Malignant migrating partial seizures in Aicardi syndrome
* Correspondence to last author at University Hospitals, KU Leuven, Department of Paediatric Neurology, Herestraat 49, 3000 Leuven, Belgium.
This article reports on a female infant with Aicardi syndrome presenting with malignant migrating partial seizures from her first day of life. Initially, unilateral tonic seizures were seen with contralateral ictal electroencephalogram findings. Typically, these tonic seizures were accompanied by head and eye deviation and were followed by a tonic seizure on the other side of the body. At 6 months of age she developed epileptic spasms. She showed no motor development, did not respond to eye contact, and was nasogastric tube-fed. The epilepsy syndrome in this child is refractory to antiepileptic treatment and there is no psychomotor development. This case expands the phenotype of this catastrophic epileptic encephalopathy and suggests that the corpus callosum is not necessary for the ‘migration’ of partial seizures in this syndrome.
Twelve years ago Coppola et al.1 first described 14 infants with malignant migrating partial seizures in infancy. This age-related epileptic encephalopathy is characterized by seizure onset between the first week of life and 7 months of age.1,2 In its typical form, a partial seizure starts in one brain region and is followed by another seizure arising from another region in the same or in the other hemisphere. In an individual child, the sequence of seizures is sometimes very stereotypical.
At present, there is no detectable cause of malignant migrating partial seizures. Brain imaging studies do not indicate cortical malformations. Metabolic and genetic studies remain negative.3 This condition has a very poor prognosis with severe psychomotor developmental delay, and intractability to antiepileptic drugs4–7 and corticosteroids.6
Aicardi syndrome8 is almost exclusively seen in females (with the exception of males with two X-chromosomes9) and is an X-linked disorder characterized by severe learning disability*, epileptic spasms, chorioretinal lacunae, agenesis of corpus callosum, and sometimes cortical malformations. Epileptic spasms are seen early in the course of the disease; later (>6mo), partial (mainly involving eyes and face) and generalized seizures can occur.
This case report describes a female with Aicardi syndrome who presented first with malignant migrating partial seizures and later with epileptic spasms. This case illustrates the expanding phenotype of this rare epileptic syndrome and shows that the corpus callosum presumably does not play a major role in the pathogenesis of migrating partial seizures. The parents of the child consented to the publication of this case report.
The patient is a 3-month-old female who experienced a seizure on the first day of her life. She was born to non-consanguineous parents. Pregnancy and delivery were normal.
The first seizure occurred when the mother started to feed her. She had a short lasting (<10 second) tonic contraction of the right arm. This seizure type was seen in the next days with increasing frequency (5–10 per day). At the age of 7 days, a seizure was seen for the first time over the left side of her body, but preceded by a tonic seizure on the right side. Phenobarbital treatment was started but without success.
When she was 5 weeks old, seizure frequency increased to 20 seizures per day that were still partial and ‘migrating’. At that time, the tonic seizures in the arms were accompanied by lateral deviation of head and eyes. These seizures were classified as frontal lobe seizures. Increasing feeding problems were noted; the child remained very hypotonic and no eye contact was observed at the age of 6 weeks. She was admitted to the hospital and valproic acid was started.
Extensive metabolic screening remained negative. Ophthalmological examination revealed a typical choreo-retinal lacuna in the right eye. Magnetic resonance imaging of the brain showed an absent corpus callosum, without other cortical malformations. At that time the diagnosis of Aicardi syndrome was made. Different antiepileptic drugs (vigabatrin, levetiracetam, topiramate, pyridoxine, clonazepam) were tried but without a lasting effect on the very frequent partial migrating seizures.
An interictal electroencephalogram (EEG) showed diffuse slowing of the background activity with multifocal (predominantly right temporal) epileptiform activity when awake and sleep.
Typically, at the age of 6 weeks, an initial ictal EEG pattern was seen over the left central region. The child showed a right-sided clinical seizure with tonic stiffening and clonic movements of the right arm and head deviation to the right side. After about 20 seconds, another ictal pattern started over the right frontal region. The child then showed a deviation of the head to the left with a seizure on the left side of her body. The whole episode lasted more than 80 seconds.
At the age of 6 months, epileptic spasms were seen, with generalized ictal EEG patterns. The background in the EEG was not organized, but did not show the typical hypsarrhythmic pattern.
The child did not show any progress in her development and still needs continuous tube feeding at the age of 1 year. She showed almost no spontaneous movement and there was no eye contact. She was admitted in the Epilepsy Centre, Pulderbos, Belgium for further (palliative) care.
