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1Embryological and Anatomical Introduction20
Fig. 1.24. Subpial space:inflammation. Inflammatory
cells (P,polymorphonuclear
leukocyte; L,lymphocyte;M,
monocyte/macrophage) enter
the subarachnoid space or the
subpial space from the veins
(right) and are then distributed into the perivascular
spaces of meningeal vessels.
There is little penetration into
the perivascular spaces of the
brain
Fig. 1.25. Subpial space:tumors. Leukemic or primary
cerebral lymphoma cells (L)
enter the subarachnoid and
subpial spaces from the vessels and form a dense reticulin network. Cells penetrate
the brain either by direct invasion or along perivascular
spaces. Carcinoma (Ca)and
malignant melanoma cells
may remain in the subarachnoid space or they may penetrate the subpial spaces and
pass along perivascular spaces
into the central nervous system. Carcinoma cells may also
penetrate directly through the
glia limitans into the brain
1.2 Leptomeninges
MRI with gadolinium enhancement (Bradley and Bydder 1990) has
proved to be of great value in detecting the two major pathologies of the
leptomeninges, i.e., inflammation and invasion by neoplastic cells
(Weller 1990). Meningeal enhancement has been reported in a number of
different conditions, including tuberculous meningitis (Kioumehr et al.
1994), Lyme disease (Demaerel 1994),and primary meningeal lymphoma
(Berciano et al. 1996); MRI appears to be more suitable than computed
tomography (CT) for the identification of leptomeningeal metastases,
particularly in the spinal cord (Chamberlain et al. 1990).
Leptomeninges cover the surface of the brain and spinal cord as well as
the nerve roots and blood vessels within the subarachnoid space (Weller
1995). The outer, arachnoid mater,is composed of multiple layers of leptomeningeal cells, which form an impermeable barrier to cerebrospinal
fluid (Alcolado et al.1988). Separating the arachnoid and pia mater is the
subarachnoid space containing cerebrospinal fluid and major arteries
and veins supplying the central nervous system. Delicate ligaments and
perforated sheets of leptomeninges traverse the subarachnoid space,
forming compartments filled with cerebrospinal fluid.
Sheet-like and filiform trabeculae traversing the subarachnoid space
are composed of bundles of collagen fibers and a thin outer coating of
leptomeningeal cells (Weller 1995; Alcolado et al. 1988; Hutchings and
We ller 1986).Blood vessels within the subarachnoid space are suspended
by such trabeculae, which have a structure similar to the major dorsal
and ventral ligaments of the spinal cord and the dentate ligaments
(Nicholas and Weller 1988).
The pia mater (Alcolado et al. 1988) is a delicate sheet, often only one
cell thick; it is in contact with the surface of the brain, spinal cord, and
nerve roots. Pia follows the gyri and sulci of the cerebral hemispheres and
the folia of the cerebellum and closely invests the surface of the spinal
cord.It is separated from the surface of the brain by the subpial pace and,
as it is reflected onto the surface of blood vessels in the subarachnoid
space, pia mater separates the subpial space from the subarachnoid
space.
Individual cells of the pia mater are joined by desmosomes and gap
junctions (Alcolaclo et al. 1988; Spray et al. 1991),and they form a designated interface between the cerebrospinal fluid of the subarachnoid
space and the surface of the brain (Feuer 1991).The pia mater appears to
act as an active barrier, and its cells actively pinocytose particulate matter and contain enzymes such as catechol-O-methyl transferase (Kaplan
1981) and glutamine synthetase (Feuer 1991),which degrade neurotransmitters. Growth factors such as transforming growth factor b (TGFb)
have also been identified in leptomeningeal cells (Johnson et al. 1992).
21Leptomeninges
1.3 Subpial Space
1.3.1 Anatomy
The anatomy of the subpial space is summarized in Fig. 1.19.The subpial
space is normally difficult to discern with light microscopy and was not
well recognized as a separate compartment until ultrastructural studies
(Huntchings 1986) confirmed that it was bound on one side by a complete
sheet of pia mater and on the other by the glia limitans (Alcolado et al.
1988; Huntchings and Weller 1986; Zhang et al. 1990).
As shown in Fig. 1.19, the pia mater is reflected onto the surface of arteries and veins in the subarachnoid space and coats collagenous trabeculae extending from the arachnoid to the pia mater.A sheath of pia mater
cells extends from the deep aspect of the pia mater proper to accompany
arteries into the brain, but this sheath is either incomplete or absent
around veins (Zhang et al.1990).
