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Cavernous Malformations of the Nervous System 1st
Edition Daniele Rigamonti Md Digital Instant Download
Author(s): Daniele Rigamonti MD
ISBN(s): 9780521764278, 0521764270
Edition: 1
File Details: PDF, 3.52 MB
Year: 2011
Language: english
Cavernous Malformations
of the Nervous System
Cavernous Malformations
of the Nervous System

Edited by
Daniele Rigamonti
Johns Hopkins University
cambridge university press Cambridge University Press has no responsibility for the
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Singapore, São Paulo, Delhi, Tokyo, Mexico City internet websites referred to in this publication, and does
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Every effort has been made in preparing this book to provide
Published in the United States of America by Cambridge
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University Press, New York
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© Cambridge University Press 2011
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This publication is in copyright. Subject to statutory
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Readers are strongly advised to pay careful attention to
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no reproduction of any part may take place without the
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permission of Cambridge University Press.

First published 2011

Printed in the United Kingdom at the University Press,

Cambridge

A catalogue record for this publication is available from the

British Library

Library of Congress Cataloging in Publication data

Cavernous malformations of the nervous system / edited by
Daniele Rigamonti.
p. cm.
ISBN 978-0-521-76427-8 (hardback)
1. Cerebral arteriovenous malformations. 2. Brain –
Hemorrhage. I. Rigamonti, Daniele, 1951–
II. Title.
RD594.2.C385 2011
616.80 1–dc22
2011008052

ISBN 978-0-521-76427-8 Hardback

I dedicate this book to my wife and children, to the memory
of my father, who exemplified for me how a physician
should practice, and to Bunny and Charles Salisbury
who supported my research over all these years.
Contents
Preface page ix
List of contributors x

Section 1. Biology 9. Hemorrhage: new and recurrent 79

Colin B. Josephson and Rustam Al-Shahi
1. Pathology of cavernous malformations 1
Salman
Sachin Batra, Barbara Crain, Rachel Engelmann,
Joaquin Camara-Quintana and Daniele 10. Cavernous malformations and epilepsy:
Rigamonti medical management of seizures and the
presurgical evaluation of medically intractable
2. Epidemiology and natural history of cavernous
epilepsy 91
malformations 9
Gregory K. Bergey
Rachel Engelmann, Sachin Batra, Angela Li,
Joaquin Camara-Quintana and Daniele
Rigamonti Section 3. Therapy
3. Familial cavernous malformations: a historical 11. The pros and cons of conservative and surgical
survey 15 treatment of cavernous malformations 103
Leslie Morrison Pablo F. Recinos, Sheng-Fu Larry Lo and Daniele
4. Clinical and molecular genetics of cerebral Rigamonti
cavernous malformations 21 12. Surgical treatment of cavernous
Xavier Ayrignac and Elisabeth Tournier-Lasserve malformations associated with epilepsy 115
5. Molecular biology of cerebral cavernous Mahua Dey and Issam Awad
malformation 31 13. Surgery of spinal cavernous
Jun Zhang malformations 127
6. Cavernous malformations and radiation 41 M. Yashar S. Kalani and Robert F. Spetzler
Eugenio Pozzati and Nicola Acciarri 14. Surgical treatment of cavernous
malformations in children 135
Edward R. Smith and R. Michael Scott
Section 2. Clinical features, imaging,
15. Resection of cavernous malformations of the
and diagnostic work-up brainstem 143
7. Neuroimaging of cavernous Helmut Bertalanffy, Jan-Karl Burkhardt, Ralf
malformations 49 Alfons Kockro, Oliver Bozinov and Johannes
Doris D. M. Lin and Wael Abdalla Sarnthein
8. Clinical features and medical management of 16. Principles for managing cavernous
cavernous malformations 65 malformations in eloquent locations 161
Michel J. Berg and Tegan Vay Uğur Türe and Ahmet Hilmi Kaya

vii
 Contents

17. Radiosurgery of cavernous malformations: the 19. Special problems in cavernous malformations:
Pittsburgh experience 173 migraine, pregnancy, hormonal replacement,
Douglas Kondziolka, L. Dade Lunsford, Hideyuki anticoagulation, NSAIDs, stress, and altitude
Kano and John C. Flickinger elevation changes 185
Richard Leigh and Robert J. Wityk

Section 4. Special aspects

18. Genetic counseling 181
Leslie Morrison Index 191

Color plate section is to be found between

pp. 102 and 103.

viii
Preface

The diagnosis and the management of cavernous the knowledge gained over past decades and the opin-
malformations (CMs) have been challenging and intri- ion of leading experts in the management of CMs. The
guing neurologists and neurosurgeons for several dec- book has been divided into four sections, each empha-
ades. Prior to the advent of MRI, the diagnosis of CM sizing specific aspects of the CMs.
was often limited to patients presenting with either Section I on basic aspects aims to provide the
hemorrhage or seizures. The advent of MRI has com- foundation for clinical decision-making regarding
pletely transformed the field and asymptomatic as medical and surgical management: it discusses the
well as symptomatic CMs are now increasingly being epidemiology and natural history of cavernomas. In
diagnosed. addition, this section contains chapters that bring
Along with an improved diagnosis, there has been to light current understanding of CM biology, molec-
an ever-improving understanding of their biology ular genetics, and the role of ionizing radiation in de
and the course of their natural history. Neurologists novo formation of CMs and the safety of radiation
and neurosurgeons nowadays still face the challenge sources frequently used for diagnostic and therapeutic
of determining the most appropriate treatment for purposes.
lesions that, even when clinically quiescent, may be Section II details imaging of CMs, the inconsisten-
characterized by evidence of hemorrhage on advanced cies in the criteria for defining hemorrhage in CMs,
imaging. Currently, there is a general consensus on and clinical features, including specifically seizures.
the conservative management of clinically benign Section III discusses therapy: the options available
CM, and on the appropriateness of surgical resection to the patient are outlined and their pros and cons
of symptomatic superficial lesions. Controversy per- discussed. The surgical chapters contain up-to-date
sists regarding the most appropriate approach to treat- information regarding the technique and outcomes
ing deep or infratentorial lesions. Surgical resection related to a specific location and problem. A radio-
performed by very experienced surgeons is a very valid surgical chapter outlines the role of radiosurgery in the
option for symptomatic deep or infratentorial lesions; management of cavernomas.
however, the risks associated with surgery in these Section IV, the last section of the book, deals with
locations are not negligible. The increased availability special aspects encountered in the management of
of radiosurgery as a tool for non-invasively reaching these patients.
deep lesions has been therefore met with enthusiasm This book is the result of tremendous efforts put in
by some physicians and patients dealing with sympto- by authors who have provided insightful guidance
matic CMs in deep or infratentorial lesions. critical in the discussion of the most appropriate man-
This book is an attempt to provide a foundation for agement of these lesions at this point in time. Special
an improved diagnosis and discussion of the treatment thanks go to the team at Cambridge University Press
options available for CMs by critically summarizing whose painstaking efforts made this book possible.

ix
 Contributors

Wael Abdalla Helmut Bertalanffy

Department of Radiology Professor of Neurosurgery
Johns Hopkins Hospital Center for Vascular Neurosurgery
Baltimore, MD International Neuroscience Institute
USA Hannover
Germany
Nicola Acciarri
Department of Neurosurgery Oliver Bozinov
Bellaria Hospital Department of Neurosurgery
Bologna University Hospital
Italy Zurich
Switzerland
Issam Awad
University of Chicago Jan-Karl Burkhardt
Pritzker School of Medicine Department of Neurosurgery
Chicago, IL University Hospital
USA Zurich
Xavier Ayrignac Switzerland
Hôpital Lariboisière Joaquin Camara-Quintana
Université Paris Departments of Neurosurgery
Paris Stanford University
France Stanford, CA
Sachin Batra USA
Department of Neurosurgery
Johns Hopkins Hospital Barbara Crain
Baltimore, MD Diagnostic Neuropathology
USA Department of Pathology
Johns Hopkins Hospital
Michel J. Berg Baltimore, MD
Strong Epilepsy Center USA
University of Rochester Medical Center
Rochester, NY Mahua Dey
USA University of Chicago
Pritzker School of Medicine
Gregory K. Bergey
Chicago, IL
Department of Neurology
USA
Johns Hopkins Hospital
Baltimore, MD
USA

x
 List of contributors

Rachel Engelmann Richard Leigh

Department of Neurosurgery Department of Neurology
Johns Hopkins Hospital Johns Hopkins Hospital
Baltimore, MD Baltimore, MD
USA USA
John C. Flickinger Angela Li
Department of Radiation Oncology Department of Neurosurgery
University of Pittsburgh Medical Center Johns Hopkins Hospital
Pittsburgh, PA Baltimore, MD
USA USA
Colin B. Josephson Doris D. M. Lin
Clinical Neurosciences, Bramwell Department of Radiology
University of Edinburgh Johns Hopkins Hospital
Western General Hospital Baltimore, MD
Edinburgh USA
UK
Sheng-Fu Larry Lo
M. Yashar S. Kalani Department of Neurosurgery
Division of Neurological Surgery Johns Hopkins Hospital
Barrow Neurological Institute Baltimore, MD
St Joseph’s Hospital and Medical USA
Phoenix, AZ
USA L. Dade Lunsford
Department of Neurological Surgery
Hideyuki Kano University of Pittsburgh Medical Center
Department of Neurological Surgery Pittsburgh, PA
University of Pittsburgh Medical Center USA
Pittsburgh, PA
USA Leslie Morrison
Department of Neurology
Ahmet Hilmi Kaya UNM School of Medicine
Department of Neurosurgery Albuquerque, NM
Faculty of Medicine USA
Ondokuz Mayis University
Kurupelit, Samsun Eugenio Pozzati
Turkey Neurosurgery Department
Bellaria-Maggiore Hospital
Ralf Alfons Kockro Bologna
Department of Neurosurgery Italy
University Hospital
Zurich Pablo F. Recinos
Switzerland Department of Neurosurgery
Johns Hopkins Hospital
Douglas Kondziolka Baltimore, MD
Department of Neurological Surgery USA
University of Pittsburgh Medical Center
Pittsburgh, PA Daniele Rigamonti
USA Department of Neurosurgery
Johns Hopkins Hospital

xi
 List of contributors

Baltimore, MD Elisabeth Tournier-Lasserve

USA Hôpital Lariboisière
Université Paris
Rustam Al-Shahi Salman
Paris
Clinical Neurosciences, Bramwell France
University of Edinburgh
Western General Hospital Uğur Türe
Edinburgh Department of Neurosurgery
UK Yeditepe University School of Medicine
Istanbul, Ankara
Johannes Sarnthein Turkey
Department of Neurosurgery
University Hospital Tegan Vay
Zurich University of Rochester
Switzerland School of Medicine and Dentistry
Rochester, NY
R. Michael Scott USA
Department of Neurosurgery
The Children’s Hospital Robert J. Wityk
Boston, MA Department of Neurology
USA Johns Hopkins Hospital
Baltimore, MD
Edward R. Smith USA
Department of Neurosurgery
The Children’s Hospital Jun Zhang
Boston, MA Department of Anesthesiology
USA Texas Tech University
Health Science Center
Robert F. Spetzler El Paso, TX
Barrow Neurological Institute USA
Phoenix, AZ
USA

xii
 Section 1 Biology

Pathology of cavernous malformations

Chapter

1 Sachin Batra, Barbara Crain, Rachel Engelmann, Joaquin

Camara-Quintana and Daniele Rigamonti

Cerebrovascular malformations are classified as caver- surrounded by a basal lamina. While capillaries have
nous malformations (CMs), arteriovenous malforma- just the endothelial cell layer, all other vessels have one
tions (AVMs), developmental venous anomalies or more layers of smooth muscle cells as well as some
(DVAs) and capillary telangiectasias (CTs). CMs are the pericytes immediately adjacent to the endothelial cells.
second most common form of cerebrovascular malfor- Surrounding the entire vessel are astrocytic endfeet
mation and constitute up to 10–15% of the total [1,2]. which comprise the glia limitans. Together, the endo-
In the past, CMs were not visualized on radiological thelial cells, their tight junctions, and the astrocytic
examinations such as CT scanning or angiography endfeet form the morphologic basis of the blood–
and were therefore referred to as angiographically brain barrier.
occult or cryptic vascular malformations. Recent Like capillaries, the blood vessels of CMs lack
studies have resurrected the old suspicion that CMs smooth muscle cells and have a homogeneous, hyali-
are vascular tumors [3], hence the alternative terms nized appearance in sections stained with hematoxylin
cavernous hemangiomas, cavernomas, or cavernous and eosin (Fig. 1A). The overall arrangement of vessels
angiomas. Clinical features of CMs include epilepsy is compact, with the classic appearance being one of
(22–50%), focal deficits (20–45%), headaches back-to-back vessels without intervening parenchyma.
(6–34%), or hemorrhages (up to 56%); CMs may However, most lesions also contain some areas with
also remain clinically silent (up to 40%) [4–8]. more loosely packed vessels [18]. Thrombosis is com-
mon in these low-flow malformations as well as acute,
Macroscopic and microscopic features organized, and recanalized thrombi, or even com-
CMs resemble well circumscribed, multilobulated, pletely occluded vessels (Fig. 1B). Calcification is com-
mulberry-like structures ranging in size from a few mon both within vessel walls and within the adjacent
millimeters to several centimeters in diameter [2,9,10]. parenchyma. In our unpublished series of 24 patients
Intracranial CMs are more frequently located supra- who underwent surgery for CMs, 58% had thrombo-
tentorially (64–84%) while spinal lesions are fre- sis, 41% had calcification, and 4% (one case) showed
quently located in the lower thoracolumbar region intervening parenchyma; the true incidence of these
(97%) [2,11,12]. They have been observed in all cort- processes was likely higher, as the volume of material
ical locations as well as in deep locations like the basal sampled was small.
ganglia, thalamus, cerebellum and the brainstem CMs are generally surrounded by a rim of fibrosis
[2,13,14]. Lesions of the cerebellopontine angle, pitui- with associated hemosiderin deposition (Fig. 1C). The
tary, and periventricular region have all been reported appearance of this tissue is distinctive enough to be
to have intraventricular CMs [15–17]. strongly suggestive of cavernous angioma in the proper
The histological features of CMs are best under- setting [19]. Hemosiderin may also be present in the
stood in the context of normal vascular anatomy. adjacent neuropil, where it may be responsible for
Normal cerebral blood vessels are lined by endothelial occurrence of seizures [20]. In our series, 92% of CMs
cells joined by tight junctions. The endothelial layer is showed hemosiderin, with reactive astrocytosis in 29%.

Cavernous Malformations of the Nervous System, ed. Daniele Rigamonti. Published by Cambridge University Press.
© Cambridge University Press 2011.

1
 Section 1: Biology

Figure 1.1. (A) The back-to-back blood

vessels of cavernous malformations have
thick, amorphous walls. (B) The blood
vessel shown here contains a recent
thrombus. (C) Densely packed
hemosiderin-laden macrophages are
often found within or around the rim of a
cavernous angioma. See color plate
section.

Immunohistochemistry of cavernous walls. However, normal endothelial cells often contain

small amounts of actin and that is also the case for the
malformations endothelial cells within CMs [23]. The subendothelial
The vessels of CMs have also been studied using layer may also contain actin immunoreactivity, likely
immunohistochemistry. Endothelial cells, astrocytes, in the basal lamina. Kilic et al. have suggested that the
and extracellular matrix proteins have all been studied. expression of smooth muscle actin-alpha could repre-
Expression of angiogenic growth factors, proliferation sent an immature molecular construction in CMs
markers, and molecules associated with angiogenesis compared to AVMS [23]. Collagen IV, fibronectin,
has also been examined. and laminin were similarly present in the endothe-
Many of the common endothelial cell markers are lium and subendothelium, but not in the amorphous
proteins that are potentially important in endothelial portion of the vessel wall. There was relatively more
cell interactions with platelets or with the coagulation fibronectin staining than laminin staining, a pattern
system. One of the endothelial cell markers that are that is also seen in early stages of angiogenesis. Faint
most commonly used for identification of endothelial staining for collagen III was present in the subendo-
cells is CD31 (platelet endothelial cell adhesion thelium only [23].
molecule PECAM 1). CD 31 is involved in endothelial There have been a number of studies examining
migration and angiogenesis and is expressed normally markers of angiogenesis in CMs. The best studied is
in CMs by both immunohistochemical and in situ vascular endothelial growth factor (VEGF), which is
hybridization techniques [21]. Expression of another found in the endothelium and subendothelium,
common marker, von Willebrand factor (a platelet- though more so in adults than in children [24–26].
vessel wall mediator in the coagulation system), is The VEGF receptor Flk-1 is found in endothelial cell
normal [21,22], as is the expression of thrombomodu- nuclei. Basic fibroblast growth factor (bFGF) and
lin [22]. Thus, there is no evidence from these immu- transforming growth factor-alpha (TGF-alpha) are
nohistochemical studies that endothelial cell abnormalities also found in the endothelial cells of adults and
are responsible for the frequent thrombosis seen children, with no difference between the two age
in CMs. groups [24–26].
As the vessel walls within CMs contain virtually no Hypoxia inducible factor-1alpha (HIF-1alpha),
smooth muscle cells, immunostains for smooth which is involved in oxygen homeostasis, is present
muscle actin-alpha show no reactivity within vessel in cavernous angiomas, in all layers in a pediatric study

2
 Chapter 1: Pathology of cavernous malformations

[26] and in endothelium in an adult study [24].

Endoglin, a normal endothelial antigen, a part of the
CMs and other vascular
TGF-beta1 and beta3 receptor complex and the gene malformations
mutated in hereditary hemorrhagic telangiectasia Like CMs, other types of vascular malformations have
Type 1, is also present in pediatric and adult samples characteristic macroscopic and microscopic features.
[24,26]. Of note, it has been suggested that endoglin Capillary telangiectasias (CTs) are composed of aggre-
may be important in vascular development and in gates of thin-walled vessels indistinguishable from
vascular remodeling in response to increased blood normal capillaries and separated by normal interven-
flow or shear stress [26,27]. ing brain parenchyma. While CMs are well circum-
Endothelial cell proliferation has been documented scribed radiologically, CTs may sometimes appear as a
by positive labeling using antibodies to proliferating nebulous blush [37]. Developmental venous anomalies
cell nuclear antigen (PCNA) and the Ki-67 epitope (DVAs, sometimes termed venous malformations) are
(MIB-1) [24,26]. collections of abnormally dilated veins forming a
caput medusa draining into a large central vein. As
described below, these frequently occur with CMs in
Etiology their vicinity. DVAs do not tend to bleed, and the
Cavernous malformations are generally believed to be intervening brain tissue appears normal. Arteriovenous
congenital lesions presenting at any age from the neo- malformations (AVMs) contain tortuous, anastomosing
natal period through adulthood. They may occur spor- blood vessels. Some of the vessels resemble true arteries
adically or with familial clustering. The familial forms or veins, but most are abnormal vessels of varying diam-
of lesions have been attributed to mutations of the eters whose walls are formed primarily by collagen
CCM1, CCM2 and CCM3 genes and are expressed as rather than by smooth muscle. Intervening parenchyma
autosomal dominant phenotypes with penetrances of is found across the lesion but is almost absent at the
60–88%, 100% and 63% respectively [28]. Although densely packed nidus of the lesion. The intervening and
the role played by the products of CCM genes is yet to surrounding parenchyma is often hemosiderin-stained
be established, animal models suggest that these are and gliotic. Calcification is common.
critical to angiogenesis and that the loss of their func- Although various intracranial vascular malforma-
tion leads to dilatation of major vessels, defective tions were initially described as distinct entities based
endothelial association and barrier function, and dys- on the factors described above, both MRI examina-
functional sprouting [29]. The detailed role of these tions and the histological features observed at surgery
genes is discussed in the chapters “Clinical and or autopsy suggest that different types of malforma-
molecular genetics of cerebral cavernous malforma- tions may exist within the same patient. Moreover,
tions” and “Molecular biology of cerebral cavernous individual lesions may have features of more than
malformation”. one type of malformation, suggesting intermediate
De novo appearance of CMs has been reported forms. In the case of CMs, coexistent DVAs or CTs
following brain irradiation [30], brain biopsy [31], have been frequently reported [38–43]. Rigamonti
and viral infection [32]. Exposure to such stimuli et al. described the coexistence of features of typical
may initiate a reactive angiogenesis or cause mutations CT as well as CM in two (10%) of 20 patients who
leading to local loss of expression of CCM genes lead- underwent resection of CM [39]. One patient had
ing to de novo appearance of CMs [33–35]. Some multiple lesions including both CT and CM. Staining
authors have associated hormonal influences with de for smooth muscle actin revealed smooth muscle in
novo occurrence of CM such as a case with follicle the walls of 20% of the lesions, indicating the presence
stimulating hormone producing pituitary adenoma of arterial or venous differentiation. Brain parenchyma
described by Pozzati et al., wherein new lesions was interspersed between vessels in 35% of the patients,
appeared [30]. Lüdemann et al. also reported de novo a feature generally attributed to CTs rather than CMs.
appearance of CM in a pregnant patient but failed to Rigamonti et al. [39] and others have concluded that
demonstrate estrogen or progesterone receptors on CM and CT constitute part of a larger spectrum of
immunohistochemical staining, suggesting that new intracranial vascular malformations. For example,
lesions appear independently of hormone levels, con- Awad et al. described two (14.2%) patients with coex-
trary to what was widely considered [36]. isting CT and CM in a series of 14 mixed vascular

3
 Section 1: Biology

malformations. Histopathological examination reveal- [43,48]. Dillon cited stenosis at the junction of the
ed zones of CTs in the surrounding brain parenchyma DVA and central vein as a possible cause of elevated
that eventually coalesced into the CMs [44]. venous pressures in DVAs [41]. It has been suggested
Rigamonti et al. reported the first evidence of a that hemorrhagic recurrences and organization of the
high association between CM and DVA and suggested resulting thrombus initiate the process of angiogene-
a possible pathogenetic relationship [38]. Abdulrauf sis, which may cause growth of CMs through an
et al. confirmed that 13 of 55 patients (24%) with CM ongoing process of hemorrhage and ischemia [48].
had associated DVA [43]. Similarly, Wurm et al. In support of this idea, others have demonstrated
reported 25.8% of CMs were associated with DVAs that DVAs are composed of mature blood vessels
in a series of 58 patients [45]. In contrast, Porter et al. and are formed earlier in embryogenesis [49], while
reported DVA associated with CMs in all of his surgi- CMs are immature vascular lesions with active angio-
cally treated patients whereas preoperative MRI genesis. More recently Abe et al. classified venous
revealed such lesions in only 32% of 73 patients [46]. anomalies into two distinct types: venous malforma-
The latter result suggests that the association may be tions which are not DVAs that are angiographi-
underestimated as MRI may not always detect DVAs cally occult and contain compact venous channels
[45,47]. Recognition of such combined pathology may devoid of smooth muscle layers; and angiographi-
be important as CMs associated with DVAs may have cally detectable dilated venous channels draining nor-
a greater predilection to bleed and be symptomatic mal white matter and communicating with cortical
than lesions which are purely CM [43]. The increased veins [47]. Abe et al. suggested that angiographically
bleeding tendency of CMs associated with DVAs has occult venous malformations can be safely resected
been hypothesized to result from venous hypertension without significant sequelae, indicating anatomical

Figure 1.2. Electron micrographs of

cavernous malformations (A-E) and
microvessels in adjacent normal brain
(F-H). (A) Ultrastructurally, these lesions
consist of endothelial cells (e) lining
vascular sinusoid lumens (l) and
surrounded by a dense collagenous matrix
(c). No perivascular cells were seen and the
endothelial basal lamina was in direct
contact with the collagenous matrix.
(B) Gaps (arrowhead) between adjacent
endothelial cells were seen in cavernous
malformations where the lumen (l) was
exposed directly to the basal lamina
(arrow). (C) In focal areas, the basal lamina
(arrows) demonstrated multiple abnormal
layers. (D,E) Haemosiderin (h) could be
seen within endothelial cells (D) and
within microns of the lumens of the
vascular sinusoids (E). A rare fibroblast
profile (f) is seen in (E) in the connective
tissue matrix. (F) A cerebral microvessel
from brain tissue adjacent to a lesion
demonstrates typical encircling pericytes
(p) separating the endothelial cell basal
lamina from the neuropil. A red blood cell
(r) is noted in the lumen. (G) Magnification
of the boxed area in F demonstrates a tight
junction (arrow) between adjacent
endothelial processes. (H) Another
microvessel from the surrounding brain is
being contacted by an astrocyte foot
process (a) containing abundant
intermediate filaments. Scale bar shown in
all images represents 1 μm. Reproduced
from [49] with permission from BMJ
Publishing Group.

