論文の公開元へAssociation of Cortical Superficial Siderosis with Post-Stroke Epilepsy
概要
Association of Cortical Superficial
Siderosis with Post-Stroke Epilepsy
Tomotaka Tanaka, MD ,1 Kazuki Fukuma, MD, PhD ,1 Soichiro Abe, MD ,1
Soichiro Matsubara, MD, PhD,2 Shuhei Ikeda, MD,1 Naruhiko Kamogawa, MD,3
Hiroyuki Ishiyama, MD,1 Satoshi Hosoki, MD, PhD,1 Katsuya Kobayashi, MD, PhD,4
Akihiro Shimotake, MD, PhD,5 Yuriko Nakaoku, MD, PhD,6 Soshiro Ogata, PhD,6
Kunihiro Nishimura, MD, PhD,6 Masatoshi Koga, MD, PhD ,3
Kazunori Toyoda, MD, PhD ,3 Riki Matsumoto, MD, PhD,7 Ryosuke Takahashi, MD, PhD,4
Akio Ikeda, MD, PhD ,5 and Masafumi Ihara, MD, PhD
1
Objective: To assess whether post-stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a
case–control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE.
Methods: We performed a post-hoc analysis of the PROgnosis of POST-Stroke Epilepsy study enrolling PSE patients at
National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced >7 days after the index stroke, as proposed by the International
League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or
continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study
period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient-echo T2*-weighted
images. A logistic regression model with ridge penalties was tuned using 10-fold cross-validation. We added the item of
cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models.
Results: The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median
age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p < 0.0001). Compared with the existing models, the new models with cSS (SeLECT-S and CAVE-S) demonstrated significantly better predictive performance of
PSE (net reclassification improvement 0.63 [p = 0.004] for SeLECT-S and 0.88 [p = 0.001] for CAVE-S at the testing data).
Interpretation: Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE.
ANN NEUROL 2023;93:357–370
P
ost-stroke epilepsy, a major complication after stroke,
affects approximately 5 to 10% of stroke survivors,1,2
and approximately half of the new-onset epilepsy cases are
attributable to stroke in the elderly.3,4 Post-stroke epilepsy
is linked to worse clinical outcomes,1,5–7 and patients with
post-stroke epilepsy have approximately twofold higher
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.26497
Received Jan 30, 2022, and in revised form Aug 6, 2022. Accepted for publication Aug 29, 2022.
Address correspondence to Dr Tanaka, Department of Neurology, National Cerebral and Cardiovascular Center, 6-1 Kishibeshimmachi, Suita, Osaka
564-8565, Japan. E-mail: tanakat@ncvc.go.jp
Dr Ihara, Department of Neurology, National Cerebral and Cardiovascular Center, 6-1 Kishibeshimmachi, Suita, Osaka 564-8565, Japan.
E-mail: ihara@ncvc.go.jp
From the 1Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan; 2Department of Neurology, Graduate School of
Medical Sciences, Kumamoto University, Kumamoto, Japan; 3Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center,
Osaka, Japan; 4Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan; 5Department of Epilepsy, Movement Disorders
and Physiology, Kyoto University Graduate School of Medicine, Kyoto, Japan; 6Departments of Preventive Medicine and Epidemiology, National Cerebral
and Cardiovascular Center, Osaka, Japan; and 7Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Japan
Additional supporting information can be found in the online version of this article.
© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. 357
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations
are made.
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RESEARCH ARTICLE
Neurology
mortality 1 year after stroke than those without poststroke epilepsy.5 Moreover, post-stroke epilepsy adversely
affects the quality of life due to unpredictable seizure
recurrence, driving restriction, and unemployment. Therefore, with the increased survival rate of stroke patients,
identifying patients at high risk of post-stroke epilepsy is
crucial for managing stroke survivors.
