Malignant progression of an extraventricular neurocytoma arising from the VIIIth cranial nerve: A case report and literature review.

A rare case of extraventricular neurocytoma (EVN) arising from the VIIIth cranial nerve in a 34-year-old woman is reported. The patient had a 20-year history of hearing loss and facial palsy. Computed tomography showed a 3-cm enhancing lesion in the left cerebellopontine angle (CPA). At operation, the tumor was seen to originate from the cochlear and vestibular nerves. The tumor was subtotally resected. Histologically, the tumor consisted of uniform cells with oval to round nuclei and scant cytoplasm. Immunohistochemically, the tumor cells were positive for synaptophysin, but negative for glial fibrillary acid protein and S-100 protein. The Ki-67 labeling index was 0%. Twelve years after the operation, magnetic resonance imaging (MRI) showed tumor recurrence at the left CPA. The tumor was subtotally resected, and radiation therapy was given. Histologically, the tumor consisted of round cells with mild atypia and one mitosis/20 high-power fields (HPF). Immunohistochemically, tumor cells showed the same findings as the first operation sample, except for the Ki-67 labeling index (3%). Twelve years after the second operation, MRI showed a second tumor recurrence at the left CPA and surroundings of the brain stem. The tumor was subtotally resected. Histologically, the tumor consisted of anaplastic short spindle cells and five mitoses/10 HPF. The immunohistochemical findings were almost the same as the earlier operation samples. However, the Ki-67 labeling index was 20%. In addition, tumor cells from the third specimen were more strongly and more diffusely positive for GAB1 (growth factor receptor-bound protein 2-associated binding protein 1) compared to those of the earlier specimens. Electron microscopy showed the presence of numerous cell processes with a dense core and clear vesicles and microtubules. GAB1 immunostaining also indicated that malignant progression might be associated with the sonic hedgehog signaling pathways. To the best of our knowledge, this is the first report of an EVN arising from the VIIIth cranial nerve with malignant progression.

Transmission electron microscopy studies of the vestibulocochlear nerve in chronic diabetic rats / Estudios de microscopía electrónica de transmisión del nervio vestibulococlear en ratas diabéticas crónicas

It is widely described in the literature that diabetic patients present hearing impairment. Despite the histological alterations of the internal ear structures in these patients as well as in experimental models of diabetes, to the best of our knowledge, an histological evaluation of the vestibulocochlear nerve have not been performed. In the present study, ultrastructural alterations are described and compared between a spinal nerves and a cranial nerve in rats with chronic induced diabetes. Male Wistar rats (n = 12), fed with standard diet from the animal care facility at 42 days of age were used. Induced diabetic animals (n=6) were fasted for 12 hours prior to being injected intraperitoneally with streptozotocin (STZ - 60mg/kg) in a single dose. Control animals (n=6) received (0.01 mol/l citrate buffer, pH 4.5) vehicle alone. Ten weeks after STZ injection the animals were perfused intracardially with Karnovsky solution. Right and left vestibulocochlear nerves were dissected and histologically processed for epoxy resin embedding. Samples were imaged with the transmission electron microscope. Large myelinated fibers with morphological signs of axonal atrophy in the vestibulocochlear nerves were readily observed. These results suggest that chronic STZ-induced diabetes in rats caused alterations in the myelinated fibers and Schwann cells, compatible to the classic diabetes signs and symptoms. Morphological alterations of the vestibulocochlear nerve in diabetes is described for the first time and contributes information for a better understanding of why there are changes in hearing observed in diabetic patients.