The perivascular space formed by this tube-like insertion of pia mater
appears to be a major pathway for the drainage of interstitial fluid from
the brain into the perivascular spaces of the leptomeningeal arteries and
thence into the subarachnoid space (Weller et al. 1992). With the barrier
and enzymatic properties of the pia mater mentioned above, the sheath
of pia mater may also form a regulatory interface separating blood vessels and their nerve supplies from the surrounding brain tissue.
The glia limitans is composed of compacted astrocyte processes, often
joined by gap junctions (Peters and Feldman 1976). A basement membrane coats the astrocytic component of the glia limitans and separates it
from the small collagen fibers that form a web-like matrix on the surface
of the brain.
Over the surface of the cerebral hemispheres,the subpial space largely
contains arterioles (Fig. 1.20), small veins (Fig. 1.21) and bundles of collagen of varying size, dissociated pia mater cells, and occasional inflammatory cells.
Bundles of collagen fibers extend from the trabeculae that cross the
subarachnoid space and expand in a fan-like manner into the subpial
space (Fig. 1.19), apparently forming an anchor for the trabecula (Alcolado et al. 1988).Similar anchorage is seen in the arachnoid mater (Weller
1995; Alcolado et al. 1988). Arterioles within the subpial space are fine
branches of the major arteries in the subarachnoid space. They have
smooth muscle coats of varying thickness and an outer coating of leptomeningeal (pia mater) cells. Small veins in the subpial space, on the
other hand, are larger in diameter and have thin walls with few smooth
muscle cells and no outer coating of pia mater cells.
The subpial space of the spinal cord contains a thicker layer of collagen
bundles (Nicholas and Weller 1988), as seen in the scanning electron micrograph in Fig. 1.22. This thick layer of collagen is continuous with the
dentate ligaments laterally and may play a role in stabilizing the cord
(Nicholas and Weller 1988).
The nerve supply of the leptomeninges and the vessels in the subpial
space has been mainly investigated at the level of the spinal cord in experimental animals.Innervation of the pia and leptomeningeal ligaments by
1Embryological and Anatomical Introduction22
small sensory fibers appears to be derived from ventral roots (Risling et
al. 1994;Parke and Whalen 1993), although this origin is disputed (Karlsson and Hildebrand 1993).
Over the surface of the cerebral cortex, some blood vessels may be supplied by branches from cortical neurons (McKenzie 1990). Small nerve
branches consisting of myelinated and nonmyelinated fibers can be identified within the spinal leptomeninges of the spinal cord in humans
(Nicholas and Weller,unpublished observations).
1.3.2 Relationships of the Subpial Space
Although the subpial space is separated from the subarachnoid space by
the pia mater, it is continuous with the perivascular spaces of the central
nervous system.A sheath of pia mater surrounds the arteries as they enter the brain and divides the periarterial space into two compartments
(Fig. 1.19). It is probably the inner space between the pia mater sheath
and the vessel that is the conduit for fluid drainage (Weller 1992), but
which of these spaces should be called the Virchow Robin space is unclear. The relationships of the subpial space are particularly important
when considering pathological reactions within the space.
1.3.3 Pathology
1.3.3.1 Inflammation
Inflammatory leptomeningitis may be due to a number of different types
of organisms or may even be due to the escape into the cerebrospinal fluid of sterile inflammatory agents,such as cholesterol or keratin,from epidermoid cysts or craniopharyngiomas. A variety of blood-borne cells
may be associated with inflammation of the leptomeninges,and the time
course and nature of the inflammation depend upon the stimulating
agent (Weller 1990).
Pyogenic bacterial infections, such as streptococcal or staphylococcal
leptomeningitis, result in exudation of large numbers of polymorphonuclear leukocytes into the subarachnoid and subpial spaces. In the later
stages of infection, when the polymorphonuclear leukocytes have ingested bacteria and died, macrophages derived from blood monocytes
(Fig. 1.23) replace and ingest the dead polymorphs, dead bacteria, fibrin,
and tissue debris. Macrophages generally arrive 2–3 days after the initial
infection.
The pattern of inflammation in viral meningitis is mainly that of lymphocyte exudation into the subarachnoid and subpial spaces; in fungal
and tuberculous infections, there is granulomatous inflammation in addition to lymphocyte infiltration, often with multinucleate macrophagederived giant cells and areas of caseation (Weller 1990).
