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Predictive Factors for Epilepsy in Moyamoya Disease
Predictive Factors for Epilepsy in Moyamoya Disease Takeshi Mikami, MD,* Satoko Ochi, MD,* Kiyohiro Houkin, MD,† Yukinori Akiyama, MD,* Masahiko Wanibuchi, MD,* and Nobuhiro Mikuni, MD*
Background: Epilepsy cannot always be recognized in patients with moyamoya disease. In this report, the clinical features of patients with epilepsy were evaluated for assessing the predictive factors of epilepsy in moyamoya disease. Methods: A total of 64 consecutive patients with moyamoya disease were included in this study. During their follow-up periods, 7 patients were diagnosed with epilepsy. Then, the patients with epilepsy were compared with the patients without epilepsy regarding their clinical features. Results: Analysis of patient background characteristics revealed a significantly higher incidence of epilepsy in patients with high modified Rankin Scale (mRS) scores, high cerebrovascular attack scores, onset age of 3 years or less, early seizures, cortical involvement, stroke subtype, and diffuse brain atrophy. A logistic analysis of epilepsy data revealed significant differences between the 2 groups in mRS score, cerebrovascular attack score, onset age 3 years or less, early seizure, cortical involvement, stroke subtype, and diffuse brain atrophy. Of these, significant differences were noted in 3 items (mRS score, early seizure, and diffuse brain atrophy) on multivariate analysis. These 3 items were selected as the basis of our new moyamoya disease epilepsy risk scale (MDERS), which we then evaluated. The cutoff value estimated by the receiver operating characteristic curve was set at 1 (sensitivity, .857; specificity, .825) or 2 (sensitivity, .571; specificity, 1.000). Conclusions: Epilepsy in moyamoya disease is associated with clinical factors and is not an independent category. For prediction of epilepsy in moyamoya disease, MDERS is a simple and convenient assessment scale. Key Words: Seizure—hemorrhage— epileptic type—stroke. Ó 2015 by National Stroke Association
Introduction Moyamoya disease is a chronic, occlusive cerebrovascular disease with unknown etiology characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain.1 The 2 cardinal clinical
From the *Department of Neurosurgery, Sapporo Medical University, Sapporo, Japan; and †Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Received May 7, 2014; revision received June 24, 2014; accepted July 23, 2014. Address correspondence to Nobuhiro Mikuni, MD, Department of Neurosurgery, Sapporo Medical University, South1 West16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.07.050
signs of moyamoya disease are ischemic attacks or intracranial hemorrhage. Epilepsy is the third most common manifestation of moyamoya disease.2 About 20%-30% of cases present with seizures.3 Recurrent seizure attacks in moyamoya disease should be regarded as symptomatic localization-related epilepsy.4 Cases in which the clinical symptom of onset is a convulsive seizure are called ‘‘epileptic-type moyamoya disease’’. However, only 3%-4% of epileptic-type moyamoya disease without vascular events have been included in recent clinical research.5-7 This may be because the causes of epilepsy in moyamoya disease are varied, and the progression of the disease in long-term follow-up is irregular, with nonspecific symptoms.8 Basically, the clinical features and course of moyamoya disease with epilepsy have been reported to be the same as moyamoya disease with stroke.9 In most cases, the cause of the epilepsy is a stroke after ischemic or hemorrhagic attacks. Postoperative
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 1 (January), 2015: pp 17-23
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hyperperfusion might also cause epilepsy. However, the clinical futures of epilepsy in patients with moyamoya disease have rarely been discussed in detail. In this study, we retrospectively analyzed patients with moyamoya disease treated at our institution regarding their clinical and radiological findings and tried to determine the risk factors of epilepsy.
Patients and Methods Patients All consecutive patients with moyamoya disease diagnosed at our hospital between January 2002 and August 2013, who had never been surgically treated for any type of moyamoya disease, were included in this study. A total of 64 patients (18 males and 46 females) with moyamoya disease were enrolled and analyzed retrospectively. The inclusion criteria were any type of moyamoya disease at any age, which was surgically treated in our institute. Unilateral involvement cases were also included, although quasi-moyamoya disease or conservatively treated cases were excluded from this study. The baseline characteristics of the 64 patients are presented in Table 1. The mean patient age at onset was 25.3 6 19.5 years (range, 169 years, with 6 patients aged 3 years or less). The initial clinical symptoms in the 64 patients were as follows: transient ischemic attack (TIA), 41 patients; ischemic stroke, 8 patients; hemorrhagic stroke, 6 patients; headache, 5 patients; epilepsy, 3 patients; involuntary movements, 3 patients and ; asymptomatic, 2 patients. Of these, multiple symptoms were found in 4 patients. Surgical treatment was considered for the patients with TIA, ischemic stroke, pediatric patients, or hemodynamic compromise as observed with single-photon emission computed tomography. The mean patient age at surgery was 29.8 6 18.9 years (range, 3-70 years). Surgical treatment was performed in all the patients on 87 sides. As for operative methods, superficial temporal artery to middle cerebral
artery (MCA) bypass was performed in 85 sides (97.7%), and encephaloduromyosynangiosis was performed in 45 sides (51.7%). The mean follow-up period was 47.0 6 33.1 months (range, 2-182 months). Diagnosis of epilepsy was determined by 2 epileptologists (S.O. and N.M.) and 4 strokologists (T.M., K.H., Y.A., and N.M.). Of the 64 patients, 7 patients (10.9%) were diagnosed with symptomatic epilepsy during the follow-up period. In these 7 patients, classification of seizure type, electroencephalogram, antiepileptic drugs, and presumed cause of epilepsy were assessed. Then, the patients with epilepsy, termed Epi(1), were compared with the patients without epilepsy, termed Epi(2), regarding the following clinical and radiological features: age at surgery, age at onset, modified Rankin Scale (mRS) score, cerebrovascular attack (CVA) score on magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) score, onset age 3 years or less or 4 years or more, sex, presence or absence of early seizure, cortical involvement, stroke subtype, diffuse brain atrophy, and postoperative hyperperfusion syndrome. In this study, seizures occurring within the first 2 weeks after stroke were defined as early seizures. Cortical involvement was defined as ischemic or hemorrhagic stroke lesions involving cortical areas. Diffuse brain atrophy was defined as brain atrophy including at least 2 vascular territories among the anterior cerebral artery (ACA), MCA, and posterior cerebral artery (PCA).