4
 Chapter 1: Pathology of cavernous malformations

and pathophysiological differences from DVAs [47]. bleed than other vascular malformations. However,
It is possible that such venous malformations may microscopic extravasations, hemorrhages, thrombosis
remain undetected on MRI until they are revealed on with areas of reorganization, calcification, and inflam-
pathological examination. mation are common features. Ultrastructural studies
have demonstrated a dysfunctional blood–brain bar-
Ultrastructure and pathophysiology rier with poorly formed tight junctions, and the pres-
ence of Weibel bodies in lesions with recurrent bleeds.
of CMs CMs and other vascular malformations are known to
The ultrastructure of blood vessels within cavernous coexist and such lesions are more likely to bleed and
angiomas differs markedly from that of normal cere- recur after resection. Further research in the etiopa-
bral vessels, with abnormalities in endothelial cells thogenesis and genetics of CMs will help elucidate the
that would predict an impaired blood–brain barrier, pathobiology of CMs.
increased extravasation of red blood cells, and struc-
tural weakness.
Such changes may help explain the pathophysiol-
ogy of the growth, hemorrhage, and epilepsy caused References
by CMs. 1. Moriarity, J., Clatterbuck, R. & Rigamonti, D.
Like their normal counterparts, the vessels of caver- The natural history of cavernous malformations.
nous angiomas are lined by endothelial cells, the somata Neurosurg Clin N Am 1999;10:411–417.
of which are relatively unremarkable. However, there are 2. Maraire, J. & Awad, I. Intracranial cavernous
associated features, which would be expected to interfere malformations: lesion behavior and management
with the normal blood–brain barrier. For example, the strategies. Neurosurgery 1995;37:591–605.
endothelial cells have been described as having few if any 3. Notelet, L., Houtteville, J., Khoury, S., Lechevalier, B. &
tight junctions [49], with those junctions that are present Chapon, F. Proliferating cell nuclear antigen (PCNA)
in cerebral cavernomas: an immunocytochemical study
being described as intermediate or poorly formed [50].
of 42 cases. Surg Neurol 1997;47:364–370.
There may be gaps between endothelial cells [49–51]
(Fig. 1.2). The basal lamina that underlies the endothelial 4. Porter, P., Willinsky, R., Harper, W. &
Wallace, M. Cerebral cavernous malformations:
cells has been reported both as present [49,50] and as natural history and prognosis after clinical
thin or absent [51], perhaps depending on whether the deterioration with or without hemorrhage.
malformation has bled [51]. Previous hemorrhage has J Neurosurg 1997;87:190–197.
also been associated with changes in the endothelial cells 5. Robinson, J., Awad, I. & Little, J. Natural history of the
themselves, including more filopodia and increased cavernous angioma. J Neurosurg 1991;75:709–714.
numbers of Weibel-Palade bodies, micropinocytotic 6. Zabramski, J., et al. The natural history of familial
vesicles, filaments, and other organelles [51]. cavernous malformations: results of an ongoing study.
In the vessel walls, pericytes and subendothelial J Neurosurg 1994;80:422–432.
smooth muscle cells are lacking or are very poorly 7. Aiba, T., et al. Natural history of intracranial cavernous
formed. The walls also lack organized collagen and malformations. J Neurosurg 1995;83:56–59.
elastic fibers, which would make them more likely to 8. Del Curling, O. J., Kelly, D. J., Elster, A. & Craven, T.
bleed [50,51]. Astrocytic endfeet are also lacking An analysis of the natural history of cavernous
[49,51]. angiomas. J Neurosurg 1991;75:702–708.
9. McCormick, W. & Nofzinger, J. “Cryptic” vascular
Summary malformations of the central nervous system.
J Neurosurg 1966;24:865–875.
CMs are vascular malformations composed of endo-
10. McCormick, W., Hardman, J. & Boulter, T. Vascular
thelial lined dilated vessels (caverns) packed together malformations (“angiomas”) of the brain, with special
without intervening neural parenchyma. CMs are both reference to those occurring in the posterior fossa.
hereditary and sporadic. They can be seen with a J Neurosurg 1968;28:241–251.
history of previous irradiation and viral infection. 11. Nozaki, K., Inomoto, T., Takagi, Y. & Hashimoto, N.
The low flow rate and luminal pressures inside CMs Spinal intradural extramedullary cavernous angioma.
make them angiographically occult and less likely to Case report. J Neurosurg 2003;99:316–319.

5
 Section 1: Biology

12. Er, U., Yigitkanli, K., Simsek, S., Adabag, A. & 26. Tirakotai, W., et al. Biological activity of paediatric
Bavbek, M. Spinal intradural extramedullary cavernous cerebral cavernomas: an immunohistochemical study
angioma: case report and review of the literature. Spinal of 28 patients. Childs Nerv Syst 2006;22:685–691.
Cord 2007;45:632–636. 27. Matsubara, S., Bourdeau, A., terBrugge, K. G.,
13. Conway, J. E. & Rigamonti, D. Cavernous Wallace, C. & Letarte, M. Analysis of endoglin
malformations: a review and current controversies. expression in normal brain tissue and in cerebral
Neurosurg Quart 2006;16:15–23. arteriovenous malformations. Stroke
14. Baumann, C. R., et al. Seizure outcome after resection 2000;31:2653–2660.
of supratentorial cavernous malformations: a study of 28. Labauge, P., Denier, C., Bergametti, F. & Tournier-
168 patients. Epilepsia 2007;48:559–563. Lasserve, E. Genetics of cavernous angiomas. Lancet
15. Simard, J., Garcia-Bengochea, F., Ballinger, W. J., Neurol 2007;6:237–244.
Mickle, J. & Quisling, R. Cavernous angioma: a review 29. Batra, S., Lin, D., Recinos, P., Zhang, J. & Rigamonti, D.
of 126 collected and 12 new clinical cases. Neurosurgery Cavernous malformations: natural history, diagnosis
1986;18:162–172. and treatment. Nat Rev Neurol 2009;5:659–670.
16. Bertalanffy, H., et al. Cerebral cavernomas in the adult. 30. Pozzati, E., Acciarri, N., Tognetti, F., Marliani, F. &
Review of the literature and analysis of 72 surgically Giangaspero, F. Growth, subsequent bleeding, and de
treated patients. Neurosurg Rev 2002;25:1–53; novo appearance of cerebral cavernous angiomas.
discussion 54–55. Neurosurgery 1996;38:662–669; discussion 669–670.
17. Wang, C., Liu, A., Zhang, J., Sun, B. & Zhao, Y. Surgical 31. Ogilvy, C., Moayeri, N. & Golden, J. Appearance of a
management of brain-stem cavernous malformations: cavernous hemangioma in the cerebral cortex after a
report of 137 cases. Surg Neurol 2003;59:444–454; biopsy of a deeper lesion. Neurosurgery
discussion 454. 1993;33:307–309; discussion 309.
18. Tomlinson, F. H., et al. Angiographically occult 32. Flocks, J., Weis, T., Kleinman, D. & Kirsten, W. Dose-
vascular malformations: a correlative study of features response studies to polyoma virus in rats. J Natl Cancer
on magnetic resonance imaging and histological Inst 1965;35:259–284.
examination. Neurosurgery 1994;34:792–799; 33. Pagenstecher, A., Stahl, S., Sure, U. & Felbor, U. A two-
discussion 799–800. hit mechanism causes cerebral cavernous
19. Burger, P., Scheithauer, B. W. & Vogel, F. S. Surgical malformations: complete inactivation of CCM1, CCM2
Pathology of the Nervous System and Its Coverings or CCM3 in affected endothelial cells. Hum Mol Genet
(New York: Churchill Livingstone, 2002). 2009;18:911–918.
20. Awad, I. & Jabbour, P. Cerebral cavernous malformations 34. Baumgartner, J., et al. Pathologically proven cavernous
and epilepsy. Neurosurg Focus 2006;21:e7. angiomas of the brain following radiation therapy for
21. Uranishi, R., Awadallah, N. A., Ogunshola, O. O. & pediatric brain tumors. Pediatr Neurosurg
Awad, I. A. Further study of CD31 protein and 2003;39:201–207.
messenger ribonucleic acid expression in human 35. Massa-Micon, B., Luparello, V., Bergui, M. & Pagni, C.
cerebral vascular malformations. Neurosurgery De novo cavernoma case report and review of
2002;50:110–115; discussion 115–116. literature. Surg Neurol 2000;53:484–487.
22. Storer, K. P., Tu, J., Karunanayaka, A., Morgan, M. K. & 36. Lüdemann, W., Ellerkamp, V., Stan, A. & Hussein, S.
Stoodley, M. A. Thrombotic molecule expression in De novo development of a cavernous malformation of
cerebral vascular malformations. J Clin Neurosci the brain: significance of factors with paracrine and
2007;14:975–980. endocrine activity: case report. Neurosurgery
23. Kilic, T., et al. Expression of structural proteins and 2002;50:646–649; discussion 649–650.
angiogenic factors in cerebrovascular anomalies. 37. Barr, R., Dillon, W. & Wilson, C. Slow-flow vascular
Neurosurgery 2000;46:1179–1191; discussion malformations of the pons: capillary telangiectasias?
1191–1172. AJNR Am J Neuroradiol 1996;17:71–78.
24. Sure, U., et al. Biological activity of adult cavernous 38. Rigamonti, D. & Spetzler, R. The association of
malformations: a study of 56 patients. J Neurosurg venous and cavernous malformations. Report of
2005;102:342–347. four cases and discussion of the pathophysiological,
25. Sure, U., et al. Endothelial proliferation, diagnostic, and therapeutic implications.
neoangiogenesis, and potential de novo generation of Acta Neurochir (Wien) 1988;92:100–105.
cerebrovascular malformations. J Neurosurg 39. Rigamonti, D., Johnson, P., Spetzler, R., Hadley, M. &
2001;94:972–977. Drayer, B. Cavernous malformations and capillary

6
 Chapter 1: Pathology of cavernous malformations

telangiectasia: a spectrum within a single pathological anomalies: surgical considerations. Neurosurgery

entity. Neurosurgery 1991;28:60–64. 2005;57:42–58; discussion 42–58.
40. Ciricillo, S., Dillon, W., Fink, M. & Edwards, M. 46. Porter, R., et al. Cavernous malformations of the
Progression of multiple cryptic vascular malformations brainstem: experience with 100 patients. J Neurosurg
associated with anomalous venous drainage. Case 1999;90:50–58.
report. J Neurosurg 1994;81:477–481. 47. Abe, M., Hagihara, N., Tabuchi, K., Uchino, A. &
41. Dillon, W. Cryptic vascular malformations: Miyasaka, Y. Histologically classified venous angiomas
controversies in terminology, diagnosis, of the brain: a controversy. Neurol Med Chir (Tokyo)
pathophysiology, and treatment. AJNR Am J 2003;43:1–10; discussion 11.
Neuroradiol 1997;18:1839–1846. 48. Wilson, C. Cryptic vascular malformations. Clin
42. Awada, A., Russell, N., Al Rajeh, S. & Omojola, M. Neurosurg 1992;38:49–84.
Non-traumatic cerebral hemorrage in Saudi Arabs: a 49. Clatterbuck, R., Eberhart, C., Crain, B. & Rigamonti, D.
hospital-based study of 243 cases. Journal of the Ultrastructural and immunocytochemical evidence
Neurological Sciences 1996;144:198–203. that an incompetent blood-brain barrier is related to
43. Abdulrauf, S., Kaynar, M. & Awad, I. A comparison the pathophysiology of cavernous malformations.
of the clinical profile of cavernous malformations J Neurol Neurosurg Psychiatry
with and without associated venous 2001;71:188–192.
malformations. Neurosurgery 1999;44:41–46;
discussion 46–47. 50. Wong, J., Awad, I. & Kim, J. Ultrastructural
pathological features of cerebrovascular
44. Awad, I., Robinson, J. J., Mohanty, S. & Estes, M. Mixed malformations: a preliminary report. Neurosurgery
vascular malformations of the brain: clinical and 2000;46:1454–1459.
pathogenetic considerations. Neurosurgery
1993;33:179–188; discussion 188. 51. Tu, J., Stoodley, M., Morgan, M. & Storer, K.
Ultrastructural characteristics of hemorrhagic,
45. Wurm, G., Schnizer, M. & Fellner, F. Cerebral nonhemorrhagic, and recurrent cavernous
cavernous malformations associated with venous malformations. J Neurosurg 2005;103:903–909.

7
 Epidemiology and natural history
Chapter

2 of cavernous malformations
Rachel Engelmann, Sachin Batra, Angela Li, Joaquin
Camara-Quintana and Daniele Rigamonti

Cavernous malformations (CM) are multilobulated brain irradiation or viral infection have been reported
lesions composed of sinusoids derived from endo- [13,14]. It is believed that de novo appearance of CMs
thelium embedded in collagen matrix without occurs in genetically predisposed individuals [15].
histological elements found in mature vasculature
[1]. CMs may be found at any location in the central Prevalence
nervous system and therefore can present with CMs constitute 10–15% of all vascular malformations
diverse clinical presentations like seizures (23–50%), and are the second most commonly found vascular
headaches (6–52%), and focal deficits (20–45%) aris- malformation after developmental venous anomalies
ing from mass effect or lesion hemorrhage; however, (DVAs), which are found in about 4% of the popula-
up to 40% of patients may be asymptomatic [2]. tion and represent up to 63% of all cerebrovascular
Most CMs are found supratentorially. They are malformations [16–18]. The estimated prevalence of
usually characterized clinically by seizures and less CM by MRI-based studies has been reported to be 0.4–
commonly by inconspicuous growth or intermittent 0.53% of the general population, while on autopsy
bleeding. Seizures caused by perilesional deposits of series the prevalence of CM is about 0.4% [19–21].
epileptogenic hemosiderin may become intractable Up to 20% of CMs are asymptomatic, making it
[3]. Hemorrhages associated with CMs are of low more difficult to accurately study their epidemiology
pressure and frequently clinically asymptomatic [4]. and natural history. CMs were frequently not detected
When a lesion is present in eloquent locations like (occult) by radiological investigations like angiogra-
the brainstem, however, even a small bleed can cause phy or CT scans. This has changed since the advent of
clinically significant neurological deficits [5]. The MRI; now these lesions are increasingly diagnosed in
natural history of CMs is affected by several factors the asymptomatic population [16,22]. Thus accurate
like gender, lesion location, and genotype. This chapter understanding of their natural history has become
discusses the natural history of CMs and its clinical critical to appropriate management of these patients.
relevance. Asymptomatic CMs are frequently diagnosed
amongst the relatives of patients harboring familial
CMs [10,12,23,24]. Rigamonti et al. diagnosed three
Etiology (27.3%) asymptomatic individuals out of 11 relatives
Cavernous malformations may be of sporadic or diagnosed with familial lesions while Zabramski et al.
familial type. Familial CMs are caused by mutations found 39% (12 individuals) prevalence of asympto-
of CCM1 or CCM2 or CCM3 genes [6–9]. Most matic lesions in a population of 31 relatives of patients
reports have described familial lesions in patients of harboring familial lesions [12,23]. Conversely, others
French or Hispanic descent, but familial occurrence have suggested a prevalence of symptomatic lesions
may be more widespread than these reports suggest (approximately 60%) amongst patients with the familial
[9–12]. Most CMs including sporadic lesions were form of cavernous malformations [25,26]. At least 6–
historically considered congenital lesions; however, 10% of all patients harboring CMs may have a pattern
several cases of their de novo appearance following of inheritance consistent with familial lesions [27,28].

Cavernous Malformations of the Nervous System, ed. Daniele Rigamonti. Published by Cambridge University Press.
© Cambridge University Press 2011.

9
 Section 1: Biology

Furthermore, it is estimated that while 10–15% of patient characteristics (pure familial cases versus com-
Caucasian patients have familial lesions, 40% of bination of familial and sporadic cases; population-
Hispanic patients have familial CM [29]. Most exist- based versus hospital-based series), study design (ret-
ing studies describe the epidemiology of familial rospective versus prospective studies) and the criteria
CMs based on screening of relatives of symptomatic defining hemorrhage (extra-lesional versus intra-
patients with multiple CMs; however, the population lesional, occult versus clinically significant bleeds)
prevalence of the sporadic type is yet to be studied. [5,12,23,38,39,45–49]. Consequently, wide variation
can be observed in reported rates of hemorrhage,
Lesion characteristics ranging between 0.25% per person years to 4.2% per
The typical measurements of cavernous malforma- person years [20,37,45,50]. Thus, it is impossible to
tions range from 0.01 to 1.7 cm [16,30,31]. Multiple make a statement regarding the natural history that is
CMs have been reported by several series, but are more consistent with all the reports in the literature. It
frequently found in patients with a history suggestive follows that clinical decisions based on the interpreta-
of inherited CMs than in sporadic cases [2,16]. tion of these studies remain challenging.
Multiple lesions are present in 50–84% of familial Despite disagreements on the natural history of
cases but in only 10–33% of sporadic cases [32,33,34]. CM and its predictors, most studies have shown a
De novo occurrence of lesions is more common in relatively benign course of superficial lesions com-
familial forms [35,36] and there exists an apparent pared to deep lesions or those located infratentorially
association between the number of lesions and the age with respect to bleeding [16,31,45]. In an MRI-based
of the patient, with older patients having a greater study Del Curling et al. reported an overall bleeding
number of lesions, suggesting de novo occurrence dur- rate of 0.25% per person years of exposure [39].
ing the life of the patient [35,36]. Multiple lesions were present in six (18.75%) of the
CMs are more often supratentorial (64–84%) than patients in this series; after accounting for the multiple
infratentorial (19–35%) [16,37,39], with a distribution lesions the risk of bleeding was reduced to 0.1% per
proportionate to the volume of neural tissue. The most lesion per person year of exposure. Similar to these
common supratentorial locations are the frontal and findings, Robinson et al. described a hemorrhage rate
temporal lobes while the most common infratentorial of 0.7% per lesion per person year of exposure in a
locations are the pons and the cerebellum [16,20]. series of 66 patients with six patients (9%) presenting
CMs may rarely be found at locations like the with a bleed at the start of the study and only one
cerebello-pontine angle, optic chiasm, pineal and pitui- patient suffering a bleed on follow-up of 143 lesion
tary gland, and third or fourth ventricles [33,40,41]. years of observation [20]. In contrast to this,
CMs may be found in association with other vascular Kondziolka et al. reported a higher overall bleeding
malformations like developmental venous anomaly rate of 2.63% per person year [47]. However, due to
(DVAs) or capillary telangiectasia [16,42]. When asso- referral bias, deep or infratentorial lesions constituted
ciated with DVAs, CMs are more likely to bleed, with over 50% of this study population. Thirty-five percent
an incidence of 62% as compared to a 38% incidence of patients harbored brainstem lesions, of which 62.8%
of hemorrhage amongst CMs without a draining DVA had a previous hemorrhage. Another 17% had thala-
[17]. These lesions also had a greater incidence of mic or basal ganglia lesions. Overall about 50% of the
recurrent bleeding (23%) than when CMs were present study population suffered at least one previous hem-
with DVA (9.6%) [17]. This has been attributed to a orrhage from the lesion as compared to the series by
higher intraluminal pressure within the lesion asso- DeCurling et al., which included no patients with a
ciated with DVA [43,44]. prior history of bleeding, and patients presented with
72% of their lesions in a supratentorial location [39].
Natural history of cavernous Similarly Porter et al. in a series of 173 patients fol-
lowed for 437 person-years reported a higher bleeding
malformations or deficit rate in deep locations as compared to super-
Although the natural history of cavernous malforma- ficial locations (10.6%/year versus 0%/year: p = 0.001)
tions has been investigated for more than 50 years, it is [45]. MRI-documented bleeding rates were 1.6% per
still difficult to clearly describe it due to a lack of year for deep versus 0% per year for superficial lesions.
comparability between studies. Most studies differ in Furthermore, the multivariate analysis in this study

10
 Chapter 2: Epidemiology and natural history of cavernous malformations

revealed deep location to be a significant predictor of bleeding in 26% and 39% of patients respectively [52].
subsequent events but not a history of past bleeding. Furthermore, the multiplicity of lesions increased with
A study of the natural history of CM by age in individuals possessing the CCM1 genotype but
Kupersmith et al. described predictors of hemorrhage not in CCM2 or CCM3 genotypes [52].
in brainstem lesions. Hemorrhage was more frequent
in lesions associated with developmental venous
anomalies, lesions symptomatic at an early age (<35 Risk of subsequent bleeding
years), and those greater than 1 cm in diameter. A greater risk of subsequent hemorrhage is anticipated
Mathiesen et al. described outcomes of conservatively in patients with a prior history of bleeding or focal
managed deep lesions and found a lower event rate deficits. Most studies have reported a rebleeding rate
(bleeding or focal deficits) in patients with asympto- ranging from 2.63 to 60% per person year, with most
matic lesions (2% per year) as compared to those with lesions rebleeding either deep or infratentorial in loca-
symptomatic lesions (7% per year) [49]. This observa- tion [37,53–55]. Kondziolka et al. reported a hemor-
tion suggests that symptomatic lesions tend to follow rhage rate of 4.5% per person year in patients with a
an aggressive course whereas incidentally found history of prior bleeding as compared to an overall
lesions with no history of related symptoms follow a hemorrhage rate of 2.63% per person year (p = 0.028).
more benign course even in deep locations. These data Similarly, Porter et al. reported seven episodes of
confirm the bias in interpreting the natural history bleeding over the study follow-up of 427 person
based on either surgical series or series containing years, six (7.40%) of which occurred in the subgroup
conservatively managed lesions. Zimmerman et al., of 81 patients who presented with hemorrhage or focal
however, reported a lower rate of hemorrhage in deficit attributable to lesions located in the brainstem
patients even with symptomatic brainstem lesions [45]. Aiba et al. in a series including both conservative
at presentation [48]. All of the eight conservatively and surgically managed patients reported a higher
managed patients who presented with symptoms due prospective hemorrhage rate of 22.9% per year per lesion
to lesions in midbrain tectum (four patients), mid- in the subgroup of patients who presented with sympto-
brain tegmentum (one patient), and pons (three matic hemorrhage, most of whom underwent resection
patients) recovered. However, one patient had a fatal of lesion. High rebleeding rates ranging from 17 to 60%
hemorrhage 1 year after initial evaluation. Similarly, have been reported in most surgical series [53–55] and
Kharkar et al. followed 14 patients harboring sympto- may represent an aggressive subclass of lesions [49].
matic spinal lesions but who were managed conserva- While risk of rebleeding is considered higher than risk
tively. Of the 10 patients (71%) who continued to be of bleeding in incidental lesions, Barker et al. reported
conservatively managed, nine (90%) were stable or temporal clustering of hemorrhages in the lesions, sug-
better over a mean follow-up of 80 months since gesting that lesions may return to baseline risk within
presentation [51]. 2–3 years following the initial bleed [56].

