"Who 'nose' when a seizure will happen?" Prodromal olfactory loss as a first clinical indicator of seizure activity in temporal lobe epilepsy.

Olfactory dysfunction in COVID-19: pathology and long-term implications for brain health.

Evidence‐based management of a patient with anosmia

Olfactory function improves following hemodialysis

The epileptogenic network in temporal lobe epilepsy (TLE) contains structures of the primary and secondary olfactory cortex such as the piriform and entorhinal cortex, the amygdala, and the hippocampus. Olfactory auras and olfactory dysfunction are relevant symptoms of TLE. This study aims to characterize olfactory function in TLE using olfactory testing and olfactory functional magnetic resonance imaging (fMRI). We prospectively enrolled 20 individuals with unilateral TLE (age 45 ± 20 years [mean ± SD], 65% female, 90% right-handed) and 20 healthy individuals (age 33 ± 15 years [mean ± SD], 35% female, 90% right-handed). In the TLE group, the presumed seizure onset zone was left-sided in 75%; in 45% of the individuals with TLE limbic encephalitis was the presumed etiology; and 15% of the individuals with TLE reported olfactory auras. Olfactory function was assessed with a Screening Sniffin' Sticks Test (Burkhart, Wedel, Germany) during a pre-assessment. During a pre-testing, all individuals were asked to rate the intensity, valence, familiarity, and associated memory of five different odors (eugenol, vanillin, phenethyl alcohol, decanoic acid, valeric acid) and a control solution. During the fMRI experiment, all individuals repeatedly smelled eugenol (positively valenced odor), valeric acid (negatively valenced odor), and the control solution and were asked to rate odor intensity on a five-point Likert scale. We acquired functional EPI sequences and structural images (T1, T2, FLAIR). Compared to healthy individuals, individuals with TLE rated the presented odors as more neutral (two-sided Mann-Whitney U tests, FDR-p < 0.05) and less familiar (two-sided Mann-Whitney U tests, FDR-p < 0.05). fMRI data analysis revealed a reduced response contrast in secondary olfactory areas (e.g., hippocampus) connected to the limbic system when comparing eugenol and valeric acid in individuals with TLE when compared with healthy individuals. However, no lateralization effect was obtained when calculating a lateralization index by the number of activated voxels in the olfactory system (two-sided Mann-Whitney U test; U = 176.0; p = 0.525). TLE is characterized by olfactory dysfunction and associated with hypoactivation of secondary olfactory structures connected to the limbic system. These findings contribute to our understanding of the pathophysiology of TLE. This study was preregistered on OSF Registries (www.osf.io).

Clinical Neurophysiology: EEG–Video Monitoring

The University of Pennsylvania Smell Identification Test is widely used to measure change in olfactory function, but a minimal clinically important difference (MCID) has not been well-established. A study published in 1997 regarding patients with head trauma reported an MCID of 4 but did not detail the methods used in the calculation. To validate the MCID for UPSIT in patients with postviral, sinusitis, and procedure-associated olfactory loss. This was a secondary analysis of prospectively collected data from 5 clinical research studies related to olfactory function. Three studies included subjects with COVID-19-related olfactory dysfunction, one with chronic sinusitis subjects, and one with subjects undergoing transsphenoidal surgery. All subjects had completed a baseline and follow-up UPSIT, baseline and follow-up Clinical Global Impression-Severity (CGI-Severity), and a follow-up CGI-Improvement. Both distribution- and anchor-based methods were used to determine the MCID of UPSIT. Distribution-based method calculated MCID using half standard deviation of baseline UPSIT and delta UPSIT scores. Clinical-anchor method determined MCID by comparing delta UPSIT scores between consecutive CGI-I clinical categories ranging from very much better to very much worse. The study population comprised 295 subjects. Subjects had a mean (SD) baseline UPSIT score of 27 (7.5), and follow-up score of 28 (7.9), and a mean UPSIT change of 0.6 (5.8). Half the baseline UPSIT SD was 3.75 and half the delta UPSIT SD was 2.9. With the anchor-based approach, an MCID of 4 was defined as clinically meaningful by exploring the relationship between delta UPSIT and CGI-Improvement. Using a more conservative approach based on the MCID values identified from both methods, we determined that a change of 4 or greater is the appropriate MCID for UPSIT. Investigators in the future should use 4 as MCID for UPSIT and report the percentage of study subjects who achieve a clinically meaningful difference. III.

