Acta Neurol Scand 2001: 104: 325–342 Copyright # Munksgaard 2001

Printed in UK. All rights reserved

ACTA NEUROLOGICA
SCANDINAVICA
ISSN 0001-6314

Review article
Normal pressure hydrocephalus and cerebral
blood flow: a review
Owler BK, Pickard JD. Normal pressure hydrocephalus and cerebral B. K. Owler1–3, J. D. Pickard1,2
blood flow: a review. 1
Academic Neurosurgery Unit, Addenbrooke’s
Acta Neurol Scand 2001: 104: 325–342. # Munksgaard 2001. Hospital, Cambridge, UK, 2Wolfson Brain Imaging
Centre, Addenbrooke’s Hospital, Cambridge, UK,
3
Department of Surgery, University of Sydney, Sydney,
Normal pressure hydrocephalus is a neurological disease which poses
Australia
both diagnostic and therapeutic problems for the clinician. The
measurement and characterisation of cerebral blood flow has been
proposed as a tool for resolving such problems as well as elucidating its
Key words: cerebral blood flow; normal pressure
pathophysiology. We review the results of studies in which this tool has hydrocephalus
been applied to normal pressure hydrocephalus patients and consider the
merits of the techniques that have been utilised. Finally, consideration is Dr Brian K. Owler, Department of Neurosurgery, Royal
Prince Alfred Hospital, Missenden Rd, Camperdown
given to feasible future studies and the methods that could be employed
NSW 2050, Australia
in the study of cerebral blood flow and metabolism in patients with Tel.: 61 2 95156111
normal pressure hydrocephalus. Fax: 61 2 95157564
e-mail: brianowl@bigpond.com

Accepted for publication May 25, 2001

Normal pressure hydrocephalus (NPH), since its
original description by Hakim & Adams in 1965 (1,
2), has remained an enigma. Although usually
defined as consisting of the clinical triad of gait
disturbance, dementia and urinary incontinence as
well as radiological hydrocephalus and normal
baseline CSF pressure – its very definition remains
controversial. Its importance as one of the reversible
causes of dementia, by means of a cerebrospinal
fluid (CSF) shunt, justifies the efforts to unravel this
complex problem.
Idiopathic NPH, primarily a condition of the
elderly, presents a diagnostic and therapeutic
Abbreviations: AR, autoregulation; CBF, cerebral blood flow;
CO2, carbon dioxide; CSF, cerebrospinal fluid; CT, computed
tomography; CVR, cerebrovascular reactivity; DAT, dementia
of the Alzheimer’s type; gCBF, global cerebral blood flow; ICP,
intracranial pressure; i.v., intravenous; MR, magnetic reso-
nance; NPH, normal pressure hydrocephalus; OER, oxygen
extraction rate; PET, positron emission tomography; PVL,
periventricular lucency; rCBF, regional cerebral blood flow;
Rcsf, resistance to CSF outflow; SPECT, single photon emission
computed tomography; Xe, xenon.
dilemma for the clinician. Occasionally a clear
cause of the condition, such as subarachnoid or
intraventricular haemorrhage, meningitis, head
trauma, basilar artery ectasia or chronic aqueduct
stenosis may be present, in which case it is termed
secondary NPH. It is considered to be a disorder of
CSF circulation as analysis of CSF pressure
recordings and infusion studies demonstrate an
increased resistance to CSF absorption and an
increased frequency of pathological vasogenic waves
(3). However, a disturbance of CSF circulation itself
is probably not always sufficient for developing the
condition.
There is some evidence, especially in idiopathic
NPH, to suggest that the cerebral vasculature may
have a role in the pathogenesis of NPH (4, 5). Thus
significant efforts have focused on the study of
cerebral blood flow (CBF). Unfortunately, studies
of CBF and NPH have neither been consistent in
their results nor improved our ability to predict the
response to shunting. Studies have been hampered
by heterogeneous patient groups, different defini-
tions of clinical outcome, the resolving power of
available technology to study periventricular

325

Owler & Pickard
regional CBF (rCBF) and whether the method is
truly quantitative. Whether changes in CBF are a
cause or effect of NPH is also at issue.
Given the advances in technology, such as high
resolution positron emission tomography (PET) and
perfusion magnetic resonance (MR) imaging, it is
timely to review these studies and propose standards
for future studies. The available literature is
reviewed pertaining to CBF in NPH and the results
discussed in the context of our current knowledge of
the nature of the condition.
Materials and methods
A search of the world literature and relevant
conference proceedings (available in English) iden-
tified 631 cases of NPH in which CBF was examined.
These studies of CBF are summarised in Tables 1
and 2.
Several difficulties arise in attempting to apply a
strict a definition of levels of evidence to these
studies (42). When considering the utility of CBF
measurements as a diagnostic or prognostic tool,
there are no reference or gold standard tests by
which patients can be assessed. In addition, the
patient groups were almost always mixed, that is,
consisted of heterogeneous groups of patients with
idiopathic and secondary NPH analysed together.
There were often mixed radiological and CSF study
results. Few studies could be regarded as providing
level II evidence. Rather, most of the literature
mostly consists of level III, IV and V evidence. The
lack of studies with high levels of evidence is not a
direct criticism of the studies themselves but is a
reflection of the nature of the subject.
In order to circumvent some of these problems,
and assist the comparison of studies we formulated
an alternate method of classification. Class A
evidence consisted of case–control studies in which
the full details of the patient and control groups were
available. Patients included in these studies needed
to satisfy the following definition: all patients had to
demonstrate: 1) the complete clinical triad or prim-
arily a disorder of gait; 2) ventricular dilatation on
CT scan without significant cerebral atrophy; 3)
absence of focal neurological deficit or focal path-
ology on CT; 4) normal CSF pressure (<15 mmHg)
with either ICP monitoring or CSF infusion study
data; and 5) objective, well documented follow-up.
Class B evidence included case–control studies in
which patient details did not necessarily satisfy the
strict criteria above but the authors had diagnosed
the syndrome of NPH. Class C studies included
case-series and case reports of patients diagnosed
with NPH whether or not the definition of NPH was
satisfied.
326
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Results and Discussion
Studies of cerebral blood flow
In reviewing the literature, the range of techniques
used for the study of CBF in NPH, each with its own
set of advantages and deficiencies, is readily appar-
ent. Interpreting the results of these studies relies
upon an understanding of these methodological
features. Therefore, in presenting the data we have
chosen to present the results under a discussion of
each technique used. Knowledge of the basis of CBF
measurement methodology is particularly important
for rCBF studies as the ability of certain techniques
to accurately measure rCBF and distinguish white
and gray matter is questionable. In addition,
reported rCBF may vary in whether or not they
are truly anatomical.
a. 133
Xenon clearance techniques
Most early studies of CBF have relied on the meas-
urement of 133Xe clearance. These methods rely on
analysis of the clearance curve of the freely diffusible
tracer, delivered either via intracarotid injection,
intravenous injection or inhalation. Analysis of the
initial slope index provides an estimate of gray
matter blood flow. Using a multi-compartmental
analysis of the extended curve, estimations of gray
and white matter may be made. Calculation of the
blood flow depends on the assumption of normal
partition co-efficients for different regions. How-
ever, these partition co-efficients have been shown to
be abnormal in NPH (20, 21). In addition, the
sensitivity and resolution of the method is dependent
on the collimator and detector design which vary
widely. Due to Compton scatter it is very difficult for
these systems to measure blood flow in deep
structures. For these reasons studies of rCBF
using such techniques must be treated with some
circumspection.
i. Pre-treatment CBF – Regarding global CBF
(gCBF), Greitz et al. (6, 7) (B), the first to examine
CBF in NPH, found mean CBF to be 33 ml/100 g/
min with a cortical blood flow of 55 ml/100 g/min.
In comparison, mean CBF was 41 ml/100 g/min
and cortical blood flow was 62 ml/100 g/min in
patients with cortical atrophy. Mathew et al. (10)
(B) confirmed these findings reporting that steady
state mean CBF values were significantly reduced
in patients with NPH and patients with dementia
of the Alzheimer’s type (DAT). However, the
reduction was greater in patients with NPH. These
patients demonstrated a greater reduction in the
region of the anterior cerebral arteries which was
not seen in patients with DAT. Thus, these studies
were the first indication of a pattern of rCBF in