Familial lesions Effect of age and sex

The bleeding rates in familial studies have varied from Cavernous malformations have been reported in
1.1% per lesion per year to 4.3% per lesion per year patients from both extremes of life, although the aver-
[10,23]. The wide difference in the bleeding rates age age of symptom onset is approximately 35 years
between these two studies may be related to relative [57,39]. In general, the prognosis for younger patients is
differences in the prevalence of CCM genotypes. worse than that for older patients as younger patients
Denier et al. reported 50% of patients with mutations are more likely to experience hemorrhage or recurrent
in CCM3 exhibiting clinical signs and symptoms hemorrhage, and are more likely to be afflicted with a
before reaching 15 years of age [52], whereas only neurological deficit [33,58–60]. In contrast to the high
17% and 19% of patients with mutations in CCM1 or rate of hemorrhage in younger patients, elderly patients
CCM2 respectively were symptomatic by this age. rarely experience symptoms in association with caver-
Lesions expressed by CCM3 mutations had bleeding nous malformations [33]. However, this age-associated
at initial presentation in 53% of cases, as compared to disparity in hemorrhage rate was not confirmed by
those due to CCM1 or CCM2 mutations, which caused Robinson et al., who found no significant difference in

11
 Section 1: Biology

hemorrhage rates between patients under age 40 and an incompetent blood-brain barrier is related to
those who were over the age of 40. the pathophysiology of cavernous malformations.
Some studies have reported differences in bleeding J Neurol Neurosurg Psychiatry 2001;71:188–192.
between males and females [31,33,61]. Males harboring 2. Batra, S., Lin, D., Recinos, P., Zhang, J. & Rigamonti, D.
CMs are more likely to become symptomatic at a Cavernous malformations: natural history, diagnosis
younger age and to experience seizures, while females and treatment. Nat Rev Neurol 2009;5:659–670.
are more likely to have later symptom onset and to 3. Awad, I. & Jabbour, P. Cerebral cavernous malformations
experience neurological deficits [62]. This has been and epilepsy. Neurosurg Focus 21, e7 (2006).
attributed to hormonal differences. Several studies have 4. Cordonnier, C., et al. Differences between intracranial
also suggested a greater likelihood of hemorrhage in vascular malformation types in the characteristics of
females irrespective of location of lesion [33,31,61]. In their presenting haemorrhages: prospective,
population-based study. J Neurol Neurosurg Psychiatry
a study conducted by Robinson et al. 86% of the subjects 2008;79:47–51.
who hemorrhaged were female despite a comparable
5. Kupersmith, M., et al. Natural history of brainstem
number of male and female subjects [31]. Based on
cavernous malformations. Neurosurgery 2001; 48:
more recent evidence, it is now generally accepted that 47–53; discussion 53–44.
CMs behave similarly in both genders [25,45,47].
6. Bergametti, F., et al. Mutations within the programmed
Several authors have cited an increased risk of cell death 10 gene cause cerebral cavernous
hemorrhage concurrent with pregnancy and possibly malformations. Am J Hum Genet 2005;76:42–51.
related to the effect of estrogen on angiogenesis and
7. Laberge-le Couteulx, S., et al. Truncating mutations in
structural integrity of the CM [63]. Evidence suggests CCM1, encoding KRIT1, cause hereditary cavernous
an increase in the size of cavernous malformations angiomas. Nat Genet 1999;23:189–193.
during pregnancy which could contribute to increased 8. Liquori, C., et al. Deletions in CCM2 are a common
risk of hemorrhage [64]. Additional research is neces- cause of cerebral cavernous malformations. Am J Hum
sary to confirm this finding and to determine the best Genet 2007;80:69–75.
method of management for pregnant women with 9. Gunel, M., et al. A founder mutation as a cause of
cavernous malformations. cerebral cavernous malformation in Hispanic
Americans. New Engl J Med 1996;334:946–951.
Summary 10. Labauge, P., Brunereau, L., Laberge, S. & Houtteville, J.
Prospective follow-up of 33 asymptomatic patients
CMs are vascular malformations found throughout the with familial cerebral cavernous malformations.
brain and spinal cord. They present primarily with Neurology 2001;57:1825–1828.
seizures or focal deficits, often caused by perilesional
11. Brunereau, L., et al. Familial form of intracranial
hemosiderin deposition or mass effect from lesion cavernous angioma: MR imaging findings in 51
growth or bleeding. Natural history studies have several families. French Society of Neurosurgery. Radiology
shortcomings; however, the majority seem to suggest 2000;214:209–216.
that most lesions have a relatively benign course. This is 12. Rigamonti, D., et al. Cerebral cavernous
particularly true when the lesions are located super- malformations. Incidence and familial occurrence. New
ficially in the supratentorial compartment. Lesions at Engl J Med 1988;319:343–347.
deep locations are more prone to become symptomatic, 13. Pozzati, E., Acciarri, N., Tognetti, F., Marliani, F. &
although they too may remain clinically quiescent. Giangaspero, F. Growth, subsequent bleeding, and de
Several aspects of lesion behaviour, such as the influ- novo appearance of cerebral cavernous angiomas.
ence of prophylactic anticoagulation, pregnancy, and Neurosurgery 1996;38:662–669; discussion 669–670.
familiality of the clinical course, remain to be clarified. 14. Ogilvy, C. S., Moayeri, N. & Golden, J. A. Appearance
Knowledge of all these aspects is critical to determining of a cavernous hemangioma in the cerebral cortex after
appropriate management strategies and therefore they a biopsy of a deeper lesion. Neurosurgery
require further investigation. 1993;33:307–309; discussion 309.
15. Pagenstecher, A., Stahl, S., Sure, U. & Felbor, U. A two-

References hit mechanism causes cerebral cavernous

malformations: complete inactivation of CCM1, CCM2
1. Clatterbuck, R., Eberhart, C., Crain, B. & Rigamonti, D. or CCM3 in affected endothelial cells. Hum Mol Genet
Ultrastructural and immunocytochemical evidence that 2009;18:911–918.

12
 Chapter 2: Epidemiology and natural history of cavernous malformations

16. Maraire, J. & Awad, I. Intracranial cavernous 31. Robinson, J. R., Awad, I. A. & Little, J. R. Natural
malformations: lesion behavior and management history of the cavernous angioma. J Neurosurg
strategies. Neurosurgery 1995;37:591–605. 1991;75:709–714.
17. Abdulrauf, S., Kaynar, M. & Awad, I. A comparison of 32. Kim, D. S., Park, Y. G., Choi, J. U., Chung, S. S. &
the clinical profile of cavernous malformations with Lee, K. C. An analysis of the natural history of
and without associated venous malformations. cavernous malformations. Surg Neurol 1997;48:9–17;
Neurosurgery 1999;44:41–46; discussion 46–47. discussion 17–18.
18. Brown Jr, R. D. Wiebers, D. O., Torner, J. C. & 33. Maraire, J. N. & Awad, I. A. Intracranial cavernous
O’Fallon, W. M. Frequency of intracranial hemorrhage malformations: lesion behavior and management
as a presenting symptom and subtype analysis: A strategies. Neurosurgery 1995;37:591–605.
population-based study of intracranial vascular 34. Vinas, F. C., Gordon, V., Guthikonda, M. & Diaz, F. G.
malformations in Olmsted County, Minnesota. J Surgical management of cavernous malformations of
Neurosurg 1996;85:29–32. the brainstem. Neurol Res 2002;24:61–72.
19. Otten, P., Pizzolato, G., Rilliet, B. & Berney, J. [131 35. Brunereau, L., Levy, C., Laberge, S., Houtteville, J. &
cases of cavernous angioma (cavernomas) of the CNS, Labauge, P. De novo lesions in familial form of cerebral
discovered by retrospective analysis of 24,535 cavernous malformations: clinical and MR features in
autopsies]. Neurochirurgie 1989;35:82–83, 128–131. 29 non-Hispanic families. Surg Neurol
20. Robinson, J., Awad, I. & Little, J. Natural history of the 2000;53:475–482; discussion 482–473.
cavernous angioma. J Neurosurg 1991;75:709–714. 36. Pozzati, E., Acciarri, N., Tognetti, F., Marliani, F. &
21. Sarwar, M. & McCormick, W. Intracerebral venous Giangaspero, F. Growth, subsequent bleeding, and de
angioma. Case report and review. Arch Neurol novo appearance of cerebral cavernous angiomas.
1978;35:323–325. Neurosurgery 1996;38:662–669; discussion 669–670.
22. Morris, Z., et al. Incidental findings on brain magnetic 37. Kondziolka, D., Lunsford, L. & Kestle, J. The natural
resonance imaging: systematic review and meta- history of cerebral cavernous malformations.
analysis. BMJ 2009;339:b3016. J Neurosurg 1995;83:820–824.
23. Zabramski, J., et al. The natural history of familial 38. Moriarity, J., Clatterbuck, R. & Rigamonti, D. The
cavernous malformations: results of an ongoing study. J natural history of cavernous malformations. Neurosurg
Neurosurg 1994;80:422–432. Clin N Am 1999;10:411–417.
24. Brunereau, L., et al. Familial form of cerebral cavernous 39. Del Curling, O., Jr., Kelly, D. L., Jr., Elster, A. D. &
malformations: evaluation of gradient-spin-echo Craven, T. E. An analysis of the natural history of
(GRASE) imaging in lesion detection and cavernous angiomas. J Neurosurg 1991;75:702–708.
characterization at 1.5 T. Neuroradiology 40. Baumann, C. R., et al. Seizure outcome after resection
2001;43:973–979. of supratentorial cavernous malformations: A study of
25. D’Angelo, V. A., et al. Supratentorial cerebral 168 patients. Epilepsia 2007;48:559–563.
cavernous malformations: clinical, surgical, and genetic 41. Simard, J., Garcia-Bengochea, F., Ballinger, W. J.,
involvement. Neurosurg Focus 2006;21:e9. Mickle, J. & Quisling, R. Cavernous angioma: a review
26. Labauge, P., Denier, C., Bergametti, F. & Tournier- of 126 collected and 12 new clinical cases. Neurosurgery
Lasserve, E. Genetics of cavernous angiomas. Lancet 1986;18:162–172.
Neurol 2007;6:237–244. 42. Rigamonti, D., Johnson, P., Spetzler, R., Hadley, M. &
27. Hsu, F. P., Rigamonti, D. & Huhn,SL. Epidemiology of Drayer, B. Cavernous malformations and capillary
Cavernous Malformation (American Association of telangiectasia: a spectrum within a single pathological
Neurological Surgeons, 1993). entity. Neurosurgery 1991;28:60–64.
28. Bertalanffy, H., et al. Cerebral cavernomas in the adult. 43. Ciricillo, S., Dillon, W., Fink, M. & Edwards, M.
Review of the literature and analysis of 72 surgically Progression of multiple cryptic vascular malformations
treated patients. Neurosurg Rev 2002;25:1–53. associated with anomalous venous drainage. Case
29. Dashti, S. R., Hoffer, A., Hu, Y. C. & Selman, W. R. report. J Neurosurg 1994;81:477–481.
Molecular genetics of familial cerebral cavernous 44. Dillon, W. Cryptic vascular malformations:
malformations. Neurosurg Focus 2006;21:e2. controversies in terminology, diagnosis,
30. Casazza, M., et al. Supratentorial cavernous angiomas pathophysiology, and treatment. AJNR Am J
and epileptic seizures: preoperative course and Neuroradiol 1997;18:1839–1846.
postoperative outcome. Neurosurgery 1996;39:26–32; 45. Porter, P., Willinsky, R., Harper, W. & Wallace, M.
discussion 32–24. Cerebral cavernous malformations: natural history and

13
 Section 1: Biology

prognosis after clinical deterioration with or without 55. Ferroli, P., et al. Brainstem cavernomas: long-term results
hemorrhage. J Neurosurg 1997;87:190–197. of microsurgical resection in 52 patients. Neurosurgery
46. Al-Shahi Salman, R., Berg, M., Morrison, L. & Awad, I. 2005;56:1203–1212; discussion 1212–1204.
Hemorrhage from cavernous malformations of the 56. Barker, F. N., et al. Temporal clustering of hemorrhages
brain: definition and reporting standards. Angioma from untreated cavernous malformations of the central
Alliance Scientific Advisory Board. Stroke nervous system. Neurosurgery 49, 15–24; discussion
2008;39:3222–3230. 24–15 (2001).
47. Kondziolka, D., Lunsford, L. D. & Kestle, J. R. The 57. Conway, J. E. & Rigamonti, D. Cavernous
natural history of cerebral cavernous malformations. malformations: a review and current controversies.
J Neurosurg 1995;83:820–824. Neurosurg Quart 2006;16:15–23.
48. Zimmerman, R., Spetzler, R., Lee, K., Zabramski, J. & 58. Aiba, T., et al. Natural history of intracranial cavernous
Hargraves, R. Cavernous malformations of the brain malformations. J Neurosurg 1995;83:56–59.
stem. J Neurosurg 1991;75:32–39. 59. Kupersmith, M. J., et al. Natural history of brainstem
49. Mathiesen, T., Edner, G. & Kihlström, L. Deep and cavernous malformations. Neurosurgery
brainstem cavernomas: a consecutive 8-year series. 2001;48:47–53; discussion 53–44.
J Neurosurg 2003;99:31–37. 60. Zabramski, J. M., et al. The natural history of familial
50. Del Curling, O. J., Kelly, D. J., Elster, A. & Craven, T. cavernous malformations: results of an ongoing study. J
An analysis of the natural history of cavernous Neurosurg 1994;80:422–432.
angiomas. J Neurosurg 1991;75:702–708. 61. Wang, C. C., Liu, A., Zhang, J. T., Sun, B. & Zhao, Y. L.
51. Kharkar, S., Shuck, J., Conway, J. & Rigamonti, D. The Surgical management of brain-stem cavernous
natural history of conservatively managed malformations: report of 137 cases. Surg Neurol
symptomatic intramedullary spinal cord cavernomas. 2003;59:444–454; discussion 454.
Neurosurgery 2007;60:865–872; discussion 865–872. 62. Casazza, M., et al. Supratentorial cavernous angiomas
52. Denier, C., et al. Genotype-phenotype correlations in and epileptic seizures: preoperative course and
cerebral cavernous malformations patients. Ann Neurol postoperative outcome. Neurosurgery 1996;39:26–32;
2006;60:550–556. discussion 32–24.
53. Fritschi, J., Reulen, H., Spetzler, R. & 63. Aiba, T., et al. Natural history of intracranial cavernous
Zabramski, J. Cavernous malformations of the brain malformations. J Neurosurg 1995;83:56–59.
stem. A review of 139 cases. Acta Neurochir (Wien) 64. Safavi-Abbasi, S., et al. Hemorrhage of cavernous
1994;130:35–46. malformations during pregnancy and in the peripartum
54. Bruneau, M., et al. Early surgery for brainstem period: causal or coincidence? Case report and review of
cavernomas. Acta Neurochir (Wien) 2006;148:405–414. the literature. Neurosurg Focus 2006;21:e12.

14
 Familial cavernous malformations: a
Chapter

3 historical survey
Leslie Morrison

In 1928, Kufs reported the first familial cavernous Prior to the availability of head CT scanning, the
hemangiomas [1]. As brain imaging technology has diagnosis of CCM depended on the pathological analy-
advanced, the detection of single or multiple CCMs sis of surgical lesions or autopsy material corroborated
has facilitated our ability to identify patients with the by pedigree analysis and plain skull films. In 1936 a
familial form in which lesions are multiple. Obtaining Swedish family was reported with multiple lesions and
detailed pedigree information remains important, but it the familial nature was also simultaneously identified
is less informative than imaging due to incomplete (Michael, Levin, 1936.) An Icelandic family of two gen-
penetrance of the gene mutation and variability of erations was reported by Kidd and Cummings (Kidd,
gene expression. Familial CCM has a disease phenotype Cummings, 1947). The third report by Clark in 1970
that spans from asymptomatic to completely neurolog- described the first pathological study of multiple family
ically disabled. The high incidence of seizures, head- members [2] with neuropsychiatric features in the
aches and strokes within the general population and father and episodic headaches in the daughter. CCMs
even in family members who are unaffected by the were considered very rare prior to the CT era [3].
gene mutation further complicates the ability to rely
exclusively on family neurological history. In this chap-
ter, the history of familial CCM is traced through radio- CT era
graphic eras, followed by gene discovery, other systemic Commercial CT scans were invented by Sir Godfrey
manifestations, disease variability and natural history. Hounsfield in Hayes, United Kingdom, at EMI Central
Research Laboratories using X-rays. Hounsfield
conceived his idea in 1967, and it was publicly
Pre-CT scans announced in 1972 (BMJ (London, UK: BMJ Group)
The contribution of brain imaging to identify familial 2004;329:687). As use of CT expanded, multiple CCMs
cases began with plain skull radiographs showing sin- became easier to identify. Multiple CCMs were found
gle calcified cavernous malformations. Interestingly, in a white male with increased intracranial pressure,
there are no reports of multiple calcified cavernous pathologically confirmed in both the hemorrhagic
malformations discovered by skull film reported in lesion, non-hemorrhagic lesion and a pulmonary hem-
the literature. Review of the record of a New Mexico orrhagic lesion [4]. The author notes that without CT,
patient with epilepsy revealed the clinical use of plain the multiplicity of lesions would have been missed.
skull radiographs that showed multiple calcified An additional large kindred of Hispanic-American
CCMs in a young girl with epilepsy, who was initially families from New Mexico was reported by Bicknell in
suspected of having multiple calcified brain tumors. 1978, introducing the utility of cranial computerized
Another of her relatives exhibited the same findings tomography and discussing the first three kindred
(personal observation Morrison 2010). Brain imaging reports [5]. Another large Hispanic family was studied
of multiple lesions was not reported in the literature by Hayman et al. through the use of CCT in 1982 [6].
until computerized tomography (CT) became avail- Mason et al. studied a large Hispanic family and
able in the 1960s. identified CCMs in 10 of 22 family members using

Cavernous Malformations of the Nervous System, ed. Daniele Rigamonti. Published by Cambridge University Press.
© Cambridge University Press 2011.

