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Springer Series in Translational Stroke Research
Min Lou · Jianmin Zhang · Yilong Wang

Yan Qu · Wuwei Feng · Xunming Ji
John H. Zhang Editors
Cerebral Venous
System in Acute
and Chronic
Brain Injuries
Series Editor
John Zhang
Loma Linda, CA, USA
More information about this series at http://www.springer.com/series/10064

Min Lou • Jianmin Zhang • Yilong Wang
Yan Qu • Wuwei Feng • Xunming Ji
John H. Zhang
Editors
Cerebral Venous System

in Acute and Chronic Brain
Injuries
Editors
Min Lou Jianmin Zhang
Department of Neurology Department of Neurosurgery
The Second Affiliated Hospital Second Affiliated Hospital, School
of School of Medicine of Medicine
Zhejiang University Zhejiang University
Hangzhou, China Hangzhou, Zhejiang, China
Yilong Wang Brain Research Institute

Beijing Tiantan Hospital Zhejiang University
Capital Medical University Hangzhou, China
Beijing, China
Collaborative Innovation Center for Brain
Wuwei Feng Science
Department of Neurology Zhejiang University
Medical University of South Carolina Hangzhou, Zhejiang, China
Charleston, SC, USA
Yan Qu
John H. Zhang Department of Neurosurgery
Department of Anesthesiology Tangdu Hospital
and Physiology PLA Air Force Medical University
Loma Linda University Xian, China
Loma Linda, CA, USA
Xunming Ji
Xuanwu Hospital Neurosurgery
Capital Medical University
Beijing, China
ISSN 2363-958X ISSN 2363-9598 (electronic)

ISBN 978-3-319-96052-4 ISBN 978-3-319-96053-1 (eBook)
https://doi.org/10.1007/978-3-319-96053-1
Library of Congress Control Number: 2018957835
© Springer International Publishing AG, part of Springer Nature 2019

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
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Contents
1 Neurovascular Network as Future Therapeutic Targets�� 1

Yujie Chen, Yang Zhang, Zhenni Guo, Ling Liu, Feng Gao,
Yanfeng Lv, Meng Zhang, Xiaochuan Sun, Andre Obenaus,
Yi Yang, Jiping Tang, Hua Feng, and John H. Zhang
2 Animal Models of Venous Stroke�� 49
Qin Hu and Anatol Manaenko
3 Imaging of Cerebral Vein in Acute Brain Injury�� 65
Xiaocheng Zhang and Min Lou
4 Cerebral Venous Regulation�� 87
Zhenni Guo, Hang Jin, Xin Sun, Lu-Sha Tong, John H. Zhang,
and Yi Yang
5 Cerebral Venous Collateral Circulation�� 103
Lu-Sha Tong, Yan-nan Yu, Jiping Tang, Min Lou, and John H. Zhang
6 Cerebral Venous System in Acute and Chronic Brain Injuries�� 119
Liang Liu and Qing-Wu Yang
7 Cerebral Venous System and Implications in Neurosurgery �� 129
Yongxin Zhang, Wanling Wen, and Qinghai Huang
8 Pediatric Cerebral Venous Sinus Thrombosis: More Questions
than Answers�� 141
Fazeel M. Siddiqui and Chirantan Banerjee
9 Idiopathic Intracranial Hypertension: A Venous Disease?�� 149
Alain Lekoubou and Wuwei Feng
10 The Role of Veins in Arteriovenous Malformation and Fistula,
Pathophysiology and Treatment �� 163
Yongxin Zhang and Qinghai Huang
v
vi Contents
11 Role of Cerebral Venous System in Hemorrhagic Stroke�� 173

Yan Qu, Lei Zhao, and Hao Guo
12 Role of Cerebral Venous System in Neurodegenerative Disorders�� 179
13 Role of Cerebral Venous System in Traumatic Brain Injury�� 187
14 Involvement of Cerebral Venous System in Ischemic Stroke�� 195
Lu-Sha Tong, Yan-nan Yu, Jiping Tang, Min Lou, and John H. Zhang
15 Spontaneous Thrombosis of the Main Draining Veins Revealing
an Unruptured Brain Arteriovenous Malformation�� 207
Feng Yan, Gao Chen, and Jianmin Zhang
16 Endovascular Treatment of Cerebral Venous Sinus Thrombosis:
A Literature Review�� 211
Liang Xu, Weilin Xu, and Jianmin Zhang
17 Functional Recovery After Cerebral Venous Thrombosis�� 221
Samir Belagaje and Wuwei Feng
18 Drug Therapy of Cerebral Venous Thrombosis�� 233
Yilong Wang
19 A Movement toward Precision Medicine in Acute Brain Injury:
The Role of the Cerebral Venous System�� 245
Jinqi Luo, Sheng Chen, Cesar Reis, and Jianmin Zhang
Chapter 1
Neurovascular Network as Future
Therapeutic Targets
Yujie Chen, Yang Zhang, Zhenni Guo, Ling Liu, Feng Gao, Yanfeng Lv,
Meng Zhang, Xiaochuan Sun, Andre Obenaus, Yi Yang, Jiping Tang,
Hua Feng, and John H. Zhang
Abstract In recent years, endovascular treatment, including pharmaceutical drugs

and intervention therapy, has become one of the most effective strategies for stroke
patients. However, neurobiological and neurovascular functions, before, during and
after endovascular therapy, have not been fully addressed and remain to be clarified.
It is extremely important for basic neurovascular scientists and clinicians to under-
stand the neurobiological and neurovascular fundamentals of neuroimaging
mismatches and the infarct size of stroke patients, hyperperfusion or hypoperfusion
after thrombolysis or thrombolectomy, and brain swelling and hemorrhage after
successful thrombolectomy. These clinical mismatches and complexities after
endovascular therapy are related to active tissue connections in the neurovascular
Author contributed equally with all other contributors.Yujie Chen and Yang Zhang
Y. Chen
Department of Neurosurgery, Southwest Hospital, Third Military Medical University,
Chongqing, China
Departments of Anesthesiology, Neurosurgery, Neurology and Physiology, Neuroscience
Research Center, Loma Linda University, Loma Linda, CA, USA
Department of Pediatrics, Loma Linda University, Loma Linda, CA, USA
Y. Zhang
Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University,
Chongqing, China
Z. Guo · Y. Yang
Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China
L. Liu
Department of Neurology, The People’s Hospital of Nanpi County, Nanpi, Hebei, China
F. Gao
Department of Interventional Neurology, Beijing Tiantan Hospital, Capital Medical
University, Beijing, China
© Springer International Publishing AG, part of Springer Nature 2019 1

M. Lou et al. (eds.), Cerebral Venous System in Acute and Chronic Brain
Injuries, Springer Series in Translational Stroke Research,
https://doi.org/10.1007/978-3-319-96053-1_1
2 Y. Chen et al.
network and the function of neurobiological and neurovascular components after

stroke. This comprehensive review summarizes the fundamental neurobiology and
neurovascular function in endovascular therapy for stroke patients, using both basic
science research and clinical studies, with a focus on cerebral hemodynamics, cell
energy metabolism, and neurovascular injuries such as brain swelling, hemorrhage or
over-reperfusion. A major emphasis is the potential role of cerebral collateral circu-
lation and venous circulation during and after endovascular therapy. It is clear that
the cerebral hemodynamic balance, venous function, and autoregulation are all
involved in endovascular therapy.
Keywords Neurovascular network · Cerebral veins · Stroke
Abbreviations
CBF Cerebral blood flow

CBF Cerebral blood flow
CFI Collateral flow index
CO2 Carbon dioxide
CPP Cerebral perfusion pressure
CT Computed tomography
CTA computed tomography angiography
CTP Computed tomography perfusion
CTV Computed tomography venography
Y. Lv
Department of Interventional Neurology, The First People’s Hospital of Shijiazhuang City,
Shijiazhuang, Hebei, China
M. Zhang
Department of Neurology, Daping Hospital, Third Military Medical University,
Chongqing, China
X. Sun
Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University,
Chongqing, China
A. Obenaus
J. Tang · J. H. Zhang (*)
Department of Anesthesiology and Physiology, Loma Linda University,
Loma Linda, CA, USA
H. Feng (*)
Department of Neurosurgery, Southwest Hospital, Third Military Medical University,
Chongqing, China
e-mail: fenghua8888@vip.163.com
1 Neurovascular Network as Future Therapeutic Targets 3
DSA Digital subtraction angiography

DVP Draining vein pressure
DWI Diffusion weighted imaging
ECD Echo color Doppler
EG Emptying gradient
ET Emptying time
FG Filling gradient
FLAIR Fluid-attenuated inversion recovery
fMUS Functional micro-ultrasound
FT Filling time
GOS Glasgow outcome scale
HBinF Head inflow
HBoutF Head outflow
MCAO Middle cerebral artery occlusion
MRA Magnetic resonance angiography
MRI Magnetic resonance imaging
MRV Magnetic resonance venography
NIHSS National Institutes of Health Stroke Scale
NO Nitric oxide
OPS Orthogonal polarized spectral
PDGF Platelet-derived growth factor
PDGF-BB Platelet-derived growth factor-BB
PPARγ Peroxisome proliferator-activated receptor-gamma
rCBF Relative cerebral blood flow
rCBV Relative cerebral blood volume
ROS Reactive oxygen species
rtPA Recombinant tissue plasminogen activator
RV Residual volume
SPECT Single photon emission computed tomography
SSS Superior sagittal sinus
SWI Susceptibility weighted imaging
VEGF Vascular endothelial growth factor
VV Venous volume
1 Introduction
Despite decades of efforts in basic and clinical research worldwide, stroke remains
an intractable disease associated with high morbidity and mortality. Since 1847,
R. Virchow’s observation that venous thrombi often migrate to the lungs and other
organs, which were subsequently named “embolism” and “thrombosis”, the origins
of ischemia, has altered our understanding of stroke [1, 2]. Since then, neurologists
started to emphasize the vascular cause of ischemic stroke and prevention in the
1950s, which was followed by the introduction of endovascular therapies in the
4 Y. Chen et al.
1980s and recombinant tissue plasminogen activator (rtPA) in the 1990s [3, 4].
These strategies tended to retard ischemia progression and to re-establish vascular
reperfusion. To date, these strategies remain at the frontline of early treatment after
stroke [5], partially due to failures related to clinical translational studies of neuro-
protective drugs based on the concept of neuroprotection to reduce infarction since
1980s [6].
Upon entering the twenty-first century, the concept of the neurovascular unit
presented by Lo del Zoppo and Iadecola et al., gained attention for the discovery of
novel strategies for stroke patients [7–9]. In this unit, neurologists attempted to
emphasize and protect connections among vulnerable neurons, simultaneously sup-
porting astrocytes and endothelial cells, not only to reduce infarction but also to
regenerate and reorganize the ischemic brain tissues after stroke [10, 11]. Thus, the
blood brain barrier, as the classical and most typical structure in the neurovascular
unit, has become the hot topic for stroke research [12]. However, additional cellular
populations and other structures are also present in the central nervous system, such
as microglia, pericytes and venules, among others, all of which influence the out-
comes of stroke patients [13–15]. Hence, the vascular neural network might provide
an advanced comprehension of the neurobiology of stroke, shedding new light on
the neurovascular network, reperfusion control and vein drainage during endovas-
cular therapies for stroke patients [16–18] (Fig. 1.1).
Fig. 1.1 History of stroke pathophysiology

