Vascular Malformations and Seizures
G. Rees Cosgrove, M.D., F.R.C.S.(C)
MGH Epilepsy Center, Neurosurgical Service,
Massachusetts General Hospital
Harvard Medical School, Boston, Massachusetts
Address for Correspondence:
N. Eskandar, M.D.
Massachusetts General Hospital
15 Parkman St. ACC # 331
Boston, MA 02114
Patient Appointments: 617.724.6590
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Occult vascular malformations are typically
defined as those vascular malformations that are not evident upon
angiographic examination of the brain. The vast majority of occult
VM's are cavernous malformations (CM) and these lesions will be
the focus of this chapter. Other terms that have been used interchangeably
to describe these lesions include cavernous angiomas, cavernous
hemangiomas or cavernomas.
Cavernous malformations are thought
to account for 5 - 13% of all intracerebral vascular malformations
and are frequently associated with intractable seizures. Multiple
lesions are identified in up to 20% of patients.22 They are a common
cause of lesional epilepsy and their incidence appears to be increasing
due to the widespread availability of advanced magnetic resonance
imaging (MRI) and computed tomography (CT). 2 Currently, many patients
with a first seizure will undergo a MRI scan and a "symptomatic
cavernoma" is discovered. In these cases, therapeutic strategies
must be guided by the natural history of the cavernous malformation
and its location in the brain because seizure control is not yet
problematic. In other cases, patients with chronic seizure disorders
of long duration may eventually undergo neuro-imaging that detects
a CM. In these patients, seizures are often quite intractable and
the surgical approach and management is guided by the objective
of improving the long-term control of seizures.
The ability to identify a cavernous
angioma as the cause of intractable epilepsy generally signifies
a more favorable surgical outcome, however two important issues
remain that guide the clinical decision-making. The first involves
the natural history of the cavernous angioma and the risk that such
pathology imparts to the patient. The second involves the localization
of the presumed epileptic focus and its relationship to the lesion.
The surgical management of seizure patients with cavernous angiomas
can therefore consist of either simple excision of the lesion itself
(lesionectomy) or excision of the structural lesion and surrounding
epileptogenic cortex (lesionectomy plus corticectomy) . The debate
over whether one surgical approach has specific advantages over
the other remains unresolved.
Clinical and Pathological Issues
Cavernous angiomas are discrete vascular
lesions comprised of multiple blood-filled channels lined by a single
layer of endothelium but lacking in elastic or muscularis layers.
In between these channels, is a connective tissue stroma that can
be quite thick and frequently calcified. On occasion, there may
even be boney spicule formation. There is no neural tissue within
these walls but the periphery is surrounded by a pseudocapsule of
gliotic brain that is stained with hemosiderin. 11 This hemosiderin
ring is felt to be evidence of prior peri-lesional micro-hemorrhages
and the likely cause of cortical irritability. Cavernous malformations
lack the high-flow arterial feeders and draining veins of the typical
arteriovenous malformations and there is no evidence of ischemia
surrounding CM's. 21
Risk of Pathology
Since the original description by Penfield
and Ward, cavernous angiomas have been recognized as a cause of
seizures, intracranial hemorrhage and progressive neurological deficit.17
Therefore, careful consideration must be given to the natural history
of the cavernous angioma identified and the risk that it imparts
to the health of the patient. In patients with significant risk
factors for hemorrhage, a more aggressive therapeutic approach may
be warranted to prevent neurological deficits from a new or recurrent
The risk of hemorrhage from a CM is relatively small and has been
described in earlier chapters but is probably between 1 - 2% annually.
8,15 The risk of hemorrhage is certainly higher in those patients
that have previously bled while the risk of bleeding in those patients
with no history of prior clinical hemorrhage has been estimated
to be between 0.4 -0.6%.20 In either situation, the risk of hemorrhage
is cumulative over the life expectancy of the patient and is therefore
more important in younger individuals. Repeated subclinical hemorrhages
may also cause progressive enlargement with accompanying focal neurological
deficit and space-occupying effect. This presentation is less common
than seizures or hemorrhage.
