Position paper on olfactory dysfunction: 2023

BACKGROUND: Since publication of the original Position Paper on Olfactory Dysfunction in 2017 (PPOD-17), the personal and societal burden of olfactory disorders has come sharply into focus through the lens of the COVID-19 pandemic. Clinicians, scientists and the public are now more aware of the importance of olfaction, and the impact of its dysfunction on quality of life, nutrition, social relationships and mental health. Accordingly, new basic, translational and clinical research has resulted in significant progress since the PPOD-17. In this updated document, we present and discuss currently available evidence for the diagnosis and management of olfactory dysfunction. Major updates to the current version include, amongst others: new recommendations on olfactory related terminology; new imaging recommendations; new sections on qualitative OD and COVID-19 OD; updated management section. Recommendations were agreed by all co-authors using a modified Delphi process. CONCLUSIONS: We have provided an overview of current evidence and expert-agreed recommendations for the definition, investigation, and management of OD. As for our original Position Paper, we hope that this updated document will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency, and generalisability of work in this field.

Rhinotopy is disrupted during the re-innervation of the olfactory bulb that follows transection of the olfactory nerve.

Re-innervation of the olfactory bulb was investigated after transection of the olfactory nerve using monoclonal antibody RB-8 to assess whether rhinotopy of the primary olfactory projection is restored. In normal animals RB-8 heavily stains the axons, and their terminals, that project from the ventrolateral olfactory epithelium onto glomeruli of the ventrolateral bulb (termed RB-8(+)). In contrast, axons from dorsomedial epithelium are unlabeled (RB-8(-)) and normally terminate in the dorsomedial bulb. Sprague-Dawley rats underwent unilateral olfactory nerve transection and survived for 6 weeks prior to perfusion, sectioning and immunostaining with RB-8. Nerve lesion does not shift the position of the boundary between RB-8(+) and RB-8(-) regions of the epithelium. However, following transection and bulb re-innervation, the distribution of RB-8(+) and RB-8(-) axons is markedly abnormal. First, in all 10 experimental animals RB-8(-) axons displace RB-8(+) axons from anterior glomeruli. Furthermore, the usual target of the RB-8(-) fibers, i.e. the dorsomedial bulb at more posterior levels of the bulb, remains denervated, judging by the lack of staining with antibodies that label axons derived from all epithelial zones. Finally, RB-8(+) fibers invade foreign territory in the dorsolateral bulb on the lesioned side in some cases. The shifts in terminal territory in the bulb after transection contrast with the restoration of the normal zonal patterning of the projection after recovery from methyl bromide lesion, but is consistent with reports of mistargeting by a receptor-defined subset of neurons after transection.

Olfactory epithelium grafts in the cerebral cortex: an immunohistochemical analysis.

OBJECTIVE: To develop an alternative model for studying the regenerative capacity of olfactory neurons. STUDY DESIGN: An immunohistochemical analysis of mouse olfactory epithelium transplanted to the cerebral cortex. METHODS: Strips of olfactory epithelium removed from donor mice at postnatal day 5 to day 20 were inserted into the parietal cortex of adult mice. Recipient animals were allowed to survive for 25 to 120 days and then perfused with 4% paraformaldehyde 1 hour after bromodeoxyuridine injection. The brains were processed, and frozen sections were obtained. Sections through transplant tissue were analyzed using immunohistochemistry and compared with normal olfactory epithelium. RESULTS: Graft survival approached 85% with mature olfactory neurons detected in 35% of the transplants stained for olfactory marker protein. Transplant epithelium resembled normal olfactory epithelium containing mature olfactory neurons and axon bundles. CONCLUSIONS: Studies of olfactory neuron regeneration have been limited by the inability to produce cultures with long-term viability. Olfactory epithelial grafts to the cerebral cortex provide an alternative approach to the study of olfactory neuron regeneration.

An immunochemical, ultrastructural, and developmental characterization of the horizontal basal cells of rat olfactory epithelium.

