Neurosurg Rev
DOI 10.1007/s10143-014-0549-3
REVIEW
Normal perfusion pressure breakthrough phenomenon:
experimental models
Raquel Gutiérrez-González & Alvaro Pérez-Zamarron &
Gregorio Rodríguez-Boto
Received: 9 February 2013 / Revised: 25 August 2013 / Accepted: 8 February 2014
# Springer-Verlag Berlin Heidelberg 2014
Abstract One of the most life-threatening complications after
the obliteration of intracranial arteriovenous malformations is
the development of oedema and/or multifocal haemorrhage.
Two main theories have been postulated so far in order to
explain this situation. On one hand, “normal perfusion pres-
sure breakthrough phenomenon” is based on the loss of cere-
bral vessel autoregulation due to the chronic vasodilation of
perinidal microcirculation. On the other hand, the “occlusive
hyperaemia” deals with thrombotic and venous obstruction
phenomena that may also generate such manifestations. The
aim of this study is to resume the main concepts of the
“normal perfusion pressure breakthrough phenomenon” theo-
ry as well as the related animal models described up to date,
their advantages and disadvantages, and the main conclusions
obtained as a result of the experimental research.
Keywords Arteriovenous malformation . Experimental .
Model . Normal perfusion pressure breakthrough . Research
R. Gutiérrez-González (*)
Department of Neurosurgery, Fundación Jiménez Díaz (IIS-FJD),
Avda Reyes Católicos 2, 28040 Madrid, Spain
e-mail: rgutierrezgonzalez@yahoo.es
A. Pérez-Zamarron
Department of Neurosurgery, La Paz University Hospital,
P Castellana 261, 28046 Madrid, Spain
G. Rodríguez-Boto
Department of Neurosurgery, Clínico San Carlos University
Hospital, Prof. Martin Lagos, 28040 Madrid, Spain
G. Rodríguez-Boto
Department of Surgery, Faculty of Medicine, Complutense
University of Madrid, 28040 Madrid, Spain
Introduction
One of the most life-threatening complications after the oblit-
eration of intracranial arteriovenous malformations (AVMs) is
the development of oedema and/or multifocal haemorrhage.
Two main theories have been postulated so far in order to
explain this situation. On one hand, “normal perfusion pres-
sure breakthrough (NPPB) phenomenon” is based on the loss
of cerebral vessel autoregulation due to the chronic vasodila-
tion of perinidal microcirculation. This vasodilation is a con-
sequence of chronic hypoperfusion secondary to a vascular
“steal phenomenon” caused by the malformation [43]. Thus,
when a high-flow shunt, such as the AVM, is surgically
excised or isolated from the rest of the normal circulation by
means of endovascular embolization procedures, the redistri-
bution of the cerebral blood flow (CBF) from the AVM to the
adjacent cerebral vessels might cause oedema and haemor-
rhage. On the other hand, a different but complementary
concept is the “occlusive hyperaemia”, which deals with
thrombotic and venous obstruction phenomena that may also
generate such manifestations [1].
The increasing knowledge and understanding of such
phenomena have been possible thanks to the experimen-
tal research that began in the late 70s as a result of the
investigations of Spetzler et al. [43], who first described
the NPPB theory. With this hypothesis, a new line of
research was developed with the aim of reproducing the
haemodynamic, histological and biochemical changes
that happen after the removal of a high-flow arteriove-
nous shunt. Several models with different animals—
achieved under controlled and reproducible physiologi-
cal conditions—have been described in the literature
since then in order to improve the understanding of
the AVM pathogenesis itself, as well as the treatment
complications [4, 5, 9, 14, 15, 19, 21, 22, 24–32, 34,
36–39, 42, 44, 46].

The aim of this study is to resume the main concepts of the
NPPB theory as well as the related animal models described
up to date, their advantages and disadvantages and the main
conclusions obtained as a result of the experimental research.
