Therapeutic diminution of Interleukin-10 with intranasal theophylline administration in hyposmic patients.

OBJECTIVE: To determine changes in nasal mucus Interleukin-10 (IL-10) before and after intranasal theophylline treatment in hyposmic patients, and the relationship of these changes to orally administered theophylline treatment. DESIGN: IL-10 was measured in nasal mucus samples of 17 normal subjects and 39 patients with hyposmia of multiple etiologies by use of a sensitive spectrophotometric ELISA assay. Hyposmia is defined clinically by standardized evaluation of impaired olfactometry, as well as subjectively self reported by the patient. RESULTS: Prior to treatment, IL-10 levels in nasal mucus were increased in hyposmic patients compared to controls. Following intranasal theophylline administration, over half of treated patients experienced a decrease of nasal mucus IL-10 toward control levels, correlated with a significant improvement in taste and smell function. Patients who increased with intranasal administration, similar to previously reported oral administration, showed no significant improvement in taste or smell function. CONCLUSIONS: Nasal mucus IL-10 decreased in patients treated with intranasal theophylline. Mechanisms of action include phosphodiesterase and nuclear factor kappa-B inhibition, correlated with an improvement in both olfaction and gustation. IL-10 is induced by therapeutic and systemic administration of theophylline as with oral dosage, but reduced by lower and localized treatment.

Sonic hedgehog is present in parotid saliva and is decreased in patients with taste dysfunction.

PURPOSE: To demonstrate that sonic hedgehog (Shh) is present in human parotid saliva and is decreased in human taste dysfunction. METHODS: Shh was measured in parotid saliva of 27 normal subjects and 81 patients with taste dysfunction of multiple etiologies using a sensitive spectrophotometric ELISA assay. Taste dysfunction was defined clinically both by subjective decreases of taste acuity and flavor perception and by impaired gustometry. RESULTS: Shh was found in parotid saliva of both normal subjects and patients with taste dysfunction. Levels were significantly lower in patients than in normal subjects. Both subjective loss of taste acuity and flavor perception and impaired gustometry was measured in untreated patients. CONCLUSIONS: This is the first demonstration of Shh in human saliva. As Shh has been related to taste bud growth and development, its presence in saliva is consistent with its role as a cell signaling moiety involved with stimulation of taste bud stem cells to generate taste receptors. Decreased saliva Shh secretion can be considered a marker of taste dysfunction in patients with multiple pathologies for their dysfunction.

Improved smell function with increased nasal mucus sonic hedgehog in hyposmic patients after treatment with oral theophylline.

PURPOSE: We previously demonstrated the presence of sonic hedgehog (Shh) in nasal mucus in normal subjects and in patients with smell loss (hyposmia). Nasal mucus Shh levels were found significantly diminished in untreated hyposmic patients of multiple etiologies. Since treatment with oral theophylline has been previously associated with improvement in smell function we wished to study if such treatment increased nasal mucus Shh as well as improved smell function in patients with hyposmia. METHODS: Forty-four patients with hyposmia of several etiologies were evaluated for changes in hyposmia by subjective measurements of smell, taste and flavor perception and by olfactometry. Measurements of nasal mucus Shh were made in relationship to each set of sensory measurements. Patients were treated with oral theophylline at doses of 200-800mg for periods of 2-10months with sensory function, nasal mucus Shh and serum theophylline levels evaluated at these time intervals. Nasal mucus Shh measurements were made with a sensitive spectrophotometric ELISA assay and theophylline with a fluorometric assay. RESULTS: There was consistent, significant improvement in subjective responses in smell, taste and flavor perception and in olfactometry associated with increased nasal mucus Shh and serum theophylline after theophylline treatment. CONCLUSIONS: Improvement in smell function and in nasal mucus Shh was positively correlated in a dose-response relationship after treatment with oral theophylline. Results are consistent with a successful role for theophylline in improvement of smell function in hyposmic patients of multiple etiologies associated with increased nasal mucus Shh which can act as a biochemical marker for smell function.

On the mechanism of smell loss in patients with Type II congenital hyposmia.