OBJECTIVES/GOALS: 1) Assess the patient-reported, perceived change in olfactory function after bimodal visual-olfactory training (OT) 2) Assess change in olfactory function after bimodal visual-olfactory training with a smell identification test 3) Assess which scents are most important to people with olfactory dysfunction (OD) METHODS/STUDY POPULATION: The participants are adults with subjective or clinically diagnosed OD with post-surgical or traumatic etiologies within the last 5 years. At the first of two study visits, participants complete the University of Pennsylvania Smell Identification Test (UPSIT) and complete general health (SF-36) and olfactory-related quality-of-life questionnaires. From a list of 34 scents, participants chose the 4 scents most important to them and smelled the scents twice daily for 3 months. Olfactory testing and the quality-of-life questionnaires were repeated at the final visit. RESULTS/ANTICIPATED RESULTS: 10 participants have enrolled in the study. There was one screen fail and one withdrawal. Six participants are currently undergoing OT and two have completed the study. Seven participants have post-surgical etiology and three have post-traumatic etiology of their OD. Of the two participants who have completed the study, one had an UPSIT score improvement from 25 to 33 out of the 40 questions correct. The minimally clinically important difference on the UPSIT is 4. She reports improvement subjectively. The second participant had a UPSIT score change from 25 to 24 and reports ability to smell is neither better nor worse. DISCUSSION/SIGNIFICANCE OF IMPACT: Traumatic and post-surgical, particularly post-transphenoidal hypophysectomy, are common etiologies of OD and no effective treatments exist. The results from our pilot study will help better inform the best way to undergo OT, how effective it is, and the planning of future studies.

Olfactory abnormalities in temporal lobe epilepsy

Olfactory dysfunction is known to occur before the appearance of the classical motor signs in Parkinson's disease (PD) and diffusion tensor imaging (DTI) studies in PD have reported fractional anisotropy (FA) reductions in the early disease stages. We aimed to investigate the relationship between olfactory dysfunction and white matter (WM) FA of central olfactory areas in early PD. Twenty-four patients at Hoehn and Yahr stages I and II and 24 healthy controls matched by age, gender and years of education participated in this study. DTI was acquired at a 3 Tesla scanner and odor identification was assessed using the University of Pennsylvania Smell Identification Test (UPSIT). We performed FA voxelwise group comparisons in the central olfactory structures using tract-based spatial statistics (TBSS) and correlation analyses between FA values in these central olfactory areas and UPSIT scores. Patients with severe microsmia (UPSIT between 19 and 25) and anosmia (UPSIT lower or equal to 18) had lower FA values than PD patients with mild/moderate or no olfactory dysfunction (UPSIT between 26 and 40) and healthy controls in the WM adjacent to gyrus rectus. In addition, patients with anosmia had reduced FA in the WM surrounding primary olfactory areas in comparison with healthy controls. FA values in the WM adjacent to primary olfactory cortex and right gyrus rectus correlated with UPSIT scores in the PD group. This study demonstrates, for the first time, that microstructural WM reductions are present in the central olfactory system of early stage PD patients and that these reductions are associated with reduced ability to smell.

OBJECTIVESThe phenomenon of interictal regional slow activity (IRSA) in temporal lobe epilepsy and its relation with cerebral glucose metabolism, clinical data, MRI, and histopathological findings was studied.METHODSInterictal18F-fluorodeoxyglucose positron emission tomography...