Se ha descrito ampliamente en la literatura que los pacientes diabéticos presentan discapacidad auditiva. En estos pacientes, a pesar de las alteraciones histológicas de las estructuras del oído interno, así como en modelos experimentales de diabetes, que mejoran nuestro conocimiento, la evaluación histológica del nervio vestibulococlear no ha sido realizada. Se describen y comparan las alteraciones ultraestructurales entre un nervio espinal y uno craneal en ratas con diabetes crónica inducida. Fueron utilizadas 12 ratas Wistar machos, de 42 días de edad, alimentadas con dieta estándar. Los animales diabéticos inducidos (n = 6) se mantuvieron en ayuno por 12 horas antes de ser inyectados por vía intraperitoneal con estreptozotocina (STZ - 60mg/kg) en una sola dosis. Los animales control (n = 6) sólo recibieron inyección de 0.01 mol/l buffer, citrato pH 4,5. Diez semanas después de la inyección de STZ, los animales fueron perfundidos intracardiacamente con solución de Karnovsky. Los nervios vestibulococlear derecho e izquierdo fueron disecados y procesados histológicamente para ser incluidos en resina epoxy. Las muestras fueron estudiadas con microscopio electrónico de transmisión. Fueron observadas fácilmente, grandes fibras mielinizadas con signos morfológicos de atrofia axonal en los nervios vestibulococlear. Estos resultados sugieren que la diabetes crónica inducida por STZ en ratas causó alteraciones en las fibras mielínicas y células del neurilema, compatible, con los signos y síntomas clásicos de la diabetes. Alteraciones morfológicas del nervio vestibulococlear en la diabetes son descritas por primera vez, lo que aporta información para una mejor comprensión de por qué hay cambios en la audición en los pacientes diabéticos.

Delayed-onset temporary auditory threshold shift following head blow in guinea pigs.

This study attempts to investigate the development of sensorineural hearing loss following a head blow without skull fracture in association with physiological and histopathologic changes in an experimental animal model. With the head in a freely movable position, albino guinea pigs were given a single blow to the occipital region by a head blow device. At 1, 7, and 14 days after the blow, the animals' auditory brainstem response (ABR) and cochlear microphonics (CM) were examined, and both the temporal bone and brain stem were observed by light and electron microscopy. The ABR threshold was unchanged at day 1, was significantly increased at day 7, and was fully recovered at day 14. The I-V and I-II interpeak latencies were significantly prolonged at days 1 and 7, and wave I latency was significantly prolonged at day 7 only. These latencies were recovered to normal limits at day 14. On the other hand, no significant change in CM versus the control group was observed at any point in the measurements. Histopathologically, no abnormal finding was seen at the light microscopic level. However, at the electron microscopic level, there were some injuries to the eighth nerve. At day 1, the lamellar structure of the myelin sheath was irregular, and the periaxonal space was expanded; at day 7, the myelin sheath was disintegrated. At day 14, however, these changes were partially reversed. These results suggest that sensorineural hearing loss following a head blow in this model is attributed to dysfunction of the eighth nerve rather than to cochlear impairment.

Trimetazidine prevents cochlear lesions induced by intraperitoneal and perilymphatic administration of kainic acid.

The protective activity of trimetazidine (TMZ) against cochlear neurotoxicity induced by intraperitoneal and intracochlear administration of kainic acid (KA) has been analyzed. The amplitude of the CAP N1 wave was significantly higher in KA rats pretreated with TMZ, independently of the administration route, than in those only treated with KA. However, CAP N1 amplitude of both TMZ pretreated and non-pretreated animals was always lesser than the N1 wave amplitude observed in the control group. The CAP N1 latency did not show any significant difference between KA and TMZ+KA groups except at high intensities of 8 and 12 kHz. As a complementary control, we have demonstrated that the intraperitoneal administration of TMZ (5 mg/kg) alone did not affect either the electrophysiological activity or the morphology of the auditory nerve. Morphological results fit well with electrophysiology. Some isolated swollen afferent fibers were observed in TMZ+KA cochleae, the swollen dendrites being sparser than in the KA only treated animals. In TMZ+KA animals, the cochlear apical coils were less affected than the basal coils. Our results are in agreement with recent clinical studies and suggest that TMZ could be an active drug on cochlear impairment linked to hypoxic-ischaemic syndromes.

Expression of cytochrome oxidase in hair cells of the teleost utricle.