Stroke Subtype, CVA Score, and MRA Score Stroke subtype was divided into the following 2 types: patients with hemorrhagic lesions or patients without hemorrhagic lesions, which included the patients with TIA, ischemic stroke, headache, epilepsy, involuntary movements, and asymptomatic cases. The size of the associated lesions was calculated by T2-weighted imaging and divided into the following categories according
Table 1. Summary of patients with epilepsy in moyamoya disease
Number
Age/ sex
Classification of seizure types
1
6/M
CPS
2 3
40/F 58/M
GTCS SPS
4 5
3/F 41/M
GTCS SPS
6 7
39/F 64/M
GTCS CPS
EEG findings Spike and wave complex in left frontal lobe Sharp wave in left frontoparietal lobe Nonspecific findings Nonspecific findings Spike and wave complex in bilateral frontal lobe Nonspecific findings Polyspike in right temporal lobe
Antiepileptic drug
Presumed cause of epilepsy
VPA
Ischemic lesion
LEV VPA
Ischemic lesion Postoperative hyperperfusion syndrome Hemorrhagic lesion Ischemic lesion
PHT VPA PHT ZNA, LEV, CLB
Hemorrhagic lesion Nonlesional ischemia
Abbreviations: CLB, clobazam; CPS, complex partial seizure; EEG, electroencephalography; F, female; GTCS, generalized tonic-clonic seizure; LEV, levetiracetam; M, male; PHT, phenytoin; SPS, simple partial seizure; VPA, valproate; ZNA, zonisamide.
EPILEPSY IN MOYAMOYA DISEASE
to the CVA score : 1 point 5 small CVA lesion (maximum diameter , 1 cm); 2 points 5 medium CVA lesion (maximum diameter 1-3 cm); and 3 points 5 large CVA lesion (maximum diameter . 3 cm). The MRA scoring and MRA score were based on the classification of Houkin et al.6 The details of this scoring method have been reported previously. Depending on the severity of the steno-occlusive change, an MRA score was assigned to each of the following: C1 portion of the internal carotid artery (ICA), M2 portion of the MCA, A1 portion of the anterior cerebral artery (ACA), and P2 portion of the PCA. The MRA score was defined as the point total for all 4 main cerebral arteries. The lowest possible score was thus 0 and the highest was 10 (ICA3 1 MCA3 1 ACA2 1 PCA2 5 10). Then, the sum total of both sides was calculated. 12,13
MRI and MRA Examination MRI examination was performed using a 3.0-T magnetic resonance system (Signa Excite, Version 11; GE Medical Systems, Milwaukee, WI). The imaging parameters of the T2-weighted fast-spin echo imaging were as follows: flip angle 5 90 ; time of repetition 5 5000 ms; echo time 5 102.0 ms; band width 5 50.0 kHz; field of view 5 200 3 200 mm; scan thickness 5 4.0 mm; slice gap 5 1.0 mm; number of slices 5 26-30; matrix 5 352 3 256; number of signals averaged 5 1; and imaging time 5 1 minute 5 seconds. MRA was performed using the 3-dimensional time-of-flight technique with a 3-dimensional spoiled gradient-recalled echo sequence using a 3.0-T machine. The imaging parameters were as follows: flip angle 5 15 ; time of repetition 5 26 ms; echo time 5 3.2 ms; band width 5 22.73 kHz; field of view 5 200 3 180 mm; scan thickness 5 .8 mm; locations per slab 5 124; number of slabs 5 1; matrix 5 384 3 320; acquisition 5 1; and imaging time 5 7 minutes 35 seconds. Volume rendering and maximum intensity projection were applied as postprocessing techniques to aid in the evaluation.
Statistical Analysis Data are expressed as means 6 standard deviation. Statistical analyses were performed using the Mann–Whitney U test for comparing the 2 groups, Epi(1) and Epi(2), adjusted for age at surgery, age at onset, mRS, CVA score, and MRA score. Fisher exact probability tests were then used for comparing the 2 groups, adjusted for sex, early seizure, cortical involvement, stroke subtype, diffuse brain atrophy, and postoperative hyperperfusion syndrome. Simple logistic regression was used for univariate analysis concerning epilepsy. Odds ratios (ORs) were obtained through these models with 95% confidence intervals (CIs). Then, each item was selected by stepwise methods (model selection criterion: a 5 .10), and a multivariate analysis was performed for all potential predictive
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factors associated with epilepsy in the univariate analyses. Three items, which showed a significant difference in multivariate analysis, were used for scoring as parts of our new moyamoya disease epilepsy risks scale (MDERS). The MDERS was calculated based on the point total for all 3 of these items. The minimum possible score was thus 0 and the highest 3. Receiver operating characteristic analysis was used for determining the most suitable cutoff value for obtaining high predictive sensitivity and specificity in the MDERS. A value of P less than .05 was considered statistically significant. SPSS software (version 13; SPSS Inc, Chicago, IL) was used to perform the analysis.
