the lateral ventricles and the basal cistern at the inferior choroidal point of the choroidal ssure16.
erefore, if the lateral ventricles and the basal cistern in iNPH are enlarged simultaneously, they may all become
smaller following shunt surgery. Depending on the decrease in the volumes of the lateral ventricles and the basal
cistern, the volume of the convexity subarachnoid space may increase. erefore, we investigated the longitudinal
change in iNPH-specic indices and the volumes in the brain parenchyma, ventricles, and subarachnoid spaces
on three-dimensional (3D) MRI before and aer shunt surgery. Additionally, because the presence of comorbid
Alzheimer’s disease (AD) is associated with smaller, shorter-lasting eects of shunt treatment in patients with
iNPH25–27, we also investigated whether the change in the indices and volumes is associated with clinical out-
comes or comorbid AD.
Results
Clinical characteristics. In 54 consecutive patients with iNPH who underwent follow-up MRI within 1
month aer ventriculo-peritoneal shunt (VPS) via parieto-occipital approach (mean age, 76.7 ± 5.8 years; range,
60 to 88 years; 35 men, 19 women), the longitudinal changes in the morphological indices for iNPH and the
segmented volumes in brain parenchyma and CSF spaces were evaluated. e mean time interval from initial
symptom onset until baseline MRI (before VPS) was 27.3 ± 19.7 months, and that from initial symptom onset
until VPS was 48.7 ± 69.1 months. Follow-up MRI was conducted < 1 month (early) aer VPS in all 54 patients,
1 month to 1 year (mid) in 28 patients, and > 1 year (late) in 16 patients. Table1 presents the baseline clinical
characteristics and outcome aer VPS. e rst 12 patients treated with a Codman Hakim programmable valve,
whereas the latter 42 patients treated with a Codman CERTAS Plus programmable valve. ere was no signicant
dierence between the two groups in the mean values of age, disease duration, or frequency of co-morbidities and
outcome. As shown in Table2, the patients with pure iNPH had signicantly larger Evans index and signicantly
Figure 1. Conventional CT scan one day before and one month aer shunt surgery. Representative cases
diagnosed with adult-onset congenital NPH (A,B), secondary NPH (C,D) and idiopathic NPH (E,F).
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smaller brain per ventricle ratios (BVRs) at the posterior commissure (PC) level at baseline MRI than those with
co-occurrence of iNPH and AD. e other the iNPH-specic indices and segmented CSF volumes were not sig-
nicantly dierent between patients with pure iNPH and those with co-occurrence of iNPH and AD.
Changes in morphological indices after shunt implantation. e mean value of the Evans index
remained unchanged throughout the follow-up period, whereas that of the z-Evans index showed gradual and
slight decrease (Table3 and Fig.2A). e mean rate of change in the BVR at the anterior commissure (AC) level
was more than two-fold than that of the z-Evans index but less than that of the BVR at the PC level. e mean rate
of change in the callosal angle was the largest among the two-dimensional (2D) parameters: it was 13% early aer
VPS, and then increased to > 30% late aer VPS.
Volumetric changes. At the early phase aer VPS, the mean volume of the total intracranial CSF decreased
by 24 ± 39 mL from the baseline due to the decrease both in the total ventricles (19 mL) and the total subarach-
noid spaces (5 mL), as shown in Table3. Conversely, the brain volume slightly increased just as much as intracra-
nial CSF decreased, but subsequently there was no further increase in the brain volume throughout the follow-up
period (Table3 and Fig.2B). At the mid phase aer VPS, the mean volumes of the total ventricles and the total
subarachnoid spaces were almost unchanged. At the late phase, however, the mean rate of change in the total ven-
tricular volume decreased < 20% again, whereas that of the total subarachnoid spaces increased < 10%. e mean
volume of the Sylvian ssure and basal cistern gradually and slightly decreased from 130 mL to 100 mL at the late
phase aer VPS (Table3 and Fig.2C). In contrast, the mean volume of the convexity subarachnoid space consid-
erably increased > 60% late aer VPS. e changing rate of the convexity subarachnoid space per ventricle ratio
(CVR), which was calculated as the volume of the convexity subarachnoid space divided by the total ventricular
volume, was greater than that of any 2D index (Fig.2A).
