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Absence epilepsy and periventricular nodular heterotopia
Seizure 19 (2010) 450–452
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Case report
Absence epilepsy and periventricular nodular heterotopia M.C.Y. de Wit a, H.M. Schippers b, I.F.M. de Coo a, W.F.M. Arts a, M.H. Lequin c, A. Brooks d, G.H. Visser e, G.M.S. Mancini d,* a
Dept. of Pediatric Neurology, Erasmus MC Sophia Children’s Hospital, P.O. Box 2040, 3000 CA, The Netherlands Dept. of Neurology, St. Antonius Hospital, Nieuwegein, The Netherlands c Dept. of Radiology, Erasmus MC, P.O. Box 2040, 3000 CA, The Netherlands d Dept. of Clinical Genetics, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands e Dept. of Clinical Neurophysiology, Erasmus MC, P.O. Box 2040, 3000 CA, The Netherlands b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 March 2010 Accepted 17 June 2010
We report a case of a girl who presented with typical absence seizures at age of 4.5 years. EEG showed absence seizures of sudden onset with 3 Hz spike-and-waves that also correlated with the clinical absences. The seizure semiology included subtle deviation of the eyes which prompted MRI investigation of the brain. This showed a periventricular nodular heterotopia in the mid to anterior horn of the right lateral ventricle. Although possibly coincidental, periventricular heterotopia are considered to be epileptogenic and this association has been reported once before. Migration disorders, such as in the periventricular heterotopia of our patient, may influence the formation and excitability of the striato–thalamo–cortical network involved in the generation of 3 Hz spike-waves. ß 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Absence epilepsy Periventricular nodular heterotopia Migration 3 Hz spike-waves Thalamus Cortex
1. Introduction The ILAE definition of childhood absence epilepsy includes very frequent (several to many per day) absences in otherwise normal children of school age (peak manifestation age 6–7 years), with a strong genetic predisposition. It appears more frequently in girls than in boys. Seizures are characterised by very brief clouding or loss of consciousness lasting usually 2–15 s (simple absences) associated with a bilateral, synchronous, and symmetrical EEG discharge of 3 Hz spike-and-wave complexes, on a normal background activity. Impairment of consciousness may be associated with mild tonic, atonic, tonic and autonomic components, and automatisms (complex absences).1 The classification of idiopathic generalised epilepsy with absences is controversial, but it is generally accepted that childhood absence epilepsy has a complex genetic background and a good prognosis. Factors indicating poor prognosis are regarded an exclusion criterion.1
* Corresponding author. Tel.: +31 107040704; fax: +31 107036345. E-mail addresses: [email protected] (M.C.Y. de Wit), [email protected] (H.M. Schippers), [email protected] (I.F.M. de Coo), [email protected] (W.F.M. Arts), [email protected] (M.H. Lequin), [email protected] (A. Brooks), [email protected] (G.H. Visser), [email protected] (G.M.S. Mancini).
Only in a few families a clear pattern of inheritance has lead to the identification of several possibly involved loci.2 2. Case We present a girl, the first and only child of non-consanguineous parents. Pregnancy, delivery and first year were unremarkable. She reached all developmental milestones on time and walked unaided on her first birthday. Since the age of 4.5 years her mother noticed short episodes with loss of contact. Two months later this evolved into brief seizures less than 10 s with loss of consciousness, staring into space, sometimes with eyes deviating to the right and sometimes with lip smacking. Upon asked, the girl herself said that at the onset of the seizure she would hear gnomes making a lot of noise. This occurred with a frequency of around 2–15 times a day. She showed no postictal confusion of drowsiness. The parents had noticed that sleep deprivation increased seizure frequency. Family history revealed that the mother had two generalised tonic–clonic seizures, at age 12 and 15 years. An EEG of the mother at that time did not show any epileptiform discharges. Brain MRI of the mother was normal. Physical examination of the proband at age 5 years showed two aspecific hyperpigmented naevi with irregular borders on the left calf and on the scalp, mild cutaneous syndactyly of digits 2 and 3 of the feet, and no other dysmorphic features. Her height was at +1.5 SD, weight at 0 SD, and occipitofrontal circumference at 0 SD. Neurological examination
1059-1311/$ – see front matter ß 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2010.06.013
[(Fig._1)TD$IG]
M.C.Y. de Wit et al. / Seizure 19 (2010) 450–452
451
Fig. 1. EEG made at the age of 4.5 years showing sudden onset of 3 Hz spike-waves.
