- Email: [email protected]
Epilepsy with myoclonic absences in siblings
Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev
Original article
Epilepsy with myoclonic absences in siblings Ajith Cherian a, Shaik Afshan Jabeen b,⇑, Rukmini Mridula Kandadai a, Thomas Iype a, Pallavi Moturi b, Muralidhar Reddy b, Meena Angamuthu Kanikannan b, Rupam Borgohain b, Sandeep Padmanabhan a b
a Department of Neurology, Medical College Hospital, Trivandrum, Kerala, India Department of Neurology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, India
Received 11 June 2013; received in revised form 16 December 2013; accepted 17 December 2013
Abstract Background: Epilepsy with myoclonic absences (EMAs) is a distinct form of childhood epilepsy characterized by a peculiar seizure type that identifies this condition. Purpose: To describe the clinical, electroencephalographic features, treatment strategies and outcome in this first case series of two siblings with normal intelligence presenting with EMAs. Materials and methods: Both siblings underwent video-polygraphic investigations (simultaneous recording of electroencephalogram [EEG] and electromyogram [EMG] from deltoids), high-resolution magnetic resonance imaging (MRI), karyotyping, neuropsychological evaluation and language assessment. Results: Both the children had a mean age of onset of prototype seizures by 3.5 years. Myoclonic absences (MAs) were characterized by rhythmic, bilateral, synchronous, symmetric 3-Hz spike–wave discharges, associated with EMG myoclonic bursts at 3 Hz, superimposed on a progressively increasing tonic muscle contraction. The interictal EEG showed a normal background activity with bursts of generalized spike and waves (SWs) as well as rare focal SWs independently over bilateral temporal and frontal regions. Increase in the seizure frequency from 5 to 100/day was observed due to use of carbamazepine and phenobarbitone which decreased with its withdrawal and introduction of valproate. Though lamotrigine was given as an add on to valproate, it did not benefit them and was therefore replaced by topiramate at 3.5 mg/kg/day which has maintained them on remission at one year follow up. Conclusions: Recognition of this ictal pattern allows identification and differentiation of EMAs from other seizure types. Idiopathic and symptomatic EMAs need to be differentiated from childhood absence epilepsy with myoclonia. MAs are worsened by drugs like carbamazepine while valproate either alone or in combination with topiramate (preferred to lamotrigine) gives excellent outcome. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Tassinari; EMAs; Valproate; Ethosuximide; 3 Hz; Polygraphic VEEG; Topiramate
1. Introduction Epilepsy with myoclonic absences (EMAs) is characterized by absence seizures associated with rhythmic, bilateral proximal myoclonic jerks of upper extremities. The diagnosis is based on clinical observation and ictal video electroencephalograph (EEG) recordings. Demonstration of myoclonic absences (MAs) is essential for the ⇑ Corresponding author. Tel.: +91 9704822022.
E-mail address: [email protected] (S.A. Jabeen).
diagnosis. In the proposed diagnostic scheme by the International League Against Epilepsy (ILAE) [1], it has been tentatively placed among the idiopathic generalized epilepsies. 2. Materials and methods 2.1. Subjects Both the subjects who are siblings presented with seizures to our institute, which is a tertiary referral centre
0387-7604/$ - see front matter Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.12.004
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
2
A. Cherian et al. / Brain & Development xxx (2014) xxx–xxx
for neurological diseases in South India. They underwent video-polygraphic investigations, high-resolution magnetic resonance imaging (MRI), karyotyping, neuropsychological evaluation and language assessment. 2.2. Electroencephalography (EEG) All recordings were carried out on a 16-channel digital EEG acquisition system (NicVue, Nicolet-Viking, USA); with the scalp electrodes placed according to the International 10–20 system. Both patients with EMAs also underwent a video-polygraphic investigation (simultaneous recording of electroencephalogram [EEG] and electromyogram [EMG] from deltoids). The distribution of interictal epileptiform discharges (IEDs) during prolonged video-EEG monitoring was assessed by visual analysis of the entire acquired data. 2.3. Neuroimaging Both the patients underwent a 1.5 Tesla magnetic resonance imaging (MRI) (1.5 T MRI, Avanto, TIM SQ engine, Siemens, Erlangen, Germany).