Ultrastructural variation in some cytoplasmic organelles and synaptic structures is one characteristic distinguishing the types of hair cells in the teleost ear. In this study, we explored differences in mitochondria by analyzing mitochondrial reactivity for cytochrome oxidase (COX) in hair cells of the teleost utricle. The reactivity for COX within mitochondria in the subcuticular compartment directly beneath the cuticular plate differentiated among hair cells in utricles of three teleost species, Carassius auratus, Pantodon buchholzi, and Astronotus ocellatus. Mitochondria in the subcuticular region of hair cells in the striola reacted intensely. Within juxtastriola and extrastriolar hair cells near the striola, mitochondria reacted at a lowered intensity than in striolar hair cells. Subcuticular mitochondria of extrastriolar hair cells located distant from the striola reacted negligibly. The reactivity of mitochondria in other cytoplasmic compartments did not provide similar evidence for distinguishing among teleost hair cells. Mitochondria within intraepithelial branches of the eighth nerve terminals in the different utricular regions reacted to COX histochemistry commensurate with their respective presynaptic hair cells. Branches of sensory afferent neurons innervating striolar hair cells displayed a dense COX reaction. Sensory afferents innervating the extrastriolar hair cells did not display many mitochondria at synapses nor, when present, was the staining as dense. The presynaptic side of the hair cell-afferent nerve synapse usually, but not always, contained reactive mitochondria. The presynaptic side of the efferent nerve-hair cell synapse did not necessarily contain mitochondria. Mitochondria filling the cytoplasm in a type of juxtamacula cell revealed uniformly dense COX reactivity.

[Dissociation and culture of primary auditory neurons in postnatal chicken].

In the present study, a primary culture of auditory neurons in 10-16-day old chickens was carried out. We observed the morphologic features of auditory neurons at different culturing stages by using phased-contrast and scanning electron microscope, and particularly described their growth and developmental process. The results indicated that a steady and reliable culturing method established here would contribute to the biological research of inner ear in vitro.

Kangaroo rats exhibit spongiform degeneration of the central auditory system similar to that found in gerbils.

Kangaroo rats develop spongiform degeneration of the central auditory system similar to that seen in the gerbil. Light microscopic and transmission electron microscopic study of the cochlear nucleus and auditory nerve root (ANR) of Dipodomys deserti and D. merriami show that spongiform lesions develop in dendrites and oligodendrocytes of the cochlear nucleus and in oligodendrocytes of the ANR that are morphologically indistinguishable from those extensively described in the Mongolian gerbil, Meriones unguiculatus. As in Mongolian gerbils, the spongiform degeneration in Dipodomys were much more numerous in animals continually exposed to modest levels of low-frequency noise (< 75 dB SPL). The kangaroo rats with extensive spongiform degeneration also show slightly, but significantly, elevated auditory brainstem evoked response (ABR) thresholds to low-frequency stimuli, a result also found in Mongolian gerbils. These results suggest that the elevated ABR thresholds may be the result of spongiform degeneration. Because low-frequency noise-induced spongiform degeneration has now been shown in the cochlear nucleus of animals from separate families of Rodentia (Heteromyidae and Muridae), the possibility should be investigated that similar noise-induced degenerative changes occur in the central auditory system of other mammals with good low-frequency hearing.

The vasculature of the peripheral portion of the human eighth cranial nerve.

The vasculature of the peripheral portion of the human eighth cranial nerve (VIIIN) was investigated by light and transmission electron microscopy. Arterioles and venules running longitudinally around the VIIIN formed the extrinsic vascular system. The anatomical relationship between these extrinsic vessels and the VIIIN sheath was similar to that between blood vessels on the surface of the brain and the pia mater. In the endoneurium, postcapillary venules and large capillaries were sparsely distributed and longitudinally arranged, and these microvessels formed the intrinsic microvascular system, which was supported by the extrinsic vascular system via anastomosing vessels. The ultrastructural features of the internal auditory artery and its main branches were the same as those of other intracranial arteries. Ultrastructural study also revealed myo-endothelial junctions in anastomosing arterioles, and endothelio-pericytic junctions in extrinsic and anastomosing venules. Microvascular endothelial cells were connected by tight junctions in both the vestibular ganglion and the rest of the VIIIN. These features of the vasculature were considered to be effective for maintenance of the endoneurial fluid and regulation of the circulation in the peripheral portion of the human VIIIN.

Age-related loss of activity of auditory-nerve fibers.

