Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev
Original article
Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study Carlotta Spagnoli a,⇑, Umaiyal Kugathasan b, Helen Brittain c, Stewart G. Boyd a b
a Neurophysiology Department, Great Ormond Street Hospital, London, UK Neurophysiology Department, National Hospital for Neurology and Neurosurgery, London, UK c Genetics Department, Great Ormond Street Hospital, London, UK
Received 10 June 2014; received in revised form 6 October 2014; accepted 9 October 2014
Abstract Introduction: Patau syndrome, trisomy 13, is the third commonest autosomal trisomy. It is associated with a 25–50% prevalence of epilepsy, but detailed electroclinical descriptions are rare. The occurrence of early-onset photosensitivity has recently been reported in single patients. Materials/patients: We collected electroclinical data on 8 infants (age range from 2 months to 3 years and 9 months, median: 17 months) with Patau syndrome referred for an EEG in our Clinical Neurophysiology Department between 1991 and 2011. Methods: All EEGs, case-notes, cytogenetic diagnosis and neuroimaging when available were reviewed; data on the occurrence of seizures, epileptiform discharges, photoparoxysmal response and their characteristics in terms of positive frequencies, latencies, grade and duration were noted and analysed. Results: Two patients had been previously diagnosed with epilepsy (one with tonic spasms and one with multiple seizure types). We found 3 patients with photosensitive myoclonic epilepsy (37.5%), and one with non-photosensitive myoclonic epilepsy. We also recorded non-epileptic myoclonic jerks in one patient known to suffer from epileptic spasms. Among photosensitive patients we found self-limited, Waltz’s grade 2–4, spike-wave/polyspike-wave discharges in low, medium and high frequency ranges in two patients and in the high frequency range in the third patient, with latencies and duration from less than 1 s to a maximum of 9 s. Conclusions: In our cohort of Patau syndrome patients, we found a high prevalence of spasms and photic-induced myoclonic jerks. Photosensitivity shows an unusual early age of onset. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Patau syndrome; Photosensitive epilepsy; Photoparoxysmal response; Myoclonic epilepsy; Chromosomal abnormalities; Trisomy 13; Infantile-onset
1. Introduction With an incidence between 1/5000 and 1/20,000 births [1], Patau syndrome is the 3rd most common autosomal trisomy, clinically defined on the basis of a ⇑ Corresponding author. Tel.: +44 20 7813 8471; fax: +44 20 7829 8627. E-mail address: [email protected] (C. Spagnoli).
triad of signs: microphthalmia/anophthalmia, cleft lip and palate and postaxial polydactyly [2]. Cytogenetic diagnosis reveals a complete trisomy in around 75% of cases, a translocation in 20% and mosaicism in less than 5% [1]. Malformations mainly affect midline development [2], with a high frequency of central nervous system involvement (76%), including corpus callosum anomalies, ventriculomegaly, neural tube defects, hydrocephalus,
http://dx.doi.org/10.1016/j.braindev.2014.10.007 0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
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holoprosencephaly, cerebellar dysplasia, olfactory aplasia and cortical dysplasia [1–3]. Survival is short, with a median survival time of 7– 10 days, though around 10% survive beyond 1 year, for reasons which are not entirely clear [4]. Although the risk of epilepsy is reportedly high (25– 50%) [2], there is a paucity of detailed descriptions of clinical and neurophysiological features. When information is available, early onset (either during the neonatal period or in infancy) [5] and a generally good seizure control with antiepileptic drugs [5,6] seem to recur as common features. Occasionally, delayed onset of seizures in childhood [7] and adolescence [8]) has also been observed. Non-specific electroencephalographic findings have been reported, including diffuse epileptic discharges, focal slowing, spike-and-wave/polyspike-and-wave complexes, and predominant theta rhythm [8]. Seizure types, seldom described in case reports, are mostly characterised as clonic [3], atonic or generalised tonic-clonic [8], but myoclonic jerks have also been reported in isolated cases [6,9,10]. Infantile photoparoxysmal response (PPR) patterns in the context of different chromosomal abnormalities have been characterised by Grosso et al. [6], demonstrating the recurrence of a core of common features: selflimited brief discharges (involving neck and upper limbs)
Isolated sharp waves (1st EEG); Bursts of SW complexes (> posteriorly) in drowsiness (2nd EEG)
Myoclonic jerks of limbs or trunk (1st EEG); Clusters of spasms (flexor/extensor ULs > LLs, lasting 100– 200 ms)
C. Spagnoli et al. / Brain & Development xxx (2014) xxx–xxx
Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
Table 2 Electro-clinical data at the time of EEG’s (compared with Grosso’s et al. [6] and Torniero’s et al. [9]).