showed a normal cranial nerves exam, normal muscle tone, symmetric normal motor and sensory functions, normal coordination and symmetric deep tendon reflexes. The EEG showed a normal background pattern with an 8 Hz alpha rhythm and a 9 Hz symmetric mu rhythm. Twelve absence
[(Fig._2)TD$IG]
seizures were recorded, both during wake and sleep, with sudden onset of 3 Hz generalised spike-waves with a duration of 5–20 s (Fig. 1). The brain MRI shows a nodule of heterotopic gray matter in the mid to anterior horn of the right lateral ventricle. There are no other abnormalities, in particular no cortical malformations (Fig. 2). 2.1. Genetic analysis Sequence analysis of the FLNA gene showed no mutations. Chromosomal abnormalities were excluded by high-resolution analysis on 250K SNP microarray. 2.2. Follow-up She was prescribed sodium valproate, which resulted in seizure reduction, but also unacceptable side effects (behavioural change). On ethosuximide she quickly developed an allergic rash. On low dose sodium valproate combined with lamotrigin the absences disappeared. Follow-up EEGs showed no epileptiform discharges. 3. Discussion
Fig. 2. Brain MRI made at the age of 5 years and 11 months, showing a nodular heterotopia in the right lateral ventricle (denoted by arrow).
In childhood absence epilepsy brain imaging usually shows no abnormalities or coincidental abnormalities not related to seizures.3,4 The seizure semiology of our patient with behavioural arrest and oro-alimentary automatisms is suggestive of absences, however the eye deviation and the auditive aura are not typical and
452
M.C.Y. de Wit et al. / Seizure 19 (2010) 450–452
were reason to perform a brain MRI. The association between an idiopathic epilepsy syndrome and the malformation of cortical development of our patient may be coincidental. Her mother’s history of two unprovoked tonic–clonic seizures without epileptiform discharges on EEG and a normal brain MRI suggests a genetic susceptibility for epilepsy. However, periventricular nodular heterotopia are considered to be epileptogenic and the association between absence seizures and unilateral rightsided PNH has been reported once before in a schoolgirl.5 Absence seizures with 3 Hz spike-and-waves can co-exist in patients with localization-related epilepsy and partial seizures, but these patients usually also show focal epileptiform EEG abnormalities that were not found in our patient.6 EEGs in patients with unilateral or bilateral simple PNH are reported to show a normal background pattern with epileptiform or non-specific focal abnormalities.7,8 The striato–thalamo–cortical network is activated during absence seizures and the thalamus is involved in the generation of 3 Hz spike-wave activity.9,10 The cortex is also needed in seizure generation. Which structure initiates seizure onset is not fully elucidated.11,12 A recent MEG study suggests that a primary frontoparietal cortical focus can be found in absences.13 This supports the hypothesis of oscillating activity initiated in the cortex and propagated through the striato–thalamo–cortical network.13 Migration disorders resulting in mislocalization of cortical neurons, such as in the periventricular heterotopia of our patient, may influence the formation and excitability of the striato– thalamo–cortical network or may act as a focus for the development of absence seizures.
