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Nationwide survey in Japan endorsed diagnostic criteria of benign adult familial myoclonus epilepsy
Accepted Manuscript Title: Nationwide survey in Japan endorsed diagnostic criteria of benign adult familial myoclonus epilepsy Authors: Katsuya Kobayashi, Takefumi Hitomi, Riki Matsumoto, Masako Watanabe, Ryosuke Takahashi, Akio Ikeda PII: DOI: Reference:
S1059-1311(18)30160-2 https://doi.org/10.1016/j.seizure.2018.07.014 YSEIZ 3240
To appear in:
Seizure
Received date: Revised date: Accepted date:
11-3-2018 31-5-2018 19-7-2018
Please cite this article as: Kobayashi K, Hitomi T, Matsumoto R, Watanabe M, Takahashi R, Ikeda A, Nationwide survey in Japan endorsed diagnostic criteria of benign adult familial myoclonus epilepsy, Seizure: European Journal of Epilepsy (2018), https://doi.org/10.1016/j.seizure.2018.07.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Kobayashi et al.
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Title: Nationwide survey in Japan endorsed diagnostic criteria of benign adult familial
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myoclonus epilepsy
Author names and affiliations:
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Katsuya Kobayashi, MD PhD1, Takefumi Hitomi, MD PhD1,2,3, Riki Matsumoto, MD
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PhD1, Masako Watanabe, MD PhD4,5, Ryosuke Takahashi, MD PhD1, Akio Ikeda, MD
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PhD6
1: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto,
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Japan
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2: Department of Respiratory Care and Sleep Control Medicine, Kyoto University
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Graduate School of Medicine, Kyoto, Japan 3: Department of Clinical Laboratory Medicine, Kyoto University Graduate School of
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Medicine, Kyoto, Japan 4: Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Japan
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Kobayashi et al.
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5: Shinjuku Neuro Clinic, Tokyo, Japan 6: Department of Epilepsy, Movement Disorders and Physiology, Kyoto University
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Graduate School of Medicine, Kyoto, Japan
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Corresponding author:
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Akio Ikeda, MD, PhD
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Department of Epilepsy, Movement Disorders and Physiology, Kyoto University
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Graduate School of Medicine
54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
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Tel. (+81)-75-751-3318, Fax. (+81)-75-751-3663, e-mail; [email protected]
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Co-Corresponding author: Takefumi Hitomi, MD, PhD
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Department of Clinical Laboratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
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Kobayashi et al.
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Tel. (+81)-75-751-3658, Fax. (+81)-75-751-9416, e-mail; [email protected]
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Number of Text pages = 25, Number of References = 34,
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Number of Figures = 5,
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Number of Supporting Information = 10,
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Number of words: Title = 99 characters, Abstract = 251, Text = 4048
Highlights
Patients with BAFME were widely distributed throughout Japan.
Ninety-two out of 101 BAFME patients (91.1%) showed cortical tremor.
Eighty-four out of 101 BAFME patients (83.2%) showed epileptic seizures.
About one fifth of BAFME patients had more than one seizure per year at
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maximum.
The older the BAFME patients were, the higher the cortical hyperexcitability was.
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Abstract
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Purpose: Benign adult familial myoclonus epilepsy (BAFME) is an autosomal dominant disease representing tremulous myoclonus or cortical tremor and infrequent
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generalized seizures. We aimed to delineate detailed epidemiological backgrounds in
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patients with Japanese BAFME and to establish diagnostic criteria based on clinical and
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electrophysiological findings.
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Methods: After a previous survey on the current nationwide state of myoclonus epilepsy of adults in Japan, we conducted this survey to delineate the clinical
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characteristics of Japanese BAFME patients, using a questionnaire to obtain details for
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individual patients. Based on clinical diagnostic criteria, we analyzed demographic and
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clinical characteristics of 101 BAFME patients in 74 families. Results: BAFME patients were predominantly female and were widely distributed
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throughout Japan. Ninety-two patients (91.1%) showed signs of cortical tremor and 84 (83.2%) showed epileptic seizures. Epileptic seizures were infrequent in BAFME patients, but 22.6% of patients had more than one seizure per year at the maximum.
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Three patients (3.0%) showed cerebellar ataxia, eight (7.9%) showed cognitive impairment, and 13 (12.9%) had psychiatric symptoms. Brain MRI was normal in 74%
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of patients, and the remaining patients had non-specific abnormal findings. Sodium valproate and clonazepam were the primary drugs used for BAFME patients. The older showed
significantly
more
severe
and
higher
rates
of
abnormal
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patients
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electrophysiological results, which were suggestive of cortical hyperexcitability.
The
correlation
between
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BAFME.
the
genetic,
clinical,
and
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Japanese
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Conclusion: Our study successfully delineated the overall clinical characteristics of
electrophysiological results will be very important to further elucidate the
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pathophysiology and treatment of BAFME in the future.
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Abbreviations:
BAFME, benign adult familial myoclonus epilepsy; CZP, clonazepam; JLA, jerk-locked
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back averaging; SEP, somatosensory evoked potential; VPA, sodium valproate.
Keywords:
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cortical tremor; epileptic seizure; cortical hyperexcitability; giant somatosensory evoked
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potential (SEP).
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Introduction
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Benign adult familial myoclonus epilepsy (BAFME) has an autosomal dominant trait,
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and its primary symptoms are cortical tremor (tremulous myoclonus) mimicking
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essential tremor and infrequent generalized seizures1,2. In Japan, BAFME has been described throughout the late 20th century and has been referred to as cortical tremor1,
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BAFME2, familial cortical myoclonic tremor3, familial cortical tremor with epilepsy4,
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and familial adult myoclonic epilepsy (FAME)5. Many similar case reports followed after 2000 in Europe, where different names have been used to refer to the condition,
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such as, autosomal dominant cortical myoclonus and epilepsy (ADCME)6, and familial
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cortical myoclonic tremor with epilepsy (FCMTE)7. Despite these various designations, Japanese and European patients have similar clinical phenotypes, and the findings of neurophysiological studies demonstrate the features of cortical reflex myoclonus,
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including giant somatosensory evoked potentials (SEPs), C-reflex and a preceding positive spike by jerk-locked back averaging (JLA). Genetic studies of these patients
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(with various names for the same conditions) have reported that patients from Japanese families, designated Japanese BAFME in this manuscript, are linked to chromosome
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8q5, whereas patients from European families, designated European BAFME in this
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manuscript, are linked to chromosome 2p8 and 5p9. A novel in-frame insertion/deletion
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in the 2-adrenergic receptor subtype B was recently shown to be associated with
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European ADCME10. The causative gene in Japanese BAFME was unclear until recently despite recent extensive genetic investigations11,12. Recently, expansions of
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intronic TTTCA and TTTTA repeats were identified as causative gene mutations for
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BAFME13. However, a diagnosis of Japanese BAFME has been done based on clinical
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and neurophysiological findings so far. Japanese and European BAFME are not currently listed in the International
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League Against Epilepsy classification. BAFME was termed “benign” based on its apparently “non-progressive” clinical course and based on infrequent generalized seizures, compared to progressive myoclonus epilepsy. Previous reviews regarded
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BAFME as an epileptic syndrome included within the idiopathic generalized epilepsies14. However, we recently reported that most Japanese BAFME patients
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showed exaggerated myoclonus and increments of cortical hyperexcitability with aging, as reflected in SEP amplitudes, suggesting a mildly progressive clinical course15.
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Additionally, we reported that the frequency of a posterior dominant rhythm in the
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EEGs of Japanese BAFME patients was significantly slower than that of age-matched
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control subjects, which suggested that Japanese BAFME patients have a mild diffuse
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brain dysfunction with minimal progression16. Therefore, Japanese BAFME is currently considered a very mild form of progressive myoclonus epilepsy.
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The number of patients who have been studied has not been sufficient to
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clarify the clinical phenotype, because BAFME is a relatively rare syndrome (the estimated incidence rate is 1/35,000)17, making analysis of a meaningful number of
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patients in a single institute technically difficult, as shown by our previous studies1,3,15,16.
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Thus, a systematic nationwide study is urgently needed for more detailed clinical characteristics in a larger population of Japanese BAFME. The present study reports a nationwide survey of Japanese BAFME patients, with the goal of delineating the
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detailed clinical characteristics and refining the current diagnostic criteria for this
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disease based on the clinical and electrophysiological findings.
Materials and Methods
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Outline of the survey
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The survey consisted of two steps. The first survey aimed to delineate the current state
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of nationwide myoclonus epilepsy throughout Japan18. It showed that the prevalence of
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BAFME was lower than that of dentatorubral-pallidoluysian atrophy (DRPLA), but higher than that of Unverricht-Lundborg disease, and that the patients with BAFME
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were widely distributed throughout Japan without endemic features. The second survey
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aimed to characterize the detailed clinical characteristics of Japanese BAFME patients.
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The study protocol was approved by the institutional ethics committee at Kyoto
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University Hospital (E1148).
Diagnostic criteria of BAFME Diagnostic criteria for BAFME were defined and adopted from our previous report
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(Supporting Information 1)15. The cardinal features consisted of six items: (1) autosomal dominant inheritance, (2) cortical tremor, (3) infrequent generalized seizures,
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(4) features of cortical reflex myoclonus demonstrated by electrophysiological studies, (5) lack of cognitive decline and other neurological symptoms appearing in the early
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stage of clinical course, and (6) lack of clear progression which impairs the ADL in the
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early stage of clinical course. “Definite” BAFME was defined when all of (1) to (6)
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were satisfied. “Probable” BAFME was defined when (1), (5), (6) and two items out of
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(2) to (4) were satisfied. “Possible” BAFME was defined when (1), (5), (6) and one either (2) or (3) were satisfied. Namely, (1), (5) and (6) were prerequisite items for the
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diagnosis of BAFME in this study. The severity of cortical tremor was classified from
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grade 0 to 4 according to the definition used in a previous report (Supporting
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Information 2)19.
