An integrated diagnosis and therapeutic system using intra-operative 5-aminolevulinic-acid-induced fluorescence guided robotic laser ablation for precision neurosurgery.

We have developed an integrated diagnosis and therapeutic system for precision malignant gliomas resection during neurosurgery. A combination of three-dimensional (3-D) magnetic resonance imaging (MRI) navigation and 5-aminolevulinic acid (5-ALA)-induced fluorescence based intra-operative tumor diagnosis technique has been incorporated into a robotic laser ablation neurosurgery system with an automatic focusing and robotic scanning mechanism. 5-ALA is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent protoporphyrins IX (PpIX) in malignant glioma. The PpIX tends to accumulate in pathological lesions, and emits red fluorescence when excited by blue light. This fluorescence is illuminated with laser excitation, enables intra-operative identification of the position of a tumor and provides guidance for resection with laser photocoagulation. The information provided by the MRI is enhanced by the intra-operative 5-ALA fluorescence data, and this enhanced information is integrated into a robotic laser ablation system. The accuracy of the fluorescent measurement of the tumor is improved using high-precision spectral analysis. The fluorescence assists in the detection of malignant brain tumors intra-operatively and improves their removal rate.

Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause?

In phenylketonuria, mental retardation is prevented by a diet that severely restricts natural protein and is supplemented with a phenylalanine-free amino acid mixture. The result is an almost normal outcome, although some neuropsychological disturbances remain. The pathology underlying cognitive dysfunction in phenylketonuria is unknown, although it is clear that the high plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into brain and restrict the entry of other large neutral amino acids. In the literature, emphasis has been on high brain phenylalanine as the pathological substrate that causes mental retardation. Phenylalanine was found to interfere with different cerebral enzyme systems. However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large neutral amino acids in brain may also be an important factor affecting cognitive function in phenylketonuria. Cerebral protein synthesis was found to be disturbed in a mouse model of phenylketonuria and could be caused by shortage of large neutral amino acids instead of high levels of phenylalanine. Therefore, in this review we emphasize the possibility of a different idea about the pathogenesis of mental dysfunction in phenylketonuria patients and the aim of treatment strategies. The aim of treatment in phenylketonuria might be to normalize cerebral concentrations of all large neutral amino acids rather than prevent high cerebral phenylalanine concentrations alone. In-depth studies are necessary to investigate the role of large neutral amino acid deficiencies in brain.