Case Study: Newborn Seizures
The following case study was used by James P. Keating, MD, MSc, medical director, St. Louis Children’s Hospital Diagnostic Center, and his co-editor, Andrews J. White, MD, division director of pediatric rheumatology/immunology, as part of the “Patient of the Week” (POW) series. Many of the POW case studies cover uncommon illnesses, or common illnesses with unusual symptoms that can be overlooked. If you would like to be added to the POW e-mail distribution list, send an e-mail to jkeating@wustl.edu or white_a@wustl.edu.
Newborn medicine: Laura Al-Sayed/Alan Barnette (Cape Girardeau)
PL-2: Clayton Sontheimer
NICU: Barbara Warner and team
Neurology: Seth Perlman/Brad Schlaggar/Amy Viehoever
Au: Robyn Puente
A 22-day-old girl with CC: seizures
HPI:This full-term infant was noted to be stuporous and jittery and startled easily on DOL#1. On DOL#2, she was loaded with phenobarbital once for clinical suspicion of seizures. However, EEG soon after showed no evidence of seizure activity. She had some improvements until DOL#10, when she had marked worsening of her neurologic status with excessive irritability and jitteriness. She was reloaded with phenobarbital and started on maintenance phenobarbital. On DOL#12, she was clinically in status with severe metabolic acidosis and poor perfusion and was reloaded with phenobarbital with improvement in her cardiovascular status. At DOL#20, she had recurrent episodes ofbody tightening with arms and legs pulled in tightly accompanied by loud grunts, eye blinking, gagging and jerking movements. Abdominal distension and increased irritability were also noted. Keppra was added with temporary improvement. She continued to get multiple boluses of Keppra, lorazepam and phenobarbital for persistent clinical seizures activities. She was subsequently started on a pentobarbital drip and intubated prior to transfer to SLCH on DOL#22.
PMHX: Pregnancy was complicated by preterm contractions at 35 weeks. Infant female was born at 37 6/7 week EGA via vaginal delivery to 44 yo G7P5 now 6 with unremarkable serologies. Apgars were 4, 6, 7 at 1, 5, 10 minutes. Delivery was spontaneous and with vacuum extraction. Nuchal cord x1 was noted. She received bag-mask ventilation for 30 seconds at birth. Spontaneous right-sided pneumothorax at birth treated with needle decompression.Cultures were negative. NBS normal. Karotype 46XX.
Rx:Pentobarbital drip at 2 mg/kg/hour (phenobarbital and levetiracetam were on hold at the time of transfer).
FH:One sibling who died at 2 months of age reportedly neurologically intact, but with Hyperbilirubinemia.
SH:Her parents are from the same area of Pakistan and are otherwise not known to be related. They live in Paducah, Ky.
PE: VS T36.9, HR 164, RR 23, BP 74/51. OFC: 36.7 cm.
General:Intubated and ventilated on SIMV. HEENT: anterior fontanelle is open, soft and flat. Palate is intact. Heart: regular rate and rhythm. Lungs: clear bilaterally. Abdomen:benign. GU: normal Tanner I female genitalia.
Neurologic exam:Did not open her eyes and did not have a vigorous cry or evidence of grimace with stimulation but moved when touched. Pupils were equal, round and reactive to light from 2 to 1.5 mm bilaterally. Positive red reflex bilaterally.Minimal squint to light. Bit on fingertip but did not suck.Increased appendicular tone with her bilateral thumbs tightly clinched inside fists when she was stimulated. Decreased axial tone at all times and seemed to have decreased appendicular tone when she was left alone for quite some time and appeared to have relaxed. Moved all extremities asynchronously and with at least antigravity strength when stimulated but had little spontaneous movement without any form of stimulation. When stimulated would tend to arch back with an extensor posture.Did not startle to a loud clap or noise. Responded to touch in all four extremities.Deep tendon reflexes were symmetric and 3+ throughout in the biceps, brachial radialis, patellar and Achilles tendons.Bilateral ankle and knee clonus for 3-4 beats, and would occasionally have some bilateral elbow clonus for 1-2 beats with stimulation.