15
 Section 1: Biology

MRI rather than CT [7]. Rigamonti confirmed the exis- 1999. This remains the only large cohort of familial
tence in Hispanic families, reporting six new families, five CCM worldwide, numbering in the thousands [15].
of the six of Hispanic origin [8]. As brain imaging tech- CHM along with other mutations in CCM1 accounts
nology progressed from CT to MRI, it became much for a total of approximately 40% of detected mutations.
easier to identify patients with multiple lesions. Another 20% are accounted for by mutation in CCM2
[24]. The third known gene is CCM3 and there is
MRI era evidence of linkage to a fourth disease-causing gene
[25]. At least 10–40% of non-Hispanic cases are fami-
Multiple lesions are best identified based on magnetic lial, and in Mexican-American families in the USA the
resonance imaging (MRI) [56,57]. familial incidence is estimated at 50% [26].
Gradient-echo and susceptibility-weighted imag-
ing techniques identify more lesions than standard
MRI sequences in familial CM [9–13]. Although gra- Genetic testing
dient images exaggerate the size of lesions that have a Genetic testing is now available for CCM1, 2, and 3 on
surrounding hemosiderin rim, this technique is more a commercial basis, with several labs still working on
sensitive for the identification of smaller lesions, pick- identification of a suspected fourth familial gene.
ing up approximately threefold the number seen on Genetic testing is further discussed in Chapter 18 on
T1, T2, and intermediate sequences [14]. Up to 400 genetic counseling.
lesions have been identified in a patient by gradient
sequence [15]. Whereas, SWI identifies numerous addi- CCM in New Mexico
tional tiny lesions, up to threefold the number seen on
gradient-echo imaging [13]. In comparing SWI and Familial forms
GRE, lesions may appear smaller on SWI than on In 1978, Bicknell et al. reported the first case of a New
GRE. Increased numbers of lesions are identified by Mexican family of Hispanic descent, with four affected
MRI with increased age [16,17].
patients (one by historic report) ranging in age from
Contrast enhancement with current standard tech-
19 to 38. Presenting diagnoses included epilepsy,
niques adds minimal information to brain imaging.
paraplegia, and hemorrhagic stroke [5]. The original
Early reports identified some lesions that showed
genetic founder of the large southwestern US Hispanic
“blush” with contrasted CT, even though most lesions
population has not yet been identified but is suspected
did not enhance with contrast on standard angiogram to be one of the original Hispanic settlers in New
or on contrasted CT. On MRI with gadolinium, some Mexico, possibly as early as 1598 with the Oñate expe-
lesions also show mild enhancement but the signifi- dition. In one large pedigree, the ancestors were born
cance of this finding remains undetermined.
in New Mexico in the early 1700s (Gonzales and
Gonzales, 2009). Outside the Southwestern United
Gene discovery States and northern Mexico, the specific gene muta-
The first genetic localization was identified on chro- tion CHM has not been identified in patients with
mosome 7 and included a large Italian-American fam- origins further south in Mexico City, nor in Spain
ily from Boston, and a large Hispanic family from New [27,28]. In Spain, a variety of other mutations have
Mexico [18,19]. Further narrowing of the disease locus been identified in CCM1, 2, and 3.
included a number of New Mexico Hispanic families The natural history of familial CCM was reported
[20] and the New Mexico cohort was attributed to a retrospectively [29]. A later study provided genotype–
genetic founder effect [21]. In 1997, linkage of the phenotype correlations. While this later study did not
locus for CCM to 7q was published about a family include patients with CCM1-CHM, these authors found
with Mexican-American descent but ancestry from that other mutations in CCM1 may have a milder
Sonora, Mexico [22]. clinical presentation than mutations in CCM2 or
The first gene was identified as KRIT1 by Labauge in CCM3. However, the proportion of symptomatic
1999 [23]. Almost simultaneously, the specific mutation patients under 15 years was higher in CCM3 kindreds
that created the large Hispanic American cohort was [30]. Overall, clinical symptomatology and the number
found in the KRIT1 gene and was deemed “the com- of lesions on MRI were very similar among the genetic
mon Hispanic mutation (CHM)” by Sahoo et al. in forms of disease. Fifteen German families were reported

16
 Chapter 3: Familial cavernous malformations: a historical survey

in 2005, finding 75% symptomatic, 40–50% with epi- generation family [45]. Choroidal hemangiomas
lepsy, 10–20% with chronic headache, and 30–40% with were reported in a California family, with localization
hemorrhage, and 15% with focal neurological deficits of the gene to 7q [46] likely CCM1, and possibly CHM.
[31]. In the only study of predictive factors for intra- The authors did not make note of the ethnicity of the
cerebral hemorrhage in CCM, familial cases had a family. In one family with autosomal dominant CCM,
decreased relative risk with a family history of epilepsy several family members were found to have twin
and lobar location of lesions [32]. Imaging features do vessels of the retina [47]. Sixty patients with familial
not differ in the three known and suspected fourth CCM were screened with retinal examinations, finding
genetic forms. In a large study comparing sporadic 5% estimated frequency in any of the three known
and familial forms of CCM, the incidence of associated genes [26].
developmental venous anomalies (DVA) was extremely
low in the familial form (mostly CCM1) with nearly Other tissues
50% of sporadic patients showing associated DVAs [15].
Lesions in liver and bone are reported in occasional
kindreds [41,48].
Multisystemic involvement
Association with other vascular brain malformations Disease variability
is rare. In 1984, Pasyk et al. reported 25 members of
In most families, disease severity is remarkably varia-
one affected family, also detailing other associated
ble. Family members may carry the mutation and
types of vascular malformations including arteriove-
remain unaffected lifelong in up to 25% (Siegal et al.
nous malformations and capillary hemangiomas co-
1998), some remaining asymptomatic despite single or
existing in some families [33]. However, familial forms
multiple CCMs noted on imaging. Still others are left
are recognized to include lesions within other tissues.
with permanent neurological disability in the form of
Approximately 5–10% of cases have cutaneous or sub-
debilitating headaches, seizures or residual neurolog-
cutaneous lesions [34], retinal lesions or both cutane-
ical impairment secondary to CNS hemorrhages or
ous and retinal involvement.
their surgical management. A recent attempt to
identify gene polymorphisms in the angiotensin-
Cutaneous converting enzyme gene was suggestive of an effect
The first case report of a 32-year-old man with a retinal on lesion number [49]. In a prospective study of 33
cavernous hemangioma, cutaneous angiomas, and CT asymptomatic patients from 29 unrelated French fam-
and MRI confirmation of cerebrovascular lesions was ilies with asymptomatic lesions, subjects were eval-
made in 1984 [35]. Since then, several families have uated with serial clinical exams and spin-echo and
been reported showing this triad of involvement, but gradient-echo MRI over a mean of 2.1 years. Only
the cutaneous findings were inconsistent within fam- two out of 33 patients became symptomatic but 46%
ilies [36–39]. A case report of a 51-year-old man with of patients showed changes in MRI that included
familial CCM had thousands of cherry angiomas with bleeding, new lesion formation in 30.3%, change in
over 150 lesions surgically removed [40]. The cutane- signal intensity, and changes in size [17,50]. Five
ous findings appear in patients with mutations in all Italian families were studied with clinical MRI and
three known genes, but there seem to be no specific genetic studies. This study included 45 at-risk,
mutations that predispose to skin lesions [41]. A rare symptom-free relatives. In this study, three new muta-
occurrence of associated cavernous malformation has tions in CCM1 were identified, and of 33 KRIT1
been reported in Klippel Trenauney Weber syndrome mutation carriers, 57.6% were asymptomatic. MRI
[42]. Cutaneous and subcutaneous angiomas have also revealed CCM lesions in only 82.3% of these asympto-
been reported with CCM1-CHM [43]. matic carriers, but MRI was performed on a 1.5 tesla
magnet and with gradient-echo but not SWI (1988
[51]). In another Italian study, another novel gene
Ocular mutation was found in CCM1 and also in CCM2.
Retinal cavernous angiomas were reported in a family A large Italian family with a CCM1 mutation has
with CNS and hepatic CMs in an Italian family [44]. been reported [52] in which genetic variations were
Retinal lesions were also reported in a large four- searched for in all three known genes to help

17
 Section 1: Biology

explain clinical variability. The spectrum of geno- 2. Clark, J. V. Familial occurrence of cavernous
type and clinical manifestation in CCM found large angiomata of the brain. J Neurol Neurosurg Psychiatry
clinical variability in CCM1 in 22 Hispanic- 1970;33:871–876.
American cases with the CHM. Interestingly, 3. Villani, R. M., Arienta, C., et al. Cavernous angiomas of
CCM1 may have a decreased risk of hemorrhage the central nervous system. J Neurosurg Sci
compared with CCM2 and CCM3 [53]. A large 1989;33:229–252.
prospective study of CCM1 common Hispanic 4. Tindall, R. S., Kirkpatrick, J. B., et al. Multiple small
mutation patients will include a genome-wide asso- cavernous angiomas of the brain with increased
intracranial pressure. Ann Neurol 1978;4:376–378.
ciation study to identify modifier genes with either
beneficial or deleterious effects. 5. Bicknell, J. M., Carlow, T. J., et al. Familial cavernous
angiomas. Arch Neurol 1978;35:746–749.

Natural history and prognosis of 6. Hayman, L. A., Evans, R. A., et al. Familial cavernous
angiomas: natural history and genetic study over a
familial CCMs 5-year period. Am J Med Genet 1982;11:147–160.
A study of 264 consecutive patients in Helsinki, 7. Mason, I., Aase, J. M., et al. Familial cavernous
Finland, reported only 33 patients with multiple angiomas of the brain in an Hispanic family. Neurology
1988;38:324–326.
CCMs. Genotyping was not performed in this study.
8. Rigamonti, D., Hadley, M. N., et al. Cerebral cavernous
Only 9% had a family history of the disease. A total of
malformations. Incidence and familial occurrence. New
416 cavernomas were found, 70% supratentorial and Engl J Med 1988;319:343–347.
30% infratentorial. Eighteen of the 33 patients had 9. Rutka, J. T., Brant-Zawadzki, M., et al. Familial
surgery, typically to remove the largest cavernoma. cavernous malformations. Diagnostic potential of
Of these 18 patients, one developed temporary hemi- magnetic resonance imaging. Surg Neurol
paresis and another had permanent motor dysphasia. 1988;29:467–474.
Of patients operated on for epileptogenic lesions, 70% 10. Labauge, P., Laberge, S., et al. Hereditary cerebral
had Engel class 1 outcome. From the 13 patients with cavernous angiomas: clinical and genetic features in
follow-up MR imaging, 52 new cavernomas were 57 French families. Societe Francaise de
Neurochirurgie. Lancet 1998;352:1892–1897.
found, with a mean follow-up of 7 years. An interesting
11. Brunereau, L., Leveque, C., et al. Familial form of
finding was that no patients who underwent surgery cerebral cavernous malformations: evaluation of
had acute hemorrhages, and no patients had hemor- gradient-spin-echo (GRASE) imaging in lesion
rhage for more than one lesion simultaneously [54]. In detection and characterization at 1.5 T. Neuroradiology
a study of Hispanic CCM patients in New Mexico 2001;43:973–979.
(presumed CCM1-CHM) by Kattapong et al., lesions 12. Cooper, A. D., Campeau, N. G., et al. Susceptibility-
increased at an average of one per decade and mean weighted imaging in familial cerebral cavernous
diameter decreased slightly [17]. The estimated rate of malformations. Neurology 2008;71:382.
de novo lesion formation is 0.2–0.4 new lesions per 13. de Souza, J. M., Domingues, R. C., et al. Susceptibility-
patient/year. weighted imaging for the evaluation of patients with
For familial CCM, recommendations regarding familial cerebral cavernous malformations: a
routine imaging are sparse at present, especially with comparison with t2-weighted fast spin-echo and
gradient-echo sequences. AJNR Am J Neuroradiol
regard to surveillance imaging for spinal cord lesions
2008;29:154–158.
[55]. As treatments become available, we will undoubt-
edly require routine imaging to assess treatment effects. 14. Lehnhardt, F. G., von Smekal, U., et al. Value of
gradient-echo magnetic resonance imaging in the
Studies of lesion permeability will be essential in this
diagnosis of familial cerebral cavernous malformation.
outcome assessment as well. Arch Neurol 2005;62:653–658.
15. Petersen, T. A., Morrison, L. A., et al. Familial versus
References sporadic cavernous malformations: differences in
1. Kufs, H. Ǘber die heredofamiläre Angiomatose des developmental venous anomaly association and lesion
Gehirns und der Retina, ihre Beziehung en zueinander phenotype. AJNR Am J Neuroradiol 2010;31:377–382.
und zur Angiomatose der Haut. Z Neurol Psychiatrie 16. Horowitz, M. & Kondziolka, D. Multiple familial
1928;113:651–686. cavernous malformations evaluated over three

18
 Chapter 3: Familial cavernous malformations: a historical survey

generations with MR. AJNR Am J Neuroradiol and genetic study of 15 German families]. Nervenarzt
1995;16:1353–1355. 2005;76:175–180.
17. Kattapong, V. J., Hart, B. L., et al. Familial cerebral 32. Cantu, C., Murillo-Bonilla, L., et al. Predictive factors
cavernous angiomas: clinical and radiologic studies. for intracerebral hemorrhage in patients with
Neurology 1995;45:492–497. cavernous angiomas. Neurol Res 2005;27:314–318.
18. Gunel, M., Awad, I. A., et al. Mapping a gene causing 33. Pasyk, K. A., Argenta, L. C., et al. Familial vascular
cerebral cavernous malformation to 7q11.2-q21. Proc malformations. Report of 25 members of one family.
Natl Acad Sci USA 1995;92:6620–6624. Clin Genet 1984;26:221–227.
19. Marchuk, D. A., Gallione, C. J., et al. A locus for 34. Kunkeler, A. C., Uitdehaag, B. M., et al. Familial
cerebral cavernous malformations maps to cavernous haemangiomas. Br J Dermatol
chromosome 7q in two families. Genomics 1998;139:166–167.
1995;28:311–314. 35. Schwartz, A. C., Weaver, R. G. Jr., et al. Cavernous
20. Johnson, E. W., Iyer, L. M., et al. Refined localization of hemangioma of the retina, cutaneous angiomas, and
the cerebral cavernous malformation gene (CCM1) to a intracranial vascular lesion by computed tomography
4-cM interval of chromosome 7q contained in a well- and nuclear magnetic resonance imaging. Am J
defined YAC contig. Genome Res 1995;5:368–380. Ophthalmol 1984;98:483–487.
21. Gunel, M., Awad, I. A., et al. A founder mutation as a 36. Dobyns, W. B., Michels, V. V., et al. Familial cavernous
cause of cerebral cavernous malformation in Hispanic malformations of the central nervous system and
Americans. New Engl J Med 1996;334:946–951. retina. Ann Neurol 1987;21:578–583.
22. Polymeropoulos, M. H., Hurko, O., et al. Linkage of the 37. Ohkuma, A., Kuroda, T., et al. [Familial cavernous
locus for cerebral cavernous hemangiomas to human angioma of the central nervous system – report of a
chromosome 7q in four families of Mexican-American family and review of literature]. No To Shinkei
descent. Neurology 1997;48:752–757. 1992;44:155–161.
23. Laberge-le Couteulx, S., Jung, H. H., et al. Truncating 38. Leblanc, R., Melanson, D., et al. Hereditary
mutations in CCM1, encoding KRIT1, cause hereditary neurocutaneous angiomatosis. Report of four cases.
cavernous angiomas. Nat Genet 1999;23:189–193. J Neurosurg 1996;85:1135–1142.
24. Liquori, C. L., M. J. Berg, et al. Deletions in CCM2 are a 39. Garcia-Moreno, J. M., Gamero, M. A., et al. [Familial
common cause of cerebral cavernous malformations. cerebral cavernomatosis associated with cutaneous
Am J Hum Genet 2007;80:69–75. angiomas]. Rev Neurol 1998;27:484–490.
25. Liquori, C. L., Berg, M. J., et al. Low frequency of 40. Clatterbuck, R. E. & Rigamonti, D. Cherry angiomas
PDCD10 mutations in a panel of CCM3 probands: associated with familial cerebral cavernous
potential for a fourth CCM locus. Hum Mutat malformations. Case illustration. J Neurosurg
2006;27:118. 2002;96:964.
26. Labauge, P., Krivosic, V., et al. Frequency of retinal
cavernomas in 60 patients with familial cerebral 41. Gianfrancesco, F., Cannella, M., et al. Highly
cavernomas: a clinical and genetic study. Arch variable penetrance in subjects affected with
Ophthalmol 2006;124:885–886. cavernous cerebral angiomas (CCM) carrying
novel CCM1 and CCM2 mutations.
27. Lucas, M., Solano, F., et al. Spanish families with Am J Med Genet B Neuropsychiatr Genet
cerebral cavernous angioma do not bear 742C–>T 2007;144:691–695.
Hispanic American mutation of the KRIT1 gene. Ann
Neurol 2000;47:836. 42. Pichierri, A., Piccirilli, M., et al. Klippel-
Trenaunay-Weber syndrome and intramedullary
28. Lucas, M., A. F. Costa, et al. Germline mutations in the cervical cavernoma: a very rare association.
CCM1 gene, encoding Krit1, cause cerebral cavernous Case report. Surg Neurol 2006;66:203–206;
malformations. Ann Neurol 2001;49:529–532. discussion 206.
29. Labauge, P., Brunereau, L., et al. The natural history of 43. Zlotoff, B. J., Bang, R. H., et al. Cutaneous
familial cerebral cavernomas: a retrospective MRI angiokeratoma and venous malformations in a
study of 40 patients. Neuroradiology 2000;42:327–332. Hispanic-American patient with cerebral
30. Denier, C., Labauge, P., et al. Genotype-phenotype cavernous malformations. Br J Dermatol
correlations in cerebral cavernous malformations 2007;157:210–212.
patients. Ann Neurol 2006;60:550–556. 44. Drigo, P., Mammi, I., et al. Familial cerebral, hepatic,
31. Siegel, A. M., Bertalanffy, H., et al. [Familial cavernous and retinal cavernous angiomas: a new syndrome.
malformations of the central nervous system. A clinical Childs Nerv Syst 1994;10:205–209.

19
 Section 1: Biology

45. Goldberg, R. E., Pheasant, T. R., et al. Cavernous families with cerebral cavernous malformation. Arch
hemangioma of the retina. A four-generation Neurol 2007;64:843–848.
pedigree with neurocutaneous manifestations 52. Pileggi, S., Buscone, S., et al. (2010). Genetic variations
and an example of bilateral retinal involvement. within KRIT1/CCM1, MGC4607/CCM2 and
Arch Ophthalmol 1979;97:2321–2324. PDCD10/CCM3 in a large Italian family harbouring a
46. Sarraf, D., Payne, A. M., et al. Familial cavernous Krit1/CCM1 mutation. J Mol Neurosci
hemangioma: An expanding ocular spectrum. Arch 2010;42:235–242.
Ophthalmol 2000;118:969–973.
53. Gault, J., Sain, S., et al. Spectrum of genotype and
47. Bottoni, F., Canevini, M. P., et al. Twin vessels in clinical manifestations in cerebral cavernous
familial retinal cavernous hemangioma. Am J malformations. Neurosurgery 2006;59:1278–1284;
Ophthalmol 1990;109:285–289. discussion 1284–1275.
48. Toldo, I., Drigo, P., et al. Vertebral and spinal 54. Kivelev, J., Niemela, M., et al. Long-term outcome of
cavernous angiomas associated with familial cerebral patients with multiple cerebral cavernous
cavernous malformation. Surg Neurol malformations. Neurosurgery 2009;65:450–455;
2009;71:167–171. discussion 455.
49. Altas, M., Bayrak, O. F., et al. Angiotensin-converting 55. Cohen-Gadol, A. A., Jacob, J. T., et al. Coexistence of
enzyme insertion/deletion gene polymorphism intracranial and spinal cavernous malformations: a
in patients with familial multiple cerebral study of prevalence and natural history. J Neurosurg
cavernous malformations. J Clin Neurosci 2006;104:376–381.
2010;17:1034–1037.
56. Rigamonti, D., Drayer, B. P., Johnson, P. C.,
50. Labauge, P., Brunereau, L., et al. Prospective follow-up Hadley, M. N., Zabramski, J., Spetzler, R. F. The
of 33 asymptomatic patients with familial cerebral MRI appearance of cavernous malformations
cavernous malformations. Neurology (angiomas). J Neurosurg 1987;67:518–524.
2001;57:1825–1828.
57. Zabramski, J., et al. The natural history of familial
51. Battistini, S., Rocchi, R., et al. Clinical, magnetic cavernous malformations: results of an ongoing study.
resonance imaging, and genetic study of 5 Italian J Neurosurg 1994;80:422–432.

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 Clinical and molecular genetics
Chapter

4 of cerebral cavernous malformations

Xavier Ayrignac and Elisabeth Tournier-Lasserve

Introduction Three CCM genes have been mapped and identified

in the last 10 years [5–12] (Fig. 4.2). These molecular
Cerebral cavernous malformations (CCM/OMIM genetics data dramatically increased our knowledge of
116860) are vascular lesions histologically character- this disease and have provided useful information for
ized by abnormally enlarged capillary cavities without clinical care and genetic counseling. They were also an
intervening brain parenchyma. From large series based important step towards the understanding of the mech-
on necropsy and/or magnetic resonance imaging (MRI) anisms of this disorder. This chapter will summarize the
studies, their prevalence in the general population has advances in CCM clinical and molecular genetics and
been estimated to be close to 0.1–0.5%. Most of them the remaining gaps in this field.
are located within the central nervous system but they
sometimes affect either the retina or the skin [1].
CCMs occur both as a sporadic or familial condition. Clinical genetics
Sporadic cases showing a single lesion on cerebral MRI
are not inherited and do not carry a germline mutation in Pattern of inheritance
CCM genes. The influence of genetics was first suspected The proportion of familial cases has been estimated as
by Kufs et al. in 1928 in a German family including a high as 50% in Hispanic-American CCM patients and
CCM patient whose 17-year-old daughter was strongly close to 10–40% in Caucasian patients. However, no
suspected to also have CCM when she presented with epidemiology-based study has been conducted so far
hemiparesia [2]. Several additional families including and these numbers should be considered as estima-
more than one affected member were thereafter pub- tions based on hospital-based recruitment of patients.
lished. However, very limited neuroradiological data The CCM pattern of inheritance is autosomal
were available until 1988 when Rigamonti et al. charac- dominant with an incomplete clinical and neuroradio-
terized the clinical and MRI features of familial CCM in a logical penetrance. The recent identification of CCM
series of six large Hispanic-American families [3]. They loci and genes allowed the identification of mutation
emphasized the higher sensitivity and specificity of mag- carriers and helped to estimate the penetrance of this
netic resonance imaging (MRI), as compared to CT disorder. In a genetic linkage analysis conducted on 20
scans, for the detection of CCM lesions, whose multi- families Craig et al. estimated the clinical penetrance at
plicity is a hallmark of familial CCM. They also estab- 88% in CCM1 families, 100% in CCM2 and 63% in
lished the incomplete penetrance of this condition. In CCM3 families [6]. However, a recent analysis con-
1998, a clinical and MRI analysis of 57 consecutive, white, ducted in a series of 64 consecutive families showed a
non-Hispanic-American probands with multiple lesions penetrance which was closer to 60% in CCM1 families
and their relatives showed that most, but not all, sporadic [13]. Additional studies conducted on large series of
cases with multiple lesions have inherited their disease CCM2 and CCM3 families are now needed to estimate
from one of their two asymptomatic parents and that precisely the penetrance in those families.
genetic CCM is an evolutive condition as assessed by the Many CCM patients who carry a mutation in one
strong correlation between patients’ age and number of of the three CCM genes nevertheless present as
lesions (Ref. 4 and Fig. 4.1). sporadic cases, due to incomplete clinical penetrance.

Cavernous Malformations of the Nervous System, ed. Daniele Rigamonti. Published by Cambridge University Press.
© Cambridge University Press 2011.

21
 Section 1: Biology

? ?

• Sporadic case • Familial case • Sporadic case

• Solitary lesion • Multiple lesions • Multiple lesions
• Non genetic • Genetic • Genetic in most likely all cases
Figure 4.1. Multiplicity of CCM lesions is a hallmark of the familial form of the disease. Left panel: a sporadic, non-genetic case with a unique
lesion on cerebral MRI. Middle panel: a familial case with multiple lesions. Right panel: a sporadic case with multiple lesions which is most likely
a genetic case due to either an incomplete clinical penetrance or a de novo mutation. See color plate section.