Relationship with clinical outcome. Among the iNPH-specic indices, the BVRs at the AC and PC levels
late aer VPS had a statistically signicant dierence between excellent and good outcomes (Fig.3A). e mean
volume of the total ventricles in the patients with excellent outcome continued gradually decreasing throughout
the follow-up period, whereas that in the patients with good outcome conversely increased at the mid phase aer
VPS (Fig.3B). However, the mean volume of the convexity subarachnoid space in the patients with excellent
outcome gradually increased until late aer VPS, whereas that in the patients with good outcome had a small
increase (Fig.3C). Although the patients with pure iNPH tended to have higher changing rates of the morpho-
logical indices and segmented volumes than those with co-occurrence of iNPH and AD, there was no statistical
dierence (Fig.4).
Discussion
Our results indicated that the brain of patients with iNPH expanded <30 mL, which was <2% of the total brain
volume, due to a decrease in the intracranial CSF volume just aer shunt surgery, but subsequently remained
unchanged throughout the follow-up period regardless of improved symptoms gradually. In addition, the dispro-
portionate CSF distribution specic to iNPH reverted to a normal distribution in three phases aer shunting as
shown in Fig.5. Early aer shunting, both the total ventricles and total subarachnoid spaces had reduced volumes,
whereas the convexity part of the subarachnoid space had increased volume. Subsequently, mid aer shunting,
both the total ventricles and total subarachnoid spaces showed unchanged volumes despite continuous redis-
tribution of the intracranial CSF from the Sylvian ssure and basal cistern to the convexity subarachnoid space.
Late aer shunting, the total ventricles had reduced volumes again, but the total subarachnoid spaces had con-
versely increased volumes. However, the callosal angle and BVRs at the AC and PC levels showed gradual increase
throughout the follow-up period, independent of the staged changes in the CSF distribution. ese ndings indi-
cated that the CSF shunt surgery in patients with iNPH causes the convexity part of the brain to move from top to
Characteristics Total
(n = 54) CHPV (n = 12)
~3. 2016 CERTUS (n = 42)
4. 2016~ P value*
Sex, men:women 35:19 9:3 26:16 0.542
Mean age ± SD, y ear s 76.7 ± 5.8 75.2 ± 6.9 77.1 ± 5.3 0.220
Mean disease duration ± SD, y ears 2.3 ± 1.6 1.5 ± 1.1 2.5 ± 1.7 0.067
Mean days from MRI to shunt surgery 48.8 ± 69.1 39.7 ± 29.1 51.3 ± 76.9 0.906
Mean days from shunt surgery to the rst follow-up MRI 12.2 ± 5.1 9.8 ± 2.6 12.9 ± 5.5 0.063
Comorbidity of Alzheimer’s disease 19 2 17 0.238
Outcome, excellent:good:unsatisfactory 43:11:0 8:4:0 35:7:0 0.217
Valve pressure at the rst follow-up MRI 14.8 ± 3.9 mmH2O 4.5 ± 1.0
Valve pressure at the second follow-up MRI 13.6 ± 3.7 mmH2O 4.1 ± 0.9
Valve pressure at the third follow-up MRI 9.3 ± 2.8 mmH2O 3.4 ± 0.9
Table 1. Clinical characteristics and outcome aer shunt surgery. Data are presented as the mean ± standard
deviation unless otherwise noted. *Probability value of the Wilcoxon rank-sum test: comparison between
CHPV vs. CERTUS. CERTUS, Codman CERTAS® Plus programmable valve with Siphon-Guard®; CHPV,
Codman Hakim programmable valve with Siphon-Guard®; MRI, magnetic resonance imaging; SD, standard
deviation.
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bottom and to regain normal shape via redistribution of intracranial CSF from the ventricles and Sylvian ssure to
the convexity subarachnoid space rather than via brain expansion (i.e., like a sponge). We also demonstrated that
the Evans index remained absolutely unchanged throughout the follow-up period. ese results are in line with
those of previous studies18–21,28,29. Some reports indicated that the Evans index was not appropriate for evaluating
the ventricular size in elderly individuals, especially under the diagnosis of iNPH7,8,30–32. erefore, these ndings
lead us to concluded that the BVRs at the AC and PC levels or z-Evans index which indicate the z-axial expan-
sion of the bilateral ventricles were appropriate for evaluating ventricular dilatation and shunt eectiveness in
patients with iNPH, rather than the Evans index. Additionally, this study revealed that the morphological recovery
from brain deformation aer shunting was greater posteriorly than anteriorly. Among the 2D indices, the greatest
changing rate was that of the callosal angle, followed by was the BVR at the PC level. Recently, Virhammar et al.
reported that the callosal angle signicantly increased 3 months aer shunting21. In this study, the increase in the
both BVRs at the AC and PC levels more than 1 year aer shunting was signicantly associated with the excellent
outcome, although the changing rate in the BVR at the PC level was larger than that of the BVR at the AC level.
