Genetic analysis in the diagnosis of familial paragangliomas.

OBJECTIVES: In the management of two related patients with multicentric glomus jugulare tumors, given the incidence of 1:30,000 with approximately 20% familial cases, our objective was to review the genetic characteristics and inheritance patterns of these tumors and to determine what molecular genetic screening possibilities exist for the phenotypically normal family members. In addition, our aim was to review the incidence of various multicentric paraganglioma (PGL) tumor location combinations. METHODS: Molecular genetic linkage analysis testing was performed on the 2 patients and 14 other unaffected family members. We report the results of this screening and review the literature on the incidence and genetics of paragangliomas. RESULTS: The inheritance pattern in the literature demonstrates autosomal dominant transmission with maternal imprinting (inactivation). The proclivity for multicentric origin increases to 26% in familial cases, as reflected in our patients. In addition to the two patients, four unaffected family members demonstrated the presence of the disease haplotype at chromosome band 11q23, which indicates a very high likelihood of developing a paraganglioma, given the highly penetrant nature of the disease. CONCLUSIONS: It is clear that the familial PGL gene locus is situated at chromosome 11q23. The gene itself and its exact degree of penetrance, however, still await identification. Since early detection of paragangliomas reduces the incidence of morbidity and mortality, genotypic analysis as a screening tool in families of affected patients should play a front-line diagnostic role, leading to more timely and cost-effective patient management.

Induction of facial muscle neurotization by temporalis muscle transposition: literature review and animal model evaluation using horseradish peroxidase uptake.

OBJECTIVE: To study the concept of facial muscle reinnervation from the trigeminal pathway following facial nerve paralysis. DESIGN AND METHODS: We studied this phenomenon in an animal model using the neuronal marker, horseradish peroxidase (HRP). The temporalis transposition procedure was performed at varying intervals post facial nerve transection. To evaluate the trigeminal-facial reinnervation process and its timing, the zygomaticus major muscle was injected with HRP at varied periods after temporalis transposition, and histologic sections of the brainstem nuclei were examined for the final location of the HRP. RESULTS: The presence of HRP in the trigeminal nucleus provided evidence of trigeminal-facial neurotization in those animals that underwent temporalis transposition up to 2 months following facial denervation and in which the HRP injection was performed 4 months after temporalis transposition. CONCLUSIONS: The findings of our pilot study are strongly supportive of the trigeminal-facial neurotization hypothesis in those animals that underwent temporalis transposition up to 2 months post facial denervation and in which 4 months were allowed thereafter for adequate neurite ingrowth and neurotization to occur. This suggests that the neurotrophic signals are greatest up to 2 months post denervation and denotes the optimal time for performance of reconstructive procedures. Future studies with a larger number of animals in each group will be necessary to ensure more potent statistical significance and to augment our experimental evidence that trigeminal-facial crossover does occur and can be used as an adjunctive concept to maximize early rehabilitation of the paralyzed face.

Yaw sensory rearrangement alters pitch vestibulo-ocular reflex responses.

Ten male subjects underwent two types of adaptation paradigm designed either to enhance or to attenuate the gain of the canal-ocular reflex (COR), before undergoing otolith-ocular reflex (OOR) testing with constant velocity, earth horizontal axis and pitch rotation. The adaptation paradigm paired a 0.2 Hz sinusoidal rotation about an earth vertical axis with a 0.2 Hz optokinetic stimulus that was deliberately mismatched in peak velocity or phase and was designed to produce short-term changes in the COR. Preadaptation and postadaptation OOR tests occurred at a constant velocity of 60 degrees/sec in the dark and produced a modulation component of the slow phase velocity with a frequency of 0.16 Hz due to otolithic stimulation by the sinusoidally changing gravity vector. Of the seven subjects who showed enhancement of the COR gain, six also showed enhancement of the OOR modulation component. Of the seven subjects who showed attenuation of the COR gain, five also showed attenuation of the OOR modulation component. The probability that these two cross-axis adaptation effects would occur by chance is less than 0.02. This suggests that visual-vestibular conditioning of the yaw axis COR also induced changes in the pitch axis OOR. We thus postulate that the central nervous system pathways that process horizontal canal yaw stimuli have elements in common with those processing otolithic stimuli about the pitch axis.

MR imaging of neuronal transport in the guinea pig facial nerve: initial findings.

Certain dextran coated iron oxides such as MION (monocrystalline iron oxide nanocompound) coupled to wheat germ agglutinin (MION-WGA) have been shown to exhibit i) neuronal uptake ii) axonal transport and iii) strong magnetic effects on tissues (superparamagnetism) in which they are localized. In the current study, we utilized such an agent to visualize axonal transport in the facial nerve in vivo by magnetic resonance (MR) imaging. Following injection of the compound into the facial nerves of guinea pigs, MR images were obtained at multiple time points (1, 3 and 5 days) and the imaged tissues were processed for subsequent histological examination. In nerves that had been injected with MION-WGA, the entire nerve appeared as a uniformly hypointense structure with a calculated transport rate of 5 mm/day. By 3 days, the agent within the facial nerve was traceable by MRI from a site of injection in the buccal branch to the stylomastoid foramen. Fluorescence and autoradiography studies confirmed axonal transport. These results show that MION-based magnetopharmaceuticals can be used to demonstrate slow axonal transport, and thereby visualize functional peripheral nerves in vivo by MR imaging. The method holds promise for developmental neuroscience research as well as a method to detect neural abnormalities by MR imaging.

Human vertical eye movement responses to earth horizontal pitch.

The vertical eye movements in humans produced in response to head-over-heels constant velocity pitch rotation about a horizontal axis resemble those from other species. At 60 degrees/s these are persistent and tend to have non-reversing slow components that are compensatory to the direction of rotation. In most, but not all subjects, the slow component velocity was well characterized by a rapid build-up followed by an exponential decay to a non-zero baseline. Super-imposed was a cyclic or modulation component whose frequency corresponded to the time for one revolution and whose maximum amplitude occurred during a specific head orientation. All response components (exponential decay, baseline and modulation) were larger during pitch backward compared to pitch forward runs. Decay time constants were shorter during the backward runs, thus, unlike left to right yaw axis rotation, pitch responses display significant asymmetries between paired forward and backward runs.