Risk of Epilepsy
Seizures are the presenting symptom
in 40 - 70% of patients with CM and are more common with frontal
and temporal lesions. The seizures are most frequently focal in
nature although many will secondarily generalize and are often refractory
to medical management. 22 In one large series, seizures were simple
partial in 14%, complex partial in 10%, complex partial with secondary
generalization in 22%, absence type seizures in 7%, and grand mal
in 47%.27 In another series, complex partial seizures and simple
partial seizures were much more common and present in the vast majority
of patients. 11
Mechanisms of Epilepsy
Although it is clear that cavernous
angiomas are highly epileptogenic, it is not known by what mechanisms
the seizures occur. However, it is generally acknowledged that the
seizures do not arise from the lesion itself but rather from the
irritated cortex immediately adjacent to the lesion. The exact mechanisms
by which CM's cause seizures are unknown although a number of electrophysiologic
and pathophysiologic theories have been proposed. These include
changes in altered neurotransmitter levels (GABA and somatostatin),
free radical formation and altered second messenger physiology.
12 Morphological changes have also been identified such as alterations
in vascular supply, neuronal cell loss, glial proliferation and
subtle subcortical disconnections. 14 Most investigators suspect
that the breakdown products caused by repeated small micro-hemorrhages
deposit ferric ions into the surrounding cortex which are known
to be highly epileptogenic. In animals, the injection of ferric
ions into the cortex and subcortical regions creates a potent and
reproducible model of recurrent and intractable seizures. 26
In order for CM's to cause seizures,
however, they generally must involve gray matter or the cortical
mantel. In addition, specific areas of the cortex are associated
with higher risks of seizures. Lesions in the Rolandic or peri-Rolandic
cortex as well as the limbic areas tend to be the most epileptogenic.
Lesions involving the temporal lobe are also associated with a higher
incidence of seizures as compared to extra-temporal locations. Lesion
size may represent an additional factor in epileptogenicity.
A final issue that must be considered
is the possibility that the CM identified on imaging is an incidental
finding and not playing any role in seizure onset. This may be the
situation in up to 6% of cases of patients with cavernous angiomas
and epilepsy. 18 It is also possible that the CM represents a structural
lesion coexistent with mesial temporal sclerosis. The presence of
"dual pathology" in a patient with intractable epilepsy
represents a particular challenge. The implications for presurgical
evaluation and subsequent surgical decision-making are obvious.
Overall, however, the general underlying assumption is that the
morphologic or physiologic changes in the cortex that result in
the epileptic condition are somehow caused by the cavernous angioma
and its interaction with the surrounding cortex.
Although the approach to patients with
intractable epilepsy and a cavernous malformation is often simplified
by the neuro-imaging data, the principles of sound presurgical evaluation
should not be ignored. A detailed description of the clinical semiology
of the habitual events is important to determine if the seizures
are consistent with the location of the cavernous angioma or whether
the lesion may be an incidental finding. At times, the clinical
features of the seizure are so distinct that it may clearly localize
the seizure onset to the identified lesion. This would be the case
in a patient having simple partial seizures with episodes of speech
arrest and a cavernous angioma in the dominate temporal operculum.
(Figure 1) Similarly, the clinical/radiological correlation is extremely
compelling in a patient with focal motor seizures of the right hand
and a lesion involving the left Rolandic cortex. In both of these
situations it might be reasonable to consider lesionectomy as an
appropriate intervention because of the likelihood of successful
control of the seizures.
Advanced neuro-imaging remains one of the most important aspects
in the presurgical evaluation by providing information about the
exact location and extent of the lesion as well as evidence of remote
hemorrhage. MR I is usually diagnostic and typically demonstrates
a well-circumscribed intraparenchymal mass lesion with a heterogenous
core of mixed signal intensity along with a prominent surrounding
rim of low signal intensity. The mixed signal intensity within the
center of the lesion is thought to represent small hemorrhages of
different ages and the low signal intensity around the lesion is
felt to represent hemosiderin staining of the surrounding cortex.
