Snow T. Nguyen

Cerebral hemispherectomy Hospital course, seizure, developmental, language, and motor outcomes

Objective: To compare hemispherectomy patients with different pathologic substrates for hospital course, seizure, developmental, language, and motor outcomes. Methods: The authors compared hemispherectomy patients (n = 115) with hemimegalencephaly (HME; n = 16), hemispheric cortical dysplasia (hemi CD; n = 39), Rasmussen encephalitis (RE; n = 21), infarct/ischemia (n = 27), and other/miscellaneous (n = 12) for differences in operative management, postsurgery seizure control, and antiepilepsy drug (AED) usage. In addition, Vineland Adaptive Behavior Scale (VABS) developmental quotients (DQ), language, and motor assessments were performed pre- or postsurgery, or both. Results: Surgically, HME patients had the greatest perioperative blood loss, and the longest surgery time. Fewer HME patients were seizure free or not taking AEDs 1 to 5 years postsurgery, but the differences between pathologic groups were not significant. Postsurgery, 66% of HME patients had little or no language and worse motor scores in the paretic limbs. By contrast, 40 to 50% of hemi CD children showed near normal language and motor assessments, similar to RE and infarct/ischemia cases. VABS DQ scores showed +5 points or more improvement postsurgery in 57% of patients, and hemi CD (+12.7) and HME (+9.1) children showed the most progress compared with RE (+4.6) and infarct/ischemia (−0.6) cases. Postsurgery VABS DQ scores correlated with seizure duration, seizure control, and presurgery DQ scores. Conclusions: The pathologic substrate predicted pre- and postsurgery differences in outcomes, with hemimegalencephaly (but not hemispheric cortical dysplasia) patients doing worse in several domains. Furthermore, shorter seizure durations, seizure control, and greater presurgery developmental quotients predicted better postsurgery developmental quotients in all patients, irrespective of pathology.

Pediatric Cortical Dysplasia: Correlations between Neuroimaging, Electrophysiology and Location of Cytomegalic Neurons and Balloon Cells and Glutamate/GABA Synaptic Circuits

Seizures in cortical dysplasia (CD) could be from cytomegalic neurons and balloon cells acting as epileptic ‘pacemakers’, or abnormal neurotransmission. This study examined these hypotheses using in vitro electrophysiological techniques to determine intrinsic membrane properties and spontaneous glutamatergic and GABAergic synaptic activity for normal-pyramidal neurons, cytomegalic neurons and balloon cells from 67 neocortical sites originating from 43 CD patients (ages 0.2–14 years). Magnetic resonance imaging (MRI), 18fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and electrocorticography graded cortical sample sites from least to worst CD abnormality. Results found that cytomegalic neurons and balloon cells were observed more frequently in areas of severe CD compared with mild or normal CD regions as assessed by FDG-PET/MRI. Cytomegalic neurons (but not balloon cells) correlated with the worst electrocorticography scores. Electrophysiological recordings demonstrated that cytomegalic and normal-pyramidal neurons displayed similar firing properties without intrinsic bursting. By contrast, balloon cells were electrically silent. Normal-pyramidal and cytomegalic neurons displayed decreased spontaneous glutamatergic synaptic activity in areas of severe FDG-PET/MRI abnormalities compared with normal regions, while GABAergic activity was unaltered. In CD, these findings indicate that cytomegalic neurons (but not balloon cells) might contribute to epileptogenesis, but are not likely to be ‘pacemaker’ cells capable of spontaneous paroxysmal depolarizations. Furthermore, there was more GABA relative to glutamate synaptic neurotransmission in areas of severe CD. Thus, in CD tissue alternate mechanisms of epileptogenesis should be considered, and we suggest that GABAergic synaptic circuits interacting with cytomegalic and normal-pyramidal neurons with immature receptor properties might contribute to seizure generation.

