行政院國家科學委員會專題研究計畫 成果報告
常壓性水腦病人腦脊髓液中血管內皮生長素及胎盤生長素
於引流術前後之變化及其臨床意義
計畫類別： 個別型計畫 計畫編號： NSC93-2314-B-002-246- 執行期間： 93 年 08 月 01 日至 94 年 07 月 31 日 執行單位： 國立臺灣大學醫學院外科 計畫主持人： 杜永光 共同主持人： 廖漢文 計畫參與人員： 賴達明 報告類型： 精簡報告 報告附件： 出席國際會議研究心得報告及發表論文 處理方式： 本計畫可公開查詢中 華 民 國 95 年 3 月 8 日
Cerebral Ischemia and CSF Placenta Growth Factor or Vascular Endothelial Growth Factor in Idiopathic Normal Pressure Hydrocephalus Patients
Dar-Ming Lai 1,Yi-Ning Su2, Hung Li 4, Chien-Nan Lee 5,Fon-Jou Hsieh 7 , Yong-Kwang Tu 1
1
Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
2
Departments of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
3
Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan
4
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
5
Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
6
Department of Forensic Medicine, Medical Center, National Taiwan University, Taipei, Taiwan
7
Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
Address correspondence to Dr Tu, Division of Neurosurgery, Department of
Surgery,National Taiwan University, No. 7, Chung-San South Road, Taipei, Taiwan E-mail:
[email protected] tel:886-2-25078228; Fax 886-2-25078228
KEY WORDS: normal pressure hydrocephalus, cerebral ischemia, placenta growth factor,
Abstract
Ideopathic normal pressure hydrocephalus is a common disease causing dementia,
gait disturbance or incontinence. Cerebral ischemia at the periventricular region, aside
from cerebrospinal fluid stagnation, was found to be a major pathophysiologic factor.
Vascular endothelial cell growth factor and placenta growth factor was found to be
elevated in the ventricular cerebrospinal fluid. Material and Methods Correlation was
done on PlGF and VEGF with xenon-computed tomography study and albumin level
or age of the patients. Results PlGF and VEGF are linearly corellated. Excluding age
factor, ventricular PlGF was related to frontal part periventricular cerebral blood flow,
yet not with ventricular albumin level. Ventricular albumin level was inversely related
to the clinical good outcome after shunting (8 l vs 21μg/d). Conclusion Ongoing
periventricular ischemia is one of the major factors in pathogenesis of INPH and
ventricular PlGF can reflect that. However, stagnation of the cerebrospinal fluid
Introduction
Normal pressure hydrocephalus (NPH), first described by Hakim and Adams in 1965,
is often diagnosed based on symptomatic triad— gait disturbance, memory
impairment and incontinence[1, 2]. On the computed tomography (CT) or magnetic
resonance imaging (MRI) examination, NPH is characterized by disproportional
enlargement of all four ventricles and frequently periventricular lucency. Patients
receiving lumbar tap or ventricular tap usually show normal intracranial pressure.
NPH can be categorized into two types, one being idiopathic NPH (INPH) and the
other being NPH with known cause (after head injury, subarachnoid hemorrhage,
meningitis etc)[3]. Treatment of either type of NPH is frequently by
ventriculo-peritoneal shunt or sometimes third ventriculostomy[4]. The improvement
rate following shunting is about 59- 73% and the complication rate of shunting is
about 6-18%[4, 5]. The reason for low response rate comes from the nature of
inhomogeneiety of the patients suspected of having INPH, making it difficult to select
those who would most likely respond to shunting[5].
The pathophysiology of the NPH is thought to be two fold—decreased cerebrospinal
fluid (CSF) turnover or periventricular ischemia[6-10]. Concerning CSF
outflow by spinal infusion test[11]. CSF outflow resistance was different in groups of
patients who were responsive or nonresponsive to shunting, and patients with CSF
outflow resistance over 20 mmHg/ml/mins were all responsive to shunt surgery[12,
13]. On the other hand, demyelination of periventricular white matters with
microinfarcts and moderate to severe arteriosclerosis were found in patients with
normal pressure hydrocephalus[14]. Concerning cerebral blood flow study by MRI or
xenon-CT, NPH patients were found to show regional decrease of the cerebral blood
flow on the periventricular area (especially frontal) or dysfunction of vasomotor tone
after diazolamide infusion[6, 7, 9]. Whether ischemia induces ventriculomegaly or
CSF stagnation resulted in periventricular distortion or vasculoinsufficiency remained
unclear[15].
Vascular endothelial growth factor (VEGF) is a homodimeric angiogenic factor
ubiquitously expressing in the brain by choroid plexus, astroytes and neurons [16, 17].
