The relationship of the uvula with snoring and obstructive sleep apnea: a systematic review.

Currently, the relationship between uvula size and sleep-disordered breathing (snoring and obstructive sleep apnea) lacks data for objective interpretation. This study conducted a systematic review of the international literature for research describing the measurable characteristics of the uvula (i.e., size, length, width) and any association with snoring and obstructive sleep apnea (OSA). PubMED, Scopus, Google Scholar, Embase, and the Cochrane Library were each systematically searched from inception through November 15, 2016. We screened 1037 titles and abstracts. We conducted a full review of 54 downloaded articles. Sixteen articles met inclusion and exclusion criteria. The 16 studies included a total of 2604 patients. The selected articles included data and information for (1) normative data for uvular size in the control groups, (2) snoring and uvula size, (3) OSA and uvula size, and (4) overall uvula function. Our review noted variability in findings; however, in general, a uvular length > 15 mm was considered elongated and a uvular width > 10 mm was considered to be wide. The studies included in this systematic review reveal a relationship between uvula size, snoring, and OSA. Further, larger uvulas appear associated with more severe snoring and OSA. The direct correlation between uvula size and its relationship specifically to snoring and OSA remain as topics for future prospective research.

Neuromuscular function of the soft palate and uvula in snoring and obstructive sleep apnea: A systematic review.

OBJECTIVE: A collapsible upper airway is a common cause of obstructive sleep apnea. The exact pathophysiology leading to a more collapsible airway is not well understood. A progressive neuropathy of the soft palate and pharyngeal dilators may be associated with the progression of snoring to OSA. The purpose of this study is to systematically review the international literature investigating the neurophysiologic changes in the soft palate and uvula that contribute to progression from snoring to OSA. METHODS: PubMed/MEDLINE and 4 other databases were systematically searched through July 4, 2017. Eligibility: (1) Patients: controls, snoring or OSA patients (2) Intervention: neuromuscular evaluation of the palate and/or uvula (3) Comparison: differences between controls, snoring and OSA patients (4) Outcomes: neuromuscular outcomes (5) Study design: Peer reviewed publications of any design. RESULTS: 845 studies were screened, 76 were downloaded in full text form and thirty-one studies met criteria. Histological studies of the soft palate demonstrated diffuse inflammatory changes, muscular changes consistent with neuropathy, and neural aberrancies. Sensory testing studies provided heterogeneous outcomes though the majority favored neuronal dysfunction. Studies have consistently demonstrated that increasing severity of snoring and sleep apnea is associated with worsening sensory nerve function of the palate in association with atrophic histological changes to the nerves and muscle fibers of the soft palate and uvula. CONCLUSIONS: Recent evidence highlighted in this systematic review implicates the role of neurogenic pathology underlying the loss of soft palate and/or uvular tone in the progression of snoring to sleep apnea.

Immunohistochemical and histomorphometric study of human uvula innervation: a comparative analysis of non-snorers versus apneic snorers.

OBJECTIVE: The objective of this study was to verify a possible correlation between the etiology of uvulopalatal ptosis and decrease in palatopharyngeal muscle tone, due to a reduction of the number of nerve fibers in surgical specimens obtained from snoring patients. DESIGN/SETTING OF THE STUDY: We have designed a comparative retrospective, case-control, double-blind, immunohistochemical and histomorphometric study of human uvula innervation in 51 apneic snoring patients who underwent uvulopalatopharyngoplasty (UPPP) and 47 normal subjects collected in a 5-year-long period in the Departments of Otolaryngology of Desio and Forlì Hospital, Italy. PATIENTS: Case study was chosen in patients who underwent UPPP, variably associated with other disobstructive surgical procedures for treatment of obstructive sleep apnea syndrome, classified according to current clinical, polysomnographic, endoscopic, and imaging criteria. Control subjects were recruited at the Institute of Legal Medicine, University of Milan, according to strong inclusion and exclusion criteria. The main outcome measure of the study was the number of nerve fibers in the patients' uvula evaluated histologically and repeated two times by two different people, in all the areas of the specimens. Finally, we correlated the area of the histological section with the number of fibers contained therein. RESULTS: The number of nerve fibers varied from a minimum of 58 to a maximum of 163 in normal subjects. In the snoring patient population, the number of nerve fibers varied from a minimum of 22 to a maximum of 126 (statistically significant difference, p < 0.0001). In conclusion, our results direct toward a clear neurogenetic predisposition to uvulopalatal ptosis, marked ab initio by a lower set of motor nerve fibers, which may be the initial stage of another subsequent morphological and functional abnormality.