AED’s: antiepileptic drugs, CPS: complex partial seizures, EEG: electroencephalogram, F: female, Hz: Hertz, LTG: lamotrigine, M: male, m: month(s), uV: microVolts, NA: not applicable, SW’s: spike-and-waves, T–P–O: temporo–parieto–occipital, T–P: temporo–parietal, VPA: valproate, y: year(s). *: age when photosensitivity first detected.
VPA GVG (2nd EEG) No No No VPA (2nd EEG) Nitrazepam, LTG, VPA No AED’s
NA Seizure-associated EEG changes
No
Runs of irregular 18–22 c/s (15–100uV) mixed with sharpened components over the C regions associated with tonic spasms (2nd EEG) PB (2nd EEG)
No preceding EEG change (1st EEG). Generalised PS&SW’s maximalposteriorly. Rhythmic 5–6 Hz (up to 100 lV) activity in the mid-C regions (2nd EEG)
Generalised polyspikes
NA
Asynchronous bilateral T–P spike-and-slowwave complexes
No preceding EEG changes (1st EEG); bursts of generalised fast activities occasionally preceded by bursts of spikes (post T region) (2nd EEG)
VPA, BDZ, TPM
NA
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not repetitive, and of short duration. No detailed description of topography was available for patient 3. They were recorded both spontaneously and in response to photic stimulation. The EEG correlate was either that of spike-and-wave, polyspike-and-wave or spike-andslow-wave complexes. Spontaneous discharges were generalised in all cases except for patient 7, in whom they were confined to temporo-parietal derivations. Three patients also showed spasms (patients 3, 4 and 8), which were tonic and associated with a run of fast activity in patients 3 and 8 (Fig. 1C), whereas the third patient (patient 4) did not show any definite EEG correlation to the clinical events, which consisted of eye deviation (either upwards or to the right) and increased muscle tone. These episodes were organised in clusters in patients 3 and 8 (Fig. 1C) and isolated in patient 4. All of these patients presented myoclonic jerks as well, either epileptic (patients 3 and 4), or non-epileptic in nature (patient 8). Evidence for photosensitivity was found in 3 out of 8 patients, i.e. 37.5% (patients 3, 4, 7), at the age of 5.5 months, 6.5 months, and 20 months respectively. Age at onset is not known, although in one case (patient 3) a first EEG performed at 2 months of age was negative. The range of frequencies involved is wide (1–60 Hz in patient 7 (Fig. 1A); 6–50 Hz in the first EEG and 2– 60 Hz in the second for patient 4, whereas for the remaining patient’s EEG, the report refers to high frequencies). Provoked discharges had either a generalised, e.g. Waltz’s PPR type 4 (patient 3) or a posterior, Waltz’s PPR type 2, location (at low frequencies in patient 4 and for all frequencies in patient 7) and grade 3 (in patient 4, at high frequencies). In patient 4, a second EEG performed one month after the first one showed a change in the degree of the discharges from posterior (with no clinical correlate) to generalised with posterior emphasis associated with myoclonic events. PPR tended to be self-limited (except at 20 and 30 Hz in patient 4) and showed a brief duration from less than 1 s to a maximum of approximately 9 s, and variable latencies (from less than 1 s up to a maximum of 9 s). Among photosensitive patients, light was identified as a possible trigger to the epileptic events from the clinical history in just one case (patient 7). Finally, no evidence of scotosensitivity was found in any of our patients. Auditory and tactile-sensitivity were assessed in patient 7 and no evidence was found for them. 5. Discussion We present a group of patients with Patau syndrome whose EEGs recorded in the infantile period demonstrate a high prevalence (37.5%) of photosensitivity
Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
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and myoclonic jerks, exceeding the PPR prevalence (14%) previously found in infantile chromosomopathies [6]). Seizure types (spasms and myoclonic jerks, the latter both spontaneous and photic-induced) found in our series match those reported previously and further define a spectrum of infantile-onset epilepsy, possibly with multiple seizure types, dominated by myoclonic jerks and spasms. The limited data on events for patient 2 precludes comparison with the complex partial seizures detected in [6]. Our cases also share electroclinical characteristics with previous reports: onset of PPR in infancy, an exceptionally early age when compared to ‘typical’ photosensitivity age-dependency [15], with one of our patients having a Waltz’s grade 2 PPR at only 5.5 months of age (increasing to grade 4 at 6.5 months) representing to the best of our knowledge the youngest positive patient with