Normal pressure hydrocephalus and cerebral blood flow
NPH and CBF appeared to be a promising
parameter for distinguishing NPH from other
dementias.
Early support for a reduction in CBF was pro-
vided by Salmon & Timperman (C), (8, 9) Hartmann
(12) (C) & Meyer et al. (19, 20) (B) although their
patient groups were not well defined. Hayashi et al.
(17) (B) studied CBF in NPH secondary to SAH and
also found that CBF was reduced. Meyer et al. (20,
21) (B) found that CBF was reduced in the frontal,
temporal and parietal cortex. A relatively greater
decrease in the frontal region was supported by
Meixensberger et al. (28) (C).
Later studies (18, 23, 29), with more detailed
patient descriptions, confirmed that gCBF was
reduced. However, Kushner et al. (18) (A) found
that gCBF was reduced by 31% in the NPH group
(31.8 ml/100 g/min) and by a similar degree in the
dementia group (31.1 ml/100 g/min) compared with
normal age-matched controls (45.6 ml/100 g/min).
In addition there was no difference between baseline
CBF measurements in patients with idiopathic and
secondary NPH. In contrast, Mamo et al. (23) (B)
found that the magnitude of the reduction of CBF in
patients with senile or presenile dementia was not as
great as the NPH group. Matsuda et al. (29) (A)
reported CBF was significantly reduced in all
regions in patients with NPH compared to controls.
In comparing CBF measurements to ICP param-
eters, Hayashi et al. (17), divided their patient group
on the basis of whether ICP abnormalities were
present on ICP monitoring. Those with abnormal-
ities demonstrated a CBF of 29 ml/100 g/min and
those without had a CBF of 23 ml/100 g/min.
Meixensberger et al. (28) (C) found no significant
difference between the two. Tamaki et al. (16) (C)
found that that there was no correlation between
CBF and the incidence of B waves during ICP
monitoring or between CBF and the pattern seen on
cisternographic studies.
ii. Prognostic significance of pre-treatment CBF –
Mathew et al. (10, 11) (B) found that the response
to surgery was inversely proportional to the pre-
operative baseline CBF and was useful in pre-
dicting response to shunting in patients with NPH
albeit on the basis of 4 patients. In agreement,
Hayashi et al. (17) (B) reported that shunting
never produced clinical improvement in patients
where the preoperative CBF was less than 25 ml/
100 g/min.
In a more detailed study, Kushner et al. (18) (A)
found that neither the baseline level nor the pattern
of preoperative rCBF appeared to be useful in pre-
dicting clinical outcome after shunting. Mamo et al.
(23) (B) could also find no relationship between the
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
initial CBF and the response to shunting. In addition
no relationship between CBF in the frontal region
and response to shunting was noted.
iii. Post-treatment CBF – Greitz et al. (6) (B)
reported CBF to be increased in 6 of 7 patients
after shunting (3–4 weeks) but the increase did
not reach significance. The authors also reported
that 3 patients had shown marked improvement
after shunting and in these patients only, the
gray matter component increased considerably.
Kushner et al. (18) (A) measured CBF around 3
months after shunting and found it not to be
significantly different to the preoperative CBF
levels. Meixensberger et al. (28) (C) were also
unable to find an increase in gCBF after shunting.
However patients who improved after shunting
demonstrated an increase in rCBF in the frontal
region.
b. Kety–Schmidt technique
The Kety–Schmidt technique for the measurement
of CBF has also been applied to NPH. Of course
with this technique, only a global estimate of CBF
can be obtained. Lying-Tunell et al. (14, 15) (B)
applied the nitrous oxide method also found that
CBF was reduced in NPH (41 ml/100 g/min)
compared to normal controls (61 ml/100 g/min).
These authors also found improved CBF with
successful shunting and in 2 patients with most
marked improvement CBF returned to normal (14).
These findings were repeated in a second study
where almost identical findings were reported (15).
c. Single photon emission computed tomography
Single photon emission computed tomography
(SPECT), although more suited to assessment of
rCBF, is also subject to limitations. It not only
detects the quantity of tracer but its distribution in
space. Studies rely on two types of tracer – those that
are freely diffusible and those that are taken up and
retained in cells. Regardless of the type of tracer
used, these techniques are still subject to problems of
tissue depth dependent sensitivity and quantification
issues.
I. SPECT studies using freely diffusible tracers –
i. Pre-treatment CBF – SPECT studies using
freely diffusible tracers (e.g. 133Xe) measure CBF
from a combination of the distribution of the
tracer and its measured clearance. In a prospective
study, Graff-Radford et al. (25) (C) demonstrated
that gCBF was significantly reduced in patients
with NPH compared to normal controls but was
similar to patients with DAT. Vorstrup (24) (A)
327
 Table 1. Studies of CBF in NPH: methods and baseline CBF findings

328
Baseline
Reference Class Method NPH Aetiology CBF Control group Other findings
133
Greitz et al., 1969 (6) B Xe IC 21 Mixed Reduced Cerebral atrophy & In cases without a vascular component, correlation between ventricular dilation
2-comp 4 Idiopathic age-matched controls and QCBF
Owler & Pickard

Greitz et al., 1969 (7) B 7 Mixed Reduced Normal controls &

1 Idiopathic other various conditions
133
Salmon & Timperman et al., 1971a (8) C Xe 5 Trauma Reduced Normal controls Unclear in diagnosis whether truly NPH but Gp2 have clinical triad
IC 2-comp CBFg and CBFw both reduced in the 5 patients of Gp2
133
Salmon & Timperman et al., 1971b (9) C Xe IC 7 Mixed Reduced Other controls –
2-comp 3 Idiopathic
133
Mathew et al., 1975 (10) B Xe IC 15 Mixed Reduced Cerebral atrophy & Not possible to distinguish between atrophy and NPH on basis of CBF
2-comp+ 5 Idiopathic age-matched controls No correlation between CBF and ventricular size but dilation of frontal horn
stochastic correlated with decrease in CBF of ACA territory
Mathew et al., 1977 (11) B 4 Not reported Reduced QCBF mostly in frontal lobe/anterior cerebral artery territory
133
Hartmann et al., 1977 (12) C Xe IC 11 Not reported Acute SAH HC & –
stochastic high pressure HC
Grubb et al., 1977 (13) B H2O15 PET IC 11 10 Idiopathic Reduced Cerebral atrophy & Not possible to distinguish between atrophy and NPH on basis of CBF
ISI/1-comp age-matched controls No definite pattern of CBF could be identified in NPH patients
Lying-Tunnell et al., 1977 & 1981 (14, 15) B AV-Difference 7 Mixed Reduced Age-matched controls & CBF reduced especially in the most demented patients
NO2 SDAT patients
133
Tamaki et al., 1984 (16) C Xe inhal 24 Not reported NA Nil No correlation between CBF and incidence of B-waves or between CBF and
ISI pattern seen on CT metrizamide cisternography
133
Hayashi et al., 1984 (17) B Xe IC 16 All SAH Reduced Normal controls & QCBF correlated with q ventricular size
ISI/2-comp other HC groups QCBF less in acute stage of HC
133
Kushner et al., 1984 (18) A Xe IC 19 Mixed Reduced Other dementias & No difference in CBF between NPH and non-NPH dementia patients
2-comp/ISI 11 Idiopathic age-matched controls
133
Meyer et al., 1984 (19) B Xe inhal 11 Mixed Reduced Cases of SDAT & –
2-comp 6 Idiopathic age-matched controls
133
Meyer et al., 1985a (20) B Xe inhal 8 Not reported Reduced Cases of SDAT & CBF and partition-coefficients decreased
2-comp & ?Idiopathic age-matched controls CBF most reduced in frontal, parietal and temporal cortex, thalamus and
Xe contrast CT fronto-temporal white matter
Meyer et al., 1985b (21) B Xe contrast CT 10 Mixed Reduced Nil Partition co-efficients most reduced in frontal white matter
6 Idiopathic
Brooks et al., 1986 (22) B C15O2 PET 3 Idiopathic Reduced Normal controls & –
inhal other types of HC
133
Mamo et al., 1987 (23) B Xe IV 25 Mixed Reduced Cases of SDAT or QCBF compared to controls
2-comp 18 Idiopathic presenile dementia No correlation between ventricular size and CBF reduction
133
Vorstrup et al., 1987 (24) A Xe inhal 17 Mixed Reduced Atherosclerotic & NPH patients had abnormal CBF maps
1-comp 14 Idiopathic age-matched controls In 14/17 cases there was correlation between QCBF and q ventricular size
SPECT No correlation between symptoms and CBF
133
Graff-Radford et al., 1987 & 89 (25, 26) C Xe inhal 2- 26 Mostly Reduced Cases of SDAT & No difference between CBF in SDAT and NPH patients
comp +35 Idiopathic age-matched controls QCBF more severe in frontal region in NPH patients
SPECT
123B
Morretti et al., 1988 (27) A AMP IV 23 Mixed NA Nil Frontal hypoactivity seen in 19/23 NPH cases
SPECT 15 Idiopathic No correlation between CBF and ventricular size

16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 133
Meixenberger et al., 1989 (28) C Xe inhal 31 Not reported Reduced Normal controls No sig difference in CBF between NPH pts with & without ICP abnormalities
2-comp NPH patients with neuro deficits had lower CBF
NPH patients with neuro deficits and ICP abnormalities had lowest CBF
133
Matsada et al., 1990 (29) A Xe inhal 13 Mixed Reduced Normal controls QCBF correlated with q ventricular size
ISI 1 Idiopathic No inter-regional differences compared to controls
99m
Granado et al., 1991 (30) B Tc-HMPAO 14 Idiopathic NA Nil QCBF in frontal region correlated with severity of dementia
SPECT
Kimura et al., 1992 (31) B Xe contrast CT 7 All SAH Reduced Age-matched controls Generally QCBF in NPH
99m
Waldemar et al., 1992 (32) A Tc-HMPAO 14 Mixed Not reduced Age-matched controls No difference in global CBF using Xe CT or 99m Tc-HMPAO SPECT
SPECT & 9/14 Slightly lower CBF in central white matter in NPH patients
133
Xe inhal Idiopathic Enlargement of area of low subcortical CBF in 9/14 NPH patients
2-comp NPH patients had lower frontal/parietal ratio CBF
SPECT No difference in frontal/temporal CBF ratio
Shimoda et al., 1994 (33) B Xe contrast CT 22 Mostly SAH NA Nil No comments on pre-operative CBF pattern
No Idiopathic
Maeder et al., 1995 (34) C Xe contrast CT 4 Mixed Reduced Age-matched controls QCBF frontal cortex and white matter
2/4 Idiopathic
99m
Shih et al., 1995 (35) C Tc-HMPAO 1 Idiopathic Reduced Nil Perfusion deficits noted in posterior temporoparietal and occipital cortices
SPECT
99m
Kristensen et al., 1996 (36) B Tc-HMPAO 31 Idiopathic Reduced Age-matched controls QCBF in Inferior frontal and temporal cortex
SPECT QCBF in frontal and parietal white matter
Nakano et al., 1996 (37) B Xe contrast CT 14 Mixed NA Nil QCBF in region of frontal periventricular lucencies
Other regions not examined
Tanaka et al., 1997 (38) A Xe contrast CT 21 Mixed Reduced Age-matched controls –
6 Idiopathic
Klinge et al., 1998 (39) B H2O15 bolus 21 Not reported Reduced Normal controls Generally QCBF
PET
Klinge et al., 1999 (40) B H2O15 bolus 10 Idiopathic Reduced Normal controls Generally QCBF
PET
Matsuda et al., 1999 (41) B Xe contrast CT 16 Not reported NA Nil Combined with NAA/Cr MR Spectroscopy

Abbreviations: CBF: Cerebral blood flow, 1-comp/2-comp: single or bi-compartmental curve analysis, HC: hydrocephalus, IC: intra-carotid, inhal: inhalation, ISI: Initial slope index curve analysis, IV: intravenous, NA: not applicable, NPH: Normal
pressure hydrocephalus, pt: patient, SDAT: Senile dementia of the Alzheimer’s type, sig: statistical significance.

