579767 research-article2015
EEGXXX10.1177/1550059415579767Clinical EEG and NeuroscienceIsobe et al
Original Article
Periodic Epileptiform Discharges in Children With Advanced Stages of Progressive Myoclonic Epilepsy
Clinical EEG and Neuroscience 1–7 © EEG and Clinical Neuroscience Society (ECNS) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1550059415579767 eeg.sagepub.com
Natsumi Isobe1,2, Yasunari Sakai1, Ryutaro Kira3, Masafumi Sanefuji1,4, Yoshito Ishizaki1, Ayumi Sakata2, Momoko Sasazuki1, Michiko Torio1, Satoshi Akamine1, Hiroyuki Torisu1,5, and Toshiro Hara1
Abstract Huntington’s disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA) are monogenic forms of neurodegenerative disorders with autosomal dominant inheritance. Compared with adult-onset HD and DRPLA, children with these disorders are more severely affected and are known to manifest the devastating symptoms of progressive myoclonic epilepsy (PME) syndrome. In this report, we present a 6-year-old girl with HD from a family, and 2 siblings with DRPLA from another unrelated family. Serial neuroimaging and electroencephalography (EEG) studies showed that periodic epileptiform discharges and synchronized paroxysmal activity became prominent with their disease progression. Periodic complexes in EEG may emerge at advanced stages of childhood PME as a consequence of rapidly degenerating processes of their brain functions. Keywords Huntington disease, dentatorubral-pallidoluysian atrophy, poly-glutamine diseases, progressive myoclonic epilepsy (PME), electroencephalography, periodic lateralized epileptiform discharges (PLEDs) Received October 2, 2014; Revised January 26, 2015; Accepted February 16, 2015.
Introduction In the past decades, genetic studies on families HD and DRPLA have identified abnormal CAG expansions in the coding regions of huntingtin (HTT) and atropthin-1 (ATN1) as diseasecausing mutations.1,2 These heritable forms of degenerative disorders have been thus classified into a group of poly-glutamine diseases. Both diseases are characterized by progressive deterioration in motor as well as cognitive functions without effective therapies.3 Notably, the mutant alleles of HTT and ATN1 in affected individuals are transmitted to the next generations with increasing number of CAG repeats. For this reason, polyglutamine diseases are thought to accelerate in their clinical severity, the ages of onsets and the speed of degeneration over generations,1,4,5 In fact, child-onset HD and DRPLA must be considered in the differential diagnoses of progressive myoclonic epilepsy (PME), one of the most devastating epilepsy syndromes in childhood with heterogeneous etiologies.6,7 HD and DRPLA show distinct patterns of clinical presentations and neuroimaging features. For example, cranial magnetic resonance imaging (MRI) identifies the caudate nucleus and putamen as primary lesions in the brain of patients with HD.8 These findings are thought correlate with the clinical onset and progressive signs of choreic involuntary movements in HD.9 Similarly, deterioration in motor functions and
progressive ataxia are the primary signs for suspecting the diagnosis of DRPLA. A few studies reported that developmental delay and autistic features were the early signs of childonset DRPLA, illustrating the distinct clinical features of DRPLA in childhood from those in adulthood.10 In both HD and DRPLA cases, cognitive functions are severely affected as the diseases progress, leading to premature deaths due to whole brain dysfunctions. Although extended trinucleotide repeats in the ATN1 gene were originally identified in patients with DRPLA as familial causes for non-HD types of degenerative diseases,5 phenotypic 1
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 2 Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan 3 Fukuoka Children’s Hospital, Fukuoka, Japan 4 Research Center for Environment and Developmental Medical Sciences, Kyushu University, Fukuoka, Japan 5 Section of Pediatrics, Department of Medicine, Fukuoka Dental College, Fukuoka, Japan Corresponding Author: Yasunari Sakai, Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582 Japan. Email: [email protected]
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overlaps between DRPLA to that of HD has been of particular interests for neurologists and neuroscientists.11 To date, however, few studies have focused on the time courses of changes in electrophysiology. In this report, we present a girl with juvenile HD from a family with HD, and 2 siblings with DRPLA from a second family. We report that all of them manifested intractable seizures, and that periodic components in EEG developed as their diseases progressed. This study first describes periodically synchronized components in epileptiform discharges as a novel electrophysiological feature in children with PME syndrome.