3. Results 3.1. Clinical, seizure and imaging characteristics The siblings were born of nonconsanguinous parentage and had normal growth and developmental milestones. The median age at seizure onset was 3.5 years. Myoclonic absence seizures were characterized by recurrent episodes of rhythmic myoclonic jerks mainly at proximal shoulder associated with progressive elevation of the arms with unresponsiveness lasting for 10 s (Video 1). The onset and offset were abrupt with no postictal confusion. They had no eyelid or perioral myoclonia. The seizures were predominantly diurnal especially in the early morning hours precipitated by hyperventilation, lasting for 10–15 s at a frequency of 4–5 per day. The girl had a past history of a single generalized tonic clonic seizure at the age of 3 years which was not associated with fever. Other than her younger brother who had EMAs no one else in the family was affected (Table 1). MRI including high resolution three-dimensional fast fluid attenuated inversion recovery (3D FLAIR) images with thin cuts were normal in both the cases.
2.4. Language and neuropsychological assessment 3.2. EEG characteristics Malin’s Intelligence Scale for Indian children, which is a validated Indian adaptation of Wechsler’s Intelligence Scale for children, was used to assess the intelligence quotient (IQ) for children [2]. Language was assessed by the local adaptation of the Receptive Expressive Emergent Language Scale (REELS) and its extended version [3]. 2.5. Follow-up and outcome assessment Both the siblings were followed up at three-monthly intervals. The seizure and cognitive outcomes were assessed at each follow-up visit.
The interictal EEG showed a normal background activity with bursts of generalized spike and waves (SWs) as well as focal SWs independently over bilateral temporal regions in the sister while her brother showed independent IEDs over bilateral frontal regions (Figs. 1– 3). The ictal EEG consisted of rhythmic SW discharges at 3 Hz, which are bilateral, synchronous, and symmetric, as observed in typical absence seizures. The onset and the end of SWs were abrupt. Polygraphic (EEG– EMG) recording disclosed the appearance of bilateral myoclonias, at the same frequency as the SWs, which began around 1000 ms after the onset of EEG paroxys-
Table 1 Electro clinical profile, treatment and outcome of siblings with EMAs. Current age/ Gender
Age of sz onset
Types of sz
Interictal SEEG
Ictal SEEG
Response of MAs to initial AEDs
Neuropsychology/ language evaluation
Sz outcome and medications at 12 month follow-up
12/F
3 yrs
MAs, single GTCs
Bursts of gen SWD, independent focal SWD over bilateral temporal regions
Frequency of MAs worsened from 4–5 per day to 80–100 per day while on CBZ and PHB
Normal
10/M
4 yrs
MAs alone
Bursts of gen SWD as well as independent focal SWD over bilateral frontal region
Rhythmic SWD at 3 Hz, which are bilateral, synchronous, and symmetrical Rhythmic SWD at 3 Hz, which are bilateral, synchronous, and symmetrical
Frequency of MAs worsened from 4–5 per day to 80–100 per day while on CBZ and PHB
Normal
In remission on VAL 25 mgm/kg/day and TPA 3.5 mgm/kg/day (LTG did not improve sz outcome) In remission on VPA25 mg/kg/day and TPM 3.5 mg/kg/day (LTG did not improve sz outcome)
AED, antiepileptic drugs; CBZ, carbamazepine; EMAs, epilepsy with myoclonic absences; F, female; gen, generalized; GTCs, generalized tonic clonic seizure; LTG, lamotrigine; M, male; MAs, myoclonic absences; PHB, phenobarbitone; SEEG, scalp electroencephalography; SWD, spike wave discharge; sz(s), seizure(s); TPM, topiramate; VPA, valproate; yrs, years.