329
Normal pressure hydrocephalus and cerebral blood flow

16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 Table 2. Studies of CBF in NPH: results of shunting

330
Reference Class Response Predictive value of baseline CBF FU Change in CBF

Greitz et al., 1969 (6) B 6/7 – 3 w– 2 mo

qCBF most marked in those with greatest clinical improvement; qCBF variable but relate to outcome
In 6/7 patients qCBF correlated to decrease in ventricular size
Salmon & Timperman et al., 1971a (8) C 4/5 – 3–8 mo –
Owler & Pickard

Salmon & Timperman et al., 1971b (9) C 6/7 – 2–4 mo qCBFg 62%, the change in CBFw was more variable
States that decrease in ICP is responsible for increase in CBF
Mathew et al., 1975 (10) B 11/17 Higher CBF related to better clinical outcome 2 w–6 mo –
Mathew et al., 1977 (11) B 3/4 Higher CBF related to better clinical outcome – –
Grubb et al., 1977 (13) B 2/5 No pattern – –
Lying-Tunnell et al., 1977 & 1981 (14, 15) B 4/7 No pattern 5 w & 5 mo qCBF but only temporary in some
Hayashi et al., 1984 (17) B 11/16 Shunt only effective if CBF >3 mo
<25ml/100 g/min
Kushner et al., 1984 (18) A 12/19 No pattern to identify shunt-responders 10 d–12 w qCBF post-op not correlated with degree of clinical improvement
Meyer et al., 1984 (19) B 7/10 No pattern to identify shunt-responders – Post-operative CBF reported in 3 patients and qCBF was reported in each. However only 2/3 patients clinically
improved. Therefore no conclusions drawn
Meyer et al., 1985a (20) B 7/7 NA 6 w & 6 mo qCBF in frontal and temporal cortex and basal ganglia; but mostly q in frontal white matter
Partition co-efficients: No change in cortex but significantly q in white matter especially in frontal lobe
Meyer et al., 1985b (21) B 6/8 No pattern Up to 8 mo Similar findings to previous study. qCBF correlated with improvement in ADLs, gait, incontinence and
MMSE. No correlation between qCBF and Q ventricular size
Brooks et al., 1986 (22) B 0/3 NA 6 w & 6 mo No qCBF post-shunt in NPH patients
Mamo et al., 1987 (23) B 22/25 No pattern re: frontal or global CBF 1 w–4 mo No correlation between qCBF and clinical improvement
Those with excellent outcome had more sustained qCBF compared to patients with good/fair outcome
Vorstrup et al., 1987 (24) A 8/17 No pattern 4 mo No significant change in CBF in either responders or non-responders
Positive correlation between qCBF and Q Evan’s ratio
Graff-Radford et al., 1987 (25) C 23/30 Pre-op CBF significant predictor of 6 mo No correlation between post-shunt CBF and clinical improvement
outcome, especially Anterior/Posterior ratio
Morretti et al., 1988 (27) A 8/12 Degree of frontal hypoactivity not – –
predictive of outcome
Graff-Radford et al., 1989 (26) C 16/26 Only Anterior/Posterior ratio CBF a 6 mo–12 mo –
significant predictor of outcome.
Meixensberger et al., 1989 (28) C – No predictive value – No significant change in post-operative CBF
Some patients did have increase in frontal CBF
Matsada et al., 1990 (29) A 13/13 NA 4–25 d No significant change in CBF
Granado et al., 1991 (30) B 10/14 Non-DAT pattern CBF predictor of <7d No significant change in CBF
improvement and DAT pattern predicts
non-improvement (see text)
Kimura et al., 1992 (31) B 7/7 NA – Restoration of CBF greatest in frontal, temporoparietal white matter and also improved in cortex and thalamus.
Clinical improvement closely correlated with restoration of CBF in white matter
Waldemar et al., 1992 (32) A 11/13 Enlargement of subcortical low flow region 3 mo–6 mo Post-operative clinical improvement did not parallel CBF changes
related to good outcome. Some patients had (9/10) had reduction in subcortical low flow region. Also normalized some cortical defects
Shimoda et al., 1994 (33) B 14/22 No pattern 2–3 w In responders there were significant qCBF in all ROIs, except in basal ganglia
In non-responders, there were no qCBF in any ROI
Maeder et al., 1995 (34) C 2/2 NA <1 mo qCBF in frontal cortex and white matter
Shih et al., 1995 (35) C 1/1 NA 5.5 mo Improvement in cerebrum/cerebellar ratio from 1.3 to 1.6
Improvement in posterior temporoparietal and occipital cortex perfusion defects
Nakano et al., 1996 (37) B 10/14 – 4–6 w Only concerned with CBF frontal peri-ventricular lucencies

16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Normal pressure hydrocephalus and cerebral blood flow

found that gCBF in patients with NPH (45 ml/100

g/min) was significantly reduced compared to both

Abbreviations: CBF: Cerebral blood flow, mo: month, NA: not applicable, NPH: Normal pressure hydrocephalus, pt: patient, ROI: region of interest, SDAT: Senile dementia of the Alzheimer’s type, sig: statistical significance, w: week.
normal controls (55 ml/100 g/min) and athero-
sclerotic controls (50 ml/100 g/min). Waldemar
et al. (32) (A) found no significant difference bet-
ween the mean gCBF of NPH patients (62.5 ml/
In non-responders, CBF marginally decreased. No patients with idiopathic NPH responded

100 g/min) and normal age-matched controls

(58.9 ml/100 g/min). This is only the study in
In responders mean CBF increased while there was no increase non-responders

which a reduced gCBF was not demonstrated in

NPH patients. The 99mTc HMPAO SPECT
In responders, CBF increased by 65% in white matter and 25% in cortex

technique was also applied to the measurement of

CBF in these patients (vide infra).
Regional analysis was also performed by Graff-
Radford et al. (25, 26) (C) who found rCBF to be
most reduced in the frontal region. Vorstrup et al.
(24) (A) also found that NPH patients demon-
strated abnormal CBF maps but no pattern of
No significant change in post-operative CBF

No significant change in post-operative CBF

rCBF was identified.

ii. Prognostic significance of pre-treatment CBF –

Graff-Radford et al. (25) (C) found no significant
difference between the gCBF values or between
individual regions. However there was a significant
difference between responders and non-responders
when frontal to posterior rCBF ratios were ana-
lysed. The frontal/posterior ratio was correct in
predicting 5/6 as unimproved and 14/16 as im-
proved. The second study (26) confirmed these
1 w–7 mo

1 w–7 mo

findings. In this study 30 patients out of a total of

2–3 w

3–4 w

35 patients underwent shunting. Using the same

criteria, it correctly classified 5/7 as unimproved
and 22/23 as improved. The authors concluded
that the frontal/posterior CBF ratio was useful in
predicting surgical outcome.
Responders had lower pre-op CBF

Responders had lower pre-op CBF

Patients only responded if CBF

compared to non-responders

compared to non-responders

iii. Post-treatment CBF – Graff-Radford et al.

(25, 26) (C) found that there was no correlation
>20 ml/100 g/min

between clinical improvement after shunting and

postoperative CBF measurements. Interestingly
No pattern

the authors found that at 2 months after operation

there were significant increases in CBF but that
these were not sustained at 6–12 months despite
12/21

11/16
9/21

5/10

continuing clinical improvement.

Vorstrup et al. (24) (A) reported that for a group
demonstrating clinical improvement, pre and post-
A

operative mean CBF were 45 and 49 ml/100 g/min,

respectively – an insignificant difference. Post-
operatively 6 patients demonstrated improvement
in the pattern of rCBF and all of these patients were
clinically improved after shunting. In the unim-
Matsuda et al., 1999 (41)

proved group, the CBF levels were unchanged.

Tanaka et al., 1997 (38)

Klinge et al., 1998 (39)

Klinge et al., 1999 (40)

II. SPECT studies using non-freely diffusible trac-

ers – Studies combining SPECT with tracers that
are taken up in brain (e.g. 123-IIAMP and 99mTc-
HMPAO) have a unique set of problems. The