Olfactory dysfunction has an important impact on quality of life. In patients with subarachnoid hemorrhage (SAH), anosmia has mainly been reported after surgery for aneurysms of the anterior communicating artery (ACoA). The authors studied whether and how frequently patients with ACoA aneurysms present with smell identification deficits in 2 treatment groups (endovascular and surgical treatment). A prospective study was conducted of patients with SAH caused by ruptured ACoAs and who had a Glasgow Outcome Scale score of 1 or 2, in comparison with a control group matched by age and sex. Olfactory function was assessed using the University of Pennsylvania Smell Identification Test (UPSIT). A total of 39 patients were enrolled. A marked olfactory impairment was observed in patients with ruptured ACoAs compared with the control group (p < 0.001). Seventeen patients with ruptured ACoAs (44%) compared with 1 patient in the control group (3%) showed a smell identification deficit according to performance on the UPSIT (p < 0.001). Both groups that underwent treatment presented with olfactory impairment. Ten (59%) of 17 patients who underwent aneurysmal clip placement versus 6 (28.5%) of 21 patients who underwent coil embolization scored below the 25th percentile on the UPSIT, and surgical patients also performed worse than endovascular patients (p = 0.048). The authors observed a worse performance on the olfactory test in patients subjected to endovascular coil embolization when cerebral vasospasm (p = 0.037) or frontal cerebral lesions (p = 0.009) were present. This difference was not observed in patients who underwent surgery. Olfactory disorders after SAH caused by rupture of the ACoA are very frequent and were present in both treatment groups. Cerebral vasospasm and frontal lobe lesions are related to worse performance on an olfactory test in patients undergoing endovascular coil embolization.

Educational objectiveTo investigate the impact of SARS-CoV-2 on sinonasal quality of life, olfaction, and cognition at different stages of viral infection and evaluate the association between olfaction and cognition in this population cohort.ObjectivesWhile olfactory dysfunction (OD) is a frequently reported symptom of COVID-19 (98% prevalence), neurocognitive symptoms are becoming more apparent as patients recover from infection. This study aims to address how different stages of infection [active infection (positive PCR test, symptomatic) vs. recovered (7 days post-symptoms)] compared to healthy control patients influence sinonasal quality of life, olfactory function, and cognition.Study designProspective, longitudinal, case-control.MethodsParticipants completed the SNOT-22, University of Pennsylvania Smell Identification Test (UPSIT) and validated cognitive examinations to assess degree of smell loss and neurocognitive function at baseline and at 1 and 3 months for the active group and 3 months for the recovered group. Self-reported olfactory function and overall health metrics were also collected.ResultsThe recovered group had the lowest average UPSIT score of 27.6 compared to 32.7 (active) and 32.6 (healthy control). 80% (n = 24) of the recovered patients and 56.3% (n = 9) of the active patients suffered from smell loss. In follow-up, the active group showed improvement in UPSIT scores while the recovered group scores worsened. In terms of neurocognitive performance, recovered patients had lower processing speed despite an improving UPSIT score.ConclusionSARS-CoV-2 infection was found to impact olfactory function in a delayed fashion with significant impact despite recovery from active infection. Although olfactory function improved, decrements in cognitive processing speed were detected in our cohort.

The number of olfactory dysfunction cases has increased dramatically because of the COVID-19 pandemic. Identifying therapies that aid and accelerate recovery is essential. To determine the efficacy of bimodal visual-olfactory training and patient-preferred scents vs unimodal olfactory training and physician-assigned scents in COVID-19 olfactory loss. This was a randomized, single-blinded trial with a 2-by-2 factorial design (bimodal, patient preferred; unimodal, physician assigned; bimodal, physician assigned; unimodal, patient preferred) and an independent control group. Enrollment occurred from February 1 to May 27, 2021. Participants were adults 18 to 71 years old with current olfactory loss defined as University of Pennsylvania Smell Identification Test (UPSIT) score less than 34 for men and less than 35 for women and duration of 3 months or longer. Olfactory loss was initially diagnosed within 2 weeks of COVID-19 infection. Participants sniffed 4 essential oils for 15 seconds with a 30-second rest in between odors for 3 months. Participants in the physician-assigned odor arms trained with rose, lemon, eucalyptus, and clove. Participants randomized to the patient-preferred arms chose 4 of 24 available scents. If assigned to the bimodal arm, participants were shown digital images of the essential oil they were smelling. The primary end point was postintervention change in UPSIT score from baseline; measures used were the UPSIT (validated, objective psychometric test of olfaction), Clinical Global Impressions Impression-Improvement (CGI-I; self-report improvement scale), and Olfactory Dysfunction Outcomes Rating (ODOR; olfaction-related quality-of-life questionnaire). Among the 275 enrolled participants, the mean (SD) age was 41 (12) years, and 236 (86%) were female. The change in UPSIT scores preintervention to postintervention was similar between the study arms. The marginal mean difference for change in UPSIT scores preintervention to postintervention between participants randomized to patient-preferred vs physician-assigned olfactory training was 0.73 (95% CI, -1.10 to 2.56), and between participants randomized to bimodal vs unimodal olfactory training was 1.10 (95% CI, -2.92 to 0.74). Five (24%) participants in the control arm had clinically important improvement on UPSIT compared with 18 (53%) in the bimodal, patient-preferred arm for a difference of 29% (95% CI, 4%-54%). Four (19%) participants in the control group self-reported improvement on CGI-I compared with 12 (35%) in the bimodal, patient-preferred arm for a difference of 16% (95% CI, -7% to 39%). The mean change in ODOR score preintervention to postintervention was 11.6 points (95% CI, 9.2-13.9), which was not deemed clinically important nor significantly different between arms. Based on the change in UPSIT scores, this randomized clinical trial did not show any difference between intervention arms, but when exploring within-patient change in UPSIT as well as self-reported impression of improvement, active interventions were associated with larger improvement than controls with a potential advantage of bimodal intervention. While not definitive, these results suggest that patients with COVID-19 olfactory loss may benefit from bimodal visual-olfactory training with patient-preferred scents. ClinicalTrials.gov Identifier: NCT04710394.