Electron microscopy study of peripheral nerves in the uvulae of snorers and obstructive sleep apnoea patients.

HYPOTHESIS: The pathophysiology of snoring and obstructive sleep apnoea is still unclear. Two theories are proposed. The first is the obstructive theory, which postulates palatopharyngeal muscle hypertrophy leading to airway narrowing; there is no neural role. The second is the neurogenic theory, which postulates neural degeneration due to vibratory stretch trauma, leading to muscle atrophy and collapse. As identification of nerve fibres in the uvula and palate is difficult and time-consuming, all previous studies aiming to differentiate between these two theories have been based on indirect observation of the muscles, rather than direct study of the nerves. METHODS: We conducted a prospective study to directly observe and study nerve fibres in uvular specimens from 10 cases of obstructive sleep apnoea, compared with specimens from 10 cases of simple snoring, using transmission electron microscopy. Five autopsy cases served as controls. RESULTS: Obstructive sleep apnoea was associated with definite degenerative changes in myelinated and unmyelinated nerve endings. These degenerative changes were present to a lesser degree and in a smaller proportion of cases of simple snoring. CONCLUSION: The events postulated by the neurogenic theory of obstructive sleep apnoea appear to play an important role in the pathophysiology of snoring and obstructive sleep apnoea.

Lesions of the cerebellar nodulus and uvula impair downward pursuit.

We studied sinusoidal (SIN) and step-ramp (SR) pursuit in two rhesus monkeys, before and after surgical lesions of the cerebellar nodulus and uvula (Nod/Uv). Eye movements were recorded using the magnetic field scleral search coil method. Pursuit targets were generated by an LCD projector and back-projected onto a tangent screen in an otherwise dark room. After the Nod/Uv lesions, both monkeys showed a reduced eye velocity during downward pursuit (SIN: 42% decrease in M1, 91% decrease in M2; SR: 37% decrease in M1, 85% decrease in M2). For SR, the decrease was seen only for the closed-loop response; initial eye acceleration did not change (P>0.05). Upward pursuit gains increased for SIN (M1: 9%, M2: 11%); they decreased for SR (M1: 27%, M2: 18%), but to a lesser degree than for downward pursuit. Horizontal pursuit was little changed in M1 but was reduced in one direction in M2, the animal with the larger lesion. The deficit in downward tracking was limited to foveal pursuit; ocular following of random-dot stimuli was retained, even when the target subtended only several degrees. Our findings support a critical role for the Nod/Uv in vertical pursuit, particularly for sustained downward pursuit. Finally, in both monkeys, the lesion increased spontaneous upward ocular drift in the dark (mean prelesion, 1.43 degrees/s; postlesion, 5.92 degrees/s), suggesting a role for the Nod/Uv in holding the eyes still and in the genesis of downbeat nystagmus.

Spatial symmetry groups as sensorimotor guidelines.

While some aspects of neuroanatomical organization are related to packing and access rather than to function, other aspects of anatomical/physiological organization are directly related to function. The mathematics of symmetry groups can be used to determine logical structure in projections and to relate it to function. This paper reviews two studies of the symmetry groups of vestibular projections that are related to the spatial functions of the vestibular complex, including gaze, posture, and movement. These logical structures have been determined by finding symmetry groups of two vestibular projections directly from physiological and anatomical data. Logical structures in vestibular projections are distinct from mapping properties such as the ability to maintain two- and three-dimensional coordinate systems; rather, they provide anatomical/physiological foundations for these mapping properties. The symmetry group of the direct projection from the semicircular canal primary afferents to neck motor neurons is that of the cube (O, the octahedral group), which can serve as a discrete skeleton for coordinate systems in three-dimensional space. The symmetry group of the canal projection from the secondary vestibular afferents to the inferior olive and thence to the cerebellar uvula-nodulus is that of the square (D8), which can support coordinates for the horizontal plane. While the mathematical relationship between these symmetry groups and functions of the vestibular complex are clear, these studies open a larger question: what is the causal logic by which neural centers and their intrinsic organization affect each other and behavior? The relationship of vestibular projection symmetry groups to spatial function make them ideal projections for investigating this causal logic. The symmetry group results are discussed in relationship to possible ways they communicate spatial structure to other neural centers and format spatial functions such as body movements. These two projection symmetry groups suggest that all vestibular projections may have symmetry groups significantly related to function, perhaps all to spatial function.

