Brain and Spinal Cavernomas : Helsinki Experience

Transcription

Brain and Spinal Cavernomas – Helsinki Experience
Juri Kivelev
Academic dissertation
To be presented for public discussion
in the Lecture hall 1 of Töölö Hospital on
December 10th, 2010 at 12 o’clock noon.
University of Helsinki 2010
Supervisors:
Professor Juha Hernesniemi, MD, PhD
Department of Neurosurgery
Helsinki University Central Hospital
Helsinki, Finland
Associate Professor Mika Niemelä, MD, PhD
Helsinki, Finland
Reviewers:
Associate Professor Esa Kotilainen, MD, PhD
Turku University Hospital
Turku, Finland
Professor Hannu Kalimo, MD, PhD
Helsinki University, Haartman Institute
Department of Pathology
Helsinki, Finland
To be discussed with:
Murat Günel MD,
Professor of Neurosurgery
Professor of Neurobiology
Chief, Section of Neurovascular Surgery
Co-Director, Yale Program of Neurogenetics
ISBN 978-952-92-8174-9 (Paperback)
ISBN 978-952-10-6665-8 (PDF)
Helsinki University Print
Helsinki 2010
2
To my mother
3
Juri Kivelev
Topeliuksenkatu 5
00260 Helsinki
Finland
mobile: +358504270383
e-mail: [email protected]
4
Table of contents
Abstract
9
Abbreviations
12
List of original publications
13
I Introduction
14
II Literature review
15
Typical cavernomas
15
Historical aspects
15
Epidemiology
16
Pathologic features
17
Genetics and molecular biology
19
Radiology
21
Clinical aspects
24
Epileptic disorder
24
Focal neurological deficits
25
Hemorrhage
26
Headaches
28
Treatment
28
Surgical series
28
Operative techniques
31
Radiotherapy
33
Uncommon cavernomas
35
Intraventricular cavernomas
35
Patients and natural course
35
Radiology
40
Treatment and operative techniques
41
Neuroendoscopy
43
Outcome
43
Multiple cavernomas
44
44
5
Symptoms
45
Epileptic disorder
45
Hemorrhage
46
Other symptoms
47
Radiological progression
47
Surgical treatment and outcome
48
Spinal cavernomas
49
Intramedullary cavernomas
50
50
Symptoms
53
Radiology
54
Surgical treatment
55
55
Monitoring
57
Outcome
58
Extramedullary cavernomas
58
Patients and symptoms
58
Radiology
60
Treatment and outcome
61
III Aims of the study
62
IV Patients and methods
63
Data collection
63
63
Multiple cavernomas
65
Spinal cavernomas
66
Temporal lobe cavernomas
67
V Results and Discussion
72
Helsinki Cavernoma Database
72
Patients
72
Symptoms
72
Radiology
74
Treatment
74
Outcome
75
Publication 1. Intraventricular cavernomas
6
76
76
Radiology
76
Treatment
77
Outcome
79
Discussion
80
Special clinical features
80
Special radiological features
81
Treatment of the IVCs, morbidity and mortality
82
Future trends
82
Publication 2. Multiple cavernomas
83
83
Radiology
84
Treatment
84
Outcome
86
Discussion
86
Publication 3. Spinal cavernomas
88
88
Treatment
90
Outcome
91
Recovery from sensorimotor paresis
92
Recovery from pain
92
Recovery from bladder dysfunction
92
Discussion
93
Prognosis
94
Patients with sensorimotor deficits
94
Patients with pain
95
Patients with bladder dysfunction
95
Publication 4. Temporal lobe cavernomas
95
95
Treatment
97
Outcome
97
Seizure outcome
97
General outcome
98
Discussion
100
Indications for surgery
100
7
General outcome
101
Predictive factors for a better outcome
102
VI Conclusions
103
Acknowledgements
104
References
105
8
Abstract
Objective
Cavernomas are rare neurovascular lesions, encountered in up to 10% of patients harboring
vascular abnormalities of the CNS. After the advent of MRI in clinical practice, the number of
patients increased markedly, allowing the main clinical features and results of surgical treatment
to be determined. Due to their rareness intraventricular, multiple, and spinal cavernomas remain
poorly described in the literature. We analyzed our own series and provided a literature review. In
addition, temporal lobe cavernomas were analyzed to better understand the prognostic factors
determining a favorable postoperative outcome.
Patients and methods
Data on 383 consecutive patients with a total of 1101 brain and spinal cavernomas treated at
Helsinki University Central Hospital from January 1, 1980 to December, 12 2009 were
retrospectively analyzed. A catchment area of this center is 1.8 million inhabitants. Most patients
were primarily examined at the neurological department of the referring hospitals and thereafter
sent to our neurosurgical center for further evaluation and treatment. The collection of the series
began in 2006, and the patient database was continuously supplemented by new cavernoma
patients recruited to the study. Twelve patients (3.1%) had intraventricular cavernomas, 44
patients (11.5%) multiple cavernomas, 14 patients (4%) spinal cavernomas, and 53 patients
(15.1%) temporal lobe cavernomas. Results of their treatment were assessed at a median of two,
eight, three, and six years, respectively. The study protocol was approved by joint Ethical
Committee of Helsinki University.
Results
Inraventricular cavernomas (n=12)
The median age of our patients on admission was 47 years (range 15 – 66 yrs). As a presenting
symptom, 11 patients (92%) had an acute mild to severe headache accompanied by nausea and
vomiting. Three patients (27%) with a cavernoma in the fourth ventricle had cranial nerve deficits
(paresis of the III, VI, and VII nerves, separately or in various combinations). Four patients
(36%) had hydrocephalus on admission, but shunting was necessary in only one patient. Eight
patients (67%) experienced extralesional hemorrhage confirmed by CT and lumber puncture. The
re-bleeding rate was 89% per patient-year. Six of the 12 IVCs were located in the lateral
ventricle, mainly on the left side. One IVC was in the third ventricle, without radiological signs
of enlarged ventricles. In five patients (45%), IVC was found in the fourth ventricle, typically in
9
the medial part of the floor. Nine patients underwent surgical excision of the IVC to prevent rebleedings or to eliminate the mass-effect, or both. Five of the nine patients operated on were
symptom-free at follow-up. Age, sex, and previous bleeding had no influence on outcome. No
mortalities occurred. Patients with fourth ventricle cavernomas had a worse outcome than those
with lateral-ventricle lesions.
Multiple cavernomas (n=44)
In our series, mean age at diagnosis was 43.6 years (range 4-69 yrs) and 36.3 years (range 0.6-71
yrs) for men and women, respectively. Nineteen patients (43.2%) had a history of one or more
symptomatic extralesional hemorrhages. Altogether, 18 patients (40.9%) had an epileptic
disorder, and in six of them (33.3%) an intracerebral hemorrhage from the cavernoma was
present on admission. A total of 762 cavernoma was found in these 44 patients. The median
number of lesions per patient was six. The largest lesion (50mm) was a Zabramski type I frontal
cavernoma that had radiologically presented as a rare cystic form. Microsurgery was performed
on 30 patients (68.2%), and a total of 34 cavernomas were removed. In the majority of cases, the
removed cavernoma was the largest lesion, and usually with signs of recent bleeding. No patients
were lost to follow-up and no deaths occurred. Thirty-four patients (77.2%) had no disability
(GOS V), nine (20.5%) had moderate disability (GOS IV), and one (2.3%) had severe disability
(GOS III). During the follow-up four patients suffered from a CT-verified intracerebral
hemorrhage. Bleedings occurred only in conservatively treated patients. MRI was performed
during follow-up on 22 patients. Altogether, 54 de novo lesions were found 48 (89%) belonging
to type IV cavernomas.
Spinal cavernomas (n=14)
The median age at presentation was 45 years (range 20-57 yrs). In nine patients (63%), the
cavernomas were intramedullary, while four patients (29%) had an extradural lesion and one had
an intradural extramedullary cavernoma with an isolated intramedullary hemorrhage. Patients
suffered from sensorimotor paresis, radicular pain, or neurogenic micturition disorders in
different combinations or separately. Three patients (21%) presented with acute onset of
symptoms and rapid neurological decline necessitating emergency surgical treatment.
Hemorrhage occurred in seven patients (50%) before surgery. Indications for microsurgical
removal of a spinal cavernoma were progressive neurological deterioration in 12 patients (86%)
and prevention of bleeding and consequent neurological decline in the remaining two patients
(14%). Nine patients (64%) underwent a hemilaminectomy and five (36%) a laminectomy. At
discharge, ten patients (71%) experienced improvement of their neurological status, three patients
(21%) had worsening of the symptoms or some new deficits, and one patient remained the same.
10
At the last follow-up, eight patients (57%) experienced further improvement of their symptoms.
One patient (7%) was worse than preoperatively. An extramedullary location proved to be better
and safer regarding outcome: four of these five patients (80%) demonstrated further improvement
of the symptoms, whereas only four of eight (50%) with an intramedullary lesion did the same.
Temporal lobe cavernomas (n=53)
The median age of patients at radiological diagnosis was 37 years (range 7-64 yrs). Epileptic
seizure was the most frequent symptom occurring in 40 patients (82%).
Before surgery, nine patients (18%) had a CT-confirmed hemorrhage. Altogether, 12 bleedings
occurred. Forty-nine patients were operated on. Lesionectomy was performed on 38 of 40
patients (95%) presenting with seizures. All ten patients with only one seizure preoperatively,
were seizure-free at follow-up. Of 16 patients who had experienced between two and five
seizures preoperatively, 11(69%) were seizure-free, and of 13 patients with numerous seizures
preoperatively, nine (69%) were seizure-free. Neither type, duration of seizures, nor location of
the cavernoma inside the temporal lobe correlated with postoperative seizure outcome. The
predictive value of preoperative EEG could be revealed. At follow-up, nine patients (18%) had a
new or worsened neurological deficit. Memory disorder was present in five patients with a
history of epilepsy, but four of these patients already had this problem preoperatively. None of
the asymptomatic patients developed neurological deficits postoperatively.
Conclusions
Microsurgical treatment of brain and spine cavernomas is safe and effective. Most operated
patients with intraventricular, multiple, spinal, and temporal lobe cavernomas had significant
improvement of their symptoms. Due to rareness of these lesions, a decision to operate may be
difficult requiring vast experience and dexterity of the neurosurgeon. In patients with cavernomas
of the fourth ventricle, surgical risks are higher than with cavernomas of other ventricles. In cases
of multiple cavernomas, removal of epileptogenic cavernomas is beneficial but antiepileptic
drugs are used due to the remaining lesions. Spinal intramedullary cavernomas carry higher risks
of permanent neurological deficits than those in extramedullary location. In these patients, the
worst prognosis was linked to bladder disorders, which occurred in 43% of patients despite
surgical treatment. In cases of temporal lobe cavernoma, favorable seizure-outcome after
lesionectomy is expected. Duration of epilepsy did not correlate with seizure prognosis. The most
frequent disabling symptom at follow-up was memory disorder, considered to be the result of a
complex interplay between chronic epilepsy and possible damage to the temporal lobe during
surgery.
11
Abbreviations
AED
antiepileptic drugs
ASO
arteriosclerotic obliterans
ATL
anterior temporal lobe
AVM
arterio-venous malformation
BBB
blood-brain barrier
CCM
cavernous malformation gene
CM
cavernous malformation
CSF
cerebro-spinal fluid
CT
computed tomography
CNS
central nervous system
DRE
drug-resistant epilepsy
DREZ dorsal root entry zone
DSA
digital selective angiography
EC
extramedullary spinal cavernomas
EEG
electro-encephalography
GOS
Glasgow Outcome Score
IC
intramedullary spinal cavernomas
IVC
intraventricular cavernomas
IOM
intraoperative monitoring
MC
multiple cavernomas
MRI
magnetic-resonance imaging
MTL
medial temporal lobe
PET
positron-emission tomography
PTL
posterior temporal lobe
SR
stereotactic radiotherapy
SEP
sensory evoked potentials
TLC
temporal lobe cavernomas
12
List of original publications
I.
Kivelev J, Niemelä M, Kivisaari R, Hernesniemi J: Intraventricular cerebral cavernomas: a
series of 12 patients and review of the literature. J Neurosurg 112(1):140-9; 2010
II. Kivelev J, Niemelä M, Kivisaari R, Dashti R, Laakso A, Hernesniemi J: Long-term outcome
of patients with multiple cerebral cavernous malformations. Neurosurgery 65:450-5, 2009.
III. Kivelev J, Niemelä M, Hernesniemi J: Outcome after microsurgery in 14 patients with spinal
cavernomas and literature review. J Neurosurg Spine 13(4):524-534, 2010
IV. Kivelev J, Niemelä M, Blomstedt G, Roivainen R, Lehecka M, Hernesniemi J: Microsurgical
treatment of temporal lobe cavernomas. Acta Neurochir (Wien), epub Sep 26, 2010
13
I Introduction
Cavernous hemangiomas, or cavernomas, of the CNS are rare neurovascular lesions. They are
usually detected between the second and fifth decade of life [57, 256, 343]. Cavernomas occur in
both sporadic and familial forms. The latter are more frequent in Hispanic-Americans, accounting
for up to 50% of cavernomas [254]. In contrast, among Caucasians, the familial forms are
encountered in only 10-20% of patients [254, 259]. Patients with familial forms are typically
affected by multiple cavernomas, whereas sporadic forms mostly present with a single lesion. In
hereditary cases, cavernomas are characterized by an autosomal-dominant pattern of inheritance
with incomplete penetrance. Three genes responsible for development of the cavernomas have
been identified to date [60, 80, 130, 170]. When their mutations express, loss of respective
proteins leads to formation of the lesion, with dilated thin-walled sinusoids or caverns covered by
a single layer of endothelium that has undeveloped interstitial junctions and subendothelial
interstitium [193, 334]. Blood flow inside the sinusoids is low, predisposing to intraluminal stasis
and thrombosis. Due to fragility of the sinusoid wall, a cavernoma causes repetitive
microhemorrhages into the surrounding neural tissue with formation of perifocal hemosiderosis
and reactive gliosis. Such local homeostatic instability produced by either genetic or reactive
environmental factors (inflammation, breakdown of the blood-brain barrier, gliosis) may provoke
intensive neoangiogenesis and proliferation of the sinusoids. Subsequently, lesions enlarge and
grow, which may coexist with clinical progression.
The natural history of brain cavernomas is relatively benign and up to 21% of patients are
asymptomatic [132]. The most frequent manifestations of the disease are seizures, focal
neurological deficits and hemorrhage. Seizure activity occurs in up to 80% of patients with
supratentorial cavernomas most probably being evoked by perilesional intraparenchymal changes
[15, 71, 223, 256, 288]. Focal neurological deficits are typical for cavernomas located close to
eloquent regions of the brain and for spinal lesions. Headaches are fairly common complaint in
many cavernoma patients, and usually lead to further clinical and radiological work-up. However,
due to their unspecific nature, headaches are not linked to the cavernoma in every patient and
frequently represent some other clinical condition.
An acute exacerbation of the symptoms of any clinical pattern of cavernomas is prevalently
related to hemorrhage. The risk of this event, 0.1-5% per patient-year, depends on the location of
the cavernoma and generally increases in deeper lesions of the brain [71, 160, 235, 256, 343]. In
most patients, bleeding is not life-threatening, but, in certain cases, it can cause devastating
neurological deficits. Furthermore, the risk of re-bleeding increases from 5% to 60% per patient-
14
year [90, 94, 235, 327] indicating active treatment of the lesion in early stages after the first
event.
Microsurgical removal of the symptomatic cavernoma is generally accepted as the most effective
and safe method. Most operated patients with a lesion in a safely accessible location usually gain
convincing relief of their symptoms. Nevertheless, deep or eloquent sites of the brain and
intramedullary spine location increase surgical invasiveness and risks of postoperative
complications.
In the present work, data on all consecutive patients suffering from cavernoma and treated at the
neurosurgical department of Helsinki University Central Hospital during the last 30 years have
been analyzed. Due to the limited literature on intraventricular, spinal, multiple, and temporal
lobe cavernomas, these entities were reviewed more extensively. The aim of this study was to
integrate our knowledge on clinical features of the cavernomas located in different compartments
of the CNS, and summarize results of their surgical treatment.
II
Literature review
Typical cavernomas
Historical aspects
The first report on brain cavernoma appeared in 1854, in a publication by Luschka, who found
tumor-like formation originating from vascular tissue and being located within cerebral
hemispheres [162]. Luschka classified angiomas into two types: 1) those arising by sequestration
of a small portion of the embryonic capillary vascular system; and 2) “true tumor” formation
originating from vascular tissue. His own case belonged to the latter type and was a cavernoma
according to the modern definition of this term. The term “cavernous angioma” itself has been
introduced by Rokitansky before Luschka’s case – these pathological masses with cavernous
structure were found and described previously elsewhere in the body [66]. The earliest report of
successful surgical removal of a brain cavernoma was introduced by Bremer and Carson in 1890
[35]. The first overview of cavernous angiomas was provided by Dandy in 1928 [66]. He
described five of his own cases and collected 44 previously published cases to date that
delineated typical macroscopic and microscopic features of this disease. To depict clinical
manifestation of the brain cavernomas, Dandy identified basic clinical signs, e.g. predisposition
to bleed and to cause focal neurological deficits, with epilepsy being the most common clinical
manifestation of these lesions. When describing technical nuances during cavernoma removal, he
emphasized: “Although they have a good venous and arterial blood supply, neither is excessive,
15
and neither is disproportionate to the other. When opened at operation, they bleed freely and in
proportion to the size of the cavernous spaces and the arterial supply.” This remark seems very
important in the sense of influencing the threshold of surgeons to remove this true vascular
lesion, which, however, is not prone to profuse intraoperative bleeding. Confirming this, Dandy
concluded: “.... the cavernous angiomas... should be treated surgically by complete removal of
the solid tumor together with a margin of contiguous brain tissue...” And still, this paradigm
remains actual in vast majority of symptomatic cavernoma patients.
Eight years after Dandy’s review, Bergstrandt, Olivecrona and Tönnis published their thorough
experience on neurovascular pathology investigated and treated at Karolinska Institute in
Stockholm [28]. This book included a literature overview of previously published cavernoma
cases together with two personal cases. Applying their own pathological classification of this
disease, the authors found that only 20 patients collected by Dandy in 1928 met the diagnostic
criteria of a cavernoma. Curiously, even one of the reported patients with transcranial growth of
the cerebellar lesion who was operated by Dandy himself was not considered by Bergstrand as a
definite case of cavernoma [28].
In 1957, Krayenbuhl and Yasargil described 82 cases of cerebral cavernomas collected from the
literature [162]. Nineteen years later, in 1976, Voigt and Yasargil published their comprehensive
review, which included 164 cases together with one of their own patients who suffered from a
temporal lobe cavernoma and was successfully operated on by Yasargil [321].
First applied to medical practice in September, 1971 at Atkinson Morley Hospital in London,
computed tomography (CT) scanning has spread throughout the world as an invaluable adjunct to
diagnostics of brain diseases. The apparatus was engineered by G.Hounsfeld and mathematically
justified by A.Cormack. Furthermore, in 1977, a magnetic resonance imaging (MRI) was
performed for the first time on humans [64]. The theoretical basis and engineering of the MRI
was provided by Lauterbur, Mansfield, and Damadian. This technique revolutionized radiological
diagnostics of any pathology in the CNS, particularly, - cavernomas. With the advent of CT and
MRI into everyday clinical practice (the so-called “modern imaging era”) the number of
cavernoma cases has increased exponentially.
Epidemiology
Among the vascular malformations of the brain and spine, cavernomas constitute 5-10%. Their
incidence in the general population is estimated to range between 0.34% and 0.8% [71, 104, 191,
240]. Prior to modern imaging, the diagnosis of cavernoma was rare and usually confirmed only
at operative exploration or autopsy. Several classic autopsy studies have reported the incidence of
cavernomas in the general population. In 1984, McCormick found 19 cavernomas in 5.734
autopsies reporting an incidence of 0.34% [191]. Just a few years later, in a consecutive series of
16
24.535 autopsies, Otten et al. reported 131 cavernoma cases, yielding an incidence of 0.53%
[218]. With the advent of MRI in clinical practice reliable imaging of the cavernoma in living
persons became possible, and a fairly similar incidence was noted. In 1991, Del Curling et al.
analyzed 8.131 MRIs and found 32 cavernomas, the incidence thus being 0.39% [71]. In the same
year, Robinson et al. published their work, where 14.035 MRIs were reviewed and 66 patients
with cavernoma were uncovered, yielding an incidence of 0.47% [256].
So far, no population-based studies on the incidence of cavernomas in Finland have been
performed. In the neurosurgical department of Helsinki University Central Hospital (serving 1.8
million inhabitants), 383 patients with cavernoma were treated over the last 30 years. This
represents a cumulative incidence of 0.62% in this given district during last 30 years. Taking into
account, that the Finnish population is epidemiologically quite homogeneous the same incidence
probably exists in other parts of the country.
Pathologic features
According to the pathological classification of neurovascular malformations suggested by
McCormick in 1966, lesions are divided to five major groups: 1) teleangiectasias; 2) varices; 3)
cavernous malformations; 4) arteriovenous malformations (AVMs); and 5) venous angiomas
[192]. This classification has thereafter been modified: varices (varicose veins) have been
combined with venous malformations/venous angiomas, and such lesions have been renamed to
developmental venous anomaly (DVA). Although pathological criteria have been suggested for
every type of malformation their structural criteria and nomenclature are somewhat ambiguous
and variable. Furthermore, reports of transitional or mixed forms exist in the literature and all of
the above-mentioned malformations can coexist with each other. The most frequent entity
associated with cavernomas appears to be DVA [230, 237, 304]. Another common combination
is a capillary teleangiectasia. Some similarities between these malformations (multiplicity,
pontine involvement, familial variety) give reason to consider teleangiectasias as a precursor of
cavernomas [252, 259].
From a macroscopic viewpoint, cavernomas are well-defined lesions and because of their
lobulated appearance often resemble a mulberry (Figure 1). They do not invade the neural tissue.
In contrast to AVMs, large feeding arteries or draining veins are not common; therefore blood
flow inside the lesion is low. Their mean size is usually 1-2 cm, with a range from punctate to
gigantic examples. The biggest lesion in our practice was 5 cm in diameter. There are anecdotal
cases of huge lesions, with the cavernoma occupying an entire lobe or even several lobes of the
brain [100, 259].
17
Figure 1 Intraoperative view of the spinal cavernoma surrounded by nerve roots
In fact, in 2008, Kan et al. published an overview of
36 collected cases of giant cavernomas emphasizing
the extreme rarity of such lesions [147]. Although no
agreement exists regarding terminology, the authors
applied the term “giant cavernoma“ to lesions
exceeding 4 cm in diameter, which seems to be
rational. In a typical case, the lesion’s core consists
of unequal sinusoids or caverns filled with blood that
are separated by fine fibrous strands. Intraluminal
thrombosis with subsequent organization is typical and this area appears more solid.
Calcifications and even bone formation may also exist [259]. Adjacent neural tissue is very
typically discoloured due to accumulation of blood breakdown products after repetitive
microhemorrhages.
Figure 2 Microscopic view of a cavernoma. The dilated vessels without intervening neural parenchyma are lined by
thin endothelium and surrounded by collagenous fibrotic tissue with blue deposits of iron (hemosiderin) after
hemorrhages
Microscopically, cavernomas are sinusoid structures
with thin walls, which are composed of collagen
lined by a single layer of endothelium [259]. Outside
the lumen there are often macrophages containing
iron pigment, hemosiderin, phagocytosed after
microbleeds (Figure 2). Electron microscopy [305]
has shown that endothelia may be fenestrated or there
are gaps at intercellular junction, all these alterations
indicating defective blood-brain barrier [54,305]. The
basal lamina outside the endothelium may be lacking or is abnormal, and astrocytic endfeet are
often absent. Some histological subtypes of cavernomas have been identified: 1) Cystic form,
which is predisposed to bleeding and growth and occurs commonly in the posterior fossa [27,
241]. This form is very rare, and only 25 cases of cystic cavernoma have been reviewed to date
[215]. The mechanisms of formation of large cysts are not understood; presumably, osmotic
transport of the fluid into the cyst combined with microhemorrhages induces progressive
enlargement of the lesion (Figure 3). This type is more frequent in females and elderly patients;
2) Dural-based form, which is usually encountered in the middle fossa close to the cavernous
sinus or within it, in the cerebellopontine angle, or on the tentorium and convexities, is prone to
18
Figure 3 MRI of the frontal cavernoma with large cystic component
a –T2-weighted image, axial view; b –T1-weighted image, axial view; c – T1 –weighted image with Gadolinium
contrast, sagittal view.
a
b
c
an aggressive clinical course [163, 197, 251, 319]. Middle fossa lesions may have abundant
vascular supply and tend to bleed profusely when excised [319]; 3) Hemangioma calcificans is
typically found in the temporal lobe and, as reflected by its name, is strongly calcified with a low
risk of hemorrhage, while still being highly epileptogenic [143].
Genetics and molecular biology
Primary evidence of hereditary mechanisms underlying cavernoma formation was elucidated in
the early 1980s, when investigators detected several families of Hispanic origin who suffered
from cavernomas [130, 189, 254, 256, 343]. These studies convincingly showed that cavernomas
can present as a familial form with an autosomal dominant pattern of inheritance. Extensive
laboratory research has been initiated to address the genetic substrate of this phenomenon, and
genes predisposing patients for cavernomas (CCM1, CCM2 and CCM3) have been identified
(Table 1). Already in 1995, Günel et al. discovered CCM1 confirming genetic mechanism of the
disease [116]. All three genes are likely involved in the same molecular pathway providing
interplay between the neural and glial elements (neurons and astrocytes) and the endothelium of
the CNS [277]. Functions of each gene were studied and certain changes in protein interactions
and consequent pathologic appearances in cytoarchitecture within the cavernoma were addressed.