As we have introduced, endovascular treatment, including pharmaceutical drugs

and intervention therapy, has become one of the most effective strategies for stroke
patients since the late twentieth century [19]. However, the neurobiological and
neurovascular functions before, during and after endovascular therapy have not
been fully addressed and remain to be clarified, which might unveil important
pathophysiologies related to clinical mismatches and complexities after endovascu-
lar therapy related to active tissue connections in the neurovascular network and the
functions of neurobiological and neurovascular components after stroke. Therefore,
in the present review, we will summarize the fundamental neurobiology and neuro-
vascular function in endovascular therapy for stroke patients, using both basic sci-
ence research and clinical studies focusing on cerebral hemodynamics, cell energy
metabolism, and neurovascular injuries such as brain swelling, hemorrhage or over-
reperfusion. A major emphasis of this review is the potential role of cerebral col-
lateral circulation and venous circulation during and after endovascular therapy.
2 he Mismatch Between Preclinical Models

T
and Clinical Types
Stroke can be divided into two main types: ischemic stroke due to lack of blood flow
and hemorrhagic stroke due to bleeding, with a subtype of subarachnoid hemor-
rhage by aneurysm rupture. Despite preventive strategies, current therapies include
intravenous thrombolysis and thrombectomy for ischemic stroke, emergent surgery
for hemorrhagic stroke, followed by monitoring and various neuroprotective treat-
ments for better outcomes [20–24]. Nevertheless, these strategies could alleviate
stroke patients at a certain level, but they supply unexpected and new problems for
the neurologist, such as cerebral hemodynamics, cell energy metabolism, as well as
neurovascular injuries such as brain swelling, hemorrhage transformation or
over-reperfusion.
Rethinking the critical reasons for these unsatisfactory outcomes and unexpected
problems in current therapies for stroke patients, we may want to know whether
previous research aims addressed the correct target and whether our research meth-
ods were appropriate. Like all disappointing experiments, the first and foremost
response is to go back to the basics, especially our preclinical models and to under-
stand the pathophysiology after stroke.
In recent years, the most popular stroke model is middle cerebral artery occlu-
sion (MCAO) in rodents, which is induced by nylon suture insertion into the unilat-
eral middle cerebral artery for 2 h, followed by suture withdrawal and recanalization.
Typically, this model causes a massive ischemic lesion in the rodent brain, similarly
to stroke patients at a certain level. Whether 2 h’ ischemia/reperfusion really
matches the clinical situation, or 1 h or 4 h or long of ischemia/reperfusion would
be optimal remains unknown. It is known that short-time ischemia might have a
neuroprotective effect and be considered an ischemic precondition, and long-term
6 Y. Chen et al.
ischemia might cause a large parenchymal lesion and hemorrhagic transformation.

Nevertheless, various types exist in the clinical setting, from transient ischemic
attack to longer term endovascular recanalization with over-perfusion, brain
swelling, hemorrhagic transformation, or non-perfusion.
2.1 Recanalization Leads to a Small Infarction
As suggested by the guidelines, if thrombolectomy is performed and the clot is

removed within 6 h after stroke onset, no infarction or a small infarction will be
detected in patients. However, after 2 h of MCAO, the large infarction observed in
rats does not match the clinical situation. For example (Fig. 1.2), a 70-year-old
female ischemic stroke patient was admitted 3 h after losing consciousness.
Immediate computed tomography angiography (CTA) indicated that her left inter-
nal carotid was occluded. Interventional surgery was performed, and the clot was
removed within the first hour after emergency administration. She then recovered
consciousness and muscle strength of the right limb back to level III. Head CT reex-
amination only showed a small infarction in the left hemisphere. In comparison to
the infarction at 2 h in the MCAO rodent model, the ischemic lesion in this patient
was much smaller. This is the first type of mismatch between the preclinical model
and the clinical type. Sometimes researchers have considered this phenomenon as a
species difference, but the precise difference is unknown.
2.2 Unsuccessful Recanalization Leads to a Small Infarction
However, a failed thrombolectomy or unsuccessful clot removal within 6 h after

stroke must also be addressed. Another 61-year-old male patient (Fig. 1.3) with a
history of smoking suffered from left limb paralysis and alalia for 5 h. Physical
examination indicated dysarthria, left facial paralysis, left arm muscle strength level
zero, left leg muscle strength level I, and National Institutes of Health Stroke Scale
(NIHSS) of 15 points. During surgery, digital subtraction angiography (DSA) indi-
cated stenosis in the proximal middle cerebral artery with thrombosis at the distal
end of this vessel. After thrombolectomy and balloon dilatation, DSA showed suc-
cessful recanalization. However, 5 min later, the artery occluded again. Clearly, this
patient experienced middle cerebral artery occlusion for a long time, greatly exceed-
ing the suggested recanalization time window. However, surprisingly, physical
examination at 24 h after surgery indicated clear consciousness, mild dysarthria, left
arm muscle strength level IV, left leg muscle strength level V, and NIHSS of 3
points. More importantly, the head computed tomography (CT) examination did not
reveal a large infarction. This phenomenon represents another type of mismatch
between the preclinical model and the clinical situation because unsuccessful
Fig. 1.2 Case I: recanalization leads to small infarction. A female ischemic stroke patient, 70-year-
old, was admitted at 3 h after conscious lost (a). Immediate digital subtraction angiography (DSA)
indicated her left internal carotid occluded (b). Interventional surgery was performed and the clot
was removed within the first hour after administration in emergency (c, d). After then, she recov-
ered consciousness and the muscle strength of right limb backed to level III. Head computed
tomography (CT) reexamination only showed small infraction in left hemisphere (e). Comparing
to the infarction in 2 h’ middle cerebral artery occlusion (MCAO) rodent model (f), the ischemic
lesion of this patient is much smaller
thrombolectomy/clot removal induced much smaller infarction than 2 h in the

MCAO rodent model. Furthermore, previous studies have indicated that the post-
stroke ischemic lesion in rodents automatically vanished after several months, even
in the absence of treatment. Whether this phenomenon can be classified as a species
difference or something else remains to be determined.
8 Y. Chen et al.
Fig. 1.3 Case II: unsuccessful recanalization leads to small infarction. Male patient, 61-year-old
with smoke history, suffered with left lime paralysis and alalia for 5 h. Physical examination indi-
cated dysarthria, left facial paralysis, left arm muscle strength level zero, left leg muscle strength
level I, and the National Institutes of Health Stroke Scale (NIHSS) is 15 point. During surgery, the
digital subtraction angiography (DSA) indicated the stenosis in the proximal of middle cerebral
artery with thrombosis in the far-end of this vessel (a, b). After thrombolectomy and balloon dilata-
tion, DSA showed successful recanalization (c). But 5 min later, the artery occluded again (d).
Clearly, this is a patient with middle cerebral artery occlusion for a long time, way beyond the
suggested recanalization time window. But, surprisingly, physical examination at 24 h after sur-
gery indicated clear consciousness, mild dysarthria, left arm muscle strength level IV, left leg
muscle strength level V, with 3 point on NIHSS. More importantly, the head computed tomography
(CT) examination did not show large infarction exist (e)
2.3 ecanalization Leads to Bleeding, Edema, and Massive

R
Infarction
Despite these two cases with surprisingly good outcomes, the following case may
attract a large amount of attention in our clinical practice. A 71-year-old male
patient (Fig. 1.4) suffered from right limb weakness and speech difficulty for 7 h.
Fig. 1.4 Case III: recanalization leads to bleeding, edema, massive infarction. Male patient,
71-year-old, suffered with right limb weakness and speaking difficulty for 7 h. Emergency com-
puted tomography (CT) showed no infarction at 4 h after stroke onset, and urikanase 60 k unit was
administrated intravenously. After admission, magnetic resonance imaging (MRI) indicated left
internal carotid artery occlusion and left basal ganglia infarction (a). digital subtraction angiogra-
phy (DSA) was performed and urikanase 30,000 unit was intraarterial injected for thrombolysis
(b, c). The left internal carotid artery recanalized (d), but unfortunately, left basal ganglia bleed at
2 h after urikanase administration (e), and this patient died at 23 h after stroke onset. Meanwhile,
the 2 h’ middle cerebral artery occlusion (MCAO) model failed to produce those pathologies, some
rodent model even followed with hemorrhagic transformation (f)
Emergency CT revealed no infarction at 4 h after stroke onset, and a 60-k unit of

urikanase was administered intravenously. After admission, magnetic resonance
imaging (MRI) indicated left internal carotid artery occlusion and left basal ganglia
infarction. DSA was performed, and 30,000 units of urikanase was injected intra-
arterially for thrombolysis. The left internal carotid artery was recanalized, but
unfortunately the left basal ganglia bled at 2 h after urikanase administration, and
the patient died at 23 h after stroke onset. Such a case may occur infrequently in the
clinic, but the reason for the occurrence of thrombolectomy or thrombolysis follow-
ing over perfusion, brain edema, hemorrhage or sometimes massive infarction
remains to be elucidated [25]. The 2-h MCAO model failed to produce those pathol-
ogies, and some rodent models even showed hemorrhagic transformation. As pro-
posed in our previous reviews and other studies, blood brain barrier disruption and
vasogenic edema may be the underlying cause of these events. However, the effects
of blood brain barrier disruption and vasogenic edema in this situation remain to be
described.
10 Y. Chen et al.
2.4 Vein Compression Involved in Reperfusion Injury
We usually focus on the arteries during the treatment of a stroke patient. However,
the following case indicates that changes occur in the cerebral venous system. An
80-year-old male patient (Fig. 1.5) suffered with aphasia and right limb paralysis for
3 h when he was transferred to the emergency room. The NIHSS was evaluated as
22 points, and rtPA was administered for 30 min without change. The head CT per-
fusion (CTP) indicated a cerebral blood volume lower than normal in the left tem-
poral lobe. CTA revealed left internal carotid artery occlusion, blood supply
compensation by the anterior communicating artery, and occlusion of the left mid-
dle cerebral artery. The neurologist made great efforts in the operating room, and the
occluded arteries finally recanalized at 10 h after stroke onset. Unfortunately, mas-
sive middle cerebral artery infarction occurred after recanalization. Magnetic reso-
nance angiography (MRA) at 16 h after surgery indicated much more abundant
vascular imaging of the left middle cerebral artery than the right side, while the
magnetic resonance susceptibility weighted imaging (SWI) indicated that ipsilateral
venous imaging was much weaker than the right side. The massive brain swelling
suggested that this patient needed decompression, but his family gave up. This
patient underwent a successful recanalization surgery but had a bad outcome. Why
the ipsilateral venous system collapsed after recanalization remains unknown. A
reasonable assumption is that the patient had venous infarction and subsequent
hemorrhagic transformation.
2.5 Infarction Is Reversible Even After Days
Traditional understanding treats stroke as a catastrophe due to unsatisfactory out-