Topography and axonal collaterals of trigeminocerebellar projection to the paramedian lobule and uvula in the rabbit cerebellum.

To study projections of the trigeminal sensory nuclei (TSN) to the rostral parts of the paramedian lobule (PML) and of the uvula of the rabbit cerebellar cortex, the retrograde double fluorescent labeling method was used. Injections of Fast Blue (FB) into PML and Diamidino Yellow (DY) into the uvula, resulted in prominent labeling neurons with FB bilaterally and with DY ipsilaterally, in the principal trigeminal nucleus, subnucleus oralis, and rostral and caudal subnucleus interpolaris. We observed topographical arrangement of neurons in such a fashion that FB labeled cells were localized in the medial and DY labeled cells in the lateral regions of TSN. Apart from this small number of double FB+DY labeled neurons (n = 138) were found in the narrow common region of single labeling. This implies that PML and the uvula receive independent trigeminal sensory information from neurons in separate regions of TSN. However, some trigeminal neurons may also exert simultaneous influences upon these hemispheral and vermal components by way of axonal branchings.

Nerve supply to the soft palate muscles with special reference to the distribution of the lesser palatine nerve.

OBJECTIVE: Descriptions of the innervation of the soft palate muscles in previous studies have varied according to the author. In the present study, distribution of the lesser palatine nerve, through which motor fibers of the facial nerve are considered to reach soft palate muscles, and that of the pharyngeal plexus in the soft palate were investigated in order to reexamine the innervation of the soft palate muscles according to anatomical evidence. RESULTS: Observations suggested that the levator veli palatini and palatopharyngeus were doubly innervated by branches of the lesser palatine nerve and pharyngeal plexus, and that the musculus uvulae was innervated by only the lesser palatine nerve. CONCLUSION: The soft palate is considered to be located in the border region between the areas of distribution of the lesser palatine nerve and pharyngeal plexus. This may be why controversies exist in previous studies about the innervation of the soft palate muscles.

Two-point palatal discrimination in patients with upper airway resistance syndrome, obstructive sleep apnea syndrome, and normal control subjects.

STUDY OBJECTIVE: To compare the results of a two-point palatal discrimination response in normal subjects (n = 15), patients with obstructive sleep apnea syndrome (OSAS) [n = 15], and patients with upper airway resistance syndrome (UARS) [n = 15] matched for age, sex, and body mass index. DESIGN: Comparison study of three subject groups. SETTING: A sleep-disorders clinic. SUBJECTS: Participants were selected based on clinical questionnaire, clinical evaluation, and polysomnography. INTERVENTION: Polysomnography involving measurement of flow limitation with a nasal cannula pressure transducer system and of respiratory effort with esophageal pressure was performed in order to recognize the presence, absence, and types of sleep-disordered breathing. The 45 subjects were submitted to a two-point palatal discrimination study during wakefulness performed by an investigator blinded to the polysomnogram results. RESULTS: Patients with OSAS had a clear impairment of their palatal sensory input with a significant decrement in two-point discrimination, but patients with UARS and normal control subjects had similar responses. Patients with UARS exhibited at least intermittent snoring in most cases. CONCLUSION: The normal responses seen in patients with UARS indicate that these patients are more capable of transmitting sensory inputs than patients with OSAS. This may be one element explaining the difference in arousal response previously documented in UARS compared to OSAS.

Secondary vestibular cholinergic projection to the cerebellum of rabbit and rat as revealed by choline acetyltransferase immunohistochemistry, retrograde and orthograde tracers.