Results Among 64 patients studied, 7 patients (10.9%) were diagnosed as having symptomatic epilepsy (4 male and 3 female). A summary of the patients according to epilepsy type is presented in Table 1. As for the classification of seizure types, 3 patients had generalized tonic-clonic seizures, 2 patients had complex partial seizures, and 2 patients had simple partial seizure. Abnormal findings were found on electroencephalograms in 4 cases. As for the antiepileptic drugs, seizures were controlled with monotherapy in 6 cases (85.7%). The presumed cause of epilepsy was ischemic lesion in 3 cases (42.9%), hemorrhagic lesion in 2 cases (28.6%), postoperative hyperperfusion in 1 case (14.3%), and nonlesional ischemia in 1 case (14.3%). The characteristics of the patients with epilepsy are presented in Table 2. The mean age at surgery in the Epi(1) group was 35.9 6 23.5 years (range, 3-64 years), whereas that in the Epi(2) group was 29.0 6 18.4 years (range, 3-70 years). Although the Epi(2) patients were somewhat younger, the difference did not reach statistical significance (P 5 .47). The mean age at onset showed the same tendency. However, the proportion of onset age 3 years or less was significantly higher in the Epi(1) group than in the Epi(2) group (P 5 .002). The mRS was significantly higher for the Epi(1) group (1.9 6 1.2) than for the Epi(2) group (.3 6 .7; P 5 .001). The CVA score was significantly higher in the Epi(1) group (2.6 6 .8) than in the Epi(2) group (1.4 6 .7; P 5 .005). Early seizure, cortical involvement, stroke subtype, and diffuse brain atrophy were all significantly higher in the Epi(1) group. There were no significant differences between these 2 groups in terms of MRA score, sex, or postoperative hyperperfusion syndrome. The predictive factors associated with epilepsy are listed in Table 3. In the univariate analysis, patients with higher mRS had higher rates of epilepsy (OR, 4.04; 95% CI, 1.62-10.08; P 5 .02). Patients with higher CVA scores had higher rates of epilepsy (OR, 5.05; 95% CI, 1.6815.20; P 5 .004). Onset age 3 years or less had higher rates of epilepsy than onset age 4 years or more (OR, 12.50; 95%
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Table 2. Clinical characteristics of patients with epilepsy and without epilepsy in moyamoya disease Characteristics
Total, N 5 64
Epi(1), N 5 7
Epi(2), N 5 57
P value
Age at surgery, mean 6 SD, y Age at onset, mean 6 SD, y Modified Rankin Scale (0-5), mean 6 SD CVA score (1-3), mean 6 SD MRA score (0-20), mean 6 SD Onset age # 3 y (cases) Sex (M/F) Early seizure (cases) Cortical involvement (cases) Stroke subtype; hemorrhagic lesion (cases) Diffuse brain atrophy (cases) Postoperative hyperperfusion syndrome (cases)
29.8 6 18.9 25.3 6 19.5 .4 6 0.9 1.5 6 0.8 10.1 6 4.0 6 18/46 5 18 9 8 5
35.9 6 23.5 25.4 6 23.6 1.9 6 1.2 2.6 6 0.8 11.4 6 5.7 3 4/3 3 6 4 3 1
29.0 6 18.4 25.3 6 19.1 .3 6 0.7 1.4 6 0.7 9.9 6 3.8 3 14/43 2 12 5 5 4
.47 .61 .001 .005 .50 .002 .07 ,.001 ,.001 ,.001 .04 .50
Abbreviations: CVA, cerebrovascular attack; F, female; M, male; MRA, magnetic resonance angiography; SD, standard deviation.
CI, 1.00-20.00; P 5 .008). Patients with epilepsy had associated with early seizure (OR, 20.63; 95% CI, 2.64-161.35; P 5 .004), cortical involvement (OR, 22.49; 95% CI, 2.47205.13; P 5 .006), hemorrhagic lesion (OR, 13.87; 95% CI, 2.40-80.27; P 5 .003), and diffuse brain atrophy (OR, 7.80; 95% CI, 1.35-45.15; P 5 .02). Three items (mRS, early seizure, and diffuse brain atrophy) were selected by stepwise methods, and significant differences were noted on multivariate analysis as follows: patients with higher mRS had higher rates of epilepsy (OR, 3.74; 95% CI, 1.50-9.31; P 5 .005) and patients with epilepsy were more likely to have early seizure (OR, 22.04; 95% CI, 1.24-390.31; P 5 .035) or diffuse brain atrophy (OR, 19.22; 95% CI, 1.21-304.58; P 5 .036). From the results of multivariate analysis, 3 items were used for MDERS scoring: (1) mRS score 2 or more; (2) early seizure; and (3) diffuse brain atrophy. Figure 1 shows the receiver operating characteristic curves for evaluating the methods of MDERS, namely, for prediction
of epilepsy in moyamoya disease. In this analysis, the suitable cutoff number for MDERS score should be 1 (sensitivity, .857; specificity, .825) or 2 (sensitivity, .571; specificity, 1.000).
Discussion Accurate diagnosis is the most critical factor in moyamoya disease patients presenting with seizures/epilepsy. In pediatric patients with moyamoya disease in particular, transient ischemic attacks are sometimes difficult to differentiate from epileptic seizures.14,15 A diagnosis of epilepsy should be confirmed based on seizure type. The detection rate of abnormal findings on electroencephalograms in this series was not high, because the measurement of brain wave activity was basically performed only once. Electroencephalograms should perform repeatedly if the diagnosis of epilepsy is not confirmed.16 The reported classification type of epilepsy in moyamoya disease is
Table 3. Univariate analysis and multivariate analysis of predictors for epilepsy in moyamoya disease Univariate analysis
Multivariate analysis
Characteristics
Odds ratio (95% CI)
P value
Age at surgery, y Age at onset, y Modified Rankin Scale (0-5) CVA score (1-3) MRA score (0-20) Onset age # 3 y (cases) Sex (M/F) Early seizure (cases) Cortical involvement (cases) Stroke subtype, hemorrhagic lesion (cases) Diffuse brain atrophy (cases) Postoperative hyperperfusion syndrome (cases)
1.22 (.79-1.87) 1.00 (.67-1.06) 4.04 (1.62-10.08) 5.05 (1.68-15.20) 1.10 (.91-1.33) 12.50 (1.00-20.00) 4.10 (.82-20.57) 20.63 (2.64-161.35) 22.49 (2.47-205.13) 13.87 (2.40-80.27) 7.80 (1.35-45.15) 2.21 (.21-23.12)
.37 .98 .02 .004 .35 .008 .09 .004 .006 .003 .02 .51
Odds ratio (95% CI)
P value
3.74 (1.50-9.31)
.005
22.04 (1.24-390.31)
.035
19.22 (1.21-304.58)
.036
Abbreviations: CI, confidence interval; CVA, cerebrovascular attack; F, female; M, male; MRA, magnetic resonance angiography.