References 1. Panayiotopoulos CP. Typical absence seizures and related epileptic syndromes: assessment of current state and directions for future research. Epilepsia 2008;49(12):2131–9. 2. Weber YG, Lerche H. Genetic mechanisms in idiopathic epilepsies. Developmental Medicine and Child Neurology 2008;50(9):648–54. 3. Duncan JS. Brain imaging in idiopathic generalized epilepsies. Epilepsia 2005;46(Suppl. 9):108–11. 4. Sinclair DB, Unwala H. Absence epilepsy in childhood: electroencephalography (EEG) does not predict outcome. Journal of Child Neurology 2007;22(7):799–802. 5. Giza CC, Kuratani JD, Cokely H, Sankar R. Periventricular nodular heterotopia and childhood absence epilepsy. Pediatric Neurology 1999;20(4):315–8. 6. Sofue A, Okumura A, Negoro T, Hayakawa F, Nakai Y, Toyota N, et al. Absence seizures in patients with localization-related epilepsy. Brain Development 2003;25(6):422–6. 7. d’Orsi G, Tinuper P, Bisulli F, Zaniboni A, Bernardi B, Rubboli G, et al. Clinical features and long term outcome of epilepsy in periventricular nodular heterotopia. Simple compared with plus forms. Journal of Neurology Neurosurgery and Psychiatry 2004;75(6):873–8. 8. Battaglia G, Chiapparini L, Franceschetti S, Freri E, Tassi L, Bassanini S, et al. Periventricular nodular heterotopia: classification, epileptic history, and genesis of epileptic discharges. Epilepsia 2006;47(1):86–97. 9. Moeller F, Siebner HR, Wolff S, Muhle H, Granert O, Jansen O, et al. Simultaneous EEG-fMRI in drug-naive children with newly diagnosed absence epilepsy. Epilepsia 2008;49(9):1510–9. 10. Labate A, Briellmann RS, Abbott DF, Waites AB, Jackson GD. Typical childhood absence seizures are associated with thalamic activation. Epileptic Disorders 2005;7(4):373–7. 11. Blumenfeld H. Cellular and network mechanisms of spike-wave seizures. Epilepsia 2005;46(Suppl. 9):21–33. 12. Meeren H, van Luijtelaar G, Lopes da Silva F, Coenen A. Evolving concepts on the pathophysiology of absence seizures: the cortical focus theory. Archives of Neurology 2005;62(3):371–6. 13. Westmijse I, Ossenblok P, Gunning B, van Luijtelaar G. Onset and propagation of spike and slow wave discharges in human absence epilepsy: a MEG study. Epilepsia 2009;50(12):2538–48.
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Case report
Absence epilepsy and periventricular nodular heterotopia M.C.Y. de Wit a, H.M. Schippers b, I.F.M. de Coo a, W.F.M. Arts a, M.H. Lequin c, A. Brooks d, G.H. Visser e, G.M.S. Mancini d,* a
Dept. of Pediatric Neurology, Erasmus MC Sophia Children’s Hospital, P.O. Box 2040, 3000 CA, The Netherlands Dept. of Neurology, St. Antonius Hospital, Nieuwegein, The Netherlands c Dept. of Radiology, Erasmus MC, P.O. Box 2040, 3000 CA, The Netherlands d Dept. of Clinical Genetics, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands e Dept. of Clinical Neurophysiology, Erasmus MC, P.O. Box 2040, 3000 CA, The Netherlands b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 March 2010 Accepted 17 June 2010
We report a case of a girl who presented with typical absence seizures at age of 4.5 years. EEG showed absence seizures of sudden onset with 3 Hz spike-and-waves that also correlated with the clinical absences. The seizure semiology included subtle deviation of the eyes which prompted MRI investigation of the brain. This showed a periventricular nodular heterotopia in the mid to anterior horn of the right lateral ventricle. Although possibly coincidental, periventricular heterotopia are considered to be epileptogenic and this association has been reported once before. Migration disorders, such as in the periventricular heterotopia of our patient, may influence the formation and excitability of the striato–thalamo–cortical network involved in the generation of 3 Hz spike-waves. ß 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Absence epilepsy Periventricular nodular heterotopia Migration 3 Hz spike-waves Thalamus Cortex
1. Introduction The ILAE definition of childhood absence epilepsy includes very frequent (several to many per day) absences in otherwise normal children of school age (peak manifestation age 6–7 years), with a strong genetic predisposition. It appears more frequently in girls than in boys. Seizures are characterised by very brief clouding or loss of consciousness lasting usually 2–15 s (simple absences) associated with a bilateral, synchronous, and symmetrical EEG discharge of 3 Hz spike-and-wave complexes, on a normal background activity. Impairment of consciousness may be associated with mild tonic, atonic, tonic and autonomic components, and automatisms (complex absences).1 The classification of idiopathic generalised epilepsy with absences is controversial, but it is generally accepted that childhood absence epilepsy has a complex genetic background and a good prognosis. Factors indicating poor prognosis are regarded an exclusion criterion.1
* Corresponding author. Tel.: +31 107040704; fax: +31 107036345. E-mail addresses: [email protected] (M.C.Y. de Wit), [email protected] (H.M. Schippers), [email protected] (I.F.M. de Coo), [email protected] (W.F.M. Arts), [email protected] (M.H. Lequin), [email protected] (A. Brooks), [email protected] (G.H. Visser), [email protected] (G.M.S. Mancini).