Concepts of NPPB theory
“Vascular steal” phenomenon
Intracranial AVMs are vascular structures with a non-capillary
nidus. The absence of capillary vessels between arteries and veins
provides the AVM with one of its most important features: the
low-resistance of the nidus. Cerebral blood flow directly depends
on cerebral perfusion pressure (CPP) and inversely on cerebro-
vascular resistance (CVR), which is also inversely proportional to
the vessel diameter according to the Poiseuille’s law (Fig. 1).
Cerebral autoregulation is the capacity that intracranial
vessels have of modifying their diameter in response to CPP
changes. This is an essential mechanism that allows the main-
tenance of a constant CBF above the ischaemic threshold
independently of any relatively extreme change in the system-
ic arterial blood pressure (SABP) or the intracranial pressure
(ICP). The lower limit of autoregulation is the value of CPP
under which the CBF decreases proportionally. The increase
over the superior limit involves that vasoconstriction depends
on the sympathetic innervation of the vascular adventitia [23].
Arteriovenous malformations behave as a low-resistance
shunt, thus creating an increase in CBF through the malfor-
mation. When such a situation is maintained over time, flow
redistribution towards the AVM may involve a decrease in
regional CBF (rCBF) of the viable parenchyma adjacent to the
vascular nidus, a fact that would provoke the so-called “vas-
cular steal” phenomenon [18, 33].
Chronic hypoperfusion and autoregulation response
The decrease in rCBF of the perinidal nervous tissue is then
responsible for the decrease in CPP, which may result from the
Fig. 1 CPP cerebral perfusion pressure, MABP mean arterial blood
pressure, ICP intracranial pressure, CBF cerebral blood flow, CVR cere-
brovascular resistance, Q flow, ΔP pressure difference, r radius, L length
of tube, η viscosity
Neurosurg Rev
combination between arterial hypotension and venous hyper-
tension [45]. This latter seems to be caused by the obstruction
of the malformation venous drainage due to structural vascular
injury (endothelial damage, thrombosis and/or stenosis phe-
nomena) related to the intravascular pressure itself and the
flow turbulence in the AVM [12].
The normal vascular response to a decrease in CPP is
the arterial and arteriolar dilation, what makes possible
the maintenance of a constant CBF. Thus, the chronic
hypoperfusion would lead to a maximal vasodilation
state and, consequently, to the dysfunction of the cere-
brovascular autoregulation.
At this stage, capillaries and veins assume a more active
role in the CVR [10, 11, 23]. In spite of the studies that defend
the existence of the so-called “vasomotor paralysis” in the
hypoperfused perinidal tissue [6, 8], other reports have
showed that autoregulation remains intact [3, 48]. Therefore,
they defend the hypothesis of an autoregulation curve dis-
placement to the left as an adaptive change to the chronic
hypoperfusion of the normal cerebral tissue surrounding the
AVM nidus. Such displacement may result in the capacity of
keeping the normal CBF in a range of pressures under the
usual ones (Fig. 2) [20, 49].
Neuropathological changes
Despite the aforementioned facts, histological studies
have revealed the presence of abnormally dilated capil-
laries in the perinidal cerebral tissue with features that
suggest congestion in more than half of the cases, as
well as the presence of a pericapillar space with in-
creased permeability [2]. Besides that, chronic tissular
hypoperfusion seems to be responsible for other neuro-
pathological changes such as the diffuse degeneration
and neuronal loss or the reactive gliosis to the steal
phenomenon [2, 7].
Reperfusion injury
The obliteration or excision of an AVM produces sudden
haemodynamic changes like the redistribution of the “stolen”
flow by the AVM towards the chronically hypoperfused
perinidal tissue, thus restoring the normal CPP [35, 47]. Such
a state of “reperfusion” would be comparable to the hyperper-
fusion syndrome after cerebral revascularization in cases of
carotid artery disease. In that case, the haemodynamic situa-
tion may have an effect on the parenchyma developing de-
structive processes such as the release of inflammatory fac-
tors, cytokines and free radicals [23]. Besides that, the injury
related to the increased transmmural pressure over a weakened
vascular wall and appeared as a result of chronic changes
should be also considered, as it might lead to inflammation,
oedema and haemorrhage [2, 47].
