Case Report: Early Neonatal EEG in Two Infants with Pallister Killian Syndrome (PKS)

Introduction

PKS is a rare genetic disorder with an incidence of one per twenty-thousand births^1,2. It is characterised by a distinct phenotype and can be associated with several complications. Epilepsy is a common neurological sequela, usually presenting in childhood. Few cases of neonatal onset seizures have been described to date and no detailed electrographic descriptions are available.

Here, we present two cases with similar phenotypical characteristics along with early EEG findings. Identification of distinctive electrographic features can aid in recognition and diagnosis of Pallister Killian Syndrome. This can ultimately lead to earlier targeted interventions. Genetic counselling can be provided, where appropriate, along with earlier engagement with multi-disciplinary teams.

Case presentations

Case one

Case 1 was a term female infant born via emergency lower segment caesarean section (LSCS) for failure to progress at forty one weeks and five days gestation. She was the first child of non-consanguineous Caucasian parents. An antenatal MRI identified mild left ventriculomegaly and shortened long bones. At birth, she had dysmorphic features; microphthalmia, a high arched palate, low set ears, micrognathia and roving eye movements. She had a good suck, but no rooting or grasp, she had an asymmetrical Moro reflex and increased upper limb tone with fisting. Reflexes were present but she had marked central hypotonia. She was admitted to the neonatal unit with hypoglycaemia (1.1mmol/L) and central hypotonia. At fifty-seven hours of life, she had generalised clonic seizures during which blood sugar was normal. Continuous video EEG (cEEG) monitoring (Nihon Kohden) was commenced using scalp electrodes at positions F3,F4,C3, C4,T3,T4,O1,O2,CZ at 58 hours. ECG and respiratory movements were also recorded simultaneously. At commencement of EEG recording, three electrographic-only seizures were captured that had an abrupt onset and termination (Figure 1a). Whilst, the first seizure was brief in duration (44 seconds), the second two each lasted over two minutes. Seizures consisted of sharp and slow wave complexes with onset in the left or right central regions with secondary generalisation. Sleep wake cycling was present but poorly defined over the initial recording but became better defined as time progressed. Quiet sleep (QS) phases were characterised by dysynchrony with long periods of suppression (Figures 1b and 1c). A loading dose of 20mg/kg of Phenobarbitone was administered and the infant remained seizure free in the neonatal period. Follow up EEG on day eleven showed an encephalopathic background with prolonged periods of suppression, absence of sleep-wake cycles and ongoing dysynchrony.

Figure 1.

(a–f) EEG recordings. (EEG displayed at sensitivity 70μV/cm, time-base 15mm/sec. aEEG displayed at 6cm/sec). (a) Case One: Electrographic seizure at 59 hrs of life consisting of generalised sharp and slow wave complexes with clear aEEG correlate (*). Sleep-wake cycling poorly defined at the beginning of the recording but improves over time as demonstrated on the aEEG (**). (b) Case One: Dysynchrony in Quiet Sleep at 61hrs of life. (c) Case One: Prolonged discontinuity in Quiet Sleep at 61 hrs of life. (d) Case Two: cEEG at 56 hrs of life showing prolonged suppression in Quiet Sleep. High amplitude activity with multifocal sharp waves. (e) Case Two: Myoclonic jerk (during Quiet sleep at 35 hours of life showing high amplitude movement activity followed by brief suppression. (f) Case Two: Active Sleep showing continuous activity but excessively low frequencies on the background pattern for gestational age at 37 hours of life (example highlighted).

Cranial ultrasound on day one was unremarkable. MRI on day three showed thinning of the corpus callosum with blunting of the rostrum and splenium (Figure 2a), bilateral perisylvian polymicrogyria (Figure 2b) and significant diffusion restriction in the periventricular regions bilaterally (Figure 2c). Echocardiogram on day seven revealed an Atrial Septal Defect(ASD) Secundum. She failed otoacoustic and auditory brainstem new-born hearing screen on day twenty-nine and subsequently required bilateral hearing aids. Given the constellation of features described, a genetic disorder was considered the most likely diagnosis. Microarray identified a gain in the short arm of chromosome 12 at 12p13.33 to p11.1, consistent with PKS.

Figure 2.

(a–f)- Brain MRI. Case One: (a) Thinning of the body of the corpus callosum. The rostrum and splenium appear blunted, likely representing partial dysgenesis, (b) Bilateral polymicrogyria in the posterosuperior aspects of the sylvian fissures, (c) Marked restriction within the periventricular regions bilaterally - involving the heterotopic grey matter. Case Two: (d) Sagital T1 View: Partial agenesis of Corpus Callosum posteriorl, (e) Coronal T2 View: Mild bilateral perisylvian microgyria, (f) Axial T2 View: Bilateral Cystic dilatation of vestibules.