The CCM1 gene (alternative name KRIT 1) is located at chromosome locus 7q and stabilizes the
interendothelial junctions associated with actin stress fibers [175]. Through integrin signaling,
CCM1 possibly mediates bidirectional signaling between the extracellular matrix and the cellular
cytoskeleton [277]. It is expressed in arterial and microvascular endothelium of the CNS [119].
More than 90 mutations of CCM1 have been reported [167].
19
The CCM2 gene (or malcavernin) located at 7p, probably determines cellular responses to
osmotic stress [175]. In a study by Plummer et al, CCM2 expression in the brain was found to be
primarily neuronal, but not endothelial [232]. This finding suggests that cavernomas may arise
from abnormalities in surrounding neuronal and glial cells rather than in vascular endothelium
[199]. The CCM3 gene is located at the chromosome locus 3q (called programmed cell death 10
or PDCD10) and is encountered in up to 40% of families with cavernomas [60]. It determines cell
proliferation and transformation (cancer cell lines), together with modulating extracellular signalregulated kinase [175].
Table 1 Genetic background of cavernomas
Genes,
clinical
penetrance
Affected
chromosome
loci
CCM1,
60-88%
7q21
KRIT1
(Krev-1
interaction
trapped 1)
KRIT1 protein localizes specifically to the
vascular endothelium. Expresses in foots
processes of astrocytes, forming BBB.
Involved in integrin signaling. Encodes a
microtubule-associated protein, binds ßcatenin, integrin cytoplasmic domain
associated protein-1 (ICAP-1 ), stabilizes
interendothelial junctions associated with
actin
stress
fibers.
Involved
in
angiogenesis.
[60, 74, 100,
105, 116-120,
175]
CCM2,
100%
7p13-15
MGC4607
Expressed in arterial and microvascular
endothelium, in brain pyramidcells and in
astrocytes. Mimics CCM1. Provides
cellular responses to osmotic stress, binds
CCM1 and MEKK3 acting like scaffolding
protein signaling through p38 after
extracellular stimulation. p38 pathway
involved in cell proliferation and
differentiation to apoptosis. Modulates
mitogen-activated protein (MAP) kinase
and Ras homolog gene family, member A
(RhoA) GTPase signaling. Involved in
angiogenesis.
[60, 63, 100,
175, 277, 310]
Provides
cell
proliferation
and
transformation, involved in apoptotic
signaling, modulates extracellular signalrelated kinase (ERK). Involved in
angiogenesis.
[51, 60, 100,
115, 296]
Alternative name
Malcavernin;
OSM
(osmosensing
scaffold for
mitogen-activated
protein kinase
kinase kinase 3, or
MEKK3)
CCM3,
63%
3q25-27
PDCD10
(programmed cell
death 10)
Ultrastructural profile
References
Carriers of the mutated genes have cavernomas on MRI in up to 69% of cases [74]. Thus, the
presence of mutations in the above-mentioned genes is necessary but not sufficient for the
development of the cavernoma [114]. Knudson’s “two-hit” mechanism, proposed to explain this
phenomenon, suggests an external trigger (“second hit”) that exacerbates the disease in a given
region [114, 175, 221]. Loss of one of the alleles (“first hit”) is the result of a germline mutation,
20
and loss of the second allele (“second hit”) will occur somatically within the brain [167]. Several
factors have been assumed to have “second-hit” abilities. For example, a somatic mutation in the
second copy of the gene or a mutation in another gene acting in the same cellular pathway is
considered to be the most probable trigger of the disease [115, 175]. Clinical observations of de
novo cavernomas after radiotherapy confirm that environmental factors also play a role in
“second hits”. Angiogenic factors, inflammatory agents and breakdown of the blood-brain barrier
may also be responsible for the development of cavernomas [54, 100, 175, 280, 291, 305].
Radiology
In 1956, Crawford and Russel proposed the term ”cryptic cerebrovascular malformations”, in
which cavernomas were traditionally grouped [217]. This subset of neurovascular lesions
included cavernomas, thrombosed arteriovenous malformations, venous malformations, capillary
teleangiectasias, and other mixed forms. The main reason why these “cryptic” or “occult” lesions
got this name was based on their scarce appearance or, more commonly, invisibility in the
angiographic view. Although some authors were able to find some prominent draining veins
[217] or small homogeneous finely stippled areas of contrast medium, no pathognomonic
angiographic features could be shown [321].
Routine use of CT scanning in patients with acute neurological events contributed considerably to
preliminary diagnosis of cavernomas. However, the sensitivity of CT in cavernoma diagnostics is
low, and specificity ranges from only 30% to 50% [217]. Thereby, one cannot reliably detect the
lesion, especially in cases of acute intracerebral hemorrhages where the lesion is mimicked by
extravascular blood. On the other hand, with an increasing frequency of CT imaging, the number
of suspected cases has increased markedly. There are certain radiological features on CT that may
correspond to cavernomas. They present as rounded, well-bordered lesions, hyperdense to
adjacent parenchyma, and in 40-60% of cases contain calcifications [217]. Usually, no perifocal
edema or pronounced enhancement exists. Due to the low blood flow inside the nidus, lesions are
negative on the CT angiography (CTA), except for large ones that may even displace major
vessels causing a mass-effect.
A true breakthrough in cavernoma diagnostics began with the widespread use of MR imaging,
which appeared to be the most sensitive tool for revealing a cavernoma throughout the
cerebrospinal axis. MRI allows cavernomas to be reliably diagnosed not only after acute
neurological decline but also in asymptomatic incidental cases. Thus, the number of detected
cavernoma patients has increased dramatically and extensive MRI-based epidemiological studies
have been performed [71, 256]. The MR appearance of a cavernoma can be quite variable
depending commonly on the amount of hemorrhage. Already in 1987, Rigamonti et al. published
their observations of ten cavernoma patients diagnosed with 1.5 Tesla MRI, depicting typical MR
21
features of the lesion [253].
Figure 4 MRI of a 4 year-old patient with acute somnolence and hemiparesis. a – T2-weighted image, sagittal view;
b - T1 –weighted image, axial view; c – T2*-GRE image showing a pontine cavernoma with a hemorrhage
a
b
c
Cavernoma commonly presents in the T1- and T2-weighted sequences with a reticulated
“popcorn ball” appearance of mixed hyper- and hypointense blood-containing locules [217]. The
lesion is surrounded by a hypointense hemosiderin rim. In FLAIR sequences, perifocal edema
can be identified, especially in acute lesions. Several hemosiderin-sensitive sequences (T2*
Gradient Echo, T2* Weighted Angiography - SWAN) are of value, having the highest accuracy
in detecting the intraparenchymal collection of extravasated hemosiderin. The hemorrhageresolving stage significantly affects the MR appearance of the cavernoma, as stated by Zabramski
et al. [343]. The authors proposed a practical classification of MR features of cavernomas,
corresponding to pathological features of the lesion and including four major types (Table 2).
Type I lesions represent subacute hemorrhage, which makes them identifiable on CT as well. On
T1- and T2-weighted MR images, they are hyperintense at the initial stage, while with hematoma
aging and methemoglobin is converted to ferritin and hemosiderin (Figure 4). Changing of
paramagnetic features starts from the margin of the hematoma, which leads to a decrease in the
size of the hyperintense core and the appearance of a hypointense halo around the lesion, known
as the hemosiderotic rim. In cases of major extralesional bleeding, a definitive description of the
cavernoma apart from the hematoma is seldom possible, usually indicating follow-up imaging
and re-evaluation of the lesion. Type II cavernomas constitute the most recognizable group, with
a classical reticulated core of mixed signal that is surrounded by a hypointense ring seen in T1and T2-weighted images (Figure 5). This appearance is considered as a pathognomonic sign of a
cavernoma and reflects the existence of partial thrombosis and organization of intralesional blood
within the sinusoids sometimes combined with calcification.
22
Figure 5 A type II frontal cavernoma with typical
Figure 6 Sagittal view of type III frontal
“pop-corn” appearance
cavernoma. T1-weighted image
a – preoperative view
b- postoperative view
Meanwhile, on CT images type II lesions are visualized quite poorly. Type III lesions look
hypointense on either T1- or T2-weighted images, representing chronic hemorrhage (Figure 6).
They are not identifiable on CT, except for large lesions containing calcifications. Type IV
lesions are best visualized on hemosiderin-sensitive sequences, like T2*-gradient echo, and look
like punctate hyperintense lesions (Figure 7). Still no consensus exists regarding the pathological
substrate of these lesions. Earlier considered as capillary teleangiectasias [252, 343], some recent
evidence shows these lesions to be true cavernomas, which can even convert into other
radiological types [53]. In general, type I and II lesions are more common in symptomatic
patients, whereas types III and IV occur in both groups equally. Furthermore, type IV lesions
more often exist in multiple forms, especially with family history [37].
Figure 7 Left frontal cavernoma of type IV. a - T2*-GRE –image, b – T2-weighted image (a lesion is not visible)
a
b
23
In some disputable cases, diagnostic workup of cavernomas can be supplemented by Positron
Emission Tomography (PET). PET findings demonstrate normal or decreased uptake of
methionine and
11
11
C-
C-glucose, which is not the case in neoplasms where methionine uptake is
increased [86]. Unfortunately, the practical value of this method is limited by its low accessibility
in routine clinical practice.
Table 2 Grading of cavernomas according to MRI appearance as proposed by Zabramski et al.
Type
MRI features
Pathology features
I
T1: hyperintense core
Subacute hemorrhage
T2: hyper- or hypointense core
II
T1: reticulated mixed signal core
Lesions with thrombosis of varying ages
T2: reticulated mixed signal core with
surrounding hypointense rim
III
T1: iso- or hypointense
Chronic hemorrhage with hemosiderin staining
T2: hypointense lesion with hypointense
within and around lesion
rim magnifying size of lesion
IV
Tiny cavernoma or teleangiectasia
T1: not seen
T2: not seen
GRE: punctate hypointense lesion
Clinical aspects
Cavernomas can be diagnosed at any age, but are most common in individuals aged 20-50 years
[104, 321], with a peak at 30 years [167]. They occur in both genders with equal frequency [132].
Most patients present with a sporadic single lesion. Supratentorial lesions comprise 70-90% of all
locations [104, 218, 321]. Meanwhile, in 10-40% of cases cavernomas are familial, and thus,
often multiple [240, 254]. The natural course of cavernomas seems to be relatively benign. Fatal
outcome of the disease is very uncommon, occurring mostly in cases of huge lesions affecting
critical brain structures that disrupt after profuse bleeding. Usually, cavernomas are characterized
by three major clinical patterns – epileptic disorders, focal neurological deficits, and hemorrhage,
which can present separately or in different combinations.
Epileptic disorders
Seizures are the most frequent clinical presentation of supratentorial cavernomas, occurring in
41-80% of patients [14, 57, 71, 104, 167, 254, 256, 282]. The annual cumulative risk of new
24
seizures in this group is estimated to be 1.34-2.8% [71, 201]. It is not uncommon that seizures
occur after a cavernoma hemorrhage. Seizure incidence in patients suffering from AVM is 2040%, and from gliomas 10-30% which are only half of that in cavernoma patients [15, 16].
Cavernomas do not invade parenchyma and are not intrinsically epileptogenic; thus,
epileptogenicity is probably due to perifocal changes in the adjacent brain parenchyma. Typical
for cavernoma perifocal collection of blood breakdown products combined with inflammatory
alterations and gliotic changes seems to be an organic substrate of epileptogenicity in these
patients [14]. Iron ions have a role in producing free radicals and lipid peroxides, which affect
functioning of certain cell receptors [283, 333]. The subsequent cascade of changes includes a
marked increase in excitatory neurotransmitter amino acids [322]. Such activation has also been
discovered in electrophysiological studies, which have shown more than two times higher evoked
activity values in cavernoma-neighboring neurons than in cells around glial tumors. Furthermore,
there are different firing patterns in adjacent hippocampal tissue in cavernoma and glioma
patients [333].
Patients with cavernomas can present with any type of seizures. For unknown reasons,
cavernoma-associated seizures are more likely intractable than those related to other vascular
malformations [15, 16]. The variability of the seizure disorder may be related to the location of
the lesion, its size, history of hemorrhage, and patients’ age. For example, temporal lobe lesions
tend to cause seizures more frequently and have an obvious propensity to intractable epilepsy [14,
15]. Less favorable seizure outcome was noted in younger persons and women [57]. Long-lasting
epileptic disorders with high frequency of seizures in certain cases can lead to development of
secondary epileptogenic foci located in remote brain regions [14]. Notably, the risk of recurrent
seizures is 5.5% per patient-year [201].
The appearance of the epileptic syndrome in cavernoma patients is not included in the framework
of the “all-or-nothing” concept, as patients with supratentorial lesions can be asymptomatic until
hemorrhage or some environmental provocative factor triggers epileptic activity. Furthermore,
patients with a similar location, size, or radiological appearance of the lesion may have
completely different patterns of epilepsy. This variability is sharply emphasized in multiple
cavernoma patients, as any of the supratentorial lesions carries a potential risk of epileptogenicity
[15].
Focal neurological deficits
Appearance of focal neurological deficits in cavernoma patients is not uncommon when lesions
affect the motor cortex, speech areas, basal ganglia, brain stem and spinal cord. Accordingly,
patients present with sensorimotor deficits, dysphasia, and cranial nerve malfunctions in 35-50%
of cases [256, 282, 288]. Due to their relatively small size and slow growth, cavernomas
25
themselves rarely cause fast deterioration, even though patients complain of fluctuating
appearance of symptoms with frequent spontaneous relief and subsequent deterioration. Acute
decline usually occurs after a cavernoma hemorrhage into surrounding parenchyma, compressing
or destroying it.
Hemorrhage
Cavernomas have a well-known tendency to bleed. In some vary rare cases, hemorrhage can be
fatal, but it is usually well tolerated depending on the volume, nearness to critical structures,
patients’ age, and comorbidities. The term “cavernoma hemorrhage” in the literature is quite
confusing and depends on the interpretation of the radiological signs of the lesion on CT and
MRI when acute onset of the symptoms occurs. The presence of a thrombus may give a false
impression of acute bleeding in projection of the cavernoma. Hemorrhagic events occurring in
cavernoma patients are divided into two groups: intra- and extralesional bleeding [15]. An
intralesional (or encapsulated) hemorrhage is limited to the border of the lesion and causes
enlargement of the cavernoma. Probably, the surrounding hemosiderotic parenchyma, which is
strengthened by gliosis, takes a role in preventing the hemorrhage from spreading outside into
healthy parenchyma. This can lead to formation of a capsule, which behaves like a membrane of
a chronic subdural hematoma, osmotically attracting fluid and leading to enlargement of the
cavernoma. A weakened capsule compatible with hemodynamic stress is a possible factor
predisposing to more prominent bleeding that invades nearby brain areas [22, 288]. An
extralesional (or overt, gross) hemorrhage extends beyond the hemosiderotic ring and on MRI
shows signs of acute or subacute bleeding (Figure 4). This “true” intracerebral bleeding can cause
marked disruption of surrounding tissue and lead to permanent deficits depending on the location.
Both intra- and extralesional hemorrhages usually manifest with acute onset of headaches
accompanied by focal deficit or seizures.
In the pre-MRI era, within the framework of cryptic vascular malformations, cavernomas were
considered lesions with very high hemorrhage potential. Early series showed hemorrhage
incidence in cavernoma patients to be up to 65% [325, 335]. However, most of the studies were
influenced by significant patient selection bias and mixing of different pathological entities; as a
rule, patients were studied after acute symptoms and hemorrhage and could have even had an
AVM, which carries a higher risk of profuse hemorrhage than a cavernoma. In more recent
studies based on MRI findings with recruited asymptomatic patients, the extralesional
hemorrhage rate appears to be quite low, on average 1% per patient-year (range 0.25% - 2.5%)
[71, 160, 169, 235, 256, 343] (Table 3). In familial cases, bleeding rates may vary depending on
the cavernoma genotype. Notably, Denier et al. in 2006, found that CCM3 carriers are more
prone than CCM2 and CCM1 patients to develop cerebral hemorrhages, especially at a younger
26
age [73]. Furthermore, the authors showed that in patients with multiple cavernomas CCM1 was
associated with a higher number of lesions than CCM2 and CCM3. Thus, the overall risk of
hemorrhage in these patients is increased due to cumulative risks from each lesion.
Lesions of the infratentorial compartment and particularly the brain stem are characterized by
higher bleeding rates than their supratentorial counterparts, ranging from 2.46% to 5% per
patient-year [160, 166, 237]. Interestingly, larger lesion size (>1 cm), early age at presentation
(<35 years), and coexistence of DVA were found to be associated with higher hemorrhage rates
[166]. Nevertheless, the mechanisms of higher bleeding risk of cavernomas in infratentorial
compartment remain obscure.
Table 3 Reported symptomatic hemorrhage rates of cerebral cavernomas
First author, year
Annual hemorrhage rate
Study design
Reference
(%)
Del Curling, 1991
0.1
Retrospective
[71]
Robinson, 1991
0.7
Prospective
[256]
Zabramski, 1994
1.2
Prospective
[343]
Kondziolka, 1995
1.3
Retrospective
[160]
2.6
Prospective
0.6
For incidental lesion
Aiba, 1995
0-0.4
Prospective
[2]
Porter, 1999
5
Retrospective
[237]
Brain stem lesion
Labauge, 2000
2.5
Retrospective, familial forms
[169]
Kupersmith, 2001
2.46
Brain stem lesions
[166]
Labauge, 2001
4.3
Prospective, familial forms
[168]
After initial decline, caused by extralesional bleeding, many patients recover well, but some can
experience re-bleedings. The risk of having recurrent extralesional hemorrhage in this selected
group varies from 5.1% to 60% per patient-year [2, 91, 94, 160, 237]. Aiba et al. found that
younger women exhibited a higher incidence of re-bleeding, possibly caused by hormonal factors
[2]. Furthermore, lesions of the brain stem seem to be more prone to re-bleed. In contrast to
previous studies, Barker et al. proposed the concept of temporal clustering of the hemorrhages
27
after the initial event [19]. Using sophisticated statistical analysis in 141 patients, the authors
discovered quantitative evidence of a spontaneous decline in the hazard of cavernoma rehemorrhage approximately two years after the first hemorrhage.
Cavernoma hemorrhage can be provoked by using anticoagulant therapy [238]. With a general
trend towards population aging and ASO diseases on the rise, the number of cavernoma patients
who need to be treated by anticoagulants will most likely increase. Management of such patients
obviously requires special attention.
Headaches
Headaches have been associated with clinical appearance of a cavernoma in 25-30% of patients
[256, 282, 288]. Due to their unspecific nature, in most of the cases, headaches are actually not
connected to the cavernoma, but appear as a clinical sign of some other condition such as tension
neck syndrome or migraine. At the same time, headaches commonly accompany acute
extralesional hemorrhages particularly when the hemorrhage extends to the subarachnoid space
or ventricles. Large lesions compressing or obstructing CSF outflow pathways may cause
hydrocephalus with subsequent headache.
Treatment
Surgical series
No unequivocal strategy of treatment exists that can be applied to all cavernoma patients. Most of
these lesions do not belong to the subset of life-threatening neurovascular lesions. They rarely
cause severe permanent disability and otherwise exhibit a fairly nonaggressive natural history.
However, certain patients have appreciable risk of developing permanent deterioration due to
hemorrhage or chronic epilepsy.
Since the first report of successful surgical removal of a
cerebral cavernoma, which was published in 1890 [35], several papers on the treatment of the
cavernous have been published. One of the first reports that thoroughly discussed literature on the
topic was introduced by Voigt and Yasargil in 1976. They reviewed 164 published cases of
cerebral cavernomas adding their own case of a temporo-occipital medio-basal lesion [321]. The
authors found only 21 cases (12.8%) of successfully operated cerebral cavernomas. With the
advent of CT in clinical practice, the sizes of the published series have increased. One of the first
reports, based on CT findings, was published by Tagle et al. and included a series of 13 patients;
12 of them underwent surgery [293]. This report elucidated the effectiveness of surgical
treatment in terms of seizure outcome. The authors showed that drug resistant epilepsy in their
cavernoma patients could be successfully treated by surgical removal of the lesion; six of the
seven patients were seizure-free at the long-term follow-up. A larger series introduced by
28
Vaquero et al. consisted of 25 successfully operated patients [314]. In this series, 17 of 19
patients with preoperative epileptic disorders were seizure-free at follow-up, and the two
remaining patients had improved significantly, having only the occasional seizures. Poor outcome
was registered in those who had a cavernoma in the brain stem or spine. In a report by Yamasaki
et al. on 22 of 30 patients treated surgically, the authors concluded that easily accessible lesions
can be removed with favorable results, whereas incidental or asymptomatic cavernomas should
only be followed [335]. With widespread use of MRI in clinical practice, the number of
publications has increased. Furthermore, MRI has allowed reliable diagnosis of lesions located in
the brain stem, enabling more accurate planning of the surgical approach to this critical structure.
One of the first reports confirming the efficacy and safety of cavernoma removal from the brain
stem and basal ganglia was published in 1991 by Bertalanffy et al [30]. The authors presented
results on 26 operated patients with deep-seated cavernomas and emphasized the importance of a
proper operative approach, careful dissection, and complete removal of the malformation to gain
a satisfactory postoperative outcome. The authors further stressed the importance of proper
selection of patients with deep-seated cavernomas located in eloquent structures that have bled or
caused sustained neurological deficits, as they have the highest morbidity after surgical
intervention [29]. In a meta-analysis by Fritschi et al. consisting of 139 patients with surgically
treated brain stem cavernomas at the follow-up, 83.9% had no or only mild neurological deficit,
15% were moderately disabled, and none had died, whereas among the conservatively managed
patients 66.6% had no or only slight neurological deficit, 6.7% were moderately disabled, 6.7%
were completely dependent, and 20% had died [94]. Most of the patients who died or had severe
disability suffered from gross extralesional hemorrhage and/or growth of the lesion. In 2003,
Wang et al. reported their experience on 137 patients with brain stem cavernomas [327]. Surgical
treatment improved the condition of 99 patients (72.3%) and none had died. To date this is the
largest published series on brain stem cavernomas.
The series of Oliveira et al. on cerebellum cavernomas showed that they are larger (median size
4.6 cm) on average being twice as larger as supratentorial cavernomas [70]. All patients included
in the study (n=10) had good or exelent long-term postoperative outcome.
The results after microsurgical removal of cavernomas in the basal ganglia and thalamus were
analyzed by Gross et al. who reviewed 103 reported cases at this location [113]; 89% were
completely removed, with a morbidity of 10% and a mortality of 1.9%.
Accumulating data on the microsurgical treatment of deep-seated cavernomas have been summed
up in several systematic reviews of extensive patient series. In 2009, Gross et al. published their
meta-analysis of 78 studies on 745 brain stem cavernoma patients; 683 (92%) had the lesion
completely removed [112]. At the postoperative follow-up, 85% of patients were reported to be
improved or the same. The surgical mortality rate was 1.9%. Half of the patients with incomplete
29
resection experienced re-bleeding, four of them being fatal.
Surgery on supratentorial cavernomas is mainly indicated when a patient has intractable epilepsy.
The goal of the operative treatment in these patients is to alleviate the epilepsy and eliminate any
future risks of hemorrhagic events. However, to achieve favorable seizure outcome, some
patients may just be observed and treated with proper antiepileptic drugs. This approach was
reported to be effective in 60% of cases in a small series of 16 patients [52]. Larger studies, by
contrast, have confirmed more favorable seizure outcome after cavernoma resection. Ferroli et al.
analyzed a series of 163 patients with epileptogenic cavernoma who underwent lesionectomy and
reported that 132 patients (81%) attained complete seizure control [90]. Longer history of
seizures was associated with worse outcome, and 17.1% of the patients remained unchanged
despite surgery. Cohen et al. analyzed 51 patients with at least one preoperative seizure. All
patients with a single seizure before surgery were seizure-free, as were also patients who had
developed seizures within two months before surgery [57]. Only 76% of those patients who had a
preoperative duration of epilepsy exceeding two months were seizure-free at follow-up.
Furthermore, younger patients had low rates of favorable seizure.
In a multicenter study of seizure outcome, Baumann et al. reviewed 168 consecutive patients
collected from seven clinics with inclusion criteria as follows: a) epilepsy before surgery with
more than three seizures; b) cavernomas surgically treated by microsurgical technique; and c)
follow-up
12 months [25]. In concordance with previous studies, the authors discovered that
patients older than 30 years at operation have better chances for a favorable seizure outcome than
younger persons. Conversely, duration of the epilepsy was not associated with seizure outcome.
Interestingly, two years postsurgery the patients with larger lesions (>1.5 cm) had worse seizure
outcome, but at three years this difference had disappeared. Patients with secondary generalized
seizures preoperatively were significantly less likely to achieve a seizure-free state than those
with simple partial and complex partial seizures (26% vs. 65% and 52%, respectively). A high
rate of preoperative seizures was not associated with better outcome.
Removal of a cavernoma in patients with intractable epilepsy should be assessed in the context of
epilepsy surgery, implying indications for tailored surgery of the epileptogenic brain tissue.
Failure to control epilepsy after an operation can be linked to incomplete resection and/or the
persistence of a hemosiderin fringe or the development of secondary epileptogenic foci in areas
remote from the primarily lesion [23]. Lesions close to limbic structures are at higher risk of
forming distant loci that with time may “learn” to generate seizures independently [14]. Still, no
uniform policy regarding additional resection has been suggested in the literature. Among the
rare reports, Paolini et al. demonstrated successful results after tailored resection of temporal
cavernomas causing intractable epilepsy in six of seven of their patients [223]. Undoubtedly,
selection of patients for additional resection requires thorough preoperative evaluation with
30
performance of EEG and video-EEG, magnetoencephalography (MEG) or PET, and WADA-test
with the purpose of lateralizing memory functions. Activity of the secondary foci tends to fade
away after resection of the epileptogenic cavernoma and they should only be removed if resection
of the cavernoma, combined with use of AED fails to attain seizure control [14, 23].
