There are a number of medical journal articles available from The National Library of Medicine (copies can be ordered from them for a fee; if you live near another medical or university library, they might have these articles as well). Some of the articles that intrigued me the most follow (not all of them have to do with anosmia; some simply examine interesting facets of olfaction).


Feldmesser E, Bercovich D, Avidan N, et al. Mutations in olfactory signal transduction genes are not a major cause of human congenital general anosmia. Chem Senses 2007;32(1):21-30.
Anosmia affects the western world population, mostly the elderly, reaching to 5% in subjects over the age of 45 years and strongly lowering their quality of life. A smaller minority (about 0.01%) is born without a sense of smell, afflicted with congenital general anosmia (CGA). No causative genes for human CGA have been identified yet, except for some syndromic cases such as Kallman syndrome. In mice, however, deletion of any of the 3 main olfactory transduction components (guanidine triphosphate binding protein, adenylyl cyclase, and the cyclic adenosine monophosphate-gated channel) causes profound reduction of physiological responses to odorants. In an attempt to identify human CGA-related mutations, we performed whole-genome linkage analysis in affected families, but no significant linkage signals were observed, probably due to the small size of families analyzed. We further carried out direct mutation screening in the 3 main olfactory transduction genes in 64 unrelated anosmic individuals. No potentially causative mutations were identified, indicating that transduction gene variations underlie human CGA rarely and that mutations in other genes have to be identified. The screened genes were found to be under purifying selection, suggesting that they play a crucial functional role not only in olfaction but also potentially in additional pathways.

Frasnelli J, Schuster B, Hummel T. Subjects with congenital anosmia have larger peripheral but similar central trigeminal responses. Cereb Cortex 2007;17(2):370-7.
Most odorants not only stimulate olfactory receptor neurons but also activate the intranasal trigeminal nerve. The simultaneous activation of the olfactory and the trigeminal system leads to an interaction in the brain. Therefore, assessment of the trigeminal impact of odorants may be difficult in subjects with a normal sense of smell. To obtain a deeper insight into both, mechanisms of changes in trigeminal sensitivity in anosmic patients and interactions between the olfactory/trigeminal systems in healthy subjects, 21 patients with isolated congenital anosmia (ICA) were investigated in this series of explorative, hypothesis-generating experiments and compared with 35 healthy controls. Trigeminal sensitivity was measured by psychophysical (lateralization task, intensity ratings) and electrophysiological (trigeminal event-related potential, negative mucosal potential) means. ICA patients were found to have higher peripheral activation than controls. On central levels, however, similar responsiveness to trigeminal stimuli was found in ICA patients when compared with healthy subjects. The results of the study are discussed by proposing a model of mixed sensory adaptation/compensation in the interactions between olfactory and the trigeminal system.

Gudziol V, Hummel C, Negoias S, et al. Lateralized differences in olfactory function. Laryngoscope 2007;117(5):808-11.
BACKGROUND: Birhinal testing of odor identification will not allow the detection of unilateral olfactory loss. The aim of the presented study was to evaluate side differences of odor identification in large groups of healthy subjects and in patients with nasal symptoms. PARTICIPANTS AND METHOD: Self-assessment of olfactory function and evaluation of olfactory function by means of a validated test were performed in 479 healthy subjects, in 765 patients with chronic rhinosinusitis (CRS), and in 53 patients with a tumor. A 12-item odor identification test (“Sniffin’ Sticks”) was used to evaluate olfactory function separately for each nostril. RESULTS: Fifteen percent of the healthy subjects demonstrated side differences in the identification of at least 3 out of 12 odors. Healthy elderly subjects showed larger side differences in identification of odor than younger ones; a general difference between odor identification with the right or left nostril was not found. Both CRS patients and patients with a tumor had larger side differences than healthy subjects. Only 20% of the patients with a tumor complained about impaired olfactory sensitivity, but more than 75% of them showed deficits in olfactory tests. CONCLUSION: Side differences of odor identification of 25% or greater should give reason for further investigation. Future studies are needed to investigate whether side differences in healthy subjects are a predicator of a higher risk for general olfactory loss.