A proportion of these patients are most likely affected

by a hereditary form of the disease since they were
shown to carry a de novo mutation in one of the three
CCM2
CCM genes [14]. These patients are therefore also true
MGC4607
genetic cases and their offspring also have a 50% risk of
inheriting the mutated gene.
In some other sporadic cases with multiple lesions,
screening of all three CCM genes does not detect any
CCM3 mutation (see below). However, the multiplicity of their
CCM1
PDCD10 lesions strongly suggests that a genetic form of the dis-
KRIT1 ease affects these patients and that their offspring are at
risk of developing CCM lesions. Several hypotheses may
be raised to explain the absence of any detected muta-
tion, including a somatic mosaicism of a de novo muta-
Chr 7 Chr 3 tion which occurred during gestation and is not
detectable in DNA extracted from peripheral blood
Figure 4.2. CCM genetic loci and genes. Three CCM genes have
been mapped on chromosomes 7 (CCM1 and CCM2) and 3 (CCM3). cells. This will be important to solve in the future since
The vast majority of CCM gene mutations are loss of function it is of interest for genetic counseling. Indeed, depending
mutations. See color plate section. of the mosaicism ratio within the gonads of this patient,
the risk for their offspring may be lower than 50%.
Indeed, a clinical and neuroradiological analysis con- Altogether, these data strongly suggest that (i) the
ducted prior to CCM gene identification in a series of vast majority, if not all, sporadic cases with multiple
22 consecutive sporadic cases with multiple lesions lesions are true genetic cases; (ii) their offspring have a
showed that 75% of them were indeed affected with a 50% risk of developing lesions; and (iii) they should be
hereditary form of the disease since one of their two managed in the same way as familial cases.
asymptomatic parents showed lesions on MRI [4].
These patients are true familial genetic cases and their Genetic counseling
offspring have a 50% risk of inheriting the mutated gene. Molecular screening of the three CCM genes is tech-
What about the 25% remaining patients whose nically feasible in any routine genetics diagnostic lab-
biological parents do not show CCM on brain MRI? oratory. Sensitivity of genetic screening is above 98%

22
 Chapter 4: Clinical and molecular genetics of cerebral cavernous malformations

in probands having an affected relative and above 60% requests for screening an asymptomatic child should
in sporadic cases with multiple lesions, providing that be managed even more cautiously since psychological
an extensive screening of all three CCM genes is con- issues are even more important than in adult asymp-
ducted, looking for both point mutations and genomic tomatic individuals. Presymptomatic screening can be
rearrangements (Ref. 14 and unpublished data). Once performed with cerebral MRI. Magnetic resonance
the mutation has been identified in a proband, sensi- imaging should include a gradient-echo (GRE) sequence
tivity is 100% when screening his/her relatives. to ensure a good sensitivity. Indeed, 18% of mutation
The main question for the clinician relates to the carriers have only one lesion on T2-weighted MRI as
utility of this molecular screening in affected and/or compared to 6% when using GRE sequences [14].
at-risk individuals in clinical practice. Another ques- However, a normal MRI (including normal GRE sequen-
tion is that of the respective indications of MRI and ces) can be observed in around 3% of asymptomatic
genetic screening in asymptomatic individuals. mutation carriers, as shown in a cross-sectional study.
Genetic screening should carry a balanced benefit/ It will be interesting to know in future large series
risk ratio. This ratio varies depending on several fac- whether susceptibility weighting MR phase imaging
tors including the clinical status of an individual and (SWI) may decrease this false-negative proportion.
his/her age. Based on clinical, MRI and molecular Alternatively, molecular screening can be used as a first
genetic data, the following algorithm may be proposed step for presymptomatic screening, providing that the
to facilitate molecular screening decisions [15]. mutation has been identified previously in a sympto-
matic member of the family; sensitivity would then be
Sporadic case with a unique lesion on MRI 100% with no false negative. If molecular screening is
The risk of having a mutation is null or extremely low, positive, MRI is recommended for follow-up.
providing that both T2-weighted and gradient-echo The choice to use MRI or molecular screening
(GRE) MRI sequences have been performed. Genetic depends on the availability of information on the
screening is not useful. mutation present in the family as well as practical
local availability of genetic testing. With regard to
Symptomatic case with multiple CCM lesions and one or ethical considerations, presymptomatic MRI screen-
more affected relatives ing should be considered as the equivalent of presymp-
The genetic nature of the disease is already known. tomatic molecular screening.
Unless genetic counseling is envisioned, molecular
genetic screening is not useful. Prenatal screening
Prenatal diagnosis requests are quite rare in CCM but
Symptomatic sporadic case with multiple CCM lesions may be encountered in families in which several
The genetic nature of the disease is most likely, but not patients have suffered severe symptoms. Prenatal diag-
proven. Genetic screening in those cases will identify a nosis may be of benefit in such families. In all cases, all
mutation in 60% of the cases. This information will available information on the disease should be given to
not change the patient’s clinical care but may be useful the parents before they make any final decision.
for genetic counseling. However, the patient has to be
aware that a negative test does not exclude a genetic
cause (see supra). Genotype–phenotype correlations
The severity of CCM is highly variable from one
Asymptomatic individual with affected relatives patient to another. The outcome is not associated
The first step will be to draw the genealogical tree of with the number of lesions, but rather with the loca-
the family to check whether this individual is or is not tion of lesions. The most severe lesions are those
at risk, depending on his/her link with the proband. In located within the brainstem or basal ganglia.
most cases, neurosurgeons recommend presympto- The identification of the three CCM genes provides
matic screening and, in positive asymptomatic adult a unique opportunity to analyze and compare clinical
individuals, MRI follow-up [16]. However, presymp- and MRI features of genetically homogeneous groups of
tomatic screening should always be envisioned with CCM mutation carriers. A cross-sectional analysis of
great caution since it is difficult at present to estimate 163 consecutive families showed that the proportion
the real benefit of presymptomatic screening. Parental of patients with a young age of onset (<15 years old) is

23
 Section 1: Biology

CCM1/Krit1 Figure 4.3. The three CCM genes encode for three
unrelated proteins, krit1 (CCM1) which contains
NH2 Ankyrin FERM COOH several ankyrin domains and a FERM domain, CCM2,
also called malcavernin, which contains a PTB
1 736 (phosphotyrosine binding) domain, and CCM3/
PCDCD10, a protein involved in apoptosis. See color
plate section.
CCM2/Malcavernin

NH2 PTB COOH

1 444

CCM3/pdcd10

NH2 COOH

1 212

significantly higher in the CCM3 group (Ref. 14 and The CCM1/KRIT1 gene contains 16 coding exons,
Fig. 4.2). CCM3 patients are also more prone than which encode for Krit1, a 736 amino-acid protein
CCM1 and CCM2 patients to develop cerebral hemor- containing three ankyrin and one FERM (F for 4.1
rhages at a young age. The collection and analysis of protein, E for Ezrin, R for radixin, and M for Moesin)
larger series of CCM3 patients is needed to fully estab- domains (Fig. 4.3). CCM2, a 10 exon gene, encodes for
lish all clinical features of this group of CCM patients. the MGC4607 protein, also called malcavernin, which
In addition to central nervous system lesions, some contains a phosphotyrosine binding (PTB) domain.
CCM patients show retinal and/or skin lesions. Retinal CCM3 includes seven exons that encode for PDCD10
CCM has been observed in approximately 5% of CCM (Programmed Cell Death 10), a protein without any
patients, and with all CCM genes [17]. With regard to known conserved functional domain. Considerable pro-
cutaneous vascular malformations, 9% of CCM patients gress has been made in the past 3 years in understanding
show either capillary malformations, hyperkeratotic the biochemical pathways in which those proteins might
cutaneous capillary venous malformations (HCCVM), be involved (see Chapter 5).
and/or venous malformations [18]. CCM1 mutated Sequencing of all coding exons and exon–intron
patients may be affected by all the types of cutaneous boundaries of the three CCM genes and searching
vascular malformations; however, HCCVM has been for genomic rearrangements using either cDNA anal-
shown to be associated only with CCM1/KRIT1 muta- ysis and/or quantitative multiplex PCR such as MLPA
tions [18–20]. Nodular venous malformations are (multiplex ligation-dependent probe amplification) or
encountered in both CCM1 and CCM3 mutants [18]. QMPSF (quantitative multiplex PCR of short fluores-
cent fragments) in Caucasian non-Hispanic-American
CCM molecular genetics CCM multiplex families led to the identification of the
causative mutation in over 98% of familial CCM (Refs.
CCM gene germline mutations 14, 21 and unpublished data). Approximately 72% of
Three CCM loci have been mapped to chromosome 7q multiplex families harbored a mutation in CCM1, 18%
(CCM1), 7p (CCM2), and 3q (CCM3) [5,6]. A strong in CCM2, and 10% in CCM3. The CCM3 proportion
founder effect has been observed in Hispanic- was much lower than expected based on previous link-
American CCM patients with most families linked to age data that suggested 40% of CCM families were
the CCM1 locus [7]. In Caucasian families, the pro- linked to the CCM3 locus.
portions of families linked to each CCM locus were The mutation detection rate is, however, much
estimated to be 40% (CCM1), 20% (CCM2), and 40% lower in sporadic cases with multiple lesions, ranging
(CCM3) [6]. The three genes located at these loci have from 45% to 67% [14,21,22]. Several hypotheses may
now been identified [8–12]. be raised to explain the absence of any detectable

24
 Chapter 4: Clinical and molecular genetics of cerebral cavernous malformations

mutation in those patients, including a somatic mosai- codon mutation in CCM1 in most families with this
cism of a de novo mutation which occured during ethnic background [9]. Recurrent mutations have also
gestation and is not detectable in DNA extracted from been identified in a few additional populations
peripheral blood cells, the existence of undetected reg- [30,32,35]. However, in most cases despite their highly
ulatory mutations located far away from coding exons, stereotyped consequences, germline CCM mutations
epigenetic silencing events and/or additional yet are “private” mutations present in only one or very few
unknown CCM genes. This will be important to solve families.
in the future since it is of interest for genetic counseling
of sporadic cases with multiple lesions. Biallelic somatic and germline mutations in
With regard to sporadic CCM cases with a unique
lesion on cerebral MRI, no mutation was detected in CCM lesions
reported series [23,24]. The combination of these data The autosomal dominant pattern of inheritance of
with those obtained in familial CCM strongly suggests CCM and the presence of multiple lesions in familial
that clinically sporadic cases with a unique lesion on CCM, contrasting with the detection of a single lesion
MRI of the brain that harbor a germline mutation are in non-hereditary cavernous angiomas, strongly sug-
most likely very rare. Therefore, molecular screening is gested a “two-hit” hypothesis might be involved in
not indicated in these cases. CCM, as reported previously in other conditions
More than 150 distinct CCM1/CCM2/CCM3 such as retinoblastoma or other vascular malforma-
germline mutations have been reported so far [8– tions [36,37]. According to this hypothesis, the com-
12,21–31]. Those mutations were highly stereotyped. plete loss within an affected cell of the two alleles of a
Almost all of them lead to a premature termination given CCM gene would lead to a CCM lesion. Loss of
codon through different mechanisms including non- the first allele (first hit) would be the result of a germ
sense, splice-site, large deletions, and frameshift muta- line mutation and loss of the second allele (second hit)
tional events. These data strongly suggest that a loss of will occur somatically.
function through mRNA decay of the mutated allele The highly heterogeneous nature of CCM lesions
is the most likely pathophysiological mechanism and the very limited number of endothelial cells lining
involved in CCM patients. the capillary cavities have rendered this hypothesis
Fewer than 10 missense mutations have been difficult to test. Direct sequencing of the DNA
reported so far in CCM genes. All of them except extracted from a heterogeneous lesion was initially
one actually activated cryptic splice sites and led to used to screen CCM lesions from both sporadic and
an aberrant splicing of CCM mRNA and a frameshift a few familial patients. This did not detect any somatic
with a premature stop codon. The mutation L198R mutation except in one sporadic case [39]. In this latter
is the only known CCM missense mutation which case, two CCM1 missense mutations, F97S and K569E,
does not affect splicing; it is located within the were detected in the CCM lesion and were shown to be
C-terminal part of the PTB domain of CCM2. It has absent in the blood of the patient. However these data
been shown to abolish the interaction of CCM2 were difficult to interpret due to the nature of the
and CCM1, strongly suggesting its causality [13,33]. mutations; they were not truncating mutations (a pos-
A total of four intragenic in-frame deletions have sible aberrant splicing effect of these two mutations
been reported of which two affect exons 17 and 18 was not investigated) and the biallelism of these muta-
of CCM1, one deleting exon 2 of CCM2, and the tions was not explored.
last one deleting exon 5 of CCM3. The last two dele- The first biallelic germ line and somatic mutations
tions have been used to map potential relevant inter- within a CCM lesion was reported by Gault et al. in
action domains of CCM2 and CCM3 [21, 34]. 2005 in a CCM1 mutated patient. This work strongly
However, it is not known so far whether these puta- supported the “two-hit” mechanism in the formation
tive truncated proteins were indeed produced and of lesions at least in CCM1 patients; this group dem-
stable in vivo. onstrated recently that the second hit occurred within
A founder effect was reported in the Hispano- the endothelial cells [40,41].
American CCM population, based on microsatellite Biallelic somatic and germline mutations in each of
haplotyping data at the CCM1 locus; this was con- the three CCM genes was recently reported by Akers
firmed by the detection of a founder Q455X stop et al. [42]. They were able to convincingly establish the

25
 Section 1: Biology

presence of a biallelic somatic and germline deleteri- screening of exonic sequences for point mutations
ous mutation in two CCM1, one CCM2, and one and deletions, no mutation is detected in 2–5% of
CCM3 lesions from four unrelated patients. None of familial CCM cases and in around 20% of sporadic
these mutations was detected through direct sequen- cases with multiple lesions. In addition, the proportion
cing of lesions’ DNA, emphasizing the lack of sensi- of families showing a mutation within CCM3/
tivity of direct sequencing. These data established the PDCD10 (10%) at the CCM3 locus on chromosome
existence of biallelic somatic and germline mutations, 3q25 is much lower than expected based on linkage
independent of the nature of the CCM gene involved. data (40%).
Using microdissection laser capture, they showed that The mosaicism of de novo mutations might likely
the somatic mutation occurred in endothelial cells and be involved in sporadic cases with multiple lesions.
not in the intervening neural tissue. The proportion of Epigenetic silencing of these three genes might also
endothelial cells that harbor the somatic mutation was be involved. Cis-regulatory mutations located far away
estimated in one lesion and shown to be close to 30%. from CCM coding sequences may explain both the
This suggests the presence of mosaicism in the somatic very small proportion of non-mutated familial cases
mutation. These data are in agreement with a recent or sporadic cases with multiple lesions. However, the
immunohistochemistry-based approach [43]. This existence of additional non-identified CCM genes, one
question would need, however, additional investiga- of which being possibly located close to PDCD10,
tion. It would also be important to analyze several cannot be excluded at this point.
lesions from a given patient to test for the presence Recently an additional gene, ZPLD1 (zona pellucida-
of the same mutation in multiple lesions. A unique like domain containing 1), has been reported to be
somatic mutation has indeed been detected in multi- disrupted in a CCM patient harbouring a balanced trans-
focal lesions in another hereditary vascular condition, location between chromosome X and chromosome 3q,
suggesting a common origin for abnormal endothelial centromeric to CCM3/PDCD10 [44]. The expression of
cells lying in distant sites [38]. ZPLD1 mRNA in lymphoblastoid cell lines of the patient
Altogether these data strongly suggest that CCM was shown to be significantly decreased, suggesting that
shows predominant inheritance like several other the interruption of this gene may be causal. However,
hereditary vascular conditions. It remains to be deter- none of the 20 additional CCM patients (without any
mined when and in which endothelial cell compart- mutation in CCM1/CCM2/CCM3) screened by the
ments second-hit somatic events occur. same group showed either a point mutation or a deletion
within this gene. These data suggest that either this gene
Are there additional CCM genes? is involved in a very small proportion of CCM patients
Previous linkage data suggested that the three CCM or its interruption does not cause CCM but that the
loci on 7p, 7q, and 3q would most likely account for translocation present in this patient deregulated the
all CCM families [6]. However, despite extensive expression of a gene that is still unidentified.

100% Figure 4.4. CCM3 patients are at higher

risk of having a cerebral hemorrhage at a
young age. In more than 50% of CCM3
80% patients the initial clinical manifestation is a
cerebral hemorrhage [14].

60%

40%

20%

0%
CCM1 CCM2 CCM3

26
 Chapter 4: Clinical and molecular genetics of cerebral cavernous malformations

The tremendous progress in sequencing technolo- 4. Labauge, P., Laberge, S., Brunereau, L., Lévy, C. &
gies should help to resolve this question in the very Tournier-Lasserve, E. Hereditary cerebral cavernous
near future [45]. angiomas: clinical and genetic features in 57 French
families. Lancet 1998;352:1892–1897.

Conclusions and future 5. Dubovsky, J., Zabramski, J. M., Kurth, J., et al. A gene
responsible for cavernous malformations of the brain
Since the identification of the first family with several maps to chromosome 7q. Hum Mol Genet
affected members, tremendous progress has been 1995;4:453–458.
made in the characterization of this condition, mainly 6. Craig, H. D., Günel, M., Cepeda, O., Johnson, E. W.,
thanks to the use of the MRI tool and the identification et al. Multilocus linkage identifies two new loci for a
of CCM genes, which with the use of molecular tools Mendelian form of stroke, cerebral cavernous
allows for the identification of mutation carriers. The malformation, at 7p15–13 and 3q25.2–27. Hum Mol
combined use of both tools helped us to clarify several Genet 1998;7:1851–1855.
features of this condition, including its incomplete 7. Gûnel, M., Awad, I. A., Finberg, K., et al. A founder
clinical and MRI penetrance as well as the molecular mutation as a cause of cerebral cavernous
malformation in Hispanic Americans. New Engl J Med
basis of sporadic cases with multiple lesions. Genetic
1996;334:946–951.
counseling is now possible.
Several additional questions, however, have to be 8. Laberge-le Couteulx, S., Jung, H. H., Labauge, P., et al.
Mutations in CCM1, encoding KRIT1, cause hereditary
addressed. What is the molecular basis in familial cavernous angiomas. Nat Genet 1999;23:189–193.
CCM cases in which no mutation of the three known
9. Sahoo, T., Johnson, E. W., Thomas, J. W., et al.
CCM genes has been detected? Are sporadic CCM
Mutations in the gene encoding KRIT1, a Krev-1/rap1a
patients with multiple lesions examples of mosaicism binding protein, cause cerebral cavernous
for a germline mutation? Are there modifying genes malformations (CCM1). Hum Mol Genet
that may explain the intra-familial clinical variability? 1999;8:2325–2333.
The ongoing progress of genotyping and sequencing 10. Liquori, C. L., Berg, M. J., Siegel, A. M., et al. Mutations
will most likely help us solve these questions in the in a gene encoding a novel protein containing a
immediate future. phosphotyrosine-binding domain cause type 2 cerebral
In addition to these questions, one main challenge cavernous malformations. Am J Hum Genet
is to understand the pathophysiological mechanisms 2003;73:1459–1464.
of this condition. The recent identification of several of 11. Denier, C., Goutagny, S., Labauge, P., et al.
the biochemical pathways involving CCM proteins as Mutations within the MGC4607 gene cause cerebral
well as the analysis of several fish and mouse CCM cavernous malformations. Am J Hum Genet
2004;74:326–337.
animal models have already provided a number of
clues to this goal. These data as well as the availability 12. Bergametti, F., Denier, C., Labauge, P., et al. Mutations
of animal models mimicking this disease will be of within the programmed cell death 10 gene cause
cerebral cavernous malformations. Am J Hum Genet
major help for the development of new approaches 2005;76:42–51.
to cure the most severe forms of this disease in the next
13. Denier, C., Labauge, P., Brunereau, L., et al. Clinical
10 years.
features of cerebral cavernous malformations
patients with KRIT1 mutations. Ann Neurol
References 2004;55:213–220.
1. Russell, D. S. & Rubinstein, L. J. Pathology of the Tumors 14. Denier, C., Labauge, P., Bergametti, F., et al.
of the Central Nervous System, 5th edn (Baltimore: Genotype-phenotype correlations in cerebral
Williams and Wilkins, 1989), pp. 730–736. cavernous malformations patients. Ann Neurol
2. Kufs H. Uber heredofamiliare Angiomatose des Gehirns 2006;60:550–556.
und der Retina, ihre Beziehungen zueinander und zur 15. Labauge, P., Denier, C., Bergametti, F. & Tournier-
Angiomatose der Haut. Z Gesamte Neurol Psychiatr Lasserve, E. Genetics of cavernous angiomas. Lancet
1928;113:651–686. Neurol 2007;6:237–244.
3. Rigamonti, D., Drayer, B. P., Johnson, P. C., et al. 16. Raychaudhuri, R., Batjer, B. A. & Awad, I.
Cerebral cavernous malformations. Incidence and Intracranial cavernous angioma: a practical review
familial occurence. New Engl J Med of clinical and biological aspects. Surg Neurol
1988;319:343–347. 2005;63:319–328.

27
 Section 1: Biology

17. Labauge, P., Krivosic, V., Denier, C., Tournier- 29. Guclu, B., Ozturk, A. K., Pricola, K. L., et al. Mutations
Lasserve, E. & Gaudric, A. Frequency of retinal in apoptosis-related gene, PDCD10, cause cerebral
cavernomas in 60 patients with familial cerebral cavernous malformation 3. Neurosurgery
cavernomas: a clinical and genetic study. Arch 2005;57:1008–1013.
Ophthalmol 2006;124:885–886. 30. Liquori, C. L., Berg, M. J., Squitieri, F., et al. Deletions
18. Sirvente, J., Enjolras, O., Wassef, M., Tournier- in CCM2 are a common cause of cerebral cavernous
Lasserve, E. & Labaug, P. Frequency and phenotypes of malformations. Am J Hum Genet 2007;80:69–75.
cutaneous vascular malformations in a consecutive
31. Verlaan, D. J., Siegel, A. M., Rouleau, G. A. Krit1
series of 417 patients with familial cerebral cavernous
missense mutations lead to splicing errors in cerebral
malformations. J Eur Acad Dermatol Venereol
cavernous malformations. Am J Hum Genet
2009;23:1066–1072.
2002;70:1564–1567.
19. Labauge, P., Enjolras, O., Bonerandi, J. J., et al. An
32. Ortiz, L., Costa, A. F., Bellido, M. L., et al. Study of
association between autosomal dominant cerebral
cerebral cavernous malformation in Spain and
cavernomas and a distinctive hyperkeratotic cutaneous
Portugal: high prevalence of a 14 bp deletion in exon
vascular malformation in 4 families. Ann Neurol
5 of MGC4607 (CCM2 gene). J Neurol
1999;45:250–254.
2007;254:322–326.
20. Eerola, I., Plate, K. H., Spiegel, R., et al. KRIT1 is
33. Zawistowski, J. S., Stalheim, L., Uhlik, M. T., et al.
mutated in hyperkeratotic cutaneous capillary-venous
CCM1 and CCM2 protein interactions in cell
malformation associated with cerebral capillary
signaling: implications for cerebral cavernous
malformation. Hum Mol Genet 2000;9:1351–1355.
malformations pathogenesis. Hum Mol Genet
21. Stahl, S., Gaetzner, S., Voss, K., et al. Novel CCM1, 2005;14:2521–2531.
CCM2, and CCM3 mutations in patients with
34. Voss, K., Stahl, S., Hogan, B. M., et al. Functional
cerebral cavernous malformations: in-frame deletion
analyses of human and zebrafish 18-amino acid in-
in CCM2 prevents formation of a CCM1/CCM2/
frame deletion pave the way for domain mapping of the
CCM3 protein complex. Hum Mutat
cerebral cavernous malformation 3 protein. Hum
2008;29:709–717.
Mutat 2009;30:1003–1011.
22. Liquori, C. L., Penco, S., Gault, J., et al. Different spectra
of genomic deletions within the CCM genes between 35. Cau, M., Loi, M., Melis, M., et al. C329X in KRIT1 is a
Italian and American CCM patient cohorts. founder mutation among CCM patients in Sardinia.
Neurogenetics 2008;9:25–31. Eur J Med Genet 2009;52:344–348.