The goal of the operative treatment of a cavernoma is gross total resection. Partial removal can
significantly increase the risk of bleeding with consequent complications. Total removal of the
lesion requires dissection of the lesion from the surrounding brain. Thus, if the cavernoma is
located within or beside critical structures of the brain (e.g. brain stem, basal ganglia, motor
cortex, speech areas), any manipulation can cause mechanical or ischemic damage with
concomitant dysfunctions of the affected centers. Use of the operating microscope and
microsurgical instruments is essential in cavernoma removal. Preoperative planning and mapping
of eloquent areas adjacent to the cavernoma are the most important part of the surgery, as any
inaccuracy in direction of approach can lead to significant difficulties in finding small lesions
within parenchyma. The most precise method is to combine knowledge of anatomical landmarks
in the affected region and use of stereotactic navigation (frame-based or frameless). Importantly,
despite seemingly correct calculations, a neurosurgeon can become lost and fail to find a lesion.
The deeper the lesion sits in the white matter, the higher the risk.
When analyzing MR-images preoperatively, several important anatomical landmarks should be
recognized and, thereafter, used in planning of the surgical trajectory. Among these are - coronal
and sagittal suture, external auditory meatus, nasion, and inion, as well as such intracranial
structures as Sylvian fissure, sulcal and gyral key points (e.g. central sulcus and precentral gyrus),
superior sagittal venous sinus, transversal sinus, prominent superficial veins (vein of Troland and
vein of Labbe), and torcular Herophilii. The first group helps to delineate the approximate
location of the lesion and extrapolate it to the surface of the skull for appropriate craniotomy. The
second group facilitates orientating after dural opening. Functional MRI and diffusion tensor
imaging (DTI) are invaluable in mapping the eloquent cortex and neural tracts, respectively. CTor MRI-navigated craniotomy is a major adjunct that can aid in intraoperative localization [279].
However, intraoperative brain shift after craniotomy and CSF removal may significantly decrease
the accuracy of the navigation system [78, 255]. In these cases, real-time ultrasonography,
especially in conjunction with neuronavigation, is particularly useful for lesions that show no
surface extensions [46, 165, 311, 323]. Due to achievements in radiological diagnostics and
mapping, awake-craniotomy is not necessary.
After craniotomy and dural opening, dissection of the cortex is performed through the overlying
gyrus or sulcus. The transsulcal approach has been suggested to minimize cortical damage and to
31
expose the lesion in a “keyhole” fashion [69, 124]. Because the cortex is thicker over the crest of
a convolution and thinner at the depth of a sulcus, the transgyral approach sacrifices a larger
number of neurons than the transsulcal approach [249]. However, disruption of the arcuate Ufibers during transsulcal exposure is not proven to be less detrimental than disruption of vertical
projection fibers after the transgyral approach [124, 249, 279]. Meticulous dissection of the
arachnoid with sufficiently long preparation of the vessels crossing or lying within the sulcus is
crucial to avoid their over-traction, stretching, or kinking, with subsequent ischemic injury to the
adjacent or remote cortex. When a patient is operated on soon after overt bleeding, entry to the
hematoma provides an initial route to the lesion. Otherwise, appearance of yellowish
discoloration indicates an underlying cavernoma. When the lesion is approached, the gliotic plane
is identified and circumferential dissection around the lesion is performed until it is free [319]. En
bloc resection is recommended, although removal in piece-meal fashion is also suitable since
cavernomas do not tend to cause any major intraoperative bleeding [279]. Dural-based
cavernomas in the middle fossa are an exception: they may cause profuse bleeding during
resection and therefore require careful handling in terms of avoiding damage to the integrity of
the nidus [319]. The resection bed should be carefully inspected under high magnification for
small satellite lesions [319]. Gliotic fringe discolored by blood breakdown products should be
removed only when a lesion is located out of eloquent areas. The extent of resection of perifocal
hemosiderotic parenchyma still remains controversial for cure or prophylaxis of epileptic
disorder. Casazza et al. and Zevgaridis et al. failed to find any correlation of extended resection
of the perilesional parenchyma with better seizure outcome, whereas the more recent studies by
Hammen et al. and Baumann et al. confirmed its efficacy during long-term follow-up [24, 25, 44,
122, 347]. After removal of the perifocal parenchyma, precise hemostasis is performed using
bipolar coagulation with minimal voltage to avoid inadvertent injury to normal vasculature.
Cavernomas of the brain stem represent one of the most challenging neurosurgical pathologies
requiring thorough knowledge of the functional anatomy of the region and superior dexterity of
the operating surgeon. The decision to perform surgical removal in these patients is mainly based
on the number of previous hemorrhages, neurological status, and precise localisation of the lesion
with regard to the fourth ventricle or CSF cisterns [267]. Traversing of even a very thin fringe of
healthy tissue between the lesion and brain stem surface during the approach may lead to
devastating deficits. Risk of postoperative deterioration may be similar to having an overt
hemorrhage from cavernoma [236]. A more favorable outcome is expected when a cavernoma
extends to the pial surface and myelotomy is not necessary or only minimal [236]. Summarizing
their recent experience of brain stem cavernoma surgery, Garrett and Spetzler recommended a
supracerebellar infratentorial or lateral supracerebellar infratentorial approach for lesions
involving the posterior or posterolateral midbrain [99]. To access lesions involving the anterior or
32
anterolateral midbrain, a full or modified orbitozygomatic craniotomy is recommended [99, 177,
342]. Lateral and anterolateral pontine lesions may be safely reached using the retrosigmoid
approach. A safe entry zone, located between the fifth cranial nerve and the corticospinal tracts
provides a reasonable pathway to the lesion of the anterior pons. A posterior pontine and
posterior medullary cavernoma abutting the floor of the fourth ventricle is best approached via a
suboccipital craniotomy, whereas lateral and anterolateral medullary lesions are reached using a
far-lateral suboccipital approach [99].
Use of neurophysiologic intraoperative monitoring (IOM) during brain stem surgery is widely
accepted as a remarkable adjunct to minimize surgical complications and improve outcome [112,
207, 236]. Brainstem auditory evoked potentials (BAEP), somatosensory evoked potentials,
mapping of cranial nerve nuclei, free-running electromyography, and muscle motor evoked
potentials are a neurosurgeon’s armamentarium to identify motor and sensory tracts and cranial
nerve nuclei [83, 236, 262]. When a cavernoma is large and/or hemorrhage causes significant
mass-effect with displacement of the tracts and nuclei, superficial anatomical landmarks, such as
the facial colliculus or the stria medullaris, are not concordant with the presumed location of
intrinsic structures [203]. In these situations, IOM is needed since it allows with a high degree of
probability identification of the safest entry point to the brain stem and avoids disintegration of
the tracts and nuclei. However, in rare cases, false-positive and false-negative responses are
observed, and the correlation between IOM and postoperative outcome may not be totally
accurate [77, 103, 262].
Radiotherapy
In several reports, patients with higher surgical risks were considered for treatment with
stereotactic radiosurgery (SR) [6, 47, 133, 134, 161, 179, 184]. The mechanism of response to
radiosurgery is thought to be a chronic inflammatory process, including endothelial cell
proliferation, vessel wall hyalinization and thickening, and eventual luminal closure with a
latency interval ranging from two to three years [161]. Mainly, SR is performed on patients with
cavernomas located in the brain stem, basal ganglia or highly eloquent cortex. Minimal
invasiveness and short hospitalization time allow SR to be performed on patients of every age
group, regardless of general condition and comorbidities. In 2010, Lunsford et al. published their
pioneering experience on 103 patients who were estimated to have a high risk of resection and
were treated with SR between 1988 and 2005 [184]. The authors reported a convincing reduction
of hemorrhage rate from 32.5% to 1.06% in two years after SR. They emphasize the role of
proper selection of patients suitable for SR of cavernomas located in high-surgical-risk areas. In
analyzing the effect of SR on epileptic activity, Hsu et al. demonstrated that 13 of 14 patients
(92.8%) had favorable seizure outcome after the procedure [133]. However, Shih and Pan had
33
provided both SR and microsurgery to 30 patients suffering from epilepsy and discovered a
significant advantage of surgical removal in terms of epilepsy treatment; 79% of surgically
treated patients were seizure-free, whereas only 25% of patients after SR showed the same
outcome [281]. Pham et al. conducted an extensive literature review of SR treatment of
cavernomas and found that of the 291 patients in the 16 studies, 66% had favorable seizure
outcome (31% were seizure-free, and 36% had reduced of seizure rate), while 11 patients (3.8%)
experienced worsening of epilepsy [231]. Sex, age, and duration of epilepsy had no prognostic
value, whereas extratemporal location and history of only simple partial seizures was related to
better seizure outcome. Summarizing their results, the authors noted at least a 25% response rate
to SR, demonstrating a potentially true effect on epileptic activity as an alternative to surgery
[231].
Despite the above-mentioned advantages, the efficacy of SR over the long term is debatable. An
irradiated cavernoma still remains in the brain, and in contrast to AVMs, the effect of SR on
intralumenal blood flow cannot be objectively confirmed by any reliable radiological
investigation. Furthermore, morbidity rates range from 2.5% to 59% and mortality ranges from
0% to 8.3% [231]. Radiation-induced complications include edema, necrosis, increased seizure
frequency, and recurrent bleeding [4, 133, 294]. Expectedly, greater dosimetry is associated with
a higher risk of complications [231]. Location in the brain stem seems to be unfavorable in terms
of radiation-induced complications; among 82 patients treated with SR, Hasegawa et al.
described complications only for lesions located in the brain stem [127]. The overall rate of
complications reported in the literature for brain stem cavernoma SR ranges from 8% to 18% [82,
178, 231]. The underlying mechanisms explaining development of adverse radiation effects
(ARE) with clinical deterioration are not fully understood. Hypothetically, AREs are related to
radiation dose delivered to the brain tissue immediately surrounding the cavernoma, which may
be more likely to release vasoactive cytokines from an iron-impregnated gliotic brain [184]. Of
note, AREs occur in cavernoma patients at a seven times higher rate than in AVM patients [148,
234]. Summarizing their experience on the SR of cavernomas, Karlsson et al. concluded that only
some protection against hemorrhage after SR is not sufficient to accept the high risk for radiationinduced damage of the brain [148]. Furthermore, in 2006, Shahid et al. conducted a literature
review on de novo formation of cavernomas after radiation therapy and found 76 patients – most
of them children - with different pathologies of the CNS who developed de novo cavernomas
[209]. The mean latency period was 8.9 years and the mean radiation dose 60.45 Gy. Although
radiation dosage during SR is usually lower (mean maximal dose range 18 – 50 Gy [231]), de
novo cavernomas appearance is plausible in terms of additional risks in delayed postradiation
period, especially in younger patients.
34
Uncommon cavernomas
Several subsets of cavernomas occur rarely, and literature on the topic is thus scarce. Many
questions regarding these entities still have no answers or are under debate. To date, there is no
explanation in the literature why cavernomas are commonly located supratentorially, accounting
for 70% of all lesions, but affect the spine very rarely. Furthermore, what limits the size of the
lesion and why gigantic lesions are extremely rare are not fully understood. The growing number
of patients with incidentally found lesions tends to increase the number of patients with lesions
previously considered rare. A clearer understanding of the basic pathological features and
treatment results of these cases is essential when making clinical decisions and planning
management adequately. Among unusual cavernomas treated at our department, we analyzed
intraventricular, multiple and spinal cavernomas; we supplemented these with a literature review.
Intraventricular Cavernomas
Intraventricular cavernomas constitute 2.5 - 10.8% of cerebral cavernomas [180, 282, 321]. The
first report of IVC was introduced in 1905 by Finkelburg [92], and so far, altogether 77 cases
have been published excluding our series (Table 4). The mean age of these patients was 35.5
years (range 2 days – 73 years). Twenty-one patients (27.3%) were younger than 18 years and
only two patients (2.6%) were older than 65 years. The female : male ratio was 1.4: 1 (Table 5).
In 38 patients (49%), IVC was located in the lateral ventricle, in seven patients (9%) in the fourth
ventricle, and in 32 patients (42%) in the third ventricle.
The histological origin of IVC still remains obscure. Chadduck et al. hypothesized that IVCs
have subependymal origin and grow inside the ventricle [45]. Kumar et al. noted in their three
cases of IVC that lesions were adherent to the ependyma only in some areas and connected this
appearance to repeated hemorrhages, organization, and gliosis [164]. In contrast, Nieto et al.
confirmed during surgery on their patients with ICV that cavernomas were independent, not
attached to the ependymal layer and without prominent feeding arteries and draining veins [208].
The course of IVCs seems to be relatively benign but their natural history is different from
intraparenchymal lesions. This could be explained be the fact that the surrounding CSF allows to
increase in size of the cavernoma without restrictions from the parenchyma [208]. Histological
profile of the IVC seems to be similar to intraparenchymal cavernomas confirming the role of
environmental factors affecting natural history of the IVC.
35
Table 4 Published series on IVCs
Case
Sex
Age,yrs
First author
Year
Location
Treatment
Outcome
1
M
2
Finkelnburg [92]
1905
fourth ventricle
partial resectiol
died
2
M
31
Dandy[66]
1928
fourth ventricle
total removal
improved
3
F
16
Merritt[198]
1940
lat.ventricle
total removal
comatose
4
M
2d
Arnstein[12]
1951
lat.ventricle
no surgery
died
5
F
68
Latterman[173]
1952
third ventricle
no surgery
died
6
F
33
Schneider[276]
1958
lat.ventricle
total removal
homonymous
hemianopsia
7
M
15
Jain[139]
1966
lat.ventricle
total removal
improved
8
F
36
Coin[58]
1977
lat. ventricle
total removal
hemianopia
9
M
43
Numaguchi[212]
1977
lat.ventricle
total removal
hemiplegia
and hemianopia
10
M
27
Giombini[104]
1978
fourth ventricle
partial resection
died
11
F
29
Terao[300]
1979
fourth ventricle
total removal
improved
12
nd
56
Pau[226]
1979
lat.ventricle
no surgery
died
13
F
45
Namba[206]
1979
lat.ventricle
partial resection
improved
14
F
18
Vaquero[315]
1980
third ventricle
total removal
improved
15
F
31
Pozzati[241]
1981
third ventricle
total removal
improved
16
F
8ds
Iwasa[138]
1983
lat.ventricle
total removal
improved
17
F
60
Kendall[152]
1983
fourth ventricle
partial resection
recurrence of
18
F
48
Lavyne[174]
1983
third ventricle
partial resection
hydrocephalus,
19
M
40
Amagasa[5]
1984
third ventricle
total removal
improved
20
F
44
Harbough[123]
1984
third ventricle
total removal
improved
21
F
21
Chadduck[45]
1985
lat.ventricle
total removal
hemianopia
22
F
29
Chadduck[45]
1985
lat.ventricle
total removal
improved
23
F
4mo
Chadduck[45]
1985
lat.ventricle
total removal
improved
24
M
22
Simard[282]
1986
lat.ventricle
not registered
not registered
25
F
13
Simard[282]
1986
lat.ventricle
not registered
not registered
26
M
73
Yamasaki[335]
1986
lat.ventricle
total removal
improved
symptoms
bleeding
27
M
9
Yamasaki[335]
1986
third ventricle
partial resection
improved
28
M
36
Yamasaki[335]
1986
third ventricle
total removal
improved
29
M
47
Yamasaki[335]
1986
fourth ventricle
total removal
improved
30
M
40
Suzuki[292]
1988
lat.ventricle
total removal
improved
31
M
9mo
Sabatier[261]
1989
lat.ventricle
no surgery
cerebellar
32
F
19
Voci[320]
1989
third ventricle
total removal
improved
33
M
16
Ogawa[213]
1990
third ventricle
total removal, shunt
improved
34
M
40
Ogawa[213]
1990
third ventricle
total removal
transient diabetes
dysfunction
insipidus,
hemianopia
35
F
62
Andoh[8]
1990
lat.ventricle
total removal
homonymous
quadrantanopsia
(continued)
36
Table 4 Published series on IVCs (continued)
36
M
33
Tatagiba[297]
1991
lat.ventricle
total removal
improved
37
M
35
Tatagiba[297]
1991
lat.ventricle
total removal
died
38
F
24
Tatagiba[297]
1991
lat.ventricle
total removal
improved
39
F
44
Itoh[137]
1991
fourth ventricle
total removal
improved
40
F
3
Miyagi[200]
1993
lat.ventricle
total removal
mild hemiparesis
41
F
39
Lynch[185]
1994
lat.ventricle
partial resection
improved
42
M
5
Lynch[185]
1994
lat.ventricle
partial resection
improved
43
F
10
Lynch[185]
1994
lat.ventricle
total removal
improved
44
F
9
Katayama[149]
1994
third ventricle
partial resection, shunt
died
45
F
50
Katayama[149]
1994
third ventricle
not registered
not registered
46
F
45
Katayama[149]
1994
third ventricle
not registered
not registered
47
M
49
Katayama[149]
1994
third ventricle
not registered
not registered
48
F
47
Katayama[149]
1994
third ventricle
total removal
transient diabetes
insipidus
49
F
43
Sinson[285]
1995
third ventricle
total removal
died
50
F
36
Sinson[285]
1995
third ventricle
total removal
hemiparesis,
hypothyroidism,
hydrocephalus
51
F
52
Sinson[285]
1995
third ventricle
total removal
improved
52
F
32
Sinson[285]
1995
third ventricle
total removal, shunt
improved
53
M
2ds
Hashimoto[129]
1997
lat.ventricle
total removal, vp-shunt
mild mental
retardation
54
M
64
Kaim[146]
1997
third ventricle
total removal
not registered
55
F
44
Gaab[98]
1999
lat.ventricle
total removal
permanent
memory loss
56
F
16
Reyns[247]
1999
lat. ventricle
total removal
improved
57
M
36
Reyns[247]
1999
lat.ventricle
total removal
right
58
M
42
Reyns[247]
1999
third ventricle
partial resection
improved
59
F
15
Fagundes-Pereyra[87]
2000
lat.ventricle
total removal
improved
60
F
36
Suess[290]
2002
third ventricle
total removal
improved
61
M
38
Crivelli[62]
2002
third ventricle
total removal
improved
62
F
11
Nieto[208]
2003
lat.ventricle
total removal
homonymous
hemihypertonia
hemianopsia
63
F
17
Tatsui[298]
2003
lat.ventricle
total removal
improved
64
M
52
Tatsui[298]
2003
lat.ventricle
total removal
improved
65
F
62
Wang[328]
2003
third ventricle
total removal
improved
66
F
45
Andersson[7]
2003
septum
total removal
improved
67
F
47
Darwish[68]
2005
third ventricle
total removal,shunt
improved
68
M
56
Milenkovic[198]
2005
third ventricle
total removal
improved
69
F
51
Chen[50]
2006
third ventricle
total removal
improved
pellusidum,
lat.ventricle
70
M
8
Kumar[164]
2006
lat.ventricle trigonum
total removal
improved
71
F
19
Kumar[164]
2006
total removal
improved,
seizures
72
M
20
Kumar[164]
2006
total removal
improved
73
M
35
Longatti [181]
2006
third ventricle
total removal
improved
(continued)
37
Table 4 Published series on IVCs (continued)
74
M
8
75
F
47
76
M
25
77
nd
56
Zakaria[344]
2006
third ventricle
total removal
improved
Sato[273]
2006
third ventricle
total removal
improved
Gonzalez-Darder [108]
2007
lat. ventricle, trigone
total removal
improved
Prat [242]
2008
third ventricle
total removal
improved
Katayama et al. reviewed 14 cases of IVC of the third ventricle and found that IVC at this
location are prone to rapid growth [149]. Furthermore, authors noted that incomplete surgical
remove can exacerbate extensive growth after long period of being stable [5, 213, 335]. Surgical
or autopsy findings suggested that such growth may be attributable to repeated intralesional
hemorrhages rather than to confluence of vascular channels [213]. Almost all patients with IVC
had experienced intermitting headaches, which may be related to repetitive intralesional
hemorrhages with consequent enlargement and rising of intracranial pressure.
IVCs frequently cause symptoms due to their mass-effect, which is more prominent in the third
ventricle. Hydrocephalus in these patients is not uncommon. The majority of patients with IVC
who have had a third ventricle lesion developed hydrocephalus because of mechanical
obstruction, and only three patients [123, 149, 320] showed no signs of raised intracranial
pressure suffering only from intraventricular hemorrhage (IVH).
Table 5 Baseline data on reported cases of
Characteristics
M:F ratio
Location
lateral ventricle
fourth ventricle
third ventricle
Clinical presentation
IVH
Mass-effect
Seizures
Incidental
Treatment modality
Surgical removal
Conservative
Not defined
Outcome
Improved
Persistent deficit
Died
Not defined
No. of patients
(%)
IVCs
1:1.4
38 (49)
7 (9)
32 (42)
Lesions of this location could cause memory
loss, behavioral alterations such as depression,
and endocrinological disorders such as diabetes
11 (14)
53 (69)
11 (14)
2 (3)
68 (88)
4 (5)
5 (7)
mellitus, sexual dysfunction, and Morgagni’s
syndrome (frontal hyperostosis accompanied by
hirsutism and obesity) [149, 173, 174, 213,
241], whereas seizures are very uncommon,
occurring in only one reported case [149].
45 (58)
18 (24)
8 (10)
6 (8)
Clinical manifestations are related to the
location within the third ventricle. Lesions in
the suprachiasmatic region tend to cause visual
field restriction or endocrine dysfunction,
38
whereas cavernomas involving the lateral wall or floor of the ventricle can affect short-term
memory functions [181]. There are observations showing enlargement of cavernomas during
pregnancy and shrinkage after delivery [335, 345]. Some authors believe that cavernomas in the
third ventricle could be under stronger hormonal influences because of their location [149], but
no data exist to confirm this.
The location of a cavernoma in the lateral ventricle is also frequently associated with raised
intracranial pressure. In 22 of 38 cases (58%) with lateral ventricle cavernomas reported in the
literature, patients suffered from mass-effect and hydrocephalus as leading symptoms. Ten
patients (13%) with this location had seizure history. The nature of the seizure activity of lateral
ventricle IVCs is not described in the literature. Unlike intraparenchymal lesions, due to their
location inside the ventricle IVCs do not extensively affect parenchyma with abundant
hemosiderosis (Figure 8). However, Tatagiba et al. noted that subependymal origin of the IVCs
seems to corroborate with epileptogenicity, as they affect parenchyma not only by mass-effect
but also by their local irritating influence on parenchyma [297]. By contrast, Nieto et al. claim
that IVCs in the trigonum, thus potentially irritating the hippocampus, should cause a higher
incidence of seizures, which is not supported by clinical evidence [208].
Figure 8 Coronal view of a lateral ventricle cavernoma.
No extensive hemosiderosis can be seen (arrow)
The least common location of IVCs was
reported to be the fourth ventricle, with only
seven cases published [66, 92, 104, 137, 152,
300, 335]. In six patients (85.7%), cavernomas
caused mass-effect. These patients suffered
from sensorimotor paresis in the extremities
[66], drop attacks [104], diplopia and ataxia
[152, 335], and dysartria [137]. All patients
with
fourth
ventricle
lesions
experienced
intermittent headaches frequently accompanied by nausea and vomiting.
In total, 11 of 77 patients (14%) with IVC presented with intraventricular hemorrhage (IVH)
(Table 5). In three cases (27.3%), IVH occurred from an IVC located in the third ventricle [123,
149, 320], in six patients (54.5%) from an IVC located in the lateral ventricle [200, 206, 226,
261, 297], and in two patients (18.2%) from an IVC located in the fourth ventricle [137, 300].
The annual rate of hemorrhage from IVCs is not precisely known due to limited data in small
series. Typically, IVH was accompanied by severe headaches, frequently leading to
39
hospitalization. In some cases, hemorrhages recurred until the lesion was removed [300].
Usually, IVH was tolerated well and caused no disastrous consequences. However, in one case, a
lesion located in the temporal horn of the lateral ventricle caused severe intraventricular bleeding
and intracerebral hematoma [226]. This was the only patient who died after extralesional
hemorrhage from IVC.
Radiology
On CT images, IVCs present with moderate hyperintensity showing mild contrast enhancement
and moderate signs of mass-effect [50]. In patients with acute onset of symptoms, CT scan is
mandatory because of its high sensitivity in detecting fresh hemorrhages. In acute intraventricular
bleeding, however, the radiological diagnosis of the IVC is unreliable, and MRI is more
informative later after resorption of extravasated blood. The typical appearance on MRI is with a
heterogeneous core, reflecting different stages of thrombus organization, but a perifocal
hypointensive rim representing hemosiderosis is frequently absent. However, in lesions with
subependymal origin, a hemosiderotic fringe could be detected [146]. Edema surrounding the
IVC is unusual and, if present, mild [50]. Due to the rarity of the disease, a radiological
misdiagnosing of IVC is not uncommon. An IVC can be interpreted as an intraventricular choroid
plexus papilloma, a trigonum meningeoma, or an ependymoma (Table 6). IVCs do not increase
CSF secretion per se, which may be useful in the differential diagnostics of CSF-secreting
choroid plexus papillomas in a similar location [208]. Furthermore, IVCs have a reported
tendency to rapid growth [149], which should be taken into account when differentiating the IVC
from benign trigonum meningeomas, which are typically slow-growing tumors. Intraventricular
ependymomas usually occur in children, whereas IVCs are more typical in adults [297].