Materials and Methods This study was conducted in accordance with the guideline of an institutional review board at Kyushu University. Written informed consents were obtained prior to genetic analyses. Genetic tests for triplet repeat expansions in the coding regions of the huntingtin, SCA1, SCA3 for case 1 and atrophin-1 (ATN1) genes were carried out using whole-blood DNAs at the Neurological Institute, Kyushu University, as previously described.12 Electroencephalography was obtained on 16-channel recordings according to the international 10-20 system.13 MRI was performed using an Intera 1.5T system (Philips Medical Systems, Best, Netherlands).14
Cases and Results Case 1 A 6-year-old Japanese girl, who had been diagnosed as juvenile HD in a previous hospital, was referred to us for treatment of intractable seizures. Her father and paternal grandfather had also been also diagnosed with HD, and they died at 41 and 53 years of age, respectively. Genetic tests in a prior hospital identified the triplet repeats in huntingtin extended to 95 to 100 times, confirming the diagnosis of HD (data not shown). On her first visit, dystonic postures and involuntary movements of choreoathetosis and myoclonus were evident, while she was able to stand still by herself and to make a few steps with assistance. The cranial MRI at 6 years of age showed moderate atrophy in the caudate nuclei and the cerebral cortex, which sustained the characteristic neuroimaging feature of HD (Figure 1A). Enlargement of lateral ventricles with diffuse cerebral atrophy was noted, as the disease progressed, over the 3 years of follow-up period (Figure 1B). The EEG at 6 years of age showed poorly organized backgrounds with frequent, diffuse and multifocal spike-and-wave complex formations (Figure 2A). Persistent periodicity in paroxysmal discharges was rarely noted at this point. The epileptic discharges have changed in appearance around 10 years of age when she was no longer able to sit alone. Notably, the EEG at this age showed a unique pattern of paroxysmal activity resembling periodic lateralized epileptic discharges (PLEDs) (Figure 2B). This EEG finding lasted for a few years until she died at 17 years of age.
Figure 1. The serial magnetic resonance imaging (MRI) studies on Case 1. The axial views of fluid attenuated inversion recovery MRIs at 7 years (A) and 12 years (B) of age depict progressive atrophy in the cerebral cortex and caudate nuclei (arrows).
Case 2 A 13-year-old Japanese girl was from a second family. She was referred to us, when she was 5 years of age, for intractable seizures and developmental delay for unknown etiology. She was born to healthy, unrelated parents at the 39th gestational week without perinatal complications. She had 2 siblings—a healthy brother 3 years older and a second brother 1 year old to her who had epilepsy (case 3). Her motor development in infancy appeared to be normal, whereas she had acquired a meaningful word at 15 months and an independent gait at 16 months of age. At 3 years of age, she had learnt less than 10 words and was unable to speak 2-word sentences. Being diagnosed as pervasive developmental delay, she started remedial educations for handicapped children from 3 years of age. She also suffered from generalized tonic-clonic seizures since 3 years old. Diffuse spike-and-wave complexes were frequently observed on EEG at the initial diagnosis of epilepsy (data not shown). Antiepileptic therapy in combination of valproic acid, carbamazepine, ethosuximide, clonazepam, and lamotrigine showed little effects for her seizure control. Her motor activity gradually deteriorated, spoken language disappeared, and cerebellar ataxia became evident by the age of 10 years. Consistently, the cranial MRI showed atrophy in the cerebral cortex, white matter, and the cerebellum at this age (Supplementary Figures S1A, S1B available online at http:// eeg.sagepub.com/content/by/supplemental-data). The cranial MRI findings at 8 years of age did not differ substantially from those at 10 years of age (data not shown). We were unable to ensure the disease progression on serial MRI studies because earlier images were no longer available. Although neither of her parents had any signs of degenerative diseases, genetic factors were strongly suspected from deterioration in her neurological signs and the presence of similar symptoms in case 3 (as described below). The genetic tests were conducted using her blood DNA to rule out the triplet-repeat expansions in ATN1. The test results showed that she had 74
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Figure 2. Serial electroencephalography (EEG) recordings for Case 1. (A) An interictal, awake EEG recording at 7 years of age. Note that frequent, but aperiodic patterns of diffuse spike-and-wave complexes (dashed square) were the dominant paroxysmal discharges at this age. (B) An awake EEG taken at 12 years of age shows poorly organized background activity with periodic discharges at 0.8 to 1 Hz of frequency (arrows).
repeats of CAG in the ATN1 gene, confirming her diagnosis as DRPLA (data not shown). Parental origins and the potential risk of DRPLA for her parents have never been examined. The awake EEG recording taken at 7 years of age detected the presence of multifocal spikes or sharp waves with poorly organized backgrounds (Supplementary Figure S2A). The paroxysms at this period occurred randomly, while periodic synchronization of epileptiform discharges were barely seen. By
contrast, the EEG at 11 years of age was dominated by clustered segments of high-voltage, slow waves and epileptic discharges that were frequently synchronized at 1.5 to 2 Hz of frequency (Supplementary Figure S2B). While the paroxysmal activity looked aperiodic, synchronized spike-and-wave activity emerged mostly in clusters by the age of 8 and it became a dominant finding on EEG (>50% of the whole recording time) at 11 years of age.