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
A. Cherian et al. / Brain & Development xxx (2014) xxx–xxx
mal discharges (Fig. 4) and were followed by a tonic contraction, maximal in the shoulder (deltoid) muscles (Video 1). VEEG analysis provided a clear relationship between the SWs and motor events, showing a strict and constant relation between the spike of the SW discharge and the myoclonia (Fig. 5). 3.3. Language and neuropsychological assessment Language and neuropsychological assessment was performed in both the cases. IQ and language were normal prior to and after seizure onset in both the children. 3.4. Response to treatment and outcome The children were initiated elsewhere on a combination of carbamazepine and phenobarbitone which initially worsened their seizure frequency from 4–5 per day to 80–100 per day. Both of them responded well to removal of carbamazepine and phenobarbitone and introduction of valproate at 25–30 mg/kg/day as MAs reduced to 1/day. Introduction of lamotrigine as the first add on did not benefit them though there was no worsening of seizures. Addition of topiramate at a dose of the 3.5 mg/kg/day induced remission initially in the brother followed by his sister. At a follow-up of one year both the siblings are in remission. 4. Discussion EMAs is a rare condition accounting for 0.5% to 1% of all epilepsies. Tassinari et al. [4] has proposed at least
3
two forms of EMAs: idiopathic EMA with a more benign course, and eventual disappearance of seizures, in which MAs are the sole, or predominant, seizure type consisting of about one third of total EMA patients; and the other symptomatic MAs associated with other seizure types (particularly, frequent generalized tonic–clonic seizures) which can appear before the onset of MAs or occur in association with MAs and bear a more severe prognosis (Table 2 provides the characteristics of idiopathic EMAs, symptomatic EMAs and CAE with myoclonia to distinguish one from the other). The mean age of onset of MAs is 7 years, with a range between 11 months and 12.2 years. MAs last for 10–60 s, and recur at a high frequency (10–100 per day), being often precipitated by hyperventilation or awakening. The seizure manifestation typically consists of bilateral myoclonic jerks involving proximal limb muscles associated with a discrete tonic contraction resulting in progressive elevation of extremities as seen in video. Interictal EEGs in one third of cases show focal or multifocal SWs as demonstrated in our case. The ictal EEG studies with polygraphic (EEG–EMG) recording has shown that there is a time lag of 1000 ms between the EEG and later surface EMG discharges. The positive transient encompassed in the SW complex, is followed on the EMG by a myoclonia with a latency of 15–40 ms for the proximal muscles like deltoids (Fig. 5). Hypotheses on the peculiar muscular pattern that characterizes MA seizures is due to the tonic muscular contraction component that is superimposed on the myoclonic activity related to the involvement of supple-
Fig. 1. EEG showing burst of generalized spike, polyspike and wave discharges.
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
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A. Cherian et al. / Brain & Development xxx (2014) xxx–xxx
Fig. 2. EEG showing bilateral independent temporal and frontal focal IEDs.
Fig. 3. EEG showing run of left frontal focal IEDs.
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
A. Cherian et al. / Brain & Development xxx (2014) xxx–xxx
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Fig. 4. Snap shot of the video showing that the rhythmic myoclonia starts 1000 ms after the onset of the EEG paroxysmal discharge. Note that the first three spike–wave complexes are not associated with any evident myoclonic activity.
mentary motor areas, possibly in the frontomesial cortex [5]. Tonic contractions occur always in MAs, but after the appearance of few SW complexes, possibly suggesting a spread of paroxysmal activity to frontomesial
areas. The evidence in some cases of associated trisomy13 has led to the hypothesis that abnormal expression of genes located in the affected chromosome segments may play a role in the pathogenesis [6]. A
Fig. 5. High-speed polygraphic recording of a myoclonic absence (MA) seizure, showing the relationship between the spike of the spike–wave (SW) complex and the myoclonic potential. There is a time delay of 39 ms from the electrical discharge to the EMG burst.
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
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Table 2 Showing comparison between 3 groups of with absence sz with myoclonia. Features
Idiopathic EMAs
Symptomatic EMAs
CAE with myoclonia
Age Sex Intellect Chromozomal anomalies MR imaging Seizure
Infancy to 12 years Boys > girls Normal None
Infancy to 12 years Boys > girls Affected Trisomy 13, Angelman syndrome, inverted chromosomal 15 duplications Abnormal MAs, GTCs
4–10 years Girls > boys.
Normal Usually MAs alone
Interictal EEG
Normal BGA; bursts of gen SWD, rarely independent focal SWD over bilateral temporal/frontal regions
Ictal EEG
Rhythmic SWD at 3 Hz, which are bilateral, synchronous, and symmetrical Bilateral myoclonias, at the same frequency as the SWs, which begin around 1 s after the onset of EEG paroxysmal discharges and are followed by a tonic contraction, maximal in the shoulder and deltoid muscles Worsened by CBZ;LTG may not benefit; Better response to VAL ± TPM Possible in 50%
EMG recording
Response to AEDs AED withdrawal on follow up
Abnormal BGA; bursts of gen SWD, independent focal SWD more common over bilateral temporal/frontal/occipital regions Rhythmic SWD at 3 Hz, which are bilateral, synchronous, and symmetrical Bilateral myoclonias, at the same frequency as the SWs, which begin around 1 s after the onset of EEG paroxysmal discharges and are followed by a tonic contraction, maximal in the shoulder and deltoid muscles Worsened by CBZ; LTG may not benefit; Better response to VPA ± TPM Unlikely; May evolve into Lennox Gestaut syndrome
None Normal Absence sz with predominant eyelid myoclonia Normal BGA; frequent OIRDA
Rhythmic SWD at 3 Hz, which are bilateral, synchronous, and symmetrical Eyelid myoclonias with fast flickering of the eyelids; proximal arm myoclonia are unusual and very rare and it has no intervening tonic contraction.