comes of patients irrespective of treatment. However, a few fortunate patients, like
this 76-year-old female patient (Fig. 1.6) with a middle cerebral artery occlusion,
had a head CT showing no infarction on the first day. Thrombolectomy surgery was
successfully performed and clots retrieved, but the patient remained in a coma.
On day 7, head CT reexamination revealed a large low density, but this patient
Fig. 1.5 (continued) changed. The head CT perfusion (CTP) indicated cerebral blood volume
lower than normal at the left temporal lobe (a). Computed tomography angiography (CTA) showed
the left internal carotid artery occlusion, blood supply was compensated with anterior communi-
cating artery, and the left middle cerebral artery also occluded (b). Neurologist made great efforts
in operation room, and the occluded arteries finally recanalized at 10 h after stroke onset (c). But
unfortunately, the massive middle cerebral artery infarction occurred after recanalization (d).
Magnetic resonance angiography (MRA) at 16 h after surgery indicated vascular imaging of left
middle cerebral artery was much abundant than right side (e), while the magnetic resonance sus-
ceptibility weighted imaging (SWI) indicated the venous imaging of ipsilateral was much weaker
than right side (f). The massive brain swelling suggested this patient needed decompression, but
his family gave up
Fig. 1.5 Case IV: veins compression involved in reperfusion injury. Male patient, 80-year-old,
suffered with aphasia and right limb paralysis for 3 h when he was transferred to emergency room.
The NIHSS was evaluated at the level of 22 point, and rtPA was given for 30 min, but nothing
12 Y. Chen et al.
Fig. 1.6 Case V: infarction is reversible even after days. Female middle cerebral artery occlusion
patient, 76-year-old, head computed tomography (CT) showed no infarction at the first day (a, c).
Then thrombolectomy surgery was successfully performed and clots were retrieved (b, c), but the
patient was still in coma. On day 7, head CT reexamination showed large low density existed (d),
but this patient recover consciousness at day 12, then CT on day 14 showed the infraction area
significantly reduced (e) and the patient awaked with aphasia
recovered consciousness on day 12. The CT on day 14 showed a significantly

reduced infarction area, and the patient woke with aphasia. This may be similar
to the long-term outcomes observed in rodents, but the brain tissues were clearly
damaged during the first few hours after stroke onset. Thus, we must determine how
to repeat this favorable outcome.
3 stablishment of New Stroke Pathophysiology to Address

E
Clinical Issues
Based on the above cases in clinical practice, we might wonder why these preclini-
cal models did not match and mimic the actual clinical manifestations. Perhaps
other pathophysiologies were missed.
3.1 mphasis on Recirculation: Both Arterial and Venous

E
Blood Flow
Since the seventeen century, stroke, known previously as cerebral apoplexy, was
identified as a major cerebral vascular disorder by Johann Jacob Wepfer [26].
Subsequently in the late eighteen century, Rudolf Virchow defined the pathophysi-
ology of apoplexy as mechanical blood clots that interrupt the blood flow to the
brain [27]. Stroke therapy then passed through the time of blood factors and vascu-
lar risk factors, entering the time of neuroprotection [26, 28]. However, large clini-
cal trials investigating neuroprotection soon followed but quickly failed due to the
difficulty protecting neurons despite ongoing vascular occlusion [6]. This unex-
pected failure at the clinical level gave rise to two notable events—the use of tPA to
recanalize the vessel, and the conceptual change from neuroprotection to neurovas-
cular protection after the early twenty-first century [17, 18, 29–31]. A neurovascular
unit takes our understanding of stroke a step further than simply neuroprotection,
which focuses more on neuronal cells but is a step short of upstream arteries/arteri-
oles and especially veins/venules, in which smooth muscle cells, pericytes, and vas-
cular endothelial cells play much more important roles in the control of vascular
tone, influence capillaries, and in particular clear the venous blood. Thus, a new
concept is beginning to take shape regarding stroke pathophysiology—the notion
that the vascular neural network may in fact be at the center stage of the entire
pathology [17, 18].
Basic Rules for Recirculation (Fig. 1.7)
One of the key issues related to the vascular neural network is that arterial and
venous blood flow must be in harmony during circulation. During normal cerebral
circulation, cerebral autoregulation prevents and protects the brain from over-flow-
induced injury. When the blood flow increases, cerebral arteries contract to prevent
excessive blood flow into the brain parenchyma, and when blood flow decreases,
cerebral arteries dilate to allow more blood into the brain, maintaining constant total
blood flow to the brain [32]. This same principle may apply to the relationship
between arterial and venous flows, and the blood entering the brain from the arterial
system is matched with the amount of blood exiting the brain via the venous system.
In this relationship, veins seem to play a more vital role than arteries in the mainte-
nance of brain blood flow physiology and brain function. Decreases in venous flow
and greater venous pressure exceeding the cerebrospinal fluid pressure cause venous
dilation and leakage of venules and capillaries, which enhances cerebrospinal fluid
pressure, reduces arterial flow and produces a vicious cycle. Reduced arterial flow
will form another vicious cycle that the body responds to by increasing blood pres-
sure and dilating arteries, increasing the brain volume and the intracerebral pres-
sure. These two vicious cycles are the basic principles of Starling Resistor Theory,
which emphasizes that venous pressure is the key for the cerebral blood supply [33].
14 Y. Chen et al.
Fig. 1.7 Diagrams for the rules of recirculation. The first and foremost rule is arterial and venous
blood flow needs to be in harmony during circulation. In normal state and compensated state,
cerebral autoregulation prevents and protects the brain from over-flow induced injury. However, in
decompensated state, the venous flow decreased and venous pressure is larger than cerebrospinal
fluid pressure, causing venous dilation and leakage of venules and capillaries which enhances
cerebrospinal fluid pressure, reduces arterial flow and produces a vicious cycle. Reduced arterial
flow will form another vicious cycle, that body responds by increase blood pressure and dilation of
arteries, increases brain volume, and increases intracerebral pressure. That is why we should exam-
ine both arterial perfusion and venous drainage before endovascular treatment. If we improved the
venous drainage at this critical moment, the arterial and venous flow may restore to hemostasis and
recirculation, and the patients could be really protected after stroke
An acute reduction of cerebral ischemia, but if the arterial flow remains but venous
flow decreases acutely by 20%, blood will subsequently accumulate in the capillary
system and lead to brain swelling [34] and an increase in intracranial pressure that
causes hyperemia [35, 36], a flow decrease to no-flow [36, 37], and even capillary
hemorrhage [35].
Anatomy of the Cerebral Venous System
The cerebral venous system contains sinuses, veins and venules of the brain and can
be divided into the superficial venous system and the deep venous system. The
superficial system comprises sagittal sinuses and cortical veins, which drain the
superficial surfaces of both cerebral hemispheres. They are interlinked with anasto-
motic veins of Trolard and Labbé. Thus, the superolateral surface of the hemisphere
drains into the superior sagittal sinus, while the posteroinferior aspect drains into the
transverse sinus. The deep system consists of the lateral sinus, straight sinus and
sigmoid sinus, along with the draining deeper cortical veins. The entire deep venous
system is drained by internal cerebral and basal veins, which join to form the great
vein of Galen that drains into the straight sinus. Both of these systems mostly drain
into internal jugular veins [38–40]. Moreover, the venous valves that prevent the
backflow of venous blood have not been described for cerebral veins [39]. Thus,
increases in central venous pressure or intracranial venous pressure could easily
retroinfluence the hydrostatic pressure of upstream veins and venules and the blood
outflow. For example, the enormous pressures generated by power athletes during
weightlifting leads to elevations in intracerebral pressure which obstruct venous out-
flow leading to conjunctival hemorrhage and elevations in intra-ocular pressure [41].
The entire cerebral venous system is surrounded by adrenergic nerve fibers [42].
However, in contrast to arteries, venules and most cerebral veins do not have smooth
muscle cells. Instead, postcapillary venules are covered with pericytes [43], while
collecting venules contain stellate periendothelial cells that form a basket-like net-
work around the vessel wall. As the size of the venous vessels increases, even in
superficial cerebral veins, no smooth muscle cells are recognizable [44]. Thus,
small veins or at least venules cannot contract strongly like arteries, but only mildly
change the diameter of the vessels due to pressure changes related to this physiolog-
ical condition [45] (Table 1.1). Although large capacitance veins are covered with
smooth muscle cells, their diameter still mainly depends on the venous pressure
because only a few vasoactive agents have the ability to contract them (Table 1.1).
Under pathological conditions, the contraction might be attributed to three interwo-
ven factors after brain injury. (1) External compression by edema due to blood brain
barrier disruption, swollen astrocyte endfeet [77, 78] and adherent leukocytes
Table 1.1 Possible agents implicated in the contraction of pericytes and smooth muscle cells in
the cerebral venous system
Contraction Dilation
Pericyte ROS [46] Angiotensin II [47–50] NO [51, 46]
K+ [52] VEGF (initial phase) [53] VEGF (follow-up phase) [53]
VEGF (initial phase) [53] VEGF (follow-up phase) [53]
Ca2+ [52] Lipopolysaccharide [54] Adenosine [55]
RhoA [56] Bradykinin [55] CO2 [57, 58]
Acetylcholine [59, 60] Serotonin [61, 55] Isoproterenol [61]
Noradrenaline [59] IL-2 [62]
Lactate [63] Endothelin 1 [64, 65]
Glucose [66, 67] (loss of Histamine [68, 50]
contractibility)
Smooth Endothelin-1 [69] (less NO [71] (but lack of NO
muscle potent [70]) (less potent synthase NO [71] (but lack of
cell [70]) NO synthase [72])
Noradrenaline [73] Histamine [74] (in dog, not
human [75])
Neuropeptide Y (less
potent) [76] Neuropeptide
Y (less potent) [76]
16 Y. Chen et al.
surrounded by other cellular aggregates consisting of fibrin and platelets [79–83].