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Case 3 The boy is presently 14 years old (1 year older than case 2). He passed regular checkups in infancy and showed intact social skills in the preschool years; however, he had difficulty with arithmetic at elementary school. He experienced the first attacks of drop and myoclonic seizures at 8 years of age, and visited our hospital for neurological assessment. Various types of general and complex partial seizures appeared at a frequency of once or twice a month thereafter. Neurological deteriorations, cerebellar ataxia and degenerative signs in MRI were absent on his first visit. However, he had progressive difficulty in walking with cerebellar ataxia while his seizure increased in frequency by the age of 12. As mentioned above, a genetic test enabled us to diagnose him as having DRPLA at 12 years of age. Serial MRIs taken at 10 and 12 years of age revealed the progressive atrophy in the cerebellum (Supplementary Figures S3A, S3B). Reciprocally, the serial EEG studies depicted the following deteriorating features: An awake EEG recorded at 10 years of age showed irregular backgrounds and diffuse multifocal spike-and-wave complex formations with few periodic synchronization (Figure 3A). When compared with this, an awake EEG recording at 12 years of age revealed the diffuse paroxysmal discharges with 1 to 1.5 Hz of periodically synchronized electrical activity that accounted for more than 90% of the whole recording time (Figure 3B).
Discussion In this report, we have presented serial EEG recordings of a girl with HD and 2 siblings with DRPLA. All these 3 patients showed deteriorating brain functions and severe myoclonic epilepsy that were hard to control by regular antiepileptic therapies. We thus considered them as having PME syndrome. Consistently, diffuse and multifocal epileptic discharges were observed in their EEG recordings from earlier periods. We found that periodic components in epileptiform discharges were evident as their diseases progressed (cases 1 and 3), and most notably that the EEG in the advanced stages of case 1 exhibited the typical appearance of periodic epileptiform discharges, namely PLEDs. PME is clinically characterized by myoclonus, epileptic seizures, and progressive neurological deterioration with manifestations of dementia and ataxia.7 Heterogeneous genetic causes have been associated with PME. For example, patients affected by metabolic diseases, such as mitochondrial encephalomyopathy with ragged red fibers, Lafora’s disease, neuronal ceroid lipofusinoses and sialidosis, can be recognized as manifesting PME at their onsets.7,15 Unverricht-Lundborg disease, HD, and DRPLA are also among well-known single-gene disorders associated with PME. Previous studies showed that EEG features of juvenile HD include posterior rhythmic delta activity and intermittent spikewave paroxysms.16,17 Various forms of epileptogenic activity have been also shown in cases with DRPLA. These include
diffuse irregular spike-and-wave complexes and slow-wave bursts.6,18 Although it is known that their EEG findings change over the course of illness, neither PLEDs nor other forms of periodic discharges have ever been noted in prior studies for HD and DRPLA children. PLEDs have been associated with various diseases in the central nervous systems. These include herpes simplex encephalitis, subacute sclerosing panencephalitis, bacterial meningoencephalitis, and Creutzfeldt-Jakob disease.19 The unique forms of discharges are defined as a pattern of repetitive paroxysmal slow or sharp waves, uni- or bilateral at intervals of between 0.5 and 3.20 The paroxysmal discharges can be recognized as either simple sharp waves or compounded forms with variable firing rates (0.1-3 Hz) and amplitudes (100-1000 µV).21 The term PLED implies lateralization, whereas such activity can be generated independently from both hemispheres. Moreover, bilateral synchronous, generalized periodic activity has been reported.13,21 The variant forms of periodic complexes were alternatively called bilateral independent periodic lateralized epileptiform discharges (BiPLEDs) and generalized periodic epileptiform discharges (GPEDs).22 Taking these into account, we regarded the EEG findings as PLEDs for case 1 and GPEDs for case 3. Given that rhythmicity and periodicity in the epileptiform discharges of our cases became obvious at later stages, neural mechanisms of PLEDs in neurodegenerative disorders might be different from those in infection-associated diseases.19,23 Former studies demonstrated that PLEDs without recognizable seizures at the time of detection were correlated with poor prognosis.24 This may account for the rapid deterioration in neurological signs of our 3 cases. Nonetheless, there are no reports describing the periodic complex presentation during the courses of adult-onset HD and DRPLA. We therefore hypothesized alternatively that emerging periodic discharges might reflect the rapid processes of devastating brain functions in PME cases with child-onset HD and DRPLA, which might not always be seen in adulthood. Although precise mechanisms underlying the unique electrical activity remain to be elusive, PLEDs can be both transiently and persistently observed as an accompanying phenotype of altered cortical activity and disconnected thalamocortical interplays.13,22,23 Asymmetrical periodic discharges may reflect interhemispheric differences in neuronal activity because of localized injury, predominantly affected neural circuits, and regional differences in degeneration.21 We therefore speculate that laterality in the periodic discharges in the EEGs of cases 2 and 3 might appear when their diseases further progress in the future. HD and DRPLA are both highly penetrant, monogenic disorders that lead to progressive degeneration of the central nervous system for affected individuals. Unifying theories of pathogenesis have been postulated for multiple degenerative diseases despite their distinct clinical pictures and genetic backgrounds. In fact, HTT and ATN1 proteins were demonstrated to share their interacting partner, CREB binding protein
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Figure 3. The serial electroencephalographic (EEG) studies on Case 3. (A) An awake EGG recoding at 10 years of age. The EEG shows the poor background activity and the brief appearance of multifocal spike-and-wave complexes lasting only for 1 to 2 seconds (dashed square). (B) An awake EGG recoding at 12 years of age. This EEG shows persistently lasting periodically synchronized discharges (arrows).