Excellent response to EXM and VPA Possible in nearly all the cases
AEDs, antiepileptic drugs; CBZ, carbamazepine; EEG, electroencephalography; EMAs, epilepsy with myoclonic absences; EXM, ethosuximide; gen, generalized; GTCs, generalized tonic clonic seizure; LTG, lamotrigine; MAs, myoclonic absences; MR, magnetic resonance; OIRDA, occipital intermittent rhythmic delta activity; sz(s), seizure(s); SWD, spike wave discharge; TPM, topiramate; VPA, valproate.
genetic susceptibility, as demonstrated by a positive family history of epilepsies, has been observed in about 20% of cases. Literature search revealed a report of a male patient with nonsyndromic intellectual; disability (ID) and EMA carrying a de novo balanced translocation with one breakpoint disrupting the SYNGAP1 gene [10]. Also there was dominantly inherited mutation in Glutamate dehydrogenase (GDH) causing EMA in association with hyperinsulinism–hyperammonemia [11]. However no cases of siblings presenting with isolated EMAs has been reported till now. Ours is a unique case series of affected siblings suggest an autosomal recessive inheritance, without any associated comorbidities though causative gene is still unknown. EMAs must be differentiated from absence seizures with rhythmic myoclonias associated with 3 Hz regular SWs observed in children with early-onset typical absences [7]. The benign course, excellent response to treatment, possible drug withdrawal in the evolution, and mild myoclonia without a background of tonic contraction help to differentiate CAE from EMAs. Severe EMAs need to be differentiated from the myoclonic status observed in nonprogressive encephalopathies [8]. As far as treatment is concerned valproic acid and ethosuximide at high doses, are effective. Topiramate, and zonisamide, may hold promise in EMAs as add
on therapy. Our report clearly shows the effectiveness of topiramate over lamotrigine as the first add on if ethosuximide is not available. Lamotrigine has been shown to worsen seizures in severe myoclonic epilepsy and exacerbate, de novo myoclonus, and myoclonic status in patients with idiopathic generalized epilepsies including juvenile myoclonic epilepsy [9]. Sodium channel blockers such as carbamazepine, phenytoin and gabaminergic drugs such as vigabatrin, gabapentin, tiagabine might worsen MAs as highlighted. 5. Conclusions Epilepsy with myoclonic absences (EMAs) is a distinct form of childhood epilepsy characterized by a peculiar seizure type that identifies this epileptic condition. Focal SWDs over frontal and temporal regions can be present. This is the first case series of siblings with normal intellect presenting with EMAs and demonstrates the usefulness of topiramate over lamotrigine as the first add on to valproate when ethosuximide is unavailable. Note A written permission from the patients mother has been taken and uploaded with the manuscript.
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
A. Cherian et al. / Brain & Development xxx (2014) xxx–xxx
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.braindev.2013.12.004. References [1] Engel JJ. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 2001;2001(42):796–803. [2] Malin AJ. Indian adaptation of Wecshler’s intelligence scale for children. Indian J Mental Retard 1979;4:15–25. [3] Bzoch K, Legue R. The receptive and expressive emergent language scale (REELS) Slough. UK: National Foundation for Educational Research; 1971. [4] Tassinari CA, Rubboli G, Gardella E. Epilepsy with myoclonic absences. In: Wallace SJ, Farrell K, editors. Epilepsy in children. London: Arnold; 2004. p. 189–94. [5] Taki W et al. Clonic convulsion caused by epileptic discharges arising from the human supplementary motor area as studied by subdural recording. Epileptic Disord 1999;1:21–6.
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[6] Elia M, Musumeci SA, Ferri R, Cammarata M. Trisomy 12p and epilepsy with myoclonic absences. Brain Dev 1998;20:127–30. [7] Capovilla G, Rubboli G, Beccaria F, Lorenzetti ME, Montagnini A, Resi C, et al. A clinical spectrum of the myoclonic manifestations associated with typical absences in childhood absence epilepsy. A video-polygraphic study. Epileptic Disord 2001;3:57–62. [8] DallaBernardina B, Fontana E, Darra F. Myoclonic status in non-progressive encephalopathies. In: Roger J, Bureau M, Dravet C, editors. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey; 2005. p. 149–57. [9] Crespel A, Genton P, Berramdane M, Coubes P, Monicard C, Baldy-Moulinier M, et al. Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies. Neurology 2005;65:762–4. [10] Bahi-Buisson N et al. Myoclonic absence epilepsy with photosensitivity and a gain of function mutation in glutamate dehydrogenase. Seizure 2008;17(7):658–64. [11] Klitten Laura L et al. A balanced translocation disrupts SYNGAP1 in a patient with intellectual disability, speech impairment, and epilepsy with myoclonic absences (EMA). Epilepsia 2011;52(12):190–3.