BACKGROUND: Smell function has been initiated with theophylline treatment in 63% of patients with Type II congenital smell loss. Based upon a systematic evaluation of the protein components of nasal mucus we have demonstrated that interactions among four chemical moieties in nasal mucus may play significant roles in this initiation. Prior to treatment three of these moieties, cAMP, cGMP and sonic hedgehog (Shh), were significantly decreased in concentration whereas one of these moieties, TNFalpha, was increased in concentration. The mechanism(s) responsible for initiation of smell function in these patients, not immediately apparent, may depend upon understanding interactions among these moieties. METHODS: Measurements of cAMP, cGMP, Shh and TNFalpha in nasal mucus by specific spectrophotometric immunoassays before and after treatment with theophylline. RESULTS: Before theophylline treatment cAMP, cGMP and Shh in nasal mucus, which act as growth factors to support olfactory receptor function, were significantly decreased below normal levels whereas TNFalpha which acts as a "death factor" to inhibit olfactory receptor function was significantly increased above normal. After theophylline treatment cAMP, cGMP and Shh increased significantly whereas TNFalpha decreased significantly. CONCLUSIONS: These results indicate that there are specific biochemical changes associated with smell loss in patients with Type II congenital smell loss and that correction of these biochemical changes are associated with initiation of smell function in these patients. Understanding these relationships play an important role in understanding receptor action in smell function.

Initiation of smell function in patients with congenital hyposmia.

BACKGROUND: Patients with congenital smell loss (hyposmia) are born without a sense of smell. They comprise two types. Type I patients have genetic abnormalities manifested by brain, gonadal and other somatic abnormalities. Type II patients have neither a family history of smell loss nor any somatic abnormalities. No systematic attempts to initiate smell function in Type II patients have been reported. METHODS: Smell function was measured in 19 Type II congenital smell loss patients by both subjective responses and by olfactometry using measurements of detection and recognition thresholds, magnitude estimation and hedonics in response to four odors (pyridine, nitrobenzene, thiophene and amyl acetate) before and after treatment with oral theophylline, 200-800mg daily for periods of 2-36months with evaluation of smell function and serum theophylline measured at intervals of 2-6months. RESULTS: In 12 of the 19 Type II patients (63%) smell function was initiated for the first time and was quantitated by both subjective responses and by olfactometry. Initiation of smell function occurred after treatment with 200-800mg of oral theophylline for periods of 2-19months. INTERPRETATION: This is the first systematic demonstration of initiation of smell in patients who were born without smell function. Oral theophylline presumably acts to increase both olfactory receptor growth, development and perpetuation and brain plasticity which enables them to recognize olfactory signals with initiation of olfactory function.

A genetic marker of the ACKR1 gene is present in patients with Type II congenital smell loss who have type I hyposmia and hypogeusia.

PURPOSE: Our previous study of Type II congenital smell loss patients revealed a statistically significant lower prevalence of an FY (ACKR1, formerly DARC) haplotype compared to controls. The present study correlates this genetic feature with subgroups of patients defined by specific smell and taste functions. METHODS: Smell and taste function measurements were performed by use of olfactometry and gustometry to define degree of abnormality of smell and taste function. Smell loss was classified as anosmia or hyposmia (types I, II or III). Taste loss was similarly classified as ageusia or hypogeusia (types I, II or III). Based upon these results patient erythrocyte antigen expression frequencies were categorized by smell and taste loss with results compared between patients within the Type II group and published controls. RESULTS: Comparison of antigen expression frequencies revealed a statistically significant decrease in incidence of an Fyb haplotype only among patients with type I hyposmia and any form of taste loss (hypogeusia). In all other patient groups erythrocyte antigens were expressed at normal frequencies. CONCLUSIONS: Data suggest that Type II congenital smell loss patients who exhibit both type I hyposmia and hypogeusia are genetically distinct from all other patients with Type II congenital smell loss. This distinction is based on decreased Fyb expression which correlated with abnormalities in two sensory modalities (hyposmia type I and hypogeusia). Only patients with these two specific sensory abnormalities expressed the Fyb antigen (encoded by the ACKR1 gene on the long arm of chromosome 1) at frequencies different from controls.

Erythrocyte membrane antigen frequencies in patients with Type II congenital smell loss.

OBJECTIVE: The objective of this study was to determine whether there are genetic factors associated with Type II congenital smell loss. STUDY DESIGN: The expression frequencies of 16 erythrocyte antigens among patients with Type II congenital smell loss were determined and compared to those of a large control group. METHODS: Blood samples were obtained from 99 patients with Type II congenital smell loss. Presence of the erythrocyte surface antigens A, B, M, N, S, s, Fy(a), Fy(b), D, C, c, E, e, K, Jk(a), and Jk(b) was analyzed by blood group serology. Comparisons of expression frequencies of these antigens were made between the patients and a large control group. RESULTS: Patients tested for the Duffy b antigen (Fy(b) haplotype) exhibited a statistically significant 11% decrease in expression frequency compared to the controls. There were no significant differences between patients and controls in the expression frequencies for all other erythrocyte antigens (A, B, M, N, S, s, Fy(a), D, C, c, E, e, K, Jk(a), or Jk(b)). CONCLUSIONS: These findings describe the presence of a previously unrevealed genetic tendency among patients with Type II congenital smell loss related to erythrocyte surface antigen expression. The deviation in expression rate of Duffy b suggests a target gene and chromosome region in which future research into this form of congenital smell loss may reveal a more specific genetic basis for Type II congenital smell loss.