(CBP), and synergistically regulate the neuronal gene expressions both in vitro and in vivo.11,25 Although these unifying models still remain controversial, it is not surprising that HD and DRPLA may overlap in their clinical features or in electrophysiological bases.3 Consistent with this concept, the epileptic seizures of the present cases were all intractable and fit well with the diagnosis of PME syndrome. This finding supported the hypothesis that HD and DRPLA in childhood may share
common neural mechanisms underlying rapidly progressive degeneration. In conclusion, we report that PLEDs and periodically synchronized epileptiform activity in child-onset HD and DRPLA are correlated with advanced stages of neurodegeneration. Future functional studies will help unravel the brain regions and mechanisms of unique epileptiform activity in these degenerative disorders.
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Acknowledgments We thank Dr Yasumasa Ohyagi and Kyoko Iinuma at the Neurological Institute, Kyushu University for genetic tests for SCAs; Tomoko Itakura and Eriko Watanabe at Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital for EEG recordings.
Author Contributions NI contributed to conception and design; contributed to acquisition, analysis, and interpretation; drafted manuscript; critically revised manuscript; agrees to be accountable for all aspects of work ensuring integrity and accuracy. YS contributed to conception and design; contributed to acquisition, analysis, and interpretation; drafted manuscript; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. RK contributed to conception; contributed to interpretation; drafted manuscript; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. MS contributed to conception; contributed to interpretation; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. YI contributed to conception; contributed to analysis; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. AS contributed to conception; contributed to analysis; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. MS contributed to conception; contributed to analysis; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. MT contributed to conception; contributed to analysis and interpretation; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. SA contributed to conception; contributed to analysis; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. HT contributed to conception and design; contributed to analysis and interpretation; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. TH contributed to conception and design; contributed to analysis and interpretation; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy.
Declaration of Conflicting Interests The author(s) declared no conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported in part by KAKEN No. 24650199 (awarded to YS), Japan Life Science Foundation (YS), Takeda Science Foundation (YS), and The Mother and Child Health Foundation (YS).
References 1. Nagafuchi S, Yanagisawa H, Sato K, et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet. 1994;6:14-18.
2. Yazawa I, Nukina N, Hashida H, Goto J, Yamada M, Kanazawa I. Abnormal gene product identified in hereditary dentatorubralpallidoluysian atrophy (DRPLA) brain. Nat Genet. 1995;10: 99-103. 3. Govert F, Schneider SA. Huntington’s disease and Huntington’s disease–like syndromes: an overview. Curr Opin Neurol. 2013;26:420-427. 4. Brunetti-Pierri N, Wilfong AA, Hunter JV, Craigen WJ. A severe case of dentatorubro-pallidoluysian atrophy (DRPLA) with microcephaly, very early onset of seizures, and cerebral white matter involvement. Neuropediatrics. 2006;37: 308-311. 5. Nagafuchi S, Yanagisawa H, Ohsaki E, et al. Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA). Nat Genet. 1994;8:177-182. 6. Hattori H, Higuchi Y, Okuno T, Asato R, Fukumoto M, Kondo I. Early-childhood progressive myoclonus epilepsy presenting as partial seizures in dentatorubral-pallidoluysian atrophy. Epilepsia. 1997;38:271-274. 7. Shahwan A, Farrell M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4:239-248. 8. Ho VB, Chuang HS, Rovira MJ, Koo B. Juvenile Huntington disease: CT and MR features. AJNR Am J Neuroradiol. 1995;16:1405-1412. 