The time course and intensity of breakdown of the blood–brain barrier is different in each of these cases. In purulent leptomeningitis, significant alteration in the blood-brain barrier may only last for a few days to
23Inflammation
1week before the barrier is restored. In more chronic infections, such as
tuberculosis, disruption of the blood-brain barrier may last much longer.
Inflammatory cells, polymorphonuclear leukocytes, monocytes, or
lymphocytes pass from the blood into either the subarachnoid space or
the subpial space through the walls of veins (Fig. 1.24). Although in the
rest of the body most of the traffic of inflammatory cells is through the
walls of postcapillary venules, they escape from large veins into the subarachnoid space.Traffic of inflammatory cells through the walls of smaller veins in the subpial space may be an important route for cells to enter
both the subpial and the subarachnoid spaces.
Figure 1.24 shows how inflammatory cells entering the subpial space
may be distributed along perivascular spaces of arteries and veins in the
subarachnoid space and penetrate the pia mater (Krahn 1981) to enter
the subpial space. By expanding the subpial space, the relationships
between the pia mater and the glia limitans become clearer by light
microscopy, and the presence of a leptomeningeal sheath around blood
vessels in the subarachnoid space is clearly demonstrated (Fig. 1.23).
Although there is a connection between the subpial space and perivascular spaces within the brain, inflammatory cells rarely extend far into
the perivascular spaces of the central nervous system.It appears that the
pia mater is an effective barrier to the spread of bacteria into the subpial
space. The pia mater also forms a barrier to the spread of red blood cells
from the subarachnoid space, and blood does not usually penetrate the
perivascular spaces of the brain following subarachnoid hemorrhage
(Hutchings and Weller 1986).
Hemorrhage does occur in the subpial space, particularly in infants
(Friede 1972). Subpial hemorrhage can be distinguished from subarachnoid hemorrhage, since subpial hemorrhage usually remains closely
confined and spreads in the subpial space into sulci rather than filling the
sulci, as occurs in subarachnoid hemorrhage.
1.3.3.2 Tumor
Breakdown of the blood-brain barrier and gadolinium enhancement is
well recognized in association with poorly differentiated glial tumors,
such as glioblastoma multiforme and anaplastic astrocytoma, as is the
absence of a blood-brain barrier in association with solid metastatic carcinomas and primary lymphomas in the nervous system (Bradley and
Bydder 1990).
Enhancement due to breakdown of the blood-brain barrier also occurs
in carcinomatous, lymphomatous, and leukemic meningitis and is well
demonstrated by MRI (Berciano et al.1996; Chamberlain et al. 1990).
Neoplastic cells enter the subarachnoid and subpial spaces by penetrating blood vessel walls. However,leukemic and lymphoma cells show a
different pattern of invasion from carcinomas. Although leukemic
involvement of the central nervous system is common, it is usually
only primary lymphomas of the central nervous system that invade the
parenchyma of the brain and spinal cord (Weller 1990; Berciano et al.
1996).
1Embryological and Anatomical Introduction24
Leukemic and lymphoma cells in the subarachnoid and subpial spaces
induce the formation of a delicate network of reticulin (small collagen;
Fig. 1.25). From the subpial space,cells penetrate the glia limitans and invade the surface of the brain or penetrate deeply into the parenchyma
along perivascular spaces (Fig. 1.25). Carcinomas and malignant
melanoma,on the other hand, invade the subarachnoid space but may be
prevented either by the pia or the glia limitans from directly invading the
brain. Some carcinomas remain almost totally confined to the subarachnoid space with minimal invasion of the brain,whereas other carcinomas
and malignant melanomas enter the subpial space and penetrate deep
into the brain along perivascular spaces (Fig. 1.25).
Direct invasion through the glia limitans is also seen in some carcinomas. Such invasion may increase the thickness of the zone of blood–brain
barrier breakdown and thus enhancement on MRI. The mechanisms of
blood–brain barrier breakdown in carcinomatous meningitis are not
entirely clear.
Once the carcinoma has entered the subpial and arachnoid spaces, it
appears that the tumor cells continue to influence the characteristics of
blood vessels in the region, as with solid metastases. Carcinoma cells are
known to produce growth factors (Wiestler 1994),which may modify the
permeability characteristics of the brain vessels in the region of leptomeningeal metastases.