Patau syndrome. In our series, both spontaneous and photic-induced discharges and myoclonic jerks were seen, resembling the earlier observations of a single case [6]. The frequency range in 2 out of 3 of our photosensitive cases (patients 4 and 7) is even wider than previously reported, whereas patient 3 is closer to Grosso’s description [6]. We found Waltz’s PPR grades 2, 3 and 4, as opposed to previous reports of grade 4 PPR’s only. Discharges were always self-limited, apart from the responses elicited at 20 and 30 Hz in patient 4. We also found variable latencies (up to 9 s, with minimum values of less than 1 s), less homogeneous than those reported by Grosso (ranging from 3 to 5 s in their Patau patient). Duration was usually short (from less than 1 s to up to 9 s), consistent with the medium range reported in the whole case-series by Grosso et al. but exceeding values reported in their single case of Patau syndrome [6]. In view of the high epilepsy prevalence in this group, we suggest that in such a young age and in the context of a chromosomal aberration, even a grade 2 self-limited PPR should be carefully evaluated in the context of the clinical history and regarded as possibly associated with epilepsy. A high prevalence of early-onset photosensitivity [15,16] which then declines with age [17] is a feature of Dravet syndrome/Severe Myoclonic Epilepsy of Infancy (SMEI) and Benign Myoclonic Epilepsy of Infancy (BMEI). The tendency of jerks to be single and not repetitive and of short duration is paralleled by that observed by Capovilla et al. in their younger BMEI patients [16] and could therefore be an age dependent clinical expression, whereas the tendency to predominate in the upper limbs is a result of the rostro-caudal pattern of muscle recruitment in cortical myoclonus [18].
The possibility that children in our series had progressive forms of myoclonic epilepsy can be excluded on the following grounds. No history of developmental regression or progressive neurological signs was reported, there is no deterioration in the background EEG activity, and signs of ocular involvement, when present, are consistent with Patau syndrome [19]. We then addressed the question of whether a specific cytogenetic diagnosis could account for the presence of photosensitivity in a subset of patients, but our data seem to disprove this hypothesis as our photosensitive population is genetically heterogeneous (see Table 1 for details). Could early-onset photosensitivity disappear as an effect of age, as reported in Dravet syndrome and BMEI cases [17]? In our cohort ages in the two subgroups overlap, and furthermore there are no patients with subsequent disappearance of earlier positive findings. Photosensitivity was not tested in the oldest patient in the series (patient 6; 3 years, 9 months), though Grosso reported persistence of photosensitivity at follow-up at 4 years of age [6]. If two separate subgroups of patients exist, factors leading to one or the other conditions are not yet explained. We therefore analysed clinical data in the 4 non-photosensitive patients to check if they constituted a homogeneous group. Two of them were not epileptic (patients 1 and 5). On the other hand, regarding the 2 epileptic, non-photosensitive patients, a contribution of polytherapy to abolishing photosensitivity is possible, particularly in the case of patient 2, since valproate is considered the first-line choice in abolishing photosensitivity and myoclonic jerks [20]. A higher prevalence of both traits cannot be completely excluded in a totally drug-naı¨ve cohort. By contrast, patient’s 3 EEG positivity while on phenobarbital is not surprising as this latter reportedly exerts minor effects on photosensitivity [21]. We also wish to highlight a worse prognosis in terms of seizure control than classically reported [5,7]. In our series, we have evidence of difficult seizure control in patient 2, who needed multi-therapy, and patient 7 who, at a clinical follow-up at 2 years of age, was experiencing around 20 episodes of myoclonic seizures/day despite being on high doses of sodium valproate. Although no evidence of a contribution of photosensitivity to the outcome worsening can be drawn from present data, worse seizure control was described in BMEI cases when photosensitivity was present [16], possibly due to stimulating behaviours leading to self-induced seizures [17]. When taken together with previous reports [9] our cases highlight that epilepsy in Patau syndrome is not as mild as previously thought [5,7]. Further followup data would be extremely informative in this regard. The report of a higher epilepsy risk in Patau syndrome is shared with numerous other chromosomal abnormalities, but the mechanism is not clarified as
Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
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yet, although two different, non-mutually exclusive hypotheses can be drawn according to the literature data. The first could be based on the presence of malformations of cortical development in these conditions. Perisylvian and rolandic cortical dysplasia in trisomy 13 have been documented once [3]. Interestingly, co-existing reflex and spontaneous seizures have been described in the setting of cortical malformations [22]. We have insufficient imaging data in our patients to resolve this notion, though no malformations were reported in either of the cases that were imaged. The second hypothesis is linked to a role for genes on chromosome 13 in epilepsy and photosensitivity, which is supported by both research studies [23–25] and single case reports [26,27]. Of interest is the recent indication of glypican-5 (GPC5) as a candidate gene for epilepsy inside the locus 13q31.3 [25]. Speculations could be made about a contribution of disrupted axon guidance and synaptic formation [28,29] in the genesis of epilepsy and/or brain malformations in trisomy 13, although, at present, there are no data to prove this hypothesis. Limitations of this study are mainly due to its retrospective nature, not allowing us to easily gather all the necessary data on intermittent photic stimulation, neuroimaging, or better characterise additional seizure types experienced by some of our patients, in order to fully describe the epilepsy spectrum in Patau syndrome. Our strengths rely in the possibility to analyse neurophysiological data in 8 patients with the same rare chromosomopathy, studied in infancy and early childhood, enabling us to recognise a cluster of recurring features with major clinical, life-style and therapeutic implications. In summary, Patau syndrome patients are at increased risk of seizures. They may present at an early age with myoclonic jerks and/or infantile spasms and show an unusual, early-onset high degree photosensitivity. Seizures might not always be easily controlled with antiepileptic medication. It is therefore important to perform photic stimulation in these patients from 1 Hz to 60 Hz and to distinguish between spasms and myoclonic events because they can both be present but may require different treatment approaches. References [1] Rios A, Furdon SA, Adams D, Clark DA. Recognizing the clinical features of Trisomy 13 syndrome. Adv Neonatal Care 2004;4:332–43. [2] Hsu HF, Hou JW. Variable expressivity in Patau syndrome is not all related to trisomy 13 mosaicism. Am J Med Genet A 2007;143A:1739–48. [3] Sener RN. Bilateral, perisylvian and rolandic cortical dysplasia in trisomy 13 syndrome. J Neuroradiol 1996;23:231–3.
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[4] Peroos S, Forsythe E, Pugh JH, Arthur-Farraj P, Hodes D. Longevity and Patau syndrome: what determines survival? BMJ Case Rep 2012 pii: bcr0620114381. [5] Yamanouchi H, Imataka G, Nakagawa E, Nitta A, Suzuki N, Hirao J, et al. An analysis of epilepsy with chromosomal abnormalities. Brain Dev 2005;27:370–7. [6] Grosso S, Pucci L, Bartalini G, Anichini C, Di Bartolo RM, Bazzotti S, et al. Photoparoxysmal responses in children with chromosomal aberrations. Epilepsy Res 2006;72:164–70. [7] Redheendran R, Neu RL, Bannerman RM. Long survival in trisomy-13-syndrome: 21 cases including prolonged survival in two patients 11 and 19 years old. Am J Med Genet 1981;8:167–72. [8] Jacob FD, Ramaswamy V, Kolski H. Long-term survival and late onset seizures in an adolescent with trisomy 13. Can J Neurol Sci 2010;37:694–6. [9] Torniero C, Zuffardi O, Darra F, Dalla Bernardina B. Scotosensitive and photosensitive myoclonic seizures in an infant with trisomy 13. Epilepsia 2007;48:2177–80. [10] Wilson MG, Melnyk J. Translocation/normal mosaicism in D1 trisomy. Pediatrics 1967;40:842–6. [11] Waltz S, Christen H-J, Doose H. The different patterns of the photoparoxysmal response – a genetic study. Electroencephalogr Clin Neurophysiol 1992;83:138–45. [12] Kasteleijn-Nolst Trenite´ DGA, Guerrini R, Binnie CD, Genton P. Visual sensitivity and epilepsy: a proposed terminology and classification for clinical and EEG phenomenology. Epilepsia 2001;42:692–701. [13] Pampiglione G. Some anatomical considerations upon electrode placement in routine EEG. Proc Electrophysiol Technol Ass 1956;7:20–30. [14] Kasteleijn-Nolst Trenite´ DGA, Binnie CD, Harding GFA, Wilkins A. Photic stimulation: standardization of screening methods. Epilepsia 1999;40:75–9. [15] Lu Y, Waltz S, Stenzel K, Muhle H, Stephani U. Photosensitivity