Description

The case is of a male infant born term via elective lower segment caesarean section due to breech presentation, at 38+5 weeks as a product of uneventful gestation. The mother was in her early 20s, gravida 2 para 1, with no significant medical history. She did not have any risk factors for infection. There was no family history of convulsions or epilepsy. The parents are not consanguineous. She was seen in the antenatal clinic 1 day before the delivery with no maternal or fetal concerns. Antenatal workup was remarkable for the third-trimester ultrasound at 27+6 weeks showing the following: ‘prominent fetal cerebral ventricles, still within normal values, for follow-up’. Otherwise, her baby was growing normally with normal amniotic fluid and Doppler indices. She had no further imaging or special follow-up under the fetal medicine unit. On the delivery day, she was admitted electively for caesarean section under spinal anaesthesia. She had uneventful delivery and perinatal course.

The infant was born cyanosed, non-vigorous with a weak cry and moderate respiratory distress. He required continuous positive airway pressure (CPAP) with positive end-expiratory pressure of 5 and a fraction of inspired oxygen of 30%. Apgar scores were 8 and 9 at 1 and 5 min, respectively.

He was admitted to the neonatal intensive care unit (NICU) as a case of transient tachypnea of the newborn. On admission, he was found to have mild tachypnea with some dysmorphic features including prominent occiput, hypertelorism, clenched hands, micrognathia, high-arched palate and short prominent chest bones, clenched fists with overlapping fingers and rocker bottom feet. Regarding his respiratory support, he was weaned from CPAP to a nasal cannula with an oxygen flow of 3 L/min. X-ray showed cardiomegaly with changes impressive of respiratory distress syndrome. Ultrasounds of the skull and abdomen were done to rule out congenital anomalies. Ultrasound skull showed capacious ventricles with irregular ependymal wall and choroid plexuses. MRI was recommended to rule out disorders of migration. Ultrasound of the abdomen was unremarkable.

On the second day of life, the infant was found to be jittery with increased tone. In addition, he was found to have a soft systolic murmur. Echocardiography showed a large 8.6 mm II atrial septal defect with a left-to-right shunt, mild tricuspid regurgitation and small 2.2 mm patent ductus arteriosus, with mainly left-to-right shunt and signs of persistent pulmonary hypertension. Microarray and fluorescence in situ hybridisation (FISH) analysis were ordered as workup features of trisomy 18.

On the third day of life, the baby was found to have abnormal multifocal movements with lip-smacking (video 1). He was loaded with phenobarbitone 20 mg/kg once. Cerebral function monitoring showed abnormal seizures activity (figure 1). The neurology team pointed out that the baby has dysmorphic features and suspected migration disorder findings on ultrasound, which put the infant at risk of refractory seizures. They decided to load the infant with levetiracetam 40 mg/kg, followed by a maintenance dose of 30 mg/kg/day every 12 hours. He continued to have seizures on levetiracetam and was given phenobarbitone 10 mg/kg. However, he continued to seize and was intubated for refractory seizures. On reassessment, he was found to have brisk reflexes and bilateral clonus. The neurology team recommended starting a midazolam drip besides levetiracetam maintenance of 30 mg/kg/day and phenobarbitone maintenance of 5 mg/kg/day after loading. Two hours of electroencephalography (EEG) was done while the patient was on a midazolam drip of 3 μg/kg/min. It showed abundant multifocal epileptic activities. Midazolam drip was increased to reach 15 μg/kg/min which decreased >50% of seizure activity. In addition, a levetiracetam maintenance dose was given during the EEG recording. Considering the worsening of the patient’s clinical condition, a blood culture was taken and he was started on ampicillin and amikacin. In addition, he was covered with the following antimicrobials for possible central nervous infection: benzylpenicillin (meningitic dose), gentamicin and acyclovir.

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Figure 1

Cerebral function monitoring shows abnormal seizures activity. aEEG, amplitude-integrated electroencephalography; EEG, electroencephalography.