Kobayashi M, Reiter ER, DiNardo LJ, Costanzo RM. A new clinical olfactory function test: cross-cultural influence. Arch Otolaryngol Head Neck Surg 2007;133(4):331-6.
OBJECTIVE: To investigate whether a new clinical olfactory test, the Odor Stick Identification Test for Japanese (OSIT-J), can be used to assess olfactory function cross-culturally in a US patient population. DESIGN: Cross-sectional prospective study. SETTING: A university medical center otolaryngology clinic. PATIENTS: Fifty US patients presenting with complaints of olfactory dysfunction from December 2004 to January 2006. INTERVENTIONS: Olfactory testing and patient interview. MAIN OUTCOME MEASURES: Comparison of test results obtained with the OSIT-J, the Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory function test, and patients’ self-reported level of olfactory function. Patients’ opinions regarding the 2 test methods were also recorded. RESULTS: The mean +/- SD time required to administer the OSIT-J (8 +/- 1 minutes) was shorter than that required for the standard CCCRC test (21 +/- 6 minutes). Significant Spearman rank correlations were found between the OSIT-J and CCCRC test scores (r(s) = 0.80, P<.001, n = 50), and patients’ self-reported level of olfactory function (r(s) = 0.73, P<.001, n = 50). Although 3 of the 13 odors used in the OSIT-J were not familiar to US subjects, patients reported that the OSIT-J was easier, more interesting, and the odors used more pleasant than the CCCRC test. CONCLUSIONS: Olfactory function tests developed in different countries should be evaluated to determine if a cross-cultural bias exists among test odorants. Although a cultural bias was detected for a few odorants, this study demonstrates that a modified version of the OSIT-J can be used to assess olfactory function in US patients.

Brämerson A, Nordin S, Bende M. Clinical experience with patients with olfactory complaints, and their quality of life. Acta Otolaryngol 2007;127(2):167-74.
A special consulting team for patients with olfactory disorders would be able to verify, describe, and explain the characteristics of the disorders, also in cases where a patient experiences a disorder, but has a normal sense of smell. OBJECTIVES. The general purpose of this paper was to present our experience with patients seeking medical attention for olfactory disorders, and to describe how quantitative and qualitative olfactory disorders are diagnosed, what the etiologies are, and how quality of life is compromised in patients with olfactory disorders. SUBJECTS AND METHODS. This investigation was performed prospectively over a 10-year period by one physician responsible for the consulting team for patients with olfactory disorders. Based on a standardized clinical examination, a structured interview, and assessment of olfactory function, its aim was to diagnose quantitative and qualitative disorders in 303 consecutive patients. Health-related quality of life was assessed with the Nottingham Health Profile (NHP) in about one-third of patients. RESULTS. In the majority of patients, a reduced sense of smell was found after testing. Often, but not always, this was combined with qualitative disorders. Dominating etiologies were infections, nasal polyposis, head trauma, and aging. Patients complaining of olfactory disorders experience a significantly reduced quality of life regarding the impact of their health problem on paid employment, household work, and social and family life.

Demarquay G, Ryvlin P, Royet JP. [Olfaction and neurological diseases: a review of the literature]. Rev Neurol (Paris) 2007;163(2):155-67. [Article in French]
Olfactory disorders are often misjudged and rarely rated in the clinical setting. They are nevertheless described in a wide range of neurological disorders, and their evaluation can be useful for diagnosis. Usually irreversible olfactory dysfunction is a well-known complication after head trauma. Severe changes in olfactory tests are observed in Parkinson’s disease. Dysfunction is present at disease onset and evidenced with all behavioral tests. Regarding other parkinsonian syndromes, olfactory performances are severely impaired in Lewy body disease, less pronounced in multiple system atrophy and usually preserved in corticobasal degeneration. Olfactory deficits are an early feature in Alzheimer’s disease and worsen with disease progression. Rarely reported by patients, they must be searched for with olfactory tests. Though epilepsy is mainly known for its olfactory hallucinatory disorders, alterations of olfactory abilities are also described, especially in mesial temporal epilepsy. Disorders of olfactory perception are finally reported in patients with multiple sclerosis and migraine. After a reminder of anatomical data on the olfactory system, and the different methods of testing used to rate olfactory performances, the current review focuses on the type of olfactory dysfunction and damaged brain areas of the olfactory system encountered in the main neurological diseases.