in epileptic syndromes of childhood and adolescence. Epileptic Disord 2008;10:136–43. [16] Capovilla G, Beccaria F, Gambardella A, Montagnini A, Avantaggiato P, Seri S. Photosensitive benign myoclonic epilepsy in infancy. Epilepsia 2007;48:96–100. [17] Bureau M, Dalla Bernardina B. Electroencephalographic characteristics of Dravet syndrome. Epilepsia 2011;52:13–23. [18] Rubboli G, Meletti S, Gardella E, Zaniboni A, d’Orsi G, Dravet C, et al. Photic reflex myoclonus: a neurophysiological study in progressive myoclonus epilepsies. Epilepsia 1999;40:50–8. [19] Sinha S, Satishchandra P, Gayathri N, Yasha TC, Shankar SK. Progressive myoclonic epilepsy: a clinical, electrophysiological and pathological study from South India. J Neurol Sci 2007;252:16–23. [20] Covanis A, Stodieck SRG, Wilkins AJ. Treatment of photosensitivity. Epilepsia 2004;45:40–5. [21] Herrlin KM. EEG with photic stimulation: a study of children with manifest or suspected epilepsy. Electroencephalogr Clin Neurophysiol 1954;6:573–89. [22] Palmini A, Halasz P, Scheffer IE, Takahashi Y, Jimenez AP, Dubeau F, et al. Reflex seizures in patients with malformations of cortical development and refractory epilepsy. Epilepsia 2005;46:1224–34. [23] Tauer U, Lorenz S, Lenzen KP, Heils A, Muhle H, Gresch M, et al. Genetic dissection of photosensitivity and its relation to idiopathic generalized epilepsy. Ann Neurol 2005;57:866–73. [24] EPICURE Consortium, Leu C, de Kovel CGF, Zara F, Striano P, Pezzella M, et al. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies. Epilepsia 2012;53:308–18.
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[25] Hempelmann A, Taylor KP, Heils A, Lorenz S, Prud’homme JF, Nabbout R, et al. Exploration of the genetic architecture of idiopathic generalized epilepsies. Epilepsia 2006;47:1682–90. [26] Milani D, D’Arrigo S, Guerneri S, Selicorni A, Riva D, Pantaleoni C. De novo duplication of chromosome 13 (q32– q34) in a child with developmental delay. J Child Neurol 2006;21:1084–5.
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Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
Original article
Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study Carlotta Spagnoli a,⇑, Umaiyal Kugathasan b, Helen Brittain c, Stewart G. Boyd a b
a Neurophysiology Department, Great Ormond Street Hospital, London, UK Neurophysiology Department, National Hospital for Neurology and Neurosurgery, London, UK c Genetics Department, Great Ormond Street Hospital, London, UK
Received 10 June 2014; received in revised form 6 October 2014; accepted 9 October 2014
Abstract Introduction: Patau syndrome, trisomy 13, is the third commonest autosomal trisomy. It is associated with a 25–50% prevalence of epilepsy, but detailed electroclinical descriptions are rare. The occurrence of early-onset photosensitivity has recently been reported in single patients. Materials/patients: We collected electroclinical data on 8 infants (age range from 2 months to 3 years and 9 months, median: 17 months) with Patau syndrome referred for an EEG in our Clinical Neurophysiology Department between 1991 and 2011. Methods: All EEGs, case-notes, cytogenetic diagnosis and neuroimaging when available were reviewed; data on the occurrence of seizures, epileptiform discharges, photoparoxysmal response and their characteristics in terms of positive frequencies, latencies, grade and duration were noted and analysed. Results: Two patients had been previously diagnosed with epilepsy (one with tonic spasms and one with multiple seizure types). We found 3 patients with photosensitive myoclonic epilepsy (37.5%), and one with non-photosensitive myoclonic epilepsy. We also recorded non-epileptic myoclonic jerks in one patient known to suffer from epileptic spasms. Among photosensitive patients we found self-limited, Waltz’s grade 2–4, spike-wave/polyspike-wave discharges in low, medium and high frequency ranges in two patients and in the high frequency range in the third patient, with latencies and duration from less than 1 s to a maximum of 9 s. Conclusions: In our cohort of Patau syndrome patients, we found a high prevalence of spasms and photic-induced myoclonic jerks. Photosensitivity shows an unusual early age of onset. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Patau syndrome; Photosensitive epilepsy; Photoparoxysmal response; Myoclonic epilepsy; Chromosomal abnormalities; Trisomy 13; Infantile-onset
1. Introduction With an incidence between 1/5000 and 1/20,000 births [1], Patau syndrome is the 3rd most common autosomal trisomy, clinically defined on the basis of a ⇑ Corresponding author. Tel.: +44 20 7813 8471; fax: +44 20 7829 8627. E-mail address: [email protected] (C. Spagnoli).