331

Owler & Pickard
tracers diffuse across the blood–brain barrier and
enter cells where they undergo a change and are
retained. This process is dependent on binding
mechanisms that are assumed not to change with
pathology which is not necessarily correct. For
example, HMPAO binds to glutathione but the
concentration of the latter may change with
different pathologies. In addition, quantification
of CBF is difficult and therefore the CBF is
expressed as a ratio to the blood flow in the
cerebellum. The cerebellum is used a reference
because it is thought that the cerebellum is not
involved in the NPH and that CBF should be
unaffected by the disease. Such assumptions
should be made with caution as we have found
blood flow in the cerebellum to be variable in
NPH patients using PET (unpublished data).
i. Pre-treatment CBF – A frontal hypoactive
pattern was identified in 19/23 patients with NPH
in the study of Moretti et al. (27) (A). Kristensen
et al. (36) (B) demonstrated that CBF was reduced
in the inferior frontal and temporal cortex as well
as the frontal and parietal white matter. A pattern
of CBF was found in 31 NPH patients which was
clearly different from the CBF pattern of the nor-
mal ageing brain. The parietal and upper frontal
gray matter regions of CBF of NPH patients were
relatively preserved. Shih & Tasdemiroglu (35)
reported a single case of idiopathic NPH in which
perfusion deficits were illustrated in the posterior
temporo-parietal and occipital cortices.
The only study that has not demonstrated a
decrease in CBF is that of Waldemar et al. (32) (A).
The authors measured CBF in each hemisphere as
well as in 16 regions of interest (ROIs). They were
not able to identify a significant difference between
gCBF or rCBF between NPH patients and controls.
However, the frontal-parietal CBF ratio was signifi-
cantly lower in patients with NPH compared to
controls. In addition, there was a small but
significant difference in CBF of the central white
matter with the value being slightly lower in patients
with NPH. The authors found an increase in the
side–side CBF asymmetry in the NPH group that
was significant for the central white matter. The
NPH patients were found to have an increase in the
relative area of the subcortical low flow region
compared to controls.
ii. Prognostic significance of pre-treatment CBF –
The pattern of relative hypoperfusion of the fron-
tal region found in the study of Moretti et al. (27)
(A) had no predictive values in terms of clinical
improvement after shunting. In contrast, Granado
et al. (30) (B) studied CBF within 1 week after
332
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
shunting and found the pre-operative CBF pattern
to be useful in predicting the response to shunting.
The CBF pattern was divided into a DAT pattern
and a non DAT pattern. The DAT pattern was
defined as decreased flow to the posterior tem-
poral and parietal areas with a relative increase in
the frontal lobes compared to controls. Of the
patients with a DAT pattern 4/4 failed to improve,
whereas 9/10 patients with a non-DAT pattern
improved.
In the study of Waldemar et al. (32) (A) all
patients with an enlarged subcortical low flow region
had a good or moderate clinical outcome after shunt
operation. The authors found that the diagnostic
sensitivity and specificity of the area of subcortical
low flow region in predicting surgical outcome was
75% and 100% respectively. There was however, no
clear correlation between the focal cortical CBF
deficits and clinical outcome.
iii. Post-treatment CBF – In regard to post-
operative CBF (3–6 months), Waldemar et al. (32)
(A) found the size of the subcortical low flow
region was normalized in 5 patients, reduced in 4
patients and in 1 patient it was unchanged or
slightly increased. Increased mean cortical blood
flow was reduced after shunt in all cases. Cortical
blood flow deficits were normalized in 3 patients
and unchanged in 4 patients (in one of the latter
there was a small cortical infarct). The case pre-
sented by Shih & Tasdemiroglu (35) demonstrated
clinical improvement with marked improvement of
perfusion at both cerebral cortices. Cerebral-to-
cerebellar ratio was 1.3 pre-operatively compared
to 1.6 post-operatively.
d. Xenon Contrast Computed Tomography
The distribution of inhaled stable xenon and its
removal from the brain can also be measured using
serial CT scanning and the change in Hounsfield
units due to the tracer. This technique of quantifying
CBF has its own set of difficulties. However, the
technique of Xe contrast CT thus provides a
tomographic representation of CBF, is not tissue
depth sensitive and has the added advantage of
allowing regional partition-coefficients to be calcu-
lated. As the method relies on serial CT scanning,
the number of slices is limited and the slice chosen
must avoid the eye as there are risks to the retina. As
with other xenon techniques, inhalation of xenon
may produce anaesthetic effects and unwanted
changes in CBF.
The higher resolution and ability of the technique
to examine rCBF, especially the deep white matter,
has provided some important results. The finding of
the increase in partition co-efficients particularly in
 16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Normal pressure hydrocephalus and cerebral blood flow

Fig. 1. T1 weighted magnetic resonance images (top) and H215O PET CBF images (middle) of a patient with NPH. The PET
image has been co-registered to the MR image which has been resliced to PET resolution. The two images have then been fused
(bottom).

Fig. 2. Imaging of function after head injury. Axial CT scan (left), H215O PET CBF image (middle) and OER image (right) of
a patient following a severe head injury. The patient has suffered a severe head injury and has undergone craniotomy and
evacuation of an extra-axial haematoma in the left fronto-parietal region. CBF is reduced in this region. By combining
CMRO2 data with CBF data the OER is obtained. The OER is increased in the area of injury indicating that cerebral
metabolism is being maintained. Figure courtesy of Prof. David Menon and Dr Jonathon Coles, Department of Anaesthetics,
Addenbrooke’s Hospital.

333
 16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Owler & Pickard

Baseline Q CMRglu had no predictive value re: response to shunt

the frontal white matter appears to be important

No correlation between Q CMRglu and cortical biopsy findings

No significant difference between hydrocephalus patients and
both in terms of pathophysiology but casts a shadow

In two patients with excellent outcome, qCMRO2 to normal

Q CMRglu in frontal region correlated with dementia score

over some of the findings of the non-tomographic
studies. These studies appear to confirm that the

OER 53% in recent onset hydrocephalus patients

gCBF is reduced, that the frontal region is often the
most severely affected region and that the reduction
in CBF appears to be greatest in the white matter.
Comments

OER 40%, i.e. normal in NPH patients

patients with cerebral atrophy

i. Pre-treatment CBF – A reduction in gCBF has

been reported by several studies (21, 33, 34).
Analysis of CBF in various tissues was conducted
Single case study
by Meyer et al. (20) (B) who found that, compared
to normal age matched controls, CBF was 51.4
ml/100 g/min versus 67.4 ml/100 g/min in cortical
gray matter, 50.0 ml/100 g/min versus 64.4 ml/100
–

g/min in subcortical gray matter and 19.2 ml/100

g/min versus 24.1 ml/100 g/min in white matter.
q global and rCMRglu over 2 years to normal values

Examination of rCBF by Meyer et al. (20) (B)

Abbreviations: CMRglu: cerebral metabolic rate glucose, CMRO2: cerebral metabolic rate oxygen, NPH: normal pressure hydrocephalus, OER: oxygen extraction rate.
qCMRO2 & uptake of glucose and no difference

revealed that CBF was most markedly reduced in the

Post-operative cerebral metabolism

frontal, parietal and temporal cortex, as well as

associated with excellent clinical outcome.

thalamus and fronto-temporal white matter bilat-

No significant change global CMRO2.

erally. Maeder and de Tribolet (34) (C) also found

that CBF was most reduced in frontal cortex and
white matter. Kimura et al. (31) (B) found that no
qin ketone body uptake.

Q CMRglu post-shunting

pattern of rCBF could be identified in NPH patients

and that it was for the most part diffuse. Compared
with normal age matched controls, CBF was
reduced in the frontal cortex (38%), frontal sub-
cortex (39.1%), thalamus (47.3%), temporo-parietal
–

cortex (35.5%), occipital cortex (24.3%) and tem-

poro-parieto-occipital subcortex (30.4%).
QCMRglu diffuse compared to temporo-parietal

Using Xe contrast CT Meyer et al. (20) were able

QCMRO2 & lower uptake of glucose and no

QCMRglu in frontal, parietal and temporal

to measure the partition co-efficients for various

Focal and diffuse, Significant asymmetry
Baseline cerebral metabolism

regions. These were most severely and consistently

Heterogeneous pattern of QCMRglu.
difference in ketone body uptake.

reduced in the fronto-temporal white matter. In

pattern in Alzheimer’s disease.

another study (21) similar reductions in CBF were

Significant Q global CMRO2.

Significant Q global CMRO2

seen although no comprehensive presentation of the

–

preoperative CBF measurements was made. Abnor-

mal partition co-efficients have not been recorded in
patients with Alzheimer’s disease or other dementias
associated with brain atrophy.
cortices.

Meyer et al. (20) also compared the CBF results

using the clearance of inhaled 133Xe and stable Xe
contrast CT. They found that white matter flow
PET: FDG/CDG
AV difference
Glucose/O2
Method

values measured with former were lower compared

PET: PDG
PET: FDG

PET: FDG
O2

O2
Table 3. Studies of cerebral metabolism in NPH

with those measured using the Xe contrast CT

15

15
PET

PET

method. Also, the increases in white matter blood

flow after shunting were greater using the 133Xe
Lying-Tunnell et al, 77 & 81 (14, 15)

clearance method. These differences are most likely

due to the assumption used in CBF calculations of
the 133Xe method, that is, that partition co-efficients
Tedeschi et al., 1995 (56)
George et al., 1986 (54)
Jagust et al., 1985 (53)

Brooks et al., 1986 (22)

are normal.
Grubb et al., 1977 (13)

Kaye et al., 1990 (55)