ese ndings help to clarify the process of recovery from the symptoms and disproportionate CSF distribution
in patients with iNPH aer CSF shunt surgery. Additionally, the time-course of the redistribution of the intracra-
nial CSF aer shunting may contribute to the next approach to adjust programmable valve pressure setting at the
proper timing. For example, the total ventricles in the patients with excellent outcome continued slightly decreas-
ing throughout the follow-up period, whereas those in the patients with good outcome conversely increased at
the mid phase aer shunting. Even if the shunt valve pressure was appropriate early aer shunting, it was actually
underdrainage at the mid phase. Because increased ventricular volume aer shunting may aect the outcome, we
suggest physicians try to lower the shunt valve pressure mid aer shunting, if iNPH-related symptoms persist with
poor changes in the volume of total ventricle and BVRs at the AC and PC levels.
Our study has some limitations. First, there was a wide range of SDs for the mean values of assessment meas-
ures, because of varied size of the ventricles and subarachnoid spaces in patients with iNPH. erefore, the
changes in the indices and segmented CSF volumes have a possibility of large uncertainty. Second, the inuence of
MRI artefacts due to the shunt valve was small but could not be ignored; nevertheless, we measured the intracra-
nial CSF volume aer VPS in patients with shunt valve placement under the occipital scalp. ird, a comorbidity
of AD was not conrmed pathologically by brain biopsy, CSF biomarkers or amyloid imaging. Additional infor-
mation could increase the diagnostic accuracy of AD comorbidity26,27,33, although CSF biomarkers at the spinal
tap test in iNPH were uctuate and it is dicult to determine clear cuto values of them between pure iNPH and
iNPH + AD34. Finally, the participants in this study did not undergo MRI at the scheduled time-point. ere is a
possibility of the selection bias that the timing of follow-up MRI was not xed. erefore, several novel ndings
in this study should be further assessed in a prospective cohort study with scheduled timing of follow-up MRI.
In conclusion, the brain parenchyma expanded only 2% from the baseline brain volume early aer shunt-
ing and remained subsequently unchanged, although CSF distribution considerably changed throughout the
follow-up period. Changes in CSF distribution occurred in three phases aer shunt implantation. e ventricu-
lar volume decreased at the early and late phases, whereas the volume of the total subarachnoid spaces slightly
Characteristics Total
(n = 54) Pure iNPH
(n = 35) iNPH + AD
(n = 19) P va lue*
Evans index (mean ± SD) 0.32 ± 0.06 0.34 ± 0.06 0.30 ± 0.05 0.017
z-Evans index (mean ± SD) 0.44 ± 0.06 0.45 ± 0.06 0.43 ± 0.06 0.173
Callosal angle (mean ± SD) 63.5 ± 18.5 61.6 ± 19.6 67.1 ± 16.2 0.193
BVR at the AC (mean ± SD) 0.72 ± 0.17 0.70 ± 0.17 0.77 ± 0.18 0.133
BVR at the PC (mean ± SD) 0.89 ± 0.23 0.82 ± 0.19 1.00 ± 0.24 0.010
CVR (mean ± SD) 0.47 ± 0.20 0.47 ± 0.21 0.48 ± 0.18 0.812
Total intracranial volume, mL 1543 ± 156 1562 ± 123 1509 ± 203 0.296
Brain parenchyma, mL (VR, %) 1107 (71.8) 1119 (71.7) 1084 (72.0) 0.388
Total CSF, mL (VR, %) 436.8 (28.2) 443.3 (28.3) 424.9 (28.0) 0.683
Total ventricle, mL (VR, %) 163.7 (10.5) 170.5 (10.9) 151.1 (9.9) 0.108
Bilateral ventricle, mL (VR, %) 155.0 (10.0) 161.5 (10.3) 143.0 (9.4) 0.126
ird ventricle, mL (VR, %) 5.2 (0.3) 5.3 (0.3) 5.0 (0.3) 0.442
Fourth ventricle, mL (VR, %) 3.6 (0.2) 3.7 (0.2) 3.5 (0.2) 0.946
Total SAS, mL (VR, %) 273.1 (17.7) 272.7 (17.4) 273.8 (18.1) 0.651
Convex part of the SAS, mL (VR, %) 72.3 (4.7) 75.3 (4.8) 66.8 (4.4) 0.159
Sylvian ssure and basal cistern, mL (VR, %) 130.2 (8.4) 127.0 (8.1) 136.1 (9.0) 0.350
SAS in the posterior fossa, mL (VR, %) 70.6 (4.6) 70.1 (4.5) 71.3 (4.7) 0.788
Table 2. Morphological indices, volumes, and VR at baseline MRI. *Probability value of the Wilcoxon rank-
sum test: comparison between pure iNPH and iNPH + AD. iNPH + AD indicates patients with iNPH who had
AD as comorbidity. VR, volume ratio which is calculated as the volume divided by the total intracranial volume.