Although the underlying mechanisms of post-stroke
epilepsy remain to be fully elucidated, different risk factors
for post-stroke epilepsy, such as stroke type, stroke severity,
cortical involvement, vascular risk factors, and early seizure,
have been reported,8 and risk models, such as CAVE score9
or SeLECT score,10 have been established to identify
patients at high risk of post-stroke epilepsy. However,
because of the relatively low frequency of post-stroke epilepsy during the study period (the prevalence of late seizures
was 8% for ischemic stroke and 11.8% for intracerebral
hemorrhage 5 years after stroke), these previous studies recruited <100 cases of post-stroke epilepsy in a derivation or
validation cohort, which might not have been sufficient to
assess brain imaging risk prediction biomarkers of poststroke epilepsy beyond stroke lesions per se.
Possible pathomechanisms of post-stroke epilepsy
include the disruption of neuronal networks for ischemic
post-stroke epilepsy, hemosiderin depositions for hemorrhagic post-stroke epilepsy, and gliotic scarring within the
cortex for both.11 Intriguingly, post-stroke epilepsy is
more prevalent in hemorrhagic stroke than in ischemic
stroke,1,11,12 and hemorrhagic transformation after endovascular therapy substantially increases the rate of poststroke seizures by fivefold within 2 years.13 Consistently,
studies showed that intracranial injection of hemoglobin
provoked focal spike activity in 89% of rats,14 and seizure
outcomes improved in cases of cerebral cavernous malformation with intractable focal epilepsy after complete
removal of the hemosiderin fringe brain tissue.15 These
findings strongly suggest that hemosiderin may cause
epileptogenesis in post-stroke epilepsy.
Accordingly, we hypothesized that hemosiderin
deposition is essential for the development of post-stroke
epilepsy after stroke. To address this hypothesis, we
explored the association between post-stroke epilepsy and
neuroimaging findings of hemosiderin, and investigated
whether the addition of hemosiderin markers improves
the risk models of post-stroke epilepsy in a case–control
study using our post-stroke epilepsy registry.
Methods
Study Design and Population
A retrospective case–control study was carried out at the
National Cerebral and Cardiovascular Center in Osaka,
358
Japan. Patients with post-stroke epilepsy were retrieved
from the PROgnosis of Post-Stroke Epilepsy (PROPOSE)
study, which was conducted from November 2014 to
September 2019.16 In accordance with the clinical definition from the International League Against Epilepsy, one
unprovoked seizure >7 days after an index stroke was diagnosed as post-stroke epilepsy.17 We excluded patients with
only early seizure within 7 days following a stroke onset,
another etiology of epilepsy, history of only asymptomatic
stroke, or potentially epileptogenic comorbidities (alcohol
or drug abuse, traumatic brain injury, brain tumors, or
other probable sources). All diagnoses of post-stroke epilepsy were verified at consensus conferences attended by
two board-certified epileptologists (K.K. and A.S.) and
neurologists based on electroencephalogram (EEG), seizure semiology, and clinical course during admission, and
therapeutic response. To assess hemorrhagic imaging brain
biomarkers, we excluded patients without gradient-echo
T2*-weighted images (GRET2*WI) on magnetic resonance imaging (MRI). For the control group, we retrospectively enrolled consecutive patients who were
admitted to our hospital due to acute stroke between
November 2014 to September 2019. The eligibility
criteria for the controls included patients with no history
or the absence of any seizure, or continuing antiseizure
medications at least 3 months after stroke. We excluded
patients with <3 months of monitoring at our hospital, those
who died during admission, or those who did not receive
GRET2*WI on MRI. Patient clinical data were retrospectively collected from our Stroke Registry database (https://
www.clinicaltrials.gov; unique identifier: NCT02251665)
and medical records.
This study was approved by our institutional ethical
committee according to the institutional guidelines
(M26-093-7). Informed consent was waived by the ethical
committees under the “opt-out” principle.
Patients’ Clinical Characteristics
We acquired data on demographics, including age, sex,
comorbidities (hypertension, atrial fibrillation, dyslipidemia, diabetes, dementia, chronic kidney diseases,
and liver cirrhosis), family history of epilepsy, and history
of craniotomy. Index strokes were categorized as ischemic
stroke, intracerebral hemorrhage (ICH), subarachnoid
hemorrhage (SAH), and transient ischemic attack. For
ischemic stroke, we also evaluated subtypes, such as cardiac embolism and large-artery atherosclerosis. ...
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