At twelve months, she developed myoclonic seizures characterised by single jerks of the upper and lower limbs symmetrically accompanied with eye rolling or deviation to the left. EEG at the time showed spike and high amplitude slow wave discharge with a slower background pattern than expected. She was commenced on Levetiracetam but despite high dose treatment, seizures continued so she was changed to a combination of Sodium Valproate and Clobazam. Clobazam was discontinued due to over sedation. Current treatment at twenty one months is Sodium Valproate monotherapy and she is experiencing ten to twenty brief myoclonic jerks daily. She has global developmental delay.

Consent

Written informed consent for publication of the clinical information was obtained from both children’s legal guardian.

Discussion

In our cases, herein described, an early genetic diagnosis was confirmed in both. The distinctive EEG features and abnormal backgrounds guided clinicians to consider an underlying genetic disorder early in the management process. Appropriate physicians and multi-disciplinary teams were involved in the care of both infants from an early stage and allowed for future focused, patient-specific follow-up.

PKS is a rare genetic syndrome secondary to a mosaic tetrasomy of the short arm of chromosome 12³. It is characterised by facial dysmorphism, congenital anomalies, global developmental delay and epilepsy. Our cases both presented in the neonatal period with varying combinations of the classical phenotype along with congenital anomalies (partial agenesis of the corpus callosum, a Patent Ductus Arteriosus and bilateral hearing impairments) and early epileptic encephalopathy. The initial hypoglycaemic episodes seen in both cases have been previously described in neonates with PKS⁴ along with distinctive neuroradiology features of corpus callosum dysgenesis, microcephaly and perislyvian polymicrogyria⁵, cardiac defects⁶ and hearing impairment^7,8 These cases are the earliest descriptions of EEG features of PKS that have been reported to date.

The incidence of epilepsy in association with PKS varies from 42%–72%^8–10. Neonatal seizures are rare and only two reports have been published in the literature. The first was that of a neonate who had ‘staring episodes’ and myoclonic jerks but no further information was provided¹⁰. The second case was that of a premature infant born at thirty two weeks gestation, which was also associated with respiratory distress and hypoglycaemia; similar to our second case¹¹. No details were available regarding seizure semiology or EEG characteristics in this case, however seizures were well controlled up until recurrence at fifteen months of age. Candee et al. report in their cohort, seizure onset by two years of age in 56% and by six years in 96% along with an association between PKS and refractory seizures⁹. In a recent case series of thirteen Italian children with PKS, infantile spams were most common, with the earliest onset of seizures occurring at seven months of age and only four cases having seizure onset within the first twelve months of life⁴.

Seizure semiology in PKS can vary from generalised, focal, myoclonic or spasms^4,12–16. Myoclonic epilepsy is common in PKS, having been reported in a case series of three patients by Ricci¹⁶, 15/27 patients in Candee’s cohort⁹, 9/22 by Blythe⁸ and only 2/13 by Giordano⁴. The earliest report of myoclonic seizures describe onset at ten months⁴. EEGs show slow and disorganised background activity and frequent bursts of diffuse or multi-focal sharp waves⁴. Seizures can be triggered by low frequency photic stimulation. Ricci et al. describe myoclonic epilepsy with photosensitivity in three patients. Both spontaneous and photo-induced jerks at low frequencies (1–6Hz) were recorded with spike and slow wave complexes in all three patients. Our electrographic recordings (though recorded much earlier) appear similar to previous reports with low frequency and multifocal sharp waves. Sleep-cycling was evident in the earliest EEG recordings of our patients though the background was excessively discontinuous in quiet sleep and excessively slow in active sleep for gestational age (Figure 1a and 1b). The best pharmacological success for seizure control has been achieved with Sodium Valproate or Levetiracetam or a combination of both^4,9,16. Our first case has trialled both to date, whilst the second is being managed successfully on Levetiracetam alone.

These cases highlight the importance of early consideration of an underlying genetic disorder in infants presenting with highly abnormal background EEG patterns in the neonatal period. Focused diagnostic methods and subsequent optimal targeted treatments may lead to improved management and future outcomes. Early directed treatment is key in the management of neonatal seizures in an effort to minimise high seizure burden and the administration of multiple anti-epileptic drugs, both of which are associated with poor outcomes¹⁷. Furthermore, genetic counselling may be required, where appropriate, for affected families.

To conclude, PKS is a rare chromosomal disorder characterised by epilepsy, congenital anomalies, global development delay and facial dysmorphism. Here, we have described, the earliest EEG features associated with neonatal seizures in PKS. Epilepsy types vary, with spasms and myoclonic seizures most common in infancy. Early electrographic features of myoclonic seizures in infancy are characterised by an encephalopathic pattern with frequent bursts of diffuse or multi-focal sharp waves. Seizures can be refractory with most pharmacological success achieved with Sodium Valproate or Levetiracetam or a combination of both^4,9,16.

Data availability

All data underlying the results are available as part of the article and no additional source data are required.