Neurosurg Rev
Fig. 2 Cerebral autoregulation
curve. CBF cerebral blood flow,
CPP cerebral perfusion pressure
Experimental models
An ideal animal model should resemble human AVMs and,
consequently, it should be based on an intracranial shunt
between a large cerebral artery and a cerebral vein with a
normal capillary network around it that enables the reproduc-
tion of rCBF changes observed in patients. Small animals
have been extensively used for experimental research due to
economical, ethical and availability reasons when compared
with large animals. However, these latter provide better hu-
man resemblance. The disadvantages that large animal models
involve (such as ethical concerns, handling difficulties, animal
facilities and higher costs) are essentially the advantages that
small animal models show. In addition to that, the anatomical
and physiological nuances related to specie differences repre-
sent an insurmountable obstacle in most cases and should be
considered before interpreting data. Moreover, haemodynam-
ic and/or neuropathological variables are frequently the end-
point in experimental research, whereas functional outcome is
the main value in most cases of clinical research.
Most of the animal models designed to study intracranial
AVMs are based on the creation of an arteriovenous fistula
(AVF)—extracranial in most of cases—that mimics the high-
flow shunt the AVM means and that would theoretically
provoke an effect of flow “steal” capable of generating cere-
bral chronic hypoperfusion.
The first model was described by Spetzler et al. [43] in an
original study dated 1978. It consisted on the creation of an
AVF in cats by means of an anastomosis between the rostral
end of the carotid artery and the caudal end of the jugular vein
(Fig. 3a) so that the afferent flow of the fistula came from the
contralateral carotid artery and the vertebral artery through the
Willis circle with a retrograde drainage through the anastomo-
sis. An extracranial “steal” phenomenon from the cerebral
circulation was then achieved. Follow-up angiography
showed significant chronic dilation of both, the afferent and
efferent vessels diameter 6 weeks after AVF creation in 5 of
the 30 cats. In the rest of cases, no changes were shown or they
were reversible during the study period. Haemodynamic pa-
rameters were recorded before, during and after temporally
occluding the fistula, encouraging SABP changes by means of
dopamine or nitroprusiate infusion, and inducing pCO2
changes by means of hyper or hypoventilation. The analysis
of the records showed in every patent fistula the loss of
autoregulation. Thus, flow through the AVF was directly
dependant from SABP and its pharmacologically-induced
changes. However, the response to pCO2 changes hardly
emerged. The temporal occlusion of the fistula gave rise to
the restoration of the autoregulation and the normal response
to pCO2 except for the five cases with significant angiograph-
ic dilation of the AVF, which showed abolished responses.
Nevertheless, histological analysis 6 weeks after surgery did
not show ischaemia.
Experimental research with primates has been very low so
far in spite of the anatomical and physiological similarities
that this animal shows when compared with the human brain.
The main reasons lie in the expertise required to restraint and
handle these animals, as well as the aforementioned econom-
ical and ethical concerns. One of the existing studies dated
1950 recreates a side-to-side fistula in most of the cases or an
end-to-end fistula in the remaining ones between the carotid
artery and the internal jugular vein (IJV) in Rhesus monkeys
[14]. Flow direction analysis showed that blood flow was not
retrograde towards the sagittal, the petrous or the straight
sinuses but towards the cervical and basilar veins as well as
the lateral sinuses. Angiographic studies evidenced that blood
could redistribute towards the intracerebral veins when a
contralateral lateral sinus was ligated too. Another study was
also based on an extracranial AVF. Cerebral blood flow, pO2
and pCO2 values suggested the lack of impact of SABP
changes on flow autoregulation through the fistula [39].
Swine models are more numerous, and they typically use
an anatomic artery-arterial model, the rete mirabile. This is a
fine net of vessels with connections that cross along the
 Neurosurg Rev

Fig. 3 Schematic drawing of the arteriovenous anastomosis and flow direction in different experimental models. ACA anterior cerebral artery, MCA
middle cerebral artery, ECA external carotid artery, CCA common carotid artery, VA vertebral artery, EJV external jugular vein, IJV internal jugular vein

midline to the contralateral rete and depends on each ascend-
ing pharyngeal artery. It is a very useful model due to the great
morphological similarity to a cerebral plexiform AVM nidus.