ii. Prognostic value of pre-treatment CBF –

Reference

Shimoda et al. (33) (B), in 22 patients with secon-

dary NPH, could find no significant differences in

334

Normal pressure hydrocephalus and cerebral blood flow
the pre-operative CBF, globally and regionally,
between shunt responders and non-responders.
Tanaka et al. (38) (A) reported that patients with
clinically suspected NPH will improve if the
hemispheric CBF is greater than 20 ml/100 g/min
but will not improve if it is less.
Nakano et al. (37) examined only the region of the
frontal white matter within the area of periventri-
cular lucency using dynamic Xe contrast CT. CBF
was significantly reduced in both shunt responders
and non-responders. Furthermore, differences in the
arrival time of a bolus injection of contrast was
noted. The authors concluded that the delay in shunt
responders was probably because the periventricular
lucency in these patients was due to increased
interstitial oedema while in shunt non-responders
arrival time was not delayed because the lucency was
due to irreversible tissue loss
iii. Post-treatment CBF – Meyer et al. (20, 21)
(B) found significant increases in the blood flow
values in the frontal and temporal cortex, basal
ganglia and frontal white matter. Significant
increases in the partition co-efficients were only
significant in the frontal white matter. Similar
findings were reported by Maeder and de Tribolet
(34) (C) although in a much less detailed study
with only 2 patients demonstrating improvement.
As the diagnosis of NPH in the study depended on
response to shunting, in the study of Kimura et al.
(31) (B), all the patients in the study responded to
shunting. Post-operatively, the restoration rate in
the various regions was recorded as 42.8% in frontal
cortex, 54.6% in frontal subcortex, 22.6% in tha-
lamus, 33.3% in temporo-parietal cortex, 19.1% in
occipital cortex and 46.7% in the temporo-parieto-
occipital cortex. Thus restoration of CBF was
greatest and was significant in the frontal subcortex
and temporo-parieto-occipital subcortex, followed
by the frontal and temporo-parietal cortex. Changes
in the thalamus and occipital cortex were not
significant. The authors found that clinical improve-
ment correlated more closely with restoration of
CBF in white matter. Takana et al. (38) found that in
shunt-responders, CBF improved. Restoration of
CBF was greatest in the subcortical white matter
compared to the thalamus and cortex. Conversely
CBF deteriorated in the patients who failed to
improve clinically.
e. Positron Emission Tomography
PET which relies on detecting the distribution of
tracers with short half-lives (e.g. O15 and C11), has
the potential to be one of the most accurate methods
for the assessment of rCBF. Theoretically, PET
relies on co-incidence detection and therefore
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
measurement of CBF should be independent of
the tissue depth of the region of interest. There are
however, the potential problems of re-circulation of
isotope, Compton scatter and false co-incidence
detection.
i. Pre-treatment CBF – Grubb et al. (13) (B)
were the first investigators to utilise a positron
emitter (C15O-haemoglobin) in the study of CBF
in patients with NPH. Global CBF was reduced
by 42% in NPH patients and 37% in the cerebral
atrophy patients compared to age matched normal
controls. Differences between cerebral atrophy
and NPH patients were not significant. No definite
pattern of CBF could be seen in either group and
was not useful in distinguishing the two groups.
CBF was also examined using PET and C15O2
inhalation by Brooks et al. (22) (B). This study
examined gCBF and other parameters in a mixed
group of hydrocephalic patients. The insidious onset
group consisted mainly of NPH patients. Both the
insidious onset (27 ml/100 g/min) and recent onset
(35 ml/100 g/min) groups were demonstrated to
have significantly decreased gCBF compared to
controls (44 ml/100 g/min).
Utilizing more modern technology, Klinge et al.
(39, 40) (B) performed two studies using PET with
H215O in order to study CBF in patients with NPH
and found gCBF to be reduced. The baseline mean
gCBF in NPH patients was 40 ml/100 g/min which
was significantly lower compared to 61 ml/100 g/min
in controls. Unfortunately, without MR co-regis-
tration, no regional analysis was performed.
ii. Prognostic significance of pre-treatment CBF –
Klinge et al. (39) found the relationship between
preoperative gCBF to be useful in predicting
response to shunting. Using PET with intravenous
H215O, gCBF was compared between shunt res-
ponders and non-responders. Pre-operative gCBF
in these groups were 33 ml/100 g/min and 45 ml/
100 g/min, respectively. In a second study (40)
similar results were found (36 ml/100 g/min vs
44 ml/100 g/min).
iii. Post-treatment CBF – Brooks et al. (22) (B)
found that gCBF improved significantly after
shunting in their insidious onset hydrocephalus
group, of which several patients probably had
NPH, but did not increase in the recent onset
group. Examination of the postoperative CBF in
both shunt responders and non-shunt responders
at 7 days and 7 months by Klinge et al. (39, 40)
(B) demonstrated no significant differences bet-
ween the two groups. Global CBF postoperatively
varied between the groups and as a result could
335
 336
Table 4. Studies of CVR and autoregulation in NPH: predictive value
Reference
Mathew et al., 1975 (10)
Mathew et al., 1977 (11)
Grubb et al., 1977 (13)
Hartmann et al., 1977 (12)
Stump et al., 1983 (73)
Kushner et al., 1984 (18)
Meyer et al., 1984 (19)
Mamo et al., 1987 (23)
Morretti et al., 1988 (27)
Schmidt et al., 1990a (75)
Schmidt et al., 1990b (74)
Shimoda et al., 1994 (33)
Kristensen et al., 1996 (36)
Lee et al., 1998 (76)
Klinge et al., 1999 (40)
Chang et al., 2000 (77)
Abbreviations: CSF: cerebrospinal fluid, CSFP: CSF pressure, CVR: cerebrovascular reactivity, 1-comp/2-comp: single or bi-compartmental curve analysis, HC: hydrocephalus, IC: intra-carotid, inhal: inhalation, ISI: initial slope index curve analysis, IV:
intravenous, LP: lumbar puncture, NPH: normal pressure hydrocephalus, pt: patient, PI: pulsatility index.
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Owler & Pickard
Methods Cases Baseline results Comments
CSF drainage 15 pts qCBF and qCBV Appears to be relationship between qCBF and response to shunting
30–40 ml/CSFP: Q50%/T: Nil
CSF drainage 3 pts qCBF Appears to be relationship between qCBF and response to shunting
30–40 ml/CSFP: Q50%/T: Nil
CSF drainage 7 pts qCBF small but significant. Also small but significant q in patients with cortical atrophy
30–40 ml/CSFP: NA/T: Nil
CSF drainage 11 pts Small qCBF and qCBV: Not significant –
NA ml/CSFP: 14 mmHg/T: NA Also an increase in CO2 reactivity.
CO2 reactivity; 133Xe inhalation 1 pt CVR pre-op 20% ie reduced. Improvement in CVR appeared to correlate with clinical improvement
CVR post-op 47%.
CSF drainage 19 pts No change in mean CBF. Not useful
25–40 ml/CSFP: Q50%/T: 1 hr qCBF just as likely as QCBF.
CSF drainage; 25–35 ml/CSFP: Q50%/T: Nil 7 pts qCBF post LP in 6/7 (other pt had SDH). CVR to 100% O2 restored to normal range after CSF removal
& 100% O2 response qCBF frontal region the greatest.
CSF drainage 25 pts No overall qCBF, some cases QCBF; qCBF related No correlation between qCBF and response to shunting
20–35 ml/CSFP: Q50%/T: 30 min to q on one side in cases of asymmetry.
CSF drainage 23 pts qCBF 7/10 & QCBF 3/10. 100% predictive value; all with qCBF responded & no cases with QCBF
10–60 ml/CSFP: Q50%/T: 30 min responded
Autoregulation: Vacuum lower 14 pts Autoregulation maintained in 13/14 pts. After Captopril autoregulation remained intact and CO2 reactivity unchanged
limbs and CO2 reactivity
Response to Nimodipine iv 8 pts – 4/8 pts had Q CPP of 20 mmHg. All of these patients experienced QCBF.
A-V O2 difference Other pts experienced no change
CVR: 10% Glycerol iv 22 pts More widespread increases in CBF post glycerol in Authors suggest glycerol is a predictor of tissue salvagability
Xe CT shunt responders.
CSF drainage 31 pts No change in CBF overall. No significant correlations between change in CBF and clinical changes. Gait
30–40 ml/CSFP: 0/T: 3–4 hr often improved after LP
TCD: ACA/MCA 11 pts QCVR and qPI in ACA and MCA. CVRq post-operatively; qCVR in ACA and MCA appeared related to
CO2 Reactivity Not predictive of outcome. improvements in gait and that of MCA related to mental impairment
CVR: Acetazolamide 1 g iv 10 pts CVR not different between responders and In responders, CVR increased post-operatively
PET: H2O15 non-responders pre-operatively. In non-responders, CVR decreased and then returned to baseline levels
CVR: Acetazolamide 500 mg iv 41 pts QCVR pre-operatively: Complete triad significantly Post-operatively q CVR in both groups
99m
Tc-HMPAO lower CVR compared to incomplete triad.

Normal pressure hydrocephalus and cerebral blood flow
find no significant difference between pre- and
post-operative gCBF in either group.
High resolution PET is now available and
accurate registration with high resolution anatomi-
cal MR imaging is also possible (Fig. 1). The
combination of these techniques is likely to allow
more accurate rCBF studies in the future. In
addition perfusion MR imaging has also been
developed. Until methods such as these are applied
to the study of CBF in NPH, issues regarding rCBF
will remain sub judice.
The relationship between CBF and NPH
Although studies of CBF in NPH remain incon-
clusive, it does appear that g CBF is reduced and
that the frontal region is most likely to be affected.
At this point, two inter-related questions must be
put. First, is a reduction in CBF responsible for the
clinical features of NPH? Second, why is CBF
reduced?
There is relatively little information regarding
accurate grading of the severity or duration of
clinical features and CBF. No study demonstrated a
relationship between duration of symptoms and
CBF. There appears to be no agreement between the
severity of symptoms such as dementia or gait and
CBF. Lying-Tunell et al. reported that the severity of
dementia was correlated with reduction in CBF.
Likewise Meixensberger et al. (28) reported that
NPH patients with neurological deficits had lower
CBF compared to those with mild symptoms and
ICP abnormalities only. In contrast, Vorstrup et al.
(24) reported that there was no relationship. Clearly
the relationship is not straightforward.
It is a matter of some debate whether changes in
the cerebral circulation are a cause or effect of NPH.
More popular theories interpret CBF reduction as a
consequence of ventricular dilatation, reduced
metabolism and other secondary changes. A possi-
ble relationship between cerebrovascular hyperten-
sive changes and NPH argue in favour of the former.
Ventricular size was recorded in most studies
either with aid of a CT or pneumo-encephalography.
It was reported to be correlated with a reduction in
CBF in the studies of Greitz et al. (6, 7) and Vorstrup
et al. (24). However Mamo et al. (23) and Moretti
et al. (27) found no such relationship. Thus a
relationship between CBF and ventricular dilatation
remains unresolved.
Despite these contradictory observations, ventri-
cular dilatation forms the core of several theories
attempting to explain the observations of reduced
CBF in NPH. Mathew et al. (10), on finding that the
reduction of CBF was most notable in the distribu-
tion of the anterior cerebral arteries, proposed that
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
the expansion of the ventricular system probably
stretched the anterior cerebral arteries over the
corpus callosum. There is some support for this in
angiographic studies and experimental hydrocepha-
lus (43) and paediatric hydrocephalus (44).
However, the segments of the anterior cerebral
artery that are likely to be stretched are those
supplying midline cortical regions rather than
frontal white matter. The most significant changes
in CBF occurred in the frontal region that is supplied
by deep penetrating arteries.
Ventricular dilatation has also been taken as
evidence that the brain is being compressed and that
an increase in intra-parenchymal pressure results (8,
9). However, there is no direct evidence to suggest
that the intra-parenchymal pressure is increased.
Distortion of the brain certainly does occur and
distortion rather than compression may be more
directly associated with a reduction in CBF. In
addition there appears to be a decrease in the
number and density of capillaries in the periven-
tricular tissue (45).
Attention should be given to the periventricular
white matter surrounding the frontal and occipital
ventricular horns. The frequent finding of periven-
tricular lucencies (PVLs) on CT in these regions is
often presumed to be due to the accumulation of
CSF in the extracellular compartment. However
PVLs may also be due to gliosis . Increased water
content of these regions, decreased tissue density
and alteration of partition co-efficients may be the
cause of reduced CBF in the frontal region.
Akai et al. (46) reported that the most prominent
post-mortem finding in NPH was demyelination of
the white matter supplied by the anterior and middle
cerebral arteries. While the peripheral arcuate region
of the white matter region was reasonably main-
tained, the deep white matter demonstrated a
marked reduction in the number of myelinated
axons. The number of axons themselves was also
reduced. Whether this is a cause or effect of reduced
blood flow in periventricular regions is not clear.
Such changes may also have distant effects due to
deafferentation. This may result in a decrease in
neuronal cell body function. As a result of a reduced
cerebral metabolic rate, CBF is then reduced in
those regions. Indeed axons may only need to be
stretched across the dilated ventricles to influence
functioning. As early as 1947 Yakovlev (47)
proposed that gait disorder was due to stretching
of axons responsible for gait (48–52).
The relationship between CBF and cerebral
metabolism has not been properly explored in
NPH. The few studies in which cerebral metabolism
has been studied in NPH are detailed in Table 3.
Most of these studies have studied cerebral meta-
337

