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:
Emad N. Eskandar, M.D.
Massachusetts General Hospital
15 Parkman St. ACC # 331
Boston, MA 02114

E-mail: eeskandar@partners.org
Patient Appointments: 617.724.6590
FAX: 617.724.0339

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Introduction

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 hemorrhage.
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.

Presurgical Evaluation

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 malformation.

Medical Management

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.

Surgical Approaches

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.

Results

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. 9

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 was recommended.

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 unnecessary. 27

Discussion

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 arise.

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.

Conclusions

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 seizures.

Figure Legends

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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