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Questionnaires The first letter survey was conducted by sending the questionnaire form and our diagnostic criteria15, as described above, by mail to the councilors (N = 548) of the
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Japan Neurology Society (N = 8500) and to the councilors (N = 176) of the Japan Epilepsy Society (N = 2000). Among 614 councilors, 302 agreed to complete the survey
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and provided primary information in the first survey. In the second survey, a questionnaire regarding the details of individual cases was sent to 35 respondents who
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had reported the clinically “definite” or “probable” BAFME patients in the first survey
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(Fig. 1). In other words, in the first survey, we asked the physicians whether they treated
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BAFME patients that they themselves clinically considered “definite” or “probable”
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cases. In this second survey, the patients were classified into “definite”, “probable”, or “possible” BAFME strictly based on the listed diagnostic criteria by the authors
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(Supporting Information 1)15.
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The questionnaires in the second survey contained the patient demographic
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profiles (age, sex, birthplace, onset age, past history, and family history), clinical features (epileptic seizures, cortical tremor, and other neurological findings),
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electrophysiological examination results (electroencephalography (EEG), SEP, C-reflex, and JLA), neuroradiological findings (brain MRI, FDG-PET (18F-fluorodeoxyglucose positron emission tomography), and IMP-SPECT ((123) I-iodoamphetamine (IMP)
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single-photon emission computed tomography), and therapies. An SEP was defined as giant as in our previous study20. A waveform example of the preceding positive spike in
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JLA in a representative BAFME patient with cortical tremor is shown in Supporting Information 3. This study does not include the results of gene analyses, because this
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survey was conducted in 2011 before the identification of the causative gene mutations.
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Genetic examinations to exclude other conditions with late onset cortical tremor and
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mild epilepsy were not performed in any of the patients.
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Our recent report on BAFME patients showed that the older patients had more severe findings. The results suggested a progressive clinical course, involving increased
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cortical hyperexcitability with aging15. To confirm the previous findings, we divided the
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patients into three groups: 1) the young group (<50 years old), 2) the middle-aged group
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(50-70 years old), and 3) the elderly group (>70 years old). We compared the clinical
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profiles between these three groups.
Statistical analysis Differences in the positive rates on these examinations suggestive of cortical
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hyperexcitability (giant SEPs, C-reflex, and a preceding spike in JLA) were examined using a Fisher’s exact test followed by comparisons between each of the two groups
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with Bonferroni correction for the multiple comparison. The results were considered significant for P<0.05. Differences in therapies between the three groups were examined
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using a Kruskal-Wallis test and a Fisher’s exact test followed by comparisons between
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each of the two groups using a Mann-Whitney U test and a Fisher’s exact test with
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Bonferroni correction for the multiple comparison. The statistical analyses were
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performed using SPSS version 15 (IBM Japan, Tokyo, Japan).
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Results Detailed information was obtained on 105 patients with Japanese BAFME. Among the
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105 patients diagnosed with BAFME by the councilors, 101 (101/105, 95.3%) in 74 families fulfilled our diagnostic criteria for BAFME (definite = 43, probable = 45,
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possible = 13). We excluded four patients due to lack of the family history of cortical
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tremor and epileptic seizures. We further analyzed the remaining 101 patients.
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Patient backgrounds
BAFME was slightly predominant among women (male/female = 41/60). The patients
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ranged in age from 19 to 87 years (median 54 years) (Supporting Information 4).
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BAFME patients were distributed throughout Japan. The highest prevalence was found
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in Hoku-shin-etsu (Supporting Information 5). Regarding family history, both epileptic seizures and cortical tremor were frequently positive in 88 (88/101, 87.1%) and 94
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(94/101, 93.1%) patients, respectively. The neurological histories were mostly unremarkable. One patient had a cerebral infarction, one had migraine, one had subarachnoid hemorrhage, two had febrile seizures, and one had meningioma.
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Clinical features
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Ninety-two patients (92/101, 91.1%) showed signs of cortical tremor, with a median onset age of 27.5 years old (Supporting Information 6). Cortical tremor was observed in
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the upper limbs in 88/92 patients (95.7%), in the lower limbs in 30/92 patients (32.6%),
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in the trunk in 10/92 (10.9%), and in the face in 6/92 (6.5%) (Fig. 2A). The cortical
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tremor was “positive myoclonic tremor” in at least 67/92 patients (72.8%), “negative
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myoclonic tremor” in 9/92 (9.8%), and unknown in 16/92 (17.4%) (Fig. 2B). Cortical tremor was observed under resting, postural and action conditions (Fig. 2C). Cortical
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tremor was exaggerated by photic stimulation in at least 11 patients and by cold stimuli
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in one patient. Among 88 patients for whom the degree of cortical tremor was well rated,
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the cortical tremor of grade 1 was found in 58/88 patients (65.9%), grade 2 in 25/88 (28.4%), grade 3 in 2/88 (2.3%) and grade 4 in 3/88 (3.4%) (Fig. 2D). Among the 68
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patients with fully reported cortical tremor, the clinical course of the cortical tremor was progressive in 16/68 (23.5%), non-progressive in 51/68 (75.0%) and “self-limited” (progressing and then ceasing) in 1/68 (1.5%) (Fig. 2E).
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Eighty-four patients (84/101, 83.2%) showed signs of epileptic seizures with a median onset age of 33 years old (Supporting Information 6). Epileptic seizures
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consisted of generalized seizures in 75/84 (89.3%) and partial seizures in 17/84 (20.2%). Both generalized and partial seizures were observed in 8/84 patients (9.5%) (Fig. 3A-B).
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The details of the semiology were reported in 11 out of 17 patients with partial seizure.
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The seizure type was heterogeneous but the visual sensory seizures were the most
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predominant, seen in 4 patients. Forty patients (40/84, 47.6%) showed photosensitivity,
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and 3/84 (3.6%) showed auditory evoked seizures (Fig. 3D-E). Epileptic seizures in BAFME patients occur infrequently, however, 19/84 (22.6%) had more than one seizure
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per year in the most active period of the disease (Fig. 3C). The median onset age of
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cortical tremor was 5.5 years lower than the median onset age for epileptic seizures.
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With respect to other neurological symptoms that fulfilled our criteria for
diagnosis, three patients (3/101, 3.0%) showed signs of cerebellar ataxia, 8/101 (7.9%)
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showed cognitive impairment, and 13/101 (12.9%) had psychiatric symptoms such as depression, anxiety neurosis, hallucinations, or panic attacks and other symptoms (Supporting Information 6).
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Electrophysiological examinations and neuroimagings
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EEG was recorded in 94 BAFME patients. The EEG typically showed a poorly organized posterior dominant background rhythm with a median frequency of 10 Hz
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(range: 5.5 to 11.5 Hz) (Supporting Information 7). Regarding paroxysmal activities,
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generalized epileptiform discharges were observed in 45/94 patients (47.9%), focal
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epileptiform discharges in 12/94 (12.8%), and both generalized and focal epileptiform
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discharges in 7/94 (7.4%) (Fig. 4A). Regarding non-paroxysmal slow activities, generalized, focal, and both types of slow activities were observed in 31/94 (33.0%),
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2/94 (2.1%), and 4/94 (4.3%) patients, respectively. Photoparoxysmal responses were
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observed in 23/94 patients (24.5%). Among the patients with photosensitivity clinically,
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35.0% of the patients presented the photoparoxysmal response in EEG. Among 67 patients for whom SEP to median nerve stimulation was recorded, 52/67 (77.6%)
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showed giant SEPs (Fig. 4B). C-reflex and a preceding spike in JLA was observed in 35/41 patients (85.4%) and 8/11 (72.7%), respectively (Fig. 4C-D). Brain MRI was performed in 84 patients, with normal findings in 62/84
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(74%) (Supporting Information 7). The reported abnormalities varied, including cerebral atrophy in 13/84 patients (15.4%), cerebellar atrophy in 2/84 (2.4%), brainstem
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atrophy in 1/84 (1.2%) and white matter hyperintensity regions in T2 weighted images in 10/84 (11.9%). An FDG-PET was performed in only six patients. Three showed
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normal metabolism; the other three showed focal hypometabolism. An IMP-SPECT was
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performed in 14 patients. Six of these were normal, two showed diffuse hypoperfusion,
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and six showed focal hypoperfusion.
Therapies
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Among 95 patients with fully reported therapy, the number of antiepileptic and
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antimyoclonic drugs used in patients with BAFME ranged from 0 to 5 (mean 1.5 ± 1)
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(Supporting Information 8). Sodium valproate (VPA) and clonazepam (CZP) were the most frequently used (in 60 and 51 patients, respectively; in combination in 27 patients).
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Levetiracetam was used in eight patients, phenytoin in seven, phenobarbital in four, zonisamide in three, piracetam in three, and carbamazepine in two. Seven patients received no drugs at the time of this survey.