Previously we have shown that four regions of the cerebellum, the uvula-nodulus, flocculus, ventral paraflocculus, and anterior lobe 1, receive extensive, but not exclusive, cholinergic mossy fiber projections. In the present experiment we have studied the origin of three of these projections in the rat and rabbit (uvula-nodulus, flocculus, ventral paraflocculus), using choline acetyltransferase (ChAT) immunohistochemistry in combination with a double label, retrogradely transported horseradish peroxidase (HRP). We have demonstrated that in both the rat and rabbit the caudal medial vestibular nucleus (MVN) and to a lesser extent the nucleus prepositus hypoglossus (NPH) contain ChAT-positive neurons. Neurons of the caudal MVN are double-labeled following HRP injections into the uvula-nodulus. HRP injections into the uvula-nodulus also labeled less than 5% of the neurons in the cholinergic vestibular efferent complex. Fewer ChAT-positive neurons in the MVN and some ChAT-positive neurons in the NPH are double-labeled following HRP injections into the flocculus. Almost no ChAT-positive neurons in the MVN and some ChAT-positive neurons in the NPH are double-labeled following HRP injections into the ventral paraflocculus. Injections of Phaseolus leucoagglutinin (PHA-L) into the caudal MVN of both the rat and rabbit demonstrated projection patterns to the uvula-nodulus and flocculus that were qualitatively similar to those observed using ChAT immunohistochemistry. We conclude that the cholinergic mossy fiber pathway to the cerebellum in general and the uvula-nodulus in particular is likely to mediate secondary vestibular information related to postural adjustments.

Cholinergic innervation of the cerebellum of rat, rabbit, cat, and monkey as revealed by choline acetyltransferase activity and immunohistochemistry.

The cholinergic innervation of the cerebellar cortex of the rat, rabbit, cat and monkey was studied by immunohistochemical localization of choline acetyltransferase (ChAT) and radiochemical measurement of regional differences in ChAT activity. Four antibodies to ChAT were used to find optimal immunohistochemical localization of this enzyme. These antibodies selectively labeled large mossy fiber rosettes as well as finely beaded terminals with different morphological characterization, laminar distribution within the cerebellar cortex, and regional differences within the cerebellum. Large "grape-like" classic ChAT-positive mossy fiber rosettes that were distributed primarily in the granule cell layer were concentrated, but not exclusively located in three separate regions of the cerebellum in each of the four species studied: 1) The uvula-nodulus (lobules 9 and 10); 2) the flocculus-ventral paraflocculus, and 3) the anterior lobe vermis (lobules 1 and 2). No intrinsic cerebellar neurons were labeled. No cells in either the inferior olive (the origin of cerebellar climbing fibers) or in the locus coeruleus (an origin of noradrenergic fibers) were ChAT-positive. Thin, finely beaded axons, similar to cholinergic axons of the cerebral cortex of the rat, were observed in both the granule cell layer and molecular layer of the cerebellar cortex of the rat, rabbit and cat. The regional differences in ChAT-positive afferent terminations in the cerebellar cortex was for the most part confirmed by regional measurements of ChAT activity in the rat, rabbit, and cat. The three cholinergic afferent projection sites correspond to regions of the cerebellar cortex that receive vestibular primary and secondary afferents. These data imply that a subset of vestibular projections to the cerebellar cortex are cholinergic.

Efferent connections of lobule IX of the posterior cerebellar cortex in the rabbit--some functional considerations.

The Purkinje cell projection from the cardiovascular region of sublobule b of the uvula (medial area of zone A) has been investigated using anterograde tracing methods in the rabbit. The importance of the integrity of the identified pathways in mediating the cardiovascular responses from the uvula has been studied in subsequent lesioning experiments. Wheat germ agglutinin-conjugated horseradish peroxidase or tritiated amino acids were microinjected into sublobule IXb. This resulted in anterogradely labelled Purkinje cell axons in both the inferior and superior cerebellar peduncle. In agreement with previous studies in rabbit we also found labelled fibres at the level of the fastigial nucleus and vestibular complex. However, the labelled fibres we observed in the parabrachial nucleus have not been reported in previous studies except in the prosimian primate. Projections from IXb showed terminal-like patterns of label in the ventromedial region of the caudal fastigial nucleus, the dorsal areas of the superior and inferior vestibular nuclei and in the medial and lateral divisions of the parabrachial nucleus. Labelled fibres were also seen coursing in the lateral vestibular nucleus. Lesioning experiments have revealed that the integrity of the superior cerebellar peduncle is essential for the expression of the cardiovascular responses (bradycardia and depressor response) elicited from the uvula in the anaesthetized rabbit. In contrast, the pattern of cardiovascular response evoked in a decerebrate rabbit (tachycardia and pressor response) was abolished when the inferior cerebellar peduncle was lesioned.