Table 6 Differential diagnostics of IVCs
Third Ventricle
Lateral Ventricle
Fourth Ventricle
low-grade and high-grade gliomas
low-grade and high-grade
gliomas
ependymoma
medulloblastoma
subependymal giant cell astrocytoma
subependymal giant cell astrocytoma
pilocytic astrocytoma
central neurocytoma
choroid plexus papilloma (carcinoma)
meningeoma
choroid plexus papilloma
(carcinoma)
metastases
meningeoma
colloid cyst
papillary craniopharyngeoma
metastases
metastases
40
Treatment and operative techniques
The lack of thorough prospective series and long-term follow-up studies makes decision-making
in the treatment of IVCs difficult. Surgery is advocated when re-hemorrhages are frequent, and
the mass-effect causes progressive neurological deficits. When estimating the operative risks, the
location of IVCs is of major importance. Surgery on the IVC in the lateral and third ventricle is
safer than in the fourth ventricle. In cases of acute hydrocephalus, temporary external ventricular
drainage was usually applied before surgical excision of the lesion, and in five reported cases
(6%) a permanent shunt was indicated [68, 128, 149, 213, 285]. In this group, the cavernoma was
in the third ventricle in four patients, and one newborn had a giant lesion in the lateral ventricle.
Patients with cavernomas close to the brain stem frequently present with cranial nerve deficits.
Thus, surgery on this already affected region can worsen neurological status and cause new
deficits, even after minimal manipulation. However, these deficits have significant recovery
potential, and many of them improve after a long recovery period [267].
Removal of a cavernoma located in the lateral ventricle may be performed via several
approaches, but all through the parenchyma (Table 7). D’Angelo et al. performed a thorough
analysis of transcortical and interhemispheric approaches for lesions in the lateral ventricles and
they found that an irreversible visual field deficit occurred after surgery in one of 14 patients after
a transtemporal approach and in one of seven patients after a transparietal approach [67].
Furthermore, in anatomic investigation of the optic radiation in relation to the operative route to
lesions of the trigonum, some authors recommend an interhemispheric parieto-occipital approach
with a mesial entry point located anterior to the calcarine and parieto-occipital sulci and posterior
and inferior to the parietal lobule [187]. By using the suggested corticotomy, the authors avoided
any disruption of the optic radiation. In the series of D’Angelo et al., two of four patients
operated on with an interhemispheric posterior transcallosal approach developed transient
mutism. However, neuropsychological tests assessing attention, verbal memory, and
disconnection showed no correlation with any of the surgical approaches. Instead, there were
correlations with preoperative clinical condition and a presumably longer or chronic history of
hydrocephalus [67]. Among drawbacks associated with transcortical approaches, the most
common appear to be postoperative seizures and intracerebral hemorrhage. The reported risk of
postoperative seizures after transcortical approaches ranges from 29% to 70%, whereas the
respective figure after transcallosal approaches is only up to 10% [13, 26, 151, 172, 352]. Among
IVC patients, we found no cases with postoperative seizures but two patients had developed a
postoperative hydrocephalus [174, 285].
IVC in the third ventricle can be exposed via different approaches tailored to the site of the lesion
inside the ventricle. Lesions located in the region of the foramen Monroe and anterior third of the
41
ventricle are exposed using an anterior interhemispheric transcallosal approach, a pterional
transsylvian approach [336], or alternatively, a transchoroidal transvelum interpositum or
interforniceal approach [11]. The latter two modifications carry additional risks of transient
memory loss and hemiparesis due to the manipulation and possible damage to the fornix or
Table 7 Surgical approaches to IVCs
Location
Approach
Reference
anteroinferior or anterosuperior transcallosal
transcortical through the middle frontal gyrus
[13, 26, 275]
Lateral venticle
Frontal horn and ventricle body
Trigonum, occipital and temporal
horn
Third ventricle
Anterior third and foramen Monroe
Mid-third
Posterior third
Fourth ventricle
- transcortical through superior parietal gyrus
- transcortical through parieto-occipital fissure
- interhemispheric parieto-occipital parasplenial
- occipital interhemispheric transsplenial
-transcortical-transtemporal through the middle and
inferior temporal gyri
- transoccipitotemporal approach
[106, 228,
243, 248,
279, 301,
336, 338]
- anterior interhemispheric transcallosal
- pterional transsylvian
- transchoroidal transvelum interpositum
- interforniceal aproaches
- interhemispheric translamina terminalis
[11, 213,
336, 340]
- subchoroidal transvelum interpositum
- interhemispheric transcallosal
- pterional transsylvian
- median or paramedian supracerebellar suboccipital
- posterior parieto-occipital interhemispheric
- median inferior suboccipital craniotomy
- through cerebello-medullary fissure (telovelar)
- transvermian
[174, 336]
[336]
[137, 336]
thalamostriate vein [11, 336]. Lavyne and Patterson accessed a lesion in the mid-third ventricle
via a subchoroidal transvelum interpositum approach, but only partial resection could be
accomplished and this patient experienced postoperative bleeding [174]. Yoshimoto and Suzuki
excised cavernomas of the suprachiasmatic compartment via an interhemispheric trans-laminaterminalis approach [340]. The same approach was successfully employed for removal of
foramen Monroe cavernomas by Ogawa et al. [213]. A lesion located in the posterior third of the
ventricle is accessed via a median or paramedian supracerebellar suboccipital approach or a
42
posterior parieto-occipital interhemispheric approach [336].
Exposure of the fourth ventricle is usually performed via median inferior suboccipital approach.
After craniotomy and dural opening, the fourth ventricle is accessed using a transvermian or
cerebello-medullary fissure (telovelar) approach [336]. The latter is preferable as division of the
vermis can be associated with cerebellar mutism, especially in children [233].
Itoh et al.
performed an incision of the posterior part of the vermis and observed ataxia in the immediate
postoperative period, but after one month all symptoms resolved fully [137].
Neuroendoscopy
To date, only one case of a successful removal of an intraventricular cavernoma by endoscopy
has been reported [98]. The role of neuroendoscopy in treatment of IVC seems to be secondary to
microsurgery, as in the literature gross total resection of the IVC using endoscopic techniques is
significantly limited by ventricle wall collapse, possible bleeding, or ineffectiveness of resection
in a piece-meal fashion due to the very firm consistency of the lesion and the narrowness of the
device’s working channel [98, 242, 273].
Outcome
In the published data, altogether 68 patients (88%) of the 77 patients with IVC were operated on,
and 45 patients (58%) improved whereas 18 patients (24%) exhibited persistent neurological
deficits at follow-up (Table 5). Seven patients (10%) developed visual field deficits [8, 45, 58,
208, 212, 213, 276]. Only one of these patients had a lesion in the third ventricle [213], whereas
others presented with an IVC in the lateral ventricle. Four patients (6%) suffered from
sensorimotor deficits after surgery [200, 212, 247, 285], three patients (4%) with a third ventricle
lesion developed endocrinological disorders (in two transient diabetes mellitus and in one
hypothyroidism) [149, 213, 285]. One newborn with a lateral ventricle cavernoma operated on at
the age of two days developed hydrocephalus, and a ventriculoperitoneal shunt was placed [128].
At follow-up, the patient had mild mental retardation. In one case, reported by Gaab, a patient
with lateral ventricle lesion had postoperative memory loss, which did not resolve during the 19months follow-up of [98].
In total, eight patients died (10%), and, notably, five of them (7%) after surgical treatment [92,
104, 149, 285, 297]. In a case reported by Katayama et al., a cavernoma of the third ventricle
demonstrated extensive re-growth after incomplete resection followed by hydrocephalus and
diencephalic compression and ischemia [149]. Tatagiba et al. described a patient with a trigonal
cavernoma that was removed completely, but after two weeks the patient developed intractable
status epilepticus and died. The postmortem revealed diffuse brain edema, transtentorial
herniation, and sinus thrombosis [297]. Another patient with a third ventricle cavernoma reported
43
by Sinson et al., became comatose eight days after surgery [285]. On CT, the ventricles were
slightly enlarged, and a ventriculostomy was inserted. Despite this, the patient remained
unchanged and died two months later. In Finkelburg’s case, a cavernoma was not found after
surgical exploration of the posterior fossa and fourth ventricle, and the patient died from
hydrocephalus [92]. Giombini et al. had a patient with a small cavernoma of the fourth ventricle,
which was exposed but not actually excised [104]. This patient received irradiation to the
posterior fossa, but died suddenly two months later. An autopsy confirmed a cavernoma
hemorrhage.
Multiple cavernomas
The first report on MCs was published in 1899 by Ohlmacher, who found three brain cavernomas
at an autopsy of a patient with intractable epilepsy [216]. Data on the frequency of MCs among
cavernoma patients, ranging from 6% to 14.4%, have varied due to an increasing number of
series including asymptomatic patients [104, 218, 321]. Russel and Rubinstein reported the
proportion of MC to exceed 25% [259]. In an analyzis of a consecutive series of 8.131
craniospinal MRIs performed in a single medical center, six (18.7%) of the 32 patients with
cavernomas had multiple lesions [71]. In a clinical study by Rigamonti et al., in which ten
patients were investigated and imaged with MRI, 50% had familial MCs [253]. Furthermore, in
1994 Zabramski et al. performed a comprehensive study on six families afflicted by cavernomas
and found that 26 of 31 patients (84%) had MCs [343]. Ten years later, in a cavernoma review,
Zabramski et al. found that more than 80% of patients with three or more lesions had a history
consistent with the familial form of the disease [341]. Special attention was paid to families of
Hispanic origin, as they seem to have inherited cavernomas [118, 130, 341, 343]. Clinical
observations were strengthened by genetic analyses, performed by Günel et al., with the
discovery of the founder 7q chromosome gene mutation responsible for cavernoma formation in
this ethnic group [116, 118]. Further investigations revealed two more genes (CCM2 and CCM3)
involved in cavernoma formations [60, 232].
While no exact data exist on gender distribution among MC patients, some women
preponderance has been noted [246]. The mean number of lesions is reported to be 5.8-7.1 per
patient [150, 168, 343]. Up to 85% of these cavernomas are supratentorial. Clinical
manifestations of MCs seem to be independent of the number of lesions in a particular patient
[37]. Macro- and microscopic appearances of MCs are the same as in sporadic solitary
cavernoma cases.
44
Symptoms
The clinical picture of MCs may vary significantly depending on the location, size, and history of
hemorrhage. It is not unusual that some lesions are symptomatic while others demonstrate no
clinical manifestations. In the clinical picture of multiple cavernoma patients, no pathognomonic
features can be noted. MCs usually cause the same symptoms as single cavernomas, but due to
the multiplicity some distinguishing differences in their behavior are evident:
Epileptic disorders
Mechanisms of seizure activity in patients harboring MCs are more complex than those of
patients with single epileptogenic cavernomas. Any of the multiple focuses may contribute to
epileptogenesis [14]. In the recent study of Rocamora et al., the authors reviewed data on 11
patients with MCs who suffered from drug resistant epilepsy (DRE) [257]. The authors noted that
epileptogenicity was not dependent on the size of the lesion or the distance to limbic structures.
In fact, the largest cavernoma was involved in the generation of seizures in only 54% of patients
[257]. The authors emphasized that active treatment should be initiated early after diagnosing
DRE. When lesions are located close to each other, the epileptogenic activity on EEG situated to
this particular zone is independent of cavernomas size or hemorrhagic events. Furthermore, the
coexistence of MCs and hippocampal sclerosis, known as dual pathology, should also be taken
into account in the diagnostic work-up of these patients [14, 257]. In such a situation,
identification of the true primary epileptogenic focus is difficult, and resection of the presumed
epileptogenic cavernoma without additional temporal resection fails to control epilepsy.
Identification of the epileptogenic focus in MC patients often requires extensive neurophysiologic
investigations, as resection of the wrong lesion will not only be useless in controlling epilepsy but
may result in devastating functional sequelae when the remaining epileptogenic lesion is located
in the contralateral temporal or frontal lobe [14]. Interictal sporadic EEG is not a reliable tool to
localize a focus in this group of patients. Long-term video-EEG monitoring is indicated with
partial or total discontinuation of AED [257]. Functional MRI, WADA-test, and
neuropsychological evaluation are valuable adjuncts to lateralize memory and speech centers
when additional temporal resection is planned. Among new non-invasive technologies,
magnetoencephalography (MEG) has been addressed to be useful in revealing the complexity of
the case, contributing to decision-making upon further invasive diagnostic methods [287]. In
controversial cases, invasive electrocorticography is warranted to precisely depict the area of
epileptogenicity and to perform a tailored resection.
45
Figure 9 Acute extralesional bleeding of periventricular cavernoma in patient with MCs.
a – axial view; b – sagittal view
a
b
Hemorrhage
Symptomatic hemorrhage in patients with MCs is not uncommon as up to 32% of patients
present with hemorrhage (Figure 9) [37, 104, 254, 256]. The annual rate of bleeding ranges from
0.25%-16.5% per patient-year or, if considering the mean number of lesions in one person, 0.1%2.5% per lesion-year [71, 169, 256, 343]. Similar to single sporadic cavernomas, MCs within the
infratentorial compartment tend to bleed at higher rates. Labauge et al. in their retrospective study
measured that supratentorial cavernomas bled at a rate of 1.9% per lesion-year whereas in
infratentorial cavernomas bleeding rate increased to 5% per lesion-year [169]. In this report,
hemorrhage was identified in 32% of type I lesions, in 14% of type II lesions and in only 2.8% of
type III lesions. Type I cavernomas carried the greatest risk to bleed, although type III lesions
also presented with extralesional hemorrhage. No correlation with size of the lesion, younger age,
or gender was discovered [169]. Zhao et al., in their report on MCs, stated that pathological
investigations of cavernomas in a group of MCs revealed signs of frequent intralesional
hemorrhages, thereby confirming aggressiveness of this disease [350].
Labauge et al., in 2001, performed a prospective analysis of asymptomatic patients with 85%
having MCs and found a hemorrhage rate of 4.3% per patient-year or 0.7% per lesion-year [168].
This finding confirms that hemorrhage potential of a particular lesion in patients with MCs is the
same as in single sporadic cavernomas, with overall bleeding risk accumulating according to the
number of cavernomas.
46
Other symptoms
Headaches are a common complaint in MC patients, occurring in up to 52% of cases [37, 343].
Due to the unspecific nature of headache, its true incidence in cavernoma patients is impossible
to delineate. They frequently accompany hemorrhages, being characterized by acute exacerbation
with gradual decrement. When patient with MCs has a lesion in the ventricle or close to the CSF
outflow pathway, headaches may be considered in the framework of symptoms related to raised
intracranial pressure.
Focal neurological deficits are common manifestations of lesions located in the brain stem or
eloquent cortex (Figure 10). They occur in MCs at the same rate as in single sporadic cavernomas
and correspond to the affected region.
Figure 10 Posterolateral pontine cavernoma in patient with MC
causing progressing hemiparesis
In some reports on MCs, the authors have noted a
pronounced tendency of affected patients to present
with psychocognitive alterations [150, 350]. In the
report of Kattapong et al., 9 of 29 patients (31%) were
afflicted by depression or some other psychiatric
disorders [150]. Some authors described a case of
severe dementia and parkinsonism in an MC patient [145]. Zhao et al. suggested that multiple
degenerations due to repetitive microhemorrhages into the surrounding parenchyma may explain
this distinguishing feature, which is very rarely observed in patients with single cavernoma [350].
Radiological progression
A cavernoma is a dynamic lesion [55, 343]. In MC cases, this feature is strongly pronounced.
Based on MRI screening and follow-up, investigators were able to identify obvious alterations in
size and number of lesions, and a change in radiological types [55, 168, 169, 343]. Zabramski et
al. showed a change in lesion size in 19% of patients, and a change in radiological signal intensity
in 38% of patients [343]. The authors hypothesized that these changes are likely to be related to
intralesional hemorrhages, with enlargement at the onset of the hemorrhage and shrinking after
resolution of the hemorrhage. Furthermore, for the first time, they noted the appearance of de
novo lesions at follow-up MRI. They identified new cavernomas in six of 21 patients (29%),
yielding a rate of 0.4 lesions per patient-year. According to the authors, de novo lesions may
represent the growth of a very small nidus due to capillary proliferation or a focal hemorrhage, or
a combination of these two factors [239, 343].
47
In the series of 29 patients of Hispanic origin reported by Kattapong et al., a regression analysis
performed to evaluate the relationship of age with number of lesions demonstrated an increase of
approximately one lesion per decade [150]. By measuring the mean diameter of the lesions, the
investigators noted a mean reduction in size from 15.7 mm in the first decade to 5 mm in the
seventh decade, with a mean decrease of 1.7 mm per decade. Based on these data, the authors had
argued for a concept of more aggressive course in Hispanic patients, which was shown in
previous reports [150].
Multicenter studies in non-Hispanic patients performed in France supported this argument. In
2000, Brunereau published an analysis of MR findings in 51 families afflicted by the familial
form of cavernomas where 83 patients were symptomatic and 73 were asymptomatic [37].
Among symptomatic patients, 83% had MCs, and among asymptomatic patients 78% had MCs.
The authors found a significant increase in the number of lesions with increasing age in both
groups, especially in type II and III cavernomas. A more rapid increase was detected after the age
of 50 years [37].
One year later, Labage et al. published their remarkable work in which they prospectively
followed 33 asymptomatic patients with familial cavernomas [168]. Mean follow-up time was 2.1
years (range 0.5 -4.5). In this series, 28 of 33 patients (85%) had MCs. The average number of
lesions was 7.1 per patient. All but two patients had clinical and MRI examinations during the
second year of follow-up. During the follow-up two patients (6%) became symptomatic. The
authors found the risk of bleeding to be 4.3% per patient-year (0.7% per lesion-year), the rate of
changes in size to be 4.3% per patient-year (0.8% per lesion-year), the rate of changing
radiological signal intensity to be 1.4% patient-year (0.2% per lesion-year); and the rate of de
novo lesions was 0.4% per lesion-year. Investigators noted that 86% of de novo lesions belonged
to type IV cavernomas, which are only seen in Gradient Echo MR-sequences [168]. The nature of
these lesions has been debated. No surgical specimens can be acquired, as type IV lesions are
very small and asymptomatic and therefore should not be removed. Some authors speculate that
they can be true cavernomas or capillary teleangiectasis [253].
In 2000, Clatterbuck et al. performed a prospective study on the issue, with a meticulous analysis
of MRI data of 68 patients, 25 of whom were affected by MCs [55]. Only 23% of the lesions
were stable in volume during the follow-up; 43% increased in volume and 35% decreased in
volume. Symptomatic hemorrhage was not a common reason for these volumetric changes, and
occurred with a rate of 3.1% per patient-year. Only two patients with MCs in this series had de
novo cavernomas.
Surgical treatment and outcome
Similar to single cavernoma cases, the role of surgery in MCs is to improve epilepsy outcome and
48
neurological deficits and to eliminate the risk of bleeding. This strategy is effective when a
patient has a particular lesion the location and radiological characteristics of which (type I, II, or
rarely III) correspond to clinical manifestations, and other cavernomas seem to be clinically
silent. In contrast, when many cavernomas have signs of recent intra- or extralesional hemorrhage
and symptoms may be caused by any of them, a decision as to which lesion should be removed
may be arbitrary. An ideal solution is removal at the same session of all radiologically active
lesions located close to each other. However, this is an uncommon situation in clinical practice.
When MCs present with epilepsy, a thorough preoperative evaluation is essential to identify a
cavernoma, which is responsible for the seizure activity. After localizing a zone of seizure onset,
one should be aware of possible secondary epileptogenic foci that can be distant to the primary
focus and maintain seizure activity even after total resection of a true epileptogenic cavernoma.
In the series of Rocamora et al., evidence of interictal epileptic activity unrelated to zone of
seizure onset was registered in 4 of 11 patients (36.4%) who had MCs manifesting with DRE
[257]. Although this finding was not suggestive regarding secondary epileptogenic foci, it did
show the complexity of epileptogenic mechanisms in MC patients. The authors registered
convincing improvement of epilepsy (Engel class 1) at the one year follow-up after lesionectomy
with some resection of the hemosiderotic fringe in 9 of 11 patients (81%). At the two-year
follow-up, no deterioration was noted. Seizure outcome did not correlate with the number of
lesions or preoperative seizure frequency. The authors emphasized the role of de novo lesions in
MC patients, which may explain seizure recurrence after primarily successful epilepsy surgery
[257]. A policy of AED administration in MC patients is controversial, as the risk of having a
seizure seems to continue even after removal of an epileptogenic lesion due to persistence of
other lesions or development of de novo cavernomas, especially in persons with a confirmed
family history. Thus, close clinical and radiological follow-up is recommended to register any
suggestive changes in clinical status and radiological findings [56]. Some authors even
recommend to perform a yearly MRI follow-up [229].
Spinal cavernomas
Spinal cavernomas are rare lesions. While the incidence is unknown they represent 5 – 12% of all
spinal vascular abnormalities [59, 171] and 5-23.9% of all intraspinal lesions in adults [75, 268,
270]. The first published case of a spinal cavernoma was by Hadlich in 1903, who revealed the
lesion in the spinal cord at autopsy [121]. In 1999, Zevgaridis et al. published their literature
review on 117 spinal cord cavernomas [348]. In this series, only 16 patients before the modern
imaging era were reported. With the advent of CT and MRI in everyday clinical practice, the
number of publications on this topic has increased dramatically. We analyzed only cases
49
diagnosed and treated using modern imaging and surgical techniques and found 437 patients with
spinal cavernomas with the earliest case in the series dating back to 1978 [33] (Table 8). Due to
their significant differences in the clinical course and treatment, dividing spinal cavernomas into
intramedullary and extramedullary groups is advocated. Published data are presented below
accordingly.
Intramedullary cavernomas (IC)
Among the published 427 spinal cavernoma cases, 374 patients (85.6%) had ICs (Table 8). In this
group, patients’ mean age was 37 years (range 12 -88 yrs) with a peak occurrence between the
third and fourth decades [32]. Some authors report that ICs are two times more common in
women than in men [346], whereas many others find no clear gender difference [32, 140, 270].
Histological structure was typical of CNS cavernomas in all cases.
There are several studies on the natural course of ICs. Ogilvy et al. published their pioneering
work on ICs, introducing the first grading system for clinical manifestations of this disease [214].
The authors analyzed their own six cases of IC, supplemented by a review of 30 previously
published cases. They distinguished four major patterns of clinical course based on
histopathological correlations: (1) acute episodes of stepwise neurological deterioration; (2) slow
progression of neurological deterioration; (3) acute onset of neurological deterioration with rapid
decline; and (4) acute onset of mild symptoms of neurological deterioration with gradual decline
over weeks to months.
Table 8 Published reports on ICs
First author
and year
Mean
duration
of
symptoms,
months
Mean
duration of
follow-up,
months
Long-term outcome
of
patients
Mean age,
years
Bicknell 1978 [33]
1
32
120
nd
1
0
0
Jellinger 1978[141]
1
62
4
nd
0
0
1
Kitahara 1982[155]
1
47
nd
nd
0
0
1
Tyndel 1985[309]
1
27
nd
48
0
0
1
Cosgrove 1988[59]
5
41
47
70
1
4
0
McCormick 1988[190]
6
33
24
43
1
2
3
Vaquero 1988[313]
2
26
30
55
1
1
0
Wang 1988[326]
1
25
48
30
0
1
0
(continued)
50
Worse
Same
Improved
Table 8 Published reports on ICs (continued)
Rutka 1988[260]
1
30
6
nd
0
0
1
Villani 1989[316]
3
38
nd
nd
0
1
2
Zentner 1989[346]
2
37
90
1
1
1
0
Barnwell 1990[20]
1
37
36
0.3
0
1
0
Lopate 1990[182]
2
30
29
nd
0
0
2
Mehdorn 1991[195]
2
34
18
4
0
0
2
Nonogaki 1992[211]
1
43
24
nd
0
0
1
Fazi 1992[88]
2
37
102
nd
0
1
1
Ogilvy 1992[214]
6
43
4
6
0
0
6
Anson 1993[9]
6
35
25
48
0
3
3
Canavero 1993[40]
1
48
168
nd
1
0
0
Lunardi 1994[183]
5
42
29
nd
0
0
2
Stone 1995[289]
1
36
24
nd
0
0
1
Cantore 1995[42]
6
53
110
nd
1
3
2
Gordon 1995[109]
3
35
70
nd
0
0
3
Harrison 1995[126]
1
36
nd
18
0
1
0
Spetzger 1995[286]
9
43
150
14
0
2
7
Turjman 1995[307]
10
47
nd
nd
nd
nd
nd
Furuya 1996[91]
4
52
9
45
0
0
4
Padovani 1997[219]
4
46
nd
24
0
1
3
Visteh 1997[318]
17
40
nd
48
1
6
10
Cristante 1998[61]
12
34
20
54
2
3
7
Tu 1999[306]
7
30
nd
nd
0
1
6
Zevgaridis 1999[348]
7
39
34
nd
1
1
5
Deutsch 2000[75]
16
39
nd
47
1
8
7
Nagib 2002[205]
2
12
nd
16
0
0
2
Barrena Caballo 2003[21]
12
33
30
nd
0
2
10
Sandalcioglu 2003[268]
10
35
29
11
0
6
4
Santoro 2004[270]
10
41
29
68
0
1
9
Bakir 2006[17]
1
14
nd
nd
0
0
1
Kim 2006[154]
53
nd
nd
45
1
9
11
Jallo 2006[140]
26
38
44
54
2
12
12
Nishikawa 2006[210]
3
48
nd
nd
0
0
3
Kondziella 2006[159]
1
40
1
14
0
1
0
Fritzsche 2006[95]
1
39
6
18
0
1
0
Biluts 2006[34]
1
27
9
nd
0
0
1
(continued)
51
Table 8 Published reports on ICs (continued)
Kharkar 2007[153]
14
42
10
42
0
2
0
Cansever 2008[41]
5
46
31
27
0
0
5
Che 2008[49]
19
39
nd
nd
0
0
9
Labauge 2008[171]
53
40
84
46
11
6
20
Bian 2009 [32]
16
38
34
6
0
4
12
374
37
39
32
26
85
180
Total
According to this study, in cases manifesting in frameworks of pattern 1, the punctuated
neurological worsening with gradual, partial improvement between events may be a result of
episodes of small either extra- or intralesional hemorrhages [214]. Pattern 2 is possibly due to the
gradual enlargement of the lesion after intralesional hemorrhage and/or gradual thrombosis.