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Comparison of cortical excitability between the groups classified by age
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The total number of patients in the young group (<50 years), the middle-aged group (50-70 years), and the elderly group (>70 years) was 42, 37, and 22, respectively
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(Supporting Information 9). The mean age and the age range of the young group was
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37.6 (ranged 19-49); for the middle-aged group 59.2 (ranged 51-69); and for the elderly
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group 77.0 (ranged 72-87). The mean disease duration after clinical onset was 14.4
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years in the young group, 25.1 years in the middle-aged group, and 34.0 years in the elderly group. The clinical course of cortical tremor showed progression in 11.1%
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(3/27), 24.0% (6/25), and 43.8% (7/16) for the young, middle-aged, and elderly group,
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respectively. The middle-aged and elderly groups showed a higher degree of cortical
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tremor, suggesting a progressive tendency for this symptom (Fig. 5A). In the young, the middle-aged, and the elderly groups, the positive rates on neurophysiological
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examinations were 68.2% (15/22), 76.7% (23/30), and 93.3% (14/15) for giant SEP, 54.5% (6/11), 100% (18/18), and 91.7 (11/12) for C-reflex, and 50.0% (1/2), 75.0% (3/4), and 80.0% (4/5) for a preceding spike in JLA, respectively (Fig. 5B-D). The
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positive rates (suggesting cortical hyperexcitability) were higher in the middle-aged and elderly groups than those in the young group, and for the with C-reflex the differences
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were significant (P<0.05). The mean number of the drugs used for therapy was 1.3 for the young group,
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1.6 for the middle-aged group, and 1.9 for the elderly group. The difference between the
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young and elderly groups was significant (P<0.05) (Supporting Information 8). VPA
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was used in 55.0% (22/40), 73.5% (25/34), and 61.9% (13/21), and CZP was used in
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32.5% (13/40), 61.8% (21/34), and 81.0% (17/21) of the young, middle-aged, and elderly group, respectively. There was a significant difference in the usage rate of CZP
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between the young and elderly groups (P<0.05).
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Discussion
In this study, we determined the clinical and neurophysiological characteristics of
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BAFME using questionnaires for 101 Japanese BAFME patients. This is the first nationwide epidemiological study in a large population of Japanese BAFME patients. Japanese BAFME patients were widely distributed throughout Japan, which is
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consistent with the previous reports from many different areas of Japan1,2,4,15,17,21,22,23,24.
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General backgrounds As previously reported1,2,15,17, Japanese BAFME showed an autosomal dominant trait
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with high penetration. The incidence of other neurological disorders in patients with
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not specific neurological comorbidities of BAFME.
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BAFME was very similar to that in the general population; thus, these disorders were
i) Cortical tremor
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Clinical Features
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In the present study, five patients (5.6%) also showed severe cortical tremor, and 16 showed a progressive course. Cortical tremor has been reported to be exaggerated by
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various stimuli3. In the present study, cortical tremor was also reportedly exaggerated by
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photic stimuli in 11 patients and cold stimuli in one patient. Cortical tremor induced by cold stimuli suggests that it can be modulated by a superficial, somatosensory input, which is a similar phenomenon to the C-reflex and further indicates that the
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hyperexcitability in primary sensorimotor cortices in Japanese BAFME.
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ii) Generalized seizures In the present study, 19 patients (18.8%) had more than one seizure per year at the
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maximum or even after an appropriate therapy. Therefore, epileptic seizures may not
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always be rare in some Japanese BAFME. Like European BAFME patients6, some
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Japanese patients had complex partial seizures. In the present study, 40 patients showed
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photosensitivity to seizures, and three showed auditory evoked epileptic seizures, which
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also supports the increased cortical irritability to non-visual external stimuli.
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iii) Other neurological features
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Eight patients (7.9%) showed mild cognitive impairment; however, its onset was after 60 years of age. Thirteen patients (12.9%) showed psychiatric symptoms or personality
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changes. Most of the patients (92.6%) took antiepileptic and/or antimyoclonic drugs, which may have influenced on cognitive functions. However, our recent study showed that the frequency of posterior dominant rhythm in Japanese BAFME was significantly
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lower than that of age-matched control subjects regardless of anticonvulsant usage16. These indicate that the mild cognitive impairment in some Japanese BAFME patients is
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probably due to disease itself. Cerebellar ataxia was observed only in three patients (3.0%) either to a very
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mild degree or in the late phase of the clinical course. Only two patients showed
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cerebellar atrophy on MRI, and no patients showed hypometabolism of the cerebellum
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in FDG-PET or hypoperfusion of the cerebellum in IMP-SPECT. Thus, the cerebellar
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dysfunction is very mild, and cerebellar symptoms, such as cerebellar ataxia or
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dysarthria, only occurred in the late phase of the disease.
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Electrophysiological and neuroradiological examinations
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In the present study, generalized, focal and both types of epileptiform discharges on EEG were observed in 47.9%, 12.8% and 7.4% of cases, respectively. The previous
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small case series reported that 94% of BAFME patients showed spikes or poly-spike wave complexes, at a higher occurrence rate than observed in this study25. The difference in the incidence of epileptiform discharges may be due to a 1) small sample
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size, 2) biased selection, 3) state of vigilance of patients during EEG, 4) administration of anticonvulsants, or 5) other factors. Electrophysiological features of cortical reflex
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myoclonus or cortical tremor, i.e., giant SEP, C-reflex and a preceding spike by JLA, were each reported in more than 70% of the examined patients. These findings were
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consistent with those of our previous report15. In the neuroradiological examinations
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used in this study, brain MRI showed either normal or non-specific abnormalities.
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Therapies
Anticonvulsants, especially VPA, CZP and levetiracetam, were effective for both
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cortical tremor and epileptic seizures15. In the current study, VPA and CZP were
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administered to more than half of the patients. However, there was some effect of
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beta-blockers on tremors, which also may differentiate BAFME from essential tremor1, and carbamazepine and gabapentin, which can worsen myoclonic seizures in general,
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should be avoided for treating BAFME6,26.
Comparison between young, middle-aged, and elderly groups
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After middle age, such as 50 years, BAFME patients were previously shown to have a slow progressive clinical course for cortical tremor and cortical hyperexcitability in the
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primary sensorimotor cortices15. The present study clearly confirmed this trend in a substantially larger nationwide population. There was a tendency for cortical tremor to
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be severer in the middle-aged group (50-70 years) than that in the young group, and also
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to be severer in the elderly group (>70 years) than that in the middle-aged group. The
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clinical course of cortical tremor showed progression with aging. The larger number of
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the drugs used for therapy and higher usage rate of CZP in the elderly group compared with the young group may imply that although the epileptic seizures were controlled to
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some extent, the cortical tremor showed progression.
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Comparison between Japanese- and European BAFME Some differences have been reported between Japanese- and European BAFME.
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Cortical tremors appeared to be more disabling27 and epileptic seizures tended to occur more frequently in European pedigrees6 than in Japanese BAFME in the current study. In European pedigrees, patients with mild cognitive impairment showed a gradual
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slowing of the posterior dominant rhythm in EEGs over a clinical course of three decades28. The same authors also reported a high prevalence of mood disorders
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associated with European BAFME, especially depression and anxiety29. In European patients, cerebellar atrophy and functional abnormality were
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detected with a sophisticated MRI technique30,31,32,33. Additionally, a postmortem
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examination of European BAFME patients showed changes in Purkinje cells in the
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cerebellum and preservation of sensorimotor cortex7,34. In the current study, cerebellar
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ataxia was observed in only three Japanese BAFME patients, and no neurophysiological or neuroimaging studies on cerebellar abnormality in association with Japanese
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BAFME have been conducted. Thus, previous studies suggested that European BAFME
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patients showed slightly more severe symptoms of cerebellar abnormality than Japanese
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BAFME patients.
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Revised diagnostic criteria of Japanese BAFME 2018 In this study, we adopted our own tentative diagnostic criteria15, and only four cases reported by councilors did not fulfill the criteria. Thus, our criteria were reasonable for
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Kobayashi et al. 27
the diagnosis of Japanese BAFME. Additionally, our study showed that a few patients also showed partial seizures and cerebellar ataxia as well as psychiatric symptoms.
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Focusing on the differences between the possible BAFME cases and the others (definite and probable BAFME), there were no patients in the possible BAFME presenting
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cortical tremor in the trunk and face, cortical tremor with the feature of negative
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myoclonus, severe cortical myoclonus, or focal slow in EEG. These differences between
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the possible BAFME and the others might in part be due to the small number of the
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possible BAFME patients.
We revise our previous criteria based on these findings (Supporting
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Information 10). The revised criteria consisted of six conditions similar to our previous
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criteria: (1) autosomal dominant inheritance with high penetration, (2) cortical tremor,
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(3) infrequent generalized and partial seizures (but sometimes more than once a year), (4) features of cortical reflex myoclonus (tremor) demonstrated by electrophysiological
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studies, (5) lack of evident cognitive decline, cerebellar ataxia and other neurological symptoms at least in the early stage of clinical course (but these neurological symptoms could be observed in the late phase of the disease), (6) lack of clear progression of
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cortical tremor which impairs the ADL in the early stage of clinical course (but worsening of cortical tremor could be observed in the late phase, especially age over 70).
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“Definite” BAFME was defined when all of (1) to (6) were satisfied. “Probable” BAFME was defined when (1), (5), (6) and two items out of (2) to (4) were satisfied.
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“Possible” BAFME was defined when (1), (5), (6) and one either (2) or (3) were
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satisfied. Namely, (1), (5) and (6) were again prerequisite items for the diagnosis of
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BAFME. These were based on the clinical and electrophysiological findings because
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the underlying gene for Japanese BAFME was not identified at the timing of this survey. These criteria are still practically important for the patient selection toward genetic
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testing even after the discovery of causative gene of BAFME. However, the diagnostic
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criteria will have to include genetic testing in the future.
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Indeed, the patients fulfilling (1), (3), (5), and (6) of the diagnostic criteria are
classified into possible BAFME but not necessarily the BAFME. In such a case,
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although we should consider the possibility of the other genetic epilepsy, one of the important points is that we should consider the BAFME as one of the differentials.
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Kobayashi et al. 29
Limitations The present study has limitations. First, although the BAFME patients were widely
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distributed throughout Japan, some clusters were observed in the Hoku-shin-etsu and Kinki regions. These clusters likely occurred because more councilors in these regions
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replied to the questionnaires. We would like to conduct a larger survey to overcome the
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primary drawback of this study. Second, some of the clinical or neurophysiological
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information for the 101 BAFME patients were missing because of the nature of the
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study. Third, investigations into the symptoms and results of examinations depended solely on the respondents. However, the style of the survey included detailed
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questionnaires; we had no alternative method. The fact that VPA and CZP were
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appropriately used for most of the patients implies that the councilors of the current
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study were reliable. Fourth, we could not investigate the follow-up period after diagnosis, as we did not include an item asking for the age at diagnosis. Since the
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disease duration in the young group was shorter than that in the middle-aged and elderly groups, it would be difficult to accurately assess the progression in the young group even if we included the follow-up period in the item. Despite these limitations, our
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study has some value for delineating the specific clinical characteristics of Japanese BAFME. In the future, analyses of the genetico-clinico-electorophysiological
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correlations would be warranted to further elucidate the pathophysiology and treatment
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of BAFME.