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
Original article
Epilepsy with myoclonic absences in siblings Ajith Cherian a, Shaik Afshan Jabeen b,⇑, Rukmini Mridula Kandadai a, Thomas Iype a, Pallavi Moturi b, Muralidhar Reddy b, Meena Angamuthu Kanikannan b, Rupam Borgohain b, Sandeep Padmanabhan a b
a Department of Neurology, Medical College Hospital, Trivandrum, Kerala, India Department of Neurology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, India
Received 11 June 2013; received in revised form 16 December 2013; accepted 17 December 2013
Abstract Background: Epilepsy with myoclonic absences (EMAs) is a distinct form of childhood epilepsy characterized by a peculiar seizure type that identifies this condition. Purpose: To describe the clinical, electroencephalographic features, treatment strategies and outcome in this first case series of two siblings with normal intelligence presenting with EMAs. Materials and methods: Both siblings underwent video-polygraphic investigations (simultaneous recording of electroencephalogram [EEG] and electromyogram [EMG] from deltoids), high-resolution magnetic resonance imaging (MRI), karyotyping, neuropsychological evaluation and language assessment. Results: Both the children had a mean age of onset of prototype seizures by 3.5 years. Myoclonic absences (MAs) were characterized by rhythmic, bilateral, synchronous, symmetric 3-Hz spike–wave discharges, associated with EMG myoclonic bursts at 3 Hz, superimposed on a progressively increasing tonic muscle contraction. The interictal EEG showed a normal background activity with bursts of generalized spike and waves (SWs) as well as rare focal SWs independently over bilateral temporal and frontal regions. Increase in the seizure frequency from 5 to 100/day was observed due to use of carbamazepine and phenobarbitone which decreased with its withdrawal and introduction of valproate. Though lamotrigine was given as an add on to valproate, it did not benefit them and was therefore replaced by topiramate at 3.5 mg/kg/day which has maintained them on remission at one year follow up. Conclusions: Recognition of this ictal pattern allows identification and differentiation of EMAs from other seizure types. Idiopathic and symptomatic EMAs need to be differentiated from childhood absence epilepsy with myoclonia. MAs are worsened by drugs like carbamazepine while valproate either alone or in combination with topiramate (preferred to lamotrigine) gives excellent outcome. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Tassinari; EMAs; Valproate; Ethosuximide; 3 Hz; Polygraphic VEEG; Topiramate
1. Introduction Epilepsy with myoclonic absences (EMAs) is characterized by absence seizures associated with rhythmic, bilateral proximal myoclonic jerks of upper extremities. The diagnosis is based on clinical observation and ictal video electroencephalograph (EEG) recordings. Demonstration of myoclonic absences (MAs) is essential for the ⇑ Corresponding author. Tel.: +91 9704822022.
E-mail address: [email protected] (S.A. Jabeen).
diagnosis. In the proposed diagnostic scheme by the International League Against Epilepsy (ILAE) [1], it has been tentatively placed among the idiopathic generalized epilepsies. 2. Materials and methods 2.1. Subjects Both the subjects who are siblings presented with seizures to our institute, which is a tertiary referral centre
0387-7604/$ - see front matter Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.12.004
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
2
A. Cherian et al. / Brain & Development xxx (2014) xxx–xxx
for neurological diseases in South India. They underwent video-polygraphic investigations, high-resolution magnetic resonance imaging (MRI), karyotyping, neuropsychological evaluation and language assessment. 2.2. Electroencephalography (EEG) All recordings were carried out on a 16-channel digital EEG acquisition system (NicVue, Nicolet-Viking, USA); with the scalp electrodes placed according to the International 10–20 system. Both patients with EMAs also underwent a video-polygraphic investigation (simultaneous recording of electroencephalogram [EEG] and electromyogram [EMG] from deltoids). The distribution of interictal epileptiform discharges (IEDs) during prolonged video-EEG monitoring was assessed by visual analysis of the entire acquired data. 2.3. Neuroimaging Both the patients underwent a 1.5 Tesla magnetic resonance imaging (MRI) (1.5 T MRI, Avanto, TIM SQ engine, Siemens, Erlangen, Germany).
