fMRI and MEG in the study of typical and atypical cognitive development.

The tremendous changes in brain structure over childhood are critical to the development of cognitive functions. Neuroimaging provides a means of linking these brain-behaviour relations, as task protocols can be adapted for use with young children to assess the development of cognitive functions in both typical and atypical populations. This paper reviews some of our research using magnetoencephalography (MEG) and functional MRI (fMRI) in the study of cognitive development, with a focus on frontal lobe functions. Working memory for complex abstract patterns showed clear development in terms of the recruitment of frontal regions, seen with fMRI, with indications of strategy differences across the age range, from 6 to 35 years of age. Right hippocampal involvement was also evident in these n-back tasks, demonstrating its involvement in recognition in simple working memory protocols. Children born very preterm (7 to 9 years of age) showed reduced fMRI activation particularly in the precuneus and right hippocampal regions relative to control children. In a large normative n-back study (n=90) with upright and inverted faces, MEG data also showed right hippocampal activation that was present across the age range; frontal sources were evident only from 10 years of age. Other studies have investigated the development of set shifting, an executive function that is often deficit in atypical populations. fMRI showed recruitment of frontal areas, including the insula, that have significantly different patterns in children (7 to 14 years of age) with autism spectrum disorder compared to typically developing children, indicating that successful performance implicated differing strategies in these two groups of children. These types of studies will help our understanding of both normal brain-behaviour development and cognitive dysfunction in atypically developing populations.

The first successful lower extremity transplantation: 6-year follow-up and implications for cortical plasticity.

Vascularized composite allotransplantation as a viable reconstructive option is gaining recognition and new cases are being reported with increasing frequency including hand, face and laryngeal transplantation. However, only one successful complete lower limb transplantation has been reported to date, in which a functioning limb from one ischiopagus twin with a lethal cardiac anomaly was transplanted to the other. Six years later, the patient is mobilizing well and engaging in sporting activities with her peers in a mainstream school. Clinical evaluation of motor and sensory modalities demonstrated a good functional result. Quality of life was assessed using the short form-36 health survey and lower extremity functional scale disclosing a high level of social and physical capacity. Functional magnetic resonance imaging was performed and showed cortical integration of the limb; the implications of cortical plasticity and vascularized composite allotransplantation for the correction of congenital limb anomalies are presented.

Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy and is not rare. The NIH and National Institute of Neurological Disorders and Stroke sponsored a 3-day multidisciplinary workshop to advance research into SUDEP and its prevention. Parallel sessions were held: one with a focus on the science of SUDEP, and the other with a focus on issues related to the education of health care practitioners and people with epilepsy. This report summarizes the discussions and recommendations of the workshop, including lessons learned from investigations of sudden infant death syndrome (SIDS), sudden cardiac death, autonomic and respiratory physiology, medical devices, genetics, and animal models. Recommendations include educating all people with epilepsy about SUDEP as part of their general education on the potential harm of seizures, except in extenuating circumstances. Increasing awareness of SUDEP may facilitate improved seizure control, possibly decreasing SUDEP incidence. There have been significant advances in our understanding of the clinical and physiologic features of SIDS, sudden cardiac death, and SUDEP in both people and animals. Research should continue to focus on the cardiac, autonomic, respiratory, and genetic factors that likely contribute to the risk of SUDEP. Multicenter collaborative research should be encouraged, especially investigations with direct implications for the prevention of SUDEP. An ongoing SUDEP Coalition has been established to facilitate this effort. With the expansion of clinical, genetic, and basic science research, there is reasonable hope of advancing our understanding of SUDEP and ultimately our ability to prevent it.

Sudden unexplained death in children with epilepsy.