AC, anterior commissure; AD, Alzheimer’s disease; BVR, brain per ventricle ratio; CSF, cerebrospinal uid;
CVR, convex subarachnoid space to ventricle ratio; iNPH, idiopathic normal pressure hydrocephalus; MRI,
magnetic resonance imaging; PC, posterior commissure; SAS, subarachnoid space; SD, standard deviation; VR,
volume ratio.
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decreased at the early phase, conversely increasing at the late phase. Especially, the volume of the convexity sub-
arachnoid space markedly increased throughout the follow-up period. Both decreased ventricular volume and
increased convexity subarachnoid space volume were important for evaluating shunt eectiveness. erefore,
we recommend CVR, which can measure directly the volumetric change both in the ventricles and convexity
subarachnoid space, as a 3D index. However, a 3D index is dicult to measure in clinical routine. As simple 2D
indices, the callosal angle, BVR at the PC level, BVR at the AC level, and z-Evans index were greatly changed aer
shunt surgery (in that order), whereas the Evans index remained unchanged throughout the follow-up period.
Among them, we recommend the BVRs at the AC and PC levels, because they were signicantly associated with
better clinical outcomes or comorbid AD. ese novel ndings may contribute to future studies of the pathogen-
esis of iNPH and to developing a future treatment approach based on the specic CSF distribution in patients
with iNPH.
Methods
Ethical approval and patient consent. e study design and protocol were approved by the ethics com-
mittee for human research at Rakuwakai Otowa Hospital (IRB Number: Rakuoto-Rin-14-003). Aer the patients
or their relatives provided written informed consent, their private information was anonymized in a linkable
manner. e methods were performed in accordance with the approved guidelines outlined in the Declaration
of Helsinki.
Study population. Details of the clinical data collection, image acquisition, and segmentation and quan-
tication of the ventricles and subarachnoid spaces are described in our previous publications7,8,16. Volumetric
data of T2-weighted 3D-SPACE sequence were prospectively collected from November 2013 to June 2018 on
3-Tesla MRI scanner (MAGNETOM Skyra; Siemens AG, Muenchen, Germany) before and aer VPS surgery
in consecutive 72 patients diagnosed with iNPH. ree patients who underwent VPS via frontal approach were
excluded, because the artefacts from the metal parts in the shunt valve aected the volumetric analysis on MRI.
ree patients who underwent lumboperitoneal shunt surgery were excluded, because the dierent locations of
CSF drainage might inuence changes in CSF distribution aer shunt surgery. Two patients who were diagnosed
with shunt malfunction and required shunt revision about 1 year aer the rst shunt surgery were excluded,
because we cannot judge when the shunt was obstructed, or how long it was eective. Additionally, 10 patients
who underwent the rst follow-up MRI > 1 month aer VPS were excluded. Finally, 54 patients with iNPH who
underwent the rst follow-up MRI within 1 month aer VPS via parieto-occipital approach were included in
this study. Among them, 19 patients with iNPH (35%) had a comorbidity of AD, based on the comprehensive
assessment of their symptoms, prescription of cholinesterase inhibitors, and ndings on MRI and single-photon
emission computed tomography, according to the current recommendation from the National Institute on
Aging–Alzheimer’s Association workgroups35.