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Disclosure of Conflicts of Interest
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Department of Epilepsy, Movement Disorders and Physiology, which Akio Ikeda
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belongs to, is an endowment department, supported by a grant from GlaxoSmithKline K.K., NIHON KOHDEN CORPORATION, Otsuka Pharmaceutical Co., and UCB
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Japan Co., Ltd. Department of Respiratory Care and Sleep Control Medicine, which
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Takefumi Hitomi belonged to, is an endowed department supported with a grant from
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Fukuda Denshi, Philips-Respironics, and Teijin Pharma. None of the authors has any
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conflicts of interest to disclose in relation to this study.
Ethical publication statement The work described is consistent with the Journal’s guidelines for ethical publication.
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Acknowledgements
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We thank all of the physicians who participated in the survey. The institutions that participated in this study were Kohnan Hospital, Fukushima Medical University
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Hospital, National Center Hospital, Nishi-Niigata Chuo National Hospital, Niigata
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Cancer Center Hospital, Asanogawa General Hospital, Aizawa Hospital, Kyoto
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University Hospital, National Hospital Organization Utano Hospital, Jyujyo Takeda
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Rehabilitation Hospital, Kawasaki Clinic, Toyonaka Municipal Hospital, Kobe University Hospital, National Hospital Organization Nara Medical Center, Okayama
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University Hospital, Kurashiki Memorial Hospital, Kyushu University Hospital,
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Hospital of the University of Occupational and Environmental Health, and National
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Hospital Organization Omuta Hospital. This work was planned, executed and supported by the Research Grant (22A-6) for
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Nervous and Mental Disorders from the Ministry of Health and Welfare, and the Grants-in-Aid for Scientific Research [KAKENHI grant number 23591275, 15H05874 (Non-linear Neuro-oscillology)] from the Japan Society for the Promotion of Science
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(JSPS).
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Supporting Information
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Supporting Information is available at Seizure online.
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myoclonus. Neurology 1990;40:1561-1565. 2. Yasuda T. Benign adult familial myoclonic epilepsy (BAFME). Kawasaki Med J
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3. Terada K, Ikeda A, Mima T, et al. Familial cortical myoclonic tremor as a unique
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form of cortical reflex myoclonus. Mov Disord 1997;12:370-377.
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4. Okuma Y, Shimo Y, Hatori K, et al. Familial cortical tremor with epilepsy. Parkinsonism & related disorders 1997;3:83-87.
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5. Plaster NM, Uyama E, Uchino M, et al. Genetic localization of the familial adult
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myoclonic epilepsy (FAME) gene to chromosome 8q24. Neurology 1999;53:1180-1183.
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6. Guerrini R, Bonanni P, Patrignani A, et al. Autosomal dominant cortical myoclonus and epilepsy (ADCME) with complex partial and generalized seizures: A newly
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recognized epilepsy syndrome with linkage to chromosome 2p11.1-q12.2. Brain 2001;124:2459-2475. 7. van Rootselaar AF, Aronica E, Jansen Steur EN, et al. Familial cortical tremor with
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epilepsy and cerebellar pathological findings. Mov Disord 2004;19:213-217. 8. Striano P, Chifari R, Striano S, et al. A new benign adult familial myoclonic epilepsy
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(BAFME) pedigree suggesting linkage to chromosome 2p11.1-q12.2. Epilepsia 2004;45:190-192.
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9. Depienne C, Magnin E, Bouteiller D, et al. Familial cortical myoclonic tremor with
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epilepsy: the third locus (FCMTE3) maps to 5p. Neurology 2010;74:2000-2003.
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10. De Fusco M, Vago R, Striano P, et al. The alpha2B-adrenergic receptor is mutant in
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cortical myoclonus and epilepsy. Ann Neurol 2014;75:77-87. 11. Mori S, Nakamura M, Yasuda T, et al. Remapping and mutation analysis of benign
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2011;56:742-747.
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adult familial myoclonic epilepsy in a Japanese pedigree. J Hum Genet
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12. Kato T, Tamiya G, Koyama S, et al. UBR5 Gene Mutation Is Associated with Familial
Adult
Myoclonic
Epilepsy
in
a
Japanese
Family.
ISRN
Neurol
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2012:2012;508308. 13. Ishiura H, Doi K, Mitsui J, et al. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat Genet. 2018;50:581-590.
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14. Panayiotopoulos CP. Syndromes of idiopathic generalized epilepsies not recognized by the International League Against Epilepsy. Epilepsia 2005;46(Suppl 9):57-66.
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15. Hitomi T, Ikeda A, Kondo T, et al. Increased cortical hyperexcitability and exaggerated myoclonus with aging in benign adult familial myoclonus epilepsy. Mov
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Disord 2011;26:1509-1514.
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16. Hitomi T, Kobayashi K, Sakurai T, et al. Benign adult familial myoclonus epilepsy
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is a progressive disorder: no longer idiopathic generalized epilepsy. Epileptic Disord
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17. Uyama E, Fu YH, Ptacek LJ. Familial adult myoclonic epilepsy (FAME). Adv
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Neurol 2005;95:281-288.
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18. Kobayashi K, Hitomi T, Matsumoto R, et al. Nationwide survey of myoclonus
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epilepsy of adult in Japan. 13th Asian Oceanian Congress of Neurology 2012:100. Abstract
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19. Ikeda A, Shibasaki H, Tashiro K, et al. Clinical trial of piracetam in patients with myoclonus: nationwide multiinstitution study in Japan. The Myoclonus/Piracetam Study Group. Mov Disord 1996;11:691-700.
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20. Ikeda A, Shibasaki H, Nagamine T, et al. Peri-rolandic and fronto-parietal components of scalp-recorded giant SEPs in cortical myoclonus. Electroencephalogr
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Clin Neurophysiol 1995;96:300-309.
Neurologia Japonica 1951;53:33-37. Article in Japanese
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21. Inoue S. A family of hereditary tremor with epileptic seizure. Psychiatria et
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22. Bunno M, Ishizaki H, Okamoto S. A family with combination of hereditary tremor
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and epilepsy. Rinsho Shinkeigaku 1969;9:729. Abstract in Japanese
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23. Kudo J, Kudo T, Yamauchi T. Seven families with heredofamilial tremor and epilepsy. Rinsho Shinkeigaku 1984;24:1-8. Article in Japanese
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24. Uyama E, Kumamoto T, Ikeda T, et al. A family with hereditary myoclonus epilepsy
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developed from finger trembling in the middle age with benign clinical course. Rinsho
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Shinkeigaku 1985;25:1491. Abstract in Japanese 25. Toyota T, Akamatsu N, Tanaka A, et al. Electroencephalographic features of benign
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adult familial myoclonic epilepsy. Clin Neurophysiol 2014;125:250-254. 26. Striano P, Coppola A, Madia F, et al. Life-threatening status epilepticus following gabapentin administration in a patient with benign adult familial myoclonic epilepsy.
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Epilepsia 2007;48:1995-1998. 27. van Rootselaar AF, van Schaik IN, van den Maagdenberg AM, et al. Familial
pedigrees bearing common features. Mov Disord 2005;20:665-673.
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cortical myoclonic tremor with epilepsy: a single syndromic classification for a group of
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28. Coppola A, Santulli L, Del Gaudio L, et al. Natural history and long-term evolution
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in families with autosomal dominant cortical tremor, myoclonus, and epilepsy.
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Epilepsia 2011;52:1245-1250.
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29. Coppola A, Caccavale C, Santulli L, et al. Psychiatric comorbidities in patients from seven families with autosomal dominant cortical tremor, myoclonus, and epilepsy.
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Epilepsy Behav 2016;56:38-43.
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30. van Rootselaar AF, Maurits NM, Renken R, et al. Simultaneous EMG-functional
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MRI recordings can directly relate hyperkinetic movements to brain activity. Hum Brain Mapp 2008;29:1430-1441.
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31. Striano P, Caranci F, Di Benedetto R, et al. (1)H-MR spectroscopy indicates prominent cerebellar dysfunction in benign adult familial myoclonic epilepsy. Epilepsia 2009;50:1491-1497.
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32. Buijink AW, Caan MW, Tijssen MA, et al. Decreased cerebellar fiber density in cortical myoclonic tremor but not in essential tremor. Cerebellum 2013;12:199-204.
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33. Buijink AW, Broersma M, van der Stouwe AM, et al. Cerebellar Atrophy in Cortical Myoclonic Tremor and Not in Hereditary Essential Tremor-a Voxel-Based
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Morphometry Study. Cerebellum 2016;15:696-704.
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34. van Rootselaar AF, van der Salm SM, Bour LJ, et al. Decreased cortical inhibition
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and yet cerebellar pathology in 'familial cortical myoclonic tremor with epilepsy'. Mov
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CC
EP
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M
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Disord 2007;22:2378-2385.
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Figure Legends
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Figure 1. Flowchart of the survey. The first letter survey was conducted among councilors of the Japan Neurology Society
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and Japan Epilepsy Society. In the second survey, a questionnaire on the details for
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individual patients was sent to 35 physicians who had reported the patients based on the
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councilors’ diagnosis in the first survey. Among the 105 cases diagnosed as BAFME by
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the councilors, 101 patients of 74 families fulfilled our diagnostic criteria for BAFME.