19 There is usually only a small degree of mass effect and generally
little or no enhancement with gadolinium. Angiography is rarely
necessary because the lesions do not have high flow arterial feeders
or anomalous venous drainage but may be worthwhile on certain occasions
to help plan a surgical approach in particularly risky lesions.
Sometimes, MRI can identify obvious dual pathology such as distinct
hippocampal atrophy or mesial temporal sclerosis associated with
a neocortical temporal lesion. Computerized tomography (CT ) scans
can occasionally be helpful in determining the presence or absence
of fine calcifications but generally adds little to the diagnostic
accuracy. Positron emission tomography (PET) scanning to demonstrate
regional hypometabolism is generally not needed for patients with
lesional epilepsy. The presence of the lesion may make accurate
interpretation of the PET scan difficult. Similarly, single photon
emission computed tomography (SPECT) provides little useful information
in the presence of a mass lesion.
Ictal video/EEG recordings are probably
necessary in most cases of epilepsy associated with a CM to confirm
that the seizure onset is indeed localized to the area of the lesion.
Demonstrating electrographically that the seizure onset is consistent
with the lesion location confirms the role of the CM in the patients
seizure disorder and imparts an excellent prognosis in terms of
surgical outcome. Consistent and convincing inter-ictal EEG evidence
of epileptiform activity originating in the area of the lesion however
may be adequate in some cases. For example, in a patient with intractable
complex partial seizures and a CM in the mesial temporal lobe, consistent
interictal epileptiform activity on scalp EEG from the same temporal
lobe would make the patient a reasonable candidate for surgery even
without ictal EEG recordings. In some instances, ictal EEG data
may be falsely localizing and geographically distant from the radiographic
lesion. These patients can still be considered for surgery but may
need more extensive presurgical evaluation.
Invasive intracranial monitoring has
frequently been used to evaluate patients with epilepsy associated
with a CM. This approach is favored by some centers that believe
lesionectomy plus corticectomy yield better overall surgical results.
Generally, large subdural grid arrays are placed over the lesion
and surrounding cortex. Ictal EEG recordings from these arrays can
often define the exact region of seizure onset in relation to the
CM and reveal pathways of seizure propagation. This information
is then used to devise a resection strategy that encompasses both
resection of the CM and the surrounding cortex. Intracranial grids
are also useful for mapping cortical function extraoperatively prior
to excision of the lesion and surrounding cortex. This is especially
true in the pediatric population. Subdural strip electrodes and
intracerebral depth electrodes can also be useful in localizing
seizure onset but the intracranial investigation strategy must be
carefully individualized. Occasionally, even intracranial EEG investigation
may be misleading if an inadequate number of electrodes are used.
The mortality and morbidity associated with subdural grid electrodes
has been estimated at @ 2 - 4% and therefore the use of invasive
intracranial monitoring must be balanced by the expense and risk
of these investigations. 23
The presurgical evaluation of patients
with intractable epilepsy generally requires detailed neuropsychological
testing and assessment of a variety of psychosocial factors. While
extremely important in certain cases as a baseline study, and as
a predictor of the risk of resective surgery, it is not mandatory
in patients undergoing simple and limited resection of the cavernous
The medical management of seizures
in patients with CM's differs little from anticonvulsant therapy
in other focal seizure disorders. Appropriate anti-seizure medications
should be used but no studies to date have demonstrated improved
efficacy of one medication over another in patients with CM's. Although
the definition of intractability is debated, it is generally felt
that seizures are intractable if they persist despite appropriate
medical management under the guidance of an experienced neurologist
over a two year period. In one large series of 84 patients with
CM's, 41 (49%) patients had no seizures, 26 (30%) had well-controlled
seizures and 17 (20%) had intractable seizures. 1 In another series
of 28 patients with seizures, 4 patients became seizure free and
one patient became completely intractable over a mean follow-up
period of 34 months. 15 In contrast, in 32 patients with seizures
and a CM, all 18 patients who were managed medically had persistent
seizures despite adequate anti-convulsant levels.20 Another report
has indicated that in 8 patients with intractable epilepsy associated
with a CM and having adequate long term follow-up, 2 patients were
seizure free, 5 had one or two seizures a year, and only one was
refractory to medical therapy. 6 Conversely, in another study looking
at 14 patients with chronic epilepsy and a CM, only two patients
had complete control of seizures with anti-convulsant medications.