Human herpesvirus-6 entry into the central nervous system through the olfactory pathway.

Viruses have been implicated in the development of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis. Human herpesvirus-6 (HHV-6) is a neurotropic virus that has been associated with a wide variety of neurologic disorders, including encephalitis, mesial temporal lobe epilepsy, and multiple sclerosis. Currently, the route of HHV-6 entry into the CNS is unknown. Using autopsy specimens, we found that the frequency of HHV-6 DNA in the olfactory bulb/tract region was among the highest in the brain regions examined. Given this finding, we investigated whether HHV-6 may infect the CNS via the olfactory pathway. HHV-6 DNA was detected in a total of 52 of 126 (41.3%) nasal mucous samples, showing the nasal cavity is a reservoir for HHV-6. Furthermore, specialized olfactory-ensheathing glial cells located in the nasal cavity were demonstrated to support HHV-6 replication in vitro. Collectively, these results support HHV-6 utilization of the olfactory pathway as a route of entry into the CNS.

Anatomic olfactory structural abnormalities in congenital smell loss: magnetic resonance imaging evaluation of olfactory bulb, groove, sulcal, and hippocampal morphology.

BACKGROUND AND PURPOSE: There are 2 groups of patients with congenital smell loss: group 1 (12% of the total), in which patients exhibit a familial smell loss in conjunction with severe anatomical, somatic, neurological, and metabolic abnormalities such as hypogonadotropic hypogonadism; and a larger group, group 2 (88% of the total), in which patients possess a similar degree of smell loss but without somatic, neurological, or anatomical abnormalities or hypogonadism. Both groups are characterized by similar olfactory dysfunction, and both have been reported to have absent or decreased olfactory bulbs and grooves, which indicates some overlap in olfactory pathophysiology and anatomy. The purpose of this study was to evaluate patients with congenital smell loss, primarily among group 2 patients, comparing brain magnetic resonance imaging (MRI) results in patients with types of hyposmia. METHODS: Forty group 2 patients were studied by measurements of taste (gustometry) and smell (olfactometry) function and by use of MRI in which measurements of olfactory bulbs, olfactory sulcus depth, olfactory grooves, and hippocampal anatomy were performed. Anatomical results were compared with similar studies in group 1 patients and in 22 control subjects with normal sensory function. RESULTS: Olfactometry was abnormal in all patients with no patient reporting ever having normal olfaction. No patient had a familial history of smell loss. On MRI, all exhibited at least 1 abnormality in olfactory system anatomy, including absence or decreased size of at least 1 olfactory bulb, decreased depth of an olfactory sulcus, and abnormalities involving hippocampal anatomy with hippocampal malrotations. One patient had bilateral bulb duplication. Normal subjects with normal smell and taste function exhibited some but very few or significant neuroanatomical changes on MRI. CONCLUSIONS: Although both groups have similar abnormalities of smell function, group 2 patients demonstrate anatomical anomalies in olfactory structures that are neither as common nor as severe as in group 1 patients. Group 2 patients can have a wide range of olfactory anatomical abnormalities.

Taste and smell function in chronic disease: a review of clinical and biochemical evaluations of taste and smell dysfunction in over 5000 patients at The Taste and Smell Clinic in Washington, DC.

PURPOSE: To describe systematic methods developed over 40 years among over 5000 patients at The Taste and Smell Clinic in Washington, DC to evaluate taste and smell dysfunction. MATERIALS AND METHODS: A tripartite methodology was developed. First, methods to determine clinical pathology underlying the multiple disease processes responsible for taste and smell dysfunction were developed. Second, methods to determine biochemical parameters responsible for these pathologies were developed. Third, methods to implement these techniques were developed to form a unified basis upon which treatment strategies can be developed to treat these patients. RESULTS: Studies were performed in 5183 patients. Taste loss was present in 62% of patients, smell loss in 87%. Most patients with taste loss (52%) exhibited Type II hypogeusia; most patients with smell loss (56%) exhibited Type II hyposmia. Sensory distortions were present in 60%. Four common diagnostic entities were found: post influenza-type hyposmia and hypogeusia (27% of patients), idiopathic causes (16%), allergic rhinitis (15%) and post head injury (14%). Regardless of clinical diagnosis the major biochemical abnormality found in most patients (~70%) was diminished parotid salivary and nasal mucus secretion of cAMP and cGMP. CONCLUSIONS: Taste and smell dysfunctions are common clinical problems associated with chronic disease processes. These symptoms require a systematic, integrated approach to understand their multiple and complex components. The approach presented here can and has led to effective treatment.