9. Martin JB, Gusella JF. Huntington’s disease. Pathogenesis and management. N Engl J Med. 1986;315:1267-1276. 10. Tomoda A, Ikezawa M, Ohtani Y, Miike T, Kumamoto T. Progressive myoclonus epilepsy: dentato-rubro-pallidoluysian atrophy (DRPLA) in childhood. Brain Dev. 1991;13: 266-269. 11. Burke JR, Enghild JJ, Martin ME, et al. Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nat Med. 1996;2:347-350. 12. Miyoshi Y, Yamada T, Tanimura M, et al. A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1-24.1. Neurology. 2001;57:96-100. 13. Kim YS, Choi SY, Kwag HJ, Kim JM. Classification and serial evolution of PLEDs. J Clin Neurol. 2006;2:179-185. 14. Lee S, Sanefuji M, Watanabe K, et al. Clinical and MRI characteristics of acute encephalopathy in congenital adrenal hyperplasia. J Neurol Sci. 2011;306:91-93. 15. Muona M, Berkovic SF, Dibbens LM, et al. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015;47:39-46. 16. Landau ME, Cannard KR. EEG characteristics in juvenile Huntington’s disease: a case report and review of the literature. Epileptic Disord. 2003;5:145-148. 17. Ullrich NJ, Riviello JJ Jr, Darras BT, Donner EJ. Electroencephalographic correlate of juvenile Huntington’s disease. J Child Neurol. 2004;19:541-543. 18. Saitoh S, Momoi MY, Yamagata T, Miyao M, Suwa K. Clinical and electroencephalographic findings in juvenile type DRPLA. Pediatr Neurol. 1998;18:265-268. 19. Au WJ, Gabor AJ, Vijayan N, Markand ON. Periodic lateralized epileptiform complexes (PLEDs) in Creutzfeldt-Jakob disease. Neurology. 1980;30:611-617. 20. Chatrian GE, Shaw CM, Leffman H. The significance of periodic lateralized epileptiform discharges in EEG: an electrographic,
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Isobe et al clinical and pathological study. Electroencephalogr Clin Neurophysiol. 1964;17:177-193. 21. Nordli DR Jr, Rivello JJ Jr, Niedermeyer E. Periodic or Quasiperiodic Discharges. Philadelphia, PA: Lippincott Williams & Wilkins; 2010. 22. San-Juan OD, Chiappa KH, Costello DJ, Cole AJ. Periodic epileptiform discharges in hypoxic encephalopathy: BiPLEDs and GPEDs as a poor prognosis for survival. Seizure. 2009;18:365-368.
23. Greenberg MK, McCarty GE. PLEDs in Creutzfeldt-Jakob disease. Neurology. 1981;31:362-363. 24. Orta DS, Chiappa KH, Quiroz AZ, Costello DJ, Cole AJ. Prognostic implications of periodic epileptiform discharges. Arch Neurol. 2009;66:985-991. 25. Nucifora FC Jr, Sasaki M, Peters MF, et al. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science. 2001;291:2423-2428.
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EEGXXX10.1177/1550059415579767Clinical EEG and NeuroscienceIsobe et al
Original Article
Periodic Epileptiform Discharges in Children With Advanced Stages of Progressive Myoclonic Epilepsy
Clinical EEG and Neuroscience 1–7 © EEG and Clinical Neuroscience Society (ECNS) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1550059415579767 eeg.sagepub.com
Natsumi Isobe1,2, Yasunari Sakai1, Ryutaro Kira3, Masafumi Sanefuji1,4, Yoshito Ishizaki1, Ayumi Sakata2, Momoko Sasazuki1, Michiko Torio1, Satoshi Akamine1, Hiroyuki Torisu1,5, and Toshiro Hara1
Abstract Huntington’s disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA) are monogenic forms of neurodegenerative disorders with autosomal dominant inheritance. Compared with adult-onset HD and DRPLA, children with these disorders are more severely affected and are known to manifest the devastating symptoms of progressive myoclonic epilepsy (PME) syndrome. In this report, we present a 6-year-old girl with HD from a family, and 2 siblings with DRPLA from another unrelated family. Serial neuroimaging and electroencephalography (EEG) studies showed that periodic epileptiform discharges and synchronized paroxysmal activity became prominent with their disease progression. Periodic complexes in EEG may emerge at advanced stages of childhood PME as a consequence of rapidly degenerating processes of their brain functions. Keywords Huntington disease, dentatorubral-pallidoluysian atrophy, poly-glutamine diseases, progressive myoclonic epilepsy (PME), electroencephalography, periodic lateralized epileptiform discharges (PLEDs) Received October 2, 2014; Revised January 26, 2015; Accepted February 16, 2015.