Olfactory changes connection to deteriorated quality of life in chronic kidney disease cases (CKD) and diabetes mellitus (DM). The nutritional status is altered in CKD and DM and it closely interconnected with olfactory function. We aimed to study the olfactory dysfunction in these populations. We conducted a cross-sectional research on CKD and DM cases aged 20-50 (27 healthy controls, 77 CKD patients, and 36 DM patients). We used the Iran Smell Identification Test (Iran-SIT) version of the University of Pennsylvania Smell Identification Test (UPSIT) to evaluate the olfactory function. The significant level was set as <0.05. Our 140 cases included 51.4% of men (mean age of 46.7±10.6 years). The total score of the Iran-SIT test indicated that olfactory impairment in the CKD was higher (16.2±4.2) than in the DM (18.8±2.1) and control groups (20.4±1.2) (P=0.001). It was determined that 54.5% of CKD patients and 38.9% of the DM group had olfactory dysfunction compared to 7.4% of the controls (P=0.001). Multiple regression analysis indicated that being men and low-density lipoprotein cholesterol (LDL-C) were related to olfactory dysfunction in the total population (OR: 4.55, P=0.037, and OR: 0.94, P=0.037). Still, it was only associated with LDL-C in the CKD group (OR: 0.93, P=0.013). Based on the findings of this study, CKD and DM patients had a higher prevalence of olfactory dysfunction than the controls, which could be associated with some preventive nutritional factors. This information may help perform a screening program and early intervention on olfactory dysfunction in these systematic diseases.

Olfactory dysfunction in Parkinson's disease is usually prodromal to other symptoms. In this study, we aimed to explore the association of olfactory function with the availabilities of striatal dopamine transporter (DAT) in healthy subjects. Data used in the preparation of this article were obtained from Parkinson's Progression Markers Initiative database ( www.ppmi-info.org/data ). The study population consisted of healthy controls with screening 123I-FP-CIT single photon emission tomography (SPECT). University of Pennsylvania Smell Identification Test (UPSIT) was assessed to evaluate the olfactory function. Totally, 181 healthy subjects (117 male, 64 female) with 123I-FP-CIT SPECT data were included in this study. Specific binding ratios (SBRs) of the caudate nucleus (rho = -0.4217, p < 0.0001), putamen (rho = -0.2292, p = 0.0019), and striatum (rho=-0.3425, p < 0.0001) showed a reduction with ageing. SBRs of the caudate nucleus, putamen, and striatum were positively correlated with UPSIT (rho = 0.3716, p < 0.0001; rho = 0.3655, p < 0.0001; rho = 0.3880, p < 0.0001). After controlling for age by partial correlation, SBRs of the caudate nucleus, putamen, and striatum showed an influence on UPSIT (rho = 0.3288, p < 0.0001; rho = 0.3374, p < 0.0001; rho = 0.3511, p < 0.0001). Olfactory function is associated with the availability of striatal DAT independent of age in healthy subjects. • Olfactory dysfunction in Parkinson's disease is prodromal to other symptoms. • The availability of dopamine transporter showed a reduction with ageing. • Olfactory function is associated with the availability of dopamine transporter.