The significance of the subpial space lies mainly in the blood vessels
that traverse it,in its proximity to the surface of the brain and in its connections with the perivascular spaces of the central nervous system. For
the most part, inflammatory cells entering the subpial space pass into the
subarachnoid space rather than into the brain. In many cases of leptomeningitis, there is only a microglial reaction in the surface regions of the
brain rather than direct invasion by inflammatory cells. The picture is
rather different in carcinomatous or lymphomatous meningitis,in which
invasion of the surface of the brain is as common as invasion of the
perivascular spaces.
25Tumor
2.1 Introduction 28
2.2 From Adults to Children 28
2.3 Vascular Lesion Types and Disease Groups 31
2.3.1 Nonproliferative Lesions 34
2.3.1.1 Arteriovenous Lesions 34
2.3.1.2 Isolated Brain AVMs 35
2.3.1.3 CAVFs 39
2.3.1.4 VGAMs 39
2.3.1.5 Cerebrofacial Arteriovenous Metameric Syndromes 39
2.3.1.6 Dural Lesions 41
2.3.1.7 Telangiectasias 41
2.3.1.8 The Blue Rubber-Bleb Nevus or Bean Syndrome 41
2.3.1.9 Venous Malformations (Cavernomas) 44
2.3.1.10 Venous Angiomas or Developmental Venous Anomalies 45
2.3.1.11 Cerebrofacial Venous Metameric Syndrome
(Formerly Sturge-Weber Syndrome) 47
2.3.1.12 Induced Pial Shunts 47
2.3.1.13 Spinal Cord AVM 48
2.3.1.14 General Conclusions on Vascular Lesions 48
2.3.2 Proliferative Lesions 49
2.3.2.1 PHACE or PHACES 51
2.3.2.2 Diffuse Angiodysplasia 51
2.4 Classification of CAVMs by Age Group 56
2.4.1 Fetal Age 56
2.4.2 Neonatal Age 59
2.4.3 Infancy 59
2.4.4 After 2 Years 62
2.5 Classification by Symptom Group 63
2.5.1 Congestive Cardiac Manifestations 63
2.5.2 Hydrodynamic Disorders 64
2.5.3 Melting-Brain Syndrome 73
2.6 Clinical Evaluation Scores 77
2.7 Revised Concept of the Congenital Nature
of Vascular Malformations 85
2.7.1 Genetics 85
2.7.1.1 Familial Hemiplegic Migraine 85
2.7.1.2 Familial Cerebral Aneurysms 86
2.7.1.3 PKD1 and Bourneville PDK1-PDK2 86
2.7.1.4 Ehlers-Danlos Type IV 87
2.7.1.5 Multiple Cutaneous Mucous Venous Malformations,
Blue Rubber Bleb Nevus Syndrome 87
2.7.1.6 CADASIL 87
2.7.1.7 Familial Paragangliomas 87
2.7.1.8 Familial Cavernomas 87
2.7.1.9 Neurofibromatosis-1 and Other Collagen Diseases 88
2.7.1.10 Hemorrhagic Hereditary Telangiectasia
or Rendu-Osler-Weber Disease 88
2Introduction and General Comments
Regarding Pediatric Intracranial
Arteriovenous Shunts
2.8 Vascular Remodeling and the Congenital Nature
of Arteriovenous Shunts 93
2.8.1 Endothelium as a Sensor and Transducer of Signals 94
2.8.2 Endothelium-Specific Receptor-Coupled Event 95
2.8.3 Endothelium and Mediator-Effector Molecules Involved
with Remodeling 95
2.8.4 Role of Matrix Modulators in Vascular Remodeling 95
2.8.5 Clinical Implications of Vascular Remodeling 95
2.1 Introduction
Since 1982, more than 3,000 patients with cerebral arteriovenous malformations (CAVMs) have been referred to the three authors, including
800 children under the age of 16 years. Our active involvement in the
management of vein of Galen aneurysmal malformations (VGAMs)
started in 1984; since then, 350 children with VGAMs have been seen by
the group in Bicêtre Hospital alone, where it accounts for 50% of total
pediatric intradural intracranial AVS patients. More than 25 new VGAM
patients are now referred to us each year. Over the past 20 years, these
centers combined have collected about 500 VGAMs. In comparison,
the two historically important series describing the surgical management
of this disease show referral patterns of roughly one new patient with
VGAM per year: the Hospital for Sick Children in Toronto (29 patients
over 30 years) and the Royal Alexandra Hospital in Sydney (13 patients in
10 years). It is also of interest to note that in these surgical series,VGAM
represented 34% of all the CAVM managed in children.