On the fourth day of life, the neurology team recommended continuing midazolam drip with a maximum dose of 18 μg/kg/min, increasing levetiracetam dose to 60 mg/kg/day, increasing phenobarbitone to 7 mg/kg/day and starting biotin 10 mg two times per day and pyridoxine 100 mg once a day. The patient was transferred to a tertiary care hospital as a case of intractable seizure requiring the maximum doses of three antiepileptic drugs (ALDs), for continuous EEG monitoring, and MRI after stabilisation and follow-up of genetic and metabolic workup.

At the tertiary care hospital, a repeat EEG was suggestive of severe epileptic encephalopathy with intermittent frequent epileptic activity more on the right side but appears all over the brain in a multifocal distribution, indicating severe brain abnormality. MRI of the brain showed the following: gross supratentorial and infratentorial malformation process as well as non-acute findings of the deep grey matter and white matter insult as follows (figure 2):

• Lissencephaly (LIS) with supratentorial volume loss and thinning of the corpus callosum.

• Basal ganglia volume loss, likely related to antenatal insult.

• Bilateral white matter venous injury/infarct also noted. No evidence of acute insult.

• Small pons and small dysplastic cerebellum.

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Figure 2

MRI of the brain shows lissencephaly, supratentorial volume loss, thinning of the corpus callosum, basal ganglia volume loss, small pons and small dysplastic cerebellum.

These findings were suggested to have a genetic aetiology, an early antenatal insult-like intrauterine infection such as cytomegalovirus (CMV) or ischaemic insult, especially given the superimposed basal ganglia and white matter findings.

The patient continued to have ongoing seizures in the form of jerking both arms, sometimes associated with eye blinking, frowning movements and excessive sucking and lip-smacking with a frequency of 4–5 times per hour for a maximum duration of 1–2 min while being covered with levetiracetam, phenobarbital, pyridoxine and topiramate. Repeated chest X-rays showed normal cardiac and thymic shadows. Repeated echocardiography was grossly normal, apart from an aneurysmal septum. The patient failed the hearing screening test. Metabolic workup showed a slightly elevated ammonia level of 104 and a normal lactate level. Toxoplasmosis, rubella, CMV, herpes simplex and HIV (TORCH) screen were remarkable for CMV immunoglobulin G (IgG) positive results. Genetic workup (DNA banking, FISH and microarray) came out normal and excluded trisomy 18 abnormality. Genome-wide oligonucleotide array-based comparative genomic hybridisation (aCGH) analysis was performed with the use of the Human Genome CGH Microarray kit (OGT). The array contains ~1 80 000 DNA oligonucleotide probes spaced approximately 30–37 kb apart genome-wide. The probe sequences and locations are from the human genome build (GRCh37). It yielded a normal hybridisation pattern for the genomic DNA obtained from the patient’s peripheral blood sample. The aCGH analysis did not identify any DNA copy number changes of known clinical significance in the patient. FISH analysis of a minimum of 200 interphase nuclei per probe for rapid detection of the copy number of chromosomes 18 was performed. The hybridisation signal pattern observed was normal, according to the performance standard. Whole exome sequencing was requested and it came back negative. The patient was extubated after 8 days of intubation. Antimicrobials were stopped after negative cultures and PCR. The patient was shifted from oral feeding to nasogastric tube feeding considering his frequent seizure activity and unsafe oral trial as per the assessment of the speech-language pathology team, with a plan of gastrostomy tube insertion for long-term feeding. The family refused gastrostomy tube insertion and the patient was kept on nasogastric tube feeding.

At 2 months of age, the patient was stepped down from NICU to the neurology floor after stabilising his condition on oral phenobarbitone 27 mg every 12 hours, oral topiramate 20 mg every 12 hours and oral levetiracetam 120 mg every 12 hours, for continuity of care and parental education. On the neurology floor, the patient was stable having seizures daily almost 3–40 episodes that last for seconds. Seizures were occasionally associated with desaturation that requires blow-by oxygen. The patient was discharged home after 12 days on oral phenobarbitone 30 mg every 12 hours, oral topiramate 25 mg every 12 hours and the same dose of oral levetiracetam 120 mg every 12 hours, rescue medications with neurology follow-up.