triad of signs: microphthalmia/anophthalmia, cleft lip and palate and postaxial polydactyly [2]. Cytogenetic diagnosis reveals a complete trisomy in around 75% of cases, a translocation in 20% and mosaicism in less than 5% [1]. Malformations mainly affect midline development [2], with a high frequency of central nervous system involvement (76%), including corpus callosum anomalies, ventriculomegaly, neural tube defects, hydrocephalus,
http://dx.doi.org/10.1016/j.braindev.2014.10.007 0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
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holoprosencephaly, cerebellar dysplasia, olfactory aplasia and cortical dysplasia [1–3]. Survival is short, with a median survival time of 7– 10 days, though around 10% survive beyond 1 year, for reasons which are not entirely clear [4]. Although the risk of epilepsy is reportedly high (25– 50%) [2], there is a paucity of detailed descriptions of clinical and neurophysiological features. When information is available, early onset (either during the neonatal period or in infancy) [5] and a generally good seizure control with antiepileptic drugs [5,6] seem to recur as common features. Occasionally, delayed onset of seizures in childhood [7] and adolescence [8]) has also been observed. Non-specific electroencephalographic findings have been reported, including diffuse epileptic discharges, focal slowing, spike-and-wave/polyspike-and-wave complexes, and predominant theta rhythm [8]. Seizure types, seldom described in case reports, are mostly characterised as clonic [3], atonic or generalised tonic-clonic [8], but myoclonic jerks have also been reported in isolated cases [6,9,10]. Infantile photoparoxysmal response (PPR) patterns in the context of different chromosomal abnormalities have been characterised by Grosso et al. [6], demonstrating the recurrence of a core of common features: selflimited brief discharges (involving neck and upper limbs)
Isolated sharp waves (1st EEG); Bursts of SW complexes (> posteriorly) in drowsiness (2nd EEG)
Myoclonic jerks of limbs or trunk (1st EEG); Clusters of spasms (flexor/extensor ULs > LLs, lasting 100– 200 ms)
C. Spagnoli et al. / Brain & Development xxx (2014) xxx–xxx
Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
Table 2 Electro-clinical data at the time of EEG’s (compared with Grosso’s et al. [6] and Torniero’s et al. [9]).
AED’s: antiepileptic drugs, CPS: complex partial seizures, EEG: electroencephalogram, F: female, Hz: Hertz, LTG: lamotrigine, M: male, m: month(s), uV: microVolts, NA: not applicable, SW’s: spike-and-waves, T–P–O: temporo–parieto–occipital, T–P: temporo–parietal, VPA: valproate, y: year(s). *: age when photosensitivity first detected.
VPA GVG (2nd EEG) No No No VPA (2nd EEG) Nitrazepam, LTG, VPA No AED’s
NA Seizure-associated EEG changes
No
Runs of irregular 18–22 c/s (15–100uV) mixed with sharpened components over the C regions associated with tonic spasms (2nd EEG) PB (2nd EEG)
No preceding EEG change (1st EEG). Generalised PS&SW’s maximalposteriorly. Rhythmic 5–6 Hz (up to 100 lV) activity in the mid-C regions (2nd EEG)
Generalised polyspikes
NA
Asynchronous bilateral T–P spike-and-slowwave complexes
No preceding EEG changes (1st EEG); bursts of generalised fast activities occasionally preceded by bursts of spikes (post T region) (2nd EEG)
VPA, BDZ, TPM
NA
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not repetitive, and of short duration. No detailed description of topography was available for patient 3. They were recorded both spontaneously and in response to photic stimulation. The EEG correlate was either that of spike-and-wave, polyspike-and-wave or spike-andslow-wave complexes. Spontaneous discharges were generalised in all cases except for patient 7, in whom they were confined to temporo-parietal derivations. Three patients also showed spasms (patients 3, 4 and 8), which were tonic and associated with a run of fast activity in patients 3 and 8 (Fig. 1C), whereas the third patient (patient 4) did not show any definite EEG correlation to the clinical events, which consisted of eye deviation (either upwards or to the right) and increased muscle tone. These episodes were organised in clusters in patients 3 and 8 (Fig. 1C) and isolated in patient 4. All of these patients presented myoclonic jerks as well, either epileptic (patients 3 and 4), or non-epileptic in nature (patient 8). Evidence for photosensitivity was found