Clinical impression: 22-day-old female infant with intractable seizures
Considerations:
1. CNS structural abnormalities
2. Perinatal hypoxic-ischemic encephalopathy
3. Metabolic disorders, including pyridoxine-dependent seizures
4. Familial seizure disorder
5. Neuroendocrinopathies
6. Hyperekplexia
7. Genetic syndromes
Course: While the patient and the EEG were recorded (Video EEG), excessive discontinuity and epileptiform activity were seen. Emergence of status epilepticus after discontinuation of pentobarbital. Dramatic elimination of the clinical seizures and flattening of the EEG when pyridoxine 100 mgm given intravenously consistent with epilepsy pyridoxine dependent (EPD).
MRI: 1. Multiple T1 hyperintensities scattered throughout the deep and periventricular white matter of the bilateral frontal, parietal and occipital lobes, right greater than left, likely representing PVL-like injuries. 2. Small subarachnoid hemorrhage involving a left inferior temporal gyrus. 3. Small subdural hematoma in the posterior fossa. 4. Normal MRV.
Hospital course: Pyridoxine 50 mg twice daily was initiated and she remained seizure free the remainder of her admission.
Special studies: CSF neurotransmitter studies obtained prior to initiation of pyridoxine showed presence ofpyridoxine-dependent seizure biomarkers. DNA analysis showed two mutations in the antiquitin gene (ALDH7A1) consistent with alpha-aminoadipic semialdehyde dehydrogenase (AASA) deficiency. She was discharged home on DOL#32 with a nearly normal neurological exam, on pyridoxine po twice daily and phenobarbital. Phenobarbital was discontinued at the Neurology follow-up visit 3 months later. Exam at that time was remarkable for only axial hypotonia. Development was age appropriate.
Discussion: Epilepsy, pyridoxine-dependent (EPD; PDS) is an autosomal recessive disorder with an estimated birth incidence between 1:400,000 and 1:750,000. There are 100 reported cases worldwide. Patients with PDS typically present with seizures activities within hours after birth that are refractory to typical anti-epileptics. Affected infants may also exhibit intrauterine seizures. Seizure types vary, including myoclonic, atonic, partial, generalized and infantile spasms. PDS also can be associated with hyper-alertness, irritability, tremulousness, abnormal cry, excessive startle response, abdominal distension, vomiting and respiratory distress. Clinical diagnosis of PDS can be made with rapid resolution of seizure activity with administration of pyridoxine. The pathophysiology of PDS is not fully understood. Pyridoxine is converted via a series of pathways to its active form, pyridoxal phosphate (LPD)—an essential cofactor for many reactions, including those involved in neurotransmitter metabolism. Mutations in the antiquitin gene cause concomitant depletion of LPD, which may contribute to neurotransmitter derangements causing seizure activity. Brain imagining of patients with PDS may show hypoplasia of the corpus callosum and cerebellum with mega cisterna magna. Untreated seizures may also be associated with intraventricular hemorrhage and/or subarachnoid hemorrhage, white matter changes and hydrocephalus. The developmental outcome of patients with pyridoxine varies, with most patients experiencing some degree of cognitive impairment, particularly expressive language and learning difficulties. Patients with a history of intrauterine seizures carry the worst outcome. Women who previous gave birth to a child with PDS are recommended to receive pyridoxine supplementation in the final half of subsequent pregnancies.
References:
- Baxter, Peter. (2001). Pyridoxine-dependent and pyridoxine-responsive seizures. Developmental Medicine & Child Neurology. 43:416-420.
- Gospe, Sidney (2002). Pyridoxine-dependent seizures: findings from recent studies pose a new question. Pediatric Neurolog.y 26:181-185.
- Gospe, Sidney. (2006). Pyridoxine-dependent seizures: new genetic and biochemical clues to help with diagnosis and treatment. Current Opinion in Neurology. 19:148-153.
- Mills, et. al. (2005). Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nature Medicin.e 12:3:307-309.
- Pearl, P.L. (2009). New treatment paradigms in neonatal metabolic epilepsies. Journal of Inherited Metabolism Disorder. 32:204-213.