Nevertheless, no typical arteriovenous shunt of AVMs can be
reproduced using it. Several studies have also added the
creation of a bilateral AVF (carotid-jugular) in order to supply
such lack [25, 31]. This is an easy model that allows good
visualization of every component of an AVM, including the
nidus, and as a result, very useful in neurointerventional
procedures (both techniques and materials for AVM emboli-
zation) and radiosurgery research [9, 21, 24, 26, 31, 32, 42].
On the other hand, the model does not seem to be suitable in
Neurosurg Rev
the study of NPPB since it recreates a nearly “physiological”
situation in the swine and thus it does not reproduce the
haemodynamic changes that occur in human cerebral AVMs.
An animal model in sheep was designed following the
same anatomical basis of the rete mirabile and with the aim
of simplifying the initial model described by Massoud et al.
[25] The model was, again, based on an extracranial fistula
(carotid-jugular) with the aim of assessing the haemodynamic
and angiographic changes related to the shunt [34]. However
and considering important morphological and haemodynamic
features of the sheep that show little resemblance to cerebral
AVMs, this animal also seems to be inappropriate for this type
of research [5, 27].
The canine model described in 1999 by Schumacher and
Schellhammer [38] consisted on an extracranial fistula (bilat-
eral carotid-jugular) with early occlusion of one of the AVF at
21 days and keeping the contralateral one permeable. The
model evidenced the vascular steal effect and the early recruit-
ment of the contralateral but mostly ipsilateral CBF. However,
the authors concluded that although the model could be useful
for endovascular training, it did not properly reproduce intra-
cranial AVMs physiopathology. On the contrary, Pietilä et al.
[36] pointed to canine models as the most suitable ones for
experimental research of AVMs, due to the brain volume of
this animal and also to the comparable physiology as well.
Unlike the previous study, the model was based on an intra-
cranial AVF between a branch of the middle cerebral artery
and the dorsal sagittal sinus and interposing a segment of the
superficial temporal artery. Follow-up angiography showed
the development of neovascularization apart from the AVF.
Postmortem exams evidenced angiogenesis areas around the
shunt that became bigger as the time passed from the surgery
increased. Besides that, no changes were observed in the
afferent artery diameter but a greater dilation of the fistula
drainage vein. Finally, histological studies showed significant
gliosis in the parenchyma adjacent to the shunt as well as areas
of mesenchymal proliferation, fibroblasts and endothelium,
mimicking areas of ischaemic infarct. Capillary proliferation
was also observed (weak vessels without arterial or venous
differentiation) in non-infarction areas, a fact that indicates the
existence of reactive changes to ischaemia but also the gener-
alized neoformation of capillaries. Another model of intracra-
nial AVF in dogs consisted on the creation of a pial fistula
between a cortical artery and a cortical vein. Another dural
AVF to a sinus was associated. This latter was created inter-
posing a free graft of the superficial temporal artery with an
end-to-lateral anastomosis between a cortical branch of the
middle cerebral artery and a drainage vessel (cortical vein or
transverse sinus). No haemodynamic, histological or bio-
chemical analysis were, however, described in association
with this model [5].
Extracranial AVF was used in all experimental models
described in cats. Thus, Sakaki et al. [37] created a shunt
between the distal common carotid artery and the proximal
IJV in order to achieve extracranial steal phenomenon. Be-
sides that, the ipsilateral vertebral artery was occluded in order
to help a more pronounced chronic ischaemic state. Six weeks
after the AVF creation, the results showed a decrease in the
restoration of the CPP threshold when a new ischaemic insult
or a hypertensive state was added to the restoration of the
normal CBF. Miyasaka et al. [28] and Tokiwa et al. [44] also
based their studies on a carotid-jugular fistula. However, no
significant histological or haemodynamic changes were ob-
served when the fistula was closed neither in the acute period
nor 8 weeks after its creation.