4 While it is difficult to compare small series from different centers,
it is clear that seizures are a serious problem in a significant
percentage of patients with CM's.
The primary goal of any surgical treatment
for intractable epilepsy is to abolish the seizures and avoid any
neurologic deficits associated with the resection. A secondary goal,
in the case of cavernous malformations is to entirely remove the
lesion for maximal therapeutic and prognostic benefit. The major
controversy in CM epilepsy surgery is whether lesionectomy alone
is adequate to achieve these goals or whether lesionectomy plus
corticectomy provides better seizure control.
For the purposes of this chapter, a
"lesionectomy" refers to the complete removal of a CM
using conventional neurosurgical operative techniques. This may
entail resection of some overlying cortex in the approach to the
CM but does not specifically or intentionally identify and resect
surrounding epileptogenic cortex. "Lesionectomy plus corticectomy"
refers to the surgical removal of the CM as well as the identification
and resection of surrounding epileptogenic cortex to improve seizure
control. This can be accomplished using either acute intraoperative
electrocorticography (EcoG) or with chronic extraoperative intracranial
recordings via implanted intracranial electrodes.
The long-standing debate over lesionectomy
versus lesionectomy plus corticectomy began with the observation
that many patients do become seizure free or have a dramatic reduction
in seizures after simple excision of a cortical CM. The patient
may be cured of seizures even though scalp EEG abnormalities remain.
Falconer described several patients with structural lesions and
EEG foci distinct from the lesion who underwent lesionectomy but
no attempt at resection of the EEG focus. 10 Many of these patients
not only had a dramatic reduction in the seizure frequency but also
had disappearance of the scalp EEG focus. 16 The disappearance of
this distinct EEG focus often took many months suggesting a "running
down" phenomenon. In other cases, the scalp EEG abnormalities
remained but no longer resulted in clinical seizures. These observations
suggest that a structural lesion does not necessarily result in
permanent epileptogenic changes in the surrounding cortex and that
lesionectomy alone may be able to reverse the epileptic condition
in certain cases.
On the other hand, there are cases
where resection of the CM alone does not relieve the patient of
their seizures. This may be due to the presence of independent epileptogenic
cortex, dual pathology, inadequate resection of the lesion, or postoperative
scar formation. The epileptogenic cortex may be geographically distant
from the CM and can become functionally independent despite lesionectomy.
16 This concept of "kindling" is well described in animal
models but less well understood in the human condition. In these
cases, resection of the lesion alone without removal of the functionally
independent epileptogenic cortex would result in a surgical failure.
In order to accurately identify these areas however requires invasive
cortical monitoring, the results of which would guide a tailored
resection of the lesion and surrounding cortex.
In order to deal with these potentially complex situations, some
centers advocate implantation of chronic subdural grids over the
lesion and surrounding cortex to accurately map out regions of seizure
onset and their propagation to other areas of the brain. 1 This
approach will generally confirm that seizures begin in the region
of the CM but may also indicate which adjacent or distant areas
of cortex are involved in the generation and propagation of the
seizure. Resection of the lesion along with cortical regions that
are involved in the seizure onset and spread are therefore resected
at the time of grid removal. This approach may be especially useful
in CM's involving the temporal lobe where lesionectomy alone has
a lower success rate than in other areas of the cortex.
An alternative surgical approach is
to suggest that patients with intractable epilepsy associated with
a CM should undergo simple resection of the lesion after appropriate
non-invasive presurgical evaluation. The rationale for this approach
is based upon the experience that about 70 to 80% of patients with
CM's will remain seizure free after lesionectomy alone. If the seizures
persist after lesionectomy, then a more detailed and comprehensive
evaluation could be undertaken with subdural grids, strips or intracerebral
electrodes. 23 This approach would minimize the expense and risk
of invasive intracranial monitoring in all patients and seems a
cost-efficient and effective compromise.