EPILEPSY IN MOYAMOYA DISEASE
Figure 1. Receiver operating characteristic curve analysis for the occurrence of epilepsy in moyamoya disease using moyamoya disease epilepsy risk scale.
partial seizure originating from the frontal lobe or temporal lobe.17-20 It should be remembered that seizures can be misdiagnosed and treated as strokes,21 especially because the focus of the epilepsy is thought to be associated with ischemic foci because of the fact that the typical epileptogenic focus of moyamoya disease is located in the territory of the ICA. In 71.4% of our cases, the presumed cause of the epilepsy was stroke. Epilepsy in moyamoya disease is one of the recognized types of poststroke epilepsy. Actually, the CVA score was significantly correlated with the development of epilepsy in our study. Many potential consequences of epilepsy that occur early or late after strokes have been studied. Possible risk factors for poststroke seizures include the following22-26: (1) stroke subtype: cerebral hemorrhage (especially subarachnoid hemorrhage); (2) location of the lesion: cortical involvement, stroke occurring within the carotid artery territory; (3) stroke severity (but correlation may be weaker after adjusting for stroke subtype and location); and (4) occurrence of poststroke bacterial infections. Strzelczyk et al27 evaluated stroke patients and determined the predictive factors for developing poststroke epilepsy using the poststroke epilepsy risks scale (PoSERS). In their study, the authors concluded that there are 7 characteristics that are useful in predicting poststroke epilepsy: (1) supratentorial stroke; (2) intracerebral hemorrhage involving cortical areas; (3) ischemia involving cortical or cortical subcortical areas; (4) ischemia with ongoing neurologic deficit; (5) stroke causing neurologic deficit with mRS score more than 3; (6) early-onset seizures (up to 14 days after stroke); (7) late-onset seizures (15 days or later after stroke). PoSERS is useful for predicting the risk of poststroke epilepsy, but other factors should be taken into account when predicting the risk of epilepsy in moyamoya disease patients. Actually, diffuse brain atrophy was not contained in the PoSERS system but was included in our MDERS system. Moreover, radiological
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factors were not contained in our MDERS system, but were included in the PoSERS system. Our results show that epilepsy in patients with moyamoya disease might be predicted based on only 3 clinical features. Reported poststroke epilepsy rates are 2%-4% among all stroke patients,22,28,29 which is lower than the rate we observed in the present series. Basically, the strokes associated with moyamoya disease are of a supratentorial location. It should be noted that all the patients underwent surgical procedures in this series, and the surgical procedure itself might be epileptogenetic.30 Thus, the findings in the present study may not represent an aberration. Furthermore, epilepsy is known to occur frequently in moyamoya disease, and this series included many cases of TIA. The vascular severity as assessed by MRA was not positively associated with epilepsy in our cases. It appears that the epileptogenesis of moyamoya disease does not depend on the severity of stroke, that is, it does not depend on the severity of the vascular lesion. As for age, both young age at surgery and young age at onset were not found to be risk factors for epilepsy. On the other hand, onset age 3 years or less posed a significantly higher OR (12.50). Children less than 3 years of age were more likely to experience major stroke,31,32 and epileptic seizures would also naturally accompany a certain percentage of these. Transient neurologic deterioration due to cerebral hyperperfusion is a potential complication of superficial temporal artery to MCA bypass surgery in patients with moyamoya disease.33 The postoperative seizures seem to be associated with this transient neurologic deterioration.11 Theoretical explanations for postoperative seizures and hyperperfusion syndrome include similar features, such as a crucial time and biological mechanisms.34,35 However, such early seizures during the unstable period after surgery are not necessarily associated with late seizures or epilepsy. In our cases, only 1 case of epilepsy was thought to be associated with postoperative hyperperfusion syndrome. There is no clear evidence concerning the best anticonvulsant agent for the treatment of epilepsy in moyamoya disease. During the period of this study, the anticonvulsant, which was effective for partial seizure (carbamazepine or zonisamide) was selected as first-line treatment. When the patients did not tolerate the medication, the anticonvulsant agent was changed to others (phenytoin or valproic acid). Based on the new National Institute for Health and Care Excellence guidelines, carbamazepine or lamotrigine should be the first treatment for newly diagnosed focal seizures.36 Clinically, epileptogenesis in poststroke epilepsy is fairly weak, which was the case with the patients with moyamoya disease in the present series. A variety of antiepileptic drugs were effective in many of the cases in our series, even in monotherapy. Consideration must be given to the tolerability of the medication and the planning of pregnancy. In poststroke epilepsy, lamotrigine was superior to carbamazepine
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regarding tolerability, although seizure control was similar.37,38 Moreover, lamotrigine or levetiracetam poses a lower fetal risk. For women who are pregnant or trying to conceive, lamotrigine is the first choice in expert opinion.39 Moyamoya disease occurs frequently in young females. Thus, our current strategy for the long-term control of epilepsy in moyamoya disease, namely, lamotrigine or levetiracetam, should be the first choice from the viewpoint of tolerability and family planning. The limitations of this study include the fact that it was a retrospective study and involved a relatively small number of subjects. However, moyamoya disease is a rare disease, and our preliminary data concerning epilepsy are essential. Based on the results of our study, epilepsy in moyamoya disease is clearly associated with specific clinical findings, and epilepsy can be accurately predicted using our MDERS system. Because epilepsy is the result of ischemic or hemorrhagic stroke, it is unreasonable to classify epileptic-type moyamoya disease as an independent category in moyamoya disease. Instead, risk factors of epilepsy should be evaluated in each case, and medication should be taken into consideration in long-term follow-up.
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EPILEPSY IN MOYAMOYA DISEASE 31. Kurokawa T, Tomita S, Ueda K, et al. Prognosis of occlusive disease of the circle of Willis (moyamoya disease) in children. Pediatr Neurol 1985;1:274-277. 32. Amlie-Lefond C, Zaidat OO, Lew SM. Moyamoya disease in early infancy: case report and literature review. Pediatr Neurol 2011;44:299-302. 33. Fujimura M, Shimizu H, Inoue T, et al. Significance of focal cerebral hyperperfusion as a cause of transient neurologic deterioration after extracranial-intracranial bypass for moyamoya disease: comparative study with non-moyamoya patients using N-isopropyl-p-[(123)I] iodoamphetamine single-photon emission computed tomography. Neurosurgery 2011;68:957-964. discussion 64-5. 34. Manaka S, Ishijima B, Mayanagi Y. Postoperative seizures: epidemiology, pathology, and prophylaxis. Neurol Med Chir (Tokyo) 2003;43:589-600. discussion 600.
