Trilateral retinoblastoma: insights into histogenesis and management.

Trilateral retinoblastoma (TRb) is a syndrome involving midline intracranial malignancies in children with the heritable form of retinoblastoma. All cases of TRb reported from 1971 to 1997 were reviewed. The histopathologic findings, clinical features, treatment modalities, and survival rates from 80 cases were evaluated. Histopathologic findings from intracranial malignancies demonstrated primitive neuroectodermal tumors in 61.5% of cases. Various degrees of neuronal or photoreceptor differentiation were seen in the other 38.5% of cases. Autopsy, histopathologic, and radiologic examinations did not show a more definitive site of origin of these intracranial tumors, although "pinealoblastoma" was often the diagnosis reported. These findings, together with analysis of the histopathologic similarities among human primitive neuroectodermal tumors, pinealoblastoma, retinoblastoma, and ependymoblastoma, suggest that TRb more likely arises from a germinal layer of predisposed primitive subependymal neuroblasts that are not necessarily destined for pineal or photoreceptor differentiation. Trilateral tumors have also been found in transgenic mice expressing the simian virus 40 T-antigen. Transgenic murine intracranial tumors are primitive neuroectodermal tumors arising from the subependymal layer. Transgenic mice with the murine interphotoreceptor cell binding protein promoter and simian virus 40 T-antigen also develop pineal tumors. Trilateral retinoblastoma is usually fatal, with an average survival time of 11.2 months. Therapies include radiation, systemic chemotherapy, intrathecal chemotherapy, and surgical resection/craniotomy in combination with radiation and/or chemotherapy. Survival may be prolonged with combination chemotherapy (24.6 months) and if neuroradiologic screening identifies TRb before symptoms are present (23.5 months). Recent success with platinum-based chemoreduction of intraocular retinoblastoma may indicate a similar role for platinum-based chemotherapy in the treatment of TRb. Routine central nervous system imaging should be considered in the management of TRb.

Brainstem motoneuron pools that are selectively resistant in amyotrophic lateral sclerosis are preferentially enriched in parvalbumin: evidence from monkey brainstem for a calcium-mediated mechanism in sporadic ALS.

Some brainstem motoneuron groups appear more resistant to the process of neurodegeneration in ALS (for example, oculomotor, trochlear, and abducens nuclei) than others (for example, trigeminal, facial, ambiguus, and hypoglossal nuclei). The possibility that the differential presence of the calcium-chelating protein parvalbumin might underlie this difference in vulnerability was examined immunohistochemically as a way to determine whether a calcium-mediated mechanism might be involved in ALS. In normal monkey brainstem, we found that the abundance of parvalbumin-containing neurons in the oculomotor, trochlear, and abducens nuclei was approximately 90% of the abundance of choline acetyltransferase (CHAT)-containing motoneurons. In contrast, the abundance of parvalbumin-containing neurons in the other brainstem motor nuclei innervating skeletal muscle (trigeminal, facial, ambiguus, and hypoglossal) was only about 30-60% of the abundance of CHAT-containing motoneurons. Since some of these motoneuron pools contain nonmotoneuron internuclear neurons that might be parvalbumin-containing, we also carried out double-label studies to specifically determine the percentage of cholinergic motoneurons that contained parvalbumin in each of these motoneuron pools. We found that 85-100% of the oculomotor, trochlear, and abducens motoneurons were parvalbumin-containing. In contrast, only 20-30% of the trigeminal, facial, ambiguus, and hypoglossal motoneurons were parvalbumin-containing. These results raise the possibility that motoneuron death in sporadic ALS is related to some defect that promotes cytosolic calcium accumulation in motoneurons. This excess calcium entry may promote cell death via an excitotoxic pathway. Motoneurons rich in parvalbumin may resist the deleterious effects of this putative calcium gating defect because they are better able to sequester the excess calcium.