23. Verlaan, D. J., Laurent, S. B., Sure, U., et al. CCM1 36. Knudson, A. G. Mutation and cancer: statistical
mutation screen of sporadic cases with cerebral analysis of retinoblastoma. Proc Natl Acad Sci USA
cavernous malformations. Neurology 1971;68:820–823.
2004;62:1213–1215. 37. Limaye, N., Boon, L. M. & Vikkula, M. From germline
24. Verlaan, D. J., Laurent, S. B., Rouleau, G. A. & towards somatic mutations in the pathophysiology of
Siegel, A. M. No CCM2 mutations in a cohort of 31 vascular anomalies. Hum Mol Genet 2009;18(R1):
sporadic cases. Neurology 2004;63:1979. R65–74.
25. Cavé-Riant, F., Denier, C., Labauge, P., et al. Spectrum 38. Limaye, N., Wouters, V., Uebelhoer, M., et al. Somatic
and expression analysis of KRIT1 mutations in 121 mutations in angiopoietin receptor gene TEK cause
consecutive and unrelated patients with cerebral solitary and multiple sporadic venous malformations.
cavernous malformations. Eur J Hum Genet Nat Genet 2009;41:118–124.
2002;10:733–740. 39. Kehrer-Sawatzki, H., et al. Mutation and expression
26. Laurans, M. S., DiLuna, M. L., Shin, D., et al. analysis of the KRIT1 gene associated with cerebral
Mutational analysis of 206 families with cavernous cavernous malformations. Acta Neuropathol
malformations. J Neurosurg 2003;99:38–43. 2002;104:231–240.
27. Liquori, C. L., Berg, M. J., Squitieri, F., et al. Low 40. Gault, J., Shenkar, R., Recksiek, P. & Awad, I. A.
frequency of PDCD10 mutations in a panel of CCM3 Biallelic somatic and germ line CCM1 truncating
probands: potential for a fourth CCM locus. Hum mutations in a cerebral cavernous malformation lesion.
Mutat 2006;27:118. Stroke 2005;36:872–874.
28. Verlaan, D. J., Roussel, J., Laurent, S. B., et al. 41. Gault, J., Awad, I. A., Recksiek, P., et al. Cerebral
CCM3 mutations are uncommon in cerebral cavernous malformations: somatic mutations in
cavernous malformations. Neurology vascular endothelial cells. Neurosurgery
2005;65:1982–1983. 2009;65:138–144; discussion 144–145.

28
 Chapter 4: Clinical and molecular genetics of cerebral cavernous malformations

42. Akers, A. L., Johnson, E., Steinberg, G. K., or CCM3 in affected endothelial cells. Hum Mol Genet
Zabramski, J. M. & Marchuk, D. A. Biallelic somatic 2009;18:911–918.
and germline mutations in cerebral cavernous 44. Gianfrancesco, F., Esposito, T., Penco, S., et al.
malformations (CCMs): evidence for a two-hit ZPLD1 gene is disrupted in a patient with
mechanism of CCM pathogenesis. Hum Mol Genet balanced translocation that exhibits cerebral
2009;18:919–930. cavernous malformations. Neuroscience
43. Pagenstecher, A., Stahl, S., Sure, U. & Felbor, U. A two- 2008;155:345–349.
hit mechanism causes cerebral cavernous 45. Biesecker, L. G. Exome sequencing makes medical
malformations: complete inactivation of CCM1, CCM2 genomics a reality. Nat Genet 2010;42:13–14.

29
 Molecular biology of cerebral cavernous
Chapter

5 malformation
Jun Zhang

Hereditary CCMs have been found to be caused by a found that MGC4607 is second numerically behind
loss-of-function mutation in one of three CCM genes: icap1α [14]. We have defined that MGC4607 indeed
KRIT1 (CCM1), MGC4607 (malcavernin, CCM2), and binds to krit1 via two (2nd or 3rd) NPXY motifs in the
PDCD10 (CCM3). Mutations seen with KRIT1 in ped- middle of krit1 compared to the first NPXY motif of
igrees with CCM1 were the first to be found [1–4]. the N-terminal krit1 binding to icap1α [15]. MGC4607
Subsequently, MGC4607, a phosphotyrosine-binding has been predicted to be a PTB protein [5]. Although
protein, was identified linked to the CCM2 locus [5], mutational studies have demonstrated that each of two
and mutations in PDCD10, an apoptotic protein, was NPXY motifs is sufficient for MGC4607 binding, two
identified in cases linked to the CCM3 locus [6]. Current NPXY motifs would significantly enhance the interac-
genetic data suggest that mutation within any of three tion. The redundancy of the NPXY motif might illus-
defined CCM genes is required for the initiation and trate the physiological importance of this interaction
progression of cerebral cavernous malformations [7]. [11,14]. The interaction between MGC4607 and
PDCD10 was also defined through affinity pull-down
with mass spectrometry, yeast two-hybrid analysis and
The interlaced CCM complex anchors co-immunoprecipation experiments [9,10].
the endothelial cell performance
Each of CCM genes interacts with their
Interaction among three CCM genes to respective cellular partners
form a CCM complex Partial truncated CCM1 gene was originally identified
To date, researchers have established that all three CCM through its interaction with the Ras-family GTPase
genes interact with each other and form a CCM complex krev1/rap1a in a two-hybrid screen as krit1 (Krev
[8–11]. While the precise pathophysiology connecting Interaction Trapped 1), inferring a potential role in
the CCM protein complex to microvascular malforma- GTPase signaling cascades [16]. Surprisingly, by two-
tion remains elusive, the complex’s critical importance is hybrid analysis and co-immunoprecipitation, we dem-
evidenced by the observation that at least one of three onstrated that full-length krit1 fails to interact with
CCM genes is disrupted in most human CCMs. rap1a but shows strong interaction with integrin
Expression studies demonstrated that three CCM pro- cytoplasmic domain-associated protein-1α (icap1α)
teins significantly parallel the expression pattern in the [15,17]. Icap1α binds to a NPXY motif in the cytoplas-
various neuronal cell layers of the brain at several time mic domain of β1 integrin [18,19]. The NPXY motif is
points during development, thereby recognizing a role a well-known binding substrate for phosphotyrosine
for these CCM proteins during the angiogenesis process binding domain (PTB) proteins, and icap1α has been
and suggesting their possible coordinated involvement proven to be a PTB protein [20]. We have shown that,
in the same cellular signal pathway that is important for like the cytoplasmic C-terminal region of β1 integrin,
neurovascular development [12,13]. the N-terminus of krit1 contains a conserved and
Through our yeast-two hybrid experiments, functionally important NPXY motif that plays a cru-
among all the krit1-interacting positive colonies, we cial role in the interaction with icap1α. Mutational

Cavernous Malformations of the Nervous System, ed. Daniele Rigamonti. Published by Cambridge University Press.
© Cambridge University Press 2011.

31
 Section 1: Biology

studies demonstrated that the Asn and Tyr residues of its related coiled-coil proteins suppressor, SIKE and
the NPXY motif are critical for icap1α binding. Also, FGFR1OP2; serine/threonine protein phosphatase
like the β1 integrin cytoplasmic domain, krit1 only subunits, PPP2CA, PPP2R1A, and PPP2R1B, the
interacts with icap1α (a full-length 200 amino acid striatins, STRN, STRN3, and STRN4, striatins associ-
protein) but not with icap1β, a shorter alternatively ated protein MOB3, and two novel proteins STRIP1
spliced (internally truncated) isoform protein of 150 and STRIP2 [29,30]. However, whether any of them
amino acids with much less cellular abundance [15]. directly binds to PDCD10 or simply to the CCM
Interestingly, full-length krit1 was further reported to complex remains to be determined.
interact with rap1a through its FERM domain [21]. The interlaced interaction among CCM proteins
Another report indicated that full-length krit1 prefers and their cellular partners is illustrated in Fig. 5.1.
to interact with rap1a-GTP, an active form of rap1a
small GTPase. However, the same paper also found Current understanding of cellular
that krit1 interacts with tubulin as well [22], which is
another controversial interaction for krit1. Krit1 was functions of CCM genes
primarily reported to interact with tubulin [23].
However, the antibody used for krit1 recognized a Molecular biology of krit1
protein of the same size as tubulin; furthermore, the Among the three CCM genes, the 84 kDa full-length
krit1 construct was a truncated form, making this CCM1 protein was the first identified and is the most
interaction spurious [22,8]. Clearly further investiga- studied. The originally identified krit1 (Krev Interaction
tion is needed to address these questions. Recently, Trapped 1) gene was a partial clone [30]. During the
krit1 has also been reported to interact with sorting cloning of the murine krit1 cDNA, we identified pre-
nexin, SNX17, further indicating its extremely impor- viously missed 50 coding exons that extend the amino
tant role in β1 integrin signaling [24]. terminus by 207 amino acids [4]. Subsequent studies
MGC4607 was reported to interact with cellular revealed that these exons are also utilized in other verte-
factors, Rac, Mekk3, and Mkk3 directly [9,25,26]. brates including humans [31,32]. This novel N-terminal
Interestingly, both icap1α and tubulin were also pulled- extension contains an NPXY motif that is used to inter-
down through affinity capture–mass spectrometry act with icap1α and a putative nuclear localization signal
experiments using MGC4607 as bait [9,26]. However, sequence (NLS) [4]. Two additional NPXY motifs were
this pull-down is highly likely through their directly found in the center of krit1, which is used to interact
binding to krit1, and then a krit1–MGC4607 inter- with MGC4607 [11,14,24,33]. Multiple ankyrin repeats
action. Cellular factors EF1A1 and RIN2 were also are also found in the center of krit1. Such domains can
pulled-down in this affinity capture–mass spectrometry be seen in actin-associated proteins and suggest inter-
experiment. Further experimental data are certainly action with the cytoskeleton. In its C-terminus, krit1
needed to confirm whether they directly interact with contains a putative nuclear export signal sequence
MGC4607 or not. (NES) and a FERM domain that is often seen in proteins
Currently, PDCD10 has been found to interact associated with the cytoplasmic aspect of the cell mem-
with the most cellular factors. PDCD10 was found to brane. Such motifs might be predicted in a protein
interact with Ste20-related kinase MST4, its relative found in a focal adhesion plaque formed by the cluster-
members of the germinal center kinase III family, ing of integrins on the intracellular surface (Fig. 5.2).
STK25 and STK24, and FAP1 through yeast two-
hybrid analysis followed by co-immunoprecipitation Krit1-mediated integrin β1 signaling in in vitro
[10,27] and affinity pull-down with mass spectrometry endothelial cell models
assay [28–30]. By analyzing a large multiprotein To further evaluate whether integrin β1 and krit1 bind
assembly, termed the striatin-interacting phosphatase to the same site in icap1α, and perhaps compete for
and kinase (STRIPAK) complex, a large group of this binding site, we determined whether induced
cellular factors potentially interacting with PDCD10 expression of krit1 could diminish the interaction
were identified. These factors include the cytoskeletal between icap1α and integrin β1 in a yeast cell system.
protein cortactin interacting proteins, CTTNBP2 and After induced expression of krit1 using a methionine-
CTTNBP2NL (CTTNBP2 N-terminal like), the sarco- responsive promoter, we observed decreased expres-
lemmal membrane-associated protein, SLMAP, and sion of β-galactosidase, an indirect measure of the

32
Discovering Diverse Content Through
Random Scribd Documents
 C H A P T E R X V.

ROMANCE AND REALITY.

Lottie was entirely unconscious of the intimation that had been made
to her father, and of the excitement which had risen among her neighbours
about Mr. Ridsdale. It did not occur to her that anyone but herself knew
anything about him. The delighted curiosity of the O’Shaughnessys and the
anxious concern of Captain Temple were equally unknown to her. Her mind
was still moved by an echo of the sentiment of their last meeting—a thrill
of emotion half from the music, half from the awakening feelings, the
curiosity, the commotion of her developing nature. Of all Law’s
communications which had excited himself so powerfully, and which had
also to some extent excited her, she remembered little in comparison. The
large dim room at the Deanery, the faint night air breathing about, blowing
the flames of the candles, the moths that circled about the lights and did
themselves to death against every flame, seemed to glimmer before her eyes
continually—everything else, even the danger of her father’s marriage, the
danger of Law’s imprudence, fell into the background and became distant;
everything receded before the perpetual attraction of this shadowy scene.
Mr. Ridsdale made a second call upon her in the morning after service,
just at the moment when Captain Temple and Major O’Shaughnessy were
talking to her father. This time he brought no note, and had no excuse ready
to explain his visit. “I came to say good-by,” he said, holding out his hand
and looking rather wistfully into her face. Lottie offered him her hand
demurely. She scarcely met his eyes. Her heart began to beat as soon as she
heard his voice asking for her at the door. It brought back all the terrors of
the previous night. She did not however ask him to sit down, but stood
faltering opposite to him, embarrassed, not knowing what to do.
“You would not accept my escort last night,” he said; “I was dreadfully
disappointed when I came out and found you gone. I had been waiting, not
wishing to hurry you. I hope you did not think I was a laggard?”
“Oh no, it was my fault,” said Lottie, not raising her eyes. “There was no
need for anyone to come with me. It is but two steps, and at that hour there
is no one about. There was no need—for any escort.”
 “May I sit down for a few minutes, Miss Despard? My train is not till
one o’clock.”
Lottie blushed crimson at this implied reproach. It might be right to be
shy of him, but not to be rude to him. “Oh, I beg your pardon,” she said,
pointing to a chair.
“You took us all by surprise last night,” he said, carefully placing hers
for her. “I think it was a revelation to everybody. We hear that music in the
Abbey, and we suppose we understand it; till someone like you suddenly
interprets it to us, and we wake up and feel that we never heard it before.”
“I never knew what it was—to sing anything like that before,” said
Lottie. It disturbed her even to think about it; “and it had all been so
different—so——”
“Commonplace? from the ridiculous to the sublime; from poor dear Aunt
Caroline on her sofa to Handel fluting among the angels. It was a step
indeed.”
“I did not mean that. It was myself I was thinking of—I had been so full
of silly fancies of my own.”
“But all at once the inspiration came? I should like to be capable of
anything like that; but I am not. I can only listen, and worship,” said Rollo.
There was fervour in his voice—a real something which was not mere
fanaticism about music. And the two young people sat for a few moments in
silence, a most dangerous thing to do, looking at each other—nay, not
looking at each other—for Lottie did not feel either able or disposed to raise
her eyes. She was the first to speak, in order to break the silence, which
alarmed her, though she did not know why.
“It is wonderful how the Signor plays. I never understood it in the
Abbey. He seems to place you up somewhere above yourself—and make
your voice come independent of you.”
“Never in his life, I am sure, did he have such a beautiful compliment
paid to him,” said Rollo; “but, Miss Despard, you do him too much credit.
You permitted even me to accompany you—and sang just as divinely——”
“Oh no,” said Lottie. Then she blushed and recollected herself. “You
play very well, Mr. Ridsdale; but we could not compare those trumpery
songs with——”
 “Trumpery songs! only Mozart and Bellini, and a few more,” he cried,
with a gasp. “Ah, I know what you mean; you meant the ‘Marta’ song,
which made your good friend, that good woman, cry——”
“I like the ‘Last Rose of Summer’ very much. I have always liked it. I
used to hear an old fiddler play it in the street when I was a child, when I
was lying in the dark, trying to go to sleep. It was like a friend keeping me
company; but a friend that had a breaking heart, that cried and took all my
thoughts off myself—I shall never forget it,” said Lottie, the tears coming to
her eyes at the recollection. “I like it better than all the rest.”
“Miss Despard, do not drive me to despair. Not better than ‘Casta Diva,’
or Margaret’s song, or——”
“You forget I don’t know where they come, nor the meaning of them,”
said Lottie, calmly. “I never heard an opera. I think these things are
beautiful, but they only sing to my ear, they don’t come in to me.”
Rollo shook his head. He was half touched, half shocked. It was her
ignorance; but then a woman destined for a prima donna, a woman with
musical genius, ought to know the best by intuition, he thought. All the
same, he was more interested than if she had raved as the commonplace,
half educated amateur raves. “But Handel does,” he said.
“Ah!” Lottie cried, her face lighting up. But she added, after a moment,
“I am too ignorant to be worth talking to; you will be disgusted. I never
thought much about Handel. It was not Handel, it was that.” A flush of
colour came over her face with the recollection. She was too uninstructed
(notwithstanding the neighbourhood of the Abbey) to have fully woke up to
Handel or anyone. “I suppose I have heard it and did not pay much attention
to it,” she said; “it was singing it. One does not understand at first—till
suddenly one hears one’s self, and you say, ‘What is this that is speaking;
what is this? it cannot be me!’ ”
“I think I understand—a little,” said Rollo doubtfully; “though it is
simply you that makes a something quite familiar, a piece of music we have
all heard a hundred times, become a new revelation to us all in a moment. I
am going away, Miss Despard, and it may be some time before I return.
Would you do me such a great favour—which I have no right to ask—as to
sing me something now before I go?”
But Lottie would not sing. She said, “Oh no, no,” with a half terror
which he did not understand, and which she did not understand herself. The
tone was one which forbade the repetition of the request. He begged her
pardon anxiously, and there was a little languid conversation about other
subjects, and then he rose. He put out his hand again, looking into her eyes,
which she raised shyly, almost for the first time. Rollo had a way of looking
into the eyes of women to whom he wished to make himself agreeable. It is
sometimes very impertinent, and always daring, but, especially when the
woman’s imagination is on the side of the gazer, it is very efficacious.
Lottie was entirely inexperienced, and she trembled under this look, but felt
it penetrate to her very heart.
“Till we meet again,” he said, with a smile, holding her hand for that
necessary moment while he said his good-by. “It will not be very long; and
I hope that you will be kind to me, Miss Despard, and let me hear you——”
“Good-by,” said Lottie. She could not bear it any longer. She blamed
herself afterwards for being rude, as she sat down and went over the
incident again and again. She seemed to herself to have dismissed him quite
rudely, pulling her hand away, cutting short what he was saying. But Rollo,
for his part, did not feel that it was rude. He went down the narrow stairs
with his heart beating a little quicker than usual, and a sense that here was
something quite fresh and novel, something not like the little flirtations with
which he was so familiar, and which amused him a great deal in general.
This he had just touched, floated over with his usual easy sentiment, was
something quite out of the common. It startled him with the throb in it. He
went away quite thoughtful, his heart in a most unusual commotion, and
forgot until he was miles away from St. Michael’s that Lottie Despard was
to be the English prima donna, who was to make his fortune, if properly
managed. “Ah, to be sure, that was it!” he said to himself suddenly in the
railway carriage, as he was going to town. He really had forgotten what it
was that took him to town at this unsuitable moment of the year.
The rest of the morning glided dreamily away after an incident like this;
and it was not till late in the afternoon that Lottie suddenly awoke to the
necessity of making an effort, and shaking off the empire of dreams: and
this was how she became convinced of the necessity for doing so. She had
been sitting, as on the former occasion, with a basket of mending by her
when Rollo came in. She had all the clothes of the household to keep in
order, and naturally they were not done in one day. After Mr. Ridsdale was
gone, she took up her work languidly, keeping it on her knee while she went
over all that had happened, again and again, as has been recorded. When, at
last startled by a sound outside, she began to work in earnest, then and there
a revelation of a character totally distinct from that made by Handel burst
upon her. It was not a revelation of the same kind, but it was very startling.
Lottie found—that she had not yet finished the hole in the sock which she
had begun to mend before Mr. Ridsdale’s first visit! She was still in the
middle of that one hole. She remembered exactly where she stuck her
needle, in the middle of a woolly hillock, as she heard him coming upstairs;
and there it was still, in precisely the same place. This discovery made her
heart jump almost as much as Mr. Ridsdale’s visit had done. What an
evidence of wicked idling, of the most foolish dreaming and unprofitable
thought was in it! Lottie blushed, though she was alone, to the roots of her
hair, and seizing the sock with an impassioned glow of energy, never took
breath till the stern evidence of that hole was done away with. And then she
could not give herself any rest. She felt her dreams floating about her with
folded pinions, ready to descend upon her and envelope her in their shadow
if she gave them the chance; but she was determined that she would not
give them the chance. As soon as she had finished the pair of socks, and
folded them carefully up, she went to look for Law to suggest that they
should go immediately to Mr. Ashford. Law had only just come in from a
furtive expedition out of doors, and had scarcely time to spread his books
open before him when she entered his room. But he would not go to Mr.
Ashford. It was time enough for that, and he meant in the meantime to
“work up” by himself, he declared. Lottie became more energetic than ever
in the revulsion of feeling, and determination not to yield further to any
vanity. She pleaded with him, stormed at him, but in vain. “At the worst I
can always ’list,” he said, half in dogged resistance to her, half in boyish
mischief to vex her. But he would not yield to her desire to consult Mr.
Ashford, though he had assented at first. He did not refuse to go “some
time,” but nothing that she could say would induce him to go now. This
brought in again all the contradictions and cares of her life to make her
heart sore when she turned back out of the enchanted land in which for a
little while she had been delivered from these cares. They all came back
upon her open-mouthed, like wild beasts, she thought. Law resisting
everything that was good for him, and her father——. But Lottie could not
realise the change that threatened to come upon her through her father. It
seemed like the suggestion of a dream. Law must be deceived, it must be all
a delusion, it was not possible, it was not credible. The Captain came in
early that night, and he came upstairs into the little drawing-room, to which
he had no habit of coming. He told his daughter in a stately way that he
heard her singing had given great satisfaction at the Deanery. “More than
one person has mentioned it to me,” he said; “that is of course a
satisfaction. And—who is the gentleman you have been having here so
much?”
“There has been no one here very much,” said Lottie; then she blushed
in spite of herself, though she did not suppose that was what he alluded to.
“You do not mean Mr. Ridsdale?” she said.
“How many visitors have you got?” he said, in high good humour.
“Perhaps it is Mr. Ridsdale—Lady Caroline’s nephew? Ah, I like the family.
It was he you sang to? Well, no harm; you’ve got a very pretty voice—and
so had your mother before you,” the Captain added, with a carefully
prepared sigh.
“It was only once,” said Lottie, confused. “Mrs. O’Shaughnessy was
here; it was after we had been singing at the Deanery; it was——”
“My child,” said the Captain, “I am not finding fault. No harm in putting
your best foot foremost. I wish you’d do it a little more. At your age you
ought to be thinking about getting married. And, to tell the truth, it would be
a great convenience to me, and suit my plans beautifully, if you would get
married. You mustn’t stand shilly-shallying; let him come to the point: or, if
he won’t, my dear, refer him to me.”
“I don’t know what you mean,” cried Lottie. Fortunately for her, he had
thought her a child up to the time of their migration to St. Michael’s, and
she had been subjected to very little advice of this description. But, though
she gazed at him with wondering eyes, she knew very well by the instinct of
horror and repulsion in her mind what he meant. It gave her a shock of pain
and shame which ran like electricity to her very finger points. “I think you
must be making a mistake,” she said. “I scarcely know Mr. Ridsdale at all.
He has called here twice—on business—for Lady Caroline—and now he
has gone away.”
“Gone away!” the Captain said, his face lengthening with
disappointment and dismay; “gone away! then you’re a fool—a greater fool
than I thought you. What’s to become of you, do you ever ask yourself?
Good lord, what a chance to throw away! One of the Courtland family—a
fellow with a turn for music—that you could have turned round your little
finger! And to let him go away! By George,” said the Captain, making a
stride towards her, and clenching his fist in the energy of his disapproval, “I
don’t believe you’re any child of mine. Clever—you think you’re clever?
and so did your mother, poor woman! but you’re an idiot, that is what you
are—an idiot! to let such a chance slip through your fingers. Good lord! to
think such a fool should be a child of mine!”
Lottie stood her ground firmly. She was not afraid of the clenched fist,
nor even of the angry voice and eyes, which were more genuine. If there
was a slight tremor in her, it was of her own excited nerves. She made no
reply; if she had spoken, what could she have done but express her own
passionate loathing for his advice, and for his disapproval, and perhaps even
for himself? for she had not been brought up to reverence the faulty father,
whose evil qualities her mother had discussed in Lottie’s presence as long
as she could remember. There had not been any illusion in his children’s
eyes after their babyhood, in respect to Captain Despard, and perhaps in the
present emergency this was well. She stood and met his fury, pale, but more
disdainful than desperate. It was no more than she would have expected of
him had she ever thought of the emergency at all.
Law had heard the sound of the battle from afar; he heard his father’s
voice raised, and the sound of the stroke upon the table with which he had
emphasised one of his sentences. It was a god-send to the unenthusiastic
student to be disturbed by anything, and he came in sauntering with his
hands in his pockets, partly with the intention of taking Lottie’s part, partly
for the sake of “the fun,” whatever it might be. “What’s the row?” he asked.
He had slippers on, and shuffled along heavily, and his coat was very old
and smelt of tobacco, though that was a luxury in which Law could indulge
but sparingly. He had his hands in his pockets, and his hair was well rubbed
in all directions by the efforts he had made over his unbeloved books. Thus
it was but a slovenly angel that came to Lottie’s aid. He stopped the yawn
which his “reading” had brought on, and looked at the belligerents with
some hope of amusement. “I say, don’t bully Lottie,” he exclaimed, but not
with any fervour. He would not have allowed anyone to lay a finger upon
her, but a little bullying, such as she administered to him daily, that perhaps
would do Lottie no harm. However, he was there in her defence if things
should come to any extremity. She was of his faction, and he of hers; but
yet he thought a little bullying of the kind she gave so liberally might do
Lottie no harm.
 “Go away, Law; it is no matter; it is nothing. Papa was only
communicating some of his ideas—forcibly,” said Lottie, with a smile of
defiance; but as there was always a fear in her mind lest these two should
get into collision, she added hastily, “Law, I don’t want you—go away.”
“He can stay,” said the Captain. “I have something to say to you both.
Look here. I thought in the first place that she had hit off something for
herself,” he said, turning half round to his son. “I thought she had caught
that fellow, that Ridsdale; from what I had heard, I thought that was certain
—that there would be no difficulty on that side.”
The Captain had left his original ground. Instead of reproaching Lottie,
in which he was strong, he was in the act of disclosing his own intentions,
and this was much less certain ground. He looked at Law, and he wavered.
Big lout! he knew a great deal too much already. Captain Despard looked at
Law as at a possible rival, a being who had been thrust into his way. The
workroom had no secrets from Law.
“I think the governor’s right there,” said Law confidentially; “he’s a big
fish, but he’s all right if you give him time.”
A gleam of sudden fury blazed over Lottie’s face. She, too, clenched her
hands passionately. She stamped her foot upon the floor. “How dare you?”
she said, “how dare you insult me in my own home, you two men? Oh, yes,
I know who you are—my father and my brother, my father and my brother!
the two who ought to protect a girl and take care of her! Oh! is it not
enough to make one hate, and loathe and despise—!” said Lottie, dashing
her white clenched hand into the air. Tears that seemed to burn her came
rushing from her eyes. She looked at them with wild indignation and rage,
in which there was still a certain appeal. How could they, how could they
shame a girl so? They looked at her for a moment in this rage, which was so
impotent and so pitiful, and then they gave a simultaneous laugh. When an
exhibition of passionate feeling does not overawe, it amuses. It is so
ludicrous to see a creature crying out, weeping, suffering for some trifle
which would not in the least affect ourselves. Lottie was struck dumb by
this laugh. She gave a startled look up at them through those hot seas of salt
scalding tears that were in her eyes.
“What a fool you are making of yourself!” said the Captain. “Women are
the greatest fools there are on this earth, always with some high-flown
rubbish or other in their stupid heads. Your own home! and who made it
your home, I should like to know? I don’t say you hadn’t a right to shelter
when you were a little thing; but that’s long out of the question. A girl of
twenty ought to be thinking about getting herself a real home of her own.
How are you going to do it? that’s the question. You are not going to stay
here to be a burden upon me all your life; and what do you mean to do?”
“I will go to-morrow!” cried Lottie, wildly; “I would go to-night if it
were not dark. I will go—and free you of the burden!” Here she stopped; all
the angry colour went out of her face. She looked at them with great wide
eyes, appalled; and clasped her hands together with a lamentable cry. “Oh!
but I never thought of it before, I never thought of it!” she cried; “where am
I to go?”
Law’s heart smote him; he drew a step nearer to her. To agree with his
father (however much in his heart he agreed with his father) was
abandoning his sister—and his own side. “He doesn’t mean it,” he said
soothingly in an undertone; “he only wants to bully you, Lottie. Never mind
him, we’ll talk it over after,” and he put his big hand upon her shoulder to
console her. Lottie turned upon him, half furious, half appealing. She could
not see him till two big tears fell out of her eyes, and cleared her sight a
little. She clutched at the hand upon her shoulder in her distraction and
despair.
“Come with me, Law. Two of us together, we can go anywhere; two can
go anywhere. Oh! how can you tell me never to mind? Do you hear me?”
she cried, seizing his arm with both her hands, half shaking him, half
clinging to him; “say you will come with me, Law!”
“Stop this stuff!” said the Captain. “I am not telling you to go; I am
telling you what is your plain duty, the only thing a woman is fit for.
Besides, this young fellow would be of great use to me; it’s your duty to get
hold of him for the good of the family. He might say a good word for me at
the Horse Guards; he might get Law something. I never expected you
would have such a chance. Do you think I want you to go away just when
there’s a chance that you might be of some use? Am I a fool, do you think?
You’ll stay where you are, Lottie Despard! you’ll not go disgracing your
family, governessing, or anything of that sort.”
“Ah!” said Law suddenly, “she’ll wish she had listened to the Signor
now.”
 “To the Signor? what of the Signor? is he after her too?” cried the
Captain eagerly. A bird in the hand is worth two in the bush; and though the
Signor had no interest with the Horse Guards, he had money, and might be
of use in many ways. Captain Despard’s eyes lighted up. “Whew!” he
whistled. “Lottie! so, my child, you’ve got two strings to your bow?”
Lottie turned upon her brother, whose arm she had been holding with
both her hands. She pushed him, flung him from her with an energy of
which she had not appeared capable, and throwing her head high, looked
her father in the face and walked out of the room. Law, confounded by the
force with which she threw him from her, caught at her angrily as she
passed; but she pulled her dress from his hand, and walked past him with a
contempt that stung him—callous as he was. As for the Captain, he made no
effort to detain her, partly because of his surprise, partly that he was anxious
to have more information about (as he supposed) this second suitor. She
went straight to her own room, while they stood listening till she had shut
the door upon herself and her passion. Then the Captain ventured to laugh
again, but low, not to be heard; for the look of any creature driven to bay is
alarming, and Lottie’s sudden withdrawal was a relief.
“Whoever gets her will catch a Tartar! eh, Law?” he said. “But now that
she’s gone, let’s hear all about the Signor.”
There was no light in Lottie’s room; nothing but the faint starlight
outside, and as much of the familiar glimmer of the few feeble lamps in the
Dean’s Walk as could get in through her small window. How is it that so
small a bit of space, such four straight walls, should hold in such a
throbbing, palpitating, agitated being, with projects wide enough and fury
hot enough to burst them like a child’s toy? It was in her to have torn her
hair or anything that came in the way of her fevered hands; to have filled
the air with cries; to have filled the whole world with her protest against the
intolerable shame and wretchedness which they were trying to force upon
her thoughts! But she only threw herself on her bed in the dark and silence,
letting no sound or movement betray her. She was not prostrated as by
unkindness, or stung by reproach; but wounded, shamed, desecrated—the
very sanctity of her dreams turned into a horror to her. And Law gone
against her—Law gone over to the other side!
 CHAPTER XVI.