3. Results 3.1. Clinical, seizure and imaging characteristics The siblings were born of nonconsanguinous parentage and had normal growth and developmental milestones. The median age at seizure onset was 3.5 years. Myoclonic absence seizures were characterized by recurrent episodes of rhythmic myoclonic jerks mainly at proximal shoulder associated with progressive elevation of the arms with unresponsiveness lasting for 10 s (Video 1). The onset and offset were abrupt with no postictal confusion. They had no eyelid or perioral myoclonia. The seizures were predominantly diurnal especially in the early morning hours precipitated by hyperventilation, lasting for 10–15 s at a frequency of 4–5 per day. The girl had a past history of a single generalized tonic clonic seizure at the age of 3 years which was not associated with fever. Other than her younger brother who had EMAs no one else in the family was affected (Table 1). MRI including high resolution three-dimensional fast fluid attenuated inversion recovery (3D FLAIR) images with thin cuts were normal in both the cases.
2.4. Language and neuropsychological assessment 3.2. EEG characteristics Malin’s Intelligence Scale for Indian children, which is a validated Indian adaptation of Wechsler’s Intelligence Scale for children, was used to assess the intelligence quotient (IQ) for children [2]. Language was assessed by the local adaptation of the Receptive Expressive Emergent Language Scale (REELS) and its extended version [3]. 2.5. Follow-up and outcome assessment Both the siblings were followed up at three-monthly intervals. The seizure and cognitive outcomes were assessed at each follow-up visit.
The interictal EEG showed a normal background activity with bursts of generalized spike and waves (SWs) as well as focal SWs independently over bilateral temporal regions in the sister while her brother showed independent IEDs over bilateral frontal regions (Figs. 1– 3). The ictal EEG consisted of rhythmic SW discharges at 3 Hz, which are bilateral, synchronous, and symmetric, as observed in typical absence seizures. The onset and the end of SWs were abrupt. Polygraphic (EEG– EMG) recording disclosed the appearance of bilateral myoclonias, at the same frequency as the SWs, which began around 1000 ms after the onset of EEG paroxys-
Table 1 Electro clinical profile, treatment and outcome of siblings with EMAs. Current age/ Gender
Age of sz onset
Types of sz
Interictal SEEG
Ictal SEEG
Response of MAs to initial AEDs
Neuropsychology/ language evaluation
Sz outcome and medications at 12 month follow-up
12/F
3 yrs
MAs, single GTCs
Bursts of gen SWD, independent focal SWD over bilateral temporal regions
Frequency of MAs worsened from 4–5 per day to 80–100 per day while on CBZ and PHB
Normal
10/M
4 yrs
MAs alone
Bursts of gen SWD as well as independent focal SWD over bilateral frontal region
Rhythmic SWD at 3 Hz, which are bilateral, synchronous, and symmetrical Rhythmic SWD at 3 Hz, which are bilateral, synchronous, and symmetrical
Frequency of MAs worsened from 4–5 per day to 80–100 per day while on CBZ and PHB
Normal
In remission on VAL 25 mgm/kg/day and TPA 3.5 mgm/kg/day (LTG did not improve sz outcome) In remission on VPA25 mg/kg/day and TPM 3.5 mg/kg/day (LTG did not improve sz outcome)
AED, antiepileptic drugs; CBZ, carbamazepine; EMAs, epilepsy with myoclonic absences; F, female; gen, generalized; GTCs, generalized tonic clonic seizure; LTG, lamotrigine; M, male; MAs, myoclonic absences; PHB, phenobarbitone; SEEG, scalp electroencephalography; SWD, spike wave discharge; sz(s), seizure(s); TPM, topiramate; VPA, valproate; yrs, years.
