162
Early Epileptic Encephalopathy with Suppression Bursts and olivary-Dentate Dysplasia By O. Robain l and O. Dulac l , 2
Abstract A case of neonatal epileptic encephalopathy with suppression-bursts associated with olivary dentate nuclei dysplasia is reported. This unusual association shows that the so-called Ohtahara syndrome could correspond to several different brain malformations sometimes disclosable only by neuropathological examination.
Keywords Suppression-bursts - Neonatal epilepsy Brain malformation
Introduction The wide range of neonatal epileptic encephalopathies remains achallenge in terms of etiology and risk for familial recurrence. Broad syndromic groups have been reported, based on clinical and EEG findings, most notably a group of early infantile epileptic encephalopathy with suppression-bursts otherwise reported as Ohtahara's syndrome (6). But groups remain most often heterogeneous. Further classification awaits either biochemieal, genetic or neuropathological markers. In order to contribute to this collection, we report a clinical neuropathological case that seems to consist of an original entity, only recognizable on post-mortem neuropathological investigation and that was mainly characterized by olivary-dentate dysplasia.
Case report DUC... H., a girl was the second child of healthy non-consanguinous parents. Her brother was healthy. The maternal grandfather had exhibited febrile seizures in infancy. H. was delivered at 39 weeks of uneventful gestation, weighing 3200 g and her cranial circumference was 36 cm. She suffered no cardiorespiratory distress. In the sixteenth hour of life, she exhibited the first seizures characterized by right deviation of head and eyes and extension of the left upper limb, lasting less than aminute. Some seizure evolved to clonic generaliReceived December 1990; accepted April 2, 1991 Neuropediatrics 23 (1992) 162-164 © Hippokrates Verlag Stuttgart
zation. There were no myoclonias. Clinical examination disclosed axial hypotonia, but neither focal deficit, nor dysmorphia, cutaneous naevi, visceral, or fundoscopic abnormalities. Interictal EEG recording at the age of 5 weeks demonstrated suppression bursts during sleep, consisting of bursts of slow waves, sharp waves and spikes asynergie on both hemispheres and alternating with 3-5 sec. periods of suppression of activity (Fig. 1). letal tracing showed diffuse suppression of activity during 20 seconds followed by rhythmic slow waves on the left hemisphere lasting one minute. CSF was normal including protein concentration (0.64 g/l.) electrophoresis of proteins, cell density (5/mm3), and serology for toxoplasmosis, rubella, measles and cytomegalovirus. CT scan disclosed no abnormalities. The clinical condition worsened, the patient suffering several seizures a day. She died at the age of 2 months. General pathological examination was normal. The brain weighed 485 g. Macroscopically, no significant abnormalities were noticeable, except for a slight widening of the sulci particularly in the left hemisphere. The cerebellum appeared to be normal. Microscopically, after celloYdin embedding and Nissl's staining, large seetions of the hemispheres showed only mild modifications at the sustentoriallevel, which consisted of nerve cellloss in the depth of several sulci, particularly in the temporal lobe. The crown of the gyri was spared and some gyri had a mushroomlike shape, but no gliosis was present. At the infratentoriallevel, there were remarkable anomalies involving both dentate nuclei and olives. The dentate nuclei had lost' their normal shape and displayed a plump profile (Fig.2). In place of an undulated ribbon, the dentate nuclei consisted of a gray matter penetrated by few myelinated fibers. The hilus itself was difficult to identify and poorly myelinated. Numerous neurones could be recognized in this gray mass, exhibiting a size (15 to 30 Ilm.) and shape (multipolar or spindIe shaped) of neurones encountered in anormal dentate nucleus. There was no decrease in neuronal density but the distribution of nerve cells was completely disorganized. They were grouped in small islands separated by thin myelinated fibers. Both olivary nuclei also showed a major dysplasia (Fig. 3). They had a greatly simplified shape, resembling a hook. Within both inferior olivary nuclei, indeed, the normal undulations had disappeared and there were thickening of segments of the nuclei, with obliteration of their undulated profiles. In spite of this pattern which is similar to immature olives, the size and the shape of the neurones were roughly spared. Neuronal density was quite normal, but distribution was COffi-
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lService de Neuropediatrie and 2INSERM U 29, Höpital Saint Vincent de Paul, 82 Avenue Denfert Rochereau, Paris cx 14, France
Suppression Bursts and Olivary-Dentate Dysplasia
Neuropediatrics 23 (1992)
163
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-+ I + ~
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Fig. 1 Interictal electroencephalographic tracing demonstrating suppression bursts during sleep. Notice that the suppression of activity is asynchronous on both hemispheres.