Ventriculo-peritoneal shunt and valve pressure adjustment. Details of the surgical procedure for
VPS via parieto-occipital approach have been described in previously36. Briey, to insert the ventricular catheter
precisely, we routinely conducted preoperative virtual 3D simulation by using the SYNAPSE 3D workstation
(Fujilm Medical Systems, Tokyo, Japan). A shunt valve system including a Codman Hakim programmable valve
Characteristics Pre-shunt (n = 54) Early (n = 54) Mid (n = 28) L ate (n = 16)
Evans index (mean ± SD) 0.32 ± 0.06 0.31 ± 0.06 0.33 ± 0.06 0.34 ± 0.05
z-Evans index (mean ± SD) 0.44 ± 0.06 0.42 ± 0.05 0.41 ± 0.05 0.41 ± 0.06
Callosal angle (mean ± SD) 63.5 ± 18.5 72.0 ± 19.6 83.5 ± 24.2 84.5 ± 20.0
BVR at the AC (mean ± SD) 0.72 ± 0.17 0.79 ± 0.16 0.83 ± 0.15 0.84 ± 0.19
BVR at the PC (mean ± SD) 0.89 ± 0.23 1.10 ± 0.25 1.07 ± 0.30 1.09 ± 0.24
CVR (mean ± SD) 0.47 ± 0.20 0.60 ± 0.29 0.66 ± 0.23 0.72 ± 0.31
Brain parenchyma, mL (VR, %) 1107 (71.8) 1131 (73.4) 1116 (73.3) 1099 (73.9)
Total CSF, mL (VR, %) 436.8 (28.2) 412.4 (26.6) 408.7 (26.7) 389.4 (26.1)
Total ventricle, mL (VR, %) 163.7 (10.5) 144.5 (9.3) 141.2 (9.2) 139.4 (9.3)
Bilateral ventricle, mL (VR, %) 155.0 (10.0) 136.3 (8.8) 134.1 (8.8) 135.8 (9.0)
ird ventricle, mL (VR, %) 5.2 (0.3) 4.8 (0.3) 4.3 (0.3) 4.1 (0.3)
Fourth ventricle, mL (VR, %) 3.6 (0.2) 3.3 (0.2) 2.9 (0.2) 2.5 (0.2)
Total SAS, mL (VR, %) 273.1 (17.7) 267.9 (17.3) 267.4 (17.5) 250.0 (16.9)
Convex part of the SAS, mL (VR, %) 72.3 (4.7) 80.2 (5.2) 88.1 (5.7) 92.7 (6.2)
Sylvian ssure and basal cistern, mL (VR, %) 130.2 (8.4) 120.7 (7.8) 116.1 (7.6) 100.1 (6.8)
SAS in the posterior fossa, mL (VR, %) 70.6 (4.6) 68.9 (4.4) 63.5 (4.1) 56.5 (3.8)
Table 3. Mean values of indices and volumes on MRI before and aer shunt surgery. *Values with signicant
changes from the pre-shunt values by the Wilcoxon signed-rank test. AC, anterior commissure; BVR, brain
per ventricle ratio; CSF, cerebrospinal uid; CVR, convex subarachnoid space to ventricle ratio; MRI, magnetic
resonance imaging; PC, posterior commissure; SAS, subarachnoid space; SD, standard deviation; VR, volume
ratio.
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with a Siphon-Guard® (Integra LifeSciences Corporation, Plainsboro, NJ, USA) was used in 12 patients until
March 2016; aer that date, 42 patients underwent VPS by using an MRI-resistant Codman CERTAS® Plus pro-
grammable valve with a Siphon-Guard® (Integra LifeSciences Corporation, Plainsboro, NJ, USA). e mean
values of age, several indices, and volumes were not signicantly dierent between the two groups. e opening
pressure of the shunt valve was set based on the patient’s height and weight per Miyake’s quick reference table37.
All patients were evaluated for over- or underdrainage of CSF based on the changes in the symptoms and CT scan
within 10 days aer shunt implantation, and subsequently, every 1 month up to 6 months and every 3 months
aer 6 months. e valve pressure was readjusted in stepwise setting for the Codman CERTAS Plus valve or by
intervals of 2 cmH2O for the Codman Hakim programmable valve as required. Concretely, in case of insu-
cient improvement of patients’ symptoms, dened as CSF underdrainage, the valve pressure was lowered; in case
of orthostatic headache or subdural eusion on CT scan, dened as CSF overdrainage, the valve pressure was
raised. If the valve pressure was readjusted, we checked the patients’ conditions and subdural eusion through
CT scan within 1 month aer readjustment. In this study, the follow-up MRI nding of apparent subdural eu-
sion or hematoma was absent, and no patient required additional surgery for subdural hematoma during the
follow-up period. Clinical outcomes were classied into excellent, good, and unsatisfactory36. An excellent out-
come was dened as the regained ability to perform outdoor activities that was grade 0 to 2 on the modied
Rankin Scale and a ≥ 2-point improvement on the Japanese iNPH grading scale. A good outcome was dened as a
1-point improvement on the modied Rankin Scale or iNPH grading scale but needing some support to perform
Figure 2. Bee swarm plots of the changing rate of indices and segmented volumes following shunt surgery
compared to those at baseline magnetic resonance imaging. Graph A shows the distribution and mean value
of the relative changes in the following indices; Evans index (brown), z-Evans index (green), callosal angle
(red), brain per ventricle ratio (BVR) at the anterior commissure (AC) level (purple) and BVR at the posterior
commissure (PC) level (blue), and convexity subarachnoid space (SAS) per ventricle ratio (CVR; orange).