Finally, research in rats continues being the most prolific
one, probably due to the economical facilities it requires as
well as the accessibility to work with this animal in spite of its
anatomical differences related to humans. One of the first
models with rats was described by Morgan et al. [29] in
1987 that took reference from models with other animals
[14, 39]. The authors created an end-to-end carotid-jugular
fistula (IJV) in Wistar rats using the rostral ends of both
vessels (intracranial afferent artery and venous drainage to
the intracranial drainage system). The external carotid artery
was also ligated (Fig. 3b). The anastomosis permeability was
angiographically checked at 24 h, 1, 3 and 6 weeks after such
intervention. After 8 weeks, endovenous Evans dye was ad-
ministered 5 min before the theoretical disruption of the
blood–brain barrier, which was provoked by the closure of
the fistula or pharmacologically inducing a hypertensive state.
Laparotomy was used for SABP continuous recording, arterial
blood gases analysis and venous access for dye infusion. Five
minutes after inducing hypertension and 10 min after Evans
dye infusion, rats were sacrificed. Brain was removed for
analysis. Three different experiments were conducted: the first
one included ligation of the AVF under normal SABP, and no
Evans blue was extravasated in any animal; the second one
included AVF ligation under a pharmacologically induced
hypertensive condition (150–180 mmHg), and the brain was
dyed in 80 % of the animals; with regard to the third experi-
ment, the rats were under a pharmacologically induced hyper-
tensive state, as in the previous one, but in absence of AVF
ligation, and no extravasation was observed. A fourth control
group included rats without fistula or with an occluded AVF
and did not show any dye extravasation. The study finally
concluded that BBB showed reproducible disruption under
moderate hypertension and mainly in the ipsilateral hemi-
sphere to the fistula. This situation was not reproducible under
normal blood pressure. Two years later, the same research
group conducted a new experiment with an AVF similar to
the aforementioned one, and compared the animals with con-
trol rats that had undergone right carotid artery ligation or with
intact rats. Twelve weeks after AVF creation, rCBF was re-
corded in rats after fistula occlusion and in rats with a perme-
able fistula and compared with the results obtained in control

animals. Thus, the results showed that rCBF was nearly 50 %
lower in the group with an open fistula whereas it was about
30 % higher in the group with an occluded fistula than in the
control group. The data suggest that AVMs may generate
hypoperfusion without infarct that may turn into hyperaemia
after nidus removal [30].
Irikura et al. [19] designed a study with the aim of assessing
the integrity of autoregulation in cases of chronic hypoperfu-
sion. Thus, they described a similar model of AVF with an
end-to-end anastomosis between the rostral ends of the com-
mon carotid artery and the external jugular vein (EJV) in
Sprague–Dawley rats (Fig. 3b). In their opinion, the IJV was
not the vein of choice due to the hypoplasia it shows in rats.
Both external carotid arteries were also ligated. In situ visual-
ization of pial microvasculature ascertained that pial arterioles
showed important dilation and tortuosity whereas pial veins
were slightly dilated. Such morphological changes were con-
firmed after comparing AVF rats with non-AVF controls. The
response arterioles showed to minor increases in blood pres-
sure (130 mmHg) was significant dilation, whereas control
animals only had such changes in cases of raised hypertension
(180 mmHg). This observation confirmed the displacement of
the superior limit of autoregulation curve when a chronic
hypoperfusion state arises. Besides that, a minimal increase
in rCBF ipsilateral to the fistula was observed by laser-
Doppler flowmetry when the fistula was suddenly closed
under normal blood pressure. This increase was significant
when the fistula was occluded under hypertension. Moreover,
ipsilateral carotid pressure rose up to 65 % in comparison with
mean arterial blood pressure (MABP) whereas this latter did
not show any change. When the closure was achieved under
normal blood pressure, arterioles showed vasoconstriction and
vasodilation if it was under minor hypertension (130 mmHg).
These results showed a direct correlation between pial arteri-
oles response to sudden closure of the fistula and SABP.
Another outstanding study published by Bederson et al. [4]
in 1991 dealt with the importance of venous hypertension as
well as the measure of arterial steal. The authors designed a
model with Sprague–Dawley rats that underwent an extracra-
nial AVF between the common carotid artery and the EJV.
