Diffusion tensor tractography can predict hemiparesis in infants with high risk factors.

Diffusion tensor tractography (DTT) is known to be useful in detecting white matter lesions. In the current study, we report on two hemiparetic patients with risk factors who showed abnormalities of the corticospinal tract (CST) on diffusion tensor tractography (DTT) prior to the manifestation of hemiparesis. Two hemiparetic patients with risk factors (preterm, low birth weight) and six age-matched normal control subjects were enrolled to this study. Diffusion tensor imaging (DTI) was performed at the age of 43 weeks (patient 1) and 33 weeks (patient 2) using 1.5-T with a Synergy-L Sensitivity Encoding (SENSE) head coil. We measured fractional anisotropy (FA), apparent diffusion coefficients (ADCs), and fiber counts of the CST. There were no definite asymmetric findings on physical examination and conventional brain MRI. By contrast, DTT showed a unilateral CST disruption at the periventricular white matter, low FA values, and low CST fiber counts compared with those of the unaffected CST and controls. These patients were diagnosed with hemiparetic cerebral palsy when we re-evaluated these patients at the age of 6 years (patient 1) and 3 years of age (patient 2), respectively. In these two patients, DTT revealed abnormalities of the CST prior to the manifestation of hemiparesis. Therefore, it seems that DTT would be a useful modality in detecting CST abnormalities in advance of clinical manifestation in infants with high risk factors.

A case of complicated spastic paraplegia 2 due to a point mutation in the proteolipid protein 1 gene.

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked dysmyelinating disorder resulting from mutation of the proteolipid protein gene (PLP1). Clinical features of PMD include progressive psychomotor developmental delay, nystagmus, spastic quadriplegia, dystonia, and cerebellar ataxia. PMD is clinically classified into three subtypes according to the severity of the disease: connatal, transitional, and classic forms. Patients with PMD have been identified with duplication, point mutations, and deletion of PLP1. In addition, spastic paraplegia 2 (SPG2) is allelic to PMD and typically caused by missense mutations in the second extracellular domain of PLP1 or in the PLP1-specific region that is spliced out during formation of the DM20 isoform. The authors describe a Korean boy diagnosed with SPG2 caused by a mutation that results in a Pro215Leu substitution in the second extracellular domain. Analysis of phenotypes resulting from mutations affecting PLP1 has been valuable in identifying functional domains of this still incompletely understood major myelin protein. Null mutations and mutations affecting the PLP1-specific domain cause peripheral neuropathy. The PLP1-specific domain also is important in the long-term maintenance of axonal integrity. This patient's phenotype was relatively mild, in contrast with other mutations at position 215 of PLP1 that cause severe PMD. One of these severe mutations is also a missense mutation substituting an aliphatic residue, alanine, for proline. The distinct severity difference between the Pro215Leu and Pro215Ala substitutions suggests that this region of the protein is very sensitive to subtle structural changes and likely plays a critical role in PLP1 function.

A multicenter trial of oxcarbazepine oral suspension monotherapy in children newly diagnosed with partial seizures: a clinical and cognitive evaluation.

PURPOSE: We conducted a prospective, multicenter, open label trial to evaluate the effectiveness of oxcarbazepine (OXC) oral suspension as monotherapy for children newly diagnosed with partial seizures. METHODS: This trial included a two- to eight-week titration and stabilization period to achieve effective target doses and a 24-week maintenance phase. The primary outcome measure was the seizure-free rate over six months, while a secondary measure was the change in cognition and behavior from screening to the end of the maintenance phase. The effectiveness of OXC was compared in intellectually normal versus intellectually impaired children (intelligence quotient <70). RESULTS: We enrolled 171 patients and analyzed 168 as the per-protocol (PP) group (3 patients had protocol violations). The mean age of the PP group was 8.4±2.7 years. The maintenance dose of OXC was 24.9±8.0mg/kg/day. Of the 168 patients included in the efficacy analysis, 122 (72.6%) completed the study and 94 (56.0%) became seizure-free after the OXC treatment. Comparing the efficacy of OXC for intellectually normal and intellectually impaired patients, 79 (56.8%) of the 139 intellectually normal patients and 15 (51.7%) of the 29 intellectually impaired patients became seizure-free (P=0.61). After treatment, intelligence scale scores improved in intellectually normal patients compared to the intellectually impaired children (P<0.05). Social problems quantified by behavior scales improved in intellectually impaired patients compared to intellectually normal children (P<0.05). CONCLUSIONS: OXC is effective and well-tolerated as monotherapy in children with partial seizures. There was no difference in the effectiveness of OXC between intellectually normal and intellectually impaired children.

Comparative trial of low- and high-dose zonisamide as monotherapy for childhood epilepsy.

PURPOSE: To evaluate the effectiveness of zonisamide (ZNS) as monotherapy in children with newly diagnosed epilepsy. METHODS: This randomized, multicenter trial included a 2-4-week titration and a 24-week maintenance phase after randomization to low-(3-4 mg/kg/day) or high-(6-8 mg/kg/day) dose groups as target maintenance dosages. The primary outcome measure was the seizure-free rate over 6 months, while a secondary measure was the change in cognition and behavior from screening to the end of the maintenance phase. RESULTS: Out of 125 patients enrolled, 90 (49 low-dose and 41 high-dose) completed the study. Forty-one patients (63.1%) in the low-dose group and 34(57.6%) in the high-dose group achieved 6 months' freedom from seizures (p=0.66). After treatment, the picture arrangement subtest improved in the low-dose group (p=0.047) while the vocabulary subtest worsened in the high-dose group (p=0.020). Comparing between the two groups, the vocabulary subtest in the high-dose group was significantly worse than that in the low-dose group (p=0.002). Social competence, somatic complaints, depression/anxiety and delinquent and aggressive behavior in the low-dose group were significantly improved (p<0.05). Moreover, total social competence, somatic complaints, delinquent behavior, externalizing, and total behavior problems were significantly more improved in the low-dose group than the high-dose group (p<0.05). CONCLUSIONS: ZNS is an effective monotherapy for newly diagnosed childhood epilepsy. Lower doses of ZNS have a similar efficacy and more beneficial neurocognitive effects compared to higher doses. When prescribing higher doses of ZNS, one must be aware of the possible manifestation of problems associated with language development, such as those affecting vocabulary acquisition.