Comparative monitoring of oral theophylline treatment in blood serum, saliva, and nasal mucus.

BACKGROUND: Theophylline, used in the treatment for various pulmonary pathologies, is usually given orally with drug levels measured primarily in blood serum and occasionally in saliva. Although theophylline treatment is now not commonly used it has been effective to correct smell loss (hyposmia). This is important because 21 million people in the United States exhibit hyposmia and oral theophylline has corrected hyposmia in about 50% of these patients. This result suggests that oral theophylline may result in the drug not only appearing in the serum but also in nasal mucus, thereby playing a role in correcting hyposmia. No prior report of theophylline in nasal mucus has been made and no comparison of levels in nasal mucus, blood serum, or saliva has been previously reported. PURPOSE: The aim was to determine, after oral theophylline treatment, if it is present in nasal mucus and, if present, to compare the levels with those in serum and saliva. METHODS: Oral theophylline was given to 23 hyposmic patients at daily doses of 200, 300, 400, 600, and 800 mg for periods of 2-10 months. During each period, blood serum, saliva, and nasal mucus were collected and theophylline measured in each fluid. RESULTS: Theophylline was found in nasal mucus and in saliva and blood serum at each drug dose in each patient to whom it was given. The mean level of theophylline in nasal mucus was 74% that of serum; mean level in saliva was 67% of serum; mean level in nasal mucus was 111% that in saliva. CONCLUSIONS: Theophylline is present in nasal mucus after oral administration. Levels in nasal mucus reflect blood and saliva levels in a consistent manner and offer a simple convenient noninvasive method to monitor theophylline doses of the oral drug.

Morphological changes of olfactory bulbs and grooves: initial report of supernumerary olfactory bulbs.

BACKGROUND: Observations and measurements of olfactory structures in humans have been difficult and not of common neuroradiological interest. Because of our interest in olfaction, we have studied the presence, size, and function of these structures in normal subjects and in patients with smell loss. METHODS: Magnetic resonance imaging studies of brain were performed in 220 consecutive patients in our medical center for a variety of clinical neurological investigations. Magnetic resonance imaging studies were performed in each subject including high-resolution coronal T2-weighted fast-spin echo images in the orbitofrontal region. Measurements of olfactory bulb diameter, olfactory sulcal depth, and morphology of the olfactory grooves were performed. RESULTS: Olfactory bulbs were present bilaterally in each patient studied. Olfactory bulbs appeared duplicated in 11 patients and triplicated in one (5.4% of the total group). Whereas olfactory sulcal depth was similar in all patients, olfactory bulb diameter in patients with duplicate or triplicate bulbs was significantly smaller than those in subjects with single bilateral olfactory bulbs. One patient with congenital hyposmia and olfactory bulb duplication had significant impairment in olfactory acuity. None of the other subjects complained of smell loss. CONCLUSIONS: Olfactory bulbs with a duplicated or triplicated appearance and associated changes in olfactory groove morphology can be present in patients examined with orbital magnetic resonance imaging, and are not uncommon. Although the mechanism(s) for this finding is unclear, it may relate to neurodevelopmental and genetic factors.

Differences between and within human parotid saliva and nasal mucus cAMP and cGMP in normal subjects and in patients with taste and smell dysfunction.

BACKGROUND: We previously described some of the moieties in human saliva and nasal mucus including cyclic nucleotides. However, comparison of levels of these latter moieties in saliva and nasal mucus has not been performed and meaning of differences found has not been discussed. PURPOSE: To compare the levels of cAMP and cGMP in saliva and nasal mucus and to describe the differences in their concentrations and function. METHODS: cAMP and cGMP in saliva and nasal mucus were compared in normal subjects and patients with taste and smell dysfunction by use of a spectrophotometric colorimetric ELISA. RESULTS: Both cAMP and cGMP were present in saliva and nasal mucus of normals and patients with levels of both moieties lower in patients than in normals. In normals, cAMP is 6½ times higher in saliva than in nasal mucus whereas cGMP in nasal mucus is 2½ times higher than in saliva. In patients, these differences persist but are less robust. In normals, within saliva, cAMP is 9½ times higher than cGMP whereas within nasal mucus cAMP is half the level of cGMP. In patients, within saliva, these differences persist but at variable differences. CONCLUSIONS: Both saliva and nasal mucus cAMP and cGMP play roles in taste and smell function, and differences in their concentrations may offer insight into these roles. In nasal mucus, cGMP may be more relevant than cAMP in activity of olfactory epithelial cell function. In saliva, cAMP may be more relevant as a growth factor in taste bud function than cGMP.