23 35. van Mook WN, Rennenberg RJ, Schurink GW, et al. Cerebral hyperperfusion syndrome. Lancet Neurol 2005; 4:877-888. 36. Nunes VD, Sawyer L, Neilson J, et al. Diagnosis and management of the epilepsies in adults and children: summary of updated NICE guidance. BMJ 2012;344:e281. 37. Rowan AJ, Ramsay RE, Collins JF, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology 2005;64:1868-1873. 38. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007;369:1000-1015. 39. Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy Behav 2005;7(Suppl 1):S1-S64. quiz S5-7.
Background: Epilepsy cannot always be recognized in patients with moyamoya disease. In this report, the clinical features of patients with epilepsy were evaluated for assessing the predictive factors of epilepsy in moyamoya disease. Methods: A total of 64 consecutive patients with moyamoya disease were included in this study. During their follow-up periods, 7 patients were diagnosed with epilepsy. Then, the patients with epilepsy were compared with the patients without epilepsy regarding their clinical features. Results: Analysis of patient background characteristics revealed a significantly higher incidence of epilepsy in patients with high modified Rankin Scale (mRS) scores, high cerebrovascular attack scores, onset age of 3 years or less, early seizures, cortical involvement, stroke subtype, and diffuse brain atrophy. A logistic analysis of epilepsy data revealed significant differences between the 2 groups in mRS score, cerebrovascular attack score, onset age 3 years or less, early seizure, cortical involvement, stroke subtype, and diffuse brain atrophy. Of these, significant differences were noted in 3 items (mRS score, early seizure, and diffuse brain atrophy) on multivariate analysis. These 3 items were selected as the basis of our new moyamoya disease epilepsy risk scale (MDERS), which we then evaluated. The cutoff value estimated by the receiver operating characteristic curve was set at 1 (sensitivity, .857; specificity, .825) or 2 (sensitivity, .571; specificity, 1.000). Conclusions: Epilepsy in moyamoya disease is associated with clinical factors and is not an independent category. For prediction of epilepsy in moyamoya disease, MDERS is a simple and convenient assessment scale. Key Words: Seizure—hemorrhage— epileptic type—stroke. Ó 2015 by National Stroke Association
Introduction Moyamoya disease is a chronic, occlusive cerebrovascular disease with unknown etiology characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain.1 The 2 cardinal clinical
From the *Department of Neurosurgery, Sapporo Medical University, Sapporo, Japan; and †Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Received May 7, 2014; revision received June 24, 2014; accepted July 23, 2014. Address correspondence to Nobuhiro Mikuni, MD, Department of Neurosurgery, Sapporo Medical University, South1 West16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.07.050
signs of moyamoya disease are ischemic attacks or intracranial hemorrhage. Epilepsy is the third most common manifestation of moyamoya disease.2 About 20%-30% of cases present with seizures.3 Recurrent seizure attacks in moyamoya disease should be regarded as symptomatic localization-related epilepsy.4 Cases in which the clinical symptom of onset is a convulsive seizure are called ‘‘epileptic-type moyamoya disease’’. However, only 3%-4% of epileptic-type moyamoya disease without vascular events have been included in recent clinical research.5-7 This may be because the causes of epilepsy in moyamoya disease are varied, and the progression of the disease in long-term follow-up is irregular, with nonspecific symptoms.8 Basically, the clinical features and course of moyamoya disease with epilepsy have been reported to be the same as moyamoya disease with stroke.9 In most cases, the cause of the epilepsy is a stroke after ischemic or hemorrhagic attacks. Postoperative
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 1 (January), 2015: pp 17-23
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hyperperfusion might also cause epilepsy. However, the clinical futures of epilepsy in patients with moyamoya disease have rarely been discussed in detail. In this study, we retrospectively analyzed patients with moyamoya disease treated at our institution regarding their clinical and radiological findings and tried to determine the risk factors of epilepsy.
Patients and Methods Patients All consecutive patients with moyamoya disease diagnosed at our hospital between January 2002 and August 2013, who had never been surgically treated for any type of moyamoya disease, were included in this study. A total of 64 patients (18 males and 46 females) with moyamoya disease were enrolled and analyzed retrospectively. The inclusion criteria were any type of moyamoya disease at any age, which was surgically treated in our institute. Unilateral involvement cases were also included, although quasi-moyamoya disease or conservatively treated cases were excluded from this study. The baseline characteristics of the 64 patients are presented in Table 1. The mean patient age at onset was 25.3 6 19.5 years (range, 169 years, with 6 patients aged 3 years or less). The initial clinical symptoms in the 64 patients were as follows: transient ischemic attack (TIA), 41 patients; ischemic stroke, 8 patients; hemorrhagic stroke, 6 patients; headache, 5 patients; epilepsy, 3 patients; involuntary movements, 3 patients and ; asymptomatic, 2 patients. Of these, multiple symptoms were found in 4 patients. Surgical treatment was considered for the patients with TIA, ischemic stroke, pediatric patients, or hemodynamic compromise as observed with single-photon emission computed tomography. The mean patient age at surgery was 29.8 6 18.9 years (range, 3-70 years). Surgical treatment was performed in all the patients on 87 sides. As for operative methods, superficial temporal artery to middle cerebral
artery (MCA) bypass was performed in 85 sides (97.7%), and encephaloduromyosynangiosis was performed in 45 sides (51.7%). The mean follow-up period was 47.0 6 33.1 months (range, 2-182 months). Diagnosis of epilepsy was determined by 2 epileptologists (S.O. and N.M.) and 4 strokologists (T.M., K.H., Y.A., and N.M.). Of the 64 patients, 7 patients (10.9%) were diagnosed with symptomatic epilepsy during the follow-up period. In these 7 patients, classification of seizure type, electroencephalogram, antiepileptic drugs, and presumed cause of epilepsy were assessed. Then, the patients with epilepsy, termed Epi(1), were compared with the patients without epilepsy, termed Epi(2), regarding the following clinical and radiological features: age at surgery, age at onset, modified Rankin Scale (mRS) score, cerebrovascular attack (CVA) score on magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) score, onset age 3 years or less or 4 years or more, sex, presence or absence of early seizure, cortical involvement, stroke subtype, diffuse brain atrophy, and postoperative hyperperfusion syndrome. In this study, seizures occurring within the first 2 weeks after stroke were defined as early seizures. Cortical involvement was defined as ischemic or hemorrhagic stroke lesions involving cortical areas. Diffuse brain atrophy was defined as brain atrophy including at least 2 vascular territories among the anterior cerebral artery (ACA), MCA, and posterior cerebral artery (PCA).
