Faculty Bibliography

The basis for cognitive impairment in Duchenne muscular dystrophy (DMD) is not well understood but may be related to abnormal expression of dystrophin in brain. The aim of this study was to determine whether regional brain glucose metabolism is altered in children with DMD and whether such metabolic disturbances are localized to regions shown to be normally rich in dystrophin expression. Ten boys (mean age, 11.8 years) with DMD and 17 normal adults as a control group (mean age, 27.6 years) underwent 2-deoxy-2[(18)F]fluoro-D-glucose positron emission tomography (PET) and neuropsychological evaluation. The PET data were analyzed by statistical parametric mapping (SPM). The SPM analysis showed five clusters of decreased glucose metabolism in children with DMD, including the medial temporal structures and cerebellum bilaterally and the sensorimotor and lateral temporal cortex on the right side. At the voxel level, significant glucose hypometabolism was found in the right postcentral and middle temporal gyri, uncus, and VIIIB cerebellar lobule, as well as in the left hippocampal gyrus and cerebellar lobule. The neuropsychological profile of the DMD group revealed borderline nonverbal intellectual functioning, impaired manual dexterity bilaterally, borderline cognitive functioning, and internalizing behavioral difficulties. Our findings demonstrate region-specific hypometabolism, as well as cognitive and behavioral deficits in DMD children. As the regions showing hypometabolism on PET include those normally rich in dystrophin expression, it will be important to determine whether the hypometabolic regions also show cytoarchitectural abnormalities related to the lack of dystrophin.

Drug-resistant partial epilepsy in children often has a major impact on cognitive development, and early surgical intervention has been advocated to prevent adverse neurobehavioral effects of seizures in such patients. We report a 5-year-old boy who had cryptogenic partial epilepsy of right parietal origin as documented by ictal electroencephalogram (EEG) and glucose metabolism positron emission tomographic (PET) scan. His atonic seizures could not be controlled by multiple antiepilepsy drugs; therefore, cortical resection was scheduled. However, his seizures remitted spontaneously after 1 year of failed medical treatment. The epileptiform abnormality disappeared on the follow-up EEGs, and a glucose PET scan also normalized. This boy has fully retained his cognitive and motor functions and has remained seizure free in the past 4z\x years off medications.

Based on previous reports suggesting a role of the neurotransmitter serotonin in the pathomechanism of alternating hemiplegia of childhood and speculation that it may be a migraine variant, we measured brain serotonin synthesis in children with alternating hemiplegia of childhood. Clinical and neurodevelopmental data, as well as standard uptake values in 25 brain regions and whole-brain serotonin synthesis capacity (unidirectional uptake rate constant or K-complex), were assessed in six patients with alternating hemiplegia of childhood (three girls and three boys; mean age = 7 6/12 years) using alpha[11C]methyl-L-tryptophan positron emission tomography (PET). The PET studies were performed interictally in three patients, during the ictal state in two patients, and postictally in one patient. The PET data were compared to those obtained interictally from six age-matched patients with focal epilepsy (two girls and four boys; mean age = 7 8/12 years) and six non-age-matched apparently normal siblings of autistic children (two girls and four boys; mean age = 9 11/12 years). Patients with alternating hemiplegia of childhood studied in the ictal or postictal state showed increased serotonin synthesis capacity in the frontoparietal cortex, lateral and medial temporal structures, striatum, and thalamus when compared to controls, and subjects with alternating hemiplegia of childhood studied interictally. The involvement of these brain regions was consistent with the semiology of the hemiplegic attacks. In patients with interictal studies and in the controls, the PET scans revealed similar and bilaterally symmetric regional patterns of serotonin synthesis capacity. Increased whole-brain serotonin synthesis capacity (reported in migraine subjects without aura) was not found in the alternating hemiplegia of childhood group. There was no correlation between the neurodevelopmental scores and regional standard uptake values; however, patients with a larger estimated lifetime attack number showed greater delay in communication (P = .005) and daily living skills (P = .042). These studies suggest increased regional serotonergic activity associated with attacks in alternating hemiplegia of childhood. Furthermore, the attack number may have an effect on neurodevelopmental delay, thus supporting the notion that alternating hemiplegia of childhood may be a progressive disorder.

Infantile spasms--seen in West's Syndrome--are often associated with cortical abnormalities. The spasms themselves, however, appear to be generated subcortically. Dr. Chugani reviews the clinical data related to the pathophysiology of infantile spasms and proposes a hypothesis which involves both cortical and subcortical mechanisms.

Functional neuroimaging, especially positron emission tomography (PET) using various tracers, provided new insights into the pathophysiology of West syndrome in the past decade. Glucose PET studies revealed a unique corticosubcortical circuitry assumed to be involved in the age-dependent generalization of seizure activity leading to symmetric spasms. The findings strongly suggested that cortical abnormalities, mostly consistent with dysplastic lesions or diffuse cortical dysfunction due to an underlying systemic disorder, trigger brain stem nuclei and activate basal ganglia bilaterally. PET is also able to investigate developmental abnormalities of serotonergic and GABAergic neurotransmitter systems in vivo. Involvement of these systems in the pathophysiology of infantile spasms is strongly supported by animal data and can be further elucidated by future PET studies. In addition, the development of new PET tracers (such as neurotracers for imaging NMDA receptors) could help further clarify the role of altered neurotransmission in generation of spasms. This review of the most important functional neuroimaging findings illustrates how human PET and single photon emission computed tomography data help answer basic questions regarding the pathomechanisms involved in this often devastating condition and how these findings might facilitate development of a useful animal model of West syndrome.