Graph B shows the distribution and mean value of the relative volume changes in the brain parenchyma
(brown), total ventricles (red), and total SAS (blue). Graph C shows the distribution and mean value of the
relative volume changes in the convexity part of SAS (blue), Sylvian ssure and basal cistern (red), and SAS in
the posterior fossa (brown).
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outdoor activities, which was graded 3 to 4 on the modified Rankin Scale. An unsatisfactory outcome was
dened as unchanged or worsening symptoms and persistent severe disability that was grade 5 on the modied
Rankin Scale. Table4 shows the changes in modied Rankin Scale, iNPH grading scale, times on the 3-m timed
up-and-go test and 10-m straight walk test and scores of mini-mental state examination and frontal assessment
battery at the baseline MRI and the rst follow-up MRI. e patients with excellent outcome had signicantly
mild grade on the baseline modied Rankin Scale and signicant improvement on modied Rankin Scale at the
rst follow-up MRI, compared with those with good outcome. Additionally, the patients with excellent outcome
signicantly improved the total and gait scores of iNPH grading scale at the rst follow-up MRI, compared with
the patients with good outcome. However, the mean values and changes of quantitative measurements did not
have signicant dierences between the excellent and good outcomes. e mean time on 3-m timed up-and-go
test was shortened by >10 seconds at the rst follow-up MRI in both groups of the excellent and good outcomes.
Image acquisition and volumetric analysis. Because all patients had shunt valve placement under the
right occipital scalp, MRI artefacts due to the shunt valve system on the T2-weighted 3D sequence slightly aected
the CSF volume of the subarachnoid space in the posterior fossa (Fig.6). e volumetric data were entered on a
3D workstation, where the intracranial space was semi-automatically segmented with recent technologies com-
bined the user-steered live-wire segmentation, edge-guided nonlinear interpolation, and automatic extraction of
Figure 3. Comparison of indices and segmented volumes aer shunt surgery between patients with excellent
outcome and those with good outcome. Asterisk (*) indicates statistically signicant dierence between the
patients with excellent outcome (solid line) and those with good outcome (dotted line). Graph A shows the
mean value of the relative changes in the following indices: Evans index (brown), z-Evans index (green), callosal
angle (red), brain per ventricle ratio (BVR) at the anterior commissure (AC) level (purple) and BVR at the
posterior commissure (PC) level (blue), and convexity subarachnoid space (SAS) per ventricle ratio (CVR;
orange). Graph B show the mean value of the relative volume changes in the brain parenchyma (brown), total
ventricles (red), and total subarachnoid space (SAS; blue). Graph C shows the mean value of the relative volume
changes in the convexity part of SAS (blue), Sylvian ssure and basal cistern (red), and SAS in the posterior
fossa (brown).
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continuous objects. Aer that, the intracranial space was subdivided into the brain parenchyma and intracranial
CSF space through a simple threshold algorithm. Finally, the intracranial CSF spaces were manually segmented
into the total ventricles, convexity subarachnoid space, Sylvian ssure and basal cistern, and subarachnoid space
in the posterior fossa (Fig.6 and Video). Each segmented volume was automatically measured by counting the
number of voxels. Volume ratios, which were calculated as the measured volumes divided by the intracranial
volume, were analyzed to eliminate the eect of head size.
Morphological indices specic to NPH. Figure7 shows the measured indices early aer VPS in the same
patient with co-occurrence of iNPH and AD as Fig.6. e Evans index (Fig.7A) was measured as the maximal
width of the frontal horns of the lateral ventricles to the maximal width of the internal diameter of the cranium
based on the x-dimension38. e z-Evans index (Fig.7B) was measured as the maximum z-axial length of the
frontal horns of the lateral ventricles to the maximum cranial z-axial length on the coronal plane, which was
perpendicular to the anteroposterior commissure plane on the AC7. e callosal angle (Fig.7C) was measured as
the angle of the roof of the bilateral ventricles on the coronal plane at the PC level5. e BVRs at the AC and PC
levels (Fig.7B,C) were calculated as the maximum width of the brain just above the lateral ventricles divided by
Figure 4. Comparison of indices and segmented volumes aer shunt surgery between patients with pure
idiopathic normal pressure hydrocephalus (iNPH) and those with co-occurrence of iNPH and Alzheimer’s
disease (AD) (iNPH + AD). Filled diamonds and solid lines indicate the patients with pure iNPH and unlled
diamonds and dotted lines indicate those with iNPH + AD. Graph A shows the mean value of the relative
changes in the following indices; Evans index (brown), z-Evans index (green), callosal angle (red), brain per
ventricle ratio (BVR) at the anterior commissure (AC) level (purple) and BVR at the posterior commissure
(PC) level (blue), and convexity subarachnoid space (SAS) per ventricle ratio (CVR; orange). Graph B shows
the mean value of the relative volume changes in the brain parenchyma (brown), total ventricles (red), and total
subarachnoid space (SAS; blue). Graph C shows the mean value of the relative volume changes in the convexity
part of SAS (blue), Sylvian ssure and basal cistern (red), and SAS in the posterior fossa (brown).