Cerebellum can be a possible generator of progressive myoclonus.

A 19-month-old girl presented with progressive myoclonic jerking of both proximal lower extremities. On her brain magnetic resonance imaging (MRI), the authors found an ill-defined mass involving cerebellar vermis and the right middle cerebellar peduncle. ( 11)C-methionine positron emission tomography (PET) showed no abnormalities, but (18)F-fluorodeoxyglucose ((18)F-FDG) PET revealed a well-defined hypermetabolic focus. Depth electrodes were inserted deep into the mass, which recorded focal slow waves associated with the clinical myoclonus. Following the removal of the tumor, the myoclonus was completely resolved with no neurological deficit. Here, the authors present a case showing progressive myoclonus associated with a cerebellar ganglioglioma with the electrophysiological data, which provides strong supportive evidence that the cerebellum can be a myoclonus generator.

A novel ATP7A gross deletion mutation in a Korean patient with Menkes disease.

Menkes disease (MD, MIM 309400) is a fatal X-linked recessive disorder that is caused by mutations in the gene encoding ATP7A, a copper-transporting, P-type ATPase. Patients with MD are characterized by progressive hypotonia, seizures, failure to thrive, and death in early childhood. Two Korean patients were diagnosed with Menkes disease by clinical and biochemical findings. We found one missense mutation and one gross deletion in the ATP7A gene in the patients. The missense mutation in Patient 1, c.3943G>A (p.G1315R) in exon 20, was identified in a previous report. Patient 2 had a gross deletion of c.1544-?_2916+?, which was a novel mutation. The patients' mothers were shown to be carriers of the respective mutations. Prenatal DNA diagnosis in the family of Patient 2 was successfully performed, showing a male fetus with the wild-type genotype. The gross deletion is the first mutation to be identified in the ATP7A gene in Korean MD patients. We expect that our findings will be helpful in understanding the wide range of genetic variation in ATP7A in Korean MD patients.

Mutations in ND subunits of complex I are an important genetic cause of childhood mitochondrial encephalopathies.

An increasing number of reports on mitochondrial DNA coding regions' mutations, especially in mitochondrial DNA- encoded NADH dehydrogenase (ND) subunit genes of the respiratory chain complex I, have been published recently, making it possible to improve the molecular diagnosis of many mitochondrial diseases in children with variable clinical features. This article describes 2 mitochondrial DNA mutations in the ND3 and ND5 genes in patients showing clinical features of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome overlap syndrome and atypical Leigh syndrome. These cases add to the increasing number of reports stating that mitochondrial DNA-encoded protein-coding regions are mutation hot spots in pediatric patients with encephalopathies with variable clinical spectra.

Diffusion tensor imaging demonstrates focal lesions of the corticospinal tract in hemiparetic patients with cerebral palsy.

The purpose of this study was to use diffusion tensor imaging (DTI) with fiber tractography (FT) to demonstrate focal lesions of the corticospinal tract (CST) in hemiparetic patients with cerebral palsy (CP) who showed no specific focal lesions on conventional brain MRI. Four hemiparetic patients with CP (three left hemiparesis, mean age: 2.5 years, range: 0.9-7.0) and four age-matched controls were recruited. DTI was performed using a 1.5-T system with a synergy-L Sensitivity Encoding head coil. Fractional anisotropy (FA) and apparent diffusion coefficients (ADC) were measured using the region of interest (ROI) method. We estimated the asymmetric anisotropy index (AA) and asymmetric mean diffusivity index (AD) to evaluate the asymmetry between right and left CSTs. All four patients showed interrupted FT at the affected periventricular white matter (PVWM) level compared to that of the opposite side; this was not detected on conventional brain MRI and explained the hemiparesis of these patients. Compared to the data of controls, all patients showed significant AA and AD only at the PVWM level. DTI with FT demonstrated focal lesions at the PVWM level. We conclude that DTI with FT may be a useful modality for investigating focal lesions in hemiparetic patients with CP.

Diffusion tensor magnetic resonance imaging of microstructural abnormalities in children with brain injury.

We present two pediatric cases demonstrating that diffusion tensor imaging is more efficient at revealing microstructural abnormalities of the brain than conventional magnetic resonance imaging because it enables measurements of the directionality and integrity of white matter fiber tracts. One patient suffered from left hemiparesis, and the other had right hemiparesis. However, whereas conventional magnetic resonance imaging showed only the findings of traumatic contusional hemorrhages in the left temporal and parietal lobes of the first patient and focal encephalomalacia in the left anterior thalamus of the second patient, diffusion tensor imaging successfully disclosed microstructural abnormalities in the right cerebral peduncle of the midbrain of the first patient and in the posterior limb of the left internal capsule of the second. Theses two cases demonstrate that diffusion tensor imaging is more capable than magnetic resonance imaging at detecting the microstructural pathologic lesions that are responsible for clinical motor weakness, especially when conventional magnetic resonance imaging has failed to detect subtle structural abnormalities.