Fig.3 Inferior olivary nuclei displaya coarse profile without normal undulation. The dorsal and medial accessory nuclei are normal. Woelcke X6.
..... Fig.2 The dentate nucleus consists of a broad band without undulations. Notice the disappearance of the external granular layer in the cerebellar cortex. Luxol fast bl ue X6.
Downloaded by: Universite Laval. Copyrighted material.
PNO
O. Robain and O. Dulac
Neuropediatrics 23 (1992)
in the development. Anomalies of the dentate nuclei are less frequently reported than olivary ones, and they have mainly been seen in cerebellar malformations, for example: agenesis of the hemispheres and agenesis of the vermis (3, 14). The relationship between the epileptic encephalopathy and the subtentorial dysplasia is difficult to determine, since this type of malformation does not produce epilepsy when restricted to the subtentorial regions, such as in Dandy-Walker or ]oubert's disease. This contrasts with Zellweger's disease (2) which is highly epileptogenic but include olivary dysplasia and anomalies of the cerebral cortex probably responsible for the seizures. In our case, supratentorial anomalies were too mild to seem significant, but this is also often the case in older epileptic patients.
Fig. 4 Inferior olivary nucleus showing the marginal disposition of the neurons. Nissl X30.
pletely disorganized. Small clusters of neurons were arranged along the margins of the nuclei (Fig. 4) and were separated by myelinated fibers. No gliosis was present. This modification was restricted to the principal inferior olivary nuclei. Both the dorsal and medial accessory olives appeared to be normal. No heterotopias of olivary neurones were visible. In addition to this major modification of dentate and olivary nuclei, the brain stern and the cerebellum appeared to be normal, except for a disappearance of the external granular layer in the cerebellar cortex which normally persists up to 9 months (8). Discussion We have presented a case of neonatal epileptic encephalopathy with suppression bursts (SB) associated with olivo-dentate nucleus dysplasia. Early epileptic encephalopathies with SB have most severe prognosis (10), and two different etiological conditions are listed in the Classification of the International League against Epilepsy (5). Early Myoclonic Encephalopathy (1) suggests a set of inherited metabolie disorders, most of which remain unrecognized. Patients without myoclonias often exhibit brain malformations, as shown by Ohtahara (12). Aicardi's syndrome (4) and hemimegalencephaly (13) are presently the main types of malformations that exhibit SB in a sizable proportion of cases. The olivo-dentate abnormality we report here is a third type of malformation, not disclosable by neuroradiological investigations and thus should stimulate the performance of complete neuropathological investigation when a patient has died from a disease with this type of clinical and EEG pattern. Olivary dysplasia in the present case, consists of unundulated massive olives. This aspect has been observed in several malformations (trisomy 8, trisomy 13, holoprosencephaly, ]oubert's syndrome, cerebellar hemispheres or vermis aplasia) (7). This type of dysplasia is usually considered as an arrest of development since the undulations of the olivary neuronal ribbon should be present at 250-300 mm length (11), corresponding to the 5th to 6th month of fetal life. However, this understanding is not consistant with the other findings in our case, since the neurons themselves have continued to develop, and the lack of external granular layer suggest an advance
Whatever, the relationship between the subtentorial dysplasia and the epilepsy, it does seem to be relevant since similar cases have been reported (9). Therefore, olivo dentate malformation is probably one of the etiological conditions included in the Ohtahara syndrome. Further data should be gathered in order to determine etiology, given the fact that symmetrical malformations such as agyria of the Bielchowsky and of the Walker types, do exhibit a risk for familial recurrence.