in 3 out of 8 patients, i.e. 37.5% (patients 3, 4, 7), at the age of 5.5 months, 6.5 months, and 20 months respectively. Age at onset is not known, although in one case (patient 3) a first EEG performed at 2 months of age was negative. The range of frequencies involved is wide (1–60 Hz in patient 7 (Fig. 1A); 6–50 Hz in the first EEG and 2– 60 Hz in the second for patient 4, whereas for the remaining patient’s EEG, the report refers to high frequencies). Provoked discharges had either a generalised, e.g. Waltz’s PPR type 4 (patient 3) or a posterior, Waltz’s PPR type 2, location (at low frequencies in patient 4 and for all frequencies in patient 7) and grade 3 (in patient 4, at high frequencies). In patient 4, a second EEG performed one month after the first one showed a change in the degree of the discharges from posterior (with no clinical correlate) to generalised with posterior emphasis associated with myoclonic events. PPR tended to be self-limited (except at 20 and 30 Hz in patient 4) and showed a brief duration from less than 1 s to a maximum of approximately 9 s, and variable latencies (from less than 1 s up to a maximum of 9 s). Among photosensitive patients, light was identified as a possible trigger to the epileptic events from the clinical history in just one case (patient 7). Finally, no evidence of scotosensitivity was found in any of our patients. Auditory and tactile-sensitivity were assessed in patient 7 and no evidence was found for them. 5. Discussion We present a group of patients with Patau syndrome whose EEGs recorded in the infantile period demonstrate a high prevalence (37.5%) of photosensitivity
Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
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and myoclonic jerks, exceeding the PPR prevalence (14%) previously found in infantile chromosomopathies [6]). Seizure types (spasms and myoclonic jerks, the latter both spontaneous and photic-induced) found in our series match those reported previously and further define a spectrum of infantile-onset epilepsy, possibly with multiple seizure types, dominated by myoclonic jerks and spasms. The limited data on events for patient 2 precludes comparison with the complex partial seizures detected in [6]. Our cases also share electroclinical characteristics with previous reports: onset of PPR in infancy, an exceptionally early age when compared to ‘typical’ photosensitivity age-dependency [15], with one of our patients having a Waltz’s grade 2 PPR at only 5.5 months of age (increasing to grade 4 at 6.5 months) representing to the best of our knowledge the youngest positive patient with Patau syndrome. In our series, both spontaneous and photic-induced discharges and myoclonic jerks were seen, resembling the earlier observations of a single case [6]. The frequency range in 2 out of 3 of our photosensitive cases (patients 4 and 7) is even wider than previously reported, whereas patient 3 is closer to Grosso’s description [6]. We found Waltz’s PPR grades 2, 3 and 4, as opposed to previous reports of grade 4 PPR’s only. Discharges were always self-limited, apart from the responses elicited at 20 and 30 Hz in patient 4. We also found variable latencies (up to 9 s, with minimum values of less than 1 s), less homogeneous than those reported by Grosso (ranging from 3 to 5 s in their Patau patient). Duration was usually short (from less than 1 s to up to 9 s), consistent with the medium range reported in the whole case-series by Grosso et al. but exceeding values reported in their single case of Patau syndrome [6]. In view of the high epilepsy prevalence in this group, we suggest that in such a young age and in the context of a chromosomal aberration, even a grade 2 self-limited PPR should be carefully evaluated in the context of the clinical history and regarded as possibly associated with epilepsy. A high prevalence of early-onset photosensitivity [15,16] which then declines with age [17] is a feature of Dravet syndrome/Severe Myoclonic Epilepsy of Infancy (SMEI) and Benign Myoclonic Epilepsy of Infancy (BMEI). The tendency of jerks to be single and not repetitive and of short duration is paralleled by that observed by Capovilla et al. in their younger BMEI patients [16] and could therefore be an age dependent clinical expression, whereas the tendency to predominate in the upper limbs is a result of the rostro-caudal pattern of muscle recruitment in cortical myoclonus [18].