Stroke Subtype, CVA Score, and MRA Score Stroke subtype was divided into the following 2 types: patients with hemorrhagic lesions or patients without hemorrhagic lesions, which included the patients with TIA, ischemic stroke, headache, epilepsy, involuntary movements, and asymptomatic cases. The size of the associated lesions was calculated by T2-weighted imaging and divided into the following categories according
Table 1. Summary of patients with epilepsy in moyamoya disease
Number
Age/ sex
Classification of seizure types
1
6/M
CPS
2 3
40/F 58/M
GTCS SPS
4 5
3/F 41/M
GTCS SPS
6 7
39/F 64/M
GTCS CPS
EEG findings Spike and wave complex in left frontal lobe Sharp wave in left frontoparietal lobe Nonspecific findings Nonspecific findings Spike and wave complex in bilateral frontal lobe Nonspecific findings Polyspike in right temporal lobe
Antiepileptic drug
Presumed cause of epilepsy
VPA
Ischemic lesion
LEV VPA
Ischemic lesion Postoperative hyperperfusion syndrome Hemorrhagic lesion Ischemic lesion
PHT VPA PHT ZNA, LEV, CLB
Hemorrhagic lesion Nonlesional ischemia
Abbreviations: CLB, clobazam; CPS, complex partial seizure; EEG, electroencephalography; F, female; GTCS, generalized tonic-clonic seizure; LEV, levetiracetam; M, male; PHT, phenytoin; SPS, simple partial seizure; VPA, valproate; ZNA, zonisamide.
EPILEPSY IN MOYAMOYA DISEASE
to the CVA score : 1 point 5 small CVA lesion (maximum diameter , 1 cm); 2 points 5 medium CVA lesion (maximum diameter 1-3 cm); and 3 points 5 large CVA lesion (maximum diameter . 3 cm). The MRA scoring and MRA score were based on the classification of Houkin et al.6 The details of this scoring method have been reported previously. Depending on the severity of the steno-occlusive change, an MRA score was assigned to each of the following: C1 portion of the internal carotid artery (ICA), M2 portion of the MCA, A1 portion of the anterior cerebral artery (ACA), and P2 portion of the PCA. The MRA score was defined as the point total for all 4 main cerebral arteries. The lowest possible score was thus 0 and the highest was 10 (ICA3 1 MCA3 1 ACA2 1 PCA2 5 10). Then, the sum total of both sides was calculated. 12,13
MRI and MRA Examination MRI examination was performed using a 3.0-T magnetic resonance system (Signa Excite, Version 11; GE Medical Systems, Milwaukee, WI). The imaging parameters of the T2-weighted fast-spin echo imaging were as follows: flip angle 5 90 ; time of repetition 5 5000 ms; echo time 5 102.0 ms; band width 5 50.0 kHz; field of view 5 200 3 200 mm; scan thickness 5 4.0 mm; slice gap 5 1.0 mm; number of slices 5 26-30; matrix 5 352 3 256; number of signals averaged 5 1; and imaging time 5 1 minute 5 seconds. MRA was performed using the 3-dimensional time-of-flight technique with a 3-dimensional spoiled gradient-recalled echo sequence using a 3.0-T machine. The imaging parameters were as follows: flip angle 5 15 ; time of repetition 5 26 ms; echo time 5 3.2 ms; band width 5 22.73 kHz; field of view 5 200 3 180 mm; scan thickness 5 .8 mm; locations per slab 5 124; number of slabs 5 1; matrix 5 384 3 320; acquisition 5 1; and imaging time 5 7 minutes 35 seconds. Volume rendering and maximum intensity projection were applied as postprocessing techniques to aid in the evaluation.
Statistical Analysis Data are expressed as means 6 standard deviation. Statistical analyses were performed using the Mann–Whitney U test for comparing the 2 groups, Epi(1) and Epi(2), adjusted for age at surgery, age at onset, mRS, CVA score, and MRA score. Fisher exact probability tests were then used for comparing the 2 groups, adjusted for sex, early seizure, cortical involvement, stroke subtype, diffuse brain atrophy, and postoperative hyperperfusion syndrome. Simple logistic regression was used for univariate analysis concerning epilepsy. Odds ratios (ORs) were obtained through these models with 95% confidence intervals (CIs). Then, each item was selected by stepwise methods (model selection criterion: a 5 .10), and a multivariate analysis was performed for all potential predictive
19
factors associated with epilepsy in the univariate analyses. Three items, which showed a significant difference in multivariate analysis, were used for scoring as parts of our new moyamoya disease epilepsy risks scale (MDERS). The MDERS was calculated based on the point total for all 3 of these items. The minimum possible score was thus 0 and the highest 3. Receiver operating characteristic analysis was used for determining the most suitable cutoff value for obtaining high predictive sensitivity and specificity in the MDERS. A value of P less than .05 was considered statistically significant. SPSS software (version 13; SPSS Inc, Chicago, IL) was used to perform the analysis.