The olfactory epithelium, which retains a capacity for neurogenesis throughout life, contains two categories of basal cells, dark/horizontal and light/globose, neither of which is fully characterized with respect to their function during the processes of neurogenesis and epithelial reconstitution after injury. The aim of this study was to define the potential biological role(s) of dark/horizontal basal cells (D/HBCs) in the epithelium by performing immunochemical, electron microscopic, and developmental analyses of this cell population. The D/HBCs express several specific immunochemical characteristics, which include the rat homologues of human cytokeratins 5 and 14, which were identified on the basis of staining with subunit-specific monoclonal antibodies and two-dimensional immunoblot analysis of the immunoreactive proteins. Indeed, the D/HBCs are the only cells in the olfactory mucosa that express these specific cytokeratins. The D/HBCs also express an alpha-galactose or alpha-N-acetyl galactosamine moiety to which the I beta 4 isolectin from Bandeiraea simplicifolia binds. Moreover, the D/HBCs are heavily labeled by two different antibodies against the EGF receptor and by a monoclonal antibody that binds to phosphotyrosine. These characteristics are also common to the basal cells of respiratory epithelium. The electron microscopic analysis of the basal region of the olfactory epithelium and the light microscopic immunofluorescence observations demonstrate that the D/HBCs provide a bridge between the basal processes of some sustentacular cells and the basal lamina. The most striking ultrastructural feature of the D/HBCs is their enfolding of virtually all bundles of olfactory axons within tunnels formed where D/HBCs arch over the basal lamina. The intimacy of the arrangement between D/HBCs and olfactory axons suggests that signals may pass from axons to D/HBCs or vice-versa. With respect to the development of D/HBCs, cells that express cytokeratins 5 and 14 and the EGF receptor first appear near the boundary with respiratory epithelium late in development, but do not extend throughout the olfactory epithelium until the middle of the first postnatal week. Taken together, the present findings and previously published data suggest that D/HBCs help to maintain the structural integrity of the olfactory epithelium, participate in its recovery from injury, and may also function to signal the status of the neuronal population of the epithelium.

Multisegmental analyses of acoustic startle in the flying cricket (Teleogryllus oceanicus): kinematics and electromyography.

Tethered, flying Australian field crickets (Teleogryllus oceanicus) stimulated with ultrasound respond with a rapid, short-latency turn from the sound source. We analyzed the kinematics of two behavioral components of this acoustic startle response and recorded electromyograms from the muscles involved in producing them. The two behavior patterns studied were the swing of the metathoracic leg, which has been shown to elicit a short-latency turn, and a lateral swing of the antennae, for which a direct role in steering has not been demonstrated. The kinematic data showed that when a pulse of ultrasound was presented to one side of the animal (1) the contralateral metathoracic leg abducted and elevated, while the ipsilateral leg remained in place, (2) both antennae swung laterally, but the contralateral antenna moved farther than the ipsilateral antenna, (3) increases in stimulus intensity elicited larger movements of the leg and contralateral antenna, while the ipsilateral antenna showed little sensitivity to stimulus intensity, and (4) for the leg, the latency to the onset of the swing decreased and the duration of the movement increased with increasing stimulus intensity. Electromyograms were recorded from the leg abductor M126 and two antennal muscles: the medial scapo-pedicellar muscle M6 and the lateral scapo-pedicellar muscle M7. M7 moves the antenna laterally, M6 moves it medially. Upon stimulation with ultrasound (1) both M126 and M7 showed increasing spike activity with increasing intensity of the ultrasound stimulus, (2) M126 showed a decrease in latency to the first spike and an increase in the duration of spike activity with increasing stimulus intensity, (3) latencies for M6 and M7 were not correlated with stimulus intensity, but M7 had significantly shorter latencies than M6 and the contralateral M7 had significantly shorter latencies than the ipsilateral M7, and (4) the ipsilateral M126 spiked in response to ultrasound in 6 of the 10 animals tested. In these cases, however, latency to the first spike was substantially longer, and the spike frequency was lower than for the muscle's response to contralateral stimuli. We attempt to correlate these electromyogram data with the kinematic data and relate them to the relevance of the two behavior patterns to the execution of an escape response.