Symptoms may be caused by direct compression of surrounding spinal cord tissue or by the
alterations in local blood circulation. Additionally, a cavernoma can expand by capillary
proliferation and recruitment of adjacent vessels [351]. The authors emphasize a hemodynamic
factor having a role in such a growth. Patients presenting with pattern 3 commonly suffer from
devastating symptoms at the onset of the disease. Most likely, the mechanism of this acute
decline is extralesional hemorrhage with disruption of neighboring neural tissue. Clinical pattern
4 is presumably related to overt, but not massive extralesional hemorrhage or intralumenal
thrombosis with enlargement of the lesion.
Zevgaridis et al. subdivided clinical symptoms in IC patients into three groups: (A) multiple
episodes of discrete neurological deterioration with varying degrees of recovery between the
acute insults; (B) slow progression of neurological deterioration; and (C) sudden onset of
symptoms with rapid decline over hours or days (C1), or gradual worsening lasting weeks to
months (C2) [348]. These three patterns were noted in the study with an almost equal frequency.
The duration of symptoms could last from one week to decades, but, commonly, 3-4 years passes
until diagnosis is established and deduced from the pattern of presentation [348].
Bian et al. categorized IC patients’ symptoms into two subgroups: the first group is characterized
by slowly progressive neurological deterioration and the second group by acute neurological
decline [32]. The authors concluded that the occurrence of the first pattern is related to several
minor bleedings followed by gliosis, or progressive growth and mass-effect, or repeated
thrombosis within the lesion. The second group of symptoms is caused by an acute extralesional
hemorrhage [32]. The same gradation was also proposed by another group of authors [268].
As can be seen from these studies, most clinical presentations are due to hemorrhagic events from
52
a cavernoma. In the vast majority of series, an annual bleeding risk is assessed retrospectively,
and this therefore does not reflect the true rate of this event, as almost all patients were
symptomatic at the moment of diagnosis. Sandalciouglu et al. presented a series of 10 patients
with ICs and observed 17 hemorrhagic events in 375 patient-years [268]. They calculated the
retrospective hemorrhage rate to be 4.5% per patient-year. Furthermore, the authors measured rehemorrhage risk as 66% per patient-year [268]. Bian et al., who analyzed a series of 16 patient,
reported the bleeding risk to be 3.1% per patient-year [32]. In a literature review by Zevgaridis et
al., an average bleeding rate of 1.4% per lesion-year was found, with the assumption that patients
were harboring ICs already at birth [348]. In contrast to this study, Kharkar et al. in their analysis
of 14 patients found no hemorrhagic events during the mean follow-up of 6.7 years [153].
Furthermore, in eight of ten patients (80%) the neurological status remained unchanged during a
long-term follow-up of 3.5 years. Therefore, the authors claimed that IC patients are a
heterogeneous group with varying natural histories; some of them may be very stable, whereas
others exhibit an aggressive clinical course [153].
Figure 11 Intramedullary cavernoma causing perifocal hemosiderosis and medullopathy
One of the largest series of ICs was published in 2008 by a French
study group conducted by Labauge [171]. The authors performed a
multicenter survey of 53 patients with a retrospective analysis of
their clinical and radiological data collected from 11 neurosurgical
centers. Acute deterioration occurred in 38% of patients,
progressive deterioration in 60%, and only one patient (2%) was
asymptomatic. A hemorrhage was registered in 39% of patients
[171].
Notably,
the
authors
identified
triggering
factors
(pregnancy, trauma and, most frequently, strenuous activity)
affecting the clinical course of disease in 26% of cases. This is
contrary to brain cavernomas, which are less sensitive to
environmental factors.
Symptoms
Due to the low tolerance of the medulla to any mass lesion, patients with spinal cavernomas
frequently present with progressive focal sensorimotor deficits, often combined with intensive
radicular or central pain [154]. Progressive myelopathy caused by typical microhemorrhages and
perifocal gliosis probably explains the neurological decline of the patients [75, 214] (Figure 11).
Moreover, extralesional hemorrhage disrupts the surrounding neural tissue and may lead to
53
significant neurological decline. Distribution of symptoms is mainly dependent on the location of
a lesion along the spinal cord, with involvement of respective segments. Among the wide
spectrum of clinical manifestations, sensory deficits are very frequent. In some reports, they
occurred in up to 45% of cases [171]. Paresthesias quite often accompany motor deficits. Their
combination occurs in up to 25% of patients. In cases of larger lesions or massive hemorrhage,
Brown-Sequard syndrome has been noted [75, 214]. When the cavernoma is located in the upper
cervical spine, tetraparesis with respiratory muscle weakness may occur [41]. Typically, a conus
medullaris lesion will lead to paraparesis and bladder dysfunction [154]. Bowel and/or bladder
disorders occurred in up to 17% of the patients with IC [154]. Pain syndrome may be very
common in IC patients manifesting in up to 50% [154, 190]. Acute local back pain may be the
first sign of a cavernoma hemorrhage with further development of other symptoms. In the
representative series of Kim et al., analyzing 53 patients with ICs, 23 patients (44%) presented
with pain symptoms; radiculopathic pain in 70% and central pain in 13% [154]. In 31% of cases,
pain was severe and affected daily living, and 43% of patients used either narcotic or neuropathic
pain medications at the time of surgery.
Radiology
MRI is the most reliable diagnostic tool to identify
an IC, with the first report appearing in 1987
[309]. Before MRI, the armamentarium of
diagnostic
tools
included
myelography,
CT
myelography, and contrast CT imaging, but none
of these could specifically distinguish ICs [93].
Myelography can only show the level of the
unspecific lesion in cases of widening of the
spinal cord. CT scans through the region of IC may
demonstrate the intramedullary lesion by visualizing
extension of the cord parenchyma. At the same time,
Figure 12 Intramedullary cavernoma with typical
reticulated appearance on MRI
findings like hemorrhage, calcifications, or syrinx
cavity can be seen [214]. On MRI, reticulated appearance with mixed signal intensity on both T1and T2-weighted images are the most common findings [307] (Figure 12). Contrast enhancement
is not typical and uniform. Notably, a rim of decreased signal intensity, most consistent with a
hemosiderin deposition, is less frequent than in the brain. Homogeneous signal intensity is more
common [307]. Ogilvy et al. depicted the basic MR signs of hemorrhagic events and showed that
the appearance of hemorrhage on MRI depends on the age of the hemorrhage [214]. During the
first days after the bleeding T1-weighted images show isointense or slightly hypointense signal
54
relative to the white matter, and hypointense signal on T2-weighted images. After a few days to
two weeks, the blood appears hyperintense on T1-weighted images and remains hypointense on
T2-weighted images. Over the next few weeks, as blood breaks down, the T1-and T2-weighted
images show hyperintense signal in the lesion. Chronic blood products are hypointense on T2weighted images and isointense or moderately hypointense on T1-weighted images. Gadolinium
enhancement is variable [214].
Along the spinal axis, ICs are most frequently seen in the thoracic region, accounting for 77% of
the cases [171]. Cervical location is less frequent, occurring in less than 23% of patients. Lumbar
region ICs are very uncommon. Among all collected cases of ICs, we found only 14 of caudal
cavernomas (4%) in the literature [81, 222, 309].
On a horizontal plane, centrally located lesions are the most frequent. In some series, they
account for 34% of cases [171]. Posterior and lateral sites are less common, occurring in 23% and
17% of cases, respectively. The rarest location is anterior, occurring in 9% of cases [171].
There are several reports of the simultaneous occurrence of ICs and multiple brain cavernomas
[75, 317, 318]. Deutsch et al. in a series of 14 IC patients reported three cases (21%) with
multiple intracranial lesions. Vishteh et al. found that 47% of 17 patients with ICs harbored
multiple intracranial cavernomas [317]. Four of these patients had a family history of
cavernomas. Thus, it may be warranted to perform an MRI of the brain in young IC patients, as
they are more likely to harbor multiple lesions. Cases of multiple spinal ICs are casuistic, with
very limited data in the literature [224, 225].
Surgical treatment
Due to the aggressive clinical course and frequent hemorrhagic events in IC patients, surgical
treatment is considered to be beneficial [75, 140, 171, 190, 214, 348]. When planning the
operative treatment, one should take into account the patient’s symptoms, age, evidence of
progression, the risk of further hemorrhages, size and accessibility of the lesion, also bearing in
mind the risks of surgical manipulations [154, 158, 205]. Surgery of deep and anteriorly locating
lesions carries obviously higher risks due to extended dissection and manipulation within the
spinal cord [102]. Longer duration of preoperative symptoms seems to be associated with less
successful outcome after surgery [348].
A laminectomy is the most conventional dorsal approach to ICs, but may result in progressively
increasing instability or deformity of the vertebral column, especially in children [32, 158, 194,
337]. In 1991, Yasargil et al. reported a series of 100 patients, who had undergone surgical
removal of extra- and intramedullary tumors and AVMs via hemilaminectomy [339]. One year
55
later, Bertalanffy et al. also demonstrated that hemilaminectomy is more beneficial than
laminectomy in management of extramedullary tumors [31]. The minimal invasiveness of this
approach has been appreciated by many and is widely used in the management of extra- and
intramedullary space-occupying lesions [18, 31, 272]. Furthermore, Koch-Wiewrodt et al.
recently suggested unilateral interlaminar fenestration to expose intraspinal space-occupying
lesions, showing a significant decrease in postoperative pain and duration of hospital stay [157].
Further studies are needed to confirm the effectiveness of such a limited approach. In any case,
the bone resection should be large enough to provide adequate space to open the dura in a
longitudinal fashion, exposing the affected area of the spinal cord. To optimize the surgical view,
lateral drilling is sometimes required [32]. Purely ventral lesions can be reached via a
posterolateral approach with spinal cord rotation and visualization of the anterior pial surface
[188]. In rare cases of anterior IC, this approach seems to be better than the complex and very
invasive anterior approaches [188].
Cavernomas demonstrating exophytic growth extending to the pial surface are the easiest lesions
to remove. They are typically exposed through a myelotomy directly over the lesion, being in
most cases relatively safe [140]. When neither discoloration nor bulging of the spine can be seen,
choosing the safest place to enter is one of the most critical steps of the procedure. Myelotomy
should be planned by taking into account such factors as remoteness of the IC from the pial
surface, dorsal median sulcus, dorsal root entry zone (DREZ), findings during intraoperative
sonography, and neurophysiologic response to local stimulation. All of these factors will help to
avoid inadvertent damage to unaffected tracts and nuclei.
The more anterior the lesion is, the more complications are to be expected due to the
corticospinal tracts located in the anterolateral aspects of the cord [104, 263]. In the series of
Labauge et al., only one of the four operated patients with anterior IC improved, whereas three
demonstrated worsening of their neurological status [171]. Furthermore, among patients with
centrally located lesions, only 64% improved, while 36% worsened. Notably, seven of eight
patients (85%) with a posterior cavernoma improved after surgery [171].
The preparation of the dorsal median sulcus when approaching centrally or anteriorly located
intramedullary cavernomas may be beneficial to gain direct access to the lesion and minimize the
intraparenchymal dissection [36, 263]. When such exposure is planned, the bony opening should
be wide enough to access the midline, and extended hemilaminectomy or conventional
laminectomy should be performed. When surgery is carried out in the acute stage of bleeding and
hematomyelia is massive, the dorsal midline sulcus can be displaced, which causes difficulties in
its identification and proper dissection. In the extreme lateral location of the cavernoma, it can be
exposed via myelotomy performed in the DREZ, although this is associated with a high risk of
significant sensory deficits [1].
56
Intraoperative ultrasound is a useful adjunct to localize a cavernoma and the extent of hematoma
in cases where no pathological signs can be seen on the surface. Ultrasound visualizes not only
normal structures of the spine but can also provide precise assessment of the size of the lesion,
thus allowing identification of an adequate site for the myelotomy [183]. When the cavernoma
compromises the central medullary canal, ultrasound may show disposition of the normal
structures, which is important during intraparenchymal dissection.
The technique of IC removal is similar to that of any intramedullary tumor. Gentle traction and
coagulation of the malformation surface allow a cleavage plane to be created [190]. Unlike with
supratentorial cavernomas, the perifocal hemosiderotic rim should not be taken out. A lesion can
be removed en bloc or in a piecemeal fashion, depending on its size and consistency. After
excision of the cavernoma, careful inspection of the cavity is essential to exclude any remnants.
A cavity can be inspected also by ultrasound to identify remnants when the size of the
myelotomy is very small and visual access is limited [183].
Monitoring
The majority of unsatisfactory outcomes after removal of an intramedullary lesion are primarily
due to ischemic derangements of the cord secondary to its sustained traction, manipulation,
rotation, and overheating produced by bipolar coagulation [72]. Intraoperative monitoring (IOM)
helps the neurosurgeon to predict the degree to which the spinal cord can tolerate any surgical
manipulations [72]. In part, modern neurophysiologic tools have decreased postoperative
morbidity after IC removal. IOM allows a direct feedback of the functional integrity of spinal
cord tracts during cavernoma surgery. The evolution of IOM during removal of intraspinal
lesions had begun in the 1980s from registering sensory evoked potentials (SEP) [330, 331],
which assesses possible dysfunction of sensory tracts, but not motor pathways. The limitations of
this method have been shown in many studies with the appearance of false-negative and falsepositive results when patients demonstrated motor deficits after awakening, although
intraoperative SEP findings were not abnormal [264]. Some authors reported an incidence of
false-negative results in up to 25% of patients [324]. Since the mid-1990s, transcranial electric
stimulation (TES) to elicit motor evoked potentials (MEP) has been used to assess the functional
integrity of motor tracts during intraspinal surgery [144, 227]. The use of multipulse transcranial
electrical stimulation and recording from limb muscles is widely accepted nowadays in many
neurosurgical centers as an effective monitoring method [263, 264, 324, 328]. A recent study has
addressed the value of the evolvement of D-waves during a single-pulse technique with
transcranial electrical stimulation and epidural recordings [262]. A D-wave is of great interest
since it represents a pool of high conduction velocity fibers supporting locomotion and not
impaired by typical anesthetics and myorelaxants [262]. To date, among the neurophysiologic
57
parameters, D-wave seems to have the strongest predictive value of favorable motor
function/recovery after surgery on intramedullary masses [72]. A few false-positive results have
been reported, but they are related to local scalp edema and do not actually argue against the
value of D-wave in neurophysiologic monitoring [186].
Outcome
In the published literature, follow-up data on operated patients were found in 351 cases. Patients
with intramedullary lesions showed improvement in 62% of the cases. The report by Labauge et
al. showed no correlation of better outcome with patients’ age, gender, and delay from onset to
surgery, lesion size, cervical or thoracic location, or severity of initial neurological deterioration
[171]. A statistically significant correlation with worse outcome was demonstrated in cases of
anterior cavernomas. Regarding duration of preoperative symptoms, Zevargidis et al.
demonstrated a correlation of shorter preoperative history with better outcome after surgery
[348]. The authors noted that 76% of patients with symptoms for less than three years improved
after surgery, whereas only 52% of patients with symptoms for more than three years showed
equal results [348]. Persistent worsening of neurological status, registered at the long-term
follow-up, occurred rarely, accounting for 9% of all cases [33, 40, 42, 59, 61, 75, 140, 171, 190,
313, 318, 346, 348]. Only 6% of the patients have had permanent disabling neurological deficits
[318, 348]. Pain relief was satisfactory immediately after surgery, but during long-term follow-up
pain may recur in up to 50% of patients [154]. The matter of micturition recovery is not well
elucidated in the literature, but some reports indicated only partial improvement or absence of
any changes in bladder functions [159, 346].
Extramedullary cavernomas (EC)
The true incidence of ECs remains unknown. In the literature on spinal cavernomas, we found 63
well documented cases (14.4% of all 427 spinal cavernomas) of extramedullary lesions (Table 9).
The largest series of ECs contained only seven patients [111, 269]. ECs represent 4% of all
epidural tumors [269, 295, 303]. Most frequently, they are encountered between the third and
fifth decade of life. In some series, a slight men preponderance was demonstrated [10].
Histological features of ECs are not different from other cavernomas. In many cases, an
extramedullary lesion was encapsulated, which was uncommon in cavernomas of other locations
[10, 299].
It is unclear whether extradural cavernomas have different growing patterns or hemorrhage rates
from those in intramedullary lesions. Zevgaridis et al. distinguished four patterns of
manifestations in published cases of ECs: 1) slow, progressive spinal cord syndrome; 2) acute
58
spinal cord syndrome; 3) local back pain; and 4) radiculopathy [349]. The authors found that in
most patients with acute or chronic spinal cord syndrome, the symptoms are related to the
hemorrhage, whereas in cases of local back pain and radiculopathy, symptoms are associated
with growth of the lesion [125, 349]. Santoro et al. noted that acute and subacute onset is not
uncommon and may be attributed to microhemorrhages or hematomas, resulting in motor or
sensory deficits; this finding is supported by other authors [111, 131, 269, 299]. Naturally,
symptoms are dependent on the affected level of the spine and the degree of compression of the
cord or nerve roots.
Table 9 Reported cases of ECs
First author
and year
No. of
patients
Mean
age, yrs
Mean
duration of
symptoms
preoperatively,
yrs
Mean
f-up,
months
Long-term outcome
Worse
Same
Improved
Richardson 1979[250]
1
nd
nd
nd
0
0
1
Padovani 1982[220]
1
78
24
nd
0
0
1
Morioka 1986[202]
1
50
3
4
0
0
1
Ueda 1987[309]
1
28
36
nd
0
0
1
Lee 1990[176]
3
38
nd
28
0
0
3
Pagni 1990[222]
1
46
48
20
0
0
1
Enomoto 1991[85]
1
42
nd
nd
0
0
1
Hillman 1991[131]
5
35
nd
nd
1
1
3
Isla 1993[136]
2
25
nd
nd
0
0
2
Singh 1993[284]
1
40
2
84
0
0
1
Graziani 1994[110]
7
46
nd
nd
0
1
6
Bruni 1994[38]
1
28
0.1
nd
0
0
1
Harrington 1995[125]
1
37
2
nd
0
0
1
Padovani 1997[219]
5
50
nd
24
0
2
3
Rao 1997[245]
4
48
16
nd
0
1
3
Zevgaridis 1998[349]
3
43
2
21
0
0
3
Duke 1998[81]
1
49
nd
3
0
0
1
Appiah 2001[10]
1
41
12
6
0
0
1
Saringer 2001[271]
1
56
11
3
0
0
1
Goyal 2002[110]
1
55
25
5
0
0
1
D'Andrea 2003[65]
1
52
6
nd
0
0
1
Thome 2004[302]
1
47
12
12
0
0
1
Tekkök 2004[299]
1
28
24
36
0
0
1
(continued)
59
Table 9 Reported cases of ECs (continued)
Santoro 2005[269]
7
77
6
nd
0
0
4
Hatiboglu 2006[129]
1
28
12
108
0
0
1
Doyle 2008[79]
1
57
4
6
0
0
1
Iglesias 2008[135]
1
57
nd
48
0
0
1
Akiyama 2009[3]
1
40
6
nd
0
0
1
Satpathy 2009[274]
1
47
nd
76
0
0
1
Feng 2009[89]
6
42
nd
nd
0
0
6
63
47
13
30
1
5
54
Total
Radiology
Typically, ECs are common in the thoracic spine and only very occasional at the cervical and
lumber levels [299]. Due to their rareness, diagnosis of ECs may be difficult. Conventional or CT
myelography can only demonstrate a block in the flow of subarachnoid contrast medium [349].
CT imaging may show a mass in the spinal canal, but sensitivity and specificity of images are
very limited. The most precise diagnostic is naturally provided by MR imaging. Zevgaridis et al.
delineated the main MR features of ECs, helping to establish a correct diagnosis and avoid
misinterpretations (Figure 13): T1-weighted images commonly show homogeneous signal
intensity similar to that of spinal cord and muscle. Contrast enhancement is homogeneous or only
slightly heterogeneous. On T2-weighted images, the signal is high, just slightly less than that of
CSF [349]. Unlike IC cases, an extramedullary lesion is not characterized by a perifocal
hemosiderotic hypointense fringe in both T1- and T2-weighted images.
It is not uncommon that a lesion extends to intervertebral foramina [93, 96]. In contrast to some
neoplasms in similar locations, ECs never cause any enlargement or bony erosion of foramina,
which helps in differential diagnostics. Among pathologies to exclude are schwannomas,
meningeomas, lymphomas, Ewing’s sarcomas, chordomas, ependymomas, spinal angiolipomas,
osteochondromas, synovial cysts, and disc herniations [107, 299, 349]. Tekkok et al. presented a
thorough overview of MR and CT findings of the vast majority of benign and malignant masses
in the extradural compartment of the spine [299]. The authors stressed that the enlargement of
neural foramina is typical for a schwannoma or neurofibroma, and destruction occurs typically in
a lymphoma, chordoma, or Ewing’s sarcoma [299]. When a lesion is located in the lumbar spine,
and especially, when it is small and occupies the intervertebral foramen, it can easily be
misinterpreted as a disc herniation [349].
60
Treatment and outcome
Due to the low number of patients and the lack of thorough prospective studies, the natural course
of the ECs is unknown. No data exist on whether symptomatic patients experience spontaneous
recovery during long-term follow-up and thus could be treated conservatively. In very rare cases,
ECs have even been irradiated, but results of this treatment are doubtful [59, 176, 220]. Surgical
removal of the symptomatic EC is considered by most authors the treatment of choice [10, 131,
219, 269, 349]. Similar to other cavernomas, total removal is the goal of surgery since cavernoma
remnants may cause further neurological deterioration due to their growth and hemorrhage. Use
of microsurgical techniques is essential to accomplish complete resection without any damage to
surrounding neural structures. Depending on their size, side and relation of the lesion to the dura,
hemilaminectomy or laminectomy is performed. After exposure of the epidural space, the lesion
is identified. The pseudocapsule, which is common in ECs, facilitates dissection of the lesion
from ligaments, dura, and nerve roots [258, 299]. If possible, integrity of the capsule should be
preserved to avoid intraoperative bleeding which usually is not intensive but may obscure the
surgical view and impede dissection. If a lesion is purely extradural, no further inspection of
intradural space is necessary. In rare cases, an EC is located intradurally requiring a dural
opening [244]. Such lesions can be adherent to the nerve roots or pial surface of the spinal cord
thus necessitating meticulous preparation and dissection of the lesion.
Of the 63 reported cases, 54 (90%) experienced postoperative improvement of neurological
deficits, which confirms the effectiveness of surgical treatment (Table 9). In five patients (8%),
no changes occurred [111, 131, 219, 245]. Only one report showed worsening of neurological
status after surgery [131]. Unfavorable outcome was due to the large size of the lesion with
intensive bleeding after manipulation even interrupting the excision.
Figure 13 Large extramedullary cavernoma mimicking benign tumor. a – sagittal view; b – axial view
a
b
61
III Aims of the study
1. To analyze main clinical features of intraventricular cavernomas and the results of their
microsurgical removal.
2. To analyze the role of surgical treatment in management of multiple cavernomas by assessing
long-term seizure and general outcome.
3. To analyze a series of patients with spinal cavernomas with a special emphasis on functional
recovery after lesionectomy.
4. To analyze the results of microsurgical treatment of temporal lobe cavernomas.
62
IV Patients and methods
Data collection
Data on 383 consecutive patients with 1101 brain or spinal cavernomas treated at Helsinki
University Central Hospital (HUCH) from January 1, 1980 to December 12, 2009 were
retrospectively analyzed. The catchment area of this center is 1.8 million inhabitants. In most of
the cases, patients were initially examined at the neurological department of the referring
hospitals and then sent to our neurosurgical center for further evaluation and treatment. The
collection of the series began in 2006, and the patient database was continuously supplemented
with new cavernoma patients recruited to the study. Accordingly, a total number of patients in
series presented below varied. The study protocol was approved by the local Ethics Committee of
HUCH.
Of the 325 patients treated at our department between January 1980 and January 2008, 12 (3.7%)
had an intraventricular cavernoma (Table 10). The 77 previous case reports of IVC were
collected via the Pub Med database and then analyzed.
All of our patients were imaged with CT and MRI prior to admittance to our department. We
classified cavernomas located in the ventricles into three main groups: A) “true” intraventricular
lesions which are attached to the ependyma or choroid plexus but do not extend outside the
ventricle wall; B) lesions with an intraparenchymal part but no more than one half of the volume;
and C) paraventricular lesions with only a minor part (less than one half of the volume) located in
the ventricle; we did not include the last group in the present study.
In patients with intraventricular hemorrhage, MRI was performed usually several months after
the resorption of extravasated blood aiming at a more definitive preoperative diagnosis. Only one
patient was imaged with CT, MRI and digital selective angiography (DSA) immediately due to a
hematoma of diameter 5 cm to exclude AVM or tumor (Figure 14). Because of progressive
somnolence this patient was operated on two days after the bleeding. Standard T1- and T2weighted imaging with a T2*-weighted Gradient Echo sequence was performed. Lesions were
classified according to the Zabramski classification scheme. In five patients (42%), DSA was
performed to exclude AVMs. In three patients, the IVC was not removed. One patient underwent
only a shunting procedure for obstructive hydrocephalus caused by a non-related aqueduct
stenosis. This was followed by significant improvement of symptoms; this patient later refused
removal of the cavernoma. Another two patients refused any operation.