In summary, this is a case of a term male baby with an uneventful antenatal course, apart from prominent fetal cerebral ventricles, still within normal values. Postnatally, he was found to have dysmorphic features, upper motor neuron signs, multifocal abnormal movements and refractory to multiple different ALDs. Workup came remarkably for severe brain malformation and LIS, CMV IgG positive and elevated ammonia of 104. Seizures were stabilised at the frequency of daily 3–40 episodes of few seconds duration, on three ALDs, phenobarbitone, topiramate and levetiracetam.

The neonatal period has a considerably higher incidence of seizures than any other time of life and the term infant is at the highest risk of seizures.1 Neonatal seizures occur in approximately 1–5 per 1000 live births in the USA and neonatal seizure is the most common neurological emergency.2 3 The fact that neonatal seizures can be extremely difficult to control with the currently available AEDs and can lead to long-term neurologic complications has been repeatedly highlighted in the literature.1 4 This is because the neonatal brain has increased excitability, decreased efficacy of neuroinhibitory mechanisms and enhanced potential for the inflammatory response to seizures.1 5 Symptomatic neonatal seizures are most commonly caused by hypoxic-ischaemic encephalopathy, which can result from birth asphyxia or respiratory distress. The next most common aetiologies include cerebrovascular disorders, infectious entities and cortical malformations. Malformations of cortical development that are frequently present with early-life seizures include LIS, polymicrogyria, focal cortical dysplasia and tuberous sclerosis.1 Conventional, prolonged, continuous video EEG is the gold standard for detecting seizures.2

In terms of management, it has been shown that phenobarbital and phenytoin control seizures only in less than 50% of EEG-confirmed neonatal seizures.1 On the other hand, Sirsi et al suggested that midazolam may be considered a safe and effective ALD in refractory neonatal seizures of diverse aetiologies.6 Similarly, Sheth et al suggested that because more than one-third of all neonatal seizures are refractory to high-dose phenobarbital and phenytoin, midazolam administered by continuous intravenous infusion may be a valuable adjunctive therapy.7 In addition, Maytal et al concluded that lorazepam may be effective in the treatment of neonatal seizures refractory to phenobarbital.8

Newer anticonvulsant medications such as topiramate and levetiracetam have been reported to improve acute neonatal seizures.1 Barr et al reported a case in which the new ALD lamotrigine induced rapid and sustained control of seizures of a newborn infant who had seizures of unknown aetiology, refractory to phenobarbitone, phenytoin, midazolam, clonazepam and vigabatrin.9 In addition, topiramate has been recommended as a useful choice in refractory neonatal seizures due to its efficacy for both seizure control and neuroprotection.10 Lidocaine can be effective in refractory neonatal seizures. However, it has limited use because of potential cardiac toxicity.1 In general, Maartens et al suggested that the number of ALDs probably reflects increased seizure burden and poor outcomes.4 Di Rosa et al reported three newborns with neonatal seizures refractory to first-line and second-line ALDs and failed therapy with levetiracetam, phenobarbital and midazolam. They were successfully treated with intravenous hydrocortisone. Modulation of brain inflammation triggered during prolonged epileptic activity has been thought to potentially explain the beneficial effects of anti-inflammatory treatment.3

LIS is a malformation of cortical development with broad gyri, shallow sulci and thickened cortex characterised by developmental delays and seizures. The recent advancement in molecular genetics has led to the identification of 31 LIS-associated genes with an overall diagnostic yield of over 80%.11 12 It can be graded clinically and radiologically as mild (subcortical band heterotopia), moderate (pachygyria) and severe (agyria). Treatment is symptomatic and supportive aiming to improve the caloric intake of nutrients and achieve steady weight gain and the use of anticonvulsants to prevent or control seizures. A genetic referral is recommended.13