Improvement in smell and taste dysfunction after repetitive transcranial magnetic stimulation.

BACKGROUND: Olfactory and gustatory distortions in the absence of odors or tastants (phantosmia and phantageusia, respectively) with accompanying loss of smell and taste acuity are relatively common symptoms that can occur without other otolaryngologic symptoms. Although treatment of these symptoms has been elusive, repetitive transcranial magnetic stimulation (rTMS) has been suggested as an effective corrective therapy. OBJECTIVE: The objective of the study was to assess the efficacy of rTMS treatment in patients with phantosmia and phantageusia. METHODS: Seventeen patients with symptoms of persistent phantosmia and phantageusia with accompanying loss of smell and taste acuity were studied. Before and after treatment, patients were monitored by subjective responses and with psychophysical tests of smell function (olfactometry) and taste function (gustometry). Each patient was treated with rTMS that consisted of 2 sham procedures followed by a real rTMS procedure. RESULTS: After sham rTMS, no change in measurements of distortions or acuity occurred in any patient; after initial real rTMS, 2 patients received no benefit; but in the other 15, distortions decreased and acuity increased. Two of these 15 exhibited total inhibition of distortions and return of normal sensory acuity that persisted for over 5 years of follow-up. In the other 13, inhibition of distortions and improvement in sensory acuity gradually decreased; but repeated rTMS again inhibited their distortions and improved their acuity. Eighty-eight percent of patients responded to this therapeutic method, although repeated rTMS was necessary to induce these positive changes. INTERPRETATION: These results suggest that rTMS is a potential future therapeutic option to treat patients with the relatively common problems of persistent phantosmia and phantageusia with accompanying loss of taste and smell acuity. Additional systematic studies are necessary to confirm these results.

ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine.

The American College of Cardiology Foundation (ACCF), along with key specialty and subspecialty societies, conducted an appropriate use review of common clinical scenarios where cardiac radionuclide imaging (RNI) is frequently considered. This document is a revision of the original Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging (SPECT MPI) Appropriateness Criteria, published 4 years earlier, written to reflect changes in test utilization and new clinical data, and to clarify RNI use where omissions or lack of clarity existed in the original criteria. This is in keeping with the commitment to revise and refine appropriate use criteria (AUC) on a frequent basis. The indications for this review were drawn from common applications or anticipated uses, as well as from current clinical practice guidelines. Sixty-seven clinical scenarios were developed by a writing group and scored by a separate technical panel on a scale of 1 to 9 to designate appropriate use, inappropriate use, or uncertain use. In general, use of cardiac RNI for diagnosis and risk assessment in intermediate- and high-risk patients with coronary artery disease (CAD) was viewed favorably, while testing in low-risk patients, routine repeat testing, and general screening in certain clinical scenarios were viewed less favorably. Additionally, use for perioperative testing was found to be inappropriate except for high selected groups of patients. It is anticipated that these results will have a significant impact on physician decision making, test performance, and reimbursement policy, and will help guide future research.

An open-label controlled trial of theophylline for treatment of patients with hyposmia.

BACKGROUND: To test the hypothesis that theophylline is effective in correcting smell loss in patients with hyposmia. METHODS: Three hundred twelve patients with smell loss (hyposmia) were evaluated to determine characteristics of their loss by psychophysical measurements of detection and recognition thresholds, magnitude estimation and hedonic values for 4 odors (pyridine, nitrobenzene, thiophene, and amyl acetate) by use of a forced-choice 3-stimuli staircase design previously documented in a double-blind study. Patients were then treated in a fixed design open-label clinical trial with oral theophylline. Drug was given in equal divided doses from 200 to 800 mg daily for 2- to 8-month periods and subjective and psychophysical measurements of smell function and blood theophylline levels were measured; results were compared with those obtained before treatment. RESULTS: Subjective smell loss improved in 157 (50.3%) patients; smell function was considered normal by 34 (21.7%). Overall, 10.9% of patients in the study considered smell function returned to normal. However, measurements of mean detection and recognition thresholds improved significantly at each drug level; measurements of mean magnitude estimation and hedonic also improved. Improvement was greater at drug doses of 600 and 800 mg than at 200 or 400 mg. Once improvement occurred, as long as treatment was maintained, it persisted for as long as follow-up was measured. CONCLUSION: Theophylline was effective in improving smell function in patients with smell loss. Improvement persisted as long as treatment was continued, which extended from 6 to 72 months.