Turgut B, Turkcuoglu P, Guler M, et al. Anosmia as an adverse effect of dorzolamid. Acta Ophthalmol Scand 2007;85(2):228-9. No abstract available.

Hutton JL, Baracos VE, Wismer WV. Chemosensory dysfunction is a primary factor in the evolution of declining nutritional status and quality of life in patients with advanced cancer. J Pain Symptom Manage 2007;33(2):156-65.
Alterations in taste and smell functions have been reported in cancer patients. Although these senses are known to be particularly affected by chemotherapy, many features of chemosensory perception in cancer patients remain obscure. The relative importance of chemosensory changes in the etiology of malnutrition and wasting is not known. To assess this relationship, self-perceived taste and smell function were evaluated using a validated questionnaire in 66 patients with advanced cancer receiving palliative care (median survival 7.4 months). Participants also completed 3-day food records to assess dietary intake, and the Functional Assessment of Anorexia/Cachexia Therapy questionnaire to assess quality of life (QOL). Total chemosensory complaint scores ranged from 0 to 14 on a 16-point scale. Only 14% of the subjects reported no chemosensory complaints of any kind, whereas 86% reported some degree of chemosensory abnormality. The most common complaints were persistent bad taste in the mouth, taste distortion, and heightened sensitivity to odors. Subjects with severe chemosensory complaints showed substantially lower energy intakes (by 900-1,100 kcal/day), higher rates of weight loss, and lower QOL scores than subjects with mild or moderate chemosensory complaints. Severe chemosensory dysfunction is persistent well beyond the window of active therapy in patients with advanced cancer and represents a primary factor relating to malnutrition, wasting, and poor QOL. Further research is required to identify appropriate strategies to alleviate this important group of symptoms, to determine whether intervention will improve QOL, and to match foods and diet to the unique chemosensory profile of advanced cancer patients.

Iannilli E, Gerber J, Frasnelli J, Hummel T. Intranasal trigeminal function in subjects with and without an intact sense of smell. Brain Res 2007;1139:235-44.
The intranasal trigeminal system is involved in the perception of odors. To investigate the cerebral processing of sensory information from the trigeminal nerve in detail we studied subjects with and without olfactory function using functional magnetic resonance imaging. A normosmic group (n=12) was compared with a group of anosmic subjects (n=11). For trigeminal stimulation gaseous CO(2) was used. Following right-sided stimulation with CO(2) controls exhibited a stronger right-sided cerebral activation than anosmic subjects. Stronger activation was found in controls compared to anosmic subjects for the right prefrontal cortex, the right somatosensory cortex (SI), and the left parietal insula. In contrast, relatively higher activation was found in anosmic subjects for the left supplementary motor area in the frontal lobe, the right superior and middle temporal lobe, the left parahippocampal gyrus in the limbic lobe, and the sub-lobar region of the left putamen and right insula which was mostly due to a decreased BOLD signal of controls in these areas. Additional conjunction analysis revealed that activated areas common to the two groups were the cerebellum and the right premotor frontal cortex. These data suggest that the processing of the trigeminally mediated information is different in the presence or absence of an intact sense of smell, pointing towards the intimate connection between the two chemosensory systems.

Trotier D, Bensimon JL, Herman P, et al. Inflammatory obstruction of the olfactory clefts and olfactory loss in humans: a new syndrome? Chem Senses 2007;32(3):285-92.
The first step in the olfactory perception is the activation by odorants of sensory neurones in the olfactory epithelium. In humans, this sensory epithelium is located at 2 narrow passages, the olfactory clefts, at the upper part of the nasal cavities. Little is known about the physiology of these clefts. We examined, in 34 patients, the impact of obstructed clefts upon detection and postlearning identification of 5 odorants. The location and extension of the obstructions were assessed using endoscopy, CT scans, and MRI. The inflammatory obstruction was usually bilateral, extending anteroposteriorly, and confined to the clefts, with no sign of obstruction or any inflammatory disease in the rest of the nasal cavities and sinuses. When tested with 5 odorants, these patients showed greatly impaired olfaction compared with a group of 73 normosmic subjects. The majority of these 34 patients had sensory deficits equivalent to that found in another group of 41 congenital anosmic patients, where inspection with MRI indicated the lack of olfactory bulbs. This study demonstrates that the olfactory clefts, in human, function as an entity that is different from other regions of the nasal cavity and is the target for local inflammatory events that are apparently not responding to corticoid and antibiotic treatments.