THE SIGNOR’S HOUSEHOLD.

The Despard family became a great centre of interest to many people

both within and without the Abbey precincts at this period of their history.
Without any doing, so to speak, of theirs, Fate mixed them up both with the
great and the small, so that their proceedings moved a great many circles of
thought and feeling beyond that in which they themselves stood. We have
said without any doing of theirs—but this, perhaps, is true only in respect to
Lottie, who took no steps consciously to produce the rapprochement which
had taken place so strangely between the heaven of the Deanery and the
earth of the Lodges. She had not done anything to recommend herself to
Lady Caroline or Lady Caroline’s nephew. And yet with both she had
become an important “factor,” to use a fashionable term, in the immediate
concerns of life. The Captain was not so innocent of purpose in the
commotion he had begun to make. But still he had not calculated upon the
interest that would be excited by his proceedings. The community at St.
Michael’s was quiet and had little to rouse its interest. Sometimes a Canon
would be translated to a higher and a better stall—sometimes an old
Chevalier would die and be replaced by another veteran not much less old
than he—sometimes a son would “go wrong” and create a great deal of
whispered communication and shaking of heads. At the present time there
were no daughters to marry except Lottie, so that the pleasanter strain of
possibility was little thought of. All this made it very inspiring, very
agitating to the dwellers round the Abbey, when a family within the
precincts gave them so much to think about. A girl likely to make a very
good match in a romantic way: a man likely to make a very bad one, in a
way which might have been quite as romantic had it not been on the wrong
side, such as would debase, not exalt his class; these two probabilities
coming together had a great effect upon the popular mind. In the
Chevaliers’ Lodges there was very little else talked about. Captain Temple,
the most respected of all the Chevaliers, could not keep still, so excited was
he. He had spoken to “the father,” he told his wife, to put him on his guard,
and to show him how necessary it was to take proper care of his child. That
was all he could do: but he could not content himself with thus doing what
he could. He paced about his little sitting-room, disturbing Mrs. Temple at
her wool-work. She was not like her husband. She was a still, composed,
almost stern woman, with a passionate heart, to which she gave very little
expression. She could not talk of her daughter as Captain Temple could.
The remembrance of the years during which her child was separated from
her was terrible to her. When her husband talked as he was accustomed to
do of this great grief of theirs, she never stopped him, but she herself was
dumb. She closed all her windows, as it were, and retired into a fortress of
silent anguish, out of which no cry came; but she listened to him all the
same. This was what she did now, though it pained her to hear of this other
girl who stood between life and death, between good and evil, as once her
child had stood. She would have helped Lottie with all her heart, but she
could not bear to hear her talked of—though this was precisely what she
had to bear.
“I told him it was his duty to look after his daughter,” said Captain
Temple, pacing—three steps one way, four the other—about the room. “But
he won’t—you will see he won’t. A beautiful girl, far too good for him, a
girl who deserves a better fate. She puts me in mind of our own dear girl,
Lucy. I have told you so before.”
To this Mrs. Temple made no reply. He had told her so a great many
times before. She selected a new shade of her Berlin wool, and set her
elbow rigidly against the arm of her chair, that she might thread her needle
without trembling, but she made no reply.
“She puts me constantly in mind of her. The way she holds her head, and
her walk, and—— I beg your pardon, my dear. I know you don’t like this
kind of talk; but if you knew how I seem to see her wherever I go—
wherever I go! I wonder if she is permitted to come and walk by her old
father’s side, God bless her. Ah! well, it was Despard’s daughter we were
talking of. To think he should have this girl who takes no care of her—and
we to whom ours was everything!”
The poor woman made a spasmodic movement, and turned her eyes
upon him dumbly. She could not bear it. The needle fell out of her hands,
and she stooped to hunt for it on the carpet. She would not stop him to
whom it was so great a relief to talk; but it was death to her.
 “But I told him,” said Captain Temple. “I showed him his duty, Lucy. I
told him he ought to be thankful he had such a daughter to watch over. And
what more could I do? I set the whole thing before him. There was nothing
more that I could do?”
“Then you must be satisfied, William, and perhaps it will have some
effect; we must wait and see,” said Mrs. Temple, coming to the surface
again with her needle, which she had found, in her hand. She managed to
get it threaded this time with great exertion, while her husband set off again
upon his restricted promenade, shaking his white head. Captain Temple, it
may be recollected, had not said so much to Captain Despard as he thought
he had said—but if he had said everything that man could say it is not
probable that it would have made much difference. The kind old Chevalier
shook his white head. His eyes were full of moisture and his heart of
tenderness. He did not feel willing to wait and see, as his wife suggested.
He wanted to do something there and then for Lottie, to go to her and warn
her, to keep watch at her door, and prevent the entrance of the wolf—
anything, he did not mind what it was so long as he could secure her safety.
The other subject was discussed that same evening in another and very
different scene, when Mrs. Purcell, the Signor’s housekeeper, asked her old
fellow-servant, Pickering, what news there was in the precincts, and if
anything was stirring. It was the most delicious moment for a gossip, when
tea was over in the kitchen, and dinner upstairs, and twilight was beginning
to drop over the country, bringing quiet and coolness after the blaze of the
day. Mrs. Purcell sat by the open window, which was cut in the very
boundary wall of the Abbey precincts, as in the side of a precipice. It was
not safe for anyone of uncertain nerves to look straight down upon the slope
of St. Michael’s Hill, on which the walls were founded, and on the steep
street winding below. But Mrs. Purcell had her nerves in the most steady
and well-regulated condition. She was not afraid to sit at the head of the
precipice, and even to look out and look down when the shop windows
began to be lighted. She liked to see the lights coming out below. It was
cheerful and felt like “company” when she sat alone. Old Pickering had just
come in after an errand into the town. He was the man-servant, while she
was the housekeeper, but the work of the establishment was chiefly done by
a sturdy young woman who was under the orders of both.
“News—I don’t know much about news,” said old Pick. “It wants young
folks to make news; and there ain’t many of that sort about here.”
 “Dear!” said Mrs. Purcell (but it must not be supposed that this
exclamation meant any special expression of affection to old Pickering).
“There’s heaps of young folks! There’s the Signor, and there’s my John
——”
“Master? you may call him young, if it don’t go again your conscience—
my notion is as he never was no younger than he is now. So you may put
what name to it you please. But you don’t ask me for news of master, nor
Mr. John neither—him, oh ah, there’ll be news of him one of these days.
He’ll get a cathedral, or he’ll be had up to London. We’ll see him, with his
baton in his hand, afore the biggest chorus as can be got together; and won’t
he lead ’em grand!” said old Pick. “When he was but a little thing in his
white surplice I seen it in his eye.”
“You were always one that did my John justice,” said the housekeeper,
warmly. “Just to think of it, Pick—one day a bit of a mite in his surplice,
and the next, as you may say, with his baton, leading the chief in the land!
We bring children into the world, but we can’t tell what’s to come of them,”
she added, with pious melancholy. “Them as is fortunate shouldn’t be
proud. The young men as I’ve seen go to the bad since I’ve been here!”
“That should be a real comfort to you,” said Pickering, and they paused
both, to take full advantage of this consolation. Then, drawing a long
breath, Mrs. Purcell resumed—
“And so it should, Pick—when I see my boy that respectable, and as
good as any gentleman’s son, and reflect on what I’ve seen! But pride’s not
for the like of us—seeing the Lord can bring us low as fast as He’s set us
up.” The good woman dropped her voice, with that curious dread lest
envious fate should take her satisfaction amiss, which seems inherent in
humanity. As for old Pick, sentiment was not in his way. He took up a little
old-fashioned silver salver which stood on the table with some notes upon
it, waiting the sound of the Signer’s bell, and began to polish it with his
handkerchief. “Them girls,” he said, “there’s no trust to be put in them. The
times I’ve told her to be careful with my plate. She says she haven’t the
time, but you and me knows better than that. What is there to do in this
house? We gives no trouble, and as for master, he’s dining out half his
time.”
“She’ll find the difference,” said Mrs. Purcell, “when she’s under a lady.
There’s many a thing I does myself. Instead of calling Maryanne till I’m
hoarse, I takes and does it myself; but a lady will never do that. Ah, Pick,
it’s experience as teaches. They don’t put any faith in what we tell them;
and her head full of soldiers, and I don’t know what—as if a soldier ever
brought anything but harm to a servant girl.”
“They are all alike,” said old Pick. “There’s them Despards in the
Lodges—all the Abbey’s talking of them. The Captain—you know the
Captain? the one as sings out as if it all belonged to him—though he’s
neither tenor, nor alto, nor bass, but a kind of a jumble, and as often as not
sings the air!” said the old chorister, with contempt which was beyond
words. Mrs. Purcell looked upon the Captain from another point of view.
“He’s a fine handsome man,” she said. “He looks like a lord when he
comes marching up the aisle, not an old Methusaleh, like most of ’em.”
“Ah!” cried Pickering, with a groan, “that’s the way the women are led
away. He’s a fine fellow, he is! oh, yes, he’s like a lord, with bills in every
shop in the town, and not a penny to pay ’em.”
“Them shops!” said Mrs. Purcell. “I don’t wonder, if a gentleman’s of a
yielding disposition. They offer you this, and they offer you that, and won’t
take an answer. It’s their own fault. They didn’t ought to put their
temptations in folk’s way. It’s like dodging a bait about a poor fish’s nose;
and then swearing it will make up lovely, and be far more becoming than
what you’ve got on. I think it’s scandalous, for my part. They deserve to
lose their money now and again.”
“They say he’s going to be married,” said old Pick, stolidly.
“Married! You’re dreaming, Pick! Lord bless us,” said Mrs. Purcell,
“that’s news, that is! Married? I don’t believe a word of it; at his age!”
“You said just now he wasn’t a Methusaleh, and no more he is; he’s a
fine handsome man. He thinks a deal of himself, and that’s what makes
other folks think a deal of him. The women’s as bad as the shops,” said old
Pick; “they bring it on themselves. Here’s a man as is never out of mischief.
I’ve seen him regularly coming home—well—none the better for his liquor;
and gamblin’ day and night, playing billiards, betting, I don’t know what.
We all know what that comes to; and a grown-up family besides——”
“Dear!” said Mrs. Purcell, in great concern. She knew a good deal about
Miss Despard, and her feelings were very mingled in respect to her. In the
first place, to know that her John was in love with a lady flattered and
excited her, and had made her very curious about Lottie, every detail of
whose looks, and appearance generally, she had studied. A Chevalier’s
daughter might not be any very great thing; but it was a wonderful rise in
the world for Mrs. Purcell’s son to be able to permit himself to fall in love
with such a person. On the other hand, Miss Despard was poor, and might
interfere with John’s chance of rising in the world. But anyhow, everything
about her was deeply interesting to John’s mother. She paused to think what
effect such a change would have upon her son before she asked any further
questions. What would Miss Despard do? It was not likely she would care
for a stepmother after being used to be mistress of the house—would she be
ready to accept anyone that asked her, in order to get “a home of her own”?
And would John insist upon marrying her? and would he be able to keep a
wife? These questions all hurried through Mrs. Purcell’s mind on receipt of
this startling news. “Dear! dear!” she said—and for a long time it was all
she could say. The interests were so mixed that she did not know what to
desire. Now or never, perhaps, was the time for John to secure the wife he
wanted; but even in that case, would it be right for him to marry? Mrs.
Purcell did not know what to think. “Did you hear who the lady was?” she
asked, in a faint voice.
“Lady?—no lady at all—a girl that works for her living. I know her well
enough by sight. One of the dressmaker’s girls in the River Lane. Ladies is
silly enough, but not so silly as that; though I don’t know neither,” said old
Pick, “what women-folks will do for a husband is wonderful. They’ll face
the world for a husband. It don’t matter what sort he is, nor if he’s worth
having——”
“They haven’t took that trouble for you, anyhow,” said Mrs. Purcell
faintly, standing up amid her preoccupations for her own side.
“I’ve never given ’em the chance,” said Pick, with a chuckle. “Lord
bless you! they’ve tried a plenty, but I’ve never given ’em the chance.
Many’s the story I could tell you. They’ve done their best, poor things.
Some has been that enterprising, I never could keep in the same room with
’em. But I’ve kep’ single, and I’ll keep single till my dying day. So will
master, if I can judge. There’s some has the way of it, and some hasn’t. It
would be a clever one,” said old Pickering, caressing his chin with an astute
smile, “to get the better of me.”
The housekeeper threw at him a glance of mingled indignation and
derision. She gave her head a toss. It was not possible for feminine flesh
and blood to hear this unmoved. “You’re so tempting,” she said, with angry
energy. “ ’Andsome and well to do, and worth a woman’s while.”
“Bless you, they don’t stick at that,” said the old man with a grin. “I
could tell you of things as has happened—some to myself—some to other
folks——”
“Dear!” cried Mrs. Purcell, “and me to think you were an old stick of an
old bachelor, because nobody would have you, Pick! There’s some, as a
body reads it in their face—as dry as an east wind, and cutting like an east
wind does, that is never happy but when it’s blighting up something. I
daresay it’s all a story about Captain Despard—just like the rest.”
“None of ’em likes it, when you speak free,” said old Pick, chuckling to
himself. “Some pretends, just to please a man; but women does hang
together, whoever says different, and they none of them likes to hear the
truth. About Captain Despard, it’s a story if you please, but it’s true. The girl
she makes no secret, she tells everybody as she’ll soon make a difference in
the house. She’ll pack off the son to do for himself, and the daughter——”
“What of the daughter, Pick? Oh, the shameless hussy, to talk like that of
a poor motherless young girl——”
“If she wasn’t motherless, what would Polly have to do with her? It can’t
be expected as a second wife should cry her eyes out because the first’s
gone.”
“Polly!” said Mrs. Purcell, with bated breath; “and she says she’ll pack
the son about his business; and the daughter?—What is she going to do
about the daughter, when she’s got the poor misfortunate man under her
thumb? And who’s Polly, that you know so much about her? She’s a pretty
kind of acquaintance, so far as I can see, for a man as considers himself
respectable, and comes out of a gentleman’s house.”
“That’s the other side,” said Pick, still chuckling to himself. “I said
women hangs together. So they do, till you come to speak of one in
particular, and then they fly at her. I don’t know nothing against Polly. If the
Captain’s in love with her, it ain’t her fault; if she wants to better herself,
it’s no more than you or me would do in her place. She’s as respectable as
most of the folks I know. To work for your living ain’t a disgrace.”
“It’s no disgrace; but a stepmother that is a dressmaking girl will be
something new to Miss Despard. Oh, I can’t smile! A dressmaker as——
And young, I suppose, like herself? Oh, trust a man for that; she’s sure to be
young. Poor thing, poor thing! I’m that sorry for her, I can’t tell what to do.
A lady, Pick; they may be poor, but I’ve always heard there was no better
gentlefolks anywhere to be found. And a woman that the likes of you calls
Polly. Oh, that’s enough, that’s enough for me! A nice, good, respectable
girl, that knows what’s her due—you don’t call her Polly. Polly—there’s a
deal in a name.”
“Aha!” said old Pick, rubbing his hands, “I knew as soon as I named one
in particular what you would say. Fly at her, that’s what all you women do.
A name is neither here nor there. I’ve known as good women called Polly as
was ever christened Mary; eh? ain’t they the same name? I had a sister
Polly; I had a——”
“Dear, dear!” said Mrs. Purcell, softly. She was paying no attention to
him; her mind was much disturbed. She turned away instinctively from the
gathering gloom of evening in which her old companion stood, and cast her
anxious eyes upon the wide landscape outside—the sky between grey and
blue, the lights beginning to twinkle far down in the steep street. There was
something in the great space and opening which seemed to give counsel and
support in her perturbation. For she did not know what to do for the best. At
such a moment would not John have a better chance than he might ever
have? And yet, if he got his heart’s desire, was it quite certain that it would
be good for John? The Signor’s housekeeper was just as anxious about her
boy as if she had been a great lady. Twinges of maternal jealousy, no doubt,
went through her mind. If John married, he would be separated from his
mother, and his wife would look down upon her and teach him to despise
her—a mother who was in service. What could she expect if her son
married a lady? All these thoughts went through her mind as she looked out
with anxiety, which drew deep lines upon her forehead. But, on the whole,
she was not selfish, and considered it all anxiously, ready to make any
sacrifice for that which in the long run would be most good for John.
In the meantime old Pickering talked on. When he was set a-going it was
difficult to bring him to a stop. He was quite aware that at the present
moment he ought not to stay there talking; he knew he ought to be lighting
the lamps, and kept listening with expectant ear for a sharp tinkle of the
Signor’s bell, which should warn him of his retarded duties. But for all that
he talked on. Dinner was over for some time, and Pick knew very well that
he ought to carry in the notes which he had piled again upon the salver after
giving it that polish with his handkerchief. However, though he knew his
duty, he took no steps towards performing it, but moved leisurely about, and
put various articles back into the old polished cupboard with glass doors,
which showed all the best china, and was the pride of Mrs. Purcell’s heart.
When Maryanne came in, he emptied the salver again and showed her how
imperfectly she had cleaned it. “I can’t think how folks can be so stupid,”
Pickering said. “How do you think you are ever to better yourself if you
don’t take a lesson when it’s giv’ you? and proud you should be that anyone
would take the trouble. If I see it like this again I’ll—I don’t know what I
shan’t do.” He knew very well that it was what ought to have been his own
work that he was thus criticising, and, as it happened, so did Maryanne,
whose spirit was working up to a determination not to be longer put upon.
But for all that he found fault, (always waiting to hear the bell ringing
sharply, with a quaver of impatience in it,) and she submitted, though she
was aware that she was being put upon. Mrs. Purcell, in the window, paid
no attention to them. She kept gazing out upon the wide world of grey-blue
clouds, and asking herself what would be best for John.
They were disturbed in all these occupations by a step which came
briskly downstairs, perhaps betokening, Pickering thought, that the Signor
was going out again, and that his own delay about the lamps had been a
wise instinct. But, after all, it was not the Signor’s step; it was young
Purcell, who came along the little winding passage full of corners, and
entered the housekeeper’s room, scattering the little party assembled there.
Maryanne fled as a visitor from the outer world flies from the chamber of a
servant of the court, at the advent of the queen. Though she would assure
herself sometimes that Mrs. Purcell’s son was “no better nor me,” yet in his
presence Maryanne recognised the difference. He was “the young master”
even in Pick’s eyes, who stopped talking, and put the notes back once more
upon the salver with a great air of business, as if in the act of hastening with
them to the Signor. Mrs. Purcell was the only one who received her son
with tranquillity. She turned her eyes upon him quietly, with a smile, with a
serene pride which would not have misbecome an empress. No one in the
house, not the Signor himself, had ascended to such a height of being as the
housekeeper; no one else had produced such a son.
“Go and light the candles in the study, Pick,” said young Purcell. “The
Signor is in the dark, and he’s composing. Quick and carry him the lights.
Don’t bother him with those letters now. He is doing something beautiful,”
he said, turning to his mother. “There’s a phrase in it I never heard equalled.
He has been sitting out on the terrace getting inspiration. I must run back
and keep old Pick from disturbing him, making a noise——”
“Stay a moment, Johnny, my own dear——”
“What’s the matter, mother? Oh, I know; you’ve heard of this last offer.
But if I take any I’ll take St. Ermengilde’s, where I could still go on living
at home, the Signor says. It’s less money, but so long as I can help him and
see her now and again, and please you——”
“Ah, John, your mother’s last; but that’s natural,” said Mrs. Purcell,
shaking her head, “quite natural. I don’t complain. Is it another organ
you’ve got the offer of? Well, to be sure! and there are folks that say merit
isn’t done justice to! John, I’ve been hearing something,” said the
housekeeper, putting out her hand to draw him to her; “something as
perhaps you ought to know.”
The young man looked at her eagerly. In this place he bore a very
different aspect from that under which he had appeared to Lottie. Here it
was he who was master of the situation, the centre of a great many hopes
and wishes. He looked at her closely in the dusk, which made it hard to see
what was in her face. He was a good son, but he was his mother’s social
superior, and there was a touch of authority, even in the kindness of his
voice.
“Something I ought to know? I know it already: that Mr. Ridsdale has
been visiting at the Lodges. That is nothing so extraordinary. If you think a
little attention from a fashionable fop will outweigh the devotion of years!”
said the young man, with a flush of high-flown feeling. He had a great deal
of sentiment and not very much education, and naturally he was high-flown.
“People may say what they like,” he went on in an agitated voice, “but
merit does carry the day. They’ve offered me St. Ermengilde over the heads
of half-a-dozen. Is it possible, can you suppose, that she should be so
blind!”
“That wasn’t it,” said Mrs. Purcell quietly; “it’s something quite
different, my dear. Shut the door, that we mayn’t have old Pick coming in
again (it was he that told me), and you shall hear.”