Introduction In the past decades, genetic studies on families HD and DRPLA have identified abnormal CAG expansions in the coding regions of huntingtin (HTT) and atropthin-1 (ATN1) as diseasecausing mutations.1,2 These heritable forms of degenerative disorders have been thus classified into a group of poly-glutamine diseases. Both diseases are characterized by progressive deterioration in motor as well as cognitive functions without effective therapies.3 Notably, the mutant alleles of HTT and ATN1 in affected individuals are transmitted to the next generations with increasing number of CAG repeats. For this reason, polyglutamine diseases are thought to accelerate in their clinical severity, the ages of onsets and the speed of degeneration over generations,1,4,5 In fact, child-onset HD and DRPLA must be considered in the differential diagnoses of progressive myoclonic epilepsy (PME), one of the most devastating epilepsy syndromes in childhood with heterogeneous etiologies.6,7 HD and DRPLA show distinct patterns of clinical presentations and neuroimaging features. For example, cranial magnetic resonance imaging (MRI) identifies the caudate nucleus and putamen as primary lesions in the brain of patients with HD.8 These findings are thought correlate with the clinical onset and progressive signs of choreic involuntary movements in HD.9 Similarly, deterioration in motor functions and
progressive ataxia are the primary signs for suspecting the diagnosis of DRPLA. A few studies reported that developmental delay and autistic features were the early signs of childonset DRPLA, illustrating the distinct clinical features of DRPLA in childhood from those in adulthood.10 In both HD and DRPLA cases, cognitive functions are severely affected as the diseases progress, leading to premature deaths due to whole brain dysfunctions. Although extended trinucleotide repeats in the ATN1 gene were originally identified in patients with DRPLA as familial causes for non-HD types of degenerative diseases,5 phenotypic 1
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 2 Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan 3 Fukuoka Children’s Hospital, Fukuoka, Japan 4 Research Center for Environment and Developmental Medical Sciences, Kyushu University, Fukuoka, Japan 5 Section of Pediatrics, Department of Medicine, Fukuoka Dental College, Fukuoka, Japan Corresponding Author: Yasunari Sakai, Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582 Japan. Email: [email protected]
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overlaps between DRPLA to that of HD has been of particular interests for neurologists and neuroscientists.11 To date, however, few studies have focused on the time courses of changes in electrophysiology. In this report, we present a girl with juvenile HD from a family with HD, and 2 siblings with DRPLA from a second family. We report that all of them manifested intractable seizures, and that periodic components in EEG developed as their diseases progressed. This study first describes periodically synchronized components in epileptiform discharges as a novel electrophysiological feature in children with PME syndrome.
Materials and Methods This study was conducted in accordance with the guideline of an institutional review board at Kyushu University. Written informed consents were obtained prior to genetic analyses. Genetic tests for triplet repeat expansions in the coding regions of the huntingtin, SCA1, SCA3 for case 1 and atrophin-1 (ATN1) genes were carried out using whole-blood DNAs at the Neurological Institute, Kyushu University, as previously described.12 Electroencephalography was obtained on 16-channel recordings according to the international 10-20 system.13 MRI was performed using an Intera 1.5T system (Philips Medical Systems, Best, Netherlands).14
Cases and Results Case 1 A 6-year-old Japanese girl, who had been diagnosed as juvenile HD in a previous hospital, was referred to us for treatment of intractable seizures. Her father and paternal grandfather had also been also diagnosed with HD, and they died at 41 and 53 years of age, respectively. Genetic tests in a prior hospital identified the triplet repeats in huntingtin extended to 95 to 100 times, confirming the diagnosis of HD (data not shown). On her first visit, dystonic postures and involuntary movements of choreoathetosis and myoclonus were evident, while she was able to stand still by herself and to make a few steps with assistance. The cranial MRI at 6 years of age showed moderate atrophy in the caudate nuclei and the cerebral cortex, which sustained the characteristic neuroimaging feature of HD (Figure 1A). Enlargement of lateral ventricles with diffuse cerebral atrophy was noted, as the disease progressed, over the 3 years of follow-up period (Figure 1B). The EEG at 6 years of age showed poorly organized backgrounds with frequent, diffuse and multifocal spike-and-wave complex formations (Figure 2A). Persistent periodicity in paroxysmal discharges was rarely noted at this point. The epileptic discharges have changed in appearance around 10 years of age when she was no longer able to sit alone. Notably, the EEG at this age showed a unique pattern of paroxysmal activity resembling periodic lateralized epileptic discharges (PLEDs) (Figure 2B). This EEG finding lasted for a few years until she died at 17 years of age.
Figure 1. The serial magnetic resonance imaging (MRI) studies on Case 1. The axial views of fluid attenuated inversion recovery MRIs at 7 years (A) and 12 years (B) of age depict progressive atrophy in the cerebral cortex and caudate nuclei (arrows).