Katotomichelakis M, Balatsouras D, Tripsianis G, et al. Normative values of olfactory function testing using the ‘sniffin’ sticks.’ Laryngoscope 2007;117(1):114-20.
OBJECTIVES: Quantitative olfactory assessment is often neglected in clinical practice, although olfactory loss can assist to diagnosis and may lead to significant morbidity. “Sniffin’ Sticks” is a modern test of nasal chemosensory performance that is based on penlike odor-dispensing devices. It consists of three tests of olfactory function: odor threshold, odor discrimination, and odor identification. The results of this test may be presented as a composite threshold-discrimination-identification (TDI) score. The aim of this study was first to develop normative data of olfactory function for the Greek population using this test and second to relate olfactory performance to age, sex, and side examined. STUDY DESIGN: The authors conducted a prospective clinical trial. METHODS: A total of 93 healthy subjects were included in the study, 48 males and 45 females, mean age of 44.5 years (range, 6-84 years). RESULTS: A database of normal values for olfactory testing was established for the Greek population. Females performed better than males and older subjects performed less efficiently in all tests. We also found a right nostril advantage compared with the left. Additionally, scores obtained from bilateral presentation were similar with scores obtained from the nostril with the better performance. CONCLUSIONS: The “Sniffin’ Sticks” can be used effectively in the Greek population to evaluate olfactory performance. Mean values of olfactory tests obtained were better in comparison with data from settings located in central and northern Europe.

Rombaux P, Weitz H, Mouraux A, et al. Olfactory function assessed with orthonasal and retronasal testing, olfactory bulb volume, and chemosensory event-related potentials. Arch Otolaryngol Head Neck Surg 2006;132(12):1346-51.
OBJECTIVE: To investigate whether differences in olfactory function between healthy individuals and patients with olfactory loss could be detected by various diagnostic tests. DESIGN: Psychophysical testing of orthonasal and retronasal olfactory functions, magnetic resonance imaging of olfactory bulb (OB) volume, and chemosensory event-related potential (ERP) measurement performed between January 1, 2005, and October 31, 2005. SETTING: Academic tertiary referral medical center. PATIENTS: Eleven healthy individuals with normal olfactory function (NL) and 11 patients with nasal polyposis (NP), 11 with posttraumatic olfactory loss (PT), and 11 with postinfectious olfactory loss (PI) were included in this study. MAIN OUTCOME MEASURES: Orthonasal and retronasal olfactory test results, magnetic resonance imaging-based OB volume, and ERPs to both olfactory and intranasal trigeminal stimulation. RESULTS: Orthonasal and retronasal testing revealed that NL individuals had higher scores than patients with NP, PT, or PI. Retronasal scores were higher in NP patients compared with PT and PI patients. The OB volumes were higher in NL individuals compared with NP, PT, and PI patients. The OB volumes in PT patients were significantly lower than those from NP and PI patients. Olfactory ERPs were different between NL individuals and NP, PT, and PI patients, and trigeminal ERPs were significantly different when comparing NL individuals with NP patients. For the entire cohort, a significant correlation was found between orthonasal testing and OB volume, between retronasal testing and OB volume, and between both orthonasal and retronasal testing and olfactory ERP amplitudes. Olfactory ERPs were recorded in the 11 NL individuals and in 3 NP, 3 PT, and 4 PI patients, defined as responders. Orthonasal and retronasal test scores, OB volume, and olfactory ERPs were significantly larger in responders compared with nonresponders. CONCLUSIONS: Significant differences in various tests that evaluate olfactory function were detectable in a cohort of NL individuals and NP, PT, and PI patients. This finding suggests that these diagnostic tools provide information in terms of the clinical assessment of olfactory function. Future studies will investigate their combined use in terms of the prognosis of olfactory function in patients with olfactory loss.

