Olfactory Disturbances —Pathophysiological Findings and the Development of New Therapeutic Procedures—

Ⅵ Sensory Organ Disorders

Olfactory Disturbances —Pathophysiological findings and the development of new therapeutic procedures—

JMAJ 47(1): 38–43, 2004

Mitsuru FURUKAWA

Professor, Department of Otorhinolaryngology, Graduate School of Medicine and School of Medicine, Kanazawa University

Abstract: Chronic rhinosinusitis is the most frequent cause of hyposmia. We established a new experimental animal model to investigate pathological findings in the olfactory epithelium and olfactory bulb of rats and describe the possible etiology of hyposmia due to rhinosinusitis. Not only dysfunction of the olfactory epithelium but a central type of hyposmia caused by disorders of the olfactory bulb was demonstrated by immunohistochemistry. The possible etiology of hyposmia after common colds and dysosmia after traumatic olfactory disorders is also described based on recent studies. Hyposmia after common colds is strongly associated with nasal obstruction, swelling of the nasal mucosa, and edema of the mucosa of the olfactory cleft observed by nasal fiberscopy. Viral infection is considered one of the etiologies of anosmia after common colds, especially in women from 40 to 60 years old, and results in a poor outcome. One possible explanation of olfactory dysosmia is misdirected connections during reinnervation of the olfactory bulb by olfactory nerve fibers after apoptotic change of olfactory receptor neurons and traumatic amputations of olfactory filla at the level of ethmoid lamina cribrosa. These findings suggested new ideas for the treatment of patients with different types of olfactory disturbances. Key words: Pathophysiology; Olfactory disturbances; Paranasal sinusitis; Common cold; Parosmia

Introduction everyday life. Due to hearing difﬁculty, aged people tend to be isolated from their commu- The research on gustatory and olfactory senses nities and also from participating in social have not been fully developed as compared to activities. Considering these aspects, gustatory those on visual and auditory functions. Yet these and olfactory disturbances among them may senses contribute signiﬁcantly to one’s QOL in interfere with their desire to live and enjoy

This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 127, No. 9, 2002, pages 1483–1486).

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their lives. (PCNA) antibody, anti-single-stranded DNA At the beginning of the 21st century, our (ssDNA) antibody, and anti-inducible nitric aging society continues to be complex and faces oxide synthase (iNOS) antibody. To ascertain further problems to be solved. The patho- the presence (or absence) of changes to the physiological elucidation of various olfactory central olfactory system, an immunohistologi- disturbances and the development of new ther- cal study was conducted on the olfactory bulb apeutic methodology are much desired. The samples of the rats affected by paranasal sinus- current situation is presented in this literature. itis by using an anti-tyrosine hydroxylase (TH) antibody. Chronic Paranasal Sinusitis The results of these observations may be summarized as follows: The onset of paranasal Paranasal sinusitis is the most frequent cause sinusitis was confirmed in 6 animals after 3 of olfactory disturbances in Japan.1) It is true days, 7 animals after 7 days, 6 animals after 14 that sequential changes that occur at the olfac- days, 6 animals after 21 days, and 7 animals tory mucosa caused by paranasal sinusitis have after 28 days following exposure to Staphylo- not been investigated sufficiently. Nor have coccus aureus. Inflammation developed in the appropriate animal models been found that are olfactory epithelium that was affected by para- suitable for such studies. Therefore, we pre- nasal sinusitis within 3 days and the inflamma- pared a model for experimental paranasal tory condition persisted even after 28 days. The sinusitis by using rats to elucidate the mecha- thickness of the olfactory epithelium, the num- nism by which olfactory disturbances develop ber of olfactory cell layers, and the count of and to conduct histological observations of the the olfactory cells per 100␮m2 of the olfactory olfactory epithelium and olfactory bulb.2) epithelium continued to be markedly reduced until after 21 days. The olfactory neurofibril 1. Pathophysiology bundles became elongated and scarce in pro- (1) Olfactory disturbance portion to the time (i.e., number of days) that (direct effects of sinusitis) the foreign body was retained in the nasal A foreign material (polyvinyl acetal) coated cavity. The olfactory cell regenerating activity with Staphylococcus aureus was inserted into was markedly reduced for the initial 7 days and one of the nasal cavities of rats and 3, 7, 14, 21, hardly recognized on the 21st or 28th day. and 28 days later, samples from the nasal cavity Apoptosis of the olfactory cells was most pro- and olfactory bulb were collected (from 10 ani- nounced on the 3rd and 7th days, after which mals at each experiment) to prepare coronal the activity was reduced and became barely sections. HE stain was applied to the samples recognizable on the 21st or 28th day. The from the nasal cavity to examine the maxillary iNOS expression in the olfactory epithelium sinus and ascertain the onset of paranasal was hardly noted in the normal olfactory epi- sinusitis. thelium. The enzyme expression was abundant The HE-stained nasal sinus section obtained around the basal cells of the samples obtained from the rats affected by paranasal sinusitis from the animals with paranasal sinusitis; but it was used to measure the thickness of the olfac- was somewhat reduced where the olfactory tory epithelium. The sections from the nasal epithelium had undergone marked degenera- cavity of the rats with paranasal sinusitis were tion. In the olfactory bulb, the TH expression of used for immunohistological observation of the the juxtaglomerular cells began to be reduced olfactory epithelium by using the following anti- on the 7th day and became much reduced on bodies: anti-protein gene product 9.5 (PGP9.5) the 21st and 28th days. antibody, anti-proliferating cell nuclear antigen It has been shown for the first time that in