63
Table 10 Own series of patients with IVC
Patient Sex Age,y
Location
Clinical presentation
Re-bleeding
Treatment of
GOS
IVC
V
no
conservative
(shunted because
of nonrelated
hydrocephalus)
total removal
IV-hemorrhage, severe
headaches, nausea and
vomiting, hydrocephalus
no
total removal
V
fourth
ventricle
group B
IV-hemorrhage, mild
vomiting, cranial nerve
deficit
once,
before
surgery
total removal
IV
20
lateral
ventricle
group B
IV-hemorrhage, mild
headaches
twice,
after first
surgery
Stereotactic biopsy
followed by two
partial resections
V
male
15
fourth
ventricle
group B
IV-hemorrhage, cranial
nerve deficit
once,
before
surgery
total removal
IV
7
male
52
headache, nausea and
vomiting
no
total removal
V
8
female 49
third
ventricle
group B
fourth
ventricle
group B
cranial nerve deficit
no
total removal
IV
9
male
conservative
V
female 49
IV-hemorrhage, acute
severe headaches, nausea
and vomiting
severe headaches,
hydrocephalus
twice
10
lateral
ventricle
group B
fourth
ventricle
group B
no
total removal
V
11
male
65
conservative
V
male
53
vomiting, hydrocephalus
IV-hemorrhage and ICH,
headaches, hemiparesis
twice
12
lateral
ventricle
group B
lateral
ventricle
group B
no
total removal
V
1
male
66
lateral
ventricle
group A
gait disturbances, mild
headaches, hydrocephalus
no
2
female 43
fourth
ventricle
group B
mild headaches, nausea
and
vomiting
3
male
65
lateral
ventricle
group A
4
female 58
5
male
6
35
V
All microsurgically treated patients (9 of 12) underwent routine CT imaging in the immediate
postoperative period. In one operated patient, follow-up MRI was performed after several months
to exclude a cavernoma residual. Furthermore, in two of the three conservatively treated patients,
MRI was performed at our department one year after the primary diagnosis. In addition to the
64
routine postoperative outpatient visit at three months, all patients were interviewed in 2008 with
health questionnaires sent by post. Patients’ general outcome was assessed on the Glasgow
Outcome Scale (GOS) [142].
Figure 14 Acute cavernoma hemorrhage in the vicinity of lateral ventricle causing mass-effect on basal ganglia
Multiple cavernomas
Altogether 44 of 383 patients (11.5%) had multiple cavernomas, which were diagnosed between
January 1980 and December 2009. A total of 762 lesions could be identified. T2*-weighted
gradient-echo (GRE) sequences had been performed on 37 patients (84%). All MR images were
re-reviewed by a radiologist and classified according to the Zabramski classification scheme.
Furthermore, supra- and infratentorial lesions and the number of lesions were analyzed
separately. The size of each cavernoma was measured, except for type IV lesions: in GRE
imaging the size of these lesions was very small and strongly dependent on the equipment used,
making measurement unreliable. In this study, cavernoma-related bleeding was defined as
extralesional symptomatic hemorrhage seen on CT scan. A follow-up MRI was performed on 22
patients. In this group, all except one patient were treated microsurgically. CT was performed
routinely on the first postoperative day in all surgically treated patients. Four patients who
suffered from acute headache during follow-up were imaged with CT to exclude hemorrhage. In
addition to the routine postoperative outpatient visit at three months, all patients were sent health
questionnaires.
65
Table 11 Outcome assessing scales
The general outcome of patients was
assessed by using the Glasgow
Grading
Characteristics
Outcome Scale (GOS) and the
outcome of epileptic symptoms in
Engel scale
Class I
Class II
Free of disabling seizures
operated patients by using the Engel
Rare disabling seizures
classification [84] (Table 11).
Class III
Worthwhile improvement
Class IV
No worthwhile improvement
Spinal cavernomas
Of the 376 consecutive patients with
Glasgow
cavernomas of the CNS treated in
Outcome Scale
January 1980 and June 2009, 14
GOS5
Good recovery
GOS4
Moderate disability
GOS3
Severe disability
GOS2
Persistent vegetative state
was performed using standard T1-
GOS1
Death
and T2-weighted sequences. On
(4%) had a spinal cavernoma (Table
12). In these cases, spinal axis MRI
MRI, cavernomas had a typical heterogeneous core surrounded by a hemosiderotic rim and also
edema when intramedullary perifocal.
Indications for microsurgical removal of a spinal cavernoma were progressive neurological
deterioration in 12 patients (86%) and prevention of bleeding and consequent neurological
decline in the remaining two patients (14%). To assess the patients' condition at the follow-up,
the most recent data from referring departments were analyzed. The median follow-up time was
three (range 1-10) years.
Table 12 Own cases of spinal cavernoma
Patient
Age, Sex
Location
Symptoms
1
50y, male
Th12-L1, intramedullary, midline
Left leg radicular pain, paraparesis
Bladder paresis. Fast progression
yes
2
52y, female
C7-Th1, extradural, right
C8 radiculopathy with motor paresis
Slow progression
no
3
26y, male
C4-5 intramedullary, left
Fast progression of tetraparesis
Bladder paresis
yes
4
45y, male
C5-6 intradural-extramedullary, left Fast progression of Brawn-Sequard
syndrome. Bladder paresis
yes
5
44y, female
C7-Th1, extradural, left
no
Fast progression of tetraparesis
Diffusive pain
(continued)
66
Bleeding
Table 12 Own cases of spinal cavernoma (continued)
6
57y, male
C1-2, intramedullary, right
Brawn-Sequard syndrom
Improved before surgery
no
7
47y,female
Th-10 intramedullary,midline
L5 and S1 radiculopathy
with motor paresis. No progression
no
8
34y, female Th4 intramedullary, left
Right sensorimotor hemiparesis
Slow progression
yes
9
46y, male
Sensorimotor paraparesis in legs
Fast progression. Bladder paresis
no
10
28y, female Th7 intramedullary, left
Low-back pain followed by acute
paraparalysis. Bladder paresis
yes
11
45y, female C3-4 intramedullary, midline
Left C8 radiculopathy with pain and
sensorimotor paresis. Improved before
surgery.
no
12
54y, female
Th11 intramedullary, midline
Numbness in both legs, right L5 paresis
Slow progression.
yes
13
40y, male
Th9 intravertebral, extradural, left
Paraparesis in both legs
Slow progression
no
14
20y,male
Th10, intramedullary, left
Lower limb paraparesis
Fast progression
yes
Th5-6 extradural, midline
Of the 360 consecutive patients treated from January 1980 to January 2009, 53 (15%) had a
single cavernoma of the temporal lobe and 49 (92%) of them were operated on and therefore
included in the study (Table 13).
EEG was performed on 30 (75%) of the 40 patients with seizures, at a median of 1.2 (range 0.12.1yrs) years before surgery. Three patients underwent a prolonged video EEG, including ictal
registration. In adults with only a single epileptic seizure, EEG was not performed, if MR
imaging verified the cavernoma soon after the event. In 11 patients (37%), EEG was within
normal limits or it showed only non-epileptiform focal or diffuse slowing. No periodic lateralized
epileptiform discharges were reported. Video EEG was performed in refractory epilepsy to assess
the magnitude of the upcoming resection.
Postoperative EEG was not performed routinely; it was carried out in only 15 patients (31%) at a
median of 2.7 (range 0.1-17) years after surgery. Indications included suspected postoperative
seizures, consideration of withdrawal of medication, or seizure recurrence after medication was
discontinued. In 11 of these 15 patients, postoperative EEG showed epileptiform interictal
activity, and AED was continued.
Prior to admission to our department, each patient had an MRI performed, except for three
67
patients admitted at a time when only CT was available. MRI was performed at a median of 0.5
(range 0.1-12) years before surgery. In the vast majority of patients, the cavernoma had a typical
heterogeneous core, seen on standard MR sequences, surrounded by a hemosiderin rim. The
median size of the cavernoma core in the series was 10 (range 7-40) mm. In patients with acute
sudden headache, a CT was performed soon after symptom onset to exclude hemorrhage.
To categorize the location of the cavernomas within the temporal lobe we divided it into three
compartments: I - medial (Figure 15), II - anterolateral (Figure 16), and III - posterolateral
(Figure 17) (Table 14). Justification for this division was based on perceived differences in
functionality and surgical risk: (I) strong tendency to be involved in epilepsy and importance in
memory processing, (II) believed to be a low-risk area, and (III) increased risk due to optic
radiation and the vein of Labbé.
The first clinical follow-up as a routine postoperative examination was performed at a median of
two months after the procedure. When needed, further follow-up was provided, mostly by
neurologists at the referring hospitals. In addition to this, 45 patients were interviewed by phone,
with special emphasis on their general condition. For six patients, we analyzed only the most
recent neurologist’s follow-up data. One patient who came to surgery from outside Finland was
lost in follow-up. Furthermore, one patient had died at the time of the study due to liver
insufficiency.
Figure 15 A cavernoma in the medial part of the temporal lobe. a – axial view; b – coronal view
a
b
68
Figure 16 A cavernoma in the antero-lateral part of the temporal lobe. a – axial view; b – coronal view; c – sagittal
view
a
b
c
General outcome was assessed using the Glasgow Outcome Scale (GOS). Epilepsy outcome
analysis after surgery was assessed according to the Engel classification. In cases of memory
disorder, a standard Mini Mental State Examination test (MMSE) was performed at the local
hospital. When needed, patients were sent to a neuropsychologist who then performed
appropriate testing.
Figure 17 A cavernoma in posterior part of the temporal lobe. Associated DVA is located anterior to the cavernoma
69
Table 13 Own patients with temporal lobe cavernoma
Characteristics
Seizure history of
40 patients
Others
Total
Females
29 (73%)
6 (66%)
35 (71%)
Males
11 (27%)
3 (34%)
14 (29%)
36 (10-60)
49 (7-64)
39 (7-64)
MTL
10 (25%)
3 (34%)
13 (27%)
ATL
13 (32%)
2 (22%)
15 (30%)
PTL
17 (43%)
4 (44%)
21 (43%)
Left
26 (65%)
5 (55%)
31 (63%)
Right
14 (35%)
4 (45%)
18 (37%)
CP
7 (18%)
-
-
SP
5 (12%)
SGTC
28 (70%)
Sex
Median age at diagnosis, years
(range)
Location in temporal lobe
Lateralization
Typeof seizure
at presentation
Median duration of
symptoms before
admission, years
(range)
3 (0.1-23)
0.6 (0.1-1.6)
3 (0.1-23)
Hemorrhage
8 (20%)*
1 (8%)**
9 (18%)
* Seven patients with one hemorrhage and one patient with three hemorrhages preoperatively
** Patient with headaches who had two hemorrhages preoperatively, not in asymptomatic patients
ATL – anterior temporal lobe, MTL – medial temporal lobe, PTL – posterior temporal lobe, SGTC – secondary
generalized tonic-clonic, SP- simple partial, CP – complex partial.
Statistics
Statistical analysis was carried out using SPSS 13.0 software (SPSS Inc., Chicago, IL). Clinical
characteristics were presented as frequencies and percentages for categorical variables and as
means +/-SD for continuous variables. Nonparametric data were analyzed using Pearson’s Chisquare test, and continuous variables were compared with Student's t-test.
significance was set at p<0.05. All tests were two-sided.
70
The level of
Table 14 Suggested compartmentalization of temporal lobe
Compartment
Borders and structures
Medial temporal lobe
Bordered by the allocortex of the temporal lobe (parahippocampal
(MTL)
gyrus, fusiform gyrus, uncus), hippocampal formation, amygdala
Anterolateral temporal lobe
Bordered anteriorly by temporal lobe apex, medially by MTL,
(ATL)
posteriorly by PTL, laterally by lateral surface of temporal lobe
Posterolateral temporal lobe
(PTL)
Bordered anteriorly by ATL (4 cm from temporal lobe apex in sagittal
direction), medially by MTL, posteriorly by posterior border of
temporal lobe
71
V Results and Discussion
Helsinki Cavernoma Database
Patients
From January 1980 to December 2009, altogether 383 patients with 1101 brain and spinal
cavernomas were treated. The mean age of patients at the radiological diagnosis of a cavernoma
was 42 years (range 0.6-81.6 yrs). Thirty-three patients (8.7%) were younger than 18 years, and
only 21 patients (5.5%) were older than 65 years. Slight women preponderance was observed,
with the women:men ratio being 1.3:1 (214 women (55.9%) and 169 men (44.1%)). The mean
age of women was 43 years (range 0.6-81.6 yrs) and of men 41 years (range 3.2 – 76.8 yrs). In
four women (1.9%), the cavernoma was diagnosed during pregnancy. A single cavernoma in the
supratentorial compartment occurred in 247 patients (64.5%), and in the infratentorial
compartment in 64 patients (16.7%) (Table 15). Multiple lesions of the brain were diagnosed in
44 patients (11.5%). One of them had exceptionally high number of lesions reaching 532 whereas
remaining 43 patients had 230 lesions. The most common location among single cavernomas was
the frontal lobe, occurring in 97 patients (25.3%). The rarest locations were the internal acoustic
meatus (one patient) and the sellar region (two patients). Of brain lesions, 52% were located on
the left side, 42% on the right side, and 6% at midline. The mean size of the cavernoma was 12
mm (range from punctate to 50mm). Associated vascular pathologies occurred in 44 patients: 33
patients (9%) had DVA, four patients (1%) had teleangiectasias, three patients (1%) had
meningeoma, and three patients (1%) had cerebral aneurysm.
Symptoms
Symptoms were reported by 83.6% of the patients, and a cavernoma was identified incidentally
in 63 patients (16.4%) (Table 16). The most frequent symptom was epileptic disorder occurring
in 141 patients (36.8%). In this group, a cavernoma was radiologically confirmed after the first
seizure in 55 of 141 patients (39%). Patients exhibited secondary generalized tonic-clonic and
simple and complex partial seizures without a specific correlation with radiological
characteristics of the cavernoma. In 74 patients (19.3%), headaches were the only symptom.
Headaches varied from slight to very severe and were frequently accompanied by nausea or
vomiting. Commonly, headaches presented when a cavernoma bled. Focal neurological deficits,
including cranial nerve deficits and sensorimotor paresis of the extremities were encountered in
76 patients (19.8%). Vertigo occurred presumably in patients with a cerebellar cavernoma in 13
cases (3.4%).
72
Table 15 Distribution of cavernomas in Helsinki Cavernoma Database*
Location
No. of patients
(%)
History of bleeding
(%)
Operated on
(%)
Supratentorial
247 (64.5)
74 (30)
200 (81)
Frontal
97 (25.3)
30 (30.9)
80 (82.5)
Parietal
35 (9.1)
14 (40)
26 (74.3)
Temporal
58 (15.1)
11 (19)
52 (89.7)
Occipital
18 (4.7)
5 (27.8)
12 (66.7)
Basal ganglia
18 (4.7)
9 (50)
11 (61.1)
Sylvian fissure
10 (2.6)
4 (40)
9 (90)
Corpus callosum
4 (1.0)
-
4 (100)
Insular
5 (1.3)
1 (20)
4 (80)
Parasellar
2 (0.5)
-
2 (100)
Intraventricular
12 (3.1)
8 (67)
10 (83)
Lateral ventricles
6 (1.6)
5 (83.3)
4 (66.7)
Third ventricle
1 (0.3)
-
1(100)
Fourth ventricle
5 (1.3)
3 (60)
5 (100)
Multiple
44 (11.5)
19 (43.2)
30 (68.2)
Infratentorial
64 (16.7)
39 (60.9)
48 (75)
Pons
26 (6.8)
22 (84.6)
21 (80.8)
Cerebellum
25 (6.5)
8 (32)
14 (56)
Medulla oblongata
8 (2.1)
6 (75)
8 (100)
Mesencephalon
4 (1.0)
3 (75)
4 (100)
Meatus acusticus internus
1 (0.3)
-
1 (100)
Spinal
14 (3.7)
7 (50)
14 (100)
Intramedullary
9 (2.3)
6 (66.7)
9 (100)
Extramedullary
5 (1.3)
1 (20)
5 (100)
* - The database was continuously supplemented by new cases. This table represents the latest version analyzed in May 2010
including 383 patients
Visual disorders were common in patients with lesions occupying the occipital or temporooccipital region and appeared in six cases. Memory disorder was an initial manifestation in six
patients. In three patients with cavernomas affecting the hypothalamus and/or hypophysis,
hormonal alterations were identified. One patient with basal ganglia cavernoma exhibited a
hyperkinetic movement disorder.
Acute exacerbation of symptoms was typically caused by a cavernoma hemorrhage. In total, 147
73
patients (38.4%) suffered from a radiologically confirmed symptomatic hemorrhage. Single
hemorrhage before admission occurred in 118 of 147 patients (80.3%). In 18 cases (12.2%), the
patients experienced two episodes of hemorrhages, in seven cases (4.8%) three hemorrhages, and
in two cases four hemorrhages before admission. Neurological deterioration caused an
emergency hospitalization in 57 patients (14.9%). Surgical removal of the lesion was performed
within one week after bleeding in 21 of 145 patients (14.5%). In 64 cases (44.1%), a hemorrhagic
cavernoma was excised within a six-month period after the bleeding.
Radiology
Due to progressive neurological deterioration patients were investigated with CT and/or MRI. A
CT-scan as a primary and easily available radiological method was performed on 327 patients
(85.4%) with a brain cavernoma. To exclude high-flow vascular anomalies, CT angiography was
performed in the same session on 88 patients (23%). Later, MRI was ultimately performed on all
patients with any suspected finding on CT to verify a cavernoma. All but ten patients were finally
imaged by MRI. Additionally, 38 patients (10%) underwent DSA. None of them showed obvious
signs of pathological vessels or abnormal filling.
On MRI, cavernomas presented with a typical heterogeneous core surrounded by a hypointense
rim in most of the cases. Perifocal edema was uncommon. In cases of acute extralesional
hemorrhage, MRI showed a hyperintensive blood clot and cavernoma could not be reliably
diagnosed. Thus, after 6-8 weeks, when extravasated blood was resorbed, patients underwent
repeated MRI to verify the source of the bleeding.
Treatment
Surgical removal of a cavernoma was performed on 303 patients (79%). Operative treatment was
mainly indicated when a lesion manifested with progressive neurological symptoms, and had
radiological signs of bleeding. Furthermore, 31 of 63 patients (49.2%) with incidentally found
asymptomatic cavernomas were operated on (Table 16). In these patients, surgery was considered
as appropriate because of a superficial location of a midsize or large lesion (more than 10 mm)
with MRI showing intraluminal blood at various stages of organization together with an easy
access to the lesion without any risk of damaging eloquent areas. Conservative treatment, by
contrast, was more rational in elderly patients who had a small, radiologically inactive lesion
without signs of hemorrhage and/or growth on follow-up MRI. Spinal lesions were excised in all
patients regardless of the severity of neurological deterioration due to their propensity for an
aggressive clinical course.
In 259 of 303 operated patients (85%), a gross total removal was provided at the first attempt.
Despite using neuronavigating assistance (frame-based or frameless), in 19 patients (6.3%) a
74
cavernoma was not found, and 15 of them were re-operated on later, whereas four refused a reoperation. Twenty-one patients (7%) underwent a re-craniotomy due to incomplete resection of a
cavernoma. One patient with an intraventricular lesion was shunted because of hydrocephalus,
but later refused cavernoma removal. In one patient with uncertain MRI diagnosis, a biopsy was
performed, which verified a cavernoma. The patient refused a re-operation and lesionectomy.
Table 16 Summary of clinical manifestations registered in the Helsinki Cavernoma Database
Symptoms
No. of patients
(%)
History of
bleeding (%)
Operated on
(%)
Epileptic disorder
141 (36.8)
48 (34)
128 (90.8)
Focal neurological deficit
76 (19.8)
23 (31)
67 (81.2)
Headaches
74 (19.3)
43 (57.3)
63 (85.1)
Vertigo
13 (3.4)
2 (15.4)
4 (30.8)
Visual disorder
6 (1.6)
-
2 (33.3)
Memory disorder
6 (1.6)
1 (16.7)
5 (83.3)
Endocrinologic disorder
3 (0.8)
-
2 (66.7)
Hyperkinetic movement disorder
1 (0.3)
-
1 (100)
63 (16.4)
-
31 (49.2)
Incidental
Outcome
The mean follow-up time in this series was five years (range 0.2 – 36.2). Operated patients were
followed on average for 5.6 years (range 0.2-36.2) and conservatively treated patients for 2.7
years (range 0.2-15.8). The vast majority of the patients showed a favorable general outcome
(GOS 5 and 4) as 342 (89.3%) had no disability or only minor symptoms without significant
limitation in every day activity. Eight patients (2%) had severe disability (GOS 3). Six of these
patients had a symptomatic brain stem lesion, which was operated on. Furthermore, in one patient
with multiple cavernomas surgical removal of a symptomatic lesion was performed at another
hospital, but inadvertent injury to the median cerebral artery occurred leading to a massive infarct
with subsequent hemiplegia and drug-resistant epilepsy. One patient had cardiac failure causing
severe disability but notably, recovery after his frontal lobe cavernoma removal was uneventful.
Four patients died during the follow-up and the overall mortality was 1%. Three of these patients
died for reasons unrelated to a cavernoma, and one patient died after surgical removal of a brain
stem cavernoma.
75
Clinical data on the 12 patients are summarized in Table 10. Patients comprised eight men (67%)
and four women (33%) showing a men preponderance of 2:1. The median age of the patients on
admission was 47 years (range 15 – 66 yrs). As a presenting symptom, 11 patients (92%) had an
acute mild to severe headache accompanied by nausea and vomiting. Three patients (27%) with a
cavernoma in the fourth ventricle had cranial nerve deficits (paresis of III, VI, and VII nerves,
separately or in various combinations). Four patients (36%) had hydrocephalus on admission but
shunting was necessary in only one patient.
Eight patients (67%) experienced extralesional hemorrhage confirmed by CT and lumbar
puncture. In all but patient 12, bleeding was clinically and radiologically mild, and none of them
required emergency surgery. Patient 12 had a large hematoma in the lateral ventricle which
invaded the basal ganglia area, and presented with contralateral hemiparesis and progressive
somnolence warranting emergency surgery.
Re-bleeding occurred in three patients before lesionectomy and in two conservatively treated
patients. One patient had two re-bleedings after partial resection of his lesion in the left lateral
ventricle. A total of eight re-bleedings occurred in five patients (42%) during a median time of
0.4 years (range 0.1–5 yrs). These patients had a cumulative follow-up time of nine patient-years
(from the first bleeding to surgery in operated patients, or from the first bleeding to the last
follow-up in conservatively treated patients), thus yielding a re-bleeding rate of 89% per patientyear. None of the re-hemorrhages caused severe neurological deterioration, but led to a shortterm hospitalization at referring hospitals. Later, patients were admitted to our department in
stable condition for further evaluation and treatment.
Radiology
The lesions and their location and size are presented in Table 17. In 11 patients, the
intraventricular cavernomas were Zabramski type II lesions and in patient 12 type I. In
comparison with the cavernomas of the group B, the typical perifocal hemosiderotic rim in group
A cavernomas was thinner or absent, and the lesion core was less heterogeneous. Altogether, ten
lesions belonging to group B were partially buried in the surrounding brain. In addition to an
IVC, three patients had multiple type IV intraparenchymal cavernomas seen only in T2*weighted Gradient-Echo sequences. In two patients, the lesion was initially interpreted as a
choroid plexus papilloma and ependymoma, respectively, but a later histological examination
confirmed it to be a cavernoma. In the other ten patients, the radiological diagnosis was initially
76
thought to be IVC.
Six of the 12 IVCs were located in the lateral ventricle, mainly on the left side (Figure 18). In
three cases, cavernomas were located on the lateral side of the body and atrium (trigonum) of the
lateral ventricle. One patient had a lesion in the occipital horn of the lateral ventricle, attached to
the choroid plexus (Figure 3a, b), and two patients had an IVC in the frontal horn, attached to the
ependyma. One IVC was in the third ventricle without radiological signs of enlarged ventricles.
In five patients (45%), an IVC was found in the fourth ventricle typically in the medial part of the
floor (Figure 4a, b).
The median size of the IVCs was 15 mm (range 10– 30 mm). IVCs of the lateral ventricles
(median size 12 mm) were smaller than the ones of the fourth ventricle (median size 17 mm). The
median size of the associated intraparenchymal cavernomas was 3 mm. Two patients, each with a
cavernoma in the lateral ventricle, had an associated MRI-confirmed developmental venous
anomaly.
Figure 18 Left lateral ventricle cavernoma. a – T2-weighted image, axial view; b - T2*-GRE image, axial view
a
b
Treatment
Nine patients underwent surgical excision of the IVC to prevent re-bleedings or to eliminate the
mass-effect, or both. Median time from diagnosis to surgery was 1.3 years (range 2 days to
11yrs).One patient underwent emergency surgery because of a large intraventricular/intracerebral
hematoma and progressive somnolence. Of the operated IVCs, three were located in the lateral,
one in the third, and five in the fourth ventricle. In patients 3 and 12, a lesion of the left frontal
77
horn was exposed by paramedian craniotomy by an interhemispheric-transcallosal approach.
Patient 5 with a cavernoma of the atrium of the left lateral ventricle was operated on three times.
Initially, he underwent diagnostic stereotactic biopsy for an undefined lesion after intraventricular
hemorrhage. Two months later he presented with intraventricular re-bleeding and was operated
on via a parieto-occipital craniotomy and a transcortical approach to the ventricle. Four months
after the first resection, he suffered from worsening headaches again; a CT scan showed
intracerebral/intraventricular bleeding which was removed together with a cavernoma remnant.
An MRI performed seven years after surgery still showed a small cavernoma remnant, but the
patient refused further surgery. Patient 7 with a cavernoma in the third ventricle was operated on
via a fronto-parietal paramedian craniotomy and an interhemispheric-transcallosal-transseptal
approach. In this case, a strongly calcified lesion was evident in the region of the foramen of
Monroe without hydrocephalus, grew upward into the septum pellucidum cavity, and had to be
removed in a piecemeal manner. In five patients with fourth ventricle lesions a median
suboccipital craniotomy was performed with the patient in a sitting position. The fourth ventricle
was exposed via a telovelar approach by retraction of the cerebellar tonsils laterally.