END OF VOL. I.
 COLLECTION
OF
BRITISH AUTHORS
TAUCHNITZ EDITION.

VOL. 1824.

WITHIN THE PRECINCTS BY MRS. OLIPHANT.

IN THREE VOLUMES.

VOL. II.
 WITHIN
THE PRECINCTS
BY

MRS. OLIPHANT,

AUTHOR OF “THE CHRONICLES OF CARLINGFORD,” ETC.

COPYRIGHT EDITION.

IN THREE VOLUMES.

VOL. II.

LEIPZIG
BERNHARD TAUCHNITZ
1879.

The Right of Translation is reserved.

 CONTENTS

OF VOLUME II.

Page
CHAPTER XXVII. The Musician at Home 7
— XVIII. Young Purcell 26
— XIX.Business, or Love? 44
— XX. An unconscious Trial 60
— XXI.Searchings of Heart 77
— XXII. A Chance for Law 97
— XXIII. Good Advice 115
— XXIV. A Crisis 134
— XXV. What Followed 150
— XXVI. The Fool’s Paradise 167
— XXVII. A Terrible Interruption 184
— XXVIII. The Captain’s Wife 202
— XXIX. The Heavings of the Earthquake 223
— XXX. Lottie’s Fate 244
— XXXI. What other People thought 261
— XXXII. What Rollo had to Marry on 277

WITHIN THE
PRECINCTS.
 CHAPTER XVII.

THE MUSICIAN AT HOME.

The Signor’s house was one of those which, when general peacefulness
had made the battlements round St. Michael’s unnecessary, had grown
within the outer wall. It was more like a growth than a building. Windows
which looked, as we have said, as if cut in the side of a precipice, gave light
to the small panelled chambers which were connected by bits of quaint
passages, here and there by a little flight of stairs, with tiny vestibules and
landing-places, wasting the little space there was. Room after room had no
doubt been added as necessity arose, and each new room had to be
connected somehow with the others. The house occupied more space than a
comfortable ugly modern house with tolerably sized rooms would have
done, and when the Signor came into possession it had been a miracle of
picturesque awkwardness, not a room in it capable of holding more than
three or four people at a time, yet as many rooms as would have lodged a
dozen—the least possible use for the greatest possible expenditure of space.
The Signor, however, had built on the inner side a dining-room in red brick,
which made existence possible, though it failed in the point of beauty. To
tell the truth, the musician’s dining-room was an eyesore to all the
antiquaries and all the critics. Nobody knew by what neglect of the
architect, by what partiality of the Board of Works, it had been permitted to
be built. It was of no style at all, neither Gothic, like the original building,
nor Queen Anne, like the fashion. He had failed in his duty in every respect.
It was a square box with a large window filling up one side. It was lighted
with gas. It had red curtains in bold and uncompromising rep, and a large
mahogany sideboard of the worst period. How he had been allowed to build
this monstrosity nobody knew. It had been made the subject of a painful
discussion in the Chapter itself, where Canon Skeffington (the Honble. and
Revd.) complained so bitterly of the injury done to his best principles and
highest feelings, that the Dean was irritated, and took up the cudgels on his
side on behalf of his favourite musician. “He has a right, I suppose, to make
himself comfortable like the rest of us,” the head of the community said.
“No right to make my life a burden to me,” said the Honourable Canon;
and, he added, almost weeping, “I cannot look out of my window without
seeing the thing. You talk at your ease, you others——” But what was to be
done? The Chapter could not take so bold a step as to invade the rights of
private property, tear down the Signor’s red curtains, burn his sideboard,
destroy his walls. He had to be left to the enjoyment of his villainous
erection. The Signor laughed in his sleeve, but in public was remorseful,
bemoaning his own ignorance of art, and declaring that if he could afford it,
rather than give pain to Canon Skeffington—but then he could not afford it
—and what was to be done? He kept his dining-room, which was big
enough to accommodate his friends, but for himself the Signor had better
taste than he professed to have. His favourite sitting-room was in the same
position and had the same view as that of his housekeeper, but its window
was between two buttresses of the wall, which held in their gigantic arms a
little square shelf of green turf, a small projection of the hill, which above
and below was covered with masonry, leaving this little ledge of grass, like
one of the hanging gardens of Scripture, hung high in the air above the town
and the landscape. The Signor’s window opened upon this little terrace. His
room within was low and dark, but in summer at least this mattered little,
for its dim light and shadowy walls made a pleasant shelter, like a bower in
a wood, from the lightness and brightness outside. There was a heavy beam
across the roof, from which hung a little chandelier of old Venice glass,
reflected in a tall old mirror among the oak panels over the mantelpiece,
and not much more bright than they were. On one side were the carved
doors of a cupboard in the wall, which was full of old music, the Signor’s
chief treasures, and on the other was a range of low bookshelves, also filled
with music books of every size and kind. The piano stood in the corner near
the window, with the keyboard close to the light. There were a few chairs
about the room, and a writing-table piled with papers. This was all the
furniture of the dim little chamber, and it was impossible to imagine a
greater contrast than existed between it and the new building which had so
shocked Canon Skeffington. And the Signor was not in this particular much
unlike his house. A touch of sentiment, which some people were disposed to
call high-flown, mingled in him with a curious undercurrent of cynicism,
which few people suspected at all. He liked to jar upon the Canon
Skeffingtons of existence and ruffle their tempers and their finest feelings.
But in his heart he had feelings equally fine, and was as easily froissé as
they. He mocked at them on the very points in which he himself was weak,
affecting an insensibility which he did not feel, building the vile modern
room with profound enjoyment of their delicate distress, but retiring out of
it himself to the shelter of this dim romantic chamber. The combination was
very like the Signor.
On this particular evening, when young Purcell went to call for lights,
the Signor was seated out on his little terrace enjoying the twilight and a
cigarette together. There were two chairs on the scrap of grass, and a little
table with an inkstand upon it, and the cup in which the Signor had taken
his black coffee after dinner. He was leaning back in his chair puffing out
the fragrant smoke from his cigarette, lazily watching it as it floated
upwards, and now and then noting down a bar or two of music upon a piece
of paper in his hand. Sometimes he took the cigarette from his mouth and
hummed a scrap of an air, keeping time with his head and hand. There was
no one who was more popular in the country as a composer of graceful
drawing-room songs than Signor Rossinetti. It was something refined,
something elegant that was expected from him, delicate soprano melodies,
fine combinations for tenors and altos. It was very seldom that he took any
trouble about the bass, but his tenor songs were justly considered exquisite.
He liked to have a pretty set of verses on hand, and “set” them in the
intervals of more serious business. The summer evening, when he sat out
after dinner upon his scrap of terrace, was the time when he had most
inspiration. His pupil and protégé, young Purcell, thought there was no
intellectual pleasure higher and more elevating, than to sit out here in the
shadow of the great grey buttresses, with the cheerful distant noises of the
High Street floating upward from the foot of the wall, and to watch the
Signor composing his song. The young fellow would run in to the piano and
“try over” every line of the symphony as it came welling out from that
fount of music. He said often that, except one thing, there was no such
delight in the world. To see genius working under his very eyes, what a
privilege it was! To Purcell it seemed that his master read his heart, and
uttered his deepest sentiments for him in those compositions. To-night his
mind had been lulled out of great commotion and disturbance by the rosy
vision of love and happiness that had breathed through the notes. It was
glad, it was sad, it was full of suggestion, it wrung the very heart of Purcell
—“ ’Twas in the time of roses, they plucked them as they passed.” Would
that time ever come for him? He thought the Signor had read the depths of
his heart, the wistful longing which was sometimes hope and sometimes
despair, the pictures he made to himself of one day wandering by her side,
one day gathering roses for her. He murmured over and over the tune of the
refrain in a kind of ecstasy as he went to his mother’s room, his fancy
excited, his head all on fire, half with the delicious sense of being friend to
such a genius, and sharing, as it were, the very inspiration that produced
such beautiful things—and half with the pride and delight of being so
deeply in love and hanging on so exquisite an edge of anguish. The Signor
himself did not know how much those pretty compositions of his went to
his pupil’s heart; but he was flattered—as who would not be?—by this
never-failing appreciation of his work, and youthful enthusiasm. It pleased
him vaguely, just as the floating sounds from below, the voices and noises,
all softened by the warm air of the summer evening, and even by the
dimness of the twilight, pleased him. How harmonious they became as they
soared upwards, all that was harsh taken out of them, filling the solitude
with a genial sense of human fellowship! Perhaps the Signor was, like many
others, not too fond of his fellow-creatures close at hand; but as they went
and came, far down at his feet, talking, calling to each other, shouting their
wares, singing now and then, making a sound of their steps upon the
pavement, and a movement of their breathing in the air, he was transported
with the hum, and felt that he loved them. This always gave him inspiration,
this and the glimmer of the river and of the distant villages scattered over
the plain, throwing up here and there a dim point of a spire among the trees.
When Purcell left him, he put aside the bit of music-paper on which he had
been jotting down his chords. He raised his eyes to the profound
unfathomable blue above, and swung back upon his chair. He was half
giddy with the sense of circling depths of infinity above him, though
himself raised so high. The Signor was not without a feeling that he was
raised very high, not only in locality, but in soul; yet there was a heaven
above which made his head giddy when he looked up—a heaven full of
stars, from Palestrina to Mendelssohn, all shining over him, serene,
unapproachable, not even holding out any encouragement to him, passive
and splendid as the other stars which hid themselves in that still-luminous
blue. Would any one ever look up at that sky and recall his name as also
among the ranks of the unapproachable? The Signor turned his eyes from it
with a sigh as he heard some one enter the room, and came down to earth,
letting his chair drop upon its four legs, and his mind return to the present.
He watched through the open window the advent of old Pickering carrying
the lamp. The old man put it down on the table, and lighted some candles
on the mantelpiece in front of the dim mirror, which gave them back with a
blurred, enlarged reflection. His master sat outside and watched him
pottering about the room, setting the chairs against the wall, and vainly
attempting to make everything “straight.” It was a standing grievance to old
Pick that he was not allowed to close the window and draw the curtains as it
was right to do. The Signor outside sat and watched him with a gentle
amusement. He liked to feel the oddness and superiority of his own tastes,
thrown into evidence by the mighty anxiety of old Pick to shut the window.
A smile came over his face. To ordinary mortals, in ordinary houses, it was
not necessary to seek inspiration from the skies and the wide world of
evening air. As Pick approached the window, with his usual look of wistful
anxiety to be allowed to do what was right, and tacit disapproval of lawless
habits, the Signor stepped through, smiling. “I think you will shut me out
some night, Pick,” he said, “and then you will have my blood on your soul
—for what could I do upon the terrace? I should fall asleep and tumble
over, and be picked up in little pieces at the foot of the hill.”
“Ah! I don’t feel no fear of that, sir,” said Pickering, shaking his head;
“you’ve got too good a voice for that, sir. I don’t make no doubt that you
could hold an A sharp till you frighted the whole Abbey. And besides I
always looks out; I’ve got the habit in this house. Even the girl, she’ll go
and stand at the window, as if the view was any matter to her; it’s a thing as
carries one away. But I don’t hold with leaving all open when the lights are
lighted. Bless you, the top windows in the street with a spyglass, or even
with good eyes like what I had when I was young, they could see in.”
“Much good it would do them,” said the Signor, sitting down before his
piano. And indeed it is quite true that as he sat close to the window, relieved
against the light of the lamp within, there were eyes at the top windows
opposite which could catch with difficulty the outline of the Signor’s pale
profile and black moustache. Some of the young ladies in the shops would
climb up occasionally and show that exciting prospect to a friend. But it
was an amusement which palled after the first moment, and certainly did no
harm to the Signor.
“Maybe not much good, sir,” said old Pick, who always would have the
last word; “but it might do harm. You never can tell what folks will say. The
less they know the more they’ll talk; and that’s true all the world over;
though I will say for the Abbey as it’s as bad or worse than most other
places.”
“Why should it be worse, Pick?”
“I don’t know, sir—unless it’s the clergy and the chevaliers. You see,
when gentlemen has little or nothing to do, they’re brought down to the
level of the women, so far as that goes—and as gentlemen always does
things more thorough than the women when they’re once started, the
consequence nat’rally is—Leastways that’s my notion of it,” said Pick;
—“the women haven’t the strength to start a real talking as does harm. They
tries hard—as hard as they knows how—but bless you, in that as in most
things, they wants a man to show ’em the way.”
“That is a new view, Pick. I thought if there was one thing in which the
ladies had the advantage of us——”
“There ain’t one thing, sir, not one. For my part, I can tell in a minute a
story as will hang together, a real crusher, one as will drive folks distracted
and ruin a family. You’ll never get that out of a woman’s tongue. Nay, nay,
they hasn’t the force for it; they’re poor creatures at the best; they can make
a person uncomfortable, but they can’t do no more. And when I say the
Abbey’s as bad or maybe worse, I mean that the gentlemen has little to do,
and they has to amuse themselves the same as the women. That’s what I
mean to say.”
The Signor gave a half attention to Pick’s long speech while he sat at his
piano. All the time he was running over his new composition with one hand,
correcting a note here and there, changing a harmony. “ ’Twas in the time of
roses—the time of roses,” he hummed softly under his breath. But the smile
on his lip was for Pick, and he gave him a negligent half attention, amused
by his chatter, and by the peculiar views he held forth. He looked up at him
as Pick stopped, singing with a little flourish in the accompaniment, which
meant satisfaction in having at last got the phrase to his mind—“ ’Twas in
the time of roses—the time of roses——” Old Pick was not surprised by the
utterance of a sentiment so foreign to his subject. He knew his master’s
ways, and he took a certain interest in his master’s productions, such as old
servants often benevolently accord to the doings of their “family.” He could
not tell what folks saw in them—still, as the Signor’s productions, he
looked upon them with kindly toleration all the same.
 “You may say, sir,” he cried, “ ‘the time o’ roses’—that’s just the very
thing; for, I daresay, but for that rose in his button-hole, and the jaunty looks
of him, a young girl wouldn’t have seen nothing in him. But I don’t know
neither—women is the queerest things on the face of this whole earth.
Flatter them, or make them think they’re bettering themselves, and there’s
nothing they won’t do.”
“Who is it that wears flowers in his button-hole?” said the Signor. He
wore them himself, and he was curious and slightly excited, wondering if
any gossip could by any chance have got up about himself. The idea of such
a thing kindled him into interest; his right hand dropped off from the piano,
though with the other hand he kept softly sounding notes in the bass, and he
turned towards his old servant with a look of animation altogether new.
What interest is there like that with which one anticipates hearing
something about oneself?
But at this moment Purcell’s steps were heard coming quickly along the
passage, and he came in with his head erect, and his eyes gleaming, and
pushed old Pick out of his way. “That will do, Pick,” he said, with a
glimmer of impatience, “that will do! I will set things right for the master,
myself.”
“What is the matter, boy?”
“Matter or no matter, if you think I’ll leave it to the first that comes to
look after my master—” said old Pick, standing his ground. He would not
yield; he was very friendly in general to Mr. John, and ready to do what he
ordered, but there are limits to everything. He stood his ground steadily,
arranging and re-arranging the papers on the table, while young Purcell
went forward to the Signor. The young fellow put himself behind the
musician, between him and the window, and stooped to whisper in his ear.
His glowing eyes, his eager aspect, made a great impression on the Signor,
who was very impressionable. He was possessed by some new thought.
“Master,” he said, breathless, “I have a hundred things to say to you. I have
heard something new. I want your advice, I want your help.” He was
breathless, as if he had been running a race, though all he had really done
had been to come along a few yards of passage. The Signor was easily
moved by the sight of emotion, and he was fond of his protégé. “Go, Pick,”
he said immediately, “and bring us some tea.”