Owler & Pickard
bolism in isolation. While global cerebral metabo-
lism appears reduced, there was no significant
pattern of reduction. In order to properly appreciate
the contribution that deafferentation and other
changes have on CBF and vice versa, studies
combining both cerebral metabolism and CBF
need to be performed. In this way parameters such
as the oxygen extraction rate (OER) can be
calculated. For example, recent studies on brain
injury have shown how OER is needed to distinguish
ischemia from low CBF coupled to depressed
metabolism (Fig. 2). To date, only Brooks et al.
(22) have studied OER in a limited number of
patients. These authors found an OER of 40%, that
is, normal, and concluded that the reduction in CBF
was due to neuronal cell loss. Further studies aimed
at elucidating this relationship are warranted but are
difficult because of the resolving power of PET.
The association of NPH with various cerebro-
vascular disease also deserves consideration. Hyper-
tension has been found to be associated with NPH
(57–61). Hypertension causes thickening of the
arterial wall as well as arteriosclerosis. The vessels
most commonly effected by this process are the
lenticulostriate vessels that have a relatively long
course through the brain parenchyma and supply
the basal ganglia and associated corona radiata.
Patients with prolonged hypertension are liable to
develop small infarcts in this region. The small
arteries of the white matter, basal ganglia and
thalamus have demonstrated marked sclerosis with
intimal thickening and hyalinisation of the wall in
post-mortem studies of NPH patients (46). Arterial
occlusion with micro-thrombi were seen along with
microinfarcts. These and similar pathological find-
ings prompted several authors to propose that such
micro-infarcts decrease the viscoelastic properties of
the brain thus allowing ventricular dilatation to
occur in the presence of normal CSF pressure and so
assist the development of NPH (4, 60–65).
The association between periventricular white
matter hyperintensities on MR and NPH has been
considered as further evidence for a vascular factor
in the pathogenesis of NPH (4, 36, 66). MR hyper-
intensities are thought to represent ischaemic
changes in the white matter region and may be
present in many normal ageing individuals (67).
There may be loss of the perivascular myelin, shrink-
age, atrophy and gliosis of the parenchyma around
blood vessels (68–70). Interestingly, Binswanger’s
disease is characterized by clinical features that are
very similar to those of NPH, radiologically by
prominent white matter hyperintensities and
pathologically by atherosclerotic changes in the
lenticulostriate arteries with micro-infarcts in the
associated territory (4). The arcuate fibres are
338
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
typically spared (70). In addition, the ventricular
system is often dilated and some patients improve
with CSF shunting. Some have debated as to
whether the two diseases are one and the same (4,
71, 72).
Clearly, there is much to be learnt about the
pathophysiology of NPH. In particular, while much
work has been done on the relationship of CBF,
there is the potential for significant advances in our
understanding of the relationship. Until studies
using technology that is accurately able to examine
rCBF are performed, with an appropriate combina-
tion of other parameters, issues of pathophysiology
are likely to remain unsolved.
Is there a diagnostic or prognostic role for CBF
measurement?
For an examination to have clinical application,
notwithstanding issues of practicality, it needs to
resolve two issues. First, it must provide a method
for differentiating NPH from other conditions such
as DAT. Second, if a patient with NPH is identified
it must be able to predict whether that patient will
respond to shunting.
a. Pre-treatment CBF – Regarding diagnosis,
results of studies in comparing NPH patients with
patients known to have cerebral atrophy or the
other forms of dementia are disappointing.
Although several studies that found that the CBF
was lower in patients with NPH compared to
patients with cerebral atrophy or DAT (10, 11,
13). However, the diagnosis of individual patients
could not be confirmed. Other studies were not
able to demonstrate any differences in gCBF
between the different groups (13, 18, 25, 26).
The prognostic value of pre-treatment CBF is also
inconclusive. Mathew et al. (10, 11) found that there
was an inverse relationship between CBF and
outcome after shunting. Likewise, Hayashi et al.
(17) found that patients with a CBF of less than
25ml/100 g/min did not respond to shunting. Klinge
et al. (39, 40) found the opposite with patients with
lower CBF more likely to respond to shunting. A
low anterior to posterior ratio (25), the presence of a
large subcortical low flow region (32) and frontal
hypoperfusion (27) have all been proposed as
predictors of a favourable response to shunting.
However these have not been confirmed in all
studies.
b. Response of CBF to temporary CSF removal –
Measurement of CBF has been performed prior
to, and after, temporary CSF drainage as a meth-
od of diagnosis and/or determining prognosis.

Normal pressure hydrocephalus and cerebral blood flow
There are 9 such studies that we have identified in
our review of the literature. Briefly, in these
studies, a moderate amount of CSF (10–60 ml) is
removed via lumbar puncture in order to decrease
the CSF pressure by a certain amount, for
example 50%. At some pre-determined time after
this manoeuvre baseline, CBF is again measured.
In early studies, small, but significant increases in
CBF after CSF removal (10–13). Meyer et al. (19)
also noted a regional difference in the increase in
CBF after CSF removal.
Mathew et al. (10, 11) reported that increases in
CBF after CSF drainage appeared to be related to
outcome after shunting. Morretti et al. (27) found
the test was correct in predicting outcome after
shunting in 10 patients of outcome.
In contrast, more recent studies (18, 23, 36) found
that the mean CBF for patients with NPH was not
increased after CSF removal and that an increase in
CBF was just as likely as a decrease. Therefore these
studies found that the change in CBF after CSF
removal via was not useful in predicting outcome.
The study of CBF after CSF removal does not
appear to have clinical utility. Given that patients
may not recover for several days, or even months
after shunting, a link between clinical change, CBF
and CSF removal is unlikely to be demonstrated
after the removal of such a small amount of CSF in
such a short period of time.
c. Other parameters – There have been numerous
methods utilized in the study of cerebrovascular
reactivity (CVR) in NPH. CVR may be defined as
the ability of the cerebrovascular bed to change in
response to certain stimuli. Studies of CVR and
autoregulation are detailed in Table 4.
The carbonic anhydrase inhibitor, acetazolamide,
when given intravenously, should cause vasodilata-
tion and an increase in CBF. The technique was
incorporated into the recent studies of both Klinge
et al. (40) and Chang et al (77). Both groups found
the response to i.v. acetazolamide to be decreased
pre-operatively. Chang et al. (77) also commented
that CVR was most reduced in NPH patients with
the complete clinical triad of NPH compared to
those with an incomplete clinical triad.
Klinge et al. (40) using PET and i.v. acetazola-
mide was performed in 10 patients at 7 days and 7
months after shunting. In the 5 patients who
demonstrated a response to CSF shunting, CVR
compared to pre-operatively values tended to be
higher at day 7 post-operatively and was signifi-
cantly so by 7 months. In contrast, CVR was
significantly decreased at day 7 and then returned to
pre-operative levels in the non-responders. Chang
et al. (77) using 99mTc-HMPAO SPECT found CVR
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
was improved after shunting in both shunt respon-
ders and non-responders.
Inhalation of CO2 was used as a stimulus to
examine CVR in the study of Lee et al. (76). Using
transcranial Doppler, the cerebral haemodynamics
of the anterior and middle cerebral arteries were
monitored at rest and during inhalation of 5% CO2.
CVR was decreased in both regions in patients with
NPH and improved after shunting. Furthermore,
improvements in CVR in the anterior and middle
cerebral artery territory correlated with gait
improvement and that in middle cerebral artery
territory correlated with improvement in cognition.
With regards to prognosis however, the pre-
operative CBF responses were of no prognostic
value in the studies of Klinge et al. (40), Chang et al.
(77) and Lee et al. (76).
Stump et al. (73) presented a case study in which
CVR to CO2 inhalation increased from 20% to 47%
post operatively. The patient was clinically im-
proved and this appeared to closely follow improve-
ment in CVR. The CVR to inhalation of 100% O2
was also restored to within the normal range in
shunted patients in the study of Meyer et al. (19).
Shimoda et al. (33) examined CBF before and
after 10% i.v. glycerol using Xe contrast CT. It is
not a strict test of CVR as the mechanism of effect
of glycerol is not known. It is thought to act as an
osmotic but may have effects such as on blood
viscosity for example. CBF increases were obser-
ved in some patients. The increases in CBF were
more widespread in shunt responders and the
authors concluded that it was a predictor of tissue
salvagability.
Using Xenon contrast CT to study CBF in the
cortex, white matter and thalamus, Tanaka et al.
(38) found that the vascular response to acetazola-
mide was impaired only in the white matter of shunt-
responders. In this region, improvement in the
vascular response was associated with clinical
improvement. In non-responders the pre-operative
vascular response was not impaired. The authors
concluded that the underlying pathophysiological
process was ischaemia associated with a loss of
autoregulatory capacity in the periventricular white
matter.
Finally Czosnyka et al. (78, 79) examined the
cerebral autoregulation in 40 patients with ventri-
cular dilatation and the clinical features of NPH.
Resistance to CSF outflow (Rcsf) as measured using
the computerized infusion test (3) was compared to
dynamic cerebral autoregulation (AR) as assessed
by the correlation coefficient between slow waves in
mean blood flow velocity and cerebral perfusion
pressure. Patients with high Rcsf demonstrated
intact regulation whereas those without a positive
339