Table 17 Radiological presentation of intraventricular cavernomas on MRI
(LV- lateral ventricle, FV- fourth ventricle, TV- third ventricle)
Patient
Location
Side
LV
left
Size
(in mm)
10
2
FV
left
18
3
LV
left
10
4
FV
left
10
5
LV
left
20
6
FV
midline
30
7
TV
midline
25
8
FV
midline
15
9
LV
right
10
10
FV
midline
10
11
LV
left
12
12
LV
left
10
1
Extremely gentle dissection of the lesion from the floor of the ventricle was performed. Tiny
arterial feeders were coagulated with bipolar forceps under minimal voltage to avoid inadvertent
damage to the subependymal vessels supplying the brain stem. In all of these patients, the
cavernoma was partially buried in the brain stem, necessitating more invasive removal.
78
Postoperative complications are summarized in Table 18. One patient had postoperative
intraventricular bleeding after partial resection.
Outcome
The median follow-up of the 12 patients was two years (range 0.5 – 20 yrs) and total follow-up
time was 70 person-years. No patients were lost to follow-up. Age, sex, and previous bleeding
had no influence on the outcome. No mortalities occurred. Patients with fourth ventricle
cavernomas had a worse outcome than did those with lateral ventricle lesions.
Five of the nine patients operated on were symptom-free at follow-up (Table 18). The IVCs in the
lateral ventricles and in the third ventricle were removed without any new permanent
neurological deficits. A new cranial nerve deficit was seen postoperatively in patients 6 and 8
with a fourth ventricle lesion. Patients 4, 6, 8 and 12 presented with focal neurological deficits
before surgery; patient 12 demonstrated complete recovery of his hemiparesis and had only mild
memory disturbances at the five-year follow-up. Patient 7 had significant memory disturbances in
the immediate postoperative period, but these completely resolved at the last follow-up at 1.7
years. One patient had a single epileptic seizure after partial resection of the lateral ventricle
cavernoma, but after a re-operation and removal of the lesion the patient was seizure-free.
Altogether, nine patients (75%) were asymptomatic or with only minor neurological problems,
and three (25%) had persistent neurological deficit at the last follow-up. Two of them had deficits
(VI, VII nerve paresis and memory disturbances in patient 4 and 12, respectively) before surgery.
No patient had a severe disability.
Table 18 Postoperative course and complications after microsurgical treatment of nine patients
with IVC
Patient
On discharge
Follow-up
2
Nausea, vomiting, gait disturbances
no neurological deficits
3
Nausea, no new deficits
4
Worsening of
preoperative CN VI, VII paresis
CN VI,VII peripheral paresis the same as
preoperatively
5
Visual disorders and epileptic fit after first
resection, no deficits after the last surgery
(continued)
79
Table 18 Postoperative course and complications after microsurgical treatment of nine patients
with IVC (continued)
6
new focal deficits –
CN VII peripheral paresis, double vision,
vertigo and gait disturbances
persistent CN VII peripheral paresis
7
emotional alteration,
severe memory disturbances
8
new focal deficit CN VI, VII paresis, worsening of preoperative
double vision, vertigo and gait disturbances
CN VI, VII paresis
10
Nausea and vomiting
12
hemiparesis and memory disturbances the
same as preoperatively,
only minor memory disturbances,
hemiparesis resolved completely
Discussion
Special clinical features
IVCs showed increased propensity for extralesional hemorrhage. In our consecutive series of the
12 IVC patients, eight (67%) experienced hemorrhage. Furthermore, the rate of re-hemorrhage
was much higher than in other locations. In the literature, the re-bleeding risk is declared to be
5.1 - 60% per patient-year [2, 91, 94, 160, 237] being significantly lower than the 89% per
patient-year demonstrated by our series. No data exists on the hemorrhage rate in IVC patients
and the value of our results may be limited by the small size of the series but aggressiveness of
previously bled IVCs was evident. In earlier reports, only 11 of 77 patients (14%) presented with
IVH which is much less than in our series. Possibly, this is due to a more active policy of local
general practitioners to send patients complaining of headaches for further evaluation. Immediate
availability of CT imaging in all local district hospitals allows these patients to be imaged quickly
after the disease onset, thus giving more chances to reliably diagnose fresh bleeding. A delay of
even a few days decreases the sensitivity of CT to identify extravasated blood, especially when
the hemorrhage is scanty. Profuse bleeding is not common in IVC patients, and in the present
series, it caused no permanent neurological deficits in 11 patients. Only one patient had major
bleeding that was potentially life-threatening and necessitated emergency treatment. During the
short period of observation, five patients (45%) had altogether eight re-bleedings. However, in all
but one neither the re-bleedings nor the primary bleedings led to any additional neurological
deficits and required no emergency surgery. This is also in concordance with previous reports,
where in the majority of cases, re-bleedings from IVC caused no significant permanent
80
neurological deficits.
In our series, four patients (36%) had a hydrocephalus on admittance, but only one of them was
shunted. In the literature, 42% of patients with IVC had a third ventricle lesion, and the majority
of them developed hydrocephalus because of mechanical obstruction, whereas only three patients
[123, 149, 320] presented with an intraventricular hemorrhage. At the same time, cavernomas of
the lateral or fourth ventricles most frequently led to focal neurological deficits as a result of the
mass-effect on the surrounding brain with acute impairment after bleeding (Figure 19).
In our series, epileptic disorders occurred in one patient but only after partial resection of a lateral
ventricle cavernoma, and this patient was seizure-free at the follow-up. In previous reports of
patients with IVC, epileptic manifestations were more frequent, occurring in up to14% and
almost exclusively in individuals with a lateral ventricle lesion. Thus, the frequency of seizures in
IVC patients is significantly lower than in patients with intraparenchymal supratentorial
cavernomas.
Figure 19 Fourth ventricle cavernoma in a patient with progressive paresis of the left hand and ataksia in legs
Special radiological features
In patients with acute severe headaches, a CT scan is mandatory because of its high sensitivity in
detecting fresh hemorrhage. However, in acute intraventricular bleeding the radiological
diagnosis of the IVC is unreliable, and MRI is more informative after the resorption of
81
extravasated blood. In our series, MRI with MRA was performed immediately after bleeding only
in patient 12 because of acute neurological deterioration to exclude tumor bleeding. DSA is also
indicated to exclude an AVM when patient presents with a major intracerebral bleeding, which,
however, is uncommon in individuals with a cavernoma. A cavernoma in the ventricle is not
always limited by the ependyma and can extend to the surrounding brain and we classified
cavernomas into three groups, accordingly. Although our classification is only empirically based,
we suppose that in clinical practice the treatment strategy of the cavernomas of group C is quite
similar to intraparenchymal ones.
Treatment of the IVC, morbidity and mortality
Surgery is advocated when re-hemorrhages are frequent and the mass-effect causes progressive
neurological deficits. In our series, repetitive re-hemorrhages accompanied by acute headaches
with nausea and vomiting occurred often and caused discomfort. Furthermore, patients with
fourth ventricle IVC developed cranial nerve deficits because of the mass-effect. A major
bleeding occurred only in one of our patients; although uncommon, this still demonstrated the
potential risk of severe hemorrhage from a cavernoma thus advocating operative treatment of the
IVC. Four of our nine patients who were operated on had neurological deficits that persisted at
follow-up, but in two of these deficits were already present before surgery (Table 18). In
estimating operative risks, the location of the IVC is of major importance. Surgery on the IVC in
the lateral or third ventricle is safer than in the fourth ventricle. Patients with cavernomas close to
the brain stem frequently present preoperatively with cranial nerve deficits as a sign of brain-stem
damage. Therefore, the increased morbidity in our series may be explained by our rather short
follow-up and also by five of the eight patients operated on (63%) having the lesion in the fourth
ventricle where surgical removal is known to entail higher risks.
Future trends
Increasing numbers of incidentally found IVCs are to be expected with the increased number of
MRI examinations. The management of these patients requires meticulous diagnostic work-up
and evaluation of morbidity during the natural course of the disease weighted against the risks of
surgical removal. The most dangerous manifestation of an IVC is a hemorrhage which,
nevertheless, can usually be tolerated well. The development of laboratory tests or new imaging
modalities allowing a lesion that is about to bleed to be recognized even in asymptomatic patients
would be an invaluable aid in a neurosurgeon’s decision-making on how to manage a particular
patient.
82
Multiple cavernomas
In our series, a slight men preponderance was identified; of 44 patients with MCs, 25 were men
(56.8%) and 19 were women (43.2%). Their mean age at diagnosis was 43.6 years (range 4-69
yrs) and 36.3 years (range 0.6-71 yrs), respectively. Five patients (11.4%) were younger than 18
years. Three patients (9%) had an MRI-confirmed family history of cavernomas in first-degree
relatives. Mutation analysis as a routine diagnostic tool was not performed. Seven patients (21%)
were admitted as emergencies with progressive worsening of symptoms, including epilepsy,
headache, nausea, or focal neurological deficits (Table 19). Two patients had significant memory
deficits, confirmed by neuropsychological testing. Three patients had incidentally revealed MCs.
Nineteen patients (43.2%) had a history of one or more symptomatic extralesional hemorrhages;
of these, 12 patients (63.2%) had one, four patients (21%) had two, two patients (10.5%) had
three, and one patient had four bleedings. No statistically significant gender preponderance for
hemorrhages was found.
Altogether, 18 patients (40.9%) had an epileptic disorder, and six of them (33.3%) had an
intracerebral hemorrhage from the cavernoma on admission. The mean age of the patients at
epilepsy diagnosis was 42.1years (range 0.6 to 69 yrs), and there were 11 men (61.1%) and seven
women (38.9%).
Table 19 Clinical presentation of patients with MCs
Symptoms
All patients
(%)
History of hemorrhage
(%)
Seizures
18 (41)
6 (33.3)
Headache
12 (27)
7 (53.8)
7 (16)
6 (85.7)
Memory disorder
2 (4.6)
-
Visual disorder
1 (2.3)
-
Vertigo
1 (2.3)
-
Asymptomatic
3 (6.8)
-
83
Figure 20 Patient with hundreds of type IV cavernomas. a - T2*-GRE image, axial view; b - T2-weighted image,
axial view. Type IV cavernomas can not be seen whereas Type II and III lesions are evident
a
b
Radiology
One patient had 532 lesions, most of them belonging to Zabramski type IV (Figure 20). This
patient was considered a statistical outlier and omitted from further analyses.
In the remaining 43 patients, a total of 230 lesions were found. There were 112 cavernomas of
type IV and 13 cavernomas of type I. The number of cavernomas of types II and III was almost
equal (51 and 54, respectively). The median number of lesions per patient was six. Type I
cavernomas were bigger than those of types II and III both supratentorially (average size 24 mm,
12 mm, and 7mm, respectively) and infratentorially (17 mm, 13 mm, and 8 mm, respectively).
The largest lesion (50mm) was a frontal cavernoma of type I that radiologically presented as a
rare cystic form.
In two patients, the measurement and radiological classification of the lesions were unreliable.
One had a conglomerate of cavernomas on the parietal region with growth even through the
parietal bone, and the other had numerous skin and bone cavernomas in the craniofacial region
and in other organs (blue rubber bleb nevus syndrome).
Ten patients (22.7%) had an associated venous anomaly (Figure 21). Three had an associated
meningeoma.
Treatment
Fourteen patients (31.8%) were treated conservatively. Three had numerous small lesions of
84
different radiological types, making removal practically impossible. In six patients, the risks of
microsurgical removal were considered too high because of eloquent location. Three patients
refused any surgical procedures. None of the patients were treated with stereotactic radiotherapy.
Microsurgery was performed on 30 patients (68.2%), and a total of 34 cavernomas were
removed. Surgical treatment was carried out in patients with hemorrhagic and/or epileptogenic
cavernomas that had led to neurological deficits or drug-resistant epilepsy and that could be
safely removed. In the majority of cases, the removed cavernoma was the largest lesion and
usually with signs of recent bleeding. Other cavernomas typically belonged to type III or IV and
were treated conservatively.
Twenty patients (45.5%) were operated on once, whereas eight patients (8.2%) underwent two
procedures, and two (4.5%) had three surgeries. In most cases, surgery entailed the removal of
one lesion. In some patients, two lesions were removed in one session. One of them had three
consecutive bleedings from both lesions, which were located in the medulla oblongata close to
each other and removable with the same approach. Another patient suffered from temporal
complex partial seizures, with transformation to generalized seizures, and the frontal and
temporal lesions on the right side were removed via a frontotemporal approach.
Gross total removal of the symptomatic lesion was accomplished in 26 of 30 cases (86.7%). In
three patients, a lesion could not be localized and removed despite use of neuronavigation, and
these patients refused further procedures. One patient underwent partial resection of the lesion,
which however, remained stable during follow-up. One patient had numerous lesions in the
parietal convexity, with extra- and intracranial growth through the parietal bone and along the left
side of the falx suggesting meningiomas, but surprisingly histology revealed a cavernoma.
Figure 21 DVA in the right basal ganglia region associated with two type IV cavernomas. a - T2*-GRE image, axial
view; b - T1 –weighted image with Gadolinium contrast, axial view; c - T1 –weighted image with Gadolinium
contrast, coronal view.
a
b
c
85
Outcome
The mean follow-up was 7.7 years (range 0.3 - 43 yrs) and the total follow-up was 254 personyears. No patients were lost to follow-up and no deaths occurred. Thirty-four patients (77.2%)
had no disability (GOS V), nine (20.5%) had moderate disability (GOS IV), and one (2.3%) had
severe disability (GOS III). No statistically significant difference in Glasgow Outcome Score was
observed between nonsurgical and surgical patients at follow-up (Pearson’s chi-square test,
p>0.05). Postoperatively, one patient experienced temporary hemiparesis, and another patient
developed mild expressive dysphasia that persisted over the four-year follow-up.
During the follow-up four patients suffered from a CT-verified intracerebral hemorrhage. All of
them presented with acute severe headache that did not lead to any permanent neurological
deficits or death. Bleedings occurred only in conservatively treated patients. A patient with 532
cavernomas suffered from three symptomatic bleedings during nine years of follow-up. She
recovered well from the hemorrhage-related focal neurological deficits but developed moderate
disability due to progressive psychiatric disorders requiring long-term hospitalization. In other
four patients with history of hemorrhage, three had no disability (GOS V) and one patient had
moderate disability (GOS IV) at the follow-up.
Fifteen patients suffering from seizures were operated on and three were treated conservatively.
Mean follow-up time in this group was 5.8 years (range 0.3-20 yrs). Ten of the 15 patients
(66.7%) became seizure-free with four of them discontinued AEDs (Engel class 1). Three (20%)
had only rare seizures, and none worsened. Of the three nonsurgical patients, one was seizurefree at follow-up whereas two had occasional epileptic seizures despite anticonvulsant therapy. In
patients with Engel I outcome, only minimal doses of anticonvulsants were recommended.
MRI was performed during follow-up on 22 patients (Case 1 was assessed separately, although
MRI follow-up was also performed). The mean time between the primary and the last MRI was
3.9 years (range 0.2 - 17 yrs). In this group, the total number of lesions of all types in the followup MRI was 173. At the primary MRI, these 22 patients had 144 lesions, 25 of which were
removed. Altogether, 54 de novo lesions were found, 48 (89%) belonging to type IV. Follow-up
MRI showed that lesions had changed from type I to II in one patient, from type II to III in one
patient, and from type III to II in one patient. In seven patients (49%), the type II cavernoma had
enlarged by a mean of 2 mm. We also found a decrease in size by 2 mm in two patients with type
II lesions and by 12 mm in one patient with type III lesions.
Discussion
In our series, almost 70% of patients with MCs were surgically treated. A decision of whether to
operate or not and which lesion to remove may be difficult due to the rare possibility to excise all
86
lesions in the same session. Furthermore, lesionectomy of the “wrong” cavernoma would not
alleviate symptoms, but may carry additional surgical risks. Although in our series, the biggest
cavernomas were usually the most active and showed signs of recent bleeding, the remaining
lesions may also bleed or cause epileptic disorder in the future. Usually, those not operated on are
smaller in size, mostly of type III or IV, which seem to be inactive. However, they possess some
potential for transforming to more aggressive types [53]. Still, we cannot predict which lesion
carries the risk for clinical manifestations and whether prophylactic removal of radiologically
inactive cavernomas is advocated. When dealing with a single cavernoma, these questions are
usually not relevant, but patients with MCs naturally necessitate a different way of planning. If
one decides not to operate, observation and follow-up MRI are essential to exclude progression of
the disease, which can be seen either as an increased number of lesions or as an enlargement of
existing cavernomas. Also, conversion to other radiological types is possible. No definitive
recommendations exist on how frequently patients should be imaged for a timely diagnosis.
The dynamic nature of cavernomas could be seen in up to 77% of patients, with lesions
undergoing some volumetric changes [55]. Furthermore, in 50% of our patients undergoing
follow-up MRI, type II lesions enlarged during the follow-up indicating progression of the
disease.
If patients have symptoms supported also by radiological progress, aggressive treatment of the
most active lesion may be warranted, especially in younger individuals. When patients remain
stable or asymptomatic but follow-up MRI shows evolution of the disease, the threshold of the
surgeon to operate should be much higher.
Risks of bleeding and epilepsy in MC patients are higher than in patients with single lesions
increasing with the number of type I-III lesions. [168, 235, 343] No data exist about the
epileptogenicity or bleeding potential of type IV cavernomas, which occur most frequently in MC
patients. However, in 89% of our cases these lesions were de novo cavernomas and reflected
radiological progression; similar data have been obtained by other authors [168, 169, 343].
In our series, no bleedings occurred in operated patients during the follow-up. We had no patients
with bleedings from two or more lesions simultaneously. Four conservatively treated patients had
a hemorrhage during the follow-up. Although we did not find a statistically significant difference
in Glasgow Outcome Score between operated and nonoperated patients, we believe that surgical
removal of the most aggressive “correct” lesion will diminish the overall hemorrhage and
epilepsy risk, and thus, is beneficial for the patient.
Epileptic seizures occurred in 41% of our patients, indicating surgery especially when epilepsy
was drug-resistant. In 35% of the patients with seizures, the lesion had bled on admission, which
was also an indication for surgery. Of the surgically treated patients, 67% were seizure-free at the
last follow-up (Engel class I), and only minimal doses of antiepileptic drugs were
87
prophylactically used. These data are comparable with previous reports on single cavernomas
[44, 57, 90], confirming the effectiveness of surgical treatment of patients with MCs.
Postoperative seizure-free state has also been reported to be associated with the number of
preoperative seizures and female gender [57]. However, we found no significant correlations
between outcome and gender or age of surgical patients, probably because of the relatively low
number of patients in our study.
Microsurgical techniques used in lesionectomy performed on MC patients are similar to those of
a single cavernoma removal. Minimal invasiveness and a simple and rational approach to avoid
any additional damage to the vasculature or parenchyma will ensure uneventful postoperative
course.
Spinal cavernomas
Basic characteristics of the patients are presented in Table 12. In nine patients (63%), the
cavernomas were intramedullary, while four patients (29%) had an extradural lesion (Table 20)
and one patient [156] had an intradural extramedullary cavernoma with an isolated
intramedullary hemorrhage (Figure 22). The median age at presentation was 45 years (range 2057 yrs), with an equal number of women and men. The median duration of symptoms before
admission to our department was one year (range 24 hrs -14 yrs).
Table 20 Presentation of intra- and extramedullary cavernomas
Characteristics
Intramedullary
(%)
Extramedullary
(%)
Number of patients
9 (63)
5 (37)
fast
slow
4 (45)
5 (55)
4 (80)
1 (20)
yes
no
6 (67)
3 (33)
1 (20)
4 (80)
Symptom
progression
Hemorrhage
Patients suffered from sensorimotor paresis, radicular pain, or neurogenic micturition disorders in
different combinations or separately as follows, a) Cervical region cavernomas (six patients): two
suffered from severe tetraparesis, two presented with Brown-Sequard syndrome with ipsilateral
paresis and contralateral pain and temperature loss below the lesion, and two had upper extremity
88
Figure 22 Case of extramedullary intradural cavernoma (arrow) causing intramedullary hemorrhage
sensorimotor deficits accompanied by severe radicular pain. Bladder functions were impaired
significantly in only one patient, b) Thoracolumbar region cavernomas (seven thoracic and one
conus medullaris lesion): four patients presented with paraparesis combined with bladder
dysfunction and numbness. Others suffered from drug-resistant radicular pain, numbness, and
motor paresis of one of the lower extremities. Micturition disorders occurred in three patients.
Three patients (21%) presented with acute onset of symptoms, with rapid neurological decline
indicating emergency surgical treatment. Five patients (36%) had a gradual progression of
neurological deficits over one month preceding surgery and six patients (46%) had slow
progression over more than a year. In two patients (14%), the symptoms improved before
admission to our hospital, but surgery was performed to prevent hemorrhage and potential
neurological decline.
Hemorrhage occurred in seven patients (50%) before surgery. Four of them experienced acute
neurological deterioration, warranting further investigations immediately after onset. However,
two patients with hemorrhage did not have acute onset of the disease, deteriorating slowly over
the course of several weeks. On MRI, signs of a recent hemorrhage were found. One patient had
symptomatic re-bleeding after 14 years of follow-up; he was intact after the first hemorrhage
which was treated conservatively, but deteriorated acutely due to re-hemorrhage, indicating
surgical removal of the lesion.
89
Treatment
Indications for microsurgical removal of a spinal cavernoma were progressive neurological
deterioration in 12 patients (86%) and prevention of bleeding and consequent neurological
decline in the remaining two patients (14%). Three patients (21%) with a sudden onset of the
disease were operated on within 24 h. Two of them with a cervical cavernoma developed severe
tetraparesis and one with a lower thoracic cavernoma developed complete paraparesis.
Nine patients (64%) underwent a hemilaminectomy and five (36%) a laminectomy. In cases of
hemilaminectomy, the exposure was performed on the appropriate side to minimize the distance
to the lesion. In patients with an epidural cavernoma, a lesion was revealed in the epidural space
immediately after removal of the ligamentum flavum. Intradural cavernomas were approached by
a sharp incision of the dura and arachnoid and exposure of the affected medullary segment.
Myelotomy was performed at the discolored or bulging medullary surface suggesting a
cavernoma or the site where the lesion had surfaced. When the location of the IC was
indistinguishable on the surface, a gentle longitudinal incision of the pia and medulla was
performed at the suspected site of the lesion until the pathology was exposed. Due to operating
neurosurgeon preferences, no neurophysiologic monitoring was performed. In cases of a
hemorrhage from a cavernoma, the hematoma was aspirated first to decompress the medulla, and
thereafter, the cavernoma was removed in a piecemeal fashion to minimize distortion of the
normal neural tissue. Accurate hemostasis was performed by low voltage bipolar coagulation and
local hemostats. The dura was closed in a watertight manner to prevent CSF leakage. After a
median of five days (range 3 -13) at our department, patients were discharged home or
transferred to referring hospitals for further rehabilitation.
Immediately after surgery, eight patients (57%) showed improvement of the symptoms, while
two (14%) remained the same and four (28%) complained of worsening of symptoms; two of
these patients experienced new neurological deficits.
At discharge, altogether ten patients (71%) experienced improvement of their neurological status,
three (21%) had worsening of the symptoms or some new deficits, while one patient remained the
same.
Four patients (28%) were re-operated on. In two of them, the cavernoma could not be found
during the first operation, one had a re-growth of the removed cavernoma, and one with a giant
cavernoma causing vertebral fracture underwent three posterior decompressions because of
progressive growth of the lesion (laminectomy, followed by re-laminectomy and postoperative
hematoma evacuation) and transpedicular fixation and biopsy of the lesion, followed by
radiotherapy; ultimately with a good outcome.
90
Outcome
Patients were followed for a median of three years (range 1-10 yrs). At the last follow-up, eight
patients (57%) experienced further improvement of their symptoms since discharge two of them
(15%) recovering fully (Table 21). Five patients (36%) had the same neurological disorders as at
discharge from the hospital. One patient (7%) was worse than preoperatively. In seven patients
(50%), their deficits did not affect everyday life, while seven (50%) had some mild limitations.
No patient had severe disability or died.
Table 21 Available postoperative outcome data in the literature and for the present series
Patients
Intramedullary
reported
Intramedullary
present series
Extramedullary
reported
Extramedullary
present series
Worsened
n (%)
Same
n (%)
Improved
n (%)
Total
n
26 (9)
85 (29)
180 (62)
291
1 (12)
4 (44)
4 (44)
9
1 (2)
5 (8)
54 (90)
60
0
1 (20)
4 (80)
5
No difference in outcome was observed between cervical and thoracolumbar cavernomas (Table
22). The extramedullary location proved to be better and safer regarding outcome; four of the five
patients (80%) demonstrated further improvement of symptoms, whereas only four of eight
(50%) with an intramedullary lesion did the same. Five of the seven patients (71%) with a history
of hemorrhage had some disability at follow-up, in contrast to only one of the seven
nonhemorrhagic patients (14%). Aggressive behavior of the disease preoperatively accompanied
by rapid neurological deterioration was detrimental regarding outcome; five of the seven patients
with fast progression (71%) had a worse outcome, while only two patients who deteriorated
slowly (33%) had a poor outcome.
91
Table 22 Follow-up data in present series
Good recovery
without
disabling
deficits
(%)
Mild
disability
(%)
Cervical
Thoracolumbar
3 (50)
4 (50)
3 (50)
4 (50)
Extramedullary
Intramedullary
4 (80)
4 (44)
1 (20)
5 (56)
yes
no
2 (29)
6 (86)
5 (71)
1 (14)
fast
slow
3 (38)
4 (67)
5 (62)
2 (33)
7 (50)
7 (50)
Characteristic
Level
Location
Hemorrhage history
Symptom progression
Total
Recovery from sensorimotor paresis
All patients underwent active rehabilitation after surgery at referring hospitals. Twelve patients
(86%) showed significant recovery of sensorimotor paresis at the last follow-up as compared with
their preoperative state. Five of them were able to walk independently and the remaining seven
with a cane or a rolling walker. Two patients experienced some new permanent sensorimotor
deficits after surgery, which impaired their mobility and ability to work.