The dorsomedial portion of trigeminal nucleus oralis (Vo) in the rat: cytology and projections to the cerebellum.

Electrophysiological studies have described four major tactile areas in the rat cerebellar cortex. These areas are in crus I, crus II, the paramedian lobule (PML), and the uvula, and a major portion of each is related to the ipsilateral orofacial region. This study demonstrates that neurons in trigeminal nucleus oralis (Vo) that project to the orofacial portions of these four major tactile areas are localized in the dorsomedial (DM) subdivision of the nucleus. The distribution, light-microscopic morphology, and relative densities of trigeminocerebellar neurons within DM, retrogradely labeled with horseradish peroxidase (HRP) following injections into each of the four major tactile areas, were analyzed and compared as well as correlated with the myelo- and cytoarchitecture of DM observed in Nissl sections, 1-micron sections, and Golgi material. On the basis of myelo- and cytoarchitectonic as well as trigeminocerebellar connectional criteria, three portions of DM were identified: caudal DM (CDM), middle DM (MDM), and rostral DM (RDM). The greatest portion of DM is made up of MDM (1.3 mm long), which can be further subdivided into dorsal (MDMd) and ventral (MDMv) zones. CDM forms the caudal 800 microns of DM, while RDM makes up the rostral 280 microns of the subdivision. Longitudinally running deep axon bundles permeate CDM, MDMv, and RDM, but are conspicuously absent from MDMd. The majority of neurons found throughout CDM, MDMv, and RDM have medium-sized (15- to 30-microns) somata and can be divided into two types on the basis of their somatodendritic morphology. CDM, MDMv, and RDM also contain a small neuronal cell type (5- to 15-microns cell body) that is encountered less frequently than either one of the two types of medium-sized cells. A fourth type of neuron with a large (25- to 50-microns) fusiform- to pyramidal-shaped cell body is the least frequently observed neuronal cell type and is located principally in CDM and MDMv. MDMd contains a fifth type of neuron characterized by a small (5- to 15-microns) oval soma. Data from the retrograde HRP experiments show that all five of these neuronal cell types in their respective portions of DM project to one or more of the orofacial portions of the four major tactile areas of the cerebellar cortex. Many medium-sized neurons of both types in CDM, MDMv, and RDM project to crus I, crus II, and/or PML.(ABSTRACT TRUNCATED AT 250 WORDS)

The pontocerebellar projection of the uvula in the cat.

The occurrence of retrogradely labeled cells in the pontine nuclei was mapped following injections of 0.3-0.4 microliter of a horseradish peroxidase suspension (50% weight/volume) into the uvula (lob. IX of Larsell) in the cat. The uvula was found to receive afferents from three pontine cell collections. One of these is situated in the paramedian pontine nucleus close to the midline. It forms a fairly distinctly outlined longitudinal column of cells and is present at all levels of the pons except most rostrally and caudally. Another group, in the dorsolateral and lateral pontine nuclei, extends as a somewhat shorter cell column in the longitudinal direction. The third region consists of cells within the rostral part of the peduncular nucleus in its dorsomedial region. The pontine projection to the uvula is bilateral, with some preponderance of crossed connections. The projection to the uvula is organized according to the pattern determined previously for pontine projections to other parts of the cerebellum. A single lobule or part of its receives afferents from more than one cell group in the pons. The projecting cells are most often arranged in longitudinal columns. Correlations with data on the termination of afferents to the pons permit some conclusions regarding the sources of information reaching the uvula via the pons. Main sources seem to be the superior and inferior colliculi, the intracerebellar nuclei and the sensorimotor cortices.