In brain hypoxia and ischemia, VEGF expression is induced through transcriptional
activation of the hypoxia-inducing factor (HIF)-1 and HIF-2 [16, 18, 19]. Following
traumatic brain injury or cerebral ischemia, VEGF showed early elevation as early as
3 hours after ischemia through the heat responsive factor 1 (HIF-1)[20, 21] Placental
growth factor (PlGF), a VEGF family pro-angiogenic cytokine that act on VEGF
ischemia[20, 21]. In NPH patients, cerebrospinal fluid (CSF) VEGF has usually been
shown to be elevated; However, the role of PlGF on the NPH cases has never been
investigated[22, 23]. Since INPH is a ischemic cerebral disease it is very possible that
VEGF and PlGF will be elevated in these patients and can reflect the degree of
cerebral ischemia[24, 25].
CSF albumin, originally thought to reflect leakage of the blood brain barrier, is found
to be mainly indicative of changing CSF flow rate or changing CSF turnover[26-28].
Protein concentration in CSF not only is influenced by CSF-blood barrier, CSF
turnover, the origin that the substances are produced (blood, meninges or brain), but
also the site of the pathology and the place from which the CSF is sampled[25, 26,
29-31]. Since that the main patholoy site in NPH is in the periventricular white
matter, that CSF turnover (or CSF outflow obstruction) is slow and that no marked
BBB breakdown is found in NPH patients, thus CSF albumin should reflects mainly
outflow obstruction status. By correlation of preoperative ventricular CSF VEGF,
PlGF and albumin level on shunt outcome or Xenon-computed tomography (XCT)
cerebral blood flow study in INPH patients, we tried to understand the role of
angiogenesis cytokine and its clinical implication. We hypothesized that in patients
with INPH, CSF VEGF and PlGF could reflect periventricular ischemia. Yet in INPH
Material and Methods Study Group
This study was performed at the National Taiwan University Hospitalwith the
approval of the internal review board. Consecutive patients under the diagnosis of
idiopathic normal pressure hydrocephalus who received ventriculo-peritoneal shunt
were enrolledas the disease group in this study. Patients having history of major head
injury, central nervous system infection, prior cerebral hemorrhage or other known
causes that might cause hydrocephalus were excluded. Patients were also excluded
when they had major organ dysfunction or systemic infection. Because of the ethical
reason normal ventricular CSF were collected only from a small group of patients
who received cranial surgery for small benign intracranial pathology without
hydrocephalus on preoperative CT or MRI scan. These normal ventricular CSF were
collected after craniotomy and before major neurological surgery. In these patients
ventricular drainage was part of the surgical procedure to achieve brain slackness.
The indication for ventriculo-peritoneal shunt surgery in INPH patients was based on the presence of symptoms (gait disturbance, mental deterioration, urinary incontinence) compatible with disproportionate ventriculomegaly relative to sulcal widening on CT scan or MRI image. In five patients, the indication for surgery was strengthened by
facility limitation only Ninteen INPH patients received Xenon CT cerebral blood flow
examination before shunting procedure. All the INPH patients underwent medium
pressure shunting without anti-siphon devise. In addition, questionnaire regarding
modified Larson scale was recorded before and 6 months after shunting surgery.
Briefly, patients’ symptom was scored according to his gait: 0 = normal, 1 = insecure,
2 = insecure (cane), 3 = bimanual support, 4 = aided, 5 = wheelchair;
living
condition:
0 = independent, 1 = at home with assistance, 2 = retirement home, 3 =nursing home, 4 = hospital; or urinary symptoms: 0 = nil, 1 = present.
In our study, intracranial pressure was not taken into account because it added little
information and was beyond the scope of our theory. In addition, serum VEGF and
PlGF were not included because they showed little difference despite significant
elevation of CSF VEGF or PlGF in a variety of diseases in our pilot study (data not
shown).
Cerebral blood flow (CBF) study with Xenon-CT scanning
AllCBF studies were performed with a CT scanner (General Electric Medical
Systems, Milwaukee, WI)equipped with a stable xenon gas delivery system.
Xenon-CBF study was performed with mixture of 26% of Xe, 30% of O2 and 44% of
matter in each patient were calculated for cerebral blood flow. Weobtained sequential
CT images, while the patient inhaled30% stable xenon gas in oxygen for 3minutes
and underwent a clearance period of 5minutes. The CBF map was created from the
end-tidal build-up and tissue build-up of xenon measuredduring this time. The CBF
values for eachregion were computedas the average values of both sides. Afterthe
baseline CBF study, each patient received 1g of acetazolamide intravenously and a
second CBFstudy was conducted 20 minutes later.