Recovery from pain
Ten of the 14 patients (71%) suffered from radicular pain before surgery. During the follow-up
nine of these patients showed significant pain relief and did not complain of any disturbing pain.
Only one patient (10%) developed permanent painful allodynia in her hand.
Recovery from bladder dysfunction
Micturition disorders were registered in six patients (43%) at follow-up, with five of these present
already before surgery. No patient experienced significant improvement of micturition after
surgery. Patients suffered from urinary incontinence, increased residual urine volume, and loss of
92
voluntary emptying of the bladder requiring bladder auto-catheterization daily. Frequent urinary
tract infections were common, often requiring oral antibiotics. Two patients developed
hyperactive bladder disorder with increased urinary frequency of up to 12 times a day
accompanied by urge incontinence. In one of these patients, this disorder was not present before
removal of the cavernoma. One patient was treated with anticholinergics followed by sacral
epidural stimulation performed by an urologist without success.
Discussion
Based on our series, spinal cavernomas can cause marked neurological deterioration due to their
mass-effect or hemorrhage. In fact, 21% of our patients developed acute severe tetra- or
paraparesis within a time span of only a few hours, requiring emergency surgery. In the literature,
acute deterioration was reported in up to 38% of patients, and 70% of these were related to
hemorrhage [75, 171]. Even without an acute onset, cavernomas affecting the spinal cord can
cause neurological deterioration by chronic microhemorrhages into the surrounding tissue, with
subsequent gliosis and progressive myelopathy. Although observation is reported to be an
alternative to active surgical treatment [153], accumulating evidence confirms the dynamic nature
of spinal cavernomas, with a tendency towards clinical deterioration often warranting operative
treatment [140, 171].
Even considering that the annual bleeding rate in spinal cavernomas is relatively low, preventive
removal of cavernomas before hemorrhage is more beneficial for patients than surgery after
bleeding. Postoperative complications are usually mild and mostly transient. Indeed, although
immediately after surgery, one-third of our patients demonstrated worsening of their neurological
status with the appearance of new deficits in some, at the three-year follow-up, only one patient
(7%) complained of significant surgery-related deficits while the others had improved or
symptoms had completely resolved.
In the literature, patients with intramedullary and extramedullary lesions showed improvement at
the last follow-up in 62% and 90% of cases, respectively, in concordance with our series with
corresponding rates of 44% and 80% (Table 21). Persistent worsening of the neurological state
registered at long-term follow-up occurs rarely in both groups, but was more frequent in the
intramedullary location both in the literature and in our series. Therefore, we suggest that the
compression of rootlets by extramedullary mass seems to be better tolerated than myelopathy
caused by intra-axial cavernoma affecting the gray and white matter of the spinal cord from
within. Furthermore, myelopathy caused by cavernoma microhemorrhages aggravated by surgical
manipulation explains the slower recovery process after intramedullary cavernoma removal.
It is unclear whether ECs have different growing patterns or hemorrhage rates than
intramedullary lesions. Interestingly, in our series ECs were characterized by a fast progression of
93
neurological deficits in 80% of the cases, in contrast to only 45% for ICs. However, only one of
the five patients with ECs presented with a hemorrhage. Thus, one of the reasons may be a faster
growing pattern of extramedullary lesions.
In our patients, thoracic cavernomas were less common than reported previously, constituting
50% of cases, while cervical cavernomas occurred in 43%. None our patients had a cavernoma
involving the cauda equina, which is extremely rare in the literature, with only 14 cases described
to date.
Prognosis
In our series, the follow-up period was a median of three years, being long enough to reliably
assess the postoperative course. An extramedullary location and slower neurological deterioration
in IC cases before surgery appeared to be beneficial regarding functional outcome. Most of our
patients (93%) improved or remained stable in concordance with previous reports [143]. Age, sex
and severity or duration of symptoms before surgery did not correlate with outcome. In contrast,
some authors have reported that shorter duration of symptoms before surgery was related to a
better outcome particularly in ECs [349]. Hemorrhage had a strong association with a worse
outcome; five of our six patients with motor disability at follow-up had a hemorrhage before
treatment, while six of seven nonhemorrhagic patients demonstrated no disability. Furthermore,
patients with a rapid progression of neurological deficits had a worse postoperative outcome in
71%, while slow deterioration led to an unfavorable outcome in only 33%.
In previous reports, scrupulous depiction of the persistent neurological status at the long-term
follow-up was uncommon; status was most frequently assessed using gradation as follows:
worse, same, or improved. In our series, we analyzed recovery from sensorimotor deficits, pain,
and bladder disorders separately.
Patients with sensorimotor deficits
Recovery from a sensorimotor deficit seems to be quite probable, as most (86%) of the patients
experienced significant improvement in mobility and all patients were able to walk with or
without aid. However, two of our patients demonstrated progressive decline of motor function
after surgery. One of them was operated on three times because the lesion could not be identified
at the first attempt, and the second surgery was limited to biopsy only. Finally, in the third
operation the cavernoma was removed, and afterwards the patient could walk with some
spasticity. The other patient with a lower cervical lesion was operated on one year after the onset
of symptoms and before surgery her deficits had disappeared. After surgery, she developed
tetraparesis which resolved significantly but her left hand remained weaker and her legs were
atactic.
94
Patients with pain
Our patients demonstrated good recovery from pain in 90% of cases. No difference existed
between extra- and intramedullary cavernomas regarding pain relief. Only one patient
complained of gradually worsening pain, which appeared after removal of the cavernoma with
only partial alleviation after medication (allodynia). In our series, there was no pain recurrence at
follow-up among those who presented with pain before surgery. This finding is opposite to the
reported data, in which long-term pain resolution was shown in up to 50% of the patients, while
others had recurrent pain [154].
Patients with bladder dysfunction
Although bladder disorders were present in one-third of our patients, comparison with other
studies can not be made since published outcome data after surgery on bladder function are
nonexistent. Naturally, this defect is important clinically and socially, especially in young adults.
Micturition disorders remained almost unchanged in all of our patients presenting with a bladder
dysfunction preoperatively. Furthermore, one patient developed micturition disorders after
surgery. Typically, at onset, patients presented with an atonic bladder with urine retention
requiring catheterization preoperatively. During the postoperative period two patients developed
hyperactivity and dyssynergy of the bladder, with high daytime urinary frequency and urge
incontinence.
In total, 49 patients were operated on. Patient demographics are presented in Table 13. The
women:men ratio was 2.5:1. The median age of the patients at radiological diagnosis was 37
years (range 7-64 yrs). Epileptic seizure was the most frequent symptom occurring in 40 patients
(82%). The median duration of seizure activity before surgery was three (range 0.1-23) years. In
these patients, the cavernoma was diagnosed at a median of 0.7 years (range 0.1-22 yrs) before
admission to our department. Seizure had begun within one year before surgery in 16 patients
(40%), between one and ten years in 14 patients (35%), and more than ten years before surgery in
ten patients (25%). Of the 40 patients with seizures, 28 (70%) presented with secondary
generalized tonic-clonic (SGTC) seizures, five (12%) with simple partial (SP) seizures and seven
(18%) with complex partial (CP) seizures. The type of epileptic seizure preoperatively was the
same as at presentation in 18 patients (45%). Notably, ten patients (25%) had not experienced any
new seizures after the first one. The median age of the patients in this group was 31 (range 10-52)
95
years. In 16 patients, the number of preoperative seizures ranged from two to five, and 14 patients
had numerous seizures before surgery. Four patients with epilepsy (10%) complained of mild
memory disorders which did not limit everyday life and the referring clinician had not considered
worthy of neuropsychological testing. The preoperative seizure type and frequency of epilepsy
are presented in Table 23. Seven patients (18%) with only one seizure did not use any
antiepileptic drugs (AEDs), 26 (65%) had monotherapy and seven (17%) had polytherapy. In 21
patients (53%), seizures occurred despite the use of at least two basic AEDs. Three patients
without a history of seizures (6%) complained of headache and two (4%) had minor short-term
memory disturbance at presentation. Three patients (6%) had an incidental cavernoma on MRI.
Before surgery, nine patients (18%) had a hemorrhage confirmed by CT. Altogether, 12
bleedings occurred; seven patients had a single event, one had a re-bleeding, and one had two rebleedings. None developed life-threatening hemorrhage. All of these patients were operated on
within six months of the event.
Table 23 Data of 40 patients with a preoperative history of epilepsy
Characteristic
SGTC (n=28)
CP (n=7)
SP (n=5)
3 (0.1-30)
5 (1-26)
1 (0.5-18)
1
7 (25%)
2 (29%)
1 (20%)
2-5
13 (46%)
1 (14%)
2 (40%)
6-10
3 (11%)
1 (14%)
-
10+
5 (18%)
3 (43%)
2 (40%)
Normal
7 (35%)
1 (14%)
3 (100%)
Pathological with
epileptiform
activity
13 (65%)
6 (86%)
-
Same as on debut
12 (43%)
3 (42%)
3 (60%)
Partial only
1 (4%)
-
-
Both partial and
secondary generalized
7 (25%)
2 (29%)
1 (20%)
Median duration of epilepsy
preoperatively, years (range)
No. of seizures
preoperatively
First EEG**
Type of
seizures
during
observation
* Type of seizure on debut
** Performed on 30 patients
96
Treatment
A decision to operate was based on our department’s policy stating that any symptomatic
cavernoma should be removed when surgery can be performed without considerable neurological
deficits. The goal of the surgery was not only to improve the persistent symptoms but also to
prevent any deterioration due to a cavernoma hemorrhage. Lesionectomy was performed in 38 of
40 patients (95%) presenting with seizures. The two remaining patients had an epilepsy history of
more than ten years and were evaluated by our epilepsy team. In both, ictal video EEG detected a
temporal epileptic focus and MRI showed an abnormal hippocampus. In addition to removal of
the cavernoma, one patient underwent amygdalo-hippocampectomy and the other temporal lobe
resection.
Cavernoma excision was performed using standard microsurgical techniques. When located in
the anteromedial part of the mesial temporal region, the cavernoma was removed via a
transsylvian approach, and in other locations transcortically using the shortest route to the lesion.
When appropriate, intersulcal dissection was used to minimize cortical damage. Surgery was
usually facilitated with a frameless neuronavigation system, and in 45 patients (85%), the
cavernoma was found and removed completely at the first attempt. Removal of surrounding
gliosis and hemosiderosis was included whenever considered safe.
In two patients, the cavernoma was not found despite neuronavigation, and a re-operation after
re-scanning became necessary. In two other patients, after a seemingly complete removal, the
MRI showed a residual cavernoma, and a re-operation was performed.
Outcome
Seizure outcome
Follow-up data were available for 39 patients with seizures. One patient coming to Finland for
surgery from abroad was lost to follow-up. Median follow-up in this group was six (range 1 – 26)
years after surgery (Table 24). All ten patients who had only one seizure preoperatively were
seizure-free during the follow-up. Of 16 patients who had experienced between two and five
seizures preoperatively, 11(69%) were seizure-free, and of 13 patients with numerous seizures
preoperatively, nine (69%) were seizure-free. Three patients (5%) had only a minor improvement
of their epilepsy (Engel class III), and one had worsening of the symptoms, all four with
numerous seizures before surgery.
Neither type, duration of seizures, nor location of the cavernoma inside the temporal lobe
correlated with postoperative seizure outcome. Only one of the ten patients who had epilepsy for
more than ten years had an unfavorable outcome. The predictive value of preoperative EEG was
stronger, and eight of the ten patients (80%) with normal preoperative EEG were seizure-free at
97
follow-up, whereas only 11 of the 18 patients (61%) with epileptiform abnormalities in
preoperative EEG were seizure-free after surgery. Seven of the eight patients with epilepsy who
had a radiologically confirmed hemorrhage from the cavernoma had a favorable seizure outcome,
five being completely seizure-free. Neither the volume nor the number of bleedings correlated
with seizure outcome.
In 15 patients (39%), AED had been withdrawn or the dosage had been decreased during the
follow-up. In some cases, an EEG abnormality had postponed the attempt to withdraw
medication, but in the majority of cases the reason for postponement was fear of seizure
recurrence.
Table 24 Seizure outcome data
Characteristic
AED after surgery
Engel outcome at the last
follow-up
History of
seizures (n=39)
Finished
10 (26%)
Dose diminished
5 (13%)
Same dose
13 (33%)
Never used
7 (18%)
Dose increased or
additional AED
4 (10%)
Class I
30 (77%)
Class II
5 (13%)
Class III
1 (2%)
Class IV
3 (8%)
At follow-up, 13 patients (33%) continued with the same AED at the same dosage as before
surgery, and three (8%) of them had numerous seizures after surgery. In the latter group, one
patient had a concurrent psychiatric disorder with drug abuse and inadequate medication
compliance. In another patient, hippocampal signal abnormality was observed on follow-up MRI.
The third patient with an unfavorable outcome had undergone temporal lobectomy due to
hippocampal sclerosis in addition to removal of the cavernoma.
General outcome
Favorable outcome (GOS 5 and 4) was seen in 46 (96%) of the 48 patients, only one patient (2%)
had a severe disability (GOS 3) because of a worsened memory deficit, and one patient (2%) died
98
(GOS 1) because of unrelated liver insufficiency. All patients were followed up for a median of
six years (0.2 – 26 yrs) after surgery. Two patients had a postoperative subdural hematoma
needing evacuation but recovered well. Two patients had a mild visual field deficit, one had mild
dysphasia, and one had mild vertigo (Table 25).
Table 25 Postoperative course
Characteristics
Before
discharge
At followup
No complications
41
36
Acute subdural hematoma
2
-
2
2
Meningitis
1
-
Wound infection
2
-
New/worsened memory
disturbances
4
4
Dysphasia
1
1
Coordination problems
-
2
12 (24%)
9 (18%)
Overall morbidity
At follow-up, nine patients (18%) had a new or worsened neurological deficit. Two of them (4%)
developed a new mild memory deficit. Of six patients with a mild memory deficit before surgery
the memory function worsened (moderate and severe) in two and improved in one. Only three
patients underwent testing by a neuropsychologist. One patient with a mild disorder was
examined with a routine MMSE test in a local hospital. Memory disorder was present in five
patients with a history of epilepsy, but four of these patients already had this problem
preoperatively (Table 26). In one patient with progressive memory decline, an MRI ten years
after the operation showed bilateral hippocampal atrophy (Scheltens grade III). Although the
continuing seizure activity was believed to have contributed to the cognitive deficits, Alzheimer's
disease was also suspected at the last follow-up visit.
Median duration of preoperative seizures in patients with memory disorder was 5.2 years (range
3-28 yrs). They were followed over a median of 4.2 years (range 0.2-20 yrs) after surgery.
99
Location of the cavernoma inside the temporal lobe did not correlate with the severity of the
memory problem. We found no correlation of general outcome with age, side or size of lesion,
bleeding status, or type or frequency of seizures. However, patients with a cavernoma in the
medial part of the temporal lobe had worse postoperative outcome compared with those patients
with the lesion in the anterior or posterior part of the temporal lobe (Table 27).
None of the asymptomatic patients developed deficits postoperatively, and all of them remained
intact during the median follow-up of eight years (range 2-9 yrs).
Table 26 Patients with memory disturbances at the last follow-up
Discussion
Characteristic
No. of patients
(%)
Gender
Indications for surgery
Temporal
Male
Female
1 (14.3)
6 (85.7)
lobe
cavernomas
are
frequently
associated with epileptic disorders and are often
drug resistant. This tendency was also discovered in
Type of
present)
seizure
(if
SGTC
CP
SP
our series, since 53% of patients had seizures
3 (42.9)
1 (14.3)
1 (14.3)
refractory to AED. No exact data explain the
mechanisms of high epileptogenicity of TLCs, but
close distance to limbic structures is likely to be a
Location
cause
MTL
ATL
PTL
3 (42.9)
2 (28.6)
2 (28.6)
Lateralization
of
intractable
Furthermore,
seizure
progressive
activity
damage
of
[15].
the
mesiotemporal region, followed by subsequent
cognitive deficits and behavioral alterations with a
left
right
6 (85.7)
1 (14.3)
higher incidence of suicide attempts or accidents is
existed preop
improved postop
new postop
worsened postop
6 (85.7)
1 (14.3)
2 (28.4)
2 (28.4)
necessitating prompt treatment of epileptogenic
Course
4 (57.1)
1 (14.3)
General outcome
good recovery
moderate disability
severe disability
in patients with temporal epilepsy
cavernomas in the temporal region [265, 266]. In
these cases, surgical removal of the epileptogenic
cavernoma is indicated to eliminate negative effects
Epilepsy outcome
favorable
not favorable
observed
of chronic epilepsy. Results of operative treatment
of TLCs reported previously and also documented
in our patients confirm the effectiveness of this
4 (57.1)
2 (28.4)
1 (14.3)
strategy. In our series, 90% of patients experienced
improvement in seizure frequency, with 77%
becoming seizure-free after surgery. Although 25% of our patients had only one seizure before
surgery, convincing improvement in close to 70% of patients with chronic epilepsy showed
100
obvious benefits of lesionectomy.
Table 27 Correlation of Glasgow Outcome Score with location of cavernoma
Glasgow Outcome Score
MTL
ATL
PTL
GOS 5
7 (58%)
13 (86%)
20 (95%)
GOS 4
4 (34%)
1 (7%)
1 (5%)
GOS 3
-
1 (7%)
-
GOS 1
1 (8%)
-
-
Predicting the development of epilepsy in an individual patient is still not possible. Only ten of
our patients had one seizure preoperatively and some of them had no AEDs before surgery. A
single seizure may not indicate major epileptogenic potential of a lesion, and it is quite possible
that no further seizures would have occurred, or if so, they might have easily been controlled by
medication. In our series, the average age of the patients with a single seizure was only 31 years.
Considering that the cavernoma is often characterized by radiological changes and clinical
progression, we felt that even one seizure warranted surgery in this particular group, thus
reducing the likelihood of adverse events and decades of costly medications.
Almost all of our patients underwent lesionectomy alone, with some resection of the
hemosiderotic perilesional tissue in safe zones. No consensus exists regarding indications for
additional mesiotemporal lobe resection. However, the likelihood of acquiring a seizure-free
stage with medication in temporal lobe epilepsy with mesiotemporal sclerosis is low [278]. When
an apparent MRI abnormality in addition to a cavernoma is seen, a larger resection should be
considered, but confirmation of the seizure focus is required. Postoperative seizure outcome
positive in patients in this series confirms the effectiveness of lesionectomy in cases without
additional MRI abnormalities.
General outcome
The general outcome was worse in patients with a cavernoma located in the mesiotemporal lobe,
mainly manifesting as memory deterioration, and in one patient as a visual field deficit. Only two
of our patients (4%) developed a new memory deficit after surgery, and two had worsening of
previous symptoms. Fifteen percent of patients in our series complained of memory problems at
follow-up, half of these were verified by a neuropsychologist. The other half of the patients had
only a temporary short-term memory decline, without need for further examination or
rehabilitation. Lesionectomy within the temporal lobe can lead to memory problems, especially
101
when the cavernoma is located in the dominant side close to the mesiotemporal region. Frequent
seizures and/or long-term epilepsy may themselves cause memory problems, which was the case
in 10% of our patients.
Atrophy of the hippocampus with subsequent memory deterioration in chronic epilepsy is a welldescribed finding [39, 48]. Nevertheless, the extent of memory deficits and the effect of
individual factors cannot be evaluated in our study since only a few patients underwent
neuropsychological evaluation pre- or postoperatively. Memory disturbance was connected with
cavernomas in all compartments of the temporal lobe, but especially with those in the mesial
compartment.
Predictive factors for a better outcome
In our study, we did not find any correlation between the location of cavernomas within the
temporal lobe and epilepsy outcome. Patients with a lesion in the mesiobasal temporal structures,
e.g. in the uncus or hippocampus, had the same chance of having a favorable seizure outcome as
those with a lateral temporal cavernoma regardless of the duration or frequency of seizures. Thus,
we observed a similar seizure potential of temporal cavernomas, regardless of the distance to the
temporal mesiobasal region. Although this may not seem important, the data may be valuable
when discussing with patients the risks and results of surgery.
Seizure outcome in our series was not dependent on the duration of epilepsy before surgery. The
literature on this issue is controversial [25, 43]. In our series, patients with a seizure history of
more than ten years had the same chance of achieving seizure freedom as those who had had
epilepsy for 0.5-2 years. This finding is not concordant with the theory of secondary
epileptogenesis, which states that a prolonged preoperative history of epilepsy brings an
increased risk for a worse seizure outcome as a result of developing remote epileptogenic foci
[57, 204]. A high seizure frequency before surgery has been shown to worsen postoperative
outcome [57]. In our series, patients with only one preoperative seizure are not relevant for
comparison, but comparing patients with two to five preoperative seizures with those with more
than five seizures revealed no difference in seizure outcome.
Preoperative EEG was performed on 75% of our patients, and those with normal findings had
better chances of being seizure-free at follow-up. This is consistent with the reported correlation
between epileptiform abnormalities after the first unprovoked seizure and seizure recurrence
[312]. However, 68% of our patients with preoperative epileptiform interictal EEG abnormality
were also seizure-free at follow-up. Postoperative EEG findings did not correlate with seizure
outcome in our study. This contradicts the literature in which interictal epileptiform activity on
postoperative EEG is associated with seizure persistence and unfavorable epilepsy outcome [76].
Nevertheless, our conclusions are limited by the small series of patients.
102
VI Conclusions
Due to advancements in neuroradiology, the number of cavernoma patients coming to be
evaluated in neurosurgical practice is increasing. This is supplemented by the growing amount of
cases earlier considered to be rare, and, thus not thoroughly investigated. In the present work, we
summarized our results on the treatment of cavernomas; our findings are supported by the
literature. Particular attention was paid to uncommon locations or insufficiently investigated
cavernomas, including 1. Intraventricular cavernomas; 2. Multiple cavernomas; 3. Spinal
cavernomas; and 4. Temporal lobe cavernomas. After analyzing the patient series with these
lesions, we concluded that:
1. IVCs are characterized by a high tendency to cause repetitive hemorrhages in a short period of
time after the first event. Although not life-threatening in most patients, the hemorrhage caused
symptoms – mainly headache and nausea - which led to short-term hospitalization. Surgery is
indicated when re-bleedings are frequent and the mass-effect causes progressive neurological
deterioration. Modern microsurgical techniques allow safe removal of the IVC, but surgery on
fourth ventricle cavernomas carries increased risk of postoperative cranial nerve deficits.
2. In MC cases, when the cavernoma bleeds or generates drug-resistant epilepsy, microsurgical
removal of the symptomatic lesion is beneficial to patients. In our series, surgical removal of the
most active cavernoma – usually the biggest lesion with signs of recent hemorrhage - was safe
and prevented further bleedings. Epilepsy outcome after surgery was comparable with previous
reports on single cavernomas, showing the effectiveness of active treatment of MCs. However,
due to the remaining cavernomas, epileptogenic activity can persist postoperatively, frequently
necessitating long-term use of antiepileptic drugs.
3. Spinal cavernomas can cause severe neurological deterioration due to low tolerance of the
spinal cord to mass-effect with progressive myelopathy. When aggravated by extralesional
massive hemorrhage, neurological decline is usually acute and requires immediate treatment.
Microsurgical removal of a cavernoma is effective and safe, improving neurological deficits by
mass removal and preventing further hemorrhage, thereby arresting progressive myelopathy.
Sensorimotor deficits and pain improved postoperatively at a high rate, whereas bladder
dysfunction remained essentially unchanged, causing social discomfort to patients.
4. Microsurgical removal of temporal lobe cavernomas is beneficial for patents suffering from
drug-resistant epilepsy. In our series, 69% of patients with this condition became seizure-free
postoperatively. Duration of epilepsy did not correlate with seizure prognosis. The most frequent
disabling symptom at follow-up was memory disorder, considered to be the result of a complex
interplay between chronic epilepsy and possible damage to the temporal lobe during surgery.
103
Acknowledgments
I wish to express my sincere gratitude to the following persons:
Juha Hernesniemi, for giving me the possibility to enter the neurosurgical world and for being
an excellent example of full commitment to the field. He inspired me to perform this work.
Mika Niemelä, whose enthusiasm and patience in conducting this study was truly unlimited.
Through our cooperation I’ve learned to concentrate only on the most important issues in writing
scientific texts.
Esa Kotilainen and Hannu Kalimo, reviewers of this thesis, for their valuable comments.
Reza Dashti, who gave me some very important advices in the early days of the work. This
allowed me to go to the right direction.
My coworkers in publications: Riku Kivisaari, Aki Laakso, Martin Lehe ka, Göran
Blomstedt, Reina Roivainen who kindly shared their experience in helping to create appropriate
manuscripts.
Ville Kärpijoki, for image preparation.
Virpi Hakala and Eveliina Salminen, for their help with matters of organization.
All my neurosurgical, neuroanesthesiological and neuroradiological colleagues who had
influenced me in terms of rational clinical thinking and self-organization. This allowed me to find
enough time to perform this thesis.
Carol Ann Pelli, for language revision.
My closest friends from very early childhood: Mihail, Vladimir, Maksim, Vadim, Pavel. Your
invisible but ever-present support is crucial in my changing surroundings.
Eeva and Esa Mahanen. Your kind hospitality and care helped me so much to go through
numerous difficulties which I experienced, being all alone in a foreign country.
S.V.Rachmaninov
My Nata. With years, I realise more and more how much you have done for me.
My wife Antonina and sons Valentin and Daniil. Nothing is more wonderful than to see you
every day.
My mother. All the crucial steps that I have taken in life were somehow overseen and
predetermined by you. I am the luckiest son to have such a mama.
In Helsinki, December 2010
104
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