Melanie A. McNally MD, Julia Johnson MD, Thierry A.G.M. Huisman MD, Andrea Poretti MD, Kristin Baranano MD, PhD, Ahmet A. Baschat MD and Carl E. Stafstrom MD, PhD. SCN8A epileptic encephalopathy: Detection of fetal seizures guides multidisciplinary approach to diagnosis and treatment . Pediatric Neurology. In press.
SCN8A mutations are rare and cause a phenotypically heterogeneous early onset epilepsy known as early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558). There are currently no clear genotype-phenotype correlations to help guide patient counseling and management.
We describe a patient with EIEE13 ( de novo heterozygous pathogenic mutation in SCN8A - p.Ile240Val (ATT>GTT)) who presented prenatally with maternally reported intermittent, rhythmic movements that, when observed on ultrasound, were concerning for fetal seizures. Ultrasound also revealed abnormal developmental states. With maternal administration of levetiracetam, the rhythmic fetal movements stopped. After birth, the patient developed treatment-refractory multi-focal epilepsy confirmed by electroencephalogram. Neuroimaging revealed restricted diffusion in the superior cerebellar peduncles, a finding not reported previously in EIEE13.
This is the first reported case of EIEE13 associated with clinical prenatal-onset seizures. Ultrasonography can be useful for identifying fetal seizures, which may be treatable in utero . Ideally, the clinical approach to fetal seizures should involve a multidisciplinary team spanning the pre- and postnatal course to expedite early diagnosis and optimize management, as illustrated by this case.
From the article
Around 26 WGA, the mother reported intermittent, rapid, repetitive, “jerky” fetal movements distinct from baseline fetal movements…
Fetal behavioral state assessment, a well-established obstetrical tool by which fetal heart rate, eye movements, limb movements, and other behavioral activity are assessed and quantified by ultrasound, revealed abnormalities in behavioral state development concerning for central nervous system dysfunction. Specifically, there were rapid eye movements during quiescence, rapid transition between states 1F (quiescence/quiet sleep) to 4F (vigorous body movements) 3 within 5 seconds, and dissociation of body movements, eye movements, and fetal heart rate variables – a profile consistent with a state of global cerebral hyperexcitability.
Serial ultrasounds also revealed epochs of rapid, repetitive movements of the extremities and trunk concerning for seizure activity. Interdisciplinary consultations with fetal therapy, pediatric neurology, and neonatology resulted in a recommendation to start the mother on anti-seizure drug (ASD) therapy. Levetiracetam (LEV) was begun at 500 mg BID, a standard adult dose, in an attempt to suppress the suspected fetal seizures. LEV was chosen because of its extensive transplacental transport, rapid titratability, and favorable side effect profile for both mother and fetus.
On LEV, the mother reported a dramatic decrease in the jerky fetal movements and any residual abnormal repetitive movements occurred only prior to the next scheduled dose, prompting dose increases to 500 mg TID and then to 750 mg TID. On LEV 750 mg TID, only rare jerky movements were reported, but some episodes concerning for seizure were captured on ultrasound three days before delivery.
Her physical examination was notable for generalized edema and multiple dysmorphic features including low-set ears, high arched palate, hypoplastic supraorbital ridges, bilateral arm and leg contractures (arthrogryposis), and bilateral clenched fists with overlapping digits. Her weight was at the 98 th percentile, length at the 5 th percentile, and head circumference at the 90 th percentile for gestational age. Her neurologic exam revealed poor reactivity, axial hypotonia, and subtle but frequent low-amplitude flexion movements at hips and shoulders, contractions of abdominal muscles, and lip smacking.
Video-EEG revealed continuous cerebral activity with moderate reactivity, good spontaneous variability, and symmetric waveforms between hemispheres with normal neonatal physiological patterns including frontal sharp transients. The flexion movements and abdominal contractions did not correlate with seizure activity on EEG. However, a few hours after birth, generalized tonic seizures occurred involving posturing of all extremities that correlated with build-up of bilateral (left maximum) frontal sharp waves. Additional multifocal electrographic seizures were noted without clinical correlate…
Whole exome sequencing revealed a de novo heterozygous mutation in SCN8A (p.Ile240Val(ATT>GTT)) that was considered to be pathogenic. Neither parent carried this mutation…
Seizures proved refractory to multiple medications. LEV was initiated and titrated up to 60 mg/kg/day and phenobarbital was increased to 6 mg/kg/day with phenobarbital levels maintained in the 50-60 mcg/mL range. Seizure clusters recurred several times per week, with seizure semiology consisting of bilateral tonic extension of upper extremities and rhythmic oromotor movements associated with tachycardia and blood oxygen desaturation. Once the mutation was identified, oxcarbazepine was added and titrated to high dose (80 mg/kg/day), because of reports that sodium channel blockers have been beneficial, at least transiently, in other patients with SCN8A mutations. Our patient’s seizures persisted so phenytoin was added and titrated to high therapeutic levels (15-20 mcg/mL), but still without improvement in seizure control. Lamotrigine, a third sodium channel blocker, was slowly uptitrated to 2 mg/kg/day, with reduction in seizure clusters to about 1-2 per week. Throughout her neonatal course, seizure exacerbations often responded transiently to phenobarbital boluses, despite a reported lack of consistent efficacy of GABA agonists in patients with SCN8A mutations. At 6 months of age, the patient was discharged to a community hospital on a combination of phenytoin, oxcarbazepine, phenobarbital, lamotrigine, and continued to have 1-2 seizure clusters per week, managed with intermittent rectal diazepam…
When considering an ASD for treatment of fetal seizures, several factors should be considered including placental transfer of the ASD, risk of teratogenicity, maternal tolerability, changes in pharmacokinetics during pregnancy, and ability to rapidly titrate.