(2) Active constriction mostly due to pericyte contraction [46, 84] (Table 1.1). (3)
Vessel lumina filled with entrapped and aggregated erythrocytes, leukocytes, and
fibrin-platelet deposits [78, 80, 81, 85–88].
Venous Flow During Ischemic Stroke
In ischemic stroke patients, blood flow instantly reduces because different kinds of
clots block artery lead to brain parenchyma infraction. In the central core regions of
the insult, there is almost total cerebral blood flow (CBF) arrest. This area evolves
rapidly toward death within minutes. Surrounding this core, CBF levels may fall
below functional thresholds yet transiently lie above the threshold of cell death—
this zone has been called the penumbra [89]. Unfortunately, edema usually appears
in penumbra [90], which leads to increased intracranial pressure. In patients with
ischemic stroke, blood flow is instantly reduced because different types of clots
blocking the artery lead to infarction of the brain parenchyma. In the central core
regions of the insult, there is almost total cerebral blood flow (CBF) arrest. This area
evolves rapidly toward death within minutes. Surrounding this core, CBF levels
may fall below functional thresholds yet transiently lie above the threshold of cell
death; this zone has been called the penumbra [89]. Unfortunately, edema usually
appears in penumbra [90], leading to increased intracranial pressure [91], secreted
cytokines and chemokines by dying neurons, glia cells [92]. This could cause endo-
thelium dysfunction of cerebral venous system and the secretion of cytokines and
chemokines by dying neurons and glial cells [92]. This process could cause endo-
thelial dysfunction of the cerebral venous system [92, 93], which is the initial factor
in secondary inflammation and death cascades. Blood brain barrier disruption then
causes more damage and forms a vicious cycle [91, 94].
However, injury to the cerebral tissue and veins are usually accomplished with
platelet aggregation [93] and thrombosis [95, 96]. A thrombus in the cerebral sinus
can cause an increase in intracranial pressure [97], while in cerebral veins, it could
lead to venous infarction and brain swelling [98]; even a solitary microthrombus in
a venule could lead to infarction followed by cognitive deficits [99]. Furthermore,
the reduced venous outflow due to the thrombus and increased intracranial pressure
may jeopardize the cerebral perfusion pressure regardless of artery recanalization
[34, 84]. This may be one of the key factors underlying the ‘no-flow’ phenomenon
[37, 100, 101] in patients with ischemic stroke.
Venous Flow During Intracranial Hemorrhage
Intracranial hemorrhage is the second most common cause of stroke, initiating with
brain parenchyma bleeding and hematoma growth, despite direct incentives [102].
Because intracerebral hemorrhage has been considered an arterial hemorrhagic
brain injury, little attention has been focused on the role of cerebral veins or venules
in its pathophysiology [102, 103]. However, during the acute phase of intracerebral
hemorrhage, a rapid increase in intracranial pressure due to hematoma formation
could cause autoregulation failure and reduced cerebral perfusion pressure [104].
Consequently, the guidelines suggest controlled blood pressure lowering treatment
rather than aggressive blood pressure lowering, to maintain the cerebral blood flow
[105]. Moreover, recent studies have described new ischemic lesions coexisting
with acute intracerebral hemorrhage [106–110], suggesting the possible involve-
ment of small vessel pathogenesis [106, 107].
The main secondary brain injury after intracerebral hemorrhage is thought to be
three intertwined degenerative cascades adjacent to the hematoma [111], including
inflammation [112], red cell lysis and iron deposition [102, 113], and thrombin
production [102, 113]. Moreover, in addition to the ischemic lesions near the
hematoma, some remote ischemic lesions have also been found [104]. Similar to
the ischemic brain injury reviewed above, all of these pathophysiological factors
could directly and indirectly cause cerebral venule endothelial dysfunction, micro-
thrombus formation and eventual out-flow reduction. Combined with other patho-
physiological mechanisms, such as oxidative stress and apoptosis, among others,
these factors could also lead to blood brain barrier disruption, brain edema, and
hydrocephalus, further increasing the intracranial pressure and initiating a vicious
cycle [111]. However, most intracranial hemorrhages occur in hypertensive
patients, the hypertensive vasculopathy, and arteries/arterioles and veins/venules
can cause a ‘stroke-prone state’ to lower the threshold threshold [104] and out-flow
dysfunction [114].
Venous Flow During Subarachnoid Hemorrhage
Subarachnoid hemorrhage is a special subtype of intracranial hemorrhage, caused

by bleeding into the subarachnoid hemorrhage. For a long time, cerebral vasospasm
has been considered the classic cause of delayed neurological deterioration after
aneurysmal subarachnoid hemorrhage, leading to cerebral ischemia and infarction
and thus to a poor outcome and occasionally death [115, 116]. However, recent
clinical trials have demonstrated marked prevention of vasospasm with the endothe-
lin receptor antagonist Clazosentan, yet the patient outcome did not improve [117,
118]. These disappointing results reminded researchers to refocus their strategy
during early brain injury [119–121], but this concept is limited to neurons and over-
looks the functions of other cell types. Fortunately, recent evolving concepts, such
as the neurovascular unit [122], vascular neural network [17, 18] and vasculo-
neuronal-glial triad model [123], have noted the contributions of cerebral microcir-
culation. However, they all maintain cerebral veins and venules at a distance.
Rethinking the failed Clazosentan clinical trials, there may be a missing factor
compared with arteries such as endothelin, which has less potent constrictor abilities
in cerebral veins [70], which means [70]. Thus, the powerful endothelin receptor
antagonist Clazosentan may not alleviate the ‘vasospasm’ in the cerebral venous
system after subarachnoid hemorrhage. Moreover, Clazosentan did not prevent the
18 Y. Chen et al.
formation of microthrombi [124]. Recent studies have also demonstrated vasospasm

in deep cerebral veins after subarachnoid hemorrhage [125], with a significant
decrease in diameter at 1 day and a peak at 5–7 days after subarachnoid hemorrhage
[17, 18]. Whether the diameter of cerebral venules decreases after subarachnoid
hemorrhage remains controversial [126–129]. In addition, subarachnoid hemor-
rhage elicited time- and size-dependent increases in rolling and adherent platelets
and leukocytes in cerebral venules [130], leading to microthrombi and microvascu-
lar stasis [126, 131]. Similarly to other brain injuries, subarachnoid hemorrhage can
also cause brain edema [123, 132, 133] and hydrocephalus [134, 135] followed by
cerebral hypoperfusion [136], as reviewed above.
Cerebral venous thrombosis [137–140] or stenosis [141] is also an uncommon
etiology of subarachnoid hemorrhage, most of which are perimesencephalic sub-
arachnoid hemorrhage [142–144]. Potential causes may be an elevated intracranial
venous pressure or mechanical swelling of the intracranial venous system, leading
to variant cerebral venous drainage [145–149], arteriovenous malformation [150],
and eventually vein or venule breakdown [136, 139, 151]. In these patients, increased
intracranial pressure forced blood into the subarachnoid space and along the optic
nerve sheath into the pre-retinal space, or decrease in venous return to the cavernous
sinus or obstruct the retinochoroidal anastomoses and central retinal vein, culminat-
ing in venous stasis and hemorrhage, then exhibit Terson Syndrome at eyes
[152–155].
Venous Flow During Traumatic Brain Injury
Traumatic brain injury is defined as impact, penetration or rapid movement of the

brain within the skull that results in an altered mental state [156]. It comprises two
injuries: primary and secondary injuries [157–160]. The primary injury occurs
simultaneously with the impact that caused the injury, which explains why this
injury is not amenable to acute intervention. This stage of cerebral injury is charac-
terized by direct tissue damage and impaired regulation of the CBF and metabolism.
Previous studies have shown that cortical CBF significantly decreases after the pre-
liminary stroke [161–163]. During this phase, when CBF does not meet the cerebral
metabolic needs of the tissue, this uncoupling can initiate interwoven pathophysio-
logical responses leading to delayed, non-mechanical impairment of neuronal struc-
ture and function.
Early after head trauma, the blood brain barrier breaks down due to direct and
indirect causes, resulting in a biphasic response [164]. There is a rapid endothelial
disruption and swelling of perivascular astrocytes near the sites of the traumatic
core, possibly correlated with transient disruption of the blood-brain barrier leading
to cerebral edema [164, 165] followed by morphological changes in the endothe-
lium of all vessels that are most marked in arterioles and venules [164], especially
venules leading to macroscopic secondary petechial hemorrhage [166, 167].
However, the early breakdown of the blood brain barrier is not correlated with leu-
kocyte adhesion [168]. Similarly to other brain injuries, edema can also lead to a
vicious cycle of brain edema between increased cerebral venous pressure and
increased ICP [91]. Additionally, endocrine dysfunction may also aggravate this
cycle by altering the variant cytokines associated with the hemodynamic changes
[169–171].
Another major secondary insult after traumatic brain injury is the microthrom-
bus, which forms in arterioles and venules of all sizes [172]. A recent study demon-
strated that microthrombi occluded up to 70% of venules and 33% of arterioles,
suggesting that the immediate post-traumatic decrease in cerebral blood flow is not
caused by arteriolar vasoconstriction but by platelet activation and the subsequent
formation of thrombi in the cerebral microcirculation [173]. This phenomenon
may be a consequence of the observation of leukocyte-platelet aggression only in
cerebral venules [173].
ecirculation as an Emerging Understanding of Stroke and Other Acute

R
Brain Injuries
Taken together, we believe that the cerebral venous system plays an important role
in the pathophysiology of brain injury. In extreme pathophysiological conditions
such as traumatic brain injury, neurodegenerative diseases, intracerebral or sub-
arachnoid hemorrhages, and cerebral ischemic patients with diabetes or hyperten-
sion, different types of direct or indirect injuries could cause cerebral venous
endothelial dysfunction and then trigger a series of interwoven secondary pathways
such as thrombosis, blood brain barrier disruption, and inflammation, among others.
Together with acute cerebral vascular autoregulation failure after brain injury, these
pathophysiological changes eventually lead to recirculation characterized by post-
capillary venule, vein and sinus stenosis or vasoconstriction, increased cerebral
venous pressure, cerebral venous reflux or steal. Recirculation ultimately reduces
the cerebral blood flow, further activating the detrimental pathophysiological mech-
anisms and then enhancing the brain injury.
Based on the close relationship between the cerebral venous system and brain
injury, we propose cerebral recirculation as a new concept that is one step closer to
the original concept of the vascular neural network based on an emerging under-
standing of the important roles of the cerebral venous system in the pathophysiology
of brain injury. The physical components of recirculation also include post-capillary
venules, small veins, sinuses and large extracranial drainage veins. The recircula-
tion, therefore, expands the concept of the vascular neural network and other patho-
physiology theories to focus on the potentially important functional roles of the
cerebral venous system during initial brain injury, evolution and outcome.
In our opinion, the concept of recirculation improves upon the vascular neural
network model of brain injury pathophysiology because most brain injury events
affect and are affected by the cerebral venous system that is not included in the
vascular neural network, excluding postcapillary venules and small veins. As a con-
sequence of cerebral blood flow autoregulation, slightly reduced damage in the
cerebral venous system does not immediately cause clinically evident brain injury,
20 Y. Chen et al.
but it could be considered as a unique underlying disease. Once this fragile balance
is broken, the arterial brain injury will be exposed to the formidable force of the
cerebral venous system. The brain needs the energy provided by normal blood flow
and its disposal of metabolic waste, not just stagnant arterial blood.
According to the concept of the vascular neural network, one of the key features
of the pathophysiology of brain injury is the potential for therapeutic targeting to
promote reperfusion [17, 18]. Clearly, our missing factor of previous treatment, the
recirculation, is another key feature of reperfusion. Considering the events after
brain injury, recirculation might be more appropriate as another essential feature of
the vascular neural network model for analysis of the pathophysiology of different
types of brain injury. Like the cerebral arterial system, veins also play a key role in
ischemic and hemorrhagic stroke, neurodegenerative diseases, multiple sclerosis,
leukoaraiosis [174], and brain surgery [175–177]. As described above, current vas-
cular recanalization treatments and neuroprotective treatments are not fully satisfied
by researchers, doctors and patients. Cerebral recirculation is, therefore, a useful
integrated model that is relevant to brain injuries involving both sides of the cerebral
vasculature.
3.2 Define Venous Function after Acute Arterial Stroke
Since the cerebral venous system also defines the course of stroke progression, we
might wonder when and how to exam venous functions during the rapid pathophysi-
ological changes that occur after stroke, which could provide useful information
and guide treatment.
Situations to Evaluate Venous Function
First and foremost, during cerebral ischemia with massive brain infarction, some-
times with early malignant brain edema, the neurologist should pay more attention
to the venous function prior to endovascular treatment. As discussed in section
“Anatomy of Cerebral Venous System”, the cerebral venous system lacks smooth
muscle cells and cannot resist compression by malignant brain edema. The venous
system will collapse, and the drainage will significantly decline or even shut down.
In 2009, Yu et al. retrospectively analyzed 14 consecutive patients with large middle
cerebral artery infarction and images of the cerebral venous system [34]. They
found that 80% of the patients suffered from abnormal ipsilateral cranial venous
drainage within 48 h after the clinical signs of fatal brain edema and transtentorial
herniation, and 100% of the patients exhibited a drainage deficit at day 5. The oth-
ers, without malignant infarction and fatal edema, all exhibited ipsilateral dominant
or symmetrical bilateral venous drainage, which may be more compensational
under the condition of increasing intracranial pressure.
Second, when patients with subarachnoid hemorrhage have clinical signs of