1. Characteristic frequencies (CF), spontaneous rates (SR), and thresholds were recorded from single fibers in the auditory nerves of gerbils aged for 36 mo in a quiet vivarium. The data from the quiet-aged animals were compared with similar data obtained previously from young controls. Fibers were classified as "low-SR" if their spontaneous rates were < or = 18 spikes/s and "high SR" for higher rates. 2. For CFs > 6 kHz, the percentage of low-SR fibers contacted declined from 57% of the population in young gerbils to 29% in the aged gerbils. This population change is statistically significant (P < 0.01). At CFs < 6 kHz, the population demographics did not change significantly with age, with the low-SR fibers comprising 30 and 39% of the population, respectively, for the young and aged animals. 3. To further test the hypothesis that low-SR fibers with CFs > 6 kHz become less active with age, additional experiments were conducted to examine the recovery of the compound action potential (CAP) response from prior high-level stimuli. Previous work has shown that the CAP recovery curve has two segments: a fast segment associated with the high-SR fibers and a slow segment associated with the low-SR fibers. The curves obtained from quiet aged gerbils show a faster recovery than young controls for probe tones at 8 and 16 kHz, but not at 2 and 4 kHz. Thus these results agree with our single-fiber data indicating that there is a loss of low-SR activity for CFs > 6 kHz in the aged animals. 4. Low-SR fibers typically have larger dynamic ranges than those of high-SR fibers, are better able to preserve information concerning stimulus timing and amplitude modulation, and their responses are more robust in the presence of masking noise. Moreover, low-SR fibers are likely inputs to the crossed-olivocochlear reflex, a reflex that serves an antimasking role in the detection of sounds in a binaural noise field. If true for humans, the loss of the low-SR system could explain many of the hearing deficits often seen in older individuals; e.g., decreased ability to understand speech in noise, changes in masking level differences, and decreased ability to localize sound sources using binaural cues.

Normal evoked otoacoustic emissions with a profound hearing loss due to a juvenile pilocytic astrocytoma.

An interesting case is reported of an 11-year-old girl who experienced a sudden, profound right-sided hearing loss at the age of 5 years after hearing a "pop" and the sound of rushing water in her right ear. At that time the patient was thought to have Mondini's deformity, and a perilymphatic fistula of the oval window in the right ear. Six years later she was diagnosed with a juvenile pilocytic astrocytoma of the pons with an exophytic component extending into the cerebellopontine angle. Of particular interest in this case is the presence of evoked otoacoustic emissions in the right ear with a profound neural hearing loss. The presence of transient evoked and distortion product otoacoustic emissions confirmed normal sensory outer hair cell function and an intact peripheral auditory system in a clinically deaf ear, thus indicating hearing loss due to a neural component instead of a sensory component, which was previously assumed.

Angiogenesis from the eighth cranial nerve to vestibular schwannomas.

Vascularization between vestibular schwannomas and the adjacent eighth cranial nerve was examined in order to elucidate the angiogenic effect of these tumours. Specimens from 12 patients were examined by light microscopy and immunohistochemistry (series 1), while specimens from another 17 patients were examined by light and transmission electron microscopy (series 2). Slight to marked angiogenesis was found in 5 patients from series 1 and 7 patients from series 2. Ultrastructural examination indicated that these blood vessels were more fragile than those in the normal eighth cranial nerve. These findings suggested that sudden hearing loss in vestibular schwannoma patients may be related to the disruption of such blood vessels. In addition, surgical injury to these blood vessels may cause postoperative hearing loss despite preservation of the cochlear nerve.

Nerve growth factor receptor expression in heterotransplanted vestibular schwannoma in athymic nude mice.

Nerve growth factor (NGF) has the potential to induce cellular differentiation in various neoplastic and non-neoplastic cell lines. The purpose of the present study was to determine by immunohistochemistry: the presence/distribution of nerve growth factor receptor (NGFr), cellular proliferation expressed by Ki-67, and intratumoral vascularization visualized by the endothelial marker CD 31, in a series of 61 human vestibular schwannoma heterotransplants in athymic nude mice. The immunohistochemical results were correlated to the observed macroscopic growth in 22 heterotransplants (36%) with obvious macroscopic growth, versus 39 heterotransplants (64%), that were stationary or regressed. The positive immunoreactivity to NGFr, number of Ki-67 positive nuclei and number of intratumoral vessels were significantly higher in the 22 (36%) growing heterotransplants than in the 39 heterotransplants (64%), which were stationary or regressed (p < 0.00005, p = 0.046, p < 0.00001). NGFr was statistically related to the vascularity of the heterotransplants expressed by CD 31 (p<0.00001). No significant relation was observed between NGFr and the proliferation, as estimated by Ki-67. The results revealed that the macroscopic growth of VS in athymic nude mice was associated with strong positive expression of NGFr, high cellular proliferation expressed by Ki-67 and vivid neovascularization expressed by CD 31. The possible clinical applicability of the achieved results is discussed.