Owler & Pickard
infusion test exhibited disturbed autoregulation.
This suggests that the spectrum of patients with
NPH includes patients with a pure CSF circulation
problem (AR intact) and patients with more of a
cerebrovascular problem (AR defective).
Conclusions
With respect to NPH and CBF, apart from a global
pre-treatment decrease, there are few conclusions
that can be reached. There is therefore much scope
for improving our knowledge in this area. There are
clearly changes in CBF and associated dynamics
that take place in NPH that may represent a
pathogenic mechanism or a secondary phenomenon.
Due weight should be given to improved patient
selection with sufficient numbers of well-documen-
ted, properly defined patient subgroups. This is
often difficult in view of the difficulties in obtaining
significant numbers and the frail nature of these
patients. New techniques, with better resolution and
sensitivity for deep tissues should provide the ability
to resolve some of the disputed issues regarding
rCBF. As lone measurements of CBF are difficult to
interpret, concomitant studies of cerebral metabo-
lism are needed. MR perfusion imaging is also a
promising technique that may be well suited to the
problems of NPH. Finally, findings need to be
transferable to the bedside so that clinicians can
apply them in the treatment of patients with this
important condition.
Acknowledgements
We would like to express our gratitude to Dr Alonso Pena and Dr
Neil Harris for their help and comments on this manuscript. Dr
Brian Owler is supported by the University of Sydney Medical
Foundation and the Madeline Foundation for Neurosurgical
Research. Professor Pickard is supported by MRC Programme
Grant No. G42,00005.
References
1. ADAMS RD, FISHER CM, HAKIM S, OJEMANN RG, SWEET WH.
Symptomatic occult hydrocephalus with ‘‘normal’’ cerebro-
spinal fluid pressure. A treatable syndrome. NEJM 1965;273:
117–26.
2. HAKIM S, ADAMS RD. The special clinical problem of sympto-
matic hydrocephalus with normal cerebrospinal fluid press-
ure. Observations in cerebrospinal fluid hydrodynamics. J
Neurol Sci 1965;2:307–27.
3. CZOSNYKA M, WHITEHOUSE H, SMIELEWSKI P, SIMAC S, PICKARD
JD. Testing of cerebrospinal compensatory reserve in shunt-
ed and non-shunted patients: a guide to interpretation based
on an observational study. J Neurol Neurosurg Psychiatry
1996;60(5):549–58.
4. BRADLEY WG, Jr., WHITTEMORE AR, WATANABE AS, DAVIS SJ,
TERESI LM, HOMYAK M. Association of deep white matter
infarction with chronic communicating hydrocephalus:
implications regarding the possible origin of normal-pressure
340
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
hydrocephalus [see comments]. AJNR Am J Neuroradiol
1991;12(1):31–9.
5. GREITZ D, HANNERZ J, RAHN T, BOLANDER H, ERICSSON A. MR
imaging of cerebrospinal fluid dynamics in health and disease.
On the vascular pathogenesis of communicating hydroce-
phalus and benign intracranial hypertension. Acta Radiol
1994;35(3):204–11.
6. GREITZ TV, GREPE AO, KALMER MS, LOPEZ J. Pre- and post-
operative evaluation of cerebral blood flow in low-pressure
hydrocephalus. J Neurosurg 1969;31(6):644–51.
7. GREITZ TV. Cerebral blood flow in occult hydrocephalus
studied with angiography and the xenon 133 clearance
method. Acta Radiol [Diagn] (Stockh) 1969;8(5):376–84.
8. SALMON JH, TIMPERMAN AL. Cerebral blood flow in post-
traumatic encephalopathy. The effect of ventriculoatrial
shunt. Neurology 1971;21(1):33–42.
9. SALMON JH, TIMPERMAN AL. Effect of intracranial hypoten-
sion on cerebral blood flow. J Neurol Neurosurg Psychiatry
1971;34(6):687–92.
10. MATHEW NT, MEYER JS, HARTMANN A, OTT EO. Abnormal
cerebrospinal fluid-blood flow dynamics. Implications in dia-
gnosis, treatment, and prognosis in normal pressure hydro-
cephalus. Arch Neurol 1975;32(10):657–64.
11. MATHEW NT, HARTMANN A, MEYER JS. The use of regional
cerebral blood flow measured with the gamma camera in
neurological diagnosis. Int J Neurol 1977;11(2–3):194–205.
12. HARTMANN A, ALBERTI E, LANGE D. Effects of CSF drainage
on CBF and CBV in subarachnoid haemorrhage and comm-
unicating hydrocephalus. Acta Neurol Scand 1977;56
(Supplement 64): 336–7.
13. GRUBB RL, Jr., RAICHLE ME, GADO MH, EICHLING JO, HUGHES
CP. Cerebral blood flow, oxygen utilization, and blood
volume in dementia. Neurology 1977;27(10):905–10.
14. LYING-TUNELL U, LINDBLAD BS, MALMLUND HO, PERSSON B.
Cerebral blood flow and metabolic rate of oxygen, glucose,
lactate, pyruvate, ketone bodies and amino acids in patients
with normal pressure hydrocephalus before and after
shunting and in normal subjects. Acta Neurol Scand Suppl
1977;64:338–9.
15. LYING-TUNELL U, LINDBLAD BS, MALMLUND HO, PERSSON B.
Cerebral blood flow and metabolic rate of oxygen, glucose,
lactate, pyruvate, ketone bodies and amino acids. Acta
Neurol Scand 1981;63(6):337–50.
16. TAMAKI N, KUSUNOKI T, WAKABAYASHI T, MATSUMOTO S. Cere-
bral hemodynamics in normal-pressure hydrocephalus. Eval-
uation by 133Xe inhalation method and dynamic CT study. J
Neurosurg 1984;61(3):510–14.
17. HAYASHI M, KOBAYASHI H, KAWANO H, YAMAMOTO S, MAEDA
T. Cerebral blood flow and ICP patterns in patients with
communicating hydrocephalus after aneurysm rupture. J
Neurosurg 1984;61(1):30–6.
18. KUSHNER M, YOUNKIN D, WEINBERGER J, HURTIG H, GOLDBERG
H, REIVICH M. Cerebral hemodynamics in the diagnosis of
normal pressure hydrocephalus. Neurology 1984;34(1):96–9.
19. MEYER JS, TACHIBANA H, HARDENBERG JP, DOWELL RE, Jr.,
KITAGAWA Y, MORTEL KF. Normal pressure hydrocephalus.
Influences on cerebral hemodynamic and cerebrospinal fluid
pressure – chemical autoregulation. Surg Neurol 1984;21(2):
195–203.
20. MEYER JS, KITAGAWA Y, TANAHASHI N et al. Pathogenesis of
normal-pressure hydrocephalus – preliminary observations.
Surg Neurol 1985;23(2):121–33.
21. MEYER JS, KITAGAWA Y, TANAHASHI N et al. Evaluation of
treatment of normal-pressure hydrocephalus. J Neurosurg
1985;62(4):513–21.
22. BROOKS DJ, BEANEY RP, POWELL M et al. Studies on cerebral
oxygen metabolism, blood flow, and blood volume, in
patients with hydrocephalus before and after surgical