JMAJ, January 2004—Vol. 47, No. 1 39 M. FURUKAWA

addition to the olfactory epithelium, histologi- position for about 5 minutes. If no improve- cal changes develop in the olfactory bulb and ment is seen within one month, the medication central olfactory disturbances may occur in is discontinued. When the patient is unable to chronic paranasal sinusitis. hold his head in the specified position or he has (2) Olfactory disturbance chronic sinusitis or has recently undergone (indirect effects of sinusitis) surgery, the same preparation is sprayed from Inflammatory changes in the olfactory cleft, an atomizer twice a day. Topical application of nasal polyps, especially those of the olfactory 2mg/0.5 mlV of dexamethasone or 40 mg/1mlV cleft, and excessive secretion that are caused of methylprednisolone to the olfactory mucosa by sinusitis have been pointed out. It is well is also recommended. Both are applied once known that these conditions are also accompa- every 2 weeks and repeated 4 to 6 times. nied by morphological deviations of the nasal (ii) Oral medication cavity, such as accentuated curved nasal sep- Recently, long-term application of a small tum and nodules of the nasal septum. The patho- amount of macrolide antibiotics has been re- physiology of olfactory disturbances caused by commended as a conservative or postoperative chronic paranasal sinusitis may therefore be adjuvant therapy for chronic paranasal sinus- summed up as the so-called mixed olfactory itis. This medication is usually combined with dysfunctions, where the aforementioned olfac- ethyl L-cysteine hydrochloride (Cystanin®) or tory epithelial changes and respiratory olfac- L-carbocysteine (Mucodyne®). tory dysfunction — due to deviations in air flow (iii) Therapeutic modalities projected in within the nasal cavity — are involved. the near future For the etiology of chronic paranasal sinus- 2. Treatment itis, it has been proven that inflammatory cyto- Needless to add, the treatment of chronic kines (e.g., IL-1␤, TNF-␣, GM-CSF, and IL-6) paranasal sinusitis, the cause of olfactory dis- are involved. Therefore, much is expected from turbances, also constitutes the basis of treat- gene therapy to control the genes responsible ment of the latter. for the expression of these cytokines at the (1) Surgical treatment genetic level or chemotherapy targeted at these Surgical correction of morphological devia- genes. tions of the nasal cavity — e.g., modification of the nasal septum, excision of the turbinate, and Olfactory Disturbances Following a elimination of nasal polyps — and endoscopic Common Cold surgery of the paranasal sinus are effective in improving respiratory or mixed olfactory dis- It is understood that olfactory disturbances turbances. However, complete recovery from complicating upper respiratory inflammation extensive and multiple polyps is difficult. It has are caused by nasal occlusion, swelling of the been reported that the recovery rate is about nasal mucosa, or edema of the mucosa of the 50%.3) olfactory cleft. Most of these symptoms are (2) Drug therapy transient, being eliminated in 2 to 3 days. How- (i) Nasal instillation, nasal spraying, or local ever, in some instances they may develop after injection of adrenal cortex hormones a cold and their prognosis is considered to be With the patient in the head-down (chin-up) poor. The condition frequently affects women position, 1 to 2 drops of a 0.1% solution of between 40 to 69 years of age.4) The question betamethasone sodium (Rinderon®) are instilled of the exaggerated susceptibility to infection in the nasal cavity 3 to 4 times a day, during by viruses from the olfactory nerve and the which time the patient is instructed to hold the resistance to recovery from disturbances in this