References Aicardi,].: Early myoclonic encephalopathy. In: Roger,]. et al: Epileptic Syndromes in Infancy, Childhood and Adolescence. London and Paris, 1. Libbey Eurotext (1985) 12-22 2 Aubourg, P., O. Robain, F. Rocchiccioli et al: The cerebro-hepato-renal (Zellweger) syndrome: lamellar lipid profiles in adrenocortical, hepatic mesenchymal, astrocyte cells and increased levels of very long chain fatty acids and phytanic acid in the plasma. J. Neurol. Sei. 69 (1985) 9-25 3 Buissonniere, R. F., V. Storni, O. Robain, G. Ponsot: Syndrome de Joubert. Ann. Pediatr. 37 (1990) 151-156 4 Chemie,].].,]. Aicardi: The Aicardi syndrome. Recent Adv. Epilepsy 3 (1986) 189-210 5 Commission on classification and terminology of the internationalleague against epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30 (1989) 389-399 6 Dulac, 0., P. Aubourg, P. Plouin: Other epileptic syndromes in neonates. In: Roger,]. et al: Epileptic Syndromes in Infancy, Childhood and Adolescence. London and Paris, J. Libbey Eurotext, (1985) 23-29 7 Friede, R. L.: Dating the development of human cerebellum. Acta Neuropathol. 23 (1973) ~8-58 8 Friede, R. L.: Developmental Neuropathology (second ed.). Berlin, Heidelberg, Springer-Verlag (1989) 347-371 9 Harding, B.: Olivary dysplasia. Colloquium of European Paediatric Neuropathology Group. June 26-27, UK, Wallingford (1990) 10 Maheshwari, M. C., P. M. ]eavons: The prognostic implications of suppression-burst activity in the EEG in infancy. Epilepsia 16 (1975) 127-131 11 MurojUshi, K.: Normalentwicklung und Dysgenesien von Dentatum und Oliva inferior. Acta Neuropathol. 27 (1974) 317-328 12 Ohtahara, s.: Clinico-electrical delineation of epileptic encephalopathies in childhood. Asian Med. J. 21 (1978) 7-17 13 Paladin, F., C. Chiron, O. Dulac, P. Plouin, G. Ponsot: Electroencephalographic aspects of hemimegalencephaly. Dev. Med. Child Neurol. 31 (1989) 377-383 14 Robain, 0., O. Dulac, C. Lejeune: Cerebellar hemispheric agenesis. Acta Neuropathol. 74 (1987) 202-206 1
O. Robain, M. D. INSERM U29 Höpital Saint Vincent de Paul 82 Avenue Denfert Rochereau F-75674 Paris Cedex 14, France
Downloaded by: Universite Laval. Copyrighted material.
164
Early Epileptic Encephalopathy with Suppression Bursts and olivary-Dentate Dysplasia By O. Robain l and O. Dulac l , 2
Abstract A case of neonatal epileptic encephalopathy with suppression-bursts associated with olivary dentate nuclei dysplasia is reported. This unusual association shows that the so-called Ohtahara syndrome could correspond to several different brain malformations sometimes disclosable only by neuropathological examination.
Keywords Suppression-bursts - Neonatal epilepsy Brain malformation
Introduction The wide range of neonatal epileptic encephalopathies remains achallenge in terms of etiology and risk for familial recurrence. Broad syndromic groups have been reported, based on clinical and EEG findings, most notably a group of early infantile epileptic encephalopathy with suppression-bursts otherwise reported as Ohtahara's syndrome (6). But groups remain most often heterogeneous. Further classification awaits either biochemieal, genetic or neuropathological markers. In order to contribute to this collection, we report a clinical neuropathological case that seems to consist of an original entity, only recognizable on post-mortem neuropathological investigation and that was mainly characterized by olivary-dentate dysplasia.
Case report DUC... H., a girl was the second child of healthy non-consanguinous parents. Her brother was healthy. The maternal grandfather had exhibited febrile seizures in infancy. H. was delivered at 39 weeks of uneventful gestation, weighing 3200 g and her cranial circumference was 36 cm. She suffered no cardiorespiratory distress. In the sixteenth hour of life, she exhibited the first seizures characterized by right deviation of head and eyes and extension of the left upper limb, lasting less than aminute. Some seizure evolved to clonic generaliReceived December 1990; accepted April 2, 1991 Neuropediatrics 23 (1992) 162-164 © Hippokrates Verlag Stuttgart