increased intracranial pressure, with or without severe brain edema, the venous
drainage function should be evaluated before anti-vasospasm treatment or triple H
therapy. In a well-known clinical observation conducted in 2003 [129], Uhl et al.
analyzed capillary density by orthogonal polarization spectral imaging in patients
with subarachnoid hemorrhage, and they found that the microvessels were com-
pressed by brain swelling and microthrombosis after aneurysm rupture. However,
after decompression and clipping to reduce intracranial pressure, they did not
observe significant changes in the arterioles, but the blood flow in the venules
increased almost 70%. These microcirculatory changes cannot be detected by tradi-
tional angiography or transcranial Doppler sonography, but they may play a pivotal
role in the clinical outcome after surgery [129]. Another case reported by Ryu et al.
in 2011 [178], described a 40-year-old female subarachnoid hemorrhage patient
with severe vasospasm in the middle cerebral artery. After symptoms of the vaso-
spasm were alleviated by intra-arterial nimodipine infusion, MR diffusion-weighted
imaging (DWI) detected a small, acute ischemic lesion in the ipsilateral basal gan-
glia and diffuse vasogenic edema in the colocalized area. This might be a typical
situation according to the Starling Resistor Theory, as we review in section “Basic
Rules for Recirculation”, indicating that possible decreases in venous flow lead to
reduced arterial flow and artery dilation-induced increases in brain volume and
intracranial pressure to form a vicious cycle. In addition, the loss of autoregulation
in smooth muscle cells of arteries and reperfusion injury could impair the blood
brain barrier, which was another cause of vasogenic edema. Therefore, in this case,
a pre-evaluation of venous function was necessary prior to anti-vasospasm
treatment.
In section “Anatomy of Cerebral Venous System”, we summarize the vasodila-
tors used for pericytes and smooth muscle cells. Clearly, the veins are not sensitive
to these factors. Therefore, before administering vasodilators to patients to increase
cerebral perfusion, cerebral venous function should be considered because the vaso-
dilators may dilate smooth muscle cells in arteries but not veins. By employing this
concept, Dr. Xiaochuan Sun in our group successfully treated the brain edema in a
patient with subarachnoid hemorrhage after clipping surgery (Fig. 1.8). This patient
suffered from aneurysm rupture and subarachnoid hemorrhage, emergency clipping
surgery was performed, and nimodipine 10 mg was administered intravenously for
the first 3 days at a rate of every 8 h to prevent vasospasm, which is the classical and
currently most frequently used treatment. The patient recovered from somnolence
to consciousness on day 3 after surgery. However, unfortunately, she worsened and
became comatose with mydriasis after only 24 h. The head CT revealed a left frontal
parietal subdural hematoma and massive brain swelling. At this critical moment, we
considered the veins, and the computed tomography venography (CTV) on day 5
showed ipsilateral transverse sinuses hypoplasia and a straight sinus diameter of
only 1.1 mm. Therefore, we stopped nimodipine and administered mannitol and
furosemide. On day 7, the patient came out of the coma, and the head CT indicated
a third ventricle reoccurrence and significantly decreased brain swelling, which
eventually disappeared by day 10. The straight sinus diameter dilated to 1.9 mm on
22 Y. Chen et al.
Fig. 1.8 Case VI: combined factors for the venous drainage. This patient suffered with aneurysm
rupture and subarachnoid hemorrhage, emergency clipping surgery was performed and nimodipine
10 mg was given intravenously for first 3 days at the rate of every 8 h to prevent vasospasm, which
is the classical and most used treatment nowadays. And she did recover from somnolence to con-
scious at day 3 after surgery. However, unfortunately, she got worse and went coma with mydriasis
only 24 h later, head computed tomography (CT) showed left frontal parietal subdural hematoma
and massive brain swelling (a). The computed tomography venography (CTV) at day 5 showed
ipsilateral transverse sinuses hypoplasia and the straight sinus diameter is only 1.1 mm (c).
Therefore, we stopped nimodipine and gave mannitol and furosemide instead. At day 7, the patient
got out of coma, and head CT indicated the third ventricle reoccurred and brain swelling signifi-
cantly decreased (b), then eventually gone by day 10. The straight sinus diameter dilated to 1.9 mm
at 14 days after surgery (d), and Glasgow Outcome Scale (GOS) was evaluated at the level of 5
points, patient was then discharged from hospital. Three month after surgery, she fully recovered
and CTV reexamination showed the straight sinus diameter is 4.5 mm this time (e)
day 14 after surgery, the Glasgow Outcome Scale (GOS) was evaluated at the level
of 5 points, and the patient was then discharged from the hospital. Three months
after surgery, she fully recovered, and CTV reexamination revealed a straight sinus
diameter of 4.5 mm.
During acute central nervous system injuries such as intracerebral hemorrhage,
subarachnoid hemorrhage, and traumatic brain injury, with elevated intracranial
pressure and brain edema, greater attention should be focused on the venous
Vessel Length (% ipsi/contra)

400
300
200
100
0
Sham 1d 3d d
Fig. 1.9 Evaluations of cerebral venous system in acute brain injuries. (a) Representative 7 T
magnetic resonance imaging (MRI) image for normal human brain. (b) Representative 1.5 T MRI
image for the brain of stroke patient. (c) Statistical analysis of the vessel length (%, ipsilateral vs.
contralateral hemisphere) in the brain of traumatic brain injury patients for 1, 3, 7 days. N = 5, Data
was presented as Mean ± SEM, * vs Sham group, P < 0.05. (d) Representative image of vessel
painting for the brain in rats. (e) Representative image of vessel painting for the brain in subarach-
noid hemorrhage (SAH) rats. The veins initially disappeared after stroke or traumatic brain injury,
but at 24 h after traumatic brain injury, more veins were observed compared to the contralateral
side. Furthermore, the vessel painting indicated microvessels significantly decreased after SAH
d rainage. Dr. Obenaus in our group analyzed the vessel density and vessel length in
rats by MRI, especially susceptibility-weighted imaging (SWI) venography
(Fig. 1.9). His results showed that the veins initially disappeared after stroke or
traumatic brain injury, but at 24 h after traumatic brain injury, more veins were
observed compared with the contralateral side. Furthermore, vessel painting indi-
cated that the microvessels significantly decreased after subarachnoid hemorrhage.
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thought that you'd be a long sight better with me and with Avis near by and
the interests of life around you, than up over in that lonesome hole. It was
nothing but a kind view of it."
"Why should you grow kind? Why should you change your nature?
Haven't I right and reason to doubt what motive is under this? 'To look after
me'? That's how Winter speaks of his daft brother. I may be daft and small
wonder—but—but——"
"Father," broke in Avis angrily, "I'm going to have a baby, and it's very
hateful and wicked of you to shout and say cruel things like this to upset
me. And it's all lies, because we meant nothing but what was right. We're
grown up, and we've got our share of sense and proper feeling."
But he had only heard her first assertion and it calmed him. He stared at
her and the anger faded out of his face.
"Why didn't you say so then? That's news."
He looked at Avis gently.
"You married Joe Elvin's son, Robert. Well, why not? Bullstones have
wedded with Elvins before to-day. I'm glad you're going to have a little one,
Avis, and I command this. If it's a girl, you call it after your mother."
"I mean to," she said, "and if it's a boy, Bob wills it shall be called after
you."
"No, no—I forbid that. We'll have no more Jacobs."
But he relented before them and grew mild.
"Come here and sit by me and take my hand," he said to Avis; and then
he turned to John Henry.
"If I was harsh, you can overlook it. I'm not the man I was. I'm a good
deal fallen down from the man I was. I'm colder than the man I was. I'll
give you credit for saying what you said in a right spirit, I believe it. That's
your mother in you. But you swear it was your own thought—not
whispered to you by Billy or some such well-wisher to me?"
"I swear before God it was my own thought, father; and I say again that
if you'll come to live with me, I'd be very glad indeed."
But Bullstone shook his head.
"I'm bound for the only place that can offer peace. Auna and I. And I
hope you'll make time as you can and come and see me now and again. I
feel friendly to you and Peter. You know that actions speak louder than
words. I hope it will be a girl for the sake of the blessed name. I'll come to
the christening. Ill do that. Mark me. I'm a man of my word. You take all
care of yourself, Avis, and don't be too busy."
Peter spoke.
"Why for can't you go to John Henry, father? Then we should have you
in the midst."
"You know we're all right, father," added the elder brother. "It isn't as if
you'd see a lot to vex you, and things being done you didn't hold with. You
could come and go and keep your eye on the dogs too."
"I'd like to believe that you could wish it. And I will believe it,"
repeated Jacob. "I'll make myself believe it, hard though it may be. It's a
sign of grace and I'm glad it came into your thoughts. And Avis is going to
have a child. That's well. Be sure to call it after your mother if it's a girl."
He stared and nodded and they were conscious that his mind had
wandered far from them.
"Let's go for a walk up the valley, father," said Auna. "You always like
to talk best in the air."
"I'm going to do so," he answered, "but I'm going alone. You children
can stop together, and I'll be back for tea drinking. I'm a good deal shaken
by this great thought of John Henry's. It means his mother in him, working
up to the surface. And he can thank the Lord she's there. She's in you all.
Not that I can change my plans, for my help comes from the hills you must
know—such as it is. But that I was wanted at Bullstone is worth a good bit
to me,—good payment, you might say, for what I've done."
He left them and they turned anxiously to Auna,
"Is he all right? Is it safe for him to go alone?" asked Avis; and her sister
answered that she need fear nothing.
"It's up and down like that. His memory fails him sometimes in little
things. Not in big things. It shook him to find John Henry and you wanting
him. But it's done him good already."
"He'll forget about it before he comes back," added Peter. "He'll often
go out to think over something, or say he's going to, and then he comes
back and you find it's slipped out of his mind altogether."
"But not a great thing like this," promised Auna.
"It's as much for you as for him," continued Avis. "It's not a place for
you to be lost in—Huntingdon isn't—and if you have to go and live with
him there, he'll very likely end by losing his reason altogether, and it's very
bad for a young creature like you."
"Don't you say that, Avis. I couldn't live away from him. And he'll get
better I expect. Days often happen when he's all right and his mind quite
peaceful."
"It would be a lot more convenient if he went to John Henry," said Avis.
"It's clear he finds it too wretched to stop here. I feel it creepy myself—with
mother's ghost in every corner, and in the garden too. She was so busy that
you can't see a thing without remembering her part of it. But he wouldn't be
haunted with her at Bullstone, and we could make jobs for him, and keep
him running about and doing something."
"I'd much like it to happen," admitted Auna, "for his sake. It's all one to
me where I go, if I see him getting better."
"I'll keep it before him, and speak up for it so much as he'll let me,"
promised Peter. "Of course it's what ought to be. But I don't think it will.
Because loneliness is his stronghold, and the lonelier he is, the better he is."
"You might put old Billy and Adam Winter on to him," said his brother.
"He sets store by what they think. Tell 'em the fine offer I've made, Auna,
and see what they say."
"I will, then. But Mr. Marydrew is always very strong that father's mind
will mend up at Huntingdon. He says that I must be wits and staff for father,
and I will be. And he'll come through. Some day he'll come through, if you
and Avis and Peter can show kindness now and then. It's kindness he
wants."
"And that shows how rocky his mind is for the minute," declared Peter,
"because anything soft, like kindness, was gall to him in the past. He was
ashamed of the kindness he did himself. And now his mind has shrunk. He
dwells on little silly things and messes about trifles that he links up with
mother."
"When is he going to divide her clothes?" asked Avis; "it's a cruel waste
and no respect to mother to let things get moth-eaten and useless, that might
be worth money to the living."
"I've been at him," answered Auna. "He says that I'm to have the
clothes, when I'm grown a bit more, because I'm mother's shape; but that's
silly. Now you've been so nice to him, I'll get on about the clothes again to-
morrow and very like he'll let me go through them, or ask you to come over
and take what you want."
The girls discussed familiar articles of their mother's wardrobe, and