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the maximum width of the lateral ventricles on the reference coronal planes at the AC and PC levels, respectively8.
e CVR was dened as the volume of the convexity-subarachnoid space divided by the total ventricular volume8.
Absolute and relative changes in the morphological indices and volumes in brain parenchyma, total ventricles,
and three parts of subarachnoid spaces aer VPS were compared to those before VPS. Absolute changes were
calculated as the baseline indices and volumes minus those aer VPS, and relative changes were calculated as the
absolute changes divided by the baseline indices or volumes × 100 (%).
Statistical analysis. Absolute and relative changes in mean values and standard deviations (SDs) for the
segmented volumes and indices aer VPS were compared using Wilcoxon signed-rank test. e frequency of
follow-up MRI examinations and the period from VPS to MRI varied widely: 54 patients underwent the rst
follow-up MRI from 5 to 29 days (median: 11 days) aer VPS, 32 patients underwent the second MRI from 36
Figure 5. Schematic diagram showing the longitudinal change of CSF in patients with iNPH. e iNPH-
specic CSF distribution named disproportionately enlarged subarachnoid space hydrocephalus (DESH)
before shunting (le) reverted to a normal distribution in the following three phases; early, mid, and late aer
ventriculoperitoneal shunt surgery.
Excellent (n = 43) Good (n = 11) P value*
At baseline At 1st MRI At baseline At 1st MRI
mRS 2.57 ± 0.67 1.84 ± 0.69 2.82 ± 0.98 2.55 ± 0.82 0.012
∆mRS 0.72 ± 0.55 0.27 ± 0.47 0.026
iNPHGS total 6.36 ± 1.96 4.28 ± 1.92 6.36 ± 2.50 5.45 ± 2.81 0.118
∆total 2.07 ± 1.47 0.91 ± 1.45 0.007
gait 2.52 ± 0.51 1.56 ± 0.59 2.45 ± 0.69 2.09 ± 0.94 0.024
∆gait 0.98 ± 0.46 0.36 ± 0.67 <0.001
cognitive 1.83 ± 0.88 1.44 ± 0.80 2.00 ± 0.89 1.73 ± 0.90 0.255
∆cognitive 0.37 ± 0.62 0.27 ± 0.47 0.743
urinary 2.00 ± 0.96 1.28 ± 0.85 1.91 ± 1.30 1.64 ± 1.21 0.387
∆urinary 0.72 ± 0.77 0.27 ± 0.47 0.060
TUG 26.2 ± 30.4 13.5 ± 10.0 32.9 ± 33.7 16.7 ± 7.67 0.058
∆TUG 12.7 ± 29.4 16.4 ± 27.0 0.761
10 M Walk 18.4 ± 17.3 10.2 ± 15.5 19.7 ± 20.9 12.2 ± 6.72 0.195
∆10 M Walk 8.2 ± 15.8 7.6 ± 21.3 0.232
MMSE 21.6 ± 5.6 23.6 ± 5.0 21.5 ± 6.7 23.1 ± 5.1 0.777
∆MMSE 1.7 ± 4.5 2.2 ± 2.6 0.986
FAB 9.58 ± 2.9 11.4 ± 3.1 10.0 ± 4.1 10.5 ± 3.5 0.573
∆FAB 1.7 ± 2.8 0.7 ± 3.2 0.240
Table 4. Change in clinical scores at the baseline and the rst follow-up MRI in the groups of excellent outcome
and good outcome. Data are presented as the mean ± standard deviation unless otherwise noted. ∆ indicates the
dierence between score at the baseline and that at the rst follow-up MRI. *Probability value of the Wilcoxon
rank-sum test: comparison between excellent and good outcomes mRS, modied Rankin Scale; iNPHGS,
idiopathic normal pressure hydrocephalus grading scale; TUG, timed 3-m up-and-go test; 10 M Walk, 10-m
straight walking test; MMSE, mini-mental state examination; FAB, frontal assessment battery.