zation. There were no myoclonias. Clinical examination disclosed axial hypotonia, but neither focal deficit, nor dysmorphia, cutaneous naevi, visceral, or fundoscopic abnormalities. Interictal EEG recording at the age of 5 weeks demonstrated suppression bursts during sleep, consisting of bursts of slow waves, sharp waves and spikes asynergie on both hemispheres and alternating with 3-5 sec. periods of suppression of activity (Fig. 1). letal tracing showed diffuse suppression of activity during 20 seconds followed by rhythmic slow waves on the left hemisphere lasting one minute. CSF was normal including protein concentration (0.64 g/l.) electrophoresis of proteins, cell density (5/mm3), and serology for toxoplasmosis, rubella, measles and cytomegalovirus. CT scan disclosed no abnormalities. The clinical condition worsened, the patient suffering several seizures a day. She died at the age of 2 months. General pathological examination was normal. The brain weighed 485 g. Macroscopically, no significant abnormalities were noticeable, except for a slight widening of the sulci particularly in the left hemisphere. The cerebellum appeared to be normal. Microscopically, after celloYdin embedding and Nissl's staining, large seetions of the hemispheres showed only mild modifications at the sustentoriallevel, which consisted of nerve cellloss in the depth of several sulci, particularly in the temporal lobe. The crown of the gyri was spared and some gyri had a mushroomlike shape, but no gliosis was present. At the infratentoriallevel, there were remarkable anomalies involving both dentate nuclei and olives. The dentate nuclei had lost' their normal shape and displayed a plump profile (Fig.2). In place of an undulated ribbon, the dentate nuclei consisted of a gray matter penetrated by few myelinated fibers. The hilus itself was difficult to identify and poorly myelinated. Numerous neurones could be recognized in this gray mass, exhibiting a size (15 to 30 Ilm.) and shape (multipolar or spindIe shaped) of neurones encountered in anormal dentate nucleus. There was no decrease in neuronal density but the distribution of nerve cells was completely disorganized. They were grouped in small islands separated by thin myelinated fibers. Both olivary nuclei also showed a major dysplasia (Fig. 3). They had a greatly simplified shape, resembling a hook. Within both inferior olivary nuclei, indeed, the normal undulations had disappeared and there were thickening of segments of the nuclei, with obliteration of their undulated profiles. In spite of this pattern which is similar to immature olives, the size and the shape of the neurones were roughly spared. Neuronal density was quite normal, but distribution was COffi-
Downloaded by: Universite Laval. Copyrighted material.
lService de Neuropediatrie and 2INSERM U 29, Höpital Saint Vincent de Paul, 82 Avenue Denfert Rochereau, Paris cx 14, France
Suppression Bursts and Olivary-Dentate Dysplasia
Neuropediatrics 23 (1992)
163
v
DEtT t ,.
'v\J\~
DEtT R -4
-+ I + ~
I I I ~ I I 1 , l ~~ , ~
4- ! (... ~+
l I ~ 4 I 4 4 I I , ~ I I , t I , ~ l. t t , ~ -l1~ I , I I I I 4 ~ I I I ~. 4 ~ , ~ I t I , ~ , I ~ ( I I i ~ ~ , I I • I' , , I I I , ,
DUC_.H.
5 weelcs
°
+, , 4 4 ,
SVP 59 412
(\;'0,
Fig. 1 Interictal electroencephalographic tracing demonstrating suppression bursts during sleep. Notice that the suppression of activity is asynchronous on both hemispheres.
Fig.3 Inferior olivary nuclei displaya coarse profile without normal undulation. The dorsal and medial accessory nuclei are normal. Woelcke X6.
..... Fig.2 The dentate nucleus consists of a broad band without undulations. Notice the disappearance of the external granular layer in the cerebellar cortex. Luxol fast bl ue X6.
Downloaded by: Universite Laval. Copyrighted material.
PNO
O. Robain and O. Dulac
Neuropediatrics 23 (1992)
in the development. Anomalies of the dentate nuclei are less frequently reported than olivary ones, and they have mainly been seen in cerebellar malformations, for example: agenesis of the hemispheres and agenesis of the vermis (3, 14). The relationship between the epileptic encephalopathy and the subtentorial dysplasia is difficult to determine, since this type of malformation does not produce epilepsy when restricted to the subtentorial regions, such as in Dandy-Walker or ]oubert's disease. This contrasts with Zellweger's disease (2) which is highly epileptogenic but include olivary dysplasia and anomalies of the cerebral cortex probably responsible for the seizures. In our case, supratentorial anomalies were too mild to seem significant, but this is also often the case in older epileptic patients.