To the authors’ knowledge, only 31 cases of malignant migrating partial seizures have been reported (Table I). The patient in this case report fulfils the criteria for malignant migrating partial seizures as originally proposed by Coppola et al:1 onset before 6 months of age, migrating focal motor seizures at onset, multifocal seizures which are intractable to conventional antiepileptic drugs, and severe psychomotor delay.
Table I. Reported cases of malignant migrating partial seizures
|Coppola et al.,1|
|1–10mo||Very frequent||B6, CBZ, CLZ, CNZ, CS, NZP, PB, PHT, STP, VGB, VPA||Two patients seizure free (STP + CNZ)||Three patients died; three resumed psychomotor development; the rest had severe delay|
|Okuda et al.,5|
|No data available||1: ACTH, B6, BR, CS, CNZ, DZP, KD, MDZ, PB, PHT, TRH, NZP, VPA.|
2: ACTH, BR, CBZ, IVIG, KD, MDZ, NZP, PB, PRM, TRH, VPA, ZNS
|1: >95% seizure reduction with BR.|
2: Seizure free with BR
|Both recovered neurological development|
|Wilmshurst et al.,13|
|Multiple seizures in cluster||1: ACTH, B6, CBZ, CS, CNZ, KD, LTG, NZP, PB, PHT, VGB.|
2: B6, CBZ, CS, LTG, MDZ, NZP, PB, PHT, VGB
|Intractable for both||1: Died at 9mo.|
2: Died at 12mo
|Veneselli et al.,7|
|1 and 2: very frequent in cluster.|
3: partial seizures
|ACTH, B6, CBZ, CNZ, PB, PHT, VGB, VPA||1–2 seizures per month to 3–4 seizures per year||1: Died at 7mo.|
2: Severe encephalopathy.
3: Severe learning disability
|Gross-Tsur et al.,4|
|Seizures in cluster||1: AEDs including B6, GBP, PB.|
2: Aggressive AED therapy including B6
|1: Seizure free at age 4y 6mo.|
2: Refractory seizures.
|1: Severe learning disability.|
2: Died at 18mo
|Marsh et al.,11|
|1d–3mo||10–35 per day||4 patients used 6 or more AEDs, 2 patients ACTH, 2 patients FA, 2 patients KD||1 patient seizure free, 2 patients infrequent seizures, 3 intractable||Profound psychomotor delay 1/5, one mild delay|
|Hemaimess et al.,10|
|1d (16h after birth)||1–186 per day||B6, BR, CNZ, LEV, LTG, MDZ, PB, PHT, VGB||One seizure per day||Died at 14mo|
|Hahn et al.,14|
|3mo||‘Frequent’||B6, FA, KD, OXC, LEV, PB, PP, steroids, SUL, TPM, VGB, VPA||Daily seizutes||No psychomotor development|
|Current study: Jocic-Jakubi and Lagae, n=1||1d||5–50 per day||B6, CNZ, LEV, PB, TPM, VPA||Intractable||Severe developmental delay|
Regarding the age of seizure onset (first day of life) the patient is one of the youngest together with the patient recently reported by Hemaimess et al.10
Despite the use of older and newer antiepileptic drugs, seizures in malignant migrating partial seizures typically remain intractable, as in this patient. Coppola et al. described a positive therapeutic response in two patients treated with a combination of stiripentol and clonazepam.3 Successful control with bromide in two patients with malignant migrating partial seizures has also been reported by Japanese authors.5 In a study by Marsh et al.11 one patient was seizure free, two had infrequent seizures, and three remained intractable. More recently, Hemaimmes et al.10 observed one patient with good seizure control (one seizure per day) treated with levetiracetam.
Among the 31 reported children in various studies, eight have died. The other patients have severe psychomotor delay, except patients reported by Marsh et al.11 In that study only one patient developed profound psychomotor delay. In this respect, malignant migrating partial seizures can be considered as a true epileptic encephalopathy. It is to yet be determined why these partial seizures are so devastating.
Whether the severe outcome is mainly related to the high seizure frequency at a young age, or to a specific epileptogenic process (which may also explain the ‘migration’ of seizures) remains to be elucidated. The present case illustrates that this syndrome can also be seen in children with a developmental brain abnormality, such as Aicardi syndrome. Unilateral retinal abnormality was identified in this case, as was described in two of 15 children in a recent review paper on Aicardi syndrome.12
As there is no (visible) corpus callosum in children with Aicardi syndrome, it indicates that the stereotypical ‘synchronization’ of the partial seizures over the two hemispheres does not require an intact corpus callosum. Therefore, it is difficult to understand how a first partial seizure on one side of the brain can induce another, seizure on the other side, and why this temporally-related pattern in a particular child remains the same in the course of the disease. It could be hypothesized that, for instance, the anterior commissure plays an important role in the ‘transfer’ of the seizure to the other hemisphere.
North American usage: mental retardation