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Figure 6. Segmentation of the total ventricles and three parts of the subarachnoid spaces. ese images were
created on the SYNAPSE 3D workstation (Fujilm Medical Systems, Tokyo, Japan) from a three-dimensional
(3D) T2-weighted 3-Tesla sequence 10 days aer ventriculoperitoneal shunting via parieto-occipital approach in
a patient diagnosed with co-occurrence of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer’s
disease (AD). e ventricles were manually extracted from intracranial cerebrospinal uid (CSF) space by
enclosing in a free shape. (A) e total subarachnoid spaces were segmented by subtraction of the total ventricles
from total intracranial CSF spaces. e convexity subarachnoid space (B) was manually segmented from the total
subarachnoid spaces per the anatomical landmarks of the basal interhemispheric cistern, Sylvian ssure, and
tentorium cerebelli. From the residual subarachnoid spaces, the subarachnoid space in the posterior fossa (D) was
segmented with reference to the anatomical landmarks of the tentorium cerebelli, chiasma and optic tract. ere was
a small MRI artefact in the right occipital posterior fossa. e Sylvian ssure and basal cistern (C) were segmented
by subtraction of the convexity subarachnoid space and subarachnoid space in the posterior fossa from the total
subarachnoid spaces. e convexity subarachnoid space per ventricle ratio (CVR), which was dened as the volume
of the convexity subarachnoid space (178 mL) divided by the total ventricular volume (118 mL), was 1.51.
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Figure 7. Morphological indices specic to idiopathic normal pressure hydrocephalus (iNPH). ese magnetic
resonance images are shown for the same patient as Fig.6. e Evans index was calculated as 0.327 (A); the
maximum length of the frontal horns of the lateral ventricles (46.0 mm) divided by the maximum cranial length
on the same axial plane (140.8 mm). e z-Evans index, which was calculated as the maximum z-axial length
of the frontal horns of the lateral ventricles (35.6 mm) divided by the maximum cranial z-axial length at the
midline (88.0 mm) on the coronal plane just on the anterior commissure (AC), was 0.405 (B). e callosal angle
was calculated as 63 degrees (C) at the roof of the bilateral ventricles on the coronal plane just on the posterior
commissure (PC). e brain per ventricle ratios (BVRs) at the AC and PC levels were calculated as 0.941 (B)
and 1.429 (C), respectively.
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to 742 days (median: 178 days), 12 patients underwent the third MRI from 366 to 1270 days (median: 559 days).
erefore, we categorized the period from VPS to follow-up MRI into <1 month (early, 54 patients), 1 month
to 1 year (mid, 28 patients), and >1 year (late, 16 patients). e Wilcoxon rank-sum test was used to compare
the mean values between patients with and without AD. Fisher’s exact test was used to compare the proportions
of the 2 groups. Statistical signicance was assumed at a probability (P) value of less than 0.05. All missing data
were treated as decit data that did not aect other variables. Statistical analysis was performed using R soware
(version 3.3.2; R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org).
Received: 19 February 2019; Accepted: 7 November 2019;
Published: xx xx xxxx
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Acknowledgements
We would like to thank the sta at the department of radiology and rehabilitation in the Rakuwakai Otowa
Hospital. This research study was partly supported by Health and Labor Sciences Research Grants for the
Research on Intractable Diseases, Ministry of Health, Labor and Welfare, Japan (2017-Nanci-General-037). e
sponsor was not involved in the study-design, collection, analysis, and interpretation of the data, writing of the
report; and in the decision to submit the paper for publication. We don’t have any other ndings.
Author contributions
Dr. Shigeki Yamada made substantial contributions to the conception and design of the work, data acquisition,
statistical analysis, and interpretation of the data. Statistical analysis was conducted by Shigeki Yamada, who
studied biostatistics at the Department of Health and Environmental Sciences, Kyoto University School of Public
Health, from 2001 to 2004. Dr. Masatsune Ishikawa made substantial contributions to the critical revision of the
manuscript for intellectual content and supervised the study. Dr. Kazuo Yamamoto and Dr. Makoto Yamaguchi
were substantially involved in the acquisition of data and supervision of the study.
Competing interests
Shigeki Yamada received speakers’ honoraria from Integra, and Fujilm Medical Systems. Masatsune Ishikawa,
Kazuo Yamamoto and Makoto Yamaguchi declare no potential conict of interest.
Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/s41598-019-53888-7.
Correspondence and requests for materials should be addressed to S.Y.
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