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Figure 2. Features of cortical tremor in BAFME. Various clinical features of cortical tremor were reported by the respondents according
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to the definition of diagnostic criteria (Supporting Information 1). The body parts involved in cortical tremor (A), the features whether the cortical tremor
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was positive or negative myoclonus (B), three conditions in which cortical tremor was
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evident (C), the severity of cortical tremor by rating scale (D), and the clinical course
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(E) are presented. The detailed results are in Supporting Information 6. The labels All,
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D, Pr, and Po represent the results of all, definite, probable, and possible BAFME patients, respectively. Each number below the four groups represents the number of
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patient from whom detailed information was obtained.
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Kobayashi et al. 41
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Figure 3. Features of epileptic seizures in BAFME. The abbreviations in the figures are the same as those in Fig. 2. The seizure type (A and
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B), the patients who had more than on seizure per year at the maximum (C), and the patients with sensitivity to visual (D) and auditory (E) stimuli are presented. The
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detailed results are in the Supporting Information 6.
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Figure 4. Findings of neurophysiological examinations in BAFME. The abbreviations in the figures are the same as the abbreviations in Fig. 2 and 3. The
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incidence of epileptiform discharges, slow activities, and photoparoxysmal response are shown in (A). The positive rate of giant SEPs (B), C-reflex (C), and a preceding spike in
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JLA (D) are presented. The detailed results are in Supporting Information 7.
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Figure 5. Correlation between age and cortical excitability in BAFME. The abbreviations in the figures are same as those used in Fig. 4. The incidence, severity,
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and clinical course of cortical tremor (A), the incidence of giant SEP (B), C-reflex (C), and a preceding spike in JLA (D) were compared between the young (<50 years), the
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middle-aged (50-70 years), and the elderly (>70 years) BAFME patients. A Fisher’s
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exact test demonstrated a statistically significant difference (*) in the incidence of
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results are in Supporting Information 9.
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C-reflex between the younger and the older (middle-aged and elderly) groups. Detailed
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S1059-1311(18)30160-2 https://doi.org/10.1016/j.seizure.2018.07.014 YSEIZ 3240
To appear in:
Seizure
Received date: Revised date: Accepted date:
11-3-2018 31-5-2018 19-7-2018
Please cite this article as: Kobayashi K, Hitomi T, Matsumoto R, Watanabe M, Takahashi R, Ikeda A, Nationwide survey in Japan endorsed diagnostic criteria of benign adult familial myoclonus epilepsy, Seizure: European Journal of Epilepsy (2018), https://doi.org/10.1016/j.seizure.2018.07.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Kobayashi et al.
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Title: Nationwide survey in Japan endorsed diagnostic criteria of benign adult familial
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myoclonus epilepsy
Author names and affiliations:
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Katsuya Kobayashi, MD PhD1, Takefumi Hitomi, MD PhD1,2,3, Riki Matsumoto, MD
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PhD1, Masako Watanabe, MD PhD4,5, Ryosuke Takahashi, MD PhD1, Akio Ikeda, MD
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PhD6
1: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto,
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Japan
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2: Department of Respiratory Care and Sleep Control Medicine, Kyoto University
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Graduate School of Medicine, Kyoto, Japan 3: Department of Clinical Laboratory Medicine, Kyoto University Graduate School of
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Medicine, Kyoto, Japan 4: Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Japan
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Kobayashi et al.
2
5: Shinjuku Neuro Clinic, Tokyo, Japan 6: Department of Epilepsy, Movement Disorders and Physiology, Kyoto University
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Graduate School of Medicine, Kyoto, Japan
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Corresponding author:
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Akio Ikeda, MD, PhD
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Department of Epilepsy, Movement Disorders and Physiology, Kyoto University
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Graduate School of Medicine
54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
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Tel. (+81)-75-751-3318, Fax. (+81)-75-751-3663, e-mail; [email protected]
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Co-Corresponding author: Takefumi Hitomi, MD, PhD
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Department of Clinical Laboratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
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Kobayashi et al.
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Tel. (+81)-75-751-3658, Fax. (+81)-75-751-9416, e-mail; [email protected]
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Number of Text pages = 25, Number of References = 34,
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Number of Figures = 5,
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Number of Supporting Information = 10,
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Number of words: Title = 99 characters, Abstract = 251, Text = 4048
Highlights
Patients with BAFME were widely distributed throughout Japan.
Ninety-two out of 101 BAFME patients (91.1%) showed cortical tremor.
Eighty-four out of 101 BAFME patients (83.2%) showed epileptic seizures.
About one fifth of BAFME patients had more than one seizure per year at
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maximum.
The older the BAFME patients were, the higher the cortical hyperexcitability was.
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Abstract
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Purpose: Benign adult familial myoclonus epilepsy (BAFME) is an autosomal dominant disease representing tremulous myoclonus or cortical tremor and infrequent
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generalized seizures. We aimed to delineate detailed epidemiological backgrounds in
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patients with Japanese BAFME and to establish diagnostic criteria based on clinical and
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electrophysiological findings.
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Methods: After a previous survey on the current nationwide state of myoclonus epilepsy of adults in Japan, we conducted this survey to delineate the clinical
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characteristics of Japanese BAFME patients, using a questionnaire to obtain details for
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individual patients. Based on clinical diagnostic criteria, we analyzed demographic and
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clinical characteristics of 101 BAFME patients in 74 families. Results: BAFME patients were predominantly female and were widely distributed
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throughout Japan. Ninety-two patients (91.1%) showed signs of cortical tremor and 84 (83.2%) showed epileptic seizures. Epileptic seizures were infrequent in BAFME patients, but 22.6% of patients had more than one seizure per year at the maximum.
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Three patients (3.0%) showed cerebellar ataxia, eight (7.9%) showed cognitive impairment, and 13 (12.9%) had psychiatric symptoms. Brain MRI was normal in 74%
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of patients, and the remaining patients had non-specific abnormal findings. Sodium valproate and clonazepam were the primary drugs used for BAFME patients. The older showed
significantly
more
severe
and
higher
rates
of
abnormal
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patients
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electrophysiological results, which were suggestive of cortical hyperexcitability.
The
correlation
between
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BAFME.
the
genetic,
clinical,
and
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Japanese
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Conclusion: Our study successfully delineated the overall clinical characteristics of
electrophysiological results will be very important to further elucidate the
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pathophysiology and treatment of BAFME in the future.
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Abbreviations:
BAFME, benign adult familial myoclonus epilepsy; CZP, clonazepam; JLA, jerk-locked
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back averaging; SEP, somatosensory evoked potential; VPA, sodium valproate.
Keywords:
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cortical tremor; epileptic seizure; cortical hyperexcitability; giant somatosensory evoked
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potential (SEP).
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Introduction
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Benign adult familial myoclonus epilepsy (BAFME) has an autosomal dominant trait,
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and its primary symptoms are cortical tremor (tremulous myoclonus) mimicking
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essential tremor and infrequent generalized seizures1,2. In Japan, BAFME has been described throughout the late 20th century and has been referred to as cortical tremor1,
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BAFME2, familial cortical myoclonic tremor3, familial cortical tremor with epilepsy4,
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and familial adult myoclonic epilepsy (FAME)5. Many similar case reports followed after 2000 in Europe, where different names have been used to refer to the condition,
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such as, autosomal dominant cortical myoclonus and epilepsy (ADCME)6, and familial
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cortical myoclonic tremor with epilepsy (FCMTE)7. Despite these various designations, Japanese and European patients have similar clinical phenotypes, and the findings of neurophysiological studies demonstrate the features of cortical reflex myoclonus,
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including giant somatosensory evoked potentials (SEPs), C-reflex and a preceding positive spike by jerk-locked back averaging (JLA). Genetic studies of these patients
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(with various names for the same conditions) have reported that patients from Japanese families, designated Japanese BAFME in this manuscript, are linked to chromosome
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8q5, whereas patients from European families, designated European BAFME in this
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manuscript, are linked to chromosome 2p8 and 5p9. A novel in-frame insertion/deletion
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in the 2-adrenergic receptor subtype B was recently shown to be associated with
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European ADCME10. The causative gene in Japanese BAFME was unclear until recently despite recent extensive genetic investigations11,12. Recently, expansions of
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intronic TTTCA and TTTTA repeats were identified as causative gene mutations for
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BAFME13. However, a diagnosis of Japanese BAFME has been done based on clinical
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and neurophysiological findings so far. Japanese and European BAFME are not currently listed in the International
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League Against Epilepsy classification. BAFME was termed “benign” based on its apparently “non-progressive” clinical course and based on infrequent generalized seizures, compared to progressive myoclonus epilepsy. Previous reviews regarded
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BAFME as an epileptic syndrome included within the idiopathic generalized epilepsies14. However, we recently reported that most Japanese BAFME patients
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showed exaggerated myoclonus and increments of cortical hyperexcitability with aging, as reflected in SEP amplitudes, suggesting a mildly progressive clinical course15.
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Additionally, we reported that the frequency of a posterior dominant rhythm in the
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EEGs of Japanese BAFME patients was significantly slower than that of age-matched
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control subjects, which suggested that Japanese BAFME patients have a mild diffuse
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brain dysfunction with minimal progression16. Therefore, Japanese BAFME is currently considered a very mild form of progressive myoclonus epilepsy.
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The number of patients who have been studied has not been sufficient to
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clarify the clinical phenotype, because BAFME is a relatively rare syndrome (the estimated incidence rate is 1/35,000)17, making analysis of a meaningful number of
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patients in a single institute technically difficult, as shown by our previous studies1,3,15,16.
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Thus, a systematic nationwide study is urgently needed for more detailed clinical characteristics in a larger population of Japanese BAFME. The present study reports a nationwide survey of Japanese BAFME patients, with the goal of delineating the
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detailed clinical characteristics and refining the current diagnostic criteria for this
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disease based on the clinical and electrophysiological findings.