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
A. Cherian et al. / Brain & Development xxx (2014) xxx–xxx
mal discharges (Fig. 4) and were followed by a tonic contraction, maximal in the shoulder (deltoid) muscles (Video 1). VEEG analysis provided a clear relationship between the SWs and motor events, showing a strict and constant relation between the spike of the SW discharge and the myoclonia (Fig. 5). 3.3. Language and neuropsychological assessment Language and neuropsychological assessment was performed in both the cases. IQ and language were normal prior to and after seizure onset in both the children. 3.4. Response to treatment and outcome The children were initiated elsewhere on a combination of carbamazepine and phenobarbitone which initially worsened their seizure frequency from 4–5 per day to 80–100 per day. Both of them responded well to removal of carbamazepine and phenobarbitone and introduction of valproate at 25–30 mg/kg/day as MAs reduced to 1/day. Introduction of lamotrigine as the first add on did not benefit them though there was no worsening of seizures. Addition of topiramate at a dose of the 3.5 mg/kg/day induced remission initially in the brother followed by his sister. At a follow-up of one year both the siblings are in remission. 4. Discussion EMAs is a rare condition accounting for 0.5% to 1% of all epilepsies. Tassinari et al. [4] has proposed at least
3
two forms of EMAs: idiopathic EMA with a more benign course, and eventual disappearance of seizures, in which MAs are the sole, or predominant, seizure type consisting of about one third of total EMA patients; and the other symptomatic MAs associated with other seizure types (particularly, frequent generalized tonic–clonic seizures) which can appear before the onset of MAs or occur in association with MAs and bear a more severe prognosis (Table 2 provides the characteristics of idiopathic EMAs, symptomatic EMAs and CAE with myoclonia to distinguish one from the other). The mean age of onset of MAs is 7 years, with a range between 11 months and 12.2 years. MAs last for 10–60 s, and recur at a high frequency (10–100 per day), being often precipitated by hyperventilation or awakening. The seizure manifestation typically consists of bilateral myoclonic jerks involving proximal limb muscles associated with a discrete tonic contraction resulting in progressive elevation of extremities as seen in video. Interictal EEGs in one third of cases show focal or multifocal SWs as demonstrated in our case. The ictal EEG studies with polygraphic (EEG–EMG) recording has shown that there is a time lag of 1000 ms between the EEG and later surface EMG discharges. The positive transient encompassed in the SW complex, is followed on the EMG by a myoclonia with a latency of 15–40 ms for the proximal muscles like deltoids (Fig. 5). Hypotheses on the peculiar muscular pattern that characterizes MA seizures is due to the tonic muscular contraction component that is superimposed on the myoclonic activity related to the involvement of supple-
Fig. 1. EEG showing burst of generalized spike, polyspike and wave discharges.
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
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A. Cherian et al. / Brain & Development xxx (2014) xxx–xxx
Fig. 2. EEG showing bilateral independent temporal and frontal focal IEDs.
Fig. 3. EEG showing run of left frontal focal IEDs.
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004
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Fig. 4. Snap shot of the video showing that the rhythmic myoclonia starts 1000 ms after the onset of the EEG paroxysmal discharge. Note that the first three spike–wave complexes are not associated with any evident myoclonic activity.
mentary motor areas, possibly in the frontomesial cortex [5]. Tonic contractions occur always in MAs, but after the appearance of few SW complexes, possibly suggesting a spread of paroxysmal activity to frontomesial
areas. The evidence in some cases of associated trisomy13 has led to the hypothesis that abnormal expression of genes located in the affected chromosome segments may play a role in the pathogenesis [6]. A
Fig. 5. High-speed polygraphic recording of a myoclonic absence (MA) seizure, showing the relationship between the spike of the spike–wave (SW) complex and the myoclonic potential. There is a time delay of 39 ms from the electrical discharge to the EMG burst.
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Table 2 Showing comparison between 3 groups of with absence sz with myoclonia. Features
Idiopathic EMAs
Symptomatic EMAs
CAE with myoclonia
Age Sex Intellect Chromozomal anomalies MR imaging Seizure
Infancy to 12 years Boys > girls Normal None
Infancy to 12 years Boys > girls Affected Trisomy 13, Angelman syndrome, inverted chromosomal 15 duplications Abnormal MAs, GTCs
4–10 years Girls > boys.
Normal Usually MAs alone
Interictal EEG
Normal BGA; bursts of gen SWD, rarely independent focal SWD over bilateral temporal/frontal regions
Ictal EEG
Rhythmic SWD at 3 Hz, which are bilateral, synchronous, and symmetrical Bilateral myoclonias, at the same frequency as the SWs, which begin around 1 s after the onset of EEG paroxysmal discharges and are followed by a tonic contraction, maximal in the shoulder and deltoid muscles Worsened by CBZ;LTG may not benefit; Better response to VAL ± TPM Possible in 50%
EMG recording
Response to AEDs AED withdrawal on follow up
Abnormal BGA; bursts of gen SWD, independent focal SWD more common over bilateral temporal/frontal/occipital regions Rhythmic SWD at 3 Hz, which are bilateral, synchronous, and symmetrical Bilateral myoclonias, at the same frequency as the SWs, which begin around 1 s after the onset of EEG paroxysmal discharges and are followed by a tonic contraction, maximal in the shoulder and deltoid muscles Worsened by CBZ; LTG may not benefit; Better response to VPA ± TPM Unlikely; May evolve into Lennox Gestaut syndrome
None Normal Absence sz with predominant eyelid myoclonia Normal BGA; frequent OIRDA
Rhythmic SWD at 3 Hz, which are bilateral, synchronous, and symmetrical Eyelid myoclonias with fast flickering of the eyelids; proximal arm myoclonia are unusual and very rare and it has no intervening tonic contraction.
