Vascular malformations in the adult brain are often accompanied by epileptic seizures and represent a common neurosurgical problem. Cerebral cavernous malformations (CCMs) account for 10–15% of all vascular malformations in the adult brain (Batra et al., 2009). The incidence of CCMs is thought to range between 0.4% and 0.8% (Del Curling et al., 1991). Forty percent to 70% of patients who have supratentorial CCM present with epilepsy (Awad & Jabbour, 2006; Ferrier et al., 2007). The risk for seizure development is estimated between 1.5% and 2.4% per patient and year (Del Curling et al., 1991; Moriarity et al., 1999). CCMs do not have any intrinsic epileptogenicity. Seizures most probably result from various effects of blood breakdown products in the perilesional cortical area (Kraemer & Awad, 1994; Raabe et al., 2012). The epileptogenicity of CCM is influenced by its localization, particularly archicortical or temporal lobe localization (Menzler et al., 2010).
Patients with symptomatic CCM may present clinically with occasional epileptic seizures but they may also lead to chronic or even drug-resistant epilepsy (DRE) in about 35–40% of all cases (Kondziolka et al., 1995; Porter et al., 1997; Chang et al., 2009). Up to 4% of all DRE patients were diagnosed with a CCM (Kuzniecky et al., 1987; Convers et al., 1990). Singularity of CCM as well as medically controlled seizures may be positive predictors of seizures outcome (Englot et al., 2011).
There are two main causes to consider resection of symptomatic CCM: to prevent renewed symptomatic hemorrhage, which can cause persistent neurologic deficits, and to cure structural DRE. In some cases mixed recommendations were given by neurosurgeons and epileptologists weighting between epilepsy without final approval of drug resistance against risk of renewed bleeding.
Seizure outcome after epilepsy surgery can be favorable in patients with single supratentorial CCMs compared with conservative treatment with antiepileptic drugs (AEDs) or other treatment modalities like irradiation (Robinson et al., 1991; Shih & Pan, 2005; Hsu et al., 2007). Microsurgical removal of CCM is a well-established treatment both for cases with sporadic seizures and for chronic and/or DRE. Up to date there is still debate if the surgical removal of the hemosiderotic rim around the CCM is making seizure outcome more favorable. Many case series of CCM surgery have been published, but the current literature often does not include sufficient description of the surgical method used, the considerations defining the area of resection, and detailed information on extent of resection as recently described in an analysis of CCM series (von der Brelie & Schramm, 2011). Published overall seizure outcome rates are often not useful, since authors most probably mix their patient populations regarding the type of epilepsy. Larger case series are needed that distinguish clearly between DRE and other, milder forms of epilepsy (occasional seizures or treatable but persistent epilepsy).
Cases of DRE require epilepsy surgery, which normally includes carefully presurgical epileptologic evaluation. One may argue if there is need for extended presurgical epileptogenic workup or whether it would be feasible to perform surgery without that.
Are there differences in seizure outcome between patients with and without formal presurgical evaluations? Are there differences in seizure outcome regarding the presurgical epilepsy type? Is the localization of CCM predictive for seizure type and postsurgical seizure outcome? The aim of this study is to answer these three relevant questions in a large patient cohort from the Bonn epilepsy and cranial surgery database.
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We present one of the largest single-center cohorts of patients with different types of CCM-associated seizures. The proportion of temporally located symptomatic CCM is 57% in the overall study population, which is more than in other studies (Zevgaridis et al., 1996; Moran et al., 1999), possibly due to the high proportion of DRE cases from the epilepsy surgery center. Nevertheless some studies focused only on temporal CCMs or predominantly included patients with temporally located CCMs (Hammen et al., 2007; Van Gompel et al., 2009; Kivelev et al., 2011). Therefore, the present patient cohort does differ somewhat from the previously published patient series. The limit of this study is its retrospective nature. Furthermore, we did not evaluate neuropsychological data to compare the potential subtle cognitive deficits after extended lesionectomy (Helmstaedter et al., 2002; Clusmann et al., 2004; Schramm & Clusmann, 2008). That is why extended lesionectomy as a standard cannot be proposed. The strengths of the study are the clear differentiation of the different types of epilepsy, the size of the study population, and the length of follow-up.
In other studies with a high percentage of CCMs in temporal localization, the predominant type of epilepsy was also intractable epilepsy (Stavrou et al., 2008; Van Gompel et al., 2009). In the two other types of epilepsy (chronic epilepsy and sporadic epilepsy), temporal localization was found in 32% and 29% of cases, respectively. The numbers correspond to the portion of temporal CCMs analyzed in a metaanalysis giving an overview about the regional distribution of symptomatic CCMs in the literature (Moran et al., 1999). Taken together, the results in this study show that temporally located CCMs predispose to develop DRE. Statistically, patients with extratemporal CCMs were not operated earlier than patients with temporal CCMs regarding duration of symptoms (149 vs. 112 months). Of interest, patients with temporally located CCMs showed superior seizure outcome compared with patients who have extratemporal CCM. This might be influenced by the fact that extended resections were performed more often in patients with temporally located CCMs.