The possibility that children in our series had progressive forms of myoclonic epilepsy can be excluded on the following grounds. No history of developmental regression or progressive neurological signs was reported, there is no deterioration in the background EEG activity, and signs of ocular involvement, when present, are consistent with Patau syndrome [19]. We then addressed the question of whether a specific cytogenetic diagnosis could account for the presence of photosensitivity in a subset of patients, but our data seem to disprove this hypothesis as our photosensitive population is genetically heterogeneous (see Table 1 for details). Could early-onset photosensitivity disappear as an effect of age, as reported in Dravet syndrome and BMEI cases [17]? In our cohort ages in the two subgroups overlap, and furthermore there are no patients with subsequent disappearance of earlier positive findings. Photosensitivity was not tested in the oldest patient in the series (patient 6; 3 years, 9 months), though Grosso reported persistence of photosensitivity at follow-up at 4 years of age [6]. If two separate subgroups of patients exist, factors leading to one or the other conditions are not yet explained. We therefore analysed clinical data in the 4 non-photosensitive patients to check if they constituted a homogeneous group. Two of them were not epileptic (patients 1 and 5). On the other hand, regarding the 2 epileptic, non-photosensitive patients, a contribution of polytherapy to abolishing photosensitivity is possible, particularly in the case of patient 2, since valproate is considered the first-line choice in abolishing photosensitivity and myoclonic jerks [20]. A higher prevalence of both traits cannot be completely excluded in a totally drug-naı¨ve cohort. By contrast, patient’s 3 EEG positivity while on phenobarbital is not surprising as this latter reportedly exerts minor effects on photosensitivity [21]. We also wish to highlight a worse prognosis in terms of seizure control than classically reported [5,7]. In our series, we have evidence of difficult seizure control in patient 2, who needed multi-therapy, and patient 7 who, at a clinical follow-up at 2 years of age, was experiencing around 20 episodes of myoclonic seizures/day despite being on high doses of sodium valproate. Although no evidence of a contribution of photosensitivity to the outcome worsening can be drawn from present data, worse seizure control was described in BMEI cases when photosensitivity was present [16], possibly due to stimulating behaviours leading to self-induced seizures [17]. When taken together with previous reports [9] our cases highlight that epilepsy in Patau syndrome is not as mild as previously thought [5,7]. Further followup data would be extremely informative in this regard. The report of a higher epilepsy risk in Patau syndrome is shared with numerous other chromosomal abnormalities, but the mechanism is not clarified as
Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
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yet, although two different, non-mutually exclusive hypotheses can be drawn according to the literature data. The first could be based on the presence of malformations of cortical development in these conditions. Perisylvian and rolandic cortical dysplasia in trisomy 13 have been documented once [3]. Interestingly, co-existing reflex and spontaneous seizures have been described in the setting of cortical malformations [22]. We have insufficient imaging data in our patients to resolve this notion, though no malformations were reported in either of the cases that were imaged. The second hypothesis is linked to a role for genes on chromosome 13 in epilepsy and photosensitivity, which is supported by both research studies [23–25] and single case reports [26,27]. Of interest is the recent indication of glypican-5 (GPC5) as a candidate gene for epilepsy inside the locus 13q31.3 [25]. Speculations could be made about a contribution of disrupted axon guidance and synaptic formation [28,29] in the genesis of epilepsy and/or brain malformations in trisomy 13, although, at present, there are no data to prove this hypothesis. Limitations of this study are mainly due to its retrospective nature, not allowing us to easily gather all the necessary data on intermittent photic stimulation, neuroimaging, or better characterise additional seizure types experienced by some of our patients, in order to fully describe the epilepsy spectrum in Patau syndrome. Our strengths rely in the possibility to analyse neurophysiological data in 8 patients with the same rare chromosomopathy, studied in infancy and early childhood, enabling us to recognise a cluster of recurring features with major clinical, life-style and therapeutic implications. In summary, Patau syndrome patients are at increased risk of seizures. They may present at an early age with myoclonic jerks and/or infantile spasms and show an unusual, early-onset high degree photosensitivity. Seizures might not always be easily controlled with antiepileptic medication. It is therefore important to perform photic stimulation in these patients from 1 Hz to 60 Hz and to distinguish between spasms and myoclonic events because they can both be present but may require different treatment approaches. References [1] Rios A, Furdon SA, Adams D, Clark DA. Recognizing the clinical features of Trisomy 13 syndrome. Adv Neonatal Care 2004;4:332–43. [2] Hsu HF, Hou JW. Variable expressivity in Patau syndrome is not all related to trisomy 13 mosaicism. Am J Med Genet A 2007;143A:1739–48. [3] Sener RN. Bilateral, perisylvian and rolandic cortical dysplasia in trisomy 13 syndrome. J Neuroradiol 1996;23:231–3.
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Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
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Please cite this article in press as: Spagnoli C et al. Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.007