Several studies in the literature have
been published that analyze the results of surgery for patients
with seizures and a CM. Some studies have evaluated lesionectomy
alone while others have addressed lesionectomy plus surrounding
epileptic cortex. One of the earliest studies was a retrospective
review of the experience at the Montreal Neurological Institute
in 31 patients with a CM. 11 Twenty-two patients were symptomatic
with seizures while 9 were discovered incidentally. Of the patients
with seizures, 11 of 12 patients available for follow-up were seizure
free while the one patient with persistent seizures had incomplete
resection of the lesion. Vaquero et al reported their experience
of 25 patients with CM's in 1987 and in 19/25 patients with seizures,
they reported that surgery provided excellent seizure control in
the majority. 24
Dodick et al reviewed the Mayo Clinic
experience in 16 CM patients with intractable epilepsy and found
that 75% were seizure free after surgery or had a >90% reduction
in seizure frequency. About half of their patients underwent resection
guided by electrocorticography while the others had lesionectomy
alone. These authors were the first to suggest that the presence
of mesial temporal sclerosis should modify the surgical strategy.
In a large series of 77 patients with
CM and epilepsy as the initial presenting symptom, Zevgaridis et
al reported that 88% were seizure free after lesionectomy at a mean
follow-up of 39 months and of these, 63% were off all anti-seizure
medications. They also observed that patients with seizures for
less than two years were more likely to be seizure free (96.8%)
than those patients with seizures for more than two years (76.7%).
These authors also reported that excision of the hemosiderin ring
around the CM seemed to have little or no effect on the success
of surgery. 27
Cassaza and colleagues retrospectively
reviewed 47 patients with a CM in the cerebral hemispheres who underwent
surgical resection. Of the 21 patients with chronic and intractable
epilepsy, 18/21 or 86% were seizure free at 2 year follow-up. 4
Lesionectomy alone was performed and no attempt was made to resect
the hemosiderin stained ring or gliotic surrounding cortex. In cases
where there was excellent concordance between the seizure onset
and the location of the CM, lesionectomy resulted in abolition of
the seizures. In the absence of clinical concordance, implantation
Cappabianca et al reported their experience
with 35 CM patients and found that all patients with < 5 seizures
or a history of seizures for less than a year were seizure free
after surgery whereas only 62.5% of patients with > 5 seizures
or a history longer than one year were seizure free. 3
Most recently, Kraemer et al reported
a well-documented series of 15 patients with CM's and intractable
epilepsy. 13 All patients underwent lesionectomy including the surrounding
hemosiderin ring. In those cases where the EEG localization was
consistent with the site of the lesion, all patients became seizure
free and remained so at long term follow-up. Surgical failures were
felt to be due to poorly localized EEG onset, discordant PET imaging
data and a lesion in proximity to the limbic system.
Overall, the experience with lesionectomy
for CM's suggests that surgery can achieve seizure free rates in
approximately 70 - 90 % of patients. 5,7 Lesionectomy plus more
extensive cortical resection may be necessary in cases where the
is poor concordance between the location of the lesion and the presurgical
localizing information. Lesionectomy plus additional cortical resection
guided by intraoperative EcoG or chronically implanted intracranial
electrodes may provide improved seizure control in patients where
localizing data is discordant with the location of the CM. It is
also generally agreed upon that the hemosiderin ring around the
CM should be removed in order to achieve complete relief of seizures
although several recent studies have suggested that this may be
It is clear that lesionectomy can provide
excellent seizure control in many patients with intractable epilepsy
caused by a CM. This is especially true for those patients with
lesions who have infrequent or rare seizures and a history of less
than a years duration. Even patients with a long history of intractable
epilepsy may be relieved of their seizures by simple resection of
the CM. However, in order to select those patients that might benefit
from lesionectomy and those that might need lesionectomy plus corticectomy,
the presurgical evaluation must be individualized. 25
In certain cases, it may be adequate
to select patients for surgery simply on the basis of MRI identification
of the lesion and the clinical semiology of the seizures. If the
clinical features of the patients habitual seizures are entirely
consistent with the location of the lesion, then lesionectomy alone
has a reasonable (60 - 70%) chance of success. This is especially
true for lesions that are small and located in highly epileptogenic
cortex such as the mesial temporal lobe or Rolandic cortex. In these
situations, resection of the lesion alone is generally associated
with a good prognosis in terms of seizure control. If seizures are
not well-controlled, then a more rigorous and intensive presurgical
investigation could be carried out.