Only in a few families a clear pattern of inheritance has lead to the identification of several possibly involved loci.2 2. Case We present a girl, the first and only child of non-consanguineous parents. Pregnancy, delivery and first year were unremarkable. She reached all developmental milestones on time and walked unaided on her first birthday. Since the age of 4.5 years her mother noticed short episodes with loss of contact. Two months later this evolved into brief seizures less than 10 s with loss of consciousness, staring into space, sometimes with eyes deviating to the right and sometimes with lip smacking. Upon asked, the girl herself said that at the onset of the seizure she would hear gnomes making a lot of noise. This occurred with a frequency of around 2–15 times a day. She showed no postictal confusion of drowsiness. The parents had noticed that sleep deprivation increased seizure frequency. Family history revealed that the mother had two generalised tonic–clonic seizures, at age 12 and 15 years. An EEG of the mother at that time did not show any epileptiform discharges. Brain MRI of the mother was normal. Physical examination of the proband at age 5 years showed two aspecific hyperpigmented naevi with irregular borders on the left calf and on the scalp, mild cutaneous syndactyly of digits 2 and 3 of the feet, and no other dysmorphic features. Her height was at +1.5 SD, weight at 0 SD, and occipitofrontal circumference at 0 SD. Neurological examination
1059-1311/$ – see front matter ß 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2010.06.013
[(Fig._1)TD$IG]
M.C.Y. de Wit et al. / Seizure 19 (2010) 450–452
451
Fig. 1. EEG made at the age of 4.5 years showing sudden onset of 3 Hz spike-waves.
showed a normal cranial nerves exam, normal muscle tone, symmetric normal motor and sensory functions, normal coordination and symmetric deep tendon reflexes. The EEG showed a normal background pattern with an 8 Hz alpha rhythm and a 9 Hz symmetric mu rhythm. Twelve absence
[(Fig._2)TD$IG]
seizures were recorded, both during wake and sleep, with sudden onset of 3 Hz generalised spike-waves with a duration of 5–20 s (Fig. 1). The brain MRI shows a nodule of heterotopic gray matter in the mid to anterior horn of the right lateral ventricle. There are no other abnormalities, in particular no cortical malformations (Fig. 2). 2.1. Genetic analysis Sequence analysis of the FLNA gene showed no mutations. Chromosomal abnormalities were excluded by high-resolution analysis on 250K SNP microarray. 2.2. Follow-up She was prescribed sodium valproate, which resulted in seizure reduction, but also unacceptable side effects (behavioural change). On ethosuximide she quickly developed an allergic rash. On low dose sodium valproate combined with lamotrigin the absences disappeared. Follow-up EEGs showed no epileptiform discharges. 3. Discussion
Fig. 2. Brain MRI made at the age of 5 years and 11 months, showing a nodular heterotopia in the right lateral ventricle (denoted by arrow).
