Hoi Sang U

A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease

Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

Cholinergic innervation of the primate hippocampal formation: II. Effects of fimbria/fornix transection

The distribution of choline acetyltransferase (ChAT)‐immunoreactive and acetylcholines‐terase (AChE)‐positive fibers and terminals was analyzed in the hippocampal formation of macaque monkeys subjected to transection of the fimbria/fornix. Cases with either unilateral or bilateral transections were prepared, with post transection survival times ranging from 2 weeks to 1.5 years. The fimbria/fornix transection resulted in a dramatic decrease in the number of cholinergic fibers in most regions of the hippocampal formation. Some hippocampal regions. however, showed relatively greater sparing of ChAT‐ or AChE‐positive fibers. In practically all regions of the hippocampal formation, residual AChE‐positive fibers were more abundant than ChAT‐immunoreactive fibers. In animals with unilateral lesions, the distribution patterns and density of AChE and ChAT staining on the side contralateral to the lesion were generally similar to those of sections from unlesioned control brains. The largest decreases in the densities of positive fibers were observed in the dentate gyrus, CA3 and CA2 fields of the hippocampus, subiculum, parasubiculum, and medial and caudal parts of the entorhinal cortex. Fibers were relatively better preserved in the rostral or uncal portion of the hippocampus and dentate gyrus and in the rostral portion of the entorhinal cortex. The presubiculum demonstrated remarkable sparing that contrasted with the almost complete loss of fibers in the parasubiculum. Interestingly, animals killed approximately 1.5 years after the fornix transection showed essentially the same pattern of fiber loss as the cases with shorter survival periods. This indicates that the residual ChAT‐immunoreactive fibers, many of which reach the hippocampal formation through a ventral cholinergic pathway, are not capable of reinnervating the denervated portions of the hippocampal formation. This appears to distinguish the monkey from the rat, for which substantial sprouting and reinnervation of cholinergic fibers have been reported after similar lesions.

The Hemodynamic Consequences of High-dose Methohexital Anesthesia in Humans

The hemodynamic, electroencephalographic (EEG), and metabolic effects of a high-dose methohexital anesthetic were examined in eight neurosurgical patients. The patients were studied at rest and at 15-min intervals during a 60-min infusion of the drug, given at a rate of 0.40 mg · kg-1 · min-1 (total dose 24 mg/kg). Ventilation was controlled with oxygentair (FIO2 = 0.50), and fluid was infused at a rate sufficient to maintain pulmonary capillary wedge (PCW) pressures at control values (8 ± 2 mmHg, mean ± SD). Serum methohexital concentrations increased progressively, reaching values of 11.7 ± 2.9 μg/ml at t = 30 min and 18.1 ± 10.8 μg/ml at t = 60 min. Characteristic barbiturate-induced EEG changes were noted, with isoelectricity achieved at t = 28 ± 13 min.Methohexital infusion resulted in significant reductions in arterial pressure (84% of control at t = 60 min), systemic vascular resistances (83% of control at t = 60 min), right and left ventricular stroke work indices (65% and 68% of control, respectively at t = 60 min), and total body O2 consumption (76% of control at t = 60 min). In addition, a progressive dose-related decrease in stroke volume index was noted (50.1 ± 90 ml ± beat-1 · m-2 at t = 0, 40.1 ± 10.2 ml · beat-1 · m-2 at t = 60 [80% of control]). This occurred in spite of unchanged ventricular filling pressures. However, cardiac index was well maintained (unchanged at t = 60 min) because of increases in heart rate (123% of control at t = 60 min). There was no change in PaO2, PaCO2, or pulmonary vascular resistance.These data demonstrate that doses of methohexital sufficient to produce profound EEG suppression are accompanied by both vasodilation and some depression of myocardial function, even when ventricular filling pressures are maintained. Nevertheless, the magnitude of these changes suggests that high doses of methohexital may be a hemodynamically acceptable form of anesthesia for certain restricted neurosurgical procedures. However, refractory postoperative seizures occurring in three patients indicate that this anesthetic technique has potentially serious associated difficulties. For this latter reason, the authors have suspended their use of methohexital and are examining the utility of alternative barbiturates.

Preoperative Versus Postoperative Neuropsychological Sequelae of Arteriovenous Malformations

In a cohort of 14 patients suffering from cerebral arteriovenous malformations (AVM), neuropsychological functioning was examined before and after AVM resection. Improvements after surgery were assumed to be due to enhanced neurocognitive functions associated with the hemisphere ipsilateral to the AVM, and to a lesser extent, with the contralateral hemisphere. Before surgical intervention, the performances of AVM patients were deficient relative to matched normals. Postoperatively, neuropsychological gains were observed particularly in the areas of learning, memory, and higher integrative thought, not only for ipsilateral, but also for contralateral functioning. Contralateral and ipsilateral improvement is consistent with the premise that cerebrovascular steal is lessened; thus, neurosurgical intervention to eliminate arteriovenous shunts was found to result in overall neurobehavioral gains.

The Inter-Mammary Sticky Roll: A Novel Technique for Securing a Doppler Ultrasonic Probe to the Precordium for Venous Air Embolism Detection

Venous air embolism is a devastating and potentially life-threatening complication that can occur during neurosurgical procedures. We report the development and use of the “inter-mammary sticky roll,” a technique to reliably secure a precordial Doppler ultrasonic probe to the chest wall during neurosurgical cases that require lateral decubitus positioning. We have found that this noninvasive technique is safe, and effectively facilitates a constant Doppler signal with no additional risk to the patient.

Intracranial Rhabdomyoma: Case Report and Review of the Literature

A 24-year-old male presented with eight months of increasingly severe frontal headaches, decreased right facial sensation, and periodic vertigo. Magnetic resonance imaging demonstrated a heterogeneously contrast-enhancing mass involving and expanding the right foramen ovale. A biopsy of the lesion was performed, and the final pathologic diagnosis revealed a neoplastic rhabdomyoma. To date, only five cases of intracranial rhabdomyoma have been reported, and a rhabdomyoma involving the trigeminal nerve has never been described in an adult. This manuscript reviews the available literature and highlights the clinical, imaging, pathologic characteristics, and surgical management of these exceedingly rare lesions.

Inflammatory Myofibroblastic Tumor of the Left Sphenoid and Cavernous Sinus Successfully Treated with Partial Resection and High Dose Radiotherapy: Case Report and Review of the Literature.

Inflammatory myofibroblastic tumors, also known as plasma cell granulomas or inflammatory pseudotumors, are uncommon lesions that are known to arise in many areas of the body. They are uncommonly found in the skull base region where effective treatment can be difficult. Steroids and radiation therapy with gross total excision when possible remain the treatments of choice. However, the dosing of radiation remains controversial and many patients develop relapse despite medical management. We present the case of a patient who had an inflammatory myofibroblastic tumor of the sphenoid bone and cavernous sinus. He underwent partial surgical resection and transient steroid therapy. This was followed by high-dose fractionated radiotherapy. The patient demonstrated significant resolution in symptomatology and evidence of disease-free progression on repeat imaging.