Fig. 4 Inferior olivary nucleus showing the marginal disposition of the neurons. Nissl X30.
pletely disorganized. Small clusters of neurons were arranged along the margins of the nuclei (Fig. 4) and were separated by myelinated fibers. No gliosis was present. This modification was restricted to the principal inferior olivary nuclei. Both the dorsal and medial accessory olives appeared to be normal. No heterotopias of olivary neurones were visible. In addition to this major modification of dentate and olivary nuclei, the brain stern and the cerebellum appeared to be normal, except for a disappearance of the external granular layer in the cerebellar cortex which normally persists up to 9 months (8). Discussion We have presented a case of neonatal epileptic encephalopathy with suppression bursts (SB) associated with olivo-dentate nucleus dysplasia. Early epileptic encephalopathies with SB have most severe prognosis (10), and two different etiological conditions are listed in the Classification of the International League against Epilepsy (5). Early Myoclonic Encephalopathy (1) suggests a set of inherited metabolie disorders, most of which remain unrecognized. Patients without myoclonias often exhibit brain malformations, as shown by Ohtahara (12). Aicardi's syndrome (4) and hemimegalencephaly (13) are presently the main types of malformations that exhibit SB in a sizable proportion of cases. The olivo-dentate abnormality we report here is a third type of malformation, not disclosable by neuroradiological investigations and thus should stimulate the performance of complete neuropathological investigation when a patient has died from a disease with this type of clinical and EEG pattern. Olivary dysplasia in the present case, consists of unundulated massive olives. This aspect has been observed in several malformations (trisomy 8, trisomy 13, holoprosencephaly, ]oubert's syndrome, cerebellar hemispheres or vermis aplasia) (7). This type of dysplasia is usually considered as an arrest of development since the undulations of the olivary neuronal ribbon should be present at 250-300 mm length (11), corresponding to the 5th to 6th month of fetal life. However, this understanding is not consistant with the other findings in our case, since the neurons themselves have continued to develop, and the lack of external granular layer suggest an advance
Whatever, the relationship between the subtentorial dysplasia and the epilepsy, it does seem to be relevant since similar cases have been reported (9). Therefore, olivo dentate malformation is probably one of the etiological conditions included in the Ohtahara syndrome. Further data should be gathered in order to determine etiology, given the fact that symmetrical malformations such as agyria of the Bielchowsky and of the Walker types, do exhibit a risk for familial recurrence.
References Aicardi,].: Early myoclonic encephalopathy. In: Roger,]. et al: Epileptic Syndromes in Infancy, Childhood and Adolescence. London and Paris, 1. Libbey Eurotext (1985) 12-22 2 Aubourg, P., O. Robain, F. Rocchiccioli et al: The cerebro-hepato-renal (Zellweger) syndrome: lamellar lipid profiles in adrenocortical, hepatic mesenchymal, astrocyte cells and increased levels of very long chain fatty acids and phytanic acid in the plasma. J. Neurol. Sei. 69 (1985) 9-25 3 Buissonniere, R. F., V. Storni, O. Robain, G. Ponsot: Syndrome de Joubert. Ann. Pediatr. 37 (1990) 151-156 4 Chemie,].].,]. Aicardi: The Aicardi syndrome. Recent Adv. Epilepsy 3 (1986) 189-210 5 Commission on classification and terminology of the internationalleague against epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30 (1989) 389-399 6 Dulac, 0., P. Aubourg, P. Plouin: Other epileptic syndromes in neonates. In: Roger,]. et al: Epileptic Syndromes in Infancy, Childhood and Adolescence. London and Paris, J. Libbey Eurotext, (1985) 23-29 7 Friede, R. L.: Dating the development of human cerebellum. Acta Neuropathol. 23 (1973) ~8-58 8 Friede, R. L.: Developmental Neuropathology (second ed.). Berlin, Heidelberg, Springer-Verlag (1989) 347-371 9 Harding, B.: Olivary dysplasia. Colloquium of European Paediatric Neuropathology Group. June 26-27, UK, Wallingford (1990) 10 Maheshwari, M. C., P. M. ]eavons: The prognostic implications of suppression-burst activity in the EEG in infancy. Epilepsia 16 (1975) 127-131 11 MurojUshi, K.: Normalentwicklung und Dysgenesien von Dentatum und Oliva inferior. Acta Neuropathol. 27 (1974) 317-328 12 Ohtahara, s.: Clinico-electrical delineation of epileptic encephalopathies in childhood. Asian Med. J. 21 (1978) 7-17 13 Paladin, F., C. Chiron, O. Dulac, P. Plouin, G. Ponsot: Electroencephalographic aspects of hemimegalencephaly. Dev. Med. Child Neurol. 31 (1989) 377-383 14 Robain, 0., O. Dulac, C. Lejeune: Cerebellar hemispheric agenesis. Acta Neuropathol. 74 (1987) 202-206 1
O. Robain, M. D. INSERM U29 Höpital Saint Vincent de Paul 82 Avenue Denfert Rochereau F-75674 Paris Cedex 14, France
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