Thus, an end-to-end anastomosis was created between the
proximal end of the artery and the distal end of the vein. The
contralateral EJV was also ligated 24 h after the beginning of
the experiment with the purpose of mimicking intracranial
drainage obstruction (Fig. 3c). Different haemodynamic pa-
rameters were analysed at different stages of the experiment.
In the results, it was observed that: (1) the creation of an AVF
involved the raise in torcular pressure and the decrease in
MABP and, therefore, the decrease in CPP too (26.9 mmHg).
Such results became more notable when the venous drainage
was obstructed by the contralateral EJV ligation; (2) the
creation of the fistula was associated with the change in the
ipsilateral transverse sinus flow direction and its velocity
Neurosurg Rev
increase, which descended when the contralateral venous
drainage was occluded. Conversely, middle cerebral artery
flow velocity significantly descended when the fistula was
opened and in an even more pronounced way when the
venous drainage was obstructed, a fact that could reflect the
decrease in CBF; (3) a positive lineal relationship was ob-
served between MABP and torcular pressure during venous
drainage occlusion in rats with a permeable fistula. Thus, an
increase in MABP was directly transmitted to cerebral venous
circulation, a fact that led to an increase in intracranial venous
pressure without changes in CPP; and (4) venous drainage
restoration and fistula closure carried out an increase in the
middle cerebral artery flow velocity up to 69 % in comparison
with the baseline conditions that the authors associated with
the presence of distal vasodilation. Besides that, histological
studies showed bilateral ischaemic changes in the frontal
cortex and basal ganglia in those rats with permeable fistula
and permanent occlusion of venous drainage. Venous infarct
changes were also observed in some of these animals. This
model managed to reproduce the vascular steal phenomenon
and emphasized on the importance of venous drainage occlu-
sion as the responsible of histological and haemodynamic
changes observed in the study. According to the authors,
venous hypertension may play a critical role in the reduction
of CPP below the ischaemic threshold and might be specifi-
cally linked to the postoperative hyperaemia that follows the
removal of certain AVMs.
Hai et al. [15] described in 2002 a chronic hypoperfusion
model in rats designed (as in the previous study) to assess the
influence of venous drainage obstruction in the pathogenesis
of post-obliteration AVMs complications. The authors used
Sprague–Dawley rats that underwent the creation of a carotid-
jugular fistula (EJV) with side-to-end anastomosis and bilat-
eral ligation of the external carotid artery (Fig. 3d). In some
cases, the drainage vein of the left transverse sinus was also
ligated. The creation of the AVF involved a significant de-
crease in MABP and CPP as well as an increase in venous
drainage pressure as well. This latter increase was more pro-
nounced in those rats with ligation of the drainage vein to the
transverse sinus. Mean arterial blood pressure recovered to
baseline values 3 months later, whereas venous drainage
pressure had descended but to above baseline values. The
occlusion of the fistula 90 days after its creation provoked
blue Evans dye extravasation and acuose content rise when
comparing AVF rats with control rats. Haematoxylin and
eosin staining did not show infarct, oedema or haemorrhage.
Similarly, electron microscopy did not evidence differences in
capillaries between AVF rats and control rats. However, a
remarkable lack of astrocytes and podocytes was noticed.
According to the authors, such findings would correlate with
the vasogenic oedema and haemorrhage that typically appear
in a subclinical NPPB syndrome and in absence of visible
findings in light microscopy. Besides that, venous drainage
Neurosurg Rev

obstruction would again be essential in order to obtain a
significant decrease in CPP.
Yassari et al. [46] described a very similar model to the
previous one, based on a carotid-jugular fistula with side-to-
end anastomosis but without contralateral venous drainage
occlusion. The model confirmed some of the results observed
previously as, for example, the appearance of haemodynamic
and angiographic changes in the vessels diameter 7 days after
the formation of the fistula and their stabilization at approxi-
mately day 21. Moreover, blood flow initially increased al-
though became stable during the 90 days the experiment
lasted. This high-flow and low-resistance state was probably
the trigger of the hypertrophic changes observed in the intra-
cranial drainage veins, with proliferation and migration of
smooth-muscle cells and therefore venous drainage
arterialization.