Frasnelli J, Schuster B, Hummel T. Interactions between Olfaction and the Trigeminal System: What Can Be Learned from Olfactory Loss. Cereb Cortex 2006 Dec 5; [Epub ahead of print].
The olfactory and the trigeminal systems have a close relationship. Most odorants also stimulate the trigeminal nerve. Further, subjects with no sense of smell exhibit a decreased trigeminal sensitivity with unclear underlying mechanisms. Previous studies indicated that single stages of trigeminal processing may differently be affected by olfactory loss. A better knowledge of adaptive and compensatory changes in the trigeminal system of subjects with acquired anosmia (AA) will improve the understanding of interactive processes between the 2 sensory systems. Thus, we aimed to assess trigeminal function on different levels of processing in subjects with AA. Subjects with AA showed larger electrophysiological responses to irritants obtained from the mucosa than healthy controls. On central levels, however, they exhibited smaller event-related potentials and psychophysical measures to irritants. Over 9 months, they exhibited an increase in trigeminal sensitivity. Subjects with recovering olfactory function showed an even more increased peripheral responsiveness to irritants. These data suggest dynamic mechanisms of mixed sensory adaptation/compensation in the interaction between the olfactory and trigeminal systems, where trigeminal activation is increased on mucosal levels in subjects with AA and amplified on central levels in subjects with a functioning olfactory system.

Bonanni E, Borghetti D, Fabbrini M, et al. Quantitative EEG analysis in post-traumatic anosmia. Brain Res Bull 2006;71(1-3):69-75.
Many objective and quantitative methods have been developed to create a procedure or a device to prove, describe and quantify olfactory deficit and anosmia, especially after a head trauma. Electrophysiological testing throughout olfactoelectroencephalography (olfactoEEG) is based on brain activity desynchronisation, and on the subsequent disappearance of alpha activity on the posterior regions after an olfactory stimulus. Yet traditional evaluation of EEG can be difficult, because of little or hardly detectable alpha activity on the posterior regions (‘alpha rare’). The aim of this study was to evaluate the Olfactory Stop Reaction (OSR) by means of frequency band power calculation and subsequent topographical mapping in patients with post-traumatic anosmia, who presented ‘alpha rare’ EEG. Twenty-five consecutive patients, affected by anosmia caused by head trauma, were submitted to an EEG recording with olfactory stimulation. After signal processing and analysis, an Olfactory Stop Reaction was detected in 17 out of 25 patients; moreover, in these patients we detected a significant decrease in alpha band power in the occipital regions and an increase in theta band power on midline frontal and central regions after olfactory stimulation. In the remaining eight patients, no significant variation in band power was observed. In conclusion, an objective evaluation of the olfactory function with this method of automatic EEG signal analysis allows the limits given by psychophysical methods and traditional EEG to be overcome and attempts to fulfil the requirements for standardization of olfactory function evalution.

Strous RD, Shoenfeld Y. To smell the immune system: olfaction, autoimmunity and brain involvement. Autoimmun Rev 2006;6(1):54-60.
Aside from its recognition and warning functions, olfaction serves many purposes in the CNS and remains one of the most important means of communication with the environment. In addition to olfactory tract input, the olfactory bulb also receives and provides input to other brain centers that modify neuronal activity. Research in the field of immunology as well as in various brain illnesses is beginning to indicate the increasing relevance of smell in pathophysiology. Much of this is based on the many intricate interactions that exist between the immune system and the nervous system, and evidence exists that there may be something unique about the olfactory system that is inextricably related to immunological function. In addition, accumulating evidence confirms the existence of olfactory dysfunction in brain disease, much of which appears at early stages including multiple sclerosis, Alzheimer’s Disease, Parkinson’s Disease, schizophrenia and depression. Such observations may further suggest that under certain circumstances, olfactory abnormalities may be associated with autoimmune conditions. Since the organization of the olfactory system is so sensitive, impairment may be noted at an early stage. This may become important in the prediction of certain brain illnesses. While preliminary evidence may suggest a role for olfaction in the management and alleviation of various disorders, investigation of its clinical relevance remains limited.

Verma P, Verma S, Jani P. Overcoming anosmia following total laryngectomy. Clin Otolaryngol. 2006 Oct;31(5):468-9. No abstract available.


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