Avis indicated much that would be useful to her and the elder Mrs. Elvin.
Auna agreed, and while they talked, Peter described his father's habits of
mind to his brother. The elder took a gloomy view.
"I don't think he will mend," said John Henry. "I think it's a lot more
likely he'll go from bad to worse and become a raving man. There's
suspicions moving deep in him. When I told him about this, you remember,
he asked if I wanted to have him locked up. People, with softening of the
brain coming on, often look ahead in that way and know, by a sort of fearful
instinct, what's going to overtake them."
They discussed the kennels and Peter's future.
"He's all right about that," declared Jacob's younger son, "but he's sharp
enough for Auna. He told me plain that he didn't trust none of us but her,
and that a hair of her head was worth the lot of us. But now belike he'll
change, if he remembers. It was a great thought to offer him to come to
Bullstone."
"If you want to please him, John Henry, put flowers on mother's grave
now and again," advised Auna. "Her grave will always draw him down
from the moor, same as it does now."
They talked until tea time, when Jacob returned, and John Henry went
to put in his horse. Their father was now calm and cheerful. He said no
more concerning the new suggestion; but he had not forgotten it, for when
Avis and her brother were gone and Peter at the kennel, he questioned
Auna.
"Can you tell me, faithful and true, that you had no part in what John
Henry said?" he asked. "Because if you, or any other, put it into his head,
then it's all in vain."
"Nobody put it in John Henry's mind, dear father," she answered. "It
was his very own thought."
"That makes it a valuable thing, Auna."
"I know it does. And Avis dearly wants it to happen too."
"And you? Would you rather be with Avis or your brother, or——?"
"Father! You know better than that," she said very earnestly. "You and
me are one, and what's right for you is right for me."
"So I think," he answered. "A very clever, deep thought in you to say
that we are one."
CHAPTER VII
WILLIAM'S BIRTHDAY
George Middleweek came to see old William with a message and a gift.
It was Mr. Marydrew's eighty-fourth birthday and Auna had sent him a very
fine ham, and a reminder that he had promised to eat his dinner at Red
House.
"You look ten years less than your age, Billy," said the kennel-man.
"We're a long-living race, George. My grandfather was thrice married,

and his last he took when he was eighty-two. Gave my old sister the slip,
for he was active as a kitten, and nipped off to spend a month with friends
in Somerset, and came back with a wife! The woman thought she'd polish
him off in a year or two and get his bit of money; but she thought wrong.
He lived for ten years and left his cash, such as it was, half and half to me
and my sister. His third was a failure, though he was too proud to own it."
"You get into your coat and boots," said George. "If you be coming with
me, we must start."
They were soon upon the road and William asked after Jacob.
"Haven't seen him this longful time," he said.
"He's up and down," declared the other. "Says silly soft things one day,
so as you think he's growing tootlish; and then, the next, he'll be short and
sharp and seemingly all right. He's going through everything that belonged
to his wife, and Miss tells me that it shakes him up. He's keeping some of
her things for himself. His old ideas—the stuff he was taught as a child—
sticks out now and again. But he's shed most of it I reckon. Life's knocked
faith out of him, William, same as it does out of most honest people. But the
old stuff clings to him. He'll often say he's a miserable sinner, though in my
experience it's only the good people yelp about being miserable sinners.
The real, right-down wicked men go on their way rejoicing."
"It ain't the sense of sin makes people miserable, because misery's a
matter of character, not conscience, George."
"A very shocking business to say anybody's born in sin," argued

Middleweek. "And it's an insult to honest matrimony in my opinion."
"You don't understand religion, and the fall of man, George," answered
Mr. Marydrew mildly. "The mysteries of faith are beyond you. Your mind
ban't built to hold 'em."
They reached Red House, where Billy thanked Auna for her gift and
bade her go on with her work and not mind him, as he was early. But she
was glad to stop a while and brought down Jacob from an upper chamber.
His present business alternately excited the widower and cast him down. He
spoke and thought much of Margery as he handled her garments; and
sometimes he was normal and uttered intelligent words; but not seldom his
memory tormented him and he said strange things.
"Every stitch dear mother ever wore puts father in mind of something,"
explained Auna. Then Jacob joined them. His eyes showed that his mind
was roaming, but he remembered the occasion.
"A man can wish you many happy returns of your birthday, Billy," he
said; "because life's good to you still. You can live on very safely, I reckon.
But I'm different from that. It's come over me strong of late that if there's a
life beyond, I must get to it soon—else there'll be more trouble. I must be
there before a certain other party, William!"
"Leave all that in Higher Hands, Jacob. The length of the thread be no
part of our business."
"I must be first, however; I must reach Margery before her mother does.
That's commonsense, because we well know that I'd get but a bleak
welcome if Judith Huxam had her daughter's ear before I did. She robbed
me before, and she would again. A fault in Margery—to say it kindly—to
listen to that old fiend. But I don't want her mind frozen against me for
eternity. I still live in hopes that we'll be very dear friends, William—so far
as a ghost man and a ghost woman can be friends."
"And why not, Jacob? Where there's no secrets hid, the people must
surely come together in love and understanding."
"I say these things, because this is one of the days when I believe in a
future life. Some days I do and some days I do not. To-day I do; and why do
I, should you think? Because my mind is a good deal filled up with my late
wife; and if there's any sort of justice and any sort of Almighty Being to do
it, then there ought to be a heaven—if it was only for her."
"We found the things she was nearly drowned in to-day," continued
Bullstone. "Oh, my God, Billy, what a mad shape life takes, if you see it
steady with a glance spread over quarter of a century! For look at it. If
Adam Winter hadn't saved her, then four lives hadn't come in the world and
my children would never have been born. And what does that mean? It
means that Winter is responsible for my children as much as I am; and why
for shouldn't they thank him for their existence instead of me? Such
thoughts go too deep for the mind of man, William; but if we could
understand them, they might throw a good deal of light on life."
"Don't you be silly, my dear. It ain't a deep thought at all, but just a
brain-sick fancy. And you mustn't feel no fear about the old witch doctor
going to glory before you do. In the course of nature, she'll be called, and I
dare say she'll hate going, quite as much as they uncommon good people
often do. By the same token I hear that she and Barlow ain't finding the
villa residence all that they hoped and deserved. And I'll tell you for why:
you can't alter the habits of a lifetime in a minute and not feel it in mind and
body. I know, because when I retired, though naturally rather a lazy old
man, I missed my work above a bit, and often did a good heavy day for a
neighbour—not so much on his account as my own."
"So you did," answered Jacob. "I'll bear you out there. You sawed a
good many hundred logs for me in your time, William."
"Barlow Huxam misses the shop and owns up; but his better half won't
own up so far, because that would be to say the wrong thing has happened.
And we well know it's a cast-iron rule the wrong thing cannot happen in
their tabernacle. Then again she's had a fearful facer, and so's Amelia
Winter. A very nasty jar has fallen upon them and it have cast them down a
lot. I heard it from Adam Winter himself, and I've felt a good bit amused
about it, though sorry for Amelia, because it looks to her as if the end of the
world had got in sight."
"Whatever's fallen out, Mr. Marydrew?" asked Auna.
"Why, Adam, after taking a good bit of thought, have chucked the
Chosen Few and joined up with the Establishment. And, of course, that
means that Sammy have done the same, for what his brother doeth, he does.
'Tis a hugeous shock to Amelia and she's very sorry for all concerned."
"Uncle Jeremy's two little boys have been taken into the Chosen Fews,"
said Auna. "Aunt Jane told me they are received in. So they'll take the place
of Mr. Winter and his brother, and the numbers will be kept up."
"The axe is at the root," declared Jacob, "and I'm glad of it. They're a
self-righteous crew and it was well within Adam Winter's nature to find
them out and leave them. I hope I'll live to see the end of them, and if that
hag died, the hornets' nest would soon empty."
"How's Huntingdon getting on?" asked William.
"I'm waiting for a fine day to ride up over on a pony. But not while the
floods are out."
"We've got everything very vitty now," added Auna, "and a nice load of
peat stacked by the door, and the new stove. The stores go up after
Christmas, and when the stores are in, our things go up."
"Peace—please God peace is in sight," said Jacob, "and I shall have a
good few of her treasures around me, William. I find they are a great help to
peace. Virtue goes out of these things. I was wondering if it would give her
any pleasure to put her favourite junket bowl on the grave, William? Auna's
against; but for my part, after deep thinking, I wouldn't be over-sure. All's
doubtful with the dead. They may like to know the grey birds are hopping
over them for all we can tell. Nobody can say they don't."
"I think mother would a lot sooner that Peter kept the junket bowl at
Red House, with all the best china," declared Auna.
"And so I say," replied William. "I believe in very plain graves myself. I
like the granite stone. That's enough—just that and the snow-drops to come
up every spring. I wouldn't do no more. There's nought so proper as the
green spine grass on the dead."
"I'm training some white heather to grow there," answered Auna.
"White heather's for the living, not the dead, my dear."
They came to table presently, ate well and drank William's health. Jacob
grew cheerful during the meal and spoke with hope about his family.
"It's a seemly thing for a man in my position to hand over his worldly
goods in his lifetime. Then the new generation comes to understand the
meaning and obligations of power and rises to it after the manner born.
Very likely, if all had been different and my wife had been spared, we
should still have withdrawn ourselves and let the young come into their
own."
He preserved an amiable and peaceful manner until the end of dinner