In childhood absence epilepsy brain imaging usually shows no abnormalities or coincidental abnormalities not related to seizures.3,4 The seizure semiology of our patient with behavioural arrest and oro-alimentary automatisms is suggestive of absences, however the eye deviation and the auditive aura are not typical and
452
M.C.Y. de Wit et al. / Seizure 19 (2010) 450–452
were reason to perform a brain MRI. The association between an idiopathic epilepsy syndrome and the malformation of cortical development of our patient may be coincidental. Her mother’s history of two unprovoked tonic–clonic seizures without epileptiform discharges on EEG and a normal brain MRI suggests a genetic susceptibility for epilepsy. However, periventricular nodular heterotopia are considered to be epileptogenic and the association between absence seizures and unilateral rightsided PNH has been reported once before in a schoolgirl.5 Absence seizures with 3 Hz spike-and-waves can co-exist in patients with localization-related epilepsy and partial seizures, but these patients usually also show focal epileptiform EEG abnormalities that were not found in our patient.6 EEGs in patients with unilateral or bilateral simple PNH are reported to show a normal background pattern with epileptiform or non-specific focal abnormalities.7,8 The striato–thalamo–cortical network is activated during absence seizures and the thalamus is involved in the generation of 3 Hz spike-wave activity.9,10 The cortex is also needed in seizure generation. Which structure initiates seizure onset is not fully elucidated.11,12 A recent MEG study suggests that a primary frontoparietal cortical focus can be found in absences.13 This supports the hypothesis of oscillating activity initiated in the cortex and propagated through the striato–thalamo–cortical network.13 Migration disorders resulting in mislocalization of cortical neurons, such as in the periventricular heterotopia of our patient, may influence the formation and excitability of the striato– thalamo–cortical network or may act as a focus for the development of absence seizures.
References 1. Panayiotopoulos CP. Typical absence seizures and related epileptic syndromes: assessment of current state and directions for future research. Epilepsia 2008;49(12):2131–9. 2. Weber YG, Lerche H. Genetic mechanisms in idiopathic epilepsies. Developmental Medicine and Child Neurology 2008;50(9):648–54. 3. Duncan JS. Brain imaging in idiopathic generalized epilepsies. Epilepsia 2005;46(Suppl. 9):108–11. 4. Sinclair DB, Unwala H. Absence epilepsy in childhood: electroencephalography (EEG) does not predict outcome. Journal of Child Neurology 2007;22(7):799–802. 5. Giza CC, Kuratani JD, Cokely H, Sankar R. Periventricular nodular heterotopia and childhood absence epilepsy. Pediatric Neurology 1999;20(4):315–8. 6. Sofue A, Okumura A, Negoro T, Hayakawa F, Nakai Y, Toyota N, et al. Absence seizures in patients with localization-related epilepsy. Brain Development 2003;25(6):422–6. 7. d’Orsi G, Tinuper P, Bisulli F, Zaniboni A, Bernardi B, Rubboli G, et al. Clinical features and long term outcome of epilepsy in periventricular nodular heterotopia. Simple compared with plus forms. Journal of Neurology Neurosurgery and Psychiatry 2004;75(6):873–8. 8. Battaglia G, Chiapparini L, Franceschetti S, Freri E, Tassi L, Bassanini S, et al. Periventricular nodular heterotopia: classification, epileptic history, and genesis of epileptic discharges. Epilepsia 2006;47(1):86–97. 9. Moeller F, Siebner HR, Wolff S, Muhle H, Granert O, Jansen O, et al. Simultaneous EEG-fMRI in drug-naive children with newly diagnosed absence epilepsy. Epilepsia 2008;49(9):1510–9. 10. Labate A, Briellmann RS, Abbott DF, Waites AB, Jackson GD. Typical childhood absence seizures are associated with thalamic activation. Epileptic Disorders 2005;7(4):373–7. 11. Blumenfeld H. Cellular and network mechanisms of spike-wave seizures. Epilepsia 2005;46(Suppl. 9):21–33. 12. Meeren H, van Luijtelaar G, Lopes da Silva F, Coenen A. Evolving concepts on the pathophysiology of absence seizures: the cortical focus theory. Archives of Neurology 2005;62(3):371–6. 13. Westmijse I, Ossenblok P, Gunning B, van Luijtelaar G. Onset and propagation of spike and slow wave discharges in human absence epilepsy: a MEG study. Epilepsia 2009;50(12):2538–48.