Pediatric hemispherectomy outcome: Adaptive functioning, intelligence, and memory.

OBJECTIVE: Our purpose was to characterize neuropsychological evaluation (NP) outcome following functional hemispherectomy in a large, representative cohort of pediatric patients. METHODS: We evaluated seizure and NP outcomes and medical variables for all post-hemispherectomy patients from Seattle Children's Hospital epilepsy surgery program between 1996 and 2020. Neuropsychological evaluation outcome tests used were not available on all patients due to the diversity of patient ages and competency that is typical of a representative pediatric cohort; all patients had at least an adaptive functioning or intelligence measure, and a subgroup had memory testing. RESULTS: A total of 71 hemispherectomy patients (37 right; 34 females) yielded 66 with both preoperative (PREOP) plus postoperative (POSTOP) NPs and 5 with POSTOP only. Median surgery age was 5.7 (IQR 2-9.9) years. Engel classification indicated excellent seizure outcomes: 59 (84%) Class I, 6 (8%) Class II, 5 (7%) Class III, and 1 (1%) Class IV. Medical variables - including seizure etiology, surgery age, side, presurgical seizure duration, unilateral or bilateral structural abnormalities, secondarily generalized motor seizures - were not associated with either Engel class or POSTOP NP scores, though considerable heterogeneity was evident. Median PREOP and POSTOP adaptive functioning (PREOP n = 45, POSTOP n = 48) and intelligence (PREOP n = 29, POSTOP n = 36) summary scores were exceptionally low and did not reveal group decline from PREOP to POSTOP. Fifty-five of 66 (85%) cases showed stability or improvement. Specifically, 5 (8%) improved; 50 (76%) showed stability; and 11 (16%) declined. Improve and decline groups showed clinically interesting, but not statistical, differences in seizure control and age. Median memory summary scores were low and also showed considerable heterogeneity. Overall median PREOP to POSTOP memory scores (PREOP n = 16, POSTOP n = 24) did not reveal declines, and verbal memory scores improved. Twenty six percent of intelligence and 33% of memory tests had verbal versus visual-spatial discrepancies; all but one favored verbal, regardless of hemispherectomy side. SIGNIFICANCE: This large, single institution study revealed excellent seizure outcome in 91% of all 71 patients plus stability and/or improvement of intelligence and adaptive functioning in 85% of 66 patients who had PREOP plus POSTOP NPs. Memory was similarly stable overall, and verbal memory improved. Medical variables did not predict group NP outcomes though heterogeneity argues for further research. This study is unique for cohort size, intelligence plus memory testing, and evidence of primacy of verbal over visual-spatial development, despite hemispherectomy side. This study reinforces the role of hemispherectomy in achieving good seizure outcome while preserving functioning.

Impact of epilepsy surgery on development of preschool children: identification of a cohort likely to benefit from early intervention.

OBJECT: Outcomes of focal resection in young children with early-onset epilepsy are varied in the literature due to study differences. In this paper, the authors sought to define the effect of focal resection in a small homogeneous sample of children who were otherwise cognitively intact, but who required early surgical treatment. Preservation of and age-appropriate development of intelligence following focal resection was hypothesized. METHODS: Cognitive outcome after focal resection was retrospectively reviewed for 15 cognitively intact children who were operated on at the ages of 2-6 years for lesion-related, early-onset epilepsy. Intelligence was tested prior to and after surgery. Effect sizes and confidence intervals for means and standard deviations were used to infer changes and differences in intelligence between 1) groups (pre vs post), 2) left versus right hemisphere resections, and 3) short versus long duration of seizures prior to resection. RESULTS: No group changes from baseline occurred in Full Scale, verbal, or nonverbal IQ. No change from baseline intelligence occurred in children who underwent left or right hemisphere surgery, including no group effect on verbal scores following surgery in the dominant hemisphere. Patients with seizure durations of less than 6 months prior to resection showed improvement from their presurgical baseline in contrast to those with seizure duration of greater than 6 months prior to surgery, particularly in Wechsler Full Scale IQ and nonverbal intelligence. CONCLUSIONS: This study suggests that surgical treatment of focal seizures in cognitively intact preschool children is likely to result in seizure remediation, antiepileptic drug discontinuation, and no significant decrement in intelligence. The latter finding is particularly significant in light of the longstanding concern associated with performing resections in the language-dominant hemisphere. Importantly, shorter seizure duration prior to resection can result in improved cognitive outcome, suggesting that surgery for this population should occur sooner to help improve intelligence outcomes.

d-orbital effects on stereochemical non-rigidity: twisted Ti(IV) intramolecular dynamics.