Synaptic input to cochlear nucleus dendrites that receive medial olivocochlear synapses.

Axons of olivocochlear neurons originate in the superior olivary complex and project to the cochlea. Along their course, medial olivocochlear axons give off branches to the cochlear nucleus. We labeled these branches with horseradish peroxidase and used electron microscopy to determine their target dendrites. Target dendrites were of two classes: "large" dendrites and "varicose" dendrites. Using serial sections, we reconstructed the dendrites and, in addition to the labeled olivocochlear input, we determined the synaptic profile of unlabeled inputs onto the dendrites. We classified the terminals on the basis of the shape and size of their synaptic vesicles. On large dendrites, the predominant type of unlabeled terminal had small round (SmRnd) vesicles. These terminals are likely to be excitatory, and some of them may originate from unlabeled medial olivocochlear branches. On varicose dendrites, the predominant type of terminal had pleomorphic vesicles. These terminals are likely to be inhibitory. They may be from descending inputs that arise in higher centers. A final type of terminal onto large dendrites exhibited signs of neuronal degeneration, possibly because the cell body of origin was damaged during the injection procedure. These terminals often had long, perforated synaptic densities and may originate from type II primary afferents. Thus, medial olivocochlear efferents and type II afferents, which both contact outer hair cells in the periphery, appear to synapse onto the same targets in the cochlear nucleus. In contrast, where examined, the target dendrites did not receive terminals with large vesicles from afferents that contact inner hair cells. Thus, target neurons appear to function in a neural circuit associated more closely with outer than with inner hair cells.

Activity-related features of synapse morphology: a study of endbulbs of held.

The myelinated fibers of the auditory nerve can be divided into two separate populations on the basis of sensitivity to sound, average levels of spike activity, and central branching patterns. The synaptic endings of these populations were investigated for the presence of structural specializations that might correlate with levels of neural activity. We applied intracellular recording and staining methods in cats to analyze directly the relationship between spike activity and the structure of synapses using endbulbs of Held, the large synaptic endings in the anteroventral cochlear nucleus. Endbulbs from fibers having low or high levels of activity were examined and compared using light and electron microscopic methods. All endbulbs exhibited relatively large but incomplete coverage by one-to-several lamellae of glial processes. Endbulbs of high activity fibers were large and contained larger mitochondria than endbulbs of low activity fibers. Furthermore, the synapses of high activity endbulbs were on average smaller but more numerous, possessed greater numbers of associated synaptic vesicles, and exhibited greater curvature of their postsynaptic densities. These structural features are hypothesized to reflect specializations that optimize synaptic transmission.

Laminin promotes differentiation, adhesion and proliferation of cell cultures derived from human acoustic nerve schwannoma.

The influence of laminin on cell cultures derived from unilateral acoustic nerve schwannomas was investigated. Cell cultures were initiated from 12 schwannomas, removed via the enlarged middle cranial fossa approach. Tumor tissue was dispersed by collagenase treatment and cells seeded in uncoated or laminin-coated culture dishes. Confluent cultures were immunocytochemically characterized with antibodies against S-100, CD 68, factor VIII-related antigen and type IV collagen. Cell adhesion in response to different doses of laminin was evaluated with an electronic cell counter. The effect of laminin on cell proliferation was assessed by measuring the incorporation of 5-bromo-2'-deoxy-uridine (BRDU) into cellular DNA. Cells cultured on laminin as substrate appeared more differentiated with long, fusiform, cytoplasmic processes. Cultured cells stained positive for S-100, not for factor VIII-related antigen or CD 68. Only cells cultured on laminin deposited a dense extracellular network of type IV collagen. When laminin was added to the culture medium, cell attachment and proliferation was stimulated in a dose dependent manner. Maximal stimulation of both was observed with a laminin concentration of 50 micrograms/ml, which induced a nearly 2-fold increase in cell attachment and an approximately 66% increase in DNA content. Since laminin is a major component of the extracellular matrix in schwannomas, the possibility exists that laminin is also mitogenic for human neoplastic Schwann cells in situ.

Neuronal organization of the cochlear nuclei in alligator lizards: a light and electron microscopic investigation.