Results Among 64 patients studied, 7 patients (10.9%) were diagnosed as having symptomatic epilepsy (4 male and 3 female). A summary of the patients according to epilepsy type is presented in Table 1. As for the classification of seizure types, 3 patients had generalized tonic-clonic seizures, 2 patients had complex partial seizures, and 2 patients had simple partial seizure. Abnormal findings were found on electroencephalograms in 4 cases. As for the antiepileptic drugs, seizures were controlled with monotherapy in 6 cases (85.7%). The presumed cause of epilepsy was ischemic lesion in 3 cases (42.9%), hemorrhagic lesion in 2 cases (28.6%), postoperative hyperperfusion in 1 case (14.3%), and nonlesional ischemia in 1 case (14.3%). The characteristics of the patients with epilepsy are presented in Table 2. The mean age at surgery in the Epi(1) group was 35.9 6 23.5 years (range, 3-64 years), whereas that in the Epi(2) group was 29.0 6 18.4 years (range, 3-70 years). Although the Epi(2) patients were somewhat younger, the difference did not reach statistical significance (P 5 .47). The mean age at onset showed the same tendency. However, the proportion of onset age 3 years or less was significantly higher in the Epi(1) group than in the Epi(2) group (P 5 .002). The mRS was significantly higher for the Epi(1) group (1.9 6 1.2) than for the Epi(2) group (.3 6 .7; P 5 .001). The CVA score was significantly higher in the Epi(1) group (2.6 6 .8) than in the Epi(2) group (1.4 6 .7; P 5 .005). Early seizure, cortical involvement, stroke subtype, and diffuse brain atrophy were all significantly higher in the Epi(1) group. There were no significant differences between these 2 groups in terms of MRA score, sex, or postoperative hyperperfusion syndrome. The predictive factors associated with epilepsy are listed in Table 3. In the univariate analysis, patients with higher mRS had higher rates of epilepsy (OR, 4.04; 95% CI, 1.62-10.08; P 5 .02). Patients with higher CVA scores had higher rates of epilepsy (OR, 5.05; 95% CI, 1.6815.20; P 5 .004). Onset age 3 years or less had higher rates of epilepsy than onset age 4 years or more (OR, 12.50; 95%
T. MIKAMI ET AL.
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Table 2. Clinical characteristics of patients with epilepsy and without epilepsy in moyamoya disease Characteristics
Total, N 5 64
Epi(1), N 5 7
Epi(2), N 5 57
P value
Age at surgery, mean 6 SD, y Age at onset, mean 6 SD, y Modified Rankin Scale (0-5), mean 6 SD CVA score (1-3), mean 6 SD MRA score (0-20), mean 6 SD Onset age # 3 y (cases) Sex (M/F) Early seizure (cases) Cortical involvement (cases) Stroke subtype; hemorrhagic lesion (cases) Diffuse brain atrophy (cases) Postoperative hyperperfusion syndrome (cases)
29.8 6 18.9 25.3 6 19.5 .4 6 0.9 1.5 6 0.8 10.1 6 4.0 6 18/46 5 18 9 8 5
35.9 6 23.5 25.4 6 23.6 1.9 6 1.2 2.6 6 0.8 11.4 6 5.7 3 4/3 3 6 4 3 1
29.0 6 18.4 25.3 6 19.1 .3 6 0.7 1.4 6 0.7 9.9 6 3.8 3 14/43 2 12 5 5 4
.47 .61 .001 .005 .50 .002 .07 ,.001 ,.001 ,.001 .04 .50
Abbreviations: CVA, cerebrovascular attack; F, female; M, male; MRA, magnetic resonance angiography; SD, standard deviation.
CI, 1.00-20.00; P 5 .008). Patients with epilepsy had associated with early seizure (OR, 20.63; 95% CI, 2.64-161.35; P 5 .004), cortical involvement (OR, 22.49; 95% CI, 2.47205.13; P 5 .006), hemorrhagic lesion (OR, 13.87; 95% CI, 2.40-80.27; P 5 .003), and diffuse brain atrophy (OR, 7.80; 95% CI, 1.35-45.15; P 5 .02). Three items (mRS, early seizure, and diffuse brain atrophy) were selected by stepwise methods, and significant differences were noted on multivariate analysis as follows: patients with higher mRS had higher rates of epilepsy (OR, 3.74; 95% CI, 1.50-9.31; P 5 .005) and patients with epilepsy were more likely to have early seizure (OR, 22.04; 95% CI, 1.24-390.31; P 5 .035) or diffuse brain atrophy (OR, 19.22; 95% CI, 1.21-304.58; P 5 .036). From the results of multivariate analysis, 3 items were used for MDERS scoring: (1) mRS score 2 or more; (2) early seizure; and (3) diffuse brain atrophy. Figure 1 shows the receiver operating characteristic curves for evaluating the methods of MDERS, namely, for prediction
of epilepsy in moyamoya disease. In this analysis, the suitable cutoff number for MDERS score should be 1 (sensitivity, .857; specificity, .825) or 2 (sensitivity, .571; specificity, 1.000).
Discussion Accurate diagnosis is the most critical factor in moyamoya disease patients presenting with seizures/epilepsy. In pediatric patients with moyamoya disease in particular, transient ischemic attacks are sometimes difficult to differentiate from epileptic seizures.14,15 A diagnosis of epilepsy should be confirmed based on seizure type. The detection rate of abnormal findings on electroencephalograms in this series was not high, because the measurement of brain wave activity was basically performed only once. Electroencephalograms should perform repeatedly if the diagnosis of epilepsy is not confirmed.16 The reported classification type of epilepsy in moyamoya disease is
Table 3. Univariate analysis and multivariate analysis of predictors for epilepsy in moyamoya disease Univariate analysis
Multivariate analysis
Characteristics
Odds ratio (95% CI)
P value
Age at surgery, y Age at onset, y Modified Rankin Scale (0-5) CVA score (1-3) MRA score (0-20) Onset age # 3 y (cases) Sex (M/F) Early seizure (cases) Cortical involvement (cases) Stroke subtype, hemorrhagic lesion (cases) Diffuse brain atrophy (cases) Postoperative hyperperfusion syndrome (cases)
1.22 (.79-1.87) 1.00 (.67-1.06) 4.04 (1.62-10.08) 5.05 (1.68-15.20) 1.10 (.91-1.33) 12.50 (1.00-20.00) 4.10 (.82-20.57) 20.63 (2.64-161.35) 22.49 (2.47-205.13) 13.87 (2.40-80.27) 7.80 (1.35-45.15) 2.21 (.21-23.12)
.37 .98 .02 .004 .35 .008 .09 .004 .006 .003 .02 .51
Odds ratio (95% CI)
P value
3.74 (1.50-9.31)
.005
22.04 (1.24-390.31)
.035
19.22 (1.21-304.58)
.036
Abbreviations: CI, confidence interval; CVA, cerebrovascular attack; F, female; M, male; MRA, magnetic resonance angiography.