Case 2 A 13-year-old Japanese girl was from a second family. She was referred to us, when she was 5 years of age, for intractable seizures and developmental delay for unknown etiology. She was born to healthy, unrelated parents at the 39th gestational week without perinatal complications. She had 2 siblings—a healthy brother 3 years older and a second brother 1 year old to her who had epilepsy (case 3). Her motor development in infancy appeared to be normal, whereas she had acquired a meaningful word at 15 months and an independent gait at 16 months of age. At 3 years of age, she had learnt less than 10 words and was unable to speak 2-word sentences. Being diagnosed as pervasive developmental delay, she started remedial educations for handicapped children from 3 years of age. She also suffered from generalized tonic-clonic seizures since 3 years old. Diffuse spike-and-wave complexes were frequently observed on EEG at the initial diagnosis of epilepsy (data not shown). Antiepileptic therapy in combination of valproic acid, carbamazepine, ethosuximide, clonazepam, and lamotrigine showed little effects for her seizure control. Her motor activity gradually deteriorated, spoken language disappeared, and cerebellar ataxia became evident by the age of 10 years. Consistently, the cranial MRI showed atrophy in the cerebral cortex, white matter, and the cerebellum at this age (Supplementary Figures S1A, S1B available online at http:// eeg.sagepub.com/content/by/supplemental-data). The cranial MRI findings at 8 years of age did not differ substantially from those at 10 years of age (data not shown). We were unable to ensure the disease progression on serial MRI studies because earlier images were no longer available. Although neither of her parents had any signs of degenerative diseases, genetic factors were strongly suspected from deterioration in her neurological signs and the presence of similar symptoms in case 3 (as described below). The genetic tests were conducted using her blood DNA to rule out the triplet-repeat expansions in ATN1. The test results showed that she had 74
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Figure 2. Serial electroencephalography (EEG) recordings for Case 1. (A) An interictal, awake EEG recording at 7 years of age. Note that frequent, but aperiodic patterns of diffuse spike-and-wave complexes (dashed square) were the dominant paroxysmal discharges at this age. (B) An awake EEG taken at 12 years of age shows poorly organized background activity with periodic discharges at 0.8 to 1 Hz of frequency (arrows).
repeats of CAG in the ATN1 gene, confirming her diagnosis as DRPLA (data not shown). Parental origins and the potential risk of DRPLA for her parents have never been examined. The awake EEG recording taken at 7 years of age detected the presence of multifocal spikes or sharp waves with poorly organized backgrounds (Supplementary Figure S2A). The paroxysms at this period occurred randomly, while periodic synchronization of epileptiform discharges were barely seen. By
contrast, the EEG at 11 years of age was dominated by clustered segments of high-voltage, slow waves and epileptic discharges that were frequently synchronized at 1.5 to 2 Hz of frequency (Supplementary Figure S2B). While the paroxysmal activity looked aperiodic, synchronized spike-and-wave activity emerged mostly in clusters by the age of 8 and it became a dominant finding on EEG (>50% of the whole recording time) at 11 years of age.
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Case 3 The boy is presently 14 years old (1 year older than case 2). He passed regular checkups in infancy and showed intact social skills in the preschool years; however, he had difficulty with arithmetic at elementary school. He experienced the first attacks of drop and myoclonic seizures at 8 years of age, and visited our hospital for neurological assessment. Various types of general and complex partial seizures appeared at a frequency of once or twice a month thereafter. Neurological deteriorations, cerebellar ataxia and degenerative signs in MRI were absent on his first visit. However, he had progressive difficulty in walking with cerebellar ataxia while his seizure increased in frequency by the age of 12. As mentioned above, a genetic test enabled us to diagnose him as having DRPLA at 12 years of age. Serial MRIs taken at 10 and 12 years of age revealed the progressive atrophy in the cerebellum (Supplementary Figures S3A, S3B). Reciprocally, the serial EEG studies depicted the following deteriorating features: An awake EEG recorded at 10 years of age showed irregular backgrounds and diffuse multifocal spike-and-wave complex formations with few periodic synchronization (Figure 3A). When compared with this, an awake EEG recording at 12 years of age revealed the diffuse paroxysmal discharges with 1 to 1.5 Hz of periodically synchronized electrical activity that accounted for more than 90% of the whole recording time (Figure 3B).
Discussion In this report, we have presented serial EEG recordings of a girl with HD and 2 siblings with DRPLA. All these 3 patients showed deteriorating brain functions and severe myoclonic epilepsy that were hard to control by regular antiepileptic therapies. We thus considered them as having PME syndrome. Consistently, diffuse and multifocal epileptic discharges were observed in their EEG recordings from earlier periods. We found that periodic components in epileptiform discharges were evident as their diseases progressed (cases 1 and 3), and most notably that the EEG in the advanced stages of case 1 exhibited the typical appearance of periodic epileptiform discharges, namely PLEDs. PME is clinically characterized by myoclonus, epileptic seizures, and progressive neurological deterioration with manifestations of dementia and ataxia.7 Heterogeneous genetic causes have been associated with PME. For example, patients affected by metabolic diseases, such as mitochondrial encephalomyopathy with ragged red fibers, Lafora’s disease, neuronal ceroid lipofusinoses and sialidosis, can be recognized as manifesting PME at their onsets.7,15 Unverricht-Lundborg disease, HD, and DRPLA are also among well-known single-gene disorders associated with PME. Previous studies showed that EEG features of juvenile HD include posterior rhythmic delta activity and intermittent spikewave paroxysms.16,17 Various forms of epileptogenic activity have been also shown in cases with DRPLA. These include