and Auna, heartened by his mood, exchanged many pleasantries with
William, George and Peter.
Mr. Marydrew praised the little feast when it was ended.
"I've ate far too much for a man my age," he said. "I'm 'filled as the
moon at the full,' Auna, and if ill overgets me, the fault is yours. You'd cram
your father's oldest friend like a Michaelmas goose."
Hope arose out of that anniversary for the girl. It proved but a respite
between storms; yet she could look back to William's birthday and
remember an interlude of peace.
CHAPTER VIII
JEREMY
Slowly but certainly Barlow Huxam discovered that his wife was
slipping from her old self, and for a time he set it down to age, but then he
discovered other reasons for the change in her outlook upon life. Stern she
had always been and definite in her pronouncements. She was not wont to
criticise and wasted no time in lamenting the evil around her; yet a certain
quality of contentment had marked Judith in the past, and now her husband
perceived that this failed her. She became very taciturn, and Barlow
wrongly decided that this silence arose from the fact that Mrs. Huxam had
so little to talk about. The shop had been her solitary subject outside
religion, and now, not only was the shop less and less upon her tongue, but
the master subject of life seemed sunk too deeply within her to offer
material for casual speech.
The disturbance that followed her daughter's death had apparently

passed, leaving only a new gravity; but it was not to their common loss that
the old postmaster attributed the change. Indeed Margery's death had been a
gain to Judith and resolved her greatest and most terrible problem. Then the
explanation of the change was, in his own opinion, clearly revealed to
Barlow, and he discovered it in his own experience. For he, too, was
changed and the expected thing—the peace of retirement, the absence of
daily demand upon his energies and time—by no means produced that state
of contentment and satisfaction he had anticipated from it. Various causes
combined to frustrate his hopes and he attributed the disappointment to one
reason; whereas in truth the explanation lay elsewhere. He suspected that
Jeremy was to blame, and Jeremy certainly did serve to keep him in an
atmosphere of anxiety, from which he had supposed retirement would set
him free; but beyond Jeremy, and the too certain fact that he was falling
short at the post-office, another and a more vital elucidation of Barlow's
disillusion lay at his hand.
He was a man without resources and his resolute endeavour, to fill life
with his villa residence, had failed him. He worked hard, because work
alone made existence tolerable. He laboured in his garden, cut the front
patch into stars and moons and planted rose trees and other shrubs. He
toiled likewise behind, where the vegetables grew, and raised crops for the
house. He read books upon the subject and proceeded intelligently. The
work kept his body strong, and the open air made him feel ten years
younger; but these energies still left a void, for Mrs. Huxam did not share
them. In the old days they had been one in every enterprise. They employed
two servants now, and Judith having trained the maidens into her way and
introduced them both into the ranks of the Chosen Few, found time hang
heavily upon her, the more so that her thoughts became darkened with
personal melancholy.
She never complained; she censured Barlow, when sometimes he

grumbled that there was so little to do; but she secretly sympathised with
him and long before he had arrived at the conclusion that an error
confronted them, she was of the same opinion. In his case frank weariness
of the present monotony began to whisper the need for change; but her
consciousness, that they were making a mistake, was wakened by more than
weariness. He wanted something to think about and something more to do,
and there was work under his own eyes that called him rather loudly; she
also wanted something to do—something to deaden thought and distract it
into other channels than those that now bred an increasing gloom within.
For some time neither would confide in the other, or confess that their
present days lacked justification; but Judith had perceived the unrest and
discontent in her husband long before he began to suspect her; and she
waited, therefore, until his emotions broke out in words. They had passed
through nearly a year of the new existence and tested its every phase, when
Barlow's wife heard much that she expected to hear, together with much
that surprised her.
It was a winter afternoon and she had been reading the Book of Exodus
until a passage familiar enough gave her pleasant pause. The fact that One
had said the Sabbath was made for man and not man for the Sabbath, had
always given her quiet regret; but where authorities differed, her bent of
mind inclined Judith to the Old Testament rather than the New. It chimed
better with her own genius and uncompromising principles. The earlier
dispensation never failed to find her in harmony; and when she read again
the Commandment and its drastic and detailed direction, she felt it was
enough. Consideration of the texts led to gloom, however. If the Lord found
one day in seven sufficient for His rest, how came it about that she and her
husband, while still in possession of energy and health, were resting seven
days a week?
Upon this question returned Barlow from the post-office and, unaware
of the matter in her mind, displayed some irritation. Not until he lighted the
gas did she observe that his face was puckered and his eyes perturbed.
"Things are coming to a climax," he said, "and after tea I should like to
have a tell, Judy. I'm not at all content with a good deal that's happening."
Mrs. Huxam rang for tea to be brought. Her dark eyes brightened.
"We'll have it and get it out of the way," she said. "And one thing I
never shall like here in the planning. The parlour is a desert island for all
you know what's doing in the kitchen."
They ate their meal, which was of a solid character and the last serious
food for the day, since they had given up taking supper and found
themselves better without it. Then the tea things were cleared, and hardly
had the door shut when Mr. Huxam began.
"It's just fifty-three years ago, Judith, since I, as a lad, took the first
telegram that ever came to Brent out to Beggar's Bush to the master of the
Otter Hounds, I was eleven years old at the time."
"And sixty-four now," she said.
"Yes, we're both sixty-four, and mark this—young for sixty-four.

Thanks to our manner of life, I wouldn't say that either of us need count
more than sixty in the things that matter."
"So far as this world's concerned, you're right," she admitted.
"Very well then. And now don't get upset or nothing like that; but I'm
going to say this: that taking one thing with another, I feel terrible doubtful
if our life in this residence is all it might be, or even all it should be."
Mrs. Huxam stared at him with deep interest.
"I half thought your views had settled down. When did this come over
you?" she asked.
"It came, as such things do come—gradual. Here a little and there a

little, till I was surrounded by a cloud of witnesses, Judy. Granted for the
sake of argument—though I won't grant it for any other sake—that we was
a bit over-moiled with work and worry, and wanted to get away from the
shop and the post-office for a rest and refreshment. Granted we did—what
then?"
"Then we've had it," she declared. "We've had a year of it."
"Exactly so; and I'm like a giant refreshed with wine. And I should say
you, in your quieter way, was up for anything also. For my part, even if all
was suent and just so with the shop—which it is not—I'd be exceeding
pleased to go back thereto, and feel myself in the heart of life and at the
helm of my own ship again."
She raised a question, though she knew the answer.
"When you say things are not 'just so,' would you mean Jane, or
Jeremy?"
"Jane's all right, as far as it's humanly possible with her growing family.
Another coming in April I hear. But she does pretty well, though the stocks
are far too low and, of course, she doesn't understand buying; but with
regard to Jeremy, it's idle to pretend, and for that matter I won't pretend.
He's letting it down—not out of malice, of course, but simply for the reason
he lacks the needful qualities. Nobody ever had a better shop manner and a
kinder heart, and nobody was ever more wishful to please his customers;
but smiles and cheerful remarks about the weather don't take the place of
the things people come into a shop to buy; and when a person hears that
Jeremy's out of this, or out of that, or don't keep a thing in stock, it won't
open the till for him to say the corn is coming on nice, or ask a woman how
her baby is. When people want to buy needles, it ain't no manner of use
telling them you've got a fine assortment of pins. Jeremy's all right, in a
manner of speaking, so long as he's got a better to boss him. The spirit is
willing, but the brain isn't built for all the work that must go on out of sight
if a business is to pay. In a word he ought to be in somebody else's shop, not
his own."
"He's going to let it down."
"He has let it down, and I tell you, when I run over the accounts and
lend Jane a hand with the books, my heart bleeds. To see what we made so
fine and four-square and the foremost affair in Brent going back, and to
know Hasking, at the corner, and that little old maid with the Berlin wools
and gim-cracks—Miss Moss I mean—to know such as them are lapping up
custom and can find what Jeremy can't—it's a punishing thing. Very soon I
shall keep out of the shop, or else my temper will suffer and I may say what
I should be sorry to say."
"I know how you feel about it. My fingers itch every time I pass the
window and I want to fly to the shelves when a customer comes in; but well
I know that if I did, I'd find little but empty cardboards."
"And no law nor order," murmured Barlow. "Not a thing in its place and
many a melancholy five minutes wasted in hunting for what ain't there to
find. Last autumn a lot of holiday people were about and I've seen strangers
come into the shop full of hope for some everyday thing—socks for their
children or sunbonnets or elastic or what not; and then Jane and Jeremy
would go pecking about, like a pair of birds in a strange field, and hope
would fade off the faces of the visitors, and they'd just creep out. And very
possibly, ten minutes after they were gone, what they wanted would be
found."
"An unexpected chastening for us," said Judith.
"I know you find it so," he answered, "but what I feel is that the
situation may not be past praying for; and that brings me to the tremendous
idea that's taking shape in my mind. It came over me like a flame of fire last
time I was with the Chosen Few. I thought of what used to be, and my
manhood rebelled, and a voice seemed to say, 'It's not too late—it's not too
late.'"
He looked at his wife and she nodded and wiped her spectacles but said
nothing. Still he fenced with the subject, though she knew to what he was
coming.
"How is it you sleep so bad nowadays?" he asked. "I'll tell you, since
you don't know. For this reason, because the residence faces different from
the old home, and there's a lot more light and air in our present chamber,
and the noise of the wild birds singing of a morning strikes in upon you. In
our old bedroom we were much more favourably situated, and custom is
everything, Judy, and I very much doubt if you can sleep in one room for
forty years and more and ever take kindly to another. And I'll be bold to say
that if you was back in our old room you'd know sleep again and wake fresh
as the dew on the fleece. All of which only points one way."
"Jeremy was saying not so long ago that he felt to be in a good deal of
need of change," murmured Mrs. Huxam. "Not grumbling, or anything like
that; but down-daunted and weary. He's getting to look too old for his years
in my opinion. Patient and sensible and no temper, but a bit under the
weather."
"As we all are when we're over-weighted," answered Barlow. "And if he

wants a change, and Jane wants a bit of peace and quiet against April, then I
say to you in all seriousness that it's well within our power to let 'em have a
change."
"Where to?"
"To the residence! Let 'em come here for a few months, and he can do
the garden and Jane can look after her family; and you and me will go back
to town. I feel, for my own part, that it would do me a power of good,
because messing with rose-bushes and French runner beans—after all it's
not man's work for a man like me. But I'm not putting myself forward. I'm
thinking a lot more about you, and I well know time's hanging terrible
heavy on your hands, else you wouldn't do such a lot of reading and look so
wisht over it."
"You voice a good bit that's in my own mind. You can think too much. I
think too much; and thought often takes you into places where the spirit had
best not to be. We'll make it a matter of prayer if you're in earnest."
"I have been making it a matter of prayer since Christmas," he replied.