Collection of CSF and PlGF, VEGF, Albumin Measurement
CSF was collected from the cerebral ventricles and centrifuged within 15 minutes of
collection. The first 2 ml CSF from ventricular drain tube was discarded then
following 4ml free of blood was collected. During ventricular tapping, The CSFwas
kept at –70°C until analysis by a technician whowas blinded to the patients' condition.
In control group, the CSF was collected during ventricular tapping (for achievement
of brain slackness during cranial surgery) before surgery on the pathology. The level
of PlGF and VEGF inthe CSF was assayed by a standardized sandwich
enzyme-linkedimmunosorbent assay method (R&D Systems, Minneapolis, MN)in
duplicate according to the manufacturer's protocol. The albumin level was measured
methods.
Data Analysis
Comparisons of PlGF or VEGF between INPH or control groups were performed by
Mann-Whitney rank sum test. The relationships between PlGF and age, CSF albumin,
improvement grade or cerebral blood flow were analyzed by linear logistic regression
or Mann-Whitneyrank sum test with the SPSS software. P < .05 was considered
Results
Patient characteristics
Forty-one patients entered our study group. Nine patients, who’s CSF were collected
from the ventricle for normal data had underlying disease being benign small
intracranial tumors (6), small metastatic tumor (1), or unruptured aneurysms (2). The
other 32 idiopathic normal pressure hydrocephalus patients were at their age ranged
from 36 to 83 years with median age being 69 years. There were 18 male and 14
females. Their symptoms range from 2 month to 7 years, with median being 16
months. Gait impairment was the major problem in 21 patients, memory impairment
in 9 patients, urinary symptoms in 1 patients and dizziness in 1 patient. After
ventriculo-peritoneal shunt, 25 patients improved (78%), while 18 patients (56%)
improved more than 2 points according to modified Larsons score. No shunt
complication (shunt infection, obstruction or intracerebral hemorrhage) was found in
the postoperative period. Demographic data were shown in table 1.
CSF PlGF and VEGF were elevated in patients with INPH
Normal people had their ventricular CSF VEGF at 23 to 113 with the median being 40,
INPH patients’ VEGF were significantly higher, CSF VEGF were 23 to 2079 with the
median being 25 (Fig.1 (b)); INPH patients’ PlGF were higher, at 11 to 221 with the
median being 73 (Fig.1 (a)). Both VEGF and PlGF were significantly higher in
patients with INPH than normal individuals (p<0.05).
Fig.1 Both VEGF and PlGF were significantly higher in patients with INPH than normal individuals (p<0.05).
(a) INPH patients’ PlGF were higher, at 11 to 221 with the median being 73. (b) CSF VEGF were 23 to 2079 with the median being 148.
PlGF level were related with age, cerebral blood flow, yet not with CSF albumin level
In INPH patients, a linear relation was found between VEGF or PlGF (fig. 2).
Considering possible causes for PlGF elevation, PlGF was related with age and
inversely related to the periventricular cerebral blood flow. Yet it was not related with
the CSF albumin level. VEGF, however, didn’t show relationship with either the CSF
Fig.2 In INPH patients, a linear relation was found between VEGF or PlGF.
Taking into account the age factor, CSF albumin are relating to shunt outcome
CSF albumin arose from the serum. Ventricular albumin elevation was thought to
caused by the stagnation of the CSF outflow. Taking into account the age factor, when
we assumed Larson’s grade improvement 2 scale as good outcome, the CSF albumin
level was inversely related to outcome (Fig 3). The patients with good outcome had
mean CSF albumin level at 8, yet patient with poor outcome had CSF albumin level at
21. Neither VEGF or PlGF was significantly related with the response to the shunt.
Fig.3 Taking into account the age factor, when we assumed Larson’s grade
improvement 2 scale as good outcome, the CSF albumin level was inversely related to outcome.
Discussion
INPH is a common disease occurred in patients at their 6th or 7th decade. Treatment
for INPH is by shunting with a variety of device including programmable shunt valve,
anti-siphon device, flow controlled device etc. The response rate is aboout 59-80%
and complication rate is about 18-36%[4, 5]. Our patients received shunt surgery at
medium age at 69 years, showed 78% responsive rate with no complication. Though
all patients received medium pressure shunt device without flow control or
programmable valve, our results were comparable with other reports[4, 5].