Other studies have also emphasized on the necessity of
recreating not only the drop in MABP when the fistula is
opened but also the venous hypertension state typical of
certain AVMs too. One of the most recent ones is that of
Kojima et al. [22], who designed an AVF between the
common carotid artery and the EJV by means of a side-to-
side anastomosis and proximal EJV ligation in the same
procedure, apart from the ligation of the contralateral posterior
facial vein 24 h later (Fig. 3d).
Haemodynamic recordings showed a significant decrease
in the CPP after the formation of the fistula that progressively
was recovered between days 1 and 28 of the experiment up to
values under baseline range in any case. Histological study
evidenced venous hypertension features (diffuse dilation of
the transverse sinus and wall thickening with fibroblasts and
connective tissue) as well as VEGF overexpression in the
endothelial layer. Such overexpression was significant on
day 7 of the experiment, but it subsequently decreased be-
tween days 7 and 28, thus showing an inverse correlation with
the CPP.
Results in experimental research
Several studies have made possible the reproduction of the
vascular steal state and the chronic hypoperfusion of the

Table 1 Summary of
experimental models Specie Shunt Advantages//disadvantages Reference

Primate Intracranial Best human resemblance//handling expertise, animal facilities, high –

cost, ethical concern
Extracranial Human resemblance//handling expertise, animal facilities, high cost, Gurdjian et al. [14]
ethical concern, circle of Willis compensation in extracranial Scott et al. [39]
shunts
Swine Rete Human AVM resemblance, morphological similarity to a cerebral Massoud et al. [25]
mirabile plexiform AVM nidus//physiological in the swine, does not Muruyama et al. [31]
reproduce haemodynamic changes of human cerebral AVMs
Sheep Intracranial Brain volume//little morphological AVM resemblance, few “en –
passange” feeders
Extracranial Brain volume//little morphological AVM resemblance, few “en Quian et al. [34]
passange” feeders
Dog Intracranial Human resemblance (brain volume, physiology and Carvi y Nievas [5]
haemodymamics)//handling expertise, animal facilities, high cost Pietilä et al. [36]
Extracranial Human resemblance (brain volume, physiology and Schumacher and
haemodymamics)//circle of Willis compensation in extracranial Schellhammer
shunts [38]
Cat Intracranial Brain volume//rete caroticum, venous outflow with intracranial –
direction
Extracranial Brain volume//rete caroticum, venous outflow with intracranial direction Miyasaka et al. [28]
Sakaki et al. [37]
Spetzler et al. [43]
Tokiwa et al. [44]
Rat Intracranial Handling expertise, animal facilities, low cost, availability//small –
brain and vessels, technical difficulties
Extracranial Handling expertise, animal facilities, low cost, availability//little Bederson et al. [4]
human resemblance, brain oedema and ischaemia may result from Hai et al. [15]
complete occlusion of extracranial arterial and venous vessels in
Irikura et al. [19]
end-to-end anastomosis
Kojima et al. [22]
Morgan et al. [29]
[30]

normal nervous tissue surrounding the arteriovenous shunt,
emphasizing on the importance of both the arterial hypoten-
sion and the venous hypertension [4, 15, 22, 30, 38]. Besides
that, it has been possible to highlight not only the loss of
vascular autoregulation under chronic hypoperfusion condi-
tions [4, 43], but also the drop in the NPPB threshold and even
the abolition of the vasomotor response following the restora-
tion of the normal CBF when the fistula is suddenly closed
and under arterial hypertension [19, 29, 37].
On the other hand, neuropathological studies have demon-
strated the presence of reactive changes to the parenchymal
ischaemia that the tissue surrounding the fistula has suffered
as well as significant vascular alterations such as the lack of
perivascular podocytes or the increased capillary density as a
manifestation of neovascularization [4, 13, 15, 36, 40, 41].
Besides that, an overexpression of VEGF has been showed in
chronic hypoperfusion and venous hypertension experimental
models. In such cases, the low CBF has been interpreted as an
angiogenic stimulus [13, 16, 22]. Finally, electron microscopy
has evidenced secondary neuronal injury related to the reper-
fusion that follows the restoration of CPP in cases of chronic
hypoperfusion [17].