"I've been taking the thing to the Throne ever since I knew the game was
up, so far as Jeremy was concerned. And it wasn't until the prayer was
answered that I've broached it to you. I see my way very clear indeed if you
do. But your word's my law now as always. The only problem that rose
before me was this house, and that won't run away because we go back to
the post-office in the fulness of our strength. Put them in here for a few
months, and then, when the Lord's solved the position so far as they're
concerned, we can let it for the summer, furnished, for very fair money
indeed."
"It's almost too good to be true in my opinion," she said.
"Far from it," he assured her. "It can come true in rather less than no
time if you think it ought."
"I'll set it before my Maker, Barlow."
"I'm sure you will," he answered with confidence, "and if you and Him
don't see eye to eye, it will be the first time."
He was much elated, for he felt that all must now happen as he desired;
and then further fortune fell out to assist the project, for his son came over
after closing time, and arrived at a moment perfectly chosen by chance to
affirm the situation for Mr. Huxam.
The ineffectual Jeremy trailed his attractive person before his parents,
announced that he had come to see his mother and declared that he was
very tired; whereupon Barlow judged it politic to leave them for a time,
feeling in no doubt as to the nature of his son's mood.
Jeremy began with his usual tact and sympathy.
"Father tells me you don't seem quite yourself, and I was a good deal
put about to hear it," he said.
She nodded.
"Who is quite themselves as you call it?" she asked. "While we're in the
flesh, we can't be quite ourselves, Jeremy. Ourselves belong somewhere
else far beyond this Vale."
"I know—I know it better and better, as I grow older, mother. I'm in
sight of forty now, remember, and if I haven't found out this life is a Vale
and no more, it's a pity. Why don't you go down to Uncle Lawrence for a bit
and get some sea air?"
She shook her head.
"My body is strong enough—too strong in a sort of way. For it shakes

the soul a bit, Jeremy, to see the body living in idleness when it might be
doing something useful."
"You've done your mountain of work I'm sure."
"So I have then, but maybe there's a molehill of work still left in me. I'm
not easy about it and your father's not easy about it either."
"As for me," he answered, "work's beginning to tell. Jane, catching the
light in my hair a few days ago, broke it to me that there's a little bald spot
showing to the naked eye on my crown. The beginning of the end I
suppose. I'm a very weary man indeed."
"Are you?"
"Yes, mother. My nature properly calls out for rest. I don't solve the
problems of life so easy as I did."
"What's the matter then?"
He did not immediately reply, but changed the subject.
"Have you heard what that man, Jacob Bullstone, has done? He made
over Bullstone Farm to John Henry on his twenty-first birthday; and he's
going to give Red House and the business to Peter presently."
"Yes—not his work but the Lord's. 'The wealth of the sinner is laid up
for the just' in Bible words."
"Now there's only Auna of them four—Margery's children."
"I had very near given up hoping for Auna; but that was wrong. Of all
the souls I've helped to bring in this world, Auna's the only doubtful one,
and I'm going to fight again in that quarter."
"She cleaves to her father, and he's dragging her up to that den on the
moors. A very wrong thing, mother."
"Very wrong, and little hope for Auna till we get her away. The time
may come. She's much in my mind."
"I went to Plymouth last week to buy a few odds and ends—not for
myself—and I looked in and had a dish of tea with Uncle Lawrence. He's
getting a lot older, I find, and a lot less peart than he was. Margery's death
hit him very hard."
"No it didn't. He's too steadfast to be hit by the death of a saved soul.
He's up home seventy, and his heart is weak, because he lived a very hard
life in early manhood following the sea."
"Seventy's nothing for a Pulleyblank. I wonder what he's done with his
money, now that poor Margery's gone home."
"I couldn't tell you."

"By rights, me being nearest, I ought to have it."
"He may see it like that."
"I took occasion to tell him that all Margery's children was well
provided for—not so mine."
"I don't like this," said Mrs. Huxam. "To be doubtful about your
children's welfare is next thing to being godless, Jeremy. You're talking in a
very loose sort of way, and to speak, or think, of your uncle's money is
indecent."
"Then I'm sorry I so far forgot myself as to do so," he answered at once.

"It wasn't for myself; and I'm well able and very willing to look after my
own. But there's a cloud. I don't mean Teddy, who will never have the full
use of his legs and be a care all his life. He came from God like that, and I
can face him according and labour double tides for him if needs must; but I
mean a passing thing, though very serious I'm afraid."
"What is it then?"
Again he evaded the great matter and dallied.
"I'll tell you, of course, mother. I'm not a man to run away from trouble.
It came over me, strangely enough, in the churchyard, where I went on
Sunday afternoon with my sons past Margery's grave. And I properly hate
that stone Bullstone has stuck there. It oughtn't to be allowed. And he's set
wild plants upon it—just moor weeds. Father's greatly vexed, as well he
may be."
"What does it matter? It's a weakness of the weak to garden on graves

and fidget over the dust of the dead. Let it go."
"Very different to my brother's grave—so dignified and all that. The

face wants a wash: it's gone green, and next Saturday I'll go up and rub it."
Mrs. Huxam had set words from the Wisdom of Solomon on the tomb
of her dead son and Jeremy brought them to her mind. She looked back

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Textbook Cerebral Venous System in Acute and Chronic Brain Injuries Min Lou Ebook All Chapter PDF

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Cerebral Venous System in Acute and

Chronic Brain Injuries Min Lou

Acute Elbow Trauma Fractures and Dislocation Injuries

Acute Brain Impairment Scientific Discoveries and

Multifractals and Chronic Diseases of the Central

The Brain Reward System 1st Edition Marc Fakhoury

Atlas of Endovascular Venous Surgery Almeida

Digital Electronic Circuits Shuqin Lou

Clinical Hematology 6th Edition Mary Lou Turgeon

Chronic Pain Management in General and Hospital

Min Lou · Jianmin Zhang · Yilong Wang

More information about this series at http://www.springer.com/series/10064

Cerebral Venous System

Yilong Wang Brain Research Institute

ISSN 2363-958X ISSN 2363-9598 (electronic)

Library of Congress Control Number: 2018957835

© Springer International Publishing AG, part of Springer Nature 2019

1 Neurovascular Network as Future Therapeutic Targets���������������������� 1

11 Role of Cerebral Venous System in Hemorrhagic Stroke�������������������� 173

Abstract In recent years, endovascular treatment, including pharmaceutical drugs

© Springer International Publishing AG, part of Springer Nature 2019 1

network and the function of neurobiological and neurovascular components after

Keywords Neurovascular network · Cerebral veins · Stroke

CBF Cerebral blood flow

DSA Digital subtraction angiography

Fig. 1.1 History of stroke pathophysiology

As we have introduced, endovascular treatment, including pharmaceutical drugs

2  he Mismatch Between Preclinical Models

ischemia might cause a large parenchymal lesion and hemorrhagic transformation.

2.1 Recanalization Leads to a Small Infarction

As suggested by the guidelines, if thrombolectomy is performed and the clot is

2.2 Unsuccessful Recanalization Leads to a Small Infarction

However, a failed thrombolectomy or unsuccessful clot removal within 6 h after

thrombolectomy/clot removal induced much smaller infarction than 2 h in the

2.3  ecanalization Leads to Bleeding, Edema, and Massive

Emergency CT revealed no infarction at 4 h after stroke onset, and a 60-k unit of

2.4 Vein Compression Involved in Reperfusion Injury

2.5 Infarction Is Reversible Even After Days

Traditional understanding treats stroke as a catastrophe due to unsatisfactory out-

recovered consciousness on day 12. The CT on day 14 showed a significantly

3  stablishment of New Stroke Pathophysiology to Address

3.1  mphasis on Recirculation: Both Arterial and Venous

Basic Rules for Recirculation (Fig. 1.7)

Anatomy of the Cerebral Venous System

surrounded by other cellular aggregates consisting of fibrin and platelets [79–83].

Venous Flow During Ischemic Stroke

Venous Flow During Intracranial Hemorrhage

Venous Flow During Subarachnoid Hemorrhage

Subarachnoid hemorrhage is a special subtype of intracranial hemorrhage, caused

formation of microthrombi [124]. Recent studies have also demonstrated vasospasm

Venous Flow During Traumatic Brain Injury

Traumatic brain injury is defined as impact, penetration or rapid movement of the

 ecirculation as an Emerging Understanding of Stroke and Other Acute

3.2 Define Venous Function after Acute Arterial Stroke

Situations to Evaluate Venous Function

Second, when patients with subarachnoid hemorrhage have clinical signs of

Vessel Length (% ipsi/contra)

"Why didn't you say so then? That's news."

He looked at Avis gently.

"No, no—I forbid that. We'll have no more Jacobs."

But he relented before them and grew mild.

But Bullstone shook his head.

He left them and they turned anxiously to Auna,

1 Neurovascular Network as Future Therapeutic Targets�� 1

11 Role of Cerebral Venous System in Hemorrhagic Stroke�� 173

2 he Mismatch Between Preclinical Models

2.1 Recanalization Leads to a Small Infarction

2.2 Unsuccessful Recanalization Leads to a Small Infarction

2.3 ecanalization Leads to Bleeding, Edema, and Massive

2.4 Vein Compression Involved in Reperfusion Injury

2.5 Infarction Is Reversible Even After Days

3 stablishment of New Stroke Pathophysiology to Address

3.1 mphasis on Recirculation: Both Arterial and Venous

Basic Rules for Recirculation (Fig. 1.7)

Anatomy of the Cerebral Venous System

Venous Flow During Ischemic Stroke

Venous Flow During Intracranial Hemorrhage

Venous Flow During Subarachnoid Hemorrhage

Venous Flow During Traumatic Brain Injury

ecirculation as an Emerging Understanding of Stroke and Other Acute

3.2 Define Venous Function after Acute Arterial Stroke

Situations to Evaluate Venous Function