Up to date, there are only a few studies available in which the authors did carefully subdivide the patient population according to seizure type, as described in a previous review (von der Brelie & Schramm, 2011). In those studies there is evidence that patients with DRE have a worse outcome compared with patients having sporadic seizures (Dodick et al., 1994; Zevgaridis et al., 1996; Rocamora et al., 2009). It has been shown previously that preoperative duration of epileptic symptoms is a prognostic factor for persisting postoperative seizures (Kim et al., 2011). Longer preoperative duration of symptoms was negatively correlated with postoperative seizure freedom in several studies (Cohen et al., 1995; Zevgaridis et al., 1996; Hammen et al., 2007).
For the two groups of more longstanding types of epilepsy (DRE and chronic epilepsy) it was shown that longer preoperative duration of symptoms was also correlated with slightly worse seizure outcome. The longer duration of seizure disorder found in the DRE group does not automatically lead to poorer seizure freedom rates. The lower rate of good ILAE grades for the chronic epilepsy group may result from the fact that detailed epileptologic workup was not done that frequently in patients with chronic epilepsy. The exact reasons for this are speculative, but apparently operative strategy in those cases was not tailored well enough to the epileptogenic zone. Possibly the invasive evaluation was not chosen as frequently because the severity of the epilepsy appeared not so grave. The good outcome in the DRE group is most likely due to the frequent use of invasive evaluation techniques. A likely explanation for the less frequent use of invasive evaluation in the other epilepsy groups is the impression that due to the lack of drug resistance a low level intensity in presurgical evaluation seemed to be adequate. One of the results of this study, therefore, is that in CCM-associated chronic epilepsy it may more frequently be justified to use invasive evaluation techniques to determine the extent of resection. Seizure-free rate of 88% in the DRE group is excellent, especially compared to results of epilepsy surgery in general, carried out in temporal, or extratemporal areas. Outcome in patients with sporadic seizures is best, however, reaching >90% in ILAE class 1. Because chances for ILAE class 1 outcome drop once patients have progressed from sporadic seizures to chronic epilepsy, it may be concluded that CCM-associated seizures should be treated by early surgery. Furthermore, it has been shown that nearly all CCM patients presenting with a first seizure will develop epilepsy within 5 years (Josephson et al., 2011). Because in this series the majority of cases presented with DRE it appears justified to argue that surgical intervention should be considered early, preferentially before seizures become drug resistant and in order to spare the unnecessary suffering of the patient from ongoing seizures and side effects of AED treatment.
Presurgical evaluation ideally delineates the extent of the epileptogenic zone. In this series the more intensive the evaluation and the more extensive the resection, the greater were the chances of postoperative seizure freedom. In temporal lobe epilepsy, invasive monitoring is usually indicated in cases of conflicting noninvasive data (Diehl & Luders, 2000). Previous data on the influence of invasive monitoring in epilepsy with single supratentorial CCMs is scarce; implantation techniques are rather used in epilepsy patients with multiple CCMs (Siegel et al., 2000; Rocamora et al., 2009). In the presented series, 23 patients received invasive monitoring. In all patients results were conclusive and a tailored epilepsy surgery strategy could be defined. ILAE class 1 was achieved in 18 (78%) of 23 patients with invasive monitoring. The procedure itself is safe; one patient developed a transient symptomatic subdural hematoma. In series dealing with temporal lobe epilepsy or other forms of epilepsy, outcome was worse in patients who underwent presurgical invasive monitoring. However, in this series, this was not the case; most likely invasive recording was not done to detect a completely unknown seizure focus, but just to outline the extent of resection of surrounding cortex in a well-known lesion.
It has been suspected that lesionectomy alone is not sufficient in surgical therapy of CCM-associated epilepsy. In the present series, most patients with DRE (87%) underwent operations with more extensive resections. This strategy leads to good seizure outcome. ILAE class 1 was achieved in 88%. In other series in which this subtype of epilepsy was defined and analyzed specifically, outcome rates vary. In the study of Baumann et al. (2007), resection type was lesionectomy including the hemosiderotic rim, and Engel class 1 outcome was 77% versus 65% in patients who underwent pure lesionectomy. In the series of Chang et al. (2009), patients with DRE underwent lesionectomy including the hemosiderotic rim, and outcome Engel class 1 was 77%. Chang et al. also used ECoG-guided extended resections and described a better outcome of 86% Engel class 1 for the ECoG group. In another series, van Gompel et al. also used ECoG guided extended lesionectomy. Outcome in the EcoG-treated group was Engel class 1 in 91% compared with 79% Engel class 1 outcome in patients who underwent only lesionectomy including the hemosiderotic rim. Therefore, the results of four studies underscore the value of detailed electrophysiologic workup followed by more extensive resections for DRE cases.
In cases with sporadic seizures the literature shows an excellent seizure outcome if lesionectomy is performed (Casazza et al., 1996; Ferroli et al., 2006). In the present series, seizure outcome in the subgroup of patients with sporadic seizures was 91% ILAE class 1. This result is in accordance with previous published data.
There is controversy about the potentially beneficial simultaneous resection of the hemosiderotic rim. Some studies favor this technique, showing a slightly superior outcome (Baumann et al., 2006). Other case series fail to show an outcome benefit correlated with removal of hemosiderin-stained tissue (Casazza et al., 1996; Zevgaridis et al., 1996). In this series the surgical technique was to remove the hemosiderotic fringe if feasible. It was removed in all but six cases, two of which were postoperatively categorized as ILAE class 4. Nevertheless, these numbers were too small to reach statistical significance.