Cytomegalic interneurons: A new abnormal cell type in severe pediatric cortical dysplasia

Abstract A defining histopathologic feature of Taylor-type cortical dysplasia (CD) is the presence of cytomegalic neurons and balloon cells. Most cytomegalic neurons appear to be pyramidal-shaped and glutamatergic. The present study demonstrates the presence of cytomegalic GABAergic interneurons in a subset of pediatric patients with severe CD. Cortical tissue samples from children with mild, severe, and non-CD pathologies were examined using morphologic and electrophysiologic techniques. By using in vitro slices, cytomegalic cells with characteristics consistent with interneurons were found in 6 of 10 patients with severe CD. Biocytin labeling demonstrated that cytomegalic interneurons had more dendrites than normal-appearing interneurons. Whole-cell patch clamp recordings showed that cytomegalic interneurons had increased membrane capacitance and time constant compared with normal-appearing interneurons. They also displayed signs of cellular hyperexcitability, evidenced by increased firing rates, decreased action potential inactivation, and the occurrence of spontaneous membrane depolarizations. Single-cell reverse transcription-polymerase chain reaction and immunohistochemistry for GABAergic markers provided further evidence that these cells were probably cytomegalic interneurons. The pathophysiologic significance of GABAergic cytomegalic interneurons in severe CD tissue is unknown, but they could inhibit glutamatergic cytomegalic pyramidal neurons, or contribute to the synchronization of neuronal networks and the propagation of ictal activity in a subset of pediatric patients with severe CD.

Infantile spasm-associated microencephaly in tuberous sclerosis complex and cortical dysplasia.

Objective: In children with and without infantile spasms, this study determined brain volumes and cell densities in epilepsy surgery patients with tuberous sclerosis complex (TSC) and cortical dysplasia with balloon cells (CD). Methods: We compared TSC (n = 18) and CD (n = 17) patients with normal/autopsy controls (n = 20) for MRI gray and white matter volumes and neuronal nuclei (NeuN) cell densities. Results: In patients without a history of infantile spasms, TSC cases showed decreased gray and white matter volumes (−16%). In cases with a history of infantile spasms, both CD (−25%) and TSC (−35%) patients showed microencephaly. This was confirmed in monozygotic twins with TSC, where the twin with a history of spasms had cerebral volumes less (−16%) than the twin without a history of seizures. Regardless of seizure history, TSC patients showed decreased NeuN cell densities in lower gray matter (−36%), whereas CD patients had increased densities in upper cortical (+52%) and white matter regions (+65%). For TSC patients, decreased lower gray matter NeuN densities correlated with reduced MRI volumes. Conclusions: Patients with tuberous sclerosis without spasms showed microencephaly associated with decreased cortical neuronal densities. In contrast, cortical dysplasia patients without spasms were normocephalic with increased cell densities. This supports the concept that tuberous sclerosis and cortical dysplasia have different pathogenetic mechanisms despite similarities in refractory epilepsy and postnatal histopathology. Furthermore, a history of infantile spasms was associated with reduced cerebral volumes in both cortical dysplasia and tuberous sclerosis patients, suggesting that spasms or their treatment may contribute to microencephaly independent of etiology.

Improving MRI differentiation of gray and white matter in epileptogenic lesions based on nonlinear feedback

A new method for enhancing MRI contrast between gray matter (GM) and white matter (WM) in epilepsy surgery patients with symptomatic lesions is presented. This method uses the radiation damping feedback interaction in high‐field MRI to amplify contrast due to small differences in resonance frequency in GM and WM corresponding to variations in tissue susceptibility. High‐resolution radiation damping‐enhanced (RD) images of in vitro brain tissue from five patients were acquired at 14 T and compared with corresponding conventional T1‐, T  2* ‐, and proton density (PD)‐weighted images. The RD images yielded a six times better contrast‐to‐noise ratio (CNR = 44.8) on average than the best optimized T1‐weighted (CNR = 7.92), T  2* ‐weighted (CNR = 4.20), and PD‐weighted images (CNR = 2.52). Regional analysis of the signal as a function of evolution time and initial pulse flip angle, and comparison with numerical simulations confirmed that radiation damping was responsible for the observed signal growth. The time evolution of the signal in different tissue regions was also used to identify subtle changes in tissue composition that were not revealed in conventional MR images. RD contrast is compared with conventional MR methods for separating different tissue types, and its value and limitations are discussed. Magn Reson Med, 2006.

Five or More Acute Postoperative Seizures Predict Hospital Course and Long-term Seizure Control after Hemispherectomy

Summary:  Purpose: Acute postoperative seizures (APOSs) are those that occur in the first 7 to 10 days after surgery, and previous studies in temporal lobe epilepsy patients support the notion that APOSs may foretell failure of long‐term seizure control. It is unknown whether APOSs also predict seizure outcome or hospital course after hemispherectomy.