The organization of neurons and fibers in the cochlear nuclei of the alligator lizard (Gerrhonotus multicarinatus) was examined with light and electron microscopy. In this species, much is known about the anatomy and physiology of the inner ear including the cochlear nerve, but little is known about the synaptic connections of cochlear fibers on second-order neurons. These data will help to develop general principles addressing the cellular organization of the vertebrate auditory system. Subdivisions of the cochlear nuclei were defined on the basis of their histologic appearance and neuronal composition. Neuron classes were proposed from their light microscopic and ultrastructural features. Nucleus magnocellularis medialis consists of a homogeneous population of neurons called "lesser ovoid" cells. Nucleus magnocellularis lateralis consists of "greater ovoid" and "small" cells. Nucleus angularis lateralis consists of "spindle" cells. Lastly, nucleus angularis medialis contains a population of large neurons called "duckhead" and "multipolar" cells, and a population of smaller neurons called "bulb" and "agranular" cells. These neuron populations are differentially innervated by tectorial and free-standing cochlear fibers that are associated with separate frequency ranges. All neuronal populations except agranular cells were observed to receive synaptic input from cochlear nerve fibers. In nucleus magnocellularis medialis and nucleus angularis medialis, primary afferents form both chemical and electrical synapses with resident neurons. These observations imply that acoustic information is synaptically processed in fundamentally distinct ways in the cochlear nuclei of alligator lizards and distributed along separate neural circuits. Thus, the characteristic structural and functional dichotomy of the alligator lizard inner ear is extended to central auditory pathways by way of cochlear nerve projections.

The limitations of hearing preservation in acoustic neuroma surgery: histological study of the interface between the eighth cranial nerve and the tumor.

The interface between the eighth cranial nerve and acoustic neuroma was investigated by light microscopy and immunohistochemistry in paraffin sections in 13 patients, and in Epon sections in 19 patients. The cochlear nerve was severely invaded by tumor cells in two of six specimens examined, moderately invaded in two specimens, and not invaded in two specimens. Gliosis was frequently found within the cochlear and vestibular nerve. Hemangioma-like tissue was occasionally found attached to the cochlear and vestibular nerve adjacent to the tumor. These findings were considered to be related to difficulty in hearing preservation in some patients although acoustic neuroma surgery was successful.

Normal and metastatic melanin in the temporal bone.

PURPOSE: Malignant melanoma is known to metastasize to the temporal bone. However, melanocytes exist in the normal inner ear and may be difficult to distinguish from metastatic melanotic cells. This study describes distribution of normal melanin in the ear and metastatic melanoma to the temporal bone. MATERIALS AND METHODS: Normal melanin distribution is described in 48 temporal bones from White (18), Native-American (19), and African-American (11) individuals and metastatic melanoma to the temporal bone is described in four cases (seven temporal bones). Temporal bones were removed at autopsy, fixed in 10% buffered formalin, and processed for routine celloidin embedding. Sections were cut at a thickness of 20 microns and every tenth section was stained with hematoxylin-eosin for light microscopic evaluation. RESULTS: Normal melanin was found in the inner ear, mainly around terminal neural structures and blood vessels, and occurred in greater quantities in African-American individuals. Metastatic melanotic cells reached the temporal bone by hematological dissemination, and by neural invasion from the central nervous system. No correlation was found between histopathological findings and clinical symptoms of patients. CONCLUSIONS: Metastatic melanoma to the temporal bone may be seen in the same areas as normal melanin. They may also be observed in bone marrow cells of the petrous bone and along the course of nerves of the internal auditory canal and cochlear vestibular labyrinth, either by following neural sheaths or blood vessels that run along the nerve. Metastatic disease to the temporal bone is often asymptomatic, or it may present with uncharacteristic symptoms that may delay diagnosis.

Ultrastructure of transitional region of the human eighth cranial nerve.

The transitional region of the eighth cranial nerve, where the central and peripheral nervous tissues are contiguous, was studied by electron microscopy using surgically resected specimens of the human eighth cranial nerve root. The astrocytic glial dome was sharply demarcated by a basement membrane from the peripheral portion of the nerve. Half-desmosomes were found on the edge of the astrocytic glial dome and at the luminal surface of the perivascular glial limiting membrane. Desmosomes and gap junctions were found between the astrocytic processes. These ultrastructural features suggest a weak link between the central and peripheral portions of the nerve which might predispose the transitional region to injury, although the peripheral and central portions have sufficient resistance to external stresses independently.