CSF VEGF and PlGF were significantly higher in our patients with INPH than control
samples (median 148 vs 40; and 73 vs 25; p<0.05). CSF VEGF obtained from spinal
tap has previously found to be higher in children hydrocephalus[22]. VEGF was also
elevated following cerebral ischema or in meningitis[25, 32]. Meanwhile, cerebral
PlGF was found to be elevated following cerebral ischemia[20]. Contrary to the early
response of VEGF following tissue ischemia, delayed elevation of PlGF mRNA was
detected by microarray analysis of rodent brain following experimental focal
ischemia-reperfusion[21]. The control group in our series includes patients with small
benign brain tumors or unruptured aneurysms who received brain surgery. All of these
9 patients had normal ventricular size, had no symptoms related to global cerebral
procedures. We therefore assume that these may represent normal ventricular CSF
data, instead of the lumbar punture samples. Our finding that CSF PlGF was higher in
INPH patient has never been reported yet.
CSF albumin can reflect hydrodynamics of the ventricular outflow. The CSF/serum
ratio of albumin, usually used as a marker for blood-CSF barrier function, is afftected
by CSF dynamics or flow pattern[29, 30]. Increase in the CSF albumin should come
from either blood-CSF barrier breakdown or decreased CSF flow[26, 27]. Different
from meningitis or Guillian-Barre syndrome that inflammation and blood brain barrier
breakdown were the major pathophysiologic finding, no major blood brain barrier
breakdown was detected in patients with INPH or aqueductal stenosis patients.
Therefore the major determinant for CSF albumin should be the local flow pattern or
global CSF absorption disturbance[28].
The pathophysiology of INPH remained inconclusive. It has be suggested that brain
distortion by ventriculomegaly, CSF stagnation with accumulation of toxic
metabolites or periventricular cerebral ischemia be the contributing factors[4, 15].
Elevation of CSF VEGF or PlGF may therefore be the consequence of either of these.
By correlation study on angiogenesis factors with cerebral blood flow or CSF
turnover related protein (CSF albumin), CSF VEGF and PlGF elevation be caused by
finding that age and frontal periventricular white matter blood flow was significantly
related to the CSF PlGF level suggested ischemic condition at the periventricular area
is a ongoing process. Because steady state decrease cerebral blood flow with
acompanying neuronal damage usually brought down the angiogenesis factor[21, 33,
34]. CSF PlGF not relating to CSF albumin level reflected that CSF flow disturbance
is not a major factor for PlGF elevation. CSF PlGF can therefore be used as indicator
for cerebral ischemia in patients with INPH.
Though a close and parallel realtionship between VEGF and PlGF was found. VEGF
was not significantly related to age, CSF albumin or cerebral blood flow in our series.
VEGF, a angiogenesis factor that was rapidly triggered by ischemic threat is also
elevated in inflammatory disorders, infection, surgery and even physical exercise[32,
35, 36]. VEGF response to ischemia or stress usually followed a rapid but highly
variated course[21]. In the brain VEGF also had other roles like neurotroprotective
effect or neurite outgrow promotion[37, 38]. Our data showed that VEGF presented at
wide range, 23-2079, this accounts for its limiting statistical analysis power.
Association of VEGF and PlGF, relationship of PlGF to periventricular blood flow
detected by Xenon computed tomography despite excluding age and CSF albumin
factor, elevation of CSF angiogenesis factor can be regarded as reflection of
Data derived from CSF samples taken from different regions can not be equally
judged. Samples are not only influenced by adjacent pathology but also CSF flow
disturbance or blood brain barrier changes. It was found that many brain or blood
derived proteins has gradients between ventricular samples or CSF taken by lumbar
puncture[25]. Even within the cerebrum, cisternal CSF or ventricular CSF samples
showed different data following subarachnoid hemorrhage. Since cerebral blood flow
decrease or water content increase in periventricular regions at MRI has been reported
to be correlated with symptom severity and adjacent axons distortion is the most
salient pathological findings, the ventricular CSF data should be best to represent the
pathophysiology of the INPH.
Albumin were found to be the factors relating to shunt outcome. When comparison
was made between patients who improved for more than 2 Larson’s score, albumin
was the sole factors that was inversely related to the patients medial term outcome (6
month). This is compatible with Tisell’s finding that ventricular CSF albumin was
inversely related to patients’ shunt outcome[39].This finding implies that CSF flow
disturbance may still be the main factor in INPH pathogenesis. Low pressure shunt
device has been found to be effective in cognitive recovery even for patients of
Alzheimer’s disease[40]. Better clearance of CSF galanin, a forebrain inhibitory
Periventricular ischemia was also an important pathophysiologic finding, yet less
predictive of shunt responsiveness.
Conclusion
VEGF and PlGF are elevated in ventricular CSF in INPH patients. They reflected
decrease of periventricular cerebral blood flow and possibly ischemia. Though
significant, the CSF albumin level is still the major determinant for shunt
.
Acknowledgements
This work was supported by grants from the National Science Council (NSC
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