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age range, as well as the higher frequency of disturbances of the same function. In clinical occurrence among women, have not been fully patients, parosmia may be found in olfactory elucidated. dysfunctions following a cold (mentioned ear- lier) and following trauma suggestive of dis- 1. Pathophysiology ruption of the olfactory fibers. Characteristi- Excessive secretion or dryness of the olfac- cally, parosmia develops after some time has tory mucosa and ciliary dysfunctions of the elapsed, instead of immediately after olfactory olfactory cells due to acute inflammation and dysfunctions.9) subsequent secondary infection following viral diseases may explain the development of olfac- 1. Pathophysiology tory disturbances. Histopathological findings Instead of remaining viable throughout one’s from the material obtained by a biopsy of the life, the olfactory cells die after a certain time, olfactory mucosa were presented by Tomlinson,5) repeating regeneration through division and who cited central nervous dysfunction via the proliferative processes.10) Specifically, the old olfactory nerve, and by Yamagishi,6) who called cells are replaced by new olfactory cells that attention to a reduction in the number of olfac- are generated by division of the stem cells of tory cells. the basal layer so that the axons of new olfactory cells may constantly project to the olfac- 2. Treatment tory bulb.11) For peripheral or central olfactory distur- According to a recent finding, the site of the bances, vitamin B12, vitamin A, and adenosine olfactory bulb to which the axons of olfactory triphosphate (ATP®) are commonly used. There cells project is well preserved in individuals is a report that extols the favorable effect of and remains constant throughout one’s life. In Oriental medicine (e.g., Toki-Shakuyaku-San other words, the axons that have newly devel- and Keishi-Bukuryo-Gan).7) Sometimes the oped accurately recognize the sites on the serum zinc content is reduced, with rapid loss glomeruli: by projecting toward these sites, the of the gustatory and olfactory sensations and a “olfactory map” on the olfactory bulb is con- resultant acute loss of taste for food. Whether tinually being recreated and maintained. the state is acute or chronic, it has been pointed In parosmia, however, it is understood that out that reductions in the serum zinc level axonal projection occurs at different sites on results in anorexia and gustatory and olfactory the olfactory bulb following regeneration.12) An disturbances. It is not certain why a drop in the olfactory stimulus may be detected by repro- serum zinc level triggers these symptoms. In jection through neural regeneration but projec- the brain, the zinc content is at the highest in tion to a different site results in the perception the hippocampus, followed by the cortex, stria, of a different type of olfactory stimulus. and cerebellum. It is also known that zinc exists at a high concentration at the terminals of the 2. Treatment mossy fibers of the cerebellum and hippocam- The current therapeutic modalities are gen- pus, suggesting that zinc is involved in the func- erally similar to those applied to the peripheral tioning of the central nervous system.8) and central olfactory disturbances described above. In addition, administration of vitamin Parosmia A, which is known to affect differentiation and proliferation of the olfactory epithelium, has If a loss or reduction in the olfactory function been reported. Leopold, et al. ruled out the represents quantitative deviations of olfactory efficacy of vitamin A: instead they cited a case functions, parosmia is typical of qualitative of parosmia in which unilateral excision of the

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