diffuse irregular spike-and-wave complexes and slow-wave bursts.6,18 Although it is known that their EEG findings change over the course of illness, neither PLEDs nor other forms of periodic discharges have ever been noted in prior studies for HD and DRPLA children. PLEDs have been associated with various diseases in the central nervous systems. These include herpes simplex encephalitis, subacute sclerosing panencephalitis, bacterial meningoencephalitis, and Creutzfeldt-Jakob disease.19 The unique forms of discharges are defined as a pattern of repetitive paroxysmal slow or sharp waves, uni- or bilateral at intervals of between 0.5 and 3.20 The paroxysmal discharges can be recognized as either simple sharp waves or compounded forms with variable firing rates (0.1-3 Hz) and amplitudes (100-1000 µV).21 The term PLED implies lateralization, whereas such activity can be generated independently from both hemispheres. Moreover, bilateral synchronous, generalized periodic activity has been reported.13,21 The variant forms of periodic complexes were alternatively called bilateral independent periodic lateralized epileptiform discharges (BiPLEDs) and generalized periodic epileptiform discharges (GPEDs).22 Taking these into account, we regarded the EEG findings as PLEDs for case 1 and GPEDs for case 3. Given that rhythmicity and periodicity in the epileptiform discharges of our cases became obvious at later stages, neural mechanisms of PLEDs in neurodegenerative disorders might be different from those in infection-associated diseases.19,23 Former studies demonstrated that PLEDs without recognizable seizures at the time of detection were correlated with poor prognosis.24 This may account for the rapid deterioration in neurological signs of our 3 cases. Nonetheless, there are no reports describing the periodic complex presentation during the courses of adult-onset HD and DRPLA. We therefore hypothesized alternatively that emerging periodic discharges might reflect the rapid processes of devastating brain functions in PME cases with child-onset HD and DRPLA, which might not always be seen in adulthood. Although precise mechanisms underlying the unique electrical activity remain to be elusive, PLEDs can be both transiently and persistently observed as an accompanying phenotype of altered cortical activity and disconnected thalamocortical interplays.13,22,23 Asymmetrical periodic discharges may reflect interhemispheric differences in neuronal activity because of localized injury, predominantly affected neural circuits, and regional differences in degeneration.21 We therefore speculate that laterality in the periodic discharges in the EEGs of cases 2 and 3 might appear when their diseases further progress in the future. HD and DRPLA are both highly penetrant, monogenic disorders that lead to progressive degeneration of the central nervous system for affected individuals. Unifying theories of pathogenesis have been postulated for multiple degenerative diseases despite their distinct clinical pictures and genetic backgrounds. In fact, HTT and ATN1 proteins were demonstrated to share their interacting partner, CREB binding protein
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Figure 3. The serial electroencephalographic (EEG) studies on Case 3. (A) An awake EGG recoding at 10 years of age. The EEG shows the poor background activity and the brief appearance of multifocal spike-and-wave complexes lasting only for 1 to 2 seconds (dashed square). (B) An awake EGG recoding at 12 years of age. This EEG shows persistently lasting periodically synchronized discharges (arrows).
(CBP), and synergistically regulate the neuronal gene expressions both in vitro and in vivo.11,25 Although these unifying models still remain controversial, it is not surprising that HD and DRPLA may overlap in their clinical features or in electrophysiological bases.3 Consistent with this concept, the epileptic seizures of the present cases were all intractable and fit well with the diagnosis of PME syndrome. This finding supported the hypothesis that HD and DRPLA in childhood may share
common neural mechanisms underlying rapidly progressive degeneration. In conclusion, we report that PLEDs and periodically synchronized epileptiform activity in child-onset HD and DRPLA are correlated with advanced stages of neurodegeneration. Future functional studies will help unravel the brain regions and mechanisms of unique epileptiform activity in these degenerative disorders.
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Acknowledgments We thank Dr Yasumasa Ohyagi and Kyoko Iinuma at the Neurological Institute, Kyushu University for genetic tests for SCAs; Tomoko Itakura and Eriko Watanabe at Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital for EEG recordings.
Author Contributions NI contributed to conception and design; contributed to acquisition, analysis, and interpretation; drafted manuscript; critically revised manuscript; agrees to be accountable for all aspects of work ensuring integrity and accuracy. YS contributed to conception and design; contributed to acquisition, analysis, and interpretation; drafted manuscript; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. RK contributed to conception; contributed to interpretation; drafted manuscript; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. MS contributed to conception; contributed to interpretation; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. YI contributed to conception; contributed to analysis; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. AS contributed to conception; contributed to analysis; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. MS contributed to conception; contributed to analysis; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. MT contributed to conception; contributed to analysis and interpretation; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. SA contributed to conception; contributed to analysis; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. HT contributed to conception and design; contributed to analysis and interpretation; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. TH contributed to conception and design; contributed to analysis and interpretation; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy.
Declaration of Conflicting Interests The author(s) declared no conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported in part by KAKEN No. 24650199 (awarded to YS), Japan Life Science Foundation (YS), Takeda Science Foundation (YS), and The Mother and Child Health Foundation (YS).
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