In most cases, however, inter-ictal
and ictal EEG recordings are necessary to better define the zone
of seizure onset in relationship to the CM. This is especially true
in patients with complex partial seizures in whom the clinical semiology
of the seizure often does not provide convincing localizing information.
Inter-ictal EEG recordings alone may be sufficient in cases where
there is good correlation between the lesion location and inter-ictal
EEG evidence of epileptogenicity. In most cases however, the principles
of multidisciplinary presurgical evaluation are followed by attempting
to localize the seizure onset to the site of the CM. Ictal-EEG recordings
that demonstrate that the seizures arise from the same region as
the lesion identified on neuroimaging, implies that resection of
the CM will impart substantial therapeutic benefit. Invasive EEG
recordings may be required when a CM is identified but seems anatomically
distinct from the area of seizure onset. Intracranial recordings
with subdural strip or intracerebral electrodes may demonstrate
that the lesion is an incidental finding and unrelated to seizure
onset or that seizures actually do arise in close proximity to the
lesion but were not detectable on scalp electrodes. Intracranial
EEG investigation may also be necessary in cases of diffuse lesions
involving large areas of cortex or in the specific situation of
dual pathology in order to identify the cortical regions where seizures
One issue that is extremely important
in terms of a favorable surgical outcome is the completeness of
resection of the lesion. Surgical approaches that do not entirely
remove the offending CM are generally less successful. In certain
situations, the location of the lesion and its involvement of essential
cortex prevents the complete removal of the lesion because of the
risk of irreversible neurological deficit.
Overall, it appears that the surgical
results following lesionectomy plus corticectomy may be slightly
superior to lesionectomy alone. This may be due to a variety of
factors including patient selection, differences in presurgical
evaluation, center experience and surgical technique. In general,
a tailored resection guided by detailed presurgical evaluation,
intracranial or intraoperative EEG recordings is more likely to
remove the causative lesion as well as surrounding epileptogenic
cortex. This approach is more likely to remove not only the regions
of seizure onset but also the areas involved in seizure propagation
and areas of secondary epileptogenesis. In the temporal lobe, lesionectomy
alone may not be successful because there are additional regions
in the involved temporal lobe that are fundamentally involved in
seizure onset and propagation. Careful presurgical consideration
and preoperative decision making must be carried out in these cases.
There is no question that modern neuroimaging
has detected an increasing number of CM's as the cause of new onset
and intractable seizures. The presence of a CM certainly increases
the localization accuracy of seizure onset and implies a better
prognosis. The presurgical evaluation and treatment however must
be tailored to the individual patients presentation and circumstances.
Lesionectomy alone is often successful in abolishing seizures associated
with a CM. If lesionectomy is unsuccessful, a more detailed and
comprehensive evaluation is often necessary. Overall, the prognosis
for seizure control is excellent in patients undergoing surgery
for a cavernous malformation with the majority being cured of their
Figure 1 Coronal T1-weighted MRI with
gadolinium demonstrates a heterogenous lesion in the left temporal
lobe consistent with a cavernous angioma. Note the heterogenous
signal of the lesion with a surrounding ring of low signal likely
representing hemosiderin. (left) This young women had intractable
simple and complex partial seizures characterized by speech arrest
which were completely cured by lesionectomy (right) despite the
fact that EEG recordings were lateralizing only but non-localizing.
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