Normal pressure hydrocephalus and cerebral blood flow
decompression, using positron emission tomography. Brain
1986;109(Pt 4):613–28.
23. MAMO HL, MERIC PC, PONSIN JC, REY AC, LUFT AG, SEYLAZ
JA. Cerebral blood flow in normal pressure hydrocephalus.
Stroke 1987;18(6):1074–80.
24. VORSTRUP S, CHRISTENSEN J, GJERRIS F, SORENSEN PS, THOMSEN
AM, PAULSON OB. Cerebral blood flow in patients with
normal-pressure hydrocephalus before and after shunting. J
Neurosurg 1987;66(3):379–87.
25. GRAFF-RADFORD NR, REZAI K, GODERSKY JC, ESLINGER P,
DAMASIO H, KIRCHNER PT. Regional cerebral blood flow in
normal pressure hydrocephalus. J Neurol Neurosurg Psych-
iatry 1987;50(12):1589–96.
26. GRAFF-RADFORD NR, GODERSKY JC, JONES MP. Variables
predicting surgical outcome in symptomatic hydrocephalus
in the elderly. Neurology 1989;39(12):1601–4.
27. MORETTI JL, SERGENT A, LOUARN F et al. Cortical perfusion
assessment with 123I-isopropyl amphetamine (123I- IAMP)
in normal pressure hydrocephalus (NPH). Eur J Nucl Med
1988;14(2):73–9.
28. MEIXENSBERGER J, BRAWANSKI A, ULLRICH OW, GUNREBEN G.
Cerebral blood flow in low pressure hydrocephalus. Psychi-
atry Res 1989;29(3):307–8.
29. MATSUDA M, NAKASU S, NAKAZAWA T, HANDA J. Cerebral
hemodynamics in patients with normal pressure hydroce-
phalus: correlation between cerebral circulation time and
dementia. Surg Neurol 1990;34(6):396–401.
30. GRANADO JM, DIAZ F, ALDAY R. Evaluation of brain SPECT
in the diagnosis and prognosis of the normal pressure
hydrocephalus syndrome. Acta Neurochir (Wien) 1991;112
(3–4):88–91.
31. KIMURA M, TANAKA A, YOSHINAGA S. Significance of periven-
tricular hemodynamics in normal pressure hydrocephalus.
Neurosurgery 1992;30(5):701–4; discussion 704–5.
32. WALDEMAR G, SCHMIDT JF, DELECLUSE F, ANDERSEN AR,
GJERRIS F, PAULSON OB. High resolution SPECT with [99mTc]-
d,l-HMPAO in normal pressure hydrocephalus before and
after shunt operation. J Neurol Neurosurg Psychiatry 1993;
56(6):655–64.
33. SHIMODA M, ODA S, SHIBATA M, MASUKO A, SATO O. Change in
regional cerebral blood flow following glycerol administra-
tion predicts. Clinical result from shunting in normal pressure
hydrocephalus. Acta Neurochir (Wien) 1994;129(3–4):
171–6.
34. MAEDER P, DE TRIBOLET N. Xenon CT measurement of cere-
bral blood flow in hydrocephalus. Childs Nerv Syst 1995;
11(7):388–91.
35. SHIH WJ, TASDEMIROGLU E. Reversible hypoperfusion of the
cerebral cortex in normal-pressure hydrocephalus on tech-
netium-99m-HMPAO brain SPECT images after shunt
operation. J Nucl Med 1995;36(3):470–3.
36. KRISTENSEN B, MALM J, FAGERLAND M et al. Regional cerebral
blood flow, white matter abnormalities, and cerebrospinal
fluid hydrodynamics in patients with idiopathic adult hydro-
cephalus syndrome. J Neurol Neurosurg Psychiatry
1996;60(3): 282–8.
37. NAKANO H, BANDOH K, MIYAOKA M, SATO K. Evaluation
of hydrocephalic periventricular radiolucency by dynamic
computed tomography and xenon-computed tomography.
Neurosurgery 1996;39(4):758–62; discussion 762–3.
38. COMONAGA M. Cerebral blood flow and autoregulation in
normal pressure hydrocephalus. Neurosurgery 1997;40(6):
1161–5; discussion 1165–7.
39. KLINGE PM, FISCHER J, BRINKER T et al. PET and CBF studies
of chronic hydrocephalus: a contribution to surgical indica-
tion and prognosis. J Neuroimaging 1998;8(4):205–9.
40. KLINGE PM, BERDING G, BRINKER T, KNAPP WH, SAMII M. A
positron emission tomography study of cerebrovascular res-
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
erve before and after shunt surgery in patients with idiopathic
chronic hydrocephalus. J Neurosurg 1999;91(4):605–9.
41. MATSUDA M, SHINO A, KITANO H, INUBUSHI T, HANDA J. Cere-
bral blood flow and N-acetylaspartate in patients with nor-
mal pressure hydrocephalus. J Cereb Blood Flow Metab
1999;19(Supplement 1):22.
42. BALL C, SACKETT D, PHILLIPS B, HAYNES B, STRAUS S. Levels of
evidence and grades of recommendations. In: NHS Research
& Development: Centre for Evidence Based Medicine; 1999.
43. WOZNIAK M, MCLONE DG, RAIMONDI AJ. Micro- and macro-
vascular changes as the direct cause of parenchymal destruc-
tion in congenital murine hydrocephalus. J Neurosurg 1975;
43(5):535–45.
44. JINDAL A, MAHAPATRA AK. Correlation of ventricular size and
transcranial Doppler findings before and after ventricular
peritoneal shunt in patients with hydrocephalus: prospective
study of 35 patients. J Neurol Neurosurg Psychiatry 1998;
65(2):269–71.
45. DEL BIGIO MR. Neuropathological changes caused by hydro-
cephalus. Acta Neuropathol (Berl) 1993;85(6):573–85.
46. AKAI K, UCHIGASAKI S, TANAKA U, KOMATSU A. Normal press-
ure hydrocephalus. Neuropathological study. Acta Pathol
Jpn 1987;37(1):97–110.
47. YAKOVLEV P. Paraplegias of hydrocephalus. Am J Men Def
1947;51:561–76.
48. PRICE TR, TUCKER GJ. Psychiatric and behavioral manifesta-
tions of normal pressure hydrocephalus. A case report and
brief review. J Nerv Ment Dis 1977;164(1):51–5.
49. FISHER CM. Hydrocephalus as a cause of disturbances of gait
in the elderly. Neurology 1982;32(12):1358–63.
50. FISHER CM. Hydrocephalus in walking problems of the
elderly. Trans Am Neurol Assoc 1980;105:29–33.
51. MESSERT B, HENKE T, LANGHEIM W. Syndrome of akinetic
mutism associated with obstructive hydrocephalus. Neuro-
logy 1966;16:635–49.
52. PENFIELD W, ELVIDGE A. Hydrocephalus and the atrophy of
cerebral compression. In: PENFIELD W, editor. Cytology and
cellular pathology of the nervous system. New York: P.S.
Hoebner, 1932;1201–17.
53. JAGUST WJ, FRIEDLAND RP, BUDINGER TF. Positron emission
tomography with [18F]fluorodeoxyglucose differentiates nor-
mal pressure hydrocephalus from Alzheimer-type dementia.
J Neurol Neurosurg Psychiatry 1985;48(11):1091–6.
54. GEORGE AE, DE LEON MJ, MILLER J et al. Positron emission
tomography of hydrocephalus. Metabolic effects of shunt
procedures. Acta Radiol Suppl 1986;369:435–9.
55. KAYE JA, GRADY CL, HAXBY JV, MOORE A, FRIEDLAND RP.
Plasticity in the aging brain. Reversibility of anatomic, meta-
bolic, and cognitive deficits in normal-pressure hydrocepha-
lus following shunt surgery. Arch Neurol 1990;47(12):
1336–41.
56. TEDESCHI E, HASSELBALCH SG, WALDEMAR G et al. Hetero-
geneous cerebral glucose metabolism in normal pressure
hydrocephalus. J Neurol Neurosurg Psychiatry 1995;59(6):
608–15.
57. SHUKLA D, SINGH BM, STROBOS RJ. Hypertensive cerebrovas-
cular disease and normal pressure hydrocephalus. Neurology
1980;30(9):998–1000.
58. CASMIRO M, D’ALESSANDRO R, CACCIATORE FM, DAIDONE R,
CALBUCCI F, LUGARESI E. Risk factors for the syndrome of
ventricular enlargement with gait apraxia (idiopathic normal
pressure hydrocephalus): a case–control study. J Neurol
Neurosurg Psychiatry 1989;52(7):847–52.
59. KRAUSS JK, REGEL JP, VACH W, DROSTE DW, BORREMANS JJ,
MERGNER T. Vascular risk factors and arteriosclerotic disease
in idiopathic normal-pressure hydrocephalus of the elderly.
Stroke 1996;27((1)):24–9.
60. KOTO A, ROSENBERG G, ZINGESSER LH, HOROUPIAN D,
341

Owler & Pickard
KATZMAN R. Syndrome of normal pressure hydrocephalus:
possible relation to hypertensive and arteriosclerotic vascu-
lopathy. J Neurol Neurosurg Psychiatry 1977;40(1):73–9.
61. HAIDRI NH, MODI SM. Normal pressure hydrocephalus and
hypertensive cerebrovascular disease. Dis Nerv Syst 1977;38
(11):918–21.
62. GESCHWIND N. The mechanism of normal pressure hydro-
cephalus. J Neurol Sci 1968;7(3):481–93.
63. EARNEST MP, FAHN S, KARP JH, ROWLAND LP. Normal press-
ure hydrocephalus and hypertensive cerebrovascular disease.
Arch Neurol 1974;31(4):262–6.
64. SHENKIN HA, GREENBERG J, BOUZARTH WF, GUTTERMAN P,
MORALES JO. Ventricular shunting for relief of senile symp-
toms. JAMA 1973;225(12):1486–9.
65. O’CONNELL JEA. Vascular factor in intracranial pressure and
maintenance of cerebro-spinal fluid circulation. Brain 1943;
66:204–55.
66. GODERSKY JC, GRAFF-RADFORD NR, YUH WT. Magnetic res-
onance imaging of patients with normal pressure hydro-
cephalus. Adv Neurol 1990;52:554.
67. DE LEEUW F-E, DE GROOT J, E A, OUDKERK M et al. Prevalence
of cerebral white matter lesions in elderly people: a
population based magnetic resonance imaging study. The
Rotterdam Scan Study. J Neurol, Neurosurg Psychiatry
2001;70:9–14.
68. AWAD I, JOHNSON P, SPETZLER R, HODAK J. Incidental sub-
cortical lesions identified on magnetic resonance imaging in
the elderly. II. Post-mortem pathological correlation. Stroke
1986;17:1090–7.
69. AWAD I, SPETZLER R, HODAK J, AWAD C, CAREY R. Incidental
subcortical lesions identified on magnetic resonance imaging
in the elderly. I. Correlation with age and cerebrovascular risk
factors. Stroke 1986;17:1084–9.
70. ROMÁN G. Senile dementia of the Binswanger type: a vascular
form of dementia in the elderly. JAMA 1987;258:1782–8.
342
16000404, 2001, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1034/j.1600-0404.2001.00092.x by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [22/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
71. GEORGE AE. Chronic communicating hydrocephalus and
periventricular white matter disease: a debate with regard to
cause and effect [comment]. AJNR Am J Neuroradiol 1991;
12(1):42–4.
72. ROMÁN GC. White matter lesions and normal-pressure
hydrocephalus: Binswanger disease or Hakim syndrome?
[comment]. AJNR Am J Neuroradiol 1991;12(1):40–1.
73. STUMP D, SIRES B, TOOLE J, MCHENRY LJ, MCWORTER J.
Regional cerebral blood flow, auto-regulations and normal
pressure hydrocephalus. Neurology 1983;33(Supplement 2):
182.
74. SCHMIDT JF, ALBECK M, GJERRIS F. The effect of nimodipine
on ICP and CBF in patients with normal- pressure hydro-
cephalus. Acta Neurochir (Wien) 1990;102(1–2):11–3.
75. SCHMIDT JF, ANDERSEN AR, PAULSON OB, GJERRIS F. Angio-
tensin converting enzyme inhibition, CBF autoregulation,
and ICP in patients with normal-pressure hydrocephalus.
Acta Neurochir (Wien) 1990;106(1–2):9–12.
76. LEE EJ, HUNG YC, CHANG CH, PAI MC, CHEN HH. Cerebral
blood flow velocity and vasomotor reactivity before and after
shunting surgery in patients with normal pressure hydro-
cephalus. Acta Neurochir (Wien) 1998;140(6):599–604; dis-
cussion 604–5.
77. CHANG C, KUWANA N, ITO S, IKEGAMI T. Impairment of cere-
brovascular reactivity to acetazolamide in patients with
normal pressure hydrocephalus. Nucl Med Commun
2000;21(2):139–41.
78. CZOSNYKA Z, CZOSNYKA M, COPEMAN J, SMIELEWSKI P, WHITE-
HOUSE H, PICKARD JD. Autoregulation in normal pressure
hydrocephalus. In: CZOSNYKA M, editor. ICP 2000; Cam-
bridge, UK; 2000.
79. CZOSNYKA Z, CZOSNYKA M, COPEMAN J et al. Autoregulation of
cerebral blood flow in patients with suspected normal press-
ure hydrocephalus. J Cereb Blood Flow Metab 1999;19
(Suppl 1):S635.