In spite of the effort to highlight the similarities with human
AVMs, animal models seem to be unable to reproduce their
complex angioarchitectural features such as the arteriovenous
shunts, the nidus compartmentalization, the afferent tortuosity,
the intranidal aneurysms, the risk of haemorrhage, the variable
haemodynamic resistance, the abnormal venous drainage, the
“steal phenomenon” or the NPPB phenomenon after AVM
therapy. Thus, it seems impossible to recognize a single ani-
mal model as the most suitable one and capable of reproduc-
ing and representing all these features. Table 1 summarizes the
main advantages and disadvantages of the different models.
However and despite its imperfections, experimental research
has made possible the knowledge and consolidation of certain
concepts with regard to the NPPB phenomenon.
Acknowledgments The authors thank Cristina Ruiz Quevedo for as-
sistance in the translation of the manuscript.
Sources of funding None.
Disclosures None.
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Comments
K.-P. Sein and I. Erol Sandalcioglu, Hannover, Germany
The treatment of cerebral arteriovenous malformations (AVM) re-
mains challenging, not only in terms of determining the right treatment
indication and treatment strategy. Once obliteration of the nidus is
achieved, the knowledge and understanding of hemodynamic changes
is of utmost importance to guide the patient after treatment through this
period in order to prevent haemorrhage. Since the normal perfusion
pressure breakthrough theory was introduced in 1978, numerous exper-
imental and animal models have been suggested. Gutierrez-Gonzalez and
coworkers nicely summarized the pathophysiological concepts and dif-
ferent animal models and their major results. As the authors also point out
the limitations of the listed studies, the need of valuable models for future
investigations becomes evident.
Peter Nakaji, Phoenix, USA
The original paper proposing the theory of normal perfusion pressure
breakthrough (NPPB) with arteriovenous malformations is now four
decades old. Since that time, much debate has been had on the subject,
though for many it has become an accepted, if uncommon, phenomenon.
More frequently, postoperative haemorrhage has been attributed to in-
complete closure of fragile AVM feeding vessels, and edema and brain
swelling have been felt to be due to loss of normal venous drainage in the
course of AVM resection. In this review by Dr. Raquel Gutierrez-
Gonzalez et al., the authors describe and examine the experimental
models for studying NPPB.
The questions that a cerebrovascular neurosurgeon has about NPPB
revolve around predicting who might have a state of chronic steal-
induced vasodilation and thus be at risk, and what to do about it,
preferably before haemorrhage and swelling occur. For example, one
strategy I routinely employ in my practice at the Barrow Neurological
Institute is to induce relative mild hypotension on an empiric basis on my
post-resection AVM patients (e.g. target SBP first 24 h 100 mmHg, then
120 mmHg for 24 h, then 140 mmHg for 24 h, followed by ‘normal’
blood pressure for that patient). However, this practice is not actually

tailored to the individual patient, about whose regional haemodynamics
we know little.
So how can the experimental models clarify things further?
Animal models often have anatomy very different from a human
and are largely based on fistula creation, which, while similar, is
not the same as an AVM. The fistulas made are often at a
distance to the brain (e.g. in the neck) and may not have the
same combination of hypotension on the brain and hypertension
in the venous drainage bed as a real AVM has. Furthermore, all
AVMs have been in place a very long time, whereas any changes
occurring in response to a fistula are relatively short term. The
authors voice similar concerns. Their review of this field leads to
Neurosurg Rev
the conclusion that despite admirable efforts of researchers to
date, better models are needed.
Perhaps the best model is the real patient. In the modern era, an
increase in observations obtained from humans with AVMs may be the
most productive direction for such investigation. Pre- and postoperative
flow imaging using perfusion MRI coupled with intraoperative pre- and
post-resection direct brain visualization using laser speckle imaging, for
example, might be more illuminating. Even the placement of a flow probe
into the brain near the operative bed for postoperative monitoring would
be both ethical and reasonable, given the risks patients must tolerate in the
periresection period. In short, the authors remind us that there are still
many opportunities for meaningful investigation in the NPPB field.