EPILEPSY IN MOYAMOYA DISEASE
Figure 1. Receiver operating characteristic curve analysis for the occurrence of epilepsy in moyamoya disease using moyamoya disease epilepsy risk scale.
partial seizure originating from the frontal lobe or temporal lobe.17-20 It should be remembered that seizures can be misdiagnosed and treated as strokes,21 especially because the focus of the epilepsy is thought to be associated with ischemic foci because of the fact that the typical epileptogenic focus of moyamoya disease is located in the territory of the ICA. In 71.4% of our cases, the presumed cause of the epilepsy was stroke. Epilepsy in moyamoya disease is one of the recognized types of poststroke epilepsy. Actually, the CVA score was significantly correlated with the development of epilepsy in our study. Many potential consequences of epilepsy that occur early or late after strokes have been studied. Possible risk factors for poststroke seizures include the following22-26: (1) stroke subtype: cerebral hemorrhage (especially subarachnoid hemorrhage); (2) location of the lesion: cortical involvement, stroke occurring within the carotid artery territory; (3) stroke severity (but correlation may be weaker after adjusting for stroke subtype and location); and (4) occurrence of poststroke bacterial infections. Strzelczyk et al27 evaluated stroke patients and determined the predictive factors for developing poststroke epilepsy using the poststroke epilepsy risks scale (PoSERS). In their study, the authors concluded that there are 7 characteristics that are useful in predicting poststroke epilepsy: (1) supratentorial stroke; (2) intracerebral hemorrhage involving cortical areas; (3) ischemia involving cortical or cortical subcortical areas; (4) ischemia with ongoing neurologic deficit; (5) stroke causing neurologic deficit with mRS score more than 3; (6) early-onset seizures (up to 14 days after stroke); (7) late-onset seizures (15 days or later after stroke). PoSERS is useful for predicting the risk of poststroke epilepsy, but other factors should be taken into account when predicting the risk of epilepsy in moyamoya disease patients. Actually, diffuse brain atrophy was not contained in the PoSERS system but was included in our MDERS system. Moreover, radiological
21
factors were not contained in our MDERS system, but were included in the PoSERS system. Our results show that epilepsy in patients with moyamoya disease might be predicted based on only 3 clinical features. Reported poststroke epilepsy rates are 2%-4% among all stroke patients,22,28,29 which is lower than the rate we observed in the present series. Basically, the strokes associated with moyamoya disease are of a supratentorial location. It should be noted that all the patients underwent surgical procedures in this series, and the surgical procedure itself might be epileptogenetic.30 Thus, the findings in the present study may not represent an aberration. Furthermore, epilepsy is known to occur frequently in moyamoya disease, and this series included many cases of TIA. The vascular severity as assessed by MRA was not positively associated with epilepsy in our cases. It appears that the epileptogenesis of moyamoya disease does not depend on the severity of stroke, that is, it does not depend on the severity of the vascular lesion. As for age, both young age at surgery and young age at onset were not found to be risk factors for epilepsy. On the other hand, onset age 3 years or less posed a significantly higher OR (12.50). Children less than 3 years of age were more likely to experience major stroke,31,32 and epileptic seizures would also naturally accompany a certain percentage of these. Transient neurologic deterioration due to cerebral hyperperfusion is a potential complication of superficial temporal artery to MCA bypass surgery in patients with moyamoya disease.33 The postoperative seizures seem to be associated with this transient neurologic deterioration.11 Theoretical explanations for postoperative seizures and hyperperfusion syndrome include similar features, such as a crucial time and biological mechanisms.34,35 However, such early seizures during the unstable period after surgery are not necessarily associated with late seizures or epilepsy. In our cases, only 1 case of epilepsy was thought to be associated with postoperative hyperperfusion syndrome. There is no clear evidence concerning the best anticonvulsant agent for the treatment of epilepsy in moyamoya disease. During the period of this study, the anticonvulsant, which was effective for partial seizure (carbamazepine or zonisamide) was selected as first-line treatment. When the patients did not tolerate the medication, the anticonvulsant agent was changed to others (phenytoin or valproic acid). Based on the new National Institute for Health and Care Excellence guidelines, carbamazepine or lamotrigine should be the first treatment for newly diagnosed focal seizures.36 Clinically, epileptogenesis in poststroke epilepsy is fairly weak, which was the case with the patients with moyamoya disease in the present series. A variety of antiepileptic drugs were effective in many of the cases in our series, even in monotherapy. Consideration must be given to the tolerability of the medication and the planning of pregnancy. In poststroke epilepsy, lamotrigine was superior to carbamazepine
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regarding tolerability, although seizure control was similar.37,38 Moreover, lamotrigine or levetiracetam poses a lower fetal risk. For women who are pregnant or trying to conceive, lamotrigine is the first choice in expert opinion.39 Moyamoya disease occurs frequently in young females. Thus, our current strategy for the long-term control of epilepsy in moyamoya disease, namely, lamotrigine or levetiracetam, should be the first choice from the viewpoint of tolerability and family planning. The limitations of this study include the fact that it was a retrospective study and involved a relatively small number of subjects. However, moyamoya disease is a rare disease, and our preliminary data concerning epilepsy are essential. Based on the results of our study, epilepsy in moyamoya disease is clearly associated with specific clinical findings, and epilepsy can be accurately predicted using our MDERS system. Because epilepsy is the result of ischemic or hemorrhagic stroke, it is unreasonable to classify epileptic-type moyamoya disease as an independent category in moyamoya disease. Instead, risk factors of epilepsy should be evaluated in each case, and medication should be taken into consideration in long-term follow-up.
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