Excellent response to EXM and VPA Possible in nearly all the cases
AEDs, antiepileptic drugs; CBZ, carbamazepine; EEG, electroencephalography; EMAs, epilepsy with myoclonic absences; EXM, ethosuximide; gen, generalized; GTCs, generalized tonic clonic seizure; LTG, lamotrigine; MAs, myoclonic absences; MR, magnetic resonance; OIRDA, occipital intermittent rhythmic delta activity; sz(s), seizure(s); SWD, spike wave discharge; TPM, topiramate; VPA, valproate.
genetic susceptibility, as demonstrated by a positive family history of epilepsies, has been observed in about 20% of cases. Literature search revealed a report of a male patient with nonsyndromic intellectual; disability (ID) and EMA carrying a de novo balanced translocation with one breakpoint disrupting the SYNGAP1 gene [10]. Also there was dominantly inherited mutation in Glutamate dehydrogenase (GDH) causing EMA in association with hyperinsulinism–hyperammonemia [11]. However no cases of siblings presenting with isolated EMAs has been reported till now. Ours is a unique case series of affected siblings suggest an autosomal recessive inheritance, without any associated comorbidities though causative gene is still unknown. EMAs must be differentiated from absence seizures with rhythmic myoclonias associated with 3 Hz regular SWs observed in children with early-onset typical absences [7]. The benign course, excellent response to treatment, possible drug withdrawal in the evolution, and mild myoclonia without a background of tonic contraction help to differentiate CAE from EMAs. Severe EMAs need to be differentiated from the myoclonic status observed in nonprogressive encephalopathies [8]. As far as treatment is concerned valproic acid and ethosuximide at high doses, are effective. Topiramate, and zonisamide, may hold promise in EMAs as add
on therapy. Our report clearly shows the effectiveness of topiramate over lamotrigine as the first add on if ethosuximide is not available. Lamotrigine has been shown to worsen seizures in severe myoclonic epilepsy and exacerbate, de novo myoclonus, and myoclonic status in patients with idiopathic generalized epilepsies including juvenile myoclonic epilepsy [9]. Sodium channel blockers such as carbamazepine, phenytoin and gabaminergic drugs such as vigabatrin, gabapentin, tiagabine might worsen MAs as highlighted. 5. Conclusions Epilepsy with myoclonic absences (EMAs) is a distinct form of childhood epilepsy characterized by a peculiar seizure type that identifies this epileptic condition. Focal SWDs over frontal and temporal regions can be present. This is the first case series of siblings with normal intellect presenting with EMAs and demonstrates the usefulness of topiramate over lamotrigine as the first add on to valproate when ethosuximide is unavailable. Note A written permission from the patients mother has been taken and uploaded with the manuscript.
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Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.braindev.2013.12.004. References [1] Engel JJ. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 2001;2001(42):796–803. [2] Malin AJ. Indian adaptation of Wecshler’s intelligence scale for children. Indian J Mental Retard 1979;4:15–25. [3] Bzoch K, Legue R. The receptive and expressive emergent language scale (REELS) Slough. UK: National Foundation for Educational Research; 1971. [4] Tassinari CA, Rubboli G, Gardella E. Epilepsy with myoclonic absences. In: Wallace SJ, Farrell K, editors. Epilepsy in children. London: Arnold; 2004. p. 189–94. [5] Taki W et al. Clonic convulsion caused by epileptic discharges arising from the human supplementary motor area as studied by subdural recording. Epileptic Disord 1999;1:21–6.
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[6] Elia M, Musumeci SA, Ferri R, Cammarata M. Trisomy 12p and epilepsy with myoclonic absences. Brain Dev 1998;20:127–30. [7] Capovilla G, Rubboli G, Beccaria F, Lorenzetti ME, Montagnini A, Resi C, et al. A clinical spectrum of the myoclonic manifestations associated with typical absences in childhood absence epilepsy. A video-polygraphic study. Epileptic Disord 2001;3:57–62. [8] DallaBernardina B, Fontana E, Darra F. Myoclonic status in non-progressive encephalopathies. In: Roger J, Bureau M, Dravet C, editors. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey; 2005. p. 149–57. [9] Crespel A, Genton P, Berramdane M, Coubes P, Monicard C, Baldy-Moulinier M, et al. Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies. Neurology 2005;65:762–4. [10] Bahi-Buisson N et al. Myoclonic absence epilepsy with photosensitivity and a gain of function mutation in glutamate dehydrogenase. Seizure 2008;17(7):658–64. [11] Klitten Laura L et al. A balanced translocation disrupts SYNGAP1 in a patient with intellectual disability, speech impairment, and epilepsy with myoclonic absences (EMA). Epilepsia 2011;52(12):190–3.
Please cite this article in press as: Cherian A et al. Epilepsy with myoclonic absences in siblings.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.12.004