Materials and Methods
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Outline of the survey
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The survey consisted of two steps. The first survey aimed to delineate the current state
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of nationwide myoclonus epilepsy throughout Japan18. It showed that the prevalence of
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BAFME was lower than that of dentatorubral-pallidoluysian atrophy (DRPLA), but higher than that of Unverricht-Lundborg disease, and that the patients with BAFME
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were widely distributed throughout Japan without endemic features. The second survey
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aimed to characterize the detailed clinical characteristics of Japanese BAFME patients.
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The study protocol was approved by the institutional ethics committee at Kyoto
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University Hospital (E1148).
Diagnostic criteria of BAFME Diagnostic criteria for BAFME were defined and adopted from our previous report
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(Supporting Information 1)15. The cardinal features consisted of six items: (1) autosomal dominant inheritance, (2) cortical tremor, (3) infrequent generalized seizures,
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(4) features of cortical reflex myoclonus demonstrated by electrophysiological studies, (5) lack of cognitive decline and other neurological symptoms appearing in the early
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stage of clinical course, and (6) lack of clear progression which impairs the ADL in the
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early stage of clinical course. “Definite” BAFME was defined when all of (1) to (6)
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were satisfied. “Probable” BAFME was defined when (1), (5), (6) and two items out of
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(2) to (4) were satisfied. “Possible” BAFME was defined when (1), (5), (6) and one either (2) or (3) were satisfied. Namely, (1), (5) and (6) were prerequisite items for the
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diagnosis of BAFME in this study. The severity of cortical tremor was classified from
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grade 0 to 4 according to the definition used in a previous report (Supporting
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Information 2)19.
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Questionnaires The first letter survey was conducted by sending the questionnaire form and our diagnostic criteria15, as described above, by mail to the councilors (N = 548) of the
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Japan Neurology Society (N = 8500) and to the councilors (N = 176) of the Japan Epilepsy Society (N = 2000). Among 614 councilors, 302 agreed to complete the survey
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and provided primary information in the first survey. In the second survey, a questionnaire regarding the details of individual cases was sent to 35 respondents who
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had reported the clinically “definite” or “probable” BAFME patients in the first survey
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(Fig. 1). In other words, in the first survey, we asked the physicians whether they treated
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BAFME patients that they themselves clinically considered “definite” or “probable”
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cases. In this second survey, the patients were classified into “definite”, “probable”, or “possible” BAFME strictly based on the listed diagnostic criteria by the authors
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(Supporting Information 1)15.
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The questionnaires in the second survey contained the patient demographic
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profiles (age, sex, birthplace, onset age, past history, and family history), clinical features (epileptic seizures, cortical tremor, and other neurological findings),
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electrophysiological examination results (electroencephalography (EEG), SEP, C-reflex, and JLA), neuroradiological findings (brain MRI, FDG-PET (18F-fluorodeoxyglucose positron emission tomography), and IMP-SPECT ((123) I-iodoamphetamine (IMP)
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Kobayashi et al. 12
single-photon emission computed tomography), and therapies. An SEP was defined as giant as in our previous study20. A waveform example of the preceding positive spike in
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JLA in a representative BAFME patient with cortical tremor is shown in Supporting Information 3. This study does not include the results of gene analyses, because this
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survey was conducted in 2011 before the identification of the causative gene mutations.
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Genetic examinations to exclude other conditions with late onset cortical tremor and
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mild epilepsy were not performed in any of the patients.
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Our recent report on BAFME patients showed that the older patients had more severe findings. The results suggested a progressive clinical course, involving increased
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cortical hyperexcitability with aging15. To confirm the previous findings, we divided the
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patients into three groups: 1) the young group (<50 years old), 2) the middle-aged group
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(50-70 years old), and 3) the elderly group (>70 years old). We compared the clinical
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profiles between these three groups.
Statistical analysis Differences in the positive rates on these examinations suggestive of cortical
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hyperexcitability (giant SEPs, C-reflex, and a preceding spike in JLA) were examined using a Fisher’s exact test followed by comparisons between each of the two groups
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with Bonferroni correction for the multiple comparison. The results were considered significant for P<0.05. Differences in therapies between the three groups were examined
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using a Kruskal-Wallis test and a Fisher’s exact test followed by comparisons between
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each of the two groups using a Mann-Whitney U test and a Fisher’s exact test with
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Bonferroni correction for the multiple comparison. The statistical analyses were
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performed using SPSS version 15 (IBM Japan, Tokyo, Japan).
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Results Detailed information was obtained on 105 patients with Japanese BAFME. Among the
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105 patients diagnosed with BAFME by the councilors, 101 (101/105, 95.3%) in 74 families fulfilled our diagnostic criteria for BAFME (definite = 43, probable = 45,
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possible = 13). We excluded four patients due to lack of the family history of cortical
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tremor and epileptic seizures. We further analyzed the remaining 101 patients.
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Patient backgrounds
BAFME was slightly predominant among women (male/female = 41/60). The patients
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ranged in age from 19 to 87 years (median 54 years) (Supporting Information 4).
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BAFME patients were distributed throughout Japan. The highest prevalence was found
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in Hoku-shin-etsu (Supporting Information 5). Regarding family history, both epileptic seizures and cortical tremor were frequently positive in 88 (88/101, 87.1%) and 94
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(94/101, 93.1%) patients, respectively. The neurological histories were mostly unremarkable. One patient had a cerebral infarction, one had migraine, one had subarachnoid hemorrhage, two had febrile seizures, and one had meningioma.
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Clinical features
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Ninety-two patients (92/101, 91.1%) showed signs of cortical tremor, with a median onset age of 27.5 years old (Supporting Information 6). Cortical tremor was observed in
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the upper limbs in 88/92 patients (95.7%), in the lower limbs in 30/92 patients (32.6%),
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in the trunk in 10/92 (10.9%), and in the face in 6/92 (6.5%) (Fig. 2A). The cortical
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tremor was “positive myoclonic tremor” in at least 67/92 patients (72.8%), “negative
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myoclonic tremor” in 9/92 (9.8%), and unknown in 16/92 (17.4%) (Fig. 2B). Cortical tremor was observed under resting, postural and action conditions (Fig. 2C). Cortical
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tremor was exaggerated by photic stimulation in at least 11 patients and by cold stimuli
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in one patient. Among 88 patients for whom the degree of cortical tremor was well rated,
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the cortical tremor of grade 1 was found in 58/88 patients (65.9%), grade 2 in 25/88 (28.4%), grade 3 in 2/88 (2.3%) and grade 4 in 3/88 (3.4%) (Fig. 2D). Among the 68
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patients with fully reported cortical tremor, the clinical course of the cortical tremor was progressive in 16/68 (23.5%), non-progressive in 51/68 (75.0%) and “self-limited” (progressing and then ceasing) in 1/68 (1.5%) (Fig. 2E).
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Kobayashi et al. 16
Eighty-four patients (84/101, 83.2%) showed signs of epileptic seizures with a median onset age of 33 years old (Supporting Information 6). Epileptic seizures
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consisted of generalized seizures in 75/84 (89.3%) and partial seizures in 17/84 (20.2%). Both generalized and partial seizures were observed in 8/84 patients (9.5%) (Fig. 3A-B).
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The details of the semiology were reported in 11 out of 17 patients with partial seizure.
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The seizure type was heterogeneous but the visual sensory seizures were the most
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predominant, seen in 4 patients. Forty patients (40/84, 47.6%) showed photosensitivity,
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and 3/84 (3.6%) showed auditory evoked seizures (Fig. 3D-E). Epileptic seizures in BAFME patients occur infrequently, however, 19/84 (22.6%) had more than one seizure
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per year in the most active period of the disease (Fig. 3C). The median onset age of
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cortical tremor was 5.5 years lower than the median onset age for epileptic seizures.
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With respect to other neurological symptoms that fulfilled our criteria for
diagnosis, three patients (3/101, 3.0%) showed signs of cerebellar ataxia, 8/101 (7.9%)
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showed cognitive impairment, and 13/101 (12.9%) had psychiatric symptoms such as depression, anxiety neurosis, hallucinations, or panic attacks and other symptoms (Supporting Information 6).
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Electrophysiological examinations and neuroimagings
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EEG was recorded in 94 BAFME patients. The EEG typically showed a poorly organized posterior dominant background rhythm with a median frequency of 10 Hz
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(range: 5.5 to 11.5 Hz) (Supporting Information 7). Regarding paroxysmal activities,
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generalized epileptiform discharges were observed in 45/94 patients (47.9%), focal
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epileptiform discharges in 12/94 (12.8%), and both generalized and focal epileptiform
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discharges in 7/94 (7.4%) (Fig. 4A). Regarding non-paroxysmal slow activities, generalized, focal, and both types of slow activities were observed in 31/94 (33.0%),
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2/94 (2.1%), and 4/94 (4.3%) patients, respectively. Photoparoxysmal responses were
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observed in 23/94 patients (24.5%). Among the patients with photosensitivity clinically,
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35.0% of the patients presented the photoparoxysmal response in EEG. Among 67 patients for whom SEP to median nerve stimulation was recorded, 52/67 (77.6%)
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showed giant SEPs (Fig. 4B). C-reflex and a preceding spike in JLA was observed in 35/41 patients (85.4%) and 8/11 (72.7%), respectively (Fig. 4C-D). Brain MRI was performed in 84 patients, with normal findings in 62/84
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(74%) (Supporting Information 7). The reported abnormalities varied, including cerebral atrophy in 13/84 patients (15.4%), cerebellar atrophy in 2/84 (2.4%), brainstem
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atrophy in 1/84 (1.2%) and white matter hyperintensity regions in T2 weighted images in 10/84 (11.9%). An FDG-PET was performed in only six patients. Three showed
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normal metabolism; the other three showed focal hypometabolism. An IMP-SPECT was
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performed in 14 patients. Six of these were normal, two showed diffuse hypoperfusion,
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and six showed focal hypoperfusion.