The isomerization dynamics of tris-catecholate complexes have been investigated by variable-temperature NMR methods, demonstrating that the intramolecular racemization of Delta and Lambda enantiomers of d0 Ti(IV) is facile and faster than that of d10 Ga(III) and Ge(IV) analogues. Activation parameters for the racemization of K2[Ti2(3)] (H(2)2 = 2,3-dihydroxy-N,N'-diisopropylterephthalamide) were determined from line shape analysis of 1H NMR spectra [methanol-d4: deltaH++ = 47(1) kJ/mol; deltaS++ = -34(4) J/mol K; deltaG++(298) = 57(3) kJ/mol; DMF-d7: deltaH++ = 55(1) kJ/mol; deltaS++ = -16(4) J/mol K; deltaG++(298) = 59(3) kJ/mol; D2O (pD* = 8.6, 20% MeOD): deltaH++ = 48(3) kJ/mol; deltaS++ = -28(10) J/mol K; deltaG++(298) = 56(3) kJ/mol]. The study of K2[Ti4(3)] (H(2)4 = 2,3-dihydroxy-N-tert-butyl-N'-benzylterephthalamide) reveals two distinct isomerization processes: faster racemization of mer-[Ti4(3)]2- by way of a Bailar twist mechanism (D3h transition state) [T(c) approximately 242 K, methanol-d4], and a slower merright harpoon over left harpoonfac [Ti4(3)]2- isomerization by way of a Rây-Dutt mechanism (C2v transition state) [T(c) approximately 281 K, methanol-d4]. The solution behavior of the Ti(IV) complexes mirrors that reported previously for analogous Ga(III) complexes, while that of analogous Ge(IV) complexes was too inert to be detected by 1H NMR up to 400 K. These experimental findings are augmented by DFT calculations of the ML3 ground states and Bailar and Rây-Dutt transition states, which correctly predict the relative kinetic barriers of complexes of the three metal ions, in addition to faithfully reproducing the ground-state structures. Orbital calculations support the conclusion that participation of the Ti(IV) d orbitals in ligand bonding contributes to the greater stabilization of the prismatic Ti(IV) transition states.

Search for improved host architectures: application of de novo structure-based design and high-throughput screening methods to identify optimal building blocks for multidentate ethers.

This paper presents a computational approach to the deliberate design of improved host architectures. The approach, which involves the use of computer-aided design software, is illustrated by application to cation hosts containing multiple aliphatic ether oxygen binding sites. De novo molecule building software, HostDesigner, is interfaced with molecular mechanics software, GMMX, providing a tool for generating and screening millions of potential bidentate building block structures. Enhanced cation binding affinity can be achieved when highly organized building blocks are used to construct macrocyclic hosts.

Structural design criteria for anion hosts: strategies for achieving anion shape recognition through the complementary placement of urea donor groups.

The arrangement of urea ligands about different shaped anions has been evaluated with electronic structure calculations. Geometries and binding energies are reported for urea complexes with Cl-, NO(3)-, and ClO(4)-. The results yield new insight into the nature of urea-anion interactions and provide structural criteria for the deliberate design of anion selective receptors containing two or more urea donor groups.

Conformational analysis and rotational barriers of alkyl- and phenyl-substituted urea derivatives.

Potential energy surfaces (PES) for rotation about the N-C(sp(3)) or N-C(aryl) bond and energies of stationary points on PES for rotation about the C(sp(2))-N bond are reported for methylurea, ethylurea, isopropylurea, tert-butylurea, and phenylurea, using the B3LYP/DZVP2 and MP2/aug-cc-pVDZ methods. The analysis of alkylureas reveals cis and (less stable) trans isomers that adopt anti geometries, whereas syn geometries do not correspond to stationary points. In contrast, the analysis of phenylurea reveals that the lowest energy form at the MP2 level is a trans isomer in a syn geometry. The fully optimized geometries are in good agreement with crystal structure data, and PESs are consistent with the experimental dihedral angle distribution. Rotation about the C(sp(2))-N bond in alkylureas and phenylurea is slightly more hindered (8.6-9.4 kcal/mol) than the analogous motion in the unsubstituted molecule (8.2 kcal/mol). At the MP2 level of theory, the maximum barriers to rotation for the methyl, ethyl, isopropyl, tert-butyl, and phenyl groups are predicted to be 0.9, 6.2, 6.0, 4.6, and 2.4 kcal/mol, respectively. The results are used to benchmark the performance of the MMFF94 force field. Systematic discrepancies between MMFF94 and MP2 results were improved by modification of several torsional parameters.

HostDesigner: a program for the de novo structure-based design of molecular receptors with binding sites that complement metal ion guests.

This paper describes a novel approach to the discovery of host structures with binding sites that complement targeted metal ion guests. This approach uses a de novo structure-based design strategy that couples molecular building algorithms with scoring functions to prioritize candidate structures. The algorithms described herein have been implemented in a program called HostDesigner, the first structure-based design software specifically created for the discovery of metal ion receptors. HostDesigner generates and evaluates millions of candidate structures within minutes, rapidly identifying three-dimensional architectures that position binding sites to provide an optimal interaction with the metal ion.