BACKGROUND: Sudden unexplained death is a significant cause of mortality in people with epilepsy. Risk factors that have been identified include male sex, poor compliance with medications, and antiepileptic drug (AED) polypharmacy. However, these may not apply to the pediatric population in which the causes of epilepsy differ from the adult population. Therefore, risk factors for sudden unexplained death in epilepsy (SUDEP) in children must be evaluated independently from those in the adult population. METHODS: Cases of SUDEP in children less than 18 years of age occurring over a 10-year period in the province of Ontario, Canada, were identified. Records were reviewed for demographic and clinical features and neuropathology findings. RESULTS: Twenty-seven cases of SUDEP in children were identified. Sixty-three percent were male. Age at death ranged from 8 months to 15 years. Fourteen children had symptomatic epilepsy (52%), five had cryptogenic epilepsy (18%), and eight had idiopathic epilepsy (30%). Twelve children were treated with one AED (46%), 10 were on two AED (38%), and three were on three AED (12%). At the time of death, seven children had one serum AED concentration below the therapeutic range (35%) and 12 children had AED levels within the therapeutic range (60%). CONCLUSIONS: This case series represents the largest series of sudden unexplained death in children with epilepsy. At least two previously described risk factors for SUDEP in adults, low serum AED levels at time of death and AED polytherapy, do not appear to be significant in children.

Fatty acid oxidation abnormalities in childhood-onset spinal muscular atrophy: primary or secondary defect(s)?

The purpose of this study was to further identify and quantify the fatty acid oxidation abnormalities in spinal muscular atrophy, correlate these with disease severity, and identify specific underlying defect(s). Fifteen children with spinal muscular atrophy (3 type I, 8 type II, 4 type III) were studied. Serum carnitine total/free ratios demonstrated a tendency toward an increased esterified fraction ranging 35-58% of total carnitine (normal: 25-30% of total) in younger children with types I and II. The remaining type II and III patients, older than 23 months of age at sampling, had normal esterified carnitine levels. Urinary organic acid analysis demonstrated mild to moderate medium-chain dicarboxylic aciduria in type I patients and normal, mild, or moderate increases in short-chain and medium-chain organic acids in type II patients. In the type III group, the organic acids were normal except for one patient with mild medium-chain dicarboxylic aciduria. Muscle intramitochondrial beta-oxidation was measured in 5 children (2 type I, 2 type II, and 1 type III) and a significant reduction in the activities of short-chain L-3-hydroxyacyl-CoA dehydrogenase, long-chain L-3-hydroxyacyl-CoA dehydrogenase, acetoacetyl-CoA thiolase, and 3-ketoacyl-CoA thiolase were found; however, normal crotonase activity was documented. Most strikingly, there was a marked increase (3- to 5-fold) in the activity ratios of crotonase to L-3-hydroxyacyl-CoA dehydrogenase and thiolase activities with both short- and long-chain substrates. The combined abnormalities suggest a defect in a mitochondrial multifunctional enzyme complex, distinct from the trifunctional enzyme. These abnormalities may be either primary or secondary and may respond to dietary measures to reduce the dependence on fatty acid oxidation.

Clinical and neurophysiologic response of myopathy and neuropathy in long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency to oral prednisone.

The purpose of this study was to evaluate the clinical and neurophysiologic responses to oral prednisone therapy in a boy with enzymatically confirmed long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in biopsied muscle and cultured skin fibroblasts. This boy presented with progressive limb girdle myopathy, recurrent myoglobinuria, peripheral sensorimotor axonopathy, and intraventricular conduction delays. Prior to prednisone therapy, at age 8 years, he exhibited marked distal weakness greater than proximal weakness with a waddling and high-steppage gait, Gowers' maneuver (10 s to rise from the floor), fatigue after 3-20 yards of walking and the ability to climb only 2 stairs. Serum levels of creatine kinase rose from 34 to 4,124 U/L following mild exertion. Nerve conduction studies revealed progressive axonopathy with secondary demyelination. Four weeks after initiation of oral prednisone (0.75 mg/kg/day) therapy, there was approximately a 100% increase in power and endurance. He was able to walk at least 100 yards before tiring, could rise from sitting on the floor in 3-4 s, and was able to climb 20 steps in 30 s. There was concurrent improvement in nerve conduction studies. Prednisone was gradually withdrawn over the next 4 months to 0.19 mg/kg/day; lower doses of 0.08 mg/kg/day resulted in a marked deterioration in power to the prior state. Although 0.19 mg/kg/day did not maintain the peak power achieved at 0.75 mg/kg/day, it provided adequate baseline power and endurance. It is concluded that there was a significant clinical and neurophysiologic response to prednisone at a dosage > or = 0.16 mg/kg/day. Prednisone may stabilize muscle and neuronal plasma membranes, as well as the fatty acid oxidation enzyme complex in the mitochondrial membrane.