A survey on the European continent (Raimondi 1992) showed that in
the year 1989 in a population of 530 million people, 189 surgical procedures were performed for vascular disease in children, i.e., about one
procedure a year per 3 million people. Most active neurosurgical centers
in Europe perform between 10 and 15 procedures for this disease in children, which in most cases consists of cavernoma removal. In our interventional centers, 100–170 pediatric neurovascular procedures are performed each year, mostly AVMs. The large number of patients seen does
not reflect a true population profile with any epidemiological significance,but rather our status as a quaternary referral center for Europe and
North America. In view of the distances involved, only the more complex
cases tend to be referred while the simpler ones are more likely managed
locally.Our current practice and management reflects both the improvement in fetal and neonatal diagnosis and care of children with neurovascular disease as well as the progressive shift toward endovascular management in the treatment of children with brain AVSs.
2.2 From Adults to Children
Cerebral arteriovenous (AV) shunts have different characteristics in children than in adults. Children can have multifocal lesions,induced remote
AV shunts (Garcia Monaco 1991c; Iizuka 1992),large venous ectasias, highflow lesions,and single hole arteriovenous fistulas (Weon et al. 2005;Yoshi-
2Introduction and General Comments Regarding Pediatric Intracranial Arteriovenous Shunts28
da et al. 2004),venous thrombosis,brain atrophy, and systemic phenomena
(Cronqvist 1972; Cumming 1980; Willinsky et al. 1990a). Conversely, highflow angiopathic changes are rare in children, as are flow-related arterial
aneurysms (Lasjaunias 1988a), while proximal occlusive arteriopathy is
more frequent.For this reason,management protocols derived from experience in adults should not be applied to the pediatric population. In particular, adult-based classifications and AVM grading according to the expected surgical outcome is particularly inappropriate in children,in whom
(a) cerebral eloquence is difficult to assess,particularly in the first few years
of life, (b) most lesions are fistulas or multifocal, (c) drainage usually affects
the entire venous system,and (d) the potential for recovery is different.It is
often believed that the adult type of classification and grading of AVMs indicates or in some way corresponds to the natural evolution of the lesion,
and, although unintentionally, this has created a significant amount of misunderstanding and confusion.A difficult to operate AVM (i. e.,a high-grade
AVM) is not necessarily a dangerous one for the patient if not operated upon or more dangerous for the patient than a low-grade AVM. In addition to
the conventional objectives,the decision-making process in children must
take into consideration additional specific details pertaining to the veins
and the myelinization process.Thereafter,staged partial treatment of progressive deficits associated with congested cerebral veins,poorly controlled
seizures,hemorrhagic episodes with or without specific changes upstream
or downstream from the AVM, or headaches in children without ventricular enlargement or macrocrania may all represent good indications for
treatment.Neurocognitive evaluation is the key follow-up criterion in children even without deficits, hemorrhage, or seizures, as it helps in the
assessment of treatment quality and success. Failure to obtain a normal
maturation process may constitute a therapeutic failure if the optimum
moment for intervention has been missed (therapeutic window).
When discussing CAVMs or vascular diseases in children, one might
wonder whether it represents an artificially created grouping. AVMs in
children are primarily characterized by diagnostic and therapeutic difficulties specific to the population in which they occur. CAVM corresponds
more to a clinical group than a nosological one. However, some rare lesions (see Chaps. 4,7,12, this volume) are exclusively encountered in children, mainly in neonates and infants.
In addition, the anatomic and physiologic characteristics of the neonatal and infant brain and the immaturity of its systemic flexibility (hydrovenous) create a specific group of nonhemorrhagic symptoms and
therapeutic challenges. This vulnerability means that the lesion rapidly
becomes lethal or creates a disabling state,whereas a similar lesion in an
adult might produce only few symptoms.
The clinical characteristics of CAVMs in children are therefore related
to the children themselves and their specific anatomy and physiology.
Children are not small adults and the therapeutic challenges cannot be
measured in terms of size of the target, but is related to our capability to
understand the other structures and processes involving the brain and its
vasculature and anticipate the potential interferences between the CAVM
and the maturing brain.
For a long time, vascular lesions in children were divided into nonproliferative and proliferative lesions. The former group comprises vascular
29From Adults to Children
2Introduction and General Comments Regarding Pediatric Intracranial Arteriovenous Shunts30
Scheme 2.1. Role of structural weaknesses in disease development
Scheme 2.2. Vascular diseases according to the arterio-veno-lymphatic tree
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