Ironing Out the Cause of Seizures

History and Physical

A 12-year-old girl had a prolonged history of severe global developmental delay, stereotyped behaviors, nocturnal awakenings, and occasional staring spells. During infancy, she was diagnosed with global developmental delay and hypotonia. At 4 years, she presented with repetitive behaviors diagnosed as stereotypies. At the age of 7, she experienced nocturnal awakenings and occasional staring spells. Overnight electroencephalography (EEG) showed occasional bifrontal interictal discharges with right-sided predominance ( Fig. 16.1 ). She was started on oxcarbazepine which improved her symptoms and behavior.

An electroencephalography tracing shows multiple channels with five arrows marking synchronous sharp waveform patterns in frontal regions. The electroencephalography tracing contains thirteen waveform channels labeled from F p 1 to O 2 along the left margin. The channels include F p 1 to F 7, F 7 to T 7, T 7 to P 7, P 7 to O 1, and others. Each channel displays continuous electrical activity with vertical grid lines dividing the recording into equal time intervals. Five bold arrows point to sharp, high-amplitude waveform complexes occurring across the upper and middle channels. A scale bar in the lower right corner shows 2 seconds. — Fig. 16.1

On physical examination, there was hypertelorism with bilateral down-slanted eyes and epicanthal folds. She was nonverbal, and her motor exam revealed axial hypotonia, distal hypertonia, and increased deep tendon reflexes. She walked with an ataxic gait. Skin examination was normal.

Diagnostic Work-up

Due to dysmorphic features and a history of developmental delay, metabolic testing, karyotype, comparative genomic hybridization (CGH) microarray, methyl CpG binding protein (MECP2), and Angelman syndrome tests were ordered and were normal.

MRI at 6 and 9 years showed restricted diffusion, T2 hypointensity, and susceptibility in the bilateral globus pallidus and substantia nigra ( Figs. 16.2 and 16.3 ). There was global cerebral and cerebellar atrophy with prominence of sulci and folia.

A set of three brain M R I scans, labeled axial and coronal, shows arrows and arrowheads marking specific bilateral deep brain regions. The left panel shows an axial T 2 magnetic resonance imaging scan with two arrows pointing to symmetrical deep structures adjacent to the internal capsule, and the label globus pallidus appears above. The middle panel presents a coronal T 2 scan with arrows marking the same deep structures and arrowheads indicating lower midbrain areas. The label T 2 sequences appears at the top center, and the word coronal is placed at the bottom left of the panel. The right panel shows another axial T 2 scan with two arrowheads pointing to paired midbrain regions and includes the label substantia nigra at the top. — Fig. 16.2

A set of six axial brain magnetic resonance imaging scans arranged in three rows shows arrows and arrowheads marking paired deep brain regions across G R E, S W I, and D W I sequences. The top row contains two axial scans labeled G R E. The left scan shows four arrows pointing to symmetrical deep brain regions below the lateral ventricles, with the label globus pallidus at the top. The right scan shows two arrowheads pointing to paired midbrain regions, with the label substantia nigra above. The middle row includes two axial scans labeled S W I. The left scan has four arrows pointing to the same bilateral deep regions as in the G R E row. The right scan includes two arrowheads indicating the same midbrain regions. The bottom row shows two axial scans labeled D W I. The left scan has arrows pointing to deep paired structures similar to the previous rows, and the right scan shows arrowheads marking the midbrain. — Fig. 16.3

Multiple EEGs showed bilateral independent epileptiform discharges over the left and right frontal and central head regions, with mild slowing of background activity.

Whole exome sequencing showed a pathogenic variant in the WDR45 gene.

Clinical Differential Diagnosis

Rett syndrome can be seen in girls with global developmental delay, stereotypies, and seizures. It is caused by pathogenic variants in the MECP2 gene, and symptoms usually start before 1 year of age. There is progressive loss of purposeful hand dexterity and development of stereotyped hand movements, speech and language regression, and progressive gait abnormalities. MRI shows nonspecific global brain atrophy.

Metabolic epilepsies can be seen with developmental delay, regression, and seizures in late infancy and childhood. These include disorders of creatine biosynthesis and transport ( Fig. 16.4 ), mitochondrial disorders ( Fig. 16.5 ), pyruvate dehydrogenase deficiency (PDH) ( Fig. 16.6 ), peroxisomal disorders, and lysosomal storage disorders ( Fig. 16.7 ).