Therapies
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Among 95 patients with fully reported therapy, the number of antiepileptic and
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antimyoclonic drugs used in patients with BAFME ranged from 0 to 5 (mean 1.5 ± 1)
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(Supporting Information 8). Sodium valproate (VPA) and clonazepam (CZP) were the most frequently used (in 60 and 51 patients, respectively; in combination in 27 patients).
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Levetiracetam was used in eight patients, phenytoin in seven, phenobarbital in four, zonisamide in three, piracetam in three, and carbamazepine in two. Seven patients received no drugs at the time of this survey.
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Comparison of cortical excitability between the groups classified by age
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The total number of patients in the young group (<50 years), the middle-aged group (50-70 years), and the elderly group (>70 years) was 42, 37, and 22, respectively
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(Supporting Information 9). The mean age and the age range of the young group was
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37.6 (ranged 19-49); for the middle-aged group 59.2 (ranged 51-69); and for the elderly
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group 77.0 (ranged 72-87). The mean disease duration after clinical onset was 14.4
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years in the young group, 25.1 years in the middle-aged group, and 34.0 years in the elderly group. The clinical course of cortical tremor showed progression in 11.1%
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(3/27), 24.0% (6/25), and 43.8% (7/16) for the young, middle-aged, and elderly group,
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respectively. The middle-aged and elderly groups showed a higher degree of cortical
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tremor, suggesting a progressive tendency for this symptom (Fig. 5A). In the young, the middle-aged, and the elderly groups, the positive rates on neurophysiological
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examinations were 68.2% (15/22), 76.7% (23/30), and 93.3% (14/15) for giant SEP, 54.5% (6/11), 100% (18/18), and 91.7 (11/12) for C-reflex, and 50.0% (1/2), 75.0% (3/4), and 80.0% (4/5) for a preceding spike in JLA, respectively (Fig. 5B-D). The
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Kobayashi et al. 20
positive rates (suggesting cortical hyperexcitability) were higher in the middle-aged and elderly groups than those in the young group, and for the with C-reflex the differences
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were significant (P<0.05). The mean number of the drugs used for therapy was 1.3 for the young group,
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1.6 for the middle-aged group, and 1.9 for the elderly group. The difference between the
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young and elderly groups was significant (P<0.05) (Supporting Information 8). VPA
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was used in 55.0% (22/40), 73.5% (25/34), and 61.9% (13/21), and CZP was used in
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32.5% (13/40), 61.8% (21/34), and 81.0% (17/21) of the young, middle-aged, and elderly group, respectively. There was a significant difference in the usage rate of CZP
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between the young and elderly groups (P<0.05).
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Discussion
In this study, we determined the clinical and neurophysiological characteristics of
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BAFME using questionnaires for 101 Japanese BAFME patients. This is the first nationwide epidemiological study in a large population of Japanese BAFME patients. Japanese BAFME patients were widely distributed throughout Japan, which is
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Kobayashi et al. 21
consistent with the previous reports from many different areas of Japan1,2,4,15,17,21,22,23,24.
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General backgrounds As previously reported1,2,15,17, Japanese BAFME showed an autosomal dominant trait
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with high penetration. The incidence of other neurological disorders in patients with
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not specific neurological comorbidities of BAFME.
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BAFME was very similar to that in the general population; thus, these disorders were
i) Cortical tremor
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Clinical Features
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In the present study, five patients (5.6%) also showed severe cortical tremor, and 16 showed a progressive course. Cortical tremor has been reported to be exaggerated by
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various stimuli3. In the present study, cortical tremor was also reportedly exaggerated by
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photic stimuli in 11 patients and cold stimuli in one patient. Cortical tremor induced by cold stimuli suggests that it can be modulated by a superficial, somatosensory input, which is a similar phenomenon to the C-reflex and further indicates that the
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hyperexcitability in primary sensorimotor cortices in Japanese BAFME.
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ii) Generalized seizures In the present study, 19 patients (18.8%) had more than one seizure per year at the
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maximum or even after an appropriate therapy. Therefore, epileptic seizures may not
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always be rare in some Japanese BAFME. Like European BAFME patients6, some
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Japanese patients had complex partial seizures. In the present study, 40 patients showed
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photosensitivity to seizures, and three showed auditory evoked epileptic seizures, which
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also supports the increased cortical irritability to non-visual external stimuli.
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iii) Other neurological features
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Eight patients (7.9%) showed mild cognitive impairment; however, its onset was after 60 years of age. Thirteen patients (12.9%) showed psychiatric symptoms or personality
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changes. Most of the patients (92.6%) took antiepileptic and/or antimyoclonic drugs, which may have influenced on cognitive functions. However, our recent study showed that the frequency of posterior dominant rhythm in Japanese BAFME was significantly
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Kobayashi et al. 23
lower than that of age-matched control subjects regardless of anticonvulsant usage16. These indicate that the mild cognitive impairment in some Japanese BAFME patients is
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probably due to disease itself. Cerebellar ataxia was observed only in three patients (3.0%) either to a very
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mild degree or in the late phase of the clinical course. Only two patients showed
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cerebellar atrophy on MRI, and no patients showed hypometabolism of the cerebellum
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in FDG-PET or hypoperfusion of the cerebellum in IMP-SPECT. Thus, the cerebellar
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dysfunction is very mild, and cerebellar symptoms, such as cerebellar ataxia or
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dysarthria, only occurred in the late phase of the disease.
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Electrophysiological and neuroradiological examinations
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In the present study, generalized, focal and both types of epileptiform discharges on EEG were observed in 47.9%, 12.8% and 7.4% of cases, respectively. The previous
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small case series reported that 94% of BAFME patients showed spikes or poly-spike wave complexes, at a higher occurrence rate than observed in this study25. The difference in the incidence of epileptiform discharges may be due to a 1) small sample
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Kobayashi et al. 24
size, 2) biased selection, 3) state of vigilance of patients during EEG, 4) administration of anticonvulsants, or 5) other factors. Electrophysiological features of cortical reflex
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myoclonus or cortical tremor, i.e., giant SEP, C-reflex and a preceding spike by JLA, were each reported in more than 70% of the examined patients. These findings were
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consistent with those of our previous report15. In the neuroradiological examinations
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used in this study, brain MRI showed either normal or non-specific abnormalities.
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Therapies
Anticonvulsants, especially VPA, CZP and levetiracetam, were effective for both
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cortical tremor and epileptic seizures15. In the current study, VPA and CZP were
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administered to more than half of the patients. However, there was some effect of
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beta-blockers on tremors, which also may differentiate BAFME from essential tremor1, and carbamazepine and gabapentin, which can worsen myoclonic seizures in general,
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should be avoided for treating BAFME6,26.
Comparison between young, middle-aged, and elderly groups
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Kobayashi et al. 25
After middle age, such as 50 years, BAFME patients were previously shown to have a slow progressive clinical course for cortical tremor and cortical hyperexcitability in the
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primary sensorimotor cortices15. The present study clearly confirmed this trend in a substantially larger nationwide population. There was a tendency for cortical tremor to
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be severer in the middle-aged group (50-70 years) than that in the young group, and also
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to be severer in the elderly group (>70 years) than that in the middle-aged group. The
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clinical course of cortical tremor showed progression with aging. The larger number of
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the drugs used for therapy and higher usage rate of CZP in the elderly group compared with the young group may imply that although the epileptic seizures were controlled to
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some extent, the cortical tremor showed progression.
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Comparison between Japanese- and European BAFME Some differences have been reported between Japanese- and European BAFME.
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Cortical tremors appeared to be more disabling27 and epileptic seizures tended to occur more frequently in European pedigrees6 than in Japanese BAFME in the current study. In European pedigrees, patients with mild cognitive impairment showed a gradual
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Kobayashi et al. 26
slowing of the posterior dominant rhythm in EEGs over a clinical course of three decades28. The same authors also reported a high prevalence of mood disorders
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associated with European BAFME, especially depression and anxiety29. In European patients, cerebellar atrophy and functional abnormality were
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detected with a sophisticated MRI technique30,31,32,33. Additionally, a postmortem
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examination of European BAFME patients showed changes in Purkinje cells in the
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cerebellum and preservation of sensorimotor cortex7,34. In the current study, cerebellar
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ataxia was observed in only three Japanese BAFME patients, and no neurophysiological or neuroimaging studies on cerebellar abnormality in association with Japanese
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BAFME have been conducted. Thus, previous studies suggested that European BAFME
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patients showed slightly more severe symptoms of cerebellar abnormality than Japanese
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BAFME patients.
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Revised diagnostic criteria of Japanese BAFME 2018 In this study, we adopted our own tentative diagnostic criteria15, and only four cases reported by councilors did not fulfill the criteria. Thus, our criteria were reasonable for
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the diagnosis of Japanese BAFME. Additionally, our study showed that a few patients also showed partial seizures and cerebellar ataxia as well as psychiatric symptoms.
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Focusing on the differences between the possible BAFME cases and the others (definite and probable BAFME), there were no patients in the possible BAFME presenting
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cortical tremor in the trunk and face, cortical tremor with the feature of negative
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myoclonus, severe cortical myoclonus, or focal slow in EEG. These differences between
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the possible BAFME and the others might in part be due to the small number of the
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possible BAFME patients.
We revise our previous criteria based on these findings (Supporting
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Information 10). The revised criteria consisted of six conditions similar to our previous
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criteria: (1) autosomal dominant inheritance with high penetration, (2) cortical tremor,
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(3) infrequent generalized and partial seizures (but sometimes more than once a year), (4) features of cortical reflex myoclonus (tremor) demonstrated by electrophysiological
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studies, (5) lack of evident cognitive decline, cerebellar ataxia and other neurological symptoms at least in the early stage of clinical course (but these neurological symptoms could be observed in the late phase of the disease), (6) lack of clear progression of
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Kobayashi et al. 28
cortical tremor which impairs the ADL in the early stage of clinical course (but worsening of cortical tremor could be observed in the late phase, especially age over 70).
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“Definite” BAFME was defined when all of (1) to (6) were satisfied. “Probable” BAFME was defined when (1), (5), (6) and two items out of (2) to (4) were satisfied.
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“Possible” BAFME was defined when (1), (5), (6) and one either (2) or (3) were
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satisfied. Namely, (1), (5) and (6) were again prerequisite items for the diagnosis of
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BAFME. These were based on the clinical and electrophysiological findings because
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the underlying gene for Japanese BAFME was not identified at the timing of this survey. These criteria are still practically important for the patient selection toward genetic
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testing even after the discovery of causative gene of BAFME. However, the diagnostic
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criteria will have to include genetic testing in the future.
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Indeed, the patients fulfilling (1), (3), (5), and (6) of the diagnostic criteria are
classified into possible BAFME but not necessarily the BAFME. In such a case,
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although we should consider the possibility of the other genetic epilepsy, one of the important points is that we should consider the BAFME as one of the differentials.
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Kobayashi et al. 29
Limitations The present study has limitations. First, although the BAFME patients were widely
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distributed throughout Japan, some clusters were observed in the Hoku-shin-etsu and Kinki regions. These clusters likely occurred because more councilors in these regions
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replied to the questionnaires. We would like to conduct a larger survey to overcome the
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primary drawback of this study. Second, some of the clinical or neurophysiological
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information for the 101 BAFME patients were missing because of the nature of the
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study. Third, investigations into the symptoms and results of examinations depended solely on the respondents. However, the style of the survey included detailed
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questionnaires; we had no alternative method. The fact that VPA and CZP were
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appropriately used for most of the patients implies that the councilors of the current
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study were reliable. Fourth, we could not investigate the follow-up period after diagnosis, as we did not include an item asking for the age at diagnosis. Since the
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disease duration in the young group was shorter than that in the middle-aged and elderly groups, it would be difficult to accurately assess the progression in the young group even if we included the follow-up period in the item. Despite these limitations, our
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study has some value for delineating the specific clinical characteristics of Japanese BAFME. In the future, analyses of the genetico-clinico-electorophysiological
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correlations would be warranted to further elucidate the pathophysiology and treatment
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of BAFME.
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Disclosure of Conflicts of Interest
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Department of Epilepsy, Movement Disorders and Physiology, which Akio Ikeda
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belongs to, is an endowment department, supported by a grant from GlaxoSmithKline K.K., NIHON KOHDEN CORPORATION, Otsuka Pharmaceutical Co., and UCB
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Japan Co., Ltd. Department of Respiratory Care and Sleep Control Medicine, which
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Takefumi Hitomi belonged to, is an endowed department supported with a grant from
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Fukuda Denshi, Philips-Respironics, and Teijin Pharma. None of the authors has any
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conflicts of interest to disclose in relation to this study.
Ethical publication statement The work described is consistent with the Journal’s guidelines for ethical publication.
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Acknowledgements
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We thank all of the physicians who participated in the survey. The institutions that participated in this study were Kohnan Hospital, Fukushima Medical University
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Hospital, National Center Hospital, Nishi-Niigata Chuo National Hospital, Niigata
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Cancer Center Hospital, Asanogawa General Hospital, Aizawa Hospital, Kyoto
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University Hospital, National Hospital Organization Utano Hospital, Jyujyo Takeda
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Rehabilitation Hospital, Kawasaki Clinic, Toyonaka Municipal Hospital, Kobe University Hospital, National Hospital Organization Nara Medical Center, Okayama
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University Hospital, Kurashiki Memorial Hospital, Kyushu University Hospital,
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Hospital of the University of Occupational and Environmental Health, and National
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Hospital Organization Omuta Hospital. This work was planned, executed and supported by the Research Grant (22A-6) for
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Nervous and Mental Disorders from the Ministry of Health and Welfare, and the Grants-in-Aid for Scientific Research [KAKENHI grant number 23591275, 15H05874 (Non-linear Neuro-oscillology)] from the Japan Society for the Promotion of Science
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(JSPS).
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Supporting Information
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Supporting Information is available at Seizure online.
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6. Guerrini R, Bonanni P, Patrignani A, et al. Autosomal dominant cortical myoclonus and epilepsy (ADCME) with complex partial and generalized seizures: A newly
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18. Kobayashi K, Hitomi T, Matsumoto R, et al. Nationwide survey of myoclonus
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19. Ikeda A, Shibasaki H, Tashiro K, et al. Clinical trial of piracetam in patients with myoclonus: nationwide multiinstitution study in Japan. The Myoclonus/Piracetam Study Group. Mov Disord 1996;11:691-700.
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21. Inoue S. A family of hereditary tremor with epileptic seizure. Psychiatria et
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22. Bunno M, Ishizaki H, Okamoto S. A family with combination of hereditary tremor
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and epilepsy. Rinsho Shinkeigaku 1969;9:729. Abstract in Japanese
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23. Kudo J, Kudo T, Yamauchi T. Seven families with heredofamilial tremor and epilepsy. Rinsho Shinkeigaku 1984;24:1-8. Article in Japanese
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24. Uyama E, Kumamoto T, Ikeda T, et al. A family with hereditary myoclonus epilepsy
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Shinkeigaku 1985;25:1491. Abstract in Japanese 25. Toyota T, Akamatsu N, Tanaka A, et al. Electroencephalographic features of benign
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adult familial myoclonic epilepsy. Clin Neurophysiol 2014;125:250-254. 26. Striano P, Coppola A, Madia F, et al. Life-threatening status epilepticus following gabapentin administration in a patient with benign adult familial myoclonic epilepsy.
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Epilepsia 2007;48:1995-1998. 27. van Rootselaar AF, van Schaik IN, van den Maagdenberg AM, et al. Familial
pedigrees bearing common features. Mov Disord 2005;20:665-673.
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cortical myoclonic tremor with epilepsy: a single syndromic classification for a group of
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28. Coppola A, Santulli L, Del Gaudio L, et al. Natural history and long-term evolution
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in families with autosomal dominant cortical tremor, myoclonus, and epilepsy.
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Epilepsia 2011;52:1245-1250.
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29. Coppola A, Caccavale C, Santulli L, et al. Psychiatric comorbidities in patients from seven families with autosomal dominant cortical tremor, myoclonus, and epilepsy.
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Epilepsy Behav 2016;56:38-43.
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30. van Rootselaar AF, Maurits NM, Renken R, et al. Simultaneous EMG-functional
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MRI recordings can directly relate hyperkinetic movements to brain activity. Hum Brain Mapp 2008;29:1430-1441.
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31. Striano P, Caranci F, Di Benedetto R, et al. (1)H-MR spectroscopy indicates prominent cerebellar dysfunction in benign adult familial myoclonic epilepsy. Epilepsia 2009;50:1491-1497.
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32. Buijink AW, Caan MW, Tijssen MA, et al. Decreased cerebellar fiber density in cortical myoclonic tremor but not in essential tremor. Cerebellum 2013;12:199-204.
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33. Buijink AW, Broersma M, van der Stouwe AM, et al. Cerebellar Atrophy in Cortical Myoclonic Tremor and Not in Hereditary Essential Tremor-a Voxel-Based
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Morphometry Study. Cerebellum 2016;15:696-704.
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34. van Rootselaar AF, van der Salm SM, Bour LJ, et al. Decreased cortical inhibition
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and yet cerebellar pathology in 'familial cortical myoclonic tremor with epilepsy'. Mov
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Disord 2007;22:2378-2385.
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Figure Legends
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Figure 1. Flowchart of the survey. The first letter survey was conducted among councilors of the Japan Neurology Society
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and Japan Epilepsy Society. In the second survey, a questionnaire on the details for
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individual patients was sent to 35 physicians who had reported the patients based on the
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councilors’ diagnosis in the first survey. Among the 105 cases diagnosed as BAFME by
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the councilors, 101 patients of 74 families fulfilled our diagnostic criteria for BAFME.
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Figure 2. Features of cortical tremor in BAFME. Various clinical features of cortical tremor were reported by the respondents according
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to the definition of diagnostic criteria (Supporting Information 1). The body parts involved in cortical tremor (A), the features whether the cortical tremor
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was positive or negative myoclonus (B), three conditions in which cortical tremor was
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evident (C), the severity of cortical tremor by rating scale (D), and the clinical course
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(E) are presented. The detailed results are in Supporting Information 6. The labels All,
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D, Pr, and Po represent the results of all, definite, probable, and possible BAFME patients, respectively. Each number below the four groups represents the number of
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patient from whom detailed information was obtained.
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Figure 3. Features of epileptic seizures in BAFME. The abbreviations in the figures are the same as those in Fig. 2. The seizure type (A and
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B), the patients who had more than on seizure per year at the maximum (C), and the patients with sensitivity to visual (D) and auditory (E) stimuli are presented. The
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detailed results are in the Supporting Information 6.
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Figure 4. Findings of neurophysiological examinations in BAFME. The abbreviations in the figures are the same as the abbreviations in Fig. 2 and 3. The
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incidence of epileptiform discharges, slow activities, and photoparoxysmal response are shown in (A). The positive rate of giant SEPs (B), C-reflex (C), and a preceding spike in
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JLA (D) are presented. The detailed results are in Supporting Information 7.
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Figure 5. Correlation between age and cortical excitability in BAFME. The abbreviations in the figures are same as those used in Fig. 4. The incidence, severity,
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and clinical course of cortical tremor (A), the incidence of giant SEP (B), C-reflex (C), and a preceding spike in JLA (D) were compared between the young (<50 years), the
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middle-aged (50-70 years), and the elderly (>70 years) BAFME patients. A Fisher’s
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exact test demonstrated a statistically significant difference (*) in the incidence of
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results are in Supporting Information 9.
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C-reflex between the younger and the older (middle-aged and elderly) groups. Detailed
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